Endocrinology

To the Editor: In 1998, the Australasian Diabetes in Pregnancy Society (ADIPS) published management guidelines for gestational diabetes mellitus (GDM).1 Recently, the American College of Obstetricians and Gynecologists (ACOG) published its clinical management guidelines for GDM.2 The Table shows there are few differences from the ADIPS guidelines. At this stage, ADIPS does not consider existing evidence warrants revision of its guidelines. ADIPS will retain its existing criteria for the diagnosis of GDM based on a 75 g oral glucose tolerance test (OGTT) pending publication of the Hyperglycaemia and Adverse Pregnancy Outcome Study.3 The results of this international prospective study of 25 000 pregnant women should be available in June 2004. A second publication, the draft National evidence-based guidelines for the management of Type 2 diabetes mellitus,4 does not include GDM, but initially recommended that "women with previous GDM should be retested every three years for undiagnosed Type 2 diabetes". This periodicity was selected to retest for undiagnosed disease when the cumulative risk of developing diabetes had reached 5%. The time interval was selected on the basis of European studies. In contrast, the ADIPS guidelines recommended testing every 1–2 years, but gave no reason for this, apart from the high risk of progression to diabetes among women of certain ethnic backgrounds who had had past GDM (as high as 47% over five years in Latino women5). A further, unstated reason for the 1–2-yearly testing was the major concern that fetal exposure to undiagnosed diabetes in any subsequent pregnancies could result in malformations. The following has now been inserted into the draft Type 2 guidelines: 4 "The guideline conclusion to retest women with previous GDM every 3 years represents minimum criteria. More frequent retesting may be appropriate depending on clinical circumstances, especially during the child bearing years." ADIPS supports this amendment fully and has revised its own guidelines in relation to maternal follow-up after GDM as follows: All women with previous GDM to be offered testing for diabetes with a 75 g OGTT 6–8 weeks after delivery; Repeat testing should be performed every 1–2 years among women with normal glucose tolerance and the potential for further pregnancies; If pregnancy is not possible, follow-up testing should be performed every 3 years, with more frequent retesting depending on clinical circumstances (eg, ethnicity, past history of insulin treatment in pregnancy, recurrent episodes of GDM). Differences between management guidelines for gestational diabetes mellitus (GDM) from the Australasian Diabetes in Pregnancy Society (ADIPS, 1998) and the American College of Obstetricians and Gynecologists (ACOG, 2001) [Table corrected on 27 August 2002.] ADIPS ACOG Universal versus selective screening by blood test Universal unless low GDM incidence or resources limited No recommendation. States that "many physicians elect to screen all pregnant patients as a practical matter" Differences in definition of low risk for GDM Age < 30 years, obesity, family history of diabetes Age < 25 years, body mass index < 25 kg/m2. No known diabetes in first-degree relative Oral glucose tolerance test used 75 g, 2-hour, 2-point blood sampling 100 g, 3-hour, 4-point blood sampling Criteria for diagnosis of GDM Plasma glucose level: Fasting, ≥ 5.5 mmol/L and/or 2-hour, ≥ 8.0 mmol/L Plasma glucose level: Fasting, ≥ 5.3 mmol/L; 1-hour, ≥ 10.0 mmol/L 2-hour, ≥ 8.6 mmol/L; 3-hour, ≥ 7.8 mmol/L; (2 or more time points need to elevated) Insulin therapy commenced after medical–nutrition therapy Plasma glucose level: Fasting, ≥ 5.5 mmol/L and/or 1-hour postprandial, ≥ 8.0 mmol/L and/or 2-hour postprandial, ≥7.0 mmol/L Plasma glucose level: Fasting, ≥ 5.3 mmol/L and/or 1-hour postprandial, ≥ 7.2–7.8 mmol/L and/or 2-hour postprandial, ≥ 6.7 mmol/L

on behalf of the Australasian Diabetes in Pregnancy Society

To the Editor: Both the American Diabetes Association (ADA)1 and the World Health Organization (WHO)2 have lowered the fasting plasma glucose (FPG) level for the diagnosis of diabetes from 7.8 mmol/L to 7.0 mmol/L. The Australian Diabetes Society (ADS) has also adopted the lower level.3 However, these organisations differ in the procedure for diagnosis they recommend. The recent article by Hilton and colleagues4 compared these procedures, with particular attention to including an oral glucose tolerance test (OGTT). We, on the other hand, have investigated the impact of lowering the diagnostic FPG level to 7.0 mmol/L. Data were obtained by the Geelong Osteoporosis Study from an age-stratified sample of women randomly selected from electoral rolls for the Barwon Statistical Division5 and adjusted to match the national age profile. Venous FPG level was determined after an overnight fast, together with blood pressure (BP, seated) and anthropometric measurements, in 944 women aged 20–91 years (mean age, 47.5 years; SD, 17.8 years). History of diabetes was ascertained by questionnaire. The prevalence of self-reported diabetes and diabetes defined by an FPG level of 7.0 mmol/L or higher was 4.3% (95% CI, 3.0%–5.6%; 41 women), whereas using an FPG level of 7.8 mmol/L or higher gave a prevalence of 3.8% (95% CI, 2.6%–5.0%; 36 women). With the lower cut-off level, 29% of women (12) were unaware of their diabetes, compared with 19% (7) using the higher FPG level cut-off point. Characteristics of those identified using the lower cut-off FPG level are shown in the Table. After age-matching all patients with diabetes with control participants, diabetes was significantly associated with obesity (body mass index, > 30; odds ratio [OR], 4.2; 95% CI, 1.5–11.6) and central body fat distribution (waist/hip ratio, > 0.8; OR, 8.0; 95% CI, 2.3–25.9); and non-significantly associated with higher blood pressure (systolic, > 140 mmHg; diastolic, > 85 mmHg; OR, 2.0; 95% CI, 0.8–4.9). The new criterion for diagnosing diabetes identifies a subgroup of the population with a high proportion of obesity and android habitus, with a tendency to higher blood pressure. The recommendation of lowering the diagnostic FPG level increases the prevalence of diabetes by an apparently small proportion, but would diagnose diabetes in an additional 34 000 women in Australia. Characteristics (mean ± SD) of diabetic women (FPG ≥ 7.0 mmol/L) and controls (FPG < 7.0 mmol/L). Characteristic Diabetics (n = 41) Controls (n = 903) P* Age (years) 65.1 ± 11.1 46.7 ± 17.7 < 0.0001 Weight (kg) 74.5 ± 16.2 68.6 ± 14.4 0.03 Height (cm) 158.6 ± 5.6 161.9 ± 6.5 0.0007 BMI (kg/m2) 29.6 ± 6.1 26.2 ± 5.3 0.001 Waist/hip ratio 0.88 ± 0.06 0.80 ± 0.07 < 0.0001 Systolic BP (mmHg) 139 ± 21 121 ± 21 < 0.0001 Diastolic BP (mmHg) 83 ± 16 76 ± 12 0.007 * t test. FPG = fasting plasma glucose; BMI = body mass index; BP = blood pressure.

Julie A Pasco PhD · Mark A Kotowicz MB BS, FRACP · Margaret J Henry PhD · Geoffrey C Nicholson PhD, FRACP, FRCP

To the Editor: The recent letter by McElduff and Hitchman1 has some very practical implications. They were able to show that pregnant women having a glucose challenge test (GCT) in the afternoon were nearly twice as likely to have a positive result as women tested in the morning, so that more women tested in the afternoon were diagnosed with gestational diabetes mellitus (GDM). If the function of the GCT is to aid in the diagnosis of GDM, then either all women should be tested in the afternoon or the glucose "cut-point" for the morning test should be reduced. But does the GCT now have any relevance? In the United States, where testing for GDM often still involves a three-hour glucose tolerance test (GTT) using a 100 g glucose load and four blood samples, the GCT was introduced to reduce the number of women who had to have this long and, because of the higher dose of glucose, relatively unpleasant procedure. In Australia, where a two-hour, 75 g GTT is used (requiring two blood samples), it is not as important to offer a simpler initial test. With the use of an initial GCT, about a quarter of women will need to have a GTT for confirmation, and the definitive diagnosis of GDM will be delayed. Further, the GCT is not specific and some women who may have GDM will not have a GTT. In addition, there will inevitably be some women who are GCT-positive, some of whom will have GDM, who do not return for the definitive GTT. Thus, while a GCT may be convenient for a busy hospital clinic with space limitations, it may not necessarily be in the best interests of the patient. Whether a GCT is ultimately helpful or possibly a hindrance requires further evaluation.

Robert G Moses MD

To the Editor: A recent editorial in the Journal attempted to define a role for angiotensin II receptor (AIIR) antagonists in patients with type 2 diabetes.1 This was in the light of recent trial evidence that these agents reduce progression to renal failure in patients with type 2 diabetes and diabetic renal disease. Unfortunately, the guidelines provided were somewhat confusing and fragmented. I believe that a simpler treatment guide can be constructed, particularly when it is emphasised that the aim in diabetes is to use agents that prevent not only renal failure but also cardiovascular events. Substantial evidence already supports a role for the angiotensin-converting enzyme (ACE) inhibitor ramipril in treatment of diabetes. The HOPE study included 3577 people with diabetes and another risk factor for cardiovascular disease who were randomised to either placebo or ramipril (10 mg) for 4.5 years.2 This group had a mean baseline blood pressure of 142/80 mmHg and no clinical proteinuria. Ramipril lowered the risk of the combined primary outcome of myocardial infarction, stroke and cardiovascular death by 25% (P ≤ 0.001), and this effect was independent of blood-pressure lowering. Furthermore, ramipril reduced progression to overt nephropathy by 22%, with a reduction evident in patients with or without proteinuria.2 This protective effect of ramipril on renal function is consistent with previous evidence that ACE inhibitors slow progression of chronic renal failure in diabetes,3,4 and that ramipril slows progression of chronic renal failure in non-diabetic nephropathy.5 Whether other ACE inhibitors have the same effect as ramipril on cardiovascular events, and what doses obtain such an effect, remains speculative. Similarly, while there is now evidence that AIIR antagonists also have renal-protective effects, there is no definitive evidence that they protect against cardiovascular events. In view of this, and in the absence of comparative trials, ramipril (and not other ACE inhibitors or AIIR antagonists) is currently the first choice for treatment for diabetic patients with hypertension, with normotension and microalbuminuria, or with hypertension and micro- or macroalbuminuria. As most patients with diabetes and hypertension require multiple agents to achieve a target blood pressure less than 130/80 mmHg, additional therapy with a β-blocker, diuretic or calcium-channel blocker is often necessary. The significance of the newly available trial data is that AIIR antagonists provide an alternative to ramipril for reducing progression to chronic renal failure in patients with diabetic nephropathy who cannot tolerate ACE inhibitors because of the side effect of cough.

Roger E Peverill PhD, FRACP

In reply: Peverill raises the question of how to integrate the new data on renal protection by angiotensin II receptor (AIIR) antagonists with existing data on cardiovascular protection by angiotensin-converting enzyme (ACE) inhibitors in patients with type 2 diabetes. An AIIR antagonist would be favoured for renal protection for a diabetic patient with hypertension and evidence of early or overt nephropathy. With regard to patients with microalbuminuria, the HOPE and MICRO-HOPE studies showed that therapy with the ACE inhibitor ramipril (10 mg/day) was associated with a 24% relative risk reduction for the development of overt nephropathy over 4.5 years.1 In contrast, treatment of similar patients with the AIIR antagonist irbesartan (300 mg/day) for 2.6 years resulted in a 70% risk reduction for the development of overt nephropathy.2 Use of an AIIR antagonist in patients with overt nephropathy has also been shown to slow progression to end-stage renal failure.3,4 As the HOPE and MICRO-HOPE studies specifically excluded such patients, evidence supporting use of an ACE inhibitor in this context is lacking. An ACE inhibitor could be used if a diabetic patient has microalbuminuria and a history of coronary heart disease or additional risk factors for cardiovascular disease, especially if normotensive. However, almost all patients with microalbuminuria require antihypertensive therapy as well as therapy to protect target organs. The relative importance of blood-pressure-lowering versus non-lowering effects of antihypertensive therapy on reducing risk of cardiovascular disease remains uncertain.5 Furthermore, a recent meta-analysis of cardiovascular protection in 62 605 patients with hypertension (including the HOPE and United Kingdom Prospective Diabetes studies) did not find that ACE inhibitors affected cardiovascular prognosis beyond their antihypertensive effects.6 Finally, it is important to note that neither ACE inhibitors nor AIIR antagonists provide total protection from cardiovascular and renal events, and that further improvements are needed for both microvascular and macrovascular protection in patients with type 2 diabetes.

George Jerums · Mark E Cooper · Richard E Gilbert · Robert C Atkins

In a rejoinder to Benjamin Franklin's observation that nothing is certain in life bar death and taxes, people's fondest wishes seem to be to live forever and pay no tax. The timely and provocative study of Weston et al in this issue of the Journal (page 208),1 reporting high acceptability of a hormonal male contraceptive among new fathers, prompts a reflection on wishful thinking, as such a new contraceptive remains unavailable. In some respects, contraception is closer to a consumer lifestyle choice than a conventional medical treatment, as illustrated by the impact of media-inspired contraceptive "scares" that have led to panic-driven abandonment of contraception and subsequent unwanted pregnancies.2 Creating a need for novel products is the raison d'être of advertising, and in the world of public relations presentation is the whole game. Responses to unfamiliar products or services are sensitive to how they are described, and almost any outcome may arise depending on how the access, convenience, safety and efficacy of hypothetical or existing contraceptive methods are described. At face value, however, the observations of Weston et al are consistent with recent findings from other cultures3,4 and earlier World Health Organization (WHO) studies,5,6 all of which similarly rely on forcing choices between hypothetical options. Even if the responses accurately reflect attitude, there is a vast gulf between human attitude and behaviour. This is the starting point for much of behavioural medicine, as illustrated by the failure of even low expectations of interventions that rely upon behavioural change (eg, interventions to deal with anger, smoking, drug addiction, obesity). Nevertheless, the strikingly positive attitudes reported by Weston et al herald major progress and the imminent availability of practical hormonal male contraceptives. Arguably, the epitome of successful applied science in the 20th century was the development of reliable and reversible contraception. The universal availability of numerous highly effective female contraceptives fostered unprecedented social change extending well beyond medicine and science. At the start of the 21st century, it is a sad reflection that the previous century passed without the addition of a single new contraceptive method that men could use to share more equitably the burden of reliable family planning.7 Historically, all deliberate family planning methods (apart from abortion) were shared responsibilities requiring active male involvement. The phenomenal success of female-oriented contraceptive development in recent decades has shifted the burden of responsibility for family planning disproportionately onto women. Worldwide, however, male involvement in family planning remains remarkably high, considering the inadequate means available.8 The central dilemma for men in stable relationships seeking to share more responsibility for family planning is that the reversible methods are not reliable and the reliable method (vasectomy) is not reversible. What is needed is a reversible male method as reliable as modern female methods. The biologically unique processes of sperm development offer ever-increasing numbers of new ways for clever biotechnology to interrupt male fertility temporarily, notably by modification of sperm and male reproductive tract ion channels. However, these require full development as new drugs, whereas hormonal methods are close to practical realisation. Although hormonal contraceptive methods were always equally feasible for men and women, during the decades when female contraceptive development flourished the development of analogous male methods languished, as it depended solely upon the limited resources available to academic researchers without pharmaceutical company product development. A decade ago, proof-of-concept for a hormonal male contraceptive was achieved jointly by the US Contraceptive Research and Development Agency and WHO's Male Task Force, which conducted the first efficacy studies for any chemical male contraceptive.9,10 These studies showed high reliability of a reversible prototype hormonal regimen, a crucial empirical finding about which the biggest surprise is that this finding lagged three decades behind the wide availability of analogous female hormonal methods. Continued impressive progress towards a practical product has been achieved. There is consensus that a combination progestin-plus-androgen approach is optimal, with several combinations approaching the ideal of universal azoospermia.7 Finally, some large pharmaceutical companies have recently upgraded their involvement from being spectators to participating in some active development of the well-advanced research produced by the academic community within the public sector. New hormonal male contraceptives are needed for couples in stable relationships rather than for those with changing partners, among whom condom use prevents sexually transmitted disease as well as pregnancy. The survey of Weston et al highlights a likely niche for the use of a hormonal male contraceptive — the postpartum period. This period is ideal, because it focuses on a stable couple with a predictable timing of contraceptive need and a situation in which reliable female contraceptives are not well suited, particularly during lactation. Other niche purposes for a hormonal male contraceptive include delaying vasectomy, offering an alternative to conventional female methods when they are not well tolerated, and replacing less reliable male methods. The finding that a hormonal male contraceptive is acceptable to an appropriate Australian target population is consistent with Australasian men having the highest rate of vasectomy in the world.11,12 These observations highlight the substantial need and market for a hormonal male contraceptive. Hopefully, this decade will see the long-overdue development of an eminently feasible and widely desirable product. The desultory response from multinational pharmaceutical companies, even after completion of much early-phase clinical research by the public sector, suggests implementation may be driven by populous countries such as China, Indonesia and India, whose family planning priorities value such developments more highly. In Western countries, development may require a more enterprising start-up company to capitalise on this opportunity, which eludes the imagination, or lurks beneath the commercial horizon, of the pharmaceutical industry behemoths.

David J Handelsman MB BS, PhD, FRACP

Aim: To survey the attitudes of a population of Australian men to potential use of male hormonal contraception (MHC). Design: Survey of male partners of women who had recently given birth. Men were approached while visiting their female partners on the ward. Participants: 118 out of 148 Australian-born English-speaking men who were approached. Setting: Postnatal ward of Monash Medical Centre (a public teaching hospital in Melbourne), between October 2000 and April 2001. Main outcome measure: Attitudes towards potential use of MHC, rated on a five-point scale. Results: 89/118 men surveyed (75.4%; 95% CI, 67.7%–83.2%) indicated that they would consider trying MHC if it were available. The three most popular choices for method of administration of MHC were (in descending order) an oral pill, a three-monthly injection, or a two-yearly injection. A statistically significant association was found between acceptability of vasectomy and acceptability of MHC (70.5% of men who indicated they would try MHC [MHC "triers"] found vasectomy acceptable versus 44.5% of MHC "non-triers"; P = 0.011). Triers reported a higher rate of approval of MHC by their female partners than non-triers (79.8% v 13.8%, respectively; P < 0.0001). Conclusions: MHC appears to be acceptable to a majority of Australian men when surveyed in a postpartum context. Attitudes of men towards existing male contraception, as well as the attitudes of their partners, appear to exert a strong influence on acceptability of MHC.

Gareth C Weston MB BS · Michelle L Schlipalius MB BS · Meabh Ni Bhuinneain MRCOG, MRCPI · Beverley J Vollenhoven PhD, FRANZCOG

In Australia, 7.5% of the adult population has diabetes, and for every one person diagnosed with diabetes there is another undiagnosed.1 The prevalence of the most common form of diabetes, type 2, is increasing worldwide because of changing lifestyle, especially increasing weight caused by nutritional excess and decreasing physical activity. Many people with type 2 diabetes have cardiovascular and renal complications on diagnosis, and early detection of diabetes is an important strategy for reducing morbidity and premature mortality.2 The diagnostic test for diabetes is measurement of plasma glucose (PG) level. Although population PG is a continuum, PG levels diagnostic of diabetes identify a subgroup of the population at increased risk of diabetes-related complications. Risk data on these complications are based on the 2 h PG level during an oral glucose tolerance test (OGTT), with risk increasing significantly at a PG ≥ 11.1 mmol/L. It has long been recognised that this 2 h level does not equate to the fasting PG level of 7.8 mmol/L that has also been used to diagnose diabetes. Recently, both the American Diabetes Association (ADA)3 and the World Health Organization (WHO)4 lowered the diagnostic fasting PG level from 7.8 mmol/L to 7.0 mmol/L to more closely align it with a 2 h PG of 11.1 mmol/L. Despite this agreement, the ADA and WHO differ fundamentally on their recommended procedure for diagnosing diabetes, in particular the role of the OGTT in routine clinical practice. WHO continues to advocate routine use of the OGTT to maximise identification of people with increased risk of diabetes complications that may be reduced or prevented by treatment. In contrast, the ADA does not recommend routine use of the OGTT, as it believes that the new lower fasting PG level will detect most people with diabetes diagnosed by the OGTT. However, if an OGTT is performed, the ADA and WHO agree completely as to how the test should be done and interpreted. The study by Hilton and colleagues published in this issue of the Journal5 compares the prevalence of diabetes diagnosed using the ADA and WHO recommendations in a high-risk cohort from the Australian Diabetes Screening Study. It reports that about 50% fewer people are diagnosed with diabetes on the basis of the fasting PG alone (ADA recommendations) compared with the fasting and/or 2 h PG levels (WHO recommendations). Similar findings have come from other populations.6 As the ADA and WHO recommendations define different, although overlapping, cohorts, both of which are labelled with diabetes, the question arises as to when is diabetes really diabetes? There are several reasons why Australia, and indeed most of the world, has adopted the WHO recommendations.7 The diagnostic criteria for diabetes were derived from the increased risk of complications defined by the 2 h PG value, not the fasting PG.3 Clearly, the new lower fasting PG cut-off of 7.0 mmol/L does not equate to a 2 h PG of 11.1 mmol/L. Also, recent evidence confirms the importance of a raised 2 h PG as an independent risk factor for mortality and cardiovascular disease, even when the fasting PG is not raised.8,9 Therefore, failure to consider the 2 h PG ignores a subgroup at particular risk of macrovascular complications. In summary, diabetes is diagnosed by one of the following: symptoms of diabetes and a casual PG level ≥ 11.1 mmol/L; fasting PG level ≥ 7.0 mmol/L; or 2 h PG level during an OGTT ≥ 11.1 mmol/L. How should this information be used by general practitioners faced daily with many people at risk of undiagnosed type 2 diabetes? In Australia, soon-to-be-released evidence-based guidelines from the National Health and Medical Research Council advocate a staged approach for case detection of undiagnosed type 2 diabetes.6 A staged approach is similarly recommended by all national diabetes guidelines in other countries. The new Australian guidelines recommend risk assessment followed by measurement of fasting PG (Box). Those with a fasting PG < 5.5 mmol/L are considered unlikely to have diabetes but should be retested every three years, while those with a fasting PG ≥ 7.0 mmol/L are very likely to have diabetes, which should be confirmed by repeat fasting PG measurement. The remainder with an equivocal result (fasting PG, 5.5–6.9 mmol/L) should have an OGTT. Our analysis of population data from the AusDiab Study (Australian Diabetes, Obesity and Lifestyle Study) shows that, if the above recommendations were followed, about 25% of people who are at risk of undiagnosed diabetes and have a fasting PG measured would require an OGTT (unpublished analysis). The study by Hilton and colleagues confirms the important role of the OGTT in identifying people with diabetes, despite the inconvenience of the test.5 However, not all people with an equivocal PG result are in fact having an OGTT when indicated. Release and adoption of the new national guideline for case detection of undiagnosed type 2 diabetes should help correct this. Indications for measuring fasting plasma glucose levels Age 55 years or over. Age 45 years or over and one of the following: - obesity; - hypertension; - first degree relative with type 2 diabetes. Age 35 or over if Aboriginal or Torres Strait Islander. Age 35 or over if from a high-risk group from non-English-speaking background (Indian subcontinent, Pacific Islands, Chinese origin). Previous history of impaired glucose tolerance or impaired fasting glycaemia. Previous history of cardiovascular event. Women with previous history of gestational diabetes. Obese women with polycystic ovary syndrome.

Stephen Colagiuri FRACP

Objectives: To study the influence of different diagnostic criteria on the prevalence of diabetes mellitus and characteristics of those diagnosed.Design and setting: Retrospective analysis of data from the general-practice-based Australian Diabetes Screening Study (January 1994 to June 1995). Participants: 5911 people with no previous diagnosis of diabetes, two or more symptoms or risk factors for diabetes, a random venous plasma glucose (PG) level > 5.5 mmol/L and a subsequent oral glucose tolerance test (OGTT) result.Main outcome measure: Prevalence of undiagnosed diabetes based on each of three sets of criteria: 1997 criteria of the American Diabetes Association (ADA), 1996 two-step screening strategy of the Australian Diabetes Society (ADS) (modified according to ADA recommendations about lowered diagnostic fasting PG level), and 1999 definition of the World Health Organization (WHO).Results: Prevalence estimates for undiagnosed diabetes using the American (ADA), Australian (ADS) and WHO criteria (95% CI) were 9.4% (8.7%–10.1%), 16.0% (15.3%–16.7%) and 18.1% (17.1%–19.1%), respectively. People diagnosed with diabetes by fasting PG level (common to all sets of criteria) were more likely to be male and younger than those diagnosed only by 2 h glucose challenge PG level (Australian and WHO criteria only). The Australian (ADS) stepwise screening strategy detected 88% of those who met the WHO criteria for diabetes, including about three-quarters of those with isolated post-challenge hyperglycaemia.Conclusion: The WHO criteria (which include an OGTT result) are preferable to the American (ADA) criteria (which rely totally on fasting PG level), as the latter underestimated the prevalence of undiagnosed diabetes by almost a half. The Australian (ADS) strategy identified most of those diagnosed with diabetes by WHO criteria.

Deborah J Hilton MPH · Christopher M Reid MSc, PhD · Peter K O'Rourke PhD · Timothy A Welborn PhD, FRACP

Amiodarone is used in the management of cardiac dysrhythmias. Accumulation of amiodarone in the thyroid gland may result in thyroid dysfunction, either hypothyroidism or thyrotoxicosis.1 Amiodarone-associated thyrotoxicosis (AAT) occurs in about 3% of patients.2 In some patients, cessation of amiodarone is not practical, as it may be the only effective anti-arrhythmic agent. Furthermore, cessation of amiodarone may be followed by a rebound rise in tri-iodothyronine, which worsens the thyrotoxic state.3,4 Even when amiodarone can be discontinued, AAT can take up to nine months to resolve. Medical management may be ineffective and can result in complications, or sometimes death.5 In these very difficult situations, surgery has an important role. In the past it was thought that the risk of thyroid storm and the risks associated with anaesthesia would preclude surgery. However, recent experience has demonstrated that surgery may be performed safely and successfully, as illustrated in the case reports summarised in Box 1. DiscussionThe patients all had severe cardiac disease and AAT refractory to medical treatment, yet general anaesthesia and total thyroidectomy were successful and uncomplicated in each case. All patients recovered rapidly and remain well and euthyroid on thyroxine replacement therapy. Patient 1 had a large multinodular goitre and the other four had normal-sized or slightly enlarged thyroid glands at the time of surgery. The histological findings in all cases showed a similar destructive thyroiditis (Box 2). Up to 1996 only 20 cases of AAT treated by surgery had been reported.3,4,6-10 However, in the past few years, a further 29 cases have been documented.5,11,12 Including the five cases described here, there have been 54 cases, of which 19 (35%) have been in Australia. Even allowing for possible publication bias, the results are exceptionally good, with no surgical mortality reported. It is standard practice to render thyrotoxic patients euthyroid preoperatively. This is not possible in AAT, yet postoperative thyroid storm appears to be an extremely rare event. Most patients are suitable for general anaesthesia, and local anaesthesia would probably be more stressful. There is discussion among anaesthetists as to the choice of anaesthetic agents, with some advocating total intravenous anaesthesia11,13 and others favouring inhalation anaesthesia.12 All authors agree that the medical management of patients with AAT is problematical and difficult.1,14 Apart from the doubtful success of medical treatment,5 it can be associated with prolonged illness and additional complications such as occurred in two of our patients, who had serious infections related to prednisone-induced immunosuppression that delayed the curative surgery. Thyroidectomy is the only treatment that reliably allows the continued use of amiodarone.15 Clinical decisions about apparent "unfitness for surgery" have sometimes been made without consulting an appropriate anaesthetist or endocrine surgeon. Despite the obvious difficulties with management of patients with AAT, anaesthesia and surgery may be performed safely and successfully. Consideration should be given to referring the patient for early surgery, particularly in cases where it would be advantageous to continue the amiodarone therapy and before complications of immunosuppression due to prednisone therapy have occurred. Lessons for practice are listed in Box 3. 1 : Summary of case reports for five patients with amiodarone-associated thyrotoxicosis who were treated successfully with total thyroidectomy Patient Age (years) Sex Clinical features Treatment preceding total thyroidectomy 1 82 F Toxic multinodular goitre treated with carbimazole for 20 years. Commenced amiodarone for atrial fibrillation and developed thyrotoxicosis after four months. Amiodarone discontinued, but patient remained thyrotoxic on propylthiouracil, prednisone and potassium perchlorate. 2 39 M Four operations for tetralogy of Fallot and on waiting list for cardiac transplantation. Recurrent ventricular tachycardia treated with amiodarone for three years. Automatic implanted cardiac defibrillator required for worsening ventricular tachycardia due to thyrotoxicosis. Amiodarone ceased, but patient remained thyrotoxic on carbimazole, prednisone, potassium perchlorate and lithium carbonate. 3 32 M Familial dilated cardiomyopathy with recurrent ventricular tachycardia treated with amiodarone for four years. Thyrotoxicosis for 18 months before referral; ejection fraction 24%. Amiodarone continued, and patient remained thyrotoxic on propylthiouracil, potassium perchlorate and lithium carbonate. 4 61 M Rheumatic heart disease with aortic valve replacement and congestive cardiac failure. Ventricular tachycardia and fibrillation treated with amiodarone for two years and also sinoatrial node ablation, pacemaker and warfarin. Thyrotoxicosis developed two months after amiodarone was discontinued. Thyrotoxicosis persisted on propylthiouracil, prednisone and lithium carbonate. 5 63 M Coronary artery bypass grafts and cardiac pacemaker. Atrial fibrillation treated for two years with amiodarone and warfarin. Thyrotoxicosis developed three months after amiodarone was discontinued. Thyrotoxicosis persisted on carbimazole and prednisolone. 2: Photomicrograph of thyroid in Patient 5 A: Destruction of follicles, with loss of follicular epithelial cells and macrophages in the colloid. B: Marked inflammatory cell infiltration. C: Fibroblasts creating fibrous tissue. Haematoxylin and eosin stain; original magnification x 350. Courtesy of Queensland Medical Laboratory. 3 : Lessons for practice Amiodarone (an iodine-containing drug used for the treatment of cardiac arrhythmias) may cause a destructive thyroiditis, resulting in long-lasting thyrotoxicosis refractory to medical management. Total thyroidectomy under general anaesthesia may be performed safely and successfully in patients with amiodarone-associated thyrotoxicosis.

Ian R Gough MD, FRACS · Jenny Gough MB BS

To the Editor: The 50 g glucose challenge test (GCT) is widely recommended as a screening test for gestational diabetes (GD).1 The test consists of a 50 g oral glucose load given at any time of the day, followed one hour later by the measurement of the plasma glucose concentration.2 This test is recognised as imperfect for screening, as sensitivity and specificity are not 100%.2,3 It is known that glucose tolerance deteriorates in the afternoon,4 which raises the question of whether time of day influences the response to the 50 g GCT. At Royal North Shore Hospital, screening for GD is performed at the 26–28-week visit by means of the 50 g GCT. In 2000, screening for GD was introduced into a morning midwives antenatal clinic, whereas previously it had only been performed in the afternoon. The population attending the clinic at the 26–28-week visit includes many women receiving shared care, and is regarded as being at low obstetric risk. The Table shows the results of screening at the morning clinic compared with screening in the afternoon over the same time period. The two groups were identical in terms of age, weight, ethnicity, and family history of diabetes or past history of GD. The percentage of women with a positive screening test result during the morning clinic (17.0%) was significantly lower than that during the afternoon clinic (31.1%). Positive screening results were followed up with a diagnostic 75 g glucose tolerance test, and GD was diagnosed according to the Australian Diabetes in Pregnancy Society criteria.5 Women with a positive screening test result confirmed with a 75 g glucose tolerance test in the afternoon were less likely to have GD than those with a positive test in the morning (31.5% v 40.0%). Despite the fact that a smaller percentage of women who screened positive in the afternoon had GD, a greater percentage of the total number screened in the afternoon had GD than in the morning group. In this cohort, the difference (9.8% v 6.8%) was not significant (Table; P = 0.15). These results are consistent with the hypothesis that a 50 g GCT test performed in the afternoon results in a greater number of positive results, a greater number of women undergoing diagnostic testing and a greater number of women identified with GD. The morning GCT appears to increase specificity, with an associated decrease in sensitivity. These results need to be taken into consideration when designing or implementing a screening program. Screening for gestational diabetes (GD): the effect of screening time Time Morning (0930–1200) Afternoon (1205–1710) Number screened 176 470 Age in years (mean ± SD) 31.2 ± 4.7 31.7 ± 5.0 Weight (mean ± SD) 59.4 kg ± 10.5 kg 60.8 kg ± 12.9 kg Family history of diabetes 27 24 Past history of gestational diabetes 1 3 % White/Asian/Middle Eastern 62.6/28.0/9.0 67.5/25.9/5.8 Positive result, 50 g glucose challenge test 30 (17.0%) 146* (31.1%) Abnormal result, 75 g glucose tolerance test 12 (6.8%)† 46‡ (9.8%)† *P < 0.001, χ2. † % Of number screened. ‡ P = 0.15, χ2.

Aidan McElduff · Rosemary Hitchman

During the past decade there have been significant advances in the prevention, diagnosis and management of endocrine disease. Here I concentrate on two disorders with significant disease burden — diabetes and obesity. Prevention. Preventing diabetes mellitus is a key goal in endocrinology. For type 1 diabetes, immunomodulation using nicotinamide and pre-emptive insulin therapy is being evaluated in high risk individuals (based on family history, autoimmune markers and metabolic profile).1 For type 2 diabetes, the key strategy is the primary prevention of obesity.1,2 Major trials in the 1990s have shown a continuous relationship between macro- and microvascular disease and hyperglycaemia, hypertension and dyslipidaemia. Current data indicate that remarkable improvements at the population level would be gained by achieving targets of glycohaemoglobin (HbA1c) < 7%, blood pressure < 130/80 mmHg, and low-density lipoprotein cholesterol < 2.6 mmol/L, using available therapies (HMGCoA reductase inhibitors, ACE inhibitors, and angiotensin 2 receptor antagonists).1 However, this knowledge is incompletely applied in practice and an important advance will be treating all patients with diabetes to established targets. Diagnosis. Refinements in existing techniques, such as immunoassay and medical imaging, have allowed previously complex diagnostic algorithms (eg, assessment of thyroid status) to be performed cheaply and with a high degree of precision. Many monogenic endocrine disorders, including the multiple endocrine neoplasia syndromes, are now also identifiable by presymptomatic gene testing. With contemporary advances in molecular biology and bioinformatics, the search for susceptibility genes for diabetes, obesity and other polygenic diseases is also progressing rapidly. Somatostatin-receptor (SR) imaging using radionuclide-labelled ligands allows localisation, staging and treatment planning in patients with SR-positive neuroendocrine tumours. An intraoperative γ-probe to localise labelled tissues (eg, with Tc-sestamibi) can also help localise occult tumour in patients with endocrine neoplasms. Interventions. Effective interventions for established obesity include bariatric and gastric bypass surgery. Laparoscopic gastric banding has the advantage that it requires minimal access and is adjustable.2 The pharmacological options for established obesity are currently limited. New drugs include the appetite suppressant sibutramine (a selective inhibitor of serotonin and noradrenaline reuptake) and orlistat (an intestinal lipase inhibitor). Individually, these agents achieve a 5%–15% weight reduction. Pharmacological agents that either suppress appetite or increase basal energy expenditure are likely to be developed over the next five years. Central factors (neuropeptide Y, melanocortins) and adipocyte hormones (leptin) are potential pharmacological targets. Drugs which increase thermogenesis (β3-adrenergic-receptor agonists and mitochondrial uncoupling proteins) are also being evaluated.2 The thiazolidinediones are a new class of insulin-sensitising agents for treating type 2 diabetes. Non-sulfonylurea insulin secretagogues, such as the glinide class (eg, repaglinide), improve meal-related insulin release, but minimise the risk of hypoglycaemia. An increasing array of insulin analogues (created by amino acid rearrangement in the insulin molecule) are available: rapid-acting agents (lispro and aspart insulin), and long-acting analogues (insulin glargine). New ways of delivering insulin and monitoring glucose are also available or under trial. Inhaled (aerosolised) insulin is showing promise in clinical trials, although problems remain with delivery efficiency and thus cost. Mechanical pumps for continuous ambulatory subcutaneous insulin infusion are used increasingly,1 offering improved glycaemic control for those willing to frequently monitor blood glucose level. Several technologies for continuous glucose sensing are also being developed, such as transcutaneous optical glucose sensing. Pancreatic transplantation for treating type 1 diabetes has long been available in Australia. Limited donor availability and a better outcome have restricted this treatment to patients requiring renal transplantation. An alternative, islet-cell transplantation using modified low-dose immunosuppressive regimens, is showing early promise in clinical trials.1 Developments in minimal-access endocrine surgery include laparoscopic adrenalectomy for benign adenoma (shorter hospital stay and lower morbidity), and minimal-access parathyroidectomy. The options for medical management of primary hyperparathyroidism are also expanding, with the identification of calcium-receptor agonists (calcimimetic drugs) which down-regulate parathyroid hormone secretion and normalise serum calcium level. Conclusion. While diagnostic and therapeutic modalities currently under development offer much promise for managing patients with endocrine disorders, significant improvements in health could also be achieved by fully applying current knowledge, technology and existing pharmaceuticals.

John R Burgess MD, FRACP

Editorial Vitamin D deficiency and multicultural Australia Oral vitamin D supplementation may be needed in women with dark skin pigmentation or dress codes which prevent adequate sunlight exposure MJA 2001; 175: 236-237 Although the first written descriptions of rickets date from the mid-1600s, it was not until the 1920s that the problem was linked to a deficiency of vitamin D. With the widespread use of vitamin D supplementation, rickets became a rare syndrome. However, in the 1970s, immigrants from the Indian subcontinent living in the United Kingdom began presenting with florid symptoms of osteomalacia — bone pain, myopathy and pseudofractures.1 Vitamin D occurs in two forms, cholecalciferol, or vitamin D3, and the plant-derived ergocalciferol, or vitamin D2. These two forms are biologically equivalent in human beings. For most ambulatory people, the majority of the vitamin D in the body is derived from the action of ultraviolet B light on 7-dehydrocholesterol in the skin, converting it to previtamin D3, which, at body temperature, thermally isomerises into vitamin D3.2 A smaller proportion of vitamin D comes from dietary sources, particularly oily fish, eggs, butter and margarine.3 In contrast to the United States, few foods in Australia are fortified with vitamin D. Vitamin D made in the skin or ingested in the diet is biologically inert and must undergo conversion to 25-hydroxyvitamin D3 in the liver and then in the kidney to 1,25-dihydroxyvitamin D3 (calcitriol). The amount of high energy ultraviolet B light reaching the skin depends on factors such as latitude, season, smog (which reduces penetration of ultraviolet light through the atmosphere), and the actual amount of direct sun exposure, which is further modified by clothing and the use of sun protection agents.2,4 Vitamin D deficiency was therefore thought to be a rare disorder in populations living at latitudes where sunlight abounds for most of the year, and for this reason no recommended daily allowance for vitamin D has been established for Australia. Vitamin D deficiency, however, is now known to affect a substantial proportion of older people in this country, including those in institutions, patients with dementia and older men with hip fracture.5-8 In older people, the factors leading to this problem are reduced mobility; limited sunlight exposure; the assiduous use of sun-protection agents; and, in particular, a reduced ability of aged skin to produce vitamin D from a given dose of ultraviolet B light. In this issue of the Journal, two independent reports by Grover and Morley9 and Nozza and Rodda 10 draw attention to a new high-risk group for vitamin D deficiency in multicultural Australia. Grover and Morley report that 80% of dark-skinned or veiled women attending an antenatal clinic at the Royal Women's Hospital in Melbourne who took part in the study had biochemical evidence of vitamin D deficiency, with values of 25-hydroxyvitamin D3, the major blood metabolite, below the reference range.9 Nozza and Rodda examined paediatric records to identify children with vitamin D deficiency.10 In just over four and a half years, 55 children had presented with clinical features of rickets, including delayed walking, leg bowing, seizures and failure to thrive. Of those tested for parathyroid hormone levels, over 80% had secondary hyperparathyroidism. At the time of each child's presentation, none of the mothers had volunteered symptoms of vitamin D deficiency in themselves, but over half had 25-hydroxyvitamin D3 concentrations measured, and 81% of these had values below the reference range (< 25 nmol/L). All except one of the mothers of the children presenting with rickets were from Africa, the Indian subcontinent, the Middle East or southern Europe. The one mother of northern European descent was agoraphobic and depressed. As well as identifying a new high-risk group for vitamin D deficiency, these two reports highlight an important message for medical practitioners -- not only patients presenting for medical attention, but also other members of the family, may have vitamin D deficiency. As most of the vitamin D in neonates is acquired from maternal transfer,11 vitamin D deficiency in mothers is likely to have adverse consequences for their infants. In adults, vitamin D depletion causes a reduction in intestinal calcium absorption, resulting initially in a negative calcium balance, leading to secondary hyperparathyoidism with high bone turnover, bone loss, low bone density and an increased risk of vertebral and hip fractures. This may occur with serum 25-hydroxyvitamin D3 concentrations of less than 40 nmol/L, a value within most reference ranges.12,13 After a prolonged period, osteomalacia may become evident, manifested by an accumulation of demineralised bone, radiological pseudofractures or progressive bone pains with myopathy and a waddling gait. These clinical findings usually occur with frankly low serum 25-hydroxyvitamin D3 concentrations of less than 20 nmol/L. Women who are veiled or have dark skin pigmentation are susceptible to vitamin D deficiency because most clothing effectively absorbs ultraviolet B irradiation and increased melanin pigmentation reduces the cutaneous production of vitamin D.2,4 The absolute ultraviolet dose required to stimulate skin synthesis of vitamin D3 is about six times higher in African-Americans than in people of European descent.14 It has been estimated that, for lightly pigmented skin, exposure of hands, face and arms to a suberythemal dose of summer sunlight for about 15 minutes about three times per week is likely to be adequate for normal vitamin D requirements, even in the north-east of the United States.4 The presence of darker pigmentation and/or veiling may significantly impair adequate sun-derived vitamin D production, even in sunny regions like Australia. It remains unclear whether dietary factors, such as low calcium intakes, contribute to the problem. During the epidemic of rickets among Asian immigrants to the United Kingdom in the 1970s, it was speculated that diets low in calcium and containing certain types of cereal contributed to the development of vitamin D deficiency.15 Furthermore, there is evidence for accelerated metabolic inactivation and removal of vitamin D in primary or secondary hyperparathyroidism.16,17 Two recent reports also noted the significant clinical morbidity associated with vitamin D deficiency in the high-risk groups identified by Grover and Morley9 and Nozza and Rodda.10 In the first, Muslim women presenting with bone densitometric evidence of osteoporosis, most of whom were veiled, were found to be 2.5 times more likely to have biochemical evidence of severe vitamin D deficiency than women of European descent.18 In the second, a group of Arab women with vitamin D deficiency living in Denmark experienced decreased muscle function and muscle pain and weakness, which improved after three months of vitamin D treatment.19 How much vitamin D is required to prevent vitamin D deficiency in multicultural Australia? In regions where sunlight abounds, educational programs should encourage cutaneous production of vitamin D, with due deference to the problems of overexposure. When dark skin and/or veiling prevent adequate exposure, supplementation with oral vitamin D is likely to be required. The active hormone, calcitriol, which requires careful monitoring of serum and urinary calcium levels, is not the agent of choice in these circumstances. As there is a large therapeutic window, the risk of hypercalcaemia with plain vitamin D, such as ergocalciferol, is low.20 Susceptible groups, including pregnant women, should have their serum 25-hydroxyvitamin D3 concentrations measured. As there are no high-dose oral or intramuscular vitamin D preparations available in Australia, supplementation with oral vitamin D (eg, ergocalciferol 1000 units daily) is indicated if serum 25-hydroxyvitamin D3 concentrations are below 20-40 nmol/L. Rebecca S Mason Associate Professor Department of Physiology, and Institute for Biomedical Research University of Sydney, NSW rebeccamATphysiol.usyd.edu.au Terrence H Diamond Senior Endocrinologist St George Hospital; and Conjoint Associate Professor Faculty of Medicine, University of New South Wales, NSW Reprints: Associate Professor T H Diamond Department of Endocrinology, St George Hospital, Private Medical Complex, Kogarah, NSW 2217 Preece MA, McIntosh WB, Tomlinson S, et al. Vitamin D deficiency among Asian immigrants to Britain. Lancet 1973; 1: 907-910. Holick MF. McCollum Award lecture, 1994: Vitamin D — new horizons for the 21st century. Am J Clin Nutr 1994; 60: 619-630. Truswell AS, Dreosti IE, English RM, et al, editors Recommended nutrient intakes, Australian papers. Sydney: Australian Professional Publications, 1990. Holick MF. Sunlight"D"lemma: risk of skin cancer or bone disease and muscle weakness. Lancet 2001; 357: 4-6. Morris HA, Morrison GW, Burr M, et al. Vitamin D deficiency and femoral neck fractures in elderly South Australian women. Med J Aust 1984; 140: 519-521. Kipen E, Helme RS, Wark JD, Flicker L. Bone density, vitamin D nutrition, and parathyroid hormone levels in women with dementia. J Am Geriatr Soc 1995; 43: 1088-1091. Stein MS, Scherer SC, Walton SL, et al. Risk factors for secondary hyperparathyroidism in a nursing home population. Clin Endocrinol 1996; 44: 375-383. Diamond T, Smerdly P, Kormas N, et al. Hip fracture in elderly men: the importance of subclinical vitamin D deficiency and hypogonadism. Med J Aust 1998; 169: 138-141. Grover SR, Morley R. Vitamin D deficiency in veiled or dark-skinned pregnant women. Med J Aust 2001; 175: 251-252. Nozza JM, Rodda CP. Vitamin D deficiency in mothers of infants with rickets. Med J Aust 2001; 175: 253-255. Clements MR, Fraser DR. Vitamin D supply to the rat fetus and neonate. J Clin Invest 1988; 81: 1768-1773. Chapuy MC, Schott AM, Garnero P, et al. Healthy elderly French women living at home have secondary hyperparathyroidism and high bone turnover during winter. EPIDOS study group. J Clin Endocrinol Metab 1996; 81: 1129-1133. Gallagher JC, Kinyamu HK, Fowler SE, et al. Calciotropic hormones and bone markers in the elderly. J Bone Miner Res 1998; 13: 475-482. Clemens TL, Henderson SL, Adams JS, Holick MF. Increased skin pigment reduces the capacity of skin to synthesise vitamin D3. Lancet 1982; I: 74-76. Ford JA, McIntosh WB, Dunnigan MG. A possible relationship between high-extraction cereal and rickets and osteomalacia. Adv Exp Med Biol 1977; 81: 353-362. Clements MR, Davies M, Fraser DR, et al. Metabolic inactivation of vitamin D is enhanced in primary hyperparathyroidism. Clin Sci 1987; 73: 659-664. Clements MR, Johnson L, Fraser DR. A new mechanism for induced vitamin D deficiency in calcium deprivation. Nature 1987; 325: 62-65. Diamond T, Levy S, Smith A, Day P. Vitamin D deficiency is common in Muslim women presenting with bone pains and osteoporosis. Proceedings of the 9th Annual Scientific Meeting of the Australia and New Zealand Bone and Mineral Society, Cairns, June 1999; p 32, abstract 3B. Glerup H, Mikkelsen K, Poulsen L, et al. Hypovitaminosis D myopathy without biochemical signs of osteomalacic bone involvement. Calcif Tissue Int 2000; 66: 419-424. Mason RS, Posen S. The relevance of 25-hydroxycalciferol measurements in the treatment of hypoparathyroidism. Clin Endocrinol 1979; 10: 265-269. Make a comment

Rebecca S Mason · Terrence H Diamond

Diagnostic Dilemmas Contaminated medication precipitating hypoglycaemia Adrian M Goudie and Joey M Kaye We report a case of hypoglycaemia in a patient with diet-controlled type 2 diabetes. Enquiries and investigations led to a diagnosis of sulfonylurea poisoning from contaminated herbal medication. MJA 2001; 175: 256-257 Clinical record - Discussion - Conclusion - References - Authors' details - - - More articles on Endocrinology Many Australians use herbal or alternative medication,1 often without informing their doctors. Side effects and interactions from these medications, including problems with contaminants, can occur, as illustrated by the case described here. Clinical record A 56-year-old Indonesian tourist presented to our emergency department in September 1999. On arrival, he appeared unable to speak English, so his history was obtained from his wife and ambulance personnel. He had arrived from Jakarta three days previously and had been vaguely unwell with "flu" for the last few days. At 11:30 pm he had awoken confused and agitated, possibly with chest pain. On arrival of the ambulance, his capillary blood glucose level was 2.1 mmol/L, so he was given 1 mg of glucagon intramuscularly. During transfer he was given aspirin (300 mg) and isosorbide mononitrate (10 mg, sublingually). His agitation and confusion settled during the transfer to hospital. On arrival at the hospital his capillary blood glucose level was 4.3 mmol/L. He was speaking Indonesian and was alert and cooperative. He reported having diet-controlled non-insulin-dependent (type 2) diabetes mellitus, ischaemic heart disease (with coronary artery bypass surgery 12 years previously), hypertension and hypercholesterolaemia. He was taking amlodipine, aspirin and atorvastatin, but denied taking any medications for his diabetes. He was given some sandwiches while the history was being taken and an examination was performed. At 2:45 pm his capillary blood glucose level was found to be 2.1 mmol/L. Shortly after this, the laboratory rang to give a formal venous glucose concentration result of 2.9 mmol/L for a sample taken at 1:48 pm. Despite being given sugary drinks, then increasing dextrose infusions and intermittent boluses of dextrose, each time his blood sugar was retested it was found to be low (see Box). A 50 mL per hour infusion of 50% dextrose was required to prevent hypoglycaemia. After the first bolus of 50% dextrose it was discovered that he could speak English fluently. He confirmed his diabetes was diet-controlled and that he was not taking any hypoglycaemic medications. The lack of any obvious cause for the hypoglycaemia prompted us to consider rarer causes, and, in response to direct questioning about herbal and traditional medication, he admitted to taking a preparation called "ZhenQi" for his diabetes, which he had purchased in Malaysia. He had been taking this medication for the last five years, initially taking five capsules per day, then having increased the dose to three capsules three times daily (with no dose alteration) for the last two years. The label on the bottle of this preparation listed the ingredients as ginseng, pearl, ram's horn, bark and "frog extract". He had started a new bottle of the preparation recently, coinciding with the onset of the "flu"-like symptoms (lethargy, feeling cold and tremor). Serum taken during the period of hypoglycaemia (when his glucose level was 2.9 mmol/L) had elevated levels of C-peptide (3.80 nmol/L; normal range, 0.20-0.90 nmol/L) and insulin (50 mU/L; normal range, 3-26 mU/L). Analysis of the herbal medication capsules by gas chromatography and mass spectrometry (by PathCentre, Perth, Western Australia) revealed the presence of glibenclamide. Infusions of 50% dextrose and potassium were required for 20 hours, then reduced gradually over the next 24 hours. The serum insulin level had returned to normal 36 hours after admission. He was discharged on Day 3. Discussion Hypoglycaemia is a common reason for patients with diabetes to present to emergency departments, and is usually the result of an imbalance between oral intake, physical activity and the effects of medication.2 However, hypoglycaemia occurring in a patient with diet-controlled type 2 diabetes is unusual, and raises the possibility of one of the many rarer causes of hypoglycaemia. The diagnosis of hypoglycaemia rests on three criteria (Whipple's triad) of plasma hypoglycaemia, symptoms attributable to a low blood sugar level and resolution of symptoms with correction of the hypoglycaemia.3 There are many causes of hypoglycaemia,2-4 but it is most commonly the result of an excess of either insulin or oral hypoglycaemic medications combined with reduced sugar intake or increased activity.2 Our patient's initial claims that he was not taking any medications for glycaemic control led to a search for other causes. Although he had been taking the same dose of the herbal preparation for two years, we felt that it was the most likely cause of the hypoglycaemia. Insulin and C-peptide levels were therefore measured and both were elevated, indicating an endogenous insulin source as the cause. This can result from either an insulinoma, sulfonylurea drug (which stimulates the pancreatic islet cells to release insulin), drugs with a sulfonylurea-like action (eg, quinine)4 or autoimmune hypoglycaemia. Insulinomas usually cause semiautonomous release of insulin, resulting in fasting hypoglycaemia. In response to meals these tumours usually respond subnormally, so that postprandial glucose levels are normal or even mildly elevated,2 although postprandial hypoglycaemia can occur. This patient's persistent hypoglycaemia despite food would therefore be atypical for an insulinoma. However, computed tomography (CT) of the abdomen was performed (prior to the insulin and C-peptide levels being available) to exclude this possibility, or that of a large sarcoma (which can cause hypoglycaemia because of insulin-like growth-factor II release) — no pancreatic or intra-abdominal masses were detected. Insulinomas may be too small to be seen on CT scans5 and further investigation with endoscopic ultrasound was considered, if no other cause for the hypoglycaemia became apparent. Sulfonylurea overdose can lead to profound hypoglycaemia, with chlorpropamide and glibenclamide being the agents most frequently implicated.6 Both prolonged and recurrent hypoglycaemia must be expected. Potassium supplementation is often required. Dextrose infusions are usually sufficient, but can stimulate further insulin release from the sulfonylurea-primed beta cells. Octreotide and diazoxide both inhibit insulin release and have been recommended for treating severe poisoning refractory to dextrose.7,8 Steroids and glucagon have also been recommended, but are thought to be less effective.8 In our patient, analysis of the herbal medication capsules revealed the presence of glibenclamide. Plasma tests to screen for sulfonylureas are available and can be used to detect inadvertent or surreptitious ingestion.9 The use of herbal and alternative medicine is becoming more common, and it has been estimated that almost half of the Australian population use some form of such products within a 12-month period.1 Many patients do not inform their doctors that they take them.10 It is therefore important to ask directly whether patients are taking such substances. Numerous herbal preparations have been shown to affect blood glucose levels through various mechanisms, although they are usually limited by toxicity or relative lack of efficacy compared with standard medications.11,12 The lack of standardisation of ingredients and preparation also causes problems.13 Contamination with "conventional" medications has been reported to cause adverse effects.14,15 In this case, we felt it most likely that the sulfonylurea had been added to the herbal ingredients in the preparation of the capsules. Conclusion The cause of hypoglycaemia, commonly seen in emergency departments, is usually obvious. When it is not, then rarer causes and factitious disorders must be considered. The use of herbal and alternative medications must be considered and specifically asked about in all patients. Competing interests: None. References MacLennan AH, Wilson DH, Taylor AW. Prevalence and cost of alternative medicine in Australia. Lancet 1996; 347: 569-573. Turner RC. Hypoglycemia. In: Weatherall DJ, Ledingham JGG, Warrell DA, editors. Oxford textbook of medicine. 3rd ed. Oxford: Oxford University Press; 1996: 1505-1502. Foster DW, Rubenstein AH. Chapter 335: Hypoglycemia. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, editors. Harrison's principles of internal medicine. 14th ed. CD-ROM. New York: McGraw Hill; 1998. Marks V, Teal JD. Drug-induced hypoglycaemia. Endocrinol Metab Clin North Am 1999; 28: 555-577. Ardengh JC, Rosenbaum P, Ganc AJ, et al. Role of EUS in the preoperative localization of insulinomas compared with spiral CT. Gastrointest Endosc 2000; 51: 552-555. Seltzer H. Drug-induced hypoglycaemia: a review of 1418 cases. Endocrinol Metab Clin North Am 1989; 18: 168-171. Boyle PJ, Justice K, Krentz AJ, et al. Octreotide reverses hyperinsulinaemia and prevents hypoglycaemia induced by sulfonylurea overdoses. J Clin Endocrinol Metab 1993; 76: 752-756. Palatnick W, Meatherall RC, Tenenbein M. Clinical spectrum of sulfonylurea overdose and experience with diazoxide therapy. Arch Intern Med 1991; 151: 1859-1862. Shenfield GM, Boutagy JS, Webb C. A screening test for detecting sulfonylureas in plasma. Ther Drug Monit 1990; 12: 393-397. Kristoffersen SS, Atkin PA, Shenfield GM. Uptake of alternative medicine [letter]. Lancet 1996; 347: 972. Bailey CJ, Day C. Traditional plant medicines as treatments for diabetes. Diabetes Care 1989; 12: 553-563. Miller LG. Herbal medicinals. Arch Intern Med 1998; 158: 2200-2211. Shaw D, Leon C, Kolev S, Murray V. Traditional remedies and food supplements. Drug Safety 1997; 17: 342-356. Rios CA, Sahud MA. Agranulocytosis caused by Chinese herbal medicines. Dangers of medications containing aminopyrine and phenylbutazone. JAMA 1975; 231: 352-355. Bury RW, Fullifaw RO, Barraclough D, et al. Problems with herbal medicines. Med J Aust 1987; 146: 324-325. (Received 30 Mar, accepted 21 Jun, 2001) Authors' details Royal Perth Hospital, Perth, WA. Adrian M Goudie, MB BS, FACEM, Emergency Department Consultant; Joey M Kaye, MB BS, Endocrinology Registrar (currently, Research Fellow, University Research Centre for Neuroendocrinology, Bristol Royal Infirmary, Bristol, UK). Reprints will not be available from the authors. Correspondence: Dr A M Goudie, Royal Perth Hospital, Box X2213, GPO, Perth, WA 6847. adriangoudieATyahoo.com.au Make a comment Back to text

Adrian M Goudie · Joey M Kaye

CLASS="LinkBox"> Editorial Priorities in polycystic ovary syndrome A common, multifaceted syndrome for which intervention may help prevent serious long term sequelae MJA 2001; 174: 554-555 The diagnosis of polycystic ovary syndrome (PCOS) has become much more common in recent years. It is now not unusual for women in the United States to come for consultation having self-diagnosed PCOS. This awareness is largely the result of the efforts of two well-organised advocacy groups in the US ...

Rogerio A Lobo

CLASS="LinkBox"> Position Statement Metformin and intervention in polycystic ovary syndrome Robert J Norman, Warren J Kidson, Ross C Cuneo, Margaret R Zacharin on behalf of the Endocrine Society of Australia, the Australian Diabetes Society and the Australasian Paediatric Endocrine Group MJA 2001; 174: 580-583 For editorial comment, see Lobo Abstract - PCOS and insulin resistance - Metformin - Published studies on metformin in PCOS - What should doctors do? - References - Authors' details - - More articles ...

Robert J Norman · Warren J Kidson · Ross C Cuneo · Margaret R Zacharin

Abstract - Mechanism - Injection therapy - Transurethral alprostadil - Selective inhibitors - Guidelines - Conclusion - References - Authors' details Abstract Erectile dysfunction (ED) is a common condition and can usually be managed pharmacologically, with drugs delivered by intracavernosal injection (ICI), transurethrally or orally. The cardiovascular status of the patient and his overall fitness for renewed sexual activity must be assessed before treatment for ED is initiated. The efficacy of sildenafil is related to the extent and severity of ED, and is significantly reduced in patients with severe vasculogenic ED, ED associated with diabetes and after radical prostatectomy. Alprostadil (prostaglandin E1) is the drug of first choice in patients treated with ICI; it is effective in 72.6% of men with ED and is associated with a low risk of priapism and cavernosal fibrosis. Transurethral alprostadil is significantly less effective than alprostadil ICI, producing improved erections in 30%-40%, but rigid erections in only 10%, of men with ED. There is Level II evidence that: alprostadil ICI is an effective treatment for ED papaverine ICI is associated with a high risk of cavernosal fibrosis and priapism papaverine ICI should be restricted to informed patients refractory to treatment with alprostadil ICI transurethral alprostadil is less effective than alprostadil ICI sildenafil is an effective treatment for ED. Erectile dysfunction (ED) is the inability to achieve and maintain an erection of sufficient rigidity for satisfactory sexual intercourse.1 Community-based epidemiological studies suggest that sexual dysfunction, particularly ED, is a common disorder in men, and is associated with reduced quality of life.2,3 While it was previously thought that most impotence in men was psychogenic, we now know that there is a physical basis for most men's impotence. One of the most significant advances in our understanding has been the recognition that blood flow into the corpora cavernosa is regulated by smooth muscle tone, and that this mechanism can be pharmacologically altered. Mechanism of erection An erection is initiated when psychoneuroendocrine stimuli activate efferent autonomic nerves to relax penile vascular and corpus cavernosal trabecular smooth muscle. The mechanism of erection is described in Box 1. The penis loses its rigidity when the activation of sympathetic constrictor nerves after ejaculation increases the tone of the smooth muscles and the helicine arteries and trabeculae, resulting in decreased arterial inflow and increased venous outlow. The mechanisms that maintain flaccidity are unknown. Priapism is an uncommon, but potentially serious, adverse effect associated with some of the therapies described below -- its management is outlined in Box 2. Intracavernosal injection therapy Self-administered intracavernosal injection (ICI) therapy, using vasodilator drugs which relax the arterial and trabecular smooth muscle, is an effective treatment for ED4 (E2). (See Box 3 for an explanation of level-of-evidence codes.5) Papaverine Papaverine is a potent, non-specific smooth muscle relaxant which increases smooth muscle intracellular adenosine 3',5'-monophosphate (cAMP) by its action as a non-selective cAMP phosphodiesterase inhibitor, causing vasodilatation of penile vascular and sinusoidal smooth muscle.6 Papaverine has a relatively short plasma half-life (1-2 hours) and is extensively metabolised in the liver. After intracavernosal injection, the peak serum concentration is several times lower than after extracavernosal injection, suggesting that the corpus cavernosum is a separate pharmacokinetic compartment from which elimination of papaverine is much slower than from the systemic circulation.7A meta-analysis of the largest published studies on the use of papaverine reports that it is effective in 53% of men with ED, as measured by the ability to produce an erection of sufficient rigidity for sexual intercourse8 (E1). However, the efficacy of ICI papaverine is limited by local adverse effects, principally priapism (in 7%)8 and intracavernosal fibrosis, presenting as penile deformity or curvature (reported in one study in 50% and 95%, respectively, of long term users).9 Fibrosis is related to poor injection technique, frequent injections and long term use. Because of these adverse effects, papaverine should be restricted to informed patients in whom other medications are ineffective. Papaverine hepatotoxicity is rarely a clinical problem and may manifest either as an increase in liver transaminase concentrations, which is relatively common (> 1%), or as a drug-induced hepatitis, which is rare (< 0.1%).10 Adrenergic blockers It is well recognised that drugs which block α-adrenoceptors (such as prazosin) can produce erection, and even priapism. Thus, intracavernosal injection of α-adrenergic-blocking drugs seems a logical way of producing penile erection. Phentolamine, a competitive α-adrenoceptor antagonist with affinity for α1- and α2-adrenoceptors, produces tumescence, but rarely an erection, when injected intracavernosally. However, when phentolamine is combined with papaverine, 68% of users respond with a rigid erection8 (E1). Alprostadil Alprostadil (prostaglandin E1, or PGE1) is an eicosanoid derived from arachidonic acid (see Box 4 for a profile of alprostadil). The mechanism of its vasodilating action is not completely understood. Alprostadil increases levels of intracellular cAMP by modulation of adenyl cyclase, leading to a decrease in the free calcium concentration and subsequently to smooth muscle relaxation.11 It may also modulate the presynaptic release of noradrenaline. Alprostadil has a short duration of action and a plasma half-life of less than one minute because of rapid pulmonary clearance of up to 80% after the first pass through the lung. When injected intracavernosally, approximately 30% of the drug is metabolised within the corpora cavernosa, which may explain why significantly fewer episodes of priapism occur with alprostadil than with papaverine. Multiple studies have shown that alprostadil has superior efficacy and reduced risk of priapism and intracavernosal fibrosis compared with papaverine (alone or combined with phentolamine). A meta-analysis found that alprostadil resulted in an erection of sufficient rigidity for sexual intercourse in 72.6% of men with ED8 (E1). The principal side effect of intracavernosal injection of alprostadil is pain at the site of injection, which occurs in up to 30% of patients. Priapism is a rare complication. Although early experience suggested that fibrosis was uncommon with alprostadil ICI, recent long term studies show an incidence of fibrosis and scar formation of 9%-23.3% in mid-term and long-term users, so patients should be warned of the possibility of penile fibrosis before starting treatment12,13 (E4). Studies in human fibroblasts have shown that alprostadil suppresses collagen synthesis induced by transforming growth factor (TGF-β1). An imbalance between PGE1 and TGF-β1 in the corpora cavernosa, as a result of anoxia or endothelial damage due to ischaemia, hypercholesterolaemia or hyperglycaemia, may cause increased extracellular matrix deposition, inhibition of smooth muscle growth, and eventually fibrosis.14 Inhibition of collagen synthesis by alprostadil may, in part, explain the low incidence of cavernosal fibrosis with this drug. Polyagent intracavernosal injection therapy Intracavernosal injection therapy with alprostadil in combination with other agents such as papaverine, phentolamine and atropine may be effective in patients in whom maximum-dose alprostadil monotherapy is ineffective.15,16 A comparative study reported a 91.6% response rate to a combination of alprostadil, papaverine and phentolamine15 (E32). Polyagent ICI appears effective as "salvage therapy" in patients with severe arteriogenic ED and mild to moderately severe cavernosal venous leakage in whom alprostadil alone is ineffective.16 However, a significant number of patients remain refractory to ICI therapy. Treatment guidelines proposed by the 1998 New South Wales Health Complaints Commission Inquiry into Impotence Treatment emphasise the importance of adhering to good manufacturing practices to ensure sterility of polyagent medication.17 Transurethral alprostadil Alprostadil can also be administered as a microsuppository into the distal urethra. A translucent hollow-stem applicator is used to insert the microsuppository after urination, the residual urine acting as both a lubricant and a diluent for the microsuppository. The drug is absorbed directly into the urethral endothelium and is transferred into the corpora cavernosa primarily by venous channels that communicate between the corpus spongiosum and the corpora cavernosa. These channels appear to increase in number, but particularly in size, with age. Alprostadil is rapidly absorbed from the urethra (only 20% remains after 10 minutes) and produces vasodilatation in the penile vasculature; plasma levels are either low or undetectable. Transurethral alprostadil has a brief serum half-life of between 30 seconds and 10 minutes because of rapid pulmonary clearance after the first pass through the lung. No effect on spermatozoa motility, viability or membrane integrity has been shown, and the mean increase in the PGE1 content of the ejaculate (123 mg) is less than the normal day-to-day variability for prostaglandins. In extensive double-blind placebo-controlled clinical trials sponsored by manufacturers, 65.9% of men achieved an erection adequate for intercourse after administration of transurethral alprostadil in a doctor's office,8 and 64.9% of these men reported intercourse at least once with home treatment, with significant improvements in quality of life, particularly in the domains of self-esteem and sexual and non-sexual aspects of their relationships with their partners17 (E2). The efficacy of alprostadil was found to be similar regardless of age or the cause of ED, including vascular disease, diabetes, surgery, and trauma. The use of an adjustable penile constriction band with transurethral alprostadil may augment the drug effect. However, several postmarketing studies failed to produce similar results to those of the trials sponsored by manufacturers. One reported that only 27% of patients achieved erections sufficient for intercourse during in-office testing, and that, because of this limited efficacy, adverse effects and cost, more than 80% of patients did not continue to use transurethral alprostadil at home18 (E4). Another study comparing transurethral and intracavernosal alprostadil reported total erectile response rates of 43% and 70%, respectively, complete rigid erections in only 10% versus 48%, and rates of penile pain or burning in 31.4% versus 10.6%19 (E4). The most frequently reported adverse effects associated with transurethral alprostadil are penile pain (32%), urethral bleeding or spotting (5%) and dizziness (3%).17 As syncope was reported in 0.4% of patients,17 the initial dose titration should be performed in the doctor's office. Discomfort after administration was commonly reported as mild and transient, but 7% of patients discontinued treatment because of adverse effects. Priapism and cavernosal fibrosis were found in less than 0.1% of patients using the transurethral preparation and less than 1% of those using the intracavernosal injection. Vaginal burning or itching was reported by 5.8% of partners. Unless a condom is used, transurethral alprostadil should not be used if the female partner is pregnant. Selective phosphodiesterase inhibitors Sildenafil Sildenafil citrate, a potent, competitive phosphodiesterase type 5 (PDE-5) isoenzyme inhibitor (see Box 4 for a profile of this drug), is the first oral medication to show significant and reliable efficacy in most patients with ED20 (E2). After the nitric oxide/cGMP pathway is activated by sexual arousal, inhibition of PDE-5 isoenzyme (see Box 1) by sildenafil results in increased cavernosal concentrations of cGMP and an augmented penile erection in men with ED. In early studies, sildenafil was effective in restoring erectile function and improving intercourse success rates in a wide range of patients, including those with hypertension, diabetes, spinal cord injury, other concomitant medical conditions, and in patients taking a wide variety of concomitant medications. Its efficacy was related to the cause, extent and severity of ED, and was significantly reduced in patients with severe vasculogenic ED, ED associated with diabetes, and after radical prostatectomy ED20,21 (E2, E32). More recent studies report a response rate to sildenafil of 65%, significant improvement in quality of life and a 35% incidence of adverse effects22 (E33). Failure to respond to sildenafil suggests severe vasculogenic ED resulting from advanced penile artery atherosclerosis or severe cavernosal venous leakage, or a combination of both. The action of sildenafil on the nitric oxide/cGMP pathway seems complementary to the action of other vasoactive agents, and combined therapy may be effective in patients who do not respond to a single therapy. A recent study reported that 34% of patients in whom maximum-dose ICI is ineffective responded to sildenafil, and a further 31% responded to a combination of the two, giving an overall "salvage" rate of 65%23 (E33). Sildenafil produces an erection within 25-60 minutes and remains active even at four to five hours after being taken. Sildenafil should be administered with caution in patients with retinitis pigmentosa, as some patients with this inherited condition have genetic disorders of retinal phosphodiesterase and there is no published safety information. Sildenafil is extensively metabolised, predominantly by CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes, and is converted to an active metabolite (M1), with an in-vitro potency for PDE-5 of approximately 50% of the parent drug, which accounts for about 20% of sildenafil's pharmacologic effects. Both sildenafil and the metabolite have terminal half-lives of about four hours. The adverse effects of sildenafil, reported in clinical trials, were transient, mild to moderate in nature, and dose-dependent. The most common adverse effects were headache (15.8%), flushing (10.5%), dyspepsia (6.5%) and nasal congestion (4.2%). Discontinuation of treatment was comparable for patients receiving sildenafil (2.6%) and placebo (2.3%). Priapism was not reported in these studies or in any of the clinical trials of sildenafil. As there is a degree of cardiac risk associated with sexual activity, doctors must assess the cardiovascular status of their patients before initiating any treatment for ED, including sildenafil. Sildenafil has been shown to potentiate the hypotensive effects of nitrates and may be associated with large and sudden drops in systemic blood pressure. It is therefore contraindicated in patients who use prescribed nitric oxide-donating drugs or nitrates in any form for ischaemic heart disease, or recreational nitrites (eg, amyl nitrite), regardless of frequency. Caution should also be exercised in patients with asymptomatic coronary artery disease stabilised with medical treatment, coronary revascularisation, congestive heart failure combined with borderline low blood pressure, or a multidrug regimen for high blood pressure.24 These patients remain at a slightly increased risk of developing angina pectoris or acute myocardial infarction, which may necessitate treatment with short-acting nitrates, including intravenous sodium nitroprusside, by ambulance or hospital emergency staff. Guidelines for the evaluation and treatment of erectile dysfunction Treatment for ED depends on both its cause and severity, but other factors, such as efficacy, adverse effects, acceptability to patient and partner, psychological effects, reversibility and cost, are also important. A guide to managing ED is shown in Box 5. Although the primary cause of most ED is organic, there are invariably compounding psychological factors, such as "performance anxiety"; psychosexual counselling may be an important option for both the patient and his partner. Patients and their partners should be informed of all available treatment options. Doctors remain responsible for conducting a thorough medical history, physical examination and appropriate investigations to establish the extent, severity and causes of ED. In patients regarded as fit for renewed sexual activity, first-line treatment with an oral phosphodiesterase inhibitor such as sildenafil is appropriate if there are no contraindications. Patients in whom sildenafil is ineffective, who can not tolerate its adverse effects or who have contraindications are best treated with alprostadil, either as ICI or the transurethral preparation. Men who fail to respond to maximum-dose alprostadil can be managed with ICI containing alprostadil combined with other agents such as papaverine and phentolamine. Men in whom drug treatment is ineffective may elect to undergo implantation of an intrapenile prosthesis, but many choose to limit their sexual activity to non-penetrative sex. Conclusion As the population ages, quality-of-life expectations will increase. Many men now recognise that ED need not be a consequence of advancing age, nor a result of chronic illness or radical prostate cancer surgery. Most patients with ED can be successfully treated with medications. Several new oral treatments for ED are currently undergoing clinical evaluation and may increase the therapeutic options considerably. Information for patients is given in Box 6. Disclosure: Chris G McMahon is a member of the speaker panels for Pharmacia Upjohn, Pfizer and Abbott/Vivus, the manufacturers of Caverject, Viagra and MUSE. He was also a member of the Caverject and MUSE medical advisory boards, a medical consultant to Pfizer, and a clinical investigator for Pharmacia Upjohn, Pfizer, Bayer, Eli Lilly, Icos Corporation, Abbott, Senetek PLC, Pentech and American Medical Systems. References NIH Consensus Conference. Impotence, NIH Consensus Development Panel on Impotence. JAMA 1993; 270: 83-90. Pinnock CB, Stapleton AM, Marshall VR. Erectile dysfunction in the community: a prevalence study. Med J Aust 1999; 171: 353-357. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999; 281: 537-544. Linet OI, Ogrinc FG. Efficacy and safety of intra-cavernosal alprostadil in men with erectile dysfunction. The Alprostadil Study Group. N Engl J Med. 1996; 334: 873-877. National Health and Medical Research Council. A guide to the development, implementation and evaluation of clinical practice guidelines. Canberra: NHMRC, AusInfo, 1999. Poch G, Kukovetz WR. Papaverine-induced inhibition of phosphodiesterase activity in various mammalian tissues. Life Sci 1971; 10: 133-144. Hakenberg O, Wetterauer U, Koppermann U, Liffimann R. Systemic pharmacokinetics of papaverine and phentolamine: Comparison of intravenous and intracorporal application. Int J Impotence Res 1990; 2 (Suppl 2): 247-248. Porst H. The rationale for prostaglandin E1 in erectile failure: a survey of world-wide experience. J Urol 1996; 155: 802-815. De Rose AF, Oppezzi GF, Scotto S. [Local complications of papaverine-induced erection: follow-up at 7 years] [Article in Italian]. Arch Ital Urol Androl 1993; 65: 289-293. Brown LS, Christopher AH, Koehler M, et al. Hepatotoxicity related to intracorporal pharmacotherapy with papaverine. Urology 1998; 52: 844-847. Paoletti R. Biochemistry and pharmacology of prostaglandin E1: introductory remarks. In: Sinzinger H, Rogatti W, editors. Prostaglandin E1 in atherosclerosis. New York: Springer-Verlag, 1986: 3-7. Chen RN, Lakin MM, Montague DK, Ausmundson S. Penile scarring with intracorporal injection therapy using prostaglandin E1: a risk factor analysis. J Urol 1996; 155: 138-140. Chew KK, Stuckey BG, Earle CM, et al. Penile fibrosis in intracavernosal prostaglandin E1 injection therapy for erectile dysfunction. Int J Impotence Res 1997; 9: 225-229; discussion, 229-230. Moreland RB, Traish A, McMillin MA, et al. PGE1 suppresses the induction of collagen synthesis by transforming growth factor-beta 1 in human corpus cavernosum smooth muscle. J Urol 1995; 153: 826-834. Padma-Nathan H. The efficacy and synergy of polypharmacotherapy in primary and salvage therapy of vasculogenic erectile failure. Int J Impotence Res 1990; 2: 257-258. McMahon CG. Comparison of the response to the intracavernosal injection of a combination of papaverine and phentolamine, prostaglandin E1 alone and a combination of all three in the management of impotence. Int J Impotence Res 1991; 3: 133-142. Padma-Nathan H, Hellstrom WJ, Kaiser FE, et al. Treatment of men with erectile dysfunction with transurethral alprostadil. Medicated Urethral System for Erection (MUSE) Study Group. N Engl J Med 1997; 336: 1-7. Fulgham PF, Cochran JS, Denman JL, et al. Disappointing initial results with transurethral alprostadil for erectile dysfunction in a urology practice setting. J Urol 1998; 160: 2041-2046. Porst H. Transurethral alprostadil with MUSE (medicated urethral system for erection) vs intracorporal alprostadil -- a comparative study in 103 patients with erectile dysfunction. Int J Impotence Res 1997; 9: 187-192. Goldstein I, Lue TF, Padma-Nathan H, et al. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med 1998; 338: 1397-1404. Dinsmore WW, Hodges M, Hargreaves C, et al. Sildenafil citrate (Viagra) in erectile dysfunction: near normalization in men with broad-spectrum erectile dysfunction compared with age-matched healthy control subjects. Urology 1999; 53: 800-805. Jarow JP, Burnett AL, Geringer AM. Clinical efficacy of sildenafil citrate based on etiology and response to prior treatment. J Urol 1999; 162: 722-725. McMahon CG, Samali R, Johnston HM. Treatment of Intracorporal Injection Non-Responders with Sildenafil Alone or in Combination with Polyagent Intracorporal Injections. J Urol 1999; 162: 1992-1997. Cheitlin MD, Hutter AM Jr, Brindis RG, et al. ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association. J Am Coll Cardiol 1999; 33: 273-282. Authors' details North Shore Private Hospital, Sydney, NSW. Chris G McMahon, MB BS, FACSHP, Sexual Health Physician. Reprints will not be available from the author. Correspondence: Dr C G McMahon, Suite 11, Level 3, North Shore Private Hospital, 1 Westbourne Street, St Leonards, NSW 2065. cmcmahonATmail.usyd.edu.au 1: Mechanism of erection Non-adrenergic, non-cholinergic nerves and vascular endothelium release nitric oxide in response to sexual arousal, which activates cytoplasmic guanylate cyclase, converting GTP into cGMP. The increased levels of cGMP alter transmembrane calcium ion flux, resulting in cavernosal smooth muscle relaxation, dilatation of cavernosal and helicine arteries and engorgement of lacunar spaces. The expanding lacunar spaces compress the subtunical venous plexus against the tunica albuginea, decreasing cavernosal venous outflow, increasing intracavernosal pressure, with resulting penile rigidity. Cyclic nucleotides, such as cGMP, are hydrolysed by cyclic nucleotide phosphodiesterases. GTP=guanosine triphosphate; GMP=guanosine monophosphate; cGMP=cyclic guanosine monophosphate. Back to text 2: Management of prolonged erection (priapism) Always use alprostadil monotherapy as first-line ICI treatment. Use lowest possible effective dose. Inform patient of the risk of prolonged erection and the procedure to be followed if the penis is still rigid, as follows: 2 hours after administration - 120mg pseudoephedrine 4 hours after administration - repeat 120mg pseudoephedrine and walk briskly for 10-15 minutes 6 hours after administration - regard as medical emergency and contact the treating doctor or a hospital emergency department immediately. Patients may require aspiration of corpora and irrigation with dilute vasoconstrictors or, in refractory priapism, surgical drainage. Back to text 3: Level-of-evidence codes Evidence for the statements made in this article is graded according to the NHMRC system5 for assessing the level of evidence. E1 Level I: Evidence obtained from a systematic review of all relevant randomised controlled trials. E2 Level II: Evidence obtained from at least one properly designed randomised controlled trial. E31 Level III-1: Evidence obtained from well-designed pseudo-randomised controlled trials (alternate allocation or some other method). E32 Level III-2: Evidence obtained from comparative studies with concurrent controls and allocation not randomised (cohort studies), case-control studies, or interrupted time series with a control group. E33 Level III-3: Evidence obtained from comparative studies with historical control, two or more single-arm studies, or interrupted time series without a parallel control group. E4 Level IV: Evidence obtained from case-series, either post-test, or pre-test and post-test. Back to text 4: Drugs: profiles of alprostadil and sildenafil Alprostadil Action and onset Alprostadil (prostaglandin E1) induces an erection by relaxation of trabecular smooth muscle and dilatation of cavernosal arteries. Alprostadil may be administered by intra-cavernosal injection (Caverject, Pharmacia Upjohn) or by a transurethral suppository (MUSE, Abbott/Vivus Corp.). An erectile response occurs within 5-15 minutes of intracavernosal injection (ICI) and within 7-25 minutes of transurethral administration. Arousal is usually required to produce a maximal response. Detumescence usually commences within 10-20 minutes of ejaculation or cessation of sexual arousal, but complete flaccidity may not occur for a further 1-2 hours. Dosage Both Caverject and MUSE are administered 10-20 minutes before planned sexual activity. Dosage is individualised by initial supervised dosage titration, with the aim of establising the lowest possible effective dose (see below). Caverject injection is available in three different concentrations in 1mL ampoules (5µg, 10µg and 20µg), with a kit containing a syringe, needle, alcohol swab and written instructions. Patients should be instructed in sterile injection technique, used needle disposal and the management of prolonged erections (&lt 2h; Box 2) by trained medical personnel. The maximum frequency of use is no more than three times a week, with at least 24 hours between doses. For ED of vasculogenic, psychogenic or mixed aetiology, start with 5µg and titrate in 5µg increments to a maximum of 40µg until an erectile response sufficient for sexual intercourse occurs or there are intolerable adverse effects. For ED of wholly neurogenic aetiology (spinal cord injury), start with 1.25µg and titrate in 1.25µg increments until an erectile response sufficient for sexual intercourse occurs or there are intolerable adverse effects. Transurethral alprostadil (MUSE) is available in dosages of 125µg, 250µg, 500µg, and 1000µg. It is administered after urination, the patient remaining standing for approximately 10 minutes. The two lower dosages are recommended for initial dosing, with stepwise dose titration to a maximum of 1000µg, until either an erectile response sufficient for sexual intercourse or intolerable adverse effects occur. Because of the potential for symptomatic hypotension and syncope, the initial dose titration should be conducted under medical supervision. The maximum frequency of use is no more than two doses per 24-hour period. Adverse effects Alprostadil ICI: Mild penile pain (15%-20%), priapism (0.25%) and cavernosal fibrosis with long term use (5%-10%). Cavernosal fibrosis may result in the formation of nodules, penile curvature or deformity, or impaired erectile function. Adverse effects of intraurethral alprostadil include penile pain (25%-35%), urethral bleeding or spotting (5%), priapism (0.1%) and symptomatic hypotension (3%) and syncope (0.4%). Drug interactions Unlikely because only low or undetectable amounts of alprostadil (< 2pg/mL) are found in the peripheral venous circulation. Slidenafil Action and onset Sildenafil citrate is a potent, competitive phosphodiesterase type 5 (PDE-5) isoenzyme inhibitor. When sexual arousal activates the nitric oxide/cGMP pathway via non-adrenergic, non-cholinergic nerves, inhibition of PDE-5 results in increased cavernosal levels of cGMP, relaxation of penile vascular and trabecular smooth muscle, increased cavernosal blood flow and augmented penile tumescence or erection. An erectile response to sexual arousal may occur 0.5-5 hours after dosing. Ingestion on an empty stomach may result in a response after 30 minutes, whereas ingestion after a high-fat meal may delay onset for up to 3 hours. Detumescence occurs immediately after ejaculation or cessation of sexual arousal. The erectile refractory period is often reduced, allowing subsequent arousal to produce a second erection in some men. Dosage Sildenafil is available in 25mg, 50mg and 100mg tablets. The recommended starting dose is 50mg, taken one hour before planned sexual activity, with subsequent dose titration (to a maximum of 100mg) until the desired erectile response is achieved. Use is limited to once-daily administration. Patients aged over 65 years, those with significant renal impairment (creatinine clearance rate, < 30mL/min) or hepatic impairment, or those taking potent cytochrome P450 3A4 inhibitors, should start with a dose of 25mg. Adverse effects Adverse effects are dose-related and are usually of mild to moderate severity. The most common are headache, facial and upper-trunk flushing, dyspepsia and nasal congestion. Transient alteration in colour vision may occur at a dose of 100mg. No cases of priapism were reported in initial studies. Drug interactions The concomitant use of potent cytochrome P450 3A4 inhibitors (eg, erythromycin, ketoconazole, itraconazole, protease inhibitors), as well as the nonspecific CYP inhibitor cimetidine, is associated with increased plasma levels of sildenafil. Concomitant administration of CYP3A4 inducers, such as rifampicin, will decrease plasma levels of sildenafil. Sildenafil potentiates the hypotensive effects of nitrates and should not be taken by patients who use nitric oxide donors or nitrates in any form. Patients' fitness for renewed sexual activity should be assessed before initiating treatment Back to text 5: Evaluation and treatment of erectile dysfuntion Back to text 6: Important messages for patients Erectile dysfunction is common and is usually due to physical disease. The speed and extent of the male and female sexual response reduces as men and women age - patient treatment expectations should be appropriate for age. Erectile dysfunction is associated with cigarette smoking, hypertension, peripheral vascular disease, diabetes mellitus and depression, and can be an indicator of other underlying, unrecognised physical disease. There is always a contributing psychological component, and psychosexual therapy may result in restoration of potency, even when there is a contributing physical cause - not all men require treatment with medication. Some men can be successfully treated with a combination of sexual education, changes in lifestyle and medication. Many couples have fulfilling sexual relationships without penetrative sexual intercourse - not all men need to have potency restored. Men with long term erectile dysfunction and chronic medical illness (eg, coronary artery disease, chronic obstructive pulmonary disease), must have their fitness for renewed sexual activity assessed before initiation of treatment. Men with angina who take prescribed nitrates should not take sildenafil. Back to text

Chris G McMahon

Editorial Lower-limb amputation and diabetes: the key is prevention Education in footcare and regular examination will reduce the burden of diabetes-related amputation MJA 2000; 173: 341-342 Diabetes-related foot problems result in significant social, medical and economic consequences, and constitute the most common reason for hospital admission for people with diabetes.1 Lower-limb amputation is one of the most feared complications of diabetes, but comprehensive Australian data for its current incidence and prevalence in people with diabetes have not been previously available. It is thus timely that the study by Payne is published in this issue of the Journal.2 By analysing the National Hospital Morbidity Database of all hospital separations for the ICD codes which shared diabetes and lower-limb amputation over the financial years 1995-96, 1996-97 and 1997-98, he found a mean of 2629 lower-limb amputations per year. This tragic figure is even more frightening as it most likely represents an underestimate, because of the under-reporting of diabetes on discharge summaries. In all countries, diabetes is the major risk factor for amputation. Data from the United States National Hospital Discharge Survey found an annual average of 110 000 amputations for the period 1989-1992. Of these, 32% were for amputation of toe, 10% foot/ankle, 23% below-knee, and 16% above-knee amputations.3 Of all discharges listing lower-limb amputation, about 51% also listed diabetes, even though people with diabetes represented only 3% of the total US population. The age-adjusted amputation rate calculated for people with diabetes is about 15 to 40 times higher than that for people without diabetes. What are the other risk factors for amputation in people with diabetes? As in Payne's Australian study, the amputation rates in the US are 1.4 and 2.4 times higher for individuals aged 65-74 and aged 75 years and over, respectively, compared with those aged under 65 years.4 Apart from sex, the other major risk factors described are race or ethnic background: a number of US studies have shown higher rates of amputation for black and Hispanic people than for non-Hispanic white people.4 It is unfortunate that Payne was unable to determine this type of demographic data for the Australian population. Other major risk factors include the presence of peripheral neuropathy and lower-limb arterial disease.5,6 In turn, many factors contribute to the development of peripheral vascular disease, including hypertension, smoking and hyperlipidaemia. Finally, duration of diabetes and glycaemic control have been documented as risk factors for amputation and clearly contribute to both peripheral neuropathy and vascular disease.5-8 So, the profile of patients with diabetes at increased risk of amputation is well known. How can we reduce the risk of amputation in people with diabetes? The categorisation of risk of developing diabetes-related foot disease is relatively easily achieved in most people by basic clinical history and examination (Box 1). Self-reported preventive practices in patients have been linked to decreased risk of lower-limb complications.3 However, among individuals with diabetes identified in the 1989 US National Heath Interview Survey, 22% stated they never checked their feet, and 52% checked their feet at least daily. In addition, 53% of patients reported no foot examination by a healthcare professional within the past six months.3 These behaviours need to be changed (Box 2). High-risk foot clinics are also very successful both in healing ulcers and in reducing amputations in patients who have had foot ulcers.11 These multidisciplinary clinics involve specialists from vascular surgery, orthopaedic surgery, endocrinology, infectious diseases, orthotics, and podiatry. Recent advances in prosthetic and orthotic materials, design and manufacturing have improved the ability of clinicians to prevent ulceration in the at-risk foot. Furthermore, advances in orthopaedic techniques now enable the reconstruction of many feet previously considered beyond salvage. What approaches are we taking in Australia to reducing diabetes-related foot problems? The National Diabetes Strategy, published in 1998, identified foot care as a major issue in the National Diabetic Foot Disease Management Program.12 Among the goals set was a 50% reduction in lower-limb amputation by the year 2005, and an 80% level of screening for diabetic foot disease risk factors each year. In addition, an increased availability of podiatry services and specialist foot clinics to provide these services was advocated. Guidelines for non-medical healthcare professionals have been formulated by the Australian Diabetes Educators Association and the Australian Podiatry Council, and Diabetes Australia has produced the Australian Podiatric Guidelines. Most States have established footcare guidelines for doctors, and national guidelines will soon be available. Furthermore, the Australian Diabetes Society position statement on the lower limb in people with diabetes is also published in this issue of the Journal.13 The position statement summarises the major issues and makes recommendations to reduce lower-limb problems for Australians with diabetes. The overriding priorities are to ensure all people with diabetes practise appropriate self-care and that healthcare professionals examine the feet of all people with diabetes regularly to identify people at high risk for ulcer and amputation. Finally, appropriate funding is required to ensure that people at risk are provided with regular podiatry care and education and that people with active foot problems are provided with multidisciplinary foot care. Only when these are achieved will we start to make progress towards reducing this tragic and feared complication of diabetes. Peter G Colman Clinical Associate Professor, and Director Department of Diabetes and Endocrinology Royal Melbourne Hospital, Melbourne, VIC Andrew D Beischer Senior Lecturer Department of Orthopaedic Surgery Royal Melbourne Hospital, Melbourne, VIC Young MJ, Veves A, Boulton AJM. The diabetic foot: aetiopathogenesis and management. Diab Metab Rev 1993; 9: 109-127. Payne CB. Diabetes-related lower-limb amputations in Australia. Med J Aust 2000; 173: 352. Reiber GE, Boyko EJ, Smith DG. Lower extremity foot ulcers and amputations in diabetes. In: Diabetes in America. 2nd ed. Bethesda, Md: National Diabetes Data Group, National Institute of Diabetes and Digestive and Kidney Diseases, 1995; 409-427. Centers for Disease Control and Prevention. Diabetes Surveillance, 1993. Atlanta, GA: US Department of Health and Human Services, 1993; 87-93. Reiber GE, Pecoraro RE, Koepsell TD. Risk factors for amputation in patients with diabetes mellitus. A case-control study. Ann Intern Med 1992; 117: 97-105. Nelson RG, Gohdes DM, Everhart JE, et al. Lower extremity amputations in NIDDM: 12-yr follow-up study in Pima Indians. Diabetes Care 1988; 11: 8-16. Lee JS, Lu M, Lee VS, et al. Lower extremity amputation. Incidence, risk factors, and mortality in the Oklahoma Indian Diabetes Study. Diabetes 1993; 42: 876-882. Klein R. Hyperglycemia and microvascular and macrovascular disease in diabetes. Kelly West Lecture, 1994. Diabetes Care 1995; 18: 258-268. Litzelman DK, Slemenda CW, Langefeld CD, Hays LM. Reduction of lower extremity clinical abnormalities in patients with non-insulin dependent diabetes. Ann Intern Med 1993; 119: 36-41. Malone JM, Snyder M, Anderson G, Bernhard VM. Prevention of amputation by diabetic education. Am J Surg 1989; 158: 520-524. Edmonds ME, Blundell MP, Morris ME, Thomas EM. Improved survival of the diabetic foot: the role of a specialized foot clinic. QJM 1986; 60: 763-771. Colagiuri S, Colagiuri R, Ward J. National Diabetes Strategy and Implementation Plan. Canberra: Diabetes Australia, 1998. Campbell LV, Graham AR, Kidd RM, et al. The lower limb in people with diabetes. Position statement of the Australian Diabetes Society. Med J Aust 2000; 173: 369-372. Make a comment 1: Assessing the risk of diabetic foot disease History Look for a history of: non-traumatic partial or total foot amputation, a diabetic foot ulcer, or admission to hospital for a diabetes-related foot infection. Examination It is not unreasonable to expect these procedures to be performed by medical and non-medical healthcare professionals in the primary care setting: Both feet should be inspected for the presence of obvious deformity and for trophic skin changes. A careful examination should be made for callosities, which may herald incipient ulceration, particularly if present on the plantar aspect of the foot. Peripheral neuropathy, with a loss of protective sensation, can be identified using a 10g Semmes-Weinstein monofilament. Peripheral vascular disease can be detected by palpation of the pedal pulses. Shoes should also be inspected to ensure proper fit and also for unusual wear that may be the result of deformity. Back to text 2: Interventions to improve footcare among people with diabetes A 12-month randomised trial evaluated the effectiveness of comprehensive patient, healthcare provider, and system interventions on risk factors for amputation in 352 patients with type 2 diabetes.9 Patients were randomised to a foot-care group that provided education, and telephone and postcard prompts. Physicians assigned to intervention patients received practice guidelines, information on amputation risk factors and footcare practice and prompts. As a result, physicians detected ulcers in the intervention group more frequently. Similarly, foot self-care behaviours were reported more frequently by intervention patients. A similar prospective randomised study used an intervention in which patients attended a one-hour class and were given written instructions for footcare.10 Clinical care for both groups was identical. After one year of follow-up, there was a threefold excess for both foot amputations and ulcers in the group receiving no education. A case-control study reported the same findings.5 Interestingly, patient education provided at the time of diabetes diagnosis and in hospital settings did not show the same benefit as formal outpatient diabetes education nearer to amputation. Back to text

Peter G Colman · Andrew D Beischer

Research Diabetes-related lower-limb amputations in Australia Craig B Payne MJA 2000; 173: 352-354 For editorial comment, see Colman & Beischer; see also Campbell et al. Abstract - Methods - Results - Discussion - Acknowledgements - References - Authors' details - - More articles on Endocrinology Abstract Objective: To identify the prevalence of diabetes-related lower-limb amputations and its regional variations in Australia. Design and setting: Cross-sectional analysis of a hospital morbidity dataset in Australia. Methods: Analysis of the National Hospital Morbidity Database of all hospital separations for the ICD codes 84.10-84.19 (lower-limb amputations) and 250.0-250.9 (diabetes and its complications) for the financial years 1995-96 to 1997-98. Main outcome measure: Number of lower-limb amputations in people with diabetes mellitus in Australia, and in each State and Territory. Results: 7887 diabetes-related lower-limb amputations were reported during the study period, with a mean ± SD of 2629 ± 47 per year. The prevalence in Australia was 13.97 per 100 000 total population, and varied from 11.34 per 100 000 in the Australian Capital Territory to 20.68 per 100 000 in South Australia. Conclusion: Diabetes-related lower-limb amputation poses a substantial personal and public health cost in Australia. The loss of a limb is a frequent complication of diabetes mellitus, most commonly the result of diabetic foot problems such as ulcers and infection. The risk of amputation of the lower limb is increased up to 15-fold in people with diabetes. Contributory factors include the loss of sensation from the sensory neuropathy; deformity and gait abnormalities from the motor neuropathy; abnormal blood flow regulation from the autonomic neuropathy; ischaemia from the macrovascular disease; limited joint mobility from the increased glycolation of collagen; poor glycaemic control; and increased risk of infection. It is usually some trigger or traumatic event superimposed on these risk factors that causes a lesion such as ulceration or infection which starts a pathway leading to amputation.2,3 Inadequate and inappropriate self-care is also a major factor. The National Diabetic Foot Disease Management Program, as part of the National Diabetes Strategy and Implementation Plan,4 has called for a 50% reduction in lower-limb amputations by the year 2005. Data on diabetes-related lower-limb amputations in Australia are lacking.4 The aim of my study was to identify the prevalence of diabetes-related lower-limb amputations in Australia, as well as variations among States and Territories. Methods Approval for the study was given by the Faculty of Health Sciences Human Ethics Committee at La Trobe University (Victoria). The dataset for my analysis was obtained from the Australian Institute of Health and Welfare (AIHW) for the financial years 1995-96, 1996-97 and 1997-98. The AIHW obtained permission from the relevant State and Territory agencies to release the information, which did not include any personal identifying data. Information was obtained from the National Hospital Morbidity Database (compiled by the AIHW) on all separations from public and private hospitals in Australia for the International Classification of Disease (ICD)5 procedure codes 84.10 to 84.19 (amputations of the lower extremity) and diagnosis codes 250.0 to 250.9 (indicating diabetes and its complications) as the principal or secondary diagnoses. Information was also obtained on sex, age, ethnicity, duration of hospital stay, and State or Territory of residence of each patient who had an amputation. A spreadsheet was used to determine the number of amputations in each region and the duration of hospital stay. The data for each State and Territory were age- and sex-standardised6 to the estimated Australian population as at 30 June 1998.7 This information was then used to determine the rate for each State and Territory. Results A total of 7887 diabetes-related lower-limb amputations (68.2% in men) were recorded as occurring in the three-year period, with an annual mean of 2629 ± 47 (SD) (Box 1). Most occurred in the 65-79 years age groups (Box 2). The age- and sex-standardised prevalence of lower-limb amputation varied among the States and Territories (Box 3), from 11.34 per 100 000 total population in the Australian Capital Territory to 20.68 per 100 000 total population in South Australia. The duration of hospital stay (Box 3) also varied among the States and Territories. The shortest mean hospital stay was 20.0 (95% CI, 17.4-22.6) days in South Australia and the longest was 40.2 (95% CI, 23.1-57.3) in the Northern Territory. It was not possible to analyse the ethnicity data, as two States/Territories would not agree to the release of this information. Discussion The 2629 diabetes-related lower-limb amputations in Australia per year represent a significant personal burden on people with diabetes and on the healthcare system. The loss of a limb is a personal tragedy for those with diabetes,8 and is associated with a deterioration of functional status and residential status,9 with a significant number requiring long term care.10 People with diabetes who have a lower-limb amputation have a higher mortality rate,1,11 especially perioperative mortality.12 Half the people with an amputation will require an amputation of the remaining limb within five years.13,14 This morbidity results in high medical and rehabilitation costs: about 10% of diabetes-related healthcare costs are associated with lower-limb amputations.15The sex differences in lower-limb amputation rates of about 2:1 for men to women reported here are consistent with previous reports,20 and may be related to the levels of adherence to advice, the amount of social support, psychological factors such as denial, or a higher prevalence of the physiological risk factors for amputation such as macrovascular disease.21 Ethnicity is a well-recognised risk factor for lower-limb amputation,22,23 but was not analysed in this project as two of the States/Territories would not release this information. The duration of hospital stay has been identified as one of the main determinants of cost associated with a lower-limb amputation.17 The mean number of bed-days reported here (24.7 days) is less than the mean in the Netherlands15 (42 days) and more than that in the United States16 (15.9 days). There was a large variation among the Australian States and Territories in the mean hospital stay; South Australia has the highest prevalence of lower-limb amputation, but the shortest mean stay. Regional variations have been reported previously in New Zealand for hospital admissions for diabetic foot complications.18 Such regional variations are most likely to be due to variations in clinical practice and access to services.19 A number of shortcomings are inherent in the type of dataset analysed here. Of primary concern is the accuracy of the recording of data. Diabetes has been reported as being under-recorded on discharge records,24,25 so the numbers reported here are most likely an underestimate. There is also concern that the dataset does not distinguish the number of multiple amputations in the same individual; this will bias the population towards the characteristics of these individuals. A number of modifiable risk factors for diabetes-related lower-limb amputation have been identified,26-28 including the lowering of blood pressure, improving glycaemic control and reducing or eliminating smoking. With proper foot care, patient education and provision of appropriate services, such as regular podiatric care, a reduction in the number of amputations can be achieved.4 A number of studies have shown the value of multidisciplinary teams in reducing amputations by up to 50%.29-32 A reduction of this magnitude has the potential to save up to $24 million (based on the assumption that the direct cost of diabetes-related lower-limb amputations in Australia is $48 million per year4). However, a significant proportion of this potential saving will need to be directed to programs to prevent the amputations. Acknowledgements Funding for this project was provided by the Australasian Podiatric and Education Foundation. References Nelson R, Gohdes DM, Everhart JE, et al. Lower extremity amputations in NIDDM: 12 year follow up study in Pima Indians. Diabetes Care 1998; 11: 8-16. Payne CB, Scott RS, Moir C. Trigger events for acute admission to hospital for diabetic foot disease. Australas J Podiatric Med 1998; 32: 57-64. Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic amputation -- basis for prevention. Diabetes Care 1990; 13: 513-521. Colagiuri S, Colagiuri R, Ward J. National Diabetes Strategy and Implementation Plan. Canberra: Diabetes Australia, 1998. The International classification of diseases. 9th Revision. Clinical modification. Commission on Professional and Hospital Activities. Michigan, 1990. Beaglehole R, Bonita R, Kjellstrom T. Basic epidemiology. Geneva: World Health Organization, 1993. Australian Bureau of Statistics. Australian demographic statistics. Canberra: ABS, 1999. (Catalogue no. 3101.0.) Fitzpatrick MC. The psychologic assessment and psychosocial recovery of the patient with an amputation. Clin Orthop 1999; 381: 98-107. Frykberg RG, Arora S, Pomposelli FB, LoGerfo F. Functional outcome in elderly following lower extremity amputation. J Foot Ankle Surg 1998; 37: 181-185. Lavery LA, van Houtum WH, Armstrong DG. Institutionalisation following diabetes related lower extremity amputation. Am J Med 1997; 103: 383-388. Faris I, Duncan H, Young C. Factors affecting the outcome of diabetic patients with foot ulcers or gangrene. J Cardiovasc Surg 1988; 29: 736-740. Ebskov LB. Relative mortality in lower limb amputees with diabetes mellitus. Prosthet Orthot Int 1996; 20: 147-152. Silbert S. Amputation of the lower extremity in diabetes mellitus. Diabetes 1952; 1: 297-299. Ebskov LB. Diabetic amputation and long-term survival. Int J Rehab Res 1998; 21: 403-408 Van Houtum WH, Lavery LA, Harkless LB. The costs of diabetes-related lower extremity amputations in the Netherlands. Diabetic Med 1995; 12: 777-781. Ashry HR, Lavery LA, Armstrong DG, et al. Cost of diabetes related amputations in minorities. J Foot Ankle Surg 1998; 37: 186-190. Solomon C, van Rij A, Barnett R, et al. Amputations in the surgical budget. N Z Med J 1994; 107: 78-80. Payne CB, Scott RS, Moir C. Hospital discharges for diabetic foot disease in New Zealand 1980-1993. Diabetes Res Clin Pract 1998; 39: 69-74. Sanders D, Coulter A, McPherson K. Variations in hospital admission rates: a review of the literature. London: King Edward's Hospital Fund, 1989. Armstrong DG, Lavery LA, van Houtum WH, Harkless LB. The impact of gender on amputation. J Foot Ankle Surg 1997; 36: 66-69. Vogt MT, Wolfson SK, Kuller LH. Lower extremity arterial disease and the aging process -- a review. J Clin Epidemiol 1992; 45: 529-542. Lavery LA, Ashry HR, van Houtum W, et al. Variation in the incidence and proportion of diabetes related amputations in minorities. Diabetes Care 1996; 19: 48-51. Simmons D, Scott D, Kenealy T, Scragg R. Foot care among diabetic patients in South Auckland. N Z Med J 1995; 108: 106-108. Williams DRR, Fuller JH, Stevens LK. Validity of routinely collected hospital admissions data on diabetes. Diabetic Med 1998; 6: 320-324. Phillips DE, Mann JI. Diabetes -- inpatient utilisation, costs and data validity. Dunedin 1985-9. N Z Med J 1992; 105: 313-315. Moss SE, Klein R, Klein BEK. The prevalence and incidence of lower extremity amputation in a diabetic population. Arch Intern Med 1992; 152: 610-616. Lehto S, Ronnemaa T, Pyorala K, Laakso M. Risk factors predicting lower extremity amputations in patients with NIDDM. Diabetes Care 1996; 19: 607-611. Hamalainen H, Ronnemaa T, Halonen JP, Toikka T. Factors predicting lower extremity amputations in patients with type 1 or type 2 diabetes mellitus: a population based 7 year follow-up study. J Intern Med 1999; 246: 97-103. Edmonds ME, Blundell MP, Morris ME, et al. Improved survival of the diabetic foot -- the role of a specialised foot clinic. QJM 1986; 60: 763-771. Malone LM, Snyder M, Anderson G, et al. Prevention of amputation. Am J Surg 1989; 158: 520-523. Ebskov LB. Epidemiology of lower extremity amputation in Denmark. Int Orthop 1991; 15: 285-288. Larson J, Apelqvist J, Agardh CD, Stenstrom A. Decreasing incidence of major amputation in diabetic patients -- a consequence of a multidisciplinary foot care team approach. Diabetic Med 1995; 12: 770-777. (Received 25 Nov 1999, accepted 20 Jul 2000) Authors' details Faculty of Health Sciences, La Trobe University, Melbourne, VIC. Craig B Payne, DipPod(NZ), MPH, Lecturer, Department of Podiatry. Reprints: Dr C B Payne, Department of Podiatry, School of Human Biosciences, Faculty of Health Sciences, La Trobe University, Bundoora, VIC 3083. c.payneATlatrobe.edu.au Make a comment 1: Number of diabetes-related lower-limb amputations in Australia Men Women Total1995-96 1996-97 1997-98 1729 1849 1804 851 824 830 2580 2673 2634 Mean ±SD 1795 ±61 834 ±14 2629 ±47 Total 5382 (68%) 2505 (32%) 7887 Back to text Click in box for larger versionBack to text 3: Age- and sex-standardised prevalence and duration of hospital stay for lower-limb amputations in Australia for 1995-1998 Mean ±SD lower extremity amputations per year Rate (95% CI) per 100000 total population New South Wales Victoria Queensland South Australia Western Australia Tasmania Northern Territory Australian Capital Territory Australia 801 ±13 695 ±12 468 ±8 308 ±6 219 ±4 67 ±2 36 ±1 35 ±1 2629 ±47 12.59 (9.54-15.78) 14.87 (11.6-18.17) 13.48 (10.56-16.45) 20.68 (17.18-24.18) 11.89 (8.90-14.88) 14.21 (12.63-16.17) 18.86 (15.53-22.19) 11.34 (8.34-13.56) 13.97 (11.98-15.87) Duration of hospital stay Mean (95% CI) bed days Median (range) bed days New South Wales Victoria Queensland South Australia Western Australia Tasmania Northern Territory Australian Capital Territory Australia 24 (23-26) 22 (21-23) 30 (28-33) 20 (17-23) 26 (22-29) 27 (19-35) 40 (23-57) 33 (18-47) 25 (24-26) 18 (1-210) 16 (1-183) 21 (1-283) 13.5 (1-176) 18 (1-183) 21 (1-197) 24 (1-224) 24 (1-223) 17 (1-283) Back to text

Craig B Payne

Long-acting testosterone/progestin combinations show great promise as contraceptives Any suggestion that men cannot be trusted with contraceptive responsibility ignores the widespread use of existing methods which involve their cooperation -- condoms, periodic abstinence and interrupted intercourse are used by millions of couples worldwide.1 For those wanting an alternative to these methods, only female contraceptive methods, permanent sterilisation or "natural" methods have been available. A wider choice of effective methods would be highly desirable, and male hormonal contraception (MHC) is likely to offer a reliable alternative in the near future. Male hormonal contraception The physiological principles of MHC have long been recognised, but the past 20 years have seen important research in this area, notably that sponsored by the World Health Organization (WHO). Real evidence for MHC effectiveness has been provided from trials involving 600 couples in 10 countries, including Australia.2,3All MHC strategies involve the administration of testosterone, which profoundly reduces serum gonadotropin (follicle-stimulating hormone [FSH] and luteinising hormone [LH]) levels.4 A reduced serum LH level markedly reduces intratesticular testosterone levels, which, in combination with a reduced serum FSH level, reversibly interrupts sperm production. (Following cessation of testosterone treatment, sperm counts return to pretreatment levels in 4-6 months.) In the WHO trials, two-thirds of men were rendered azoospermic (ie, having sperm counts of zero), while 91% of the men achieved sperm counts below 1 x 106/mL (normal value, > 20 x 106/mL).3 The pharmaceutical industry has not been active in the MHC area in the past, perhaps because of a belief that the potential market was small, or because of concerns about product litigation. Very recently, the industry has cautiously entered the area. Fortuitously for MHC development, current pharmaceutical interest in new types of androgen replacement therapies will assist this process. Marketing male hormonal contraceptives Key factors to consider in planning a marketing strategy for male hormonal contraceptives are contraceptive effectiveness, acceptability and safety. Contraceptive effectiveness. No contraceptive is 100% effective. For the female contraceptive pill the failure rate is approximately 3 conceptions per 100 person-years in the first year of use, a figure which represents a reasonable target comparator for MHC. The WHO study showed that azoospermia confers high contraceptive cover (0.8 conceptions/100 person-years; 95% CI, 0.02-4.5).2 While azoospermia continues to be the goal, the WHO data suggest that the suppression of sperm counts to very low levels (eg, less than 1 x 106/mL) may provide contraceptive cover comparable to that of the female contraceptive pill, and would almost certainly be superior to other widely used methods such as condoms.3 No pretreatment marker predicts whether an individual will attain azoospermia using MHC. Apart from interracial variation (eg, 98% of Chinese men become azoospermic2,3), there appear to be no differences in serum gonadotropin or testosterone levels, or in testosterone pharmacokinetics, between those who become azoospermic and those who do not.5 Some data suggest that men in whom sperm production is not fully suppressed have a higher level of 5a-reductase enzyme activity, which converts testosterone to the potent androgen metabolite dihydrotestosterone and thus maintains spermatogenesis.6 Understanding the variability of response to MHC is important in formulating regimens which produce the highest rates of azoospermia. Acceptability. Men's willingness to use MHC will depend upon its effectiveness, convenience of use and side effect profile. Methods which are painful, costly, or inconvenient, or which require extensive monitoring or interfere with sexual function or general health, will be declined or soon discarded. Current MHC treatments encounter problems in this area, particularly the need for frequent testosterone injections (every 1-2 weeks) or testosterone implants (every 4-6 months). Supraphysiological doses of testosterone given by intramuscular injection in the WHO studies led to androgenic side effects (acne, mood change) in 21% of men,2,3 but more physiological testosterone levels achieved with implants can reduce these problems.7 Safety. The effects of male hormonal contraceptives on prostate and cardiovascular health are of prime concern in assessing the safety of MHC. So far, prostate problems have not been encountered in MHC trials of up to 18 months' duration. Furthermore, there is no evidence for the induction or acceleration of benign or malignant prostate disease with androgen replacement therapy in hypogonadal men. A fall of around 15% in HDL-cholesterol levels was observed in MHC trials using injectable testosterone;8,9 however, these changes were not seen with the more physiological profile of testosterone delivery via implants.7 Such physiological androgen delivery should reduce androgenic side effects (eg, polycythaemia) associated with intramuscular testosterone replacement, while maintaining libido and sexual function. MHC using combined preparations Testosterone treatment alone will not reliably suppress sperm production to the point of azoospermia. The addition of a gonadotropin-releasing hormone antagonist to testosterone treatment effectively suppresses sperm production,4 but practical difficulties and expense make this a non-viable option. The combination of testosterone and a progestin promotes rapid and profound suppression of serum gonadotropins and sperm counts, and the search for the ideal testosterone-plus-progestin regimen is now the main focus of MHC research. Recent studies have used levonorgestrel,8 desogestrel and medroxyprogesterone acetate.7 One study using cyproterone acetate, an antiandrogenic progestin, produced azoospermia very rapidly and consistently.10 It was proposed that the efficacy of cyproterone acetate was due to its inhibition of testosterone action within the testis (which has a unique need for high testosterone levels) while not interfering with androgen action elsewhere in the body. The question of whether the progestin component of combined male hormonal contraceptives may have specific effects (eg, mood change) in some men requires further study. Delivery methods Delivery methods providing stable physiological levels of testosterone are critical to male hormonal contraceptive development. Delivery could be either oral or by infrequent injection or implants (the latter perhaps being preferable, to assist with compliance). In this area, there is renewed interest from the pharmaceutical industry to work collaboratively with clinical scientists. Testosterone undecanoate or buciclate are esters which are slowly absorbed from intramuscular injection sites and provide testosterone delivery for 2-3 months. Methylnortestosterone is a more potent androgen than testosterone (reducing the mass of steroid to be delivered),11 and, furthermore, its 5a-reduced metabolite is inactive and thus avoids stimulation of the prostate. Finally, our improved knowledge of steroid ligand/receptor interaction may permit the synthesis of a single agent which activates both androgen and progestin receptors in the male, thereby providing gonadotropin suppression within the testis while maintaining androgen activity elsewhere in the body. Conclusions The combination of testosterone and progestin, delivered in the form of a single long-acting injection, shows great promise for providing equally effective (or better) contraception than current widely used male contraception methods. Large and long-term MHC trials are needed to establish the optimal formulations, to provide essential safety and efficacy data, and to spur the interest of industry, which is essential in bringing these products to the market. Robert I McLachlan Associate Professor and Principal Research Fellow Prince Henry's Institute of Medical Research Monash Medical Centre, Clayton, VIC Handelsman DJ. Contraception in the male. In: DeGroot LJ, editor. Endocrinology. 3rd edition. Philadelphia: WB Saunders, 1995: 2449-2458. World Health Organization Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia in normal men. Lancet 1990; 336: 955-959. World Health Organization Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil Steril 1996; 65: 821-829. Amory JK, Bremner WJ. The use of testosterone as a male contraceptive. Baillieres Clin Endocrinol Metab 1998; 12: 471-484. Handelsman DJ, Farley TMM, Peregoudov A, et al. World Health Organization Task Force on Methods for the Regulation of Male Fertility. Factors in non-uniform induction of azoospermia by testosterone enanthate in normal men. Fertil Steril 1995; 63: 125-133. Anderson RA, Wallace AM, Wu FCW. Comparison between testosterone enanthate-induced azoospermia and oligozoospermia in a male contraceptive study. III. Higher 5a-reductase activity in oligozoospermic men administered supraphysiological doses of testosterone. J Clin Endocrinol Metab 1996; 81: 902-908. Handelsman DJ, Conway AJ, Howe CJ, et al. Establishing the minimum effective dose and additive effects of depot progestin in suppression of human spermatogenesis by a testosterone depot. J Clin Endocrinol Metab 1996; 81: 4113-4121. Wu FCW, Farley TMM, Peregoudov A, et al. Effects of testosterone enanthate in normal men: experience from a multicentre contraceptive efficacy study. Fertil Steril 1996; 65: 626-636. Bebb RA, Anawalt BD, Christensen RB, et al. A promising male contraceptive approach: combined administration of testosterone and levonorgestrel. J Clin Endocrinol Metab 1996; 81: 757-762. Meriggiola MC, Bremner WJ, Paulsen CA, et al. Cyproterone acetate and testosterone enanthate as a potentially highly effective male contraceptive. J Clin Endocrinol Metab 1996, 81: 3018-3023. Noe G, Suvisaari J, Martin C, et al. Gonadotropin and testosterone suppression by 7α-methyl-19-nortestosterone acetate administered by subdermal implant to healthy men. Hum Reprod 1999, 14: 2200-2206.

Robert I McLachlan

Position Statement Use, misuse and abuse of androgens The Endocrine Society of Australia consensus guidelines for androgen prescribing Ann J Conway, David J Handelsman, Douglas W Lording, Bronwyn Stuckey, Jeffrey D Zajac on behalf of the Endocrine Society of Australia MJA 2000; 172: 220-224 Abstract - Use of androgens - Misuse of androgens - Abuse of androgens - Key references - Authors' details - - More articles on Endocrinology Abstract Androgen replacement therapy (ART) is usually life-long, and should only be started after androgen deficiency has been proven by hormone assays. The therapeutic goal is to maintain physiological testosterone levels. Testosterone rather than synthetic androgens should be used. Oral 17α-alkylated androgens are hepatotoxic and should not be used for ART. There is no indication for androgen therapy in male infertility. Although androgen deficiency is an uncommon cause of erectile dysfunction, all men presenting with erectile dysfunction should be evaluated for androgen deficiency. If androgen deficiency is confirmed, investigation for the underlying pathological cause is required. Contraindications to androgen therapy are prostate and breast cancer. Precautions include using lower starting doses for older men and induction of puberty. Intramuscular injections should be avoided in men with bleeding disorders. Androgen-sensitive epilepsy, migraine, sleep apnoea, polycythaemia or fluid overload need to be considered. Competitive athletes should be warned about the risks of disqualification. ART should be initiated with intramuscular injections of testosterone esters, 250 mg every two weeks. Maintenance requires tailoring treatment modality to the patient's convenience. Modalities currently available include testosterone injections, implants, or capsules. Choice depends on convenience, cost, availability and familiarity. There is no convincing evidence that, in the absence of proven androgen deficiency, androgen therapy is effective and safe for older men per se, in men with chronic non-gonadal disease, or for treatment of non-specific symptoms. Until further evidence is available, such treatment cannot be recommended. Androgens are hormones that are based on the structure of testosterone, the major male sex hormone, and are capable of developing and maintaining masculine sexual characteristics (including the genital tract, secondary sexual characteristics, and fertility) and the anabolic status of somatic tissues. All androgens have similar biological effects because they all act through the single androgen receptor. Their effects in different tissues are diversified by metabolism of testosterone to its active metabolites by the enzymes 5α reductase (which converts testosterone to 5α-dihydrotestosterone, an androgen with enhanced potency acting on the androgen receptor) and aromatase (which converts testosterone to oestradiol, which acts on the oestrogen receptor). Use of androgens The main medical use of androgens (Box 1) is as androgen replacement therapy (ART) for established androgen deficiency.1-3 Classical androgen deficiency occurs in about 1 in 200 men, due to testicular disorders that directly reduce testosterone output, or hypothalamic-pituitary disorders that reduce pituitary luteinising hormone (LH) secretion, which is the main drive to testosterone production by the interstitial (Leydig) cells of the testes. Although classical androgen deficiency is relatively easy to recognise, diagnosis of less severe androgen deficiency can be more difficult. Owing to its subtle and variable clinical features, the diagnosis may easily be missed, denying patients simple and effective medical treatment with often striking subjective benefits. Potential extensions of classical indications to partial androgen deficiency remain to be fully evaluated for clinical safety and efficacy. These indications include age, androgen deficiency secondary to a chronic medical condition or its treatment, hormonal male contraception, and postmenopausal symptoms.4-6 Until more definitive objective evidence is available regarding the safety and efficacy of prescribing androgens for these indications, they remain suitable for carefully monitored, controlled clinical research trials, but not for routine medical treatment. Pharmacological applications of androgens (Box 1) usually represent second-line therapy where more specific treatments are not yet available or have failed. Androgen treatment can evoke a strong placebo response. In men without genuine androgen deficiency, this placebo effect invariably wanes with time, leading to confusion and dissatisfaction with treatment. In addition, once androgen therapy has commenced, the biochemical changes can cloud further interpretation of results for months. Therefore, androgen replacement therapy should be commenced only after androgen deficiency is clearly established.2,3 Diagnosis of androgen deficiency1-3 Diagnosis of androgen deficiency involves the recognition of appropriate clinical features, with confirmation by biochemical testing. Important clinical features required to evaluate testicular function include reproductive history (including pubertal development), fertility status, changes in sexual function and body hair growth, known testicular pathology, drug use, and occupation. Physical examination should record androgenisation (secondary sexual characteristics, especially body hair distribution, musculature and gynaecomastia) and testis volumes (by orchidometry). Serum LH, follicle-stimulating hormone and testosterone levels should be measured, on at least two separate days and preferably in the morning, to minimise the effects of random and laboratory fluctuations and diurnal rhythms. Direct measurements of free testosterone, if available, may help establish the diagnosis of androgen deficiency, but require extensive validation. Indirect measurements of free testosterone, such as the free androgen index (testosterone/sex hormone binding globulin [SHBG] ratio), correspond poorly with direct measurements and lack empirical validation as a diagnostic test. Additional tests that may be required to identify underlying disorders include karyotyping, pituitary radiology and measurement of prolactin levels, serum ferritin levels, iron saturation and, increasingly, genetic diagnosis. Androgen deficiency is unlikely in men with mean testis volume > 20 mL without atrophy, with a plasma testosterone level consistently above 20 nmol/L, or presenting with erectile dysfunction and a plasma testosterone level consistently above 8 nmol/L (Box 2). Where the diagnosis is not clear, referral to a clinical endocrinologist with experience in this area is recommended.1 Androgen replacement therapy1-3 ART is indicated to rectify androgen deficiency of any cause sufficient to cause clinical consequences. After puberty, there is no age limit to ART. Androgen-deficiency effects may manifest as changes in one or more androgen-sensitive functions; for example, psychosexual function, or loss of anabolic effects on bone, muscle, blood-forming marrow and other androgen-responsive tissues. Apart from decreased spermatogenesis, ART can rectify all clinical features of androgen deficiency, which usually respond within 1-2 months of starting therapy, although the full effect may take longer. Dosage: Standard ART is either testosterone enanthate (Primoteston in castor oil; Schering) or mixed testosterone esters (Sustanon in arachis oil; Organon) as 250 mg in 1 mL oil at 14-day intervals. Deep intramuscular injections are usually given into the upper and outer quadrant of the buttock, although some patients prefer the deltoid or lateral thigh muscle sites. Few men can manage self-injection with the viscous oil vehicle. For all ART, testosterone and its esters should be used in preference to synthetic androgens, because of their established safety and efficacy, as well as ease of dose-titration and assay monitoring. Lower starting doses may occasionally be needed, especially in previously untreated elderly men and during first induction of puberty. Less frequent dosing intervals (eg, every three weeks) are occasionally necessary for those unable or unwilling to have standard dosage, but are accompanied by more extreme peaks and troughs in blood testosterone levels, which may exaggerate symptom fluctuations. An inadequate clinical response raises doubt about androgen deficiency as the cause of recalcitrant symptoms. Rarely, an inadequate clinical response may require increased dosage. If suboptimal symptomatic benefit is supported by biochemical evidence of inadequate maintenance of androgen levels (low trough testosterone levels with or without persistently supranormal LH levels in primary hypogonadism), the same dose may be injected at 10-day intervals. Persistently inadequate responses indicate that unresponsive symptoms are not due to androgen deficiency; further escalation in dose or frequency is not warranted. Men with mild or partial androgen resistance due to androgen-receptor mutations may benefit from high-dose androgen therapy. As the underlying disorders are almost always permanent, life-long ART after the age of puberty is usually necessary. Long term therapeutic compliance depends on an acceptable regimen. Crossover studies indicate that patients strongly prefer the stable testosterone levels and smoother clinical effects provided by implants or transdermal formulations, compared with the wide fluctuations in testosterone levels and symptoms during intramuscular testosterone ester injections. Thus, although ART should commence with injections, alternative modalities (Box 3) may improve compliance. Factors to consider include cost, convenience, availability, familiarity with alternatives, and tolerance for frequent injections. Monitoring: Monitoring of ART is mainly to ensure effective androgen replacement by a regimen tailored to the patient's needs, aiming to maintain adequate therapeutic compliance by continuation of treatment. Serial clinical observation of clinical well-being and major symptoms of androgen deficiency, together with limited numbers of hormonal assays, is usually adequate. Restoration of sexual function has a low threshold for androgen action, so adequate libido and potency is a necessary, but not sufficient, indication of clinically adequate androgen replacement. Blood hormone assays have limited utility in optimising an ART regimen at the start of treatment and in evaluating androgen replacement. Trough blood testosterone levels (ie, before the next scheduled dose) within the eugonadal reference range can be a valuable guide to the adequacy of parenteral androgen replacement, but random blood testosterone levels are not useful for monitoring with either oral or injectable testosterone. In men with hypergonadotropic hypogonadism, suppression of blood LH levels into the eugonadal reference range indicates adequate ART, whereas persistent non-suppression of LH after 3-6 months of regular treatment indicates inadequate dosage or compliance. In hypogonadotropic hypogonadism, blood gonadotropin levels are uninterpretable. Serial evaluation of bone density (especially vertebral trabecular bone) by dual-photon absorptiometry at 1-2-year intervals may be useful in evaluating the adequacy of long-term androgen effects on bone. Other biochemical indices of androgen action, such as haemoglobin, SHBG, and high density lipoprotein cholesterol levels, reflect only supraphysiological effects and are too insensitive for routine monitoring of ART. Androgen deficiency is protective against prostate disease, and ART may restore the risks to those equivalent to, but no more than, eugonadal men of similar age. Screening of men receiving ART for cardiovascular and prostate disease need be no more intensive than for men of similar age not on ART. Precautions and side effects14-17 Adverse effects of androgen treatment are uncommon. Virilisation may occur with androgen therapy in women or children; androgen therapy in these settings requires expert management. Truncal acne and hair growth, weight gain, gynaecomastia and male-pattern hair loss may be observed, and should be managed symptomatically. Certain side effects are characteristic of specific therapeutic modalities (eg, discomfort from intramuscular injections, extrusion of subdermal implants, gastrointestinal disturbance from oral testosterone undecanoate). Polycythaemia may occur disproportionately often in older men treated with testosterone ester injections. In addition, certain testosterone formulations have distinctive effects due to their pharmacokinetic features (eg, reduced levels of SHBG, high density lipoprotein cholesterol and other hepatic proteins due to supraphysiological hepatic testosterone exposure). This may be due to injectable testosterone esters (via high peak blood testosterone concentrations) or oral testosterone undecanoate (via high first-pass portal testosterone concentrations), whereas more steady formulations (transdermal, implants) exhibit fewer or no such effects. Oral synthetic androgens that have a 17α-alkyl substituent (oxandrolone, fluoxymesterone, danazol) are inherently hepatotoxic, causing cholestatic hepatitis, peliosis hepatis and hepatic tumours. Other classes of synthetic androgen, such as 19-nortestosterone derivatives (nandrolone, MENT) and the 1-methyl androgens (mesterolone, methenolone), are not hepatotoxic. Absolute contraindications to androgen therapy are prostate or breast cancer in men. Androgen therapy should be started in men over the age of 40 only after exclusion of undiagnosed prostate disease. Precautions are required for: older men starting androgen treatment, where it may precipitate urinary obstruction or unfamiliar increases in libido; pubertal boys, in whom excessive dosage may accelerate epiphyseal closure, leading to shortened final stature; parenteral androgen therapy in men with bleeding disorders; competitive athletes, who may be disqualified; androgen-sensitive epilepsy, migraine, sleep apnoea or polycythaemia; and cardiac or renal failure or severe hypertension susceptible to fluid overload from sodium and fluid retention. Misuse of androgens Medical misuse of androgens involves prescription with no acceptable medical indication. Some common examples of misguided prescribing of androgens in the absence of established androgen deficiency include: Male infertility: There is no indication for androgen therapy in male infertility. The only likely consequence is an adverse effect of suppressing spermatogenesis. Male sexual dysfunction or impotence: Androgen deficiency (with or without hyperprolactinaemia) is an uncommon (< 5%) cause of men presenting with erectile dysfunction. In such men, excluding androgen deficiency as a readily treatable underlying cause is essential. In the unusual event of severe androgen deficiency presenting with erectile dysfunction, the underlying cause needs to be identified, and plans for life-long ART need to be established. "Male menopause" or "andropause": There is still no evidence that the modest decreases in circulating blood testosterone levels which commence during mid-life have any clinical importance. The risks and benefits of androgen supplementation for partially androgen-deficient older men require further evaluation by placebo-controlled studies. Androgen treatment may be inappropriate, wasteful, and involve placebo effects. Terms such as "male menopause" and "andropause" are misleading; they have little place in meaningful medical or scientific discourse. Elderly men (> 65 years):18 There is no basis for androgen therapy based on age per se. Further controlled clinical trials are needed to evaluate the potential role of androgen supplementation in ageing. While some preliminary placebo-controlled studies suggest short-term benefits for muscle, bone and quality of life, findings are not yet consistent and the identification of appropriate treatment objectives and target subgroups, as well as overall analyses of risks, benefits and costs, are lacking. Specifically, it remains to be determined whether androgen supplementation has significant and sustained clinical benefits in older men with low-normal plasma total testosterone and normal LH levels. At present, there is no basis for androgen treatment outside properly designed clinical trials. Treatment of non-specific symptoms: There is no basis for androgen therapy based on symptoms in the absence of established androgen deficiency. In addition to the unproven safety and efficacy, the placebo effect of androgen injections may be confusing to both doctor and patient. When placebo effects wane, further confusion and dissatisfaction with treatment may be expected. Abuse of androgens Illicit use of androgens19-24 ("anabolic steroids") depends largely on obtaining androgens without legal prescription to be used in the absence of any medical indication. Illicit androgen use became epidemic over the past four decades, since androgens were reportedly first used in elite competitive power sports. A recent placebo-controlled study has shown that high-dose androgen administration does improve muscle size and strength in healthy eugonadal men. Whether these changes enhance athletic performance, whether they are sustained, and whether they apply to older men remains to be clarified. Medical prescription appears to support only a small proportion of illicit androgen use, but such activity has been formally ruled as a breach of professional standards by medical boards in most States and by the Royal Australasian College of Physicians. Highly motivated young men can be very sophisticated in manipulating and pressuring general practitioners while attempting to obtain prescriptions for androgens. The doctor is often led to believe that other practitioners are prescribing androgens for young men, and that he or she is being uncaring or negligent by not acceding to the patient's wishes. We recommend that general practitioners resist these pressures. Fortunately, most people appear ultimately to lose interest in this form of drug abuse. Background and evidence basis of recommendations The Endocrine Society of Australia (ESA) Consensus Guidelines for Androgen Prescribing were written on behalf of the Endocrine Society of Australia. The ad hoc Writing Committee commissioned by the ESA's Council was Dr A J Conway, Professor D J Handelsman (Chair), Associate Professor D W Lording, Dr B Stuckey, and Associate Professor J D Zajac. The draft guidelines were extensively circulated for comment to active members of the ESA with clinical expertise or interests in male reproductive endocrinology. Comments were incorporated into the final document, which was ratified by the ESA's Council. Androgen therapy, in regular clinical use for over 60 years, is one of the oldest hormonal regimens in modern therapeutics. As a long established standard and effective form of hormone replacement for many decades, placebo-controlled studies are unavailable and now unacceptable. Consequently, the NHMRC Quality of Evidence Ratings for these recommendations are those appropriate to an expert committee reviewing all available evidence from controlled experimental and observational studies as well as clinical experience. Key references Diagnosis and management of androgen deficiency Behre HM, Yeung CH, Nieschlag E. Diagnosis of male infertility and hypogonadism. In: Nieschlag E, Behre HM (eds): Andrology: Male Reproductive Health and Dysfunction. Berlin:Springer, 1997: 87-111. Plymate SR. Male Hypogonadism. In: Becker KL (ed): Principles and Practice of Endocrinology and Metabolism. 2nd ed. Philadelphia: J B Lippincott Company, 1995: 1056-1082. Nieschlag E, Wang C, Handelsman DJ, et al (eds) (1992). Guidelines for the use of androgens in men. Geneva, Special Programme of Research, Development and Research Training in Human Reproduction of the World Health Organisation. Male contraception Cummings DE, Bremner WJ. Prospects for new hormonal male contraceptives. In: Bremner WJ (ed): Clinical Andrology. Philadelphia: W B Saunders Company, 1994: 893-922. Handelsman DJ. Contraception in the male. In: DeGroot LJ (ed): Endocrinology. 3rd ed. Philadelphia: W B Saunders, 1994: 2449-2458. Androgen therapy in systemic disease Liu PY, Handelsman DJ. Androgen therapy in non-gonadal disease. In: Nieschlag E, Behre HM (eds):Testosterone: Action, Deficiency and Substitution. 2nd ed. E Nieschlag, Behre HM (eds), Berlin, Springer-Verlag, 1998. Comparative pharmacology of androgen formulations Bals-Pratsch M, Langer K, Place VA, Nieschlag E. Substitution therapy of hypogonadal men with transdermal testosterone over one year. Acta Endocrinologica 1988; 118: 7-13. Behre HM, Oberpenning F, Nieschlag E. Comparative pharmacokinetics of androgen preparations: application of computer analysis and simulation. In: Nieschlag E, Behre HM (eds): Testosterone: Action, Deficiency and Substitution. Berlin: Springer-Verlag, 1990: 115-135. Cantrill JA, Dewis P, Large DM et al. Which testosterone replacement therapy? Clin Endocrinol (Oxf) 1984; 24: 97-107. Conway AJ, Boylan LM, Howe C, Ross G, Handelsman DJ. A randomised clinical trial of testosterone replacement therapy in hypogonadal men. Int J Androl 1988; 11: 247-264. Handelsman DJ, Conway AJ, Boylan LM. Pharmacokinetics and pharmacodynamics of testosterone pellets in man. J Clin Endocrinol Metab 1990; 71: 216-222. Meikle AW, Mazer NA, Moellmer JF, et al. Enhanced transdermal delivery of testosterone across nonscrotal skin produces physiological concentrations of testosterone and its metabolites in hypogonadal men. J Clin Endocrinol Metab 1992; 74: 623-628. Snyder PJ, Lawrence DA. Treatment of male hypogonadism with testosterone enanthate. J Clin Endocrinol Metab 1980; 51: 1335-1339. Safety of androgens Alexandersen P, Haarbo J, Christiansen C. The relationship of natural androgens to coronary heart disease in males: a review. Atherosclerosis 1996; 125: 1-13. Barrett-Connor E. Testosterone, HDL-cholesterol and cardiovascular disease. In: Bhasin S, Gabelnick HL, Spieler JM et al (eds): Pharmacology, Biology, and Clinical Applications of Androgens: Current Status and Future Prospects. New York: Wiley-Liss, 1996: 215-223. Behre HM, Bohmeyer J, Nieschlag E. Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clin Endocrinol (Oxf) 1994; 40: 341-349. Gooren LJ, Polderman KH. Safety aspects of androgen therapy. In: Nieschlag E, Behre HM (eds): Testosterone: Action, Deficiency and Substitution. Berlin: Springer-Verlag, 1990: 182-203. Androgen and the ageing male Tenover JL. Androgen therapy in aging men. In: Bhasin S, Gabelnick HL, Spieler JM, et al (eds): Pharmacology, Biology, and Clinical Applications of Androgens: Current Status and Future Prospects. New York: Wiley-Liss, 1996: 309-318. Androgen abuse Bhasin S, Storer TW, Berman N, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 1996; 335: 1-7. Handelsman DJ, Gupta L. Prevalence and risk factors for anabolic-androgenic steroid abuse in Australian secondary school students. Int J Androl 1997; 20: 159-164. Lin GC, Erinoff L (eds). (1990). Anabolic Steroid Abuse. National Institute on Drug Abuse Research Monograph Series. Rockville, US Department of Health and Human Services. Wilson JD. Androgen abuse by athletes. Endocr Rev 1988; 9: 181-199. Yesalis CE, Kennedy NJ, Kopstein AN, Bahrke MS. Anabolic-androgenic steroid use in the United States. JAMA 1993; 270: 1217-1221. Young NR, Baker HWG, Liu G, Seeman E. Body composition and muscle strength in healthy men receiving testosterone enanthate for contraception. J Clin Endocrinol Metab 1993; 77: 1028-1032. Authors' details Endocrine Society of Australia, Sydney, NSW. Ann J Conway, MB BS, FRACP; David J Handelsman, MB BS, PhD, FRACP; Douglas W Lording, MB BS, FRACP; Bronwyn Stuckey, MB BS, FRACP; Jeffrey D Zajac, PhD, FRACP. Reprints will not be available from the authors. Correspondence: Associate Professor J D Zajac, Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC 3050. j.zajacATmedicine.unimelb.edu.au Make a comment 1: Use, misuse and abuse of androgens Use Physiological (androgen deficiency) 1-3 Classical androgen deficiency ("hypogonadism") Age-related partial androgen deficiency Micropenis (neonatal) Delayed puberty Aged men* Androgen deficiency secondary to chronic disease* Induced androgen deficiency Hormonal male contraception* Pharmacological (non-androgen deficiency)4-6 Osteoporosis Anaemia due to marrow or renal failure Advanced breast cancer Excessively tall stature in boys Misuse Inappropriate indications In absence of proven androgen deficiency: Male infertility Sexual dysfunction/impotence "Male menopause", "andropause" Older men (>65 years) Non-specific symptoms Abuse19-24 Absence of medical indication Sporting Competitive power sports (athletics, weightlifting, football, swimming, rowing, boxing) RecreationalBodybuilding Cosmetic"Body beautiful" subculture OccupationalSecurity, police, armed forces, professional sports * These indications remain to be fully evaluated for safety and efficacy in controlled clinical trials. Back to text 2: Biochemical evaluation of the diagnosis of androgen deficiency in men with clinical features consistent with hypogonadism* Testosterone level†Luteinising hormone level†Diagnosis<8 nMHigh‡Androgen deficiency (hypergonadotropic hypogonadism§)<8 nMNot highAndrogen deficiency (hypogonadotropic hypogonadism§)8-15 nMHigh‡Androgen deficiency (Leydig cell failure)8-15 nMNot highAndrogen deficiency not confirmed: unproven therapeutic benefit of androgen replacement therapy>20 nMAnyExcludes androgen deficiency>30 nM**High‡Androgen resistance*There is necessarily an arbitrary component to this type of table. It is based on current experience and should be subject to changes according to further clinical evidence. †Blood sample classification based on at least two separate morning blood samples. ‡"High" luteinising hormone level is defined as > 1.5 times the upper limit of the eugonadal reference range for young men. §Hypergonadotropic and hypogonadotropic hypogonadism are also referred to as primary and secondary hypogonadism, respectively. Compensated Leydig cell failure is a form of partial androgen deficiency in which androgen replacement is often beneficial. **Elevated testosterone is defined as above the upper limit of the eugonadal reference range for young men. Back to text 3: Androgen treatment modalities7-13 Testosterone implants Fused cylindrical pellets of pure crystalline testosterone that form a subdermal depot Provide stable, physiological levels of testosterone for 4-6 months following a single implantation of four 200 mg (800 mg) implants Implantation uses a trochar and cannula technique under office sterile conditions, and requires local anaesthesia Main adverse effect is extrusion of implants via the insertion site 1-2 months after implantation Extrusion rate (about 10%) depends on operator experience and patient's physical activity Minor adverse effects related to the minor office surgery (bleeding, infection) are infrequent (<5%) Should only be used for patients who have demonstrated satisfactory tolerance of androgen effects with shorter-acting preparations Transdermal testosterone Administered daily via androgen-impregnated adhesive skin patches or hydroalcoholic gels (not yet available in Australia) Other depot testosterone formulations Newer injectable esters (testosterone undecanoate, testosterone buciclate) Testosterone-laden biodegradable microspheres Both these formulations deliver stable, physiological testosterone levels for 2-3 months following injection Oral testosterone undecanoate Useful where parenteral testosterone is undesirable (eg, bleeding disorders or anticoagulation) or poorly tolerated Administered as 160-240 mg (four to six 40 mg capsules), divided into 2-4 doses per day Second-line formulation for routine ART, because of frequency of administration, high hepatic load, gastrointestinal intolerance, and higher cost Back to text

Ann J Conway · David J Handelsman · Douglas W Lording · Bronwyn Stuckey · Jeffrey D Zajac

New Drugs, Old Drugs Osteoporosis prevention and treatment Phillip N Sambrook and John A Eisman MJA 2000; 172: 226-229 Abstract - Introduction - Overview of the evidence - Recommendations - Disclosure - References - Authors' details - - More articles on Endocrinology Abstract Patients with low bone density or any prior low trauma fracture should be considered for therapeutic intervention. Oestrogen replacement therapy remains the first choice for prevention of bone loss in early postmenopausal women with low bone density In postmenopausal women with existing fractures, the rank order of treatments is firstly alendronate, secondly raloxifene and thirdly less potent bisphosphonates, such as etidronate, or active vitamin D metabolites, such as calcitriol. For men with osteoporosis, if hypogonadism is present, it should be treated with testosterone replacement therapy. Despite limited data, a bisphosphonate should then be considered in conjunction with calcium. Supplementation with simple vitamin D should be considered in elderly patients who are housebound or live in institutions, as they are at risk of vitamin D deficiency and osteomalacia. Introduction The prevention and treatment of osteoporosis (low bone density) was reviewed at the Australian Consensus Conference on Osteoporosis, held in 1996, and a series of position statements about its management were developed.1 For the treatment of postmenopausal osteoporosis, these statements ranked hormone replacement therapy (HRT) with oestrogen as first-line therapy for most patients, but in those intolerant or unable to take this medication the rank order of choice was considered to be alendronate, followed by etidronate or calcitriol. Since that meeting, the results of new trials with drugs such as raloxifene, further efficacy data for bisphosphonates, and postmarketing safety data for alendronate and calcitriol have become available. Moreover, increased dietary calcium intake and phyto-oestrogens are promoted in the media. The benefit of all these various agents versus their risk of side effects in this epidemic condition is gradually becoming clearer. Overview of the evidence Drugs used for treating and preventing osteoporosis, and the relevant evidence for this, are discussed below, and brief drug profiles, including recommended doses, are given in Box 1. Calcium Controlled trials6 have shown that calcium supplementation can prevent bone loss in postmenopausal women (E1) (see Box 2 for an explanation of level-of-evidence codes) and this has been associated with a modest reduction in fracture risk in longer-term studies (E2). There is also evidence (E1) to suggest calcium supplementation augments the effect of oestrogen on bone density.8 Gastrointestinal absorption appears to be similar from milk or soy-drink products and supplements. As most controlled trials of new agents have used calcium as baseline therapy, it is appropriate to add a calcium supplement to most active agents described below. Calcium supplements have a better bone-sparing effect when taken at night. Vitamin D A study in institutionalised elderly people in France showed treatment with calcium plus vitamin D significantly reduced the rate of hip fractures (E2),9 but a similar effect could not be shown in those who lived in the community.10 Australian data also indicate a substantial proportion of institutionalised (or housebound) elderly people may be vitamin D deficient,11 and the observed reduction in fractures in the French study may have reflected treatment of subclinical osteomalacia. Hence, vitamin D supplementation is recommended in institutionalised or housebound elderly people who have limited exposure to sunlight. Calcitriol Calcitriol is the active hormonal form of vitamin D. Controlled trials of its effect on bone density have shown conflicting effects,12,13 with studies showing increases, no change or even apparent loss of bone density with calcitriol therapy (although suboptimal doses may account for some of these discrepancies). A recent larger study suggests the effect on bone density is less than that seen with oestrogen.14 One large controlled trial addressing the efficacy of calcitriol in preventing fractures found a threefold difference in vertebral deformity rates favouring calcitriol15 (E2), but used a less strict fracture criterion than in more recent studies. In that study, fracture rates remained stable in calcitriol-treated patients but increased in the calcium-treated patients. Calcitriol treatment may be appropriate in patients with known or presumed calcium malabsorption. Although calcitriol is approved for osteoporosis in men in Australia, a recent small study suggested that calcitriol may be less effective than calcium supplementation alone.16 Etidronate Etidronate was the first bisphosphonate developed for clinical use, and there is extensive experience of its use in Paget's disease. There have been a number of relatively small controlled trials with etidronate, showing increases in bone density averaging 5% over 2-3 years17 and suggesting a 50% reduction in vertebral fracture rate (E1). However, these trials also used fracture criteria less strict than those used in more recent clinical trials.18-21 Non-randomised studies based in general practice suggest its effectiveness increases with duration of use.3 Alendronate Several controlled clinical trials of the bisphosphonate alendronate have shown a reduction of vertebral, and even peripheral, fracture rates by about 50%18-20 (E1). Some, but not all, studies have shown a reduction in hip fracture rates.4,19 Reduction of fracture rates was apparent in individuals with bone mineral density (BMD) T scores below - 2.5 (T scores are multiples of the standard deviation from the population mean, based on a young, healthy, sex-matched reference population), even without prior fractures,20 suggesting an important threshold at which to consider intervention. Oestrogen While calcium supplementation may reduce bone loss, a number of controlled clinical trials with oestrogen have shown long-term increases in bone density averaging 5% over three years (E1).22 Lower doses may be effective with concomitant calcium.8 Although only a few randomised clinical trials have addressed the effect on fractures,23,24 epidemiological studies indicate antifracture efficacy at all sites for oestrogen is comparable to that of other agents (E32).25 Epidemiological studies also suggest primary cardioprotective effects of oestrogen. However, this was not observed in a recent trial of the effects of oestrogen on secondary prevention of cardiovascular mortality and morbidity, despite improvements in surrogate measures of efficacy such as total and low density lipoprotein cholesterol levels.26 Raloxifene This selective oestrogen-receptor modulator, as well as acting to decrease bone resorption, improves lipid profiles (thought to be surrogates for cardiovascular risk) and reduces breast cancer incidence (in studies at 3.5 years).27 Importantly, raloxifene does not cause breast or uterine symptoms. Controlled clinical trials have shown modest increases in bone density, generally somewhat less than those seen with hormone replacement therapy.28 However, a 50% reduction in vertebral, but not as yet peripheral, fractures has been observed (E2).21 This may be a statistical power effect and longer-term studies are ongoing. Anabolic steroids Forearm bone mass has been shown to increase modestly after treatment with nandrolone decanoate (E33), but at higher dosages and shorter intervals than are generally used in Australia. The effect on spinal bone density is unclear.29 Although nandrolone is commonly used in general practice in Australia, and may have a beneficial effect on muscle mass which may help to reduce the risk of falls in the elderly, there have been no studies showing antifracture efficacy. "Natural therapies" A variety of so called "natural" therapies, including soy, red clover (Promensil [Novogen]), black cohosh (Remifemin [Scinat]), wild yam and topical progesterone, are frequently used for treating menopausal symptoms in Australia. Soy products have been associated with small effects on bone density in animal studies.30 There are no studies addressing either their efficacy on fractures or long term safety in humans at this time. The risk of adverse events with these agents is unclear, as there have been no controlled studies of long-term safety. The efficacy and safety of these agents are yet to be documented in controlled clinical trials. Topical progesterone does not provide protection from endometrial changes of unopposed oestrogen in a woman with an intact uterus. Recommendations Adequate dietary calcium intake, regular exercise and avoidance of risk factors, such as smoking and excessive alcohol intake, are important lifestyle recommendations for preventing osteoporosis, but they have only modest efficacy. For people with low BMD, and particularly those with any prior low trauma fracture, these measures will be insufficient to prevent further osteoporotic fractures and pharmacological therapy must be considered. Box 3 shows an appropriate approach to managing osteoporosis in postmenopausal women. HRT remains the mainstay of therapy for osteoporosis, particularly in early postmenopause. Although most women are at relatively low risk of osteoporotic fracture for the first five to 10 years after menopause, this will vary according to their bone density and other risk factors, such as propensity to falls. Although "natural" therapies may have some effect on menopausal symptoms, there is currently no evidence for their efficacy or safety in the prevention or treatment of osteoporosis. Older postmenopausal women, especially those with existing fractures, are at high risk of further osteoporotic fractures. The rank order of treatments of osteoporosis in this group, based on the current published evidence, is alendronate, followed by raloxifene, before less potent bisphosphonates, such as etidronate, or active vitamin D compounds, such as calcitriol. Simple vitamin D should be considered in house-bound or institutionalised elderly people, who are at risk of vitamin D deficiency and osteomalacia. Dietary calcium supplementation should be used in conjunction with all of the above therapies except calcitriol, with which overall calcium intake should be limited. For men with osteoporosis, hypogonadism, if present, should be treated with testosterone replacement therapy. In the absence of hypogonadism, although there are limited data, the rank order of treatment of osteoporosis in men is a bisphosphonate and calcium supplementation. Most importantly, the benefit in fracture prevention from treatment increases progressively with worsening osteoporosis. As a result, while it is never too early to consider prevention, it is never too late to start treatment. Failure to at least consider therapeutic options in a patient who has sustained an osteoporotic fracture is not reasonable medical practice. As in many other chronic diseases, no therapy can be effective without long term compliance. This is strongly dependent on regular positive feedback to patients from their general practitioners. Important messages for patients are given in Box 4. Disclosure The authors act as advisers to, and receive funding from, Roche; Merck, Sharpe & Dohme; Lilly; Pharmacia & Upjohn; Aventis; Novartis; and the Australian Dairy Corporation. References O'Neill S, Eisman JA, Glasziou P, et al. The prevention and treatment of osteoporosis [consensus statement]. Med J Aust 1997; 167 (Suppl): S4-S15. Calcitriol and hypercalcaemia. Aust Adverse Drug React Bull 1997; 16: 2. Van Staa T, Abenheim L, Cooper C. Upper gastrointestinal adverse events and cyclical etidronate. Am J Med 1997; 103: 462-467. A gut feeling for alendronate. Aust Adverse Drug React Bull 1999; 18 (3): 11. Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. New Engl J Med 1995; 332: 1589-1593. Nordin BEC. Calcium and osteoporosis. Nutrition 1997; 13: 664-686. National Health and Medical Research Council. A guide to the development, implementation and evaluation of clinical practice guidelines. Canberra: NHMRC, AusInfo 1999. Nieves JW, Komar L, Cosman F, Lindsay R. Calcium potentiates the effect of oestrogen and calcitonin on bone mass: review and analysis. Am J Clin Nutr 1998; 67: 18-24. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. New Engl J Med 1992; 327: 1637-1642. Lips P, Graafmans WC, Ooms ME, et al. Vitamin D supplementation and fracture incidence in elderly persons. Ann Intern Med 1996; 124: 400-406. Brock KE, Reid JF, Greenoak GG, Fraser DR, The effect of sunlight on 25-hydroxy vitamin D plasma levels in an elderly Sydney population [abstract]. Australian and New Zealand Bone and Mineral Society Proceedings, 1997, Abstract No. 38. Gallagher JC, Goldgar D. Treatment of postmenopausal osteoporosis with high dose synthetic calcitriol. Ann Intern Med 1990; 113: 649-655. Ott SM, Chestnut CH. Calcitriol is not effective in postmenopausal osteoporosis. Ann Intern Med 1989; 110: 267-274. Gallagher JC, Fowler S. Effect of estrogen, calcitriol and a combination of estrogen and calcitriol on bone mineral density and fractures in elderly women [abstract]. J Bone Mineral Res 1999; 14: Abstract no. T364. Tilyard MW, Spears GF, Thomson J, Dovey S. Treatment of postmenopausal osteoporosis with calcitriol or calcium. New Engl J Med 1992; 326: 357-362. Ebeling PR, Yeung S, Poon C, et al. Effects of baseline active calcium absorption on bone mineral density responses to calcitriol or calcium treatment in men with idiopathic osteoporosis [abstract]. J Bone Mineral Res 1999; 14: Abstract no. SA419. Storm T, Thamsborg G, Steiniche T, et al. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in postmenopausal osteoporosis. New Engl J Med 1990; 322: 1265-1271. Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. New Engl J Med 1995; 333: 1437-1443. Black DM, Cummings SR, Karpf D, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348: 1535-1541. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures. JAMA 1998; 280: 2077-2082. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3 year randomised controlled trial. JAMA 1999; 282: 637-645. Writing group for the PEPI trial. Effects of hormone therapy on bone mineral density. JAMA 1996; 276: 1389-1396. Lufkin EG, Wahner HW, O'Fallon WM, et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med 1992; 117: 1-9. Windeler J, Lange S. Events per person year -- a dubious concept. BMJ 1995; 310: 454-456. Cauley JA, Seeley, Ensrud K, et al. Estrogen replacement therapy and fractures in older women. Ann Intern Med 1995; 122: 9-16. Hulley S, Grady D, Bush T, et al. Randomised trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280: 605-613. Cummings SR, Eckert S, Krueger KA. The effect of raloxifene on risk of breast cancer in postmenopausal women. JAMA 1999; 281: 2189-2197. Delmas PD, Bjarnason NH, Mitlak BH, et al. Effect of raloxifene on bone mineral density, serum cholesterol concentrations and uterine endometrium in postmenopausal women. New Engl J Med 1997; 337: 1641-1647. Flicker L, Hopper JL, Larkins RG, et al. Nandrolone decanoate and intranasal calcitonin as therapy in established osteoporosis. Osteoporosis Int 1997; 7: 29-35. Arjmandi BH, Birnbaum R, Goyal NV, et al. Bone sparing effect of soy protein in ovarian hormone deficient rats is related to its isoflavone content. Am J Clin Nutr 1998; 68 (Suppl): 1364S-1368S. Authors' details The Institute of Bone and Joint Research, University of Sydney, Royal North Shore Hospital, Sydney, NSW. Phillip N Sambrook, MD, FRACP, Professor of Rheumatology. Garvan Institute, St Vincent's Hospital, Sydney, NSW. John A Eisman, PhD, FRACP, Professor of Medicine, and Head of Bone and Mineral Research Program. Reprints will not be available from the authors. Correspondence: Professor P N Sambrook, The Institute of Bone and Joint Research, Level 4, Block 4, Royal North Shore Hospital, St Leonards, NSW 2065. sambrookATmed.usyd.edu.au Make a comment 1: Profiles of agents for prevention and treatment of osteoporosis Calcium Action: Calcium is weakly antiresorptive and supplementation may reduce negative calcium balance and so reduce bone resorption, particularly in older patients. Dosing: Balance studies suggest a daily intake of 1500mg per day is required in postmenopausal women not using hormone replacement therapy. Adverse effects: Calcium is a relatively safe medication but may cause mild gastrointestinal intolerance. The risk of renal calculi is very low except in those at risk. Vitamin D Action: Vitamin D undergoes several metabolic steps in the body, so it is important to distinguish between simple vitamin D and its active metabolites (such as calcitriol), which have distinctly different pharmacological profiles. Simple vitamin D can be converted to calcitriol, and has a similar, but less potent, effect on increasing gastrointestinal absorption. Dosing: Simple vitamin D is mainly available in Australia as ergocalciferol (1000IU per capsule; Ostelin 1000; Boots Healthcare Australia). It is no longer available on the Pharmaceutical Benefits Scheme, but is a relatively inexpensive over-the-counter medication. Small amounts of vitamin D are contained in some calcium and vitamin supplements (eg, Caltrate + Vitamin D [Whitehall Laboratories] contains 200IU per tablet and cod liver oil tablets approximately 400IU). An appropriate dose for supplementation is 1000IU daily. Adverse effects: Chronic ingestion of large doses of vitamin D, usually at doses in excess of 50000 to 100000IU per day, is required to produce hypercalcaemia in normal patients. Thus, given the amounts of vitamin D contained in available preparations, intoxication is practically impossible. Calcitriol Action: The primary action of calcitriol is thought to be to increase gastrointestinal calcium absorption, and so indirectly reduce bone resorption. It may also increase bone formation, but at higher doses that may increase bone resorption. Dosing: The usual dose is 0.5mg daily. Adverse effects: Hypercalcaemia and hypercalciuria are uncommon in patients treated with the usual dose (above), but may occur in patients who increase their calcium intake substantially. Hence, calcium supplements should be avoided and dietary intake should be limited to less than 800mg daily. The Adverse Drug Reactions Advisory Committee (ADRAC) reported four cases of calcitriol-related hypercalcaemia in four years of postmarketing surveillance up to 1997.2 Etidronate Action: Etidronate is a first-generation bisphosphonate, and is relatively less potent in its effects on inhibiting bone resorption than later bisphosphonates. The balance of these effects can result in osteomalacia if the drug is used continuously in doses effective on bone resorption for osteoporosis. Dosing: In osteoporosis, etidronate is used in a cyclical regimen at 400mg daily usually for two weeks every three months to reduce the risk of mineralisation defects. Adverse effects: Etidronate has been associated with lower, but not upper, gastrointestinal events.3 The risk of mineralisation defect with the cyclical regimen is very low. Alendronate Action: This aminobisphosphonate is a potent inhibitor of bone resorption at doses that do not affect bone formation or mineralisation. Dosing: 10mg daily. Adverse effects: Clinical trials with alendronate have repeatedly shown no increase in adverse effects compared with control groups. However, there have been reports of oesophagitis after alendronate therapy, and recent postmarketing surveillance by ADRAC listed 331 adverse event reports among approximately 49000 patients in Australia taking alendronate.4 These included dyspepsia (44), nausea (43) and abdominal pain (37), and ulceration or stricture was confirmed endoscopically in 26 of 52 reports of oesophagitis. Although a causal relationship remains unproven, there appears to be a real but low incidence of upper gastrointestinal problems with alendronate. This is consistent with precautions in its administration requiring the patient to stay in an upright position and to fast for half an hour after taking it in the morning (as is required for adequate absorption). Oestrogen Action: Oestrogen is an antiresorptive drug, possibly mediated by effects on local release of various cytokines and growth factors in bone. Dosing: Conjugated equine, 0.625mg daily; piperazine oestrone sulfate, 1.25mg daily; transdermal oestradiol, 4mg patch. Adverse effects: Breast tenderness and abdominal swelling are not uncommon, but these problems usually settle, and starting with low doses can minimise them. Hormone replacement therapy has been associated with an increased risk of deep venous thrombosis. Transdermal routes of administration may reduce this risk. Controversy exists as to whether there may be an increased risk of breast cancer with long term oestrogen use. Studies that do suggest a small increase in risk indicate that they show no increase in risk in the first five years of treatment.5 Raloxifene Action: Like oestrogen, raloxifene is a selective oestrogen receptor modulator (SERM) which acts to decrease bone resorption, but, unlike oestrogen, it does not stimulate the breast or uterus. Dosing: 60mg daily. Adverse effects: An increased risk of venous thrombosis has been reported with raloxifene users, similar in extent to that seen with hormone replacement therapy. Unlike hormone replacement therapy, raloxifene is not useful for control of, and may worsen, menopausal symptoms. Anabolic steroids Action: Anabolic steroids are weak androgens and appear to exert a weak inhibitory effect on bone resporption. However, any effect on bone mass may in fact be secondary to effects on muscle mass. Dosing: Nandrolone decanoate, 50mg intramuscular injection every three weeks. Adverse effects: There is a high incidence of virilisation with these dosages and there are no long term safety data. Back to text 2: Level-of-evidence codes Evidence for the statements made in this article is graded according to the NHMRC system7 for assessing the level of evidence: E1Level I: Evidence obtained from a systematic review of all relevant randomised controlled trials. E2Level II: Evidence obtained from at least one properly designed randomised controlled trial. E31Level III-1: Evidence obtained from well-designed pseudo-randomised controlled trials (alternate allocation or some other method). E32Level III-2: Evidence obtained from comparative studies with concurrent controls and allocation not randomised (cohort studies), case-control studies, or interrupted time series without a parallel control group. E33Level III-3: Evidence obtained from comparative studies with historical control, two or more single-arm studies, or interrupted time series without a parallel control group. E4Level IV: Evidence obtained from case-series, either post-test or pre-test and post-test. Back to text Back to text 4: Important messages for patients It is never too late to start treatment. A number of new therapies have been shown to significantly reduce fracture risk. The overall risk of gastrointestinal problems with bisphosphonates is low. The effects of natural therapies in preventing osteoporosis are unproven. Back to text

Phillip N Sambrook · John A Eisman

Editorial Where has all our iodine gone? The possible re-emergence of iodine deficiency in Australia needs to be investigated in national surveys MJA 1999; 171: 455-456 Most countries in the world, including Australia, are signatories to the United Nations-sponsored "Declaration for the Survival, Protection and Development of Children", which states that "every child has the right to an adequate supply of iodine to ensure its normal development".1 One teaspoon of iodine is all a person requires in a lifetime, yet iodine deficiency at critical stages of development in fetal life and early childhood remains the world's single most important and preventable cause of mental retardation.2For the past three to four decades iodine deficiency has not been of significant concern in Australia (except in Tasmania); it was considered largely a problem of developing countries. That is what we thought until Gunton and colleagues give us a wake-up call with their article in this issue of the Journal 3. They found evidence of mild to moderate iodine deficiency in pregnant women, patients with diabetes and a small group of volunteers attending a Sydney teaching hospital. In their study, median urinary iodine concentrations ranged from 64 µg/L in the volunteers to 104 µg/L in pregnant women. The World Health Organization's standard for iodine-deficiency disorders in population surveys recommends that a median urinary iodine concentration above 100 µg/L is evidence against significant iodine deficiency in that population.4 Other population indicators of iodine deficiency, including total goitre rates in school-age children and serum thyrotropin (TSH) levels in the newborn, were not assessed in the Sydney study. The data of Gunton and colleagues indicate that the pregnant women they tested are ingesting less than half the recommended iodine intake in pregnancy of 200 µg/day. Although this study was not a national survey, and the sample size was small, the findings are alarming and raise concern that a major public health problem may be developing in the Australian community which could put future generations at risk of iodine-deficiency disorders. The key factor in the genesis of iodine-deficiency disorders is decreased production of thyroxine from the thyroid gland. While endemic goitre is the most easily recognised and best-known consequence of iodine deficiency, it is probably the least important. At critical periods in fetal development and in early childhood, biochemical hypothyroidism, due to iodine deficiency, results in a wide range of devastating and irreversible effects now known as iodine-deficiency disorders.5 More recently, we have come to appreciate that there is a general diminution in intelligence in iodine-deficient communities such that iodine deficiency is considered to be the commonest cause of preventable intellectual disability worldwide.2 Further, there is now very good evidence that a small decrease in serum free thyroxine level during pregnancy, either because of iodine deficiency or thyroid disease, is an important risk factor for impaired psychomotor development in infants.6,7 The recent demonstration of intellectual impairment in the children of American women who had mild hypothyroidism in pregnancy highlights the need for better detection and treatment of hypothyroidism in early pregnancy, irrespective of its cause.8 Tasmania is the only Australian State where regular surveillance of iodine nutrition is undertaken and records are maintained. Other data are available from the Australian Centre for Control of Iodine Deficiency Disorders (ACCIDD), located at Westmead Hospital, which has performed sporadic surveys of urinary iodine excretion levels in small samples of Australians for the past two decades. In 1992 we reported that the mean urinary iodine excretion level in Sydney residents was 180 µg/L, and over 200 µg/L in Tasmanian children.9 Since then, our sporadic surveys have shown a gradual but sustained decline in urinary iodine excretion levels in Sydney residents. We recently found similar results to those of Gunton et al 3 in a survey of primary schoolchildren from western Sydney who had a median urinary iodine concentration of 84 µg/L, and in 16% of whom the iodine concentration was less than 100 µg/L. Further, unpublished results we obtained in healthy pregnant women were also very similar to those of Gunton et al, indicating that widespread mild iodine deficiency threatens to affect the most vulnerable in our community. Why is our iodine intake decreasing in Australia? Gunton and colleagues implicate a combination of factors. Firstly, for over three decades, we have been dependent on iodine in milk contaminated by cleaning solutions used in the dairy industry; these solutions are gradually being replaced by others which leave less iodine in milk. Secondly, we seem to be using less iodised salt, through a combination of purchasing uniodised salt for domestic consumption, probably decreasing our salt consumption, and consuming most of our salt in processed foods, which, as far as we can ascertain, is uniodised. The problem is not unique to Australia, as similar downward trends in iodine intake have recently been noted in other developed countries such as the United States10 and New Zealand.11 What actions should be taken in response to these findings? Firstly, we need more information through a national survey of urinary iodine excretion and goitre rates to determine the status of iodine nutrition throughout Australia. Secondly, we need to educate the population and healthcare providers about the insidious and harmful effects of iodine deficiency, especially during pregnancy and early childhood. Finally, we must institute effective and sustainable means of iodine supplementation to our whole community through legislating for universal salt iodisation, so that all salt used for human and animal consumption in Australia is iodised. Iodising all edible salt will cost less than 10 cents per person annually. In the past this intervention has been viewed as politically unacceptable, but the debate was conducted with a view to eliminating endemic goitre without any real understanding of the often subtle, but devastating, consequences of impaired brain development. In the interim, every effort should be made to ensure every pregnant woman ingests an adequate amount of iodine to ensure her unborn child experiences normal mental development. Until we have educated the population as a whole about the risks of iodine deficiency and instituted mandatory iodisation of all salt for human and animal consumption, it may be prudent to recommend supplementary iodine for all pregnant women from the time of conception until weaning of the infant. Creswell J Eastman, AM Director, Institute of Clinical Pathology and Medical Research Westmead Hospital, Westmead, and Clinical Professor of Medicine University of Sydney, Sydney, NSW World Declaration on the survival, protection and development of children and a plan of action for implementing the world declaration on the survival, protection and development of children in the 1990s. New York: United Nations, 1990. World Health Organization. Progress towards the elimination of Iodine Deficiency Disorders (IDD). WHO/NHD/99.4. Geneva: WHO, 1999. Gunton JE, Hams G, Fiegert M, McElduff A. Iodine deficiency in ambulatory patients attending a Sydney teaching hospital: Is Australia truly iodine replete? Med J Aust 1999; 171: 467-470. World Health Organization. WHO, UNICEF, ICCIDD. Indicators for assessing iodine deficiency disorders and their control through salt iodisation. WHO/NUT/94.6. Geneva: WHO, 1994. Boyages SC. Clinical Review 49, Iodine deficiency disorders. J Clin Endocrinol Metab 1993; 77: 587-591. Pop VJ, Kuijpens JL, van Baar AL, et al. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol 1999; 50: 149-155. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neurological development of the child. N Engl J Med 1999; 341: 549-555. Utiger RD. Maternal hypothyroidism and fetal development. N Engl J Med 1999; 341: 601-602. Eastman CJ. The status of iodine nutrition in Australia. In: Delange F, Dunn JT, Glinoer D, editors. Iodine deficiency in Europe -- a continuing concern. New York: Plenum Press, 1993: 133-139. Dunn JT. What's happening to our iodine? [editorial]. J Clin Endocrinol Metab 1998; 83: 3398-3400. Thomson CD, Colls AJ, Conaglen JV, et al. Iodine status of New Zealand residents as assessed by urinary iodide excretion and thyroid hormones. Br J Nutrition 1997; 78: 901-912.

Creswell J Eastman

Research Iodine deficiency in ambulatory participants at a Sydney teaching hospital: is Australia truly iodine replete? Jenny E Gunton, Graham Hams, Marcelle Fiegert and Aidan McElduff MJA 1999; 171: 467-470 For editorial comment, see Eastman Abstract - Introduction - Methods - Results - Discussion - References - Authors' details - - More articles on Endocrinology Abstract Objective: To assess iodine status in four separate groups -- pregnant women, postpartum women, patients with diabetes mellitus and volunteers. Design and setting: Prospective cross-sectional study at a tertiary referral hospital in Sydney. Participants: 81 pregnant women attending a "high risk" obstetric clinic; 26 of these same women who attended three months postpartum; 135 consecutive patients with diabetes mellitus attending the diabetes clinic for an annual complications screen; and 19 volunteers. There were no exclusion criteria. Methods: Spot urine samples were obtained, and urinary iodine was measured by inductively coupled plasma mass spectrometer. Outcome measures: Iodine status based on urinary iodine concentration categorised as normal (> 100 µg/L), mild deficiency (51-100 µg/L) and moderate to severe deficiency (< 50 µg/L). Results: Moderate to severe iodine deficiency was found in 16 pregnant women (19.8%), five postpartum women (19.2%), 46 patients with diabetes (34.1%) and five volunteers (26.3%). Mild iodine deficiency was found in an additional 24 pregnant women (29.6%), nine postpartum women (34.6%), 51 patients with diabetes (37.8%) and 9 normal volunteers (47.4%). Median urinary iodine concentration was 104 µg/L in pregnant women, 79 µg/L in postpartum women, 65 µg/L in patients with diabetes mellitus and 64 µg/L in volunteers. Conclusions: The high frequency of iodine deficiency found in our participants suggests that dietary sources of iodine in this country may no longer be sufficient. Further population studies are required. Introduction It is currently believed that iodine deficiency does not exist in Australia.1,2 However, iodine status is seldom, if ever, measured in routine clinical care, and iodine deficiency may have significant adverse consequences, particularly during pregnancy (Box 1). Box 2 shows some of the reasons why iodine intake in Australia may be inadequate. The recommended daily intake (RDI) of iodine is 100 µg daily for the general population and 150-200 µg daily for women who are pregnant or breastfeeding6-8,10 (iodine demand increases during pregnancy because of increased renal clearance and fetal iodine transfer). Approximately 90% of iodine is excreted in the urine,1,11 and iodine status is usually assessed by measuring urinary iodine concentration. The accepted minimum adequate level of urinary iodine is 100 µg/L, and levels above this are considered normal.1,6-9,12 Urinary iodine concentrations below 25 µg/L are classified as severe deficiency, and are associated with an increased risk of cretinism; 26-50 µg/L is classified as moderate deficiency, and 51-100 µg/L is regarded as mild iodine deficiency.1,6-9,12 The World Health Organization (WHO) recommends that the median urinary iodine concentration for populations as a whole should be more than 100 µg/L, that less than 20% of the population should have a urinary iodine concentration below 50 µg/L, and that no cretinism occurs.12 Having previously found low levels of free thyroxine in pregnant women,13 and in light of the adverse consequences of iodine deficiency during pregnancy, we initially set out to test the iodine status of a group of pregnant women. We subsequently included other groups to widen our investigation of iodine status. Methods Study participants Our study was conducted at a tertiary referral hospital in Sydney. Participants in the study included women who attended a specialist "high risk" obstetric clinic, patients of both sexes with diabetes who attended the hospital's diabetes clinic, and healthy, non-pregnant volunteers recruited after a presentation about iodine. Participants thus comprised 81 consecutive pregnant women who attended the obstetric clinic between 1 August 1998 and 1 April 1999, 26 of these same women who were reassessed at three months postpartum, 135 consecutive patients who attended the diabetes clinic for an annual complications screen between 1 November 1998 and 1 February 1999, and 19 volunteers recruited between 1 February and 1 July 1999. All participants provided a routine urine sample. There were no exclusion criteria. One of the 81 pregnant women had thyrotoxicosis as a result of Graves' disease -- she particpated before commencing therapy. Twenty-two of the patients attending the diabetes clinic (16.1%) had type 1 diabetes, 103 (76.3%) had type 2 diabetes and 10 (7.5%) had impaired glucose tolerance. One of the patients with diabetes had recently received iodine-containing intravenous contrast medium during a coronary angiogram, and one was taking amiodarone. No other participant was known to have received contrast medium, or to be taking amiodarone or iodine supplements. Urinary iodine measurement Urinary iodine concentrations were determined by means of a Varian UltraMass inductively coupled plasma mass spectrometer with SPS-5 autosampler (Varian Inc., Palo Alto, California, USA). The measurement was calibrated over a range of 0-1000 µg iodine per litre. The lower limit of detection for the assay was 2 µg/L. The reproducibility of the assay as represented by the 100 µg/L calibrator assessed over three months was ± 6 µg/L (± 2 SD). Comparison with the colorimetric/Sandell-Koltkoff reaction method showed a highly significant correlation (P < 0.001; see Box 3). Other authors have also compared the methods and found high correlation.14 In particular, no systematic biases were found at low iodine concentrations. Some investigators use the urinary iodine/creatinine ratio to determine iodine status.1,14 We thus measured urinary creatinine by the Creatinine Jaffa method (Boehringer Mannheim Systems, Mannheim, Germany) and calculated iodine/creatinine ratios (µg iodine/g creatinine) for each participant. The correlation between urinary iodine and iodine/creatinine ratio was high for non-pregnant participants (r = 0.969; P < 0.001) and lower for the pregnant group (r = 0.419; P < 0.001). Twenty-four-hour urinary iodine measurement may be used to assess iodine status,6 but this method can be unreliable because of incorrect or incomplete collection,15 and is less practical than spot samples for population surveys.9,12 To compare this method with our spot sampling, we selected six pregnant women (on the basis of their spot urine concentrations to cover a range of values) who collected 24-hour urine samples for iodine content measurement. The correlation was highly significant (r2 = 0.82), thus confirming that spot urine samples were a reliable way of measuring iodine status. As part of routine care, 70 of the 81 pregnant women and 121 of the 135 patients with diabetes had thyroid function tests. Free thyroxine (FT4) and thyroid-stimulating hormone (TSH) levels were measured by means of an automated chemiluminescence system (Chiron Diagnostics, Scoresby, Vic.). We did not seek ethical approval for this study as it involved no deviation from usual care, except in the case of the 19 volunteers who agreed to provide a urine sample. Statistical analysis We used SPSS for statistical analysis.16 Means are expressed with ± 2 standard deviations, and medians with 95% confidence intervals (CI) are shown where data were not normally distributed. The results of non-parametric variables (including iodine results) were compared by means of the Mann-Whitney Wilcoxon rank sum test. Results Box 4 shows the mean and median ages and the results of spot urinary iodine concentration for the four groups. The three non-pregnant groups had similar urinary iodine concentration results, with a slightly higher median in the postpartum group compared with the group with diabetes. As expected,17-19 the pregnant women had higher urinary iodine concentrations than the other groups as a whole (P = 0.004). The iodine/creatinine ratios also show a high proportion of abnormal results (Box 4). The median iodine concentration in the 26 postpartum women (79 µg/L) who provided repeat urine samples for iodine measurement three months after delivery was considerably lower than that in the 81 pregnant women (104 µg/L). However, this difference was not statistically significant (P = 0.249). The patient with diabetes who had received iodine-containing intravenous contrast medium during a coronary angiogram in the month before the urinary spot test had a urinary iodine concentration of 2170 µg/L. Box 5 shows TSH levels and FT4 levels versus iodine status in pregnant and non-pregnant participants. There was no significant relationship between iodine status and FT4 or TSH levels in either the pregnant group or non-pregnant group. Separate analysis of patients with diabetes and postpartum women did not significantly alter these results. However, there was a weak correlation between FT4 and urinary iodine levels when examined as a continuous variable (Pearson correlation coefficient, 0.26; P = 0.016). Discussion By WHO criteria,12 the median iodine levels in our pregnant participants were only just adequate, while those in postpartum women, patients with diabetes and normal volunteers were inadequate. The slightly higher median iodine level in the postpartum group compared with that in the group with diabetes may have been the result of this concentration not having returned to baseline after pregnancy, although further study is required to document the rate of change post partum. We believe the low values in patients with diabetes was not a problem specific to diabetes, but merely a reflection of low urinary iodine levels in the general population. The similarity between the patients with diabetes and our small group of volunteers supports this view. Our data are consistent with generally low iodine intake. Our findings mirror recent reports from other countries.9,11,20 A United States study showed that the median urinary iodine concentration in 1988-1994 had decreased by more than 50% from that in 1971-1974.9,11 The 1988-1994 results showed 11.7% of the US population to be iodine deficient (a 4.5-fold increase since 1971-1974). The mean urinary iodine concentration in that population was 265 µg/L, and people from higher socioeconomic groups were more likely to be iodine deficient. Our data may also reflect this effect, as, although our patients were attending a public clinic, the hospital catchment area is a relatively high socioeconomic group. Our data suggest that Australia may be experiencing a similar trend to that seen in the US. Iodine deficiency during pregnancy can affect the thyroid glands of both the mother and baby,10,17-19 and may have many adverse health consequences (Box 1). Some, but not all, researchers have found an increase in urinary iodine levels during pregnancy.10,17-19 Smyth et al studied urinary iodine concentration in a group of pregnant women in an area of Ireland with known borderline iodine deficiency.10 In the third trimester, they found a mean urinary iodine concentration of 132 µg/L (standard error of the mean, 6.8), and found that urinary iodine concentration increased during pregnancy. In a more iodine-deficient area, Glinoer et al found that urinary iodine concentration did not increase during pregnancy (median iodine concentration 45 µg/L after 20 weeks' gestation, no mean given).19 So, it is not clear whether the apparently higher levels in our pregnant women were pregnancy related or, in fact, masked iodine deficiency in pregnancy. We found that a considerable percentage of pregnant women (4.9%) were severely iodine deficient, with spot urine results of < 25 µg/L. While this is the threshold below which cretinism may occur, other factors, such as selenium deficiency and the presence of dietary goitrogens, also play a part in determining cretinism,21 and these two factors are not usually seen in Sydney. Therefore, we would not expect to see an increased incidence of cretinism in Sydney on the basis of these results alone. However, more subtle adverse fetal outcomes may occur. Our findings suggest that we should no longer automatically consider Australia an iodine-replete country. We found that iodine deficiency was common among 235 people attending a Sydney teaching hospital and speculate that these data are applicable to the general population, although this will require independent confirmation. The frequency of iodine deficiency in our pregnant population (18.8%) approaches the maximum acceptable level recommended by WHO (20%); this recommendation was exceeded in our group with diabetes (34.1%) and the normal volunteers (26.3%). The postpartum women had a median iodine concentration of 79 µg/L, which is lower than the WHO recommendation of 100 µg/L. This has important public health implications. The weaknesses of this study include the small group of normal volunteers, and perhaps the use of a sample from a teaching hospital rather than the community. The normal volunteers had results which are equivalent to those seen in postpartum women and non-pregnant patients with diabetes. Our subjects were all ambulatory, not inpatients at the time of testing, and generally well. Although 24-hour urinary iodine excretion studies may be the ideal method of assessing iodine status, these are not generally performed in large numbers for a variety of technical and practical reasons. A weak correlation between urinary iodine and free thyroxine was observed for all non-pregnant participants in total, and for the participants with diabetes mellitus. Because of the large number of other factors which influence thyroid function (including pregnancy),13 the relatively loose correlations are an expected finding. Further studies are needed, and these include (i) population surveys in Sydney and elsewhere in Australia; (ii) assessment of thyroid size (eg, by ultrasound) in relation to iodine status; and (iii) detailed assessment of neonates, including thyroid size, neonatal TSH levels, and detailed neurological outcomes. References Hetzel BS. Iodine deficiency disorders. In: Garrow JS, James WPT, editors. Human nutrition and dietetics. Edinburgh: Churchill Livingstone, 1993: 534-555. Mortimer RH. Thyroid disease and pregnancy. Aust N Z J Med 1998; 28: 647-653. Tasmanian Thyroid Advisory Committee. Study in disease surveillance. 1950-1979. Med J Aust 1981; 2: 234-238. Clements FW. Goitre studies. 1. The incidence of endemic goitre in three areas in Australia. Med J Aust 1948; 21: 637-639. Hales I. Studies in diseases of the thyroid gland [MD thesis] Sydney: University of Sydney, 1971. Boyages S. Iodine deficiency disorders. J Clin Endocrinol Metab 1993; 77: 587-591. Clugston GA, Hetzel BS. Iodine. In: Shils ME, Olson JA, Shike M, editors. Modern nutrition in health and disease. 8th ed. Vol. 1. Philadelphia: Lea and Febiger, 1994; 252-263. Delange F. The disorders induced by iodine deficiency. Thyroid 1994; 4: 107-128. Hollowell JG, Staehling NW, Hannon WH, et al. Iodine nutrition in the United States. Trends and public health implications: iodine excretion data from the National Health and Nutrition Examination Surveys I and III (1971-1974 and 1988-1994). J Clin Endocrinol Metab 1998; 83: 3401-3408. Smyth PPA, Hetherton AMT, Smith DF, et al. Maternal iodine status and thyroid volume during pregnancy: correlation with neonatal iodine intake. J Clin Endocrinol Metab 1997; 82: 2840-2843. Dunn JT. What's happening to our iodine? [editorial]. J Clin Endocrinol Metab 1998; 83: 3398-3400. World Health Organization Nutrition Unit. Indicators for assessing iodine deficiency disorders and their control through salt iodization. Document No. WHO/NUT 94.6. Geneva: WHO, 1994: 36. McElduff A. Measurement of free thyroxine levels (fT4) in pregnancy. Aust N Z J Obstet Gynaecol 1999; 39: 158-161. May SL, May WA, Bourdoux PP, et al. Validation of a simple, manual urinary iodine method for estimating the prevalence of iodine-deficiency disorders, and interlaboratory comparison with other methods. Am J Clin Nutr 1997; 65: 1441-1445. McElduff A, Shuter B, Cooper R, et al. Measuring renal function in patients with diabetes mellitus. J Diabetes Complications 1997; 11: 225-229. SPSS [computer program], version 6.0. Chicago, Ill: SPSS Inc, 1996. Silva JE, Silva S. Interrelationships among serum thyroxine, triiodothyronine, reverse triiodothyronine, and thyroid-stimulating hormone in iodine-deficient pregnant women and their offspring: effects of iodine supplementation. J Clin Endocrinol Metab 1981; 52: 671-677. Glinoer D, De Nayer P, Bourdoux et al. Regulation of maternal thyroid during pregnancy. J Clin Endocrinol Metab 1990; 71: 276-287. Glinoer D, Delange F, Laboureur I, et al. Maternal and neonatal thyroid function at birth in an area of marginally low iodine intake. J Clin Endocrinol Metab 1992; 75: 800-805. Valiex P, Zarabska M, Preziosi P, et al. Iodine deficiency in France [letter]. Lancet 1999; 353: 1766-1767. Moreno-Reyes R, Suetens C, Mathieu F, et al. Kashin-Beck osteoarthropathy in rural Tibet in relation to selenium and iodine status. N Engl J Med 1998; 339: 1112-1120. Received 13 Apr, accepted 21 Aug, 1999 Authors' details Royal North Shore Hospital, St Leonards, NSW. Jenny E Gunton, MB BS, Endocrine Fellow, Department of Endocrinology. Graham Hams, MAppSc, Senior Staff Scientist, Pacific Laboratory Medicine Services. Marcelle Fiegert, BEd, MNutri Diet, Dietitian, Department of Nutrition. Aidan McElduff, FRACP, PhD, Senior Staff Specialist in Endocrinology, Department of Endocrinology. Reprints: Dr J E Gunton, C/- Clinic 1, Royal North Shore Hospital, St Leonards, NSW 2065. jennyegAThotmail.com. 1: Iodine deficiency disorders Maternal Goitre Hypothyroidism Decreased fertility Miscarriage Fetal Stillbirth Neonatal Cretinism Increased mortality Goitre Hypothyroidism Back to text 2: The iodine situation in AustraliaIn the past, an increased incidence of goitre and iodine deficiency was documented in certain parts of Australia.3-5 Prevention of iodine deficiency in industrialised countries most commonly relies on iodised salt, iodine in milk, or iodine-supplemented bread.1,6-8 The upper limit of the recommended daily intake of salt (NaCl) is 100 mmol, or 6 g (a heaped teaspoon); 100 mmol of iodised salt per day would provide 175-240 µg of iodine. However, most salt is incorporated into foods before purchase, and the three major Australian manufacturers of processed food we contacted all reported using non-iodised salt only. Non-iodised table salt is readily available, and may be used more frequently than in the past as campaigns to use iodised salt are forgotten. (We reviewed supermarket shelves in our local area, and found that the space allocated for display suggests that more non-iodised than iodised salt is purchased.) In the United States, only 50%-60% of salt currently consumed is iodised.9 Milk products, which used to contain significant concentrations of iodine (up to 300 µg/100 mL) by virtue of iodine-containing solutions used to clean the milk vats, now contain low levels of iodine because volatile cleaning solutions are used (Dairy Farmers Association, Nutrition Panel for Milks, personal communication). While the incidence of iodine deficiency and goitre was decreased by legislation requiring iodine supplementation of bread in 1966,3 this is no longer a requirement (because of concerns about an increased incidence of thyrotoxicosis). Marine fish, shellfish, seaweed and kelp contain high amounts of iodine,1,7 and such ocean seafood, as well as added iodised salt, provide most of the iodine in the Australian diet. However, many people may consume these products rarely, if at all. Back to text Back to text 4: Iodine status resultsGroupPregnant womenPostpartum womenPatients with diabetesVolunteersNumber of participants8126135 19Age (years)Mean (± 2 SD)32.9 ± 9.835.3 ± 11.350.1 ± 35.3*49.5 ± 17.4*Median (95% CI)34 (24-42)35 (25-42)50 (25.7-83.0)49 (45.3-53.8)Spot iodine concentration (µg/L)Median10479‡65† 64(95% CI)(89-129)(44-229)(58-89)(54-75)No. of participants (%) withSevere to moderate deficiency < 50 µg/L16 (19.8%)5 (19.2%)46 (34.1%)5 (26.3%)Mild deficiency 51-100 µg/L24 (29.6%)9 (34.6%)51 (37.8%)9 (47.4%)Normal iodine status > 100 µg/L41 (50.6%)12 (46.1%)38 (28.1%)5 (26.3%)Iodine/creatinine ratio (µg iodine/g creatinine)Median159131114 108(95% CI)(169-232)(106-218)(93-505)(84-209)No. of participants (%) withSevere to moderate deficiency< 50 µg iodine/g creatinine6 (7.4%)2 (7.7%)7 (5.2%)1 (5.3%)Mild deficiency 51-100 µg iodine/g creatinine 22 (27.2%)9 (34.6%) 50 (37.0%)5 (26.3%)Normal iodine status > 100 µg iodine/g creatinine53 (65.4%)15 (57.7%)78 (57.8%)13 (68.4%)* P < 0.001 for comparison with pregnant women. †P < 0.01 for comparison with pregnant women. ‡P < 0.05 for comparison with patients with diabetes. Back to text 5: Levels of thyroid-stimulating hormone and free thyroxine compared with iodine status in pregnant women and patients with diabetesThyroid-stimulating hormone (µIU/mL)Free thyroxine (pmol/L)GroupNo. Mean (± 2 SD)Mean (± 2 SD)Pregnant women70Normal iodine status*411.56 ± 0.8012.9 ± 3.70Mild deficiency†231.67 ± 0.9012.5 ± 3.00Severe to moderate deficiency‡16 1.56 ± 0.7712.1 ± 2.25Patients with diabetes121Normal iodine status*342.1 ± 3.1015.0 ± 2.60Mild deficiency†451.9 ± 1.2015.0 ± 2.60Severe to moderate deficiency‡42 2.6 ± 2.4014.5 ± 2.90 * > 100µg/L. † 51-100 µg/L. ‡ < 50 µg/L. Back to text

Jenny E Gunton · Graham Hams · Marcelle Fiegert · Aidan McElduff

Editorial Diagnosing osteoporosis: the value of quantitative ultrasound Currently, screening by quantitative ultrasound does not appear to be a good deal MJA 1999; 171: 295-296 For related articles see Maguire, Lobb et al & Naganathan et al Towards the end of the 20th century, the problems of diagnosis have not really changed. These remain how to evaluate the risk of disease, and then how to explain risk reduction clearly to patients. What has changed is our ability to predict risk, and to reduce that risk by the powerful public health, pharmacological or surgical interventions now available. What has this to do with osteoporosis, a microarchitectural disorder leading to fragility fracture? Osteoporosis is a classic chronic disorder in which the actual individual risk of clinical disease (in this case future fracture) is often difficult to quantify. The situation is similar for hypertension and hypercholesterolaemia. A few statistics may aid risk evaluation. A risk of 5%-10% or greater over five years of any osteoporotic fracture (arms, legs, pelvis, spine or rib) is generally regarded as requiring intervention. Interventions can reduce fracture risk by about 15%-50%.1,2 To prevent one fracture in such a population, between 20 and 133 patients need to be treated for five years. The risk of osteoporotic fracture depends on age. In women over the age of 65 years, the five-year risk rises dramatically from 5%, and to 20% in women over the age of 90 years.3 The presence of a previous osteoporotic fracture at least doubles the risk of future fracture.4-6 What does bone densitometry have to do with risk evaluation? It is this: when bone density is measured by dual energy x-ray absorptiometry (DEXA), then, for each standard deviation that the result falls below the mean for the individual's age (the Z score), the future risk of fracture doubles. Thus, an individual with a Z score of 22 has a fourfold greater risk of fracture than the average person of the same age. In a 65-year-old, this would give an actual five-year risk of fracture of about 30%. Because the bone density of fracture populations is independent of age, the concept of a standard deviation unit with respect to a fixed, low-risk population -- healthy 20-30-year-olds -- has been introduced (the T score) (see Figure). Significant microarchitectural deterioration (osteoporosis) is defined in bone density terms as a T score of -2.5 or less. Patients with a T score in this range have at least 5.65 times the risk of fracture relative to normal young individuals. However, their absolute five-year risk of fracture is related to the actual population risk at their age; for women aged 65-70 years this is about 18%.2 Factors other than age and bone density contribute to calculation of absolute fracture risk. Particularly important is a previous history of osteoporotic fracture. Currently, bone density risk evaluation by DEXA or quantitative computed tomography is supported by rebates from the Health Insurance Commission (HIC) for patients at high risk based on clinical information. Rebates are for evaluation of individuals who have had an osteoporotic fracture; who have clinical risk factors, such as corticosteroid treatment or premature menopause; or who have had osteoporosis diagnosed on a previous bone density test. The HIC will not fund the first bone density test in unselected individuals, otherwise known as population screening. This is because it is currently considered that bone density testing and the interventions consequent on finding high-risk individuals do not fulfil Australian cost-effectiveness criteria. However, individuals who do not meet current HIC criteria for bone density testing often decide to pay for the test themselves. How should we advise the HIC or the individual patient about the most effective screening for osteoporosis? Based on the epidemiology of fracture in Australia, it could be argued that, as well as the categories of high risk patients already outlined, all women aged 65-75 years should have bone density testing. This is because the population risk of future fracture rises dramatically in this age group. If screening is performed at an earlier age, the benefits are diluted by the small number of patients with detectable osteoporosis and the lack of controlled trial evidence that treatment prevents fracture at these ages when event rates are low. Could ultrasound become a "front end" to DEXA testing? In this issue of the Journal, the article by Naganathan et al7 is a useful contribution to the debate, providing a framework for considering the value of ultrasound screening. Naganathan et al report a simple method for calculating the benefits of testing bone structure by ultrasound compared with the current "gold standard" of DEXA. They achieved this by comparing the pre- and post-test probabilities of DEXA-defined osteoporosis (T score ≤ -2.5 at spine or hip sites) after ultrasound testing. Interestingly, they showed that 37% of their selected population had a normal combined quantitative ultrasound score, and that this finding completely excluded DEXA-defined osteoporosis. However, based on these data, an ultrasound test does not seem to be a good deal either for the individual patient or for the HIC, should it fund screening. The cost of screening 100 patients with ultrasound ($40 each) plus DEXA for those with abnormal ultrasound results ($80 x 63) would be $9040; the cost of screening with DEXA alone would be only $8000. Thus, both patients and the HIC should be advised not to pay for commercial ultrasound testing as a "front end" to DEXA at present. What about the future -- could ultrasound replace DEXA as the "gold standard" for predicting fracture? The answer is yes, possibly. The evidence-based approach would demand large prospective studies showing that ultrasound is better and cheaper than DEXA in predicting fracture, and that patients treated on the basis of ultrasound testing have a reduced risk of fracture compared with those who are not treated. To date, a couple of studies have taken the first steps to show effective fracture prediction in elderly women.8,9 It has taken 20 years to validate DEXA as a clinically useful predictor of patients who should be treated to prevent fracture, so don't hold your breath over ultrasound! Richard L Prince Associate Professor, University Department of Medicine Sir Charles Gairdner Hospital, Perth, WA Reprints: Associate Professor R L Prince, University Department of Medicine, Sir Charles Gairdner Hospital, Nedlands, WA 6009. Eddy DM, Johnston CC, Cummings SR, et al. Osteoporosis: review of the evidence for prevention, diagnosis and treatment and cost-effectiveness analysis. Osteoporos Int 1998; 8 Suppl 4: S7-S80. Cummings SR. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fracture: Results from the Fracture Intervention Trial. JAMA 1998; 280: 2077-2082. Sanders KM, Seeman E, Ugoni AM, et al. The age- and gender-specific rate of fractures in Australia: a population based study. Osteoporos Int 1999. In press. Ross PD, Genant HK, Davis JW, et al. Predicting vertebral fracture incidence from prevalent fractures and bone density among non-black, osteoporotic women. Osteoporos Int 1993; 3: 120-126. Wasnich RD, Davis JW, Ross PD. Spine fracture risk is predicted by non-spine fractures. Osteoporos Int 1994; 4: 1-5. Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for hip fracture in white women. N Engl J Med 1995; 332: 767-773. Naganathan V, March L, Hunter D, et al. Quantitative heel ultrasound as a predictor of osteoporosis. Med J Aust 1999; 171: 297-300. Bauer DC, Gluer CC, Cauley JA, et al. Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women. Arch Intern Med 1997; 157: 629-634. Porter RW, Miller C, Grainger D, Palmer SB. Prediction of hip fracture in elderly women: a prospective study. BMJ 1990; 301: 638-641. Back to text

Richard L Prince