Volume 170 Issue 11

Research Why do preterm infants die in the 1990s? Lex W Doyle, Sheryle Rogerson, Shu-Ling Chuang, Matthew James, Ellen D Bowman and Peter G Davis MJA 1999; 170: 528-532 Abstract - Introduction - Methods - Results - Discussion - References - Authors' details - - Articles on similar material Abstract Objectives: To describe the mortality rate for preterm infants (born 23-36 completed weeks' gestational age) and to determine the causes of death, focusing on avoidable causes. Design and setting: Prospective cohort study of preterm infants born at Royal Women's Hospital, Melbourne (a tertiary referral hospital with a neonatal intensive care unit and a special care nursery) from January 1994 to December 1996. Subjects: 2475 consecutive liveborn infants with gestational ages from 23 to 36 weeks. Main outcome measures: Mortality rate during the primary hospitalisation, and causes of death. Results: The total mortality rate was 4.8% (118/2475). The mortality rate declined with increasing maturity. The decrease in mortality was rapid between 23 and 28 weeks' gestational age, from 64.5% at 23 weeks to 4.0% at 28 weeks, then slower, falling to 0.4% at 36 weeks. Fifty of the 118 infants who died had lethal congenital anomalies. Lethal anomalies accounted for three-quarters of deaths in infants aged 28-36 weeks. The mortality rate in infants free of lethal anomalies was 2.8% (68/2425) and only 0.2% (4/1759) for infants aged 32-36 weeks. In the 68 infants without lethal anomalies who died, few obvious preventable causes were identified. Conclusions: Mortality rates fell rapidly between 23 and 28 weeks' gestational age. Survival rates for preterm infants born after 31 weeks' gestational age approached the survival rates of term infants. Lethal congenital anomalies were the most common cause of death; preventable causes of death were rare. Introduction The survival rate for very preterm infants (born at 23-27 weeks' gestational age) has improved dramatically with advances in perinatal care,1 particularly efforts to reduce neonatal respiratory distress syndrome (hyaline membrane disease), such as administering corticosteroids to the mother before delivery,2 administering exogenous surfactant to preterm infants,3 and assisted ventilation.4 However, mortality rates and causes of death for more mature but still preterm infants (28-36 weeks' gestational age) have received little attention, especially since the advent of exogenous surfactant in Australia in 1991. As hyaline membrane disease has diminished as a cause of death of preterm infants, other causes of death, some of which may be preventable, have assumed more prominence. The aim of this study of preterm infants 23-36 weeks' gestational age born in 1994-1996 in a hospital with neonatal intensive care facilities was to describe the variation with gestational age in the mortality rate and the causes of death, focusing on avoidable causes. Methods Setting This was a prospective cohort study of consecutive livebirths between 23 and 36 completed weeks of gestational age in the Royal Women's Hospital, Melbourne, over the three years from 1 January 1994 to 31 December 1996. Data collection Data have been collected prospectively since 1977 on all infants admitted to the neonatal intensive care unit (NICU), all infants of birthweight below 1500 g, and all infants below 32 weeks' gestational age, whether admitted to the NICU or not. Data on infants 32 to 36 weeks were collected from the special care nursery (SCN) admissions book, and the hospital's main computer database was checked to obtain data on those not admitted to either the NICU or SCN. Data collected included gestational age, birthweight, and mortality during the primary hospitalisation, whether during the neonatal period (first 28 days after birth) or later. Data were included for infants transferred from our hospital to another. Gestational age in completed weeks was assigned according to the first antenatal ultrasound scan, or maternal dates if no ultrasound report was available. Birthweight ratio was calculated by dividing the infant's birthweight by the expected gender-specific median birthweight for that gestational age.5 Causes of death For infants who died, the major causes of death were determined after the regular monthly clinicopathological conference at which the deaths of all livebirths within the hospital were discussed, and which was chaired by one of the authors ( LW D), who retained all records from the meeting. Causes of death included lethal congenital anomalies, complications of prematurity, perinatal asphyxia, or sepsis (Box 1). Preventable causes of death For each infant who died, avoidable factors included whether antenatal corticosteroids or surfactant had been given to infants who died from respiratory causes, whether intramuscular vitamin K had been given to those who died from pulmonary haemorrhage, whether appropriate anti-infective therapies were given to those who died from infection, and whether antenatal corticosteroids had been given to those who died from cerebroventricular haemorrhage or cystic periventricular leukomalacia. Data analysis Mortality data for preterm births at the Royal Women's Hospital were compared with published data for livebirths in Victoria in 1994,7 1995,8 and 1996,9 and for admissions to neonatal intensive care units in Australia and New Zealand in 1994.10Data were edited and analysed with SPSS for Windows.11 Dichotomous variables were contrasted by 2 analysis, and continuous variables were compared by Mann-Whitney U test,12 as most data were skewed. Results Causes of death There were 2475 infants of 23-36 weeks' gestational age born during the study period, of whom 118 died (4.8%). The mortality rate diminished rapidly between 23 and 28 weeks' gestational age (from 64.5% at 23 weeks to 4.0% at 28 weeks), then more slowly, to reach 0.4% at 36 weeks (Box 2). The autopsy rate in the infants who died was 51.8% (59/114), with no data on autopsies for four infants who died after transfer to other hospitals. Fifty infants died of lethal anomalies, all but two within 28 days of birth (Box 3). Lethal anomalies accounted for 11 of 67 deaths (16.4%) in infants born at 23-27 weeks' gestational age, 16 of 24 deaths (66.7%) in infants born at 28-31 weeks' gestational age, and 23 of 27 deaths (85.2%) in those born at 32-36 weeks' gestational age. Sixty-eight infants died who were without lethal anomalies: 2.8% of the 2425 livebirths, but only 0.2% of infants of 32-36 weeks' gestational age (4/1759) (Box 4). Sixty-one died within 28 days of birth and seven (10.3%) died later during the primary hospitalisation. In the Australian and New Zealand Neonatal Network, 35 of 256 deaths (13.7%) of infants of less than 32 weeks' gestational age without lethal anomalies died during the primary hospitalisation but after 28 days of age.10 Preventable causes of death Respiratory problems: The mothers of 23 of the 30 infants who died from HMD or BPD had received antenatal corticosteroids. In the remaining seven cases, the gestational ages were 23 or 24 weeks. In six cases there was not enough time to give corticosteroids, five mothers presenting in advanced preterm labour and one with eclampsia. In the seventh case, the gestational age was 23 weeks and before birth the infant was considered incapable of surviving, yet was given full intensive care postnatally. All 30 infants who died from HMD or BPD received exogenous surfactant after birth. The one infant who died from pulmonary haemorrhage without HMD received antenatal corticosteroids and did not have respiratory distress after birth and therefore did not re- ceive exogenous surfactant; the fatal pulmonary haemorrhage occurred at three days of age. The two infants who had HMD and pulmonary haemorrhage also received antenatal corticosteroids. All three infants who died from pulmonary haemorrhage had received intramuscular vitamin K at birth. None had clinical signs of heart failure or a patent ductus arteriosus before the haemorrhage. None had clinical indications for an echocardiogram, hence subclinical cardiac dysfunction cannot be excluded. Considering the 12 infants in the gestational age range 28-36 weeks who died without lethal anomalies, six died from sepsis, two from asphyxia, two from BPD, one from pulmonary haemorrhage, and one from SIDS. None died acutely from HMD. Infections: In the 22 infants who died from sepsis without NEC, there were only two in whom the management might have been different. In one infant of 30 weeks' gestational age the mother ignored the antenatal signs of sepsis for several days before presenting to hospital and delivering a moribund infant who died at 11 hours of age from E. coli pneumonia, despite full treatment, including appropriate antibiotics. In the other infant, of 33 weeks' gestation, who died of herpes simplex, the clinical presentation was that of sepsis several days before death, but, in the absence of other features of herpes in the mother or infant, no antiviral therapy was given. CVH and CPVL: Antenatal corticosteroids were given to the mothers of all nine infants in whom CVH or CPVL were major contributing causes of death. In addition to the five infants in whom CVH was a major cause of death, another 12 infants who died had a grade 3 or 4 CVH that was thought not to contribute substantially to their deaths. Comparison with regional outcomes The neonatal survival rate for infants of 24-31 weeks' gestational age at our hospital was similar to that reported in regional data from Victoria for the same three years7-9 (Box 5). In livebirths of less than 2500 g birthweight in Victoria in 1994-1996, 377 infants died within 28 days; 33.4% with lethal anomalies (compared with 44.0% in our hospital cohort; 2 = 3.7, not significant) and 5.6% died from infections (compared with 24.8% in our hospital; 2 = 32.9, P < 0.0001). The neonatal mortality rate in livebirths free of lethal malformations with birthweights greater than 2499 g was 0.45 per 1000 (81/178834) in Victoria in 1994-1996,7-9 compared with 2.27 per 1000 (4/1735) in infants of 32-36 weeks' gestational age in our hospital. The survival rate to hospital discharge in 1994 for infants free of lethal malformations cared for in neonatal nurseries at 23-31 weeks' gestational age was higher in our hospital than in reported data from the Australian and New Zealand Neonatal Network (Box 6). Discussion Comparing our data with regional data in Australia is difficult. States and territories provide data to the Australian Institute of Health and Welfare (AIHW), which then produces an annual report.13 However, the denominator in the AIHW report is predominantly determined by birthweight; gestational age is reported for confinements (ie, mothers), or for births, but not for all livebirths. Regional reports from Victoria provide data for births, including stillbirths and livebirths, by gestational age, but in two-week intervals, and only up to 31 weeks' gestational age.7-9 Moreover, the numerator in both of these regional data sets is usually limited to the neonatal period, rather than the primary hospitalisation. The Australian and New Zealand Neonatal Network collects data from all the Australian and New Zealand Neonatal Intensive Care Units.10 In this data set, the denominator is limited to admissions to neonatal units, eliminating livebirths who die outside the neonatal unit, and hence augmenting the reported survival rates. Moreover, this data set is limited to infants up to 31 weeks' gestation and excludes those with lethal malformations. The numerator, however, includes deaths in the neonatal period and those beyond 28 days of age that occur during the primary hospitalisation. Comparing data on cause of death is also difficult. Most government data collection sources, such as those in Victoria7-9 and other States, rely on confidential reports. They may not obtain enough data to classify the cause of death, and rarely can they confirm the gestational age. The final report includes an individual infant under only one cause of death, even though there may be several equally contributing causes of death, such as the common combination of HMD and airleak, which caused 25% of deaths from non-lethal causes in our study. Our system of clinicopathological conferences for each death, although not perfect, provided more detailed information about causes of death. As regional data sources do not provide complete data on deaths during the primary hospitalisation at all gestational ages, we cannot compare survival rates for preterm infants (32-36 weeks) with those of term infants (37-42 weeks). However, we have calculated rates of neonatal survival in Victoria for livebirths free of lethal malformations with birthweight greater than 2499 g, assuming that the results would be similar for infants of 37-42 weeks' gestation. In our hospital, the neonatal survival rate for infants of 32-36 weeks' gestational age (99.77%) approached the neonatal survival rate expected of term infants in Victoria (99.95%). The commonest causes of death were lethal anomalies, sepsis, and HMD. Deaths from lethal anomalies are over-represented in our hospital compared with Victoria as a whole as most have been diagnosed antenatally, and, in many cases, the mother has been transferred before birth from another hospital for management because of the fetal anomaly. The death rate from infection is higher in our hospital than for Victoria, but this is probably because infants in our hospital live longer, and hence acquire infections, rather than dying soon after birth from other problems related to prematurity. E. coli and Group B streptococci remain the chief cause of septic deaths, particularly soon after birth, consistent with the observations of Isaacs et al.14 Staphylococcus species are an increasingly frequent cause of late infections,15 and of late deaths in our study. HMD remains a leading cause of death for very preterm infants despite the fact that most mothers receive antenatal corticosteroid therapy and all infants receive exogenous surfactant. Improvements in exogenous surfactant offer hope of reducing mortality further, but other antenatal interventions, such as thyrotropin stimulating hormone,16 have been disappointing in large randomised controlled trials. HMD did not cause any deaths in our hospital in more mature preterm infants (28-36 weeks). Within the infants who died from HMD, the observation that those who also had an airleak were not as growth restricted as those who had no airleak might reflect some structural change within the lung or with use of pulmonary surfactant that is associated with growth restriction. The problem of extreme intrauterine growth restriction is highlighted by the deaths from pulmonary haemorrhage in three infants, all with birthweight ratios below 0.55. The pulmonary haemorrhage was not caused by failure to give intramuscular vitamin K at birth.17 The mechanism for fatal pulmonary haemorrhage is unclear, but may represent acute left heart failure, contributed to by a patent ductus arteriosus. The association of pulmonary haemorrhage and fetal growth restriction is well known and may be related to histological changes in the ductus arteriosus in growth-restricted fetuses.18 Pulmonary haemorrhage is also seen more frequently with exogenous surfactant therapy,19 which was given to two of the three infants in our study who died of pulmonary haemorrhage. Preventing prematurity, an obvious solution to the problem of higher death rates in preterm infants, remains an elusive goal. In all infants who died, few obvious preventable factors, apart from avoiding preterm birth, were evident. The Annual Report from the Victorian Consultative Council on Obstetric and Paediatric Mortality and Morbidity consistently identifies more avoidable factors in stillbirths than neonatal deaths.7-9 In summary, mortality rates fell sharply between 23 and 28 weeks' gestational age, and few infants of more than 28 weeks' gestational age without lethal anomalies died. Survival rates for preterm infants of more than 31 weeks' gestational age approached the survival rates expected of term infants. There were few obvious avoidable factors in the deaths of any of the infants who died, either in the very preterm infants of 23-27 weeks' gestational age, or the more numerous preterm infants of 28-36 weeks' gestational age. References The Victorian Infant Collaborative Study Group. Outcome at 2 years of children 23-27 weeks' gestation born in Victoria in 1991-92. J Paediatr Child Health 1997; 33: 161-165. Crowley P. Corticosteroids before preterm delivery (Cochrane Review). In: The Cochrane Library, Issue 2. Oxford: Update Software, 1998. [Updated quarterly.] Soll RF. Natural surfactant extract vs synthetic surfactant in the treatment of established respiratory distress syndrome (Cochrane Review). In: The Cochrane Library, Issue 2. Oxford: Update Software, 1998. [Updated quarterly.] Doyle LW, Davis P, Dharmalingam A, Bowman E. Assisted ventilation and survival of extremely low birthweight infants. J Paediatr Child Health 1996; 32:138-142. Beeby PJ, Bhutap (sic) T, Taylor LK. New South Wales population-based birthweight percentile charts. J Paediatr Child Health 1996; 32: 512-518. Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline- membrane disease: bronchopulmonary dysplasia. N Engl J Med 1967; 276: 357-368. The Consultative Council on Obstetric and Paediatric Mortality and Morbidity. Annual report for the year 1994. Melbourne: Department of Human Services, 1995. The Consultative Council on Obstetric and Paediatric Mortality and Morbidity. Annual Report for the Year 1995: Incorporating the 34th Survey of Perinatal Deaths in Victoria. Melbourne: Department of Human Services, 1996. <http://hna.ffh.vic.gov.au/phb/hce/peri/ob95/index.htm> Accessed 11 May 1999. The Consultative Council on Obstetric and Paediatric Mortality and Morbidity. Annual report for the year 1996. Melbourne: Department of Human Services, 1997. <http://hna.ffh.vic.gov.au/phb/hce/peri/rep_96/contents.htm> Accessed 11 May 1999. Donoghue DA. Australian and New Zealand Neonatal Network, 1994. Sydney: AIHW National Perinatal Statistics Unit, 1996. [Neonatal Network Series no. 1.] SPSS for Windows version 6.1 [computer program]. Chicago: SPSS Inc, 1994. Moses LE, Emerson JD, Hosseini H. Analyzing data from ordered categories. N Engl J Med 1984; 311: 442-448. Lancaster P, Huang J, Lin M. Australia's mothers and babies 1993. Sydney: AIHW National Perinatal Statistics Unit, 1996. [Perinatal Statistics Series No. 3.] Isaacs D, Barfield C, Clothier T, et al. Early-onset group B streptococcal infections in Aboriginal and non- Aboriginal infants. Med J Aust 1995; 163: 302-306. Isaacs D, Barfield C, Clothier T, et al. Late-onset infections of infants in neonatal units. J Paediatr Child Health 1996; 32:158-161. Actobat Study Group. Australian collaborative trial of antenatal thyrotropin-releasing hormone (ACTOBAT) for prevention of neonatal respiratory disease. Lancet 1995; 345: 877-882. Loughnan PM, McDougall PN, Balvin H, et al. Late onset haemorrhagic disease in premature infants who received intravenous vitamin K1. J Paediatr Child Health 1996; 32: 268-269. Ibara S, Tokunaga M, Ikenoue T, et al. Histologic observation of the ductus arteriosus in premature infants with intrauterine growth retardation. J Perinatol 1994; 14: 411-416. Raju TN, Langenberg P. Pulmonary hemorrhage and exogenous surfactant therapy: a metaanalysis. J Pediatr 1996; 123: 603-610. (Received 29 Jun 1998, accepted 25 Mar 1999) Authors' details Division of Paediatrics, The Royal Women's Hospital, Melbourne, VIC. Lex W Doyle, MD, MSc, FRACP, Paediatrician, and Associate Professor, Department of Obstetrics and Gynaecology, University of Melbourne; Sheryle Rogerson, MB BS, Paediatric Fellow; Shu-Ling Chuang, MB BCh, MRCP, Paediatric Fellow; Matthew James, MB ChB, MRCP, Paediatric Fellow; Ellen D Bowman, MB BS, FRACP, Paediatrician; Peter G Davis, MD, BS, FRACP, Paediatrician. Reprints will not be available from the authors. Correspondence: Associate Professor Lex Doyle, Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC 3052. Email: l.doyle@obgyn-rwh.unimelb.edu.au ©MJA 1999 Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> © 1999 Medical Journal of Australia. 1: Causes of death defined Lethal congenital anomalies: Any infants with major malformations that were considered untreatable or who died despite attempts at surgical correction, and infants with untreatable inborn errors of metabolism, chromosomal abnormalities, or overwhelming congenital infection acquired early in pregnancy. Complications of prematurity: Hyaline membrane disease (HMD), with or without an airleak: clinical signs of respiratory distress in the first days after birth, supported by radiological and/or autopsy evidence. Airleak comprised any air not confined to normal airspaces, such as pulmonary interstitial emphysema or pneumothorax. Bronchopulmonary dysplasia (BPD): respiratory distress beyond four weeks of age requiring oxygen therapy, and radiographic changes typical of bronchopulmonary dysplasia,6 or a pathological diagnosis of bronchopulmonary dysplasia at autopsy. Necrotising enterocolitis (NEC): confirmed by definite radiological, operative, or autopsy evidence. Cerebroventricular haemorrhage (CVH): included any evidence of haemorrhage of any degree identified by ultrasound examination or autopsy. Cerebroventricular haemorrhage was considered a substantial contributor to death when knowledge of an intracerebral haemorrhage (grade 4) led to withdrawal of intensive care and the infant subsequently died. Cystic periventricular leukomalacia (CPVL): included any cystic degeneration within the cerebral cortex. Cystic periventricular leukomalacia was considered the cause of death when it was severe enough to lead to the withdrawal of intensive care. Ultrasound scanning was routine within the first three days after birth, at the end of the first week, then monthly until discharge as a minimum. Pulmonary haemorrhage was diagnosed in infants with frothy, blood-stained tracheal fluid and clinical deterioration in respiratory function, or at autopsy. Perinatal asphyxia: Infants who were liveborn but failed to respond adequately to resuscitation at birth. Neonatal sepsis: Infants who died with clinical signs of sepsis supported by positive blood or cerebrospinal fluid (CSF) culture, but also included the occasional infant in whom sepsis was considered likely, but in whom blood or CSF cultures were sterile because of prior treatment with antibiotics, most commonly via the mother before birth. Pneumonia was diagnosed in infants with respiratory distress, signs of sepsis and a chest x-ray consistent with pneumonia, or at autopsy. Back to textBack to textBack to text 4: Causes of death in 68 preterm infants without lethal anomalies born at Royal Women's Hospital, Melbourne, January 1994-December 1996Median gestationalMedianMajorNumberage in weeksbirthweightcause*(%)(range)(range)Not offered intensive care7 (10.3%)23 (23-23)580 (545-725)Perinatal asphyxia5 (7.6%)26 (24-28.5)725 (630-1322)Sepsis27 (39.7%)25 (23-26)751 (606-896)NEC5 (7.4%)24 (23-29.5)756 (610-916)HMD23 (33.8%)24 (23-26)600 (522-750)HMD with airleak17 (25.0%)24 (23-25.5)670 (561-853)HMD without airleak6 (8.8%)25.5 (23-27) 509 (371-582)BPD7 (10.3%)26 (24-28)711 (640-751)CPVL4 (5.9%)25 (24-27)765 (568-858)Pulmonary haemorrhage3 (4.4%)27 (27-30)¶390 (315-756)¶Other**5 (7.4%)Total6825 (23-27)721 (590-856)MedianMedian days ofMajorbirthweight ratioage at deathcause*(range)(range)Not offered intensive care1.03 (0.94-1.23)1 (1-1)Perinatal asphyxia0.96 (0.83-1.13)1 (1-1)Sepsis1.00 (0.90-1.09)8 (1-15)NEC1.02 (0.68-1.16)14 (10-22.5)HMD0.92 (0.82-1.07)2 (1-4)HMD with airleak0.99 (0.89-1.13)2 (1-3.5)HMD without airleak0.66 (0.36-0.92)1.5 (1-5)BPH0.80 (0.66-0.92)38 (19-141)CPVL0.82 (0.76-1.13)49 (22-55)Pulmonary haemorrhage0.37 (0.30-0.54)¶5 (3-5)¶Other**Total0.95 (0.82-1.07)* Some infants had more than one major cause of death. Range = interquartile range. BPD = bronchopulmonary dysplasia Includes five infants who died with NEC. Six also had HMD, two had both HMD and CVH, and two had CVH. CPVL = cystic periventricular leukomalacia Three infants also had CVH and two had pulmonary haemorrhage. CVH = cerebroventricular haemorrhage¶ Range = complete range. HMD = Hyaline membrane disease** Two with cardiomyopathy following twin-twin transfusion syndrome, one spontaneous gut perforation, one neuroblastoma, one sudden infant death syndrome. NEC = necrotising enterocolitisInfants not offered intensive care were significantly less mature than those who died after intensive care (median gestational age 23, interquartile range 23-23 v. median gestational age 25, interquartile range 24-27; z = 3.0, P < 0.01). Excluding those with lethal anomalies and those not offered intensive care, children dying with HMD were less mature than those dying without HMD (median gestational age 24, interquartile range 23-26 v. median gestational age 26, interquartile range 24-28; z = 2.9, P < 0.01) and lighter at birth (median birthweight 600 g, interquartile range 522-750 g v. median birthweight 758 g, interquartile range 683-888 g; z = 3.0, P < 0.01), but had similar birthweight ratios (median 0.92, interquartile range 0.82-1.07 v. median 0.96, interquartile range 0.81-1.05, not significant). Within the group of infants who died of HMD, those who also had airleak were not significantly different in maturity, but were significantly heavier (z = 2.7, P < 0.01) and had higher birthweight ratios (z = 2.5, P < 0.02). The three infants who died of pulmonary haemorrhage were particularly growth restricted, with birthweight ratios of 0.30, 0.37, and 0.54, respectively; their median birthweight ratio of 0.37 was substantially below that of the infants who died of other causes (median birthweight ratio 0.96, interquartile range 0.85-1.07; z = 2.8, P < 0.01). Most infants who died did so soon after birth, except those who died of sepsis, BPD, or CPVL. Infants who died of sepsis were generally quite immature and small at birth, but were not particularly growth restricted. In infants without NEC who died of sepsis, the infectious organisms were Escherichia coli (8), Group B streptococci (3), Staphylococcus aureus(5), S epidermidis (1), Haemophilus influenzae (1), Klebsiella and Pseudomonas spp. combined (1), Streptococcus viridans (1), Candida albicans (1) and herpes simplex (1). E. coli and Group B streptococci were the predominant organisms causing early infections, and Staphylococcus species, later infections. Back to textBack to textBack to text

Lex W Doyle · Sheryle Rogerson · Shu-Ling Chuang · Matthew James · Ellen D Bowman · Peter G Davis

Healthcare A primary stenting strategy as an alternative to fibrinolytic therapy in acute myocardial infarction An analysis of results in hospital and at 6 weeks and 6 months Peter S Hansen, Helge H Rasmussen, John Vinen and Gregory I C Nelson MJA 1999; 170: 537-540 For editorial comment, see Meredith Abstract - Introduction - Methods - Results - Discussion - Acknowledgements - References - Authors' details - - More articles on Cardiology and cardiac surgery Abstract Objective: To report the feasibility and results to 6 months of a primary stenting strategy in patients with acute myocardial infarction (AMI). Design: Prospective, single-centre, observational study. Setting: A tertiary referral teaching hospital (Royal North Shore Hospital, Sydney), July 1997 to November 1998. Subjects: 102 (of 194) consecutive patients presenting to the emergency department with AMI who were eligible for fibrinolytic therapy, and for a primary stenting strategy. The first 50 patients were under 70 years of age, and had not had previous coronary artery bypass grafting (CABG). The following 52 patients included patients up to 80 years and with previous CABG. Outcome measures: Major adverse cardiac and cerebrovascular events: death, reinfarction, cerebrovascular accident (CVA) and repeat target lesion revascularisation, in hospital, and at 6 weeks and 6 months. Minor inhospital adverse events: bleeding requiring blood transfusion, vascular complications and new-onset heart failure. Time delays to treatment, and duration of hospital stay. Results: Normal flow was established in the infarct-related artery in 97/102 patients (95%). Stenting, percutaneous transluminal coronary angioplasty (PTCA), CABG or medical therapy was performed in 74, 11, 9 and 8 patients, respectively. Minor inhospital events, time delays and hospital stay were similar to those reported previously. At 6 weeks, major adverse cardiac and cerebrovascular events had occurred in 5% of patients (four repeat target lesion revascularisation and one reinfarction). By 6 months, repeat target lesion revascularisation had been performed in an additional 10% of patients. No deaths had occurred. Conclusions: A primary stenting strategy can be performed safely, without significant delays and with excellent short and intermediate term outcomes. Introduction Early patency of the infarct-related artery after acute myocardial infarction (AMI) (defined as patency 90 minutes after the start of fibrinolytic therapy) improves early and late survival.1-3 With fibrinolytic therapy, the key treatment of AMI for the past 12 years,4,5 at best only about half the patients treated achieve early patency, the proportion varying with the fibrinolytic agent used (29% with streptokinase and 54% with tissue plasminogen activator [t-PA]).1 Moreover, in up to 30% of patients the artery reoccludes within 3 months.6 Prospective randomised trials of primary percutaneous transluminal coronary angioplasty (PTCA) have shown improved early patency and short-term clinical outcomes in comparison with fibrinolytic therapy.7-10 However, the benefits of primary PTCA are attenuated, as reocclusion occurs in 5%-10% of patients, reinfarction in 3%-5%, angiographic restenosis in 35%-45%, and recurrent ischaemia requiring repeat target lesion revascularisation in about 20% of patients.7-13Primary stenting in selected patients with AMI appears to be more effective than PTCA or fibrinolytic therapy,2,3,6-18 but not all infarct-related arteries are suitable for stenting. A primary stenting strategy incorporating primary stenting, PTCA, coronary artery bypass grafting (CABG) or medical treatment (except fibrinolytic therapy) is expected to cater for all patients. We examined prospectively the feasibility and clinical outcomes to 6 months of a primary stenting strategy in patients with AMI who were eligible for fibrinolysis. Methods During the period July 1997 to November 1998, we studied prospectively 194 consecutive patients who presented with AMI to the emergency department at Royal North Shore Hospital. Patients with contraindications to heparin, aspirin, ticlopidine or fibrinolytic therapy, and those with established cardiogenic shock, were not eligible for the study. Patient selection Patients included: 102 patients fulfilled GUSTO criteria for AMI,5 and were eligible for fibrinolysis. A lower age limit was imposed during the first half of the study (during the learning curve for the stenting team), and patients with previous CABG were excluded because stenting was initially thought to be less effective in vein-graft occlusion. Accordingly, the first 50 patients were under 70 years and had not had CABG. The following 52 patients, two of whom had had CABG, were under 80 years. Patients excluded: Reasons for non-entry to the study in 92 patients were age limit exceeded (over 70 years, 47 patients; over 80 years, 23 patients); transfer from other hospitals for primary intervention (5 patients); not eligible for fibrinolysis, including two with cardiogenic shock (8 patients); no vascular access (2 patients); prior CABG (2 patients); cardiogenic shock (1 patient); eligible but refused (2 patients); and eligible but interventional cardiologist unavailable (2 patients). Ethical approval The protocol was approved by the hospital's Human Research and Ethics Committee. All patients gave informed consent. Study protocol Patients were given aspirin (300 mg), ticlopidine (500 mg) and an intravenous heparin bolus (150 U/kg), and transferred immediately to the catheterisation laboratory, or, out of working hours, as soon as the interventional team arrived. Low-osmolar ionic contrast medium (sodium ioxaglate) was used to minimise thromboembolic complications.19 Blood flow was re-established in the occluded infarct-related arteries with Magnum (Schneider, Bulach, Switzerland) 0.014 inch wire through a 6 French (2 mm diameter) guide. Placement of a stainless steel stent (the majority were GFX (Arterial Vascular Engineering, Santa Rosa, Calif, USA) by high pressure balloon inflation (> 10 atmospheres) was attempted in vessels with a reference segment diameter of more than 2.5 mm and a lesion length of less than 32 mm. Thrombus was not considered a contraindication to stenting. Fibrinolytic therapy was not given. Medical treatment only was given (aspirin, heparin, β-blockers) if, after cardiac catheterisation, the infarct-related artery was patent with normal brisk flow (ie, grade 3 flow as defined by the Thrombolysis in Myocardial Infarction [TIMI] trial20), and had residual stenosis of less than 50% of vessel diameter. Emergency (immediate) or inhospital CABG was performed for left main coronary artery and/or severe triple-vessel disease, and PTCA was performed when the diameter of the infarct-related artery was less than 2.5 mm. A glycoprotein IIb/IIIa receptor antagonist (abciximab) was given to 23 of the 102 patients: 11 patients having primary PTCA, 3 patients in whom reflow did not occur, and 9 patients with persistent filling defects or a long stented segment (> 18 mm). Further heparin was given if activated clotting time (for monitoring high dose heparin) was under 300 seconds. No further heparin was given after the procedure and patients were mobilised 12 hours after femoral sheath removal. Ticlopidine (250 mg daily) was administered for 4 weeks and patients were monitored for side effects (neutropenia, thrombocytopenia). All patients were followed up by their general practitioner and specialist physician. Follow-up for the trial was at 6 weeks and 6 months; patients completed questionnaires or, if necessary, were interviewed by phone. Outcome measures Study outcome measures were major adverse cardiac and cerebrovascular events: death, reinfarction, cerebrovascular accident (CVA) and repeat target lesion revascularisation, in hospital, and at 6 weeks and 6 months. Reinfarction was defined as recurrent ischaemic symptoms with changes noted on the electrocardiogram (ECG) (ST-segment elevation or new Q waves) and elevation in the level of creatine kinase (MB fraction) to more than twice the upper limit (normal range, 0-7 µg/L) or any rise above a previously elevated level. CVA was defined as new persistent (> 24 hours) neurological deficit consistent with a stroke, confirmed by a physician or by computed tomography scan of the brain. Patency of the infarct-related artery was determined by TIMI classification.20 Minor inhospital adverse events included bleeding requiring blood transfusion, vascular complications and new-onset heart failure. Successful procedural outcome was a patent infarct-related artery with residual stenosis of less than 30% of vessel diameter (without major adverse cardiac and cerebrovascular events in hospital), or uncomplicated CABG. Results The baseline clinical characteristics of the 102 consecutive eligible patients with AMI are shown in Box 1, and their treatment and outcome in hospital are shown in the Figure. Overall, TIMI 3 flow in the infarct-related artery was restored in 97/102 (95%) patients within a mean of 64 minutes (range, 30-130 minutes) of notifying the interventional team. There were no inhospital deaths, reinfarctions or CVAs. Four patients (4%) required repeat target lesion revascularisation (three had been treated initially with PTCA and one with stenting). Unscheduled recatheterisation was performed in another four patients with chest pain, without ECG changes. All showed a widely patent stent. No patient developed recurrent chest pain with ECG changes while in hospital. Minor inhospital events included blood transfusion, all after CABG (7/102; 7%), new-onset heart failure (2/102; 2%), and femoral artery pseudoaneurysm requiring surgical repair (2/102; 2%). For more information see flow chart Six-week and 6-month follow-up Follow-up was completed for all patients due for follow-up at 6 weeks (n = 102) and at 6 months (n = 58). At 6 weeks no deaths or CVAs had occurred. One patient had had a reinfarction after a subacute stent thrombosis on Day 10. He underwent successful repeat PTCA (reperfusion at sites other than the target lesion was not performed). Major adverse cardiac or cerebrovascular events had occurred in 5/102 patients: one had a reinfarction after discharge and four required repeat target lesion reperfusion. At 6 months, still no deaths had occurred, and there had been no further reinfarctions or CVAs. Clinical restenosis requiring repeat target lesion revascularisation occurred in an additional 6/58 patients (10%). Revascularisation at a new site of stenosis was performed in 1/58 patients (2%). No deaths, reinfarctions or CVAs had occurred since discharge, and at 6 months there had not been any requirement for revascularisation in 51/58 patients (88%). Hospital stay Mean hospital stay was 5.0 days (95% confidence interval (CI), 4.5-5.5 days). Mean coronary care, intensive care and general ward stays were 1.5 (95% CI, 1.4-1.6), 0.5 (95% CI, 0.3-0.7) and 3.0 days (95% CI, 2.7-3.3), respectively. Median hospital stay was 3 days. Time delays Time delays between the onset of chest pain and re-establishment of TIMI 3 flow of the infarct-related artery are shown in Box 2. Although 58% of patients presented out of working hours, only 10% of "call-backs" for the intervention team took place between 23:00 and 04:00. Discussion We examined the feasibility and clinical outcomes to 6 months of a primary stenting strategy. Expected advantages of such an approach, compared with fibrinolytic therapy, are greater patency of the infarct-related artery with improved outcome, early recognition of high risk patients for surgical revascularisation and low risk patients for early discharge, reduced rate of CVA, and lower acute complication rate and need for reperfusion of the target lesion compared with primary PTCA.14 Our results support these expectations. Coronary artery patency with the primary stenting strategy was achieved in 95% of patients, similar to reports for primary stenting in selected patients,14-18 but higher than reported for primary PTCA (73%-87%) and fibrinolysis with t-PA (54%).1,3,7-9 Interestingly, 25% of patients in our study had TIMI 3 flow at cardiac catheterisation, a rate higher than reported by some investigators (7%-11%)14 and similar to rates after fibrinolysis with streptokinase (29%-32%). We gave a 150 U/kg bolus dose of intravenous heparin, which may explain this difference.21 Our results compare favourably with those of other primary stenting studies.14-18 A 30-day rate of 3% for major adverse cardiac and cerebrovascular events has been reported for patients undergoing primary stenting.14,15 However, in one of these studies,14 up to 15% of patients screened were excluded, owing to unsuitable anatomy of the infarct-related artery (eg, diffuse disease), and events in such patients were not included. Several studies report outcomes of patients treated by primary PTCA separately to those treated by stenting,14-18 making it difficult to directly compare the results with those of trials of fibrinolytic therapy in which all patients are included. We included all patients eligible for fibrinolysis who fulfilled the inclusion criteria in our analysis. This allows a more realistic impression of the benefits of a primary stenting strategy, as our data can be compared with data from trials of fibrinolytic therapy (the alternative treatment offered to all patients at enrolment). Feasibility In order to test the feasibility of a primary stenting strategy (our main aim), our emergency department had to triage patients without delay and the interventional team had to respond swiftly at all hours. Time delays (mean and median) from arrival at the emergency department to notification of the interventional team (42 and 35 minutes), from notification of the team to TIMI 3 flow (64 and 60 minutes), and from arrival at the emergency department to TIMI 3 flow (106 and 95 minutes), compare well with time delays from trials of fibrinolysis and angioplasty. The GUSTO investigators reported a median interval of 64 minutes from randomisation to administration of fibrinolytic therapy,5 and the GUSTO IIb investigators reported a median interval of 114 minutes from emergency department arrival to first balloon inflation in the primary PTCA group.10 Patency rates are reported 90 minutes after starting fibrinolytic therapy.1 Assuming a mean delay of 42 minutes in the emergency department to administration of fibrinolytic therapy, the equivalent inhospital delay from emergency department arrival to TIMI 3 flow with fibrinolytic therapy would be a mean of 132 minutes (but TIMI 3 flow would actually be achieved in only 54% of patients). We achieved TIMI 3 flow in 95% of patients within a mean of 106 minutes of arrival at the emergency department. Limitations of the study This study was a non-randomised, single-centre study with a small sample size. For the first half of the study, enrolment was restricted to a relatively low risk group under 70 years of age without previous CABG. Interventions were performed by two experienced operators. Thus, comparison of our data with results from much larger trials of fibrinolytic therapy must be performed with caution. Conclusions A primary stenting strategy is feasible and safe, with an excellent clinical outcome to 6 months. We are now planning a larger, randomised phase of this study, with patients from the Northern Sydney Area Health Region (which includes four district hospitals) outside the Royal North Shore Hospital (RNSH) catchment area being allocated at random to either conventional treatment with fibrinolytic therapy at the district hospital or a primary stenting strategy at RNSH. We hypothesise that mechanical reperfusion therapy will prove the superior strategy because of its higher early patency rate3 and offset any disadvantages of the small time difference imposed by a longer ambulance journey. Acknowledgements This study was supported by the North Shore Heart Research Foundation (NSHRF). GFX (AVE) stents and Magnum (Schneider) guide wires were donated. Dr P S Hansen received a Cordis-Johnson & Johnson Interventional Fellowship (1997) and a NSHRF Fellowship (1998). The study would not have been possible without the unselfish support from radiographers, technicians and nursing staff of the Royal North Shore Hospital cardiac catheterisation laboratories as well as all staff involved from the Cardiology, Emergency and Cardiothoracic departments. References The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993; 329: 1615-1622. Califf RM, White H, Van de Werf F, et al. One-year results from the global utilization of streptokinase and TPA for occluded coronary arteries (GUSTO-I) trial. Circulation 1996; 94: 1233-1238. Ross AM, Coyne KS, Moreyra E, et al, for the GUSTO-I Angiographic Investigators. Extended mortality benefit of early postinfarction reperfusion. Circulation 1998; 97: 1549-1556. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomized trials of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2: 349-360. The GUSTO investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329: 673-682. Meijer A, Verheugt FWA, Werter CJPJ, et al. Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Circulation 1993; 87: 1524-1530. Grines CL, Browne KF, Marco J, et al. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. N Engl J Med 1993; 328: 673-679. Zijlstra F, de Boer JM, Hoorntje JC, et al. A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. N Engl J Med 1993; 328: 680-684. Gibbons RJ, Holmes DR, Reeder GS, et al. Immediate angioplasty compared with the administration of a thrombolytic agent followed by conservative treatment for myocardial infarction. N Engl J Med 1993; 328: 685-691. The GUSTO-IIb angioplasty substudy investigators. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction. N Engl J Med 1997; 336: 1621-1628. Stone GW, Grines CL, Browne KF, et al. Predictors of in-hospital and 6 month outcome after acute myocardial infarction in the reperfusion era: the Primary Angioplasty in Myocardial Infarction (PAMI) trial. J Am Coll Cardiol 1995; 25: 370-377. Ohman EM, Califf RM, Topol EJ, et al. Consequences of reocclusion after successful reperfusion therapy in acute myocardial infarction. Circulation 1990; 82: 781-791. Weaver WD, Simes J, Amadeo B, et al. Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction. A quantitative review. JAMA 1997; 278: 2093-2098. Stone GW, Brodie B, Griffin J, et al. Prospective, multicentre study of the safety and feasibility of primary stenting in acute myocardial infarction: In-hospital and 30-day results of the PAMI Stent Pilot Trial. J Am Coll Cardiol 1998; 31: 23-30. Suryapranata H, van't Hof AWJ, Hoorntje JCA, et al. Randomized comparison of coronary stenting with balloon angioplasty in selected patients with acute myocardial infarction. Circulation 1998; 97: 2502-2505. Antoniucci D, Santoro GM, Bolognese L, et al. A clinical trial comparing primary stenting of the infarct-related artery with optimal primary angioplasty for acute myocardial infarction. Results from the Florence Randomized Elective Stenting in Acute Coronary Occlusions (FRESCO) Trial. J Am Coll Cardiol 1998; 31: 1234-1239. Saito S, Hosokawa G. Primary Palmaz-Schatz stent implantation for acute myocardial infarction: the final results of Japanese PASTA (Primary Angioplasty vs Stent Implantation in AMI in Japan) trial [abstract]. Circulation 1997; 96: A3320. Serruys PW, Garcia-Fernandez E, Kiemeney F, et al. Stenting in acute MI: A pilot study as preamble to a randomized trial comparing balloon angioplasty and stenting [abstract]. Circulation 1997; 96: A1822. Grines CL, Schreiber TL, Savas V, et al. A randomized trial of low osmolar ionic versus nonionic contrast media in patients with myocardial infarction or unstable angina undergoing percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1996; 27: 1381-1386. The TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) Trial: Phase 1 findings. N Engl J Med 1985; 312: 1073-1092. Verheugt FWA, Liem A, Zijlstra F, et al. High dose bolus heparin as initial therapy before primary angioplasty for acute myocardial infarction: results of the heparin in early patency (HEAP) pilot study. J Am Coll Cardiol 1998; 31: 289-293. (Received 3 Jul 1998, accepted 15 Feb 1999) Authors' details Department of Cardiology, Royal North Shore Hospital, Sydney, NSW. Peter S Hansen, FRACP, Interventional Fellow. Helge H Rasmussen, DMSc, FRACP, Professor of Cardiology. John Vinen, FACEM, Director, Emergency Department. Gregory I C Nelson, FRACP, Director, Cardiac Catheterisation Laboratory and Coronary Care Unit. Reprints: Dr G I C Nelson, Department of Cardiology, Royal North Shore Hospital, St Leonards, NSW 2065. Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> 1: Baseline clinical and angiographic characteristics of the study population (n = 102)Age in years, median (range) 60 (35-79)Women18 (18%)Hypertension (< 160/190 mmHg) 46 (45%)Diabetes mellitus13 (13%)Current cigarette smoking28 (27%)Hypercholesterolaemia (< 5.5 mmol/L)62 (61%)Family history of IHD47 (46%)Prior AMI14 (14%)Prior PTCA2 (2%)Prior CVA or transient ischaemic attack7 (7%)Infarct-related artery: Left anterior descending artery (40), diagonal branch of left anterior descending artery (1), left main coronary artery (1) 42 (41%) Right coronary artery40 (39%) Left circumflex artery (12), obtuse marginal artery (2)14 (14%) Saphenous vein graft2 (2%)No infarct-related artery identified (3), normal coronary arteries (1) 4 (4%)Multivessel disease48 (47%)Admission Killip class < I6 (6%)Killip class > I = the presence of either lung crepitations and a third heart sound gallop, frank pulmonary oedema or cardiogenic shock. PTCA = percutaneous transluminal coronary angioplasty. CVA = cerebrovascular accident. IHD = ischaemic heart disease. AMI = acute myocardial infarction. Back to textBack to textBack to text

Peter S Hansen · Helge H Rasmussen · John Vinen

Clinical Update Androgen treatment in women Susan R Davis MJA 1999; 170: 545-549 Many women, both before and after menopause, may have symptoms of androgen deficiency: unexplained fatigue, lack of well-being and diminished libido. If plasma levels of bioavailable testosterone are low, these symptoms will mostly be relieved by judicious administration of testosterone. The addition of testosterone to postmenopausal hormone replacement regimens is becoming more widespread, and other potential uses include prevention and treatment of bone loss, treatment of spontaneous or iatrogenic androgen deficiency in premenopausal women, and, possibly, management of the premenstrual syndrome. Introduction - Physiological effects - Androgen deficiency - Measurement of - Clinical indications - Administering testosterone - Conclusions - References - Authors' details - - Articles on similar material Introduction No longer can it be said that androgens make boys as boys, and oestrogens, girls as girls. It is now known that high levels of oestrogen in the male brain in early life are necessary for male sexual imprinting,1 and that oestrogen has a fundamental role in spermatogenesis2 and maintenance of bone mineralisation in men.3 The reverse also applies. Androgens have important and varied physiological actions in women. Physiological effects of androgens in women During the reproductive years androgens are produced by the adrenal glands and the ovaries (Figure). Androgens act directly via the androgen receptor in tissues, such as bone, skin fibroblasts, hair follicles and sebaceous glands,4 and also have a vital role as the precursor steroids for oestrogen biosynthesis in the ovaries and extragonadal sites, including bone, brain, cardiovascular and adipose tissues. Hence, maintenance of physiological circulating androgen levels is important for an adequate supply of substrate hormone for oestrogen production at these sites. The physiological significance of this is best exemplified by osteoporosis in men, with a mutation in the aromatase enzyme gene which affects the conversion of androgens to oestrogens; oestrogen replacement increases bone mineral density.3It seems well established that testosterone is an important determinant of female sexuality,5-9 and that it has a physiological role in the development and maintenance of bone mineralisation.10,11 Other aspects of testosterone action in women currently being investigated include variations in testosterone level during the menstrual cycle and the behavioural changes in the premenstrual syndrome,12 as well as the effect of androgens on the immune response and autoimmune diseases.13,14 Androgen deficiency in women The prevalence of "androgen deficiency" in women has never been systematically evaluated, and there is no consensus clinical definition of this condition in women. Furthermore, a biochemical definition of androgen deficiency has been hampered by the insensitivity of most testosterone assays at the lower end of the normal range in women in their reproductive years. Women most likely to respond to androgen therapy have the following features: low libido, blunted motivation, fatigue and lack of well-being, associated with normal plasma oestrogen levels and low levels of bioavailable testosterone. Symptoms of "androgen deficiency" are often attributed to psychosocial and environmental factors, and many affected women, unaware that their problems may have a biological basis and apprehensive about the response such problems will elicit, often do not report them. Moreover, the basis of each of the symptoms listed above is likely to be multifactorial, making it important for treating physicians to evaluate and deal with other factors before considering androgen replacement. In general, the concept of androgen deficiency has been most widely accepted for women who have had bilateral oophorectomy. However, women who have undergone a natural menopause not infrequently experience "androgen deficiency" symptoms, as do a subset of women in their late reproductive years. Young women who have suffered either primary or secondary ovarian failure may also experience low libido in association with low blood androgen levels. A general approach to evaluating women with symptoms suggestive of androgen deficiency, as well as the possible causes of androgen deficiency, are outlined in Boxes 1 and 2, respectively. Measurement of androgen level Before commencing testosterone therapy in any woman, levels of testosterone and sex hormone binding globulin (SHBG), and the free androgen index (calculated to adjust for variations in SHBG), should be evaluated. Low bioavailability of testosterone is indicated by either a low ratio of levels of total testosterone to SHBG, or a free testosterone level in the lower third of the normal range in women in their reproductive years. A diagnosis of symptomatic androgen deficiency would be highly questionable with a total testosterone level in the upper third of the normal reproductive age range and a normal free androgen index. However, it is not uncommon for a midrange level of testosterone to be associated with androgen deficiency because of a very high SHBG level secondary to exogenous oestrogen replacement in postmenopausal women. Although DHEA-S and androstenedione are important precursors of testosterone, their measurement does not aid in diagnosis. Clinical indications for androgen therapy in women Sexual dysfunction There are multiple influences on libido and frequency and enjoyment of sexual activity in women. However, androgens appear to be important determinants of female sexuality and low circulating levels are associated with diminished libido. The relationship between androgens and the female sexual response has been reviewed recently.22 Bilateral oophorectomy: Anecdotal accounts suggest that the women most likely to respond to testosterone are those who have undergone bilateral oophorectomy. Premature menopause: Testosterone replacement should also be considered part of the management of young women with premature menopause, particularly those with Turner's syndrome (45,XO). In general, women who undergo menopause in their reproductive prime suffer considerably from symptoms related to androgen deficiency, particularly diminished libido. Alternatively, young women with premature menopause who have not previously been sexually active should be made fully aware of the availability of androgen replacement and, in some instances, offered low dose androgen therapy as part of their hormone replacement. Premenopausal women: It is not uncommon for premenopausal women to complain of diminished libido, and, when other potential influences on sexual dysfunction can be excluded and they have low levels of bioavailable testosterone, androgen replacement therapy is likely to be beneficial. Postmenopausal women: Most women do not report loss of sexual desire after spontaneous menopause, but there is generally an age-related reduction in sexual frequency associated with the menopausal transition.23 In a study of sexagenarian women, the only hormone to positively correlate with sexual desire was circulating free testosterone.9 Although oestrogen replacement improves vasomotor symptoms, such as vaginal dryness and possibly general well-being, it has little effect on libido.24 In contrast, the addition of testosterone to a hormone replacement regimen results in improvement in several aspects of sexuality in postmenopausal women.5-7,25 As a general rule, testosterone replacement should not be administered to postmenopausal women who are not taking concurrent oestrogen replacement. Oestrogen alone may relieve other postmenopausal symptoms, alleviate vaginal dryness and enhance sexuality, obviating the need for androgen therapy. Furthermore, suppression of SHBG with testosterone alone may increase the possibility of adverse side effects. The only exception to this rule is the use of nandrolone decanoate (see below) in postmenopausal women for the prevention of osteoporosis. Prevention and treatment of bone loss In premenopausal women: Bone loss (particularly in the hip) is associated with low total and free testosterone levels.11 Increased circulating androgen levels are associated with higher bone mineral densities.26 In postmenopausal women: Low circulating free testosterone is predictive of subsequent height loss (a surrogate marker of vertebral compression fracture), and hip fracture.27,28 Treatment with either oral or parenteral oestrogen-plus-testosterone therapy results in beneficial effects on bone mineral density over and above those seen with oestrogen alone.22,29 Oral esterified oestrogen with methyltestosterone not only increases spinal bone mineral density but also suppresses biochemical markers of bone resorption, with an increase in markers of bone formation over two years.30 Circulating levels of DHEA and DHEA-S are positively correlated with bone mineral density in older women.31,32 The daily application of a 10% DHEA cream resulted in an increase in bone mineral density of the hip in older women.33As yet, no studies have addressed the impact of androgen therapy on fracture incidence, although the effects of androgens on the mechanical properties of bone have been studied in female cynomolgus monkeys:34 testosterone therapy resulted in increases in intrinsic bone strength and resistance to mechanical stress, as well as increases in bone mineral density, bone torsional rigidity and bending stiffness.34 Potential and more controversial uses for androgen therapy are described in Box 3. Administering testosterone to women Availability: Testosterone has been available as oral methyltestosterone on prescription in North America for many years, and testosterone implants were approved for replacement therapy in postmenopausal women in the United Kingdom in the early 1990s. These and all other available testosterone preparations have primarily been formulated for use in men. Currently, the use of testosterone for hormone therapy in women is not approved in Australia. Despite the lack of approval, specialist menopause clinics in Australia have had more than a decade of experience of testosterone use in menopausal women, and hence management advice based on clinical experience is available. Nandrolone decanoate: Nandrolone decanoate (Deca-Durabolin, Organon) is a very weak aromatisable androgen, available in Australia on authority for treating postmenopausal osteoporosis, and administered intramuscularly. The dose should not exceed 50 mg, with the frequency of administration being titrated against the patient's build (ie, it is recommended that it is given 6 weekly, but 8-12 weekly in women with a body mass index lower than 20 kg/m2, otherwise virilising effects such as hirsutism and voice deepening are not uncommon). This drug will result in cessation of bone loss in most older postmenopausal women and, in some women, in an absolute increase in bone mineral density. When given 6-8 weekly this therapy does not usually improve libido. Testosterone implants: Women experiencing diminished libido are usually treated with testosterone implants and, less commonly, with mixed testosterone esters. Subcutaneous testosterone pellet implants (fused crystalline implants 4.5 mm in diameter) are the most common form of androgen therapy in women in Australia. The implant is usually inserted subcutaneously in the lower anterior abdominal wall under local anaesthesia using a trochar and cannula. A dose of 50 mg, obtained from a 100 mg implant, is extremely effective in enhancing libido and improving bone mineral density without generating unwanted virilising side effects.7,22 It is usually effective for between three and six months, but, because of marked individual variation, testosterone levels should be measured before each subsequent implant is inserted. Rarely are testosterone implants of 100 mg necessary to achieve adequate clinical effects. Indeed, circulating testosterone levels about three times the upper limit of normal have been reported four weeks after insertion of a 100 mg testosterone pellet,40 and six weeks after insertion of a 50 mg implant mean circulating testosterone levels were just above the upper limit of normal for ovulating women.22 A 100 mg dose may be needed in young women with premature ovarian failure or after early oophorectomy. Mixed testosterone esters: Although there are no published studies to support their use in women, mixed testosterone esters 50-100 mg (Sustanon, Organon) are occasionally administered 4-6 weekly as an intramuscular injection to women with androgen-deficiency symptoms. Anecodotally, this therapy results in a much more rapid onset of effects; women report enhanced libido after 2-3 days of treatment, compared with after 7-10 days with testosterone implants. The pharmocokinetics of mixed testosterone esters in women have not been studied, but women more commonly report an increase in acne and other virilising effects due to apparent peaks in testosterone levels after injection. Transdermal testosterone matrix patch: A transdermal testosterone matrix patch intended specifically for use in women has been developed and is currently undergoing early clinical trials. The patch is designed to deliver 150 µg of testosterone per day with twice-weekly application, resulting in an average increase in circulating testosterone levels of about 1 nmol/L. For more information see Box 4 Adverse effects Clinical experience suggests that, to achieve a good response in terms of libido, the testosterone level often needs to be restored to at least the upper end of the normal physiological range in young ovulating women. However, the dose needs to be titrated to keep circulating testosterone close to physiological levels to avoid adverse masculinising effects. Side effects of testosterone in women are rare when the hormone is appropriately administered. However, with excessive dosage, virilisation and fluid retention may occur. Potentially adverse lipoprotein-lipid effects (eg, reductions in high density lipoprotein cholesterol and apolipoprotein A1 levels) may occur with excessive oral administration, but have not been reported with parenteral therapy.22 Clinical data to hand do not indicate that testosterone therapy, with testosterone levels kept close to and within the normal physiological range for women, has any undesirable metabolic consequences.22,41 It is not known whether there is any relationship between exogenous androgen therapy and the incidence of breast cancer, as epidemiological studies have shown both positive and negative associations between endogenous androgen levels and risk of breast cancer. Androgen receptors are found in over 50% of breast tumours,42 and are associated with longer survival in women with operable breast cancer and a favourable response to hormone treatment in advanced disease.43 There are also some data to suggest that the therapeutic effect of high dose medroxyprogesterone acetate on breast cancer is mediated via the androgen receptor.44 Contraindications Pregnancy and lactation, as well as known or suspected androgen-dependent neoplasia, are absolute contraindications to testosterone therapy. Relative contraindications include moderate to severe acne, hirsutism, androgenic alopecia and any circumstance in which enhancement of libido would be undesirable. It is now recognised that the treatment of the postmenopausal woman with testosterone replacement may result in an ethical dilemma if the woman is a participant in older-age competitive sport. This is a controversial issue that is yet to be resolved. Conclusions Women reporting loss of libido may find physicians insufficiently empathetic, and a biological cause for sexual dysfunction in women is rarely sought. However, it is gradually becoming more accepted that androgen deficiency in women may underpin a variety of symptoms and pathophysiological conditions and that, in selected women, androgen replacement therapy is of clinical benefit. References Honda S, Harada N, Ito S, et al. Disruption of sexual behavior in male aromatase-deficient mice lacking exons 1 and 2 of the cyp19 gene. Biochem Biophys Res Commun 1998; 252: 445-449. Sharpe RM. Do males rely on female hormones? Nature 1998; 390: 447-448. Morishima A, Grumbach MM, Simpson ER. Aromatase deficiency in male and female siblings caused by a novel mutuation and the physiological role of estrogens. J Clin Endocrinol Metab 1995; 80: 3689-3698. Colvard DS, Eriksen EF, Keeting PE. Identification of androgen receptors in normal human osteoblast-like cells. Proc Natl Acad Sci USA 1989; 86: 854-857. Studd JWW, Colins WP, Chakravarti S. Estradiol and testosterone implants in the treatment of psychosexual problems in postmenopausal women. Br J Obstet Gynaecol 1977; 84: 314-315. Burger HG, Hailes J, Menelaus M. The management of persistent symptoms with estradiol-testosterone implants: clinical, lipid and hormonal results. Maturitas 1984; 6: 351-358. Burger HG, Hailes J, Nelson J, Menelaus M. Effect of combined implants of estradiol and testosterone on libido in postmenopausal women. BMJ 1987; 294: 936-937. Hickok LR, Toomey C, Speroff L. A comparison of esterified estrogens with and without methyltestosterone: effects on endometrial histology and serum lipoproteins in postmenopausal women. Obstet Gynecol 1993; 82: 919-924. Bachmann GA, Leiblum SR. Sexuality in sexagenarian women. Maturitas 1991; 13: 45-50. Nilas L, Christiansen C. Bone mass and its relationship to age and the menopause. J Clin Endocrinol Metab 1987; 65: 697-699. Slemenda C, Longcope C, Peacock M, et al. Sex steroids, bone mass, and bone loss. A prospective study of pre-, peri- and postmenopausal women. J Clin Invest 1996; 97: 14-21. Rubinow DR, Roy-Byrne P. Premenstrual syndromes: overview from a methodological perspective. Am J Psychiatry 1984; 141: 163-172. Booij A, Biewenga-Booij CM, Huber-Bruning O, et al. Androgens as adjuvant treatment in postmenopausal female patients with rheumatoid arthritis. Ann Rheum Dis 1996; 55: 811-886. Cutolo M, Seriolo B, Sulli A, Accardo S. Androgens in rheumatoid arthritis. In: Bijlsma JWJ, Linden S van der Barnes CG, editors. Rheumatology highlights 1995. Rheumatol Eur 1995; 24: 211-214. Zumoff B, Strain GW, Miller LK, Rosner W. Twenty-four hour mean plasma testosterone concentration declines with age in normal premenopausal women. J Clin Endocrinol Metab 1995; 80: 1429-1430. Zumoff B, Rosenfeld RS, Strain GW. Sex differences in the 24 hour mean plasma concentrations of dehydroisoandrosterone (DHA) and dehydroisoandrosterone sulfate (DHAS) and the DHA to DHAS ratio in normal adults. J Clin Endocrinol Metab 1980; 51: 330-334. Mushayandebvu T, Castracane DV, Gimpel T, et al. Evidence for diminished midcycle ovarian androgen production in older reproductive aged women. Fertil Steril 1996; 65: 721-723. Mathur RS, Landgreve SC, Moody LO, et al. The effect of estrogen treatment on plasma concentrations of steroid hormones, gonadotropins, prolactin and sex hormone-binding globulin in post-menopausal women. Maturitas 1985; 7: 129-133. Krug R, Psych D, Pietrowsky R, et al. Selective influence of menstrual cycle on perception of stimuli with reproductive significance. Psychosom Med 1994; 56: 410-417. Abraham GE. Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle. J Clin Endocrinol Metab 1974; 39: 340-346. Anasti JN, Kalankaridou SN, Kimzey LM, et al. Bone loss in young women with karyotypically normal spontaneous premature ovarian failure. Obstet Gynecol 1998; 91: 12-15. Davis SR, McCloud PI, Strauss BJG, Burger HG. Testosterone enhances estradiol's effects on postmenopausal bone density and sexuality. Maturitas 1995; 21: 227-236. Frock J, Money J. Sexuality and the menopause. Psychother Psychosom 1992; 57: 29-33. Campbell S, Whitehead M. Oestrogen therapy and the menopausal syndrome. Clin Obstet Gynecol 1977; 4: 31-47. Sherwin BN, Gelfand MM, Brender W. Androgen enhances sexual motivation in females: a prespective, crossover study of sex steroid administration in surgical menopause. Psychosom Med 1997; 47: 339-351. Simberg N, Titinen A, Silfrast A, et al. High bone density in hyperandrogenic women: effect of gonadotropin-releasing hormone agonist alone or in conjunction with estrogen-progestin replacement. J Clin Endocrinol Metab 1995; 81: 646-651. Jassal SK, Barrett-Connor E, Edelstein S. Low bioavailable testosterone levels predict future height loss in postmenopausal women. J Bone Miner Res 1995; 10: 650-653. Davidson BJ, Ross RK, Paganni Hill A, et al. Total free estrogens and androgens in postmenopausal women with hip fractures. J Clin Endocrinol Metab 1982; 54: 115-120. Watts NB, Notelovitz M, Timmons MC. Comparison of oral estrogens and estrogens plus androgen on bone mineral density, menopausal symptoms and lipid-lipoprotein profiles in surgical menopause. Obstet Gynecol 1995; 85: 529-537. Raisz LG, Witta B, Artis A, et al. Comparison of the effects of estrogen alone and estrogen plus androgen on biochemical markers of bone formation and resorption in postmenopausal women. J Clin Endocrinol Metab 1995; 81: 37-43. Nawata H, Tariaka S. Aromatase in bone cell: association with osteoporosis in postmenopausal women. J Steroid Biochem Molec Biol 1995; 53: 165-174. Nordin BEC, Robertson A, Seamark RF, et al. The relation between calcium absorption serum DHEA and vertebral mineral density in postmenopausal women. J Clin Endocrinol Metab 1985; 60: 651-657. Labrie F, Diamond P, Cusan L, et al. Effect of 12-month dehydroepiandrosterone replacement therapy on bone, vagina and endometrium in postmenopausal women. J Clin Endocrinol Metab 1997; 82: 3498-3505. Kasra M, Grynpas MD. The effects of androgens on the mechanical properties of primate bone. Bone 1995; 17: 265-270. Engelson ES, Goggin KJ, Rabkin JG, Kotler DP. Nutrition and testosterone status of HIV positive women [Abstract]. Proceedings of the XI International Conference on AIDS, Vancouver, 1996. Miller K, Corcoran C, Armstrong C, et al. Transdermal testosterone administration in women with acquired immunodeficiency syndrome wasting: a pilot study. J Clin Endocrinol Metab 1998; 83: 2717-2725. Bloch M, Schmidt PJ, Su T-P, et al. Pituitary-adrenal hormones and testosterone across the menstrual cycle in women with premenstrual syndrome and controls. Biol Psychiatry 1998; 43: 897-903. Masi AT, Feigenbaum SL, Chatterton RT. Hormonal and pregnancy relationships to rheumatoid arthritis: convergent effects with immunological and microvascular systems. Semin Arthritis Rheum 1995; 25: 1-27. van Vollenhoven RF, Morabito LM, Engleman EG, McGuire JL. Treatment of systemic lupus erythematosus with dehydroepiandrosterone: 50 patients treated up to 12 months. J Reheumatol 1998; 25: 285-289. Buckler HM, Robertson WR, Wu FCW. Which androgen replacement therapy for women? J Clin Endocrinol Metab 1998; 83: 3920-3924. Davis SR, Burger HG. The rationale for physiological testosterone replacement in women. Baillieres Clin Endocrinol Metab 1998. In press. Recchione C, Venturelli E, Manzari A, et al. Testosterone, dihydrotestosterone and oestradiol levels in postmenopausal breast cancer tissues. J Steroid Biochem Mol Biol 1995; 52: 541-546. Bryan RM, Mercer RJ, Rennie GC, et al. Androgen receptors in breast cancer. Cancer 1984; 54: 2436-2440. Birrell SN, Roder DM, Horsfall DJ, et al. Medroxyprogesterone acetate therapy in advanced breast cancer: the predictive value of androgen receptor expression. J Clin Oncol 1995; 13: 1572-1577. Authors' details The Jean Hailes Foundation Research Unit, Melbourne, VIC. Susan R Davis, FRACP, PhD, Director of Research; and Senior Lecturer Department of Preventive Medicine and Epidemiology, Monash Medical School, Alfred Hospital, Melbourne. Reprints will not be available from the author. Correspondence: Dr S R Davis, The Jean Hailes Foundation Research Unit, 173 Carinish Road, Clayton, VIC 3168. Email: suedavis@netlink.com.au ©MJA 1999 Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> © 1999 Medical Journal of Australia. Back to text 1: Evaluation of androgen deficiency in women Clinical suspicion of androgen deficiency Gradual loss of sexual desire in otherwise satisfying sexual relationship Persistent fatigue with no clear cause Premature ovarian failure Bilateral oophorectomy Exclusion of other causes of symptoms Full psychosocial history Assess adequacy of oestrogen therapy in postmenopausal women Exclude other causes of fatigue (eg, iron deficiency, hypothyroidism) Tests to establish androgen deficiency Total testosterone level Sex hormone binding globulin (SHBG) level Free androgen index Dehydroepiandrosterone-sulfate (DHEA-S) level Consider androgen therapy for women with: Symptomatic testosterone deficiency after natural menopause Symptomatic testosterone deficiency following oophorectomy, chemotherapy or radiotherapy Premature ovarian failure -- primary or secondary Premenopausal loss of libido with low level of bioavailable testosterone. Back to text 2: Causes of androgen deficiency in women Age-related Physiological circulating androgen levels (total and free testosterone, dehydroepiandrosterone [DHEA], and dehydroepiandrosterone-sulfate [DHEA-S]) fall continuously with age,15,16 commencing in the decade preceding the average age of natural menopause. This is a consequence of the concurrent decline with age in adrenal production of the preandrogens DHEA, DHEA-S and androstenedione, and diminished testosterone production by the ovaries.16,17 Iatrogenic Oophorectomy -- bilateral oophorectomy results in a 50% fall in testosterone and androstenedione. Chemical oophorectomy results from administration of gonadotropin-releasing hormone antagonists, chemotherapy or radiotherapy. Administration of exogenous oestrogen -- combined oral contraceptive pill or oral postmenopausal oestrogen therapy increases sex hormone binding globulin (SHBG) levels (thus reducing free testosterone), and suppresses pituitary luteinising hormone production (hence lessening stimulation of ovarian androgen biosynthesis).18,19Administration of exogenous glucocorticosteroids -- glucocorticosteroids reduce adrenal androgen production by suppressing ACTH.20 This appears to contribute to the pathogenesis of osteopenia and osteoporosis, the side effects of long term glucocorticosteroid therapy. Pathological Hypothalamic amenorrhoea or hyperprolactinaemia in premenopausal women. Premature primary or secondary ovarian failure. Bone loss complicates each of these conditions and appears to progress despite adequate oestrogen-progestin therapy.21 Young women with these conditions may also require testosterone replacement to prevent progressive bone resorption. Back to text 3: Potential indications for androgen use in women Postmenopausal loss of muscle mass: In postmenopausal women testosterone therapy is associated with an increase in fat-free mass and a reduction in the fat mass to fat-free mass ratio.22 As this gain in fat-free mass probably reflects increased muscle mass, and ageing is associated with loss of muscle mass, testosterone therapy is beneficial in older women. Management of wasting in HIV infection: Testosterone levels are lower in HIV-positive premenopausal women.35 Augmentation of testosterone levels with a transdermal testosterone patch is associated with increased mean body weight and body mass index as well as improved quality of life.36Testosterone and the premenstrual syndrome: Significantly lower levels of testosterone throughout the menstrual cycle have been reported in women who suffer premenstrual syndrome compared with controls.12,37 Testosterone is being used in selected patients with premenstrual syndrome in specialised centres in the United Kingdom and Australia, and randomised trials evaluating the effects are under way. Testosterone and autoimmune disease: Sex differences in the pattern of autoimmune disease are well recognised, and may be related to higher testosterone levels in men, with some studies indicating that androgens suppress both cell-mediated and humeral immune responses.14,38 Reports in postmenopausal women with rheumatoid arthritis indicate symptomatic improvement with testosterone replacement,13 and reductions in disease activity with DHEA therapy.39 However, apart from its use to counteract the side effects of long term glucocorticosteroid therapy (muscle wasting and bone loss) in autoimmune disease, much more substantial evidence is required before testosterone can be advocated as adjunctive therapy in autoimmune diseases. Back to text 4: Prescribing androgen replacementNandrolone decanoateApproved for use in postmenopausal women with osteoporosis, on authorityDose range:25-50 mgRoute:IntramuscularFrequency:6-12 weekly Testosterone implantsApproved for use in women in the UK, but not in AustraliaDose range:50 mg (rarely, 100 mg)Route:SubcutaneousFrequency:3-6 monthly Mixed testosterone estersNot approved for use in women. No published data pertaining to use in womenDose range:50-100 mgRoute:IntramuscularFrequency:4-6 weekly Testosterone undecanoateLimited data in women indicate high circulating peak levels. Not approved for use in womenDose range:40 mgRoute:OralFrequency:Alternate days/daily MethyltestosteroneIn combination with esterified oestrogen, approved for women in USADose range:1.25-2.5 mgRoute:TransdermalFrequency:Daily Transdermal testosterone matrix patchUndergoing clinical trialDose range:150 µgRoute:TransdermalFrequency:Changed twice weeklyBack to text

Susan R Davis