Connect
MJA
MJA

Transdermal progesterone creams for postmenopausal women: more hype than hope?

Barry G Wren
Med J Aust 2005; 182 (5): 237-239.
Published online: 7 March 2005

Abstract

  • Various claims have been made about the benefits of transdermal progesterone creams for relieving symptoms of menopause.

  • Peer-reviewed articles have reported that the creams can raise plasma progesterone levels slightly, but have no effect on vasomotor, psychosexual or mood symptoms, bone metabolism or plasma lipid levels.

  • Currently available progesterone creams can not be recommended for treatment of symptoms associated with menopause.

In July 2002, the Women’s Health Initiative Investigators1 published an article suggesting that the use of combined oestrogen and progestogen therapy was associated with an increased risk of morbidity. Consequently, many women sought alternative treatment to relieve menopausal symptoms. One alternative that was promoted was a transdermal cream containing bio-identical progesterone. Clinical information on the benefits and use of transdermal progesterone, without the addition of oestrogen, was based on reports mostly from the United States. The veracity of these reports was brought into question when it was revealed that these data had not been accepted for publication in peer-reviewed scientific journals. Studies involving transdermal progesterone that had been accepted by reputable journals were not generally supportive.

Here, I review the evolution of transdermal progesterone cream, the claims for its benefits and the outcomes of peer-reviewed studies.

Transdermal progesterone creams

Over the past 70 years, hormonal therapy for postmenopausal women has evolved from unopposed synthetic compounds with oestrogenic activity (diethylstilboestrol) to complex regimens containing bio-identical oestrogen plus a progestogen.

For the first 20 years following their introduction, oestrogens alone were prescribed for postmenopausal women, until it was realised that this regimen was associated with a 5–10-fold increase in the risk of endometrial cancer.2-4 To reduce this risk, it was advised that a progestogen be added to the oestrogen.5,6

Following ovulation, the secretion of progesterone increases from about 1–2 nmol/L (0.2–1.0 ng/mL) to between 15 and 45 nmol/L (4.7–15.7 ng/mL). These levels of progesterone for five or more days are capable of inhibiting endometrial gland mitosis,7 inducing a secretory phase and reducing the production of angiogenic growth factor.

Bio-identical progesterone, produced by a multi-step process involving enzymatic conversion of diosgenin (found in Mexican wild yam), is rapidly metabolised by enzymes in the gut and the liver and therefore results in an unreliable endometrial response. For this reason, stable synthetic progestogens were added to the oestrogen therapy.8

It was suggested that progesterone, absorbed through the skin, might provide endometrial protection. In 1974, John Lee, a Californian general practitioner with a background in pharmacology, developed a cream containing bio-identical progesterone. The cream was intended to deliver 10–12 mg progesterone daily.

Lee reported that most patients using the cream experienced an improved sense of well-being.9,10 On the basis of these anecdotal responses, he developed and promoted progesterone cream as a commercial product.9-12

Pharmaceutical companies in the United States, France, and Australia marketed the progesterone creams.

Claims

The claims made about transdermal progesterone cream included that it:9,10,13

  • inhibits endometrial growth,

  • reduces uterine cancer,

  • increases osteoblastic stimulation (resulting in fewer fractures),

  • improves libido,

  • controls flushing and sweating,

  • reduces fibrocystic breast disease,

  • reduces breast cancer,

  • increases metabolism of fat for energy,

  • acts as a natural antidepressant,

  • facilitates thyroid hormone action,

  • normalises zinc and copper levels,

  • helps restore proper oxygen levels, and

  • acts as a natural diuretic.

However, the paucity of credible supportive scientific data raised considerable concern regarding the potency of transdermal progesterone.14-17 To explain why other clinicians had difficulty replicating his results, Lee developed a complex hypothesis based on the lipophilic properties of progesterone,18,19 claiming that progesterone was transported preferentially in the membrane of red cells, to be released later along a diffusion gradient when it reached its target.11,12 Because of the diffusion gradient from high levels in red-cell membrane to low levels in tissue, saliva was regarded as ideal for monitoring progesterone levels in postmenopausal women.12,13,20 However, peer-reviewed studies have failed to confirm the expectations expounded by proponents of this treatment regimen.

Evidence

Eight studies of transdermal progesterone have been published in peer-reviewed journals (Box). Their results are not generally supportive of the therapy.

One study did find that 25 of 30 women (83%) applying progesterone cream had remission of hot flushes, whereas only 5 of 26 (19%) taking placebo experienced relief after 12 months,21 but this rate of remission among women taking a placebo is much lower than expected (40%–70%) and casts some doubt on the validity of this study. Another study involved 32 women taking conjugated equine oestrogen (0.625 mg) with a twice-daily application of a cream containing either a placebo or 1.5% or 4.0% bio-identical progesterone for 28 days.25 Results suggested that endometrial mitosis was reduced by progesterone. However, a study of 27 women using continuous transdermal oestrogen and sequential transdermal progesterone cream providing either 16 mg, 32 mg or 64 mg of progesterone daily for 14 days each month found that, although there was an increase in circulating levels of progesterone from a mean baseline of 0.4 nmol/L to a mean of 1.2 nmo1/L, this was insufficient to inhibit endometrial proliferation.23

In another double-blind, randomised study,26 either transdermal progesterone cream (32 mg daily) alone or a placebo cream was administered to 80 postmenopausal women. After 3 months, there was no evidence that the progesterone delivered in the cream had any discernible effect on any of the clinical parameters being investigated. When compared with the placebo, climacteric symptoms such as hot flushes, muscle aches and discomfort, anxiety, depression and lowered libido were not alleviated by transdermal progesterone. Total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides and lipoprotein (a) levels were not statistically different between placebo and active progesterone therapy after 3 months. Bone mineral activity markers such as N-telopeptide, osteocalcin and C-telopeptide were unaffected by administering transdermal progesterone.

Several studies detected a small rise in progesterone levels with transdermal progesterone cream (Box),14,22-24,26 but there was no indication that menopausal symptoms responded to these small increases. The level of progesterone detected in saliva was up to several hundred times greater than that measured in blood.17,23 This suggests that progesterone is probably concentrated and excreted by the salivary glands instead of filtering passively down a diffusion gradient from red blood cells to saliva.

Another study involved 24 postmenopausal women who received either placebo, or creams containing 20 mg or 40 mg progesterone, twice daily; progesterone levels were measured in red blood cells, in plasma and in saliva.17 There was no significant increase in progesterone in plasma as a result of applying the progesterone cream, nor was there evidence that progesterone was transported in any significant amount in the membrane of red blood cells. However, salivary progesterone levels were high and variable, thus presenting a paradox when attempting to evaluate the amount of progesterone being absorbed. Lewis cautioned against the use of saliva to monitor progesterone absorption.

Several studies27-29 using creams and gels containing high dose bio-identical progesterone (90–100 mg daily) administered in the vagina on a daily basis have shown that progesterone, in constant contact with the vaginal epithelium, can be absorbed in sufficient amounts to affect the endometrium. One small study using vaginal progesterone resulted in remission of mastodynia,30 but, in another study, applying progesterone cream directly to the breast failed to relieve pain.31 A further study found a 60% reduction in mitotic activity of subjacent breast cells when progesterone cream was applied directly to the skin of women about to have breast surgery,32 but could not detect an increase in plasma levels of progesterone.

It remains a possibility that a transdermal cream containing progesterone at levels many times greater than those recommended by Lee may have some beneficial effects, but to date there is insufficient clinical or pharmacological evidence to endorse the use of this therapy in postmenopausal women.

Conclusion

The claims for transdermal progesterone creams and the hypothesis on which they are based have been founded on anecdotal information rather than on sound scientific research. In a number of small but carefully conducted prospective, double-blind, randomised studies, progesterone cream has been shown to be no different from placebo in its ability to control vasomotor, psychosexual or mood symptoms. It does not induce a positive response in the biochemical markers for bone metabolic activity or plasma lipid levels. Creams containing progesterone in the doses currently available for clinical use do not fulfil the criteria necessary for them to be endorsed as a therapeutic agent to treat menopausal hormone deficiency.

The use of saliva to monitor levels of progesterone has been shown to be based on erroneous assumptions and should be abandoned as a means of managing postmenopausal women.

Studies involving transdermal progesterone cream

Study

Number of patients

Dose

Result


Cooper et al (1998)14

20

20–40 mg daily

No significant increase in plasma progesterone

Leonetti et al (1999)21

102

20 mg daily

Reduction in flushes

No effect on bone

Burry et al (1999)22

6

60 mg

Slight increase in plasma progesterone

Wren et al (2000)23

27

16, 32, 64 mg

Slight increase in plasma progesterone

No inhibition of proliferation of endometrium

High and variable saliva levels of progesterone

Lewis et al (2002)17

24

20–40 mg

Slight increase in plasma progesterone

High and variable saliva levels of progesterone

Carey et al (2000)24

24

40 mg

Slight increase in plasma progesterone

Leonetti et al (2003)25

37

20–50 mg

Inhibition of mitosis

Wren et al (2003)26

80

32 mg

Slight increase in plasma progesterone

No effect on flushes, moods, libido, bone metabolism, lipid levels

  • Barry G Wren

  • 506/180 Ocean Street, Edgecliff, NSW.

Correspondence: 

Competing interests:

None identified.

  • 1. Writing Group for Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288: 321-333.
  • 2. Smith DC, Prentice R, Thompson DJ, Herrman WL. Association of exogenous estrogens and endometrial cancer. N Engl J Med 1975; 293: 1164-1168.
  • 3. Antunes CMF, Stolley PD, Rosenstein NB, et al. Endometrial cancer and estrogen use. N Engl J Med 1979; 300: 9-13.
  • 4. Mack TM, Pike MC, Henderson BE, et al. Estrogens and endometrial cancer in a retirement community. N Engl J Med 1976; 294: 1264-1267.
  • 5. Sturdee DW, Wade-Evans T, Paterson MEL, et al. Relations between bleeding pattern, endometrial histology and oestrogen treatment in menopausal women. BMJ 1978; 1: 1575-1577.
  • 6. Gambrell RD, Massey FM, Castaneda TA, et al. Reduced incidence of endometrial cancer among post-menopausal women treated with progestogens. Am Geriatric Soc 1979; 27: 389-394.
  • 7. Ferenczy A, Gelfand M, Tzipris F. The cyto-dynamics of endometrial hyperplasia and carcinoma: a review. Ann Pathol 1983; 3: 189-198.
  • 8. Speroff L, Glass RH, Kase NG. The ovary from conception to senescence. In: Clinical Gynecological Endocrinology and Infertility. Chapter 4. Baltimore: Williams and Wilkins, 1989.
  • 9. Highlights from an interview with Dr. John Lee. Partners Magazine (AIM International) 2001; 1-3.
  • 10. Lee JR. What your doctor may not tell you about menopause. Transcript of a lecture given by Dr Lee in 2002. Available at: allonhealth.com/natural-progesterone/lee-menopause.htm (accessed Jan 2005).
  • 11. Lee JR. Osteoporosis reversal with transdermal progesterone [letter]. Lancet 1990; 336: 1327.
  • 12. Lee JR. Use of Pro-Gest cream in post-menopausal women [letter]. Lancet 1998; 352: 905.
  • 13. Lee JR, editor. What your doctor may not tell you about menopause. New York: Warner Books, 1996.
  • 14. Cooper A, Spencer C, Whitehead MI, et al. Systemic absorption of progesterone from Progest Cream in menopausal women [letter]. Lancet 1998; 351: 1255-1256.
  • 15. Wren BG. Progesterone creams: do they work? [editorial]. Climacteric 2003; 6: 184-187.
  • 16. Stevenson JC, Purdie DW. Use of Pro-Gest cream in postmenopausal women [letter]. Lancet 1998; 352: 905-906.
  • 17. Lewis JG, McGill H, Patton VM, Elder PA. Caution on the use of saliva to monitor absorption of progesterone from transdermal creams in postmenopausal women. Maturitas 2002; 41: 1-6.
  • 18. Devenuto F, Ligon D, Friedrichsen D, et al. Human erythrocyte membrane: uptake of progesterone and alterations. Biochim Biophys Acta 1969; 193: 36-47.
  • 19. Koefoed P, Brahm J. The permeability of the human red cell membrane to steroid sex hormones. Biochim Biophys Acta 1994; 1195: 55-62.
  • 20. Lee JR. Topical progesterone [letter]. Menopause 2003; 10: 374-377.
  • 21. Leonetti HB, Longo S, Anasti JM. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol 1999; 94: 225-228.
  • 22. Burry KA, Patton PE, Hermsmayer K. Percutaneous absorption of progesterone in postmenopausal women treated with transdermal estrogen. Am J Obstet Gynecol 1999; 180: 1504-1511.
  • 23. Wren BG, McFarland K, Edwards L, et al. Effect of sequential transdermal progesterone cream on endometrium, bleeding pattern and plasma progesterone and salivary progesterone levels in postmenopausal women. Climacteric 2000; 3: 155-160.
  • 24. Carey BJ, Carey AH, Patel S, et al. A study to evaluate serum and urinary hormone levels following short and long term administration of two regimens of progesterone cream in postmenopausal women. BJOG 2000; 107: 722-726.
  • 25. Leonetti H, Wilson KJ, Anasti JN. Topical progesterone cream has an antiproliferative effect on estrogen-stimulated endometrium [letter]. Fertil Steril 2003; 79: 221-222.
  • 26. Wren BG, Champion SM, Willets K, et al. Transdermal progesterone and its effect on vasomotor symptoms, blood lipid levels, bone metabolic markers, mood, and quality of life for postmenopausal women. Menopause 2003; 10: 13-18.
  • 27. Ferrero S, Gerbaldo D, Fulcheri E, Cristoforoni P. Vaginal micronised progesterone in continuous hormone replacement therapy. A prospective randomized study. Minerva Ginecol 2000; 54: 519-530.
  • 28. Artini PG, Volpe A, Angioni S, et al. A comparative, randomized study of three different progestin support of the luteal phase following IVF/ET program. J Endocrinol Invest 1995; 18: 51-56.
  • 29. Elkind-Hirsch KE, Phillips K, Bello SM, et al. Sequential hormonal supplementation with vaginal estradiol and progesterone gel corrects the effect of clomiphene on the endometrium in oligo-ovulatory women. Hum Reprod 2002; 17: 295-298.
  • 30. Nappi C, Affinito P, DiCarlo C, et al. Double blind controlled trial of progesterone vaginal cream treatment for cyclic mastodynia in women with benign breast disease. J Endocrinol Invest 1995; 15: 801-806.
  • 31. McFayden IJ, Raab GM, MacIntyre CC, Forrest AP. Progesterone cream for cyclic breast pain. BMJ 1989; 298: 931.
  • 32. Chang K-J, Lee TTY, Linares-Cruz G, et al. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cells in vivo. Fertil Steril 1995; 63: 785-791.

Author

remove_circle_outline Delete Author
add_circle_outline Add Author

Comment
Do you have any competing interests to declare? *

I/we agree to assign copyright to the Medical Journal of Australia and agree to the Conditions of publication *
I/we agree to the Terms of use of the Medical Journal of Australia *
Email me when people comment on this article

Responses are now closed for this article.