Progesterone Cream in Menopause
By Judith L. Balk, MD, MPH, FACOG. Dr. Balk is Assistant Professor, Magee-Womens Hospital, University of Pittsburgh; she reports no financial relationship to this field of study.
Lay books and web sites tout the benefits of progesterone cream for use in menopausal women. A Google search reveals roughly 338,000 results when the term "progesterone cream" is entered. In contrast, when the term "progesterone" is combined with the term "cream" in Medline, 62 results are obtained. When the term "menopause" is added to the Medline search, only 11 articles remain, and when the term "perimenopause" is used, no articles appear.
The Google search reveals many sites that sell progesterone cream for use in menopause, with claims such as, "Many of the so-called 'modern' diseases can be prevented or overcome by progesterone therapy."1 Thus, it is not surprising when our patients present either using or asking about progesterone cream. The purpose of this article is to review the use of progesterone transdermal cream in menopause. This review will not specifically address vaginal or oral progesterone, which are only available with a prescription.
Progesterone is produced from cholesterol by the ovaries, the placenta, the adrenal glands, the testes, and the central nervous system.2,3 However, most of the associated research has focused on its pro-gestational effects, hence the name progesterone. With recent concern about menopausal hormone therapy, and specifically the progestin component, women are turning to progesterone as a possibly safe and effective approach to treat menopausal symptoms. The term progestin is used to signify a molecule that is chemically different from progesterone, but that has some similar effects. It is important to keep in mind that progesterone and synthetic progestins may induce different responses, such as on the breast.4 It is likewise important to note that many authors use the term progesterone when what is being studied is actually a progestin-like medroxyprogesterone acetate. Progestagen is the term that encompasses both progesterone and progestins.
Effects on Menopausal Symptoms
In one study, transdermal progesterone at 32 mg daily for 12 weeks did not affect vasomotor symptoms, mood, or sexual feelings in postmenopausal women. The authors postulate that insufficient hormone entered the body to achieve a biological effect.5 Progesterone concentrations rose slightly, but in a statistically significant fashion, in the treatment group, demonstrating good absorption of the cream, although blood levels remained low. All women were mildly symptomatic at baseline with a Kupperman Index over 16 (out of 51). It is possible that perimenopausal women, or those who are more symptomatic, might have a different outcome.
A one-year randomized, placebo-controlled trial compared the effects of 20 mg of progesterone cream vs. placebo in postmenopausal women.6 Only 55% and 69% of women had vasomotor symptoms at baseline in the placebo vs. progesterone group, respectively. Of those who had hot flushes, 83% experienced improvement in the progesterone group, compared to 19% in the control group (P < 0.001). Eight subjects in the progesterone group had vaginal spotting that was self-limited and resolved within 1-2 days.
An abstract described a study in which postmenopausal women received placebo or 20 mg of progesterone cream for 4 weeks, and then were crossed over to the opposite group.7 The authors noted a decline in menopausal symptoms in the treatment group, but not in the placebo group. There is typically a large placebo response in short-term menopause studies.
Effects on the Cardiovascular System
The impact of progesterone on cardiovascular disease risk can include effects on lipids and on vascular function. In both non-atherosclerotic and pre-atherosclerotic surgically menopausal monkeys, progesterone cream prevented coronary hyperreactivity when compared to placebo cream.8 In this study, progesterone cream protected against severe prolonged vasoconstriction from a challenge injection, in contrast to data indicating that oral medroxyprogesterone acetate adversely affects coronary reactivity and increases the risk of coronary vasospasm.9 Route of administration and dosage may play a role in the effects seen. In another trial, 400 mg of vaginal progesterone acutely increased vascular resistance in 12 postmenopausal women at 3 hours post-administration, but after 8 hours a vasodilatory reaction was noted.10 Transdermal progesterone in a dose of 32 mg daily for 12 weeks did not affect lipid levels in postmenopausal women; the authors postulated that insufficient hormone entered the body to achieve a biological effect.5 Topical progesterone at 20 mg/d for 4 weeks did not increase thrombotic or inflammatory factors in postmenopausal women.7
Effects on Breast
Both progesterone and estrogen receptors exist in the breast, so it is possible that progesterone or estrogen or an interaction between the two, could have stimulatory or inhibitory effects on breast cells. The influence of progesterone on breast tissue has been debated for two decades, as results can differ based on the model used (animal vs. human, in vitro, or in vivo), the timing of progesterone administration, and the method of evaluation used (mitotic index, proliferating cell nuclear antigen, 3H-thymidine labeling).4 For instance, the mitotic index is highest in the midluteal phase in premenopausal women, which is when progesterone peaks11; however, in one study, the mitotic index declined with every decade of life, meaning that at the time of highest breast cancer risk, the mitotic index was lowest. The actions of progesterone on breast tissue are likely complex and dependent on many factors, including duration of exposure.12
In a double-blind, randomized study, postmenopausal women scheduled for benign breast surgery applied either topical estradiol, progesterone, placebo, or a combination of estradiol and progesterone for the 14 days prior to surgery.4 Estradiol induced cell growth based on the mitotic index, whereas findings for the progesterone and combined estradiol/progesterone groups did not differ from placebo. The authors concluded that the application of progesterone limited the estradiol-induced proliferation of normal breast cells. A similar design was used for premenopausal women, and the findings were the same: Exposure to topical progesterone for 10-13 days reduced estradiol-induced cell proliferation.13
Luteal phase breast pain has no clear etiology, but an insufficiency of progesterone has been postulated.14 A small randomized trial (n = 32) comparing luteal phase application of 5 g of cream containing either 1% progesterone (50 mg) or placebo found no improvement with progesterone.14 In contrast, a larger study (n = 80) found that vaginal application of 4 g containing 2.5% progesterone (100 mg/application) improved breast pain and tenderness, while having no effect on breast nodularity.15 No major side effects were seen. Possible differences between these studies could be the bioavailability of transdermal vs. vaginal cream, inadequate sample size for the first study, or dosage of progesterone.
Effects on Bone
The effects of progesterone cream on bone health are controversial. Bone mineral density was assessed in postmenopausal women in one trial before and after one year of 20 mg progesterone cream daily vs. placebo.6 Both groups had small, nonsignificant decreases in mean bone mineral density at the post-treatment DXA scan. Bone turnover markers did not differ between 32 mg/d progesterone cream vs. placebo when given for 3 months in another trial.5 However, a two-year study in postmenopausal women with either osteoporosis or three risk factors for osteoporosis found that progesterone cream at roughly 25 mg/d attenuated bone loss over a two-year period.16 Interestingly, soy milk had the same effect, but when soy milk and progesterone cream were taken in combination, a negative interaction occurred, resulting in more bone loss than either treatment alone. A letter to the editor notes an increase in bone density as determined by dual photon absorptiometry with the use of 330-500 mg of transdermal progesterone monthly.17 This study was a retrospective chart review, uncontrolled, and some of the patients were also on estrogen.
Effects on Endometrium
To be useful in postmenopausal estrogen-progestagen therapy, progesterone must protect the endometrium. Importantly, blood or salivary concentrations are not the best indicator; rather, tissue sampling must demonstrate endometrial protection. In one pilot randomized crossover trial, healthy menopausal women had a baseline endometrial biopsy, and then were randomized to 0.625 mg conjugated equine estrogen (CEE) daily and 2.5 mg medroxyprogesterone acetate or daily 0.625 mg CEE and twice daily transdermal cream containing 20 mg progesterone.18 At the end of 6 months, a repeat endometrial biopsy was obtained, and the women were crossed over to other treatment. A final endometrial biopsy was performed after the final 6 months. Twenty-six women completed both arms of the study. Of the 52 post-treatment endometrial biopsies, 40 revealed atrophic endometrium and 12 proliferative endometrium (7 in the oral progestin group and 5 in the progesterone cream group). There was no evidence of endometrial hyperplasia in either group, and the incidence of vaginal spotting was similar in both groups.
Another study by the same investigative team was a 28-day randomized, double-blind, placebo-controlled trial assessing endometrial safety of various concentrations of progesterone cream.19 The article notes that the pharmacy formulated the cream's concentration based on the patient's weight, but it is not clear how the progesterone cream concentrations of 0%, 1.5%, or 4.0% were adjusted based on patient weight when the subjects were randomized to one of these groups. Thus, it is not clear what the exact dosages of progesterone used were. Both dosages of progesterone cream decreased endometrial stimulation compared to placebo and to baseline.
Other studies have not found adequate endometrial protection. When postmenopausal women used transdermal estrogen and a cream containing 16 mg, 32 mg, or 64 mg of progesterone, endometrial biopsies did not demonstrate a change from baseline after 14 days of progesterone.20 In a different study, a combination of 40 mg progesterone cream and 1 mg estradiol, given transdermally for 48 weeks in 54 postmenopausal women, did not prevent endometrial stimulation.21 Thirty-two percent of subjects had either proliferative or hyperplastic endometrium at 48 weeks. Researchers have recommended that transdermal progesterone not be used for endometrial suppression at the current time.18,19,21
Absorption, Distribution, and Measurement of Progesterone
Ideally, topical progesterone will distribute to the organs where it has beneficial effects, such as the uterus. An experimental rat model demonstrates that progesterone cream is absorbed transdermally and then distributed and metabolized in the same manner as progesterone that enters the blood directly.22 Progesterone accumulates in progesterone target areas, such as the uterus, lung, and saliva, at concentrations in excess of plasma levels.
The measurement of progesterone concentrations when using the cream remains controversial. An editorial in Menopause discusses the issues of salivary vs. serum testing of progesterone.23 On one hand, salivary progesterone measurements confirm that progesterone cream is absorbed.24 Also, due to the lipophilic nature of progesterone, it is not thought to be absorbed into plasma, but rather into red blood cells, which deliver progesterone to target tissues and to saliva, making salivary concentrations more relevant for measurement than blood levels25; but even so, salivary levels can be so variable that some investigators found the levels to be completely unreliable.20 In addition, it is not clear what salivary concentration of progesterone is sufficient to protect the endometrium or bone, and thus salivary measurement is less clinically useful. No empirical association between progesterone dosage and salivary concentrations exists that can be used to treat menopausal symptoms.24 Salivary measurements of progesterone were found to be inaccurate in one study, due to contamination from cream on the subjects' fingers.14
Serum concentrations did not change when women applied a single dosage of 64 mg of topical progesterone.24 However, serum concentrations did increase somewhat after 10 days of progesterone cream use,26 and luteal phase concentrations were obtained in some women after 4 weeks of 30-60 mg/d application of progesterone.27 Whole blood progesterone concentrations, as opposed to serum concentrations, demonstrate significant absorption, with a dosage of 40 mg twice daily being roughly equivalent to the prescription 200 mg oral dosage of progesterone.28
Safety
No studies have specifically addressed the safety of progesterone cream, but in the clinical trials noted above, no adverse events were noted. Given what appears to be minimal absorption of the cream, especially at dosages available over the counter (up to 30 mg/mL), the most significant risk may be when patients use the cream assuming it is protective of the endometrium. Given that it is most likely not protective, the use of the cream instead of a well-studied medication places the patient at risk for endometrial cancer. Also, in women with hormonally dependent cancers such as breast cancer, the use of progesterone cream is likely premature until more research is done on its safety.
Conclusion
Transdermal progesterone administration may be useful when subphysiological levels are required, such as for mastodynia.29 The literature supports that some women may achieve relief from menopausal symptoms with progesterone cream, but it is likely that only a subset of women will respond. We currently do not know who will respond to transdermal progesterone for symptom relief; it is possible that those with elevated endogenous estrogen, like obese women, would benefit more from progesterone.
Recommendation
Given the available literature, I would recommend that transdermal progesterone not be used for endometrial protection, osteoporosis, or in breast cancer patients. It is possible that progesterone may be helpful with symptoms of menopause, but more research is necessary to delineate the ideal clinical scenarios in which transdermal progesterone is most effective.
References
1. Progesterone therapy web site. Available at: www.progesteronetherapy.com. Accessed July 6, 2009.
2. Schumacher M, et al. Novel perspectives for progesterone in hormone replacement therapy, with special reference to the nervous system. Endocr Rev 2007;28:387-439.
3. Parrish A, Vlahos N. Progesterone and progestins: Physiologic role, preparations, and indications for therapy. Postgrad Obstet Gynecol 2000;20:1-6.
4. Foidart J-M, et al. Estradiol and progesterone regulate the proliferation of human breast epithelial cells. Fertil Steril 1998;69:963-969.
5. Wren B, et al. Transdermal progesterone and its effect on vasomotor symptoms, blood lipid levels, bone metabolic markers, moods, and quality of life for postmenopausal women. Menopause 2003;10:13-18.
6. Leonetti HB, et al. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol 1999;94:225-228.
7. Stephenson K, et al. Topical progesterone cream does not increase thrombotic and inflammatory factors in postmenopausal women. Blood 2004;104:Abstract 5318.
8. Hermsmeyer R, et al. Prevention of coronary hyperreactivity in preatherogenic menopausal rhesus monkeys by transdermal progesterone. Arterioscler Thromb Vasc Biol 2004;24:955-961.
9. Miyagawa K, et al. Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nat Med 1997;3:324-327.
10. Mercuro G, et al. Effects of acute administration of natural progesterone on peripheral vascular responsiveness in healthy postmenopausal women. Am J Cardiol 1999;84: 214-218.
11. Potten CS, et al. The effect of age and menstrual cycle upon proliferative activity of the normal human breast. Br J Cancer 1988;58:163-170.
12. Eden J. Progestins and breast cancer. Am J Obstet Gynecol 2003;188:1123-1131.
13. Chang KJ, et al. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertil Steril 1995;63:785-791.
14. McFadyen IJ, et al. Progesterone for cyclic breast pain. BMJ 1989;298:931.
15. Nappi C, et al. Double-blind controlled trial of progesterone vaginal cream treatment for cyclical mastodynia in women with benign breast disease. J Endocrinol Invest 1992;15:801-806.
16. Lydeking-Olsen E, et al. Soymilk or progesterone for prevention of bone lossA 2-year randomized, placebo-controlled trial. Eur J Nutr 2004;43:246-257.
17. Lee JR. Osteoporosis reversal with transdermal progesterone. Lancet 1990;336:1327.
18. Leonetti HB, et al. Transdermal progesterone cream as an alternative progestin in hormone therapy. Altern Ther Health Med 2005;11:36-38.
19. Leonetti HB, et al. Topical progesterone cream has an antiproliferative effect on estrogen-stimulated endometrium. Fertil Steril 2003;79:221-222.
20. Wren BG, 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.
21. Vashisht A, et al. Bleeding profiles and effects on the endometrium for women using a novel combination of transdermal oestradiol and natural progesterone cream as part of a continuous combined hormone replacement regime. BJOG 2005;112:1402-1406.
22. Waddell BJ, O'Leary PC. Distribution and metabolism of topically applied progesterone in a rat model. J Steroid Biochem Mol Biol 2002;80:449-455.
23. Gambrell RD Jr. Progesterone skin cream and measurements of absorption. Menopause 2003;10:1-3.
24. O'Leary P, et al. Salivary, but not serum or urinary levels of progesterone are elevated after topical application of progesterone cream to pre- and postmenopausal women. Clin Endocrinol (Oxf) 2000;53:615-620.
25. Lee JR. Use of Pro-Gest cream in postmenopausal women. Lancet 1998;352:905.
26. Cooper A, et al. Systemic absorption of progesterone from Progest cream in postmenopausal women. Lancet 1998;351:1255-1256.
27. Burry KA, et al. Percutaneous absorption of progesterone in postmenopausal women treated with transdermal estrogen. Am J Obstet Gynecol 1999;180(6 Pt 1): 1504-1511.
28. Hermann AC, et al. Over-the-counter progesterone cream produces significant drug exposure compared to a Food and Drug Administration-approved oral progesterone product. J Clin Pharmacol 2005;45:614-619.
29. Warren MP, Shantha S. Uses of progesterone in clinical practice. Int J Fertil Womens Med 1999;44:96-103.
Lay books and web sites tout the benefits of progesterone cream for use in menopausal women. A Google search reveals roughly 338,000 results when the term "progesterone cream" is entered.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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