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Progesterone

Pronunciation

Common Name(s): Natural progesterone , progesterone cream , micronized progesterone . Commercial preparations include MyGest , Pro-Gest , Prov-Juven , Hormonil , Women to Women Body Cream , Phytoprolief , Progestelle , Progesta-Eze , and Young Again Natural Progesterone Cream .

Uses

Topical progesterone is used to manage menopause-related symptoms, such as hot flashes, low libido, and mood swings. Clear evidence of a progesterone benefit in improving bone density or cardiovascular markers, or for the prevention of endometrial proliferation, is lacking. Topical progesterone has also been studied for the management of cyclic breast pain and for skin elasticity and firmness in postmenopausal women.

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Dosing

Most trials evaluated topical progesterone 40 mg daily either as a single dose or 20 mg twice daily for menopausal symptoms.

Contraindications

None documented.

Pregnancy/Lactation

Information regarding topically applied progesterone in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

Clinical trials report few adverse events, with most no different from those of the placebo comparator. A higher incidence of headache and postmenopausal bleeding has been reported.

Toxicology

Research reveals no information regarding the toxicity of topical progesterone.

Phytoestrogens, structurally similar to human progesterone, are synthesized by more than 5,000 plants. Progesterone can be converted from the sterol diosgenin found in plants such as soybeans and wild yam. 1 This monograph is limited to evidence for progesterone cream and does not include references to wild yam or soy. (See Wild Yam or Soy monographs for more information.) Despite claims that natural progesterone is plant-based and therefore from a natural source, many synthesized progesterones are also plant-derived and are chemically identical to progesterone of the ovarian origin. 2

History

“Natural” progesterone cream has been available in the United States for at least 20 years as an over-the-counter preparation and is not regulated by the FDA. 1 , 3 , 4 Transdermal delivery was proposed as an alternative to the oral route because approximately 90% of progesterone is enzymatically inactivated in the gut and liver, and results in undesirable metabolites are produced. 1

Claims for the use of topical natural progesterone include the prevention and treatment of osteoporosis and low libido, as well as the management of menopausal symptoms, including hot flashes, and enhancement of mood and psychological well being. 1 , 3

Chemistry

Progesterone, a principle of corpus luteum, is the primary endogenous progestational substance. Progestins (progesterone and derivatives) transform proliferative endometrium into secretory endometrium. Progesterone is necessary to increase endometrial receptivity for implantation of an embryo. 5

Progesterone receptors have been identified in whole skin, keratinocytes, and fibroblasts. 1

Micronized progesterone is used in oral and topical preparations to enhance absorption. 2

Uses and Pharmacology

Clinical studies have been conducted to describe the pharmacokinetics of topical progesterone, with most studies finding major increases in salivary progesterone and only moderate increases in serum progesterone levels. Wide variations in measured progesterone levels are also a feature of these studies. 1 , 6 , 7 , 8 , 9 , 10 In a crossover study, topical progesterone 40 mg twice daily showed no difference compared with oral progesterone 200 mg in the 24-hour area under the curve (AUC) for whole blood progesterone, 3 while another kinetic study using a daily progesterone 60 mg cream achieved serum progesterone levels similar to luteal levels (more than 3 ng/mL). 11 A clinical trial evaluating the effect of progesterone on bone density found increases in serum progesterone for up to 6 months with no further accumulation. At 3 years, the mean serum progesterone level was 3.54 nmol/L. 12

Various mechanisms have been proposed to explain the observed low plasma levels of progesterone following topical application. These include uptake by the red blood cells, rapid conversion to 5-alpha-reduced progestin, and rapid clearance from the serum by salivary and hepatic excretion, combined with slow transdermal absorption. 1 , 7 , 9 A “priming” effect of the skin resulting in increased absorption after a few days of administration has also been suggested. 7 , 13

Menopause/Menopausal symptoms
Animal data

Studies in animals are limited. In a study conducted in rats, topical progesterone was found to be effectively and biologically actively absorbed. A similar distribution in tissues was found following intramuscular administration. Metabolism was also similar. 14

Clinical data

Debate exists about the relevance of plasma and salivary progesterone as surrogate indicators of clinical efficacy. 1 , 8 , 9 , 15 Clear evidence of a progesterone benefit in improving bone density or cardiovascular markers, or for the prevention of endometrial proliferation is lacking. 6 , 16 , 17 , 18 , 19

In an open-label study, topical progesterone 40 mg daily applied for over 1 year did not provide adequate opposition to endometrial hyperplasia as determined by endometrial histology and bleeding patterns in 41 postmenopausal women. 20 , 21 A small clinical crossover trial (N = 26) found topical progesterone 40 mg daily to exert a similar effect on the endometrium as standard oral progesterone. 22 In a large (N = 223), double-blind, randomized trial, topical progesterone ( Progestelle ) applied for over 6 months showed no difference compared with placebo for psychological, somatic, or vasomotor menopause-related symptoms. Dosages of progesterone 5, 20, 40, and 60 mg daily were tested. A string placebo effect was observed. No histological effect of topical progesterone on the endometrium was demonstrated. 23 In a randomized clinical study, results with topical progesterone 32 mg did not differ from those with placebo for vasomotor symptoms, mood, or libido, and showed no effect on blood lipids or bone metabolic markers. 10

In a randomized clinical trial (N = 102), topical progesterone 20 mg daily showed no protective effect on bone density at 1 year and no change in the lipid profile versus placebo. However, an improvement in vasomotor symptoms was recorded. 24 A 2-year study evaluating the effect of soy and transdermal progesterone on bone mineral density in postmenopausal women found progesterone alone to have protective effects on the lumbar spine but not hip bone, but the positive effect was attenuated when used in combination with soy milk. 25 No effect on bone density or plasma lipids was found for topical progesterone 40 mg daily in a large, double-blind, randomized clinical trial (N = 131 postmenopausal women). 12

Other uses

Topical progesterone was no better than placebo for the management of cyclic breast pain in a small clinical trial. 26 A progesterone 2% cream increased the elasticity and firmness of skin in postmenopausal women in a small study. 13

Dosage

Commercial progesterone creams vary in concentration but are generally in the range of 1.5% to 3% progesterone. Most trials evaluated progesterone 40 mg daily either as a single dose or 20 mg twice daily for menopausal symptoms. 12 , 20 , 21

Pregnancy/Lactation

Information regarding topically applied progesterone in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

Clinical trials report few adverse events, with most no different from those of the placebo comparator. 11 , 23 A higher incidence of headache and postmenopausal bleeding was associated with topical progesterone in 1 large clinical study. 23 Water retention, breast engorgement, increased body weight, and mild to moderate depression have been documented in case reports following long-term use. 27

While progesterone cream may be helpful for women with proven low progesterone levels, for women experiencing symptoms due to relative progesterone deficits, meaning more or less normal progesterone levels but with estrogen excess, progesterone cream may increase the hormonal load in the body. Aromatase enzymes in adipose cells below the dermis convert androgens, including progesterone, into estrogen. Therefore, women with hyperestrogenism may not benefit and may even be harmed by progesterone supplementation if it is not prescribed appropriately. 28 , 29

Toxicology

Research reveals no information regarding the toxicity of topical progesterone.

Bibliography

1. Elshafie MA, Ewies AA. Transdermal natural progesterone cream for postmenopausal women: inconsistent data and complex pharmacokinetics. J Obstet Gynaecol . 2007;27(7):655-659.
2. “Natural” progesterone creams for postmenopausal women. Drug Ther Bull . 2001;39(2):10-11.
3. Hermann AC, Nafziger AN, Victory J, Kulawy R, Rocci ML Jr, Bertino JS Jr. 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(6):614-619.
4. MacFarland SA. Use of Pro-Gest cream in postmenopausal women. Lancet . 1998;352(9131):905.
5. Progesterone. Drug Facts and Comparisons . Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health Inc ; May 2010. Accessed June 9, 2011.
6. Gambrell RD Jr. Progesterone skin cream and measurements of absorption. Menopause . 2003;10(1):1-3.
7. Carey BJ, Carey AH, Patel S, Carter G, Studd JW. 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(6):722-726.
8. O'Leary P, Feddema P, Chan K, Taranto M, Smith M, Evans S. 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(5):615-620.
9. Lewis JG, McGill H, Patton VM, Elder PA. Caution on the use of saliva measurements to monitor absorption of progesterone from transdermal creams in postmenopausal women. Maturitas . 2002;41(1):1-6.
10. Wren BG, Champion SM, Willetts K, Manga RZ, Eden JA. 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(1):13-18.
11. Burry KA, Patton PE, Hermsmeyer K. Percutaneous absorption of progesterone in postmenopausal women treated with transdermal estrogen. Am J Obstet Gynecol . 1999;180(6, pt 1):1504-1511.
12. Benster B, Carey A, Wadsworth F, Griffin M, Nicolaides A, Studd J. Double-blind placebo-controlled study to evaluate the effect of Pro-Juven progesterone cream on atherosclerosis and bone density. Menopause Int . 2009;15(3):100-106.
13. Holzer G, Riegler E, Hönigsmann H, Farokhina S, Schmidt JB. Effects and side-effects of 2% progesterone cream on the skin of peri- and postmenopausal women: results from a double-blind, vehicle-controlled, randomized study [published correction appears in Br J Dermatol . 2005;153(3):1092]. Br J Dermatol . 2005;153(3):626-634.
14. Waddell BJ, O'Leary PC. Distribution and metabolism of topically applied progesterone in a rat model. J Steroid Biochem Mol Biol . 2002;80(4-5):449-455.
15. Lee JR. Use of Pro-Gest cream in postmenopausal women. Lancet . 1998;352(9131):905.
16. Stevenson JC, Purdie DW. Use of Pro-Gest cream in postmenopausal women. Lancet . 1998;352(9131):905-906.
17. Cooper A, Spencer C, Whitehead MI, Ross D, Barnard GJ, Collins WP. Systemic absorption of progesterone from Progest cream in postmenopausal women. Lancet . 1998;351(9111):1255-1256.
18. Scant evidence for progesterone cream. Harv Womens Health Watch . 1999;7(2):7.
19. Leonetti HB, Wilson KJ, Anasti JN. Topical progesterone cream has an antiproliferative effect on estrogen-stimulated endometrium. Fertil Steril . 2003;79(1):221-222.
20. Vashisht A, Wadsworth F, Carey A, Carey B, Studd J. 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(10):1402-1406.
21. Vashisht A, Wadsworth F, Carey A, Carey B, Studd J. A study to look at hormonal absorption of progesterone cream used in conjunction with transdermal estrogen. Gynecol Endocrinol . 2005;21(2):101-105.
22. Leonetti HB, Landes J, Steinberg D, Anasti JN. Transdermal progesterone cream as an alternative progestin in hormone therapy. Altern Ther Health Med . 2005;11(6):36-38.
23. Benster B, Carey A, Wadsworth F, Vashisht A, Domoney C, Studd J. A double-blind placebo-controlled study to evaluate the effect of Progestelle progesterone cream on postmenopausal women. Menopause Int . 2009;15(2):63-69.
24. Leonetti HB, Longo S, Anasti JN. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol . 1999;94(2):225-228.
25. Lydeking-Olsen E, Beck-Jensen JE, Setchell KD, Holm-Jensen T. Soymilk or progesterone for prevention of bone loss—a 2 year randomized, placebo-controlled trial. Eur J Nutr . 2004;43(4):246-257.
26. McFadyen IJ, Raab GM, Macintyre CC, Forrest AP. Progesterone cream for cyclic breast pain. BMJ . 1989;298(6678):931.
27. Ilyia EF, McLure D, Farhat MY. Topical progesterone cream application and overdosing. J Altern Complement Med . 1998;4(1):5-6.
28. Reed MJ. The role of aromatase in breast tumors. Breast Cancer Res Treat . 1994;30(1):7-17.
29. Pasqualini JR. Breast cancer and steroid meatabolizing enzymes: the role of progestogens. Maturitas . 2009;65(suppl 1):S17-S21.

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