Progesterone

What does it do? The hormone, progesterone, is the natural equivalent of synthetic progestins and is closely related to estrogen. However, natural progesterone and synthetic progestins are structurally different and have differing effects in the body. Progesterone is necessary for proper uterine and breast development and function. Progestins are recommended by doctors if estrogen is prescribed during or after menopause, because prolonged estrogen replacement therapy without the addition of progestins (or large amounts of natural progesterone), increases the risk of uterine cancer.1 However, women who have had a hysterectomy—and therefore no longer have a uterus—are typically prescribed estrogens without progestins. Although natural progesterone is considered by some doctors to be safer and more effective for a variety of health problems, researchers have studied the effects of supplemental natural progesterone much less than the effects of synthetic progestins.

Preliminary evidence suggests that progesterone plays a role in bone metabolism and could help reduce the risk of osteoporosis.2 An uncontrolled study, using topically applied natural progesterone cream in combination with diet, exercise, and vitamin and calcium supplementation, reported consistent gains in bone density over a three-year period in postmenopausal women. However, no comparison was made to a similar program without progesterone.3

One trial found that adding natural progesterone to estrogen therapy had no better effect on bone mass than estrogen therapy alone4 and another trial reported that progesterone applied topically over a one-year period had no effect on bone loss.5 Thus no consistent support for the use of topical progesterone in the treatment or prevention of osteoporosis has appeared in published research.

Some doctors have observed that progesterone administered vaginally, rectally, or topically (to the skin) can relieve the symptoms of premenstrual syndrome (PMS).6 However, most well-controlled studies have not found natural progesterone to be effective against PMS.7

One double-blind study found that topical administration of natural progesterone led to a reduction in hot flashes in 83% of women, compared with improvement in only 19% of those given a placebo.8 Synthetic progestins have also been reported to reduce symptoms of menopause.9

Some studies have linked synthetic progestins to increased risk of breast cancer.10 In contrast, topical progesterone has produced changes in breast tissue that may have a cancer prevention effect.11 12 Other researchers, however, have reported essentially opposite effects, suggesting that natural progesterone may increase proliferation of breast cells.13

The research, however, remains incomplete and inconsistent. In one trial, (natural) progesterone deficiency was linked with an increased risk, but only when the breast cancer was diagnosed before menopause.14 Such a finding fits with the idea that natural progesterone might be protective. This position is further strengthened by a preliminary trial showing that a raised level of progesterone in the blood at the time of breast cancer surgery is associated with an improved prognosis for premenopausal women with operable breast cancer.15 However, most breast cancer begins postmenopausally, and one trial found that progesterone deficiency was associated with a large (though statistically nonsignificant) decreased risk of postmenopausal breast cancer.16 If duplicated by future research, this finding would not suggest protection, nor even necessarily safety.

A recent report found that long-term topical use of natural progesterone on the breast neither increased nor decreased the risk of women eventually being diagnosed with breast cancer.17 In this trial, some women were also taking oral synthetic progesterone-like drugs. Remarkably, women using this combination experienced a 50% decreased risk of eventually being diagnosed with breast cancer. More research is needed to understand the effects of both synthetic and natural progesterone in both pre- and postmenopausal women.

Synthetic progestins have been linked to effects that might increase the risk of heart disease.18 However, vaginally applied natural progesterone has been reported to significantly enhance the benefits of estrogen replacement therapy on heart function in women with coronary artery disease.19 More research is needed to evaluate the effects of natural progesterone on heart disease.

Although the differences in the chemical structure of natural progesterone and synthetic progestins are slight, their effects in the body differ considerably and the two forms should not be considered interchangeable. Synthetic progestins may be useful for endometriosis and menorrhagia (prolonged or profuse menstrual flow) because of their specific effects on progesterone receptors in the brain and on the glandular response of the uterine lining. However, these same effects may be detrimental for women with PMS, and may be associated with increased symptoms, such as depression, headaches, and water retention. Thus, natural progesterone may be preferable to synthetic progestins for PMS.20

Where is it found? Progesterone is produced in the female body in the ovaries. Progesterone production is high during the luteal phase (second portion) of the menstrual cycle and low during the follicular phase (first portion), as well as being low before puberty and after menopause.

Supplemental sources of progesterone are available in oral and cream forms, as well as lozenges, suppositories, and injectable forms. “Natural” progesterone refers to the molecule that is identical in chemical structure to the progesterone produced in the body, even if the molecule is synthesized in a laboratory.

Progestins are found in oral contraceptive pills and are used in conventional hormone replacement therapy.

Wild yam contains precursors to progesterone (such as diosgenin) that can be converted through a chemical process in the laboratory into progesterone—the exact same molecule made in the human body. However, contrary to popular claims, the diosgenin in wild yams cannot be converted into progesterone in the body.21 22 Women who require progesterone should consult their physician and not rely on wild yam or other herbs.

Pregnenolone, another hormone produced by the body, is converted by the body into progesterone. However, it is not clear what effect supplementing with pregnenolone will have on progesterone production in the body.

Progesterone has been used in connection with the following conditions (refer to the individual health concern for complete information):

Rating Health Concerns
2Stars Amenorrhea
Menopause
1Star Dysmenorrhea (topical cream)
Heart disease
Premenstrual syndrome
3Stars Reliable and relatively consistent scientific data showing a substantial health benefit.
2Stars Contradictory, insufficient, or preliminary studies suggesting a health benefit or minimal health benefit.
1Star An herb is primarily supported by traditional use, or the herb or supplement has little scientific support and/or minimal health benefit.

Who is likely to be deficient? Postmenopausal women have reduced production of progesterone. While this “deficiency” is normal, progesterone, including the natural forms of progesterone, has been found to relieve menopausal symptoms when used in combination with estrogen replacement therapy.23

How much is usually taken? The proper amount of progesterone for a woman should be determined in consultation with a doctor. Some research with the natural, oral form of progesterone has used 200 mg per day.24 Progesterone is used in much lower amounts—such as 20–70 mg per day—by most doctors who prescribe topical natural progesterone. However, the ability of skin-applied progesterone to achieve effective levels in the body is the source of considerable debate.25 Although progesterone is a natural substance, oral progesterone supplements are available by prescription only. High-dose topical progesterone cream is also treated like a drug and requires a prescription. A few creams containing lower amounts of progesterone are sold without prescription.

Are there any side effects or interactions? Progesterone is a hormone and, as such, concerns about its inappropriate use have been raised. A physician should be consulted before using this hormone as a supplement. Few side effects have been associated with topical progesterone creams but can include skin reactions. Effects of natural progesterone on breast cancer risk remain unclear. Research has suggested both increased and reduced risk.

Synthetic progestins have many well-known side effects, including the increase of LDL (“bad”) cholesterol and the decrease of HDL (“good”) cholesterol. Other side effects reported with synthetic progestins include bloating, breast soreness, depression, and mood swings. Natural progesterone has been shown to have no adverse effect on HDL cholesterol levels.26 Overall, natural progesterone is considerably safer than progestins and is therefore preferred by many doctors in situations where either would be effective.27

At the time of writing, there were no well-known drug interactions with progesterone.

References:

1. Smith DC, Prentice R, Thompson DJ, et al. Association of exogenous estrogen and endometrial carcinoma. N Engl J Med 1975;293:1164–7.

2. Prior JC. Progesterone as a bone-trophic hormone. Endocr Rev 1990;11:386–98.

3. Lee JR. Osteoporosis reversal: the role of progesterone. Int Clin Nutr Rev 1990;10:384–91.

4. Riis BJ, Thomsen K, Strom V, Christiansen C. The effect of percutaneous estradiol and natural progesterone on postmenopausal bone loss. Am J Obstet Gynecol 1987;156:61–5.

5. Leonetti HB, Longo S, Anasti JM. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol 1999;94:225–8.

6. Martorano JT, Ahlgrimm M, Colbert T. Differentiating between natural progesterone and synthetic progestins: clinical implications for premenstrual syndrome and perimenopause management. Comp Ther 1998;24:336–9.

7. Freeman E, Rickels K, Sondheimer SJ, et al. Ineffectiveness of progesterone suppository treatment for premenstrual syndrome. JAMA. 1990;264:349–53.

8. Leonetti HB, Long S, Anasti JM. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obtstet Gynecol 1999;94:225–8.

9. Lobo RA, McCormick W, Singer F, Roy S. Depo-medroxyprogesterone acetate compared with conjugated estrogens for the treatment of postmenopausal women. Obstet Gynecol 1984;63:1–5

10. Skegg DCG, Noonan EA, Paul C, et al. Depot medroxyprogesterone acetate and breast cancer; a pooled analysis of the World Health Organization and New Zealand studies. JAMA 1995;273:799–804.

11. Foidart JM, Colin C, Denoo X, et al. Estradiol and progesterone regulate the proliferation of human breast epithelial cells. Fertil Steril 1998;69:963–9.

12. Chang KJ, Fournier S, Lee TTY, et al. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertil Steril 1995;63:785–91.

13. Söderqvist G, Isaksson E, von Schoultz B, et al. Proliferation of breast epithelial cells in healthy women during the menstrual cycle. Obstet Gynecol 1997;176:123–8.

14. Cowan LD, Gordis L, Tonascia JA, Jones GS. Breast cancer incidence in women with a history of progesterone deficiency. Am J Epidemiol 1981;114:209–17.

15. Mohr PE, Wang DY, Gregory WM, et al. Serum progesterone and prognosis in operable breast cancer. Br J Cancer 1996;73:1552–5.

16. Cowan LD, Gordis L, Tonascia JA, Jones GS. Breast cancer incidence in women with a history of progesterone deficiency. Am J Epidemiol 1981;114:209–17.

17. Plu-Bureau G, Lê MG, Thalabard MC, et al. Percutaneous progesterone use and risk of breast cancer: results from a French cohort study of premenopausal women with benign breast disease. Cancer Detect Prev 1999;23:290–6.

18. Adams MR, Register TC, Golden DL, et al. Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis. Arterioscler Thromb Vasc Biol 1997;17:217–21.

19. Rosano GMC. Presentation to the American Heart Association’s Scientific Sessions. New Orleans, Louisiana, 1996.

20. Martorano JT, Ahlgrimm M, Colbert T. Differentiating between natural progesterone and synthetic progestins: clinical implications for premenstrual syndrome and perimenopause management. Comp Ther 1998;24:336–9 [review].

21. Araghiniknam M, Chung S, Nelson-White T, et al. Antioxidant activity of dioscorea and dehydroepiandrosterone (DHEA) in older humans. Life Sci 1996;11:147–57.

22. Dollbaum CM. Lab analyses of salivary DHEA and progesterone following ingestion of yam-containing products. Townsend Letter for Doctors and Patients: Oct 1995, 104.

23. Hargrove JT, Maxson WS, Wentz AC, et al. Menopausal hormone replacement therapy with continuous daily oral micronized estradiol and progesterone. Obstet Gynecol 1989;73:606–12.

24. Hargrove JT, Osteen KG. An alternative method of hormone replacement therapy using the natural sex steroids. Infert Repro Med Clin N Am 1995;6:653–74.

25. Cooper A, Spencer C, Whitehead MI, et al. Systemic absorption of progesterone from Progest cream in postmenopausal women. Lancet 1998;351:1255–56 [letter] and Lancet 1998;352:905–6 [comments].

26. Ottosson UB, Johansson BG, von Schoultz B. Subfractions of high-density lipoprotein cholesterol during estrogen replacement therapy: a comparison between progestogens and natural progesterone. Am J Obstet Gynecol. 1985;151:746–50.

27. Hargrove JT, Osteen KG. An alternative method of hormone replacement therapy using the natural sex steroids. Infert Repro Med Clin N Am 1995;6:653–74.