Progesterone as a therapeutic supplement

DEFINITION: Natural substance of the human body used as a supplement to treat specific health conditions.

PRINCIPAL PROPOSED USES: Replacement for standard progestins

OTHER PROPOSED USES: Menopausal symptoms, opposing estrogen, preventing or treating osteoporosis

Overview

Progesterone is one of the two primary female hormones. As the name implies, progesterone prepares (pro) the womb for pregnancy (gestation). Progesterone works in tandem with estrogen; indeed, if estrogen is taken as a medication without being balanced by progesterone (so-called unopposed estrogen), there is an increased risk of uterine cancer.

However, standard progesterone is not well absorbed orally. For this reason, pharmaceutical manufacturers developed progestins, substances similar to progesterone that are more easily absorbed. Most of the time, a woman prescribed progesterone is really being given a progestin. Two of the most commonly used progestins are medroxyprogesterone and norethindrone. However, it has been suggested that actual progesterone may offer benefits over progestins, such as fewer side effects and lower breast cancer risk.

Progesterone can be absorbed through the skin to some extent, and some alternative practitioners have, for years, promoted the use of progesterone creams, vaginal gels, medicated patches, and suppositories. Such progesterone creams are typically, but misleadingly, said to contain natural progesterone. This is an oddly chosen term, as the progesterone in these creams is actually produced in a laboratory, just like other synthetic hormones. To avoid confusion in this article, herein progesterone will be called true progesterone or just progesterone. Besides creams, a special form of true progesterone that can be absorbed orally, micronized progesterone became available as a prescription drug.

Inconsistent evidence suggests that progesterone cream might help reduce symptoms of menopause. However, it does not appear to be strong enough to balance the effects of estrogen, thus reducing the risk of uterine cancer. (Oral micronized progesterone is strong enough for this purpose.) However, scientific evidence that progesterone cream alone offers benefits for osteoporosis is weak, but in combined creams with estrogen, other hormones, or other hormone-inducing substances like soy, benefits are more common.

Requirements and Sources

Progesterone is synthesized in the body and is not found in appreciable quantities in food. For use as a drug or dietary supplement, progesterone is synthesized from chemicals found in soy and Mexican yams. Foods that support the body's natural production of progesterone include leafy greens, nuts, legumes, fish, dark chocolate, and avocados.

Another aspect of the widespread misinformation involving progesterone cream is the concept that Mexican yam itself contains progesterone or substances that the body can convert into progesterone. This is incorrect. Industrial chemists can convert a constituent of Mexican yam (diosgenin) into progesterone, but only by using chemical pathways not found in the body. Over-the-counter creams marketed as menopause support contain the raw version of this compound, which offers no real benefit for its purported purpose.

Therapeutic Dosages

The dose recommendations for progesterone differ based on the strength of the cream, its intended use, and the potential for side effects. If it is used as part of a hormone replacement therapy (HRT) plan, the dose will vary according to the other hormones used. The usual dose of progesterone in topical cream form is 20 milligrams (mg) twice or 40 mg once daily. Although this dose might decrease menopausal hot flashes, most studies found that even doses as high as 64 mg daily do not provide enough progesterone to protect the uterus from the effects of estrogen. However, one study found that the use of micronized progesterone cream at 80 mg daily produced about the same progesterone levels in the body as an oral dose of 200 mg daily; oral micronized progesterone taken at a dose of 200 to 400 mg daily is approximately as effective as the standard dosage of the more commonly used progestins.

Therapeutic Uses

Progesterone cream was widely promoted in the 1990s as a treatment for osteoporosis based on studies whose designs were too poor to establish anything. When properly designed studies were performed, the results were, at best, inconsistent.

Studies conflict on whether progesterone cream can help hot flashes. One double-blind, placebo-controlled study failed to find any improvements in mood or general well-being in menopausal women using progesterone cream. Like progestins, oral progesterone protects the uterus from the stimulating effects of unopposed estrogen. However, standard doses of progesterone cream probably provide too little progesterone to serve this purpose.

Scientific Evidence

Osteoporosis. Despite widespread reporting that true progesterone is effective for treating or preventing osteoporosis, the evidence for such an effect is, at best, inconsistent. This notion originated with test tubes and other preliminary studies suggesting that progesterone or progestins can stimulate the activity of cells that build bone. Subsequently, a poorly designed and uncontrolled study (a series of case histories from one physician’s practice) demonstrated that progesterone cream can slow or even reverse osteoporosis.

However, a one-year double-blind trial of 102 women given either progesterone cream (providing 20 mg progesterone daily) or placebo cream, along with calcium and multivitamins, found no evidence of any improvements in bone density attributable to progesterone. A smaller, short-term trial found that progesterone cream has no effect on bone metabolism.

In contrast to these negative results, benefits were seen in a small two-year, double-blind, placebo-controlled study in which twenty-two women were given progesterone cream. (Interestingly, in this study, the use of progesterone cream plus soy isoflavones produced benefits inferior to those of progesterone cream alone.) Soy isoflavones showed further positive potential in several studies of postmenopausal women. Soy isoflavone cream used with or without progesterone may be helpful for osteoporosis. Another study found that oral estrogen-progesterone therapy was more effective than either hormone on its own in preventing spinal bone density loss.

Menopausal symptoms. In the one-year double-blind trial of 102 women described above, progesterone cream significantly reduced hot flashes and related symptoms. However, a slightly smaller twelve-week double-blind trial failed to find progesterone cream helpful for reducing menopausal symptoms. The authors of this second study point out that the first study was statistically flawed. Further research supported using around 20 mg per milliliter of topical cream for hot flashes alone.

By the end of the 2010s, researchers had begun to place more focus on conducting studies to determine the effects and potential benefits of using oral micronized progesterone as a treatment for menopausal hot flashes and sleeping difficulties. However, by that point, scientists had not yet completed large randomized controlled trials for that purpose. Additionally, the long-term use of progesterone had not been adequately studied.

Opposing estrogen. Unless a woman has had a hysterectomy, if she takes estrogen, she needs to take progesterone, too, or run the risk of uterine cancer. Two twelve-week double-blind studies enrolling about one hundred women found that progesterone cream (at doses up to 64 mg) did not have the required protective effect on uterine cells. However, one study found benefits at dosages of either 15 or 40 mg daily. The explanation for these disparate results may lie in the results of two other studies, which suggest that progesterone cream is erratically absorbed.

Safety Issues

Even though progesterone is sold as a dietary supplement, it is a hormone, not a food. Its use is not recommended except under a physician’s supervision. Like progestins, true progesterone causes side effects. In one study, oral micronized progesterone at a dose of 400 mg per day was associated with dizziness, abdominal cramping, headache, breast pain, muscle pain, irritability, nausea, fatigue, diarrhea, and viral infections.

Long-term use of progesterone may increase the risk of stroke, heart attack, breast or ovarian cancer, endometriosis, or uterine fibroids. The use of estrogen with progesterone also increases these risks.

Bibliography

Barańska, Agnieszka, et al. "The Role of Soy Isoflavones in the Prevention of Bone Loss in Postmenopausal Women: A Systematic Review with Meta-Analysis of Randomized Controlled Trials" Journal of Clinical Medicine, vol. 11, no. 16, 2022, p. 4676. doi.org/10.3390/jcm11164676.

Hermann, A. C., et al. “Over-the-counter Progesterone Cream Produces Significant Drug Exposure Compared to a Food and Drug Administration-Approved Oral Progesterone Product.” Journal of Clinical Pharmacology 45, no. 6 (2005): 614-619.

Leonetti, H. B., K. J. Wilson, and J. N. Anasti. “Topical Progesterone Cream Has an Antiproliferative Effect on Estrogen-Stimulated Endometrium.” Fertility and Sterility 79 (2003): 221-22.

Lydeking-Olsen, E., et al. “Soymilk or Progesterone for Prevention of Bone Loss.” European Journal of Nutrition, vol. 4, no. 4, 2004, pp. 246-257. doi:10.1007/s00394-004-0497-8.

Nonacs, Ruta. "In Brief: Does Micronized Progesterone Relieve Perimenopausal Symptoms?" MGH Center for Women's Mental Health, 27 Mar. 2018, womensmentalhealth.org/posts/in-brief-does-micronized-progesterone-relieve-perimenopausal-symptoms. Accessed 25 June 2020.

“Progesterone.” MedlinePlus, 15 Apr. 2016, medlineplus.gov/druginfo/meds/a604017.html. Accessed 20 Dec. 2022.

Wong, Cathy. "Progesterone Cream Benefits, Risks, and Alternatives." Verywell Health, 6 Nov. 2023, www.verywellhealth.com/what-to-know-about-progesterone-cream-89503. Accessed 20 Sept. 2024.

Wren, B. G., 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, 10 (2003): 13-18.