Progesterone (micronized, bioidentical)

What progesterone is

Progesterone is produced by the corpus luteum after ovulation. It prepares the uterine lining for a possible pregnancy and limits its growth. After menopause it is no longer produced, and anyone who then takes estrogen and has a uterus needs a counterpart so that the lining does not grow excessively. More on the overall treatment is on the page on menopausal hormone therapy.

Micronized progesterone is finely ground progesterone, identical to the body’s own hormone, that is adequately absorbed as a capsule. This distinguishes it from synthetic progestins such as medroxyprogesterone acetate, which was used in the large WHI study. This distinction is at the core of the debate about “bioidentical” hormones.

How it works

In the uterine lining, progesterone counteracts the growth-promoting effect of estrogen. In the brain, breakdown products of progesterone have a calming effect; this could explain the drowsiness after taking it and the possible effect on disturbed sleep (Caufriez 2011).

Progesterone is itself a link in a hormone chain that begins with pregnenolone. The page on cycle biohacking covers its role in the menstrual cycle.

What the studies show

PEPI 1996: protection of the uterine lining compared

596 women aged 45 to 64 received placebo, estrogen alone, or estrogen with one of three progestin regimens for 3 years, including 200 mg micronized progesterone on 12 days per cycle. Under estrogen alone, hyperplasia frequently developed; with all three progestin regimens the rate was as low as under placebo. 34 of 36 women with hyperplasia returned to normal under progestin treatment.

WHI 2002: what the early stop means and what it does not

The Women’s Health Initiative randomized 16,608 women aged 50 to 79 to conjugated estrogens plus medroxyprogesterone acetate or placebo and was stopped after 5.2 years. Per 10,000 women per year there were 7 more cardiac events, 8 more strokes, 8 more pulmonary embolisms and 8 more breast cancer cases, but 6 fewer colorectal cancer cases and 5 fewer hip fractures; overall mortality was unchanged. What was tested was a synthetic progestin, not micronized progesterone.

E3N 2008: breast cancer by progestin

The French E3N cohort followed 80,377 postmenopausal women for an average of 8.1 years. Compared with women without hormone therapy, the relative breast cancer risk was 1.00 for estrogen plus progesterone, 1.16 for estrogen plus dydrogesterone and 1.69 for estrogen plus other progestins (Fournier 2008). That is a clear difference, but from an observational study: who received which product was not randomly assigned.

ESTHER 2007: thrombosis by route and progestin

The case-control study ESTHER compared 271 women with a first thrombosis with 610 controls. Oral estrogen was associated with a fourfold risk (OR 4.2), transdermal estrogen was not (0.9). Micronized progesterone was not associated with an increased risk (OR 0.7), whereas norpregnane progestins were (OR 3.9). This too is an observational finding (Canonico 2007).

Hot flashes: two studies, two results

After menopause, 300 mg progesterone at bedtime relieved hot flashes considerably more than placebo in a randomized trial with 133 women (Hitchcock and Prior 2012). In perimenopause, a randomized trial with 189 women found no significant difference in the primary measure; the women did, however, report fewer night sweats and better sleep. The authors consider the trial too small to rule out a relevant effect (Prior 2023).

Where the data stop

• That bioidentical progesterone is safer than synthetic progestins. The indications on breast cancer and thrombosis are impressive but come from observational studies. There is no randomized comparison with hard endpoints.
• Progesterone as a sleeping pill. The sleep finding is based on 8 women, and undisturbed sleep did not change. Progesterone is not approved for sleep disorders.
• Hot flashes in perimenopause. Here the only large randomized trial showed no significant effect on the primary measure.
• Progesterone creams. In two of three randomized trials, ready-made creams were no better than placebo against hot flashes; only a specially compounded cream worked. Protection of the uterine lining has been shown for the capsule (PEPI), not for creams.

Status, approval and legal

Progesterone is prescription-only in Germany. As a capsule, micronized progesterone, for example Utrogest, is approved in adults for cycle disorders caused by progesterone deficiency and as add-on therapy to estrogen hormone replacement treatment in postmenopausal women who still have a uterus.

For hormone therapy, the summary of product characteristics specifies 200 mg as a single dose before bedtime on at least 12 to 14 days per month. Use as a sleeping pill, against hot flashes without estrogen or as an anti-aging agent is not approved.

Safety

According to the summary of product characteristics, progesterone taken by mouth can cause drowsiness and dizziness, especially with concurrent estrogen deficiency; it is therefore taken in the evening and can impair the ability to drive. Contraindications include undiagnosed bleeding, severe liver dysfunction, liver tumors, known or suspected malignant tumors of the breast or genital organs, and previous or existing thromboembolism.

The known risks of hormone therapy from the WHI concern the combination with a synthetic progestin. Whether micronized progesterone actually lowers these risks is derived from observational studies; the summary of product characteristics continues to treat thromboembolism as a risk of hormone replacement therapy.

Sources

• Rossouw JE et al., JAMA 2002 – Women’s Health Initiative, conjugated estrogens plus medroxyprogesterone acetate, 16,608 women
• PEPI Writing Group, JAMA 1996 – endometrium under estrogen alone or with progestin or micronized progesterone, 596 women
• Fournier A et al., Breast Cancer Res Treat 2008 – E3N cohort, breast cancer risk by progestin, 80,377 women
• Canonico M et al., Circulation 2007 – ESTHER, thrombosis risk by route of estrogen administration and progestin, case-control study
• Hitchcock CL and Prior JC, Menopause 2012 – micronized progesterone against hot flashes, RCT with 133 postmenopausal women
• Prior JC et al., Sci Rep 2023 – micronized progesterone for hot flashes in perimenopause, RCT with 189 women
• Caufriez A et al., J Clin Endocrinol Metab 2011 – progesterone and sleep in 8 postmenopausal women, randomized, placebo-controlled
• Whelan AM et al., Ann Pharmacother 2013 – progesterone cream against hot flashes, systematic review of 3 RCTs
• Summary of product characteristics (Fachinformation) Utrogest 100 mg/200 mg soft capsules (as of January 2023)
• German Ordinance on Prescription-Only Medicines (AMVV), Annex 1 – progesterone prescription-only