Progesterone is a hormone made by the ovary and the placenta. As a medicine it is used in two ways: to protect the uterine lining during estrogen therapy, and, less often, for sleep and symptoms. The trials and cohorts behind it are not all about the same form, and the differences matter.
Why it is paired with estrogen
The PEPI trial enrolled 875 healthy postmenopausal women aged 45 to 64 and followed them for 3 years on placebo, estrogen alone, or estrogen with a progestin. Unopposed estrogen produced endometrial hyperplasia in 34% of women, against 1% in the other active arms. The estrogen-alone arm had the largest HDL rise, but the high rate of lining changes is why the trial's authors favored combined therapy for women with a uterus.
Lipids and blood pressure in PEPI
Active arms lowered LDL cholesterol by about 14.5 to 17.7 mg/dL against placebo and raised triglycerides slightly. Systolic blood pressure did not differ significantly between groups. The trial measured these markers, not heart attacks or strokes, and it was not designed to show clinical outcomes.
Breast cancer: the type of progestogen matters
In the E3N cohort of 54,548 French women, the relative risk for synthetic progestins was 1.4 and for micronized progesterone 0.9 (P<0.001). A 2008 follow-up of 80,377 women with 2,354 breast cancers found estrogen alone at a relative risk of 1.29, no significant association for estrogen with progesterone, and the highest estimate (1.69) for estrogen with other progestogens. These are observational cohorts; they show associations and cannot prove safety.
Creams and blood levels
A small 2000 study gave one 64 mg topical dose of micronized progesterone cream to six premenopausal and six postmenopausal women. Serum progesterone did not rise in the first 3 hours, while saliva levels did. The authors concluded that serum levels from the cream were lower than after oral or vaginal dosing, and that higher doses may be needed for an effect on the lining. Creams have much less trial evidence than the oral form.
What this does not say
- The trials tested oral micronized progesterone and synthetic progestins. Compounded creams, troches and dissolving tablets were not tested in the trials cited here.
- PEPI's lipid results are surrogate markers; they do not show fewer heart events.
- The E3N results are from observational cohorts and cannot prove that micronized progesterone is safe.
How we use this
When a woman with a uterus takes estrogen, we consider a progestogen to protect the lining. The trial evidence favors the form studied in PEPI and E3N over synthetic progestins. We do not present creams as equivalent to oral micronized progesterone.
We describe what each form does and does not have in trials, so the choice is yours with your physician.
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- 1.The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995;273:199-208. JAMA
- 2.Fournier A et al. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer 2005;114:448-454. Int J Cancer
- 3.Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008;107:103-111. Breast Cancer Research and Treatment
- 4.Clinical Endocrinology study of salivary, serum and urinary progesterone after topical progesterone cream in pre- and postmenopausal women. Clin Endocrinol (Oxf) 2000;53:615-620. Clinical Endocrinology
- 5.Faubion SS et al. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause 2022;29(7):767-794. Menopause (NAMS)