Progesterone for Prevention of Endometrial Hyperplasia by Jeffrey Dach MD

Unopposed Premarin Causes Endometrial Cancer

In 1975, Dr. Donald Smith discovered that unopposed exogenous estrogen increases risk for endometrial cancer by 4.5 times greater than controls. In 1975, Dr. Harry Ziel found the risk for endometrial cancer using Premarin type estrogen products was increased by 7.6 times, rising to 13.9 with greater than 7 years’ of use. In 1976, Dr. Thomas M. Mack confirmed these same findings. (2-4)

15,000 Cases of Iatrogenic Endometrial Cancer

In 1975, Dr. Hershel Jick estimated that in the years from 1971-1975  that an estimated 15,000 cases of iatrogenic endometrial cancer caused by use of unopposed Premarin (CEE, conjugated equine estrogen). Unopposed Premarin causes endometrial hyperplasia and increases risk for endometrial cancer. Note: Unopposed estrogen means estreogen was used without the added progestin or progesterone which prevents endometrial hyperplasia and prevents endometrial cancer. (5)

Prevention of endometrial hyperplasia and risk for endometrial cancer is main reason why a progestin such as medroxyprogesterone (Prevera MPA) 2.5 mg/day is added to the estrogen (Premarin or estradiol).  Natural progesterone is also FDA approved for prevention of endometrial hyperplasia (Solvay). (2-14)

FDA Approval for Prometrium (natural progesterone)

The 1996 PEPI papers by Dr. Howard Judd are the primary modern RCTs most directly tied to micronized progesterone’s endometrial protection data used around the time of Prometrium’s approval. The label’s described 36-month trial is FDA-submitted clinical evidence. Later reviews and systematic analyses continue to cite PEPI as the cornerstone for oral micronized progesterone at 200 mg sequential dosing for 12 days per month. Dr. Howard Judd writes:

Of the 45 women with complex (adenomatous) or atypical hyperplasia, study medications were discontinued in all, and the biopsy results of 34 (94%) of 36 women with hyperplasia reverted to normal with progestin therapy. The remainder had dilatation and curettage (n=2) or hysterectomy with (n=2) or without (n=6) prior medical therapy, or refused further biopsies (n=1). One woman developed adenocarcinoma of the endometrium while receiving placebo….  At a dosage of 0.625 mg, the daily administration of CEE enhanced the development of endometrial hyperplasia. Combining CEE with cyclic or continuous MPA (medroxyprogesterone) or cyclic MP (micronized progesterone) protected the endometrium from hyperplastic changes associated with estrogen-only therapy. (8)

100 mg PO QHS Continuous Micronized Progesterone PO

The landmark 2018 RCT by Dr. Rogerio A Lobo, showed no endometrial hyperplasia with continuous 100 mg oral micronized progesterone combined with 1 mg oral 17-Beta-estradiol. (9-14)

The 2002 WHI, Women’s Health Initiative Study

How many cases of endometrial cancer in women taking Premarin/MPA combination in the Women’s Health Initiative? There were about 25 cases, about the same for each arm. See Table 2 (below):
Endometrial cancer:
22 cases in Premarin MPA group and
25 cases placebo group. (HR=.83 nonsignificant). (10)

The 2002 Women’s Health Initiative (WHI) estrogen/ MPA progestin trial  randomized 16,608 postmenopausal women aged 50–79 with an intact uterus: 8,506 to daily conjugated equine estrogens (Premarin 0.625 mg) + medroxyprogesterone acetate (MPA 2.5 mg) and 8,102 to placebo. The trial (planned for ~8.5 years) was stopped early after a mean of 5.2 years of follow-up (data through April 30, 2002; recommendation on May 31, 2002) because risks exceeded benefits. See below Table 2. for Key results after mean 5.2 years follow up. (1)

Table 2. Coronary heart disease (CHD; nonfatal MI + CHD death): HR 1.29 (1.02–1.63); ~7 more events.
Invasive breast cancer: HR 1.26 (1.00–1.59); ~8 more.
Stroke: HR 1.41 (1.07–1.85); ~8 more.
Pulmonary embolism (PE): HR 2.13 (1.39–3.25); ~8 more.
Colorectal cancer: HR 0.63 (0.43–0.92); ~6 fewer.
Hip fracture: HR 0.66 (0.45–0.98); ~5 fewer.
Endometrial cancer: HR 0.83 (0.47–1.47) (nonsignificant).
Death from other causes: HR 0.92 (0.74–1.14) (nonsignificant).
Total cardiovascular disease: HR 1.22 (1.09–1.36).
Total cancer: HR 1.03 (0.90–1.17).
Combined fractures: HR 0.76 (0.69–0.85).
Total mortality: HR 0.98 (0.82–1.18) (no significant difference).
Global index (CHD, invasive breast cancer, stroke, PE, endometrial cancer, colorectal cancer, hip fracture, or death from other causes): HR 1.15 (1.03–1.28); absolute excess of 19 events per 10,000 person-years.

Above Table 2. Courtesy of : Rossouw, Jacques E., et al. “Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial.” JAMA: the journal of the American Medical Association 288.3 (2002): 321-333. (1)

Conclusion: The use of natural progesterone or a progestin such as MPA is required to prevent endometrial hyperplasia and risk for endometrial cancer. The medical literature suggests 2.5  mg of MPA or 100 mg PO micronized progresterone per day is a suitable dosage. For sequental use, 12 days per month, 200 mg oral progesterone nightly was used. When endometrial hyperplasia is found  on endometrial biopsy,  94% of patients revert to normal after stopping the hormones and taking a progestin. In 1996, Dr. Howard Judd of the PEPI Trial writes:

Of the 45 women with complex (adenomatous) or atypical hyperplasia, study medications were discontinued in all, and the biopsy results of 34 (94%) of 36 women with hyperplasia reverted to normal with progestin therapy. (8)

Jeffrey Dach MD
7450 Griffin Road Suite 180/190
Davie, Fl 33314
954-792-4663

References:

1) Rossouw, Jacques E., et al. “Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial.” JAMA: the journal of the American Medical Association 288.3 (2002): 321-333.

2) Smith, Donald C., et al. “Association of Exogenous Estrogen and Endometrial Carcinoma.” The New England Journal of Medicine, vol. 293, no. 23, 4 Dec. 1975, pp. 1164–67.

URL: https://www.nejm.org/doi/full/10.1056/NEJM197512042932302
(Risk ~4.5-fold higher among estrogen users; 317 cases vs. matched controls.)

3) Ziel, Harry K., and William D. Finkle. “Increased Risk of Endometrial Carcinoma among Users of Conjugated Estrogens.” *The New England Journal of Medicine*, vol. 293, no. 23, 4 Dec. 1975, pp. 1167–70. https://doi.org/10.1056/NEJM197512042932303.
URL: https://www.nejm.org/doi/full/10.1056/NEJM197512042932303
(Specifically for conjugated estrogens/Premarin-type products; risk ratio 7.6 overall, rising to 13.9 with ≥7 years’ use; etiologic fraction ~50%.)

4) Mack, Thomas M., et al. “Estrogens and Endometrial Cancer in a Retirement Community.” *The New England Journal of Medicine*, vol. 294, no. 23, 3 June 1976, pp. 1262–67. https://doi.org/10.1056/NEJM197606032942304.
URL: https://www.nejm.org/doi/full/10.1056/NEJM197606032942304
(Risk ratio ~8.0 for any estrogen use and ~5.6 for conjugated estrogens; dose-response shown; risk exceeded baseline risk from other single cancers.)

5) Jick, Hershel, et al. “The Epidemic of Endometrial Cancer: A Commentary.” *American Journal of Public Health*, vol. 70, no. 3, Mar. 1980, pp. 264–67. https://doi.org/10.2105/AJPH.70.3.264.
URL (PMC full text): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1619376/
(or direct PDF: https://pmc.ncbi.nlm.nih.gov/articles/instance/1619376/pdf/amjph00676-0058.pdf)

6) Smith DC, Prentice R, Thompson DJ, Herrmann WL.** “Association of Exogenous Estrogen and Endometrial Carcinoma.” *New England Journal of Medicine*, vol. 293, no. 23, 4 Dec. 1975, pp. 1164–67. https://doi.org/10.1056/NEJM197512042932302
URL: https://www.nejm.org/doi/full/10.1056/NEJM197512042932302
(Classic case-control study showing ~4.5-fold increased risk of endometrial carcinoma with exogenous estrogen use; highly cited foundational paper.)

7) Ziel HK, Finkle WD.** “Increased Risk of Endometrial Carcinoma among Users of Conjugated Estrogens.” *New England Journal of Medicine*, vol. 293, no. 23, 4 Dec. 1975, pp. 1167–70. https://doi.org/10.1056/NEJM197512042932303
URL: https://www.nejm.org/doi/full/10.1056/NEJM197512042932303
(Companion classic case-control study focused on conjugated estrogens, showing risk ratio ~7.6 overall and higher with longer duration; also highly cited and specifically relevant to Premarin-type products.)

8) Judd, Howard L., et al. “Effects of hormone replacement therapy on endometrial histology in postmenopausal women: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.” Jama 275.5 (1996): 370-375.

Writing Group for the PEPI Trial. “Effects of Hormone Replacement Therapy on Endometrial Histology in Postmenopausal Women: The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.” JAMA, vol. 275, no. 5, 7 Feb. 1996, pp. 370–75.

https://doi.org/10.1001/jama.1996.03530290040035
URL: https://jamanetwork.com/journals/jama/fullarticle/395611
(Key randomized trial using CEE 0.625 mg [Premarin] alone vs. CEE + progestins [including micronized progesterone]. Unopposed CEE produced high rates of simple, complex, and atypical hyperplasia; adding progestin [MPA or micronized progesterone] reduced rates to placebo levels. This trial provided key evidence for endometrial protection and informed FDA labeling for Prometrium.)

9) Lobo, Rogerio A., et al. “A 17β-Estradiol–Progesterone Oral Capsule for Vasomotor Symptoms in Postmenopausal Women: A Randomized Controlled Trial.” Obstetrics & Gynecology, vol. 132, no. 1, July 2018, pp. 161–70.
https://doi.org/10.1097/AOG.0000000000002645.
URL: https://journals.lww.com/greenjournal/fulltext/2018/07000/a_17__estradiol_progesterone_oral_capsule_for.23.aspx
(Alternative stable link:
https://journals.lww.com/greenjournal/fulltext/10.1097/aog.0000000000002645~a-17-estradiolprogesterone-oral-capsule-for-vasomotor)
This is the primary published report of the phase 3 REPLENISH trial (NCT01942668). It evaluated continuous combined daily oral 17β-estradiol + micronized progesterone (including the 1 mg/100 mg and 0.5 mg/100 mg doses) and reported no endometrial hyperplasia at 12 months while showing efficacy for vasomotor symptoms. (A related follow-up paper focusing more on endometrial safety and bleeding is available in Menopause, but the 2018 Obstetrics & Gynecology paper is the main trial publication referenced for the continuous 100 mg progesterone data.)

Conclusion: No endometrial hyperplasia was observed while single-capsule estradiol–progesterone provided clinically meaningfully improvements in moderate-to-severe vasomotor symptoms. This estradiol–progesterone formulation may represent a new option, using naturally occurring hormones, for the estimated millions of women using nonregulatory-approved, compounded hormone therapy.

10) (Schering Corporation; marketed/promoted by Solvay Pharmaceuticals) for FDA approval of Prometrium (micronized progesterone) for prevention of endometrial hyperplasia.

The supporting data came from a proprietary randomized, double-blind clinical trial submitted as part of NDA 020843 (approved 26 December 1998). Results are summarized in the FDA product labeling and NDA review documents rather than a standalone published paper.

Description of the study (from FDA labeling)
Randomized, double-blind trial in 358 postmenopausal women with an intact uterus, treated for up to 36 months:
PROMETRIUM Capsules 200 mg/day for 12 days per 28-day cycle + conjugated estrogens 0.625 mg/day (n ≈ 120)
Conjugated estrogens 0.625 mg/day alone (n ≈ 119)
Placebo (n ≈ 119)

Incidence of endometrial hyperplasia: 6% (combination) vs. 64% (estrogen alone) vs. 3% (placebo).

11) FDA Drug Approval Package (primary source for the submitted study data)  U.S. Food and Drug Administration. Drug Approval Package:

Prometrium (Progesterone) Capsules, NDA #020843. 26 Dec. 1998.
URL: https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/020843_s000_PrometriumTOC.cfm

12) Current / historical product labeling that reports the study results
“PROMETRIUM (progesterone, USP) Capsules.” DailyMed, U.S. National Library of Medicine.
URL: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1cf237ff-c4f8-4faa-a7aa-77599c856889
(or the FDA label PDF archives, e.g., historical versions such as https://www.accessdata.fda.gov/drugsatfda_docs/label/1998/20843lbl.pdf)

Solvay’s 1998 press release announcing approval also referenced the NIH-sponsored PEPI trial (which included a 200 mg sequential micronized progesterone arm), but PEPI was not the proprietary study submitted in the NDA for Prometrium’s hyperplasia indication.

13) Lobo, Rogerio A., et al. “Estradiol and Progesterone Bioavailability for Moderate to Severe Vasomotor Symptom Treatment and Endometrial Protection with the Continuous-Combined Regimen of TX-001HR (Oral Estradiol and Progesterone Capsules).” *Menopause*, vol. 26, no. 7, July 2019, pp. 720–27.
https://doi.org/10.1097/GME.0000000000001306.
URL: https://journals.lww.com/menopausejournal/fulltext/2019/07000/estradiol_and_progesterone_bioavailability_for.8.aspx
(or PMC open access: https://pmc.ncbi.nlm.nih.gov/articles/PMC6636803/)
(REPLENISH secondary analysis focusing on pharmacokinetic levels of continuous 100 mg progesterone with 1 mg or 0.5 mg estradiol and confirmation of endometrial protection.)

Results: In REPLENISH (n = 1,835), mean P4 levels were 0.39 to 0.55 ng/mL with 100-mg P4 doses;
E2 levels were 42.3 to 45.6 pg/mL and 23.0 to 27.4 pg/mL for the 1-mg and 0.5-mg E2 doses, respectively;
E1 levels were 214 to 242 pg/mL and 114 to 129 pg/mL for the 1-mg and 0.5-mg E2 doses.
In the phase 1 study (n = 40; day 7), mean C(avg) for P4 was 0.66 ng/mL with 100-mg P4 doses;
E2 was 38.1 pg/mL and 29.2 pg/mL for 1 mg and 0.5 mg E2, respectively; and E1 was 211 and 106 pg/mL for 1 mg and 0.5 mg E2.
All three analytes reached steady state within 7 days; accumulation ratios were 1.36 to 1.94.
Conclusions: P4 levels observed with TX-001HR were similar in the phase 1 and 3 studies, and were associated with no endometrial hyperplasia with either E2 daily dose over 1 year in the REPLENISH phase 3 study, which showed significant improvements in menopausal vasomotor symptoms.

14) Mirkin, Sebastian, et al. “Endometrial safety and bleeding profile of a 17β-estradiol/progesterone oral softgel capsule (TX-001HR)∗.” Menopause (New York, NY) 27.4 (2020): 410.

https://doi.org/10.1097/GME.0000000000001480.
URL: https://journals.lww.com/menopausejournal/fulltext/2020/04000/endometrial_safety_and_bleeding_profile_of_a.7.aspx
(or PMC: https://pmc.ncbi.nlm.nih.gov/articles/PMC7147409/)
(Detailed endometrial histology and amenorrhea results from REPLENISH with continuous 100 mg progesterone doses; incidence of hyperplasia ≤0.36%.)