Hormone Therapy: Continuous Progesterone Safer

Which is better: to take progesterone continuously or sequentially (e.g., day 12-26 each month)? There are arguments on both sides, but this latest study shows that continuous progesterone has a 76% lower risk of endometrial cancer after 3-5 years. That is why I recommend regular uterine monitoring every 6+ months in women on sequential progesterone. -- SG

The long-term safety of different hormone therapy regimens has not been adequately studied in the context of endometrial cancer risk. In a national cohort study, investigators followed 224,000 Finnish women (age, >50) who used oral or transdermal estrogen-progestin (E+P) HT from 1994 to 2006. HT regimens were considered to be sequential if daily estradiol was accompanied by 10 to 14 days of progestin monthly or, in long-cycle regimens, during each 3-month interval. In continuous regimens, both estradiol and progestin were used nonstop. Incidence of endometrial cancer in E+P users was compared with that in all Finnish women.

A total of 1402 cases of incident endometrial cancer were identified. Compared with the general population, E+P users overall had 54% and 23% higher relative risk for type I and type II endometrial tumors, respectively. Monthly sequential E+P HT was associated with 69% (5 years' use) and 156% (10 years' use) higher risk for type I tumors. At 5 and 10 years of use, long-cycle sequential HT was associated with substantially higher risk for type I tumors than was monthly sequential HT. The endometrial safety of transdermal and oral sequential HT was similar; sequential HT with medroxyprogesterone acetate and norethindrone acetate also exhibited similar endometrial safety. Use of continuous E+P HT was associated with lower risk for type I tumors than in the overall population (76% risk reduction after 3–5 years' use).

Comment: Unopposed estrogen therapy or E+P hormone therapy with inadequate progestin raises risk for low-grade endometrial adenocarcinoma (i.e., type I) in menopausal women. Risks for high-grade serous papillary carcinoma and clear-cell adenocarcinoma (i.e., type II) are less clearly associated with HT use. These results are important in clarifying that, although long-term continuous E+P HT is protective, sequential therapy substantially raises risk for endometrial adenocarcinoma. The authors estimate that among 1000 women who use E+P HT for 10 years, eight additional cancer cases will be diagnosed if HT is sequential and monthly, whereas three to four fewer cases will be diagnosed if HT is continuous. For women who use sequential E+P HT long term, endometrial monitoring is appropriate.
— Andrew M. Kaunitz, MD

Published in Journal Watch Women's Health December 17, 2009

Citation(s):
Jaakkola S et al. Endometrial cancer in postmenopausal women using estradiol–progestin therapy. Obstet Gynecol 2009 Dec; 114:1197.