Research: Progesterone & the Uterus

Overview

Progesterone or progestins are a necessary adjunct to estrogen therapy in women who have a uterus (i.e., who have not had a hysterectomy) because of the risk of endometrial (uterine) cancer when estrogen is given alone. Progesterone has an antiproliferative effect and therefore protects the uterus.

Research

Leonetti HB, Landes J, Steinberg D, Anasti JN. Topical progesterone cream as an alternative progestin in hormone therapy. Altern Ther Health Med 2005; 11(6):36-38.
This study evaluated the endometrial effects and determined patients’ acceptance of transdermal progesterone cream compared to standard hormone therapy. Healthy menopausal women were recruited and received a pretreatment endometrial biopsy (EMB). They were randomized to 0.625 mg conjugated equine estrogen (CEE) daily and 2.5 mg medroxyprogesterone acetate (MPA) (Prempro^TM) or daily 0.625 mg CEE and twice daily 20 mg transdermal PC (Pro-gest®). At the end of 6 months, a repeat EMB was obtained, and the women were crossed over to other treatment. A final EMB was performed after the final 6 months. Twenty-six women completed both arms of the study. Seventy-seven percent of women preferred the CEE/PC to the CEE/MPA (P<.001). Of the 52 post-treatment endometrial biopsies: 40 revealed atrophic endometrium and 12 proliferative endometrium (7 in the oral progestin group and 5 in the PC group). There was no evidence of endometrial hyperplasia in any of the specimens. The incidence of vaginal spotting was similar in both groups. Conclusion: Patients preferred transdermal PC over oral MPA. These preliminary data indicate that CEE/PC has a similar effect on the endometrium as standard oral HT over a 6-month period.
Anasti JN, Leonetti HB, Wilson KJ. Topical progesterone cream has antiproliferative effect on estrogen-stimulated endometrium. Obstet & Gynecol 2001; 97(4 Suppl.):10S and Fertil Steril 2003;79(1):221-2.
This randomized, controlled study involving 58 postmenopausal women demonstrated that topically applied progesterone cream (Pro-gest®) had an antiproliferative effect in postmenopausal women who had been given oral estrogens x 14 days prior to progesterone treatment. Treatment with topical progesterone did not differ in effects from vaginally applied progesterone (Crinone®), and both progesterone applications demonstrated a significant effect over placebo. Patients preferred the topical application of progesterone cream.
Leonetti HB, Anasti JN, Landes J. Topical progesterone cream: an alternative progestin in hormone replacement therapy. Obstet & Gynecol 2003; 101(4 Suppl.):85.
20 women completed a 1 year randomized, controlled, cross-over study comparing conjugated equine estrogen (Premarin®, 0.625 mg) paired with progesterone cream (Pro-gest®, 20 mg) vs. conjugated equine estrogen paired with medroxyprogesterone acetate (Prempro^TM). Endometrial biopsies were performed at the end of each 6-month arm of the study. No hyperplasia was found in either group. Incidence of spotting was similar in both groups. Participants preferred the progesterone cream formulation (76% vs 5%, p<0.001).
Cicinelli E, de Ziegler D, Galantino P, Pinto V, Barba B, Morgese S, Schonauer S. Twice-weekly transdermal estradiol and vaginal progesterone as continuous combined hormone replacement therapy in postmenopausal women: a 1-year prospective study. Am J Obstet Gynecol 2002 Sep;187(3):556-60.
In this study of 35 postmenopausal women, twice-weekly administration of a progesterone vaginal gel (45 mg P4/day) sufficiently protected the endometrium in women receiving transdermal estradiol (0.05 mg/d) as revealed by endometrial thickness and histology. The authors present vaginally applied progesterone as a viable option for hormone replacement therapy at menopause.
Montz FJ, Bristow RE, Bovicelli A, Tomacruz R, Kurman RJ. Intrauterine progesterone treatment of early endometrial cancer. Am J Obstet Gynecol 2002 Apr;186(4):651-7.
This study evaluated the use of a progesterone-releasing IUD as a feasible treatment for early stage endometrial cancer (IA, grade 1). Twelve subjects were followed for 36 months. Results suggested IUD progesterone appeared to resolve some cases of early endometrial cancer.
Ferrero S, Gerbaldo D, Fulcheri E, Cristoforoni P. Vaginal micronized progesterone in continuous hormone replacement therapy. A prospective randomized study. Minerva Ginecol 2002; 54(6):519-30.
Transvaginal micronized progesterone (100 mg/day for 12 days/month) effectively promoted a functional, secretory endometrium, while cyclic oral MPA or transdermal norethisterone acetate more often produced endometrial atrophy, in women receiving continuous transdermal estradiol.
Fanchin R, De Ziegler D, Bergeron C, et al. Transvaginal administration of progesterone. Obstet Gynecol 1997;90:396-401.

Three different doses of transvaginal progesterone gel were administered to 40 estrogen-deprived women aged 25-41 years. Estradiol was administered orally for 28 days, with progesterone added vaginally on alternate days from days 15-27. Plasma gonadotropins, E1, E2 and progesterone were measured, and an endometrial biopsy was obtained to assess endometrial status and estrogen and progesterone receptor determinations. Transvaginal progesterone induced normal secretory transformation despite low serum progesterone levels, suggesting a direct transit of progesterone into the uterus, or “first uterine pass effect.”
Casanas-Roux F, Nisolle M, Marbaix E, et al. Morphometric, immunohistological and three-dimensional evaluation of the endometrium of menopausal women treated by oestrogen and Crinone®, a new slow-release vaginal progesterone. Human Reprod 1996;11:357-63.
Twenty estrogen-deprived women were given oral estrogen for 12 days followed by oral estrogen- vaginal progesterone gel for 12 days. Endometrial evaluation occurred before treatment, after the estrogen-only phase and after estrogen-progesterone gel treatment. Atrophy was present before treatment in all patients. Typical proliferative changes occurred after estrogen-only treatment, and secretory transformation occurred after estrogen-progesterone treatment, indicating that sustained-release progesterone gel can effectively counteract the proliferative effects of estrogen treatment in postmenopausal women.
Moyer DL, de Lignieres B, Driguez P, Pez JP. Prevention of endometrial hyperplasia by progesterone during long-term estradiol replacement: influence of bleeding pattern and secretory changes. Fertil Steril 1993 May;59(5):992-7.
It is often presumed that progesterone levels must be high enough to induce endometrial bleeding by withdrawal in order to convey protection during estrogen replacement therapy. In this expanded observational study, the authors sought to determine the influence of withdrawal bleedings, secretory transformation, and reduction of mitosis on the prevention of endometrial hyperplasia during long-term estrogen-replacement therapy. Hysteroscopy and endometrial biopsies were utilized to establish maturation patterns, glandular epithelial mitosis rates, and macroscopic endometrial appearance. The results showed an increase in withdrawal bleeding with higher levels of progesterone, with those levels producing distinct secretory responses. However, incidence of endometrial hyperplasia after 5 years of E2/P therapy was independent of secretory changes and withdrawal bleeding, and was more related to the control of mitosis, which was seen even with low doses of progesterone. The authors conclude that a relatively low dose of P may be offered to women seeking hormone replacement therapy with similar levels of endometrial safety.
Whitehead MI, Fraser D, Schenkel L, et al. Transdermal administration of oestrogen/progestogen hormone replacement therapy. The Lancet 1990; 335:310-2.
Sixteen estrogen-deficient women were evaluated on a course of transdermal estradiol and transdermal progestogen for five cycles. Regular withdrawal bleeding was noted in all but one patient. Fourteen endometrial biopsies were performed after the fifth cycle, with no evidence of endometrial hyperplasia.