Women in Balance

Progesterone & the Uterus

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 Ò ) 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 Ò ), and both progesterone applications demonstrated a significant effect over placebo. Patients preferred the topical application of progesterone cream.
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 Ò , 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.
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.
Dai D, Wolf DM, Litman ES, White MJ, Leslie KK. Progesterone inhibits human endometrial cancer cell growth and invasiveness: down-regulation of cellular adhesion molecules through progesterone B receptors. Cancer Res 2002 Feb;62(3):881-6.

This in vitro study demonstrated that progesterone acts through progesterone receptor B to inhibit endometrial cancer cell invasiveness via the down-regulation of adhesion molecules.
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.”
Hodges LC, Houston KD, Hunter DS, Fuchs-Young R, Zhang Z, Wineker RC, Walker CL. Transdominant suppression of estrogen receptor signaling by progesterone receptor ligands in uterine leiomyoma cells. Mol Cell Endocrinol 2002 Oct 31;196(1-2):11-20.

Although estrogen is known to stimulate the growth of uterine fibroids, the effect of progesterone is unclear. The role of progesterone in the development of uterine fibroids (leiomyoma) is examined in this study in an in vivo/in vitro mouse model. Progestins and antiprogestins were utilized to investigate progesterone receptor (PR) signaling in a leiomyoma cell line. Both progestins and antiprogestins inhibited estrogen-mediated growth. PR ligands were also shown to suppress estrogen receptor signaling and leiomyoma cell growth.
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 Ò , 0.625 mg) paired with progesterone cream (Pro-Gest Ò , 20 mg) vs. conjugated equine estrogen paired with medroxyprogesterone acetate (Prempro Ò ). 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 composition (76% vs 5%, p<0.001).
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.
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 yrs 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.
Sager G, Orbo A, Jaeger R, Engstrom C. Non-genomic effects of progestins-inhibition of cell growth and increased intracellular levels of cyclic nucleotides. J Steroid Biochem Mol Biol 2003 Jan;84(1):1-8.

The anti-proliferative effects of three different progestins were compared using 3 human uterine cervix cell lines. In one cell line (C-41) devoid of progesterone receptors (PR) all progestogens studied inhibited growth in the following potency - progesterone (56%) > medroxyprogesterone (38%) > megestrol acetate (25%). Sensitivity demonstrated the same order, with progesterone being the most sensitive to inhibiting growth. This suggests there is a non-genomic action of progestogens that is anti-proliferative. The progestins studied also had anti-proliferative effects on the cell lines exhibiting PR.
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.

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