Postmenopausal Tibolone Therapy: Biologic Principles and Applied Clinical Practice

Morris Notelovitz, MD, PhD, MB, BCh, FACOG, FRCOG

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The Endometrium, Endometrial Bleeding, and Compliance

Both ERalpha and ERbeta are expressed with ERalpha, the predominant ER.[40] ERalpha is downregulated by ERbeta,[41] and its activation is inhibited by progesterone. Both stromal and glandular cells express PRA and PRB during the proliferative phase of the menstrual cycle; PRA is the only PR present in the secretory phase and is found primarily in stromal cells.[42] Endometrial proliferation is induced by both ERalpha and PRB and is inhibited by PRA.[13]

The human endometrium synthesizes estrogen via a number of enzymes: sulfatase, which converts inactive estrone sulfate to estrone; aromatase and 17beta-HSD type 1 activity, both of which stimulate the metabolism of androgens, androstenedione, and testosterone to estradiol (Figure 1).

Progestogens downregulate the estrogen-forming enzymes and also induce estrogen-inactivating enzymes such as 17beta-HSD type 2 (Figure 1).[43] The latter results in the endometrial conversion of estradiol to the less bioactive estrogen, estrone. Tibolone opposes the endometrial estrogenic activity of both endogenous estrogen and its own estrogenic metabolites via its endometrial conversion of the tibolone molecule to delta4-tibolone and inhibition of sulfatase along with stimulation of sulfotransferase enzymes.[17] The net effect of both progestin and tibolone therapy is to prevent estrogen-induced endometrial proliferation and hyperplasia.

Amenorrhea is achieved by about 80% of women after the first month of treatment with tibolone and over 90% after the third month of therapy.[44] When compared with various CCHT preparations (E2/NETA[44]; CEE/MPA[30]), tibolone has better bleeding control within the first 1-3 and 4-6 posttreatment cycles. There is no difference in the degree of bleeding control beyond 6 months between treatment groups. The incidence of bleeding is lower in older women. Unwanted uterine spotting and bleeding is directly related to women discontinuing therapy.

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