John Pryse-Davies

Effects of Estrogens and Progestins on the Biochemistry and Morphology of the Postmenopausal Endometrium

To study the effects of exogenous estrogens on the postmenopausal endometrium, and to determine the time course and minimum dosage of added progestins necessary to oppose estrogen stimulation, we obtained endometrial specimens from symptomatic postmenopausal women being treated with various preparations of estrogens and progestins. Morphologic changes were assessed with light and electron microscopy, and biochemical effects through measurement of DNA synthesis, estradiol and progesterone receptors, and isocitric and estradiol dehydrogenase activity. For comparison, identical studies were carried out on specimens from premenopausal women in the proliferative and secretory phases of their cycle. All the estrogens exerted stimulatory effects in the postmenopausal specimens that were comparable to those observed in the premenopausal proliferative-phase specimens. Estropipate, subcutaneous estradiol, and conjugated estrogens had some hyperphysiologic effects. Maximal progestational effects occurred in the postmenopausal specimens only after norethindrone was administered for six days, and a constant level of activity equal to that in premenopausal secretory-phase specimens was then observed until the 10th day of exposure. Similar maximal effects occurred after six days of treatment with D/L-norgestrel (150 and 5 mg daily [10 mg daily produced less complete changes]). We conclude that many estrogen preparations subject the endometrium to a potent stimulus. Norethindrone and norgestrel are protective because they counteract the proliferative effects of estrogens, but the currently recommended daily dosages of these progestins can be greatly reduced without loss of response.

A Simple Method for Determining the Optimal Dosage of Progestin in Postmenopausal Women Receiving Estrogens

Abstract Progestin is often added to regimens of estrogen therapy in postmenopausal women to reduce the risk of endometrial hyperstimulation, but it may cause undesirable metabolic effects. Therefo...

Continuous combined conjugated equine estrogen—progestogen therapy: Effects of medroxyprogesterone acetate and norethindrone acetate on bleeding patterns and endometrial histologic diagnosis*

OBJECTIVES: This study was designed to assess the incidence of amenorrhea with continuous combined therapy by using two different progestogens and to determine whether early bleeding predicts subsequent bleeding and endometrial response. STUDY DESIGN: Seventy-nine postmenopausal women on sequential estrogen-progestogen treatment were switched to continuous combined estrogen-progestogen therapy comprising conjugated equine estrogens 0.625 mg daily with either norethindrone acetate 0.35 mg twice daily or medroxyprogesterone acetate 2.5 mg twice daily added continuously for 78 weeks. All bleeding was recorded, and endometrial biopsies were performed at 26 and 78 weeks. RESULTS: Only one third of the women who starting the study had amenorrhea by week 78, but 46 (62%) of these women had withdrawn, mainly because of chronic irregular bleeding. Endometrial atrophy was observed in the majority of biopsy specimens. The two progestogens had similar effects. Bleeding patterns were useful predictors of subsequent bleeding, but not of endometrial response. CONCLUSIONS: Persistent irregular bleeding is common with continuous combined estrogen-progestogen therapy. Women with persistent early bleeding should probably revert to sequential treatment. Regular endometrial sampling is advised.

Actions of progestins on the morphology and biochemistry of the endometrium of postmenopausal women receiving low-dose estrogen therapy.

Endometrial biopsies were obtained from postmenopausal women receiving 0.625 mg Premarin daily and either 2.5 or 5 mg norethindrone daily or 150 or 500 microgram dl-norgestrel daily for 10 days each month. Sample were taken during the estrogen-only phase of treatment and on the sixth day of combined estrogen/progestin administration. Progestin exposure caused marked morphologic and biochemical changes as well as features comparable with the premenopausal luteal phase. Thus, progestins oppose the stimulation of premarin to the postmenopausal endometrium. However, the currently recommended dosage of norethindrone and dl-norgestrel greatly exceed those necessary to suppress endometrial proliferation effectively. The recommended daily dosage may be lowered without losing protective effect. This reduction will probably minimize the risk of dose-dependent progestin side effects.

Influence of superovulation on endometrial and embryonic development

The authors have studied the temporal relationship between follicular rupture and endometrial development in 13 women during a natural ovarian cycle (length 25 to 35 days), and subsequently after standard treatment with clomiphene citrate, human menopausal gonadotropin and human chorionic gonadotropin (hCG) to induce multiple folliculogenesis for oocyte recovery, in vitro fertilization, and embryo freezing (cycle length 23 to 27 days). An endometrial biopsy was taken during both cycles 1.5 to 2.0 days after the oocytes had been released or removed. The samples were examined by light and transmission electron microscopy. Samples of peripheral blood were taken at defined times for hormone analysis. After treatment 11 subjects (85%) had advanced morphological development of the endometrium (8 women by 3 to 4 days, 3 women by 1 to 2 days). The concentrations of plasma estradiol (E2) and progesterone (P) on the days of follicular rupture and endometrial biopsy were significantly raised in the treatment cycles. The concentration of total urinary estrogens on the day of hCG administration and the mean change in the concentration of plasma E2 (treatment/control) on the days of endometrial biopsy were positively correlated with the extent of endometrial advancement. In addition, the mean change in the concentration of plasma P (treatment/control) was markedly increased on the days of follicular rupture and endometrial biopsy in those subjects with an advanced endometrium. Embryonic development was not so obviously related to the extent of superovulation. Asynchronous endometrial and embryonic development may therefore contribute to the low pregnancy rate in these patients.

Is Provera* the ideal progestogen for addition to postmenopausal estrogen therapy?†

In a dose-ranging study, medroxyprogesterone acetate, 2.5, 5, or 10 mg daily, was given for 12 days of each calendar month to postmenopausal women also receiving conjugated estrogens, 0.625 mg daily, continuously. Endometrial biopsy specimens were taken on the sixth day of combined therapy for histologic, ultrastructural and biochemical evaluation. Medroxyprogesterone acetate induced secretory and ultrastructural changes within the endometrium, but the responses were variable and inconsistent. Suppression of epithelial deoxyribonucleic acid synthesis appeared dose-dependent. The levels of nuclear estradiol receptor, although reduced to within the secretory phase range, were not significantly lower than the values observed during the estrogen-only phase of treatment. Induction of both estradiol and isocitrate dehydrogenase activities was to within the secretory phase ranges, but the magnitude of these responses appeared less than those observed previously with other progestogens. Both morphologically and biochemically, medroxyprogesterone acetate, even at high dosage, produced suboptimal responses. Further studies are required to establish whether this is a dose-related effect.

Endometrial responses to transdermal estradiol in postmenopausal women

In prospective studies, we have determined the endometrial histologic characteristics and patterns of vaginal bleeding in 12 perimenopausal or postmenopausal women during administration of transdermal estradiol, 0.05 mg daily, given either alone or in combination with a progestogen. In the first study, we administered transdermal estradiol in cyclical fashion for 3 months. Outpatient curettage at pretreatment produced no endometrial sample or tissue too scant for assessment from 10 of the 12 patients (83%). At the end of therapy, proliferative or nonsecretory endometrium was diagnosed in nine patients (75%). Eight patients experienced treatment-related vaginal bleeding but no regular pattern, and seven patients reported breakthrough bleeding. Eight patients participated in the second study in which transdermal estradiol was administered continuously and norethindrone, 0.35 mg, was added for 12 days of each calendar month. A further curettage was performed at the end of treatment, and proliferative endometrium was the most common finding. No endometrial hyperplasia was observed. Only one patient experienced breakthrough bleeding. There were no consistent changes with time in the number of patients bleeding each month or in the duration or heaviness of the bleeding.

The optimal dose of oral norethindrone acetate for addition to transdermal estradiol: a multicenter study *

The effects of adding one of three doses (0.5, 0.75, or 1.0 mg/d) of norethindrone acetate for 12 days each month to continuous, transdermal estradiol (0.05 mg/d) have been determined in a prospective, randomized, multicenter study. Significant symptomatic and psychological improvements were observed and, with one exception, were not opposed by the added progestogen. Distinct redness at the site of last patch application was reported by 10% of patients and faint erythema by 30%. However, less than 5% of patients discontinued treatment because of skin problems. Breakthrough bleeding occurred infrequently and all three doses of norethindrone acetate induced a regular pattern of bleeding with secretory transformation in the endometrium. There was no hyperplasia or carcinoma.