Nick Siddle

The effect of hysterectomy on the age at ovarian failure: identification of a subgroup of women with premature loss of ovarian function and literature review.

The age at ovarian failure was determined in 90 women who had previously undergone abdominal hysterectomy with bilateral ovarian conservation and in 226 women who had undergone a spontaneous menopause. The mean age of ovarian failure in the hysterectomized group was 45.4 +/- 4.0 years (standard deviation), and this was significantly lower than the mean age of 49.5 +/- 4.04 years in the nonhysterectomized control group (P less than 0.001). There was a significant correlation between the age at hysterectomy and the age of ovarian failure in the women who were 44 years or less at the time of ovarian failure (r = 0.62, P less than 0.001), implying a causal relationship. The indication for hysterectomy did not influence the time of ovarian failure. Two explanations are proposed as to how conventional surgery for hysterectomy may adversely affect ovarian function.

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RESULTS: Only one third of the women who starting the study had amenorrhea by week 78, but 46 (62%) of these women had withdrawn, mainly because of chronic irregular bleeding.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.

Regulation of estrogen and progesterone receptor levels in epithelium and stroma from pre-and postmenopausal endometria

Abstract Endometria from premenopausal women and from postmenopausal women receiving estrogens and progestins have been separated into epithelial and stromal fractions by collagenase digestion. Nuclear and total estradiol receptor content, soluble progesterone receptor and DNA synthesis have been compared in these epithelia and stroma. Epithelial cells from all types of endometria contained similar amounts of nuclear and total estradiol receptor to those found in stroma from comparable endometria. Progesterone receptor content of epithelium was appreciably higher than in stroma. Both epithelium and stroma from secretory phase, premenopausal endometria contained lower amounts of all types of receptor relative to comparable samples from proliferative phase endometria. Epithelial cells from postmenopausal women taking estrogen alone contained more nuclear and total estradiol receptor and progesterone receptor than those exposed to estrogen plus progestin; progestins decreased the stromal estradiol but not progesterone receptor content. In epithelium and stroma from both pre- and postmenopausal endometria, progestin inhibition ofestrogen-induced DNA synthesis was accompanied by a fall in nuclear estradiol receptor. These effects of progestins were accompanied by a marked rise in estradiol dehydrogenase activity in epithelium but not stroma. Thus, there is a need to re-assess the role of estradiol dehydrogenase in regulating estrogen action, at least in the stromal cells. The receptors have been partially characterized. The soluble estradiol receptor from stroma had a higher affinity for estradiol (Kd 0.9 × 10−1 M) than did the epithelial receptor (Kd 3.8 × 10−10 M). Very little specific binding of weaker affinity (Type II sites) was detected in intact endometrium. The soluble progesterone receptors from epithelium and stroma also have similar Kd values (5 × 10−9 M). The nuclear estradiol receptors from epithelium and stroma exhibited similar binding properties and no Type II sites were detected in intact endometrium.

Effects of dydrogesterone on the oestrogenized postmenopausal endometrium

Summary. Postmenopausal women receiving conjugated oestrogens 1·25 mg daily continuously were also given dydrogesterone either 5, 10 or 20 mg daily for the first 12 days of each calendar month. Endometrial tissue obtained on the sixth day of combined therapy in the third or subsequent treatment cycle was subjected to histological, ultrastructural and biochemical assessments. Dydrogesterone provoked secretory histological and ultrastructural changes within the endometrium in a dose‐dependent manner. A daily dose of 5 mg produced sub‐optimal responses but 10 and 20 mg daily produced effects similar to those observed in the secretory phase of the ovulatory cycle. Dydrogesterone 10 mg and 20 mg daily reduced epithelial DNA synthesis and nuclear oestradiol receptor levels to values within the secretory phase range. A dose‐response relation was seen in the induction of oestradiol‐17β and isocitrate dehydrogenase activities; hyperphysiological values were observed with 20 mg of dydrogesterone daily. This study has dernonstrated that dydrogesterone exerts potent anti‐oestrogenic and progestational effects on the human endometrium which are dose‐related. The 10 and 20 mg doses induced responses equal to or greater than those observed in the secretory phase of the ovulatory cycle and both dosages can be recommended for use in combination with exogenous oestrogens in postmenopausal women: and they may also have a role in the management of anovulatory dysfunctional uterine bleeding.

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.

Oestriol with oestradiol verses oestradiol alone: a comparison of endometrial, symptomatic and psychological effects

Summary. In a prospective, double‐blind, randomized, cross‐over trial, the effects of oral oestradiol, 2 mg daily, on the endometrial histology, frequency and severity of vaginal bleeding, and the symptomatic and psychological status of postmenopausal women were compared with those of oral oestradiol, 2 mg daily, plus oestriol, 1 mg daily. Both therapies were prescribed for 3 months on a cyclical basis. The addition of oestriol to oestradiol did not modify the endometrial response. The prevalence of proliferative/hyperplastic endometrium (64%: 9 of 14 biopsies) was similar after both treatments and there were no significant differences in either the frequency or heaviness of vaginal bleeding. Both therapies significantly reduced hot flushes, night sweats and vaginal dryness: no significant differences in effect on the symptomatic and psychological status were recorded. The addition of 1 mg of oestriol to 2 mg of oestradiol did not confer any benefit and the value of such an addition is challenged.

Assessment of oestrogen and progestin effects on epithelium and stroma from pre- and postmenopausal endometria

The efficacy of commercially available progestin preparations were investigated with a view toward determining the optimum type, dose, duration, and route of administration required to protect the endometrium. Biochemical indices of estrogen and progestin action in endometria from postmenopausal women receiving various hormone therapies were monitored. The premenopausal samples obtained during the proliferative and secretory phases of the cycle can be compared with physiologically normal activities. Estrogen effects were monitored by nuclear estradiol receptor (REN) and soluble progesterone receptor (RP) content and DNA synthesis by autoradiography after [3-H]-thymidine labelling. Progestin action was assayed by inhibition of estrogen-induced REN and DNA synthesis by induction of isocritic and estradiol dehydrogenases and by morphological criteria. Postmenopausal patients were attending the menopause clinics at Kings College Hospital or the Chelsea Hospital for Women in London for symptoms associated with the climacteric. Premenopausal samples were obtained from women attending the above hospitals as well as St. Thomas Hospital in London. There are no differences in REN or estradiol receptor content (RET) between epithelium and stroma for any of the groups. Progestins, regardless of whether they are derived from exogenous (postmenopausal) or endogenous (premenopausal sources, decrease REN and RET in both fractions. Progestins also decreased DNA synthesis in both cell types and this suppression correlates with the fall in REN. The RP content of epithelium is greater than stroma, but the 2 enzymes are markedly stimulated by progestins in epithelium but not stroma. The lower RP content of the stromal fraction could be because of cellular heterogeneity, differential loss of receptor during processing, or to genuine differences between epithelium and stroma. Estrogen induced DNA synthesis is inhibited by progestins in both epithelium ans stroma but the induction of some enzymes is dissimilar in the 2 cell populations. Marked increases in activity of isocitric and estradiol dehydrogenases take place in epithelium but not stroma under the influence of progestins. Enzymes such as acid and alkaline phosphatase do not exhibit this uneven cellular distribution. For the clinical studies on progestin effects, it was decided to analyze DNA synthesis, REN, and estradiol and isocritric dehydrogenase activities. All estrogenic medications in clinical use in the U.K. produce levels of REN and RP that are at least equivalent to those found in the proliferative phase of the premenopausal endometrium. No differences in REN, RP, or DNA synthesis were observed between the 0.625 and 1.25 mg doses of Premarin so it appears that even the low dose of estrogen is maximally stimulating the endometrium. The study results strongly indicate that the addition of a progestin to estrogen medication is efficacious in preventing continued cell multiplication of both epithelium and stroma. They also show that unnecessarily high doses of progestin are in current use.

Dose-Dependent Effects of Synthetic Progestins on the Biochemistry of the Estrogenized Post-Menopausal Endometrium

Abstract. Symptomatic post‐menopausal women were treated with conjugated equine estrogens (Premarin; Ayerst International) 1.25 mg daily, continuously, adding either norethisterone (Primolut N; Schering Chemicals) 1, 2.5, 5 or 10 mg daily or D/L norgestrel (Wyeth Laboratories) 150 or 500 μg daily for 10 days each calendar month. Endometrial biopsies were obtained during estrogen therapy alone and oh the 6th day of combined estrogen/progestin administration.