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Objectives: To investigate in depth the metabolic effects of oestradiol-17 beta both alone and in combination with the progestagen dydrogesterone., Methods: Fifteen hysterectomised postmenopausal women were studied before treatment and after 24 weeks taking oestradiol-17 beta alone (2 mg per day), then following a further 6 (oestrogen-alone phase) and 12 (oestrogen plus progestagen phase) weeks with inclusion of dydrogesterone (10 mg per day for days 17-28 of each 28 day cycle). Measurements at each visit included fasting serum lipid and lipoprotein concentrations, insulin sensitivity, secretion and elimination by modelling analysis of intravenous glucose tolerance test glucose, insulin and C-peptide concentrations, body fat distribution by dual-energy X-ray absorptiometry (DXA) and arterial function by carotid artery ultrasound., Results: Significant reductions were seen throughout in total and LDL cholesterol. The net reductions in total and LDL cholesterol by the end of the study were 5.8% (P<0.05) and 18.4% (P<0.001), respectively. HDL and HDL subfraction cholesterol concentrations rose during treatment with oestradiol alone, the rise being primarily in the HDL(2) subfraction (+21.6%, P<0.001). Fasting serum triglycerides rose 30% on oestradiol treatment. These increases were unaffected by the addition of dydrogesterone. Insulin sensitivity, secretion and elimination, body fat distribution and arterial function were not significantly affected at any stage of the therapy., Conclusions: The small study sample and high variability in measures of glucose and insulin metabolism may have contributed to the absence of the expected significant improvement in these parameters. Orally administered oestradiol had beneficial effects on total, LDL and HDL cholesterol which were unaffected by the addition of dydrogesterone.

A quantitative assessment has been made of nucleolar channel systems (NCS) in the endometrial glands of postmenopausal women receiving hormone replacement therapy. The women were taking conjugated equine oestrogen and one of five progestins. The number of NCS induced was related to the dose of progestin administered. The minimum doses of progestin inducing a comparable response to premenopausal secretory phase endometria were found to be 1-2.5 mg norethindrone, 150 micrograms norgestrel and 20 mg dydrogesterone. Progesterone and medroxyprogesterone acetate were inadequate at the doses tested. The results show that the quantification of endometrial gland NCS would be a useful addition to the biochemical and morphological assessments made of any new progestin treatment.

Cyclical regimes of unopposed oestrogens are associated with the development of both cystic glandular and atypical hyperplasia, and the incidence of hyperplasia is related to the dose of oestrogen prescribed. Atypical hyperplasia develops later than, and perhaps from, cystic glandular hyperplasia. With sequential oestrogen/progestogen therapy the incidence of this condition was greatly reduced, and therefore, progestogens appear to protect against the development of this condition. In all cases but one, sequential regimes also reversed both spontaneously-arising and oestrogen-induced hyperplasia to a normal endometrium. Cyclical high-dose unopposed oestrogen therapy may not be capable of reversing spontaneously-arising hyperplasia, and this condition may progress to endometrial adenocarcinoma. Spontaneously-arising hyperplasia can be present before therapy commences, but may be unsuspected, as it can occur in the absence of abnormal vaginal bleeding. Therefore, cyclical oestrogen therapy should not be prescribed unless pre-treatment curettage has been performed and spontaneously-arising hyperplasia has been excluded; and unless subsequent monitoring of the endometrial response is being performed by serial biopsy.

Exogenous oestrogens prescribed for the relief of menopausal symptoms are being given in pharmacological doses and the term 'hormone replacement therapy' is inappropriate. The frequent development of endometrial hyperplasia during unopposed cyclical oestrogen therapy is therefore to be expected, but no single pattern of vaginal bleeding accurately reflected the histology of the endometrium. As such doses of oestrogens are required for effective relief of symptoms, progestogens must be given to protect against endometrial hyperstimulation. Patient acceptability of sequential oestrogen/progestogen therapy is high (90%) and with such therapy breakthrough bleeding may subsequently be shown to be a reliable indicator of underlying endometrial pathology.

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 micrograms daily for 10 days each calendar month. Endometrial biopsies were obtained during estrogen therapy alone and on the 6th day of combined estrogen/progestin administration. Sensitive biochemical indices of estrogen and progestogenic activities were measured in th endometrial samples. These included measurements of DNA synthesis in epithelium and stroma by tritiated thymidine autoradiography; nuclear estradiol receptor content, and the activities of estradiol 17 beta and isocitric dehydrogenase and acid and alkaline phosphatase. Low dosages of progestins achieved maximal biochemical effects and the larger doses failed to enhance these responses. It is concluded that the dosages of progestins currently added in post-menopausal estrogen therapy are greatly in excess of those necessary to suppress endometrial proliferation effectively; lowering the daily progestin dosage is unlikely to result in any lessening of this protective effect and will probably reduce the incidence of side effects, as these appear to be dose-dependent.

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.

The effects of at least three doses of each of five orally administered progestins on estrogen-primed, postmenopausal endometrial biochemistry and morphologic features were analyzed. The progestins tested were norethindrone, medroxyprogesterone acetate (MPA), norgestrel, dydrogesterone, and progesterone. The dose required to elicit responses similar to those seen in premenopausal, secretory endometria was assessed for each of the parameters measured, and the relative potencies were calculated. Potencies, relative to a value of 1 for norethindrone, are L norgestrel 8 (D/L norgestrel 4), MPA 0.1, dydrogesterone 0.02, and progesterone 0.002. The dose of norethindrone required to elicit secretory phase activity was about 0.35 mg/day. These values agree with published data obtained with the use of different methods (delay of menstruation in premenopausal women, endometrial histologic features of estrogen-primed, ovariectomized women).