Hormonal regulation of HSP27 expression in human endometrial epithelial and stromal cells.

HSP27 has been analysed immunohistochemically in epithelium and stroma of premenopausal endometria obtained at different stages of the menstrual cycle and in endometria from postmenopausal women receiving oestrogens either alone or in combination with a progestin. The data indicate that HSP27 is increased by oestrogen and inhibited by progestins in glandular epithelium but not stroma. Oestrogen does not increase HSP27 in stromal cells and HSP27 is only present in stromal decidual cells seen in the late secretory phase where it continues to be detectable until the tenth week of gestation. Hormonal regulation of HSP27 is clearly different in endometrial epithelium and stroma and additional regulatory factors may be important as oestrogen alone does not increase postmenopausal epithelial HSP27 to the levels seen in the proliferative phase of premenopausal samples.

Absorption and metabolism of oral progesterone when administered twice daily.

The absorption, metabolism, and clearance of progesterone (P) from the peripheral circulation were investigated in five postmenopausal women after oral administration of 100 mg at 9:00 A.M. and 200 mg at 9:00 P.M. for 5 consecutive days. Mean peak plasma concentrations of P were observed 2 hours after ingestion of both the 100 and 200 mg doses and were 22.7 and 47.7 nmol/l, respectively. Of the three metabolites studied, the plasma concentrations of pregnanediol-3 alpha-glucuronide were most raised by treatment; those of 17-hydroxyprogesterone were least raised. Increases in the plasma levels of 20 alpha-dihydroprogesterone were more sustained than those of P, and the plasma concentrations remained elevated at approximately 20 nmol/l for at least 12 hours after P administration. We conclude that administration of oral P 100 mg in the morning and 200 mg at night increases the circulating concentrations of P and the biologically active metabolite 20 alpha-dihydroprogesterone, and that the duration of these increases is sufficient to evoke progestational responses in responsive end-organs.

The effects of the addition of nomegestrol acetate to post-menopausal oestrogen therapy.

Progestogens are added to the oestrogen treatment for 10-12 days each cycle in order to prevent endometrial abnormalities. However, concern has been expressed about the safety of certain of the currently available progestogens because of the potential adverse metabolic effects. We have evaluated the effects of nomegestrol acetate - non-androgenic progestogen - for administration to post-menopausal oestrogen users. Thirty-six (36) women receiving 50 mg oestradiol implants at regular intervals also took nomegestrol acetate for 12 days each calendar month at doses of 0.5 mg, 1.0 mg and 2.5 mg daily. Allocation to one of the dose regimens was random. Physical and psychological side-effects were recorded and all vaginal bleeding was noted: an endometrial biopsy was performed on the sixth day of progestogen addition for histological, ultrastructural and biochemical evaluation. Adverse side-effects were responsible for a dose-dependent drop out rates of 17%. All patients experienced a regular, progestogen-induced withdrawal bleed each month; and histological, ultrastructural and biochemical changes were induced within the endometrium by all 3 doses. Nomegestrol acetate is a potent progestogen and further studies are required to determine its lowest effective dose.

Case report: serial serum HCG measurements in a patient with an ectopic pregnancy: a case for caution.

Improvements in the use of ultrasound in early pregnancy have resulted in improved diagnosis of miscarriage and ectopic pregnancy. There are still, however, a significant number of women with a suspected abnormal pregnancy, where transvaginal ultrasound is unable to locate the pregnancy. The concern is the possibility of ectopic pregnancy. An alternative diagnostic tool is required and it has been suggested that it is possible to monitor serum beta human chorionic gonadotrophin. The present case highlights the potential dangers of this management.

Efficacy, acceptability, and metabolic effects of transdermal estradiol in the management of postmenopausal women.

Systemic side effects that result from oral administration of estrogens to postmenopausal women may be minimized by use of the transdermal route. We administered transdermal estradiol, 0.05 mg/day, cyclically for 3 months to 12 postmenopausal and perimenopausal women to study the efficacy, acceptability, and metabolic effects of this dosage form. The results showed that transdermal estradiol significantly increased plasma levels of estradiol and estrone and urinary concentrations of estradiol conjugates, and produced significant improvement in menopausal symptoms and vaginal cytologic findings. The patches were well tolerated and no systemic side effects were reported. No clinically significant adverse biochemical changes were observed. Plasma renin substrate and renin activity were unchanged during therapy.

A simple method for determining the optimal dosage of progestin in postmenopausal women receiving estrogens.

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. Therefore, a low dosage is recommended. At present, the only way to determine whether the dosage of progestin is causing the desired secretory transformation of the endometrium is by endometrial sampling, which is invasive. We studied 102 postmenopausal women undergoing estrogen therapy who also took a progestin for 12 days each month, and we correlated the day of onset of bleeding with the endometrial histology over a three-month period. A bleeding pattern suitable for interpretation was observed in 96 women. Regardless of the preparation and dosage of the estrogen and progestin used, wholly or predominantly proliferative endometrium was always associated with bleeding on or before day 10 after the addition of progestin; wholly or predominantly secretory endometrium, or a lack of endometrial tissue, was associated with bleeding on day 11 or later. We conclude that the bleeding pattern reflected the histologic condition of the endometrium and that adjustment of the dosage of progestin so that regular bleeding is induced on or after day 11 may obviate the need for endometrial biopsy.

Absorption and metabolism of oral progesterone when administered twice daily.

PIP: The absorption, metabolism, and clearance of progesterone (P) from the peripheral circulation were investigated in 5 postmenopausal women after oral administration of 100 mg at 9:00 AM and 200 mg at 9:00 PM for 5 consecutive days. Mean peak plasma concentrations of P were observed 2 hours after ingestion of both the 100 and 200 mg doses and were 22.7 and 47.7 nmol/1, respectively. Of the 3 metabolites studied, the plasma concentrations of pregnanediol-3alpha-glucuronide were most raised by treatment; those of 17-hydroxyprogesterone were least raised. Increases in the plasma levels of 20alpha-dihydroprogesterone were more sustained than those of p, and the plasma concentrations remained elevated at approximately 20 nmol/1 for at least 12 hours after P administration. The authors conclude that administration of oral P 100 mg in the morning and 200 mg at night increases the circulating concentrations of P and the biologically active metabolite 20alpha-dihydroprogesterone, and that the duration of these increases is sufficient to evoke progestational responses in responsive end-organs. Results indicate that oral P can be considered a realistic alternative to synthetic progrestogens for addition to postmenopausal estrogen therapy. A desirable aspect to this alternative is its lack of adverse effects upon HDL2 cholesterol levels when given at dosages of 200 mg daily and 300 mg daily. Oral P may also have potential in controlling other progestogen-responsive conditions such as anovulatory dysfunctional uterine bleeding. Further studies are needed to determine both benefits and possible side effects of Oral P such as its conversion to deoxycorticosterone, which may cause fluid retention.^ieng

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.

Presence of an oestradiol receptor-related protein in the skin: changes during the normal menstrual cycle.

OBJECTIVE: To investigate the presence of an oestradiol receptor-related protein (P29) in skin and skin organelles, and to assess changes in its content during the normal menstrual cycle. DESIGN: An observational study. SETTING: King's College School of Medicine and Dentistry, London. SUBJECTS: Twenty-one premenopausal women with regular menstrual cycles undergoing gynaecological surgery. They were allocated to proliferative or secretory phases of the menstrual cycle on the basis of menstrual dating and histological examination of an endometrial sample. INTERVENTIONS: Small full thickness sections of skin (about 5 mm in depth) taken from the anterior abdominal wall at hysterectomy or laparoscopic sterilization. MAIN OUTCOME MEASURES: The concentration of the oestradiol receptor-related protein in skin and its organelles was assessed semi-quantitatively, using a monoclonal antibody technique. The intensity of staining was compared between the proliferative and secretory phases of the cycle. RESULTS: The receptor-related protein was consistently observed in epidermis, sebaceous glands, hair follicles and sweat ducts; there was no significant difference in its concentration between the proliferative and secretory phases of the menstrual cycle. The protein was not present in dermis and sweat ducts. CONCLUSIONS: Epidermis and some skin organelles contain an oestradiol receptor-related protein and must be considered as oestrogen target tissues. However, the content of this protein does not appear to change significantly during the normal menstrual cycle.

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

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.