In vitro and in vivo interactions of [3H]dimethylstilbestrol with the estrogen receptor.
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Male rats were castrated on the day of birth (day 1) and injected with either testosterone, dihydrotestosterone, a synthetic oestrogen (RU 2858 + dihydrotestosterone, or oil from days 1 to 5. The aromatizable androgen, testosterone, and RU 2858 suppressed both cyclic gonadotrophin secretion, indicated by the absence of corpora lutea from implanted ovarian grafts, and the behavioural response to oestradiol benzoate + progesterone injections in adulthood. The 5alpha-reduced androgen, dihydrotestosterone alone did not affect gonadotrophin secretion or female receptive behaviour, but like testosterone, it increased penis development in response to testosterone propionate, and this was positively correlated with copulatory efficiency, i.e. the ratio of intromission to mount frequencies. Nevertheless, ejaculation only occurred among animals that had received testosterone or RU 2858 + dihydrotestosterone. The results support the concept that during the preinatal period, neural conversion of androgens to oestrogens is important both for the suppression of female gonadotrophin secretion and behaviour patterns as well as for the organization of male behaviour patterns. The 5alpha-reduction of unsaturated C19-steriods to dihydrotestosterone in peripheral tissues is also required to complete the development of the male genital tract.
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Effects of progesterone on production of androgen-dependent aggression-eliciting pheromones were investigated. Two groups of anosmic (non-fighting) castrated mice treated with testosterone or with testosterone and progesterone, respectively, were attacked to the same degree by intact, isolated (fighting) mice while control mice (castrated only) were attacked less. The findings support the ideas that progesterone may inhibit androgen-induced aggression via a neural and not via a somatic mechanism.
The influence of estrogen, progesterone and testosterone on the activities of alkaline and acid phosphatases, adenosine triphosphatase and succinate dehydrogenase were determined by cytochemical methods in sarcoma 180 and Ehrlich's carcinoma cells transplanted in male and female Swiss mice. The results revealed differential effects of the sex hormones on different enzymes which seemed to depend on the type of tumour cell studied and the sex of the host mice.
The effects of medroxyprogesterone acetate (Provera), testosterone propionate (TP), ethinyl estradiol (EE), and ethynodiol diacetate (ED) treatments on sperm population in different segments of the male rat reproductive tract, reproductive organ weights, circulating androgens and fertility were studied. Ten microgram TP given for five days reduced the sperm population and organ weights. A marked reduction in the number of sperm and reproductive organ weights was observed in males orally treated with estrogens. Only long-term (20 days) treatment with Provera (1 mg/day) significantly reduced sperm population and reproductive organ weights. Combination of TP and Provera resulted in a more pronounced reduction in sperm counts and organ weights. Among steroids studied, estrogen was the only compound which suppressed fertility and circulating steroid levels.
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A potential male contraceptive approach was evaluated in clinical trials involving monthly injections of depot medroxyprogesterone acetate and either subdermal implants of testosterone propionate or monthly injections of testosterone enanthate. Pregnancies occurred in partners of 9 men with recent sperm counts of 10 million/ml or below. In 5 of the 9 instances, the sperm counts were less than 1 million/ml. It appears that male contraceptive methods involving spermatogenic suppression may require attainment and maintenance of azoospermia. The pregnancy rate cannot be calculated, because the extent of other contraceptive use is uncertain. There were no spontaneous abortions. 6 pregnancies were carried to term, and all progeny were normal, based on physical examination at birth or 3 months after birth.
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Line 1, a chemically induced guinea pig hepatoma, is susceptible to killing by anti-Forssman immunoglobulin M antibody and guinea pig complement. When these tumor cells are pretreated at 37 degrees with 10(-4) to 10(-11) M concentrations of the polypeptide hormone insulin, with the catecholamine L-epinephrine-HCl, or with the glucocorticoid steroids hydrocortisone sodium succinate or prednisolone sodium succinate, the cells show a marked reduction in their suseptibility to killing by antibody and guinea pig complement; pretreatment at 0 degrees is ineffective. Similar results were obtained with another antigenically distinct guinea pig hepatoma (line 10) when tested with anti-Forssman immuno-globulin M or specific antitumor antibodies and human complement. The ability of the hormones to render the cells resistant is dependent on time, temperature, and hormone concentration. The effect of hormone treatment is maximal between 30 and 60 min and is reversible within 4 hr even in the continued presence of hormone. Treatment of line 1 cells with up to 10,000-fold greater concentrations of the less biologically active or inactive analogs, DL-epinephrine, beta-estradiol, testosterone, or proinsulin has no effect on the susceptibility of the cells to killing by antibody and guinea pig complement. The effect of hormone treatment is not due to a direct inactivation of bound or fluid-phase complement components by the hormones or to a decrease in the ability of the cells to bind complement-fixing antibody.
A retrospective study was made of 74 women who had received estrogen continuously, cycled with progesterone, for menopausal symptoms over an average 57-month period. Treated patients were compared with control patients from the same private practice. Vabra endometrial aspiration biopsies showed no statistical differences between 25 treated and 28 untreated patients in the frequency of normal, inactive, hyperplastic or neoplastic specimens. The most common finding in the treated group was a secretory response, which suggests that progesterone exerts an antiestrogen effect even when estrogen is given on a continuing basis. There is evidence that the vaginal maturation index in the postmenopausal patient, although helpful in determining the current state of her systemic estrogen activity, may not reflect the effect of estrogen on the endometrium. Estrogen therapy has no absolute predictable correlation with endometrial histology. Thus, the information from routine endometrial curettage is essential to evaluate the status of all treated patients. Among all hormone-treated patients (74), weight decreased over time, blood pressure, blood sugar and cholesterol levels were relatively unchanged, and Papanicolaou smear classes improved.
In the androgen-sterile rats given 10-250 mug of testosterone-propionate there was observed at the early postnatal period a reduction in the LH-RP level in the hypothalamus, of the LH in the hypophysis and the blood, of the weight of the ovaries and of the corporal luteum count in them, as well as an increase in the dopamine level in the anterior portion of the hypothalamus. Klomiphen administration for 5 days in a dose of 20 mug led to the normalization of these indices and to the appearance of ovulation, but failed to restore the capacity to pregnancy. Prolonged klomiphen administration (20 mug every 3 days for a period of 1 month) also failed to restore this capacity.
Six normal male volunteers ingested a dose of 400 mg free testosterone daily as tablets over 21 days. By the end of treatment intravenous antipyrine half-life had decreased significantly from 8.0 +/- 2.7 to 5.7 +/- 2.6 hr. The subjects eliminated testosterone from serum more rapidly on the twenty-first day of testosterone ingestion than on the first day. Serum albumin, bilirubin, prothrombin, alanine-amino-transferase, and alkaline phosphatases were unchanged during the experiment. It is concluded that oral testosterone treatment induces the hepatic drug-metabolizing system including that of testosterone.