High-affinity steroid binding to rat testis 17 alpha-hydroxylase and human placental aromatase.
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Biomedical subjects
Publications and source records attributed to K J Ryan.
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Estrogen treatment of 16 hypogonadal women showed lessening of gonadotrophins, vasomotor symptoms, psychometrically measured aggression, and average sleep latency, but more Rapid Eye Movement sleep in a 100-day cross-over, double-blind comparison with placebo treatment. Of eight insomniac subjects, four showed decreased, but four showed increased insomnia scores and sleep latencies. Clinical rank of psychological intactness correlated with sleep latency and with total sleep time during the estrogen condition. Although estrogen altered both physiological and psychological states, such effects were characterized by different time courses and different degrees of consistency among the subjects.
The serum concentration of human chorionic gonadotropin (hCG) was measured at 10- to 60-minute intervals for 4-24 hours in 5 women at 5-8 weeks of pregnancy. hCG was found to be secreted episodically with pulses observed every 2-4 hours. The episodic secretion of hCG may have important implications to our understanding of both normal and abnormal reproduction.
In human corpus luteum (CL) microsomes, danazol inhibited 3 beta-hydroxysteroid dehydrogenase, 17,20-lyase, 17 alpha-hydroxylase, and 17 beta-hydroxysteroid dehydrogenase enzymes. Danazol did not inhibit aromatase. The observation that danazol can directly inhibit multiple enzymes of CL steroidogenesis may provide a molecular basis for explaining previous reports that danazol inhibits CL steroidogenesis in the monkey in vivo.
A study was designed to compared the metabolic fate and the biologic effects of 4 mg of estriol (E3) administered either orally or vaginally to six postmenopausal women. Blood samples were collected every hour for 6 hours and five different estriol fractions as well as gonadotropins were measured. Vaginal E3 administration resulted in a decline of 45% in luteinizing hormone (LH) levels and 17% in follicle-stimulating hormone (FSH) levels at 6 hours after treatment (p < 0.05). In contrast, the administration of 4 mg of E3 orally did not produce a decline of LH and FSH, despite the fact that the serum levels of E3-3-sulfate, E3-3-sulfate-16-glucosiduronate, estriol-3-glucosiduronate, and estriol-16-glucosiduronate were all fourfold to 24-fold higher after oral administration than after vaginal estriol administration. However, since the levels of unconjugated E3 were higher after the vaginal than after the oral administration of estriol, we conclude that only unconjugated E3 suppresses gonadotropins.
Cells obtained from turtle forebrain can be maintained in culture for at least 3 weeks. The cells are capable of aromatizing [3H]androstenedione and [3H]testosterone to estrone and estradiol and several C-19 metabolites. There are marked differences in the quality and quantity of the products formed from the two substrates. Conditions in living cells favor accumulation of 17-hydroxylated steroids. Aromatase activity as measured by estrogen yield increases with time in culture. Estrogen content of 14-day-old cultures may be enhanced or reduced by addition of natural or synthetic steroids. This system may provide a model for studying the regulation of brain aromatization, an essential step in the expression of androgen action on certain behavioral and neuroendocrine responses.
A double-blind crossover study was designed to compare the effects of placebo and medroxyprogesterone acetate, 20 mg, on vasomotor flushes and blood hormones in 27 postmenopausal women. In women receiving placebo, vasomotor flushes were decreased by 25.9% during the last four weeks of treatment compared with baseline, and a further decrease of 34.5% was achieved by the last four weeks after patients were given medroxyprogesterone. In women who initially took medroxyprogesterone, there a 73.9% decline by the last four weeks in the number of vasomotor flushes. However, when these women were given placebo, an immediate worsening of their symptoms occurred. The drug produced a decline of 27% and 29% in serum levels of follicle-stimulating hormone and luteinizing hormone, respectively, while the serum prolactin level rose slightly. Thus, medroxyprogesterone can be used to treat the vasomotor flushes of postmenopausal women when estrogen use is undesirable.
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We compared prior pregnancy histories of two groups of multigravidas--240 women having a pregnancy loss up to 28 weeks' gestation and 1,072 women having a term delivery. Women who had had two or more prior induced abortions had a twofold to threefold increase in risk of first-trimester spontaneous abortion, loss between 14 to 19 and 20 to 27 weeks. The increased risk was present for women who had legal induced abortions since 1973. It was not explained by smoking status, history of prior spontaneous loss, prior abortion method, or degree of cervical dilatation. No increase in risk of pregnancy loss was detected among women with a single prior induced abortion. We conclude that multiple induced abortions do increase the risk of subsequent pregnancy losses up to 28 weeks' gestation.
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We reviewed 5,003 records of consecutive deliveries in 1975 and 1976 at Boston Hospital for Women, abstracted demographic and obstetric data, and analyzed singleton deliveries at 27 weeks' gestation or greater. We compared women with exactly one prior proximate induced or spontaneous abortion with women of similar gravidity or parity with no prior pregnancy losses. Offspring of women with a proximate induced abortion had no higher frequency of short gestations, low Apgar scores, or congenital malformations than those born of women with no prior loss. Offspring of secundigravidas with a proximate abortion had birth weights similar to those of other primigravidas. Thus we have found that women with a single prior induced abortion have no increased risk of poor outcome of the next pregnancy after 27 weeks' gestation. In contrast, offspring of secundigravidas with a proximate spontaneous abortion had an increased frequency of short gestations, low birth weights, low Apgar scores, and congenital malformations, indicating that these women are a high-risk group for subsequent poor late pregnancy outcomes.
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The effects of danazol on steroidogenesis in vitro in the 16-20 week old human fetal adrenal were examined by studying: 1) danazol binding to adrenal microsomal and mitochondrial cytochrome P-450, and 2) enzyme kinetics of danazol inhibition of the adrenal microsomal 21-hydroxylase and the mitochondrial 11 beta-hydroxylase. The addition of danazol to preparations of adrenal microsomes or mitochondria elicited a type I cytochrome P-450 binding spectrum. Danazol bound to microsomal cytochrome P-450 binding spectrum. Danazol bound to microsomal cytochrome P-450 with a high affinity apparent spectral dissociation constant (KS) of 1 microM and with a lower affinity K's of 10 microM. Danazol bound to mitochondrial cytochrome P-450 with a KS of 5 microM. In addition, danazol competitively inhibited the microsomal 21-hydroxylase (apparent enzymatic inhibition constant KI = 0.8 microM) and the mitochondrial 11 beta-hydroxylase (KI = 3 microM). These findings demonstrate that low concentrations of danazol directly inhibit steroidogenesis in the human fetal adrenal in vitro.
The steroidogenic responsiveness of human thecal tissue to different doses of LH was investigated in vitro in relation to the health of the follicle and to the responsiveness of stromal tissue. The results show that small incremental increases in LH, over a low range of concentrations (1 to 10 ng/ml), markedly increased the thecal output of androstenedione from healthy and/or atretic follicles. Theca from healthy follicles were also stimulated to increase their output of progesterone and estradiol in response to small increases in LH whereas theca from atretic follicles produced more variable amounts of progesterone and were unable to generate estradiol. In contrast, relatively high concentrations of LH (50 ng/ml) reduced the total steroid output from the theca of both healthy and atretic follicles while 'switching on' a low level of steroidogenesis in stromal tissue. These data suggest that the steroidogenic response of thecal tissue is related to the mass of tissue (i.e., the size of the follicle), the health of the follicle and the amount of LH to which it is exposed.
The ability of the human oocyte-cumulus cell complex to synthesize progesterone, androgens and estrogens and to modify its endocrine environment in vitro was investigated. Germinal-vesicle stage oocytes with adhering layers of cumulus cells were recovered from human ovaries and maintained for 40--50 h in vitro in a culture medium with or without antral fluid. The results show that oocyte-cumulus (O-C) cell complexes were capable of synthesizing progesterone, androgens and estrogens. Oocytes with the capacity of resuming meiosis in vitro were part of an O-C complex producing significantly more progesterone than those O-C complexes containing oocytes incapable of resuming meiosis. Irrespective of the stage of oocyte maturation at the end of culture, testosterone and estrone were respectively the major androgen and estrogen produced. It is concluded that the oocyte-cumulus compartment of the antral follicle is a steroidogenically competent unit and that it has the capacity to modify the endocrine microenvironment of the follicle.
The comparative ability of granulosa cells and theca of the hamster preovulatory follicle to produce androgens in vitro from endogenous and exogenous substrates was assessed. The results indicate that theca are the major source of follicular androstenedione, but that the granulosa cells may be the major source of follicular testosterone. Theca and granulosa cells accumulate comparable amounts of dihydrotestosterone from exogenous androstenedione and testosterone and both may be a significant source of follicular DHT. LH stimulates the conversion of progesterone and 17 alpha-OH progesterone to androstenedione, testosterone and DHT in theca. LH does not stimulate the conversion of androstenedione to testosterone or DHT, and that of testosterone to DHT in either granulosa cells or theca. FSH, in granulosa cells but not in theca, stimulates the conversion of adrostenedione to testosterone but it has no effect in DHT accumulation from exogenous testosterone.
The effects of conjugated oestrogens 0.625 mg and placebo on adrenal and pituitary hormones were compared in 10 postmenopausal women during their sleep by means of double blind prospective crossover study. On placebo, the women had nocturnal variations in LH, prolactin and cortisol concentrations. However, oestrogen administration selectively blunted LH and prolactin changes, but not the rise in cortisol.
The characterization of the hyperandrogenism of two sisters with type A insulin-resistant diabetes and hirsutism is presented. Testosterone (T) and androstenedione levels were elevated in peripheral serum. These were not markedly affected by infusion of adrenocorticotropic hormone. In patient 1 glucocorticoid suppression decreased T levels by 50% and androstenedione levels by 30% but had no effect on them in patient 2. Estrogen-progestin suppression markedly reduced testosterone levels in both patients. The blood production of T in patient 1 was 0.8 mg/day and in patient 2 was 4.5 mg/day, both of which are elevated. Selective venous catheterization in patient 2 revealed markedly elevated testosterone levels in the ovarian veins, and polycystic ovaries were found at subsequent laparotomy. These endocrine studies have shown that the source of excessive testosterone in these patients is excessive production by the ovaries, and it can be suppressed by oral contraceptives.