Block of gonadotropic activity with a long-acting estroprogestogen.
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A study was made of the dynamics of the synthesis and secretion of the luteinizing hormone in the course of the sexual cycle in female rats by its determination by the radioimmunological method. Depending on the stages of the sexual cycle there were seen regular changes in the LH content in the hypophysis and the blood of female rats. LH content in the hypophysis was the minimal at 3 p.m. at the estrus stage and the maximal at 6 p.m. at the proestrus stage.
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Plasma renin activity (PRA), Growth hormone (GH) and immunoreactive insulin (IRI) were studied in seven healthy subjects during the ovulatory menstrual cycle and during the first and third cycles of oral contraception with 0.05 mg of ethinylestradiol and 0.100 mg or 0.125 mg of a new progestogen, 17 alpha-ethinyl-18-methylene-4-estren-17 beta-ol. The PRA level in the second half of the control cycle was significantly higher than in the beginning of the cycle. At the end of the treated cycles it was significantly higher than at the end of the control cycle. Neither GH nor IRI showed significant changes during the control cycle. GH was significantly higher at the end of the first and third treated cycles than at the end of the control cycle. IRI was significantly higher both in the beginning and at the end of the first treated cycle than the corresponding IRI levels in the control cycle. IRI at the end of the third treatment cycle was not significantly different from corresponding means at the end of the control cycle or the first treated cycle.
A considerable number of women receiving antiovulatory compounds or estrogens complain of weakness and fatigability, suggesting a state of clinical hypoadrenalism. For this reason, levels of plasma ACTH and plasma cortisol were determined in 25 women with such complaints both during treatment and at various intervals after cessation of this treatment. The results obtained showed that there was a significant inhibition of ACTH secretion during long-term treatment with antiovulatory compounds or estrogens, and in half of the cases, there was a delay in normalization of the pituitary-adrenal axis following interruption of the drug, supporting a state of transitory hypoadrenalism.
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In men suffering from prostatic cancer, i.v. administration of 12 g diethylstilboestrol diphosphate within 20 days resulted in a decrease of the LH serum level to about 50% (P less than 0.05), whereas the total testosterone level decreased to less than 5% (P less than 0.001) and the apparently free testosterone level to less than 2% of the initial values (P less than 0.001). Hence, the "systemic antiandrogenic effect" of oestrogen can be explained (1) by indirect inhibition of testicular androgen secretion via diminution of hypophyseal gonadotrophin secretion, (2) by direct inhibition of testicular androgen secretion and (3) by elevation of the capacity of testosterone binding beta-globulin.
In early pregnancy up the 7th week of pregnancy PGF2alpha was infused and 15(S)-methyl-PGF2alpha was applied i. m. to induce menstruation in 20 or 19 cases, respectively. In the tested form of application 15(S)-methyl-PGF2alpha is effective in 89 per cent of the cases and in 74 per cent complete abortion was achieved. PGF2alpha produced bleeding in 80 per cent only and complete abortion in 55 per cent. The differences in these two groups were not statistically significant. The steroid hormones estradiol and progesterone decrease in a successful application of PGs for induction of abortion and reach a value of 75 per cent at the onset of bleeding. The LH concentration in plasma becomes smaller too. In some cases there is a temporary increase in hormones shortly after starting treatment. The results could indicate that the considerable decrease in hormones before the onset of bleeding might be caused by an alteration of the corpus luteum, which is effective during early pregnancy.
The authors have studied the long-term effects of combined oestrogen-progestogen on the secretion of gonadotrophins and on ovarian function. Estimation of the radio-immune levels of the plasma concentrations of the pituitary luteinizing hormone (LH), of oestradiol (E2), of progesterone (P) and of 20 alpha hydroxyprogesterone (20 alpha OHP) and of testosterone (T) served as a base for this study. A test cycle and 8 cycles in which a combination of 50 micrograms of ethinyl-oestradiol and 0.5 mg of norgestrel were administered were studied in 4 normal volunteer women. A pituitary stimulation test using 50 micrograms of gonadotrophin "releasing factor" (LH-RH) was given during the 7th cycle. Ovarian stimulation using human menopausal gonadotrophins (HMG) was given during the 8th cycle of treatment in 3 of the women and in 3 other subjects. Pituitary secretion of LH and ovarian secretion of E2 and P are partially inhibited. Pituitary response to the injection of LH-RH stays normal but 5 out 6 patients had no response to stimulation by gonadotrophins. These results allow us to conclude that the lowering of production of gonadotrophins during treatment with combination oestrogen and progestagens is responsible for inhibition of ovarian activity, and that there is a delay before the latter respond to stimulation by either endogenous or exogenous gonadotrophins.
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The magnitude and frequency of episodic LH-fluctuations have been observed to change during the different phases of the menstrual cycle. A hypothalamic control center appears to be responsible for these variations. Disturbances of the hypothalamus often make themselves known through a lack of LH-episodes. Ahypothalamic derangement in women with functional amenorrhoea can result in a disregulation of gonadotropins as well as prolactin, thereby leading to hyperprolactinemia. One finds an inverse relationship between high prolactin secretion and cessation of or decreased pulsatile LH-secretion (spiking). LH-spiking was tested in physiological post partum, functional pathological and TRH-induced hyperprolactinemias. No LH-episodes were observed post partum after the end of HCG clearance although prolactin had returned to normal levels at 12 days p.p. The mode of LH-secretion in a group of functionally amenorrhoic patients was changed by a TRH-induced prolactin increase: the previously observed LH-spikes in these women could no longer be seen. Normal cycling women, however, were not affected. In patients with hyperprolactinemic anovulatory syndromes, prolactin suppressed LH-fluctuations reappeared after administration of 2-Bromo-alpha-ergocryptin. The inhibitory influence of hyperprolactinemia on the function of the gonadostat will be discussed. High plasma prolactin levels influence the cyclic and tonic hypothalamic function. Furthermore, prolactin appears to have a peripheral inhibitory influence on ovarian gonadotropin stimulation. Post partum anovulation and amenorrhoea can be caused by an antigonadotropic and antigonadic effect of prolactin.
Retrospective analysis of 103 samples of amniotic fluid was performed. Twenty-four samples were obtained prior to midtrimester abortion, 31 were from patients who delivered spontaneously, 14 were from patients in whom labor was induced, and the remaining samples were obtained from patients who were delivered by cesarean section. In all normal pregnancies, there was a rising trend in corticosteroid levels in amniotic fluid as the gestation advanced. This was less marked in abnormal pregnancies. There is a suggestive fetal role in initiation of normal spontaneous labor, as reflected by a significant increase in amniotic fluid corticosteroid levels, in patients immediately prior to vaginal delivery as opposed to abdominal delivery. There was a significant correlation between the birthweight of babies born vaginally with the amniotic fluid corticosteroid levels, as compared to the weight of babies born by cesarean section.
The action spectrum of an oral contraceptive which contained a reduced amount of the oestrogen component (0.04 mg ethinyl-oestradiol and 2.0 mg lynoestrenol) was investigated in 4 volunteer subjects. Serum levels of LH, 17 beta-oestradiol and progesterone were determined by radioimmunoassay and, in addition, the karyopyknotic index and cervical function were studied daily from the 8th day of the cycle. These parameters were determined in a control cycle, in the cycle during administration of the oral contraceptive and in the subsequent treatment-free cycle. Furthermore, the bleeding patterns were studied in 284 treatment cycles of 26 patients. Results of these studies indicate complete contraceptive protection by inhibition of ovulation and by an efficient cervical barrier action already during the first treatment cycle. Withdrawal bleeding was observed 3 to 4 days after ingestion of the last tablet. Spotting was recorded in 11 subjects during the first treatment cycle but was rarely observed during further treatment. Blood loss and bleeding control is comparable to that of other combined oral contraceptives with reduced oestrogen content.
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The enzymes amino peptidase and esterase were identified in human cervical mucus. Their concentration was serially determined during a menstrual cycle in 5 normal ovulatory women and correlated with the time of ovulation as monitored by the basal body temperature and radioimmunoassay of serum luteinizing hormone (LH), progesterone, and estradiol (E2). The activity of both enzymes decreased at midcycle just before the LH surge and began to rise after ovulation. The preovulatory decline in enzyme activity was significant for esterase but not for amino peptidase. The site of production and functional significance of these enzymes are not at present identified.
Basal body temperature (BBT) as a predictor of ovulation was assessed by examining the temporal relationship between the BBT shift and the luteinizing hormone (LH) surge in individual cycles of 27 normal women. For 22 of the subjects, the LH surge occurred on the same day or within one day of the BBT nadir. For the remaining five subjects, the surge fell within 2 days after or 3 days before the nadir. Despite the BBT nadir's close temporal association with the LH surge, daily examination of BBT for the purpose of predicting the day of ovulation during a given cycle is unsatisfactory. By 48 hours following the nadir, when one could usually be certain that temperature elevation had occurred, all subjects had already exhibited the LH surge.