[Current concept of the hormonal state in menopause].
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The experiment conditions for the evaluation of Norethindrone (17 alpha-Ethynyl-17 beta-hydroxy-4-estren-3-one, NET) and Ethynyl-estradiol (17 alpha-ethynyl-1, 3, 5 (10) estratrien-3, 17 beta-diol, EE) by radioimmunoassay are described. A minimal quantity of 25 pg of these two steroids could be evaluated using different reduced metabolites of NET, very little cross reaction is observed with 200 pg of these metabolites. No effect was observed with estradiol for the EE-antiserum. The NET-antiserum was used to evaluate this steroid and ethynodiol diacetate after oral administration to female volunteers. Maximal values in the plasma (2-3% of the administered dose) was found between 1-3 h after administration and at 24 h a concentration of 0.1-0.3% still remained in the plasma.
The ultrastructural study of the intra-arterial trophoblast has revealed in the pregnant Rat a steroidogenic activity which has been confirmed by histoenzymologic observations (presence of delta 5-3 beta-HSDH and 17 beta-HSDH). At the 15th day postcoitum an in vitro investigation upon the metabolism of steroid hormone precursors suggests that the steroids (oestrogens, progestogens and androgens) secreted by the intra-arterial trophoblast have a local action upon the wall of the uterine placental arteries and are actively concerned with an important part upon the utero-placental hemodynamic as a whole.
An investigation on the influence of different types of oral contraceptives upon serum gonadotropins, estradiol and progesterone was carried out in 10 volunteers. The effect of a change from a normophasic type preparation to a sequential preparation (Ovanon and Kombiquens) and from a combined preparation to a minipill (Neogynon and Exlutona) was studied. Two new 3-phase step-up preparations were also tested. Ovulation was inhibited in each case as the preovulatory LH-peak and the subsequent rise of serum progesterone were found to be missing. The basal LH- and FSH-secretion and serum estradiol were demonstrated to be significantly diminished in the volunteers taking combined and sequential preparations. The release of gonadotropines was not inhibited as much when the 3-phase step-up preparations (SHB 261 AB and SHB 264 AB) were used. When Exlutona was taken, the basal LH-secretion was lower than during the pre- and postovulatory phase of the normal cycle, but follicular development did not appear to be inhibited much as both FSH and estradiol were found to be in the normal range.
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Reserpine treatment produced a marked decrease of the in vitro binding of estradiol to the nuclear fraction of the uterus. A similar observation was made when reserpine was given into the incubation medium of uterine tissue. In contrast to these findings both in vitro and in vivo reserpine administration resulted in an increase of the estradiol binding to the nuclear fraction of the anterior pituitary in ovariectomized rats. The binding capacity of cytosol fraction after reserpine administration did not show significant alterations. In addition to these observations it is worth to mention that reserpine treatment resulted in a significant decrease of the estradiol-induced increase of uterus weight in ovariectomized rats.
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The LH FSH estradiol and progesterone responses to acute stimulation with LH-RH were studied in 12 normal women with ovulatory cycles (4 in the initial follicular phase, 4 in the mid-follicular phase and 4 in the late follicular phase) and in two castrated women, two under hormonal contraception, two with ovarian amenorrhea, twelve with central amenorrhea of no detectable origin (6 with normal and 6 with low basal gonadotrophins), eleven anovulatory patients with pseudomenstruation, two with anorexia nervosa, and two with pituitary amenorrhea. Each woman received a rapid i.v. injection of 100 microgram synthetic LH-RH at 9:00 a.m. Serum levels of LH, FSH, estradiol and progesterone were determined by radioimmunoassay in samples collected before and 60, 120, 240 and 480 minutes after injection. The findings were : 1) A significant rise in estradiol and progesterone levels, in addition to LH and FSH elevation, in normal women; 2) A lack of ovarian steroid response in the castrated women and in ovarian amenorrheas, which suggests that the source of steroid response to stimulation is not extragonadal; 3) Significant differences in the responses of the four hormones to LH-RH in the women with central amenorrhea in comparison with the normal group with great variability of results; the steroid response in the presence of a positive LH response might correlate with the severity and/or prognosis of the disorder, a point deserving further study; 4) In anovulatory women with pseudomenstruation, LH responses for the most part normal, and particularly, progesterone responses.
OBJECTIVE: To study the endocrinologic profile of regularly menstruating users of levonorgestrel subdermal implants. DESIGN: Observational, prospective, case-controlled comparative study. SETTING: The Family Planning Clinic of PROFAMILIA, in Santo Domingo, Dominican Republic. PATIENTS, PARTICIPANTS: Thirty one regularly cycling Norplant users and 12 nonhormonal contraceptors who volunteered to participate. INTERVENTIONS: Norplant contraceptive implants were inserted in 31 subjects between 13 and 77 months before this study. MAIN OUTCOME MEASURES: Follicle-stimulating hormone, luteinizing hormone, estradiol (E2), and progesterone (P) were serially assayed for one menstrual cycle. RESULTS: Almost half of the cycles among Norplant users were anovulatory; all the rest (55%) had some form of dysfunction: diminished gonadotropin surge, luteal phase insufficiency (low P levels and shortened luteal phase), and E2 profiles different from normal controls. CONCLUSIONS: Anovulation is clearly one of the main mechanisms of action of Norplant, but even in presumptive ovulatory cycles, the dysfunctions described possibly contribute to the high contraceptive effectiveness of Norplant.
Sequential blockade of gonadotropin-releasing hormone (GnRH) and progesterone (P) receptors by potent antagonists (Nal-Glu GnRH antagonist and RU486) was conducted in late-luteal phase women to develop a once-a-month birth control method by timed advancement of ongoing luteolysis and endometriolysis. Hormonal dynamics and timing of uterine bleeding during the antagonists' imposed luteal-follicular transition were compared with spontaneous (1st to 2nd) and recovery (2nd to 3rd) cycles in 10 normally cycling women. Serum luteinizing hormone (LH) and follicle-stimulating hormone levels declined (47 +/- 4.3% and 24 +/- 3.0%, respectively) by 24 hours after Nal-Glu injection, which accelerated the ongoing luteolytic process, as evidenced by more rapid declines of serum concentrations of estradiol, P, and ir-inhibin, as compared with the corresponding control cycle. This was accompanied by the prompt (16 +/- 3.2 hours after RU486) onset of a single episode of uterine bleeding, which was advanced by 2 days. Whereas the luteal phase length was foreshortened by 2 days, the subsequent follicular phase duration was prolonged by 2 days with a normal sequence of follicular maturation, LH surge, and luteal function during the recovery cycle. We conclude that the late-luteal sequential administration of antagonists of GnRH and P resulted in acceleration of the ongoing luteolytic and endometriolytic processes without functional alterations of the subsequent cycle.
Authors removed dextro-ovary of a patient having 7-9th week of gestation for ovarian cyst during abortion. Preoperative cervical dilation was performed by Enzaprost-F cervical tablet containing 20 mg PGF2 agent. Before and 2, 4 and 6 hours after treatment, serum-progesterone and 17-beta-estradiol level was determined. Drug cervical dilation enabled instrumental termination of pregnancy within 4 hours. Histological finding of yellow body showed initial signs of colloid-cystic degeneration, which was followed by minimal decrease of values of serum-steroid concentrations. Authors presume that change in histological picture of yellow body was caused by effect of cervical tablet containing PGF2 agent.
The first of a second generation of slow-release injectable contraceptives is the norethindrone (NET) microspheres with a 90-day duration of action. It was evaluated at 65-mg and 100-mg doses for safety and contraceptive effectiveness in two randomized, single-blind trials among 131 women: 94 women for 12 months and 37 women for 6 months. The 6-month trial included additional evaluations of ovarian function and serum NET values. In the 6-month trial, no indication of ovulation was detected in the 100-mg dose group, while 3 of the 19 women in the 65-mg group showed signs of ovulation (progesterone greater than 3 ng/ml). No pregnancies were reported in the 100-mg group and one pregnancy in the 65-mg group resulted in a life-table pregnancy rate for that dose of 2.6 per 100 woman-years (95% confidence interval, 0 to 7.5). Days of vaginal bleeding were analyzed for 30 days before treatment and in 90-day reference periods after treatment. The mean number of vaginal bleeding and spotting days increased initially after the first injection in both dose groups, but decreased to below baseline in both dose groups after 6 months. The two doses appear comparable in clinical safety, side effects, vaginal bleeding patterns, and laboratory measures. With the preliminary estimate of efficacy, the 65-mg dose would be the minimally effective dose for the NET 90-day injectable contraceptive.
Twenty-five healthy women volunteers were selected to evaluate ovulation inhibition by a monophasic oral contraceptive preparation containing 75 micrograms gestodene and 30 micrograms ethinyl estradiol. Each subject participated for eight consecutive cycles, consisting of a pretreatment cycle, six treatment cycles, and a posttreatment cycle. During five explored cycles, serum LH, FSH, estradiol, and progesterone levels were measured daily on cycle days 8 through 17; in addition, progesterone was measured once, around cycle day 21. Pelvic ultrasounds were performed on cycle days 6, 8, 10, 12, 14, and 16. In the 18 volunteers completing the entire study, LH and FSH levels were strongly depressed, in equivalent degree, during the first, third, and sixth treated cycles. From treated cycle days 8 to 17, a significant decline of LH and FSH levels occurred, reaching values on the lower limit of detection. Luteal activity was not detected in any of the treated cycles. Follicular activity, as reflected by estradiol levels, was more strongly depressed during the first treated cycle (first contraceptive pill taken on day 1 of menstruation) than in the third and sixth treated cycles (the first pill taken after a seven-day pill-free interval). The excellent inhibition of follicular maturation was confirmed by ultrasonic assessment of the ovaries. Restoration of ovarian function during the first posttreatment cycle was excellent, showing a midcycle hormonal profile identical to that of the pretrial cycle.
RU 486 has wide potential utility as an abortifacient drug when used within the first 6 weeks of pregnancy and has the ability to induce an abortion in about 80% of subjects. Administration of low doses of prostaglandins together with RU 486 increases the success rate. It is possible that alterations in metabolism of RU 486 may explain non-responsiveness to the drug in some women. Mid-luteal phase administration of RU 486 produces bleeding within 72 h and in one-third of subjects there was luteolysis with decrease in serum FSH, oestradiol and progesterone concentrations. Administration of RU 486 in the late luteal phase does not disturb menstrual cycle length, bleeding patterns, ovulation, or hormonal parameters in treatment or posttreatment cycles. However, the drug alone cannot be used as a 'menses regulator' or 'once monthly pill' since some pregnancies do continue. Possibly the efficacy of RU 486 may be enhanced when it is combined with prostaglandins or other agents. Administration of RU 486 in the follicular phase blocks ovulation, delays the LH surge, and is associated with low concentrations of oestradiol. This is presumably the result of gonadotrophin inhibition.
The authors reviewed the connection between sexual hormones and migraine crisis. Besides other exogenous factors, the fall of estradiol blood levels in the late luteal and premenstrual phase seems a causal factor in the origin of menstrual-related headache crisis. The behaviour of migraine crisis during the various events of female reproductive life, support this view. The role of PRL, T, FSH and LH was also discussed. On the other hand, menstrual migraine represents a model that fits perfectly with a neuroendocrine hypothesis which is based upon a faulty chronobiological response of the so-called antinociceptive system.
The subcutaneous implantation of estradiol pellets was found to be a simple and effective contraceptive method with good patient acceptance and minimal untoward effects. The pellets (25 mg each) were implanted through a Kearn's trocar into the abdominal wall, 2.5 to 5 cm above and parallel to Poupart's ligament. The regimen began with four pellets, and the dose was maintained or decreased by one pellet every 6 months (four, three, two, one). A potent progestogen was utilized monthly for induction of withdrawal bleeding. Altogether, 236 patients were followed for a total of 1,060 courses in 6,360 cycles (489,02 woman-years). Two pregnancies occurred during therapy. Pearl's index was 0.37. No significant alterations occurred in body weight and blood pressure. Glucose tolerance test, standard blood profiles, and Papanicolaou smears were normal during therapy. No cases of thrombophlebitis, blurred vision, headaches, gastric symptoms, or amenorrhea-galactorrhea were observed. The suppression of ovulation was confirmed by endometrial biopsies, basal body temperature, and serum follicle-stimulating hormone, luteinizing hormone, estradiol, and progesterone in a selected group of patients.
In order to determine the pituitary or ovarian site of the anti-gonadotrophic action of prolactin (PRL), ten women with hyperprolactinaemia were studied in the following way: 1) Repeated estimations of PRL, gonadotrophins (LH and FSH), plasma estradiol and progesterone during six weeks of treatment with bromocriptine. 2) Verification of the effects of estradiol benzoate on LH and FSH levels before and after normalisation of prolactin. 3) Exploration of the ovarian response to the administration of human menopausal gonadotrophin. Without it being possible to exclude any direct effect of prolactin on the ovary, it may be affirmed that the hormone decreases the sensitivity of the gonadotrophic cells to the positive feedback mechanism exerted by plasma estradiol.
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