[Contraception with progesterone pellets during lactation].
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Abortion was performed by curettage on 71 women with pregnancies between the 7th and the 13th week of gestation seven to eight hours after intracervical application of a tylose gel containing 3mg prostaglandin F2 alpha. Prior to the application of the prostaglandin and immediately before the surgical intervention a sonographic examination for determining the vitality of the pregnancy was carried out.--Plasma progesteron, estradiol and HPL levels were determined radioimmunologically prior to the application of prostaglandin, at four-hour intervals on the day of intervention, and 24, 48 and 72 hours after the intervention. In 22 women a complete or an incomplete abortion occurred; in two cases a blighted ovum was observed; 47 pregnancies, according to sonographic examination, remained intact until curettage. After seven to eight hours duration of the effect of the prostaglandin gel, progesterone levels were found to be reduced to 60.5 per cent and 17-beta-estradiol to 31.4 per cent of the initial values, whereas the HPL values fell below the specificity of the testing procedure (12.5 ng/ml). Comparative investigations of the pregnancies which, according to sonographic findings, remained intact until curettage and those which were aborted after the application of prostaglandin did not, in spite of low plasma progesterone and estradiol levels in the abortive group, reveal any statistically significant differences. The abortive effect--even with local application--of the prostaglandins was confirmed. Conclusions regarding the effective mechanism of the prostaglandins upon the fetoplacental unit and the function of the corpus luteum remain subject to speculation.
The effects of a 6-month contraceptive system of biodegradable norethisterone (NET) implants on the menstrual cycle, estradiol and progesterone levels, the presence of side effects, its contraceptive effectiveness, and the NET levels achieved were studied in a group of nine women. There was practically no disruption of the menstrual cycle and no important side effects. Ovulation was inhibited in four subjects, and another four subjects remained ovulatory. In all the subjects a cyclic secretion of estradiol was maintained. No pregnancies occurred. The circulatory levels of NET were very stable throughout the 6-month period of implant use.
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One hundred seventy-seven women have been studied over the periovulatory period, in order to obtain detailed information on temporal relationships between ovulation and defined changes in the concentrations of estradiol-17 beta (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and progesterone (P) in peripheral plasma. Serial samples of blood were taken, the surfaces of the ovaries were examined at laparotomy, and the mature follicle or corpus luteum was removed for histologic examination. The results in 107 cases fulfilled the criteria for statistical analysis, and in 78 the operation was performed after the follicle had ruptured. A probit analysis was undertaken with use of the proportion of women who had ovulated at a given time in relation to the interval from a defined rise or peak in the concentration of a circulating hormone. The median time intervals (in hours) from the hormonal event to ovulation and the 95% confidence limits of the estimates are as follows: 17 beta-estradiol--rise 82.5 (54.0 to 100.5), peak 24.0 (16.9 to 32.1); LH--rise 32.0 (23.6 to 38.2), peak 16.5 (9.5 to 23.0); FSH--rise 21.1 (14.1 to 30.9), peak 15.3 (8.1 to 21.7); progesterone--rise 7.8 (-12.5 to 15.9). From the statistical model for LH it was possible to estimate that ovulation in 90% of the cases had occurred between 16 (+/- 6) and 48 (+/- 6) hours after the first significant rise in the concentration of this hormone and between -3 (+/- 5) and 36 (+/- 5) hours after the peak. An examination of the individual results in every woman gave corresponding ranges of between 24 and 56 hours from the first significant rise in LH and between 8 and 40 hours after the peak. From a practical standpoint, the conclusion is that a defined rise in the concentration of circulating LH is the best indirect parameter of impending ovulation.
In 5 normocyclic women, firstly taking a conventional oral contraceptive, Neogynon (50 mcg EE + 250 mcg levo-norgestrel) for 6 months, the levels of LH, 17 beta-E2 and progesterone did not rise after changeover to a dose-reduced pill, Microgynon 30 (30 mcg EE + 150 mcg levo-norgestrel). This fact indicates maintained central suppression. Examination of the hypothalamic-hypophyseal axis by the Gn-RH test (50 mcg) with Microgynon 30 showed negative results during the first treatment cycle in 13 out of 18 women. In the 6th treatment cycle only 7 Gn-RH non-reactive women were observed and after stimulation with 100 mcg Gn-RH only 5 women remained with negative Gn-RH tests. Of the 20 women who took conventional oral contraceptives over a period of 6 months to 6 years (7 took Eugynon: 50 mcg EE + 500 mcg D,L-norgestrel, 5 Lyndiol: 75 mcg mestranol + 2.5 mg lynoestrenol, 8 Neogynon, only one from the Neogynon group showed a positive result. On the other hand there was a positive reaction in 4 out of 7 women using the two step dose-reduced preparation Sequilar (11 tablets of 50 mcg EE + 50 mct levo-norgestrel and 10 tablets of 50 mcg EE + 125 mcg levo-norgestrel).
Fifty-one female volunteers used a superactive stimulatory luteinizing hormone-releasing hormone (LH-RH) analog for suppression of ovulation for 3 to 12 months. The potent LH-RH agonist D-Ser(TBU)6-EA10-LH-RH was administered intranasally once daily in a dose of 400 or 600 micrograms. No pregnancies occurred during the 283 treatment months. Severe bleeding disturbances were not observed during the long-term treatment. No signs of hyperplastic changes were found in endometrial biopsies. There were no serious side effects. Ovulation promptly returned after cessation of treatment even in women with amenorrhea during treatment periods of 1 year or more. Thus, long-term LH-RH agonist treatment proved to be a safe, effective, and rapidly reversible new method for peptide contraception.
Many women appear to experience menstrual disturbances after tubal sterilization. In this study the ovarian function in such women was investigated. Serial measurements of FSH, LH, estradiol and progesterone were performed throughout the study cycle in 23 previously sterilized patients, 14 with menstrual disturbances (group I--symptomatic) and 9 with normal cycles (group II--asymptomatic). A group of 28 parous women served as controls. Among 23 patients, luteal phase progesterone was elevated in 19, and in 4 it was undetectable (anovulatory). All four anovulatory patients belonged to group I. Anovulatory cycles were also characterized by tonic elevated LH levels. Mean midluteal progesterone values were lower in group I (8.5 ng/ml) than in group II (13.8 ng/ml) and in the controls (16.5 ng/ml). Mean midluteal progesterone was lower than 10 ng/ml in 78% of group I, 44% of group II and 15% of the control patients.
The importance of predicting human ovulation for either optimizing or avoiding conception has been considered from an endocrine, morphological and clinical view point. Of the biochemical markers in peripheral blood, a knowledge of the LH peak is the most clearly defined, with a two to four fold increase above baseline levels for a relatively short 24-30 hour preovulatory period. Ovulation is considered to occur 28-36 hours after the beginning of the LH rise or 8-20 hours after the LH peak. Daily assessment of the rise in preovular oestrogen reflects Graafian follicle development but the rise is less distinct and spread over 3-4 days with marked day to day fluctuations. LH induces a marked reduction in oestrogen production some 12 hours prior to ovulation and at the same time induces a two to three fold increase in progesterone production above baseline levels. While these changes in themselves are not great enough for day to day discrimination, a knowledge of their reciprocal relationship may be. The preovular rise in FSH is relatively small compared to LH and the radioimmunoassay technique has not generally been refined to be as rapid and reliable. Monitoring the day to day growth of the preovular follicle ultrasonically is both linear and potentially predictable but there is a wide range of its final diameter (17-26 mm) prior to ovulation making prediction inaccurate. With further refinements in ultrasonic resolution, detection of intrafollicular changes of the cumulus oophorus and granulosal cell layer configuration and thickness may give a closer prediction of the time of ovulation. At a clinical level a knowledge of menstrual cycle length in association with body messages which herald ovulation are useful and may forewarn that ovulation in terms of days is approaching. Such markers as preovulation pain, the detection of periovular cervical mucus and the change in physical character and position of the cervix are reliable signs of preovulation for many well motivated and informed women for either promoting or avoiding conception. A knowledge of the basal body temperature is not a prospective guide to ovulation, but once the thermal shift is established in association with loss of periovular mucus symptoms, the fertile period can be considered to have passed. Because we do not have a precise and simple marker of human ovulation, it is necessary that the most suitable marker of pre- or postovulation is chosen for the particular need in a given individual.
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.
In man both basal gonadotrophin levels and the pituitary responses to LHRH remained relatively constant throughout life. In women the pituitary sensitivity varied in the menstrual cycle due to the typical cyclic variation of oestradiol and progesterone. The max delta LH increase to 100 mug LHRH was observed in the periovulatory period (183 +/- 41 mU/ml); it was also significantly higher in the luteal (49 +/- 7 mu/ml) than in the early follicular phase (18 +/- 3 mU/ml). The effect of exogenous sex steroid hormones taken as contraceptive drugs was then studied in 15 women. Significantly lower LH and FSH basal values as well as responses to LHRH were observed in 8 normal women under oral combined contraceptives. Conversely, in 7 women under oral sequential contraceptives, basal LH and FSH remained in the normal range. The LH-FSH responses were increased and delayed when these tests were performed during the period of estrogen treatment. Thus, with combined oral contraceptives, constant and high levels of estrogens and progesterone not only inhibit the LH peak, but also decrease the basal LH-FSH levels and responses to releasing hormone. Conversely, with sequential oral contraceptives, the low level of estradiol does not inhibit these responses and even enhances them. In menopausal women both basal and gonadotrophin responses to LHRH were increased indicating an important pituitary reserve. In menstruating women a significant estradiol increase is observed 2 and 4 hours after a 100 mug LHRH injection, both during the follicular and the luteal phases whereas progesterone increases only in the luteal phase. In men, testosterone was found to increase 4 hours after a 100 mug LHRH injection. These studies show that in normal subjects, sex steroid hormones are important regulators of the sensitivity of the pituitary responsiveness to releasing hormone.
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The effect of intramuscular triamcinolone acetonide (TCA-A) on pituitary gonadotropins and ovarian hormones was studied in a normally menstruating woman. Serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well estradiol 17-beta (E2) and progesterone (P), were determined daily in a normal "ovulatory" pretreatment cycle. A total of 160 mg of TCA-A was then administered in four injections over two and a half months. Daily serum levels of LH, FHS, E2, and P were again measured during a period beginning thirty days after the last injection of TCA-A. Cyclicity of all these hormones was absent after treatment. Both LH and FSH were suppressed in the first half of the post-treatment period when compared with the pretreatment ovulatory cycle. A potent corticosteroid such as TCA-A is apparently capable of producing anovulatory cycles in humans by disruption of cyclic pituitary gonadotropin secretion.
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