Vaccination against pregnancy.
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PURPOSE: To determine the effect of progestin therapy on bone mineral density in postmenopausal women and to compare its effects to those of estrogen. SUBJECTS AND METHODS: A prospective, randomized clinical trial was performed in 81 postmenopausal women aged 51.7 +/- 4.4 years (mean +/- SD). They were assigned to one of four groups: Provera 20 mg, Premarin 0.6 mg, Premarin 0.3 mg plus Provera 10 mg, and a placebo. In addition, all women received calcium supplementation, if necessary, to a calcium intake of 1,000 mg/day. We used single- and dual-photon absorpiometry, metacarpal radiogrammetry, and computed axial tomography to measure bone mineral density in the total skeleton, spine, radius, and metacarpal. RESULTS: Women receiving placebo lost bone at all sites (p less than 0.01). The Provera-treated group showed no change in total body calcium, but there were decreases in radial density (p less than 0.01), metacarpal cortex (p less than 0.01), and spine density (p less than 0.01). The Premarin-treated group had an increase in spine density and total body density (p less than 0.05), but a decrease in radial density (p less than 0.05). The Premarin-plus-Provera group showed no change in spine density, total body calcium, or radial density but had a decrease in metacarpal cortex (p less than 0.01). CONCLUSIONS: Compared to placebo, Provera reduced the rate of loss in cortical areas of the skeleton, but not in the spine, which contains more trabecular bone. In contrast, Premarin reduced the rate of loss in both cortical and trabecular areas of the skeleton. The low-dose combination of Premarin plus Provera was similar in its effect on bone to that of Premarin alone, suggesting that there may be a synergistic effect of this hormone combination on bone. Serum cholesterol levels decreased with Provera, Premarin, and the combination of both, whereas levels of serum triglycerides increased with Premarin treatment, decreased with the Provera regimen, and were unchanged with the combination therapy. Provera does not adversely affect the lipid profile.
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Atherosclerosis, lipoprotein structure, lipoprotein metabolism and role in atherogenesis, epidemiology of lipoproteins and coronary artery disease, and current public health guidelines for cholesterol control are described. Low density lipoprotein cholesterol levels rise with age in both men and women. High density lipoprotein (HDL) levels decline after menopause. Special aspects of coronary risk in women include the stronger role of diabetes, hypertriglyceridemia and HDL. In addition, the effects of exogenous hormone therapy, both in the form or oral contraceptives and post menopausal hormone replacement should be considered. Careful attention to these issues may reduce cardiovascular morbidity in adult women.
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.
Concentration of cytosolic progesterone receptor (PR) was measured by means of an exchange procedure in the endometria of 80 women. Investigations carried out in 35 normal menstruating females showed a gradual increase of PR during the preovulatory and immediate postovulatory phases, decreasing to the lowest level at the end of the cycle. Measurements in endometrial samples obtained from women on combined hormonal contraceptives demonstrated a significant decline of PR concentration in the periovulatory phase resulting in a flattening of the sinusoid PR concentration curve. The stronger down regulation effect of the preparation containing 1.5 mg of dienogest is due to the higher progestogenic efficacy of dienogest in the respective dosage. We consider the down regulation phenomenon a useful means among others to characterize the progestogenic potency of a steroid.
The development of the blastocyst from ovulation to implantation is discussed with particular reference to control mechanisms that enable the embryo to attach to the uterine wall, using the mouse as a laboratory model. The physical and chemical changes in the uterus and within the blastocyst are seen as essential steps towards implantation. Evidence that the oestrogen plays a fundamental part in the overall control of these changes is demonstrated. The interrelationship between the hormones of early pregnancy and the uterine production of histamine and cycle AMP is viewed in conjunction with the development of the blastocyst and the decidual changes that occur in the uterus which are essential for nidation.
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A clinical study was designed to test whether sustained administration of progesterone to nursing mothers could prolong lactation and delay the postpartum recovery of fertility. The hormone was administered by subdermal implantation of six pellets that each contained 100 mg of progesterone. This treatment was administered to 84 fully nursing women on day 30 post partum. Control groups were composed of 130 fully nursing women who received an injectably placebo, and by 125 fully nursing women who received a TCu 200 intrauterine contraceptive device. An exacting list of requirements for admission to and continuation in the study was applied to all groups. No pregnancies occurred in the progesterone-treated group from the second to the sixth postpartum month. This period coincided with the period of elevation plasma progesterone attributable to hormone released from the implants. The cumulative probability of pregnancy in the placebo group was 10.2 per 100 women at the sixth month. Treatment with progesterone did not change the duration of lactation or the rate of child growth, and no adverse effects were recorded. These results warrant further investagation of the use of progesterone as an alternative method to prevent conception in nursing women.
Pulmonary artery thrombosis and an anti-ethinyl-oestradiol monoclonal IgGlambda were found to be associated in a 36-year-old woman (Mrs MAI.) who took an oral contraceptive containing 50 mug ethinyl-oestradiol and 500 mug nor-ethisterone daily. After appropriate purification including methods by which the IgG was separated of bound circulating hormones, its binding activity was demonstrated by several methods: passive haemagglutination of oestradiol-benzoate sensitized red blood cells; gel filtration on Sephadex G-25; ultracentrifugation and equilibrium dialysis. IgGlambda MAI bound ethinyl oestradiol (Ka=2-7 X 10(1) M-1) and also 17-beta-oestradiol, with a lower affinity (Ka=0-4 X 10(7) M-1). The valency for these two hormones was near 2. Ethinyl-oestradiol bound to the IgG was displaced by ethinyl-oestradiol itself and in decreasing order of potency by 17-beta-oestradiol, progesterone, oestriol, and testosterone. Oestrone and hydrocortisone had no effect. Although the localization of the binding sites of this IgGlambda was not studied, it is likely that they were the antibody sites of the molecule and, according to immunochemical criteria, it may be classified as a monoclonal anti-ethinyl-oestradiol antibody. It is felt that its association with the pulmonary thrombosis and the oral contraceptive may be significant. This supports the hypothesis of an immunological mechanism for the unexplained thrombotic risk of oral contraceptives.
Sterilization affects measurably the circulation and the functioning of the ovaries, but further studies are required to estimate the clinical meaning of the change.
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Estradiol and progesterone receptor sites (empty or filled with endogenous hormone)have been measured in the cytoplasm and nuclei of human endometrium. Receptor changes have been observed throughout the normal menstrual cycle. During the preovulatory phase the cytoplasmic estradiol receptor sites do not change while the nuclear receptor sites more than double. Cytoplasmic estradiol receptor sites decrease very early in the secretory phase, whereas the decrease in nuclear sites occurs later. Cytoplasmic progesterone receptor sites more than double during the preovulatory phase and show a large decrease immediately after ovulation, when the concentration of nuclear receptor is at its highest. Thus the total cellular concentrations of both estradiol and progesterone receptors are lowest in the late secretory phase. It was found that they are positively correlated with the concentration of plasma estradiol only during the proliferative phase. The concentration of cytoplasmic progesterone receptor is negatively correlated with 17 beta-hydroxysteroid oxidoreductase activity during the secretory phase. In anovulatory cycles the concentrations of estradiol and progesterone receptors are high, similar to those of the late proliferative phase. "luteal insufficiency" is characterized by a very low concentration of estradiol receptor. Early pregnancy endometrium (8 to 10 weeks' gestation) is characterized by a large concentration of progesterone receptor, exceeding those of any period of the menstrual cycle.
A short review on steroid absorption and enterohepatic recycling in man with special emphasis on contraceptive and related steroids is presented. Some new experimental data on the intestinal metabolism of steroids is described and includes further observations on the effect of antimicrobial agents on steroid hormone metabolism. Evidence is presented that plasma levels of steroids may be influenced if the intestinal microflora is altered. Some formation of biologically active steroids, like estradiol, may occur in the intestinal tract and this may have both biological and pathological consequences and may be influenced by such factors as diet and sex. It is concluded that our knowledge of the intestinal and especially, the mucosal metabolism of steroids is scanty and further studies are needed to clarify the role of the intestine and enterohepatic circulation in determining the bioavailability of natural and synthetic steroids.
Three different regimens of RU 486, a progesterone receptor blocking agent, were compared for their ability to terminate early human pregnancy. One-hundred-fifty-three healthy women with a gestational length less than 49 days from the last menstrual period were recruited to the study and randomly allocated to one of three treatment regimens: 1) RU 486 10 mg x 2 for seven days; 2) RU 486 25 mg x 2 for seven days; or 3) RU 486 50 mg x 2 for seven days. No significant difference in efficacy was seen between the three dose regimens. Treatment with 10 mg x 2 x VII resulted in 73 per cent complete abortions, 25 mg x 2 x VII in 66 per cent and 50 mg x 2 x VII in 64 per cent complete abortions. Response to treatment, measured as reported onset of bleeding and passage of products of conception, however, occurred significantly later on the 10 mg x 2 regimen than on the other two dose regimens. In each treatment group, women who subsequently aborted completely had significantly lower pretreatment levels of hCG than women with incomplete abortion or continuing pregnancy. The treatment was well tolerated by the women and except for one woman who experienced a profound bleeding necessitating a blood transfusion, no serious side effects were seen.
A pharmacodynamic and pharmacokinetic study of the Chinese No. 1 pill, a combined oral contraceptive containing 35 micrograms ethynyloestradiol (EE) and 600 micrograms norethisterone (NET), was performed in 29 women over a period of six months. Blood samples for analysis were taken during a pretreatment cycle, the first and 6th treatment cycles and post-treatment. Minor changes in carbohydrate metabolism occurred and these were particularly noticeable when the incremental areas under the serum concentration-time curves for both glucose and insulin in response to a glucose tolerance test were calculated. No changes occurred in the serum glycosylated haemoglobin levels. The serum concentrations of all the lipids measured (total cholesterol, triglycerides, LDL-C, HDL-C and apolipoproteins AI, AII and B) were significantly increased on treatment as were levels of Factor X, SHBG and caeruloplasmin whereas antithrombin III decreased. In 38 of the 40 treatment cycles, ovulation was suppressed. In one cycle serum oestradiol and progesterone levels showed a typical ovulatory pattern and in another there was evidence of follicular activity without ovulation. Serum EE concentrations showed a similar pattern in both treatment cycles showing that co-administration of NET did not affect EE metabolism. Serum NET levels were higher in the 6th than in the first treatment cycles. On comparing pharmacodynamic and pharmacokinetic parameters, the only statistically significant correlations were between the percentage change in triglycerides and SHBG and serum NET, but not EE concentrations, and between apolipoproteins AI and serum EE.
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