Investigation of Danazol as a contraceptive agent.
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Body Temperature↗
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Studies on ovarian and adrenal steroids at different phases of the menstrual cycle. III. Steroid and lutropin levels before and after the administration of a single contraceptive dose of depot-medroxyprogesterone acetate (DMPA).
Ovarian and adrenal steroids and biologically active lutropin were measured in peripheral plasma samples obtained from 5 normally menstruating women. Plasma samples were collected every 3 h for a period of 39 hours in the periovulatory period of a pretreatment (control) cycle and then 16 and 54 days after a single i.m. injection of 150 mg of depot-medroxyprogesterone acetate (DMPA). Sixteen days after DMA administration, the levels of estradiol, progesterone, 17-hydroxyprogesterone, and lutropin were reduced to early follicular phase levels. No further decrease was found in 17-hydroxyprogesterone and lutropin levels; however an additional decrease occurred in the levels of estradiol and in the "morning" levels of progesterone 54 days after the administration of DMPA. Furthermore, the levels of pregnenolone, androstenedione, testosterone and dihydrotestosterone were significantly diminished in all samples collected after the administration of DMPA. Fifty-four days following the administration of DMPA, the levels of cortisol and 17-hydroxypregnenolone were significantly reduced. The administration of DMPA did not interfere with the circadian rhythm of cortisol, pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone, 17-hydroxyprogesterone, and androstenedione levels. A significant circadian rhythm was also found in testosterone (after 16 days) and lutropin (after 54 days) levels. No circadian variation was found in estradiol, progesterone and dihydrotestosterone levels.
Adrenal Glands↗
Hormonal consequences of "missing the pill".
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Adolescent↗
The cytoplasmic progesterone receptor of human endometrium during the menstrual cycle.
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Adult↗
The in vivo metabolism of progestins. IV. The metabolic clearance rate and plasma binding of 6alpha-methylpregn-4-ene-3, 20-dione in women.
[3H]6alpha-methylprogesterone (6MP) was synthesized by selective catalytic tritiation of the delta1-olefinic bond of 6alpha-methylpregna-1,4-diene-3,20-dione. The metabolic clearance rate of 6MP (MCR6MP) was determined in 6 women by the single injection technique. The plasma MCR6MP was 4047 +/- 298 L/day (59 +/- 15 L/day/kg) which was higher than the MCR of progesterone and medroxyprogesterone acetate (6alpha-methyl-17alpha-hydroxy-pregna-4-ene-3,20-dione acetate). The high clearance was not due to binding or metabolism of 6MP by red cells. Although 6MP was bound to CBG with a lower affinity than progesterone, this could not entirely explain the high MCR6MP. When considered with the reports of progesterone and medroxyprogesterone acetate clearance, the present studies suggest that the 6alpha-substitution of progesterone leads to an increased rate of steroid metabolism in women.
Carrier Proteins↗
Midtrimester pregnancy interruption and the placental progesterone levels.
Placental progesterone contents were studied in 10 patients therapeutically aborted at midtrimester by intraamniotic infusions of hypertonic saline, and from 14 patients (12-20 weeks) aborted by intraamniotic instillation of prostaglandin F-2alpha. The mean S.E. of the progesterone was 1.99 plus or minus 0.07 ug/g. placental tissue in the first group, while with prostaglandin abortion the placental progesterone was 1.45 plus or minus 0.08 ug/g. tissue, which is significantly lower than the results in the first group (P equals 0.001). The possible mechanism of action of prostaglandin as an effective abortifacient is discussed.
Abortion, Induced↗
In vitro and in vivo interactions of [3H]dimethylstilbestrol with the estrogen receptor.
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Cell Nucleus↗
Endocrine basis for the initiation, maintenance and termination of pregnancy in humans.
Channels of hormonal communication between the embryo and the mother are established early in the conceptual process. The preimplantation embryo exerts local uterine and systemic effects on the maternal organism to provide a suitable environment for embryonic development, to enable the development of a receptive endometrium for implantation, and to maintain corpus luteum function. In primates, implantation can be induced with progesterone alone if the proliferative effects of estrogens on the endometrium have already been achieved; estrogens may have a priming effect for progesterone on the endometrium, but it is not obligatory for implantation. Progesterone secretion from the corpus luteum is essential for the maintenance of early pregnancy until the placenta takes over the major role of steroidogenesis. This luteo-placental shift is completed at about the 50th day of human gestation. Withdrawal of progesterone effects by the administration of the competitive progesterone antagonist, RU 486, within 24 days after conception will terminate 85% of human pregnancies. Other nonsteroidal functions of the corpus luteum have been recently suggested. Relaxin and prorenin are peptides secreted by corpus luteum of pregnancy but their role remains putative at the present time.
Abortion, Spontaneous↗
Interruption of endometrial maturation without hormonal changes by an antiprogesterone during the first half of luteal phase of the menstrual cycle: a contraceptive potential.
OBJECTIVE: To examine hormonal and endometrial responses to intermittent low-dose RU486 administration in the luteal phase of the menstrual cycle. DESIGN: Prospective open trial in which subjects serve as their own controls. PATIENTS/PARTICIPANTS: Eight normal cycling women. INTERVENTIONS: RU486 (10 mg, orally) was administered 5 and 8 days after urinary luteinizing hormone (LH) surge of treatment cycle. MAIN OUTCOME MEASURES: Daily serum concentrations of LH, follicle-stimulating hormone, estradiol (E2), and progesterone (P) were determined in control, treatment, and recovery cycles (n = 5) or treatment and recovery cycles (n = 3). Changes in endometrial morphology and immunohistochemical staining for P receptor (PR) and E2 receptor (ER) were determined during control (or recovery) and treatment cycles. RESULTS: Cycle length and hormonal patterns were unaltered after treatment with RU486. As demonstrated by reduced stromal edema and delayed glandular development, endometrial dyssynchrony occurred in all eight treatment cycles. In addition, seven of eight treatment cycle endometria demonstrated a decrease in PR staining without consistent change in ER staining. CONCLUSIONS: Two low doses of RU486 given 72 hours apart during the luteal phase of the cycle disrupted ongoing endometrial maturation without altering the hormonal and time course of the menstrual cycle. This study provides a basis for the development of a novel form of luteal contraception.
Adult↗
Prognostic assessment of female fecundity.
A clomiphene citrate (CC) challenge test was used to prospectively assess future fertility potential in 51 women aged 35 or more with unexplained infertility. Baseline (day 2-3 of the menstrual cycle) and response levels (day 9-11) of follicle stimulating hormone (FSH), luteinising hormone (LH), and 17-beta oestradiol were measured before and after administration of 100 mg clomiphene on days 5-9 of the menstrual cycle. Although all the women had a normal baseline FSH, 18 had an exaggerated FSH response of 26 mIU/ml or more (over 2 standard deviations above control values); this was regarded as a diminished ovarian reserve (DOR). In the DOR group mean response FSH was 38.9 mIU/ml (SD 13.8) and in 33 women with adequate ovarian reserve (AOR) it was 11.5 (4.9) mIU/ml (p less than 0.0001). In the DOR group 1 of 18 patients and in the AOR group 14 of 33 (42%) conceived (p less than 0.05). It is suggested that despite apparently normal ovulatory cycles, the DOR group has a compromised follicular apparatus. Disparity between normal oestradiol secretory capacity of the granulosa and diminished capacity to secrete inhibin could explain the inappropriately high FSH levels in response to the CC challenge.
Adult↗
Reduced endothelial cell migratory signal production by endometrial explants from women using Norplant contraception.
Bleeding problems can be one of the major reasons for women to discontinue the use of hormonal contraceptives. Causes of endometrial bleeding can include disturbances in endometrial regeneration and angiogenesis. Endothelial cells migrate and proliferate rapidly as part of the angiogenic process under the influence of appropriate stimuli. The aim of this study is to investigate the production of endothelial cell migratory signals by endometrial explants from women receiving Norplant and to compare it to that of those with a normal menstrual cycle. The subjects were selected from Norplant users with an exposure of 3-9 months. The endothelial cell migratory signal production was assayed using the Folkman method (1989), modified by Rogers (1992). Blood serum concentrations of oestradiol, progesterone and sex hormone binding globulin were monitored for 2 weeks prior to endometrial biopsy. Endothelial cell migration toward endometrial explants of 30 women as control and 46 Norplant acceptors was assayed. The results showed that endothelial cell migratory activity toward endometrial explants from the control group was significantly higher than toward those from Norplant acceptors (z = 3.89, P < 0.001). There were no differences between endometrial endothelial cell migratory activities in Norplant acceptors with bleeding or without bleeding problems.
Adolescent↗
Seasonality of reproductive function and weight loss in rural Nepali women.
Menstrual and hormonal disturbances have been reported in thin, dieting and exercising Western women, and also recently in rural African women. A study of salivary progesterone profiles was undertaken in a Nepali population to examine whether seasonal increases in workload and changes in energy balance influenced ovarian function. Women's energy expenditure levels were moderately heavy in the winter and very heavy in the monsoon, and body mass fluctuated by -2.8 to +4.8 kg. Samples were collected from 24 normally menstruating women in two seasons, each individual serving as her own control. Progesterone levels were significantly depressed in the monsoon relative to winter for women who lost weight, but not for women who gained weight, indicating that energy imbalance is associated with a loss of fecundity. No differences in body mass index were found between women who lost or gained weight. Progesterone levels were age-dependent, and the degree of hormonal disturbance between age-groups was related to weight loss. The study demonstrates seasonal changes in the fecundity of hard-working Nepali women and a direct link between ovarian function and weight loss (negative energy balance), which is independent of current nutritional status.
Adolescent↗
Endometrial carcinoma after cyclical oestrogen-progestogen therapy for Turner's syndrome.
A case of endometrial adenocarcinoma in a patient with Turner's syndrome who had received long term combined oestrogen-progestogen therapy is described.
Adenocarcinoma↗
Steroid receptors in normal and neoplastic female reproductive tissues.
The presence of cytosol estrogen (ER) and progestin (PR) receptors in specimens of normal uterine cervix, endometrium, myometrium, Fallopian tubes and corpora lutei or in samples of neoplastic female reproductive tissues was investigated. The material consisted of PR and ER measurements of tissue samples obtained from fertile and postmenopausal women, receptor assays were performed by a dextran-coated charcoal technique. The radio PR/ER was highest in specimens from the Fallopian tubes (44) and endometrium (4-10),2-3 in specimens of uterine ecto- or endocervical epithelium and about 4 in the myometrium. No ER or PR were found in the four corpora lutei examined. PR or PR/ER ratio in specimens of myoma tissues did not differ from that found in the myometrium specimens. The highest ER and PR values in the endometrium were measured in specimens taken during the late proliferative or intermediate phase of the menstrual cycle. The PR values in specimens from postmenopausal myometrium were lower in comparison with the samples taken from the myometrium of fertile women in contrast to ER values. In the specimens of carcinoma of the vulva and the uterine cervix ER levels were very low, with no measureable values of PR. In the endometrial carcinoma samples the PR/ER ratio was lower than in the normal endometrium. 4 out of 7 specimens taken from ovarian adenocarcinoma had a measureable amount of ER and in 2 out of 7 cases PR.
Female↗
Contraceptive steroid toxicology in the Beagle dog and its relevance to human carcinogenicity.
Problems associated with the use of the Beagle dog in chronic toxicological studies of contraceptive steroids are described. A short review is presented on the occurrence of spontaneous tumours in dogs and in bitches of various breeds. The current status of knowledge of canine reproductive hormones and endocrinology is outlined, together with effects of contraceptive steroids. The pathology and histological classification of spontaneous and induced mammary neoplasia in the dog is discussed and compared with breast cancer in women. A series of recommendations are included for future research in this field which it is hoped may resolve some of the outstanding issues and lead to a more suitable toxicological model for contraceptive steroids.
Animals↗
The effects of RU 486 on immune function and steroid-induced immunosuppression in vitro.
The effect of RU 486 [17 beta-hydroxy-11 beta-(4-dimethylamino-phenol)17 alpha-(prop-1-ynyl)estra- 4,9diene-3-one] on [3H]thymidine incorporation into Concanavalin-A-stimulated human peripheral blood mononuclear cells and its influence on the suppressive effects of cortisol and progesterone were investigated. Cortisol suppressed lymphocyte thymidine incorporation at 10(-5), 10(-6), and 10(-7) M (17.6%, 20%, and 38% of control, respectively; P less than 0.01). Cortisol-induced suppression was reversed when low concentrations of RU 486 (10(-7) and 10(-6) M) were added. RU 486 at 10(-5) M further suppressed lymphocyte thymidine incorporation when added to cultures with cortisol. Progesterone significantly inhibited lymphocyte thymidine incorporation at 10(-5) M (8.2% of control; P less than 0.01). No reversal of progesterone-induced suppression of thymidine incorporation was seen when RU 486 was added to cultures; rather, further suppression of thymidine incorporation was seen. RU 486 alone in culture at concentrations achieved therapeutically (10(-5) M) significantly inhibited thymidine incorporation (7.2% of control; P less than 0.01). These findings suggest that RU 486 may have dose-dependent mixed agonist/antagonist effects on cortisol-induced immunosuppression. The lack of an antagonist effect of RU 486 on progesterone suggests that progesterone's immunosuppressive effects may not be receptor mediated. Finally, our findings would suggest that some immunosuppression may be seen at currently used doses of RU 486.
Adult↗
The increase in plasma and saliva cortisol levels in pregnancy is not due to the increase in corticosteroid-binding globulin levels.
Total and free cortisol levels are significantly elevated in pregnancy, but the reasons for this are not clear. The relationships between the diurnal variation in saliva (free) cortisol and baseline levels of total cortisol, corticosterone-binding globulin (CBG), progesterone, and estrogens were studied in several groups of women (normal nonpregnant, taking a combined oral contraceptive pill, after superovulation therapy, during early and late pregnancy, and postpartum). Saliva cortisol levels were significantly elevated in late pregnancy throughout the day, with preservation of diurnal variation. Total cortisol and CBG levels were also significantly raised in pregnancy, but total cortisol levels were normal in women taking a combined oral contraceptive pill in spite of significantly elevated CBG. There was no relationship between saliva cortisol and progesterone levels, and it is unlikely that the increase in cortisol is due to displacement of cortisol from CBG by progesterone. Cortisol levels fell slowly postpartum over several days, making it improbable that the increase in cortisol is solely due to elevated CRH levels. It appears that increased free and total cortisol levels in pregnancy are related to resetting of the sensitivity of the hypothalamic-pituitary-adrenal axis and not merely to raised CBG, progesterone, or CRH levels.
Adult↗
Sphenoid wing meningioma progression after placement of a subcutaneous progesterone agonist contraceptive implant.
A causal relationship between sex steroids and meningioma proliferation has long been suspected. We report a case of the clinical progression of a sphenoid wing meningioma after the placement of Norplant, a subcutaneous contraceptive implant containing levonorgestrel, a progesterone agonist. Although not proof of causation, this observation lends further credence to the importance of progesterone receptors in the growth and possible treatment of meningiomas.
Adult↗