Plasma levels of progesterone were measured during the luteal phase in 10 of 15 women with clinical histories of at least three spontaneous abortions in the last three gestations, and in 15 healthy nonpregnant women during the same phase of the ovarian cycle. Progesterone values found in the women with habitual abortion were lower (P less than 0.05-0.005) than in the nonpregnant group almost throughout the period of observation. The habitually aborting women who became pregnant again aborted between the seventh and 12th weeks. Their progesterone concentrations were less than 6 ng/ml, 48-72 hours before vaginal bleeding or abortion. These values were compared with those found during the first 12 weeks in normal pregnancy (P less than 0.001). The results suggest a useful method of evaluating the treatment of habitual abortion.
A series of semi-structured qualitative interviews were undertaken with civil society stakeholders as part of this project. This project explored the role of trust and transparency within the context of multi-level governance. The research examined the interplay of trust and transparency within the UK. The project focused on one strong identity and one 'instrumental' region to explore the impact of factors such as varying identities, institutional configurations and resource profiles on trust and transparency. Interviews were Wales and the North West of England. This proposal is for a National Research Centre (WISERD/Civil Society) to undertake a five year programme of policy relevant research addressing Civil Society in Wales. Established in 2008, WISERD provides an 'All-Wales' focus for research and has had a major impact on the quantity and quality of social science research undertaken in Wales. As part of WISERD, WISERD/Civil Society will enable this work to be deepened and sustained through a focused research programme that further develops our research expertise, intensifies our policy impact and knowledge exchange work and strengthens our research capacity and career development activities. WISERD/Civil Society will therefore aim to develop key aspects of the multidisciplinary research initiated during the first phase of WISERD's work to produce new empirical evidence to inform our understanding of the changing nature of civil society in the context of devolved government and processes of profound social and economic change. There are many disagreements over what civil society is and how it may be changing. We do know that over the last forty years there have been unprecedented changes in the spheres of economy and industry, politics and governance, social relations and individual life courses. How individuals in local contexts are affected by and respond to dramatic institutional changes is not well understood. An important gap in our knowledge is in describing and explaining the impact of social change on local forms of civil society and civil society organisations and what this means for social cohesion and well-being. In addition how different forms of civil society are developing in the context of multi-level and devolved government is not well understood. Because of its size and devolved government, Wales offers a unique context for studying these issues. Viewing Wales as a 'laboratory for social science' the proposed centre will build on existing networks of researchers who have a wide range of expertise and skills. Large survey data sets will be exploited and analysed and new data collected on civil society in Wales, the UK and Europe. Inter-disciplinarity and multi-method approaches applied to longitudinal and comparative data will be a key feature and strength of the WISERD/Civil Society research programme. Our research will be underpinned (i) to maximise research impact, (ii) to become a centre of excellence for comparative, longitudinal, and relational research methods and (iii) to contribute to the growth of research capacity in Wales. We will also extend our research out from Wales to undertake comparative studies at different regional, national and international levels. In this way WISERD will make substantive and novel contributions to the advancement of social theory applied to researching contemporary civil society and to methodological approaches to describing and explaining patterns of civic participation in the context of devolution and multi-level governance. Substantive research will be applied to real and timely research problems conducted under 1) Locality, Community and Civil Society 2) Individuals, Institutions and Governance 3) Economic Austerity, Social Enterprise and Inequality 4) Generation, Life Course and Social Participation Our aim will be to produce a wide range of outputs accessible to a variety of different audiences, academic papers; books; working papers; seminars; web based material; video and e-learning materials; as well as disseminating our work through a diversity of activities. Public awareness will be raised through events; activities; and exhibitions, designed to foster interest and encourage discussion and debate. WISERD/Civil Society will have a strong management structure, substantial institutional support, and close links with relevant organisations, and will provide substantive career development for new and early-career researchers and PhD students.
DiagnosticsProgesterone vs Endometrial BiopsyLuteal Phase EvaluationOvulation Assessment
An endometrial biopsy and a blood sample for progesterone determination obtained simultaneously in the midluteal phase of the cycles of 55 infertile women were compared for reliability for confirmation of presumptive ovulation and evaluation of luteal function. Progesterone levels of 3 ng/ml or greater were found in 90.5% of the cycles. Secretory endometrium was identified in 81% of the cycles. Thirty-three cycles yielded sufficient information to compare the two methods for evaluation of luteal function. Histology and progesterone levels were consistent with each other and the presumed time of ovulation in only 11 cycles. Histology was inconsistent with the presumed time of ovulation in 20 cycles, while progesterone was inconsistent in only two cycles. Additional samples for progesterone determinations were obtained during the biopsy cycles of 15 patients who presented adequate data for evaluation of luteal function. A single, well-timed progesterone determination appeared adequately to reflect the data obtained from serial samples in the same cycle. These results support the thesis that a single, well-timed serum progesterone determination is superior to a single endometrial biopsy as a screening method for confirmation of presumptive ovulation and for evaluation of luteal function.
The ovulation method of natural family planning is described in detail as taught in the ovulation method centers with an account of its development in Australia and the underlying philosophy. Hormonal studies supporting its scientific bases are given including recent work on the hormonal events of the menstrual cycle. The teaching of the method for the avoidance and achievement of pregnancy is outlined including special circumstances such as lactation premenopause stress situations abnormal vaginal discharges and formal oral contraceptive use. The failure rate of the ovulation method has been shown by a number of surveys as between that of the pill and the IUD. It is the fastest spreading method of natural family planning currently in use in 50 countries.
Reproductive EndocrinologyPreterm LaborHormonal FactorsProgesterone and Estradiol in Pregnancy
A total of 30 to 50 per cent of premature labors occur without identifiable predisposing conditions. To evaluate the hormonal status of these pregnancies, serum progesterone (P) and estradiol (E2) were measured by radioimmunoassay singly in 60 premature labor patients and serially in 19 normal pregnancies. Premature labor patients as a group have significantly lower P and E2 levels than controls. Pregnancies complcated by idiopathic premature labor (IPL) (p less than 0.01), premature labor secondary to abruptio-marginal separation (A-MS) (p less than 0.05), and premature rupture of membranes (PROM) (p less than 0.05) have significantly lower P levels than controls. Patients with IPL and A-MS have significantly lower P levels (p less than 0.01) than PROM patients. No significant change in P or E2 occurs immediately prior to normal term labor. Conclusions are that (1) premature labor patients have significantly lower Pand E2 levels than controls, (2) the degree of P depression varies according to the type of premature labor and (3) IPL is characterized by premature labor with no identifiable predisposing factors.
Research MethodologyCell Culture StudiesRadiation Biology
Summary Many recent fertility studies in developing societies put forward the hypothesis of a negative relation between economic class and fertility. Data showing a positive relationship are frequently dismissed a priori as resulting from the reporting errors of illiterate women. This study draws on data from Indonesia's 1971 Census, a 1973 sample survey of fertility and mortality, and an intensive community study in Java, to argue that an observed positive relation between class and fertility is real, and is related to differences in patterns of marital disruption, postpartum abstinence, and fecundity. The positive relation may be reversed in the future as changes in these patterns, and the impact of the national family planning programme, affect the family structure of each class differently. Had the positive relation in this context been attributed offhand to reporting errors, these important socio-economic changes would have been misunderstood, and possibly ignored.
From January 1, 1968 to May 31, 1973, 100 patients received first kidney transplants from sibling donors. All recipients have been followed for at least two years and several as long as 7.5 years. One hundred per cent follow-up information is available. The absolute two-year patient survival is 85% and the absolute two-year kidney function survival is 76%. Patients with diabetes (especially males) have less success following transplantation than do patients without diabetes. When diabetic patients are excluded, older patients appear to do slightly less well than younger patients. Patients with phenotypically identical HL-A matches with the donor do better than patients without such matches. In the nondiabetic technically perfect transplant recepient, better than 90% long-term transplant function can be expectedwith no kidney losses after the first few months. In contrast, the less well-matched transplant demonstrated both an increased early rejection rate and a high rate of loss after the third to fifth year. Increasing doses of anti-lymphoblast globulin (ALG) had beneficial results in HL-A mismatched sibling transplants, but were slightly detrimental in phenotypically identical HL-A donor-recipient pairs because of an increased rate of infection. The results are compared with the results of transplants from other related donors and from cadavers performed during the same period.
Medroxyprogesterone acetate (MPA) was given once daily sc at 0.1-3,000 mg/kg/day for 3, 6, or 9 consecutive days during gestation days 7 to 15 to CD1 and A/J mice, and New Zealand (NZ) and Dutch Belted (DB) rabbits, and during days 8 to 16 to CD rats. Malformations attributable to MPA did not occur in fetuses of mice or rats exposed to the largest dosage tested. However, 1, 3, or 10 mg/kg on days 13 to 15 to NZ rabbits resulted in 6, 28, and 42% cleft palate, respectively. Comparable cleft palate frequencies were seen in DB offspring.
In a cohort of 50,282 pregnancies 19 children with cardiovascular defects were born to 1042 women who received female hormones during early pregnancy (18.2 per 1000). Among 49,240 children not exposed in utero to these agents there were 385 with cardiovascular malformations (7.8 per 1000). Six children with cardiovascular defects were born to a sub-group of 278 women who used oral contraceptives during early pregnancy (21.5 per 1000). After the data were controlled for a wide variety of potentially confounding factors by multivariate methods, the association between in utero exposure to female hormones and cardiovascular birth defects was statistically significant.
Clinical and experimental studies have suggested that intraperitoneal noxytiolin prevents adhesion formation. A reliable experimental animal model was therefore established and the effect of noxytiolin on adhesion formation was evaluated in a controlled trial using 80 rats. All 40 rats given Ringer solution developed adhesions, whereas in 7 out of 40 given noxytiolin no adhesions were found (P less than 0-02). Noxytiolin reduced both the total and the mean number of adhesions formed (P less than 0-2) and their mean length of attachment (P less than 0-05). The anti-adhesive effect of noxytiolin may be due to its anticoagulant, cytotoxic or antibacterial properties.
Children whose mothers received prenatal progesterone have been shown to be advanced in development at one year and to have greater academic achievement at 9-10 years. This study compares the educational attainments at 17-20 years of 34 progesterone children with 37 normal and 12 toxaemic controls. More progesterone children continued schooling after 16 years compared with controls; a higher proportion left school with 'O' level and 'A' level passes, the average number of passes per child was greater at both levels and more obtained a university place. The best academic results were in those whose mothers had received over 5 grams of prenatal progesterone, and for whom administration commenced before the sixteenth week and treatment lasted longer than eight weeks.
Summary In 1968, a prospective study was started in collaboration with the Family Planning Association to try to provide a balanced view of the beneficial and harmful effects of different methods of contraception. This investigation is now in progress at seventeen clinics and over 17,000 women are under observation. At the time of recruitment, all these women were married white British subjects, aged 25–39 years, who voluntarily agreed to participate. Fifty-six per cent were using oral contraceptives, 25% were using a diaphragm and 19% were using an intrauterine device (IUD). During follow-up each woman is questioned at return visits to the clinic and a record of pregnancies and their outcome, hospital referrals (inpatient or outpatient), changes in contraceptive methods and the results of cervical smears, is accumulated. Women who default are sent a postal questionnaire and, if this is not returned, are telephoned or visited in their homes to collect the necessary information. So far, data obtained during 56,000 woman-years of observation are available for analysis. Follow-up has been maintained with an annual lapse rate of about 0.3%due to withdrawal of co-operation or loss of contact; adherence to the method of contraception in use at recruitment has been reasonably good, and the reporting of pregnancies and hospital admissions appears to have been both reliable and unbiased. The present data include only 24 deaths, so the mortality associated with different contraceptive methods cannot yet be estimated. With regard to morbidity, however, our preliminary results closely resemble those obtained in the prospective study carried out by the Royal College of General Practitioners (1974) and in the principal retrospective studies carried out in Britain and the United States. Women who used oral contraceptives at the start of the study experienced a deficiency of hospital referrals for cancer, benign lesions of the breast, menstrual disorders other than amenorrhoea, duodenal ulcer, and retention cysts of the ovary; they showed an excess of referrals for cerebrovascular disease, cervical erosion, skin disorders, self-poisoning, migraine, venous thrombosis and embolism, hayfever, gallbladder disease, amenorrhoea, and sterility. Women who used a diaphragm showed a deficiency of hospital referrals for carcinoma-in-situ and dysplastic lesions of the cervix uteri and accidental injury; and an excess of referrals for haemorrhoids and cystitis. Women who used an IUD experienced an excess of hospital referrals for anaemia, varicose veins and salpingitis. About half of these differences (12 out of 23) were predicted from other studies while some suggestive evidence already existed for a further five. Of the remaining six, some probably reflect the influence of selective factors or chance. Multiple pregnancies, stillbirths, malformations, the sex ratio and birthweight showed no consistent relationship to method of contraception. The outcome of unplanned pregnancies occurring in women using an IUD, however, was remarkably unfavourable both in terms of ectopic gestation and miscarriage. Clear evidence was found of impairment of fertility after discontinuation of oral contraceptives. Whether this is likely to lead to permanent sterility in some women is uncertain. The study has provided data on the efficacy of a wide variety of contraceptive methods. In general the failure rates are in keeping with those obtained in other large-scale studies, save that those for the diaphragm and the sheath are much lower than those usually quoted. The available evidence does not yet allow a final balance to be struck between the benefits and risks associated with the new methods of contraception that have become widely used during the last two decades. It seems clear, however, that there are no material risks associated with the use of the diaphragm apart from the risk of pregnancy and that there may be some unintended benefits.
General OB/GYNDiethylstilbestrolDES ExposureFetal Effects
Since in utero exposure to diethylstilbestrol (DES) is known to cause abnormalities of the female genital tract later in life, exposed male offspring were located, surveyed by mail, and compared with unexposed male offspring from the same period and medical practices. The exposed and unexposed respondents appeared comparable and did not differ in their response to most medical questions. However, a larger proportion of exposed than of unexposed boys had experienced problems in passing urine (12.9% vs. 1.8%, P = .0003) and abnormalities of the penile urethra (4.4% vs. 0%; P = .017).
Menstrual CycleInternational ComparisonsBreast Cancer RiskHormonal Etiology
The plasma concentrations of oestrone, oestradiol-17β and progesterone, and the urinary excretion of oestrone, oestradiol-17β, oestriol and pregnanediol have been determined in normal Japanese and British adolescent, pre-menopausal, menopausal and post-menopausal women.
The amounts of plasma oestrogen in British and Japanese women were not significantly different except in the adolescent group. In this latter category the mean level of plasma oestrone and oestradiol-17β in the luteal phase was significantly higher in Japanese compared with British women. The mean excretion of urinary oestrogens in the two races was similar for all age groups studied, as was plasma progesterone and urinary pregnanediol.
The mean ratio of oestriol to oestrone and oestradiol-17β for Japanese was higher than that for British women in the two pre-menopausal groups, although the difference was not statistically significant. The difference in the incidence rates of breast cancer in Britain and Japan does not appear to be related to differences in plasma levels of oestrogens or progesterone.
Fifteen years have passed since our group first proposed the use of clomiphene citrate as an ovulation-inducing agent. Our 15-year experience with over 2,000 patients has not dampened our enthusiasm for this drug. The benefits have far outweighted the minor side effects or the possibility of multiple births. Serious birth defects were minimal and have been no greater than what one may expect in the general population. Clomiphene citrate has been a boon to womankind and deserves the confidence it is a drug with a record of utility and with but minor risks.
PregnancyPrior Pregnancy Loss EffectsPreterm Birth HistoryPregnancy Risk Assessment
Data from 25,958 consecutive UCLA deliveries were analyzed to determine the effect of prior abortions and premature births on current pregnancy outcome. Perinatal death rate, combining stillbirths and neonatal deaths, increased more than threefold among women with at least one prior premature in birth and at least one prior abortion and approached 18 per cent of current deliveries when there were three or more prior premature births. Abnormal live births, defined as infants with either birth weight under 2,501 grams, gestational age less than 37 weeks, or congenital anomalies, significantly increased as the number of prior abortions and premature births increased, each in a range of 0 through 3 or more. For example, among women with at least three prior premature births, there were greater than 50 per cent abnormal live births. The risk was mostly that of low birth weight and low gestational age, although there was a slight increase in congenital anomalies. The risk was reduced considerably when there were previous term births and was influenced variably by race, clinic classification, maternal illness, and prior pregnancy complications. This empirical data on pregnancy outcome should be useful in reproductive counseling among women with pregnancy losses and premature births.
Progesterone, at five times normal 24 h endogenous production rates, was administered daily to 37 rats over Days 2 to 10, 11 to 17 or 2 to 21 term is Day 23. Peanut oil, the vehicle, was administered alone to 18 control rats over Days 2 to 21. The effect of treatment on fetal, placental and corpus luteal weights was examined on Day 22 of gestation. The administration of progesterone had no apparent effect on the maternal weight gain with pregnancy, myometrial, fetal or placental weights. No external malformations or abnormalities of the internal genitalia were detected in any of the fetuses examined. The mean number of dead fetuses per litter, 0.72 ± 0.19 (SEM) in the control rats, was significantly increased to 1.57 ± 0.34 and 2.25 ± 0.54 in rats treated with progesterone over Days 11 to 17 and 2 to 21 respectively. Male fetuses were about 7.4 percent heavier than female fetuses in the control rats but this difference was significantly less in rats treated with progesterone over Days 11 to 17(3.4 percent). Progesterone treatment had no apparent effect on the mean corpus luteal weight per rat. Over all groups combined, the mean corpus luteal weight was negatively related to the number of corpora lutea per rat. This relationship was unlikely to have been due to local nutritional or overcrowding factors since there was no apparent relationship between corpus luteal weight and the number of corpora lutea in the one ovary.
Nine healthy fertile women were studied during 29 menstrual cycles. A cervical mucus grading system, assessed by the patient and used in conjunction with basal body temperature, was correlated with plasma levels of luteinizing hormone (LH), oestradiol and plasma progesterone. The results show that a patient can be taught to predict the time of ovulation by observing the changes in the cervical mucus.
Serum progesterone was measured by competitive protein-binding assay in 331 cases of normal pregnancy ranging from 6 to 42 weeks. Serial estimations of serum progesterone were performed in nine cases of severe hypertensive disorder of pregnancy, eight cases of twin pregnancy, three cases of twin pregnancy complicated by severe hypertensive disorder of pregnancy, three cases of triplet pregnancy, three cases of previous bad obstetric history, one case of anencephaly, and seven cases of intrauterine fetal death. Serum progesterone remained within normal range in severe hypertensive disorder of pregnancy and the levels were indistinguishable in cases of fetal growth retardation from those without growth retardation. In twin and triplet pregnancies, serum progesterone was within normal range or elevated and was usually higher than normal in twin pregnancies after weeks 33 to 34. Serum progesterone levels were normal in anencephalic pregnancy and in most cases of intrauterine fetal death. The findings are discussed with reference to placental hormonal activity. It is concluded that serum progesterone is a poor index of placental function.
Androstenedione, testosterone, progesterone and human chorionic gonadotrophin (HCG) in plasma and total oestrogens, luteinizing hormone (LH) and HCG in urine were measured in five women during conceptual cycles and in early pregnancy. There were increased levels in plasma and urine of all the hormones measured between 12 to 48 days after ovulation except progesterone. The concentration of this hormone in plasma decreased during this time. The possible sources of these hormones in early pregnancy are discussed.
Reproductive EndocrinologyTestosterone and Breast CancerPlasma Hormone MeasurementHormonal Risk Factors
Multiple plasma-hormone concentrations were measured in sequential plasma-samples from six women with breast cancer and were compared to concentrations in six control women matched for age, years since menopause, and parity. All hormone concentrations in all the women studied were within normal limits. However, within the normal range the plasma-testosterone concentrations in each cancer patient were significantly higher than in each matched control.
Reproductive EndocrinologyLuteal Phase DefectLuteal Phase InsufficiencyHistologic Dating
In summary, the luteal phase defect is a deficiency of corpus luteum progesterone steroidogenesis, either in amount or duration, or both. The clinical manifestations include either primary infertility or repeated first trimester abortions. The diagnosis can only be made clinically on the basis of a well-timed endometrial biopsy that is read histologically as 2 or more days out of phase with the next period in at least two cycles.
Reproductive EndocrinologyGnRH ResponseEstradiol Effects on GonadotropinsHormonal Regulation
This study was designed to investigate the effect of varying concentrations of estradiol, administered to normal women, upon the gonadotropin response to synthetic gonadotropin-releasing hormone (GnRH or LRF). Beginning at 4 pm on the first day of the menstrual cycle, 19 studies were performed in subjects who received injections of estradiol benzoate (E2B every 12 h for 6 days). Concentrations of E2B administered (mug/kg/12 h) 0.3, 0.6, 1.25, 2.5, 3.75, and 5.0. Mean serum estradiol concentrations achieved at these respective concentrations of E2B were 43, 53, 91, 145, 195, and 305 pg/ml. Twelve h after the last E2B injection, an intravenous bolus of 100 mug GnRH was administered. Gonadotropin response to this dose of GnRH after E2B was compared with each subject's response in the early follicular phase of a previous (control) cycle during which no exogenous estradiol was administered.
Forty-eight uterine strips were excised from 24 New Zealand white rabbits and studied in vitro. Sixteen strips were examined when eight animals were 25 days pregnant, 24 strips when 12 animals were about 12 hours postpartum, and eight strips about 12 hours after four animals received a single dose of 5 mg. progesterone (P) at spontaneous delivery. When after repeated exposures to electric fields (60 cycles per second, alternating current, of optimum strength, four seconds' duration at intervals of 30 seconds) the approximately 0.5 Gm. strips developed approximately 40-50g wall tension (WT) in steady state, the field strength was reduced in graded steps from 12 v per 5 cm. to 10, 8, 6, 4 and 3 v per 5 cm. and WT recorded. By measuring the effect on WT of "decreasing electric field stimulation" (DEFS), myometrical excitably and threshold were characterized and quantitated. The technique is based on the relationship between the fraction of myometrial cells activated in the total cell population and WT. As the stimulus is decreased in graded steps from optimal to increasingly suboptimal, DEFS activates fewer and fewer cells reflected by the decrease in WT. Threshold is defined by the strength of the minimum electric field which provokes WT and subthreshold by the field strength which fails to excite. Thus fractional WT averages the excitability of cells in the tissue and thus DEFS characterizes this important parameter of uterine function and quantitates threshold under a variety of regulatory conditions. The comparative study of excised uteri in three different endocrine states showed that the regulatory conditions of normal pregnancy (P levels 9 ng. per milliliter) suppressed excitability and increased threshold (to 6 v per 5 cm.). Post partum (P levels 1 ng. per milliliter) excitability increased and threshold decreased (to 4 v per 5 cm.), unless P treatment prevented this characteristic change by suppressing excitability and increasing threshold (to 6 v per 5 cm.). Both regulatory agents, prostaglandin F2alpha (PGF2alpha) and its analogue ICI 81008, increased excitability and decreased threshold significantly in picogram per milliliter concentrations. However, this effect was observed only when the P levels were low. These compounds had little effect, even in manogram per milliliter concentrations, when the P levels were high. The studies also revealed a close relationship between threshold and spontaneous uterine activity. Low threshold promoted while high threshold suppressed spontaneous activity. In similar concentrations the oxytocic actions of PGF2alpha and ICI 81008 were similar but the effect of ICI 81008 was prolonged through strong binding at myometrical sites.
Evrard JR et al., 1976·American Journal of Obstetrics and Gynecology
A prospective study was done on 326 nulliparous women who ceased oral contraception. Follow-up was obtained on 311. The mean age was 20.3 years (SD 2.5). Eighty-nine per cent began menstruating within 60 days after stopping therapy, and only 7 took 180 days or longer to menstruate. Late menarche strongly correlated with post-pill amenorrhea (PPA), but continuous length of time on oral contraceptives and type of oral contraceptive showed no significant relationship. The incidence of PPA was 2.2 per cent. All women did eventually menstruate spontaneously, the longest period of amenorrhea being 540 days. The less the number of years between menarche and the beginning of oral contraceptives, the longer it took these patients to menstruate.
InfertilityClomiphene and GonadotropinsAnovulation TreatmentHMG-HCG Therapy
In an effort to diminish the incidence of multiple pregnancy, ovarian hyper-stimulation syndrome, and the excessive cost of human menopausal gonadotropin (HMG) administration, a sequence of Clomid-HMG-human chorionic gonadotropin (HCG) was used in 80 patients with infertility due to prolonged amenorrhea. Criteria for (1) normal seminal fluid analysis and postcoital test; (2) lack of withdrawal bleeding from progesterone following amenorrhea of more than 6 months' duration; (3) normal x-ray of the sella turcica and visual fields; (4) low serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels; (5) normal endoscopic examination; and (6) lack of response to clomiphene in excessive dose (200 mg daily for 5 days) or prolonged dose (100 mg daily for 10 days) with or without HCG, or apparent ovulatory response to the above sequence for five or six consecutive cycles without pregnancy. Clomiphene was administered in a dose of 100 mg daily for 7 days. HMG was then two ampules daily for 4 days, then one ampule daily for 2 days (75 IU of FSH and 75 IU of LH/ampule). After a 24-hour interval without treatment, 10,000 IU of HCG were given and 2000 IU of HCG 4 days later. Twenty-three pregnancies occurred in 80 patients. However, 15 of the first 25 patients became pregnant--in these patients the only abnormality noted was lack of ovulation. Six additional pregnancies occurred subsequent to one or more unsuccessful cycles. Multiple pregnancies occurred in only two patients (twins delivered at 32 weeks in one and an abortion of five fetuses at 20 weeks in another). However, multiple pregnancy did not occur in any patient whose urinary estrogen level was monitored and in whom the level was 100 mug or less when the HCG was given. The ovarian hyperstimulation syndrome did not occur in any patient.
Seven cases of polycystic ovarian disease were investigated by laparoscopy and endocrinologic tests after failure of ovarian resection to restore fertility. One case of bilateral and two cases of unilateral ovarian atrophy were recorded. In all seven patients the common features were extensive perivarian and peritubal adhesions. Four of the six patients amenable to cure were submitted to reconstructive surgery; three of them conceived and had normal deliveries. The present observations support the plea to relegate the surgical approach to a minor position in patients with Stein-Leventhal syndrome and stress the importance of meticulous surgical technique in the performance of ovarian surgery. Laparoscopic investigation is mandatory in all cases of unsuccessful ovarian resection.
Of 159 pregnancies conceived after clomiphene therapy, 141 ended in childbirth, including seven sets of twins. There was a probable increase in the number of infants born with major malformations. These were exclusively to women who had not previously borne a normal infant. The incidence of malformed infants compares well with that published after gonadotropin therapy. The possibly higher incidence of malformations seen after drug-induced ovulation would therefore seem to be due to the underlying subfertility state and thus not a direct drug effect.
A personal series of 600 private patients using natural family planning techniques is presented. The total failure rate was 4.7 pregnancies per 100 woman-years. The advantages of this method over conventional contraceptive techniques are stressed.
Enkephalin, a natural ligand for opiate receptors is composed of the pentapepides H-Tyr-Gly-Gly-Phe-Met-OH and H-Tyr-Gly-Gly-Phe-Leu-OH. The evidence is based on the determination of the amino acid sequence of natural enkephalin by the dansyl-Edman procedure and by mass spectrometry followed by synthesis and comparison of the natural and synthetic peptides.
Sixty in-depth interviews with mothers living in a urban slum of Morocco probed resistances to practicing modern methods of fertility control and began to shed light on some of the reasons family planning programs often fail to reach illiterate target populations. Economic insecurity and the disintegration of the support networks of the traditional extended family complicate the difficult lives of young mothers in the urban slum. While such factors tend to encourage smaller families, the uncertainties and complexities of the socioeconomic structure contribute to the problems blocking access to modern methods of fertility control.
We conducted a double-blind study to determine the efficacy of 17alpha-hydroxyprogesterone caproate in preventing premature delivery in 43 high-risk patients. Premature delivery did not occur in 18 patients receiving the progestational agent, whereas 41 per cent of the 22 receiving the palcebo had premature delivery (P less than 0.01). The mean duration of pregnancy and the mean birth weight in the former group (38.6 weeks +/- 1.6 S.D., and 2836 g +/- 412 S.D.) were both significantly greater (P less than 0.025) than that in the latter (35.2 weeks +/- 6.7 S.D.; 2361 g +/- 1085 S.D.). The perinatal mortality rate in the group given the progestational agent (O per cent) was significantly less than that observed in the placebo group (27 per cent) (P less than 0.05). Although there were no complications attributable to the progestational drug, the study population was too small for assessment of immediate or long term safety. However, the results indicate a possible obstetric use for this drug.
Reproductive EndocrinologyProgesterone MetabolitesAntibiotic Effects on HormonesUrinary and Fecal Steroids
Progesterone metabolites and estriol were determined in urine and faeces collected daily from three pregnant women (33–37 weeks) before and during ampicillin administration (2 g/day orally).
Two of the three subjects showed marked changes in their faecal steroid excretion during the faecal progesterone-metabolite pattern changed from containing 69–79% unconjugated metabolites and 19–26% glucuronides under control conditions, to high steroid sulphate content (28–44%); the faecal elimination of 3β-hydroxy-5α-pregnan-20-one and 5α-pregnane-3β,20α-diol glucuronide all but ceased; two 16α-hydroxylated progesterone metabolites were detected in significant amounts in faeces during ampicillin administration but not under normal conditions. Steroid sulphate hydrolysis, epimerization of 3α,5αto 3β,5α-steroids and 16α-dehydroxylation are all well known actions of intestinal bacteria on biliary steroids. It thus seems clear that the changes found in the faecal progesterone metabolite pattern are due to the reduction of the intestinal flora by ampicillin.
Under control conditions the bulk of the faecal estriol was unconjugated. During ampicillin administration this excretion remained unchanged but in addition large quantities of conjugated estriol appeared in the faeces, apparently as a result of inhibition of bacterial deconjugation.
Ampicillin administration also caused decreased urinary excretion of estriol and pregnanediol glucuronide. It seems likely that these well documented effects of ampicillin on urinary steroid excretion are caused by an interruption of the enterohepatic circulation of steroids which results from the inhibition of intestinal steroid metabolism described above.
PregnancyChromosomal AbnormalitiesKaryotype AnalysisRetrospective and Prospective
Epidemiologic studies, retrospective and prospective, were done on 1500 abortions collected from 1966-1972. No secular or seasonal variations were observed. From the analysis of the relative frequencies of the different types of chromsome anomalies it is estimated that 1 out of every 2 conceptions has a chromosome anomaly. Maternal-age influence was found only for the autosomal trisomy group, mainly D and G trisomies. No effect of oral contraceptives were discovered. An increased frequency of chromosome anomalies occurred after ovulation-inducing therapy and after occupational exposure of the father to irradiation. No variations in the fertility rate and in the frequency of congenital malformations in births following abortions was noted. The incidence of recurring abortion was mainly influenced by the reproductive history of the couple before the karyotyped abortion.
Reproductive EndocrinologyOpioid EffectsDrug-Induced AmenorrheaSubstance Abuse Related
The ability of morphine to block ovulation in animals prompted investigation of the frequency and mechanisms of menstrual abnormalities in women addicted to narcotic analgesics. Menstrual histories obtained from 76 former heroin addicts receiving daily methadone maintenance revealed that more than one-half of these women had experienced menstrual abnormalities while taking heroin or methadone. In order to determine the specific physiologic effects of narcotic analgesics on reproductive function, detailed endocrinologic studies were carried out in seven of these patients who complained of amenorrhea or irregular menses while receiving methadone. Four of the seven women manifested abnormalities of the control of gonadotropin secretion. Three of these four failed to exhibit cyclic gonadotropin release, as evidenced by an absence of increased levels of follicular phase follicle-stimulating hormone, midcycle gonadotropin peaks or luteal phase progesterone increments. In the fourth patient a prolonged follicular phase (30 days) of the menstrual cycle was detected. One of these four patients also had low basal gonadotropin levels and failed to exhibit luteinizing hormone increments greater than control levels in response to ethinyl estradiol (positive feedback). The remaining three women exhibited normal patterns of gonadotropin secretion during the observation period. In these women, menstrual bleeding occurred in response to withdrawal from luteal phase (10 to 20 ng/ml) progesterone levels and to exogenous ethinyl estradiol, suggesting normal uterine responsivity to progesterone and estrogen. Although not documented, it is likely that oligo-ovulation was the cause of the irregular menses in these three patients. Amenorrhea is commonly associated with methadone ingestion or heroin addiction and appears to be related to an alteration of the hypothalamic mechanisms controlling gonadotropin secretion. Tolerance to these effects of methadone may develop after chronic ingestion.
Psychological data was obtained from 1009 couples located in 5 countries who were practicing the temperature-rhythm method of birth control. In the U.S., survey instruments were distributed to 160 couples by mail with a 58% (92) return rate of completed questionnaires. The educational attainment of both men and women exceeded senior high school. Most wives were not gainfully employed, and 87% of the wives indicated that religious beliefs were considered important. The average couple had employed the rhythm method for 4 years and 9 months at the time of the survey. Independently, both husbands and wives completed a Byrne's Revised Repression-Sensitization scale, Rotter's I-E scale, and Attitude Toward Sex scale, a Reaction to the Temperature-Rhythm Method scale, and a sexual behavior inventory. Data indicated that the rhythm method was acceptable despite difficulties with periods of abstinence, with 84% regarding abstinence as relatively difficult or very diffiucult. Other results indicated that there was a relatively low response concordance between husbands and wives, and that couples who had pregnancies with the method or had abandoned the method had more liberal sexual attitudes than those who did not have pregnancies and continued the method.
Ingestion of a single tablet containing 2 mg micronized 17beta-estradiol (E-2) produced marked increases in the serum concentrations of E-2 and estrone (E-1) in 9 postmenopausal women. The rise in circulating E-2 became significant within 2 h, reached a maximum (110 pg/ML; 437% increase) at 5 h, and remained significantly elevated at 8 h posttreatment. By 24 h, the serum E-2 concentration was not significantly different than baseline. In contrast, a more rapid (within 1 h) and pronounced (4-fold) increase in the serum concentration of E-1 was observed. This rise continued until a peak (467 pg/ml; 2000%) was reached 6 h posttreatment. Thereafter, the serum E-1 concentration declined progressively but was still significantly elevated (140 pg/ml; P smaller than 0.01) 24 h after treatment. Serum concentrations of FSH AND LH were significantly decreased within 6 and 3 h, respectively and both gonadotropins remained significantly suppressed 24 h following the ingestion of E-2. The ratios of circulating E-1: E-2 reported herein (ca. 3-6) were much higher than those observed by other investigators following iv E-2 (I.E., smaller than 1). Thus the data indicate that micronized E-2 peros is readily absorbed and that during this process a significant portion of the hormone is converted to E-1 by the gstrointestinal tract. In addition, 2 mg oral E-2 exerts significant biologic activity as assessed by serum gonadotropin suppression.