Prorenin in high concentrations in human ovarian follicular fluid.

Although the kidney is a major source of prorenin, the precursor of renin, there are extrarenal sources for plasma prorenin that have not been identified. The selective increase in plasma prorenin at the time of ovulation suggested that one of these sources might be the ovary. Prorenin was therefore measured in fluid aspirated from 18 ovarian follicles and in plasma collected from three women who were undergoing in vitro fertilization. The follicular fluid contained high concentrations of prorenin that were approximately 12 times higher than plasma prorenin. The prorenin from follicular fluid was immunochemically identical to kidney and plasma prorenin. Thus, the ovary is a likely source for the ovulatory peak of plasma prorenin.

Sustained effects of opioid antagonism during the normal human luteal phase.

The luteal phase of the menstrual cycle is characterized by a progressive decrease in LH pulse frequency. Short term administration of opiate receptor antagonists during the luteal phase increases the release of both LH and PRL. However, the effects of prolonged opioid antagonism throughout the luteal phase are unknown and, hence, the precise role of endogenous opioid peptides in the reproductive cycle remains to be elucidated. In this study, we examine the ability of longer term opioid antagonism during the luteal phase to alter pulsatile LH and PRL release. Naltrexone (NTX), a long-acting oral opioid antagonist, at a dose of 50 mg, was administered daily for 7 days during the luteal phase in five women. Blood samples were obtained at intervals of 10 min starting at 0800 h for 11-12 h on matched days of the luteal phase of both a control and the experimental cycle. LH and PRL pulse frequencies were significantly increased at the end of the 7-day NTX administration period compared to those in the control cycle [LH, 0.22 +/- 0.04 (+/- SE) vs. 0.07 +/- 0.03 pulse/h (P less than 0.01); PRL, 0.20 +/- 0.02 vs. 0.13 +/- 0.02 pulse/h (P less than 0.05)]. The concordance between LH and PRL pulses increased from 50% in the control cycle to 70% in the NTX cycle, and there was a significant positive correlation between the amplitudes of the concomitant LH and PRL pulses (r = 0.72; P = 0.01). In conclusion, prolonged oral opioid antagonism increased pulsatile LH and PRL secretion during the luteal phase in normal women. The results underscore the important role of endogenous opioid peptides in controlling LH pulse frequency during the luteal phase of the cycle.

The significance of weight loss in the evaluation of pituitary response to LH-RH in women with secondary amenorrhea.

Sixteen women with amenorrhea occurring in the setting of severe self-imposed weight loss and 18 women with secondary amenorrhea due to other causes were given LH-RH (luteinizing hormone-releasing hormone). Women with weight loss were found to be unresponsive to LH-RH when severely underweight. FSH responsiveness returned in a linear fashion as weight gain occurred and was not related to estrogen levels. LH responsiveness also returned with weight gain although the relationship was not linear but exponential and a sudden increase in responsiveness occurred at 15% below ideal weight. No relationship to estrogen levels could be found. Women who experienced amenorrhea in a setting other than weight loss did not demonstrate responsiveness to LH-RH which could be correlated with body mass, even when underweight. Women who experienced amenorrhea with weight loss had a consistently lower LH response to LH-RH than the second group and their LH response was always lower than the FSH response. On the other hand, a variety of patterns was found in women with amenorrhea due to other causes.

Gonadotropin, estrogen and progesterone response to long term gonadotropin-releasing hormone infusion at various stages of the menstrual cycle.

PIP: 6 normally menstruating women, aged 22-27, were given constant infusions of 12.5-25 mcg/hour gonadotropin releasing hormone (GnRH) for 24 hours during 10 cycles. 4 were infused in the early follicular, 3 in the late follicular, and 3 in the luteal phase. Frequent blood samples were assayed for luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol, progesterone, and GnRH. The increase in gonadotropin and patterns of response varied in the different stages of the cycle. Quantitatively the response was minimal in the early follicular phase, maximal at midcycle, and moderate in midluteal phase. In the latter 2 phases most of the gonadotropins were released during the first 8 hours of infusion. The ratio of the LH-FSH areas under the curves favored FSH in the early follicular phase and LH at midcycle and luteal phase. In all the cycles there was an initial increase in both gonadotropins which lasted 6-8 hours after which the levels declined but nevertheless remained above baseline as long as the infusion was continued. Plasma GnRH measured during 6 infusions was undetectable prior to the starting and after discontinuation of the infusion, but during infusion fluctuations were considerable ranging from 150 to 500 pg/ml. These studies bring additional evidence to the possible existence of 2 gonadotropin pools in the human pituitary and point to the complexity of the response mechanism to GnRH stimulation and its relation to ovarian secretion.^ieng

Comparison of thyroid stimulators and thyroid hormone concentrations in the sera of pregnant women.

To clarify the role of various thyroid stimulators in normal human pregnancy, we measured serum TSH, chorionic TSH (hCT), hCG, bioassayable thyroid-stimulating activity, T4, T3, T3 uptake, free T4 and free T3 indexes, free T4, and free T3 by dialysis in 339 serum samples from pregnant women at various intervals of pregnancy and in 40 normal female controls. Serum T4 and T3 and free T4 and free T3 indexes were significantly elevated throughout pregnancy in comparison with controls. Free T4 concentration was elevated after 10 weeks of pregnancy and free T3 concentration was elevated at 13--20 weeks. Bioassayable thyroid-stimulating activity was elevated from 9--16 weeks when serum hCG concentrations were highest. Serum TSH levels were significantly lower at 9--12 weeks compared with the rest of pregnancy. hCT was detected in only 35% of sera tested; the mean detectable value was 0.60 +/- 0.04 (SE) microU/ml; only 15% of the detectable values exceeded 1 microU/ml. The level of hCG correlated with bioassayable thyroid-stimulating activity (P less than 0.01). The data indicate that hCT is not a significant thyroid stimulator. We propose that hCG, as a weak thyroid stimulator, causes a modest rise in free thyroid hormone levels early in pregnancy which in turn causes a modest reduction in pituitary TSH secretion.

Ileal resection in the operative treatment of endometriosis.

Endometriosis is a common gynecologic condition in which the small intestine is often involved. Anatomic involvement of the appendix and ileum can be catastrophic, leading, respectively, to intussusception and obstruction with potential perforation. We present a case of subclinical ileal endometriosis and recommend careful examination of the ileocecal region during laparotomy when endometriosis is present. Operative treatment is discussed.

Obstetric complications after treatment of intrauterine synechiae (Asherman's syndrome).

This review comprises 36 patients who were treated for Asherman's syndrome from 1968 to 1974 at the Sloane Hospital for Women. Of the 18 patients who later conceived only 6 had uncomplicated term deliveries. Four had premature deliveries resulting in neonatal death. Three had placenta accreta and postpartum hemorrhage, necessitating a cesarean hysterectomy in 1. Two patients required cesarean section for complications due to the syndrome, 2 had spontaneous abortion, and 1 had a cervical pregnancy requiring total hysterectomy. Only 10 babies survived. The incidence and severity of complications in conceptions following treatment for Asherman's syndrome is high, and the obstetrician must be prepared to manage them.

Relaxin in normal and pathogenic pregnancies.

Serum relaxin concentrations were quantitated throughout pregnancy. Relaxin levels were higher in the first than in either succeeding trimester of pregnancy. Relaxin concentrations in third-trimester twin pregnancies were not significantly different from those in singleton pregnancies. Relaxin levels in toxemic pregnancies were similar to those of normal pregnancy. In contrast, relaxin concentrations in pregnancies beyond 43 weeks' gestation and in women with premature labor were significantly lower than levels in normal women in the third trimester of pregnancy.

New developments in topical estrogen therapy.

OBJECTIVE: To review new developments in transdermal E2 therapy in postmenopausal women. DESIGN: A bibliographic search (Medline) of the medical literature from 1966 through 1995 was used to identify new studies evaluating transdermal E2. PATIENT(S): Menopausal and postmenopausal women. RESULT(S): Like oral estrogen, transdermal E2 relieves menopausal symptoms, reverses urogenital atrophy, and conserves bone economy. Initial studies have demonstrated beneficial effects of transdermal E2 on cardiovascular function. Quality of life, patient satisfaction, and compliance also improve with transdermal E2. Advances in transdermal delivery continue to emerge, including low-dose systems and patches that maintain serum E2 levels for a full 7-day period. CONCLUSION(S): New developments in transdermal administration have the potential to increase the number of postmenopausal women who accept and are compliant with long-term estrogen replacement therapy.

The diagnosis and treatment of amenorrheas.

Correct diagnosis and treatment of amenorrhea is a challenging problem to the clinician. A systematic approach to the differential diagnosis and treatment, based on functional activity along the hypothalamic-pituitary-ovarian axis, is presented. By obtaining a detailed history, performing a meticulous physical examination, and utilizing several simple clinical and laboratory tests, a correct diagnosis can be reached for the majority of patients. Treatment is relatively simple and geared to the patient's desires. In most instances, understanding of the basic problem helps the patient to cope with it and no treatment is needed. If lack of menses is a problem, cyclic bleeding at regular intervals can be induced. When fertility is a problem, ovulation can be induced, provided that there is no ovarian failure. By spending sufficient time with the patient, paying attention to detail, and giving some thought, a correct diagnosis can be reached and adequate treatment given to most amenorrheic patients.

PIP: Correct diagnosis and treatment of amenorrhea is best based on functional activity along the hypothalamic-pituitary-ovarian axis. A detailed history, a meticulous physical examination, and utilization of several simple clinical and laboratory tests will provide a correct diagnosis for most patients. Treatment is relatively simple and geared to the patient's desires. In most cases understanding of the problem helps the patient to cope, and no treatment is needed. Amenorrhea during early adolescence is considered normal. Absence of signs of puberty by age 16 suggests abnormal ovarian function. Gonadal abnormalities are responsible for about 60% of cases of primary amenorrhea. Extragonadal anomalies account for about 40% of cases of primary amenorrhea. Congenital adrenal hyperplasia is another cause of extragonadal primary amenorrhea. Some of these patients may successfully menstruate and ovulate, but most are amenorrheic or oligomenorrheic. Cyclic bleeding at regular intervals can be induced if lack of menses is a problem. When fertility is a problem, ovulation can be induced if there is no ovarian failure.

The use of gonadotropins for induction of ovulation.

There has been impressive progress in the treatment of anovulation with gonadotropins in the last two decades. At the present time most patients can be helped. The treatment is expensive and complicated. To obtain good results with the fewest complications, patients should be closely monitored by measuring urinary or plasma estrogen levels, and treatment should be given only in centers where the estrogen assay is readily available. Severe hyperstimulation is avoidable, but the high rate of multiple gestations remains unavoidable. Possibly with sonographic monitoring of follicular development this problem will be solved.

Cervical incompetence.

In the early 1950s, when treatment of cervical incompetence was first described, diagnosis seemed relatively simple and management favorable, but after more than 35 years of trying multiple variations of procedures and treatment regimens, no advances have been made. In 1959, Neser questioned the very existence of cervical incompetence as an entity, and concluded that, in the final analysis, the problem is a diagnostic one. Liberal use of cerclage in situations of moderate risk of preterm delivery or as a prophylactic measure for multiple gestation does not appear to improve outcome, as judged by prematurity or survival. Because of advances in neonatal care in the last decade, fetal survival has improved tremendously. It is hoped that, in the future, more objective and accurate criteria for the diagnosis of cervical incompetence will emerge, and that outcome of treatment will be measured not by fetal survival, but by prolongation of pregnancy and by birth weight. At present, making an unequivocal diagnosis of cervical incompetence remains an elusive, challenging, and unsolved problem.

Reproductive potential in the older woman.

There is a definite increase in the number of women bearing children in the 30- and 40-year-old age groups. The total number of women who are 35 to 40 years of age in the United States is projected to increase 42% and the percent births to this age group is projected to increase 37%. This is apparently because of a trend to postpone childbearing and first birth due to women's career priorities, advanced education, control over fertility, financial concerns, late and second marriages, and infertility. Associated with this is an increase in visits to the infertility specialist for older women who have an intrinsic decrease in fecundity with advancing age. Although, on the average, a woman will not experience menopause until about 50 years of age, her effective childbearing period may stop almost a decade earlier. A woman in her late 30s and, especially, early 40s is at some disadvantage in terms of conception delay, ability to carry a chromosomally normal fetus until term, and risk of trisomic conception. Certain endocrinologic parameters have been identified for the woman entering the transition to menopause. Biologic aging of the hypothalamic-pituitary-ovarian axis is intertwined with changes in the endocrine milieu of the perimenopause and preperimenopause. Despite a clear association of decreased fecundity in older women due to multiple biologic and social influences, so long as the individual has regular cycles and essentially normal endocrine parameters, she should be a candidate for an expedited infertility workup and ovulation induction, if not more aggressive treatment. Her obstetric profile is much improved, except for an increase in congenital anomalies and chromosomal defects. Chorionic villus biopsy study or amniocentesis is advised in all cases, regardless of therapy.

PIP: This discussion and review of the literature of the reproductive potential in the older woman covers the following: the physiology of the transition to menopause, the endocrinology of the older woman; the aging of the female reproductive system; factors affecting the age at menopause; patterns of fertility in the older woman, the epidemiology of late fertility (levels and trends of late fertility and characters of birth order); biologic and social interactions in the determination of fertility in the older woman (factors affecting probability of conception and factors affecting the frequency of spontaneous abortion); genetics and maternal aging; obstetric implications of the older gravid woman; and the treatment of the older infertile woman. Experimental data from animal studies have implicated an aging process in the hypothalamic-pituitary-ovarian axis. The influence of this aging process on the intactness and functioning of ova and their genetic material and on the pattern of oocyte depletion and atresia chronologic, age is the main determinant. To advise an older woman about her reproductive capacity and potential, the physican needs to be aware of the natural endocrinologic history of menstrual physiology during these years, which coincide in many instances with the preperimenopause or the perimenopause. The prodromal period of failing ovarian function may cover 5-10 yars before the complete cessantion of menses at menopause. Even after menopause, there is some evidence of cyclic changes in the ovary. The peroid of reproductive potential cannot extend much beyond the menopause in humans due to progressive atresia and exhaustion of all oocytes. In an indefinite percentage of women, reproduction ceases up to several years before this time, either naturally or prematurely, which may result from age-related changes in the hypothalamic-pituitary axis. The potential for ovulation during the perimenopausal period is present, although reduced. No basis is know, other than clinical experience, for determining whether a given interval without menses is likely to represent permanent amenorrhea. Demographic studies have shown that there is a consistnt decline in fecundity with advancing age after 30-35 years. In many societies this fall in birthrate is due to deliberate fertility control by the use of contraception, abortion, or decreased frequency of sexual intercourse. Such factors can mask any interactions between biologic factors of the aging female reproductive system and other social factors that might otherwise detemine fertility during the later reproductive years. The risk of a trisomic birth remains the singel most outstanding problem for the older woman who does conceive successfully. Despite modern perinatal and neonatal care, several series continued to show a high fetal wastage from variety of causes. The probability of the older woman ovulating, conceiving, and having a normal child are compromised as the chronologic age of the individual approaches menopause.

Current management of the amenorrhea-galactorrhea syndrome.

Management of the amenorrhea-galactorrhea syndrome has changed considerably in the last 5 years. Better understanding of the neuroendocrine physiology of the central nervous system in general, and of the hypothalamic-pituitary region in particular, have contributed significantly to our understanding of the pathophysiology of this syndrome. Greater awareness by physicians, improved neuroradiologic techniques, and the development of immunoassays for prolactin have markedly improved our diagnostic abilities. Many more patients are being diagnosed as having a pituitary tumor. The recent introduction of microneurosurgical techniques and the new medications (ergolines) are changing the treatment of this syndrome. Women in the childbearing age--who are affected most often--can expect successful treatment in the majority of cases with resumption of normal menstrual function and fertility. However, certain risks are still posed, particularly during pregnancy. In spite of improved diagnosis and treatment, the natural history of prolactin-secreting pituitary tumors and the long-range effects are still not fully appreciated. More experience in time will be needed before the indications for and the efficacy of various treatment regimens are fully known.

Alternate regimens for ovulation induction in polycystic ovarian disease.

The patient with PCOD remains a challenge to the reproductive endocrinologist. Although successful induction of ovulation can often be achieved using standard therapeutic regimens of CC or hMG, too often this group of anovulatory patients fails to respond as expected. Over the past 10 to 15 years, alternate approaches to ovulation induction have been investigated with encouraging results. Whereas no one method is productive in all patients, these varied regimens offer us a number of options in dealing with this difficult clinical problem.

Current concepts in estrogen replacement therapy in the menopause.

OBJECTIVE: To provide a review of the risks and benefits of hormonal replacement therapy in the menopause, including new therapeutic regimens and modes of delivery. DESIGN: A review of the literature to identify published studies was accomplished using a computerized bibliographical search (Medline). RESULTS: Replacement therapy is effective in treating symptoms of estrogen deficiency and in lowering the risk of osteoporosis and cardiovascular disease. The daily administration of an estrogen and progestin eliminates the withdrawal bleed and increases patient compliance. This continuous form of therapy also consistently suppresses the endometrium, decreasing the risk of hyperplasia. More studies investigating the effect of continuous therapy on the lipid profile and cardiovascular disease are needed. CONCLUSIONS: New therapeutic regimens and modes of delivery decrease risk and increase patient acceptance of hormonal replacement therapy.

Application of Orthodox Jewish law to reproductive medicine.

The evaluation and management of fertility problems in Jewish Orthodox patients who strictly follow the Biblical teachings post special problems to the physician. Understanding of the religious, social, and cultural background is of paramount importance in the management of these patients. In this paper some of these problems are discussed.

Congenital atresia of the uterine cervix and vagina: three cases.

The outcome of surgical intervention in three patients with congenital atresia of the cervix seen at our institution is reviewed. The results are compared with results in all cases reported in the literature. The embryologic mechanisms that are involved in lower Müllerian tract formation are discussed. In our opinion surgery to preserve fertility in these patients offers little chance of success at great risk and should not be attempted.

Further demonstration of induction of ovulation with a hybrid human chorionic gonadotropin compound (AB1ER-CR-2XY).

Further demonstration of the ability of the hybrid human chorionic gonadotropin (hCG) compound, AB1ER-CR-2XY, to induce ovulation is presented. Nineteen patients previously treated with human menopausal gonadotropin (hMG) and commercial hCG were selected for the study. The patients received 37 courses of treatment with dosages of hMG ranging from 1200 IU (16 ampules) to 8400 IU (112 ampules), followed by the administration of 5000 or 10,000 IU of the hybrid hCG. Of the total number of courses given, 75.5% were ovulatory; serum progesterone levels at midluteal phase of the cycle were within normal range, and the cycle length was about 12 days. Seven patients became pregnant, three with twins, one with triplets, and three with aborted single fetuses. Before the hybrid hCG was administered the serum estrogen levels were less than 1200 pg/ml in 12 cycles (32.4%), and the estrogen levels ranged from 1400 to 7400 pg/ml in 25 (67.6%). However, in spite of high estrogen levels, clinical hyperstimulation, which occurred in 22.4% of previous treatments with conventional hMG-commercial hCG, did not develop when the hybrid hCG was administered, an effect which could be attributed to its short circulatory half-life. Studies are in progress to confirm whether the hybrid hCG may provide a better margin of safety than commercial hCG for ovulation induction in patients pretreated with hMG.

Treatment of hyperprolactinemic amenorrhea with pulsatile gonadotropin-releasing hormone therapy.

Pulsatile GnRH therapy has been shown effective in the treatment of infertility associated with hyperprolactinemia by direct action on the pituitary. Gonadotropin secretion was restored in the setting of moderate hyperprolactinemia. GnRH should be considered as a potential alternative to BCPT therapy in this setting.