Inhibition of rat ovarian [3H]thymidine uptake by luteinizing hormone-releasing hormone agonists: a possible mechanism for preventing damage by cytotoxic agents.

To investigate the mechanism involved in luteinizing hormone-releasing hormone (LHRH) agonists' protective effects against chemotherapy-induced ovarian damage, female rats were either implanted with 1-mg pellets of LHRH agonist Zoladex (LHRHz) or sham operated. All rats were implanted with osmotic minipumps loaded with [3H]thymidine 48 h before sacrifice in diestrus. Ovaries were combusted in a biological material oxidizer. Tritiated water was recovered in a special cocktail, and ovarian tritiated thymidine uptake (3HTU) was calculated. In five experiments, LHRHz significantly reduced ovarian 3HTU. This was observed 5 days after implanting LHRHz pellets. Ovarian 3HTU correlated significantly with serum estradiol, LH, and ovarian and uterine weights. Autoradiography showed that almost all ovarian 3HTU is by granulosa cells. These data suggest that LHRHz suppresses ovarian mitotic activity. Since cytotoxic agents preferentially destroy rapidly dividing cells, our findings may represent a mechanism for ovarian protection.

Effect of oral contraceptive agents on nutrients: I. Minerals.

The epidemiological aspects of oral contraceptive agents on nutrient metabolism were studied in a large population of women. Incidence of clinical abnormalities, related to malnutrition, were more frequently observed in the lower (B) as compared to the higher (A) socioeconomic groups. In the A groups some clinical signs were more common in the nonsupplemented groups of subjects. In general, the intake of oral contraceptive agent subjects for calories, protein, calcium, magnesium, iron, copper and zinc did not differ from the controls. The intake of the above nutrients in group A subjects were higher than those of group B except for calories. The subjects who took supplements had higher intakes of calcium, iron, magnesium and copper. No effect of oral contraceptive agents was seen on hemoglobin, hematocrit and erythrocyte count. Serum iron was increased due to "Norinyl." Total iron binding capacity was increased as a result of oral contraceptive agent administration. Total iron binding capacity values were higher in group B as compared to group A and in the nonsupplemented as compared to the supplemented groups. Plasma copper was increased and plasma zinc was decreased as a result of oral contraceptive agent administration. An increase in erythrocyte zinc was observed due to "Norinyl." No effect of oral contraceptive agents on plasma calcium, magnesium and erythrocyte magnesium was observed. Although no effect of oral contraceptive agents on plasma total protein was found, serum albumin was decreased.

Effect of oral contraceptive agents on nutrients: II. Vitamins.

Clinical, biochemical and nutritional data were collected from a large population of women using oral contraceptive agents. Higher incidence of abnormal clinical signs related to malnutrition were observed in the lower (B) as compared to the higher (A) socioeconomic groups, and also in the nonsupplemented groups as compared to the supplemented groups in the B subjects. As a rule the intake of oral contraceptive agent subjects of vitamin A, C, B6 and folic acid did not differ from that of the controls As expected, subjects from the supplemented groups had higher intake of vitamin A, C, B6, thiamin, riboflavin and folic acid, and A groups had higher intake of vitamin C, B6, riboflavin and folic acid. Increased plasma vitamin A and decreased carotene levels were observed in oral contraceptive agent users. In general oral contraceptive agents had little or no effect on plasma ascorbic acid. Urinary excretion of both thiamin and riboflavin in subjects using oral contraceptive agents were lower in A groups. Erythrocyte folate and plasma pyridoxal phosphate was decreased in A groups due to oral contraceptive agents. Subjects who took supplements had higher levels of plasma vitamin A, ascorbic acid and folate. But urinary thiamin and riboflavin were higher only in group A subjects who took supplements.

PIP: 18-45 year old women were tested to determine if the use of oral contraceptive agents (OCAs) affects the metabolism of vitamins. 4 different hormonal conditions and 2 socioeconomic levels in 8 groups were considered. Some of each socioeconomic level had taken Norinyl (1 mg norethisterone and 50 mcg mestranol) for 3 months or more. Others had used Ovral (.5 mg norgestrel and 5 mcg ethinyl estradiol) for equal periods. There were some in each group who had resumed use of OCAs during lactation within 5 weeks after pregnancy. Vitamins and mineral supplements were given to groups in each socioeconomic classification. They had a higher intake of Vitamins-A, C, thiamin, riboflavin, and folic acid. Incidence of clinical sings of malnutrition, such as dry skin, easily pluckable hair, angular lesions of the mouth, dental caries, bleeding gums, glossitis, and scaling of the skin, were significantly more frequently observed in the lower socioeconomic groups, and especially in nonsupplemented groups of women taking OCAs than in others. OCA administration increased plasma Vitamin-A levels but no socioeconomic effect was found. Plasma carotene levels were decreased by OCA therapy, but less so in the higher socioeconomic subjects. Plasma ascorbate was not affected by OCA use. Urinary excretion of thiamin annd riboflavin was decreased in subjects using OCAs. Erythrocyte folate and plasma pyridoxal phosphate (PLP) were also decreased. Results show a definite lowering effect of OCAs on red cell folate in subjects in the upper socioeconomic levels. There may also be a depletion of body stores of folic acid. It has been suggested that women who become pregnant soon after discontinuing OCA therapy have a high chance of developing folic acid deficiency during pregnancy. The lower socioeconomic group may be marginally deficient in folic acid. Similar results were obtained with thiamin and riboflavin. Changes due to OCA use with respect to thiamin, riboflavin, folate, and PLP were seen mainly in subjects in the upper lower socioeconomic groups may have prevented detection of smaller similar alterations due to OCA use.

Ovulation detection.

Despite major achievements in elucidating many details of the physiologic processes of human reproduction during the past 2 decades, a simple, reliable, and inexpensive method for the prediction and detection of the time of ovulation is still not available. For clinical purposes, studies of BBT and biophysical and biochemical constituents of cervical mucus appear to be the most practical methods of ovulation detection. The development of rapid and easy-to-use urinary LH assays and steroid assay kits for measurement of urinary and salivary estrogen and progesterone or their metabolites may further improve the precision of ovulation timing.

Clinical applications of gonadotropin-releasing hormones in reproductive disorders.

Gonadotropin-releasing hormone (GnRH) agonists show promise as new therapeutic agents with considerable potential for clinical applications in endocrinology, gynecology, pediatrics, and oncology. GnRH agonists are derived from GnRH. This article reviews the physiology and neuroendocrine effects of GnRH and discusses clinical applications of the native substance and its analogs.

Risks and benefits of nutritional supplements during pregnancy.

This review emphasizes the role of minerals and vitamins in pregnancy. Of the trace elements, iron, copper, zinc, and iodine have a fundamental role in human nutrition. Supplementation of iron, zinc, and iodine in the diet of all pregnant women, when dietary deficiencies exist, seems justified. The average diet in developed countries contains sufficient amounts of various vitamins, with the exception of folic acid, which may require supplementation. However, in developing nations and among poor populations in which the diet is inadequate, additional supplies of micronutrients are advisable.

Gastric perforation during pelvic laparoscopy.

Gastric perforation is one of the recognized hazards of pelvic laparoscopy. Two such instances of perforation are presented and the role of gastric distention in causing this complication is examined. This article also reviews the literature and outlines the measures which can be taken to prevent and treat this complication.

Management of endometriosis with oral medroxyprogesterone acetate.

Efficacy of oral medroxyprogesterone acetate (MPA) was assessed in 35 women with an established diagnosis of endometriosis (33 pelvic and 2 abdominal). MPA was given in a dosage of 30 mg daily for 90 days. Results indicated improvement or remission in all cases, even though breakthrough bleeding occurred in 8. Twenty-six were treated for associated infertility. Twelve of these became pregnant following treatment. Pregnancy rate in those women whose husbands were fertile was 90%. Side effects included spotting and breakthrough bleeding. The patients usually remained amenorrheic and anovulatory while receiving MPA. Posttreatment resumption of ovulation was prompt. The findings indicate that oral MPA is a useful therapeutic agent in the management of minimal to moderate endometriosis, particularly when it is associated with infertility.

Luteal phase support with hCG does not improve fecundity rate in human menopausal gonadotropin-stimulated cycles.

The luteal phase of cycles stimulated with human menopausal gonadotropins (hMG) may be characterized by aberrant hormone levels, altered endometrial development, and shortened length. Luteal phase support with supplemental progesterone or hCG has been recommended to help correct these problems and thus improve pregnancy rates, but the efficacy of such regimens is controversial. Therefore, a randomized cross-over study was performed to evaluate the effects of luteal phase hCG administration on pregnancy rates during ovulation induction with hMG. Sixty-seven infertile women were randomly assigned to either group A (N = 33) or group B (N = 34). Non-treatment cycles (no luteal phase support) were alternated with treatment cycles, in which patients received 2500 IU hCG on the third, sixth, and ninth days after the ovulatory dose of 10,000 IU hCG. Patients in group A received supplemental hCG in odd-numbered cycles, whereas group B was given luteal support in even-numbered cycles. The mean number of cycles per patient was 2.2 and 2.3 for groups A and B, respectively. Analysis of 151 cycles revealed a cycle fecundity of 0.15 for 72 hCG-supported cycles, versus 0.13 for 79 nonsupported cycles (P = not significant). Midluteal progesterone levels were significantly higher in supported (45.6 ng/mL) versus unsupported cycles (31.9 ng/mL) (P less than .001). There were no significant differences in the mean peak estradiol levels in hCG-supported versus -unsupported cycles. We conclude that hCG support of the luteal phase is not routinely warranted in hMG-stimulated cycles.

Cyclic changes of cervical mucus enzymes related to the time of ovulation II. Amino peptidase and esterase.

The enzymes amino peptidase and esterase were identified in human cervical mucus. Their concentration was serially determined during a menstrual cycle in 5 normal ovulatory women and correlated with the time of ovulation as monitored by the basal body temperature and radioimmunoassay of serum luteinizing hormone (LH), progesterone, and estradiol (E2). The activity of both enzymes decreased at midcycle just before the LH surge and began to rise after ovulation. The preovulatory decline in enzyme activity was significant for esterase but not for amino peptidase. The site of production and functional significance of these enzymes are not at present identified.

PIP: Changes in the cervical mucus content of the enzymes amino peptidase and esterase were determined over the menstrual cycle in 5 normal ovulatory women. The time of ovulation was estimated by recording basal body temperature and radioimmunoassay of serum luteinizing hormone (LH), progesterone and estradiol. Immediately prior to the midcycle surge of LH, both enzymes showed decreased activity, with the decrease in esterase activity being statistically significant (p less than .008). After ovulation, both enzymes showed increased activity. It remains to determine whether these enzymes play a role in the interaction between sperm and cervical mucus.

Contraceptive mechanism of microdose norethindrone.

PIP: To determine how microdose progestogens exert their contraceptive mechanism, 5 normal 20-40 year old women (each acting as her own control) were studied during a normal menstral cycle followed by a cycle in which each received orrally 350 mcg norethindrone per day beginning on Cycle Day 1 for 30 days. Results indicated that all control cycles were ovulatory. In the treated cycle, endometrial morphology was altered. There was also significant suppression of preovulatory FSH and LH peaks, alteration of urinary estrogens (either increase or decrease), and marked suppression of progesterone production during the luteal phase. Cervical mucus properties and sperm penetration were inhibited during the treatment cycle. These findings suggest that at least 3 different factors were involved in the contraceptive mechanism of microdose norethindrone: 1) alteration of ovulation and progesterone production by the corpus luteum, 2) cervical mucus changes and inhibition of sperm transport, and 3) endometrial changes.^ieng

Hypothalamic-pituitary-adrenocortical function after the dexamethasone-promethazine adhesion regimen.

Dexamethasone and promethazine are widely used as an antiadhesion regimen in infertility surgery. A major argument against the routine use of dexamethasone has been the concern that suppression of the hypothalamic-pituitary-adrenal axis may result. To investigate this concern, 25 healthy women undergoing surgery for infertility were administered dexamethasone and promethazine preoperatively, intraoperatively, and postoperatively for 48 hours. Insulin hypoglycemia testing was performed on postoperative day 6. A normal rise in cortisol of at least 7 micrograms/dl was observed in 19 of 21 women. Two women failed to achieve this rise, despite adequate hypoglycemia. Short-term suppression of the hypothalamic-pituitary-adrenal axis may occur after administration of the dexamethasone-promethazine regimen. Patients receiving this regimen should be carefully supervised during the postoperative period.

Oral contraceptives and the hemostatic system.

We studied 30 control women and 131 pill users to evaluate effects of birth control pills and clinical factors on hemostasis. When control patients were matched with an equal number of pill users, none of the direct markers of activated hemostasis (fibrinopeptide A, platelet factor 4, and beta thromboglobulin) were increased. Plasminogen, prekallikrein, and protein C (protective against clotting) were significantly higher in pill users. Fibrinogen, antithrombin, alpha-2 antiplasmin, and fibronectin were comparable. Among the 131 pill users, antithrombin levels decreased with a family history of thromboembolism. Fibrinogen and fibronectin were increased with obesity, but there was no evidence of activated hemostasis. Overall, pill use did not appear to result in hypercoagulability. Considering family history of thromboembolism might further improve the safety of oral contraceptive use.

Pseudocorpus luteum insufficiency: a study of cytosol progesterone receptors in human endometrium.

This prospective, controlled study of 38 women was designed to compare the number of endometrial cytosol progesterone receptor (PRc) binding sites in infertile women with documented luteal phase defect with those of similar women without luteal phase defect. A 25% reduction in PRc binding sites was observed in women with luteal phase defect (P less than .05). Considerable overlap was noted between luteal phase defect and control groups; thus, no definite range of binding site numbers was predictive of luteal phase defect. The results of this study, therefore, suggest that an end-organ receptor defect may exist in some women with luteal phase abnormalities.

Prenatal genetic diagnosis following recurrent early pregnancy loss.

Recurrent pregnancy loss affects 1% of patients, an incidence higher than expected from the prevalence of spontaneous abortion in the general population. Some couples may show a tendency for aneuploid conceptions. Genetic counseling and amniocentesis or chorionic villus sampling were offered to 305 couples with a history of two or more pregnancy losses and normal parental karyotypes, with no additional known risk factors for aneuploidy. Prenatal diagnostic procedures were performed in 96 pregnancies. Two hundred nine couples declined active intervention, and these pregnancies were followed to delivery. Five chromosomal abnormalities (1.6%) were diagnosed in the study group. A group of 979 prenatal diagnostic procedures performed in "low-risk" pregnancies in Hutzel Hospital was used as controls, and three chromosomal anomalies (0.3%) were diagnosed. That the rate of aneuploid conceptions was statistically significantly (P = .02) higher in low-risk couples experiencing recurrent pregnancy loss than in controls points to a tendency for chromosomal aberrations in their offspring and suggests a place for prenatal diagnosis in subsequent pregnancies.

Sequential invasive assessment of fetal renal function and the intrauterine treatment of fetal obstructive uropathies.

Persistent fetal lower urinary tract obstruction carries a very poor prognosis secondary to damaged renal capacity and oligohydramnios, with its related pulmonary hypoplasia. Several attempts in the past several years to divert urinary flow via an intrauterine shunt have generally been disappointing, primarily because of poor patient selection. In this study we report our experiences with aggressive decompression of megacystis in 11 patients, the value in selected cases of sequential evaluations of fetal urine biochemistry, and the success of intrauterine bladder shunting procedures in appropriately chosen patients. Our data suggest that a single fetal urine determination may be insufficient to declare irreversible damage. Following decompression, improvement in urine biochemistry or its lack may be more likely representative of ultimate outcome. Decompression by either needle aspiration or intrauterine shunting is warranted in carefully selected cases and can save fetuses that are otherwise very likely doomed.

Postcoital test: physiologic basis, technique, and interpretation.

The postcoital test determines the adequacy of sperm and the receptivity of cervical mucus. It is the only test which evaluates the interaction between sperm and the female genital tract fluids. The Sims-Huhner test should be an integral part of an infertility investigation, but it must not be used as a substitute for semen analysis. Since cervical mucus accurately reflects the ovarian cycle, the PC test is a useful indicator of the endocrine preparation of the female reproductive system. It is also an important method for the evaluation of a variety of contraceptive steroids which may act directly or indirectly upon cervical secretion. For best results the test should be properly timed, meticulously performed, and knowledgeably interpreted.

Accuracy of basal body temperature for ovulation detection.

In 30 normally menstruating women, ages 19 to 41 (mean 24), gravida 0 to 5 (mean 0.7), basal body temperature (BBT) was correlated with serum luteinizing hormone (LH), progesterone, and estradiol or urinary estrogen levels assayed serially during one menstrual cycle. In 21 subjects (70%), a biphasic BBT correlated with an ovulatory hormonal pattern. Six women (20%) had a monophasic BBT but demonstrated a preovulatory estrogen peak, a midcycle LH surge, and a significant rise in serum progesterone levels during the luteal phase. The remaining three women (10%) showed anovulatory cycles (two women) or a deficient luteal phase (one woman) as determined by BBT and hormonal assays. The results indicate that in approximately 20% of ovulatory cycles the BBT failed to demonstrate ovulation.

The function of the cervix in fertility.

PIP: Recent advances and new findings relative to the role of cervix in fertility are reported in this review. Cervical mucus, which may include small amounts of endometrial, tubal, and possibly, follicular secretions, is produced at a rate of 20-60 mg/day in normal reproductive age women. This rate increases up to 700 mg/day during the immediate preovulation phase. To examine the physical properties of the cervical factor, assessments should include determination of amount, viscosity, ferning, spinnbarkeit, cellularity, pH, and cultural studies, if infection is suspected. The clinical evaluation of cervical mucus properties requires evaluation of the quality of the mucus, its functional ability, and its interaction with sperm, since it now appears that sperm are stored in the cervix and are released continuously to the upper part of the reproductive tract; in addition, present evidence indicates that cervical mucus acts as a barrier or trap for sluggish and abnormal sperms. In terms of infertility assessments, postcoital tests are the most useful, and if an adequate number of motile sperm are present in the endocervix, favorable cervical factor is assumed and mucus can be ruled out as the cause of infertility.^ieng

Prediction and detection of ovulation.

PIP: This paper reviews and evaluates various methods for the prediction and detection of ovulation, with emphasis on the role this plays in management of infertility and in natural family planning. After spelling out the hormonal events which control the ovulatory process, techniques for ovulation detection and timing are discussed. These fall into 2 classifications: 1) direct assays of gonadotropins or steroid hormones in the serum or urine; and 2) evaluation of peripheral changes preceding, coinciding with, or succeeding ovulation. Since serial hormone assays are not practical in routine clinical practice, clinicians generally rely on peripheral or end-organ changes to determine alteration in circulating steroid hermone levels, but direct assays of gonadotropins and sex steroids would have to supplement these methods to determine the accuracy of commonly performed methods of ovulation detection. Tests based on hormone assays include daily assays of 1) serum or urinary lutienizing hormone (LH), 2) urinary estrogens (or estrogen metabolites) or serum estradiol, and 3) serum progesterone or urinary pregnanediol. Each assay is described in the text. Tests based on peripheral and systemic changes include ]) basal body temperature changes, 2) tests of physical properties of cervical mucus (appearance, spinnbarkheit, ferning, and burn test), 3) tests of the chemical content of cervical mucus (protein constituents and enzymes), 4) endometrial biopsy, 5) vaginal cytology, and 6) saliva sampling (measuring alkaline phosphatase levels which generally increase at time of ovulation). Tests based on hematologic changes, especially the decrease of blood basophil count at ovulation, are also discussed. Among the possible techniques of natural family planning discussed are the calendar method (Ogino-Knaus), the cervical mucus (ovulation) method, and the symptothermic method (basal temperature and calender combined) method.^ieng