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Recent research has not been able to demonstrate close endometrial morphological correlations with specific abnormalities of menstrual bleeding, but has pointed to an increasing number of molecular mechanisms that may be involved in the occurrence of certain forms of abnormal uterine bleeding. Ovulatory and anovulatory dysfunctional uterine bleeding (DUB) and progestogen-related breakthrough bleeding (BTB) are three conditions with quite different clinical characteristics. It is also probable that the local endometrial molecular mechanisms associated with these three menstrual disturbances are quite different. Ovulatory DUB is associated with a series of vascular and haemostatic disturbances that all appear to contribute to increased loss of blood and tissue fluid at menstruation. Anovulatory DUB is associated with obvious disturbances of endometrial histology, vascular morphology and fragility, with variable and increased blood flow. Progestogen-related BTB is associated with a multitude of morphological and functional endometrial changes that appear to relate predominantly to a patchy capillary origin for the bleeding. Many molecular and cellular changes have been observed in all three conditions. It is not yet known whether there is a single, but different, underlying mechanism responsible for these multiple abnormalities in each of the three clinical situations.

Background: The aim of this study was to evaluate the action of tamoxifen on the endometrium in states of chronic anovulation., Methods: Thirty-eight rats inducted to persistent estrous (testosterone propionate) confirmed by hormonal colpocytology were divided into a control and an experimental group; the latter received tamoxifen and had fragments of the uterine horns processed for morphological and morphometrical analysis. Data were analysed statistically by the Mann-Whitney and Student's t tests., Results: Our findings revealed minor uterine weight, epithelial thickness; number of endometrial glands and low eosinophil counts in the group that received tamoxifen. These results were statistically significant. We often observed areas of metaplasic stratified squamous epithelium between cylindrical epithelial cells in both groups., Conclusions: Our results indicate that antiestrogenic effect of tamoxifen was only partial in persistent estrous, since there was no blocking against the squamous metaplasia of the endometrium.

Objective: To evaluate the effect on ovulation of a 10-day course of dexamethasone (DEX) initiated concurrently with a 5-day course of clomiphene citrate (CC) in CC-resistant patients with normal DHEAS levels., Design: Retrospective review., Settings: Patients from the clinical practice of the authors at the Medical College of Georgia, Augusta, Georgia., Patients: Thirteen oligomenorrheic women with normal DHEAS levels who failed to ovulate on a graduated regimen of CC up to a dose of 150 mg for 5 days., Interventions: Ten-day course of DEX initiated concurrently with a 5-day course of CC; ovulation and pregnancy outcomes recorded., Main Outcome Measure: Pregnancy., Results: Eleven of 13 women had evidence of ovulation. Five clinical pregnancies were achieved., Conclusion: These initial data support improvements in follicular development with an overlapping follicular phase regimen of CC and DEX in patients with normal DHEAS levels and a previous poor response.

The case histories of three young women with ankylosing spondylitis, rheumatoid arthritis and a seronegative inflammatory polyarthritis undergoing investigations for infertility are presented. In each, non-steroidal anti-inflammatory drug (NSAID) therapy was associated with the recurrent development of luteinized unruptured ovarian follicles and normal ovulation following drug withdrawal. It is suggested that NSAID therapy may be an important and frequently overlooked cause of anovulation and infertility.

The results of histological examination of the endometrium are normal in most patients with unexplained sterility. Cathepsin D is a ubiquitous lysosomal protease regulated by progesterone in the endometrium. Assays of concentrations of cathepsin D might be useful in determining the functional responses of the endometrium to progesterone. To examine this possibility, we quantified immunostaining of endometrial cathepsin D using an image analysis system in women with regular menstrual cycles. An endometrial sample was obtained during the proliferative and luteal phases from 17 women with ovulatory menstrual cycles and at the beginning and during the last 14 days of a cycle from 15 women having anovulatory menstrual cycles. In endometrial glands of ovulatory women, cathepsin D protein immunostaining increased during the cycle and was significantly higher during the luteal than during the proliferative phase [51 +/- 38.1 arbitrary units (AU) versus 118.2 +/- 58.9 AU; P < 0.01]. This increase was also observed in stromal cells, although to a lesser extent (28.6 +/- 26.9 versus 41.5 +/- 43.1 AU; P = NS). In the endometrium of women with anovulatory menstrual cycles, cathepsin D staining was high both for the proliferative and the luteal biopsies in glands (respectively 95 +/- 43 and 104 +/- 51.3 AU) and stromal cells (respectively 61.8 +/- 33.8 and 75 +/- 32.6 AU). In women with ovulatory cycles, cathepsin D staining was localized in the apical part of glandular cells during the proliferative phase and diffused throughout the cytoplasm during the luteal phase. In contrast, in women with anovulatory cycles, cellular localization of cathepsin D remained apical in glands, regardless of the day of biopsy. In conclusion, this study shows that the cytoplasmic localization of cathepsin D might be a qualitative biological indicator of endometrial gland responses to progesterone. This could be a useful tool for evaluating cell function, which is poorly tested by histology alone.

Women with occasional anovulatory or short luteal phase menstrual cycles have been reported to lose bone mineral density (BMD) at a greatly accelerated rate compared to women without such abnormalities. To investigate this association, we performed a longitudinal study of BMD in a group of healthy premenopausal women enrolled in a comprehensive study of ovulatory function. Subjects had collected daily urine samples that were analyzed for estrone and progesterone metabolites by enzyme-linked immunoassay. The 53 participants collected urine for an average of 4.1 cycles. Computer algorithms identified 7 (13.2%) women with luteal phase abnormalities (> 1 anovulatory cycle or cycle with luteal phase length < or = 10 days) and 17 (32.1%) women with other menstrual abnormalities. Areal BMD (grams per cm2) was measured at the lumbar spine, hip, and whole body using dual energy x-ray absorptiometry; BMD was measured 2-3 times over an average observation period of 17.5 months. At baseline, women with luteal abnormalities had mean BMD similar to those of the 29 women with no abnormal cycles: lumbar spine, 1.06 vs. 1.09 g/cm2; total hip, 0.95 vs. 0.94 g/cm2; whole body, 1.15 vs. 1.11 g/cm2 (P > 0.10; adjusted for age and weight at baseline, parity, physical activity level, and calcium intake). When compared at follow-up to women with no abnormal cycles, women with luteal abnormalities tended to gain BMD at the spine and hip (P > 0.10). On whole body measurement, women with luteal abnormalities tended to lose BMD compared to women with no abnormal cycles (-1.1%/yr vs. 0%/yr; P = 0.08); however, the magnitude of loss was not unusual for women in this age range and was within the coefficient of variation for replicate measurements. Neither mean luteal phase length, percent time in luteal phase, nor average daily excretion of progesterone metabolites was associated with baseline BMD or percent annual change in BMD at any measurement site. Thus, we did not confirm a relationship between luteal abnormalities and accelerated bone loss in this population of healthy premenopausal women.

The effect of the removal of pineal gland, performed in adult age or during perinatal life, was investigated in the neonatal androgen sterility (NA-CEA) syndrome, in combination with drugs acting on serotonergic neurons. Perinatal pinealectomy (Px) was more potent in preventing the development of NA-CEA state than Px performed in the adult age. These data indicate that the masculinized hypothalamus becomes less sensitive to pineal influences during the lifespan. Effect of Px was potentiated by drugs increasing the central serotonergic tone. The results lead to the assumption that pineal hormones are influential on the maturation of serotonergic neurons, which might interfere with the sterilizing property of neonatal androgen treatment during the "critical" period of sexual differentiation.

The anovulatory syndrome in adult female rats occurred after subcutaneous implantation of silastic capsules with testosterone. Acceleration of testosterone conversion into estradiol in the hypothalamus, suppression of pituitary LH responsiveness to LHRH, increase of blood plasma bioactive LH, estrous cycle disorder as well as morphological changes in ovaries demonstrate the alterations in neuroendocrine control of ovulation.

A partly synchronized pulsatile secretion of luteinizing hormone (LH) and prolactin has previously been suggested as an indication of the coupling of the respective pulse generators under certain conditions. In women with hyperandrogenemic chronic anovulation, episodic LH secretion is disturbed. It was, therefore, the aim of the present study to evaluate possible changes in episodic prolactin secretion pattern and in LH/prolactin co-pulsatility, and to relate the results to the accelerated LH pulse frequencies often seen in patients with hyperandrogenemic chronic anovulation. Blood samples of 32 patients with hyperandrogenemia were taken at 10-min intervals between 10.00 and 20.00. Nine regularly cycling women with normal hormone levels served as controls. In the women with hyperandrogenemia, despite an average 41% rise of LH pulse frequency, prolactin pulse frequency decreased slightly by 14% as compared to controls; no correlation between the two parameters was found (r = 0.162). The number of coincident LH and prolactin pulses increased continuously with accelerating LH frequency. The best fitting function was a hyperbola which was limited by the maximal observed prolactin frequency. As a consequence, the fraction of LH pulses that were co-secreted with prolactin episodes decreased with higher LH pulse frequencies, while the fraction of prolactin pulses concomitant with LH pulses increased. Our data provide evidence that in women with hyperandrogenemic chronic anovulation a pathological LH pulse frequency is no longer coupled with pulsatile prolactin secretion, suggesting an isolated alteration of the central neuronal control mechanism for LH secretion.

Objective: A previously published study has identified that anovulatory women with PCOS have an increased response of 17 alpha-hydroxyprogesterone (17OHP) and androstenedione to a GnRH analogue suggesting dysregulation of cytochrome P450c17 alpha. The object of this study was to compare the responses of the pituitary-ovarian axis to a single dose of a long-acting GnRH agonist (GnRHa) in both ovulatory and anovulatory women with PCOS with those in normal subjects., Design: Comparative study of responses of LH, FSH and ovarian steroids to buserelin and the adrenal steroid response to synthetic ACTH in two groups of women with hyperandrogenaemia and polycystic ovaries: those with anovulatory menses or amenorrhoea and those with equally elevated serum testosterone concentrations but regular menses. Results in both groups of women with PCO were compared with those in normal subjects., Subjects and Methods: Twenty-four women with hyperandrogenism and PCO (14 had oligo or amenorrhoea, 10 regular cycles) and 12 weight matched controls with normal ovaries, regular cycles and neither clinical nor biochemical evidence of hyperandrogenism. Subjects were given synthetic ACTH (Synacthen) 250 micrograms i.v. on day 1 of the study and blood collected at 30 and 60 minutes thereafter. On the evening of day 1, dexamethasone treatment was commenced to suppress adrenal androgens. GnRHa 100 micrograms s.c. was given on day 2 and blood samples collected at 30-minute intervals for 4 hours and once more at 24 hours after the injection., Results: The acute responses of both immunoactive and bioactive LH to GnRHa were significantly greater in the ovulatory PCO group (ovPCO) than controls but the response was greater in anovulatory women with polycystic ovaries (anovPCO) than in either ovPCO or controls, throughout the 24-hour study period. Despite the discrepancy in LH concentrations, basal serum concentrations of androstenedione were equally elevated in anovulatory and ovulatory women with PCO, compared with controls. There was a small but significant increase in androstenedione following GnRHa in both PCO groups at 24 hours but not in controls. A similar pattern was observed in the response of 17OHP to GnRHa although the response was significantly higher than controls in anovPCO women only. By contrast, the responses of both androstenedione and 17OHP to 250 micrograms synthetic ACTH were similar in PCO women to those in controls., Conclusions: These data provide evidence for ovarian hypersecretion of androgens in ovulatory, as well as anovulatory women with PCO, supporting the concept of abnormal regulation of 17-hydroxylase and (17,20-lyase activity in the ovary. The finding of an equal degree of hyperandrogenaemia in ovPCO and anovPCO groups, even though LH levels were much higher in the latter, suggests that hypersecretion of LH is not the primary cause of ovarian hyperandrogenism. Hyperandrogenism in PCOs may therefore represent an intrinsic abnormality of ovarian theca-interstitial cell function.

Women with epilepsy have lower fertility rates than women without epilepsy. We hypothesized that limbic dysfunction in temporal lobe epilepsy (TLE) alters the release of hypothalamic trophic hormones that secondarily affect release of the pituitary gonadotropins, causing ovulatory failure. We assessed ovulatory function over three consecutive menstrual cycles in 17 women with partial seizures arising from the temporal lobe (TLE), 7 women with primary generalized epilepsy (PGE), and 12 controls. We devised scores to reflect ovulatory function that were based on daily basal body temperature and monthly serum progesterone levels. Seizure frequency, antiepileptic drugs (AEDs), and depressive symptomatology were also evaluated. Anovulation was more frequent in subjects with TLE (35.3%) than in subjects with PGE (0%) or in controls (8.3%). Anovulatory cycles tended to occur more frequently in subjects with TLE who were treated with polytherapy than in those receiving monotherapy, but this result was not statistically significant. Seizure frequency and symptoms of depression did not affect ovulatory function. Although AED polytherapy may increase the likelihood of anovulation, our results suggest a mechanism of infertility related to temporal lobe dysfunction.

To examine the impact of amenorrhea on bone mineral density in women of reproductive age, we performed a cross sectional study in 190 amenorrheic women, comprising 113 premature ovarian failure, 27 primary hypothalamic amenorrhea, 38 hyperprolactinemia and 12 Sheehan's syndrome. Measurement of bone mineral density was carried out using dual photon absorptiometry at four sites: femur neck, ward's triangle, trochanter and spine (L2-4) and we compared the result with that of 163 normal-cycle control women with age matched. Bone mineral densities was significantly low in patients with primary hypothalamic amenorrhea and premature ovarian failure at all four sites. In those with hyperprolactinemia a decrease in bone mineral density was noted at femur neck and spine while those with Sheehan's syndrome is associated with decreased bone density at femur neck, ward's triangle and trochanter. The degree of bone loss and the affected sites seems differ depending on the type of amenorrhea. In patients with primary hypothalamic amenorrhea, significant bone loss was already noted at all four sites by age 20. The decrement in bone density continued rapidly during the early twenties up to age 25 and then slowed after age 25. In those with premature ovarian failure with secondary amenorrhea there were no decrease in bone mineral density within the first year after onset of amenorrhea, however, in the subsequent 2 years, the reduction in BMD was rapid and thereafter the reduction slowed remarkably. The BMD in this study positively correlated with the body mass index and negatively with the phosphorus intake.

Polycystic ovary syndrome is the most common endocrine disorder in women of reproductive age. Recent prevalence estimates suggest that 5-10% of premenopausal women have the full-blown syndrome of hyperandrogenism, chronic anovulation, and polycystic ovaries. Evidence suggests that women with polycystic ovary syndrome have a unique disorder of insulin action and are at increased risk to develop non-insulin-dependent diabetes mellitus. Further, non-insulin-dependent diabetes mellitus in women with polycystic ovary syndrome has a substantially earlier age of onset (third to fourth decades) than it does in the general population (sixth to seventh decades). Studies assessing whether abnormalities in insulin action are intrinsic or secondary to the hormonal milieu have found that insulin-induced receptor autophosphorylation is markedly diminished in approximately 50% of polycystic ovary syndrome women. This defect is unique to women with polycystic ovary syndrome and is not seen in other common insulin-resistant states of obesity and non-insulin-dependent diabetes mellitus. In polycystic ovary syndrome women who have normal receptor autophosphorylation, it remains likely that signaling mechanisms downstream of the receptor are abnormal, since these women are also insulin resistant. This distinctive post-insulin-binding defect appears to be genetic, since it is present in cells removed from the in vivo environment for generations.

A major limiting factor in the resumption of postpartum ovarian cycles in cattle is the inhibitory influence of the suckling calf on central regulatory elements controlling the release of GnRH from the median eminence. This inhibitory influence occurs only as a consequence of specifically defined behavioural interactions between the cow and calf in the presence of a maternal bond, cannot be simulated experimentally using thermal, electrical or mechanical stimuli, and is not dependent upon sensory ennervation within the udder. Indeed, the identity of the calf, either own or unrelated, appears to define the neuroendocrine events that attend the maintenance of the anovulatory state under controlled experimental conditions. Hence, new hypotheses that focus upon the relationship between physiological correlates of maternal behaviour and hypothalamic regulation of LH secretion are currently being tested. Specific aspects of these relationships remain conjectural, but are postulated to include the regulation of opioid tone, intracerebral oxytocin, and modulation of synthetic or excitatory activity of GnRH secretory neurones. Defining the role of the special senses in transduction of signals from calves that influence these neuronal processes may provide insight for developing practical intervention strategies of the future.

Objective: We aimed at inducing multifollicular recruitment in patients with chronic anovulation-resistant to Clomiphene Citrate (CC) and/or exogenous gonadotropins., Design: At the II Department of Obstetrics and Gynecology we treated our patients with exogenous gonadotropins and concomitant endogenous gonadotropin suppression obtained by the use of a GnRH analog (Buserelin)., Patients: We studied 14 patients with chronic anovulation due to either hypothalamic dysfunction or polycystic ovarian syndrome., Measurements: We monitored the follicular growth ultrasonographically from the eighth day of the menstrual cycle, and assessed E2 and LH daily dosage from the tenth day., Results: With this protocol we obtained 2 or 3 mature follicles, and reached an ovulatory rate of 80.7% and a pregnancy rate of 71.4%. Premature luteinization never occurred, and progesterone increase took place only after human chorionic gonadotropins administration.

To examine the extent to which congenital heart disease (CHD) influences ovarian function, 98 women (mean age 32.7 years) were asked to complete a mailed questionnaire regarding their menstrual patterns. Patients were divided into acyanotic (60%) and cyanotic (38.8%) groups. Cycle lengths, duration of menstrual cycle, regularity of menses, amount of flow, and breakthrough bleeding were compared in these two groups and against age-matched controls. The mean age of menarche for the sample (13.4 years) was significantly different (p < 0.004) when compared to their controls (12.5 years). With the exception of breakthrough bleeding, statistical differences were not found between the study population and the controls. When the menstrual histories of cyanotic women were compared with those of acyanotic women, differences were found for all categories of menstrual patterns with the exception of the amount of menstrual flow. Menstrual patterns of cyanotic women compared to controls were found to be significantly different for all categories with the exception of amount of flow. In general, women with CHD have menstrual patterns similar to those in the general population.

Two commercially available progestogen products for cattle, melengestrol acetate (MGA) and norgestomet (SMB), were evaluated for their ability to induce synchronized estrus in anovulatory ewes. Seasonally anestrous ewes (n = 232) were randomly assigned to one of seven treatments: 1) control (C); 2) MGA only (OMGA; .3 mg of MGA/d); 3) MGA+zeranol (RMGA; 2.5 mg of zeranol); 4) MGA+PG-600 (PMGA; 400 IU of PMSG + 200 IU of hCG in a 5-mL dose); 5) SMB only (OSMB); 6) SMB + zeranol (RSMB); and 7) SMB + PG-600 (PSMB). Treatments were initiated 10 d before breeding. Immediately preceding progestogen treatment, RMGA and RSMB ewes were given a single i.m. injection of zeranol. Concomitant to progestogen removal, PMGA and PSMB ewes were given a single i.m. injection of PG-600. On May 4, 1992, all treatment groups were combined into one breeding group for a 30-d breeding period. Mating at synchronized estrus was greater (P < .001) for progestogen-treated ewes. Within progestogen treatments, more (P < .001) SMB ewes than MGA ewes were marked within the first 5 d of breeding. Overall, there were no treatment differences in estrus response for the 30-d breeding period. Progestogen-treated ewes had a shorter (P < .001) mean interval from ram introduction to lambing. Fertility and prolificacy were not different for C, MGA, or SMB ewes. Ewes primed with zeranol before MGA or SMB treatment had fertility and intervals from ram introduction to lambing similar to those of ewes receiving an injection of PG-600 after progestogen treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Polycystic ovary syndrome (PCOS) is a complex and still poorly understood process. This review examines current theories regarding the development of PCOS and focuses on the physiologic processes involved in the pubertal and adolescent period and their relationship with pathogenesis of PCOS.

Dopamine is an important neurotransmitter in the hypothalamic control of gonadotrophin secretion. Neuron response is mediated through one of five different dopamine receptors. We explored the association of D2 receptor gene polymorphisms with disorders of ovulation. We utilized a multiplex allele specific polymerase chain reaction (PCR) to detect two bi-allelic polymorphisms (four potential haplotypes) in intron 5 and exon 6 of the D2 receptor gene. A second PCR/restriction endonuclease digest was utilized to verify this. Using these assays, 185 female Hispanics (51% with known ovulatory dysfunction and 49% with normal function) were haplotyped. One allele (3) was not present in the population and there were no significant differences in remaining allele distribution between ovulatory and anovulatory patients. However, significant associations were noted between alleles and gonadotrophins and fecundity. The 4 allele had a different reproductive profile compared to the 2 allele. The 4 allele was associated with significantly higher concentrations of luteinizing hormone (LH) (means +/- SE) (19.2 +/- 2.2 versus 12.3 +/- 1.3 mIU/ml, P < 0.02) and follicle stimulating hormone (FSH) (13.2 +/- 2.0 versus 10.0 +/- 0.6 mIU/ml, P < 0.05), significantly lower concentrations of prolactin (7.9 +/- 0.8 versus 14.9 +/- 3.5 ng/ml, P < 0.02) and higher parity (1.4 +/- 0.12 versus 0.92 +/- 0.13) and lower miscarriage rates (0.89 +/- 0.1 versus 1.33 +/- 0.24, P < 0.04). We conclude that D2 receptor alleles may be associated with reproductive success through altered gonadotrophin secretion and that this effect may be independent of ovulatory function.

To investigate an involvement of endogenous opioids in the regulation of circannual changes in reproductive activity, effects of the opioid antagonist naloxone on the concentration of immunoreactive and bioactive luteinizing hormone (LH) in plasma were measured in mares during the anovulatory season. Naloxone (0.5 mg/kg i.v.) caused a significant increase (P < 0.05) in immunoreactive as well as bioactive LH concentration in plasma. The amplitude of the increase in LH concentrations measured with an in vitro bioassay was more pronounced than the amplitude of the increase in LH secretion determined by radioimmunoassay. This indicates that although in seasonal anovulatory mares the bioactivity of LH in plasma is low, highly bioactive LH is present in the anterior pituitary and can be released by naloxone. The LH response to naloxone did not depend on the degree of ovarian follicular activity. It can be concluded that a tonic opioid inhibition of LH release is present in mares during at least part of the anovulatory season and that endogenous opioids seem to be involved in the regulation of seasonal reproductive activity in the horse. In contrast to the situation during the breeding season, the opioid systems regulating LH release are activated independently of luteal progesterone.

To evaluate the relationship between pituitary reserve and efficacy of bromocriptine therapy in patients with euprolactinemic ovulatory dysfunction, the responses of prolactin (PRL) to thyrotropin-releasing hormone (TRH) and luteinizing hormone (LH), follicle-stimulating hormone (FSH) to gonadotropin-releasing hormone (GnRH) provocation in 46 anovulatory patients were compared with 15 normally cycling ovulatory women. After provocation, the patients were treated with bromocriptine 2.5 mg twice a day for two weeks from the day of menstruation or withdrawal bleeding. Within 12 weeks, 29 of 46 (63.0%) patients had resumption of ovulatory menstruation, and 11 of them became pregnant. There were a significantly (P < 0.001) exaggerated responses of PRL to TRH in bromocriptine responders compared to controls and nonresponders. Also, LH responses to GnRH were higher in responders than in controls and nonresponders, although there was no significant differences. However, FSH responses to GnRH were significantly (P < 0.005) lower in bromocriptine nonresponders, as compared with the controls and responders. These results demonstrate that pituitary reserve of PRL and gonadotropin may correlate with the efficacy of bromocriptine and aid to predict the outcome of therapy in patients with euprolactinemic ovulatory dysfunction.

Objective: To compare the midluteal uterine artery impedance to blood flow as measured by the pulsatility index in women with different causes of infertility with that of women with normal fertility and to correlate this with endometrial thickness., Design: A prospective study of normal women undergoing insemination with donor semen and subfertile women with tubal damage, endometriosis, premature ovarian failure, anovulation, or unexplained infertility., Setting: A tertiary infertility center., Patients: One-hundred sixty-one women (25 to 40 years of age) who were attending the clinic for subfertility treatment and 23 normal women who were having artificial insemination with donor sperm because their partners were azoospermic., Interventions: All women were examined by transvaginal ultrasonography, with color flow imaging and blood flow analysis, on day 21 of an unstimulated ovarian cycle., Main Outcome Measures: The mean pulsatility index of the left and right uterine arteries and the endometrial thickness., Results: The patients were grouped according to the causes of infertility and compared with normal women. There were 23 women in the normal group (median pulsatility index, 1.91; range, 0.84 to 2.95), 35 with unexplained infertility (median pulsatility index, 2.45; range, 1.0 to 7.0), 91 with tubal damage (median pulsatility index, 2.65; range, 1.25 to 8.0), 8 with endometriosis (median pulsatility index, 2.32; range, 2.05 to 5.7), and 22 with anovulatory infertility (median pulsatility index, 3.03; range, 1.6 to 7.0). All the infertile groups had significantly different median pulsatility indexes when compared with the normal group, and the pulsatility indexes correlated with endometrial thickness., Conclusions: The impedance to uterine artery blood flow is significantly different in women with different causes of infertility as compared with women of normal fertility. Increased resistance to uterine blood flow in the midluteal phase may be an important contributing factor to some causes of infertility and the cause of some previously "unexplained" infertility.

Ovulatory cycles in women result from sequential stimulation of ovarian follicular development by pituitary follicle stimulating hormone (FSH) and luteinizing hormone (LH). In the follicular phase the initial FSH stimulus declines and LH secretion increases toward the mid-cycle ovulatory surge. During the luteal phase gonadotrophin secretion is reduced. This reflects the effects of ovarian steroids inhibiting the frequency of gonadotrophin releasing hormone (GnRH) secretion by the hypothalamus, and the direct effects of oestradiol and inhibin to reduce gonadotroph (FSH) secretion. The frequency of GnRH stimulation of the gonadotroph is a selective regulator of gonadotrophin synthesis, with slow frequency stimuli favouring FSH and faster frequency stimuli favouring LH secretion. Current research has only revealed a single gonadotrophin releasing hormone. Thus, the ability to change the pattern (particularly frequency) of GnRH stimulation of the gonadotroph is proposed as an important regulator of differential FSH and LH synthesis, and hence of ovulatory cycles. In some disorders of ovulation the ability to regulate GnRH pulse frequency appears to have been lost. Slow frequency GnRH pulses are consistently seen in women with hypothalamic amenorrhoea and hyperprolactinaemia. The reduced GnRH secretion appears to reflect increased hypothalamic opiate tone and can be rapidly reversed with an opiate receptor blocker. Other disorders associated with anovulation show rapid frequency GnRH secretion, and polycystic ovarian syndrome (PCO) is commonly associated with fast-frequency, high-amplitude LH (GnRH) pulses. Such a GnRH stimulus would favour LH and androgen production and the failure of ovarian follicular maturation in PCO may reflect inappropriate sequential FSH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

While ovulation induction with human menopausal gonadotropins (hMG) is commonly used to treat refractory ovulatory disorders, little is known about the characteristics of multiple consecutive treatment cycles. Since such cycles may be required to achieve pregnancy, it is important to ensure that the ovarian response is not compromised during consecutive cycles. We examined the ovarian response and cycle characteristics of 25 women with World Health Organization (WHO) group II ovulatory disorders who underwent three consecutive ovulatory hMG cycles. The total hMG dose and duration of treatment increased significantly between the first and third consecutive hMG cycles, although the final estradiol levels remained similar. While the mean numbers of follicles > or = 14 mm in diameter were comparable, the size of the largest follicle was significantly greater during the third cycle as compared to the first. These results suggest that while the ovary required more vigorous stimulation during subsequent cycles, the ultimate hormonal and follicular response did not appear to be compromised during this series of three consecutive cycles.

The effects of a phytoestrogen diet on sexual differentiation were examined in lactationally exposed rat pups. Rat dams were provided a semipurified diet containing the isoflavonoid coumestrol at a concentration (0.01%) previously found to be uterotrophic. Coumestrol treatment did not significantly alter the time of vaginal opening, although vaginal opening did occur at a lighter body weight. By 132 days of age, 83% of coumestrol-treated females exhibited the cornified smears of a persistent estrous state. By contrast, 91% of control animals were cycling regularly at 132 days of age. Estradiol stimulation failed to elicit an LH elevation in the coumestrol-treated animals, suggesting the possibility of neuroendocrine impairments. These findings indicate that the female offspring of mothers fed a low-level phytoestrogen diet during lactation manifest early and nearly universal disruption of cyclicity of the persistent-estrus type.

The pattern of episodic gonadotrophin releasing hormone (GnRH)-driven luteinizing hormone (LH) secretion changes dynamically across the human menstrual cycle. Adherence to a specific regimen of pulse amplitude and frequency is critical for normal ovulation, menstrual cyclicity and reproductive function. Derangements of episodic LH secretion are associated with anovulation. We have shown that in the human slowing of GnRH-induced LH pulses results in lower ovulatory rates and dysfunctions of the mid-cycle LH surge. This information is relevant for the understanding of the endocrine dynamics of the menstrual cycle both in normal and anovulatory subjects.

A first case of successful induction of ovulation with recombinant human FSH administered subcutaneously to a WHO group II anovulatory patient is reported. Using a chronic low-dose protocol, recombinant human FSH, a preparation with no LH activity, led to a clear and even supraphysiological increase of inhibin and E2 and the development of four follicles among which one was dominant. The treatment cycle resulted in an ongoing pregnancy.

Dysfunctional uterine bleeding is a common gynecologic disorder that can affect any woman during her reproductive years. It is a diagnosis of exclusion, and the clinician must proceed through a logical stepwise evaluation to rule out all other causes of the abnormal bleeding. In most cases dysfunctional uterine bleeding is associated with anovulation. During the pubertal and perimenopausal periods, anovulatory bleeding is a common occurrence. During these transitional states, the abnormal bleeding has a physiological basis and is secondary to an estrogen withdrawal. Anovulatory bleeding can also be associated with chronic anovulation. The chronic unopposed estrogen that characterizes this disorder causes a continuous proliferation of the endometrium; this can result in abnormal bleeding and place the patient at risk for endometrial cancer. The goals of treatment for anovulatory bleeding are to stop the acute bleeding, avert future episodes, and prevent long-term complications. In some cases surgical intervention is indicated, but the foundation of treatment has been a medical approach. Several progestational agents have demonstrated effectiveness and can be administered either orally or by intramuscular injection. If the patient fails to have resolution of the bleeding with medical therapy, another cause of the bleeding must be suspected, and reevaluation is necessary.

The data reviewed in this chapter provide evidence that the pattern of GnRH secretion appears to be an important factor in regulating gonadotropin subunit gene expression, gonadotropin synthesis and hormone secretion. The data on gonadotropin synthesis were obtained in rodents and hence, must be interpreted with caution when applied to primates. Despite this reservation, the data suggest a similarity of regulatory mechanisms in mammalian species. The data also provide an explanation for the mechanisms whereby a single gonadotropin-releasing hormone can differentially regulate the three gonadotropin genes and allow differential hormone secretion. In overall agreement with this view, the observations during pubertal maturation reveal increasing GnRH pulsatile secretion during puberty with an evolution from predominant FSH to a predominant LH secretion by the gonadotropes. In males, the patterns of GnRH secretion appear to be fairly consistent throughout adult life, but in women cyclic changes occur which perhaps are important in maintaining cyclic ovulation. It is proposed that once pubertal maturation has been established, GnRH is secreted at a relatively fast frequency (one pulse per hour), and an essential feature of repeated ovulatory cycles is the slowing of this GnRH stimulus during the luteal phase: to allow subsequent preferential FSH release. This slowing of GnRH secretion appears to be effected by estradiol and progesterone acting to enhance hypothalamic opioid activity. Similar mechanisms involving increased opioid tone appear to be causally related to the reduced frequency and irregular GnRH stimulus seen in hypothalamic amenorrhea and hyperprolactinemia. In contrast, some forms of polycystic ovarian disease may reflect abnormalities of the estradiol-progesterone/opioid/GnRH neuron feedback mechanisms, with failure to establish slowing in the peripubertal anovulatory cycles. The resulting persistent GnRH stimulus increases LH with consequent effects of abnormal follicular maturation and enhanced ovarian androgen production. Present data are supportive of these hypotheses, but future studies will determine whether these views prove to be correct. However, current data provide strong support for the view that the pattern of GnRH secretion is a critical factor in the regulation of differential gonadotropin synthesis and secretion in mammalian species.

Although it is clear that the initial endocrine deficit contributing to the length of the postpartum anovulatory period in suckled cows is of pituitary origin, this limitation is only operative for about the first 2 weeks of the puerperium. Thereafter, the pattern of LH secretion required for the final stages of follicular development and ovulation is blocked or attenuated through a more centrally regulated phenomenon. Hence, much of the recently published work in this area has focused on regulatory processes within the hypothalamus. This focus ignores the critical issue of exteroceptive signalling. Recent observations in this laboratory suggest that exteroceptive cues responsible for suckling-mediated anovulation are specifically attributable to the dams' own calf, but are not teat-specific. In fact, suckling does not produce an extended anovulatory state in the absence of a maternal-offspring bond. This review provides an historical perspective of investigations leading to this conclusion, and proposes a conceptual working model that links the special senses, maternal behavior and neuroendocrine centers that drive gonadotropin secretion during the puerperium.

In female rat age-related reproductive decline is accompanied by progressive impairment of the neuroendocrine mechanisms that regulate LH secretion. The biosynthetic activity of the pineal gland is markedly depressed and the nocturnal secretion of melatonin decreases significantly. The aim of the present study was to evaluate whether the nocturnal administration of melatonin via the drinking water (0.4 micrograms/ml) throughout the course of aging from 14 to 24 months of age could (1) influence the age-related changes that occur in basal serum levels of LH and in the LH response to GnRH or to naloxone stimulation at 16, 18 and 20 months of age, and (2) delay the onset of the postreproductive constant estrous-anovulatory state as evaluated by the daily recording of vaginal smears and by occurrence of polyfollicular ovaries at 24 months of age. Our results demonstrate that melatonin replacement delays the increase in LH serum levels and the decrease in LH response to GnRH that occur in 18-month-old control animals. Furthermore, they show that melatonin treatment prevents the loss of LH response to naloxone manifested in control rats between 16 and 20 months of age. Melatonin also appears to prevent the progressive increase in the monthly occurrence of estrus phases as well as to decrease the number of rats with polyfollicular ovaries at 24 months of age in comparison to control animals. These results suggest that the age-related decrease in circulating melatonin during the night may contribute to the reproductive decline of aging, and that this effect may involve the central opioid system.

DUB is a common adolescent problem usually related to HPO axis immaturity and anovulation. Modern hormonal and other medical therapies enable physicians to treat DUB effectively, regardless of the cause. The evaluation provides the physician with an opportunity to offer confidential education, reassurance, treatment, and appropriate intervention in cases in which a systemic or coagulation disorder may be the underlying pathophysiology involved.

Problems of hyperandrogenism are becoming increasingly recognized in the female adolescent. Manifestations of androgen excess can have both far-reaching metabolic implications and significant effects on body image. At a crucial time in personality development, these problems should not be taken lightly. A common pathophysiology associated with androgen excess is PCOS. Awareness of this fascinating syndrome and its metabolic implications can alert health-care professionals so that the adolescent's metabolic, physical, and psychological needs are best addressed. Individualization of treatment is the rule. Team approaches to the diagnosis and treatment of the disorder have proven effective in reversing pathophysiology that has led to hirsutism.

This study was designed to establish the normal pattern of serum progesterone and the origin of its secretion during the follicular phase of the normal menstrual cycle. In the first study, 12 normal women were studied on 3 occasions each at different times during a single follicular phase. Serum samples were collected every 10 min over 8 h, for 6 h before and 2 h after an injection of naloxone (5 mg iv). The mean serum progesterone remained constant (0.9 nmol/L) across the follicular phase until just before ovulation; individual subjects showed pulsatility of progesterone (1-6 pulses/6 h) but there was no relationship of this to LH pulsatility and no variation of progesterone pulsatility across the follicular phase. Naloxone caused an increase in the mean serum progesterone in the early follicular phase to 1.9 +/- 0.7 nmol/L and in the mid and late follicular phase to 2.1 +/- 0.7 nmol/L and 3.4 +/- 2.5 nmol/L, respectively. The second study was performed to assess the contribution of the residual corpus luteum and the developing follicle to the pulsatile secretion of progesterone. Seven anovulatory women with low levels of serum LH and absent LH pulsatility were studied before and after clomiphene (100 mg/day for 5 days) by collecting blood samples every 15 min for 6 h before GnRH (10 mg iv) and for 2 h afterwards. The anovulatory women had comparable mean serum concentration of progesterone (0.9 +/- 0.5 nmol/L) to normal women and similar frequency of progesterone pulsatility (2.1 +/- 1.1 pulses/6 h). After administration of clomiphene, there was no significant change in progesterone pulsatility (1.7 +/- 1.0 pulses/6 h) despite a substantial increase in LH pulsatility (from none to 3.0 +/- 1.0 pulses/6 h). There was no significant increase in serum progesterone after clomiphene or GnRH which both caused a substantial increase in serum LH. The third study involved eight normal women studied before and after treatment with dexamethasone (2 mg/day for 2 days) to assess the adrenal component of progesterone secretion. Blood samples were collected every 10 min for 6 h before and 2 h after naloxone (5 mg iv). Dexamethasone reduced serum progesterone to below assay sensitivity (less than 0.2 nmol/L) and obliterated progesterone pulsatility. The increase in serum progesterone and cortisol induced by naloxone was blocked by dexamethasone; the naloxone-induced rise of serum LH was not affected by dexamethasone. We conclude that neither the preceding corpus luteum nor the developing follicle are important contributors to the serum concentration of progesterone during the normal follicular phase.(ABSTRACT TRUNCATED AT 400 WORDS)

Objective: To test the hypothesis that anovulation and infertility in women is associated with an impaired secretory capacity for growth hormone (GH)., Design: Comparison of the hormonal and metabolic response to two GH stimulation tests in a patient group and in a control group., Setting: Outpatients and healthy volunteers studied at a clinical research unit of a university hospital., Patients, Participants: Eight infertile, anovulatory women (luteal phase serum progesterone [P] less than 25 nmol/L) with regular cyclic bleeding. Eight age- and body mass index-matched healthy volunteers with luteal phase serum P levels greater than 25 nmol/L., Interventions: After an overnight fast, each subject underwent a standardized GH stimulation test composed of sequential arginine infusion and heat exposure on days 5 to 8 of the menstrual cycle., Main Outcome Measures: Serum GH, insulin-like growth factor I (IGF-I), insulin and non-esterified fatty acids (NEFA)., Results: Serum GH increased in both groups but was significantly lower in the study group (P less than 0.03). No difference was found in the circulating levels of IGF-I, insulin, and NEFA., Conclusions: Relative GH insufficiency seems to be present in these patients, but the clinical significance of this finding remains to be elucidated.

Objective: Since LH secretion occurs as a series of pulses, relationships between mean LH levels and LH pulse characteristics are to be expected. The aim of this study was to determine whether such relationships are similar in normal women and anovulatory patients., Design: We studied the correlations between mean LH levels and the products amplitude x frequency and area x frequency of LH pulses in normal women and in patients with disorders of ovulation. Blood samples were taken from each subject every 10 minutes during 6 hours on the 8th day after the last menses., Patients: The patients were divided into three groups: patients with polycystic ovary syndrome (n = 11), patients with idiopathic anovulation (n = 14) and patients with short luteal phase (n = 13). Their results were compared to those of 12 normal women., Measurements: LH was evaluated with an immunoradiometric assay. LH data were analysed with a 3 standard deviation threshold criterion for significant peaks, and with cluster analysis algorithm using 1, 2.5 and 5% false positive error rates and 'optimal parameters' (which give less than 5% false positive and false negative error rates in LH male data)., Results: Highly significant correlations between amplitude x frequency, area x frequency and mean LH were found in normals and patients with short luteal phase; no significant correlation was found in patients with polycystic ovary syndrome, while significant correlations were found in patients with idiopathic anovulation only with some of our criteria for peak detection., Conclusion: The differences that we found between the groups suggest that when commonly used methods are employed to determine LH pulse characteristics, most of the significant LH pulses are taken into account in normals and patients with short luteal phase, but not in anovulatory patients, especially in patients with polycystic ovary syndrome. This method using two correlations appears to be a simple and useful way to show the differences in the mechanisms by which mean LH levels are achieved in normal subjects and patients.

To evaluate whether repeated gonadotropin releasing hormone (GnRH) stimulations were superior to single GnRH administrations for the accurate assessment of pituitary gonadotropin responsiveness, the GnRH-stimulated luteinizing hormone (LH) and follicle stimulating hormone (FSH) responses of 49 hyperandrogenic patients (HA) were compared with those of 20 hypogonadotropic patients (HH) and of 24 normally cycling women (N). Blood samples were obtained at frequent intervals during GnRH administrations (25 micrograms twice within 2 h). Unstimulated LH concentrations were higher (p less than 0.001) in HA than in N and HH women. However, basal FSH levels differed only in HA from HH women (p less than 0.001). Following either GnRH stimulation, increased (p less than 0.01) LH and FSH releases were noted in all N, HA and HH women. The GnRH-stimulated LH and FSH responses to either GnRH injections were highest (p less than 0.01) in HA and lowest (p less than 0.01 vs. N) in HH women. The net LH and FSH increases over unstimulated concentrations (delta LH or FSH) in response to either GnRH stimulation were highest (p less than 0.01 or less) in HA women. By contrast, no differences were determined in the delta LH and FSH levels between the first and second GnRH stimulations within each group. These observations document different unstimulated and stimulated gonadotropin concentrations in normal cycling and anovulatory women. Gonadotropin responses to single GnRH administrations differ for anovulatory patients. Since the gonadotropin responses to the second GnRH stimulation are comparable to those during the first GnRH injections, repeated GnRH stimulations may not help to distinguish the degree of pituitary responsiveness in ovulatory from anovulatory women.

The intact luteinized follicle is closely related to minimal endometriosis. This one alters the biology of pelvic peritoneum in ways about which there is not accord or agreement, but that surely influence clinical manifestations of disease. In fact, fertility is altered, but the intimal mechanism for it, is unknown.

Objective: Luteal phase abnormalities are known to complicate ovulation induction with gonadotropins. This study was performed to test the effect of a modified human chorionic gonadotropin (hCG) regimen on the luteal phase during gonadotropin treatment., Design: Fifteen women from a private practice setting volunteered to be studied during each of two nonconception, gonadotropin-stimulated cycles. After ovarian stimulation with human menopausal gonadotropins (hMG), hCG was administered either as a single dose of 10,000 IU (single dose) or in two divided doses of 5,000 IU given 1 week apart (split dose)., Main Outcome Measures: Early, midluteal, and late luteal estradiol (E2) and progesterone (P) levels and luteal phase lengths were measured, and their median values and intraquartile ranges (IQR) compared using nonparametric analysis., Results: Early and midluteal E2 and P levels were similar regardless of which hCG regimen was administered. The median late luteal E2 level was 1,146.0 pg/mL (the IQR ranged from 633 to 1,650, IQR = 1,017) with the split-dose regimen and 240.0 pg/mL (the IQR ranged from 150 to 460, IQR = 310) with the single-dose regimen. The median late luteal P level was 108.0 ng/mL (the IQR ranged from 58.5 to 129, IQR = 70.5) with the split-dose regimen and 4.2 ng/mL (the IQR ranged from 1.9 to 11.7, IQR = 9.8) with the single-dose regimen. Median luteal phase lengths were 16 days (the IQR ranged from 15 to 17, IQR = 2) for the split-dose regimen and 11 days (the IQR ranged from 10 to 12, IQR = 2) for the single-dose regimen., Conclusion: In hMG-stimulated cycles, a second dose of hCG given during the midluteal phase significantly increases late luteal E2 and P levels and consistently lengthens the luteal phase.

In a prospective study, 140 patients with infertility because of ovulatory factors (group A) were followed up for 6 months after failure to achieve pregnancy using human menopausal gonadotropin (hMG) therapy. They included cases of oligomenorrhea, polycystic ovarian disease (PCOD), and hypogonadotropic amenorrhea. They were treated with hMG alone or in combination with clomiphene citrate or gonadotropin-releasing hormone agonist analog. The control group (B) included 83 infertile patients because of similar ovulatory factors. They were followed up for 6 months not preceded by ovulation induction. The overall pregnancy rate (PR) in group A (20.7%) was significantly higher than group B (7.2%). The PR was significantly higher in oligomenorrhea and PCOD patients when compared with the control group. There was no significant difference in the hypogonadotropic group.

The study of local blood flow in the uterus in 100 cases of uterine fibromyoma established increased blood levels of estradiol and progesteron. Blood estradiol level in the local flow of the uterus was relatively high in postmenopausal women, particularly, in those suffering uterine myoma. "Foreign" estradiol-dependent tissue substrates such as myoma and hyperplastic lesions of the endometrium were found to be responsible for potentiating local transfer and thus raising local concentration of ovarian hormones. Regulation of subovarian transfer and accumulation of hormones was shown to be to a large extent independent of levels of basic sex steroids in the general blood flow of the female body. Chronic local hyperestradiolemia in the uterus is the key factor for hyperplastic lesions development in the endometrium.