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To characterize the spectrum of pulsatile gonadotropin secretion during the postmenarchal period, we studied 24 adolescents whose gynecological age was 1-4 yr. Six women with ovulatory cycles formed a control group. Eighteen women with anovulatory cycles were grouped on the basis of mean plasma LH values: group 1 (n = 8) with high LH values and group 2 (n = 10) with normal LH values. In all women, plasma gonadotropin concentrations were measured at 10-min intervals for 8 h on day 4 of the cycle. Pulsatile gonadotropin secretion was also studied a second time in 7 women from group 1 and 7 from group 2 after 5 days of progesterone (P) in oil treatment to assess the role of P in regulating gonadotropin secretion in the postmenarchal period. Group 1 had more frequent and greater LH pulses than the other two groups (which were very similar) and had the highest plasma 17 beta-estradiol, testosterone (T), androstenedione (A), and 17-hydroxyprogesterone concentrations. In all anovulatory women, basal LH values were correlated with the LH interpulse interval (r = -0.65; P less than 0.01) and pulse amplitude (r = 0.86; P less than 0.001). LH pulse amplitude was correlated with basal 17 beta-estradiol values (r = 0.74; P less than 0.001), and LH interpulse interval with basal T (r = -0.83; P less than 0.001), A (r = -0.51; P less than 0.05), and 17-hydroxyprogesterone (r = -0.79; P less than 0.001) values. P administration decreased LH pulse frequency and increased LH pulse amplitude more in group 2 than in group 1 with high LH values; a clear reduction was also found in A, T, and 5 alpha-dihydrotestosterone values. These results indicate that 1) anovulatory young women with high plasma LH values have an alternative maturational pathway, different from that of anovulatory women with normal plasma LH values, who are similar to ovulatory adolescents; 2) the pulsatile pattern of gonadotropin secretion has specific roles linked separately to amplitude and frequency in controlling ovarian steroidogenesis, which accounts for the endocrine differences between groups; and 3) in the postmenarchal period, by modulating LH and FSH pulsatility and thus reducing androgen levels and their atretic action on follicles, P may be a basic regulatory factor in enhancing functional cyclicity.

Pituitary reactivity to GnRH, characteristic of polycystic ovarian disease (PCOD), has been attributed both to a primary ovarian cause and to hypothalamic-pituitary dysfunction. If the heightened pituitary reactivity characteristic of PCOD patients is secondary to chronic anovulation, ovulatory cycles should produce changes in the LH to FSH ratio and reduce the augmented response to GnRH. In a randomized cross-over study of 10 women with PCOD, GnRH (100 micrograms) was injected iv on the fifth day of 2 consecutive cycles, 1 of them following anovulation and progesterone withdrawal bleeding and the other following an induced ovulatory cycle. Mean basal plasma 17 beta-estradiol, progesterone, and FSH levels were similar after ovulatory and anovulatory cycles. However, mean basal serum testosterone (P less than 0.05) and LH (P less than 0.01) levels were significantly lower, as were LH levels 30, 60, and 90 min (P less than 0.01) and FSH levels 60 and 90 min (P less than 0.05) after GnRH injection, after an ovulatory cycle than after an anovulatory cycle. The pituitary response to GnRH in those PCOD patients, therefore, was more normal after an ovulatory cycle than after an anovulatory cycle. We conclude that the heightened pituitary reactivity characteristic of PCOD patients is associated with chronic anovulation.

Failure of the hypothalamic-pituitary unit to release LH in response to oestrogen may be encountered with or without associated disturbance of negative feedback. Such positive feedback failures can be detected with the aid of an oestrogen provocation test. Application of this test in women presenting with anovulatory cycles permits one to distinguish between an hypothalamic or ovarian cause (e.g. deficient follicular development) for anovulation. In women with infrequent or absent menstruation and infertility an oestrogen provocation test, combined with basal gonadotrophin and prolactin measurement and pituitary response to LH-RH, may prove to be useful in selecting the appropriate treatment for induction of ovulation.

Clinical examinations including morphometry, mammography, x-ray examination of the cranium, ultrasonic examination of the small pelvic organs help detect the patients with hypogonadotropic amenorrhea and predict the efficacy of ovulation induction with menopausal gonadotropin. Women with a positive reaction to administration of progesterone and LH releasing factor make up the group most promising in respect of ovulation induction with menopausal gonadotropin.

We studied the interrelationships between insulin resistance, obesity, and abnormal ovarian androgen secretion in chronically anovulatory women with clinical or biochemical evidence of hyperandrogenism. Four groups of six subjects each were studied: (1) normal weight (within 10% ideal body weight) anovulatory, (2) obese (greater than 120% ideal body weight) anovulatory, (3) normal weight eumenorrheic, and (4) obese eumenorrheic. After dexamethasone suppression, human chorionic gonadotropin (2000 IU/1.5m2 body surface area intramuscularly) was administered to each subject. Serum testosterone levels were subsequently determined hourly for 17 hours. On a separate occasion, an oral glucose tolerance test was administered to five subjects from each group. Serum glucose and immunoreactive insulin levels were determined before and after the ingestion of a standard 100 gm glucose load. As a group, the anovulatory women had higher (p less than 0.05) basal testosterone levels (1005 +/- 97 pg/ml) than did the ovulatory women (241 +/- 21 pg/ml) (values +/- SE). Obesity per se was not associated with increased basal testosterone levels. Testosterone levels rose in response to human chorionic gonadotropin (p less than 0.005) only in obese anovulatory women, reached maximal levels after 3 hours, and subsequently remained stable. Basal immunoreactive insulin levels were elevated (p less than 0.05) only in obese anovulatory women (52.4 +/- 20 microU/ml) compared with obese eumenorrheic (8.7 +/- 1.0 microU/ml), normal weight anovulatory (5.8 +/- 2.4 microU/ml), and normal weight eumenorrheic (4.6 +/- 0.4 microU/ml) women. Similarly, maximal increases in immunoreactive insulin levels after glucose ingestion were significantly greater (p less than 0.01) in obese anovulatory women compared with other groups. Of note is the observation that maximal changes in testosterone observed within the first 3 hours after human chorionic gonadotropin and maximal changes in insulin were correlated (r = 0.91, p less than 0.01). These data suggest that (1) both insulin resistance and an abnormal acute response to human chorionic gonadotropin are seen only in obese anovulatory women and (2) the degree to which these two abnormalities are manifested is clearly correlated. The mechanism(s) responsible for this interrelationship, as well as the underlying cause(s) of these biochemical defects, remain to be elucidated.

Thirty infertile patients with ovulation defects and galactorrhea conceived after medical therapy: four after clomiphene stimulation (with or without hCG) and 26 after receiving CB-154 (2-Br-alpha-ergocryptine or bromergocryptine). Pregnancies were followed closely; sellar tomography and perimetry were repeated at 36 weeks' and 8 weeks' post partum. One patient required transsphenoidal adenectomy because of acute pituitary enlargement. Two developed minimal asymptomatic fossa enlargement. Lactation was suppressed with Lactostat in the first eight patients delivered; hyperprolactinemia, amenorrhea, and galactorrhea recurred. Five of eight showed asymptomatic enlargement of the sella. Bromergocryptine was used to suppress lactation in the rest. Long-term bromergocryptine therapy resulted in the restoration of euprolactinemic ovulatory cycles in all patients. These data suggest that patients with ovulation defects associated with galactorrhea can conceive with medical therapy now available. However, there is a risk of significant pituitary enlargement during pregnancy and the puerperium. Lactation should be suppressed with bromergocryptine.

Daily concentrations of salivary progesterone (P) were measured from 32 women during a complete menstrual cycle. Seventeen of the subjects were university students and 15 were patients of an infertility clinic (a severe male-factor was verified as the cause of infertility in all of them). Commercially available reagents for radio-immunoassay of serum P were modified for salivary measurements, to yield acceptable precision and sensitivity (40 pmol/l). Good correlation (r = 0.93) was found between salivary and serum P concentrations in samples collected simultaneously. The follicular phase levels of salivary P were below 100 pmol/l, and those at the luteal peak were 390 +/- 45 pmol/l (mean +/- SEM, n = 24). From the menstrual salivary P concentration curves we identified the first day of significant elevation above mean follicular levels (T2) and thereafter calculated the cumulative sum of daily P concentrations until 95% of the luteal phase secretion had accumulated (C95). The time needed to reach C95 (designated T95) and logC95 were plotted in coordinates and used as the basis of evaluation of normal menstrual P secretion. The observations were distributed in two groups, one with clearly identifiable T2 and a distinct luteal-phase P (ovulation had occurred) and one with no identifiable T2 and absent luteal-phase P peak (indicative of anovulation). Interestingly, 47% of the student population had an abnormally low menstrual P profile while all the other subjects displayed a clear luteal-phase peak of salivary P. These data provide more evidence for applicability of salivary P measurements for diagnosis of corpus luteam function and highlight the difficulty of selecting representative reference populations in studies on female reproductive endocrinology.

Hyperandrogenism, whether of ovarian or adrenal etiology, can be associated with impairment of folliculogenesis, resulting in anovulation. Various therapeutic modalities can be utilized to reestablish ovulation, including correction of the underlying pathophysiology, the use of fertility-promoting drugs and surgery.

The luteinized unruptured follicle syndrome is a form of anovulation and a subtle cause of female infertility. The syndrome cannot be diagnosed by traditional progesterone-dependent ovulation detection methods. Without the use of invasive procedures or sophisticated equipment, the luteinized unruptured follicle syndrome may go unnoticed. The patient diagnosed as ovulatory, on the basis of traditional ovulation detection methods, who does not conceive may be experiencing the luteinized unruptured follicle syndrome, and thus infertility. The syndrome's incidence, detection, etiology, and treatment are described.

Changes in numbers of ovarian follicles and coincident secretion of pituitary gonadotropins were characterized in suckled, anovulatory beef cows injected iv with 500 ng of luteinizing hormone-releasing hormone (LHRH) every 2 h for 48 or 96 h, starting 21.4 +/- .4 d after parturition. Two hours after the last injection, all cows were ovariectomized. Compared with saline-injected controls, LHRH had no effect on baseline or overall concentrations of luteinizing hormone (LH) in serum (P greater than .10), but increased (P less than .05) frequency and decreased (P less than .05) amplitude of LH pulses. Luteinizing hormone-releasing hormone increased (P less than .05) baseline concentration of follicle stimulating hormone (FSH) in serum and frequency of FSH pulses, but decreased (P less than .05) pulse amplitude. Overall concentrations of FSH increased 20% (P less than .10). Exogenous LHRH did not affect diameter of the two largest follicles or numbers of follicles 1.0 to 3.9 mm, 4.0 to 7.9 mm or greater than or equal to 8.0 mm in diameter. These data suggest that increasing the frequency of episodic LH and FSH pulses in postpartum cattle by intermittent administration of LHRH did not increase mean circulating levels of LH, or alter size and numbers of ovarian follicles within the 96-h period of injections. Thus, induction of ovulation in anovulatory cows treated with low-dose injections of LHRH cannot be explained on the basis of an increase in mean concentrations of LH or numbers of antral follicles within 96 h after initiation of injections.

The two step clomiphene citrate (CL) administration therapy was performed in 89 patients with first grade amenorrhea during 1980 through 1983, and clinical data in 89 patients and daily serum hormone levels in 20 patients were investigated. Out of the 89 women, ovulation occurred in 71 (79.8%). As to the treatment cycles, ovulation occurred in 158 cycles (53.4%) out of the total 296 cycles. Pregnancy was achieved in 16 women, among whom 2 women ended in spontaneous abortion and one had a multiple pregnancy. (1) As for 9 women in whom ovulation was induced by this treatment, the serum level of LH in the follicular phase and that of estradiol in the late follicular phase and luteal phase were higher than those of women who had normal ovulatory cycles. (2) No significant differences were observed between the serum levels of FSH and progesterone of the 9 women and those of women with normal ovulatory cycles. (3) As for 11 women in whom ovulation was not induced by this treatment, a transient increase in serum levels of LH and estradiol were observed after the first step administration of CL. This change also appeared soon after completion of the second step administration of CL and became more significant as additional stepwise administration of CL was performed. In view of observations, it was concluded that CL two step administration is effective for anovulatory women who did not respond to one step use of CL. As previously reported, CL exerts its action on the central nervous system to promote ovulation, but it is also strongly suggested that CL has its direct action on the ovary too.

A comparative assessment of variations in sex hormone levels and echographic parameters of fertile and infertile cycles was carried out in patients with gonadotrophic deficiency during pergonal induction of the ovulation. It was demonstrated that 83% of the infertile cycles were the first stimulation cycles. Basic differences were identified in the variation of sex hormone levels and echographic parameters of target organs between the fertile and infertile cycles. It is concluded that the first ovulation-induction course should be regarded as a preventive or preparatory one, where an optimum drug dosage is adjusted while the gonads and target organs are getting ready for the ovulation.

The LH FSH estradiol and progesterone responses to acute stimulation with LH-RH were studied in 12 normal women with ovulatory cycles (4 in the initial follicular phase, 4 in the mid-follicular phase and 4 in the late follicular phase) and in two castrated women, two under hormonal contraception, two with ovarian amenorrhea, twelve with central amenorrhea of no detectable origin (6 with normal and 6 with low basal gonadotrophins), eleven anovulatory patients with pseudomenstruation, two with anorexia nervosa, and two with pituitary amenorrhea. Each woman received a rapid i.v. injection of 100 microgram synthetic LH-RH at 9:00 a.m. Serum levels of LH, FSH, estradiol and progesterone were determined by radioimmunoassay in samples collected before and 60, 120, 240 and 480 minutes after injection. The findings were : 1) A significant rise in estradiol and progesterone levels, in addition to LH and FSH elevation, in normal women; 2) A lack of ovarian steroid response in the castrated women and in ovarian amenorrheas, which suggests that the source of steroid response to stimulation is not extragonadal; 3) Significant differences in the responses of the four hormones to LH-RH in the women with central amenorrhea in comparison with the normal group with great variability of results; the steroid response in the presence of a positive LH response might correlate with the severity and/or prognosis of the disorder, a point deserving further study; 4) In anovulatory women with pseudomenstruation, LH responses for the most part normal, and particularly, progesterone responses.

The stimulation regimens and the results of ovulation induction in anovulatory patients and in patients suffering from a Luteinized Unruptured Follicle (LUF) syndrome are discussed as well as the findings concerning superovulation in IVF cycles. The percentage of multiple pregnancies (less than or equal to 20 p. cent) is acceptable, due to the accurate daily performance of hormonal determinations. The pregnancy rate is lower in a LUF population, than in anovulatory patients. This is likely due to the unknown pathophysiology of the LUF syndrome. Compared to natural cycles, the maximum serum LH concentration is reduced in stimulated cycles although multiple oocytes have to mature in superovulated patients. A possible explanation for these reduced LH surges could be an increase in inhibin -like substances. There is still a need for more research to find out the real interaction between the follicle and the hypothalamic-hypophysial axis.

In the course of an investigation of 60 patients with clomiphene-resistant anovulation, 35 cases of androgenic hyperacitvity were detected. Fractionation of urinary 17-ketosteroids (17-KS) by a rapid method of chromatography proved to be both practical and reliable for the detection and classification of androgenic disorders of adrenal, ovarian, or mixed origin. In contrast to the total 17-KS values, the fractionated 17-KS values were elevated in all but one of these cases. Following dexamethasone suppression, individual 17-KS showed significant decreases in both adrenal and mixed adrenal-ovarian cases, in contrast to ovarian cases in which no significant change was detected. Human chorionic gonadotropin (HCG) stimulation combined with dexamethasone suppression did not cause any significant change in individual 17-KS values in the adrenal group, whereas both the mixed adrenal-ovarian and ovarian cases showed significant increases. Of 34 treated patients, 22 conceived, 21 had normal deliveries, and 1 aborted. Twelve became ovulatory. Eleven patients were treated with dexamethasone, nineteen with combined dexamethasone and clomiphene, two with dexamethasone and HCG, and two with HCG only.

With the use of pelvic ultrasound imaging we have found that more than half of the women presenting to our clinic with ovulatory disturbances have polycystic ovaries. As a group hirsutism is common, the serum LH, the LH:FSH ratio and serum androgen levels are higher than in other groups of patients with anovulation, but many of the women we studied were non-hirsute and had normal levels of these hormones. The aetiology of PCOS remains obscure and there is probably more than one cause. Disturbance of hypothalamic/pituitary, ovarian or adrenal function could all result in the development of polycystic ovaries. Our own data, based on pelvic ultrasound and measurement of serum androgen levels, suggest that an ovarian abnormality, other than the obvious morphological one, may be identified in most women although this does not prove (except perhaps in those women with unilateral PCOS) that the ovary is the primary site of the disturbance. Management of ovulatory disturbances includes symptomatic treatment of dysfunctional uterine bleeding and induction of ovulation. Although the ovulation rate following clomiphene is quoted as about 75%, this is probably an overestimate; less than half the 'ovulators' become pregnant and in those who do there is a high risk of early pregnancy loss. Induction of ovulation in clomiphene non-responders remains a difficult problem. The results of ovarian wedge resection are variable and any beneficial effect is short-lived with the risk of long-term infertility due to pelvic adhesions. Laparoscopic electrocautery may be a useful alternative, but it is too early to assess this form of treatment. Of the medical methods of ovulation induction in clomiphene non-responders, two methods have emerged as being highly promising: the first is administration of HMG following suppression of the pituitary by an LH-RH analogue; so far only a very small number of patients have been treated. The second is low-dose FSH. Initial studies, including our own, have shown a high incidence of ovulation and a pregnancy rate of 50%.

Uterine contractions were studied in two experiments utilizing ultrasonography and seasonally anovulatory mares. A one-minute ultrasound scan was done to produce longitudinal real-time images of the uterine body and an overall uterine contractile activity score (0 = no or minimal activity to 4 = maximal activity) was assigned to each scan. In experiment 1, a two-hour uterine activity trial (one score every 10 minutes) was done in mares given a single injection of prostaglandin F2 alpha (PGF2 alpha group; n = 4) and in control mares (n = 4). There was no difference between the two groups over the two-hour trial (mean activity score averaged over the two-hour trial: PGF2 alpha group, 0.2; control group, 0.1). In experiment 2, 16 mares were randomly assigned to one of four groups: 1) controls (corn oil vehicle), 2) 1 mg estradiol 17 beta on days 0 to 9 and 100 mg progesterone on days 10 to 20 (E2--greater than P4 group), 3) 100 mg progesterone on days 0 to 20 (P4 group), and 4) 100 mg progesterone on days 0 to 9 and 1 mg estradiol 17 beta + 100 mg progesterone on days 10 to 20 (P4--greater than E2 + P4 group). Uterine activity was assessed for each mare daily. The day by group interaction was significant. Scores for the E2--greater than P4 group were greater on days 4 to 11 (P less than .05) than for the other three groups. From day 14 to 21, scores did not differ among the three steroid-treated groups (except on day 15), but the scores averaged over each steroid-treated group were greater for each day (P less than .1 or .05) than for the controls (except on day 17).(ABSTRACT TRUNCATED AT 250 WORDS)

In 65 patients with menstrual cycle alterations--in it's length and/or amount of bleeding--estradiol-progesterone relationship was studied. The plasma levels of these hormones were correlated with basal temperature, length of menstrual cycle and histologic study of endometrium. The patient- were grouped as follows: I excessive menstrual bleeding; II short menstrual cycles; III long menstrual cycles; IV increment of bleeding period and, V uterine hemorrhage. All patients had an anovulatory menstrual cycle; peripheral concentration of progeseterone was less than 6 ng/ml and mean concentration of estradiol was not statistically higher than that found in normal patients (83+/-23 pg/ml). Based upon these findings, it is postulated that the term of hyperestrogenism or excessive estrogen production should not be used when referring to these menstrual cycle alterations.

Nine anovulatory patients with hypothalamic-pituitary dysfunction were treated with d-Trp6-luteinizing hormone-releasing hormone, an analog with far greater gonadotropin-releasing activity than luteinizing hormone-releasing hormone. Four of eight patients, who were formerly unsuccessfully treated with clomiphene, human chorionic gonadotropin, and human menopausal gonadotropin, ovulated after treatment with the peptide alone or with peptide preceded by clomiphene, and three became pregnant. The ninth patient, who had amenorrhea and anovulation due to excessive loss of weight caused by anorexia nervosa, also ovulated after treatment with the analog. These results demonstrate the effectiveness of this potent analog for induction of ovulation and pregnancy and point favorably toward clinical applications.

An LHRH test was performed before and at both 44 and 92 h after the administration of 2.5 mg oestradiol benzoate in eleven patients with hyperprolactinaemia, eight with idiopathic secondary amenorrhoea and seven with oligomenorrhoea. The basal serum hormone concentrations and the responses to LHRH were compared with the same tests performed on ten normal subjects during the early follicular phase of their menstrual cycles (days 4--6). Mean basal concentrations of oestradiol in each group of patients and oestrone in those with hyperprolactinaemia were significantly lower than in the normal subjects. The mean concentration of prolactin in women with secondary amenorrhoea remained lower than in the normal women throught the tests (P less than 0.05). The LH and FSH responses to LHRH before oestrogen in patients with hyperprolactinaemia and of FSH in those with secondary amenorrhoea, were greater than in the normal subjects (P less than 0.001). After oestrogen treatment the responses were similar in all groups except in those with oligomenorrhoea where LH and FSH responses at 44 h (P less than 0.05 and P less than 0.01 respectively) and LH responses at 92 h (P less than 0.01) were lower than in normal controls. The responses at 92 h in all groups were greater than at 44 h (amplification) but the amplification at 92 h and at 44 h compared to the pre-treatment responses, tended to be lower in each group of patients compared to the normal controls. In the hyperprolactinaemic group of patients there was a negative correlation between the basal prolactin concentration and the gonadotrophin amplifications at 92 h (P less than 0.01), and a positive correlation between the basal oestrone levels and the amplifications at 92 h (P less than 0.01). The results of the oestrogen amplification test in eleven of the non-hyperprolactinaemic anovular patients were compared with the ovulatory response to 100 mg clomiphene given for 5 days. Six showed a normal oestrogen amplification and they all ovulated. Two patients failed to show greater amplification at 92 than at 44 h and required human chorionic gonadotrophin (HCG) as well as clomiphene to ovulate. The other three showed a diminished LH amplification at 92 h; they required 200 mg clomiphene and showed a prolonged follicular phase. The responses of the hyperprolactinaemic patients to clomiphene were poor and there was a negative correlation between prolactin concentration and oestrogen production (P less than 0.01). All ten hyperprolactinaemic patients treated with bromocriptine ovulated and eight conceived. The oestrogen amplification test appears to have some value in predicting the subsequent response to clomiphene in non-hyperprolactinaemic anovular women.

A study was made of the long-term evolution of 64 women with PCO in order to identify the clinical and/or endocrine alterations that may modify the prognosis of each case. The patients were divided into two groups: Group A, where at the conclusion of the observation period disorders were present, and Group B, where they were not. A comparison between the clinical and endocrine data obtained from the two groups at the first observation showed only one significant difference, concerning the time of onset of menstrual irregularities; these coincided with the menarche in only 57.6% of the cases in Group A, but in 94.7% of those in Group B.

Administration to female rats of 250 micrograms of testosterone propionate (TSP) on the 3rd day of postnatal life led to reduction of estradiol, progesterone, and, to a lesser degree, of lutropin in the blood plasma of these animals at the age of 3 months. There was an increase of the lutropin content in the adenohypophysis and of luliberin in the hypothalamus. Combined with TSP administration of alpha-methyl-p-tyrosine, p-chlorphenylalanine or droperidol promoted preservation of cyclic changes in the hypothalamic gonadotropin activity and partially prevented disturbances of estradiol and progesteron secretion caused by neonatal androgenization. The mechanisms of participation of biogenic monoamines in sex differentiation of the hypothalamus are discussed.

Serum prolactin (PRL) was significantly lower in smokers, compared with non-smokers in 233 males and 250 females referred to our infertility clinics. In subjects smoking 10 cigarettes or more per day, the mean serum PRL was 22% and 20% lower in men and women, respectively. In cigarette smoking men serum testosterone was significantly higher and semen volume lower, while neither serum luteinizing hormone (LH) or follicle stimulating hormone (FSH), sperm density, motility of morphology differed between smokers and non-smokers. It is possible that the higher serum testosterone levels in smokers are due to their lower bodyweight, and that the lower semen volume may be due to an effect of nicotine on the contractility of the deferental ducts. Cigarette smoking may increase central dopaminergic tonus and reduce PRL levels, but it is unknown whether or not this is of biological significance in relation to reproductive function.

A method is presented of gonadotrophin administration and serum 17beta-oestradiol monitoring for the treatment of anovulation. Four of the 6 patients treated have conceived without any undesirable effects due to hyperstimulation. The advantages of this method of treatment and monitoring are discussed.

Many factors associated with hormone function have an impact on the course of epilepsy. Patients with epilepsy may have disturbances in sexual function such as anovulatory cycles in women and decreased libido and potency in men. Data indicate seizures, especially those arising in the limbic system, may influence the hypothalamic pituitary axis. Antiepileptic drugs also influence sexual function through direct brain effects as well as through induced changes in pharmacokinetics of the sex steroid hormones. Pregnancy has been reported to be a time of increased seizures; however, this has often been associated with low drug levels, for reasons that include inadequate drug dose, possible changes in pharmacokinetics, and noncompliance. Some evidence suggests that hormones affect seizure frequency. Changes in seizures during the menstrual cycle (catamenial epilepsy) have been found in some women: seizures were fewer during the luteal phase but increased when progesterone levels declined. Some improvement in seizure frequency has been shown in pilot studies using medroxyprogesterone acetate, a synthetic progesterone. Current concepts of the interrelationship among epilepsy, sex hormones, and antiepileptic drugs are discussed.

Using feedback circuits, light exposure was linked to wheel-running activity in female albino rats. Because the photosensitive portions of the circadian cycle are known to coincide with wheel-running activity, the feedback circuits concentrated light on the photosensitive portions of the cycle. In this type of lighting, the free-running period of locomotor activity was directly proportional to the light intensity (i.e., the Aschoff effect), and at an intensity of 100 1x, cyclic ovulation caused. Both these effects, which were previously thought to result only from exposure to continuous light (LL), occurred even though these rats were exposed to only 4 h of light per circadian cycle. These results indicate that the consequences of LL are not due to the continuity of the light per se but represent the effects of light falling on discrete photosensitive portions of the circadian cycle.

In order to investigate the hypothalamic function of anovulatory women serial determinations of the serum gonadotropins (LH and FSH) were made over a period of 120 h following the intramuscular injection of 1 mg of estradiol benzoate (E.B.). Ten women with normal menstrual cycles and 57 anovulatory women were subjected to this study. The positive release of LH in serum (exceeding at least 150% of basal level) in response to E.B. was noted in follicular phase of the cycles, but not in luteal phase, and in 31 of 57 patients the release came between 48 to 96 h after the E.B. injection. The LH surge after E.B. injection was difficult to provoke when the basal serum LH and estradiol (E2) levels were low: less than 10 mIU/ml and 50 pg/ml, respectively. Thirteen of 27 patients, who showed LH surge, ovulated because of Clomid. Only three of 17 patients, who did not show LH surge, ovulated as a response to Clomid. Ten of 14 patients, who showed LH surge after E.B. but did not ovulate after Clomid, revealed a polycystic ovarian disease (PCO), and the responsiveness to both E.B. and Clomid improved after wedge-resection of the ovaries. These results suggest that the serum E2 level is closely correlated to the ability for LH-RH production in the hypothalamic "surge center," and that the E.B. provocation test is useful for investigating the hypothalamic function of anovulatory women and for diagnosing preoperatively the PCO resistant to Clomid treatment.

A review of 26 unusual patients indicates that a combined luteinizing hormone-releasing hormone (LRH)-clomiphene test in conjunction with an estrogen provocation test not only was helpful in identifying underlying pathophysiology of anovulation but also proved useful in the clinical management of the patients. Dynamic testing per se does not establish a diagnosis but, in conjunction with history and other laboratory findings, it does make possible further subdivisions of groups of patients who otherwise appear similar, both clinically and from routine laboratory evaluations. It, therefore, tends to pinpoint a lesion and establish the area in which further tests should be made. It is concluded that the value of such investigations will be more evident as gynecologic endocrinology moves into investigation of the supratentorial control of hypothalamic function and as hypothalamic LRH becomes available as a therapeutic agent.

To clarify the mechanism of hyperandrogenic anovulation, the binding capacity of sex-hormone-binding globulin (SHBG-BC), the levels of free steroid hormones, and the levels of basal serum testosterone (T), estradiol (E2), estrone (E1) and gonadotropins were determined in 42 hyperandrogenic anovulatory women. The mean levels of basal T (0.74 +/- 0.04 ng/ml, p less than 0.001), free T (3.07 +/- 0.51 ng/dl, p less than 0.01) and free E2 (2.26 +/- 0.27 pg/ml, p less than 0.05), basal luteinizing hormone (LH) (33.4 +/- 2.7 mIU/ml, p less than 0.001), responsiveness of LH (180.7 +/- 21.5 mIU/ml, p less than 0.001) after luteinizing hormone releasing hormone (LHRH) administration, and the basal LH/basal follicle stimulating hormone (FSH) ratio (3.42 +/- 0.25, p less than 0.001) in the patients were significantly higher, the SHBG-BC level (1.76 +/- 0.33 micrograms DHT bound/dl, p less than 0.05) significantly reduced, and basal levels of E2 (38.0 +/- 3.2 pg/ml) and E1 (110 +/- 13 pg/ml) unchanged compared to the controls. These findings suggest that increased T in hyperandrogenic anovulatory women results in decreased SHBG-BC and increased free T and E2 which might be the cause of inappropriate gonadotropin secretion followed by chronic anovulation.

Changes in sizes and numbers of ovarian antral follicles, uterine size and weight, serum hormones, and frequency and duration of suckling were examined during the postpartum anovulatory period in primiparous, suckled beef cows. Twenty-one anovulatory, suckled cows (n = 4 to 6/d) were slaughtered on d 7, 14, 28 and 42 to 56 after parturition. In addition, a total of 11 postpartum cows that had begun cyclic activity were slaughtered on d 28, 42 or 56. Blood was collected at 10-min intervals for 6 h 1 d before slaughter for measurement of prolactin, cortisol and progesterone in serum. Numbers of medium (4.0 to 7.9 mm) follicles increased fourfold (P less than .05) between d 7 and 42 to 56 in anovulatory cows, whereas numbers of small (1.0 to 3.9 mm) and large (greater than or equal to 8.0 mm) follicles did not change (P greater than .10). Uterine involution was complete by d 28. In anovulatory cows, a higher (P less than .05) proportion of largest (but not second-largest) follicles was opposite the ovary containing the corpus albicans from pregnancy (CAP). In addition, 90% of these largest follicles opposite the CAP had concentrations of estradiol greater than progesterone. In cyclic cows, however, first ovulations occurred with equal frequency on either ovary. Concentrations of prolactin or cortisol in serum or duration of suckling were not associated with changes in uterine or ovarian measurements. In conclusion, growth and function of the largest (but not second-largest) follicle were reduced when located on the ovary containing the CAP.(ABSTRACT TRUNCATED AT 250 WORDS)

A penicillinase linked enzyme immunoassay was developed for the estimation of pregnanediol-3 alpha-glucuronide (PdG) in urine. The immunoassay satisfied all the validity criteria and was used in detecting ovulation and in the assessment of corpus luteal function (CLF) during spontaneous or induced cycles. Reference values were established by estimating PdG levels in daily early morning urine samples during 31 menstrual cycles obtained from 17 regularly menstruating women. A PdG value of 1.7 micrograms/mg creatinine (micrograms/mgC) (90th Centile of follicular phase) in any MLP (mid-luteal phase) sample was considered as indicating ovulation. A value of 4.6 micrograms/mgC (20th centile of MLP) was considered to be evidence of sufficient CLF. When this approach was applied to 20 infertile cases, detection of the occurrence of ovulation/anovulation was made correctly in 19 out of 20 cases (95%). Accuracy was poor (55.6%) when the aim of the diagnosis was corpus luteal deficiency. Higher accuracy (88.9%) for corpus luteal deficiency/corpus luteal adequacy was obtained when the sum of PdG concentrations in three MLP samples were taken into consideration. A total of 13.8 micrograms/mgC (thrice the 20th centile for MLP) indicated probable corpus luteal deficiency, and values above this limit were considered to indicate corpus luteal adequacy.

Circadian profile and responsiveness of prolactin to TRH administration were examined in 21 women with ovulatory disturbances. The data were analyzed with reference to the clinical effectiveness of bromocriptine administration. Resting levels of serum prolactin in the patients studied were lower than 25 ng/ml. 14 patients out of 16 cases (Group A) responded to bromocriptine, whose prolactin levels were more than 30 ng/ml during the night in the circadian studies. On the other hand, none of 5 patient (group B) responded to bromocriptine, whose prolactin levels were not more than 30 ng/ml during the night. Group A showed hyper-responsiveness of prolactin to TRH higher than that of Group B. These results suggested that 1) In euprolactinemic ovulatory disturbances there are cases with nocturnal hyperprolactinemia, whose prolactin levels are normal during the day time. These cases will be referred to as occult hyperprolactinemia. 2) Those with occult hyperprolactinemia show increased prolactin-secreting-capacity, which is able to be diagnosed by the hyper-responsiveness of prolactin to TRH administration. 3) The effectiveness of bromocriptine in treating euprolactinemic ovulatory disturbances is due to the suppressive effect of bromocriptine on the hyperprolactinemic states of occult hyperprolactinemia.

Life-table analysis was performed for the cumulative spontaneous pregnancy rate (CSPR) of 56 patients with oligomenorrhea and anovulatory cycles who had been treated with gonadotropin for ovulation induction between 1963 and 1985. Twenty-seven had at least one spontaneous pregnancy, giving rise to a CSPR of 66.4% (95% confidence limit [CL] 42.4% to 90.4%) at 115 months for the first spontaneous pregnancy, which is significantly lower than the cumulative induced pregnancy rate (CIPR) of 88.6% at 23 months for the first course of gonadotropin therapy (P less than 0.0001). This fertility potential was not affected by the baseline estrogen and follicle-stimulating hormone levels, diagnosis, result of gonadotropin therapy, and age and menstrual pattern during exposure to spontaneous pregnancy by Cox regression analysis. More multiple births occurred in the induced pregnancies than in the spontaneous pregnancies (P = 0.005).