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Objective: The purpose of this study was to assess the characteristics of women with epilepsy who developed polycystic ovary syndrome (PCOS) owing to therapy with valproate sodium (VPA)., Methods: Our study comprised 77 patients on therapy with VPA--20 patients with PCOS and 57 without PCOS (control group). We assessed their epilepsy type, status of seizure control, and mental and physical statuses as well as the starting age, administration period, total dosage, and the highest value of blood concentration of VPA., Results: As compared with the control group, the PCOS group showed significantly high rates of association with mental retardation, severe physical disabilities, and poor seizure control, and symptomatic generalized epilepsy. However, the starting age, administration period, total dosage, and the highest value of blood concentration of VPA were not significantly different between the 2 groups. Nineteen of the 20 patients with PCOS had characteristically high androstenedione levels., Conclusions: Our study demonstrated that refractory symptomatic generalized epilepsy, polypharmacy including VPA and severe motor and intellectual disabilities are risk factors of developing PCOS.

Soskin, in his 1946 textbook, stated that insulin may be regarded as the dominant instrument in the symphony of endocrine action that results in normal carbohydrate metabolism. After almost half a century, great progress in the medical field has revealed that insulin plays more than even he described. Some aspects of important actions of insulin in our field as investigated in our laboratory are summarized below. 1. Role of insulin in reproductive endocrinology. (1) Correlation of insulin and testosterone in normal young women and patients with polycystic ovary syndrome (PCO). The sum of serum insulin values during 75g OGTT and serum testosterone values were positively correlated in normal women and patients with PCO. Glucose transport activities in isolated adipocytes from a typical PCO patient were decreased, but insulin binding activities were not, which indicates that insulin resistance in this patients is due to some post-receptor defects. (2) Insulin may be a risk factor of endometrial carcinoma. It is well-recognized that several diseases associate with hyperinsulinemia, such as obesity, PCO, diabetes mellitus, and hypertension are risk factors for endometrial carcinoma. The sum of the insulin values during OGTT was significantly higher in patients with endometrial carcinoma than in those without. 2. Role of insulin in perinatal medicine. (1) Increase in insulin secretion during pregnancy. High serum insulin concentration during OGTT, increased secretion of urinary C-peptide, and enhanced staining of insulin in B cells by the PAP method suggest that insulin secretion is enhanced during pregnancy. (2) Insulin resistance during pregnancy. Glucose utilization rate in both pregnant and progesterone-treated rats, as assessed by a glucose clamp technique, is significantly decreased as compared to nonpregnant rats. The technique of 2-deoxyglucose injection revealed that whole body insulin resistance is due to insulin resistance in individual insulin-sensitive tissues. The activities of 3-0-methyl-D-glucose transport in isolated rat skeletal muscle and human adipocytes were found to decrease during late pregnancy, but insulin binding activities were not. These results suggest that insulin resistance during pregnancy is due to some post-receptor mechanisms. (3) Physiological meaning of insulin in fetal growth.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to determine the difference between steroidogenesis in normal and polycystic ovaries (PCO), endocrinological analysis of follicular fluid and monolayer cell culture of human granulosa cells were carried out, and human LH and dibutyryl cyclic AMP were added to the cultures. The concentrations of LH and androstenedione in the follicular fluid from PCO ovaries were significantly higher than those found in normal ovaries in the early and mid-follicular phases. The cultured granulosa cells from the mid-follicular phase of normal women responded significantly to LH, showing an 8 to 10 fold increase in progesterone production. In contrast, exogenous LH caused only a slight stimulation (2 to 4 fold increase) in progesterone production by granulosa cells from PCO follicles. The cultured granulosa cells from normal women and PCO ovaries responded significantly to dibutyryl cyclic AMP, showing an 8 to 10 fold increase in progesterone production. These results strongly suggest that there is no alteration in the steroidogenic pathway after the cyclic AMP stage and that the persistent elevation of LH in serum and follicular fluid may lead to a disturbance of progesterone production in response to exogenous LH in the cultured granulosa cells from PCO ovaries.

The purpose of this study is to determine the steroidogenesis of polycystic ovary syndrome (PCO), through the comparison of steroidogenic potential between polycystic and normal ovarian cells harvested from follicles under 6 mm in diameter in vitro. 1) The granulosa cells were cultured by monolayer culture method, while the thecal tissue by explant culture method, at 37 degrees C using 5% CO2 in air for 18 days. 2) The cultured granulosa cells and thecal tissue grew successfully under 20% fetal calf serum with 80% medium 199. 3) The major product secreted by the cultured granulosa cells was progesterone, and the difference of steroidogenic potential between normal ovary and PCO was not significant. 4) The major products of isolated thecal tissue were delta 4-androstenedione and testosterone. Particularly, the cultured thecal tissue from PCO accumulated more androgens, in comparison with that from normal ovary. 5) The secretion of estradiol by the cultured granulosa cells was low in the absence of estrogen substrate and FSH. There was not appreciable difference in the capacity of granulosa cells from normal ovary and PCO to secrete estradiol. These results suggest that steroidogenic potential of isolated granulosa cells from PCO is comparable to that from normal ovary, whereas thecal tissue from PCO has more androgenic capacity than that from normal ovary.

Eleven women with polycystic ovary syndrome (PCO) were treated with Laparoscopic Multiple Punch Resection (MPR) of the ovarian follicle and capsule and studied by hormone analysis before and after MPR. In 90.9% of the patients, ovulation appeared to occur within 9 weeks and 63.6% conceived within 26 weeks. No changes in serum LH and FSH levels were seen before and after MPR, but testosterone levels which were in the upper normal range or slightly elevated before treatment were reduced after MPR. Endocrine responses to MPR were similar to those described previously after wedge resection. Laparoscopic MPR is a simple and least invasive method and makes it unnecessary to worry about periovarian adhesion after operation. Furthermore, other causes of infertility can be examined by laparoscopy. MPR appeared to be a promising alternative treatment for patients with PCO.

T elucidate the possible intraovarian site for androgen overproduction in the polycystic ovary (PCO), we investigated relative contribution of follicular and stromal compartments in steroidogenesis by in vitro experiments. The largest follicle and stoma were dissected from the PCO tissue obtained by wedge resection. A portion of each tissue was taken for histology and slices of each tissue were incubated with acetate-1-14C for 3 hours. Incorporation into progestins, androgens and estrogens was assessed by the reverse isotope dilution technique. Qualitatively, a predominant incorporation into androstenedione (76-88%) with little incorporation into estrogens (0.6-2.5%) was commonly observed in the follicle with marked hyperthecosis found in 3 typical PCOs, whereas a lesser incorporation into androstenedione (51-57%) with a slight increase into estrogens (6.4-14.6%) was verified in the follicles with mild hyperthecosis in 2 atypical PCOs. Quantitatively, actual incorporation into androstenedione was the greatest in the typical PCO follicles, followed by the atypical PCO follicles and the least or almost negligible in the stroma of PCOs. We concluded that atretic follicles rather than the stroma are principal sites of androgen overproduction by PCOs, and the androgenic capacity is related positively to the grade of hyperthecosis.

The exact mechanism(s) by which WR induces ovulation in women with PCOD is still uncertain. The aim of this study is to observe the change in sex steroids and pulsatile LH release (pul-LH-R) after WR. Before and either 7-8 days after the surgery (n = 8) or after 30 days of spironolactone treatment (n = 4), serum LH levels were measured every 15 min for 2-4 hours in PCOD women. Sex steroids were radioimmunoassayed before, and 3-4 and 7-8 days after WR. Testosterone (T) and androstenedione (A) in 7 women in whom spontaneous ovulation occurred after WR decreased significantly either 3-4 or 7-8 days after the surgery (p less than 0.001). Estrone decreased significantly (p less than 0.001) 7-8 days after the operation. The mean level of LH after WR in the 7 women decreased significantly (p less than 0.001). Furthermore, significant decreases both in the mean values of LH pulse amplitude (p less than 0.001) and frequency (p less than 0.01) were observed after WR. Ovulation occurred after 45 and 58 days of spironolactone administration in 2 PCOD women who showed changes in pul-LH-R and a drop in serum testosterone levels after 30 days of treatment. The data suggested that changes in pul-LH-R and decreased sex steroids after WR seemed to play key roles in the mechanism(s) by which WR induces ovulation.

To investigate the significance of changes in ovarian inhibin in gonadal dysfunction with persistent estrus, female rats with persistent estrus were studied as animal model for polycystic ovaries (PCO). Newborn female Wistar rats treated with testosterone propionate s. c. (TP) and female rats raised under continuous light (LL) started at 9 weeks of age entered into continuous estrus 5 and 2 or 3 weeks after the treatment, respectively. Ovaries in both groups had many polycystic follicles Normal adult female rats with 4 day cycles were served as control. Ovarian inhibin content was measured by FSH suppressing activity of charcoal-treated ovarian homogenates using a rat anterior pituitary cell culture system. Blood samples were obtained at 11:00 a. m. and plasma levels of LH, FSH, PRL, estradiol (E2), progesterone (P) and testosterone were measured by RIA. Comparisons were made statistically between each experimental group and normal proestrus (PE). Both LH and FSH were similar to normal PE in TP LL, suggesting a lack of LH and FSH surges probably through hypothalamic dysfunction in TP and LL. Plasma PRL levels were variably elevated in both groups. Ovarian inhibin contents were comparably high to PE in both groups with parallel increases in plasma E2 and P. Plasma testosterone was elevated only in TP. In conclusion, female rats with persistent estrus induced by TP or LL exhibited polycystic ovarian changes similar to PCO. Increased inhibin content in TP and LL may reflect persistent follicular activity.