Development Of Polycystic Ovaries Research Articles

Hsa_circ_0043533 modulates apoptosis and viability of granulosa cells via miR-409-3p/BCL2 and EMT signalling in PCOS: Providing novel perspective of metformin

Polycystic ovary syndrome (PCOS) represents a significant cause of infertility among women of reproductive age. Studies have established a close association between granulosa cells (GCs) and the abnormal follicle formation and ovulation processes characteristic of PCOS. The interactions among hsa_circ_0043533, miR-409–3p, and BCL2 were verified through luciferase activity assays. In PCOS patients, granulosa cells exhibit notably reduced apoptosis but enhanced growth, leading to their accumulation and the development of polycystic ovaries. The involvement of non-coding RNAs in PCOS has been documented, with elevated levels of hsa_circ_0043533 observed in this condition. A comprehensive series of experiments were conducted to explore the role of hsa_circ_0043533 in PCOS and elucidate its underlying mechanisms. Silencing hsa_circ_0043533 was found to promote apoptosis and hinder the migration, proliferation, and viability of KGN cells. Furthermore, we uncovered the regulatory effects of hsa_circ_0043533 on the miR-409–3p/BCL2 axis and key markers of Epithelial-Mesenchymal Transition (EMT). Additionally, it was observed that metformin modulates the hsa_circ_0043533/miR-409–3p/BCL2 axis. Overall, this study provides novel insights into the molecular mechanisms regulating granulosa cell proliferation and apoptosis in PCOS, further elucidating the molecular pathogenesis of this condition.

Individual and joint associations of urinary phthalate metabolites with polycystic ovary and polycystic ovary syndrome: Results from the TREE cohort

Phthalates are widespread endocrine disrupting chemicals that adversely affect female reproductive health. We aimed to investigate the individual and joint associations of phthalate exposures measured by repeated urinary metabolites with polycystic ovary (PCO) and polycystic ovary syndrome (PCOS) (96 PCO cases, 96 PCOS cases and 370 controls). In single-pollutant analyses, mono-isobutyl phthalate (MiBP), monobenzyl phthalate (MBzP) and the sum of di(2-ethylhexyl) phthalate (∑DEHP) were associated with increased prevalence of PCO. Mono(2-ethylhexyl) phthalate (MEHP), MBzP and ∑DEHP were associated with elevated prevalence of PCOS. In multiple-pollutant analyses, one-quartile increase of weighted quantile sum index in phthalate metabolite mixtures was associated with increased prevalence of PCO and PCOS, and MBzP was the most major contributor. Our findings suggest a potential role for phthalate exposures, both individually and in mixtures, in the development of PCO and PCOS.

Violation of the Hormonal Spectrum in Polycystic Ovaries in Combination with Insulin Resistance. What is the Trigger: Insulin Resistance or Polycystic Ovary Disease?

Polycystic ovary syndrome (PCOS) is the main cause of female infertility. The role of insulin resistance in the development of polycystic ovary is actively discussed here. The study included patients with PCOS without insulin resistance (n = 48) and with insulin resistance (n = 39). The comparison groups were patients with no history of PCOS: a control group without insulin resistance (n = 46) and a group of patients with insulin resistance (n = 45). The following parameters were determined in patients: FSH, LH, TSH, T3f, T4f, PRL, E2, 17-OHd, Pr, AMH, Test total, Testf, DHEAS, DHEASs, SHBG, ACTH, cortisol, IRI, IGF-1, C-peptide, and glucose level. The HOMA-IR index and the LH / FSH ratio and the total / SHBG test were calculated. Correlation analysis was also performed between HOMA IR and indicators of the hormonal profile, IGF-1, and C-peptide.Unidirectional changes in the levels of the following hormones were found in insulin resistance, PCOS and / or insulin resistance relative to control values: estradiol, total testosterone, cortisol, prolactin, AMG, and SHBG. As a result of the correlation analysis, negative relationships were established between the HOMA IR Index and the levels of E2, cortisol and AMH in patients (except for the control group).We assume that the formation of the phenotype of polycystic ovary with a combination of insulin resistance can be formed in patients with insulin resistance as a result of a decrease in the level of estradiol, SHBG and an increase in the content of total testosterone and AMH.

A Short-Term Altrenogest Treatment Post-weaning Followed by Superovulation Reduces Pregnancy Rates and Embryo Production Efficiency in Multiparous Sows.

Although embryo transfer (ET) is a biotechnology ready for the swine industry, there are factors to be solved, the availability of embryo donors as one. Multiparous sows as donors ought to be considered since weaning is a natural and efficient method for estrus synchronization. In addition, superovulation treatments at weaning are effective in increasing the efficiency of donor embryo production. However, ET programs typically require more donors than those available from a single weaning, imposing grouping several weanings to establish a batch for ET. Since short-term administration of Altrenogest is effective in delaying estrus after weaning without effects on ovulation and embryo development, we investigated how Altrenogest combined with superovulation would affect reproductive parameters and embryo quality and quantity of weaned multiparous donor sows. The sows were administered Altrenogest from the day of weaning for 14 (SS-14 group; N = 26), 7 (SS-7 group; N = 31) and 4 (SS-4 group; N = 32) days. The sows were superovulated with eCG 24 h after the last administration of Altrenogest and with hCG at the onset of estrus. Sows not treated with Altrenogest that were superovulated with eCG 24 h post-weaning and hCG at the onset of estrus (SC group; N = 37) and sows with natural estrus after weaning (C group; N = 34) were used as control groups. The percentage of sows showing estrus within 10 days was not affected by the treatment, but the interval from Altrenogest withdrawal to estrus was longer (P < 0.05) in the SS groups than the interval from weaning to estrus in the controls. SS treatments increased (P < 0.05) the percentage of sows with ovarian cysts and the development of polycystic ovaries. The pregnancy and the fertilization rates, and the overall embryo production efficiency were also negatively affected by the SS treatments (P < 0.05). Interestingly, almost 70% of the structures classified as unfertilized oocytes or degenerated embryos in sows from the SS groups were immature oocytes. In conclusion, although superovulation of weaned sows was highly efficient, short-term administration of Altrenogest in combination with superovulation had negative effects on most of the reproductive parameters assessed, particularly affecting the overall efficiency of pregnancy and embryo production.

Effect of 150\u2009kHz electromagnetic radiation on the development of polycystic ovaries induced by estradiol Valerate in Sprague Dawley rats

BackgroundPolycystic ovary syndrome (PCOS) is the most common complex endocrine disorder affecting approximately 2–20% of reproductive aged females. Tumour Treating Fields (100–300 kHz) is a recent innovative, non-invasive therapeutic approach to cancer therapy. This frequency as an alternative therapy for the management of polycystic ovaries has not yet been explored.ObjectivesTo explore the effect of full-body exposure of 150 kHz Electromagnetic Radiation (EMR), on the development of polycystic ovaries in an estradiol valerate-induced PCO rat model.MethodTwenty-one female adult rats were divided into three groups (n = 7 each): control, Estradiol Valerate (EV) and EV + EMR groups. The EV + EMR group was subjected to full body exposure at 150 kHz EMR continuously for eight consecutive weeks. Estradiol valerate was administered orally to induce polycystic ovaries in EV and EV + EMR groups. Body and ovarian weights were recorded and analysed. The regularity of the estrous cycle was assessed in all three groups. The histological study of ovarian tissue was carried out by haematoxylin and eosin staining. The serum concentration levels of Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH) and testosterone were measured using the ELISA method.ResultsThe body and ovary weights did not differ significantly between the EV and EV + EMR groups. The estrous cycle was found to be irregular in both the EV and EV + EMR groups. Ovarian histology revealed near normal morphology with little or no degenerative and morphological changes in developing follicles in the exposed group. Histometrical analysis showed an increased number of developing follicles and a significant reduction in the number and size of follicular cysts (p < 0.05) in the EV + EMR group. Hormonal analysis revealed no significant difference in the testosterone and FSH levels between the EV + EMR and EV groups. However, the LH, LH/FSH ratio decreased significantly in the EV + EMR group compares to the EV group.ConclusionThe 150 kHz EMR appear to have little or no degenerative and morphological changes in the developing follicles, an increased number of typical developing follicles and a significant reduction in the number and size of the follicular cysts (p < 0.05).

Differential expression of genes involved in steroidogenesis pathway in human oocytes obtained from patients with polycystic ovaries

ObjectiveFollicular development can be disturbed due to many factors, including having polycystic ovaries. Aberrant expression of genes involved in steroidogenesis pathway could lead to aberrant oocyte development. In this study, the gene expression levels of a number of genes that is functioning in steroidogenesis pathway were investigated. Materials and methodsThe spare oocytes were collected from NEU Hospital IVF Center following controlled ovarian stimulation cycle. RNA was extracted using RNA/DNA Purification Kit (Norgen, Canada) and reverse transcription was performed using TruScript First Strand cDNA Synthesis Kit (Norgen, Canada). Real time PCR was conducted using LightCycler® 480 SYBR Green I Master (Roche, UK). Results and conclusionThe expression levels of CYP11, CYP17, CYP19, HSD17B1, HSD3B2 and ACTB were detected in human MII stage oocytes obtained from oocyte donors aged between 18–30 years. The number of follicles and oocytes collected from the patients with polycystic ovaries were slightly higher compared to the control group. The expression level of CYP11A1 was shown to be statistically different in the oocytes obtained from the patients who do not have polycystic ovaries (p < 0.05), whereas statistically significant expression levels were observed for CYP17 in the oocytes obtained from patients with polycystic ovaries (p < 0.05). The expression level of HSD17B1 was also shown to be statistically different in the oocytes (p < 0.05). The extrapolation of the results indicates that the genes involved in steroidogenesis pathway are altered in cases of polycystic ovaries. Thus, it may have a role in the development of polycystic ovaries.

PATHOGENETIC ASPECTS OF THE INTERMITTENT OF THE DEVELOPMENT OF THE POLYCYSTIC OVARY SYNDROME WITH PROLONGED COLD INFLUENCES IN THE EXPERIMENT

The aim of the research was to study the effect of intermittent cold effects (ICE) on the experimentally induced polycystic ovary syndrome (PCOS) in female rats to prevent the development of polycystic ovaries and elaboration the pathogenesis of its development. Simulation of PCOS was performed by subcutaneous injection of dehydroepiandrosterone acetate (DHEA) in rats for 25 days. A ICE was carried out by daily keeping the animals for 4 hours in a chamber in which the light regime and a temperature of + 4 °C were maintained. As a result of the experiments, it has been proved that after intracellular adaptive-compensatory reactions are activated in the ovarian tissue, which helps prevent the development of PCOS. In addition, ICE leads to an increase in the level of adipocytokines (adiponectin and leptin), which can indirectly affect the secretion of reproduction hormones and inhibit the development of cystic changes in the ovary. Stimulation of adaptive physiological reactions against the background of ICE blocks the development of signs of PCOS in rats.

Transitory Activation of the Central and Ovarian Norepinephrine Systems During Cold Stress‐Induced Polycystic Ovary in Rats

Cold stress-induced ovarian sympathetic activation is associated with the development of ovarian cysts in rats. Although we have hypothesised that polycystic ovary (PCO) features induced by cold stress, as prevented by lesion of the noradrenergic nucleus locus coeruleus (LC), were a result of the increased activity of the ovarian norepinephrine (NE) system, this was not evident after 8 weeks of stress. In the present study, we investigated the temporal changes in LC and ovarian NE activities and steroid secretion in rats exposed to single (SS) or repeated (RS) cold stress. SS and 4 week (4W)-RS but not 8 week (8W)-RS increased c-Fos expression in the LC and ovarian NE release. Plasma oestradiol, testosterone and progesterone levels tended to increase in 4W-RS and were elevated in 8W-RS rats, which displayed PCO morphology. β-adrenergic receptor agonist increased steroid hormone release from the ovary of unstressed (US) but not from 8W-RS rats. To determine whether increased activity of noradrenergic system during the initial 4 weeks of RS would be sufficient to promote PCO, rats were exposed to 4 weeks of cold stress and kept in ambient temperature for the next 4 weeks (4W-RS/4W-US). Accordingly, PCO morphology, increased steroid secretion and decreased ovulation rate were found in 4W-RS/4W-US rats, strengthening the hypothesis that the initial increase in NE release triggers the development of PCO. The correlated activity of LC neurones and ovarian noradrenergic terminals and the induction of PCO in 4W-RS/4W-US rats provide functional evidence for a major role of NE in disrupting follicular development and causing the long-lasting endocrine abnormalities found in stress-induced PCO.

Polycystic ovarian disease unmasked by pulsatile GnRH therapy in a subgroup of women with hypothalamic amenorrhea

To present the observation in six out of 120 women treated with pulsatile GnRH for ovulation induction, who developed hyperandrogenemia and polycystic ovaries during treatment. Clinical observation. Department of Gynecologic Endocrinology and Reproductive Medicine, Medical University of Innsbruck, Austria. A total of 120 women initially diagnosed as suffering from primary or secondary hypothalamic amenorrhea were treated for ovulation induction with pulsatile administration of GnRH for up to 140 days. There was no indication of the presence of polycystic ovaries or hyperandrogenemia before therapy. Pulsatile GnRH therapy using the Zyklomat pump. Ovulatory menstrual cycles. Initially, all patients responded to pulsatile GnRH administration with ovulation and corpus luteum formation. During continuation of treatment, 6 patients developed an increase in LH and LH/FSH ratio as well as a progressive rise in serum T levels resulting in hyperandrogenemia. This was accompanied by the development of polycystic ovaries and cessation of follicular maturation. We conclude from these observations that restoration of normal GnRH stimulation of the pituitary gland can result in the development of hyperandrogenemia and polycystic ovaries, suggesting a pituitary or ovarian defect underlying the pathogenesis of this disorder.

Sodium Valproate, Hyperandrogenism and Altered Ovarian Function in Indian Women with Epilepsy: A Prospective Study

To assess the association of long-term sodium valproate therapy with reproductive endocrine disorders in Indian women with generalized epilepsy. Clinical parameters, ovarian morphology, and serum reproductive hormone concentrations were evaluated in 30 clinically normal and eumenorrheic reproductive age women with generalized epilepsy who were newly initiated on valproate. Longitudinal evaluations were done in 25 of these women after 1 year, and in some of them after 2 and 3 years of therapy. Of the 25 women who completed 1 year follow-up, we observed clinically relevant weight gain in 40%, hirsutism in 20%, menstrual abnormalities in 24%, polycystic ovaries (PCO) in 16%, polycystic ovarian syndrome (PCOS) in 20%, and a significant increase in mean serum testosterone (p=0.046). A significant positive correlation existed between weight gain and the development of menstrual abnormalities (r=0.66, p<0.0001), hirsutism (r=0.53, p=0.006) and PCO (r=0.51, p=0.012). No correlation existed between weight change and serum reproductive hormonal changes. Yearly follow-up for next 2 years in some of these women revealed persistence of menstrual abnormalities, hirsutism and PCO, a significant linear increase in mean body weight, body mass index, and serum testosterone concentrations, and an increase in serum LH levels from second year onwards. Limitations include small sample size and a high dropout rate on follow-up. Long-term valproate therapy in Indian women with generalized epilepsy is associated with development of hirsutism, significant weight gain, stable or progressive alterations in reproductive hormonal function, and ultimately a higher occurrence of PCOS.

Follow-up study of two sisters with type A syndrome of severe insulin resistance gives a new insight into PCOS pathogenesis in relation to puberty and pregnancy outcome: a case report

We report two sisters with profound insulin resistance associated with a novel heterozygous missense mutation in exon 19 (His1130Arg) of the insulin receptor gene. The eldest was seen after puberty at age 15 and she presented a severe form of polycystic ovary syndrome (PCOS) with biological hyperandrogenism (HA) mimicking a virilizing tumour. However, she has been able to ovulate under clomiphene citrate (CC) and to achieve two uneventful pregnancies. The patient had no glucose tolerance abnormality during pregnancies. The outcome of pregnancy was good except for a low birthweight. The youngest sister was seen earlier in life (at age 11) before puberty. First, she developed polycystic ovaries (PCO), seen under ultrasound scan, and later also developed full PCOS. This second finding gave us the opportunity to observe that PCO developed before and at the beginning of puberty despite low LH levels. We postulate that the development of PCO was the consequence of an LH-independent intra-ovarian HA likely induced by the severe hyperinsulinism in the context of genetic abnormalities.

Effect of anti-NGF on ovarian expression of α1- and β2-adrenoceptors, TrkA, p75NTR, and tyrosine hydroxylase in rats with steroid-induced polycystic ovaries

Estradiol valerate (EV)-induced polycystic ovaries (PCO) in rats are associated with higher ovarian release and content of norepinephrine, decreased beta2-adrenoceptors (ARs), and dysregulated expression of alpha1-AR subtypes, all preceded by an increase in the production of ovarian NGF. The aim of this study was to further elucidate the role of NGF in the ovaries by blocking the action of NGF during development of EV-induced PCO in rats. Control and EV-injected rats were treated with intraperitoneal injections of IgG (control and PCO groups) or with anti-NGF antibodies (anti-NGF and PCO anti-NGF groups) every third day for 5 wk starting from the day of PCO induction. Rat weight, estrous cyclicity, ovarian morphology, ovarian mRNA, and protein expression of alpha1-AR subtypes, beta2-AR, the NGF receptor tyrosine kinase A (TrkA), p75 neurotrophin receptor (p75NTR), and tyrosine hydroxylase (TH) were analyzed. Ovaries in both PCO and PCO anti-NGF groups decreased in size as well as in number and size of corpora lutea. mRNA expression of alpha1a-AR and TrkA in the ovaries was lower, whereas expression of alpha1b- and alpha1d-AR and TH was higher, in the PCO group than in controls. Protein quantities of alpha1-ARs, TrkA, p75NTR, and TH were higher in the PCO group compared with controls, whereas the protein content of beta2-AR was lower. Anti-NGF treatment in the PCO group restored all changes in mRNA and protein content, except that of alpha1b-AR and TrkA mRNAs, to control levels. The results indicate that the NGF/NGF receptor system plays a role in the pathogenesis of EV-induced PCO in rats.

Hyperandrogenemic-hypothalamic ovarian insufficiency – a new disease entity

Six women initially diagnosed as suffering from primary or secondary hypothalamic amenorrhea were treated for ovulation induction for up to 140 days with pulsatile administration of GnRH. All women had low circulating LH and FSH levels, normal prolactin concentrations and testosterone serum levels in the low normal range. None of the patients was suffering from insulin resistance as determined by glucose tolerance test. There was no indication for the presence of polycystic ovaries. Initially, all patients did respond to pulsatile GnRH administration with ovulation and corpus luteum formation. However, during continuation of treatment, there was a continuing increase of LH and the LH/FSH ratio as well as a progressive rise in serum testoterone levels resulting in hyperandrogenemia. This was accompagnied by the development of polycystic ovaries and cessation of follicular maturation. We conclude from these observations that restoration of normal GnRH stimulation of the pituitary gland can result in the development of hyperandrogenemia and polycystic ovaries, suggesting a pituitary or primary ovarian defect underlying the pathogenesis of this disorder.

The effect of herbal medicine on nerve growth factor in estradiol valerate-induced polycystic ovaries in rats.

A type of polycystic ovary resembling some aspects of human polycystic ovarian syndrome (PCOS) can be induced in the rat with a single injection of long-acting estradiol valerate. Among several theories behind the development of polycystic ovaries (PCO), the involvement of the sympathetic nervous system draws much attention, and herbal medicine is known to relieve the abnormal symptoms of PCO. Two herbal formulas, Changbudodam-Tang (cang fu dao tan tang) and Yongdamsagan-Tang (long dan xie gan tang), were used in the present study. The administration of herbal medicine was done every other day for 60 days. The morphological changes of ovaries from herbal medicine treatment were compared to those from an oil-treated control group and an estradiol valerate-injected group. This study also examined the possible hypothesis of neurogenic participation in terms of nerve growth factor (NGF) in the pathology of ovarian dysfunction. The nerve growth factor was analyzed in the central nervous system and ovaries by immunohistochemistry. The main findings of the present study were: (1) PCO were fully developed in rats with a single intramuscular injection of estradiol valerate, (2) PCO resulted in the expression of NGF in the ovaries and the brain tissues, and (3) herbal medicine administration significantly decreased the elevated NGF staining in the ovaries without affecting the brain tissues significantly.

Polycystic ovaries, obesity and insulin resistance in women with epilepsy

In order to investigate the possible role of valproic acid therapy in the development of obesity, hyperinsulinism and polycystic ovaries (PCOs), we have studied metabolic parameters and ovarian morphology in epileptic women. A total of 105 women, who were treated for at least 2 years with valproate (n = 52) or carbamazepine monotherapy (n = 53), were included in the examination. Menstrual disturbances were reported by 29 (28 %) of the women, 12 (11 %) of the VPA treated women, and 17 (16 %) in the CBZ group. On ultrasound scan polycystic ovaries were found in 28 patients (27 %) of the whole study population, of whom 13 (12 %) received VPA and 15 (14 %) CBZ. The mean body mass index (BMI) was significantly higher in the VPA group (24.4 kg/m(2) +/- 4.1) than in CBZ treated patients (22.9 kg/m(2) +/- 2.4;p < 0.022), and serum triglycerides tended to be increased, while total cholesterol values (178.9 +/- 30.5) and LDL-cholesterol values (92.6 +/- 27.4) were significantly lower in the valproate group, than in the carbamazepine group (207.1 +/- 43.0 vs 115.1 +/- 42.0; p < 0.001). Postprandial insulin, C-peptide and proinsulin levels were significantly higher in VPA treated patients compared with those treated with CBZ, while no differences could be found in the fasting state. In conclusion we could thus demonstrate that the frequency of PCOs in 27 % of epileptic women seems to be similar to that in the general population with a frequency of 20-30 %. The development of PCOs did not reveal a difference with the administration of VPA or CBZ. With respect to the metabolic side-effects of VPA therapy our data indicate that VPA increases glucose stimulated pancreatic insulin secretion, which might be followed by an increase in body weight.

Valproate, but not lamotrigine, induces ovarian morphological changes in Wistar rats

Valproate (VPA) medication is associated with development of polycystic ovaries, menstrual disorders and hormonal changes in women with epilepsy. We sought to determine if changes in the ovaries also occurred in an animal model without epilepsy, and whether this effect could be related to a carcinogenic effect expressed by overexpression of p53. A potentially alternative antiepileptic drug, lamotrigine (LTG), was evaluated simultaneously. To this end, female Wistar rats were fed perorally with VPA 400 mg/kg/day (n = 15), VPA 600 mg/kg/day (n = 20), LTG 10 mg/kg/day (n = 15) or control solution (n = 15) for 90-95 days. There was a significant, dose-dependent increase in the number of follicular cysts, reduction in the number of corpora lutea and reduction of ovarian weight in the VPA group. No ovarian pathology was observed in the LTG group. In neither of the groups were morphological changes seen in other organs, nor was there any overexpression of the tumor suppressor gene p53 found. An alternative antiepileptic drug, LTG, showed no ovarian pathology, and there were no light microscopic changes in other organs, or evidence of pathologic p53 overexpression in the LTG-treated animals.

The effect of seizures and kindling on reproductive hormones in the rat

Reproductive dysfunction and endocrine disorders are common among both women and men with epilepsy, and, in particular, with temporal lobe epilepsy. In clinical studies, it is hard to separate the effects of seizures from the effects of medication and life style. Studies in rodents, however, suggest that seizures per se can contribute to reproductive dysfunction. In female rats, generalized seizures disrupt normal ovarian cyclicity in adults, and repeated electroshock seizures delay the onset of puberty in juveniles. Right amygdala kindling in adult female rats causes acyclicity, the development of polycystic ovaries and premature aging of the hypothalamic-pituitary neuroendocrine axis, leading to chronic anovulation and continuous estrogen exposure. In adult male rats, repeated electroshock seizures result in transient hypogonadism, characterized by decreased serum testosterone levels and lowered gonadal tissue weight. In contrast, right amygdala kindling increases serum testosterone, estradiol levels and gonadal weight. These findings suggest that reproductive dysfunction in women and men with epilepsy may result from recurrent seizure activity, due to seizure-related interference with the normal functions of the hypothalamic-pituitary-gonadal axis.

Polycystic ovaries in adolescents and the relationship with menstrual cycle patterns, luteinizing hormone, androgens, and insulin

Study Objective: To evaluate the possible role of inappropriate LH secretion, hyperandrogenism, and hyperinsulinemia in the development of polycystic ovaries (PCO) and the polycystic ovary syndrome. Design: Observational. Setting: General population samples. Participants: 58 adolescents with regular menstrual cycles, 50 with irregular menstrual cycles, and 29 with oligomenorrhea (age 16.7 ± 0.9 years). Interventions: Transabdominal pelvic ultrasonography and vena puncture. Main Outcome Measures: PCO; LH, androstenedione, and testosterone levels; overnight fasting insulin concentrations; and oligomenorrhea. Results: The prevalence of PCO increased significantly with the irregularity of the menstrual cycle pattern, as illustrated by the study, finding PCO in 9% of the girls with regular menstrual cycles, 28% of those with irregular menstrual cycles, and 45% of oligomenorrheic girls. The LH and androgen concentrations were significantly higher in girls with PCO; the insulin levels and the glucose–insulin ratio did not differ when the girls with PCO were compared with girls with normal ovaries. Oligomenorrheic girls with PCO had the highest androgen and LH concentrations; their insulin concentrations and glucose–insulin ratio were in the same range as girls with regular menstrual cycles and normal ovaries; and both their hip and waist girths were wider, although their waist–hip ratio was normal. Conclusions: PCO in adolescents is associated with irregular menstrual cycles, oligomenorrhea, and/or high androgen and LH levels; but no relationship was found with the insulin level or glucose–insulin ratio. Thus, it is doubtful that hyperinsulinemia is an important factor in the development of PCO or polycystic ovary syndrome.

Estrogen: consequences and implications of human mutations in synthesis and action.

Recent developments have advanced our knowledge of the role of estrogen in the male. Studies of the mutations in CYP19, the gene encoding aromatase, in six females and two males and a mutant estrogen receptor alpha in a man are described. These observations provide illuminating new insights into the critical role of estrogen in the male (as well as female) in the pubertal growth spurt and skeletal maturation, and in the importance of estrogen sufficiency in the accrual and maintenance of bone mass. The weight of evidence supports an effect of androgens on the latter processes, but this effect has not been quantitated. There is a discordance in the estrogen-deficient male between skeletal growth and skeletal maturation and the accrual of bone mass and density. Estrogen synthesis by the testis is limited before puberty, and estrogen deficiency does not affect the age of pubertal onset. Estrogen deficiency in men leads to hypergonadotropism, macroorchidism, and increased testosterone levels. Estrogen lack has a significant effect on carbohydrate and lipid metabolism, and estrogen resistance was associated with evidence of premature coronary atherosclerosis in a man. These observations have highlighted the role of extraglandular estrogen synthesis and intracrine and paracrine actions. In the human, in contrast to nonprimate vertebrates, aromatase deficiency and estrogen resistance (alpha) does not seem to affect gender identity or psychosexual development. The clinical repercussions of mutations in CYP19 on the fetal-placental unit have highlighted the major role of placental aromatase in the protection of the female fetus from androgen excess, thus preventing androgen-induced pseudohermaphrodism and virilization of the mother. These features are compared with the virilization that occurs in utero in the female spotted hyena. The novel features of the aromatase deficiency syndrome in the affected female--in the fetus, during childhood, and at puberty--are discussed, including virilization at puberty and development of polycystic ovaries. The severity of the syndrome correlates with the severity of impairment of aromatase formation in expression systems. Finally, the structural consequences of missense mutations in CYP19 are described in accordance with a model of the structure of human aromatase.

Is valproate pharmacotherapy associated with polycystic ovaries?

To review and evaluate the published data associating the use of valproate with the development of polycystic ovaries. A computerized search of MEDLINE (1966-May 1999) and Current Contents was performed. Also, bibliographies were cross-referenced to yield additional pertinent publications. All articles written in English were considered for review. All pertinent clinical studies and review articles associating valproate with polycystic ovaries and other endocrinologic disorders were evaluated. Valproate is among the most commonly used medications today effective in the treatment of a variety of neurologic and psychiatric disorders. An accumulating body of literature has suggested an increase in the incidence of polycystic ovarian syndrome among women treated with valproate. The syndrome is characterized as hyperandrogenism and chronic anovulation in the absence of identifiable adrenal or pituitary pathology. It is a highly prevalent syndrome, affecting 2-22% of women in the general population. Although a number of studies have found clear evidence of neuroendocrine perturbations in patients treated with valproate, there are presently limited data from large controlled studies involving valproate monotherapy. Nonetheless, there appears to be a greater incidence of polycystic ovaries associated with valproate use in comparison with other anticonvulsants. The mechanism by which valproate may induce polycystic ovarian syndrome is unknown, but could possibly be secondary to valproate-induced weight gain or direct interference with steroid metabolism. Further study of the potential association of valproate treatment with the development of polycystic ovarian syndrome is warranted. Until the issue is clarified, clinicians should at least be aware of the possibility of valproate-induced polycystic ovarian syndrome and monitor patients accordingly.