Endocrinological and Metabolic Heterogeneity Is Low in Japanese Women With Polycystic Ovary Syndrome.

OBJECTIVES: This study aims to evaluate the endocrine differences among polycystic ovary syndrome (PCOS) phenotypes in Japanese women. METHODS: 118 Japanese women that we diagnosed with PCOS agreed to be included in the study. The study group was classified into the following 4 phenotypes: (A) hyperandrogenism (HA); ovulatory disorder (OvD) and polycystic ovary morphology (PCOM); (B) HA and OvD; (C) HA and PCOM; and (D) OvD and PCOM. We also recruited 66 healthy Japanese women to the study as control participants. Age, body mass index, androgens, luteinizing hormone, follicle-stimulating hormone, and insulin resistance (IR) index were evaluated and compared. RESULTS: The proportions of phenotypes A, B, C, and D were 57/120 (47.5%), 4/120 (3.3%), 13/120 (10.8%), and 46/120 (38.3%), respectively. The proportion of phenotype B was too small; therefore, phenotypes A and B were grouped as classical PCOS for intergroup comparisons. The luteinizing hormone/follicle-stimulating hormone ratio in the classical PCOS group was higher than that in the phenotype D group (P < 0.001). Androgen concentrations in the phenotype D group were significantly lower than those in the other groups (P < 0.01). Phenotype D was more common in lean women with PCOS. The surrogate marker of IR (homeostasis model assessment of IR) was not different irrespective of PCOS and its phenotypes. CONCLUSIONS: Except for androgens, endocrine differences by PCOS phenotype are not evident, suggesting that diversity among patients with PCOS is relatively low in Japanese women.

Letrozole increases preantral follicle growth and decreases estradiol production without impairing follicle survival.

BACKGROUND: Letrozole has been reported to be effective in treating anovulation, preventing ovarian hyperstimulation syndrome (OHSS), and retrieving oocytes in breast cancer patients. However, the role and mechanism of letrozole in follicular development remain unclear. RESULTS: We treated mouse preantral follicles with various treatments; we found no significant difference in follicle survival rates in the letrozole (LET) group compared with the control group, but the average diameter of follicles in the LET group tended to be larger (CTRL vs. LET 30, p = 0.064; CTRL vs. LET 100, p = 0.025). The estradiol concentrations in culture media of the LET group were significantly lower than those observed in the control group (CTRL vs. LET 30, p = 0.038; CTRL vs. LET 100, p = 0.025). We further found a marked increase in follicle-stimulating hormone receptor (FSHR) gene expression in response to letrozole treatment (CTRL vs. LET 30, p = 0.075; CTRL vs. LET 100, p = 0.034). This result suggested that increased FSHR expression promotes follicle development. Letrozole inhibited aromatase activity, but the effect was limited. Letrozole did not significantly reduce vascular endothelial growth factor (VEGF) gene expression. CONCLUSIONS: Letrozole may promote follicle development by increasing the expression of FSHR. Letrozole may be useful for fertility preservation of patients with estrogen-dependent cancers such as breast cancer and various other cancers. Whether letrozole has a direct effect in reducing OHSS requires further investigation.

Pioglitazone suppresses excessive follicular development in murine preantral follicles.

Polycystic ovary syndrome (PCOS) is an endocrine disease that is common in women in their reproductive period. Patients with this disease suffer from anovulation and hyperandrogenism. Ovulation induction with exogenous gonadotropin often causes ovarian hyperstimulation syndrome because many small antral follicles pause in their growth. Treatment with insulin sensitizers is reportedly effective for both anovulation associated with PCOS, and suppression of excessive follicular growth; however, the underlying mechanism of action remains unknown. Although pioglitazone is known as an insulin sensitizer, it also has a potent modulator of cell growth and apoptosis irrespective of insulin resistance. To clarify the effect of pioglitazone on follicular growth, we performed in vitro culture of murine preantral follicles. Secondary follicles (100-160 µm in diameter) isolated from 6-week-old ICR mice were individually cultured for 13 days. Culture conditions were as follows: 1) follicle-stimulating hormone (FSH; 33 mIU/mL; control), 2) FSH plus dihydrotestosterone (DHT; 500 ng/mL), 3) FSH plus pioglitazone (5 ng/mL), and 4) FSH plus DHT/pioglitazone. Survival rate and follicle diameter were evaluated, and concentrations of estradiol (E2) and vascular endothelial growth factor (VEGF) in culture media were measured. mRNA expression of various growth-promoting factors and Vegf within follicles were also assessed. Although no significant differences were observed with regard to survival rate, follicle diameters on day 13 were significantly different.Compared with the control group, the DHT group showed enhanced growth, while groups administered pioglitazone showed stagnation of the accelerated growth induced by DHT. Although DHT treatment enhanced the expression of bone morphogenetic protein 2 (Bmp2) mRNA, pioglitazone exposure suppressed induction of Bmp2 mRNA by DHT. Vegf mRNA and protein expression were also significantly reduced when pioglitazone was added to culture media containing DHT.Administration of pioglitazone negatively affected follicular growth and VEGF levels, which may suppress excessive follicular growth and prevent ovarian hyperstimulation syndrome.

Androgen potentiates the expression of FSH receptor and supports preantral follicle development in mice.

Hyperandrogenism is one of the cardinal symptoms in polycystic ovary syndrome and plays a key role in the pathogenesis of polycystic ovary syndrome. However, the precise effects and mechanisms of excess androgen during follicular development are still unclear. Here we investigated the effects of androgen on mouse follicle development in vitro. Androgen did not affect the growth of follicles smaller than 160-180 µm in the presence of follicle-stimulating hormone (FSH). However, in the presence of low FSH, androgen supported the growth of follicles larger than 160-180 µm, a size at which growing follicles acquire FSH-dependency. Androgen did not change the mRNA expression of various growth-promoting factors but did increase mRNA expression of the FSH receptor. We suggest that androgen has a positive impact on follicle development by augmentation of the actions of FSH. Therefore, FSH-responsive but FSH-independent follicles grow in the presence of a certain level of FSH or androgen, and androgen compensates for FSH deficiency in FSH-dependent follicles.

Pioglitazone is effective for multiple phenotyepes of the Zucker fa/fa rat with polycystc ovary morphology and insulin resistance.

BACKGROUND: Hyperandrogenism and insulin resistance may be related to the etiology of PCOS. Zucker fa/fa rats with polycystic ovary are obese, have insulin resistance without diabetes mellitus or hyperandrogenism and can be utilized as PCOS model rats without effects of hyperandrogenemia. PCOS patients are reported to have elevated levels of serum anti-Mullerian hormone (AMH), which has an inhibitory action on folliculogenesis, and low levels of serum adiponectin, which blocks apoptosis and induces biological effects in some tissues. Pioglitazone, an insulin sensitizer, is administered to PCOS patients with insulin resistance to induce ovulation but the mechanisms by which this occurs have not been elucidated. METHODS: We purchased 4-week-old female fatty Zucker fa/fa rats as well as lean Zucker +/+ rats for use as control rats with normal insulin sensitivity. The Zucker fa/fa rats were administered pioglitazone (2.5 mg/kg body weight/day) or a vehicle every day for 14 days in separate groups. The Zucker +/+ rats were also administered the vehicle. After 2 weeks of treatment, they were euthanized and we obtained serum samples and both ovaries and determined the body weight, ovarian weight, and serum AMH, adiponectin, testosterone, and androstenedione levels. We also examined ovarian histology to check follicle numbers by using hematoxylin-eosin staining, and the number of atretic follicles using Tdt-mediated dUTP nick end labeling (TUNEL) methods. RESULTS: The Zucker fa/fa rats used as PCO model rats and Pioglitazone treated PCO model rats were significantly heavier than the Zucker +/+ control rats (p < 0.05) at 15 day old. Pioglitazone treatment did not influence body weight or ovarian weight in either group. However, the total number of follicles was significantly larger in the PCO model rats than in the control rats (P < 0.05). Although pioglitazone treatment appeared to decrease the total number of follicles in the PCO model rats, the decrease was not statistically significant. However, pioglitazone treatment significantly decreased the total number of atretic follicles and the rate of atreteic follicles in the PCO model rats (P < 0.05). The serum AMH level was significantly higher in the PCO model rats than in the control rats. Pioglitazone treatment significantly decreased the serum AMH level and significantly increased the serum adiponectin level in the PCO model rats (P < 0.05). Serum testosterone and androstenedione levels were quite low or undetectable in the 3 groups of rats, and were not influenced by pioglitazone treatment. CONCLUSION: In this study, pioglitazone treatment reduced the serum AMH level and increased the serum adiponectin level in PCO model rats. These effects are related to reduction of the total number of atretic follicles and rate of atretic follicles. This proves that pioglitazone treatment improves healthy follicle growth in these PCO model rats with insulin resistance.

Long-term treatment with dehydroepiandrosterone may lead to follicular atresia through interaction with anti-Mullerian hormone.

BACKGROUND: Hyperandrogenism is the primary manifestation of polycystic ovary syndrome (PCOS), which appears to be caused by excess exposure to androgen. As such, androgenized animal models have been developed and investigated to study the etiology of PCOS. Anti-Mullerian hormone (AMH) is known to be associated with follicle growth, and its levels are two to three times higher in women with PCOS than in those with normal ovaries. We studied how duration of androgen administration affects folliculogenesis and AMH expression. METHODS: We divided 30 immature (3-week-old) Sprague Dawley rats into six groups. Three groups were injected each evening with dehydroepiandrosterone (DHEA) (6 mg/100 g body weight/0.2 ml sesame oil) for 7, 15 or 30 days, respectively. The three control groups were injected with 0.2 ml of sesame oil for the corresponding lengths of time. Resected ovaries were sectioned and examined to determine follicle numbers at each developmental stage, and immunostained to assess AMH expression. RESULTS: On day 7, follicle numbers and AMH expression levels at each developmental stage of follicle growth were similar in the respective control and DHEA groups. On day 15, the total follicle number (P = 0.041), the percentage of primordial follicles (P = 0.039) and AMH expression were significantly greater in the DHEA than the control group. On day 30, the percentages of primordial (P = 0.005), primary (P = 0.0002) and atretic (P = 0.03) follicles were significantly greater in the DHEA group, whereas the percentage of intermediary follicles (early pre-antral, late preantral, and early antral follicles) was significantly lower in the DHEA group (P = <0.0001). AMH expression in DHEA-treated rats on day 30 was seen exclusively in the primordial (P = 0.0413) and late antral follicles (p = 0.028). CONCLUSIONS: Androgen administration increases AMH production in a process that regulates the growth of primordial follicles. That is, androgen-induced AMH expression provides local negative feedback to folliculogenesis augmented by androgen.

Continuous high-dose estrogen controls serum FSH and LH levels: new treatment strategy for extremely low ovarian reserve patients, two case reports.

At present, there are no proven therapies to improve ovarian function in women with premature ovarian insufficiency (POI) or in those with extremely low ovarian reserve (LOR). We report successful IVF outcomes achieved with continuous high-dose estrogen supplementation in patients with LOR. Patients were 33- and 42-year-old nulligravidae with high-serum FSH (over 30 IU/L) and undetectable serum AMH (under 0.1 ng/mL) levels; however, neither patient fulfilled the diagnostic criteria for POI. After cycle cancellation and unsuccessful IVF treatment, both patients received conjugated estrogen (CE) supplementation (2.5-3.75 mg/day) from day 2 of their menstrual cycle to the day of HCG administration in their IVF treatment cycles. Following continuous high-dose estrogen supplementation, oocytes were successfully retrieved from both patients and fertilized. Both patients also achieved ongoing pregnancy through frozen-thawed embryo transfer cycles. In conclusion, high-dose estrogen supplementation down-regulated serum FSH and LH within their physiological ranges, which led to functional follicle growth and prevented early luteinization. Further studies will be needed to confirm the effect of this treatment on POI patients and to establish a new and individualized protocol for LOR patients.

Assisted reproductive technique increases the risk of placental polyp.

The purpose of this study was to clarify the risk factors and outcomes of placental polyp. This retrospective study was conducted on 1645 patients delivered or aborted in Sapporo Medical University from 2007 through 2011. Transvaginal color Doppler ultrasonography, hysteroscopy, contrast-enhanced MRI or 3D-CT angiography were performed. There were 1532 deliveries and 113 abortions. Seventy-one (4.3%) were ART-conceived and the remaining 1574 (95.7%) were non-ART pregnancies. Fifteen (0.91%) cases were confirmed as having placental polyp. Nine cases of placental polyp were identified among the 1574 (0.57%) as non-ART-related pregnancies, and 6 were identified among the 71 (8.5%) as ART-related pregnancies. Thus, pregnancies achieved through ART showed 20x greater incidence of complicating placental polyp than pregnancies achieved through without ART (p = 9.02 × 10(-6); odds ratio, 19.59; 95% confidence interval, 5.27-72.84, logistic regression analysis). Evaluation of blood flow within the polyp showed that in five of seven patients with low blood flow, the polyps spontaneously dropped off 79-115 days postpartum. Thus, ART-related pregnancies may be a risk factor of placental polyp, and spontaneous drop-off of the polyp is often observed in cases with low blood flow within the mass.

Failure of GnRH agonist-triggered oocyte maturation: its cause and management.

OBJECTIVE: In the present study we investigated the cause of GnRHa's failure to trigger oocyte maturation and present an effective rescue protocol for use when failure occurs. DESIGN: Case reports. SETTING: One in vitro fertilization (IVF) center. PATIENT(S): Eight cases of failure of GnRH agonist (GnRHa)-triggered oocyte maturation and one case of GnRHa successfully triggered oocyte maturation, despite a weak response in the LH-RH test. MAIN OUTCOME MEASURE(S): All cases were successfully rescued by re-triggering maturation using HCG, with seven of the eight patients achieving ongoing pregnancy and successful delivery. RESULT(S): In three patients the cause of the oocyte maturation failure was likely temporal or continuous severe down-regulation of the hypothalamus-pituitary-axis, the cause was unknown in the other five patients. CONCLUSION(S): In cases where GnRHa fails to trigger oocyte maturation, a rescue protocol entailing re-triggering with HCG can produce successful outcomes.

Weight reduction and pioglitazone ameliorate polycystic ovary syndrome after removal of a Sertoli-stromal cell tumor.

This report presents an unusual case of Sertoli-stromal cell tumor and polycystic ovary syndrome successfully treated with weight reduction and an insulin-sensitizing agent. A 22-year-old woman, gravida 0, para 0, visited our hospital for the first time with a 12-year history of secondary amenorrhea and hypertrichosis. Transvaginal ultrasonography revealed a solid tumor in the right ovary. Right salpingo-oophorectomy was performed and pathological examination confirmed a Sertoli-stromal cell tumor. The patient's serum androgen levels declined postoperatively, but remained above normal. Pioglitazone treatment for 6 months also significantly reduced serum androgen levels, but they still remained above normal. However, after losing 12 kg of body weight, the patient's serum androgen levels declined to normal, and spontaneous menstruation became regular. Weight reduction with pioglitazone is an effective means of treating hyperandrogenism.

Continuous follicle-stimulating hormone exposure from pituitary adenoma causes periodic follicle recruitment and atresia, which mimics ovarian hyperstimulation syndrome.

CONTEXT: Follicle-stimulating hormone (FSH)-secreting pituitary adenoma is usually a nonfunctioning tumor, but in rare cases it may develop into ovarian hyperstimulation. Several reports have revealed that serum FSH levels are normal to slightly high in patients with combined FSH-secreting pituitary adenoma with ovarian hyperstimulation. This finding is different from iatrogenic ovarian hyperstimulation syndrome (OHSS), which is associated with extremely high levels of FSH. OBJECTIVE: To describe the clinical course of two patients who developed OHSS from FSH-secreting pituitary adenoma. RESULTS: Endocrine studies of the two cases revealed that FSH levels were normal or slightly increased, but luteinizing hormone levels were low to undetectable. Their estradiol (E2) levels were intriguing: levels fluctuated drastically over 6 weeks in Case 1, but stayed flat in Case 2. Ultrasonographic examinations showed bilaterally enlarged multicystic ovaries, and magnetic resonance imaging indicated pituitary tumors. Transsephenoidal resection of the tumors ameliorated the symptoms and pathological diagnosis revealed FSH-secreting pituitary adenomas. CONCLUSION: As is not the case in iatrogenic OHSS, even a small to moderate amount of FSH stimulation, which is continuously secreted by a pituitary adenoma, can cause ovarian hyperstimulation. Although FSH-secreting pituitary adenoma can cause ovarian hyperstimulation, an extremely high amount of E2 biosynthesis from granulosa cells seldom occurs.

Simultaneous presentation of tubal and primary abdominal pregnancies following clomiphene citrate treatment.

Abdominal pregnancy is a rare condition that is potentially life-threatening for the mother. We present a case of simultaneous ectopic pregnancies (EPs) in the right fallopian tube and in the vesicouterine pouch. A 26-year-old woman had undergone prior ovulation induction with clomiphene citrate and human chorionic gonadotropin (hCG) at an outside hospital for unexplained infertility. The patient was referred to our hospital for a suspected ectopic pregnancy at 6 weeks gestation. Transvaginal ultrasonography detected a viable fetus at the anterior left side of the uterus; therefore, we suspected a left tubal pregnancy. However, laparoscopic surgery revealed that EPs were located in both the left vesicouterine pouch and in the right fallopian tube. Resection of the right salpinx and abdominal implant were performed. Histopathological examination confirmed the simultaneous presentation of a primary abdominal pregnancy and a right tubal pregnancy. After surgery, the patient's serum hCG level returned to normal. Concurrent EPs and abdominal pregnancy are very rare. However, it should be noted that reproductive technologies sometimes cause unusual clinical situations. A thorough abdominal inspection is needed.

Different ovarian response by age in an anti-Müllerian hormone-matched group undergoing in vitro fertilization.

BACKGROUND: Recently, serum anti-Müllerian hormone (AMH) has been used as a good marker of ovarian response during in vitro fertilization (IVF). However, in the clinical setting, we felt that ovarian response was clearly different by age with the same AMH level. Then in this study we evaluated the relationship between serum AMH, age and parameters related to ovarian response and compared these parameters in regard to age within serum AMH-matched group. METHODS AND RESULTS: The relationship of these parameters were evaluated retrospectively in patients undergoing their first IVF cycle under a GnRH agonist flare up protocol (n = 456) between October 2008 and October 2010 in our clinic. To understand the relations between variables described above, principal component analysis (PCA) was performed. PCA revealed patients' age was at the different dimension from serum AMH and other variables. Therefore at first we segregated all patients into Low, Normal and High responder groups by their serum AMH using cut-off value of receiver operator characteristics curve analysis. Secondary, we divided each responder group into four subgroups according to patients' age. The high aged subgroups required a significantly higher dose of gonadotropin and a longer duration of stimulation; however, they had significantly lower peak E2 and a smaller number of total oocytes as well as M2 oocytes compared to the low aged subgroups. CONCLUSIONS: The influence of aging on the ovarian response was clearly seen in all groups; the ovarian response tended to decrease as patients' age increased with the same AMH level. Therefore serum AMH in combination with age is a better indicator than AMH alone.

Distinctive features of female-to-male transsexualism and prevalence of gender identity disorder in Japan.

INTRODUCTION: The prevalence of transsexualism is thought to differ among socio-geographic backgrounds, and little is known about its prevalence in Japan. Polycystic ovary syndrome (PCOS), which is known to be associated with insulin resistance and metabolic syndrome, is often seen in female-to-male (FTM) transsexual patients. Consequently, detection of PCOS is an important part of health care for these individuals. AIM: The purpose of this study was to assess the prevalence of transsexuality in Japan, as well as the incidences of PCOS and insulin resistance among Japanese FTM transsexual patients. METHODS: One hundred four male-to-female (MTF) and 238 FTM Japanese transsexual patients were studied. Medical histories, including histories of menstrual cycling and hormone treatment, were taken. To exclude other diseases, such as congenital adrenal hyperplasia and hormone-secreting tumors, thorough medical assessments, including transvaginal or transrectal ultrasonography and measurement of serum hormone levels and insulin resistance indexes, were performed. MAIN OUTCOME MEASURES: The diagnosis of PCOS was based on the Rotterdam 2003 criteria. RESULTS: Based on demographic statistics, the prevalences of MTF and FTM transsexuality are about 3.97 and 8.20 per 100,000 people, respectively, making the MTF-to-FTM ratio about 1:2. Of the FTM transsexual patients studied, 128 had not taken hormones before their initial assessment (untreated group); the remaining 50 self-administered androgen. Among the untreated group, 32.0% were diagnosed with PCOS, 30.1% were insulin-resistant, and 31.1% showed hypoadiponectinemia. CONCLUSIONS: The sex ratio among Japanese transsexuals is different than among Caucasians. PCOS and insulin resistance are common findings in FTM transsexual patients at initial presentation.

Remarkable features of ovarian morphology and reproductive hormones in insulin-resistant Zucker fatty (fa/fa) rats.

BACKGROUND: Zucker fatty (fa/fa) rats are a well-understood model of obesity and hyperinsulinemia. It is now thought that obesity/hyperinsulinemia is an important cause of endocrinological abnormality, but to date there have been no reports on the changes in ovarian morphology or the ovarian androgen profile in rat models of obesity and insulin resistance. METHODS: In this study we investigated the effects of obesity and hyperinsulinemia on ovarian morphology and the hormone profile in insulin-resistant Zucker fatty rats (5, 8, 12 and 16 weeks of age, n = 6-7). RESULTS: Ovaries from 5-week-old fatty rats had significantly greater total and atretic follicle numbers, and higher atretic-to-total follicle ratios than those from lean rats. Ovaries from 12- and 16-week-old fatty rats showed interstitial cell hyperplasia and numerous cysts with features of advanced follicular atresia. In addition, serum testosterone and androstenedione levels significantly declined in fatty rats from age 8 to 16 weeks, so that fatty rats showed significantly lower levels of serum testosterone (12 and 16 weeks) and androstenedione (all weeks) than lean rats. This may reflect a reduction of androgen synthesis during follicular atresia. Serum adiponectin levels were high in immature fatty rats, and although the levels declined significantly as they matured, it remained significantly higher in fatty rats than in lean rats. On the other hand, levels of ovarian adiponectin and its receptors were significantly lower in mature fatty rats than in lean mature rats or immature fatty rats. CONCLUSIONS: Our findings indicate that ovarian morphology and hormone profiles are significantly altered by the continuous insulin resistance in Zucker fatty rats. Simultaneously, abrupt reductions in serum and ovarian adiponectin also likely contribute to the infertility seen in fatty rats.

The contributions of resistin and adiponectin gene single nucleotide polymorphisms to the genetic risk for polycystic ovary syndrome in a Japanese population.

Polycystic ovary syndrome (PCOS) is a heterogeneous group of disorders that occur fairly commonly in women of reproductive age and are characterized by a variety of clinical manifestations, including insulin resistance that is independent of obesity. Recent studies suggest that altered adipocytokine gene expression is closely associated with insulin resistance and that single nucleotide polymorphisms (SNPs) modulate the expression and/or function of these genes, thereby affecting insulin sensitivity. With that in mind, we investigated whether SNPs at position -420 of the resistin gene (RETN) and/or -11377 of the adiponectin gene (ADIPOQ) modulate the susceptibility to PCOS. We evaluated the genotypes of 117 women with PCOS and 380 healthy fertile controls and measured the index of insulin resistance and hormonal profiles in the PCOS women. The RETN-420G/G homozygous variant genotype occurred significantly more frequently among the PCOS group than among the control group (15.4% vs. 8.4%, p = 0.035). PCOS women with the RETN-420G/G genotype also showed significantly higher BMIs and greater insulin resistance than those with RETN-420 C/C or C/G genotypes. The ADIPOQ SNP at -11377 showed no association with PCOS. We conclude that the RETN G/G at -420 genotype is associated with PCOS in Japanese women.

Polycystic ovary syndrome is associated with genetic polymorphism in the insulin signaling gene IRS-1 but not ENPP1 in a Japanese population.

Recent studies indicate that insulin resistance resulting from altered post-receptor signaling is associated with polycystic ovary syndrome (PCOS). We hypothesized that insulin receptor substrate-1 (IRS-1) Gly972Arg polymorphism and/or ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) Lys121Gln polymorphism predisposes women to PCOS and that these polymorphisms also affect anthropometric variables, glucose metabolism and androgen synthesis. To test those ideas, we studied the genotypes, indexes of insulin resistance, and hormone profiles in 123 Japanese women with PCOS and 380 healthy Japanese controls. We found that there were significantly more IRS-1 972Arg carriers among the PCOS patients than among the healthy controls (10.6% vs. 4.8%, p=0.029), which is consistent with our finding that women carrying the IRS-1 972Arg allele had a significantly increased risk of developing PCOS (odds ratio: 3.31, 95% confidence interval: 1.49-7.35). By contrast, the ENPP1 Lys121Arg polymorphism was distributed equally among PCOS patients and controls. In addition, neither of these polymorphisms studied affected the anthropometric variables, metabolic parameters or androgen levels of women with PCOS. We conclude that the IRS-1 Gly972Arg polymorphism is associated with PCOS in the Japanese population.

Association between polycystic ovary syndrome and female-to-male transsexuality.

BACKGROUND: The aim of this study is to understand the relationship between polycystic ovary syndrome (PCOS), altered hormonal characteristics and insulin resistance in female-to-male (FTM) transsexual patients. METHODS: We studied 69 Japanese FTM cases, aged 17-47 years, who were seen in the Gender Identity Disorder Clinic of Sapporo Medical University Hospital between December 2003 and May 2006. The subjects had never received hormonal treatment or sex re-assignment surgery. Prior to treatment, they received physical examinations entailing measurement of anthropometric, metabolic and endocrine parameters, after which we compared the values obtained according to the presence or absence of PCOS and/or obesity. Insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Of the 69 participating FTM cases, 40 (58.0%) were found to have PCOS. Of the 49 for whom HOMA-IR was calculated, 15 (30.6%) also showed insulin resistance, whereas of the 59 for whom adiponectin was measured, 18 (30.5%) showed hypoadiponectinaemia. Of 69 for whom androgens were measured, 29 (39.1%) showed hyperandrogenaemia. Insulin resistance was associated with obesity but not with PCOS. In contrast, hyperandrogenaemia was associated with both PCOS and obesity. CONCLUSION: FTM transsexual patients have a high prevalence of PCOS and hyperandrogenaemia.

Altered expression of Fas/Fas ligand/caspase 8 and membrane type 1-matrix metalloproteinase in atretic follicles within dehydroepiandrosterone-induced polycystic ovaries in rats.

One of the characteristics of polycystic ovary syndrome (PCOS) is the presence of cystic follicles in various stages of growth and atresia, the latter of which is known to be the result of apoptosis and tissue remodeling. To further investigate the process of follicular atresia, we compared ovarian expression and localization of Fas, Fas ligand (FasL), casapse-8 and membrane-type1 matrix metalloproteinase (MT1-MMP) in rats treated with dehydroepiandrosterone (DHEA) as a model of PCOS, and in control rats. We found that the numbers of TdT-mediated dUTP-biotin nick end-labeling (TUNEL)-positive follicles were significantly higher in ovaries from PCOS rats than in those from control rats (P < 0.05), as were ovarian levels of FasL mRNA and protein, processed caspase-8 protein and MT1-MMP mRNA. Correspondingly, we also observed an increase in the level of MTI-MMP catalytic activity and a decrease in the level of pro-caspase-8 protein. In addition, immunohistochemical analyses showed that MT1-MMP and FasL co-localize with TUNEL-positive apoptotic granulosa cells within atretic follicles of PCOS ovaries. Our results suggest that under the PCOS-like conditions induced by DHEA, the Fas/FasL/Caspase-8 (death receptor dependent) pathway is pivotal for follicular atresia, and that increased levels of MT1-MMP likely play an important role in tissue remodeling during structural luteolysis.