Polycystic ovary syndrome (PCOS) is a common endocrinopathy characterized by increased ovarian androgen biosynthesis, anovulation, and infertility. PCOS has a strong heritable component based on familial clustering and twin studies. Genome-wide association studies (GWAS) identified several PCOS candidate loci including LHCGR, FSHR, ZNF217, YAP1, INSR, RAB5B, and C9orf3. We review the functional roles of strong PCOS candidate loci focusing on FSHR, LHCGR, INSR, and DENND1A. We propose that these candidates comprise a hierarchical signaling network by which DENND1A, LHCGR, INSR, RAB5B, adapter proteins, and associated downstream signaling cascades converge to regulate theca cell androgen biosynthesis. Future elucidation of the functional gene networks predicted by the PCOS GWAS will result in new diagnostic and therapeutic approaches for women with PCOS.

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Functional genomics of PCOS: from GWAS to molecular mechanisms.

We have found recently that exercise training is effective in the treatment of the postural orthostatic tachycardia syndrome (POTS). Whether this nondrug treatment is superior to "standard" drug therapies, such as β-blockade, is unknown. We tested the hypothesis that exercise training but not β-blockade treatment improves symptoms, hemodynamics, and renal-adrenal responses in POTS patients. Nineteen patients (18 women and 1 man) completed a double-blind drug trial (propranolol or placebo) for 4 weeks, followed by 3 months of exercise training. Fifteen age-matched healthy individuals (14 women and 1 man) served as controls. A 2-hour standing test was performed before and after drug treatment and training. Hemodynamics, catecholamines, plasma renin activity, and aldosterone were measured supine and during 2-hour standing. We found that both propranolol and training significantly lowered standing heart rate. Standing cardiac output was lowered after propranolol treatment (P=0.01) but was minimally changed after training. The aldosterone:renin ratio during 2-hour standing remained unchanged after propranolol treatment (4.1±1.7 [SD] before versus 3.9±2.0 after; P=0.46) but modestly increased after training (5.2±2.9 versus 6.5±3.0; P=0.05). Plasma catecholamines were not affected by propranolol or training. Patient quality of life, assessed using the 36-item Short-Form Health Survey, was improved after training (physical functioning score 33±10 before versus 50±9 after; social functioning score 37±9 versus 48±6; both P<0.01) but not after propranolol treatment (34±10 versus 36±11, P=0.63; 39±7 versus 39±5, P=0.73). These results suggest that, for patients with POTS, exercise training is superior to propranolol at restoring upright hemodynamics, normalizing renal-adrenal responsiveness, and improving quality of life.

Exercise Training Versus Propranolol in the Treatment of the Postural Orthostatic Tachycardia Syndrome

To evaluate gonadotropin release in polycystic ovary syndrome (PCO), one or more of the following hypothalamic-pituitary function tests were performed on 24 patients with the syndrome. These tests included (a) the pulsatile pattern and day-to-day fluctuation of gonadotropin release; (b) effects of exogenous estrogen and antiestrogen (clomiphene) administration on gonadotropin release; and (c) pituitary responsiveness to maximal (150 mug) and submaximal (10 mug) luteinizing hormone-releasing factor (LRF) injections. In 10 of the 14 patients sampled frequently (15 min) for 6 h, luteinizing hormone (LH) levels were elevated above the concentration seen in normal cycling women (except the LH surge). These high LH concentrations appeared to be maintained by and temporally related to the presence of exaggerated pulsatile LH release, either in the form of enhanced amplitude or increased frequency. In all subjects, levels of follicle-stimulating hormone (FSH) were low or low normal, and a pulsatile pattern was not discernible. In four patients, daily sampling revealed marked day-to-day fluctuation of LH but not FSH. That the elevated LH levels were not related to a defect in the negative-feedback effect of estrogen was suggested by the appropriate fall of LH in four patients given an acute intravenous infusion of 17beta-estradiol. This infusion had no effect on FSH levels. In addition, clomiphene elicited rises of both LH and FSH that were comparable to the ones observed in normal women given the same treatment. The clomiphene study also suggested that the positive-feed-back mechanism of estrogen on LH release was intact when the preovulatory rises of 17beta-estradiol induced appropriate LH surges. The elevated LH levels appeared to be related to a heightened pituitary responsiveness to the LRF. This was found in the 11 and 2 patients given maximal (150 mug) and submaximal (10 mug) doses of LRF, respectively. The augmented pituitary sensitivity for LH release correlated with the basal levels of both estrone (P less than 0.025) and 17beta-estradiol (P less than 0.02). The net increase in FSH was significantly greater (P less than 0.001) in the PCO patients than the normal women with maximal doses of LRF. With the smaller dose study none of the injections had a discernible effect on FSH concentrations in either subject. The disparity between LH and FSH secretion could be explained by the preferential inhibitory action of estrogen on FSH release, coupled with a relative insensitivity of FSH release. These data indicate that in these PCO patients the abnormalities of the hypothalamic-pituitary regulation of gonadotropin secretion was not an inherent defect but represented a functional derangement consequent to inappropriate estrogen feedback, which led to a vicious cycle of chronic anovulation and inappropriate gonadotropin secretion.

Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome

https://eprints.lib.hokudai.ac.jp/dspace/bitstream/2115/71600/3/ENVINT-D-15-01711R2%283%29%281%29-2.pdf

Association of perfluoroalkyl substances exposure in utero with reproductive hormone levels in cord blood in the Hokkaido Study on Environment and Children's Health.

Development and validation of LC-MS/MS method for quantification of bisphenol A and estrogens in human plasma and seminal fluid

The proposed hypothesis for this study was that seminal testosterone/estradiol levels and/or their ratios may be a good indicator for predicting normal spermatogenesis. The concentrations of estradiol and testosterone in seminal fluid were measured using competitive immunoassay techniques in specimens collected from 192 infertile patients and 103 normospermic men. Infertile patients were subdivided into three groups according to their semen analysis results and testicular biopsy: oligozoospermia, obstructive azoospermia (OA), and nonobstructive azoospermia (NOA). Results showed that seminal testosterone levels in the infertile groups were lower than in the normospermic individuals (P < .01), whereas seminal estradiol levels in the OA group were significantly higher than those in normospermic and NOA groups (P < .01). Testosterone/estradiol ratios in the seminal plasma from the infertile groups were significantly lower than that in the normospermic group (P < .01). However, seminal estradiol levels among normospermic and NOA groups showed no significant differences. These results suggest that the local balance between androgen and estrogen, or their ratios, may play an important role in maintaining normal spermatogenesis. Also, decreased seminal testosterone/estradiol ratio may be a good indicator for identifying the absence of sperm production in NOA patients.

Assessment of seminal estradiol and testosterone levels as predictors of human spermatogenesis.

High circulating luteinizing hormone (LH) level is a typical biochemical feature of polycystic ovary syndrome (PCOS) whose pathophysiology is still unclear. Certain mutations of LH and LH receptor (LHR) may lead to changes in bioactivity of these hormones. The aim of this study was determine the role of the LH and LHR polymorphisms in the pathogenesis of PCOS using a genetic approach. 315 PCOS women and 212 controls were screened for the gene variants of LH G1052A and LHR rs61996318 polymorphisms by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). PCOS patients had significantly more A allele frequency of LH G1052A mutations than controls (p=0.001). Within PCOS group, carriers of LH 1052A allele had lower LH (p=0.05) and higher fasting glucose levels (p=0.04). No subjects were identified with LHR rs61996318 polymorphisms. A new LHR single nucleotide polymorphism (SNP) was found without clear association with PCOS. Results suggested LH G1052A mutation might influence PCOS susceptibility and phenotypes.

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Association of the genetic variants of luteinizing hormone, luteinizing hormone receptor and polycystic ovary syndrome

OBJECTIVE Syncope is a common pediatric emergency. Based on an epidemiologic survey in the USA, around 15% of children experienced syncopal attack, which strongly influenced the life, study and hurt the children mentally and physiologically. Therefore, exploring the therapeutic regimen has become a hot topic in the field of pediatric cardiology. The aim of this study was to examine the effect of beta receptor blocker in the treatment of children with autonomous nerve mediated syncope. METHODS Totally 103 children (43 males, 60 females, age 5 - 19 yrs, median 12.0 +/- 2.6 yrs) with autonomous nerve mediated syncope from Beijing, Hunan, Hubei and Shanghai, were included in this study. Forty-nine of them suffered from vasovagal syncope (VVS) and 54 suffered from postural tachycardia syndrome (POTS). They were randomly divided into treatment group accepting oral metoprolol treatment and control group accepting oral rehydration salt treatment. The frequency of syncopal episodes and the outcome of head-up tilt (HUT) test were observed. SPSS 10.0 software was used for the statistical analysis of these data. RESULTS The cure rate of children who suffered from VVS and POTS and took oral metoprolol was 60.61% and 68.75%, respectively, but in the control group, the cure rate was only 18.75% and 0.00%, respectively. The rate of improvement of children who suffered from VVS and POTS and were treated with oral metoprolol was 15.15% and 15.63%, respectively, and in the control group, it was 6.25% and 40.91%, respectively. The effective rates for cases of VVS and POTS treated with oral metoprolol were higher than those of cases received oral rehydration salt treatment (P < 0.01). The percentage of the change from positive HUT to negative for children with VVS and POTS who took oral metoprolol therapy was 60.61% and 68.75%, respectively, but in control group, it was only 18.75% and 9.09%, respectively (P < 0.01). There was a significant difference in the percentage of the change from positive HUT to negative between children with VVS treated with oral metoprolol and with oral rehydration salt (P < 0.01). Also, a significant difference was found in the percentage of the change from positive HUT to negative between children with POTS treated with oral metoprolol and with oral rehydration salt (P < 0.01). CONCLUSION beta receptor blocker is effective in the treatment of children with VVS or POTS.

[A multicenter study on treatment of autonomous nerve-mediated syncope in children with beta-receptor blocker].

OBJECTIVE To investigate the value of hemodynamic changes during head-up tilt (HUT) test and predictive value thereof in evaluating the efficacy of metoprolol therapy in children with vasovagal syncope (VSS). METHODS Twenty-six consecutive children with history of VSS diagnosed by head-up tilt (HUT) or sublingual nitroglycerin potentiated head-up tilt (SNHUT), who were treated with metoprolol for 6 approximately 12 months and followed up for (18 +/- 9) months (12 approximately 36 months), were divided into two groups according to effect of metoprolol: effective treatment group (n = 16, aged 12 +/- 2) without VSS recurrence during treatment and fellow-up, and futile treatment group (n = 10, aged 12 +/- 3). The heart rate changes during HUT or SNHUT were evaluated between the two groups. RESULTS There were no significant differences between these 2 groups with regard to the demographic and clinical characteristics including age, gender, history, syncope spells, follow-up time and heart rate, mean blood pressure in supine position and during positive response. For example, the baseline heart rate of the effective treatment group was 81 +/- 12 beats/min, not significantly different from that of the futile treatment group (78 +/- 8 beats/min, P = 0.804). However, during tilt test 16 of the 26 patients in the effective treatment group showed tachycardia before positive response, with the mean heart rate of (123 +/- 15) beats/min, whereas all 10 patients in the futile group did not have tachycardia before positive response, with the mean heart rate of (96 +/- 17) beats/min. If an increase of 30 beats/min was taken as a borderline in heart rate during positive response in HUT compared with that of baseline value, in respect of predicting the metoprolol efficacy in the treatment of VVS, the sensitivity was 81% (13/16), the specificity was 80% (8/10), and the diagnostic value was 81% (21/26). CONCLUSION A marked increase in heart rate in HUT or SNHUT is a better predictor of metoprolol efficacy in the treatment of children with VVS.

[Hemodynamic changes during head-up tilt test and predictive value thereof in predicting the efficacy of metoprolol therapy in children with vasovagal syncope].

OBJECTIVE The study was designed to examine the effect of selective alpha1 receptor agonist midodrine hydrochloride in the treatment of children with postural orthostatic tachycardia syndrome. METHODS Fifty-five children (23 male, 32 female, age 5 - 19 yrs, mean age 12.3 +/- 3.1 yrs) who came from Peking University First Hospital were included in the study and clinical investigations as well as standing test, basic head-up tilt test and sublingual nitroglycerin-provocated head-up tilt test under quiet circumstance were conducted. They were randomly divided into treatment group (with midodrine hydrochloride and oral rehydration salt treatment) and control group (with oral rehydration salt treatment only). At last, the disease-free rate, improvement rate and effective rate of symptoms, and the rate of HUT from positive to negative response were compared between control group and treatment group. SPSS 10.0 software was used for the statistical analysis of these data. RESULTS The symptom improvement rate in treatment group was significantly higher than that of control group after three and six weeks of treatment (100.0% vs. 42.4%, P 0.05), but it was significantly different (81.0% vs. 48.5%, P < 0.05) after six weeks of treatment. CONCLUSION Selective alpha1 receptor agonist midodrine hydrochloride is effective in the treatment of children with postural orthostatic tachycardia syndrome.

Qiu-Fang Zhang

Papers

Assessment of seminal estradiol and testosterone levels as predictors of human spermatogenesis.

Association of the genetic variants of luteinizing hormone, luteinizing hormone receptor and polycystic ovary syndrome

[A multicenter study on treatment of autonomous nerve-mediated syncope in children with beta-receptor blocker].

[Hemodynamic changes during head-up tilt test and predictive value thereof in predicting the efficacy of metoprolol therapy in children with vasovagal syncope].

Effect of selective alpha1 receptor agonist in the treatment of children with postural orthostatic tachycardia syndrome