Objective: Polycystic ovary syndrome (PCOS) is a multigenic disorder, and insulin resistance is one of its hallmark features. Polymorphisms in exon 17 of insulin receptor (INSR) gene are reported to be associated with PCOS. We investigated this association in Indian women and its putative relationship with PCOS associated traits, which has not been explored so far. Methods: In this case control study, the polymorphisms were investigated by direct sequencing in 180 women with PCOS and 144 age matched controls. Clinical, anthropometric, biochemical, and hormonal parameters were also estimated. Results: The silent C/T polymorphism at His1058 in exon 17 of INSR was found to be present in our study population. The polymorphic genotype (CTCTT) was significantly associated with PCOS in lean women (c 2 Z8.493, dfZ1, PZ0.004). It showed association with higher fasting insulin levels (PZ0.02), homeostasis model assessment of insulin resistance (PZ0.005), free androgen index (PZ0.03), and lower quantitative insulin sensitivity check index (PZ0.004) in lean PCOS women. No other novel or known polymorphism was identified in exon 17 in this cohort. Conclusions: The study shows significant association of C/T polymorphism at His1058 of INSR with PCOS in the lean rather than obese Indian women. Its association with indices of insulin resistance and hyperandrogenemia is also seen in the same group. The findings strengthen the concept that pathogenesis of PCOS is different in lean and obese women.

The genetic basis of infertility has received increasing recognition in recent years, particularly with the advent of assisted reproductive technology. It is now becoming obvious that genetic etiology for infertility is an important cause of disrupted spermatogenesis. Y-chromosome microdeletions and abnormal karyotype are the two major causes of altered spermatogenesis. To achieve biological fatherhood, intracytoplasmic sperm injection (ICSI) is performed in cases of severe infertility with or without genetic abnormalities. There is a concern that these genetic abnormalities can be transmitted to the male progeny, who may subsequently have a more severe phenotype of infertility. A total of 200 men were recruited for clinical examinations, spermiograms, hormonal profiles, and cytogenetic and Yq microdeletion profiles. Testicular biopsy was also performed whenever possible and histologically evaluated. Genetic abnormalities were seen in 7.1% of cases, of which 4.1% had chromosomal aberrations, namely Klinefelter's mosaic (47XXY) and Robertsonian translocation, and 3.0% had Yq microdeletions, which is very low as compared to other populations. Follicle stimulating hormone (FSH) and luteinizing hormone (LH) were significantly increased in men with nonobstructive azoospermia (NOA) as compared to severe oligoasthenozoospermia (Po0.0001), whereas testosterone levels were significantly decreased in men with microdeletions as compared to men with no microdeletions (Po0.0083). Low levels of androgen in men with microdeletions indicate a need to followup for early andropause. Patients with microdeletions had more severe testicular histology as compared to subjects without deletions. Our studies showed a significant decrease (Po0.002) in the serum inhibin B values in men with NOA, whereas FSH was seen to be significantly higher as compared to men with severe oligoasthenozoospermia (SOAS), indicating that both the Sertoli cells as well the germ cells were significantly compromised in cases of NOA and partially affected in SOAS. Overall inhibin B in combination with serum FSH would thus be a better marker than serum FSH alone for impaired spermatogenesis. In view of the genetic and hormonal abnormalities in the group of infertile men with idiopathic severe oligozoospermia and NOA cases, who are potential candidates for ICSI, genetic testing for Y-chromosome microdeletions, karyotype, and biochemical parameters is advocated.

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The effects of melatonin on steroidogenesis and gene expression of CYP 11A, CYP 17, and CYP 19 were investigated using a porcine antral follicle culture model. Follicles were cultured with melatonin at doses of 10, 50, and 100 ng/mL in the presence and absence of an optimum dose of luteinizing hormone (LH) (100 ng/mL) for a period of 30 hours. It was found that melatonin stimulated progesterone production both in the presence and absence of LH. Androstenedione production was stimulated by melatonin at the highest dose of 100 ng/mL but melatonin had an inhibitory effect in the presence of LH. Estradiol production was not affected by melatonin alone, while in the presence of LH it showed a bimodal effect. Expression of genes for steroidogenic enzymes specific for the production of progesterone, androstenedione and estradiol (CYP 11A, CYP 17, and CYP 19, respectively) were also analyzed in the theca of follicles cultured with and without LH. Results showed an inhibition of CYP 11A and CYP 17 expression both in the presence and absence of LH. However, the expression of CYP 19 was not affected. Our results indicate that melatonin modulates ovarian theca cell steroidogenesis at the molecular level and this modulation may be mediated by its effects on the transcriptional activity of the steroidogenic enzymes.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Isoniazid is the most widely used first line antituberculosis drug.• It is considered safe during lactation, but limited data are available on the transfer of isoniazid from circulation to milk in lactating women, which can provide an assessment of extent of exposure to the nursling. WHAT THIS STUDY ADDS• The study documents the transfer pattern and milk to plasma (M : P) ratio of isoniazid at a steady state.• Peak plasma and milk concentrations of isoniazid were reached within 1 h and the projected exposure of the drug to the infant is much lower than the prophylactic dose, supporting its safety during breast feeding. AIMTo determine milk to plasma (M : P) ratios and infant dose (absolute and relative) for isoniazid in lactating women on antituberculosis therapy. METHODSConcentrations of isoniazid in plasma and milk were measured in exclusively breast feeding women taking 300 mg day -1 as treatment for tuberculosis. RESULTSPeak plasma and milk concentrations of isoniazid were observed at 1 h. A mean M : PAUC value of 0.89 (95% CI 0.7, 1.1) was calculated for isoniazid from seven women over 24 h. The mean absolute infant dose was estimated to be 89.9 mg kg day -1 (95% CI 65.6, 114) and the relative infant dose was 1.2% of the weight adjusted maternal dose. CONCLUSIONSThe mean relative dose of isoniazid (1.2%) transmitted to the infant via breast milk is below the 10% notional level of concern. These data suggest that isoniazid therapy is safe during breastfeeding.

Progesterone has been implicated in the process of spermatogenesis. This study aimed to investigate the association of progesterone receptor (PR) expression with spermatogenesis in the testis of infertile men. PR mRNA and protein were assessed by in-situ hybridization and immunohistochemistry in testicular biopsies obtained from 18 infertile men. The extent of spermatogenesis was assessed by Johnsen scoring. None of the patients included in the study had Yq microdeletions. PR expression was almost undetectable in all the testicular sections displaying Sertoli cell only (SCO) or arrest at spermatogonia. Weak cytoplasmic expression was observed in biopsies showing arrest at different stages of meiosis. In biopsies displaying spermatogenesis up to the round spermatid stages, PR expression was observed in both nucleus and cytoplasm of different cell types at intensity lower than that detected in normal biopsies. Normal PR expression was observed in biopsies demonstrating hypospermatogenesis. In biopsies showing mixed phenotypes, the tubules with SCO or spermatogonia arrest showed absence of PR expression; normal PR expression was observed in adjacent tubules showing complete spermatogenesis. Semi-quantitative assessment of PR expression and Johnsen scores in the testicular biopsies of infertile men demonstrating different phenotypes indicated a direct relationship between PR expression and extent of spermatogenesis.

The CGG repeat stretch in the FMR1 gene is polymorphic, ranging from 5 to 50 repeats in the normal population. Expansion of the repeats to the premutation range (50-200) has been associated with premature ovarian failure (POF). This case-control study was conducted to enumerate CGG repeats in the FMR1 gene in 80 Indian women with non-familial, non-syndromic POF, and 70 controls from the same ethnicity. A possible association between CGG repeats and endocrine profile of these cases was investigated. All patients and controls had CGG repeats in the normal polymorphic range. Serum FSH concentrations were significantly raised in both POF cases and controls having CGG repeats in the 31-40 repeats range (P < 0.0001). POF cases and controls had FSH concentrations of 133.7 versus 84.2 mIU/ml and 16.0 versus 6.2 mIU/ml for >30 repeats versus <30 repeats respectively. Inhibin B concentrations were not associated with CGG repeats. The results of this study indicate that FMR1 premutations are rare in sporadic cases of POF with no family history of fragile X syndrome. However, although in the normal polymorphic range, expansion of the CGG repeat tract to beyond 30 repeats was associated with serum FSH concentrations in both POF cases and controls.