Relevance of augmented kisspeptin signaling through H364 KISS1R in central precocious puberty.

Understanding the pathophysiology of idiopathic central precocious puberty (ICPP) is essential, in view of its consequences on reproductive health and metabolic disorders in later life. Towards this, estimation of circulating levels of the neuropeptides, viz; Kisspeptin (Kp-10), Neurokinin B (NKB) and Neuropeptide Y (NPY), acting upstream to Gonadotropin-Releasing Hormone (GnRH), has shown promise. Insights can also be gained from functional studies on genetic variations implicated in ICPP. This study investigated the pathophysiology of ICPP in a girl by exploring the therapeutic relevance of the circulating levels of Kp-10, NKB, NPY and characterizing the nonsynonymous KISS1R variant, L364H, that she harbours, in a homozygous condition. Plasma levels of Kp-10, NKB and NPY before and after GnRH analog (GnRHa) treatment, were determined by ELISA. It was observed that GnRHa treatment resulted in suppression of circulating levels of Kp-10, NKB and NPY. Further, the H364 variant in KISS1R was generated by site directed mutagenesis. Post transient transfection of either L364 or H364 KISS1R variant in CHO cells, receptor expression was ascertained by western blotting, indirect immunofluorescence and flow cytometry. Kp-10 stimulated signalling response was also determined by phospho-ERK and inositol phosphate production. Structure-function studies revealed that, although the receptor expression in H364 KISS1R was comparable to L364 KISS1R, there was an enhanced signalling response through this variant at high doses of Kp-10. Thus, elevated levels of Kp-10, acting through H364 KISS1R, contributed to the manifestation of ICPP, providing further evidence that dysregulation of Kp-10/KISS1R axis impacts the onset of puberty.

Outcomes in neonates born to mothers with COVID-19 during the second wave in India.

COVID-19 pandemic has affected all age groups globally including pregnant women and their neonates. The aim of the study was to understand outcomes in neonates of mothers with COVID-19 during the first and second waves of COVID-19 pandemic. A retrospective analysis of 2524 neonates born to SARS-CoV-2-infected mothers was conducted during the first wave (n = 1782) and second wave (n = 742) of the COVID-19 pandemic at five study sites of the PregCovid registry in Maharashtra, India. A significant difference was noted in preterm birth, which was higher in the second wave (15.0%, 111/742) compared to the first wave (7.8%, 139/1782) (P < 0.001). The proportion of neonates requiring NICU admission was significantly higher in the second wave (19.0%, 141/742) as compared to that in the first wave (14.8%, 264/1782) (P < 0.05). On comparing regional differences, significantly higher neonatal complications were reported from Mumbai metropolitan region (P < 0.05). During the second wave of COVID-19, birth asphyxia and prematurity were 3.8- and 2.1-fold higher respectively (P < 0.001). Neonatal resuscitation at birth was significantly higher in second wave (3.4%, 25/742 vs 1.8%, 32/1782) (P < 0.05). The prevalence of SARS-CoV-2 infection in neonates was comparable (4.2% vs 4.6%) with no significant difference between the two waves. CONCLUSION: Higher incidence of adverse outcomes in neonates born to SARS-CoV-2-infected mothers in the second wave of COVID-19 as compared to the first wave. TRIAL REGISTRATION: PregCovid study is registered with the Clinical Trial Registry of India (CTRI/2020/05/025423, Registered on 28/05/2020). WHAT IS KNOWN: • The second wave of COVID-19 was more lethal to pregnant women than the first wave. Newborns are at risk of developing complications. WHAT IS NEW: • Birth asphyxia, prematurity, and neonatal resuscitation at birth were significantly higher in the second wave as compared to those in the first wave of the COVID-19 pandemic in India.

Protocol for a prospective, hospital-based registry of pregnant women with SARS-CoV-2 infection in India: PregCovid Registry study.

INTRODUCTION: Pregnant women are at increased risk of contracting COVID-19 due to several factors and therefore require special attention. However, the consequences of the COVID-19 pandemic on pregnant women and their newborns remain uncharted. The PregCovid registry aims to document the impact of SARS-CoV-2 infection on pregnant, postpartum women and their newborns. The aim of the registry is also to determine mother-to-child transmission of SARS-CoV-2 infection in India. METHODS AND ANALYSIS: PregCovid is a hospital-based registry for capturing information of pregnant, postpartum women with COVID-19 and their newborns in India. Medical case records of pregnant and postpartum women with a laboratory-confirmed diagnosis of COVID-19 will be captured in real-time using an online electronic patient record software. The data analysis will be carried out for symptoms, the severity of COVID-19, pregnancy complications, maternal morbidity and mortality, neonatal complications, mother-to-child transmission, etc. Data analysis will be carried out for different waves of the COVID-19 pandemic for rapid response and developing strategies well in advance to manage pregnant women infected with SARS-CoV-2. The evidence generated from the registry will be regularly shared with the appropriate authorities for policy decisions. Thus, the registry data may be useful for planning the strategies for better management of pregnant women with COVID-19. ETHICS AND DISSEMINATION: The study has been approved by the Institutional Ethics Committees of all the participating study sites under the Medical Education and Drugs Department, Government of Maharashtra, Topiwala National Medical College & BYL Nair Charitable Hospital, Mumbai and ICMR-National Institute for Research in Reproductive and Child Health, Mumbai, India. The results from this study will be disseminated with local, state, and national health authorities, collaborators and the general population on the study website (https://pregcovid.com) as well as dissemination through scientific meetings and publications. TRIAL REGISTRATION NUMBER: CTRI/2020/05/025423.

Clinical characteristics, outcomes, & mortality in pregnant women with COVID-19 in Maharashtra, India: Results from PregCovid registry.

Background & objectives: The PregCovid registry was established to document the clinical presentations, pregnancy outcomes and mortality of pregnant and post-partum women with COVID-19. Methods: The PregCovid registry prospectively collects information in near-real time on pregnant and post-partum women with a laboratory-confirmed diagnosis of SARS-CoV-2 from 19 medical colleges across the State of Maharashtra, India. Data of 4203 pregnant women collected during the first wave of the COVID-19 pandemic (March 2020-January 2021) was analyzed. Results: There were 3213 live births, 77 miscarriages and 834 undelivered pregnancies. The proportion of pregnancy/foetal loss including stillbirths was six per cent. Five hundred and thirty-four women (13%) were symptomatic, of which 382 (72%) had mild, 112 (21%) had moderate, and 40 (7.5%) had severe disease. The most common complication was preterm delivery (528, 16.3%) and hypertensive disorders in pregnancy (328, 10.1%). A total of 158 (3.8%) pregnant and post-partum women required intensive care, of which 152 (96%) were due to COVID-19 related complications. The overall case fatality rate (CFR) in pregnant and post-partum women with COVID-19 was 0.8 per cent (34/4203). Higher CFR was observed in Pune (9/853, 1.1%), Marathwada (4/351, 1.1%) regions as compared to Vidarbha (9/1155, 0.8%), Mumbai Metropolitan (11/1684, 0.7%), and Khandesh (1/160, 0.6%) regions. Comorbidities of anaemia, tuberculosis and diabetes mellitus were associated with maternal deaths. Interpretation & conclusions: The study demonstrates the adverse outcomes including severe COVID-19 disease, pregnancy loss and maternal death in women with COVID-19 in Maharashtra, India.

Differential impact of COVID-19 in pregnant women from high-income countries and low- to middle-income countries: A systematic review and meta-analysis.

BACKGROUND: SARS-CoV-2 has infected a large number of pregnant women. OBJECTIVE: To compare clinical, perinatal outcomes of women with COVID-19 from high-income countries (HICs) and low- to middle-income countries (LMICs). SEARCH STRATEGY: Online databases were searched. SELECTION CRITERIA: Original studies on pregnant women with COVID-19 were included. DATA COLLECTION AND ANALYSIS: Information on clinical presentation, co-morbidities, pregnancy outcomes, neonatal outcomes, and SARS-CoV-2 infection in neonates was extracted. MAIN RESULTS: The pooled estimate of SARS-CoV-2 positive neonates is 3.7%. Symptomatic presentations are less common in LMICs compared to HICs (odds ratio [OR] 0.38). Diabetes (OR 0.5), hypertension (OR 0.5), and asthma (OR 0.14) are commonly reported from HICs; hypothyroidism (OR 2.2), anemia (OR 3.2), and co-infections (OR 6.0) are commonly reported in LMICs. The overall risk of adverse pregnancy outcomes is higher in LMICs compared to HICs (OR 2.4). Abortion (OR 6.2), stillbirths (OR 2.0), and maternal death (OR 7.8) are more common in LMICs. Preterm births and premature rupture of membranes are comparable in both groups. Neonatal deaths (OR 3.7), pneumonia (OR 7.5), and neonatal SARS-CoV-2 infection (OR 1.8) are commonly reported in LMICs. CONCLUSIONS: In LMICs, pregnant women and neonates are more vulnerable to adverse outcomes due to COVID-19. PROSPERO registration no: CRD42020198743.

Clinical Characteristics, Management, and Short-Term Outcome of Neonates Born to Mothers with COVID-19 in a Tertiary Care Hospital in India.

INTRODUCTION: We describe the clinical characteristics, management, and short-term outcomes of SARS-CoV-2 neonates born to mothers with COVID-19 in a tertiary care hospital in Mumbai, India. METHODS: The study is a retrospective analysis of 524 neonates born to mothers with COVID-19 admitted from 14th April 2020 to 31st July 2020. RESULTS: SARS-CoV-2 infection was detected in 6.3% of the newborns of the mothers with COVID-19. No significant differences were observed between maturity at gestation, birth weight and sex of SARS-CoV-2 infected and noninfected newborns. The risk of sepsis was 4.09 [95% confidence interval (95% CI) 1.28-13.00] fold higher in the neonates with SARS-CoV-2 as compared to the noninfected group (p = 0.031). Poor feeding was significantly more common among SARS-CoV-2 infected neonates (12.1%) as compared to the noninfected neonates (2.7%) (p = 0.017). There was a total of 13 neonatal deaths, of which 3 deaths occurred in SARS-CoV-2 infected neonates (9%) while 10 (2.04%) in the SAR-CoV-2 negative group. The risk of neonatal death was higher in SARS-CoV-2 infected newborns [odds ratio (OR) 4.8; 95% CI 1.25-18.36]. CONCLUSION: Neonatal SARS-CoV-2 infection is observed in almost 6% of neonates born to mothers with perinatal COVID-19. There is a higher risk of adverse outcomes such as neonatal sepsis and death in the SARS-CoV-2 infected as compared to the noninfected neonates.

The current pandemic of COVID-19 has affected all the countries globally. However, the adverse impact of the pandemic is more seen in the low-income and middle-income countries (LMICs). Although there is evidence on the adverse impact of the SARS-CoV-2 on the health of mothers and neonates, the evidence is mainly from high-income countries. For reducing the mortality and morbidity due to COVID-19 in LMICs, there is a need to generate evidence from the LMICs. The present study is a part of the National Registry of pregnant women with COVID-19 in India (PregCovid registry). Our study demonstrates a higher risk of adverse outcomes such as neonatal sepsis and death in the SARS-CoV-2 infected as compared to the noninfected neonates. The study also showed the risk of SARS-CoV-2 infection in 6.3% of neonates born to mothers with COVID-19.

Clinical Presentations and Semen Characteristics of Men Attending the Secondary Referral Infertility Clinic at Mumbai, India.

BACKGROUND: Limited information is available on the aetiology and semen profiles of male infertility in Indian population. AIM: The aim of this study is to study the clinical and semen characteristics of men attending the infertility clinic and also to understand the impact of World Health Organization (WHO) 2010 reference values on the diagnosis of male infertility. SETTING AND DESIGN: A retrospective study evaluating the medical case records (January 2005 to December 2015, [n = 1906]) of men attending infertility clinic in Mumbai, India. MATERIALS AND METHODS: The aetiology was classified based on the andrology evaluation and other investigations. Semen profiles were compared during the years 2005-2010 and 2011-2015 using WHO 1999 and WHO 2010 criteria, respectively. STATISTICAL ANALYSIS: The Chi-square and Mann-Whitney U tests were performed using Open Source Epidemiological software and Social science calculators. RESULTS: The aetiology of male infertility was determined in 62% of the men; while the cause remained undetermined in 38%. Varicocele (25%), urogenital infections (10%), sexual dysfunctions (8%) and vas aplasia (8%) were identified as major aetiologies in our cohort. Men with sexual dysfunctions and vas aplasia were significantly higher during the years 2011-2015 as compared to 2005-2010. Men having normozoospermia (10%) and azoospermia (3%) were increased, whereas those having oligoasthenozoospermia (17%) were reduced in 2011-2015 as compared to 2005-2010. According to WHO 1999 criteria , 12-15% of men showed abnormal semen profiles. The semen parameters of these men became normal on using WHO 2010 reference values. CONCLUSIONS: Varicocele is the most common aetiology in infertile men. Idiopathic infertility was seen in a higher proportion among the infertile men.

Impact of SARS-CoV-2 on multiple gestation pregnancy.

OBJECTIVE: To assess clinical presentations, pregnancy complications, and maternal and neonatal outcomes among women with multiple gestation pregnancy (MGP) and confirmed SARS-CoV-2 (COVID-19) infection and to compare the data with a pre-pandemic period. METHODS: A retrospective study at a dedicated COVID-19 Hospital in Mumbai, India. Data were obtained from the PregCovid Registry of pregnant and postpartum women with PCR-confirmed SARS-CoV-2 infection from April to September, 2020. Data were also compared with a cohort of women with MGP attending the hospital pre-pandemic (n = 63). RESULTS: Data from 879 women (singleton pregnancy, n = 859; MGP, n = 20) with COVID-19 were assessed. The twinning rate was 34.2 per 1000 births. As compared with singleton pregnancies, a higher proportion of women with MGP and Covid-19 delivered preterm (P = 0.001). Spontaneous abortions were also higher in the MGP group than in the singleton group (P = 0.055). The incidence of pre-eclampsia/eclampsia was higher in the COVID-19 MGP group than in both the COVID-19 singleton (41.6% vs. 7.9%) and pre-pandemic MGP (50.0% vs. 12.7%) groups. CONCLUSION: There was a higher risk of pre-eclampsia among women with MGP and COVID-19. Women with MGP and COVID-19 infection should receive special attention with a multidisciplinary approach to both maternal and neonatal care during the pandemic.

HIV gp120 induced gene expression signatures in vaginal epithelial cells.

Gp120 is the envelope protein of HIV which binds to CD4 independent proteins on vaginal epithelial cells. HIV-gp120 has been reported to modulate gene expression in several cell types. How this interaction may alter the physiologic vaginal milieu during the earliest stages of vaginal transmission of HIV, is currently unknown. Vaginal epithelial cells were treated with HIV-gp120, and a global snapshot of changes in gene expression profiles, were unraveled by microarray analysis. The differentially expressed genes were involved in diverse cellular functions. Genes of immunomodulatory processes and induction of proteases were highly enriched. We propose that the induction of inflammation and proteases may act in concert to weaken the vaginal epithelium, making it more permeable to viral entry. Identification of the gene signatures involved in vaginal-HIV dialogue would aid in understanding the environ induced by HIV itself, as the virus invades and gains entry into its host.

AP-1 transcription factors, mucin-type molecules and MMPs regulate the IL-11 mediated invasiveness of JEG-3 and HTR-8/SVneo trophoblastic cells.

This study examines the IL-11 mediated activation of downstream signaling and expression of effector molecules to resolve the controversies associated with the IL-11 mediated regulation of the invasiveness of two commonly used trophoblastic cell models viz. JEG-3 and HTR-8/SVneo cells. It has been reported that IL-11 increases the invasiveness of JEG-3 cells while, reduces the invasiveness of HTR-8/SVneo cells. Invasion assay performed simultaneously for both the cell lines confirmed the above findings. In addition, HTR-8/SVneo cells showed a higher basal invasiveness than JEG-3 cells. Western blot showed the IL-11 mediated activation of STAT3(tyr705) and STAT1(tyr701) in both the cell lines. However, IL-11 activated the ERK1/2 phosphorylation in JEG-3 cells but, inhibited it in HTR-8/SVneo cells. Within 10 min of IL-11 treatment, p-STAT3(tyr705) was localized inside the nucleus of both the cell lines but, there was enhanced co-localization of protein inhibitor of activated STAT1/3 (PIAS1/3) and p-STAT3(tyr705) in HTR-8/SVneo cells and not in JEG-3 cells. This could be reason for the poor responsiveness of STAT3 responsive genes like mucin 1 (MUC1) in HTR-8/SVneo cells and not in JEG-3 cells. Further, microarray analysis of the IL-11 treated cells revealed differential responsiveness of JEG-3 as compared to HTR-8/SVneo cells. Several family of genes like activator protein-1 (AP-1) transcription factors (Jun and Fos), mucin-type molecules, MMP23B etc showed enhanced expression in IL-11 treated JEG-3 cells while, there was no response or decrease in their expression in IL-11 treated HTR-8/SVneo cells. Expression of these molecules was confirmed by quantitative RT-PCR. In addition, HTR-8/SVneo cells also showed a significant decrease in the expression of MMP2, MMP3 and MMP9 upon IL-11 treatment. Hence, IL-11 mediated differential activation of signaling and expression of effector molecules is responsible for the differential invasive response of JEG-3 and HTR-8/SVneo cells.

HIV gp120 binds to mannose receptor on vaginal epithelial cells and induces production of matrix metalloproteinases.

BACKGROUND: During sexual transmission of HIV in women, the virus breaches the multi-layered CD4 negative stratified squamous epithelial barrier of the vagina, to infect the sub-epithelial CD4 positive immune cells. However the mechanisms by which HIV gains entry into the sub-epithelial zone is hitherto unknown. We have previously reported human mannose receptor (hMR) as a CD4 independent receptor playing a role in HIV transmission on human spermatozoa. The current study was undertaken to investigate the expression of hMR in vaginal epithelial cells, its HIV gp120 binding potential, affinity constants and the induction of matrix metalloproteinases (MMPs) downstream of HIV gp120 binding to hMR. PRINCIPAL FINDINGS: Human vaginal epithelial cells and the immortalized vaginal epithelial cell line Vk2/E6E7 were used in this study. hMR mRNA and protein were expressed in vaginal epithelial cells and cell line, with a molecular weight of 155 kDa. HIV gp120 bound to vaginal proteins with high affinity, (Kd = 1.2±0.2 nM for vaginal cells, 1.4±0.2 nM for cell line) and the hMR antagonist mannan dose dependently inhibited this binding. Both HIV gp120 binding and hMR exhibited identical patterns of localization in the epithelial cells by immunofluorescence. HIV gp120 bound to immunopurified hMR and affinity constants were 2.9±0.4 nM and 3.2±0.6 nM for vaginal cells and Vk2/E6E7 cell line respectively. HIV gp120 induced an increase in MMP-9 mRNA expression and activity by zymography, which could be inhibited by an anti-hMR antibody. CONCLUSION: hMR expressed by vaginal epithelial cells has high affinity for HIV gp120 and this binding induces production of MMPs. We propose that the induction of MMPs in response to HIV gp120 may lead to degradation of tight junction proteins and the extracellular matrix proteins in the vaginal epithelium and basement membrane, leading to weakening of the epithelial barrier; thereby facilitating transport of HIV across the vaginal epithelium.

High-affinity binding of seminal plasma PSP94 to human immunoglobulin is through the Fab domain.

Prostate secretory protein of 94 amino acids (PSP94) is one of the major proteins present in human seminal plasma. We had earlier reported that PSP94 has the ability to bind to human IgG. The aims of the present study were to further delineate the PSP94-IgG interaction and to understand whether this could have any significance in sperm function. Direct binding of IgG fragments to PSP94 showed maximal binding with F(ab')(2) followed by Fab, while Fc displayed least binding in ELISA. Binding kinetics of PSP94-IgG interaction using surface plasmon resonance (SPR) revealed high-affinity binding of IgG to PSP94 with a dissociation constant (K(D)) of 8.8 x 10(-)(11)M. PSP94-IgG interaction was found to be through the Fab domains of IgG. Real-time interaction kinetics revealed association constants for binding of IgG, Fab, and F(ab')(2) towards PSP94 to be of the same order but with altered dissociation constants. IgG and its F(ab')(2) fragment once complexed to PSP94 demonstrated negligible dissociation, while dissociation rate of Fab fragment was 6.6 x 10(-)(4). In silico molecular modeling of PSP94-IgG complex identified N- and C-terminal beta-strands of PSP94 to be the most plausible region involved in IgG interaction. Immunofluorescence studies revealed that IgG bound to human spermatozoa predominantly in the tail region, which could be prevented when IgG was preincubated with PSP94. This study reports for the first time that IgG forms a high-affinity complex with PSP94 through its F(ab')(2) domain and reveals the ability of PSP94 to prevent binding of IgG to spermatozoa.

Follicle stimulating hormone receptor gene variants in women with primary and secondary amenorrhea.

PURPOSE: This retrospective study was designed to analyze the FSHR gene variants in subjects with primary and secondary amenorrhea with hypergonadotropic hypogonadism. MATERIALS AND METHODS: Eighty six women with primary or secondary amenorrhea and 100 normally cycling proven fertile women of Indian origin were retrospectively studied. These subjects were systematically screened for entire FSHR gene. RESULTS: The frequency distribution of polymorphism at -29 position of FSHR gene is altered in women with primary and secondary amenorrhea as compared to controls. AA genotype at -29 position of FSHR gene seems to be associated with increased serum FSH levels in the study subjects. We have identified a novel homozygous mutation C(1723)T (Ala(575)Val) in one woman with primary amenorrhea. CONCLUSIONS: Our findings suggest that increased serum FSH levels in subjects with primary amenorrhea correlated to FSHR genotype at position -29. We identified a novel homozygous mutation C(1723)T (Ala(575)Val) in a woman with primary amenorrhea.

Expression of endometrial protein kinase a during early pregnancy in bonnet monkeys (Macaca radiata).

Embryo-induced signaling pathways are considered to be important for initiation and sustenance of pregnancy. However many of these pathways remain to be deciphered in primates. In the present study, differential display RT-PCR was used to identify genes or gene fragments that are differentially expressed in endometrium of bonnet monkeys (Macaca radiata) on Day 6 of pregnancy. Of several fragments found to be differentially expressed, a fragment of 567 base pair (named GG1) was characterized in detail. GG1 was highly represented in endometrium of pregnant animals compared with that of nonpregnant animals. Sequencing analysis revealed homology of this fragment to exons 7, 8, 9, and 10 and surprisingly to intron 6 of cAMP-dependent protein kinase A (PKA) regulatory type I alpha (tissue-specific extinguisher 1) (PRKAR1A). The increased expression of this fragment in gestational endometrium was confirmed by quantitative PCR studies. Two transcripts of 3.0 kilobase (kb) and 1.5 kb were detected in Northern blot probed with labeled GG1. Protein expressions of alpha regulatory (PRKAR1A) and alpha catalytic (PRKCA) subunits of PKA were also higher in gestational endometrium compared with that in nongestational endometrium. Further in vitro studies using human endometrial explants demonstrated regulation of PRKAR1A (or GG1) and prostaglandin-endoperoxide synthase 2 or cyclooxygenase 2 (PTGS2) by estradiol. This is the first study to date on the differential expression of PKA in primate endometrium during early pregnancy and its in vitro regulation by estradiol.

Stage-specific localization and expression of c-kit in the adult human testis.

The c-kit receptor (KIT) and its ligand, stem cell factor (SCF), represent one of the key regulators of testicular formation, development, and function and have been extensively studied in various animal models. The present study was undertaken to characterize the pattern of localization and expression of c-kit in normal adult human testis. Immunohistochemical analysis showed that KIT is expressed in the cytoplasm of spermatogonia, acrosomal granules of spermatids, and Leydig cells. Interestingly, a rather heterogenous pattern of expression of the protein along the basement membrane was observed. Intense protein localization in spermatogonia was detected in stages I-III, whereas low expression was observed in stages IV-VI of the seminiferous epithelium, indicating that the expression of the molecule was stage specific. In situ hybridization studies revealed that the transcripts of the gene were also localized in a similar non-uniform pattern. To the best of our knowledge, such a stage-specific expression of KIT has not been reported previously in the human testis. The results of the present study may expand current knowledge about the c-kit/SCF system in human spermatogenesis.

Poor ovarian response to gonadotrophin stimulation is associated with FSH receptor polymorphism.

Similarities in the phenotype observed in women with FSH receptor mutation and in FSH receptor knockout mice have clearly established a critical role of this protein in normal gonadal function. Two common single nucleotide polymorphisms in the exonic region of the FSH receptor gene have been shown to be associated with altered ovarian response in subjects undergoing gonadotrophin treatment. Recent in-vitro studies have shown that the A allele at the -29 position in the 5 untranslated region of the FSH receptor gene is associated with impaired transcriptional activity. Differential expression of the FSH receptor and its function may be one of the factors responsible for altered ovarian response. These observations prompted a study of the association between FSH receptor genotype at the -29 position and ovarian response in women undergoing gonadotrophin treatment. Analysis of the data revealed that the subjects with AA genotype at the -29 position required the highest amount of exogenous FSH for ovulation induction, and oestradiol concentrations before the day of human chorionic gonadotrophin administration were significantly lower (P = 0.015) compared with the GA genotype. The number of pre-ovulatory follicles and retrieved oocytes were lowest in the subjects with AA genotype. These results indicate that the AA genotype at position -29 may be associated with the poor ovarian response.

Follicle-stimulating hormone receptor polymorphism (Thr307Ala) is associated with variable ovarian response and ovarian hyperstimulation syndrome in Indian women.

OBJECTIVE: To evaluate the association of FSH receptor polymorphism and ovarian response. DESIGN: Retrospective study. SETTING: Academic research institute and private IVF clinic. PATIENT(S): Fifty women were recruited in an assisted reproductive technology program (ART) and 100 proven fertile women of Indian origin. INTERVENTION(S): Polymerase chain reaction, restriction fragment-length polymorphism for detecting polymorphisms at T(307)A and N(680)S. MAIN OUTCOME MEASURE(S): FSH receptor polymorphisms, serum FSH, and estradiol levels, amount of FSH administered, occurrence of ovarian hyperstimulation syndrome (OHSS). RESULT(S): Prevalence of polymorphism at 307 position was 24%, 53%, and 23% in controls and 24%, 62%, and 14% in ART subjects for TT, TA, and AA, respectively, whereas at position 680, it was 31%, 56%, and 13% in controls and 42%, 46%, and 12% in ART subjects for NN, NS, and SS, respectively. The amount of FSH required for ovulation induction was low in AA compared with TT and TA subjects; the estradiol levels before and on the day of hCG administration were significantly higher. Eighty-five percent of the subjects with AA genotype developed OHSS. CONCLUSION(S): In Indian women, the subjects with AA genotype require low amounts of FSH for ovarian stimulation and have an increased risk of developing OHSS.