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The aim of the present study is to investigate whether the low circulating systemic Anti-Müllerian hormone (AMH) can be a biomarker to diagnose Premature Ovarian Failure (POF) and used as a prognostic tool to predict POF in southern Indian women. A case-control study conducted in 150 subjects by enrolling 75 POF patients and 75 healthy controls from June, 2012 through November, 2014. Hormonal profile of AMH and FSH levels were assayed and correlated with age. Patients and controls were categorised into three age groups GroupI (17-24 years), GroupII (25-32 years) and GroupIII (33-39years). Results revealed that the mean age at onset of the patients was 26.14 ± 5.74 years. Seven percent of the patients were with family history of infertility, in whom 80% showed undetectable AMH levels (<0.029ng/ml). Significantly decreased AMH levels were recorded in patients than controls (0.05±0.10ng/ml, range 0-0.6ng/ml vs 2.60±0.95ng/ml, range 0.8-4.2ng/ml; p<0.001) suggesting the low ovarian reserve in POF women. The AMH levels in both patients and controls were negatively correlated with their age, whereas, a week positive correlation was observed between FSH and AMH levels (p<0.05). Age stratified data proved that irrespective of age POF women have very low/undetectable AMH levels. Our findings suggest that AMH is a potential biomarker for POF and the patients with family history of infertility are prudent to estimate their AMH levels at an early age for further implementation of pregnancy strategies. To support our results from this preliminary study among south Indian women, further studies are warranted with large sample size to implement in the reproductive medicine.
Age stratification, Anti-Müllerian Hormone, Family History of Infertility, Ovarian Reserve Premature Ovarian Failure, South India
Premature ovarian failure (POF) is one of the infertility associated endocrine disorders characterised by the loss of functional ovarian follicles during the reproductive age that affects 0.9-2% of females prior to 40 years and 0.1% of women before 30 years [1,2]. Till date, the cause for POF is largely unexplained; however, various rationales based on iatrogenic, infections, autoimmunity, X-chromosome abnormalities and autosomal genetic conditions have been advanced to explain this heterogeneous condition . The condition occurs in 10-28% of women with primary amenorrhoea and 4-18% in those with secondary amenorrhoea . The disease is idiopathic in 90% of cases but can be familial (4-33%) or sporadic . Idiopathic POF represents the most extreme phenotype of diminished ovarian reserve (OR) at younger age. Clinically, POF is recognized as secondary amenorrhoea lasting for at least 4-6 months with Follicle stimulating hormone (FSH) levels exceeding 40 IU/l before 40 years. It is a complicated multifactorial disorder that hampers the fertility potential of younger women years before normal menopause and generally characterised by decreased Anti-Müllerian hormone (AMH) secretion . Infertility, the most distressing consequence of POF is associated with diminished OR, and women with family history of infertility might be at risk in the predisposition of this clinical condition at an early age. Prediction of OR has long been the best tool through various endocrine [FSH, AMH, inhibin-B, estradiol etc] and ultrasound [ovarian volume, antral follicle counts (AFCs)] tests to clinically assess fertility potential, guide infertility treatment and also to estimate time to the final menstrual period . AMH is a paracrine modulator of follicular development and dominant follicle selection produced by ovarian granulose cells . The hormone originally known to inhibit the development of Mullerian ducts in male embryos and also proved to be an excellent marker in assessing OR in women .
The AMH, also known as Mullerian Inhibiting Substance (MIS) is a glycoprotein and a member of the transforming growth factor-β family produced by granulosa cells of preantral and small antral follicles. Serum AMH levels rise in the weeks following birth and reach its highest level after puberty . Studies reported that AMH is expressed only in healthy follicles; whereas, the levels decline with increasing age in women over 25 years, disappear at menopause, and correlate with the number of remaining primordial follicles [11-13]. In addition to the support that AMH gained from several studies as a good predictor of OR, the circulating AMH serum levels exhibit less intra and intercycle fluctuations .
It has been stated in the literature that the mean of AMH levels differ among races and ethnicities . The cut-off values of AMH levels found in various studies differ between 0.1 and 2.97 ng/ml (0.7 and 20 pmol/l) for low response to ovarian hyperstimulation . Hence, improving our understanding of racial differences in ovarian reserve and their underlying causes may be essential for timely interventions which may prolong reproductive lifespan in women. The follicle populations as well as the serum AMH levels change with advancing age, therefore we expect AMH may differently reflect the OR at different age groups. The present study focuses to estimate and analyse age related AMH levels among POF patients and controls. The significance in estimating the AMH levels at different age groups may provide vital information in the fertility treatment strategies. There have been various national and international studies that reported low serum AMH levels in sub-fertile women , PCOS women , POF women  and women carrying Fragile X mental retardation gene 1 (FMR1) CGG permutation allele , compared to normal menstruating females. However, AMH based reports in relation to POF conditions are not to be found among south Indian women.
In the light of literature support, for the first time from southern India we conducted a case-control study to investigate whether AMH could be considered as a prognostic biomarker of functional OR in POF patients. Further, we hypothesise that family history of infertility may be considered as one of the characteristic features to predict POF in the family. Our results may help the clinicians to provide necessary management to south Indian POF patients in the reproductive treatment.
For the first time from south India the present study deals with the assessment of AMH levels in POF women and healthy controls. The outcome of our preliminary study with limited samples, certainly suggested that AMH could be considered as a better future marker by the clinicians to assess OR in the fertility treatment options. Comparatively, patients showed significant high FSH and low AMH levels
than controls. The age stratified data with varying levels of AMH in younger and older group of patients, could be explained by the ovarian heterogeneity at extreme age groups that might be genetically predetermined. AMH is a marker for predicting the earliest signs of POF rather than the onset of infertility among women with family history of infertility. To address the epidemic of infertility, if a woman is offered an indication of her OR at an early stage through AMH estimation, pregnancy may still be viable to the patient perhaps with suitable assisted reproductive technique. Based on our findings, we also propose that future studies should involve various familial factors including familial infertility in causing the POF condition on par with hormonal estimation to recognize persistent follicles and to decide on quick management strategies. However, the results showed and the suggestions made in our study should be viewed with caution and replicated in large samples before implementing clinically. Results obtained from control data can be exploited by future studies that involve AMH levels to predict the OR in south Indian women which facilitate reproductive life planning.
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