Follicle-stimulating hormone receptor (FSHR) polymorphisms and polycystic ovary syndrome (PCOS)

23 07 2009

To the Editor:

We were very pleased to read the recent report by Achrekar et al., in which the authors studied the association between the FSHR gene and occurrence of ovarian hyperstimulation syndrome (OHSS) in Indian patients (1). We would like to make some comments.

It has been reported that follicle-stimulating hormone (FSH) is associated with reproduction in both females and males, and with diverse diseases (2, 3). FSH is difficult to study because its levels fluctuate depending on the individual’s condition. Therefore, many studies have been performed through genetic analyses, including a single nucleotide polymorphisms (SNP) study (4). The authors also designed an SNP study using the restriction fragment-length polymorphism (RFLP) method to identify the FSHR gene polymorphisms at codons 307 and 680.

Regarding the polymorphisms, many studies have reported that Ala was changed to Thr by G-to-A nucleotide substitution at the 307 codon (Ala307Thr) and that Ser was changed to Asn by G-to-A nucleotide substitution at the 680 codon (Ser680Asn) in the polymorphism of the FSHR gene (5-8). We recently confirmed each variant for the two polymorphisms of FSHR by direct sequence for the disease we are studying. However, in this study, authors reported the A-to-G nucleotide substitution (Thr307Ala) and the A-to-G nucleotide substitution (Ser680Asn) of the FSHR gene, respectively. Furthermore, the authors mentioned that the polymorphism of FSHR at codon 307 is located at a different nucleotide number (978 instead of 919) (Accession No. NM_000145), which is not a right position for Thr or Ala.

We believe that this study is important based on the fact that patients with the specific genotype for FSHR have more susceptibility to OHSS development and will contribute to further diagnostic study. Therefore, accurate information including association possibility is required.

Bon-Hee Gu, M.Sc.
Kwang-Hyun Baek, Ph.D.
Department of Biomedical Science
Fertility Center
CHA University
CHA General Hospital,
Seoul, Korea

References
1. Achrekar SK, Modi DN, Desai SK, Mangoli VS, Mangoli RV, Mahale SD. Follicle-stimulating hormone receptor polymorphism (Thr307Ala) is associated with variable ovarian response and ovarian hyperstimulation syndrome in Indian women. Fertil Steril 2009;91:432-9.

2. Kwok HF, So WK, Wang Y, Ge W. Zebrafish gonadotropins and their receptors: I. Cloning and characterization of zebrafish follicle-stimulating hormone and luteinizing hormone receptors–evidence for their distinct functions in follicle development. Biol Reprod 2005;72:1370-81.

3. Yamamura N, Takeishi M, Goto H, Tagami M, Mizutani T, Miyamoto K, et al. Expression of messenger RNA for gonadotropin receptor in the granulose layer during the ovulatory cycle of hens. Comp Biochem Physiol, Part A Mol Integr Physiol 2001;129:327-37.

4. Simoni M, Tempfer CB, Destenaves B, Fauser BC. Functional genetic polymorphisms and female reproductive disorders: Part I: Polycystic ovary syndrome and ovarian response. Hum Reprod Update 2008;14:459-84.

5. d’Alva CB, Serafini P, Motta E, Kohek MB, Latronico AC, Mendonca BB. Absence of follicle-stimulating hormone receptor activating mutations in women with iatrogenic ovarian hyperstimulation syndrome. Fertil Steril 2005;83:1695-9.

6. Ferlin A, Pengo M, Selice R, Salmaso L, Garolla A, Foresta C. Analysis of single nucleotide polymorphisms of FSH receptor gene suggests association with testicular cancer susceptibility. Endocr Relat Cancer 2008;15:429-37.

7. Nakamura Y, Maekawa R, Yamagata Y, Tamura I, Sugino N. A novel mutation in exon8 of the follicle-stimulating hormone receptor in a woman with primary amenorrhea. Gynecol Endocrinol 2008;24:708-12.

8. Valkenburg O, Uitterlinden AG, Piersma D, Hofman A, Themmen AP, de Jong FH. Genetic polymorphisms of GnRH and gonadotrophic hormone receptors affect the phenotype of polycystic ovary syndrome. Hum Reprod 2009; in press.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.07.1011

The Authors Respond:

We thank Bon-Hee Gu and Kwang-Hyun Baek for their interest in our paper published in Fertility and Sterility (1).

We agree that in the FSHR gene at the 307 position, Ala is changed to Thr as a result of nucleotide change from G to A. In figure 1B, we have shown that when it is Thr (labeled as TT), the corresponding nucleotide is A, and in the case of Ala (labeled as AA) the corresponding nucleotide is G. We also agree that the polymorphism at the 307 position (Thr/Ala) is located at 919 nucleotide position and not at 978 as reported in the paper. This was due to typographic error.

In the case of FSHR polymorphism at position 680, we wish to clarify that the electropherogram shown in Figure 2B is from 3′ to 5′ direction. In case of Asn the corresponding nucleotide is T (which corresponds to A in 5′ to 3′ direction), and for Ser the corresponding nucleotide is C (which corresponds to G in 5′ to 3′ direction).

Smita D. Mahale, Ph.D.
National Institute for Research in Reproductive Health
Mumbai, India

Reference
1. Achreker SK, Modi DN, Desai SK, Mangoli VS, Mangoli RV, Mahale SD. Follicle-stimulating hormone receptor polymorphism (Thr307Ala) is associated with variable ovarian response and ovarian hyper stimulation syndrome in Indian women. Fertil Steril 2009; 91:432-9.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.07.1012

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