Hum. Reprod. Advance Access originally published online on September 30, 2005
Human Reproduction 2006 21(2):443-446; doi:10.1093/humrep/dei317
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The distribution of FSH receptor isoforms is related to basal FSH levels in subfertile women with normal menstrual cycles
1 Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, Vrije Universiteit Medical Centre, P.O.Box 7057, 1007 MB Amsterdam, The Netherlands and 2 Institute for Reproductive Medicine, University of Münster, Germany
3 To whom correspondence should be addressed. E-mail: cb.lambalk{at}vumc.nl
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Abstract |
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BACKGROUND: Recently a polymorphic variant of the FSH receptor in which amino acid asparagine (Asn) at position 680 is replaced by serine (Ser) was found. This is associated with higher FSH levels in the early follicular phase and an increased FSH requirement to obtain follicular response in IVF patients. The aim of our study was to test the hypothesis that this receptor isoform occurs more often in regularly menstruating subfertility patients with elevated basal FSH than in those with normal early follicular phase FSH. METHODS: A retrospective cohort study of 38 subfertility patients with a regular menstrual cycle and elevated FSH (>10 IU/l) compared to 40 patients with normal early follicular phase FSH was carried out. DNA was analysed to determine the FSH receptor genotype. RESULTS: The N680S variant on one or both alleles of the FSH receptor gene was significantly more prevalent in patients with elevated FSH (P < 0.05). The homozygous Asn/Asn variant at codon 680 was found in 45% of women with normal FSH and in 21% of women with elevated FSH. The homozygous Ser/Ser receptor variant was present in 12.5% of women with normal FSH and in 21% of patients with elevated FSH. Also the heterozygous combination of both variants Asn/Ser occurred more often in women with elevated FSH (58 versus 42.5%). CONCLUSIONS: The N680S sequence variation of the FSH receptor is found in >75% of the cases with elevated basal FSH and suggests a higher FSH threshold.
Key words: basal FSH/elevated FSH/FSH receptor/FSH receptor mutations/polymorphisms
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Introduction |
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It has been known for many years that raised FSH levels in the early follicular phase of the menstrual cycle are present in normal older women (Sherman and Korenman, 1975
) as well as in subfertile older women (Ahmed Ebbiary et al., 1994; Lambalk, 1998a). Many studies have indicated that elevated basal FSH concentrations in the early follicular phase have a strong negative impact on pregnancy outcome in assisted reproduction (Scott et al., 1989; Toner et al., 1991). Some reports suggest that a distinction should be made between younger and older patients with elevated FSH in the early follicular phase (Check et al., 1998; van Rooij et al., 2003). It seems, however, that the predictive value of basal FSH in the general subfertility patient is of much less value and is unable, even with high threshold values, to distinguish clearly between those patients who will have a baby and those who will not (Van Montfrans et al., 2000; van Rooij et al., 2004).
The monotropic rise of FSH in association with ageing is the result of a decline in ovarian hormonal feedback, in particular that of inhibin B (Welt et al., 1999; Klein et al., 2004). Also in younger subfertility patients with elevated FSH, lower inhibin levels are found, indicating limited ovarian function (de Koning et al., 2000a). This limitation is the result of a quantitative and qualitative demise of available follicles. In subfertility patients with elevated FSH it has been shown that the threshold for FSH of the follicle is slightly increased (de Koning et al., 2004) which suggests that the ovary is less sensitive to FSH. Theoretically such patients may have FSH receptors which are less sensitive to FSH.
Recently a polymorphic variant of the FSH receptor was found in which the amino acid asparagine (Asn) at position 680 is replaced by serine (Ser) (N680S). The N680S variant was associated with higher FSH levels in the follicular phase starting from luteal–follicular transition (Greb et al., 2005) and more FSH was needed to obtain normal follicular response in IVF patients (Perez Mayorga et al., 2000; Sudo et al., 2002). The latter findings suggest that this receptor variant is less sensitive to FSH and that higher endogenous FSH levels may represent a natural compensation which is needed to enable normal follicle growth. In a group of normogonadotropic anovulatory women, the homozygous N680S variant was found to be more prevalent with higher basal FSH levels (Laven et al., 2003). So far, in vitro experiments have not shown differences in activity between the various allelic variants of the FSH receptor (Simoni et al., 1999; Sudo et al., 2002). FSH receptor sequence variation does not play a role in complete ovarian failure (Conway et al., 1999).
The aim of the present study was to test the hypothesis that in regularly menstruating subfertility patients with elevated basal FSH the N680S variant of the FSH receptor occurs more often. We investigated the distribution of these polymorphisms in a group of ovulatory subfertility patients with and without elevated FSH.
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Materials and methods |
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The current study was approved by the Institutional Review Board and written, informed consent was obtained from all participants. For the purpose of this study we approached patients that had participated in an earlier study. The original investigation was a nested case–control study in 50 consecutive patients diagnosed as having a diminished ovarian reserve according to elevated basal FSH concentrations (>10.0 IU/l), and in 50 controls. This was a questionnaire study that investigated occurrence of pregnancy (van Montfrans et al., 2000
). From this study cohort, 38 patients with basal FSH >10.0 IU/l and 40 controls gave written, informed consent allowing us to sample blood for FSH receptor DNA analysis. In the patient group, 36 women were Caucasian and two Asian, and in the control group all women were Caucasian.
Original patient cohort and control group
Basal FSH concentrations, taken on day 2, 3 or 4 of the menstrual cycle, were measured routinely in all newly registered subfertility patients in our department from January 1, 1995. Using a computerized database of patients registered after this date, we identified a cohort of 50 consecutive patients with elevated basal FSH concentrations (>10.0 IU/l) that fulfilled all inclusion and exclusion criteria. Inclusion criteria were a basal FSH concentration >10.0 IU/l, maximum age at registration 40 years, subfertility of 
12 months and ovulatory menstrual cycles (assessed by basal body temperature chart, serum progesterone levels in the luteal phase or by a luteal phase endometrial biopsy). Patients with a history of unilateral ovariectomy, chemotherapy or irradiation were excluded. Eleven patients with basal FSH concentrations >10.0 IU/l were not included in the study for the following reasons: age at registration >40 years (n = 4), history of unilateral ovariectomy (n = 6) or a history of chemotherapy (n = 1). In the same database we identified the first 50 age-matched controls with basal FSH concentrations <10.0 IU/l and concurrent estradiol concentrations <200 pmol/l. Other inclusion and exclusion criteria were the same as in the study group.
Laboratory assays
Basal FSH concentrations were measured with an immunometric assay (Amerlite, Amersham, UK). The assay was calibrated against the second International Reference Preparation for FSH (78/549). The intra- and inter-assay coefficients of variation (CV) were 9 and 8% for FSH values <25 IU/l respectively. Estradiol concentrations were measured with a competitive immunoassay (Amerlite, Amersham, UK), with intra- and inter-assay CV of 13 and 11% respectively for estradiol concentrations <500 pmol/l. All samples were run in duplicate.
DNA analysis
Genomic DNA was isolated from EDTA blood samples using the FlexiGene DNA extraction kit (Qiagen, Germany). PCR amplification of the two DNA portions containing SNP at nucleotide positions 919 and 2038 within exon 10 of the FSHR gene were performed according to Gromoll et al. (2000). The detection of the SNP distribution was conducted using an allelic discrimination assay based on TaqMan technology (Simoni et al., 2002). Homozygous controls for each of the polymorphisms were included in each run.
Statistical analysis
Statistical tests were performed using SPSS Base 7.5 for Windows 9 (SPSS inc., Chicago, IL, USA). We performed analysis of variance and Student’s t-test, linear-by-linear association analysis and 
2-tests when appropriate. Values for age, FSH, estradiol and cycle length were normally distributed after logarithmic transformation. Statistical significance was set at P < 0.05.
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Results |
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Baseline characteristics are given in Table I. Statistically significant differences between the groups with elevated and normal basal FSH concentrations were noted for menstrual cycle length and for day 3 FSH concentrations.
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There was a significantly larger number of patients with elevated FSH who had the N680S variant on one or both alleles of the FSH receptor gene (P < 0.05). The homozygous Asn/Asn receptor type was found in 45% of women with normal FSH and only in 21% of women with elevated FSH whereas the homozygous Ser/Ser state was present only in 12.5% of women with normal FSH and in 21% of patients with elevated FSH. Also the heterozygous Asn/Ser state occurred more often in women with elevated FSH (Table II). This distribution was significantly different (P < 0.05).
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The length of follow-up with regard to take home baby rate was 7.5 years (follow-up: period between the moment the couple attempted to achieve a pregnancy and the most recent patient contact). Of the women with elevated FSH, 37.5% with homozygous Asn/Asn FSH receptor had a baby while this was the case in 59 and 50% women with respectively heterozygous or homozygous N680S variant (by linear association P = 0.8) (Table III). In the control group 50% of women with Asn/Asn, 58% of those with Ser/Asn and 40% of women with Ser/Ser FSH receptor had an ongoing pregnancy. No significant differences with regard to take home baby rate in relation to FSH receptor polymorphism was seen.
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In the elevated FSH group, 12 women conceived naturally and eight pregnancies were achieved after assisted reproduction treatment (60 and 40% respectively, not significant). Women with normal basal FSH values had naturally conceived pregnancies in 52% of cases and 48% after assisted reproduction treatment.
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Discussion |
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This study confirms our hypothesis that in subfertility patients with elevated FSH and regular menstrual cycles, the N680S FSH receptor sequence variation, either on one or both alleles, occurs more frequently than in patients with normal FSH. The distribution of the FSH receptor genotypes among the women with normal FSH agrees with that described in ovulating Japanese women (Sudo et al., 2002
). In the present study the occurrence of the Asn/Asn FSH receptor genotype in 45% in the women with normal FSH was higher compared to the 29–31% found in earlier studies in assisted reproduction treatment patients or healthy controls (Perez Mayorga et al., 2000; Laven et al., 2003; Daelemans et al., 2004). The most likely explanation for this difference is that the patient population in the other studies was a random mixture of IVF patients or controls with normal and potentially elevated FSH, which was not the case in the control group of the current study.
It seems that the Ser/Ser and Ser/Asn genotypes occur very frequently in the various populations without fertility disorders and it is therefore most likely not a marker for a certain type of reproductive failure. It is nevertheless remarkably associated with higher FSH levels. Assisted reproduction treatment patients with these receptor variants, undergoing stimulation with FSH for induction of multiple follicle growth, required higher dosages in order to obtain a normal response (Perez Mayorga et al., 2000). A retrospective study in IVF patients has shown an association between the presence of Ser at codon 680 and poor responses to gonadotrophin stimulation (de Castro et al., 2003). Recently, a prospective study showed a lower estradiol response in IVF stimulation in women with the Ser/Ser genotype, compared to women with Asn/Asn with the same gonadotrophin dose (Behre et al., 2005). Such clinical observations suggest that the N680S allele is associated with a receptor protein slightly less sensitive to FSH. Subsequently, an altered set point of ovarian feedback mechanisms provides the higher FSH as a natural compensation allowing normal follicle growth.
Currently, measuring basal FSH is a routine procedure during the diagnostic work-up of the subfertile couple for prognostic evaluation and to predict ovarian response to gonadotrophin stimulation (Kwee et al., 2003).
In our clinic, elevated FSH ( >8 IU/l) occurs in 
2.5% of the female patient population (Lambalk et al., 1998a). We think that in at least a number of these subfertility patients, particularly in the presence of a regular ovulatory cycle, elevated FSH is not an indication of limited ovarian reserve but rather a representation of a different FSH receptor genotype.
Should we now perform a genotype analysis in all patients with an elevated FSH? It is too early for such a conclusion based on the current study. It seems, however, worthwhile to evaluate in a prospective study the contribution of FSH receptor polymorphisms in IVF stimulation in relation to gonadotrophin stimulation dose, and in terms of number of live births.
The notion that a patient has elevated FSH as a result of a less sensitive receptor may have practical implications when FSH stimulation is needed to obtain multiple follicle development. In IVF stimulations an a priori higher FSH starting dose with FSH would be logically justified. Another implication seems to be the grade of severity of ovarian hyperstimulation syndrome (OHSS) that may occur upon standard ovarian stimulation in IVF (Daelemans et al., 2004).
In patients with a less sensitive FSH receptor, elevated FSH is not a good parameter for fecundity prognosis. Indeed, recently several studies have indicated that basal FSH in the general subfertility patient with a regular menstrual cycle is of limited value to predict ongoing pregnancy (van Montfrans et al., 2000; van Rooij et al., 2004).
Theoretically it could be expected that patients with the Asn/Asn receptor and elevated FSH are more likely to be close to imminent ovarian failure. Nevertheless, it appeared from our study that about one-third of these women subsequently delivered a child. This was not significantly different compared to the women in the other groups. It is likely that in this matter the limited size of the groups excludes any statistically justified outcome.
It should be realized that there are also other causes of elevated FSH that are not associated with FSH receptor polymorphisms or imminent ovarian failure (Lambalk, 2003). Hereditary dizygotic twinning is associated with elevated early follicular phase FSH concentrations (Lambalk et al., 1998b). However, a negative logarithm of the odds (LOD) score for markers at the locus of the FSH receptor in a large sib pair study of mothers with dizygotic twins, makes involvement of the FSH receptor in this natural condition unlikely (Lambalk, 2001; Montgomery et al., 2001). Furthermore, heterophilic antibodies disturbing the FSH assay may be responsible for spuriously elevated FSH (de Koning et al., 2000b). This was ruled out in all patients who had participated in the current study.
In conclusion, the N680S allele of the FSH receptor is indeed associated with elevated basal FSH in >75% of the cases and suggests a higher FSH threshold. From this study we cannot conclude that patients with Asn/Asn FSH receptor and elevated FSH have a less favourable chance of pregnancy. However, with the interpretation of elevated early follicular phase FSH in infertility patients with a regular menstrual cycle, we have to consider that it may represent a frequently occurring isoform of the FSH receptor.
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Submitted on March 21, 2005; resubmitted on August 25, 2005; accepted on August 26, 2005.
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