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Department of Obstetrics and Gynecology (R.R.G., K.G., B.S., L.K.) and Institute for Reproductive Medicine (J.G., E.N., M.S.), Münster University Hospital, D-48149 Münster, Germany
Address all correspondence and requests for reprints to: Prof. Dr. Manuela Simoni, Institute for Reproductive Medicine, Münster University Hospital, Domagkstrasse 11, D-48149 Muenster, Germany. E-mail: manuela.simoni{at}ukmuenster.de.
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Abstract |
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Objective: We hypothesized that the FSH receptor genotype influences menstrual cycle dynamics.
Design: Menstrual cycle was monitored from the midluteal phase through ovulation until the consecutive menstruation.
Setting: The study was conducted at the University research center.
Subjects: Women homozygous for the Asn680 (n = 12) and Ser680 (n = 9) variants with normal menstrual cycles volunteered for the study.
Interventions: There were no interventions.
Main Outcome Measurements: Follicular growth, serum LH, FSH, estradiol, progesterone, inhibin A, inhibin B and antimullerian hormone were measured.
Results: During the luteo-follicular transition, serum levels of estradiol, progesterone, and inhibin A were significantly lower, and FSH started to rise earlier in the Ser680/Ser680 group. FSH levels were steadily and significantly higher, and the mean area under the FSH curve was 31% greater in this group (P < 0.002). No differences were observed in estradiol, inhibin B, and growth velocities of dominant follicles. The time from luteolysis to ovulation was significantly longer in women with the Ser680/Ser680 (13.6 ± 1.01 d) compared with Asn680/Asn680 (11.3 ± 0.61 d, P < 0.05) genotype with a significant difference in total menstrual cycle length (29.3 vs. 27.0 d, respectively; P < 0.05).
Conclusions: The FSH receptor Ser680/Ser680 genotype is associated with higher ovarian threshold to FSH, decreased negative feedback of luteal secretion to the pituitary during the intercycle transition, and longer menstrual cycles.
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Introduction |
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The biological actions of FSH depend on the FSH receptor, expressed in women exclusively in granulosa cells (6). The FSH receptor belongs to the family of G protein-coupled receptors inducing signal transduction by the protein kinase A/cAMP pathway (7). Apart from rare mutations, two common single nucleotide polymorphisms (SNP) were identified in exon 10 of the FSH receptor gene at nucleotide position 919 and 2039, respectively. The first SNP is located in the extracellular domain at codon position 307, which can be occupied either by alanine (Ala) or by threonine (Thr). The second SNP, located in the intracellular domain at codon position 680 changes an asparagine (Asn) to serine (Ser). The two SNP are mostly in linkage dysequilibrium in the Caucasian population, resulting in two discrete allelic variants, i.e. Thr307-Asn680 and Ala307-Ser680 (8), the latter representing about 40% of FSH receptor alleles worldwide.
Studies investigating the distribution of the two variants between women with different forms of ovarian dysfunction and the normal population showed no or, at the most, marginal differences (9, 10, 11). However, in recent studies in controlled ovarian hyperstimulation cycles we and others could provide compelling evidence that the amino acid transition Asn680 to Ser680 results in subtle differences in receptor function as reflected by basal FSH levels in the early follicular phase and/or the number of FSH ampoules required for effective ovarian stimulation (12, 13, 14, 15, 16). These data suggested for the first time that the FSH receptor genotype might be an important determinant of the ovarian response to FSH, especially when the homozygous genotypes Asn680/Asn680 and Ser680/Ser680 are compared (12). Follicular estradiol secretion and basal FSH levels in these studies suggested that the Ser680/Ser680 genotype is more "resistant" to FSH action, and thus requires a stronger stimulus for the same biological response, possibly resulting in a higher FSH threshold in women with this variant. If this concept is true, it would have important implications for controlled ovarian hyperstimulation protocols, which, in women with normal ovarian function, should be based more rationally on the knowledge of the FSH receptor genotype. Because homozygous women carrying the Ser680/Ser680 genotype are fertile and comprise approximately 20% of the female population (9, 13), we reasoned that a different FSH threshold does not impair the capacity of the follicle to ovulate and should be evident by cycle monitoring in healthy normal ovulatory women carrying the homozygous Ser680 compared with the homozygous Asn680 genotype. Assuming an unchanged ovarian feedback to the pituitary, we hypothesized that women with the Ser680/Ser680 variant would require a more prolonged and/or more extensive FSH stimulus for the selection of the dominant follicle (higher FSH threshold) or might follow different kinetics of the FSH increase during the luteo-follicular transition possibly resulting in different length of the menstrual cycle.
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Subjects and Methods |
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Women were recruited by advertisement in local newspapers. The study was approved by the institutional ethics committee (Reg.-Nr. 2IXSimoni) and written informed consent was obtained from all participants. Volunteers were screened for FSH receptor genotype (n = 125) if they met the following criteria: age between 18–34 yr, eumenorrhea and a cycle length between 25 and 32 d, body mass index between 19 and 28 kg/m2, and normal pelvic exam including transvaginal ultrasound. Exclusion criteria were: history of any endocrine disorders, e.g. thyroid gland dysfunction, diabetes, or treatment for menstrual cycle disorders, history of ovarian surgery, and use of hormonal contraception or any other hormonal treatments within 6 months before entering the study. Subjects were reimbursed for their expenses to participate in the study. All women were of Caucasian origin. After genotyping, only women homozygous for Asn680 (n = 42) or Ser680 (n = 22) who fulfilled the inclusion/exclusion criteria were further considered. Thirteen women homozygous for Asn680 and 10 women homozygous for Ser680 completed menstrual cycle monitoring according to the study design.
Study design
Monitoring of menstrual cycles was performed by transvaginal ultrasound and serum hormone analyses. All transvaginal ultrasound measurements were performed by the same observer (K.G.) blinded to the results of the FSH receptor genotyping, using a 7.5-MHz transvaginal probe on a Siemens Sonoline (Sienna; Siemens AG, Erlangen, Germany). The first baseline transvaginal ultrasound was performed in the late follicular phase of the menstrual cycle (cycle d 10–12) to confirm normal ovulatory function and the presence of a dominant follicle. Two additional ultrasound examinations were scheduled in the luteal phase (9 and 2 d before the expected onset of menstruation based upon menstrual history) and three examinations in the subsequent follicular phase on cycle d 3, 6, and 9, respectively. If no clear-cut dominance of one tertiary follicle could be visualized on cycle d 9, another ultrasound scan was performed on cycle d 12. At all ultrasound examinations, the size and number of antral follicles and the volume of both ovaries was measured as described previously (17). Ovaries were scanned from the outer to the inner margin, and round or oval echo-free structures inside the ovaries were regarded as antral follicles and were counted and measured as such. The detection limit for antral follicles by ultrasound is approximately 2–3 mm. Both ovaries were considered for the total antral follicle count equivalent to the total number of visible antral follicles. Follicle diameter was calculated from the mean of two perpendicular measurements if a follicle measured less than 10 mm and from the mean of three perpendicular measurements if a follicle measured more than or equal to 10 mm. The volume of each ovary was calculated by measuring the three perpendicular diameters and applying the formula for an ellipsoid: (L x W x H x 
)/6. The volumes of both ovaries were added for the total ovarian volume.
All participating subjects underwent daily blood sampling starting in the luteal phase 9 d before the expected onset of menses based upon the previous menstrual history until 9 d after the onset of menstrual flow or until a dominant follicle was discernible on the ultrasound scan. Blood sampling was then continued throughout the cycle every other day until the day of onset of the next menstrual period. Of 23 subjects who completed monitoring according to the study protocol, two women were excluded from the final data analysis because their last menstrual cycles during the monitoring were anovulatory based upon progesterone levels less than 1 ng/ml between 5 and 10 d before their last menstruation occurred, whereas in all other participants, the growth of a dominant follicle and luteal progesterone levels of at least 8 ng/ml could be confirmed. The genotype of the two women excluded was Ser680/Ser680 and Asn680/Asn680, respectively.
Serum hormone analyses
All hormone analyses were performed in duplicate. FSH and LH were measured by an immunofluorimetric assay and estradiol by fluoroimmunoassay using the Autodelfia system (Perkin-Elmer, Freiburg, Germany) as described previously (8). Progesterone was measured by RIA using the Coat-a-Count RIA kit by DPC (Bad Nauheim, Germany) according to the instructions of the manufacturer. Inhibin A, inhibin B, and antimullerian hormone (AMH) were measured by highly specific ELISA using the Serotec kits purchased from DSL (Sinsheim, Germany) according to the instructions of the manufacturer. The sensitivities of the assays were: 0.05 IU/liter (FSH), 0.025 IU/liter (LH), 25 pmol/liter (estradiol), 0.1 ng/ml (progesterone), 3.9 pg/ml (inhibin A), 7.8 pg/ml (inhibin B), and 0.05 ng/ml (AMH). The following intra and interassay coefficient of variations (CV) were obtained: less than 3% for both intra and interassay CV for FSH and LH; 3.7% (intraassay CV) and 6.1% (interassay CV) for progesterone; 2.2% (intraassay CV) and 2.7% (interassay CV) for estradiol; 6.3% (intraassay CV) and 7.0% (interassay CV) for inhibin A; 5.3% (intraassay CV) and 7.0% (interassay CV) for inhibin B; 4.2% (intraassay CV, only one assay performed) for AMH.
Analysis of the SNPs at nucleotide positions 919 (codon 307) and 2039 (codon 680)
Genomic DNA was extracted from peripheral blood using FlexiGene DNA extraction kit (QIAGEN, Hilden, Germany) according to the manufacturer’s instruction. All women were first screened for the SNP at position 2039 (codon 680) of exon 10 by the TaqMan allelic discrimination assay, using the ABI Prism 7000 sequence detection system (Applied Biosystems, Darmstadt, Germany). The probes (SNP indicated in bold lowercase letter) were 5'-AGAGTCACCAgTGGTT-3' (6-carboxyfluorescein fluorescence) and 5'-AGTCACCAaTGGTTC-3' (VIC fluorescence). The primers were 5'-AAGGAATGGCCACTGCTCTTC-3' (forward) and 5'-GGGCTAAATGACTTAGAGGGACAA-3' (reverse). In women homozygous for Ser680 or Asn680, the SNP at position 919 (codon 307) was then screened using the primers 5'-CTTCATCCAATTTGCAACAAATCTAT-3' (forward) and 5'-TGTCTTCTGCCAGAGAGGATCTC-3' (reverse) and the probes 5'-ATTATATGACTCAGaCTAGG-3' (6-carboxyfluorescein fluorescence) and 5'-TTATATGACTCAGgCTAGG-3' (VIC fluorescence). Each PCR (25 µl) contained 2 µl DEPC-treated water, 12.5 µl Universal master mix, 0.25 µl of each probe, and 4.5 µl of each primer (5 pmol). Using the TaqMan machine, PCR was performed in two steps, i.e. absolute quantification and allelic discrimination. For absolute quantification, the cycles are as follows: stage 1: 50 C, 2 min (1 cycle) for probe binding; stage 2: denaturation at 95 C, 10 min (1 cycle); and followed by 35 cycles at 95 C for 15 sec, and 60 C for 1 min (stage 3), whereas allelic discrimination assay took 1 min at 60 C.
Statistical analysis
Menstrual cycle-dependent data were aligned on two different time scales. The first time scale was based on the day of onset of menstruation. Subsequently, data were aligned on a time scale based on the day when the midcycle LH surge before the last menstruation during the study period was detected, which was arbitrarily set as day LH 0. Nonparametric Mann-Whitney U test was used to determine differences between genotype groups. Regression analysis was used to describe growth patterns of follicles between groups (Statistical Package for Social Sciences, SPSS, Inc., Chicago, IL, for Windows release 11.5.1). Data are presented as the mean ± SEM. P < 0.05 was considered to be significant.
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Results |
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Twelve women homozygous for the FSH receptor Asn680 genotype and nine women homozygous for the Ser680 genotype who completed the monitoring of a mono-ovulatory menstrual cycle were finally considered in the study. Women in both groups were comparable in terms of age (25.85 ± 1.06 vs. 25.74 ± 1.30 yr) and body mass index (22.18 ± 0.59 vs. 21.59 ± 0.91 kg/m2) for Asn680/Asn680 and Ser680/Ser680 genotypes, respectively (P > 0.05).
Serum LH levels were indistinguishable between the two groups (Figs. 1A
and 2A). When the hormone levels during the luteo-follicular transition were analyzed in relation to the onset of menses, significantly higher serum FSH levels were observed both in the luteal and in the follicular phase (Fig. 1B). This difference was even more striking when the data were aligned based on the day of the midcycle LH surge; women with the Ser680/Ser680 genotype had higher FSH levels from day LH –18 onward until the LH peak, reaching statistical significance on most days (Fig. 2B). The luteal FSH levels before day LH –18 were not significantly different (Fig. 2B). Between the luteo-follicular transition (day LH –19) and the LH surge the area under the curve of FSH levels was 31% higher in subjects with the Ser680/Ser680 genotype compared with the Asn680/Asn680 genotype (Table 1; P < 0.002) The kinetics of the intercycle/follicular phase FSH levels were similar in both groups; the average day of maximum FSH levels during this time period was observed 10–11 d preceding the LH surge in both Ser680/Ser680 and Asn680/Asn680 subjects (Table 1).
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, C–F. Relative to the subsequent midcycle LH peak luteal levels of estradiol, progesterone and inhibin A were decreasing earlier in the Ser680/Ser680 than in the Asn680/Asn680 group. Statistical significance was observed on days LH –19, –18, –17, and –15 for estradiol, on days LH –19, –18, and –10 for progesterone and on days LH –21 and –18 for inhibin A. Accordingly, the mean duration between completion of luteolysis, defined by progesterone levels falling less than 1 ng/ml, and the subsequent midcycle LH peak was significantly longer in the Ser680/Ser680 compared with the Asn680/Asn680 group (13.6 ± 1.01 vs. 11.3 ± 0.61 d, respectively, P < 0.05; Table 1). The higher concentrations of progesterone, estradiol, and inhibin A in the luteo-follicular transition indicate a stronger negative feedback signal in the Asn680/Asn680 group, possibly at the pituitary level, as reflected by the lower FSH but not LH levels. However, this effect is not evident when the onset of menstruation instead of the midcycle LH peak is taken as the reference day to align the hormone data (Fig. 1, C–F). This suggests that the dynamics of luteolysis are similar in the two groups, and that the significant differences in estradiol, progesterone, inhibin A, and inhibin B evident in Fig. 2 are due to the longer length of the subsequent follicular phase in Ser680/Ser680 women.
No significant differences were observed in estradiol levels during the follicular phase from LH –14 until LH 0 (Fig. 2C). These data suggest that higher FSH levels are necessary to achieve the same estradiol concentrations in the Ser680/Ser680 group. In addition, the average number of visible antral follicles was significantly higher in the Ser680/Ser680 compared with the Asn680/Asn680 group (22.6 vs. 17.8, respectively, P < 0.005; Table 1). Accordingly, during the luteo-follicular transition inhibin B levels, an indicator of growing follicles, started to rise earlier in Ser680/Ser680-type women (significant differences on LH –18, –16, and –15), but comparable levels were observed throughout the remaining follicular phase (Fig. 2F). The dynamics of follicular growth were similar in both groups. Slopes and intercepts of linear regression lines plotted for sizes of dominant follicles against the progression of the menstrual cycle were not significantly different between groups (P > 0.05; Fig. 3).
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and Fig. 4). The difference in cycle length could be attributed especially to the longer interval between luteolysis and ovulation (Table 1; P < 0.05; Fig. 4).
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Discussion |
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Clear-cut differences in ovarian secretion patterns were observed between the two groups during the luteo-follicular transition phase. The decrease in estradiol, progesterone, and inhibin A levels associated with the regression of the corpus luteum occurred earlier in women with the Ser680/Ser680 genotype. Accordingly, this earlier drop in ovarian feedback hormones in Ser680/Ser680 women appears not only to trigger an earlier rise in FSH levels but also constantly higher levels throughout the follicular phase. The longer period of time elapsing from luteolysis until the subsequent ovulation in women carrying the Ser680/Ser680 compared with the Asn680/Asn680 genotype suggests that the time needed for maturation of the FSH-dependent cohort of follicles is increased in Ser680/Ser680-type women. This is in agreement with the significant 3-d difference in total length of menstrual cycles between groups.
Interestingly, the different levels and dynamics of ovarian hormones affect FSH but not LH levels, which were identical in the two groups. Because GnRH stimulates both LH and FSH secretion and assuming the same negative feedback sensitivity, these data suggest that the main site of negative feedback action by ovarian hormones on FSH secretion is the pituitary, at least during the luteo-follicular transition. FSH levels were significantly higher in the Ser680/Ser680 group also around ovulation, while LH levels were increased as well, although not significantly. These data suggest that the pituitary produces steadily more FSH in the Ser680/Ser680 group. The role of the hypothalamus cannot be defined by the present study and could be investigated by analyzing LH pulsatile secretion in women selected according to their FSH receptor genotype.
This study helps to further understand the role of inhibins in the regulation of FSH secretion. In particular, as suggested by the higher levels in the Asn680/Asn680 group, inhibin A, a luteal product, appears to be more efficient than inhibin B in inhibiting FSH secretion during the luteo-follicular transition. In this phase, inhibin B levels paralleled the FSH increase and started to rise earlier in the Ser680/Ser680 group, reflecting the recruitment of a larger number of antral follicles (18). However, during the mid to late follicular phase no significant differences were observed in inhibin B levels between the two genotypes. Therefore, the significantly higher serum FSH levels observed in the Ser680/Ser680 group during the entire follicular phase are maintained despite the same degree of negative feedback signal deriving from inhibin B and estradiol, suggesting that these two hormones are not the only players in the pituitary regulation of FSH secretion during the follicular phase. Although activin and its binding protein, follistatin are unlikely to exert a significant endocrine effect on FSH secretion, their well-established paracrine effects at the pituitary level in regulating FSH biosynthesis (19) might be instrumental. However, the exact mechanism maintaining increased FSH levels during the follicular phase in the Ser680/Ser680 group remains to be established.
The maximum of the intercycle FSH secretion is reached at around day LH –11 in both groups. However, as suggested by the area under the curve of FSH levels, women with the Ser680/Ser680 genotype exhibit a more than 30% increase in total FSH exposure compared with the Asn680/Asn680 group. The increased pituitary FSH secretion apparently compensates for the relative resistance of the FSH receptor because both follicular phase levels of estradiol and the growth dynamics of the dominant follicle are similar between groups. In accordance with the known function of FSH, follicular maturation is affected only before the selection of the dominant follicle and similar growth velocities were observed between genotypes as soon as the dominant follicle was selected. However, ovaries from women with the Ser680/Ser680 genotype contain approximately 20% more visible antral follicles. Thus, women with the Ser680/Ser680 genotype might need more follicles to be recruited in order for one to reach dominance and to eventually ovulate. Alternatively, the increased number of follicles in the Ser680/Ser680 group might be explained by the elevation of FSH for a longer period of time compared with the Asn680/Asn680 group.
So far, the molecular mechanisms explaining the differences in FSH-receptor function remain unclear. Functional studies in vitro using the FSH receptor variants Thr307-Asn680 and Ala307-Ser680 in a transient transfection setting showed no significant differences for hormone binding and cAMP or inositole phosphate 3 production in COS7 and HEK293 cells (8, 9), but to pick up subtle functional differences it might be essential to use granulosa cells which are the natural endocrine target of FSH in women.
The FSH receptor genotype might explain some well-known inter-individual variability in menstrual cycle characteristics. In young women with a normal ovarian function, 2.5-fold differences in FSH threshold concentrations for follicle recruitment were described (20) with a lack of correlation between peak serum FSH concentrations in the follicular phase and parameters of ovarian ageing (21). Two thirds of women exhibit two waves of follicle development during the interovulatory interval, one third exhibits three waves (22). We speculate that distinct individual differences in the intraovarian action of FSH could depend on differences in the FSH threshold due to the Asn680Ser polymorphism.
Our findings have important clinical implications for the optimization of controlled ovarian hyperstimulation regimens for assisted reproduction. The different FSH threshold depending on the FSH receptor genetic background implies that different FSH doses, and possibly a different timing of exogenous FSH administration (23) might be instrumental to achieve the desired ovarian response avoiding side effects. Clinical studies performed so far support the validity of such a pharmacogenetic approach, e.g. by adjusting the starting dose of FSH administration depending on the patients FSH receptor genotype (9, 12, 14, 15). A prospective randomized study based upon other clinical parameters confirmed that individualizing the starting dose is important to improve the outcome in patients undergoing in vitro fertilization treatment (24).
Finally, the results of this study have important evolutionary implications. In fact, the amino acid asparagine at position 680 in exon 10 of the FSH receptor is highly conserved in other species and only in humans has the replacement by serine been detected so far (13). This would suggest that the Ser680 genotype arose very recently in evolution. The occurrence of the Ser680 genotype in now about 40% of all human alleles suggests a strong evolutionary pressure of this variant that cannot be explained by a mere reproductive advantage. So far, there is no evidence of differences in the fertility potential between women with different polymorphisms (10, 25), and the present study showed similar dynamics in the growth of dominant follicles. In addition, AMH levels, an endocrine marker for ovarian reserve and aging (26), were similar in both groups despite the presence of more visible antral follicles in women with the Ser680/Ser680 genotype. These findings suggest that fertility and ovarian ageing could be similar in both groups of women despite a different length of the menstrual cycle and are in line with observations indicating an FSH-independent mechanism of follicular depletion (27). Differences in menstrual cycle length between the Ser680/Ser680 and the Asn680/Asn680 group result in 12.5 vs. 13.5 menstrual cycles per year, respectively. Assuming no difference in the age of menopause, women with the Ser680/Ser680 genotype would experience 30–40 cycles less than women with Asn680/Asn680 genotype during their reproductive life. Therefore, while maintaining normal fertility, women with the Ser680/Ser680 genotype would be globally exposed to a lower incidence of pregnancies and related risks. It is estimated that maternity-related lifetime risk of death is still as high as one in 12 in underdeveloped countries (28), a risk that must have been much higher in the earlier times of human evolution, possibly making pregnancy-related death a very strong factor in determining a rapid evolutionary selection of this genotype. Pregnancy-associated risks have been recognized as a strong evolutionary factor to promote gene polymorphisms demonstrated, e.g. by carriers of the factor V Leiden (29). In addition, menstrual periods are a stressful event and have certain disadvantages, such as blood loss, menstrual discomfort, and effects of hormone fluctuations on mood and on breast and other estrogen-dependent organs. Therefore, we speculate that fewer menstrual cycles during the reproductive life span might represent an evolutionary advantage, provided that the fertility of the species is maintained.
In conclusion, we have demonstrated that the pituitary and ovarian hormone secretion, the FSH threshold, and the menstrual cycle length are dependent on the type of the Asn680/Ser680 polymorphism of the FSH receptor. A higher pituitary FSH secretion, a longer interval from luteolysis until the subsequent ovulation and a longer duration of menstrual cycles in women with the Ser680/Ser680 compared with the Asn680/Asn680 genotype suggest that granulosa cells of Ser680/Ser680 type women are more resistant to FSH action. This should be considered in designing patient-tailored protocols of controlled ovarian hyperstimulation in women with normal ovarian function undergoing assisted reproduction.
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Acknowledgments |
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Footnotes |
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First Published Online May 10, 2005
1 R.R.G. and K.G. contributed equally to the study. 
Abbreviations: AMH, Antimullerian hormone; CV, coefficient of variation; SNP, single nucleotide polymorphism.
Received November 18, 2004.
Accepted May 3, 2005.
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