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Original Studies |
Institute of Reproductive Medicine (M.P.M., J.G., E.N., M.S.) and Department of Obstetrics and Gynecology (H.M.B., C.G.) of the University, D-48129 Münster, Germany
Address correspondence and requests for reprints to: Prof. Dr. E. Nieschlag, F.R.C.P., Institute of Reproductive Medicine of the University, Domagkstrasse 11, D-48129 Münster, Germany.
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Abstract |
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The FSHR polymorphism at position 680 was analyzed by restriction-fragment-length polymorphism in 161 ovulatory women below the age of 40 yr. With reference to the couple, infertility has been diagnosed as being attributable to male causes (76%), tubal factor (11%), or both (13%). The distribution was 29% for the Asn/Asn, 45% for the Asn/Ser, and 26% for the Ser/Ser FSHR variant. Peak estradiol levels, number of preovulatory follicles, and number of retrieved oocytes were similar in the 3 groups. However, basal FSH levels were significantly different among the 3 groups (6.4 ± 0.4 IU/L, 7.9 ± 0.3 IU/L, and 8.3 ± 0.6 IU/L for the Asn/Asn, Asn/Ser, and Ser/Ser groups, respectively, P < 0.01). The number of FSH ampoules required for successful stimulation was significantly different among the 3 groups (31.8 ± 2.4, 40.7 ± 2.3, and 46.8 ± 5.0 for the Asn/Asn, Asn/Ser, and Ser/Ser groups, respectively, P < 0.05). According to multiple linear regression analysis, the number of ampoules needed could be predicted from a linear combination of both the type of polymorphism and basal FSH levels (P < 0.001).
These clinical findings demonstrate that the ovarian response to FSH stimulation depends on the FSHR genotype.
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Introduction |
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Given the crucial function of FSH action on gametogenesis, screening for mutations in the FSHR has been implemented in the search for causes of infertility (3, 4, 5). An inactivating mutation located in the extracellular domain of the FSHR could be identified, leading to a FSH resistance syndrome characterized by streak gonads and primary amenorrhea (3). However, primary follicles could be observed in ovarian biopsies of the affected patients, suggesting that FSH action is dispensable up to this stage of follicle maturation (6). It then became evident that partially inactivating mutations of the FSHR can cause arrest at the antral or later stages of follicular growth, indicating that different degrees of FSH-FSHR activity are required to promote maturation (6). In such cases, follicular growth seems to be arrested at various stages, depending on how severely FSH/FSHR interaction is impaired. Conversely, in preovulatory follicles, follicular development proceeds independently of the FSH concentration, once a given threshold concentration of FSH has been reached (6).
During screening for mutations of the FSHR gene, two polymorphisms were identified: one located in the extracellular domain at position 307, occupied by either alanine (Ala) or threonine (Thr); and a second one, located in the intracellular domain at position 680, occupied either by asparagine (Asn) or serine (Ser). Both polymorphic sites are within exon 10 and give rise to two discrete allelic variants of the FSHR, i.e. Thr307/Asn680 and Ala307/Ser680 (7). No difference in the distribution of the two variants has been found when comparing infertile men or women to the normal population (7, 8, 9).
In assisted reproduction programs, the response of ovulating women to exogenous FSH therapy is quite variable. Notwithstanding several years of clinical experience, the ovarian response to intense gonadotropin stimulation is difficult to predict. Patient characteristics, rather than the stimulation protocol, seem to determine the individual response. In young ovulating women undergoing in vitro fertilization (IVF) treatment, the standard stimulation protocol can result in either poor response (requiring adjustment of the FSH doses) or in ovarian hyperstimulation syndrome. This is a serious, potentially life-threatening complication of IVF characterized by enlarged ovaries and extravasation of fluid to the abdominal cavity, resulting in ascites, hypovolemia, and hemoconcentration (10, 11). Advance identification of patients who will elicit a poor response or hyperresponse to standard treatment would be of great clinical advantage.
Several parameters have been postulated as predictors of the ovarian response (12, 13, 14, 15, 16, 17, 18), all of which strive to assess ovarian reserve. Of these, FSH seems to be the best predictive value, but a significant intraindividual variability from cycle to cycle has to be noted (19). Other factors proposed to affect ovarian response to FSH are the distribution of FSH isoforms (20) and the interference of circulating FSH binding inhibitors or FSH antibodies (21). Intraovarian interference, at the level of FSH binding to its cognate receptor, and the presence of FSHR isoforms with altered signal transduction have also been discussed (22, 23). However, none of these hypotheses have been proven up to now. In this paper, we demonstrate that the FSHR genotype is a major determinant of ovarian responsiveness to FSH in ovulation induction.
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Subjects and Methods |
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One hundred sixty-one ovulatory women with infertility caused by male factor or tubal factor were included in this study. Ovulation was documented indirectly by midluteal progesterone levels. Eighty-five patients were recruited prospectively from the ongoing assisted-reproduction program. Another group of 115 women who had previously been treated in our IVF clinic, selected by the above mentioned inclusion criteria, was asked, by letter, to participate in the study. Seventy-six patients responded by returning an EDTA blood sample, together with a signed, written consent. A 3-ml EDTA blood sample was obtained from each woman and was stored at -20 C. Each patient received a full explanation of the purpose of the study and gave written informed consent.
Treatment
In all cases, controlled ovarian stimulation, according to standard protocols, was performed before genetic analysis.
In general, follicular development was monitored by transvaginal sonography, after 6 days of stimulation and then every other day. In cases of insufficient follicular growth and low estradiol serum levels, FSH dosage was increased gradually. Sonography was performed daily when the leading follicle exceeded 14 mm in diameter. Ovulation was induced by 10,000 IU human CG (hCG), im, when at least one follicle was 20 mm in diameter. Oocytes were collected by transvaginal, ultrasound-guided aspiration. Conventional IVF was performed in 38 patients. To this end, up to 10 mature oocytes were inseminated, depending on sperm motility (24). A total of 32,000–200,000 sperm were incubated overnight with a single oocyte in a 100-µL droplet of Medi-Cult universal IVF medium (Medi-Cult, Jyllinge, Denmark). Intracytoplasmic sperm injection was performed in 125 patients, according to the protocol of Van Steirteghem et al. (25).
DNA isolation and polymorphism analysis
All DNA analyses were performed after completion of ovarian stimulation. Genomic DNA was extracted from white blood cells with the Blood and Cell Culture DNA kit (QIAGEN, Düsseldorf, Germany), according to the manufacturer’s instructions.
A fragment of exon 10 of the FSHR gene, 10D to 10G (4), was amplified from genomic DNA by PCR and analyzed by electrophoresis in a 2% agarose gel. After analysis, the segment was subjected to phenolchloroform extraction. The purified fragment was digested by Bsr1 (Biolabs, Schwabach, Germany), and the fragments were run on a 2.5% agarose gel electrophoresis. The uncleaved fragment, indicating homozygosity for Asn, has a size of 755 bp; whereas the cleaved fragment, indicating homozygosity for serine, gives rise to 612- and 143-bp fragments (7). The presence of all three fragments indicated a heterozygous state. Single-stranded conformation polymorphism analysis was employed for the characterization of the polymorphism at position 307, in 20 samples, and was performed as previously described (7).
Hormonal and clinical data
Basal FSH levels (day 3 of the menstrual cycle) were obtained in one of the previous cycles before ovarian stimulation. The peak estradiol levels considered here were those of the day of hCG administration. Serum levels of FSH and estradiol were measured by standard specific immunoassays on the respective cycle days (Vitros EC, Ortho-Clinical Diagnostics, Schwabach, Germany).
Statistical analysis
Statistical analysis was performed by one-way ANOVA, applying the Sigmastat statistical software package, version 2.03 (Jandel, Erkrath, Germany). For data not normally distributed, the Kruskal-Wallis test was used. Multiple linear regression was used to evaluate the association of basal FSH levels, type of polymorphism, and number of FSH ampoules required. Data are presented as the mean ± SEM and median and range, respectively. P values < 0.05 were considered statistically significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. The overall frequency distribution was
29% for the Asn/Asn variant, 45% for the Asn/Ser variant, and 26%
for the Ser/Ser variant. SSCP analysis of the polymorphic site at
position 307 displayed a linkage of Thr307 to Asn680 and of Ala307 to
Ser680 variants in all patients investigated (data not shown).
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When the patients were grouped according to their FSHR genotype, the
basal levels of FSH (day 3) were significantly different among the
three groups (Fig. 1). The FSH
concentrations were 6.4 ± 0.4 IU/L, 7.9 ± 0.3 IU/L, and
8.3 ± 0.6 IU/L for the Asn/Asn, Asn/Ser, and Ser/Ser groups,
respectively (P < 0.01).
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No statistically significant differences among the three groups were
observed, suggesting that the treatment was equally successful,
independent of the FSHR isoform. Moreover, no correlation between these
variables and the FSHR genotype was found. However, the number of FSH
ampoules required for achieving this effect was significantly different
among the groups. As shown in Fig. 2, the
number of ampoules was 31.8 ± 2.4, 40.7 ± 2.3, and
46.8 ± 5.0 for the Asn/Asn, Asn/Ser, and Ser/Ser groups,
respectively (P < 0.01) (Fig. 2).
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Discussion |
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The fact that a different ovarian response to FSH stimulation occurs,
depending on the FSHR genotype, gives important insights into the
hormonal regulation of reproduction. The patients investigated in this
clinical setting were ovulating women with FSH levels within the normal
range. Previous studies have shown that mutations in the FSHR are
extremely rare, show a distinct phenotype, and occur only in severe
cases of infertility. Therefore, the presence of such mutations in our
patient population is highly improbable. Our results suggest that
subtle genetic differences in the FSHR result in different hormone
levels within the normal range. Obviously, the allelic variants must
have slightly different activities in vivo, as reflected by
the significantly different FSH levels observed when the patients were
subdivided into the homozygous Ser, heterozygous Asn/Ser, and
homozygous Asn groups (Fig. 1
). This indicates a fine tuning in the
feedback regulation of FSH, dependent on the FSHR genotype. Inhibin B
might be the mediator of such precise control of FSH secretion.
Unfortunately, because of the lack of serum, day 3 inhibin B could not
be measured in this group of retrospectively selected patients.
With regard to FSH, different isoforms have been described, characterized by variations in oligosaccharide structure, as well as in the number of terminal sialic acid residues. These isoforms can probably elicit different kinds of ovarian response (20). The FSHR isoforms might further contribute to such pleotropic answers by a molecular mechanism, which could reside in the potential for glycosylation/phosphorylation that each isoform possesses. It has been reported that the FSHR is capable of coupling with more than one G protein subtype, depending on the glycosylation pattern of the ligand and on the degree of receptor transducer activation (26), culminating in differential actions at the target site.
The possible mechanism of different receptor activity, depending on the genotype, could be attributed to various aspects. For example, each isoform could show different expression at the cell surface, determining the probability of interaction with the hormone. Moreover, each receptor isoform could show differences in the turnover or in the down-regulation rate. Finally, each receptor isoform might have different affinity for more- or less-active FSH isoforms (23). The presence of an Asn residue at position 680 introduces a consensus sequence for glycosylation, which might be important for posttranslational receptor processing and expression at the cell surface; whereas a Ser residue contributes potential phosphorylation, which might be involved in the receptor turnover (27).
All these hypotheses need to be tested in an appropriate in vitro system. In previous experiments, we were unable to find significant differences in binding characteristics and receptor activation between the two isoforms (7). Such experiments were performed in transiently transfected COS7 cells, i.e. in a cell system that does not necessarily reflect the physiological setting of granulosa cells. Because the expression reflects physiological diversity and is not pathological, it could be expected that FSHR isoforms will not possess drastically different binding and signal transduction characteristics. This challenges the experimental setting in which to study such isoforms. In fact, the use of cell lines, such as COS-7 cells, transiently transfected with different receptor constructs, completely neglects the presence of cell-specific elements such as the different G proteins or phosphodiesterases present in granulosa and Sertoli cells (2). In addition, cAMP production is the only parameter of receptor activation considered so far. There are indications that FSH action can be mediated by signal transduction pathways distinct from the cAMP/protein kinase A route, and it is tempting to speculate that a different combination of second-messenger systems is activated, depending on the nature of the FSH isoform-FSHR isoform interaction. Investigations of subtle changes of receptor activity, using a cell system not fully representative of the cell that naturally hosts the receptor, might not lead to a proper evaluation. Therefore, we propose that, in the future, a granulosa cell-based system should be used for the functional characterization of FSHR isoforms. In addition, the different receptor activity observed in vivo might be mediated by cellular effects beyond, or other than, the cAMP production.
The finding that allelic variants of the FSHR determine FSH sensitivity opens a new perspective in endocrinology and indicates that subtle genetic changes might fine-tune the hormonal regulation of reproduction. In an elegant study, Cargill et al. (28) recently showed the presence of single-nucleotide polymorphisms in nearly all the key players of the hypothalamo-pituitary-gonadal axis, i.e. the GnRH receptor, LH and its receptor, and FSH and the FSHR. This group also confirmed the presence of the polymorphisms of the FSHR described here. The presence of single-nucleotide polymorphisms in these genes points to individual genetic heterogeneity, resulting in individual hormone profiles. This concept of fine-tuning of FSH action in the ovary becomes more complex when considering that there are not only genetic variants of the hormone but also differently glycosylated isoforms that might have different bioactivity. Future studies have to take into account a more complex setting of FSH isoforms interacting with different FSHR isoforms.
Our study also has important clinical implications. In agreement with
previous studies, to improve ovarian response, we used a long
stimulation protocol employing a GnRH agonist in the large majority of
the patients (29). This protocol also aims at optimizing the response
in patients expected to be poor responders, such as patients with high
basal FSH levels (30). Indeed, the response to ovulation induction was
similar among the three groups, although the group with higher basal
FSH levels required more ampoules to reach the same result (Fig. 2).
Basal day-3 FSH level has been used as a measure of ovarian reserve,
with high levels predicting poor response (14, 31, 32, 33). However, high
FSH levels can also be found in fertile patients, and the sensitivity
of this parameter alone has been estimated to be only 8% (3). FSH
levels in our patients showed a wide variation, as was also observed in
young patients with normal ovarian function (34). It has been suggested
that this feature could be related to intraovarian modification of FSH
action owing to the presence of inhibitors and/or enhancers of the
binding to the receptor (35), principally to growth factors (36)
or to individual differences in the FSHR (22). Each receptor isoform
might mediate a different level of intraovarian FSH action, explaining
the parallelism between FSH levels and therapeutic requirements. Our
data suggest that the different responsiveness of each FSHR genotype is
reflected by the basal FSH levels, and only when a supraphysiological
response is required, as in ovarian stimulation, does the different
capacity of responsiveness becomes evident.
Using standard stimulation protocols, a highly significant difference could be observed in the number of ampoules required to achieve ovulation. The marked difference, of more than 10 ampoules, between the homozygous Asn group and the homozygous Ser group is also reflected by the different FSH serum levels in these groups. However, because FSH values show wide interindividual variations, even within the same FSHR group, the subdivision of the patients solely according to their serum FSH concentrations is not clinically useful, whereas identification of the FSHR genotype permits better classification. This underlines the clinical significance of our findings, which goes far beyond the mere description of an indirect association of two markers, as shown in other polymorphism studies.
Knowing the different sensitivity to FSH, depending on the FSHR genotype, could be important to prevent ovarian hyperstimulation syndrome, a complication with increasing incidence after the introduction of GnRH agonists, which involves the administration of higher doses of gonadotropins (10). It is difficult to prevent this complication because of the narrow therapeutic margin of the ovulation induction agents and because of the impossibility of predicting individual response. Knowledge of the FSHR genotype might provide a means of assessing this individual factor, assuming that pertinent modifications of the ovarian stimulation treatment can be made.
The finding that the FSHR genotype determines ovarian response to FSH should have impact on the delineation of stimulation protocols. In the future, it should be possible to tailor FSH therapy to the patient’s genetic background and to design an individualized ovarian stimulation protocol in advance, adjusting not only doses administered but also the timing of stimulation.
Among the possible benefits of adjusting stimulation protocols according to the expected response could be that the duration and the total amount of FSH needed decreases. Immediate implications are benefits not only from the economic point of view but also in terms of treatment acceptance.
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Acknowledgments |
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Footnotes |
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Received March 13, 2000.
Revised May 25, 2000.
Accepted June 5, 2000.
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References |
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