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. 2012 Aug 23;29(11):1185–1191. doi: 10.1007/s10815-012-9849-0

The ovarian response to standard gonadotrophin stimulation depends on FSHR, SHBG and CYP19 gene synergism

Leandros A Lazaros 1, Elissavet G Hatzi 1, Christina E Pamporaki 2, Prodromos I Sakaloglou 1, Nectaria V Xita 2, Sophia I Markoula 1, Theodoros I Stefos 1, Konstantinos A Zikopoulos 1, Ioannis A Georgiou 1,✉
PMCID: PMC3510364  PMID: 22915343

Abstract

Purpose

Follicle stimulating hormone, sex hormone-binding globulin and cytochrome P450 aromatase play crucial roles in the regulation of mammalian reproduction. The synergistic effect of FSHR 307(T/A)/FSHR 680(N/S), SHBG(TAAAA)n and CYP19(TTTA)n genotypes on ovarian response to standard gonadotrophin stimulation of women undergoing medically assisted reproduction (IVF/ICSI) was explored.

Methods

The study population consisted of 300 women under IVF/ICSI treatment and 300 women with at least with at least one successful child birth as controls. The polymorphisms were genotyped while the follicular size, the follicle and oocyte numbers were recorded during oocyte retrieval.

Results

The genotype analysis, excluding heterozygotes for each particular polymorphism, revealed eight combined homozygotic FSHR/SHBG/CYP19 genotypes. A gradual reduction in the number of follicles and oocytes from FSHR 307Thr/680Asn allele/long SHBG allele/long CYP19 allele homozygotes to FSHR 307Ala/680Ser allele/short SHBG allele/short CYP19 allele homozygotes was observed (20.36 ± 6.74 vs. 8.05 ± 2.47, p < 0.008 and 13 ± 4.63 vs. 6.1 ± 2.32, p < 0.02, respectively).

Conclusions

FSHR/SHBG/CYP19 combined genotypes are associated with ovarian response to standard gonadotrophin stimulation of women undergoing medically assisted reproduction.

Keywords: Controlled ovarian stimulation, CYP19, FSHR, IVF, SHBG

Introduction

During the last decades a growing body of evidence has accumulated regarding the regulation of ovarian function and consequently of female reproduction. A large number of molecules participate in this organ specific regulatory system, among which follicle stimulating hormone (FSH), sex hormone-binding globulin (SHBG) and cytochrome P450 aromatase (CYP19) play fundamental roles. FSH, which is produced and secreted by gonadotrope cells of the anterior pituitary gland, has been implicated in follicular growth and maturation, in granulosa cell proliferation and in estradiol/aromatase synthesis [1, 2]. FSH effects are mediated by FSH receptor (FSHR), a G-protein-coupled receptor expressed in granulosa cells [3]. On the other hand, the ovarian function is influenced by the granulosa lutein cell synthesized SHBG [4, 5], which constitutes the main transport protein of sex steroids to target tissues [6]. Finally, cytochrome P450 aromatase, also expressed in ovarian granulosa cells and luteal corpus [7], participates in human reproduction by catalyzing the irreversible transformation of androgen to estrogen.

The effects of FSHR, SHBG, CYP19 gene variants on the respective protein activity have been investigated in a wide range of clinically important disorders. The most frequent polymorphisms of the FSHR coding region are situated within exon 10. The first is located in the extracellular domain, changing codon 307 from threonine (Thr) to alanine (Ala), whereas the second is located in the intracellular domain, changing codon 680 from asparagine (Asn) to serine (Ser) [8]. Concerning SHBG gene, a (TAAAA)n pentanucleotide repeat polymorphism at the 5΄-boundary of the gene promoter has been described, which has been shown to influence its transcriptional activity in vitro [9]. Furthermore, the most studied polymorphism of CYP19 gene, which encodes human cytochrome P450 aromatase, is a short tetranucleotide tandem repeat (TTTA)n in intron 4 of the gene. This polymorphism has been involved in steroid hormone regulation [10].

Previous studies of our group have shown significant associations of FSHR 307(T/A)/FSHR 680(N/S), SHBG(TAAAA)n and CYP19(TTTA)n polymorphisms with the ovarian response to standard gonadotrophin stimulation [11–13]. The aim of the current study was to investigate the potential synergistic effect of the above polymorphisms on the follicular numbers and size, the oocyte numbers, the serum hormone levels and the pregnancy rate of women undergoing FSH stimulation for in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), due to tubal or male infertility factor.

Materials and methods

Subjects

300 Caucasian women with tubal or male-factor infertility, who referred to the IVF Unit of the Department of Obstetrics and Gynecology, Ioannina University Medical School, Greece, for IVF/ICSI, participated in the current study. Furthermore, 300 women with at least one successful child birth took part as a control group. All women had ages from 28 to 38 years, normal body mass index (BMI), normal menstrual cycles (28–30 days) and no signs of hyperandrogenism.

All subjects gave a detailed medical history, while physical examination was performed. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2) were determined at the third day of the menstrual cycle by chemiluminescent microparticle immunoassay using an Abbott-ARCHITECT Immunoanalyzer (Abbott Laboratories, Abbott Park, IL, USA). The intra-assay coefficients of variation were 3.5 % for LH, 4 % for FSH and 4.9 % for E2, while the inter-assay coefficients of variation were 8 % for LH, 6.7 % for FSH and 6.4 % for E2. The SHBG concentration was measured using commercial ELISA kit (SHBG ELISA kit, BioSource, Nivelles, Belgium). The intra- and inter-assay coefficients of variation for SHBG were 3.8 % and 7.9 %, respectively. Samples were assayed in duplicate.

All women of the study population underwent a long GnRH agonist stimulation protocol as previously described [11, 14]. Oocytes were retrieved by follicle aspiration by the transvaginal route under ultrasound guidance and the follicles were stratified into two groups according to their diameter (small follicles with diameter ≤12 mm and large follicles with diameter ≥18 mm).

Three embryos with the highest respective blastomere number and the best morphology were transferred the third day of each cycle. The remaining high-grade embryos were cryopreserved the same day. Pregnancy was diagnosed by β-hCG quantification, 2 weeks after embryo transfer. Clinical pregnancy was confirmed by observing fetal cardiac activity on transvaginal ultrasound 4 weeks after a positive pregnancy test.

The Institutional Ethics Committee approved the study protocol in accordance to the Helsinki declaration and all participants gave informed consent.

Genotype analysis

DNA was extracted from peripheral blood leukocytes. FSHR 307 and FSHR 680 polymorphisms amplification was accomplished with polymerase chain reaction (PCR) using two primer pairs and PCR thermal cyclings previously described [12]. FSHR 307 PCR products were subsequently digested with restriction endonuclease Bsu36BI, while FSHR 680 PCR products with BsrI. Nucleotide change T > A at position 307 introduces a recognition site for Bsu36BI underlining the presence of Ala. The resulting genotypes were characterized as TT(307Thr/Thr), TA(307Thr/Ala), AA(307Ala/Ala). Change N > S at position 680 introduces a recognition site for BsrI underlining the presence of Ser. The resulting genotypes were characterized as NN(680Asn/Asn), NS(680Asn/Ser) and SS(680Ser/Ser). Enzyme cleavage products were separated by 3 % agarose gel electrophoresis and visualized by exposure to ultraviolet light after ethidium bromide staining. All reactions were run in duplicates with negative and positive controls and blanks.

The SHBG(TAAAA)n and CYP19(TTTA)n repeat regions were amplified by PCR using primer pairs and thermal cyclings previously described [11, 13]. The PCR products were separated by 10 % polyacrylamide gel electrophoresis and visualized after silver staining. Genotyping error was avoided in our analysis because all PCR products were run in duplicates with short and long genotype controls and other intermediate samples of known (TAAAA)n and (TTTA)n repeats, respectively. The controls were previously analyzed by sequencing. In case of discrepant results, a second round of duplicates was run. Also random sampling and sequencing were done for quality control purposes.

Statistical analysis

Statistical analysis was performed using the chi-square test. Normal distribution of continuous parameters was tested by Kolmogorov-Smirnov test. Differences in continuous parameters between groups and genotypes were assessed with t-test and confirmed with the non-parametric Kruskal–Wallis test. P-value of <0.05 was set as statistically significant. All results are reported as the mean ± SD. All analyzes used the SPSS statistical package (version 14.0, SPSS Inc, Chicago, IL, USA).

Results

Clinical characteristics

The clinical characteristic of the study population and the control group are presented in Table 1. No significant differences were observed in the age, BMI and serum FSH, LH, E2 and SHBG levels between the two groups using the t-test.

Table 1.

Characteristics of the study population and the control group

Study population Control group p-value
Number of patients 300 300
Age of patients (years) 29.2 ± 7.3 28.9 ± 7.7 ns
Body mass index (kg/m2) 22.8 ± 3.2 23.1 ± 3.8 ns
FSH (mIU/ml) 6.4 ± 2.8 6.8 ± 2.2 ns
LH (mIU/ml) 5.1 ± 2.9 4.6 ± 2.8 ns
E2 (pg/ml) 124 ± 35.9 133 ± 40.5 ns
SHBG (nmol/l) 69.1 ± 34.5 72.2 ± 35.1 ns
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Data shown as mean value ± standard deviation

ns non significant

During oocyte retrieval, the 300 women of the study population were presented with 14.1 ± 7.2 follicles, of which 6.9 ± 4.5 had large size while 4.5 ± 4.3 had small size, as well as with 8.5 ± 5.1 oocytes.

Genotype analysis

The FSHR 307(T/A)/FSHR 680(N/S) diplotype analysis revealed three diplotypes: Thr307Thr/Asn680Asn, Thr307Ala/Asn680Ser, Ala307Ala/Ser680Ser, proving the linkage of the polymorphisms [8]. No significant differences in FSHR 307(T/A)/FSHR 680(N/S) diplotype frequencies were observed between the study population and the control group (data not shown). These diplotypes were in Hardy-Weinberg equilibrium in both study population (x2 = 0.05; p > 0.05) and control group (x2 = 0.13; p > 0.05).

The genotype analysis of the SHBG(TAAAA)n polymorphism resulted in 5 (TAAAA)n alleles with 6–11 repeats. For the analysis of the effect of this polymorphism, the study population was subdivided in subgroups using as cut off the (TAAAA)8 allele of the SHBG gene: women with short SHBG genotypes (both alleles with ≤8 TAAAA repeats) and women with long SHBG genotypes (both alleles with >8 TAAAA repeats) . The same cut-off allele has been used in previous studies exploring the distribution of the SHBG(TAAAA)n polymorphism [13, 15]. The SHBG(TAAAA)n genotype frequencies did not present significant differences between the study population and the control group (p > 0.05).

Finally, the genotype analysis of the CYP19(TTTA)n polymorphism revealed 6 CYP19(TTTA)n alleles with 7 to 12 repeats. To analyze the association of this polymorphism with ovarian response to standard gonadotrophin stimulation, the CYP19(TTTA)n alleles were divided into 2 subgroups using the (TTTA)9 allele as a cut-off point (based on the median number of TTTA repeats): short CYP19 alleles with nine or fewer TTTA repeats and long CYP19 alleles with more than nine TTTA repeats. The same cut-off allele has been used in previous studies exploring the distribution of the CYP19(TTTA)n polymorphism [12, 16, 17]. The genotype frequencies of the CYP19(TTTA)n polymorphism did not show significant differences between the two groups (p > 0.05).

The combined FSHR/SHBG/CYP19 genotype analysis resulted in eight homozygotic genotypes, after excluding FSHR 307(T/A)/FSHR 680(N/S), SHBG(TAAAA)n and CYP19(TTTA)n heterozygotes so as to explore the true allelic impact on ovarian response to standard gonadotrophin stimulation. The total number of the homozygotic combined genotypes in the study population was 113 while in the control group 104 (Table 2). The combined FSHR/SHBG/CYP19 genotype frequencies did not differ significantly between the study population and the control group.

Table 2.

The distribution of the combined homozygotic FSHR/SHBG/CYP19 genotypes in the study population and in the control group

Combined homozygotic FSHR/SHBG/CYP19 genotypes Study population group Control group
N N
CG1 FSHR 307Thr/680Asn allele/long SHBG allele/long CYP19 allele homozygotes 12 10
CG2 FSHR 307Thr/680Asn allele/short SHBG allele/long CYP19 allele homozygotes 11 11
CG3 FSHR 307Thr/680Asn allele/long SHBG allele/short CYP19 allele homozygotes 12 11
CG4 FSHR 307Thr/680Asn allele/short SHBG allele/short CYP19 allele homozygotes 14 13
CG5 FSHR 307Ala/680Ser allele/long SHBG allele/long CYP19 allele homozygotes 13 14
CG6 FSHR 307Ala/680Ser allele/short SHBG allele/long CYP19 allele homozygotes 13 12
CG7 FSHR 307Ala/680Ser allele/long SHBG allele/short CYP19 allele homozygotes 15 13
CG8 FSHR 307Ala/680Ser allele/short SHBG allele/short CYP19 allele homozygotes 23 20
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Data shown as number (N)

The association of the combined FSHR/SHBG/CYP19 genotypes with ovarian response to standard gonadotrophin stimulation

The analyzed genotypes were associated with the data collection during previous IVF-ICSI cycles. A gradual reduction in the number of follicles from FSHR 307Thr/680Asn allele/long SHBG allele/long CYP19 allele homozygotes to FSHR307Ala/680Ser allele/short SHBG allele/short CYP19 allele homozygotes was detected (20.36 ± 6.74 vs. 8.05 ± 2.47, p < 0.008) (Fig. 1a). Similar results were found for oocytes. In specific, from FSHR 307Thr/680Asn allele/long SHBG allele/long CYP19 allele homozygotes to FSHR307Ala/680Ser allele/short SHBG allele/short CYP19 allele homozygotes, a gradual decrease in oocyte number was observed (13 ± 4.63 vs. 6.1 ± 2.32, p < 0.02) (Fig. 1b). The presence of FSHR 307Thr/680Asn, long SHBG and long CYP19 alleles was associated with higher follicle and oocytes numbers, while the presence of FSHR307Ala/680Ser, short SHBG and short CYP19 alleles was associated with lower follicle and oocytes numbers.

Fig. 1.

Fig. 1

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Association of the combined homozygotic FSHR/SHBG/CYP19 genotypes with a the follicle numbers (p < 0.008) and b the oocyte numbers (p < 0.02) in the study population. Genotype definition as in Table 2. Data shown as mean value ± sd

However, no statistical significant association was observed between the combined FSHR/SHBG/CYP19 genotypes and the follicular size or the pregnancy rates. Finally, the association analysis of the combined FSHR/SHBG/CYP19 genotypes with serum FSH, LH, E2 and SHBG levels at the third day of the menstrual cycle, revealed no significant correlations.

Discussion

Intrafollicular steroids and their metabolism are crucial for the response and fate of individual follicles [18, 19]. The intrafollicular estrogen production takes place in follicular granulosa cells using as substrate androgens, which are synthesized in theca cells under the catalytic action of cytochrome P450 aromatase [7]. However, estrogen and aromatase production depends on granulosa cell synthesized FSHR [2, 3], the mediator of FSH effects. On the other hand, the transport of intraovarian/intrafollicular sex steroids to target cells/tissues is relied upon SHBG [6], also expressed in granulosa cells. Therefore, the reduced gene activity of the above factors would probably affect the follicular fluid protein content. In the present study, we sought to explore the potential synergistic effect of FSHR 307(T/A)/FSHR 680(N/S), SHBG(TAAAA)n and CYP19(TTTA)n polymorphisms on the ovarian response to standard gonadotrophin stimulation. Indeed, a gradual reduction in the follicle/oocyte number from FSHR 307Thr/680Asn allele/long SHBG allele/long CYP19 allele homozygotes to FSHR 307Ala/680Ser allele/short SHBG allele/short CYP19 allele homozygotes was observed, indicating the significance of these genes for the follicular growth and oocyte maturation during FSH stimulations.

The role of FSHR in the local regulation of ovarian function has been highlighted, studying female FSHR-knockout mice. These mice are characterized by smaller ovaries, atrophic uterus and imperforate vagina [20] probably due to the lack of circulating biologically active estrogen, while their elevated serum and pituitary FSH concentrations lead to follicular arrest at the primordial, primary and preantral stages [21, 22]. In the current study, the combined FSHR/SHBG/CYP19 genotype analysis revealed increased follicle/oocytes numbers in Thr307Thr/Asn680Asn carriers compared to Ala307Ala/Ser680Ser carriers. These findings are in accordance with previous studies [12, 13, 23–28]. The higher follicle and oocyte numbers of Thr307Thr/Asn680Asn women compared to Ala307Ala/Ser680Ser women suggest a putative association of Ala307Ala/Ser680Ser genotype with a poorer response to controlled ovarian stimulation [12, 13, 23–25] and with a need of higher recombinant FSH units administration in Thr307Thr/Asn680Asn women [26–28]. Furthermore, Ser680Ser women have been characterized by longer follicular phase duration [27] compared to the Asn680Asn women, while the Ser680Ser genotype has been observed more frequently in women with ovarian dysfunction [25] and in normogonadotropic anovulatory infertile women [29]. Therefore, women with Ala307Ala/Ser680Ser diplotypes are possibly more resistant to FSH action and they may need increased amounts of gonadotrophins during COS so as to achieve follicle and oocytes numbers as high as those observed in Thr307Thr/Asn680Asn women.

On the other hand, the increased follicle/oocyte numbers of long SHBG(TAAAA)n allele homozygotes compared to short SHBG(TAAAA)n allele homozygotes, which were observed during the combined FSHR/SHBG/CYP19 genotype analysis, put forward the potential significance of this polymorphism alone for the controlled ovarian stimulation outcome. Indeed, a previous study of our group has shown that women with short SHBG(TAAAA)n genotypes have higher numbers of small follicles and decreased numbers of oocytes [11]. Clinical studies have shown that SHBG(TAAAA)n polymorphism affects the transcriptional activity of the SHBG gene leading to variations of serum [30–32] and follicular [11] SHBG levels. Specifically, healthy as well as polycystic ovary syndrome (PCOS) women with long SHBG(TAAAA)n alleles have been characterized by lower SHBG levels. Low serum/follicular SHBG levels leave a considerable amount of androgens unbound and active, which promote both theca and granulosa cell proliferation [33, 34] leading to greater amounts of large follicles and oocytes. However, in the current study the combined FSHR/SHBG/CYP19 genotypes did not show any association with serum SHBG levels at the third day of the menstrual cycle. Taking into consideration that the simultaneous analysis of the three polymorphisms causes a broad combined genotype distribution as well as the reduction in the number of the studied subjects due to the exclusion of heterozygotes, further studies in larger populations are needed to confirm the actual association of the combined FSHR/SHBG/CYP19 genotypes with serum and/or follicular SHBG levels.

The critical role of CYP19 in the local regulation of ovarian function has been found by studying female CYP19-knockout mice. These mice are characterized by hyperandrogenism, congenital genital ambiguity, hypergonadotropic hypogonadism, pubertal failure, virilisation, multicystic ovaries, breast development absence and infertility [35–38]. The combined FSHR/SHBG/CYP19 genotype analysis of the current study showed increased follicle/oocyte numbers in long CYP19(TTTA)n allele homozygotes compared to short CYP19(TTTA)n allele homozygotes. Similar findings have been observed in two previous reports [12, 39]. Short CYP19(TTTA)n allele carriers are probably in need of increased gonadotrophin administration during a controlled ovarian stimulation in order to achieve follicle numbers as high as those observed in long CYP19(TTTA)n allele carriers. The increased estrogen biosynthesis in endometrial tumours of long CYP19(TTTA)n allele homozygotes [40] as well as the higher testosterone/estradiol ratios of short CYP19(TTTA)n allele PCOS homozygotes [10], have suggested a potential association of short CYP19 alleles with reduced aromatase activity. A reduced aromatase activity would probably lead to androgen excess in utero, affecting negatively the anti-Mullerian hormone production by granulosa cells of growing pre-antral and small antral follicles and consequently the ovarian follicle cohort size and reserve [41, 42]. In the current study, although the combined FSHR/SHBG/CYP19 genotypes were not associated with serum estradiol and testosterone levels, their implication in ovarian/follicular estrogen/androgen level regulation, needs to be clarified studying considerably larger population groups.

In the present study, the extremely decreased follicle/oocyte numbers of FSHR307Ala/680Ser allele/short SHBG allele/short CYP19 allele homozygotes are probably found, due to the additive effect of the separate unfavorable genotypes. According to the literature, the Ala307Ala/Ser680Ser genotype has been associated with increased FSH levels, which in turn could affect negatively the synthesis of cytochrome P450 aromatase in granulosa cells [2]. Additionally, the short CYP19(TTTA)n alleles on their own, which have been associated with a reduced aromatase activity [10], could cause an extra impairment in the protein synthesis or sensitivity. Finally, the higher SHBG levels of short SHBG(TAAAA)n homozygotes [11, 30] would probably reduce the levels of unbound/active androgens that could be used by cytochrome P450 aromatase for the biosynthesis of estrogens. Therefore, the consequent estrogen/androgen imbalance would probably lead to a defective maturation of follicles and to decreased follicle/oocyte numbers.

The above results put forward the association of FSHR 307(T/A)/FSHR 680(N/S), SHBG(TAAAA)n and CYP19(TTTA)n combined genotypes with the ovarian response to standard gonadotrophin stimulation of women undergoing medically assisted reproduction and confirm the significance of FSHR, SHBG and CYP19 genes for the female reproductive outcome under stimulation. After the validation of our results in larger patient groups, this combined genotype analysis could help in the selection of the proper stimulation protocol so as to achieve a sufficient number of mature oocytes.

Acknowledgments

Conflict of interest

Authors have no conflicts of interest or any financial support to declare.

Footnotes

Capsule The synergistic effect of FSHR, SHBG and CYP19 genetic variants on ovarian response to standard gonadotrophin stimulation of women undergoing medically assisted reproduction (IVF/ICSI).

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