Hum. Reprod. Advance Access originally published online on July 18, 2007
Human Reproduction 2007 22(9):2382-2388; doi:10.1093/humrep/dem176
A polymorphism in the AMH type II receptor gene is associated with age at menopause in interaction with parity
1 Department of Internal Medicine, Room Ee532, PO Box 2040, Erasmus MC, 3000 CA Rotterdam, The Netherlands 2 Department of Epidemiology and Biostatistics, Erasmus MC, 3000 CA Rotterdam, The Netherlands 3 Department of Clinical Chemistry, Erasmus MC, 3000 CA Rotterdam, The Netherlands 4 Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, Erasmus MC, 3000 CA Rotterdam, The Netherlands 5 Institute for Research in Extramural Medicine, VU University Medical Center, 1081 BT Amsterdam, The Netherlands 6 Department of Endocrinology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands
7 Correspondence address. Tel: +31-10-4087346; Fax: +31-10-4635430; E-mail: m.kevenaar{at}erasmusmc.nl
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
|---|
BACKGROUND: Anti-Müllerian hormone (AMH) inhibits primordial follicle recruitment in the mouse ovary. We hypothesize that in women AMH signaling also regulates the usage of the primordial follicle pool and hence influences the onset of menopause. Since age at menopause has a strong genetic component, we investigated the role of AMH signaling using a candidate gene approach.
METHODS: In two large population-based cohorts of Dutch post-menopausal women (n = 2381 and n = 248), we examined the association between two polymorphisms, one in the AMH gene and one in the AMH type II receptor (AMHR2) gene, and natural age at menopause.
RESULTS: The AMH Ile49Ser polymorphism (rs10407022) was not associated with age at menopause in either cohort. In the Rotterdam cohort, the AMHR2 –482 A > G polymorphism (rs2002555) was associated with age at menopause in interaction with the number of offspring (P = 0.001). Nulliparous women homozygous for the G-allele entered menopause 2.6 years earlier compared with nulliparous women homozygous for the A-allele (P = 0.005). In the LASA cohort, women with the G/G genotype tended to enter menopause 2.8 years earlier compared with the A/A genotype (P = 0.063).
CONCLUSIONS: The observed association of the AMHR2 –482 A > G polymorphism with natural age at menopause suggests a role for AMH signaling in the usage of the primordial follicle pool in women.
Key words: anti-Müllerian hormone/menopause/follicle recruitment/polymorphism
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
|---|
Menopause marks a dramatic change in the endocrine and reproductive status of women. In women, the onset of menopause is determined by the exhaustion of the ovarian follicle pool (te Velde et al., 1998b
). From the establishment of the primordial follicle pool onwards, just before (for primates) or directly after (for mice) birth, dormant primordial follicles are continuously recruited into the growing follicle pool, a process called initial recruitment. After pubertal onset, a cohort of antral follicles is selected from this growing follicle pool as a result of the increase in circulating FSH levels during each reproductive cycle (McGee and Hsueh, 2000). From this rescued cohort, only one (for primates) or several (for rodents) follicle(s) will ovulate during each cycle, whereas most growing follicles will die as a result of atresia.
Primordial follicle recruitment is predominantly regulated by intra-ovarian factors. One of the factors known to regulate initial recruitment in mice is anti-Müllerian hormone (AMH), also known as Müllerian inhibiting substance (MIS). AMH, a member of the transforming growth factor-
(TGF-) family, is expressed in the ovary from the onset of primordial recruitment onwards in a similar pattern in women and mice (Weenen et al., 2004). AMH expression starts in the granulosa cells of primary follicles, is highest in granulosa cells of pre-antral and small antral follicles and gradually diminishes in the subsequent stages of follicle development (Durlinger et al., 2002b). Studies of the AMH knockout (AMHKO) mice revealed that primordial follicles are recruited at a faster rate in the absence of AMH, illustrating that AMH plays an inhibitory role in the recruitment of primordial follicles. The absence of AMH results in a prematurely exhausted follicle pool and, subsequently, an earlier cessation of the estrus cycle (Durlinger et al., 1999). AMH inhibits mouse, bovine and human primordial follicle growth in vitro (Durlinger et al., 2002a; Gigli et al., 2005; Carlsson et al., 2006), although conflicting results have been reported (Schmidt et al., 2005). In addition to recruitment, AMH attenuates FSH sensitivity in mice (Durlinger et al., 2001; Visser et al., 2007), albeit also for this role of AMH contrary results have been found (McGee et al., 2001). On the basis of the similar expression pattern of AMH in women and in mice, we hypothesize that also in women AMH inhibits primordial follicle recruitment and thus might influence the onset of menopause.
In Western countries, the average age at menopause is 50–51 years, but ranges from 40 to 60 years (te Velde et al., 1998a). Environmental factors and personal history (e.g. smoking and parity) explain only a minor part of the variety in natural age at menopause, whereas the main part is explained by genetic factors (Kok et al., 2005b). This conclusion is mainly based on the strong correlation of age at menopause in monozygotic twins, in whom heritability estimates range from 0.63 to 0.72 (Snieder et al., 1998; de Bruin et al., 2001). In addition, a genetic component of age at menopause was suggested by several candidate gene studies. For example, polymorphisms in genes involved in estrogen metabolism have been associated with age at menopause, e.g. ER
(Weel et al., 1999), CYP 17 (Gorai et al., 2003) and CYP1B1 (Hefler et al., 2005), although these findings have not been replicated (Gorai et al., 2003; Hefler et al., 2005; Kok et al., 2005a).
In a recent study, we have shown that in premenopausal women, genetic variants in AMH and its specific AMH type II receptor (AMHR2) gene are associated with estradiol levels, suggesting modulation of intra-ovarian FSH sensitivity by these variants (Kevenaar et al., 2007). In the present study, we have evaluated whether the AMH Ile49Ser (rs10407022) and the AMHR2 –482 A > G (rs2002555) polymorphisms are associated, independently and in interaction with environmental factors, with age at menopause in two large cohorts of Dutch postmenopausal women.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
|---|
Subjects
The first study cohort was derived from women from the Rotterdam Study (n = 7983, 61.6% women), a prospective population-based study of determinants of chronic disabling diseases in the elderly. The design and rationale of this study have been described earlier (Hofman et al., 1991
). Written informed consent was obtained from each participant and the Rotterdam study was approved by the Medical Ethics Review board of Erasmus MC. During the home interview, each woman provided information on her reproductive and gynecological history, including the use of sex steroids at any time (Weel et al., 1999). Confounding factors, such as height, weight, smoking and socio-economic status, were defined as described previously (Weel et al., 1999). For this study, only women with a natural age at menopause were selected (n = 3256). Natural age at menopause was defined as the age at the last menstrual period, which can only be defined retrospectively after at least 12 consecutive months of amenorrhoe. This last menstrual period should not be induced by surgery or other obvious causes, such as irradiation or hormone therapy (WHO Scientific Group, 1996). Women who reported hormone use during the onset of menopause were excluded to avoid uncertainty on menopausal age. DNA was available for 2564 eligible women, of whom 92.9% was successfully genotyped for the AMH and AMHR2 polymorphism, resulting in a final study cohort of 2381 women.
The second study cohort was derived from the Longitudinal Aging Study Amsterdam (LASA), an ongoing interdisciplinary cohort study on predictors and consequences of changes in autonomy and wellbeing in an aging population in The Netherlands (Deeg et al., 1993). The design of this study has been described previously (Pluijm et al., 2004; Schaap et al., 2005). Informed consent was obtained from all respondents and the study was approved by the Medical Ethics Review board of the VUMC. Information on oral contraceptive use and age at menarche was provided in the main interview of the first examination (1992/1993). At the medical interview during the second data collection (1995/1996), other gynecological and reproductive information was provided, including age at menopause, number of children and sex steroid use, along with the confounding factors height, weight, smoking (ever versus never smoking) and socio-economic status. DNA was available from 966 of the 1509 participants of the medical interview (471 men and 495 women) (Pluijm et al., 2004). In 461 of the women, the AMH and AMHR2 polymorphism were successfully genotyped. For the present study, only women with a natural menopause were selected. Furthermore, women who had ever used HRT or oral contraceptives were excluded, resulting in a final study cohort of 248 women.
Genotyping
Genomic DNA was extracted from peripheral blood using standard DNA extraction methods. The AMH Ile49Ser and AMHR2 –482 A > G genotypes were determined using Taqman allelic discrimination assays. For the AMH Ile49Ser polymorphism, an Assay-by-Design with the following probes was used: 5'-CTCCAGGCAtCCCACAA-3' and 5'-CCAGGCAgCCCACAA-3'. For the AMHR2 –482 A > G promoter SNP, we used an Assay-on-Demand, Assay ID C_ 1673084_10 (Applied Biosystems, Nieuwerkerk aan den IJssel, The Netherlands). Reactions were performed as described previously (Kevenaar et al., 2007). A random selection of 5% of samples was independently repeated to confirm genotyping results. In the Rotterdam Study, the disagreement rate for the AMH Ile49Ser SNP was 0.4%, whereas it was 0.0% in the LASA study. The disagreement rate for the AMHR2 –482 A > G SNP was 0.0% in both study cohorts.
Statistical analysis
In both populations, genotype frequencies were tested for Hardy–Weinberg equilibrium proportions using the ARLEQUIN package (Schneider et al., 2000). Differences between the cohorts and differences between genotype groups within each cohort were tested using one-way analysis of variance (ANOVA) for continuous variables and the chi-squared test for categorical variables. Differences in age at menopause between genotype groups were adjusted for potential confounders (age, BMI, smoking, socio-economic status, age at menarche, parity and use of oral contraceptives and hormone replacement therapy) using ANCOVA. Possible interactions between genotypes and covariates were explored in plots and tested using the general linear model procedure of ANCOVA including product terms of main effects. In the Rotterdam cohort, stratified analysis for the number of offspring was performed. Because of the relatively small sample size, this stratified analysis was not performed in the LASA cohort. Subsequently, to increase statistical power, both cohorts were combined and differences in age at menopause between the AMHR2 genotype groups were analyzed using ANCOVA. All analyses were performed using Statistical Package for Social Sciences, SPSS, version 11.0.1 (SPSS Inc., Chicago, IL, USA). P-value 
0.05 was considered to be significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
|---|
Characteristics of the two study cohorts
Women in the Rotterdam cohort had on average a lower age at the time of the interview and a lower BMI compared with women in the LASA cohort, although these differences were only minor. The mean age at natural menopause was similar in both cohorts. Possible confounding factors for age at menopause, such as smoking and age at menarche, were not different between both cohorts, whereas the average number of offspring and socio-economic status were different between the cohorts (Table 1). In addition, age at natural menopause (49.6 ± 4.4 year, mean ± SD) in our study subset of the Rotterdam cohort was nearly identical to the mean age at natural menopause (49.6 ± 4.5 year) in the total Rotterdam cohort.
|
Genotype distributions in the study populations
The allele and genotype frequencies of the AMH Ile49Ser and the AMHR2 –482 A > G polymorphism were similar in the Rotterdam study and the LASA study and did not differ from the frequencies in premenopausal women (Kevenaar et al., 2007
) or in Caucasians in the NCBI database (www.ncbi.nlm.nig.gov) and in the HapMap database (www.hapmap.org) (The International HapMap Project, 2003). In both study cohorts, the genotype frequencies were in Hardy–Weinberg equilibrium proportions (Tables 2 and 3).
|
|
Analysis of the AMH Ile49Ser polymorphism
No differences were observed in the basal characteristics between the genotype groups of the AMH Ile49Ser polymorphism in both cohorts (Table 2). Age at natural menopause was similar between the genotype groups of the AMH Ile49Ser polymorphism, as were age at menarche, number of offspring (Table 2), smoking, socio-economic status and sex steroid use, including hormone replacement therapy and oral contraceptive use (results not shown). Adjustment of age at menopause for possible confounders did not affect the results.
Analysis of the AMHR2 –482 A > G polymorphism
Basal characteristics were similar between the genotype groups of the AMHR2 –482 A > G polymorphism in both cohorts (Table 3). In the Rotterdam cohort, crude age at menopause was not different between the AMHR2 genotypes, as were age at menarche and hormone use, whereas for the number of offspring, a significant difference was observed (P = 0.01). Homozygous carriers of the –482G allele were more frequently nulliparous (31.6%) compared with women with the AMHR2 –482 A/A genotype (22.5%) or AMHR2 –482 A/G genotype (18.2%) (Table 3). Since the number of offspring was different between the AMHR2 genotypes and the number of offspring is associated with age at menopause, we stratified the association analysis of age at menopause for this parameter. We observed a significant influence of the number of children on age at menopause in the AMHR2 –482 G/G homozygous group (n = 79). Nulliparous women with the G/G genotype had a 2.6 years earlier onset of menopause (46.6 ± 0.9 year, mean ± SEM) compared with nulliparous women with the AMHR2 A/A genotype (49.2 ± 0.2 year, P = 0.005) (Fig. 1). Women with one or two children and the G/G genotype had a similar onset of menopause compared with the other AMHR2 genotypes (P = 0.51), whereas women with the G/G genotype and more than two children tended to have a 1.5 years later onset of menopause (51.4 ± 0.8) compared with the A/A genotype (49.9 ± 0.2), although this does not reach significance (P = 0.072) (Fig. 1). When differences in age at menopause among genotype groups were tested in an univariate regression model, adjusted for all possible confounders, a strong synergistic interaction (P = 0.001) between the AMHR2 G/G genotype and the number of offspring was observed.
|
In the LASA cohort, women homozygous for the AMHR2 –482G allele tended to enter menopause 2.8 years earlier compared with women homozygous for the –482A allele (P = 0.054) (Table 3). After adjustment of age at menopause for possible confounders, this difference remained borderline significant (P = 0.063). In the LASA cohort, no differences were observed between the AMHR2 genotype groups in age at menarche, number of offspring (Table 3), smoking and socio-economic status (results not shown).
When the Rotterdam cohort and the LASA cohort were analyzed together with adjustment for possible confounders, the AMHR2 –482 A > G polymorphism tended to be associated with age at menopause (A/A 49.7 ± 0.1, A/G 49.4 ± 0.2, G/G 48.9 ± 0.5, mean ± SEM, P = 0.068). Combined analysis of the AMH Ile49Ser polymorphism and the AMHR2 –482 A > G polymorphism revealed no additional associations with age at menopause (results not shown).
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
|---|
In the present study, we investigated for the first time whether genetic variants in the AMH signaling pathway influence the onset of natural menopause. In two Dutch cohorts of post-menopausal women, the association of two polymorphisms in the AMH and AMHR2 gene, which both capture the common genetic variation in the gene (Kevenaar et al., 2007
), with age at menopause was studied. In the Rotterdam study, the AMHR2 –482 A > G polymorphism was associated with age at menopause in interaction with parity. Also in the LASA cohort and when both cohorts were combined, the AMHR2 –482 A > G polymorphism tended to be associated with age at menopause.
Women with the AMHR2 –482 G/G genotype tended to have an earlier onset of menopause compared with women with the A/A genotype, which is indicative of less inhibition of primordial follicle recruitment. Hence, the AMHR2 –482 G/G genotype could result in diminished AMH signaling, which is in concordance with a previous study (Kevenaar et al., 2007), in which the –482G allele was associated with higher estradiol levels in premenopausal women, correlating with less inhibition of FSH sensitivity by AMH. Indeed, the –482 A > G polymorphism is located at a potential c-Myb and c-Myc transcription factor-binding site (www.cbil.upenn.edu/tess) (Schug and Overton, 1997), and therefore may modify promoter activity.
Besides the subtle differences in age at menopause between the AMHR2 genotypes in the combined cohort, we observed a strong synergistic interaction between the AMHR2 G/G genotype and the number of children in the Rotterdam cohort. This interaction suggests that the –482 A > G polymorphism influences the relation between age at menopause and parity. The relation between age at menopause and parity has been demonstrated in many epidemiological studies (Stanford et al., 1987; Whelan et al., 1990; Cramer et al., 1995; Cassou et al., 1997; van Noord et al., 1997). Nulliparous women enter menopause 0.5 (Whelan et al., 1990) to 1.5 years (Stanford et al., 1987) earlier compared with parous women, as is also observed in the Rotterdam study (0.6 years difference) (results not shown). Nevertheless, little is known about the underlying mechanism of this relation between age at menopause and parity. Two possible explanations have been proposed. First, it has been suggested that age at menopause and parity are not causally related but are both reflecting the process of ovarian aging (Kok et al., 2003). The second explanation is that during pregnancy, less primordial follicles are recruited, resulting in a delayed onset of menopause (Stanford et al., 1987; Whelan et al., 1990; McGee and Hsueh, 2000). The latter explanation is supported by rodent studies. In mice, the number of follicles that start growing is reduced during pregnancy (Pedersen and Peters, 1971), and rats allowed to undergo multiple pregnancies show a delay in reproductive aging (Matt et al., 1987). Furthermore, prolonged elevation of circulating progesterone in rats suppresses initial follicle recruitment, thus maintaining a larger primordial follicle pool (Lapolt et al., 1988; Lapolt et al., 1998). During pregnancy in women, AMH serum levels, which reflect the size of the growing and, indirectly, the primordial follicle pool (van Rooij et al., 2002; Visser et al., 2006), apparently do not change (La Marca et al., 2005), suggesting that during pregnancy initial recruitment continues. Alternatively, initial recruitment might halt but growing follicles might be rescued from atresia during pregnancy.
In view of the effects of AMH and possibly also parity on primordial follicle recruitment, it is intriguing that the relation between parity and age at menopause appears to be influenced by the AMHR2 –482 A > G polymorphism. The –482 A > G SNP, located in the promoter region of the gene, is in linkage disequilibrium with several other SNPs (Kevenaar et al., 2007), and therefore also other variants can drive the observed association. However, it is possible that changes in hormone levels during pregnancy, such as progesterone, prolactin and estradiol, alter the expression or function of the receptor. Although signaling of the G-allele derived AMHRII in regularly cycling women is probably less compared with the A-allele derived AMHRII, altered hormone levels during pregnancy might have a stronger effect on the G-allele AMHRII than on the A-allele AMHRII. This may result in increased expression and/or activity of the G-allele derived AMHRII and thereby a stronger inhibition of primordial follicle recruitment during pregnancy. However, functional studies and additional replication studies are necessary to obtain definite conclusions regarding the effect of the AMHR2 –482 A > G polymorphism on age at menopause.
For the AMH Ile49Ser polymorphism, no association with age at menopause is observed in both cohorts, suggesting that this polymorphism does not affect AMH function in follicle recruitment. In contrast, in our previous study (Kevenaar et al., 2007), we observed that the AMH Ile49Ser polymorphism is associated with altered FSH sensitivity. It is possible that the effect of this polymorphism on primordial follicle recruitment is masked or compensated by other factors.
In the Rotterdam and the LASA cohort, age at menopause was determined retrospectively, which has been shown to be susceptible to bias (den Tonkelaar, 1997; Hahn et al., 1997). Nevertheless, it seems unlikely that misclassification due to recall bias is different across genotypes.
In conclusion, the observed association of genetic variation in the AMHR2 gene with age at menopause suggests a role for AMH signaling in the complex process of human ovarian aging. Although the potential consequences of the AMHR2 –482 A > G polymorphism on receptor function still need to be elucidated, our results suggest that the AMHR2 polymorphism contributes to the wide range in onset of menopause. Furthermore, our results may provide more insight into the mechanism that drives the relationship between age at menopause and parity. It will be interesting to determine whether the AMHR2 polymorphism also influences the risk of menopause-related diseases, such as osteoporosis and breast cancer.
|
Acknowledgements |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
|---|
The Longitudinal Aging Study Amsterdam is largely supported by a grant from the Netherlands Ministry of Health Welfare and Sports, Directorate of Nursing Care and Older persons. The authors are very grateful to the participants of the LASA study and the Rotterdam study and acknowledge all participating general practitioners and the many field workers in the research center of the Rotterdam Study in Ommoord, Rotterdam, The Netherlands.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
|---|
de Bruin JP, Bovenhuis H, van Noord PA, Pearson PL, van Arendonk JA, te Velde ER, Kuurman WW, Dorland M. The role of genetic factors in age at natural menopause. Hum Reprod (2001) 16:2014–2018.
Carlsson IB, Scott JE, Visser JA, Ritvos O, Themmen APN, Hovatta O. Anti-Mullerian hormone inhibits initiation of growth of human primordial ovarian follicles in vitro. Hum Reprod (2006) 21:2223–2227.
Cassou B, Derriennic F, Monfort C, Dell'Accio P, Touranchet A. Risk factors of early menopause in two generations of gainfully employed French women. Maturitas (1997) 26:165–174.[CrossRef][ISI][Medline]
Cramer DW, Xu H, Harlow BL. Does "incessant" ovulation increase risk for early menopause? Am J Obstet Gynecol (1995) 172:568–573.[CrossRef][ISI][Medline]
Deeg D, Knipscheer C, van Tilburg W. Autonomy and Well-being in the Aging Population: Concepts and Design of the Longitudinal Aging Study Amsterdam (1993) Bunnili: Netherlands Institute of Gerontology.
Durlinger ALL, Kramer P, Karels B, de Jong FH, Uilenbroek JTJ, Grootegoed JA, Themmen APN. Control of primordial follicle recruitment by anti-Mullerian hormone in the mouse ovary. Endocrinology (1999) 140:5789–5796.
Durlinger ALL, Gruijters MJG, Kramer P, Karels B, Kumar TR, Matzuk MM, Rose UM, de Jong FH, Uilenbroek JTJ, Grootegoed JA, et al. Anti-Mullerian hormone attenuates the effects of FSH on follicle development in the mouse ovary. Endocrinology (2001) 142:4891–4899.
Durlinger ALL, Gruijters MJG, Kramer P, Karels B, Ingraham HA, Nachtigal MW, Uilenbroek JTJ, Grootegoed JA, Themmen APN. Anti-Mullerian hormone inhibits initiation of primordial follicle growth in the mouse ovary. Endocrinology (2002a) 143:1076–1084.
Durlinger ALL, Visser JA, Themmen APN. Regulation of ovarian function: the role of anti-Mullerian hormone. Reproduction (2002b) 124:601–609.[Abstract]
Gigli I, Cushman RA, Wahl CM, Fortune JE. Evidence for a role for anti-Mullerian hormone in the suppression of follicle activation in mouse ovaries and bovine ovarian cortex grafted beneath the chick chorioallantoic membrane. Mol Reprod Dev (2005) 71:480–488.[CrossRef][ISI][Medline]
Gorai I, Tanaka K, Inada M, Morinaga H, Uchiyama Y, Kikuchi R, Chaki O, Hirahara F. Estrogen-metabolizing gene polymorphisms, but not estrogen receptor-alpha gene polymorphisms, are associated with the onset of menarche in healthy postmenopausal Japanese women. J Clin Endocrinol Metab (2003) 88:799–803.
Hahn RA, Eaker E, Rolka H. Reliability of reported age at menopause. Am J Epidemiol (1997) 146:771–775.
Hefler LA, Grimm C, Heinze G, Schneeberger C, Mueller MW, Muendlein A, Huber JC, Leodolter S, Tempfer CB. Estrogen-metabolizing gene polymorphisms and age at natural menopause in Caucasian women. Hum Reprod (2005) 20:1422–1427.
Hofman A, Grobbee DE, de Jong PT, van den Ouweland FA. Determinants of disease and disability in the elderly: the Rotterdam Elderly Study. Eur J Epidemiol (1991) 7:403–422.[CrossRef][ISI][Medline]
Kevenaar ME, Themmen APN, Laven JSE, Sonntag B, Lie Fong S, Uitterlinden AG, de Jong FH, Pols HAP, Simoni M, Visser JA. Anti-Mullerian hormone and anti-Mullerian hormone type II receptor polymorphisms are associated with follicular phase estradiol levels in normo-ovulatory women. Hum Reprod (2007) 22:1547–1554.
Kok HS, van Asselt KM, van der Schouw YT, Grobbee DE, te Velde ER, Pearson PL, Peeters PHM. Subfertility reflects accelerated ovarian ageing. Hum Reprod (2003) 18:644–648.
Kok HS, Onland-Moret NC, van Asselt KM, van Gils CH, van der Schouw YT, Grobbee DE, Peeters PHM. No association of estrogen receptor alpha and cytochrome P450c17alpha polymorphisms with age at menopause in a Dutch cohort. Hum Reprod (2005a) 20:536–542.
Kok HS, van Asselt KM, van der Schouw YT, Peeters PHM, Wijmenga C. Genetic studies to identify genes underlying menopausal age. Hum Reprod Update (2005b) 11:483–493.
La Marca A, Giulini S, Orvieto R, De Leo V, Volpe A. Anti-Mullerian hormone concentrations in maternal serum during pregnancy. Hum Reprod (2005) 20:1569–1572.
Lapolt PS, Yu SM, Lu JK. Early treatment of young female rats with progesterone delays the aging-associated reproductive decline: a counteraction by estradiol. Biol Reprod (1988) 38:987–995.[Abstract]
Lapolt PS, Matt DW, Lu JK. Progesterone implants delay age-related declines in regular estrous cyclicity and the ovarian follicular reserve in Long-Evans rats. Biol Reprod (1998) 59:197–201.
Matt DW, Sarver PL, Lu JK. Relation of parity and estrous cyclicity to the biology of pregnancy in aging female rats. Biol Reprod (1987) 37:421–430.[Abstract]
McGee EA, Hsueh AJ. Initial and cyclic recruitment of ovarian follicles. Endocr Rev (2000) 21:200–214.
McGee EA, Smith R, Spears N, Nachtigal MW, Ingraham H, Hsueh AJ. Mullerian inhibitory substance induces growth of rat preantral ovarian follicles. Biol Reprod (2001) 64:293–298.
van Noord PAH, Dubas JS, Dorland M, Boersma H, te Velde E. Age at natural menopause in a population-based screening cohort: the role of menarche, fecundity, and lifestyle factors. Fertil Steril (1997) 68:95–102.[CrossRef][ISI][Medline]
Pedersen T, Peters H. Follicle growth and cell dynamics in the mouse ovary during pregnancy. Fertil Steril (1971) 22:42–52.[ISI][Medline]
Pluijm SM, van Essen HW, Bravenboer N, Uitterlinden AG, Smit JH, Pols HA, Lips P. Collagen type I alpha1 Sp1 polymorphism, osteoporosis, and intervertebral disc degeneration in older men and women. Ann Rheum Dis (2004) 63:71–77.
van Rooij IAJ, Broekmans FJM, te Velde ER, Fauser BCJM, Bancsi LF, de Jong FH, Themmen APN. Serum anti-Mullerian hormone levels: a novel measure of ovarian reserve. Hum Reprod (2002) 17:3065–3071.
Schaap LA, Pluijm SM, Smit JH, van Schoor NM, Visser M, Gooren LJ, Lips P. The association of sex hormone levels with poor mobility, low muscle strength and incidence of falls among older men and women. Clin Endocrinol (Oxf) (2005) 63:152–160.[CrossRef][Medline]
Schmidt KL, Kryger-Baggesen N, Byskov AG, Andersen CY. Anti-Mullerian hormone initiates growth of human primordial follicles in vitro. Mol Cell Endocrinol (2005) 234:87–93.[CrossRef][ISI][Medline]
Schneider S, Roessli D, Excoffier L. Arlequin Version 2.000: A Software for Population Genetics Data Analysis (2000) Geneva: Genetics and Biometry Laboratory, University of Geneva. 2.000.
Schug J, Overton GC. TESS: Transcription Element Search Software (1997.) Computational Biology and Informatics Laboratory, University of Pennsylvania.
Snieder H, MacGregor AJ, Spector TD. Genes control the cessation of a woman's reproductive life: a twin study of hysterectomy and age at menopause. J Clin Endocrinol Metab (1998) 83:1875–1880.
Stanford JL, Hartge P, Brinton LA, Hoover RN, Brookmeyer R. Factors influencing the age at natural menopause. J Chronic Dis (1987) 40:995–1002.[CrossRef][ISI][Medline]
The International HapMap consortium. The International HapMap Project. Nature (2003) 426:789–796.[CrossRef][Medline]
den Tonkelaar I. Validity and reproducibility of self-reported age at menopause in women participating in the DOM-project. Maturitas (1997) 27:117–123.[CrossRef][ISI][Medline]
te Velde ER, Dorland M, Broekmans FJ. Age at menopause as a marker of reproductive ageing. Maturitas (1998a) 30:119–125.[CrossRef][ISI][Medline]
te Velde ER, Scheffer GJ, Dorland M, Broekmans FJM, Fauser BCJM. Developmental and endocrine aspects of normal ovarian aging. Mol Cell Endocrinol (1998b) 145:67–73.[CrossRef][ISI][Medline]
Visser JA, de Jong FH, Laven JSE, Themmen APN. Anti-Mullerian hormone: a new marker for ovarian function. Reproduction (2006) 131:1–9.
Visser JA, Durlinger AL, Peters IJ, van den Heuvel ER, Rose UM, Kramer P, de Jong FH, Themmen AP. Increased Oocyte Degeneration and Follicular Atresia during the Estrous Cycle in Anti-Mullerian Hormone Null Mice. Endocrinology (2007) 148:2301–2308.
Weel AEAM, Uitterlinden AG, Westendorp ICD, Burger H, Schuit SCE, Hofman A, Helmerhorst TJM, van Leeuwen JPTM, Pols HAP. Estrogen receptor polymorphism predicts the onset of natural and surgical menopause. J Clin Endocrinol Metab (1999) 84:3146–3150.
Weenen C, Laven JSE, Von Bergh AR, Cranfield M, Groome NP, Visser JA, Kramer P, Fauser BCJM, Themmen APN. Anti-Mullerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod (2004) 10:77–83.
Whelan EA, Sandler DP, McConnaughey DR, Weinberg CR. Menstrual and reproductive characteristics and age at natural menopause. Am J Epidemiol (1990) 131:625–632.
WHO Scientific Group. Research on the menopause in the 1990s. World Health Organ Tech Rep Ser (1996) 866:1–107.[Medline]
Submitted on March 28, 2007; resubmitted on May 1, 2007; accepted on May 21, 2007.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||