Genetic Variants, Environmental Factors, and Ovarian Reserve
Genetic Variants, Environmental Factors, and Ovarian Reserve
BACKGROUND The ovarian reserve (number and quality of oocytes) is correlated with reproductive potential as well as somatic health, and is likely to have multiple genetic and environmental determinants. Several reproductive hormones are closely linked with the oocyte pool and thus can serve as surrogate markers of ovarian reserve. However, we know little about the underlying genes or genetic variants.
METHODS We analyzed genetic variants across the genome associated with two hormonal markers of ovarian reserve, FSH and anti-Mullerian hormone, in a reproductively normal population of Caucasian (n = 232) and African American (n = 200) women, aged 25–45 years. We also examined the effects of environmental or lifestyle factors on ovarian reserve phenotypes.
RESULTS We identified one variant approaching genome-wide significance (rs6543833; P= 8.07 × 10) and several nominal variants nearby and within the myeloid-associated differentiation marker-like (MYADML) gene, that were associated with FSH levels in African American women; these were validated in Caucasian women. We also discovered effects of smoking and oral contraceptive use on ovarian reserve phenotypes, with alterations in several reproductive hormones.
CONCLUSIONS This work is the largest study on ovarian reserve in women of reproductive age and is the only genome-wide study on ovarian reserve markers. The genes containing or near the identified variants have no known roles in ovarian biology and represent interesting candidate genes for future investigations. The discovery of genetic markers may lead to better long-range predictions of declining ovarian function, with implications for reproductive and somatic health.
Infertility is a significant problem in society, affecting 15% of reproductive-aged couples (Hull et al., 1985; Menken and Larsen, 1994; Reijo et al., 1995). Many cases of infertility appear to be the result of defects in germ cell development that lead to reduced numbers or quality of gametes. The quantity and quality of oocytes within the ovaries, or ovarian reserve, are closely correlated with reproductive potential and are likely to have multiple genetic and environmental determinants. Further, ovarian reserve is affected by aging and disease, and is closely tied to both reproductive and somatic health. Many diseases including osteoporosis, cardiovascular disease and various cancers are associated with loss of oocytes/follicles, ovarian dysfunction and/or the length of the female reproductive lifespan (Cooper and Sandler, 1998; Hartge, 2009). Hence, better prediction of both normal and aberrant oocyte depletion would have significant clinical implications.
Several reproductive hormones are closely correlated with the ovarian reserve and the inevitable process of follicle depletion. Current methods for measuring ovarian reserve and predicting age at fertility loss and menopause include assessment of serum levels of FSH, inhibin B and anti-Mullerian hormone (AMH), which decreases ~10 years prior to menopause (van Rooij et al., 2004). AMH and FSH are direct and indirect reflections of follicle number, respectively. AMH is a member of the transforming growth factor-β superfamily; it suppresses the cyclical recruitment of primordial follicles into the pool of growing follicles and is specifically secreted by the granulosa cells of pre-antral and antral follicles in the ovary (Durlinger et al., 2002). Thus, AMH is present in proportion to the number of antral follicles. FSH on the other hand, is an indirect reflection of the follicle pool; it is a gonadotrophin secreted by the anterior pituitary in response to hypothalamic release of GnRH. It stimulates follicular growth and is a key component of the brain-pituitary-ovary axis (Gromoll and Simoni, 2005). FSH is sensitive to the inhibitory influence of inhibin B. Inhibin B is secreted by the granulosa cells of developing and early antral follicles. So as the number of follicles declines, so do inhibin levels and FSH begins to rise. Thus, there is an association between high FSH and low follicle number with ovarian aging.
Antral follicle count (AFC), transvaginal ultrasound-guided assessment of follicles, is routinely performed during fertility assessments. We have recently analyzed the correlations of several hormonal markers and AFC with age in Caucasian women (unpublished data), finding that only AFC and AMH parallel the decline of follicles with age noted in histological ovarian specimens (Hansen et al., 2008). In contrast, FSH shows an inverse relationship with AFC and follicle number in vivo; as follicle number and AMH decline, FSH rises. It is noteworthy that both AMH and FSH levels are highly variable among women, even measured at the same point in the menstrual cycle.
The age of menopause has a strong heritability (Snieder et al., 1998; de Bruin et al., 2001; Murabito et al., 2005). Ovarian aging (OVA), which leads to menopause with the exhaustion of the follicular pool, also seems to have a genetic component (Rosen et al., 2010a). Genetic markers associated with ovarian reserve may have the advantage of providing better long-range predictions of risk for declining ovarian reserve. Thus, determining the genetic associations of rising FSH and declining AMH may allow for improved counseling regarding reproductive health and aging.
Most previous work has focused on measuring the reproductive events of menarche and menopause, or comparing ovarian reserve markers and their ability to predict reproductive outcomes in the context of infertile populations or small observational studies. Moreover, few studies have investigated the genes or variants associated with specific reproductive hormones. Therefore, we sought to identify genes and variants across the genome associated with hormonal markers of ovarian reserve in a multi-ethnic cohort recruited from the general population. We also sought to examine the effects of environmental or lifestyle factors including smoking and oral contraceptive use, on ovarian reserve phenotypes.
Abstract and Introduction
Abstract
BACKGROUND The ovarian reserve (number and quality of oocytes) is correlated with reproductive potential as well as somatic health, and is likely to have multiple genetic and environmental determinants. Several reproductive hormones are closely linked with the oocyte pool and thus can serve as surrogate markers of ovarian reserve. However, we know little about the underlying genes or genetic variants.
METHODS We analyzed genetic variants across the genome associated with two hormonal markers of ovarian reserve, FSH and anti-Mullerian hormone, in a reproductively normal population of Caucasian (n = 232) and African American (n = 200) women, aged 25–45 years. We also examined the effects of environmental or lifestyle factors on ovarian reserve phenotypes.
RESULTS We identified one variant approaching genome-wide significance (rs6543833; P= 8.07 × 10) and several nominal variants nearby and within the myeloid-associated differentiation marker-like (MYADML) gene, that were associated with FSH levels in African American women; these were validated in Caucasian women. We also discovered effects of smoking and oral contraceptive use on ovarian reserve phenotypes, with alterations in several reproductive hormones.
CONCLUSIONS This work is the largest study on ovarian reserve in women of reproductive age and is the only genome-wide study on ovarian reserve markers. The genes containing or near the identified variants have no known roles in ovarian biology and represent interesting candidate genes for future investigations. The discovery of genetic markers may lead to better long-range predictions of declining ovarian function, with implications for reproductive and somatic health.
Introduction
Infertility is a significant problem in society, affecting 15% of reproductive-aged couples (Hull et al., 1985; Menken and Larsen, 1994; Reijo et al., 1995). Many cases of infertility appear to be the result of defects in germ cell development that lead to reduced numbers or quality of gametes. The quantity and quality of oocytes within the ovaries, or ovarian reserve, are closely correlated with reproductive potential and are likely to have multiple genetic and environmental determinants. Further, ovarian reserve is affected by aging and disease, and is closely tied to both reproductive and somatic health. Many diseases including osteoporosis, cardiovascular disease and various cancers are associated with loss of oocytes/follicles, ovarian dysfunction and/or the length of the female reproductive lifespan (Cooper and Sandler, 1998; Hartge, 2009). Hence, better prediction of both normal and aberrant oocyte depletion would have significant clinical implications.
Several reproductive hormones are closely correlated with the ovarian reserve and the inevitable process of follicle depletion. Current methods for measuring ovarian reserve and predicting age at fertility loss and menopause include assessment of serum levels of FSH, inhibin B and anti-Mullerian hormone (AMH), which decreases ~10 years prior to menopause (van Rooij et al., 2004). AMH and FSH are direct and indirect reflections of follicle number, respectively. AMH is a member of the transforming growth factor-β superfamily; it suppresses the cyclical recruitment of primordial follicles into the pool of growing follicles and is specifically secreted by the granulosa cells of pre-antral and antral follicles in the ovary (Durlinger et al., 2002). Thus, AMH is present in proportion to the number of antral follicles. FSH on the other hand, is an indirect reflection of the follicle pool; it is a gonadotrophin secreted by the anterior pituitary in response to hypothalamic release of GnRH. It stimulates follicular growth and is a key component of the brain-pituitary-ovary axis (Gromoll and Simoni, 2005). FSH is sensitive to the inhibitory influence of inhibin B. Inhibin B is secreted by the granulosa cells of developing and early antral follicles. So as the number of follicles declines, so do inhibin levels and FSH begins to rise. Thus, there is an association between high FSH and low follicle number with ovarian aging.
Antral follicle count (AFC), transvaginal ultrasound-guided assessment of follicles, is routinely performed during fertility assessments. We have recently analyzed the correlations of several hormonal markers and AFC with age in Caucasian women (unpublished data), finding that only AFC and AMH parallel the decline of follicles with age noted in histological ovarian specimens (Hansen et al., 2008). In contrast, FSH shows an inverse relationship with AFC and follicle number in vivo; as follicle number and AMH decline, FSH rises. It is noteworthy that both AMH and FSH levels are highly variable among women, even measured at the same point in the menstrual cycle.
The age of menopause has a strong heritability (Snieder et al., 1998; de Bruin et al., 2001; Murabito et al., 2005). Ovarian aging (OVA), which leads to menopause with the exhaustion of the follicular pool, also seems to have a genetic component (Rosen et al., 2010a). Genetic markers associated with ovarian reserve may have the advantage of providing better long-range predictions of risk for declining ovarian reserve. Thus, determining the genetic associations of rising FSH and declining AMH may allow for improved counseling regarding reproductive health and aging.
Most previous work has focused on measuring the reproductive events of menarche and menopause, or comparing ovarian reserve markers and their ability to predict reproductive outcomes in the context of infertile populations or small observational studies. Moreover, few studies have investigated the genes or variants associated with specific reproductive hormones. Therefore, we sought to identify genes and variants across the genome associated with hormonal markers of ovarian reserve in a multi-ethnic cohort recruited from the general population. We also sought to examine the effects of environmental or lifestyle factors including smoking and oral contraceptive use, on ovarian reserve phenotypes.
Source...