Genetic Epidemiology of Ovarian Aging
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Women's Studies, Infertility |
| Therapuetic Areas: | Reproductive |
| Healthy: | No |
| Age Range: | 25 - 45 |
| Updated: | 1/11/2019 |
| Start Date: | November 2006 |
| End Date: | December 2020 |
The purpose of this study is to identify clinical and genetic markers of ovarian aging. In
this process, we will evaluate environmental factors that may affect fertility and the age at
which fertility declines, and may influence the age at which women enter menopause. Wide
variability exists between women both in the age at which menopause occurs and the rate of
decline in oocyte number and reproductive capability. As the loss of ovarian function has
profound impact on women's hormonal milieu and their subsequent risk for the development of
disease, improving our understanding of the factors that determine the timing and rate of
reproductive aging is critical to improving quality of life for all women. In addition,
improving our understanding of reproductive aging has profound economic, and social,
implications given the complex choices women face regarding the timing of childbearing and
the growing burden of infertility. While the inter-individual variability in age at menopause
has a large genetic component and possible environmental influences, to date no studies have
addressed the relationship between oocyte number as reflected by antral follicle count (AFC)
and genetic inheritance.
We hypothesize that ovarian aging, as reflected by antral follicle count, is largely
determined by common genetic polymorphisms that impact the initial oocyte endowment and/or
the rate of oocyte loss over time thus lowering antral follicle count for any given age. We
further hypothesize that antral follicle count will be an improved marker of ovarian aging.
Thus, we propose a study of the genetic and environmental factors that influence age-specific
variability in antral follicle count.
this process, we will evaluate environmental factors that may affect fertility and the age at
which fertility declines, and may influence the age at which women enter menopause. Wide
variability exists between women both in the age at which menopause occurs and the rate of
decline in oocyte number and reproductive capability. As the loss of ovarian function has
profound impact on women's hormonal milieu and their subsequent risk for the development of
disease, improving our understanding of the factors that determine the timing and rate of
reproductive aging is critical to improving quality of life for all women. In addition,
improving our understanding of reproductive aging has profound economic, and social,
implications given the complex choices women face regarding the timing of childbearing and
the growing burden of infertility. While the inter-individual variability in age at menopause
has a large genetic component and possible environmental influences, to date no studies have
addressed the relationship between oocyte number as reflected by antral follicle count (AFC)
and genetic inheritance.
We hypothesize that ovarian aging, as reflected by antral follicle count, is largely
determined by common genetic polymorphisms that impact the initial oocyte endowment and/or
the rate of oocyte loss over time thus lowering antral follicle count for any given age. We
further hypothesize that antral follicle count will be an improved marker of ovarian aging.
Thus, we propose a study of the genetic and environmental factors that influence age-specific
variability in antral follicle count.
This is a cross-sectional study with a subgroup followed longitudinally over time. This study
consists of four basic components:
- identification and recruitment of a population-based sample of 1,250 regularly cycling
women of diverse ethnicities, ages 25-45;
- a baseline examination on days 2-4 of the menstrual cycle, including a blood draw,
transvaginal ultrasound examination, body size measurements, and questionnaires, to
establish cross-sectional relations between the AFC and the genetic and environmental
exposures of interest (see Specific Aims);
- genetic analyses of X-chromosome and autosomal mutations, deletions, and polymorphisms,
implicated in the control of ovarian function; and
- follow-up examination, 3 years after baseline, completed by approximately one-third of
the cohort (n=450), to begin to describe longitudinal relations between AFC and the
exposures of interest and to identify markers predictive of accelerated follicle loss.
Specific Aims:
1. Characterize antral follicle count (AFC) as a marker of ovarian age by comparing it to
other available biomarkers, FSH, FSH/LH, and inhibin B, and determine effect
modification of these relationships by age.
2. Examine the relationship between antral follicle counts and the frequencies of specific
genetic polymorphisms in the DAZL (Deleted in AZoospermia-Like) and interacting protein
genes.
3. Determine the associations between race/ethnicity, body fat, and active and passive
smoking and AFC, independently of age; if main effects are observed between genetic
polymorphisms and AFC (Specific Aim 2), explore the effect modification of those
relationships by race/ethnicity, body fat and active and passive smoking.
4. Determine the change in AFC over a three-year period and its relation to genetic and
environmental characteristics, based on the approximately 450 women who complete a
3-year follow-up examination.
The primary goal of this study is to demonstrate the relationship between antral follicle
count and common genetic polymorphisms and the effect of modification of environmental
factors. To achieve this goal, our multidisciplinary team proposes to recruit a random sample
of 1,250 regularly cycling, ethnically diverse women, ages 25-45, who belong to the Northern
California Kaiser Permanente Medical Care (KPMC) Program in San Francisco.
This study will provide evidence to support ultrasound evaluation as a non-invasive marker of
ovarian aging. This and the genetic testing may lead to an opportunity for prospective
identification of patients at risk for early decline in ovarian function. The ability to
accurately generate and share this type of information will allow women to become proactive
in managing their fertility as well as to better understand their risks associated with
reproductive aging. The recruitment of a large, population-based cohort will increase the
generalizability of the data generated. The ethnic diversity of this population will allow
multiple comparisons to identify true "risk factors" for early, and/or accelerated, ovarian
aging and their correlation with ethnicity.
consists of four basic components:
- identification and recruitment of a population-based sample of 1,250 regularly cycling
women of diverse ethnicities, ages 25-45;
- a baseline examination on days 2-4 of the menstrual cycle, including a blood draw,
transvaginal ultrasound examination, body size measurements, and questionnaires, to
establish cross-sectional relations between the AFC and the genetic and environmental
exposures of interest (see Specific Aims);
- genetic analyses of X-chromosome and autosomal mutations, deletions, and polymorphisms,
implicated in the control of ovarian function; and
- follow-up examination, 3 years after baseline, completed by approximately one-third of
the cohort (n=450), to begin to describe longitudinal relations between AFC and the
exposures of interest and to identify markers predictive of accelerated follicle loss.
Specific Aims:
1. Characterize antral follicle count (AFC) as a marker of ovarian age by comparing it to
other available biomarkers, FSH, FSH/LH, and inhibin B, and determine effect
modification of these relationships by age.
2. Examine the relationship between antral follicle counts and the frequencies of specific
genetic polymorphisms in the DAZL (Deleted in AZoospermia-Like) and interacting protein
genes.
3. Determine the associations between race/ethnicity, body fat, and active and passive
smoking and AFC, independently of age; if main effects are observed between genetic
polymorphisms and AFC (Specific Aim 2), explore the effect modification of those
relationships by race/ethnicity, body fat and active and passive smoking.
4. Determine the change in AFC over a three-year period and its relation to genetic and
environmental characteristics, based on the approximately 450 women who complete a
3-year follow-up examination.
The primary goal of this study is to demonstrate the relationship between antral follicle
count and common genetic polymorphisms and the effect of modification of environmental
factors. To achieve this goal, our multidisciplinary team proposes to recruit a random sample
of 1,250 regularly cycling, ethnically diverse women, ages 25-45, who belong to the Northern
California Kaiser Permanente Medical Care (KPMC) Program in San Francisco.
This study will provide evidence to support ultrasound evaluation as a non-invasive marker of
ovarian aging. This and the genetic testing may lead to an opportunity for prospective
identification of patients at risk for early decline in ovarian function. The ability to
accurately generate and share this type of information will allow women to become proactive
in managing their fertility as well as to better understand their risks associated with
reproductive aging. The recruitment of a large, population-based cohort will increase the
generalizability of the data generated. The ethnic diversity of this population will allow
multiple comparisons to identify true "risk factors" for early, and/or accelerated, ovarian
aging and their correlation with ethnicity.
Inclusion Criteria:
- Age 25-45 years
- Self-identifying as one of five specified race/ethnicities - Caucasian, Chinese,
Filipino, African-American, or Hispanic (Mexican or Central American).
- Regular menstrual cycles (monthly bleeding with an interval of 25-35 days)
- Uterus and ovaries required.
Exclusion Criteria:
- Chronic medical illness such as heart, kidney, or liver disease or diabetes
- Endometriosis of ovary
- Prior surgical procedure for removal of ovarian cyst(s)
- Epilepsy
- Lupus
- Invasive cancer excluding squamous or basal cell skin cancers
- Prior treatment with chemotherapy or radiation therapy
- Use of any oral/systemic estrogen or progestin containing medication within a 3-month
period
- Use of any central nervous system active medications known to disrupt the menstrual
cycle (e.g. clonidine, aldomet)
- Psychiatric history involving functionally debilitating disturbance such as psychosis
or major mood disorder requiring hospitalization or change in occupational or social
functioning.
- Currently pregnant or breastfeeding
- Unable to speak and read English, Cantonese, or Spanish
- Concurrent participation in a clinical drug trial.
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