Female Reproductive Physiology

The female reproductive physiology program in the REU is led by Drs. Hall and Welt.

RESEARCH PROGRAM

Senior Investigator: Janet Hall MD

Dr. Hall’s research focuses on the neuroendocrine interactions underlying normal female reproduction and the changes that occur at both ends of reproductive life (puberty and the menopause) as well as in clinical disorders of ovulation including hypothalamic amenorrhea, polycystic ovarian syndrome, premature ovarian insufficiency and GnRH deficiency. Dr. Hall’s research group has used a combination of clinical investigative approaches in normal women, women with GnRH deficiency and menopausal women to understand the dynamic changes in GnRH secretion that occur across the normal menstrual cycle and the steroidal and non-steroidal feedback responsible for these neuroendocrine changes. Her studies of inhibin have provided evidence for endocrine feedback of inhibin B on FSH in normal women. She has recently shown that African-American women have higher estradiol levels throughout the menstrual cycle compared with Caucasian women due to up-regulation of aromatase activity, a finding that may help to explain the disparities in disease prevalence in these two populations.

Dr. Hall’s research has also shown that sleep has a profound inhibitory effect on GnRH pulse frequency in women in the early follicular phase while circadian factors do not appear to influence gonadotropin secretion in women. Her group is actively investigating the link between sleep and activation of the neuroendocrine components of the reproductive system that are responsible for puberty and have provided evidence that sleep disruption in girls with sleep apnea may alter the course of puberty.

RESEARCH PROGRAM

Senior Investigator: Corrinne Welt MD

Dr. Welt’s laboratory studies the etiology of ovulatory disorders. Her initial work examined the ovarian proteins inhibin A and inhibin B; mapping their physiology and demonstrating their important negative feedback role on follicle stimulating hormone, the driving hormone for follicle development. These studies led to the use of inhibin A and B as biomarkers of ovarian follicle number, function and fertility status, shedding light on pathophysiology of primary ovarian insufficiency, i.e. loss of ovarian function and reproductive capacity by age 40, in women carrying the fragile X premutation and in autoimmune oophoritis.

Her laboratory has also investigated the pathophysiology of ovulatory disorders at the hypothalamic level. Her work demonstrated that leptin is the signal from the periphery to the hypothalamus indicating that energy stores are adequate for reproduction. In addition, her lab demonstrated that prolactin can directly disrupt gonadotropin-releasing hormone secretion from the hypothalamus, in the absence of dopamine mediation that was previously thought critical. She successfully performed a clinical trial of recombinant human prolactin in women with lactation insufficiency. The use of recombinant human prolactin represents the only available treatment for women with prolactin deficiency related to the absence of functioning lactotrophs (prolactin-secreting cells). In a recent collaboration she also helped document the first case of autoimmune prolactin deficiency in one of the mothers in her study.

Building on work using ovarian markers, her laboratory now works on the early identification of reproductive disease and its clinical consequences using genetic markers. Two disorders, polycystic ovary syndrome (PCOS) and primary ovarian insufficiency are particularly compelling for early identification based on their prevalence, the difficulty treating infertility in these patients and the failure to understand the underlying etiology of the disorders. In both cases, determining the underlying genetic cause will shed light on the etiology and will provide markers to predict fertility problems in advance. As a result, her current research program examines the genetics of PCOS, a complex genetic disorder, and primary ovarian insufficiency (POI), a disorder characterized by rare mutations inherited in a Mendelian manner.

PCOS occurs in up to 10% of reproductive age women. The etiology of PCOS, a disorder of anovulatory infertility, hyperandrogenism, the metabolic syndrome, diabetes, endometrial cancer risk and cardiovascular risk, has defied all phenotyping efforts to date. Therefore, Dr. Welt has collaborated with international laboratories to examine the genetics of PCOS through a genome-wide association study (GWAS). Her laboratory has assembled a large patient cohort in Boston with extensive phenotype data and genetic information. The large genotype and phenotype dataset has enabled me to move quickly from genetic risk variants to the phenotypic features of PCOS that are continually emerging from the study. Her laboratory has now completed the initial GWAS study for PCOS and is participating in an international meta-analysis to document risk variants in women of European ethnicity. Her laboratory has also replicated additional genetic risk variants identified by other investigators and was able to determine the cardinal PCOS phenotypic features associated with these risk variants.

In addition to the very large studies that are necessary to identify risk variants in PCOS, her lab used a different set of Mendelian genetic tools to examine causes of primary ovarian insufficiency that lack an etiology. Her laboratory, in collaboration with the Analytical and Translational Genetics Unit, used whole exome sequencing and segregation analysis to identify a novel gene in a family in which three generations of women experienced menopause at the age of 30 years. The gene (eIF4ENIF1) is a binding protein for a ubiquitous eukaryotic translation initiation factor. However, the binding protein is specifically localized to the developing oocytes. The nonsense mutation appears to act in a dominant negative manner and the lab moving this research forward. The work represents the tip of an iceberg because more than 70% of patients with primary ovarian insufficiency have no identifiable etiology for their ovarian dysfunction. The lab will study additional large families and women with sporadic ovarian insufficiency, forming the basis of a new program to study the genetic basis of primary ovarian insufficiency.