Ovarian Folliculogenesis

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

Genetic studies have identified several loci at Xq22, Xq26-28, and Xp11.2-p22.1 whose disruption has been associated with the development of spontaneous POI. Fragile X syndrome, an X-linked disorder, is the most common hereditary cause of mental retardation and developmental delay. In nearly all cases the disorder is caused by an expansion of CGG trinucleotide repeats in the 5 untranslated region of FMR1 (Fragile Site Mental Retardation 1 Gene). Interestingly, premutations in the FMR1 gene, located at Xq27.3, have been associated with the development of spontaneous 46,XX POI. We previously reported a case of a young woman with established spontaneous POI who conceived subsequent to the diagnosis and had a child who manifests mental retardation due to fragile X syndrome. The case illustrates the need to inform patients with POI regarding their increased risk of carrying a premutation in FMR1, their options for testing, and the potential implications for family members with regard to diagnosis of menstrual irregularity, developmental delay, and neurological symptoms.[unreadable] [unreadable] The forkhead transcription factor Foxo3 is a master regulator and potent suppressor of primordial follicle activation. Loss of Foxo3 function in the mouse leads to primary ovarian insufficiency due to global follicle activation. The mouse Foxo3 locus is haploinsufficient and Foxo3-/+ females undergo early reproductive senescence consistent with an increased rate of primordial follicle utilization. As part of an international collaboration we sought to determine if heterozygous or homozygous polymorphisms or mutations of the human orthologue FOXO3 contribute to primary ovarian insufficiency. The exons and flanking splice sequences of the gene were sequenced in a large number of women with idiopathic primary ovarian insufficiency (n = 302). A total of eight single-nucleotide polymorphisms (SNPs) were identified, revealing a substantial amount of genetic variation at this locus. Allelic frequencies in control samples excluded several of these variants as causal. For the remaining variants, site-directed mutagenesis was performed to assess their functional impact. However, these rare sequence variants were not associated with significant decreases in FOXO3 activity. Taken together, the findings suggest that, despite the potential for FOXO3 haploinsufficiency to cause primary ovarian insufficiency, FOXO3 mutations are not a common cause of primary ovarian insufficiency.[unreadable] [unreadable] We have been investigating womens psychological response to the diagnosis of spontaneous POI. We previously demonstrated that over two-thirds of women with POI were unsatisfied with the manner in which they were informed of the diagnosis. Nearly 90% reported that they experienced moderate to severe emotional distress at the time, the degree of which was positively correlated with the degree of dissatisfaction with the manner in which they had been informed of the diagnosis. They perceived that thorough and accurate medical information on POI, support of others, and spirituality were helpful in coping. The findings suggest that the manner in which patients are informed of this diagnosis can significantly impact their level of distress. Patients perceive a need for clinicians to spend more time with them and provide more information about primary ovarian insufficiency. [unreadable] [unreadable] Ninety percent of women with spontaneous POI reported to us in structured interviews that spirituality plays an important role in helping them cope with the emotional sequelae of this diagnosis. In a follow-up study, we demonstrated a statistically significant positive correlation between functional well-being and spiritual well-being by employing an instrument specifically designed and validated to measure spirituality apart from religiosity. Our findings suggest a need for a controlled interventional clinical trial to test the hypothesis that strategies to assist women in finding meaning and purpose in the diagnosis of spontaneous POI would improve their functional well-being and quality of life. A group of women with the disorder who receive standard management would serve as controls.[unreadable] [unreadable] We also tested the hypothesis that women with spontaneous primary ovarian insufficiency differ from control women with regard to perceived social support and investigated the relationship between perceived social support and self-esteem. We found that women with primary ovarian insufficiency had significantly lower scores than controls on the perceived social support scale and the self-esteem scale. Patients had a significant positive correlation between self-esteem scores and perceived social support. This supports the need for prospective controlled studies. Strategies to improve social support and self-esteem might provide an approach to reduce the emotional suffering that accompanies the life-altering diagnosis of spontaneous primary ovarian insufficiency.[unreadable] [unreadable] We are also investigating methods that might improve fertility in women with POI. In POI the normal process of ovulation usually fails to occur despite the presence of antral follicles in up to 78% of women with this disorder. We demonstrated previously that many of these follicles fail to function normally because they become lutienized prematurely due to the associated chronically elevated serum LH levels. Theoretically estrogen replacement therapy might improve ovulation rates in women with spontaneous POI by reducing the associated chronically elevated serum LH levels to normal. We found that a regimen of 100 microgram per day of transdermal estradiol replacement achieves normal serum LH levels in approximately one-half of women with spontaneous POI. Theoretically, physiologic estradiol replacement therapy might improve follicle function in these women. We are planning controlled studies to assess the effect of estradiol replacement on ovulation in these women.[unreadable] [unreadable] The normal premenopausal ovary is an important source of androgen as well as estrogen production. In premenopausal women the daily testosterone production is approximately 300 micrograms, of which approximately half is derived from the ovaries and half from the adrenal glands. While off estrogen therapy, we found that patients with POI had median serum free testosterone concentrations that were significantly lower than those in controls. While on physiologic transdermal estradiol therapy, their median serum free testosterone dropped significantly lower even though their sex hormone binding globulin levels did not change. While on estradiol replacement 13% of women (95% confidence interval 7.9-20.3%) had serum free testosterone levels below the lower limit of normal. [unreadable] [unreadable] No controlled studies to date have specifically evaluated sexual function in women who have spontaneous 46,XX POI. We sought to determine if women with this condition who have been given estradiol replacement have sexual dysfunction as compared to young women of similar age who have normal ovarian function. Sexual dysfunction can have harmful effects on relationships, self-esteem, and quality of life. We assessed sexual function in women with spontaneous 46,XX POI (N=143) after at least 3 months of a standardized hormone replacement regimen (100 micrograms/day estradiol patch, oral medroxyprogesterone acetate 10 mg for 12 days each month). We compared our findings to control women (N=70) who had normal ovarian function and regular menstrual periods. We employed the Derogatis Interview for Sexual Function Self Report (DISF-SR), a validated self-administered questionnaire. Women with POI had significantly lower DISF-SR composite scores as compared to control women. Their serum total testosterone levels were significantly correlated with DISF-SR composite score, although this accounted for only 4% of the variance in this measure.