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 primary ovarian insufficiency (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 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.? ? Members of the TGF beta superfamily play a role in supporting normal ovarian function. One member of this family, the gene for bone morphogenic protein 15 (BMP 15), is located at Xp11.2. Based on evidence in animal models, as well as a case report linking an A to G transition at position 704 of the BMP15 gene with familial POI, we participated in an international collaboration to perform BMP15 genetic analysis in a large series of women with spontaneous POI. We found heterozygous gene BMP15 gene variants in 7 of 166 patients, significantly more than in controls. Given that BMP15 is within the Xp locus linked to POI, the findings support the concept that BMP15 represents one of the genes whose haploinsufficiency significantly contributes to the POI in Turner syndrome.? ? Deleted in AZoospermia-Like (DAZL), located at 3p24, is another candidate gene for POI. Rather than focusing on rare amino acid changes that severely impair protein function, this effort primarily tested the hypothesis that common variants, or SNPs (single nucleotide polymorphisms) might in aggregate have a measurable effect on the development of POI. We found that SNPs in the DAZL gene may act singly or jointly to affect reproductive characteristics of women. In addition, sequencing of the entire coding region of DAZL, including all exons and flanking regions, identified four putative missense mutations. Further studies may shed light on the role of DAZL in the development of spontaneous POI.? ? Foxo3-null female mice exhibit a distinctive ovarian phenotype of global follicle activation leading to early depletion of functional follicles. Foxo3 functions at the earliest stages of follicle growth as a suppressor of follicle activation. We participated in an international collaboration to test the hypothesis that sequence variation at the human FOXO3 locus is a mechanism of POI and primary amenorrhea. Taken together, our findings do not exclude the possibility that FOXO3 mutations contribute to POI or primary amenorrhea in some individuals, but argue that de novo FOXO3 mutations are not a common cause of either condition.? ? Mice with mutations in the c-kit tyrosine kinase receptor Kit (W) and the c-kit ligand Kitlg (Steel) have impaired development of primordial germ cells. Both KIT and KITLG play critical roles in gametogenesis, as well as hematopoiesis and melanogenesis. Point mutations in the mouse Kit receptor tyrosine kinase can selectively impair fertility without inducing detectable abnormalities in hematopoiesis or pigmentation. However, in previous experiments, we found that mutation of the KIT gene appears not to be a common cause of 46,XX spontaneous POI in women. We recently demonstrated that mutations in the coding regions of the KITLG gene also appear not to be a common cause of this condition. ? ? The normal premenopausal ovary is an important source of androgen as well as estrogen production. We thus undertook a study using the rigorous method of equilibrium dialysis to measure levels of circulating free testosterone in women with 46,XX spontaneous POI. We evaluated 130 such women while they were off any estrogen replacement therapy and then again 3 months later while receiving a standardized estradiol regimen. We sampled regularly menstruating control women during the mid follicular phase. While on estradiol replacement 13% of women had serum free testosterone levels below the lower limit of normal. The clinical implications of this testosterone deficiency may be significant, and we are currently investigating them further.? ? No controlled studies to date have specifically evaluated sexual function in women who have spontaneous 46,XX POI. We assessed sexual function in women with spontaneous 46,XX POI (N=143) after at least 3 months of a standardized hormone replacement regimen. We compared our findings to control women (N=70). Sexual function is in the normal range for most young women with 46,XX spontaneous POI who are receiving physiologic estradiol replacement. As a group, however, these young women score significantly lower on a sexual function scale than control women. We are currently investigating the relative contributions of psychosocial factors and testosterone deficiency on the sexual function of these patients.? ? We have been investigating womens psychological response to the diagnosis of spontaneous POI. In general, given that the inability to reproduce creates a profound loss for most women and affects their self-esteem and relationships with others, the literature has thoroughly documented the psychological distress of women with infertility. We previously demonstrated that over two-thirds of women with POI were unsatisfied with the manner in which they were 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. ? ? 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.? ? We are also investigating methods to improve fertility in women with POI. We demonstrated previously that many of these follicles fail to function normally because they become lutienized prematurely due to chronically elevated serum LH levels. 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, by avoiding inappropriate luteinization, physiologic estradiol replacement therapy might improve follicle function in these women. We are undertaking controlled studies to assess the effect of estrogen replacement on follicle function in these women.
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