Faculty Bibliography

BACKGROUND: It is unknown whether etiologies differ between milder forms of premature ovarian senescence (the acronym given here 'premature ovarian aging, POA'), and premature ovarian failure (POF). METHODS: We assessed presumed pathophysiologies in 74 consecutive POA patients, diagnosed based on elevated age-specific baseline follicle stimulating hormone and/or abnormally low anti-Mullerian hormone levels (<1.5 ng/ml). A genetic etiology was presumed with > or = 34 triple CGG expansions on the FMR1 gene. An autoimmune etiology was assumed with at least one abnormality in a laboratory panel, involving antinuclear, antiphospholipid and thyroid antibodies, total immunoglobulin levels and anti-ovarian as well as anti-adrenal autoantibodies. A combined etiology was presumed with both autoimmune and genetic etiologies, and a patient was considered idiopathic when no abnormalities were found. RESULTS: Twelve of 74 (16.2%) women demonstrated a genetic, 28 (37.8%) an autoimmune, 9 (12.2%) combined and 25 (33.8%) idiopathic etiologies. CONCLUSIONS: Presumed underlying etiologies with POA follow a similar distribution pattern as reported for POF. POA and POF may, therefore, represent a continuum in phenotypical expression of different etiologies of premature ovarian senescence. Like POF, POA should be considered reason to investigate underlying etiologies.

Most individuals demonstrate 29-30 CGG triple repeats on the FMR1 gene. This may functionally represent a normal range in regard to ovarian reserve. Higher counts reflect risk towards premature ovarian senescence, but lower counts have not been investigated before and, therefore, were the principal subject of this investigation. Amongst 316 consecutive infertility patients, 94 demonstrated <28 repeats (group A), 163 28-33 repeats (group B, considered normal repeat numbers) and 59 > or =34 repeats (group C). The three groups did not differ in age, FSH or anti-Mullerian hormone (AMH) concentrations. Neither FSH nor AMH correlated in linear regression with <28 CGG repeats. In logistic regression, AMH of < or =0.8 ng/ml (indicative of diminished ovarian reserve at all ages) was, however, significantly associated with number of repeats (P < 0.001). Every decrease by five CGG repeats in group A increased the likelihood of diminished ovarian reserve by 40%, while every increase by five CGG repeats in group C increased risk by 50% (both P < 0.002). AMH of < or =0.8 ng/ml statistically correlated overall with decreasing triple CGG repeats throughout all ranges (P < 0.001). Approximately 29-30 CGG repeats appear reflective of normal ovarian reserve, with higher and lower counts denoting similar risks towards premature ovarian senescence.

Treatment modalities for numerous oncological and non-oncological conditions result in gonadal insufficiency and infertility. Furthermore, pelvic-abdominal radiation may result in uterine damage resulting in poor reproductive outcomes such as preterm birth, low birth weight, and spontaneous abortion in adult survivors of childhood cancers. In response to the recognition of the impact of cancer treatments on fertility, several fertility preservation techniques have been developed. In prepubertal children, fertility preservation options are usually limited to ovarian cryopreservation because of sexual immaturity, but oocyte freezing can be performed in adolescent children. Two prospective randomized studies showed no benefit of gonadal suppression with GnRH analogs to preserve gonadal function and thus this treatment should not be recommended. For adult survivors of childhood cancer who experienced reproductive failure, third party reproduction techniques are highly successful.

OBJECTIVE: The risk for premature ovarian failure increases in association with two principal known etiologies: in the presence of excessive triple CGG expansions on the FMR1 (fragile X) gene (genetic etiology) and in association with a variety of autoimmune conditions (autoimmune etiology). To what degree milder forms of premature ovarian aging are also associated with these two etiologies is, however, unknown. METHODS: We, therefore, investigated 119 consecutive, so identified, infertile women and statistically correlated by linear and logistic regression analyses ovarian function parameters to markers of a possible genetic etiology (number of CGG triple repeats on the FMR1 gene) and to markers of possible abnormal immune function (immune panel). RESULTS: Sixty (50.4%) of 119 participants demonstrated at least one immune abnormality. Both groups did not differ statistically in age, mean follicle-stimulating hormone, estradiol, and antimullerian hormone levels, although antimullerian hormone suggested a trend toward higher levels in autoimmune participants (P = 0.19). Autoimmune participants also demonstrated lower mean triple CGG expansion sizes (P < 0.05) and included fewer women with greater than or equal to 35 triple repeats (relative risk, 4.0; 95% CI, 1.3-11.9; P < 0.01), previously reported to demarcate increased risk for premature ovarian aging. CONCLUSIONS: Even minimal evidence of abnormal autoimmune function ("immunological noise") seems to increase risk toward premature ovarian aging, often manifesting as infertility. Evidence of abnormal autoimmune function, such as increased CGG triple expansion sizes, in young women, therefore, warrants vigilance for development of prematurely diminished ovarian reserve and infertility.

Integrins, by signaling between extracellular matrix and cell nucleus, serve critical roles in cell proliferation and survival. A knock-in mice was developed by a targeted deletion of the C-terminal segment of the cytoplasmic tail of beta 4-integrin (beta 4-1355T). The beta 4-1355T mice had a longer gestational length, smaller litter sizes, lower fecundity rate, and higher frequency of early pregnancy loss. beta 4-1355T embryos demonstrated a high degree of fragmentation and asymmetry, with fewer surviving to either a morula or blastocyst stage. In wild-type oocytes and embryos, beta1, beta 4, and laminin-5 signals colocalized at the opposing surfaces of blastomeres and between the polar bodies and oocytes. Blastomeres within the beta 4-1355T embryos were less cohesive, with a more diffuse expression of beta 4 and laminin-5 compared with wild type. The alpha 6 beta 4_laminin-5 interaction appears to be vital for maintaining the cohesiveness between the cells of the embryo. Deciphering the role of integrins such as beta 4 in embryogenesis may help explain in vitro fertilization failures.

It is a central dogma in reproductive biology that oogenesis is completed before or just after birth and that the postnatal ovary is endowed by a fixed and non-renewing number of oocytes in mammals. However, this widely accepted doctrine was recently challenged by studies showing regeneration of oocytes from putative germ cells in bone marrow and peripheral blood. These results not only triggered an enormous amount of interest among reproductive biologists but also a great deal of debate. In this review we will provide an update on the molecular aspects of the formation of primordial germ cells (PGC), the precursors of adult gametocytes, beginning from their specification to their migration to prospective gonads and formation of the ovary and follicular structures. We will also discuss more recent studies that showed in vivo regeneration of germ cells in the postnatal ovary in situ, along with other pioneering works that demonstrated generation of germ cells in vitro from embryonic and somatic stem cells.

OBJECTIVE:There is limited data about fertility in multiple sclerosis (MS) patients using immunomodulating drugs and no data exists regarding the ovarian reserve of these patients. Therefore, we aimed to evaluate, the ovarian reserve and doppler characteristics of MS patients using immunomodulating drugs. MATERIAL AND METHODS/METHODS:MS patients using immunomodulating drugs (interferon (IFN) β and glatiramer acetate) and age-matched healthy controls were included in the study. Subjects were examined in the early follicular phase of the menstrual cycle with transvaginal ultrasound to evaluate ovarian volume, antral follicle count (AFC) and ovarian stromal artery Doppler. On the same day, blood was taken for determining serum follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2) levels. A subgroup analysis was also carried out between MS patients using only IFN β and controls to compare the same parameters. RESULTS:Mean ovarian volume and total AFC were lower in MS patients using immunomodulating drugs than in the controls. FSH and E2 levels did not show any differences between the groups, but LH levels were significantly higher in MS patients. All the Doppler parameters of the ovarian stromal artery were higher in MS patients but not significantly. In the subgroup analysis, the same significant differences were found for ovarian volume, AFC and LH levels. In addition, MS patients showed significantly higher mean pulsatility index measurement than the controls. CONCLUSION/CONCLUSIONS:The findings of this study demonstrated diminished ovarian volume and follicular reserve in MS patients using immunomodulating drugs compared to age matched healthy controls. However, further studies are required to elucidate whether compromised ovarian reserve in MS patients is due to drugs or the disease itself.