Faculty Bibliography

AIM/OBJECTIVE:To determine whether monitoring follicle stimulating hormone (FSH) levels in over-responding patients whom the gonadotropins were withheld would predict pregnancy outcome. METHODS:A group of 33 female infertility patients aged between 20-40 years who had to be coasted during controlled ovarian hyperstimulation were recruited for this study. The FSH concentrations on human chorionic gonadotropin (HCG) day and on the four preceding days were measured to determine the threshold FSH concentration for follicular growth and conception. Mean and standard deviation were used for presenting parametric data. Student's t test and the Mann Whitney U test were used for statistical analysis. Two-tailed P < 0.05 was taken as significant. Receiver-operating characteristic (ROC) curves were performed to identify the cutoff level for FSH and E2 at HCG day and four preceding days. RESULTS:Of 33 cycles, 16 were stimulated with recombinant FSH and 17 with recombinant FSH and human menopausal gonadotropin (HMG). The basal and mean coasting FSH levels of FSH and FSH + HMG cycles did not reveal any differences. FSH concentrations decreased the day after coasting began in 26 cycles and fell by 30.2 +/- 2.7% (range 2-53). In 7 cycles, we observed 34.5 +/- 7.4% (range 6-56) declines in FSH levels beginning 2 days after coasting. Of the 31 women who received HCG, 21 conceived during in vitro fertilization and embryo transfer (IVF-ET). Gestational sac and fetal heart activity were visualized in 14 patients. ROC analysis releaved a cutoff value of 4.9 in FSH level at HCG day discriminative of conception or nonconception. CONCLUSION/CONCLUSIONS:The results from this study show that monitoring serum FSH levels during coasting may be helpful in predicting the pregnancy outcome.

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.

Breast cancer is the most common neoplasm in women and accounts for 26% (182,460) of all new cancer cases among women. With the use of screening mammography and advancement in other diagnostic modalities, many cases of breast cancer now can be diagnosed and treated at early stages of the disease. Unfortunately, adjuvant chemotherapy regimens commonly used in the treatment of breast cancer may cause premature ovarian failure due to their cytotoxic effects on the germ cells in the ovary. Therefore preservation of fertility in breast cancer survivors at reproductive age has become an important quality of life issue. Fertility preservation is a recently emerged field of reproductive medicine that may help protect the reproductive capability of the cancer survivors and allow them to have children in the future. Embryo freezing is the most established fertility preservation strategy. But conventional ovarian stimulation protocols are contraindicated in breast cancer patients because of the rise of estrogen and its metabolites to supraphysiological levels. Recently developed ovarian stimulation protocols with aromatase inhibitor letrozole and tamoxifen appear to provide a safe stimulation with endogenous estrogen levels comparable with those achieved in the natural cycle. Oocyte freezing can be considered in single women and in those who do not wish donor sperm. Ovarian tissue freezing could also be an option in breast cancer patients who do not wish or have a time for an in vitro fertilization cycle, which requires 10 to 14 days of ovarian stimulation.

Two patients with severely diminished ovarian reserve who were refractory to aggressive ovarian stimulation conceived with oocytes from prematurely developing antral follicles after dehydroepiandrosterone supplementation. The first patient had 11 and 14.5 mm, and the second patient had 13 mm antral follicles on cycle days 2 and 3 respectively. In the first case, no ovarian stimulation was performed, while the second case received one dose of gonadotrophins with a gonadotrophin-releasing hormone antagonist. Following very early human chorionic gonadotrophin (HCG) triggering on cycle day 5, when antral follicles reached 15 and 18.5 mm in the first case, and 19 mm in the second case, IVF intracytoplasmic sperm injection treatment resulted in pregnancies in both cases, which are currently ongoing at 35 and 14 weeks of gestation. The results in these patients show that pregnancy can be achieved in poor responder patients with prematurely developing antral follicles following early HCG triggering based on follicle size rather than cycle day, with no or minimal stimulation. Whether DHEA supplementation had any impact on the success of these cycles remains to be determined.

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.

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.