Clinical parameters that predict a premature LH rise in patients undergoing ovarian stimulation for IVF.

Background: Normal reproductive function requires adequate regulation of follicle stimulating hormone (FSH) and luteinizing hormone (LH) secretion. During ovarian stimulation for in-vitro fertilization (IVF), some patients will demonstrate an early rise in LH despite being treated with a gonadotropin releasing-hormone (GnRH) antagonist, sometimes necessitating cycle cancellation. Previous studies have demonstrated a possible link between a premature LH rise with ovarian response to gonadotropins. We sought to determine what clinical parameters can predict this premature LH rise and their relative contribution. Methods: A retrospective study of 382 patients who underwent IVF treatment at Rambam Medical Center. The patients were stratified into age groups. A model predicting premature LH rise based on clinical and demographic parameters was developed using both multiple linear regression and a machine-learning-based algorithm. Results: LH rise was defined as the difference between pre-trigger and basal LH levels. The clinical parameters that significantly predicted an LH rise were patient age, BMI, LH levels at stimulation outset, LH levels on day of antagonist administration, and total number of stimulation days. Importantly, when analyzing the data of specific age groups, the model's prediction was strongest in young patients (age 25-30 years, R2 = 0.88, p < .001) and weakest in older patients (age > 41 years, R2 = 0.23, p = .003). Conclusions: Using both multiple linear regression and a machine-learning-based algorithm of patient data from IVF cycles, we were able to predict patients at risk for premature LH rise and/or LH surge. Utilizing this model may help prevent IVF cycle cancellation and better timing of ovulation triggering.

Hypoxia leads to diminished ovarian reserve in an age dependent manner.

OBJECTIVES: Perinatal hypoxia causes premature activation and initiation of growth in dormant follicles, leading to diminished ovarian reserve. An indirect mechanism such as the release of stress-related hormones, may influence ovarian follicle recruitment under hypoxic conditions. We wanted to determine whether hypoxic ovarian damage results from increased follicle growth and "burnout" or from increased apoptosis, and whether this damage is age-dependent. DESIGN: Animal study Participants/Materials, Setting, Methods: Using adult 6-week-old (n=8) and one-day-old newborn (n=20) ICR (CD-1) female mice, ovarian follicular counts were conducted on H&E-stained sections. METHODS: Immunohistochemistry was performed on sections stained with Ki-67, anti-Caspase 3 and anti-FOXO3A. RESULTS: Exposure to hypoxia resulted in significantly reduced proportion of primordial follicles vs normoxia in both adult dams and newborn pups (3.17±2.75% vs. 17.89±4.4%; p=0.004; 40.59±14.88% vs. 81.92±31.56%, p=0.001, respectively), concomitant with increased growing- primary and secondary follicles, and more pronounced in adult dams vs newborn pups (6-fold vs. 2-fold, respectively). Ki67 staining revealed higher scores of cell proliferation in follicular granulosa cells after exposure to hypoxia than normoxia. However, Caspase 3 and Foxo3A staining did not show any differences in these markers of apoptosis in oocytes, granulosa cells, theca cells, or stromal cells when exposed to hypoxia versus normoxia. LIMITATIONS: The current study has several limitations; first, the sample size for each group is relatively small, which could limit the generalizability of the findings. Second, the study uses an ex vivo culture system, which may not fully capture the complex interactions that occur in the whole animal. Third, the exposure to hypoxia only lasted for 3 hours, which may not be long enough to observe all the potential effects. In addition, the study only analyzed specific markers of apoptosis in a few cell types, and other cell types or apoptotic pathways might be involved. Lastly, the study provides evidence for accelerated follicular activation and decreased ovarian reserve, but the underlying mechanisms are not fully explored. Conclusions Direct tissue hypoxia led to premature activation and initiation of growth in dormant follicles leading to diminished ovarian reserve. Hypoxic damage is age-dependent, with adult ovaries more susceptible than newborn ovaries. These findings support the possibility of follicular "burn out" as a potential mechanism responsible for hypoxia-induced loss of ovarian reserve.