This report describes the development of a specific and sensitive assay for inhibin B and its application to the measurement of inhibin B concentrations in plasma during the human menstrual cycle. A monoclonal antibody raised against a synthetic peptide from the betaB-subunit was combined with an antibody to an inhibin alpha-subunit sequence in a double antibody enzyme-linked immunosorbent assay format. The validated assay had a limit of detection of 10 pg/mL and 0.5% cross-reactivity with inhibin A. Using this immunoassay, we found that the plasma concentration of inhibin B rose rapidly in the early follicular phase to a peak of 85.2 +/- 9.6 pg/mL on the day after the intercycle FSH rise, then fell progressively during the remainder of the follicular phase. Two days after the midcycle LH peak, there was a short lived peak in the inhibin B concentration (133.6 +/- 31.2 pg/mL), which then fell to a low concentration (<20 pg/mL) for the remainder of the luteal phase. In contrast, the inhibin A concentration was low in the early follicular phase, rose at ovulation, and was maximal during the midluteal phase. The concentration of inhibin B in individual follicular fluid samples was 20- to 200-fold higher than the concentration of inhibin A and was highest in follicular fluid samples from the early follicular phase. Inhibin B appears to be the predominant form of inhibin in the preovulatory follicle. The different patterns of circulating inhibin B and inhibin A concentrations observed during the human menstrual cycle suggest that these forms may have different physiological roles.

The human ovary, in particular the corpus luteum, secretes significant amounts of dimeric and therefore biologically active inhibin.

The role of classical genomic androgen receptor (AR) mediated actions in female reproductive physiology remains unclear. Female mice homozygous for an in-frame deletion of exon 3 of the Ar (AR(-/-)) were subfertile, exhibiting delayed production of their first litter (AR(+/+) = 22 d vs. AR(-/-) = 61 d, P < 0.05) and producing 60% fewer pups/litter (AR(+/+): 8.1 +/- 0.4 vs. AR(-/-): 3.2 +/- 0.9, P < 0.01). Heterozygous females (AR(+/-)) exhibited an age-dependent 55% reduction (P < 0.01) in pups per litter, evident from 6 months of age (P < 0.05), compared with AR(+/+), indicating a significant gene dosage effect on female fertility. Ovulation was defective with a significant reduction in corpora lutea numbers (48-79%, P < 0.01) in 10- to 12- and 26-wk-old AR(+/-) and AR(-/-) females and a 57% reduction in oocytes recovered from naturally mated AR(-/-) females (AR(+/+): 9.8 +/- 1.0 vs. AR(-/-): 4.2 +/- 1.2, P < 0.01); however, early embryo development to the two-cell stage was unaltered. The delay in first litter, reduction in natural ovulation rate, and aromatase expression in AR(+/-) and AR(-/-) ovaries, coupled with the restored ovulation rate by gonadotropin hyperstimulation in AR(-/-) females, suggest aberrant gonadotropin regulation. A 2.7-fold increase (AR(+/+): 35.4 +/- 13.4 vs. AR(-/-): 93.9 +/- 6.1, P < 0.01) in morphologically unhealthy antral follicles demonstrated deficiencies in late follicular development, although growing follicle populations and growth rates were unaltered. This novel model reveals that classical genomic AR action is critical for normal ovarian function, although not for follicle depletion and that haploinsufficiency for an inactivated AR may contribute to a premature reduction in female fecundity.

STUDY QUESTION Can a deep learning model predict the probability of pregnancy with fetal heart (FH) from time-lapse videos? SUMMARY ANSWER We created a deep learning model named IVY, which was an objective and fully automated system that predicts the probability of FH pregnancy directly from raw time-lapse videos without the need for any manual morphokinetic annotation or blastocyst morphology assessment. WHAT IS KNOWN ALREADY The contribution of time-lapse imaging in effective embryo selection is promising. Existing algorithms for the analysis of time-lapse imaging are based on morphology and morphokinetic parameters that require subjective human annotation and thus have intrinsic inter-reader and intra-reader variability. Deep learning offers promise for the automation and standardization of embryo selection. STUDY DESIGN, SIZE, DURATION A retrospective analysis of time-lapse videos and clinical outcomes of 10 638 embryos from eight different IVF clinics, across four different countries, between January 2014 and December 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS The deep learning model was trained using time-lapse videos with known FH pregnancy outcome to perform a binary classification task of predicting the probability of pregnancy with FH given time-lapse video sequence. The predictive power of the model was measured using the average area under the curve (AUC) of the receiver operating characteristic curve over 5-fold stratified cross-validation. MAIN RESULTS AND THE ROLE OF CHANCE The deep learning model was able to predict FH pregnancy from time-lapse videos with an AUC of 0.93 [95% CI 0.92–0.94] in 5-fold stratified cross-validation. A hold-out validation test across eight laboratories showed that the AUC was reproducible, ranging from 0.95 to 0.90 across different laboratories with different culture and laboratory processes. LIMITATIONS, REASONS FOR CAUTION This study is a retrospective analysis demonstrating that the deep learning model has a high level of predictability of the likelihood that an embryo will implant. The clinical impacts of these findings are still uncertain. Further studies, including prospective randomized controlled trials, are required to evaluate the clinical significance of this deep learning model. The time-lapse videos collected for training and validation are Day 5 embryos; hence, additional adjustment would need to be made for the model to be used in the context of Day 3 transfer. WIDER IMPLICATIONS OF THE FINDINGS The high predictive value for embryo implantation obtained by the deep learning model may improve the effectiveness of previous approaches used for time-lapse imaging in embryo selection. This may improve the prioritization of the most viable embryo for a single embryo transfer. The deep learning model may also prove to be usef...

Inhibin is a glycoprotein hormone that is defined on the basis of inhibition of pituitary FSH production, However, previous data have not shown any correlation between RIA measurements of inhibin and FSH in men. New enzyme-linked immunosorbent assays, specific for inhibin A, inhibin B, and inhibin pro-alphaC-related immunoreactivity, were applied to the measurement of inhibin in 32 healthy men. Further measurements of inhibin B and pro-alphaC-RI were carried out on groups of men exhibiting a wide range of FSH concentrations, including semen donors, infertile men, and men with elevated FSH concentrations. Inhibin A was undetectable (<2 pg/mL) in all men studied. The healthy men studied all had measurable concentrations of inhibin B (135.6 pg/mL; confidence interval, 108.4-169.4) and pro-alphaC-RI (426.3 pg/mL; confidence interval, 378.4-480.2). A close negative correlation was found between the inhibin B and FSH concentrations in the semen donors (r = -0.69; P < 0.001), the infertile men (r = -0.81; P < 0.001), and the men with elevated FSH concentrations (r = -0.54; P < 0.01), but not in a group of healthy volunteers (r = -0.08; P = NS). No correlation was observed between concentrations of pro-alphaC-RI and FSH in any of the groups studied. These results strongly suggest that the physiologically important form of inhibin in men is inhibin B, which has a critical effect on FSH release. Inhibin B may offer a clinically useful serum marker of testicular function.

Given the uncertain role of PGD-A techniques, high-quality experimental studies using intention-to-treat analysis and cumulative live birth rates including the comparative outcomes from remaining cryopreserved embryos are needed to evaluate the overall role of PGD-A in the clinical setting. It is only in this way that the true contribution of PGD-A to ART can be understood.

Older women developed a dominant follicle sooner, meeting criteria for hCG cycle day 10.6 +/- 0.4 vs. 14.5 +/- 1.0 p < 0.001. As expected, the older group had higher maximal serum FSH concentrations compared to the younger women (11.4 +/- 0.5 vs. 8.0 +/- 0.4 IU/L, p < 0.001). We compared hormone concentrations from days-1 to 3 (where day 0 = day of maximal FSH concentration). E2 concentration was higher in the older women (p = 0.002), and there was no significant difference in inhibin A secretion (p = 0.61). In contrast, mean inhibin B concentration was significantly lower in the older women (p = 0.04). On the day of aspiration of the dominant follicle, serum inhibin B was decreased in the older subjects (42.6 +/- 6.5 vs. 153.1 +/- 53 pg/ml, p = 0.02), whereas older subjects had higher levels of inhibin A (106 +/- 16 vs. 60.4 +/- 9.4 pg/ml, p = 0.04) and similar E2 levels (665 +/- 35.2 vs. 687 +/- 92 pmol/L, p = 0.83). There were no differences in FF concentrations of inhibin B (164 +/- 31 vs. 174 +/- 37 ng/ml, p = 0.85), inhibin A (317.7 +/- 38 vs. 248 +/- 57 ng/ml, p = 0.16), or E2 (2074 +/- 294 vs. 2474 +/- 338 nmol/L, p = 0.82) in the older and younger women. CONCLUSION. Follicular phase inhibin B secretion is decreased in older ovulatory women who demonstrate a monotropic FSH rise, whereas inhibin A secretion is similar to that in younger women. The dominant follicle in these older women appears to be normal in terms of FF E2 and inhibin content. We speculate that decreased inhibin B secretion most likely reflects a diminished follicular pool in older women and may be an important regulator of the monotropic FSH rise.

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