Human INHBB gene variant (c.1079T>C:p.Met360Thr) alters testis germ cell content, but does not impact fertility in mice

Testicular derived inhibin B (α/βB dimers) acts in an endocrine manner to suppress pituitary production of follicle stimulating hormone (FSH), by blocking the actions of activins (βA/B/βA/B dimers). Previously, we identified a homozygous genetic variant (c.1079T>C:p.Met360Thr) arising from uniparental disomy of chromosome 2 in the INHBB gene (βB-subunit of inhibin B and activin B) in a man suffering from infertility (azoospermia). In this study, we aimed to test the causality of the p.Met360Thr variant in INHBB and testis function. Here, we used CRISPR/Cas9 technology to generate Inhbb M364T/M364T mice, where mouse INHBB p.Met364 corresponds with human p.Met360. Surprisingly, we found that the testes of male Inhbb M364T/M364T mutant mice were significantly larger compared with those of aged-matched wildtype littermates at 12 and 24 weeks of age. This was attributed to a significant increase in Sertoli cell and round spermatid number and, consequently, seminiferous tubule area, in Inhbb M364T/M364T males compared to wildtype males. Despite this testis phenotype, male Inhbb M364T/M364T mutant mice retained normal fertility. Serum hormone analyses however, indicated that the Inhbb M364T variant resulted in reduced circulating levels of activin B, but did not affect FSH production. We also examined the effect of this p.Met360Thr, and an additional INHBB variant (c.314C>T: p.Thr105Met) found in another infertile man, on inhibin B and activin B in vitro biosynthesis. It was found that both INHBB variants resulted in a significant disruption to activin B in vitro biosynthesis. Together, this analysis supports that INHBB variants that limit activin B production have consequences for testis composition in males.

Serial Inhibin B Measurements in Boys with Congenital Monorchism Indicate Compensatory Testicular Hypertrophy in Early Infancy

Aim Congenital monorchism is considered a condition in which an initially normal testis has existed but subsequently atrophied and disappeared due to a third trimester catastrophe (presumably torsion). Since inhibin B concentrations appear related to Sertoli and germ cells number, we evaluated pre- and postoperative inhibin B of boys with congenital monorchism to determine whether the well-known hypertrophy of the contralateral testis was reflected in inhibin B concentrations. Materials and Methods Twenty-seven boys consecutively diagnosed with congenital monorchism (median age 12 months) underwent follow-up with reproductive hormones 1 year postoperatively (median age 25 months). The results were compared with inhibin B of 225 boys with congenital nonsyndromic unilateral cryptorchidism, by converting values to multiple of the median (MoM) for age in normal boys. Results Ten boys (37%) had blind-ending vessels and ductus deferens (vanished testis) and the remaining (63%) had testicular remnants. At the time of diagnostic procedure, monorchid boys did not have significantly lower inhibin B (median 114, range 20–208) than unilateral cryptorchid boys (136, 47–393) (p = 0.27). During follow-up, MoM values of inhibin B increased in monorchid boys (median 0.59 to 0.98) and in unilateral cryptorchid boys (0.69 to 0.89) (both p < 0.0001). Compared with the concentration at surgery, an additional 44% monorchid boys had inhibin B MoM values higher than 1.0, whereas only additional 23% of unilateral cryptorchid boys exhibited such values (p = 0.04). Conclusion Generally, inhibin B MoM values were normalized during follow-up in boys with congenital monorchism, reflecting compensatory hypertrophy within the first 2.5 years of life. The compensatory capacity to increase was better in monorchism than in unilateral cryptorchidism.

Lower Circulating Sertoli and Leydig Cell Hormone Levels During Puberty in Obese Boys: A Cross-sectional Study

Context Alterations in semen characteristics and circulating Sertoli and Leydig cell hormones have been described in obese male adults. Whether hormonal alterations occur before adulthood has not been fully evaluated. Objective We describe circulating Sertoli and Leydig cell hormone levels in overweight–obese (ow/ob) boys through childhood and adolescence in a cross-sectional study. Methods Monocentric study in the Pediatric Endocrinology Unit of Angers University Hospital. Three hundred and fifty-one obese and overweight boys aged 5-19 years underwent physical examination, dual-energy X-ray absorptiometry for body composition, oral glucose tolerance test on insulin and glucose, and measurements of follicle-stimulating hormone, luteinizing hormone, anti-Müllerian hormone (AMH), inhibin B, testosterone, and estradiol. Hormonal levels were compared with normative data obtained from 652 healthy nonoverweight nonobese boys of similar age or Tanner stage. Results Median inhibin B and testosterone levels during puberty were significantly lower in ow/ob than in healthy boys (1) from age &gt;12 years and thereafter for inhibin B, and (2) from age &gt;14 years and thereafter for testosterone. At Tanner stages 4 and 5, 26%, 31%, and 18% of inhibin B, testosterone, and AMH values were below the 5th percentile in ow/ob subjects (P &lt; .01). In multiple regression analyses, estradiol and total bone mineral density Z-score were negative predictors of inhibin B, fat mass percentage was a negative predictor of testosterone, and insulin was a negative predictor of AMH. Conclusion Lower Sertoli and Leydig cell hormone levels during puberty were observed in the ow/ob boys.

Сondition of urogenital tract microbiotes and pro- and antioxidant system in male azoospermia

Over the past 20 years, there has been a clear trend to increase in the number of infertile men in Ukraine, their percentage reaches 50% in infertile couples. There is a significant percentage of male infertility caused by azoospermia – the lack of sperm in the ejaculate. In male infertility, azoospermia is found in 10–15% of patients, among other forms of pathospermia. Given the ambiguity of ideas about the etiology, pathogenesis and treatment and diagnostic approaches for various types of infertility, it remains important to clarify the relationship of urogenital infections with the regulatory systems of cells, including the state of the pro- and antioxidant system and the search for additional markers. 119 patients with various forms of azoospermia were examined. All patients underwent the following studies: spermogram, infectious screening, inhibin B, lipid peroxidation, activity of enzymes of the glutathione antioxidant system in sperm plasma and blood serum. Infectious screening included analysis of urethral secretions, bacteriological examination of sperm or prostate secretion, assessment of the species and quantitative composition of the microflora of the male urogenital tract. According to the results of spermogram and other diagnostic methods, a non-obstructive form of azoospermia was detected in 69 patients. In obstructive azoospermia, ejaculate as such was absent. It is suggested that inhibin B may be an important medical diagnostic test for azoospermia. As a result of the conducted researches the importance of determining the concentration of inhibin B as a marker of azoospermia was demonstrated and a negative correlation of moderate strength between the content of inhibin B and testosterone level in the plasma of men with non-obstructive azoospermia was revealed. It was found that Ureaplasma pervum and Ureaplasma urealyticum infect the male genitourinary system to the greatest extent among a number of microorganisms, both in non-obstructive and obstructive forms of azoospermia. Enterococcus faecalis is more pronounced in the sperm fluid in the non-obstructive form of azoospermia and prostate secreton in the obstructive form of azoospermia. In the non-obstructive form of azoospermia in the seminal plasma and serum, the processes of lipid peroxidation intensify, the concentration of reduced glutathione decreases and the activities of the enzymes of the glutathione antioxidant system (glutathione peroxidase and glutathione transferase) decrease. It can be considered that an important diagnostic test for the nonobstructive form of azoospermia is the ratio of reduced glutathione to oxidized glutathione in sperm plasma.

Assessment of different markers of ovarian reserve in women with papillary thyroid cancer treated with radioactive iodine

Treatment with radioactive iodine (RAI) in women with differentiated thyroid cancer is associated with decreased serum concentrations of anti-Müllerian hormone (AMH); however, other markers have not been investigated. Therefore, this study aimed to evaluate the effect of RAI on antral follicle count (AFC) and the serum concentration of inhibin B, follicle-stimulating hormone (FSH), and AMH in women with papillary thyroid cancer (PTC) treated with RAI. We examined 25 women at a median age of 33 years treated with a single dose of RAI. We divided the participants into women over (n = 11) and under 35 years of age (n = 14). Serum concentrations of inhibin B, FSH, AMH, and AFC were assessed at baseline and one year after RAI treatment. We found decreased AFC (p = 0.03), serum levels of AMH (p < 0.01), inhibin B (p = 0.03), but not FSH (p = 0.23), one year after RAI treatment in comparison to baseline in the whole group. When we compared serum levels of AMH in younger vs. older women separately, we observed a significant reduction of this hormone’s serum level after RAI treatment in both groups (p < 0.01; p = 0.04, respectively). We concluded that RAI treatment significantly impacts the functional ovarian reserve in premenopausal women with PTC.