Loss of function of cyclin E1 or E2, important regulators of the mitotic cell cycle, yields viable mice, but E2-deficient males display reduced fertility. To elucidate the role of E-type cyclins during spermatogenesis, we characterized their expression patterns and produced additional deletions of Ccne1 and Ccne2 alleles in the germline, revealing unexpected meiotic functions. While Ccne2 mRNA and protein are abundantly expressed in spermatocytes, Ccne1 mRNA is present but its protein is detected only at low levels. However, abundant levels of cyclin E1 protein are detected in spermatocytes deficient in cyclin E2 protein. Additional depletion of E-type cyclins in the germline resulted in increasingly enhanced spermatogenic abnormalities and corresponding decreased fertility and loss of germ cells by apoptosis. Profound meiotic defects were observed in spermatocytes, including abnormal pairing and synapsis of homologous chromosomes, heterologous chromosome associations, unrepaired double-strand DNA breaks, disruptions in telomeric structure and defects in cyclin-dependent-kinase 2 localization. These results highlight a new role for E-type cyclins as important regulators of male meiosis. Understanding the control of meiosis is fundamental to deciphering the origin of male infertility. Although the mechanisms controlling meiosis are poorly understood, key regulators of mitosis, such as cyclins, appear to be critical. In this regard, male mice deficient for cyclin E2 exhibit subfertility and defects in spermatogenesis; however, neither the stages of germ cell differentiation affected nor the responsible mechanisms are known. We investigated how E-type cyclins control male meiosis by examining their expression in spermatogenesis and the consequences that multiple deletions of Ccne1 and Ccne2 alleles produce. Loss of Ccne2 expression increases cyclin E1 levels as a compensatory effect, but there are still meiotic defects and subfertility. Further, loss of one Ccne1 allele in the absence of cyclin E2 results in infertility as does loss of the remaining Ccne1 allele, but with even more severe meiotic abnormalities. We further found that cyclin E1 is involved in sex chromosome synapsis while E2 is involved with homologous pairing and chromosome and telomere integrity. These processes and structures were severely disrupted in absence of both cyclin E1 and E2, uncovering new roles for the E-type cyclins in regulating male meiosis.

Objective: Few studies of patients with a 45,X/46,XY mosaicism have considered those with normal male phenotype. The purpose of this study was to evaluate the clinical outcome of 45,X/46,XY boys born with normal or minor abnormalities of external genitalia, notably in terms of growth and pubertal development.Methods: Retrospective longitudinal study of 40 patients followed between 1982 and 2017 in France.Results: Twenty patients had a prenatal diagnosis, whereas 20 patients had a postnatal diagnosis, mainly for short stature. Most patients had stunted growth, with abnormal growth spurt during puberty and a mean adult height of 158 ± 7.6 cm, i.e. −2.3 DS with correction for target height. Seventy percent of patients presented Turner-like syndrome features including cardiac (6/23 patients investigated) and renal malformations (3/19 patients investigated). Twenty-two patients had minor abnormalities of external genitalia. One patient developed a testicular embryonic carcinoma, suggesting evidence of partial gonadal dysgenesis. Moreover, puberty occurred spontaneously in 93% of patients but 71% (n = 5) of those evaluated at the end of puberty presented signs of declined Sertoli cell function (low inhibin B levels and increased FSH levels).Conclusion: This study emphasizes the need to identify and follow-up 45,X/46,XY patients born with normal male phenotype until adulthood, as they present similar prognosis than those born with severe genital anomalies. Currently, most patients are diagnosed in adulthood with azoospermia, consistent with our observations of decreased testicular function at the end of puberty. Early management of these patients may lead to fertility preservation strategies.

Over the past 20 years, the care for transgender adolescents has developed throughout many countries following the ‘Dutch Approach’ initiated in the 90s in pioneer countries as the Netherlands, United States and Canada, with increasing numbers of children and adolescents seeking care in transgender clinics. This medical approach has considerable positive impacts on the psychological outcomes of these adolescents, and several studies have been recently published underlining the relative safety of such treatments. This paper reviews the current standards of care for transgender children and adolescents with particular emphasis on disparities among countries and short-to-medium-term outcomes. Finally, it highlights ethical considerations regarding categorization of gender dysphoria, timing of treatment initiation, infertility and how to deal with the long-term consequences.

Sexual dimorphism involves differences between biological sexes that go beyond sexual characteristics. In mammals, differences between sexes have been demonstrated regarding various biological processes, including blood pressure and predisposition to develop hypertension early in adulthood, which may rely on early events during development and in the neonatal period. Recent studies suggest that corticosteroid signaling pathways (comprising glucocorticoid and mineralocorticoid signaling pathways) have distinct tissue-specific expression and regulation during this specific temporal window in a sex-dependent manner, most notably in the kidney. This review outlines the evidence for a gender differential expression and activation of renal corticosteroid signaling pathways in the mammalian fetus and neonate, from mouse to human, that may favor mineralocorticoid signaling in females and glucocorticoid signaling in males. Determining the effects of such differences may shed light on short term and long term pathophysiological consequences, markedly for males.