Among these immunoglobulins, nanobodies against the FSHR, with small molecular weight and low predicted immunogenicity in humans, can inhibit cAMP production129. Antibodies targeting a placental bovine hCG-like LH (equine chorionic gonadotropin), with both FSH and LH activity in other mammals, would be responsible for forming hormone–antibody complexes with increased β-arrestin–dependent signaling and activity in vivo124,125. Instead, molecules with NAM activity at the gonadotropin receptor, inhibiting the follicle growth without impairing steroid production, could become an option for contraceptive purposes. Although the debate over the pathophysiological impact of hCG glycoforms is far from being fully clarified, findings in vitro demonstrated that the glycosylation pattern of these molecules might modulate the intracellular signaling and gene expression9. However, this issue is controversial since another study found no TGF-β receptor activation by hCG and, instead, suggested the presence of growth factor contamination in the gonadotropin preparations68. This action would be exerted via cross-interaction between the hormone and the tumor growth factor beta (TGF-β) receptor67. During the first trimester of pregnancy, the quantitative and qualitative production of hCG glycoforms is exceptionally variable, starting with hyperglycosylated forms (H-hCG) of trophoblastic origin, followed by less glycosylated isoforms63. Biosynthesis of estrogens from androgens is catalyzed bycP450arom, an enzyme located in the endoplasmic reticulum of estrogen-producing cells. In this line, it has been proposed that serum inhibin B, FSH, and the inhibin B/FSH ratio are useful biomarkers of impaired spermatogenesis (91). At 8 years of age, the affected patient presented with normal basal and stimulated serum LH and FSH levels along with normal serum inhibin B and AMH concentrations. Since this is the only aromatase-deficient male reported with atypical genitalia, and a causative role of aromatase deficiency in the development of male external genitalia was not explored, a relationship between aromatase deficiency and genital phenotype has not been shown. Serum FSH, LH, testosterone, AMH, and inhibin B levels were assessed at the age of 4 and 6 years and were within the normal reference range for age and sex. Moreover, serum androgen levels were high postnatally but decreased to the normal range during the first month of life, while serum levels of inhibin B were within the normal range for sex and age (80). In contrast, gonadotropin replacement not only promotes androgenization, but could potentially prevent infertility, oligo-spermatogenesis, and testicular atrophy from prolonged exogenous androgen exposure. Our results show that in adolescent pre-pubertal males with HH, pubertal induction with hCG therapy yields significantly better outcomes for testicular size when compared to testosterone therapy after about 12 months of therapy, with no difference in testosterone levels between the 2 groups. We compared the pubertal effects of human chorionic gonadotropin (hCG) versus testosterone in adolescent males with HH. Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. TRT, testosterone replacement therapy; AAS, anabolic androgenic steroids; hCG, human chorionic gonadotropin; FSH, follicle stimulating hormone; rhFSH, recombinant human FSH. In addition, a large variability in the number and quality of sperm was reported in the few affected cases studied. Moreover, a role in the mitochondria has been proposed. Estrogens also exert rapid membrane-initiated effects that are known to impact on cell signaling and influence nuclear gene transcription. GnRH and gonadotropin secretion are modulated by sex steroids acting both on the hypothalamus and the pituitary gland through feedback-regulating mechanisms. The mutations described to date in 46, XY patients are shown in Figure 1A. Most providers (20/21; 95%) initiate therapy for pubertal induction when patients are between ages 14 and 17 years, whereas one provider reported starting patients before 14 years of age. Of the 4 patients in the hCG group, 3 were being managed by Urology and only one by Endocrinology. Of the remaining 46 patients whose charts lacked documentation of such a discussion, 10 patients had grade 1 disability and 36 patients had no or grade 0 disability. We had a total of 42 patients with grade 0 disability and 10 patients with grade 1 disability. FSH, LH and progesterone levels are low at this time; the drop in these levels causes the endometrial lining to shed. Because the average length of a female’s uterine cycle is 28 days, this is the time period used to identify the timing of events in the cycle. The timing of the uterine cycle starts with the first day of menses, referred to as day one of a females’s period.
