Loss-of-function mutations in the X-linked immunoglobulin superfamily, member 1 (IGSF1) gene result in central hypothyroidism, often associated with macroorchidism. Testicular enlargement in these patients might be caused by increases in follicle-stimulating hormone (FSH) levels, as IGSF1 has been proposed to function as an inhibin B receptor or as an inhibitor of activin type I receptor (ALK4) activity in pituitary gonadotrope cells. If true, loss of IGSF1 should lead to reduced inhibin B action or disinhibition of activin signaling, thereby increasing FSH synthesis. Here, we show that FSH levels and sperm counts are normal in male Igsf1 knockout mice, although testis size is mildly increased. Sperm parameters are also normal in men with IGSF1 deficiency, although their FSH levels may trend higher and their testes are enlarged. Inhibin B retains the ability to suppress FSH synthesis in pituitaries of Igsf1-knockout mice and IGSF1 does not interact with ALK4 or alter activin A/ALK4 stimulation of FSHβ (Fshb/FSHB) subunit transcription or expression. In light of these results, it is unlikely that macroorchidism in IGSF1 deficiency derives from alterations in spermatogenesis or inhibin/activin regulation of FSH.

An important safety consideration in the use of antagonists of myostatin and activins is whether these drugs induce myocardial hypertrophy and impair cardiac function. The current study evaluated the effects of a soluble ActRIIB receptor Fc fusion protein (ActRIIB.Fc), a ligand trap for TGF-β/activin family members including myostatin, on myocardial mass and function in simian immunodeficiency virus (SIV)-infected juvenile rhesus macaques (Macaca mulatta). Fourteen pair-housed, juvenile male rhesus macaques were inoculated with SIVmac239; 4 weeks postinoculation, they were treated with weekly injections of 10 mg/kg ActRIIB.Fc or saline for 12 weeks. Myocardial mass and function were evaluated using two-dimensional echocardiography at baseline and after 12 weeks. The administration of ActRIIB.Fc was associated with a significantly greater increase in thickness of left ventricular posterior wall and interventricular septum both in diastole and systole. Cardiac output and cardiac index increased with time, more in animals treated with ActRIIB.Fc than in those treated with saline, but the difference was not statistically significant. The changes in ejection fraction, fractional shortening, and stroke volume did not differ significantly between groups. The changes in end-diastolic and end-systolic volumes did not differ between groups. In addition to a large reduction in IGF1 mRNA expression in the ActRIIB.Fc-treated animals, complex changes were detected in the myocardial expression of proteins related to calcium transport and storage. In conclusion, ActRIIB.Fc administration for 12 weeks was associated with increased myocardial mass but did not adversely affect myocardial function in juvenile SIV-infected rhesus macaques. Further studies are necessary to establish long-term cardiac safety.