Recombinant Human FSH Treatment Outcomes in Five Boys With Severe Congenital Hypogonadotropic Hypogonadism

Abstract

ContextRecombinant human FSH (r-hFSH), given to prepubertal boys with hypogonadotropic hypogonadism (HH), may induce Sertoli cell proliferation and thereby increase sperm-producing capacity later in life.ObjectiveTo evaluate the effects of r-hFSH, human chorionic gonadotropin (hCG), and testosterone (T) in such patients.Design and SettingRetrospective review in three tertiary centers in Finland between 2006 and 2016.PatientsFive boys: ANOS1 mutation in two, homozygous PROKR2 mutation in one, FGFR1 mutation in one, and homozygous GNRHR mutation in one. Prepubertal testicular volume (TV) varied between 0.3 and 2.3 mL; three boys had micropenis, three had undergone orchidopexy.InterventionsTwo boys received r-hFSH (6 to 7 months) followed by r-hFSH plus hCG (33 to 34 months); one received T (6 months), then r-hFSH plus T (29 months) followed by hCG (25 months); two received T (3 months) followed by r-hFSH (7 months) or r-hFSH plus T (8 months).Main Outcome MeasuresTV, inhibin B, anti-Müllerian hormone, T, puberty, sperm count.Resultsr-hFSH doubled TV (from a mean ± SD of 0.9 ± 0.9 mL to 1.9 ± 1.7 mL; P < 0.05) and increased serum inhibin B (from 15 ± 5 ng/L to 85 ± 40 ng/L; P < 0.05). hCG further increased TV (from 2.1 ± 2.3 mL to 8.6 ± 1.7 mL). Two boys with initially extremely small testis size (0.3 mL) developed sperm (maximal sperm count range, 2.8 to 13.8 million/mL), which was cryopreserved.ConclusionsSpermatogenesis can be induced with gonadotropins even in boys with HH who have extremely small testes, and despite low-dose T treatment given in early puberty. Induction of puberty with gonadotropins allows preservation of fertility.

Anti-Müllerian hormone and letrozole levels in boys with constitutional delay of growth and puberty treated with letrozole or testosterone

“…These findings are in agreement with earlier reports showing a strong suppressing effect of T on AMH (Young et al, 1999;Young et al, 2003;Young et al, 2005). It is important to note that, in boys (Kohva et al, 2018) and men (Young et al, 2005) with gonadotrophin deficiency, recombinant FSH increases AMH, whereas in healthy boys, this effect appears to be overcome by the pubertal increase in intratesticular T levels (Rey, 1998;Grinspon et al, 2013). Indeed, the expression of androgen receptors in Sertoli cells increases significantly at the age of 4 to 8 years (Chemes et al, 2008), and the pubertal decrease in AMH has been shown to be an early, androgen-dependent event (Hero et al, 2012).…”

Hypogonadism and Cryptorchidism

“…Therefore, some studies investigated the role of replacement of deficient mini-pubertal hormones by using GnRH, or gonadotropins during infancy in patients with CHH to improve reproductive health, especially fertility, later in life (237). However, only some of these studies included cryptorchid boys, and testicular descent was not the primary outcome of most of these studies, making it difficult to assess the effect of this approach on testicular descent (41, 133,[239][240][241][242][243]. As far as we know, only two small studies in France and Greece have investigated the effects of gonadotropin administration during infancy in boys with CHH associated with cryptorchidism, and aimed at induction of testicular descent, or had testicular descent as one of the primary outcome (244,245).…”

Treatment of gonadotropin deficiency during the first year of life: long-term observation and outcome in five boys

“…One of the patients (C8) was diagnosed with CHH as a part of CPHD at the age of one month due to low gonadotropin and testosterone levels. The remaining seven boys had no hormonal measurements in infancy available, but they presented other signs of absent minipuberty: six had bilateral cryptorchidism and/or micropenis, and one was diagnosed with biallelic loss-of-function GNRHR mutation (C2) with completely absent LH response in a GnRH stimulation test (Kohva et al 2018). We have earlier described induction of puberty with gonadotropin treatment in five of these boys (patients C1 to C5) (Kohva et al , 2018) and the pubertal status of two of the boys (patients C6 and C7) (Varimo et al , 2017).…”

“…We have earlier described induction of puberty with gonadotropin treatment in five of these boys (patients C1 to C5) (Kohva et al , 2018) and the pubertal status of two of the boys (patients C6 and C7) (Varimo et al , 2017).…”

“… KS Kallmann syndrome, nCHH normosmic congenital hypogonadotropic hypogonadism, CPHD combined pituitary hormone deficiency SOD septo-optic dysplasia, CHARGE syndrome (acronym from coloboma, heart defects, atresia of the choanae, retarded growth and development, genital hypoplasia and ear abnormalities) a Patients C1 to C5 are described previously by Kohva et al (2018) and patients C6 to C7 by Varimo et al (2017). …”