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

Ella Kohva; Hanna Huopio; Matti Hero; Päivi J. Miettinen; Kirsi Vaaralahti; Virpi Sidoroff; Jorma Toppari; Taneli Raivio


J Endo Soc. 2018;2(12):1345-1356. 

In This Article

Abstract and Introduction


Context: Recombinant 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.

Objective: To evaluate the effects of r-hFSH, human chorionic gonadotropin (hCG), and testosterone (T) in such patients.

Design and Setting: Retrospective review in three tertiary centers in Finland between 2006 and 2016.

Patients: Five boys: ANOS1 mutation in two, homozygous PROKR2 mutation in one, FGFR1mutation 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.

Interventions: Two 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 Measures: TV, inhibin B, anti-Müllerian hormone, T, puberty, sperm count.

Results: r-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.

Conclusions: Spermatogenesis 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.


Congenital hypogonadotropic hypogonadism (CHH) is a rare and heterogeneous genetic disorder diagnosed typically in adolescence due to delayed puberty.[1] CHH is caused by impaired production, secretion, or action of GnRH.[2] Approximately half of patients with CHH exhibit impaired sense of smell, a condition termed Kallmann syndrome (KS), and the other half have normosmic HH.[2] CHH can also rarely present as a part of a wider syndrome [e.g., CHARGE (Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies and/or deafness) and Waardenburg syndrome].[3] Estimates of CHH and KS incidence are scarce; studies based on French and Sardinian military screening suggest varied incidences from 1 in 10,000 for CHH[4] and 1 in 84,000 for KS[5] in men, whereas in Finnish population the incidence of KS is estimated at 1:30,000 for males and 1:125,000 for females.[6]

Adolescent boys with CHH require hormonal treatment to induce puberty. The goals in treatment are to promote virilization, height growth, sexual function, bone health, psychological and emotional well-being, and future fertility.[2] Although boys with CHH achieve virilization with exogenous testosterone, testicular maturation and induction of spermatogenesis require treatment with gonadotropins or pulsatile GnRH.[7–9] However, in the most severe forms of GnRH deficiency, characterized by cryptorchidism and small adult testicular volume (TV) (<4 mL), the outcomes of the above-mentioned fertility-inducing treatments tend to be poor.[10]

Prepubertal testis size comprises interstitial tissue and seminiferous cords, formed by somatic Sertoli cells enveloping spermatogonia. In puberty, the seminiferous cords grow in diameter and obtain lumen as Sertoli cells enter a mature, nonproliferative state to support and nurture the developing spermatogenic cells.[11] Subsequently, the number of Sertoli cells in adulthood correlates with sperm output.[12] The stage for future spermatogenesis is, however, already set before puberty. Because only 10% of the Sertoli cell number is reached within the neonatal period, proliferation of immature Sertoli cells continues in the minipuberty of infancy, and the final proliferation phase occurs in early puberty.[13,14] At this time, Sertoli cells also differentiate and stop proliferating, which is linked to their increased expression of androgen receptors and increasing intratesticular testosterone levels.[15,16] Consequently, a decline in the high circulating levels of anti-Müllerian hormone (AMH) secreted by immature, prepubertal Sertoli cells occurs, which reflects androgen-mediated differentiation of Sertoli cells.[17] However, the role of exogenously administered testosterone in this process is unclear.

More than 20 years ago, we introduced the concept of treating boys with prepubertal onset of HH by using recombinant human FSH (r-hFSH),[18] and 10 years later we reported the long-term outcome of this treatment modality in a heterogeneous group of patients.[19] Subsequently, Dwyer et al.[20] showed data on men with CHH suggesting proliferation and maturation of Sertoli cells in response to r-hFSH, but their randomized study did not reach conclusive evidence for the superiority of r-hFSH pretreatment on sperm parameters. Although the long-term outcomes of r-hFSH pretreatment are promising, and the European consensus statement on CHH[2] suggests that it may benefit most severely affected patients (i.e., those with small testis size and history of cryptorchidism), there is no conclusive evidence on the possible benefits of this treatment. At the same time, it is unclear whether exogenous testosterone (T), widely used in the induction of puberty in patients with CHH, induces premature differentiation of Sertoli cells and thereby reduces sperm-producing capacity.

In this study, we describe biochemical and clinical markers of puberty and testicular function during and after r-hFSH treatment in five prepubertal patients with CHH who have a molecular genetic diagnosis. Three of the boys had very small prepubertal testis size, and three boys had a history of cryptorchidism, both known risk factors for poor spermatogenesis later in life.[10,21] In addition, we describe clinical and hormonal data pertinent to Sertoli cell function in boys with CHH treated with exogenous T.