Growth and descent of the testes in infants with hypogonadotropic hypogonadism receiving subcutaneous gonadotropin infusion

Hypogonadotropic hypogonadism (HH) is observed at birth in infants who have combined pituitary hormone deficits (CPHD) or isolated hypogonadotropic hypogonadism (IHH), two separate entities that have separate and multiple genetic etiologies. Cryptorchid or maldescended testes and small testicular volume are clinical hallmarks of congenital hypogonadotropic hypogonadism (CHH) [1]. We carried out a Pubmed search with the keywords “cryptorchidism”, “cryptorchid testes”, “testes descent”, “CHH”, “CPHD”, “hypopituitarism”, “Kallman”, “isolated HH or idiopathic HH”. Unexpectedly, this search retrieved only two studies allowing an estimation of the prevalence of cryptorchidism in patients with HH. These two studies were carried out in the same group of patients with IHH [2, 3]. Cryptorchidism was reported in one third of these patients and was bilateral in half of them or unilateral in the other half [2, 3]. Cryptorchidism, particularly if bilateral, is considered to have additional negative effects on the future fertility of patients with IHH [2].

A number of studies have examined the effect of human chorionic gonadotropin (hCG) or recombinant human LH (rhLH) and FSH (rhFSH) injections upon testicular descent in common cryptorchidism [4, 5]. Hormonal treatment is associated with testicular descent in some of these children, but rates generally do not exceed those seen with placebo by more than 10 % [6]. Surprisingly, a literature search found no comparable study in infants with CHH, in whom hCG was largely used to test testosterone secretion [1], but not for therapeutic purposes. In the absence of a systematic study of hCG treatment upon testes descent in infants with either IHH or combined pituitary deficits, the data collected in common cryptorchidism are often used instead, but this extrapolation may not be justified. We know of only two studies, totaling 3 infants with CHH, that have used gonadotropins in a therapeutic perspective. In the unique patient treated by Main et al., six months of twice-weekly subcutaneous injections of rhLH (20 IU) and rhFSH (21.3 IU) allowed a limited growth of the penis from 1.6 to 2.4 cm and a 1.7-fold increase of testes volume [7]. In the two patients treated by Bougnères et al., subcutaneous infusion of rhLH and rhFSH at much higher daily doses of 50 IU and 100 IU were used to mimic mini-puberty in two infants with CHH [8]. This treatment induced a tripling of penile length and a 4-fold increase in testes volume.

The other hormonal treatment that is classically used in infants with CHH is depot esters of testosterone [9]. Testosterone can be administered im, locally by a testosterone lotion or gel, transdermally by a testosterone patch or suppository. This treatment induces durable phallic growth but has no effect on testicular volume or descent. The lack of effect of testosterone alone upon testis descent contrasts with the classical hypothesis that the inguinoscrotal phase of testis descent, which takes place between the 25th and the 35th week of gestation but often occurs after birth in humans, is androgen-mediated and is directly affected by the lack of testosterone production in fetuses with CHH [10].

The usual treatment of maldescended testes is surgical orchiopexy. For children with common, so-called “idiopathic” cryptorchidism, recommendations advocate orchiopexy at 6–12 months [11]. These recommandations contrasts with the report collected by Pitteloud et al. in patients with IHH [3]. This report indicates that surgical repair was performed in 86 % of patients with cryptorchidism only between 4 and 35 years of age, at a mean age of 13?±?2 years [3]. We have not been able to find a publication that has specifically examined or reviewed the indication, prevalence and long term results of orchiopexy in infants or children with CHH and cryptorchidism, whether they have IHH, including Kallman syndromes, or CPHD. This is even more surprising considering the fact that the surgical correction of cryptorchidism is advocated as a possible means for increasing the likelihood of future fertility [12, 13]. Anecdotical reports of orchiopexy were found in a number of publications following a Pubmed search using keywords such as “orchiopexy”, “CPHD”, “hypopituitarism”, “IHH”, “Kallmann”. See detailed comments and preferences in Additional file 1. These publications seems to indicate that orchiopexy is often used for the treatment of cryptorchidism in children with various genetic etiologies of CHH, and that in most cases, orchiopexy is performed at age 4 years or later, confirming the observation of Pitteloud et al. [3]. The treatment of cryptorchidism thus remains a yet-to-be explored clinical field of research aiming at the preservation of fertility potential in patients affected with CHH. The current study focuses on the effects of subcutaneous continuous recombinant LH and FSH infusion on the mal-descended testes in neonates with CHH, with the idea of proposing this treatment as an alternative to orchiopexy.