A treatment regimen beginning with testosterone for induction of puberty stimulates normal linear growth, pubertal virilization and psycho-sexual maturation in congenital HH. However, this traditional approach neglects testicular growth and the acquisition of fertility as components of normal puberty. The testes remain immature and small, i.e. in a prepubertal state, and spermatogenesis is not initiated. Meanwhile, there is sufficient evidence that complete male puberty, comprising pubertal virilisation in concert with testicular growth and initiation of spermatogenesis, can be successfully achieved during adolescence by replacement with gonadotropins (hCG/FSH) [7, 8, 30, 33–36] (Table 20.3).

Gonadotropin treatment may be suggested for pubertal induction, even if fertility is a matter for the future. Even though rFSH is costly, normalization of testicular size and initiation of spermatogenesis at a peer-related time may positively affect body image and fertility concerns, and thus provide self-assurance and confidence for the future in teenage boys with HH [36, 37]. In addition, spermatogenesis, once driven to full maturation, can be re-stimulated much faster when fertility is desired later in life [5, 38]. Subsequent treatment with testosterone does not seem to jeopardize the outcome of later stimulation therapy [36]. This is important for prepubertal boys who are unwilling to commit to five s.c. injections per week for 2–3 years. However, some of these young patients may be more agreeable to gonadotropin stimulation once pubertal induction with testosterone is accomplished [39].

In adolescent patients with open epiphyses (i.e. with a bone age < 16 years), the dose of hCG should be escalated in small increments over the first year (until serum testosterone levels are in the normal adult range). The goal is a pubertal growth spurt and attainment of final height in the range of mid-parental expectations. Adverse effects, including severe acne or gynecomastia, can generally be avoided by this regimen. Subsequent combined hCG/rFSH replacement over two to three years is required for testicular growth and to fully activate the individual’s spermatogenic potential. Over 70% of adolescents will thereby reach normal adult testicular size, and sperm will appear in semen in over 90% of patient [35, 36].

In view of the challenging differential diagnosis of constitutional delay of puberty (CDGP), this regimen bears an important further advantage: low hCG doses have only weak suppressive effects at the hypothalamic or pituitary level; therefore, the pubertal GnRH pulse generator may activate in cases of unrecognized CDGP. Patients misdiagnosed as HH may thus be recognized if special attention to a potential rise in serum LH levels is given during the first phase of gonadotropin replacement.

In patients with lack of pubertal development but a late diagnosis of CHH in adulthood, or those with previous testosterone treatment, final height may already have been attained. In these adult men, higher initial hCG replacement doses and faster dose escalations can be applied than in HH boys with open epiphyses/immature growth plates. Success rates for spermatogenic induction in adults are slightly below those of adolescents, ranging from 65 to 90% [5, 17, 18, 40].

A starting dose of (250−) 500 IU hCG, injected subcutaneously on Mondays and Fridays, with increments of 250–500 IU hCG per injection every 6 months, to a maximum of 3 × 2500 IU hCG s.c./week, is recommended. The aim is to achieve pubertal levels [serum testosterone ≥ 1.5 ng/ml, (5.2 nmol/l)] after approximately 6 months, and levels in the mid-normal adult range [testosterone > 3.5 ng/ml, (12 nmol/l)] by one year. rFSH (follitropin alpha) 3 × (75−)150 IU s.c./week (injected Mondays, Wednesdays and Fridays) is added when pubertal serum testosterone levels (>5.2 nmol/l) are reached. Subsequent rFSH dosage modifications above 150 IU per injection are not recommended as they do not further stimulate spermatogenesis.

A full hCG starting dose of 1500 IU s.c. may initially be applied twice weekly. hCG dose reduction is recommended if polycythemia, gynecomastia or excessive acne occur. If testosterone levels remain below the normal adult range (<12 nmol/l) after 6–9 months, the hCG dose can be increased by increments of 500–1000 IU per injection (to a maximum of 3 × 2500 IU s.c./week). rFSH (follitropin alpha) 3 × (75−) 150 IU is additionally injected thrice weekly after 3–6 months of hCG without subsequent dose modifications.

In patients with HH acquired post-pubertally, testicular maturation has already been completed, as indicated by adult testicular size. If the patient has been gonadotropin deficient for a prolonged period, however, paused spermatogenesis may have led to a reduction in testicular volume. Hormone replacement can be initiated either with testosterone or gonadotropins. Since gonadotropins are costly, this therapeutic investment is justified only if paternity is desired. In all other cases, testosterone is the preferred modality for replacement. When stimulation therapy for fertility induction is initiated in patients with previously accomplished testicular maturation, Leydig cell response (as indicated by a rise in serum testosterone levels to the adult range) to hCG occurs within 1–3 months. In some cases this is sufficient for initiation of spermatogenesis [27]. However, prolonged treatment with hCG alone will suppress endogenous residual FSH secretion. Therefore, addition of FSH is often required. Spermatozoa appear in semen after 3–9 months of combined hCG/FSH replacement. Stimulation of spermatogenesis will not proceed further when the sperm concentration in the ejaculate reaches a plateau that is indicative of the individual’s spermatogenic capacity. Once spermatogenesis is fully activated by combined hCG/FSH replacement, sperm production may be maintained with hCG alone for several months (in patients with residual endogenous gonadotropin secretion) [41, 42].