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

Abstract

STUDY QUESTION What is the peripubertal outcome of recombinant human FSH (r-hFSH) treatment during minipuberty in boys with congenital hypogonadotropic hypogonadism (CHH)? SUMMARY ANSWER Sertoli-cell response to r-hFSH, given during the minipuberty of infancy, appears insufficient to maintain Sertoli cell function throughout childhood, as evaluated by inhibin B measurements. WHAT IS KNOWN ALREADY Severe CHH in boys can be diagnosed during the minipuberty of infancy. Combined gonadotropin treatment at that age is suggested to improve testicular endocrine function and future fertility, yet long-term evidence is lacking. STUDY DESIGN, SIZE, DURATION In this retrospective cohort study, we describe five CHH boys treated with r-hFSH in Helsinki University Hospital or Kuopio University Hospital between 2004 and 2018. Immediate follow-up data (0.1–1.4 months after cessation of the gonadotropin therapy) was available for four boys and long-term observations (at the age of 10.0–12.8 years) was available for three boys. As a retrospective control cohort, we provide inhibin B values of eight untreated CHH boys at the age of 12.7–17.8 years. PARTICIPANTS/MATERIALS, SETTING, METHODS Four patients had combined pituitary hormone deficiency, and one had CHARGE syndrome due to a CHD7 mutation. The patients were treated at the age of 0.7–4.2 months with r-hFSH (3.4 IU/kg–7.5 IU/kg per week in 2 or 3 s.c. doses for 3–4.5 months) combined with T (25 mg i.m. monthly for three months for the treatment of micropenis). Inhibin B was chosen as the primary outcome measure. MAIN RESULTS AND THE ROLE OF CHANCE During the r-hFSH + T treatment, inhibin B increased from 76 ± 18 ng/l to 176 ± 80 ng/l ( P = 0.04) and penile length increased by 81 ± 50% ( P = 0.04). Unexpectedly, two boys with robust inhibin B responses in infancy demonstrated low inhibin B values in peripuberty: declining from 290 ng/l (4 months) to 16 ng/l (12.4 years), and from 207 ng/l (6 months) to 21 ng/l (12.8 years). All boys underwent orchiopexy at 2.0 ± 0.7 years of age. Inhibin B values in long-term follow-up, available for the three boys, did not significantly differ from the untreated CHH controls. LIMITATIONS, REASONS FOR CAUTION Limitations of this retrospective study are the small number and heterogeneity of the patients and their treatment schemes. WIDER IMPLICATIONS OF THE FINDINGS We describe the first long-term follow-up data on CHH boys treated with r-hFSH and T as infants. The results from this small patient series suggest that the effects of infant r-hFSH treatment may be transient, and further longitudinal studies are required to determine the efficacy of this treatment approach to optimise the fertility potential in this patient population. ...

Hypogonadism and Cryptorchidism

“…The inhibin B levels between these two groups were not different. The results of this study suggested a transient effect of the combined rhFSH and testosterone treatment on Sertoli cell function (242). Table 3 summarizes the studies on hormonal treatment during infancy in CHH boys with congenital cryptorchidism.…”

“…At the last visit, all testes were still in the scrotal position, but the size measured by the Prader orchidometer was marginally reduced, from a mean of 1.5 (1.0-2.5) mL during treatment to 1.0 (0.5-2.0) mL at the last visit (244). In a small study in Finland, five CHH boys with cryptorchidism were treated with rhFSH and testosterone enanthate during infancy (242). All of them underwent orchiopexy at the age of 2.0 ± 0.7 years.…”

“…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).…”

Ontogeny of Hypothalamus-Pituitary Gonadal Axis and Minipuberty: An Ongoing Debate?

“…However, targeted neonatal treatment for cryptorchid boys with absent minipuberty might reveal significantly higher success rates (75,76). Table 1 summarizes available studies on gonadotropin treatment in order to replace minipuberty in infants with congenital hypogonadotrophic hypogonadism (77)(78)(79)(80)(81)(82)(83). In patient with congenital central hypogonadism, the impairment of HPG axis ontogeny results in a profound perturbation of germ cell-specific gene expression during late gestation with cryptorchidism at birth, and abnormal germ cell development and differentiation during minipuberty (31).…”

Minipuberty: A Primer for Pediatric Nurses

“…Notably, tailored hormonal treatments can effectively induce development of secondary sexual characteristics and fertility in most patients (Dwyer, Phan-Hug, Hauschild, Elowe-Gruau, & Pitteloud, 2015). Some have proposed neonatal hormone treatment to optimize fertility potential in patients lacking minipuberty and long term outcome data show promising results (Kohva et al, 2019).…”