Hypogonadotropic hypogonadism is defined as a deficiency of the pituitary secretion of follicle-stimulating hormone and luteinizing hormone, which results in the impairment of pubertal maturation and of reproductive function. In the absence of pituitary or hypothalamic anatomical lesions and of anosmia (Kallmann syndrome), hypogonadotropic hypogonadism is referred to as isolated hypogonadotropic hypogonadism (IHH). A limited number of IHH cases are due to loss-of-function mutations of the gonadotropin-releasing hormone receptor. To identify additional gene defects leading to IHH, a large consanguineous family with five affected siblings and with a normal gonadotropin-releasing hormone receptor coding sequence was studied. Homozygosity whole-genome mapping allowed the localization of a new locus within the short arm of chromosome 19 (19p13). Sequencing of several genes localized within this region showed that all affected siblings of the family carried a homozygous deletion of 155 nucleotides in the GPR54 gene. This deletion encompassed the splicing acceptor site of intron 4 -exon 5 junction and part of exon 5. The deletion was absent or present on only one allele in unaffected family members. GPR54 has been initially identified as an orphan G proteincoupled receptor with 40% homology to galanin receptors. Recently, a 54-aa peptide derived from the KiSS1 protein was identified as a ligand of GPR54. The present study shows that loss of function of GPR54 is a cause of IHH, and it identifies GPR54 and possibly KiSS1 protein-derived peptide as playing a major and previously unsuspected role in the physiology of the gonadotropic axis.

Precocious puberty results mostly from the precocious activation of the gonadotropic axis. Although the age limits have recently been discussed, most physicians consider that onset of pubertal development before the age of 8 years in a girl or 9 years in a boy warrants at least a clinical and bone age evaluation by a paediatric endocrinologist. The major concern in precocious puberty is the underlying condition, and central nervous system or gonadal neoplasm have to be formally excluded as a first step in the diagnosis. A secondary concern is height, since precocious puberty leads to accelerated growth, accelerated bone maturation and ultimately reduced stature. Precocious puberty is heterogeneous and strict criteria should be used to define it, both in terms of age and in terms of potential for progression. Depot forms of GnRH agonists are now the standard treatment for progressive central precocious puberty and aim at alleviating the clinical symptoms of early pubertal development, their psychological consequences and the effects on growth. Here, we review the consequences of both central and gonadotropin-independent precocious puberty on adult stature and the information available on outcomes using the therapeutic regimens currently available. In girls with progressive precocious puberty, all published evidence indicates a gain of adult height over height predicted before treatment or over untreated historical controls. However, the apparent height gain (derived from the comparison of predicted and actual heights) is very variable, in large part due to the inaccuracy of height prediction methods. In girls with onset of puberty at the lower half of the normal age (8-10 years) distribution, trials using GnRH agonists have given negative results (no benefit of treatment). In boys, precocious puberty is rare and fewer results are available but point in the same direction. The most appropriate time for interrupting the treatment is still controversial. In conclusion, GnRH agonists restore adult height in children when it is compromised by precocious puberty.

Since 1981, GnRH agonist administration has been the treatment of choice for central precocious puberty. Continuous administration of the agonist, instead of permanently stimulating gonadotropin secretion, deeply suppresses LH and FSH levels and induces a marked inhibition of gonadal activity and regression of clinical symptoms. This inhibitory effect is due both to specific kinetic parameters relative to natural GnRH, and to marked alterations of the biosynthetic pathways of gonadotropin subunits. The half disappearance time of infused agonists is 3-10 fold that of natural GnRH. This means that the residence time of GnRH agonists is significantly longer than that of GnRH. The resistance of agonist to enzymatic degradation, mainly due to the substitution of a hydrophobic D-amino acid for glycine 6, is one of the factors involved in the increased availability of GnRH superagonists. The paradoxical effects of GnRH superagonists are still incompletely understood. In children long-term treated with depot formulations of triptorelin or leuprorelin, alpha-subunit secretion is markedly increased, and remains sensitive to exogenous GnRH, which demonstrates that the gonadotrophs are not totally desensitized. Despite the sustained stimulation of a-subunit secretion, no deleterious side effects, either during therapy or during post-therapy follow-up, have been reported in children treated with GnRH agonists. It should be noted that alpha-subunit responsiveness to exogenous GnRH decreases progressively after several years of treatment, although it is never completely abolished. On the other hand, LH beta-subunit secretion is suppressed as evidenced by radioimmunoassay of LH beta-subunit in serum chromatographic fractions from children treated with triptorelin. This differential pattern of secretion parallels that of mRNA levels in rat pituitary after in vivo exposure to triptorelin. Both pharmacodynamic and pharmacokinetic data can help diagnose the situations of resistance or escape. The lack of clinical effect of GnRH in the treatment of precocious puberty can be due to true resistance, or to an inappropriate injection schedule, or to abnormal metabolism. Measurement of serum alpha-subunit level, and, if needed, of serum agonist level, generally provides the answer.

Anti-Müllerian hormone (AMH), also called Müllerian inhibiting substance or factor, is produced by Sertoli cells from fetal life until puberty. In the present study, AMH, testosterone (T), LH, and FSH were measured by immunochemical methods in the serum of 50 boys with normal or delayed pubertal development, 4 patients with suspected androgen insensitivity, and 11 patients with either central (CPP) or gonadotropin-independent (GIPP) precocious puberty to investigate the hormonal regulatory mechanisms of AMH secretion at puberty. An inverse relationship between AMH and T levels was demonstrated. In boys with normal or delayed puberty with T concentrations below 6.7 nmol/L, AMH values were elevated (mean +/- SEM, 22.4 +/- 3.1 micrograms/L) and widely dispersed. In subjects with T levels over 6.7 nmol/L, AMH levels were uniformly low (3.4 +/- 0.5 micrograms/L), except in patients with suspected androgen insensitivity. No significant relationship was found between AMH and gonadotropin levels. Similar results were obtained in patients with either CPP or GIPP. Longitudinal studies were performed on four boys with CPP and two with GIPP before and after treatment. At the time of diagnosis, the T concentration was high, and AMH levels were usually low in CPP and GIPP patients alike. When appropriate treatment was initiated, the T concentration was normalized within 2-4 weeks, but restoration of prepubertal AMH levels required several months. Mature Sertoli cells were observed in testicular biopsies performed in three patients with untreated GIPP. Our results suggest that gonadotropins are not directly implicated in repression of AMH synthesis at puberty, but, rather, that the decrease in AMH production is the consequence of an androgen-mediated, long term, reversible chain of events leading to morphological and functional maturation of the Sertoli cells. Thus, the fall in serum AMH levels appears to be an excellent marker of Sertoli cell pubertal development.

Depot GnRH agonists are widely used for the treatment of precocious puberty. Leuprorelin 3-month depot is currently used in adults but has not been evaluated in children. We evaluated the efficacy of this new formulation (11.25 mg every 3 months), for the suppression of gonadotropic activation and pubertal signs in children with central precocious puberty. We included 44 children (40 girls) with early-onset pubertal development in a 6-month open trial. The inclusion criteria were clinical pubertal development before the age of 8 (girls) or 10 (boys), advanced bone age, enlarged uterus (>36 mm), testosterone more than 1.7 nmol/liter (boys), and pubertal response of LH to GnRH (peak >5 IU/liter). The principal criterion for efficacy assessment, GnRH-stimulated LH peak less than 3 IU/liter, was met in 81 of 85 (95%) of the tests performed at months 3 and 6. The remaining four values were slightly above the threshold. The levels of sex steroids were also significantly reduced and clinical pubertal development was arrested. Plasma leuprorelin levels, measured every 30 d, were essentially stable after d 60. Local intolerance was noted after 10 of 86 injections (12%), and was mild in four cases, moderate in five cases, and severe in one. Among these 10 events, 4 consisted in local pain at injection's site. In conclusion, leuprorelin 3-month depot efficiently inhibits the gonadotropic axis in 95% of children with central precocious puberty studied for a 6-month period. This regimen allows the reduction of the number of yearly injections from 12 to 4.