Isolated Hypogonadotropic Hypogonadism: New Insights into Relationships Between Genotype and Reproductive Phenotype

Isolated hypogonadotropic hypogonadism (IHH)—congenital hypogonadotropic hypogonadism (CHH) in European nomenclature—is characterized by severe impairment of gonadotropin-releasing hormone (GnRH) secretion or action; features of puberty at presentation may be completely absent (around 2/3 of cases) or only partially developed (around 1/3). IHH is phenotypically and genetically heterogeneous, with loss-of-function variants hitherto identified in more than 60 genes, albeit still accounting for less than 50% of cases. This genetic complexity, featuring allelic heterogeneity and oligogenicity, contributes to phenotypic variability. Previous studies have explored the relationship between the genetic severity gradient and the occurrence of nonreproductive features, principally anosmia that defines Kallmann syndrome (KS), but also hearing loss, craniofacial clefting, deafness, digital abnormalities, dental agenesis, renal aplasia, and synkinesis (mirror movements) (1-3).

The authors of the present study have a track record of according equal respect and effort to meticulous documentation of clinical phenotype in IHH as to its molecular genetic characterization, and they have again leveraged this to deliver some novel insights from this examination of a cohort of 242 well-characterized IHH males, comprising 131 KS and 111 normosmic cases (1). Their starting point was the observation that IHH partly shares its genetic architecture with constitutional delay of puberty (4) and hypothalamic amenorrhea, both conditions characterized by less severe genetic defects and, accordingly, far milder reproductive phenotypes. Hence, Dwyer et al (1) hypothesized that an analogous gradient of genetic burden might underpin differences in the observed severity of reproductive phenotype within IHH. Accordingly, they focused on protein-truncating variants (PTVs)—the most functionally severe gene mutations—in a cohort of meticulously phenotyped IHH men.

The present study confirms an association between the genetic severity gradient and the severity of the reproductive phenotype in IHH men (1). Notably, this is the first genotype-phenotype study to examine the relationship between the cumulative burden of PTVs across 62 IHH genes and the reproductive phenotype. The authors systematically characterized the resulting reproductive phenotype (ie, the severity of the neuroendocrine defect) according to a checklist of validated clinical and biochemical parameters. These comprised the degree of spontaneous pubertal development (whether absent or partial); basal gonadotropin levels (whether undetectable or detectable); the pattern of luteinizing hormone (LH) secretion on frequent sampling (whether apulsatile or hypopulsatile), and basal levels of inhibin-B.

Dwyer et al (1) identified PTVs in IHH genes through whole-exome sequencing of peripheral lymphocyte DNA. Oligogenic PTVs were found to be enriched among IHH men with absent puberty and apulsatile LH, with ANOS1 emerging as the primary driver of a more severe reproductive phenotype, in line with prior observations (5). By contrast, PTVs in other IHH genes (whether singly or along with secondary variants) were associated with a milder reproductive phenotype, indicating considerable resilience of the hypothalamus-pituitary-gonadal axis to even severe genetic defects of most other IHH genes. This neuroendocrine resilience is likely mediated by overlapping functionality and/or redundancy among several molecular-developmental pathways, which are not able to similarly backfill ANOS1-determined pathways in the absence of ANOSMIN1 protein.

Such neurodevelopmental plasticity in the face of even severe genetic insults may also underpin several other clinical observations, comprising the phenomenon of IHH-reversal (occurring in 10%-15% of IHH men) (6), the significantly lower prevalence of IHH among females despite—aside from hemizygosity for ANOS1—a shared genetic milieu (2, 3), and the relatively low prevalence of IHH in the general population, albeit with enrichment in genetic variants among females (7), with HH arising from relative energy deficit, but not in males (8).

Partial spontaneous pubertal development, higher inhibin-B levels, and serum LH levels greater than or equal to 2.10 IU/L were strong predictors for pulsatile LH secretion. Similar rates of absent vs partial puberty, undetectable vs detectable LH, and apulsatile vs pulsatile LH secretion occurred across KS and normosmic IHH. Men with KS (or having another nonreproductive defect) did have a higher prevalence of neonatal cryptorchidism and micropenis, indicative of impaired neonatal minipuberty, and lower inhibin-B levels. However, apart from the single parameter of lower inhibin-B basal concentration, the occurrence of cryptorchidism and micropenis was not obviously associated with the severity of the adult reproductive phenotype in this cohort IHH patients as a whole (1). This was an unexpected finding, but should cause us to reflect that the relative contributions to the adult reproductive phenotype of impaired neonatal minipuberty vs impaired adolescent puberty in IHH are difficult to quantify; particularly with respect to testes volume in the context of prior cryptorchidism. Moreover, it is equally difficult to disentangle cause and effect regarding basal inhibin-B levels. A lower level at presentation may reflect similarly low levels in neonatal life due to more severe neuroendocrine phenotype, and this may in turn predispose to testicular maldescent; alternatively, incident cryptorchidism may result in a depleted Sertoli cell mass and, hence, lower inhibin-B levels in adult life, independent of the severity of GnRH deficiency.

In summary, this study confirms some established hypotheses with regard to genotype-phenotype relationships in IHH males, and provides novel insights into the relationships between genotype and reproductive phenotype, but does not confirm the anticipated close linkage between the severity of the neonatal reproductive phenotype and the corresponding severity of reproductive phenotype at presentation in adolescence or later life. We anticipate that these observations will be further clarified in the future by studying even larger patient numbers and using ultrasensitive gonadotropin assays, underpinned by an expanded palette of the known IHH-associated genes and their respective molecular mechanisms underlying the deficiency of GnRH secretion and/or action. The authors also present a more realistic framework for reclassifying IHH, according to whether there is a pure neuroendocrine phenotype (19% of cases), or whether a characteristic nonreproductive defect (not just anosmia) is also present (81%). Indeed, perhaps the time has come for KS (IHH with anosmia) to be superseded as an eponymous syndrome by one defined by IHH with nonreproductive defect?

Disclosures

R.Q. has received speaker's honoraria from Sandoz UK, Bayer UK, Besins UK & Ireland, and Thornton & Ross Pharmaceuticals. L.G. has nothing to disclose.

References

Abbreviations

 
• CHH

  congenital hypogonadotropic hypogonadism

 
• GnRH

  gonadotropin-releasing hormone

 
• IHH

  isolated hypogonadotropic hypogonadism

 
• KS

  Kallmann syndrome

 
• LH

  luteinizing hormone

 
• PTV

  protein-truncating variant