A Developmental Perspective Sheds Light on Reproductive Differences Between Congenital and Acquired Hypogonadism

Intact function of the hypothalamic–pituitary–gonadal (HPG) axis is essential for normal reproductive capacity. The pulsatile secretion of gonadotrophin-releasing hormone (GnRH) from specialized hypothalamic neurons stimulates secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gonadotrophs, which in turn stimulate testicular development, testosterone (T) production, and spermatogenesis/reproductive capacity. Neuroendocrine disruption of the HPG axis results in hypogonadotropic hypogonadism (HH) and infertility. Notably, the HPG axis is active during late gestation and the neonatal period (minipuberty) before falling quiescent during childhood then reactivating during puberty, culminating in full reproductive capacity in adulthood (1).

In their single-center retrospective study, Maione and colleagues report reproductive phenotypes in large cohorts of men with congenital HH (CHH) (n = 668), acquired organic HH (n = 467), and a reference group of healthy men with normal reproductive function (n = 172) (2). An interesting aspect of this study is that the authors undertook the comparison through a developmental prism. CHH is caused by deficient secretion or action of GnRH resulting in hypogonadotropism that clinically manifests as absent/incomplete puberty and infertility. The cohort of men with acquired HH (AHH) comprised men with parasellar tumors, primarily pituitary adenomas (74.5%), but also cases of pituitary apoplexy, craniopharyngioma, other intracranial lesions, and infiltrative diseases. Relative strengths of the article include the sizeable cohorts, rigorous and detailed phenotyping, sound methods, and comprehensive biochemical characterization, which included a battery of hormonal assessments including gonadotropins, sex steroids, sex hormone–binding globulin, inhibin B, and insulin-like peptide-3. While both the CHH and AHH cohorts exhibited superficially similar clinical characteristics (ie, low gonadotropins, hypogonadal T, and infertility), juxtaposition of the authors’ developmental perspective with their detailed reproductive phenotyping studies revealed some notable differences between the CHH and AHH groups in respect of their reproductive potential.

This study is important because it extends the work of Bonomi and colleagues, who reported systematic phenotypic characterization of a cohort of 503 patients with HH—including hormonal profiling, olfactory function, and presence of developmental anomalies—in 459 cases of prepubertal onset (ie, CHH) and 43 “idiopathic” AHH cases (ie, lacking any structural cause, but with significantly milder endocrine deficits than Maione’s “lesional” AHH cohort) (3). Maione et al identified the age of diagnosis/onset as a key determinant of reproductive phenotype. But for hypogonadal sex steroid levels, the reproductive phenotypes of men with AHH overlap substantially with those of healthy controls. These observations help explain previous retrospective studies reporting better fertility outcomes in CHH men with partial pubertal development (4) and faster time to achieving sperm in the ejaculate (5).

Inducing spermatogenesis in CHH requires high intratesticular concentrations of T—which can only be achieved through local paracrine secretion by Leydig cells, combined with systemic FSH stimulation of Sertoli cells. In a 2015 retrospective cohort study, Mao and colleagues reported 22/22 men with acquired hypopituitarism achieved sperm in the ejaculate on combined gonadotropin therapy (ie, FSH + human chorionic gonadotropin [hCG]) compared with only 85% of men with CHH (n = 53) (6). Notably, testicular volume (TV) in the CHH group was significantly smaller at baseline and at 6, 12, 18, and 24 months of treatment. The detailed phenotyping of the large cohorts reported by Maione et al helps to explain these earlier observations. Men with CHH who were diagnosed before age 18 had smaller baseline TV than men with lesional HH (who were similarly diagnosed before 18 years). The observation underscores the important role of neonatal activation of the HPG axis (ie, minipuberty) in priming the reproductive axis for future fertility. This “early life determinant” of future fertility can be disrupted in cases of severe GnRH deficiency—manifesting in cryptorchidism and/or micropenis in a significant proportion of male infants with CHH (7).

The early window of HPG activity is thought to be critical for Sertoli cell and spermatogonial proliferation. Indeed, serum LH, FSH, and T levels during minipuberty approximate adult levels—yet the Sertoli cells remain immature as they do not yet express the androgen receptor (1). Thus, although FSH stimulation increases inhibin B secretion, spermatogenesis does not occur due to the absence paracrine T action (ie, lack of androgen receptor expression). Compared with the lesional AHH group, men with CHH had significantly lower inhibin B levels—consistent with a history of disrupted minipuberty. Sequential gonadotropin treatment in CHH aims to maximize fertility potential in CHH by recapitulating the hormonal dynamics of minipuberty and early puberty (when nocturnally entrained GnRH pulses favor FSH over LH secretion). Sequential therapy employs FSH monotherapy to proliferate Sertoli cells and spermatogonia prior to paracrine T-induced maturation with hCG or pulsatile GnRH (8). A number of single-center studies provide evidence that such an approach can improve fertility outcomes in men with severe GnRH deficiency. However, a large, multicenter comparative effectiveness trial is needed to make appropriately powered comparisons between sequential and traditional combined gonadotropin therapy (ie, hCG + FSH without pretreatment).

Randomized controlled studies offer the highest levels of evidence, but are exceedingly difficult in rare disorders. As such, much of the published literature reports retrospective data on cohorts from single-center studies. Although there are limits to conclusions that can be drawn from retrospective studies, the study by Maione and colleagues supports the critical importance of natural history studies for rare endocrine disorders. The careful, systematic phenotyping of the CHH and AHH cohorts provide physiologic insights that are highly relevant for both clinical management and counseling patients regarding the outcomes to fertility-inducing treatments. Importantly, the age at diagnosis (or lesion) is a critical factor when considering reproductive phenotype. The fact that the AHH men exhibited larger TV (often overlapping with healthy controls) and preserved inhibin B levels point to a history of intact minipuberty. Conversely, the CHH group’s reproductive phenotypes were consistent with disrupted minipuberty. Such studies provide insight into the early life hormonal dynamics that play critical roles in future fertility potential and can inform more tailored approaches to fertility-inducing treatment for men with CHH and severe GnRH deficiency.

Glossary

Abbreviations

AHH

acquired hypogonadotropic hypogonadism

CHH

congenital hypogonadotropic hypogonadism

FSH

follicle-stimulating hormone

GnRH

gonadotrophin-releasing hormone

hCG

human chorionic gonadotropin

HH

hypogonadotropic hypogonadism

HPG

hypothalamic–pituitary–gonadal

LH

luteinizing hormone

T

testosterone

TV

testicular volume

Disclosure Summary

Dr. Dwyer has no financial conflicts to report. He has previously collaborated with and published with some of the authors on this paper.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.