Mini-Puberty, Physiological and Disordered: Consequences, and Potential for Therapeutic Replacement

Abstract

There are 3 physiological waves of central hypothalamic-pituitary-gonadal (HPG) axis activity over the lifetime. The first occurs during fetal life, the second-termed "mini-puberty"-in the first months after birth, and the third at puberty. After adolescence, the axis remains active all through adulthood. Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by a deficiency in hypothalamic gonadotropin-releasing hormone (GnRH) secretion or action. In cases of severe CHH, all 3 waves of GnRH pulsatility are absent. The absence of fetal HPG axis activation manifests in around 50% of male newborns with micropenis and/or undescended testes (cryptorchidism). In these boys, the lack of the mini-puberty phase accentuates testicular immaturity. This is characterized by a low number of Sertoli cells, which are important for future reproductive capacity. Thus, absent mini-puberty will have detrimental effects on later fertility in these males. The diagnosis of CHH is often missed in infants, and even if recognized, there is no consensus on optimal therapeutic management. Here we review physiological mini-puberty and consequences of central HPG axis disorders; provide a diagnostic approach to allow for early identification of these conditions; and review current treatment options for replacement of mini-puberty in male infants with CHH. There is evidence from small case series that replacement with gonadotropins to mimic "mini-puberty" in males could have beneficial outcomes not only regarding testis descent, but also normalization of testis and penile sizes. Moreover, such therapeutic replacement regimens in disordered mini-puberty could address both reproductive and nonreproductive implications.

Keywords: Kallmann syndrome; congenital hypogonadotropic hypogonadism; cryptorchidism; gonadotropins; hypogonadism; infancy; micropenis; mini-puberty; puberty.

Graphical Abstract

Figure 1.

A, Physiologic waves of male hypothalamic-pituitary-gonadal (HPG) axis activity, with consequences for testicular growth and cellular composition of the testes. Created with BioRender. B, Absent HPG axis activity in males with severe congenital hypogonadotropic hypogonadism, with consequences of reduced testicular growth and development. Created with BioRender.

Figure 2.

Histology of A to C, primate testes and D, human testes. A, Photomicrograph of testis of 1- to 2-day-old neonatal rhesus monkey showing Sertoli cells (SC) and type A pale and type A dark spermatogonia (Ap and Ad); B, Photomicrograph of testis of 4- to 5-month-old infant rhesus monkey, post mini-puberty, showing increased numbers of Sertoli cells. C, Sections of seminiferous tubules in a prepubertal healthy marmoset, histologically identical to that of a prepubertal human testis containing spermatogonia and Sertoli cells. The spermatogonia have not yet undergone any meiotic divisions. D, Sections of seminiferous tubules of a testis in a healthy postpubertal adolescent. The tubules contain all stages of spermatogonial meiosis, including elongated spermatids (mature sperm). Ad, A dark spermatogonia; Ap, A pale spermatogonia; eS, elongated spermatid; Gc, gonocyte; L, Leydig cell; P, pachytene spermatocyte; PmSptc, premeiotic spermatocyte; ptC, peritubular myoid cell; ; rS, round spermatid; SC, Sertoli cell; Spg, spermatogonia. Both (A) and (B) from Simorangkir et al (36), (C) and (D) authors’ own images. Scale bar A, B + C is 20 µm, D is 50 µm.

Figure 3.

Long-term consequences of absent mini-puberty and delayed puberty, with late or nonphysiological therapeutic intervention in males with congenital hypogonadotropic hypogonadism (CHH).

Figure 4.

Identification of male infants with suspected congenital hypogonadotropic hypogonadism (CHH): investigations to confirm the diagnosis, exclude differences of sexual development, and detect associated malformations.

Figure 5.

A, Change in testicular volume (pre to post treatment) with gonadotropin or gonadotropin-releasing hormone (GnRH) therapy used to replace mini-puberty in male infants with congenital hypogonadotropic hypogonadism (CHH), according to published case series (until June 2023). Size of study participants in the respective studies are illustrated by the size of the black circle (see sample size legend). Normal range varies by ethnicity and method of measurement (see Table 3), therefore no normal range has been plotted. For one study (Papadimitriou et al (315)) pretreatment values were not available; for one subgroup (Avril et al (310)) injection subgroup data were not available; both not plotted. All values represent means or medians measured with ultrasound (where specified). B, Change in average penile length (from pre to post treatment) with gonadotropin or GnRH therapy used to replace mini-puberty in male infants with CHH, according to published case series (until June 2023). Size of study participants is shown by the size of the black circle (see sample size legend). Stretched penile length of healthy male infants is shown as mean (horizontal dashed line) ± 2 SD (gray-shaded area), results from Boas et al (51), the largest study to date (see also in Table 3).

Figure 6.

Therapeutic options for central hormone replacement during mini-puberty for male infants with suspected congenital hypogonadotropic hypogonadism (CHH), and recommended monitoring.