The physiology of the transient postnatal activation of the hypothalamic–pituitary–testicular axis

Rodolfo A. Rey

Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE), CONICET – FEI – División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina.
Correspondence: Prof.Dr. MD, PhD Rodolfo Rey Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE), Argentina

Table of contents

Abstract
Résumé
Paper
References
Author

Abstract

The male hypothalamic–pituitary–testicular (HPT) axis is activated three times across the life course: during fetal life, transiently in early infancy (mini-puberty), and again with the onset of true puberty. Although both mini-puberty and puberty feature hypothalamic–pituitary activation, mini-puberty is a developmentally distinct program: Leydig cells secrete testosterone and INSL3, Sertoli cells proliferate and secrete AMH and inhibin B, but spermatogenesis does not start because Sertoli cells are physiologically androgen-insensitive in this window. The first trimester of fetal life is unique in that masculinization is pituitary-independent and driven by placental hCG acting on LHCGR; by contrast, from mid-gestation onward and postnatally, pituitary control predominates. In this proceedings contribution, I synthesize cellular ontogeny (Leydig, Sertoli and germ cells), endocrine dynamics (LH/FSH, testosterone, INSL3, AMH, inhibin B), and clinical correlates (cryptorchidism, micropenis, congenital hypogonadotropic hypogonadism), integrating new molecular and single-cell insights. Mini-puberty is clinically invaluable: it offers a diagnostic window for central hypogonadism, explains phenotypic differences according to timing of androgen insufficiency, and informs management of undescended testes. Physiologic replacement strategies that mimic mini-puberty in boys with congenital hypogonadotropic hypogonadism (CHH) are emerging and appear to improve penile growth, Sertoli-cell output, and sometimes testicular descent. Finally, I frame practical implications for testing and timing of orchiopexy and articulate research priorities linking early endocrine programming to later fertility.

Key words: Mini-puberty, fetal life, gonadotropins

Résumé

L’axe hypothalamo–hypophyso–testiculaire (HPT) masculin s’active à trois périodes de la vie : pendant la vie fœtale, transitoirement au début de la vie (« mini-puberté ») et à l’adolescence lors de la puberté. Bien que mini-puberté et puberté impliquent une activation hypothalamo–hypophysaire, la mini-puberté constitue un programme développemental distinct : les cellules de Leydig sécrètent testostérone et INSL3, les cellules de Sertoli prolifèrent et sécrètent AMH et inhibine B, mais la spermatogenèse ne débute pas en raison de l’insensibilité physiologique des cellules de Sertoli aux androgènes dans cette fenêtre. Au premier trimestre fœtal, la masculinisation est indépendante de l’hypophyse et dépend de l’hCG placentaire agissant sur LHCGR ; à partir du milieu de la gestation et en période postnatale, le contrôle hypophysaire devient prépondérant. Cette contribution synthétise l’ontogénie cellulaire (Leydig, Sertoli, cellules germinales), les dynamiques endocriniennes (LH/FSH, testostérone, INSL3, AMH, inhibine B) et leurs corrélats cliniques (cryptorchidie, micropénis, hypogonadisme hypogonadotrope congénital), en intégrant de nouveaux éclairages moléculaires et unicellulaires. La mini-puberté offre une fenêtre diagnostique cruciale pour l’hypogonadisme central, explique les phénotypes selon le moment de l’insuffisance androgénique et guide la prise en charge des testicules non descendus. Des stratégies de remplacement physiologique mimant la mini-puberté émergent chez les garçons atteints de CHH et améliorent la croissance pénienne, la fonction sertolienne et parfois la descente testiculaire. Enfin, sont proposées des implications pratiques pour les tests hormonaux, le moment optimal de l’orchidopexie et les priorités de recherche reliant la programmation endocrine précoce à la fertilité future.

Mots-clés: Mini-puberté, vie fœtale, gonadotrophines

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Introduction

The HPT axis follows a multi-phase developmental choreography. The first trimester is dominated by placental hCG acting on the shared LH/CG receptor (LHCGR) to drive fetal Leydig-cell steroidogenesis underlying male genital differentiation—independently of fetal pituitary function. In the second and third trimesters, fetal pituitary LH/FSH increasingly contribute to testicular function. Shortly after birth, and following a brief suppression during the first days of life, the axis is reactivated for several months: LH and FSH rise, Leydig products (testosterone and INSL3) peak, and Sertoli-cell markers (AMH, inhibin B) are conspicuously elevated. Then the axis becomes quiescent until true puberty, when GnRH pulsatility resumes and spermatogenesis begins [1]. The contribution to the meeting emphasized these contrasts and their clinical consequences: ambiguous genitalia if androgen insufficiency occurs in the first trimester, versus micropenis and cryptorchidism (without ambiguity) if hypogonadism arises later; Leydig cells in childhood are hard to stimulate with a single LH/hCG dose; and Sertoli cells, although active, are immature and lack androgen receptor (AR) function in infancy, explaining high AMH and absent spermatogenesis.

Fetal life, placental hCG, and the timing principle

First trimester: masculinization under placental control

In the first trimester, placental hCG engages LHCGR on fetal Leydig cells to stimulate testosterone (and downstream DHT) needed for male external genitalia and urogenital tract masculinization. Because this step is pituitary-independent, defects in fetal pituitary GnRH/LH will not cause undervirilization; instead, defects in LHCGR function or androgen synthesis/action will [2]. Clinically, therefore, in 46,XY fetuses, ambiguous genitalia/DSD point upstream to placental/Leydig/androgen pathways rather than central hypogonadism when the insult occurs in the fi trimester.

Second–third trimesters: increasing pituitary contribution

From mid-gestation onward, the fetal pituitary becomes an active partner. Hypogonadism arising in this window or postnatally will usually spare virilization (already completed under hCG drive) yet predispose to micropenis and cryptorchidism because penile growth, testicular descent (and Leydig trophism) depend on later androgen and INSL3 output. The distinction by timing explains divergent phenotypes seen in clinic and underpins rational work-ups [3-5]

Cellular ontogeny across epochs

Leydig cells: fetal/infantile vs adult populations

Fetal (and early infantile) Leydig cells are hCG/LH-responsive, produce testosterone and INSL3, and regress during later infancy/childhood; adult Leydig cells emerge at puberty. INSL3, an RLF/insulin superfamily peptide, reflects Leydig-cell functional capacity and displays a characteristic postnatal peak (~2–3 months), falls to near-undetectable levels through childhood, and rises again across puberty. Longitudinal and cross-sectional studies position INSL3 as a robust biomarker complementing testosterone, with distinct kinetics [6-8].  

Functional stimulation. In the quiescent years, a single hCG/LH injection yields a blunted testosterone response; repeated stimuli or physiologic pulsatility better reveal Leydig capacity—consistent with clinical observations and with the idea that central hypogonadism (never exposed to LH in utero/mini-puberty) leaves Leydig cells even less responsive [9].

Sertoli cells: proliferation and endocrine signatures

Sertoli cells proliferate during fetal life, mini-puberty, and childhood under FSH influence; they secrete AMH and inhibin B and remain immature until puberty [10].  A cardinal mechanism explains why spermatogenesis does not start in infancy despite high testosterone: in early postnatal life, Sertoli cells lack androgen receptor (AR), so AMH remains high (androgen-repressible only after AR expression at later ages), seminiferous tubules remain small, and meiosis/spermiogenesis do not occur [11].

AMH and inhibin B thus serve as Sertoli biomarkers: AMH is high from fetal life through childhood, falls with pubertal AR activation; inhibin B is measurable and tracks Sertoli number/function. These insights power pediatric diagnosis where testosterone may be uninformative, and they are central to distinguishing selective Leydig defects from global testicular failure [1].

Germ cells: from PGCs to spermatogonia—what single-cell maps add

Primordial germ cells (PGCs) migrate to the genital ridges, differentiate into gonocytes/prospermatogonia, then spermatogonia. Single-cell RNA-seq atlases across fetal, neonatal and adult testes now chart molecular states of Sertoli, Leydig, peritubular, and germ-cell populations, clarifying that neonatal testes host undifferentiated SSC-like pools and prospermatogonia that do not enter meiosis until puberty. These datasets provide the cellular scaffold for interpreting endocrine signals across mini-puberty and puberty [7].

The transient postnatal activation (mini-puberty)

Temporal profile in term boys

In human males, the HPT axis is transiently suppressed at birth (first 1–2 days), then activates: LH/FSH rise within the first week [12]. peaking around 1–2 months [13].Testosterone and INSL3 follow the LH peak by several weeks. Sertoli outputs are also robust: AMH stays high; inhibin B is elevated in early infancy and declines partially thereafter but remains measurable—unlike testosterone, which falls to very low/undetectable levels through mid-childhood. (Oxford Academic)

During mini-puberty, testicular volume increases about 2–3-fold, predominantly from Sertoli proliferation and seminiferous-tubule lengthening (not diameter) [14]. This has methodological implications: cross-sectional histologic counts may paradoxically show fewer Sertoli cells per cross-section even when total Sertoli number is rising, simply because cells are distributed along longer tubules. Ultrasound is superior to orchidometry for precise testicular volume estimates in this window  [15].

Preterm vs term infants: corrected age matters

Preterm boys demonstrate higher and more prolonged LH/FSH and testosterone profiles and a later decline than term boys; however, when indexed to corrected gestational age, levels converge. The axis thus appears to follow an intrinsic developmental clock rather than chronological time—a crucial nuance for interpreting laboratory results and deciding when to investigate [16,17].

Predictive value

Observational cohorts suggest that testosterone levels during mini-puberty correlate with later sperm counts in adulthood—consistent with the concept that the infant surge tunes later testicular capacity, though effect sizes and confounding require more study [18]. INSL3 may emerge as a complementary predictor, given its reflection of Leydig cell functional mass, but longitudinal validation is ongoing [19].  

Why mini-puberty is not puberty

Despite shared features (GnRH/LH/FSH activation), mini-puberty lacks the Sertoli-cell androgen responsiveness required for spermatogenic maturation [20].  AR is not expressed in Sertoli cells during early human testis development, explaining persistent high AMH and absence of meiosis/spermiogenesis [21]; with puberty, intratesticular testosterone rises, AR is expressed in Sertoli (and peritubular) cells, AMH falls, inhibin B rises further, and full spermatogenesis begins. This developmental staging clarifies why robust infant testosterone does not trigger puberty and why testicular volume growth at this age reflects Sertoli proliferation rather than germ-cell mass [22].

Clinical mapping by timing of hypogonadism

First trimester androgen pathway defects (DSD)

Defects in androgen synthesis/action or LHCGR during the first trimester cause ambiguous genitalia/DSD because masculinization is hCG/LHCGR-dependent in that window and pituitary-independent. AMH is present (Sertoli-derived) and useful to assess Sertoli activity and Müllerian regression, distinguishing primary gonadal failure from androgen-pathway defects in the DSD work-up [2].

Mid-gestation/postnatal central hypogonadism (CHH)

Central defects (GnRH/LH/FSH deficiency) arising after first-trimester virilization typically present without genital ambiguity but with micropenis and cryptorchidism due to insufficient later testosterone/INSL3. In CHH, mini-puberty is absent or blunted: LH/FSH/testosterone are low, AMH/inhibin B lower than age norms, and testicular volume small. Recognizing this pattern in the 1–6-month window enables early diagnosis and appropriately timed physiologic replacement [23-26].

Cryptorchidism: endocrine window, biomarkers, and surgery

Testicular descent comprises a transabdominal phase (largely INSL3–RXFP2-driven) and an inguinoscrotal phase (androgen-dependent). Mini-puberty supplies critical androgen/INSL3 trophism in the final window for spontaneous descent (3). If the testis has not descended by approximately 6 months (corrected for gestational age), spontaneous descent thereafter is unlikely [27].

Biochemical evaluation may include LH, FSH, testosterone, INSL3, AMH, and inhibin B. Patterns and ratios (e.g., LH/testosterone, LH/INSL3) can reveal Leydig inefficiency even when single analytes overlap reference intervals. AMH/inhibin B help differentiate global testicular dysfunction (low) from selective Leydig failure (AMH/inhibin B preserved) [28,29].

Inducing mini-puberty in CHH: proof-of-concept and practice

Given the developmental rationale, physiologic replacement to mimic mini-puberty in boys with CHH has been explored using recombinant LH/FSH (via pumps or injections) or hCG/FSH combinations [23,25,30]. Across case series and small cohorts, therapy during the first months of life increases penile length, testicular volume, and Sertoli outputs (AMH, inhibin B) and can assist testicular descent in some cases. Protocols vary in dosing and duration, and long-term fertility outcomes require careful follow-up, but accumulating evidence supports the safety and physiologic logic of time-locked gonadotropin replacement when mini-puberty is missing.

Practical points. Replacement is ideally delivered in specialized centers; monitoring includes LH/FSH (if endogenous), testosterone, INSL3, AMH, inhibin B, penile length, and testicular volume by ultrasound. Because Leydig responsiveness in childhood requires repeated stimulation, pulsed or recurrent dosing regimens are physiologically sound.

Quantitative features of mini-puberty hormones

LH/FSH

LH and FSH rise within the first week, peak around 1–2 months, and decline to low levels by 4–6 months. FSH tends to remain relatively higher than LH across childhood, reflecting persistent Sertoli activity [31]. These patterns must be interpreted with age-appropriate (and gestation-corrected) reference intervals.

Testosterone

Serum testosterone (T) peaks after the LH surge and then falls to very low levels through childhood [31]. Importantly, intratesticular testosterone at early puberty may be high even when serum levels still appear prepubertal—a key reason why spermatogenesis can initiate before marked serum T elevation in adolescence [32].

INSL3

INSL3 peaks around 3 months, then becomes low/undetectable in mid-childhood, rising again with pubertal Leydig differentiation [33,34]. As a relatively stable secretion reflecting Leydig mass, INSL3 may be less acutely variable than testosterone and thus useful when assessing Leydig capacity longitudinally.

AMH and inhibin B

AMH is high from fetal life through childhood, declining at puberty when androgens repress Sertoli transcription via AR [29]; inhibin B is measurable throughout infancy and childhood and rises further at puberty with germ-cell expansion [35]. Together, they provide a Sertoli-centric window into the testis when LH/testosterone are uninformative.

Methodological considerations

Assay and sampling caveats

Neonatal and infant assays require sensitive platforms and strict pre-analytical control (timing, posture, illness). For INSL3, LC-MS/MS and validated immunoassays with pediatric reference data are preferred; for AMH/inhibin B, harmonization across platforms is improving but inter-assay variation persists. Clinicians should rely on laboratory-specific pediatric reference intervals and consider corrected gestational age in preterm infants.

Imaging and volumetry

Ultrasound-based ellipsoid models outperform orchidometry in small testes and are sensitive to the 2–3-fold volume increase observed during mini-puberty [15].  Given seminiferous tubule lengthening rather than diameter expansion, histologic quantification should avoid naïve cross-sectional counts as proxies for Sertoli number [14,22].

Integrating single-cell genome biology with endocrine dynamics

Single-cell atlases [7,36]. reveal transitional states of Sertoli cells through fetal/neonatal stages and at puberty, with gene modules for FSH responsiveness, AR acquisition, and paracrine cross-talk to germ cells and peritubular myoid cells. These maps help formulate mechanistic models in which FSH drives proliferation and secretory programs (AMH, inhibin B) during infancy; only later does AR-dependent maturation permit meiosis. They also raise testable hypotheses: e.g., whether FSH exposure during mini-puberty expands the future SSC niche and whether INSL3 dynamics influence adult Leydig-cell ontogeny.

Practical algorithm (0–12 months)

  1. History & exam. Note prematurity, birth weight/length, family history, genital exam (phallus length, testis position/size).
  2. When to test. In suspected endocrine etiologies of micropenis/cryptorchidism, assess LH/FSH, testosterone, INSL3, AMH, inhibin B between 1–6 months; preterm infants should be interpreted against corrected age.
  3. Interpretation.
  • Low LH/FSH/testosterone with low AMH/inhibin B → central hypogonadism with global gonadal under-stimulation likely.
  • Low testosterone with normal AMH/inhibin B → selective Leydig dysfunction.
  • Ambiguous genitalia in 46,XY → prioritize androgen synthesis/action and LHCGR pathways (first-trimester issues), not central hypogonadism.
  1. Management.
  • No descent by 6 months → plan hormonal treatment or orchiopexy  depending on testis position and etiological diagnosis.
  • CHH with absent mini-puberty → discuss physiologic gonadotropin replacement (LH/FSH or hCG/FSH), delivered in expert centers with careful monitoring.

Future directions

  1. Normative pediatric INSL3/AMH networks. Larger, multi-ethnic longitudinal cohorts with harmonized assays are needed to define reference curves across gestation-corrected ages and to validate predictive links to adult fertility.
  2. Randomized trials of mini-puberty replacement. Existing case series and systematic reviews justify controlled trials comparing pump vs injections, dosing schedules, and long-term outcomes (fertility, testicular growth, descent durability).
  3. Single-cell–guided therapeutics. Targeting Sertoli maturation pathways and SSC niche signals could optimize timing/sequence of FSH and LH/hCG in replacement regimens.
  4. Neuroendocrine patterning. Although beyond the scope of a purely testicular focus, work on GnRH/LH pulsatility underscores that pattern communicates biology; infant timing may have broader developmental consequences worth integrating with andrologic endpoints.
  5.  

Conclusions

  1. Mini-puberty is a time-locked, physiologically necessary activation of the HPT axis that calibrates Leydig and Sertoli compartments, supports penile growth, and creates a last endocrine window for testicular descent. It is not a miniature puberty: Sertoli cells remain androgen-insensitive, AMH stays high, and spermatogenesis awaits AR-dependent maturation at adolescence. Clinically, recognizing the endocrine signatures of mini-puberty—particularly in infants with micropenis and/or cryptorchidism—enables early diagnosis of central hypogonadism and justifies physiologic gonadotropin replacement in specialized settings. Integrating endocrine dynamics with single-cell maps and rigorous biomarker analytics offers a coherent framework to improve lifelong reproductive health.

Declaration Section

a) Ethics Approval and Consent to Participate Investigations were carried out in accordance 326 with the Declaration of Helsinki of 1975, revised in 2008.

b) Consent for publication Not applicable

c) Availability of data and supporting material  Not applicable

d) Competing interests  Author/s declare that they have no competing interests

e) Funding none

Acknowledgments

I acknowledge long-standing collaborations with colleagues at CEDIE–CONICET–FEI (Buenos Aires) and international partners who contributed to the body of work on AMH, inhibin B, INSL3, and pediatric hypogonadism. I also thank the organizers and attendees of the Vassalli Hall session for the stimulating discussion that inspired this synthesis.

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Rodolfo A. Rey

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