5th International Andrology Symposium
5th International Andrology Symposium
Dimitrios T. Papadimitriou
Department of Pediatric-Adolescent Endocrinology & Diabetes, Athens Medical Center, Athens, Greece.
Correspondence: jnfo@pedoendo.gr
Background. “Mini-puberty” is the transient activation of the hypothalamic–pituitary–gonadal (HPG) axis from ~2 weeks to 3–6 months in boys, driving Leydig- and Sertoli-cell activity, penile and testicular growth, and programming of future fertility. In congenital hypogonadotropic hypogonadism (CHH)—including Kallmann syndrome—this surge is absent, leading to micropenis and bilateral cryptorchidism despite otherwise normal anatomy. Because classical treatment paradigms address phenotype later (testosterone for penile length; surgery for testicular position), they often miss this early physiologic window and may not fully rescue fertility potential.
Objective. To synthesize the rationale, physiology, and clinical evidence for replacement of male mini-puberty using exogenous gonadotropins (recombinant LH/FSH) and related strategies, anchored in the author’s REMAP program and subsequent literature.
Methods & Sources. Narrative review with emphasis on endocrine physiology, translational studies, and prospective case series/registries. Core primary sources include the author’s REMAP study (“Replacement of Male Mini-Puberty”), ESPE abstracts, and the ISRCTN registry, alongside contemporary reviews and consensus statements.
Findings. In neonates/infants with CHH and absent mini-puberty, daily subcutaneous recombinant LH/FSH (typically 75/150 IU; Pergoveris®) for 3 months reproducibly: (i) raises LH/FSH to postnatal physiologic ranges; (ii) drives testosterone into pubertal levels; (iii) normalizes inhibin B and AMH; (iv) increases penile length from <2 cm to ≈3.5–4.0 cm median; (v) induces testicular descent to the scrotum or low inguinal canal with volumes
~1.5–2.5 mL; and (vi) initiates catch-up growth—all with acceptable short-term safety. Limited follow-up suggests sustained scrotal position in most; occasional low inguinal re-migration is manageable surgically. Mechanistically, therapy mimics the physiologic surge, restoring Leydig/Sertoli interplay that can never be recaptured by late adolescence-onset induction alone.
Conclusions. For appropriately selected boys with documented absence of mini-puberty and CHH (especially those with bilateral non-palpable testes and micropenis), gonadotropin replacement in early infancy provides a physiologic, noninvasive means to repair micropenis, facilitate or complete testicular descent, and likely preserve fertility potential. Programs should be embedded within multidisciplinary DSD/andrology networks with standardized diagnostics, dosing, monitoring, and long-term outcome registries.
Key words: Cryptorchidism, hyogonagotrope hypogonadism, pergoveris treatment
Contexte. La « mini-puberté » correspond à l’activation transitoire de l’axe hypothalamo–hypophyso–gonadique (HPG) entre ~2 semaines et 3–6 mois chez le garçon, stimulant l’activité des cellules de Leydig et de Sertoli, la croissance pénienne et testiculaire, ainsi que la programmation de la fertilité future. Dans l’hypogonadisme hypogonadotrope congénital (CHH), incluant le syndrome de Kallmann, cette activation est absente, entraînant micropénis et cryptorchidie bilatérale malgré une anatomie par ailleurs normale. Les approches classiques, intervenant tardivement, ne restaurent pas cette fenêtre physiologique précoce.
Objectif. Présenter la physiologie, la justification et les preuves cliniques du remplacement de la mini-puberté masculine par gonadotrophines exogènes (LH/FSH recombinantes), en s’appuyant sur le programme REMAP et la littérature ultérieure.
Méthodes. Revue narrative centrée sur la physiologie endocrinienne, les données translationnelles et les séries prospectives provenant notamment de REMAP, des abstracts ESPE, du registre ISRCTN et de revues/consensus contemporains.
Résultats. Chez les nourrissons CHH dépourvus de mini-puberté, l’administration quotidienne de LH/FSH recombinantes (≈75/150 UI pendant 3 mois) : (i) restaure des taux physiologiques de LH/FSH ; (ii) élève la testostéronémie à des niveaux pubertaires ; (iii) normalise l’inhibine B et l’AMH ; (iv) augmente la longueur pénienne (<2 cm → ≈3,5–4,0 cm) ;
(v) induit une descente testiculaire avec volumes de 1,5–2,5 mL ; et (vi) initie une croissance de rattrapage, avec un profil de tolérance satisfaisant. Les données limitées de suivi suggèrent une stabilité majoritaire de la position scrotale.
Conclusions. Chez les garçons soigneusement sélectionnés présentant une absence documentée de mini-puberté et un CHH (notamment en cas de micropénis et de cryptorchidie bilatérale), le remplacement gonadotrope précoce offre une stratégie physiologique, non invasive, pour corriger le micropénis, faciliter la descente testiculaire et potentiellement préserver la fertilité. Ces programmes doivent être intégrés à des réseaux DSD/andrologie avec protocoles standardisés et registres longitudinaux.
Mots-clés: Cryptorchidie, hypogonadisme hypogonadotrope, traitement par Pergoveris
Mini-puberty is a time-limited, developmentally programmed burst of GnRH-driven gonadotropin secretion in early infancy. In boys, LH rises within 1–2 weeks, peaks at 1–3 months, then wanes by 4–6 months; FSH peaks slightly later; testosterone follows LH by ~1 week, reaching pubertal levels around 1–3 months before returning to prepubertal levels by ~6 months [1-9]. This signal underwrites Leydig-cell proliferation, testosterone production, Sertoli-cell proliferation (despite immature androgen receptor expression), inhibin B production, and AMH dynamics; clinically, it supports penile growth, testicular growth, epididymal/wolffian maturation, and aspects of neurobehavioral sexual differentiation [6–9,11,14,16].
In CHH, the surge is absent. Affected boys present with micropenis and bilateral cryptorchidism and, left uncorrected endocrinologically, risk persistent Sertoli-cell immaturity, poor germ-cell endowment, and infertility even when orchiopexy is technically successful [6–9,14,16,17]. Traditional care—testosterone injections for micropenis and two-stage orchiopexy—addresses anatomical and short-term phenotypes but does not replace the physiology that mini-puberty supplies.
This paper advances a physiology-first approach: replace mini-puberty when the body expects it—with gonadotropins, not just androgens—so that the Leydig/Sertoli axis learns the proper “language” and the testes mature in the right hormonal context [1–3,10,12,13,15,16,18,19].
Pulsatile GnRH. GnRH receptor signaling in pituitary gonadotropes requires pulsatility; continuous occupancy down-regulates receptors and suppresses gonadotropins (as exploited by depot GnRH analogs to suppress puberty) [6–9]. Peripheral cues (leptin, insulin/IGF-1, ghrelin) modulate GnRH neurons and kisspeptinergic inputs, aligning growth and energy balance with reproductive timing [6–9]. The Vassalli Hall remarks stressed the “push-and-release” nature of GnRH—akin to a light switch repeatedly pressed—needed to stimulate LH/FSH release.
Fetal and neonatal timing. Fetal LH/FSH production emerges by 9–12 weeks; hCG dominates early Leydig stimulation; by mid-gestation, testosterone peaks at pubertal levels and falls thereafter. Neonatally, the second activation (mini-puberty) is GnRH-dependent and independent of gestational age at birth; in preterms, it starts at the same postnatal age, often lasts longer and is more intense [6–9,16,17].
Cellular consequences. Mini-puberty promotes Leydig-cell proliferation and testosterone secretion, Sertoli-cell proliferation (rising AMH/inhibin B despite limited androgen receptor expression), increases testicular volume, contributes to inguinoscrotal descent, and correlates with penile growth and early sex-typed behaviors [6–9,10,16,17].
Why replace it? If mini-puberty fails (as in CHH), boys are “born late”: the testis never sees the right conversation between LH/FSH and Sertoli/Leydig cells. Waiting until puberty and “speaking only testosterone” cannot fully remedy what required two voices (LH and FSH) in infancy [6–9,10,16]. Hence replacement aims to restore both signals at the right time.
When: 15 days to 3–6 months in boys is the unique diagnostic window to prove or refute CHH via two blood samples (e.g., at ~2–4 weeks and ~6–10 weeks): LH, FSH, testosterone, inhibin B, AMH, ± DHT; screen adrenal function as indicated. In CHH, LH/FSH and testosterone are undetectable/very low; inhibin B and AMH are often low for age [6–9,16,17].
Who: Any boy with micropenis (stretched penile length < 2.5 cm at term) and/or bilateral cryptorchidism should prompt urgent endocrine evaluation [6–9,16,20]. The transcript underscores that even NICU preterms share the same postnatal timing—call endocrinology or the window will be lost.
Why it matters for DSD: Beyond CHH, mini-puberty testing refines evaluation of 46,XY DSD, 46,XX DSD, and sex chromosome aneuploidies; it informs sex assignment and surgical timing through a one-tube workup aligned to imaging and karyotype [6–9,10,16].
CHH prevalence is low, but among boys with bilateral UDT + micropenis, an endocrine etiology is common. Kallmann syndrome (CHH with anosmia) and normosmic CHH are genetically heterogeneous (dozens of genes governing GnRH neuron development/migration/function) and can show variable associated pituitary and neurodevelopmental features [7–9,17]. Absence of mini-puberty translates to hypoplastic testes (difficult to find or mobilize), micropenis, and a high burden of surgery if endocrine physiology is not restored [7–9,18].
Use-case: Micropenis only, or as adjunct before hypospadias repair. Pros: Simple, inexpensive; 15 mg IM every 4–12 weeks x 2–3 doses is traditional; enlarges penile length without altering final adult size or bone age. Cons: Does not stimulate Sertoli cells or recreate the biphasic Leydig–Sertoli dialogue; won’t descend high intra-abdominal testes; won’t normalize inhibin B/AMH. It fixes the look, not the system [6–9,10,16].
Conceptually physiologic but impractical in neonates; requires a pump and intact pituitary; experience is limited [6–9].
Rationale: Replace both pituitary outputs (LH/FSH) to mimic mini-puberty during the exact
window it should occur.
Protocol: Daily subcutaneous recombinant LH/FSH (commonly 75/150 IU; Pergoveris® pen now available with 150/300 options) for 3 months; evening dosing aligns with half-lives [1–3,12].
Mechanism: LH → Leydig testosterone; FSH → Sertoli proliferation/inhibin B/AMH; jointly promote testicular growth, penile growth, and descent [1–3,6–10,12,13,15,16,18,19].
Evidence (REMAP & related):
These outcomes reproduce the physiologic phenotype of mini-puberty across hormones and anatomy, with functional implications for future spermatogenesis that purely androgenic or purely surgical approaches cannot ensure [1–3,6–9,12].
Eligibility
Dosing
Monitoring
Endpoints
Mini-puberty is not optional—it is instructional. In CHH, the instruction set is missing, and time-aligned replacement is the only way to convey it. The REMAP experience demonstrates that daily LH/FSH in early infancy can repair micropenis, induce/assist descent, normalize Leydig/Sertoli biomarkers, and launch a healthier developmental trajectory with minimal burden to families. Implementation requires systems that move fast, teams that coordinate, and registries that learn. The payoff is substantial: fewer operations, better anatomy, and—most importantly—a more fertility-capable testis for adult life.
Lorem ipsum dolor sit amet consectetur. Id mollis nulla maecenas at vestibulum blandit consectetur. Vulputate libero turpis diam eu rhoncus arcu. Donec at imperdiet viverra ut eu sagittis nunc volutpat. Sem nisi turpis venenatis non sed adipiscing donec dignissim.