Jorma Toppari
Research Centre for Integrative Physiology and Pharmacology, and Centre for Population Health Research, and In Flames Research Flagship Center, Institute of Biomedicine, University of Turku, Turku, Finland, and Department of Pediatrics, Turku University Hospital, Turku, Finland
Correspondence; Prof Dr med , PhD Jorma Toppari Kiinamyllynkatu 10 20520 Turku Finland
Key words: cryptorchidism, mini puberty, Sertoli cell, treatment
Cryptorchidism affects ~1–9% of term male newborns globally, with pronounced geographic variation even across closely related Nordic populations [1,5]. In the turn of the millenium, harmonized examinations in Copenhagen (Denmark) and Turku (Finland) demonstrated a roughly four-fold higher prevalence in Denmark than Finland, catalyzing the modern “testicular dysgenesis syndrome” (TDS) discourse spanning impaired fetal Leydig/Sertoli function, cryptorchidism, hypospadias, reduced semen quality, and testicular cancer [1,5–7]. Puberty is the life stage when testicular function recovers (or fails to recover) from earlier insults: gonadotropin pulsatility resumes, Sertoli cells complete maturation, the blood-testis barrier consolidates, and spermatogenesis scales up. Consequently, pubertal outcomes in boys with prior cryptorchidism provide an integrated readout of the testis’ biological reserve built during fetal life and “mini-puberty” and modified by surgical timing and postnatal environment.
Historically, concerns in cryptorchidism focused on testicular cancer risk and fertility; however, contemporary longitudinal studies show that the tempo and quality of pubertal testicular growth—rather than age of pubertal onset—best differentiates formerly cryptorchid boys from controls [2,4]. This review organizes current evidence with an emphasis on Nordic prospective cohorts, laboratory phenotypes, and modifiable determinants of testicular growth trajectories.
Fetal testicular differentiation depends on placental hCG acting via the LH/CG receptor before the fetal pituitary–gonadal loop matures; in the second and third trimesters, fetal pituitary LH/FSH takes over steroidogenic regulation. After birth, an HPT “mini-puberty” (weeks 1–16) features rising LH/FSH, peaking total testosterone (~1–3 months), and robust Sertoli-cell outputs (inhibin B, AMH). This surge supports penile growth, scrotal pigmentation, and testis descent completion, but—critically—also expands Sertoli-cell number, which constrains future spermatogenic capacity. Disruption of this window leaves a durable imprint on adolescent fertility potential [2-4, 6-10].
Across birth cohorts that sampled at ~3 months (the compromise time point when FSH/inhibin B are near peak, and LH/testosterone are declining from peak), cryptorchid boys—particularly those with higher-lying testes—exhibit lower inhibin B and/or higher FSH, consistent with a Sertoli-cell deficit; serum testosterone is often comparable to controls, suggesting relatively preserved Leydig-cell steroidogenesis at a population level [11]. In the joint Danish–Finnish cohorts, mini-puberty hormones differed by testis position: suprascrotal/inguinal and non-palpable testes showed the most adverse Sertoli signals compared with boys whose testes were scrotal at exam [11]. These findings align with the pathophysiology whereby impaired Sertoli proliferation is an early, salient lesion in cryptorchidism, with lasting consequences for pubertal Sertoli mass and inhibin B later on [2–4].
The Danish–Finnish comparative birth cohorts quantified marked prevalence differences (e.g., ~9% Denmark vs ~2–3% Finland at standardized exams), provided a robust platform for hormone phenotyping during mini-puberty, and enabled tracking of spontaneous descent [1,2,4-7]. Spontaneous descent commonly occurs by 6 months corrected age; persistence beyond this window predicts need for orchiopexy. Guideline statements (Nordic 2007, AUA 2014, EAU/ESPU 2016) converged on recommending orchiopexy by 6–12 months to optimize testicular growth and reduce later risks [3,8,10]. The timing of orchiopexy becomes pivotal for pubertal trajectories: early relocation likely preserves more of the Sertoli/germ-cell niche than late surgery, even though puberty itself reactivates gonadotropin support [3,8-10].
Multiple cohorts (including Turku and Copenhagen, with standardized anthropometry and repeated testicular volume assessments) indicate that the calendar age at pubertal onset is not materially delayed in boys with a history of cryptorchidism compared with peers [2,4]. The more discriminating signal is testicular growth velocity once puberty begins. In the Turku study of formerly cryptorchid boys followed across adolescence, testicular volumes at the same Tanner genital stages were smaller than in controls, particularly in bilateral and previously non-palpable/abdominal cases [2,4].
Sadov et al. (2016) and Rodprasert et al. (2022) provided a detailed analysis of pubertal testicular growth in formerly cryptorchid boys versus controls, stratified by important clinical modifiers (laterality, whether descent was spontaneous or surgical, and age at orchiopexy). They reported:
These data operationalize the clinical intuition taught in pediatric endocrinology/urology: puberty does not “fix” a depleted Sertoli pool; rather, pubertal gonadotropin drive unmasks the anatomic constraint as a blunted volumetric trajectory. Replication and extensions of these observations in national registries and clinic-based cohorts support the same direction of effect [10].
Sertoli-cell axis (FSH–inhibin B): Relative to controls, formerly cryptorchid adolescents commonly show higher FSH and lower inhibin B, pointing to suboptimal Sertoli mass/germ-cell output. Differences scale with bilateral disease, non-palpable position, and later surgery [2]. This discordant Sertoli signal in the face of normal or near-normal testosterone is the hallmark endocrine phenotype and has direct fertility implications.
Leydig-cell axis (LH–testosterone): Most cohorts report no major difference in serum testosterone at comparable pubertal stages; LH can be slightly higher on average in bilateral/operated groups, but within reference ranges [2]. This suggests that Leydig-cell function—at least as captured by circulating testosterone under pubertal LH drive—is relatively preserved in many formerly cryptorchid boys, even when seminiferous expansion lags.
AMH: Pubertal AMH normally falls as Sertoli cells mature under intratesticular testosterone. AMH patterns in formerly cryptorchid cohorts are heterogeneous, reflecting the interplay of delayed Sertoli maturation and reduced Sertoli mass; AMH is generally not the preferred monitoring biomarker in mid-to-late puberty compared with inhibin B/FSH. [2,3,12]
Testicular volume is best tracked longitudinally using the same method. Orchidometry (Prader beads) remains widely used, but ultrasound provides more precise estimates and can detect modest inter-testis asymmetries important in unilateral disease. Scandinavian pubertal studies have often combined both methods to strengthen inferences and added also ruler measurements [2,4,13].
Bilateral cryptorchidism predicts smaller pubertal testicular volumes, lower inhibin B, and higher FSH compared with unilateral cases and controls [2,4,13]. Within each laterality stratum, higher-lying/non-palpable testes have worse trajectories than suprascrotal/low-inguinal positions, consistent with the gradient of thermal and developmental insult inferred in infancy [2,4,13,14].
Boys with spontaneous descent generally perform better in adolescence than those who required orchiopexy, supporting the concept that spontaneous descent is a biomarker of a more competent testis at baseline. Among the surgically corrected, earlier operation is associated with better pubertal testicular growth and Sertoli-axis labs [13,14].
Nordic and European guidelines recommend orchiopexy between 6 and 12 months, certainly before 18 months, to optimize later testicular growth and fertility potential [3,10]. Adolescent follow-ups confirm that earlier repair tracks with larger pubertal testicular volumes and more favorable inhibin B/FSH than late repair, though surgery cannot fully normalize outcomes in bilateral/non-palpable disease [3,8,13,14].
Inhibin B and FSH measured at ~3 months stratify later risk: lower inhibin B/higher FSH in cryptorchid infants (especially in those with higher-lying testes) predict more attenuated pubertal seminiferous growth and a higher likelihood of adverse adolescent Sertoli-axis profiles [2,13]. Such associations bind infancy to adolescence and rationalize early endocrine testing in persistent cryptorchidism.
Two nonexclusive mechanisms bridge cryptorchid infancy to pubertal outcomes:
At puberty, GnRH/LH/FSH activation drives Leydig testosterone and FSH-mediated Sertoli support. If the Sertoli-cell pool is small, FSH rises and inhibin B remains low despite normal LH/testosterone, and testicular volume grows along a shallower slope—the quintessential cryptorchid adolescent signature [2,3,13].
All boys with bilateral cryptorchidism, non-palpable/abdominal testes, late orchiopexy (>12–18 months), or abnormal mini-puberty labs warrant structured adolescent follow-up (growth, genital staging, testicular volume, and selective labs). Unilateral low-inguinal cases repaired early and boys with spontaneous descent have lower risk but still merit counselling and a baseline pubertal assessment. [2,14]
The adolescent phenotype (smaller testicular volumes, low inhibin B/high FSH) correlates with reduced adult semen quality in population studies; bilateral cryptorchidism and late surgery carry the highest odds of oligo/azoospermia. Early orchiopexy and spontaneous descent are favorable signs but do not guarantee normal fertility, especially after bilateral disease. Counselling should be realistic and individualized, and in late adolescence/young adulthood, semen analysis provides the definitive assessment. [3,8,10]
1. Risk stratification at or after repair:
2. Monitoring plan:
3. Transition planning:
Late-adolescent/young adulthood semen analysis for intermediate/high-risk groups; endocrine referral if FSH persistently high/inhibin B low or volumes plateau <15–20 mL combined.
This pragmatic approach operationalizes what the longitudinal literature—especially the Copenhagen/Turku experiences—has taught us about the shape of pubertal development after cryptorchidism. [1-4,6,13,14]
Boys with a history of cryptorchidism, especially bilateral or non-palpable disease and those repaired after the first year of life, typically enter puberty at the usual age but show constrained testicular growth and a Sertoli-axis signature (low inhibin B, elevated FSH) consistent with reduced seminiferous capacity. These pubertal findings echo endocrine phenotypes already visible during mini-puberty, binding fetal–neonatal events to adolescent outcomes. Early orchiopexy and spontaneous descent are favorable modifiers but do not fully normalize pubertal trajectories in higher-risk subgroups. A risk-tiered, biomarker-informed adolescent follow-up can sharpen counselling about fertility and guide timely referral for semen analysis and adult-care transition. Continued collaboration across Nordic and international cohorts will refine individualized prediction—transforming the epidemiologic signal of cryptorchid infancy into actionable pubertal care.
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: see manuscript 4,10,12
I thank colleagues and collaborators in Copenhagen and Turku for two decades of joint cohort work, and the families who made longitudinal follow-up possible.
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.
