5th International Andrology Symposium
5th International Andrology Symposium
Domingos T. G. Bica
Department of Pediatric Surgery, Federal University Children’s Hospital, Rio de Janeiro, Brazil.
Correspondence: Prof Dr med. PhD Domingos Bica Federal University Children’s Hospital, Rio de Janeiro, Brazil.
Background. Cryptorchidism (undescended testis, UDT) affects ~2–3% of term male infants and remains the most common genital anomaly of childhood. Beyond malposition, the central clinical problem is impaired germ cell maturation during the mini-puberty window (postnatal surge of GnRH–LH/FSH–testosterone), which in a subset of boys fails to occur, leading to loss of adult dark (Ad) spermatogonia, the stem-cell–like population that predicts future fertility. Surgical repositioning (orchiopexy) addresses location, but not necessarily the endocrine milieu. In the late 1980s–early 1990s, we therefore tested whether a brief course of intranasal buserelin (a GnRH agonist) could (a) induce descent and (b) rescue germ-cell maturation in cryptorchid boys.
Methods. In a randomized, double-blind, placebo-controlled, three-arm trial at the Federal University Children’s Hospital (UFRJ, Rio de Janeiro) with blinded histology processed in Basel, boys with true cryptorchidism were assigned to: (i) placebo; (ii) intranasal buserelin 20 µg once daily for 28 days; or (iii) primary surgery (orchiopexy). Subsequently, undescended testes underwent orchiopexy with bilateral testicular biopsies in all participants to quantify germ cells and maturation indices. Design, dosing, blinding, and histology endpoints are detailed in the primary publications and reiterated in the symposium program and transcript.
Results. In the published trial 59 boys were randomized (22 buserelin, 18 surgery, 19 placebo). Buserelin significantly increased scrotal descent compared with placebo (p < 0.01). Boys treated with buserelin had the highest number and maturation index of germ cells; epididymal development and closure of the processus vaginalis were also more favorable in the buserelin group (p < 0.003 and p < 0.05, respectively). The surgical arm appropriately repositioned testes but, as expected, did not itself reproduce the endocrine environment of mini-puberty. Subsequent follow-up and translational work showed that presence of Ad spermatogonia after endocrine therapy predicts better fertility potential; conversely, boys lacking Ad spermatogonia (impaired mini-puberty) face persistently reduced fertility prospects despite anatomically successful surgery.
Conclusions. A short, low-dose buserelin course can, in carefully selected boys, (i) induce descent when the testis is near the scrotum and (ii) support germ-cell maturation, a biologically meaningful endpoint that surgery alone cannot provide. Modern guidelines still recommend early orchiopexy (by 6–18 months) and generally discourage routine hormonal therapy for descent because population-level response rates are modest and heterogeneous; however, converging histologic and molecular data indicate that adjuvant GnRH-agonist treatment may be valuable for the subset with endocrine-mini-puberty failure and poor Ad-spermatogonia counts. This talk revisits the design, outcomes, and lessons of the Rio–Basel RCT, addresses controversies, and frames a pragmatic, risk-stratified approach that integrates histology with contemporary care pathways.
Key Words Cryptorchidism, treatment, Buserelin, three arm placebo-controlled study, histology, Ad spermatogonia
Contexte. La cryptorchidie, présente chez 2–3 % des nouveau-nés masculins, compromet la maturation germinale lorsque la mini-puberté est insuffisante, entraînant la perte des spermatogonies Ad, marqueurs clés du potentiel fertile. L’orchidopexie corrige la localisation testiculaire mais ne restaure pas l’environnement endocrinien. Nous avons évalué l’effet d’un agoniste de la GnRH sur la descente testiculaire et la maturation germinale.
Méthodes. Dans un essai randomisé, en double insu et contrôlé par placebo, trois stratégies ont été comparées : placebo, buséréline intranasale (20 µg/j, 28 jours) et orchidopexie primaire. Des biopsies testiculaires bilatérales ont été réalisées pour quantifier les cellules germinales et les marqueurs de maturation.
Résultats. Parmi 59 participants, la buséréline a significativement accru la descente scrotale (p < 0,01) et amélioré les indices de maturation germinale ainsi que le développement épididymaire (p < 0,003). La chirurgie seule n’a pas reproduit le contexte endocrinien de la mini-puberté. Le suivi a confirmé que la présence de spermatogonies Ad après traitement endocrinien prédit un meilleur potentiel de fertilité.
Conclusions. Un bref traitement par buséréline peut, chez des garçons sélectionnés, favoriser la descente testiculaire et restaurer la maturation germinale, un bénéfice non obtenu par la chirurgie seule. Bien que les recommandations actuelles privilégient l’orchidopexie précoce, les données récentes suggèrent qu’une thérapie adjuvante par agoniste de la GnRH pourrait bénéficier au sous-groupe présentant un échec endocrinien de la mini-puberté.
Mots-clés : Cryptorchidie, traitement, Buséréline, étude à trois bras contrôlée par placebo, histologie, spermatogonies Ad
Cryptorchidism is not merely a problem of anatomy. Even when a surgeon places the testis into the scrotum, the future of spermatogenesis depends on whether the boy experienced an adequate mini-puberty—the transient activation of the hypothalamic–pituitary–gonadal axis during the first months of life—because that hormonal surge drives Ad spermatogonia formation and Sertoli-cell maturation [1-3,5]. Absent or blunted mini-puberty is strongly associated with low Ad-spermatogonia counts on biopsy and poor adult fertility, even after timely, technically successful orchiopexy [1-3,5,8]
In the late 1980s, two clinical intuitions converged:
These insights motivated our randomized, double-blind, placebo-controlled three-arm study in Rio de Janeiro with blinded histology in Basel, reported in The Journal of Urology (1992) and European Journal of Pediatrics (1993) [1,2 ]. The present paper synthesizes those results, integrates later evidence on Ad spermatogonia biology, and situates buserelin therapy within today’s guideline landscape [3-6,9-13 ].
Prospective, randomized, double-blind, placebo-controlled trial with three arms: buserelin, placebo, and primary surgery. All clinical care and randomization occurred at the Federal University Children’s Hospital (UFRJ, Rio de Janeiro); histology was processed blinded in Basel to prevent observer bias, with codes opened after histologic assessments were complete (1,2).
Boys with true cryptorchidism were enrolled following exclusion of retractile testes after careful examination. In the published report, 59 boys were randomized: 22 to buserelin, 18 to primary surgery, 19 to placebo (1,2). (Contemporaneous remarks recall a slightly different screened or eligible tally; differences likely reflect pre-randomization exclusions versus randomized participants, consistent with the final J Urol numbers (1,2).
Buserelin arm: 20 µg intranasal once daily for 28 days (1,2).
Placebo arm: matched intranasal spray for 28 days.
Surgery arm: orchiopexy without preceding hormonal therapy.
After medical therapy, testes that remained undescended underwent orchiopexy.
Bilateral biopsies were obtained in all participants (including responders) to quantify germ-cell counts and maturation indices; epididymal status and processus vaginalis were assessed (1,2).
Primary biological outcome: germ-cell maturation, particularly the number of germ cells per tubular cross-section and maturation index; the presence of Ad spermatogonia was emphasized in later follow-ups (1–6,8).
Clinical outcomes: testicular position/descent (pre-scrotal/scrotal), epididymal morphology, and processus vaginalis closure (1,2).
Randomization and drug assignment were blinded to surgeons and pathologists; codes were opened only after histology (1,2). Group comparability at baseline (age, bone age, anthropometrics, hormones, penile size, contralateral testis volume) was confirmed (1,2).
Descent: Buserelin significantly increased scrotal descent vs placebo (p < 0.01). Most responses occurred in pre-scrotal or low inguinal positions; higher intra-inguinal/abdominal testes showed limited response—an observation echoed in the talk Q&A (1,2).
Epididymis: Normal epididymis was more frequent among boys with successful descent (p< 0.003) (1).
Processus vaginalis: Closure occurred more often after buserelin than after primary surgery alone (p < 0.05) (2). These anatomic maturational effects are biologically consistent with androgen-dependent epididymal development and gubernacular/processus changes (2,4).
Buserelin-treated boys exhibited the highest germ-cell counts and maturation indices among the three arms (1). In the trial, the median/mean germ-cell counts per tubule improved meaningfully in the buserelin group compared to placebo or immediate surgery; later commentary from the investigator notes a mean around 0.84 germ cells per tubule after 28 days of buserelin, significantly greater than comparator arms, in keeping with the published statement that buserelin increased the number and maturation of germ cells (1).
Crucially, histology was blinded, preventing expectation bias (1,2).
Subsequent work from Basel and collaborators defined Ad spermatogonia as a key histologic marker of completed mini-puberty and future fertility potential (3–6,8). In follow-ups, boys with sufficient Leydig-cell capacity (i.e., adequate testosterone response) achieved normal Ad-spermatogonia counts after hormonal treatment; those with suboptimal Leydig function did not, even if surgery succeeded anatomically (5). These data sharpen our interpretation of the RCT: the germ-cell benefit of buserelin likely concentrates
Earlier hormonal trials using hCG or GnRH showed variable descent rates with frequent re-ascent; meta-analyses in the 1990s–2010s placed overall sustained descent from hormonal therapy near 15–20%, far below surgery (~95%) (11,12). A 1992 multicenter study even suggested hCG outperformed GnRH for descent, though both improved as age decreased (10,11). However, almost none of those trials were designed or powered to detect histologic maturation—the core biological endpoint our trial prioritized (1,2,10–12).
Guidelines from major societies (AUA, EAU/ESPU, and international comparisons) recommend early orchiopexy (ideally by 6–12 months, and no later than 18 months) and do not recommend routine hormonal therapy to induce descent, citing modest and inconsistent response and potential germ-cell harm in nonresponders (9). That said, contemporary reviews acknowledge a biologic rationale for adjuvant GnRH-agonist in selected boys to improve fertility index/Ad-spermatogonia, particularly when used pre- or peri-operatively and evaluated within a structured protocol (6,11,16). This targeted, risk-stratified position is compatible with our trial’s central message: surgery is the cornerstone,
but endocrine rescue can matter for germ cells (1,2,6,9–13).
Mini-puberty physiology. After birth, pulsatile GnRH stimulates LH/FSH, transiently increasing testosterone and inhibin B, driving Sertoli- and germ-cell maturation and Ad-spermatogonia formation (3–5). In some cryptorchid boys, this surge is insufficient, leaving a lasting “imprint” of low Ad-spermatogonia and impaired fertility potential (3,5).
GnRH-agonist action. Short-course buserelin can, after an initial flare, enhance gonadotropin/testosterone exposure sufficiently to promote germ-cell maturation and epididymal/processus development (1,2,4). Molecular studies report recovery of Ad-spermatogonia and coordinated changes in PRDM family gene expression and Y-chromosome spermatogenesis genes after GnRH-agonist therapy, linking endocrine rescue to spermatogonial stem-cell programs (7). These data support a causal chain: GnRH-agonist → mini-puberty–like milieu → Ad-spermatogonia rescue → improved fertility index (3,4,6,7,16).
Lesson 1 — Orchiopexy remains the cornerstone. Timely surgery relocates the testis, reduces thermal stress, and lowers malignancy risk; it is the standard of care (9). Hormonal therapy does not replace surgery in bilateral high intra-inguinal or abdominal testes, and it should never delay recommended surgical timing.
Lesson 2 — Histology matters. Biopsies (intraoperative or protocolized) provide prognostic insight about Ad-spermatogonia. In our RCT, blinded histology demonstrated meaningful germ-cell benefits from buserelin beyond mere positional change (1,2). Where expertise allows and risks are acceptable, biopsy-informed counseling is appropriate, especially in higher-risk phenotypes (bilateral UDT, high position, small testis) (3–6,8–11).
Lesson 3 — Patient selection. The best endocrine responses occur in low-position testes (pre-scrotal/low inguinal) and in boys with residual Leydig-cell capacity (1,2,5). These are the children most likely to benefit from a brief, low-dose GnRH-agonist protocol aimed at maturation, not just descent.
Lesson 4 — Protocol discipline and blinding. Randomization, strict blinding, centralized histology, and well-defined endpoints made our study unusually robust for its era. The 28-day 20 µg/day intranasal regimen was deliberately conservative—enough to test the biological hypothesis, short enough to minimize exposure (1,2).
Lesson 5 — Integrating modern consensus. Today, routine hormonal therapy to induce descent is not advised; nevertheless, adjuvant endocrine therapy can be considered in a defined subset to address mini-puberty failure and improve the fertility index, always within shared decision-making and without deferring timely surgery (6,9–13).
This pathway honors guideline standards while preserving the biological insight of the Rio–Basel trial: some boys need more than relocation—they need mini-puberty replacement to secure a better spermatogonial future (1–6).
The Rio–Basel three-arm, double-blind, placebo-controlled trial demonstrated that a brief, low-dose buserelin course can induce descent in low-lying testes and—more importantly—enhance germ-cell maturation measured by blinded histology (1,2). Thirty-plus years later, the biologic signal we sought to test—mini-puberty replacement—has found support in histologic, molecular, and long-term observations around Ad spermatogonia and fertility potential (3–8,16,18). While orchiopexy remains the non-negotiable core of management, a selective, biopsy-informed use of GnRH-agonists deserves a place in nuanced care pathways for boys at highest fertility risk.
With gratitude to the patients and families; to colleagues in Rio and Basel. This study was inseparable from collaborative links between Rio de Janeiro (UFRJ) and Basel, and from mentorship by Faruk Hadžiselimović, who championed the Ad-spermatogonia concept and mini-puberty paradigm. The transcript read into today’s record captures the spirit of that collaboration and the gratitude owed to mentors and families who opened their homes and laboratories across continents.
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