5th International Andrology Symposium
5th International Andrology Symposium
Dina Cortes
Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital Hvidovre; Department of Clinical Medicine, University of Copenhagen; in collaboration with the Department of Paediatric Surgery, Copenhagen University Hospital Rigshospitalet, Denmark.
Correspondence: Professor, overlæge, r. med. Dina Cortes Clinical Professor, Department of Clinical Medicine, Department of Clinical Medicine
Whether exogenous hormones should be used in boys with cryptorchidism (undescended testis, UDT) remains one of the most debated questions in paediatric andrology and urology. European/American practice guidelines no longer recommend hormonal therapy to induce descent, citing low success rates and uncertain long-term benefit, whereas a European panel has a weak recommendation of gonadotropin-releasing hormone (GnRH) analogues as adjuvant therapy to potentially preserve fertility indices in selected boys—especially bilateral cases—after orchidopexy.
This paper reviews histological, endocrine, and clinical evidence for adverse effects of hormonal treatment administered in the prepubertal years, with focus on hCG (human chorionic gonadotropin) and GnRH (LHRH) regimens used historically for “therapeutic descent.” It synthesizes data from Danish and Nordic cohorts (including our own), randomized/controlled studies, and translational work on germ cell apoptosis and suppression of Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH). Key findings are:
Taken together, available evidence supports the American, Nordic and European consensus position that routine hormonal treatment for cryptorchidism is not recommended—given poor efficacy for descent and possible adverse effects on spermatogenesis—while acknowledging that post-orchiopexy, low-dose adjuvant GnRH analogues may be studied for patients with biopsy-defined reduced germ cell counts and germ cell transformation, and endocrine evaluation revealing insufficient genuine gonadotropin stimulation, under robust protocols.
Key words: Cryptorchidism, hormonal side effects, histology
L’utilisation d’hormonothérapie chez les garçons cryptorchides demeure l’un des sujets les plus controversés en andrologie et urologie pédiatriques. Les recommandations européennes et américaines ne préconisent plus l’hormonothérapie pour induire la descente, en raison de son efficacité limitée et de l’absence de bénéfice durable démontré. Un panel européen propose toutefois, avec un faible niveau de recommandation, l’emploi d’analogues de la GnRH comme traitement adjuvant après orchidopexie afin de préserver, chez des garçons sélectionnés — notamment en cas de cryptorchidie bilatérale — certains indices de fertilité.
Cet article analyse les données histologiques, endocriniennes et cliniques relatives aux effets indésirables des traitements hormonaux prépubertaires, en particulier les schémas à base d’hCG et de GnRH historiquement utilisés pour la « descente thérapeutique ». Les résultats issus des cohortes danoises/nordiques, des essais contrôlés et des travaux translationnels sur l’apoptose germinale et la suppression hypophysaire FSH/LH montrent notamment : (i) une réduction du nombre de spermatogonies par tube séminifère après traitements inefficaces chez les garçons de 1 à 3 ans ; (ii) une élévation aiguë de la testostérone à des niveaux adultes sous hCG avec suppression hypophysaire concomitante ; (iii) une augmentation de l’apoptose germinale après hCG dans plusieurs études humaines ; et (iv) des signaux négatifs particulièrement associés aux fortes doses administrées avant 4–6 ans.
Dans l’ensemble, les preuves disponibles soutiennent le consensus américain, nordique et européen selon lequel l’hormonothérapie ne doit pas être utilisée de manière routinière dans la cryptorchidie, compte tenu de sa faible efficacité et de ses effets potentiellement délétères sur la spermatogenèse. Après orchidopexie, l’utilisation adjuvante d’analogues de la GnRH à faible dose pourrait toutefois être envisagée, dans des protocoles contrôlés, chez des enfants présentant une histologie défavorable et un profil endocrinien suggérant une stimulation gonadotrope insuffisante.
Mots clés : Cryptorchidie, effets secondaires hormonaux, histologie
Cryptorchidism affects 2–4% of full-term neonates and ~1–2% at 12 months, with sequelae that include subfertility, infertility and increased risk of testicular germ-cell tumors. The primary treatment is timely orchiopexy (ideally by 6–12 months corrected age, 18 months the latest), a consensus position shared across major guidelines [1–4,].
Where controversies persist is the role of hormonal therapy—either to induce descent or to augment fertility potential. The AUA guideline (2014; validity confirmed 2025) states: “Providers should not use hormonal therapy to induce testicular descent as evidence shows low response rates and lack of evidence for long-term efficacy.” [1]. Similarly, the Nordic Consensus concludes that, in general, hormonal treatment is not recommended because of poor immediate results and possible long-term adverse effects on spermatogenesis [2].
By contrast, the EAU/ESPU pocket guideline (2025) (4) and the full EAU/ESPU guideline (2025)(3) have a weak recommendation of offering endocrine treatment (GnRH analogues) in bilateral cases to preserve future fertility potential. The full EAU guideline (2025) emphasizes surgical management and elaborates that identification of specific subgroups of boys with undescended testes who would benefit from using hormones is challenging [3].
This paper is reviewing negative effects observed in prepubertal testes after hormonal therapy, integrating our Danish experience with the broader literature, and clarifying how dose, timing, and endocrine feedback may drive harm.
The mini-puberty (peaking around 1–3 months) activates LH, resulting in testosterone production from the Leydig cells, and FSH stimulating the Sertoli cells. These hormonal changes enabling gonocyte → spermatogonia transformation and setting up the Ad (adult dark) spermatogonial stem-cell pool. Disruption of this period (by congenital hypogonadotropic states or testicular dysgenesis) correlates with long-term subfertility or infertility. In 1–4 years there is generally low plateau of the LH/FSH/testosterone levels, but germ-cell proliferation and transformation also take place, and at 4 years of age primary spermatocytes appear [5-7].
Earlier clinical practice attempted to mimic hormonal signals: hCG (primarily with LH effect) to stimulate Leydig cells to produce testosterone (and presumed descent via androgen-dependent pathways), or GnRH (with LH and FSH effect) nasal sprays to drive the axis. But in prepubertal boys, hCG can raise testosterone to adult levels and suppress FSH/LH, producing a non-physiological milieu. In a Danish cohort, hCG caused total FSH/LH suppression and very high testosterone [8]; this, resulted in unfavorable germ-cell endpoints when treatment failed to achieve descent [9].
In a consecutive series of 72 boys aged 1–3 years undergoing biopsies at orchiopexy, those with prior unsuccessful hormonal therapy (GnRH or hCG) had fewer spermatogonia per tubule (S/T) compared with boys who had surgery only; normal S/T values occurred only in the surgery-only group (p≈0.06), le adding to the conclusion that hormonal treatment may harm germ cells in this age bracket [9].
The clinical protocol that underpinned these observations, daily GnRH 1.2 mg for 28 days, repeat course if no descent, common in Denmark at the time, did not produce descent in boys < 4 years. The boys who were hCG-treated had 100 IU/kg (max 1,500 IU per injection) twice weekly for 3 weeks; six injections, also common in Denmark at the time [9].
Randomized trials elsewhere reported low complete-descent rates with LHRH sprays (e.g.,
0.8 mg/day × 28 days improved “some descent” vs placebo without robust complete descent), supporting the guideline stance against hormonal induction [1,2,3,10-12].
Multiple human studies from Finland and elsewhere show a transient spike in germ-cell apoptosis in both cryptorchid and contralateral (scrotal) testes within the first month after hCG exposure [13]. Increased apoptosis after hCG was in adulthood associated with smaller testicular volume of the undescended testis, and elevated FSH, but the sperm count was not reduced [14].
Abrupt androgen rises coupled with pituitary FSH/LH suppression may deprive immature Sertoli–germ cell units of coordinated trophic support; FSH is thought to be permissive for Sertoli proliferation and germ-cell survival in early life. The Danish endocrine studies in cryptorchid boys documented complete suppression of FSH/LH after hCG-courses, with testosterone in the adult range, exactly the pattern that raises concern for desynchrony [8,9].
Follow-up cohorts that included boys exposed to pre-orchiopexy hormones versus surgery only report mixed outcomes, complicated by selection Some series found smaller adult testicular volumes in hormonally pretreated patients [14-16], in some no sperm counts were reported [14,15], and others reported similar semen values [14]. At least one study linked prior hCG treatment to worse adult sperm outcomes in subsets, however there was a selection bias as only patients with bilateral cryptorchidism or those with non-palpable testes were offered hormonal treatment [17]. The heterogeneity underscores the risk of confounding but does not negate tissue-level harm signals in the 1–3-year window.
Historical Danish protocols used hCG 100 IU/kg twice weekly for 3 weeks (max 1500 IU per injection; six injections) and daily LHRH 1.2 mg/day for 28 days (with repeat cycles if no descent) [8,9]. These are high exposures relative to more recent adjuvant GnRH proposals. The negative histology signal in 1–3-year-olds emerged under these doses.
Key principle: the young children (1-4 (6) years with low plateau LH/FSH/testosterone levels) versus older children, and the higher the cumulative hormonal exposure, the greater the concern for germ-cell toxicity and FSH/LH suppression effects.
The EAU/ESPU 2025 pocket has a weak recommendation of GnRH analogues as adjuvant to surgery in bilateral cases to preserve fertility indices[4]. Yet the 2025 EAU full guideline stresses that evidence is heterogeneous, and not to use hormones as primary therapy for descent, and that identification of specific subgroups of boys with undescended testes who would benefit from using hormones is challenging [3]. Our own pilot, post-orchiopexy low-dose GnRH-analog trial (Kryptokur® 0.2 mg 2x every second day in 16 weeks) at boys with reduced number of germ cells and no Ad spermatogonia, and despite of this no elevated FHS/LH and therefore signs of a hypogonadotropic state, was stopped for regulatory reasons unrelated to safety, and—while a few boys showed increased number of Ad spermatogonia at re-biopsy—most had no change. We only treated boys with GnRH-analog if they had hypogonadism and insufficient genuine gonadotropin stimulation to avoid pituitary suppression and negative effect on the germ cells [18]. These observations argue for cautious, biopsy-and endocrinological- stratified trials rather than routine use.
AUA 2014/2025: Do not use hormonal therapy to induce descent (low response, no durable benefit). Orchiopexy at 6–12 months, 18 months at least [1].
Nordic Consensus 2007: In general, do not use hormonal therapy—poor efficacy plus possible adverse effects on spermatogenesis. Orchiopexy at 6–12 months[2].
EAU/ ESPU 2025: Orchiopexy at 6–12 months, 18 months at least. Hormonal therapy not recommended as primary treatment; panel has a weak recommendation of adjuvant GnRH in cases of bilateral UDT to improve fertility indices [3,4]. The full EAU guideline (2025) elaborates that identification of specific subgroups of boys with undescended testes who would benefit from using hormones is challenging [3].
Recent reviews echo that most guidelines discourage primary hormonal therapy; if considered for fertility indices, it should be adjuvant, selective, and preferably within trials/registries.
These findings underpin our cautionary stance: routine pre-orchiopexy hormonal treatment in this window can be more harmful than helpful.
Not all studies demonstrated long-term harm. Some follow-ups found smaller testis volumes but similar sperm counts between pretreated and surgery-only groups, suggesting compensation by the contralateral testis[14]. Others reported no sustained increase in apoptosis if surgery occurred > 1 month after hCG [13]. The literature is also complicated by selection bias (hormones given to more severe bilateral/nonpalpable cases) [17]. and variable doses.
Nonetheless, taken in aggregate—with randomized trials showing low descent efficacy and tissue data documenting apoptosis/reduced spermatogonia under high-dose regimens in 1–3-year-olds—the precautionary interpretation remains justified.
Where available, we favor randomized/controlled designs for descent efficacy and human tissue studies for germ-cell outcomes with histological analyses and analyses of endocrine dynamics (FSH/LH/testosterone/inhibin B), and rely on prospective sampling around treatment windows. Long-term outcomes are from retrospective cohorts with acknowledged selection biases.
The weight of evidence indicates that prepubertal hormonal therapy—particularly high-dose hCG and course-repeated GnRH regimens historically used to induce descent—can negatively affect the prepubertal testis, chiefly by (i) provoking germ-cell apoptosis and (ii) suppressing pituitary FSH/LH at a time when coordinated, low-level trophic support is crucial for establishing the spermatogonial stem-cell pool, transformation of spermatogonia to A dark spermatogonia and to primary spermatocytes. Tissue read-outs at orchidopexy in 1–3-year-olds show fewer spermatogonia per tubule after unsuccessful hormonal therapy than after surgery alone.
In line with AUA, Nordic and European recommendations, routine hormonal therapy to induce descent should be avoided. If hormonal modulation is contemplated post-orchidopexy to rescue fertility potential, it should be restricted to clinical trials with biopsy-based selection (low number of spermatogonia per tubule and no A dark spermatogonia), and simultaneously a hypogonadotropic state (not elevated FSH/LH – despite germ cell hypoplasia), low-GnRH dose regimens, and independent ethical oversight.
The author thanks colleagues in Denmark (Copenhagen University Hospital Rigshospitalet) and Nordic collaborators for patient care and study designs. Supervision and mentorship roles are acknowledged in works from our group.
Lacking outcome (spermiograms) Cortes et al. concluded that HCG treatment administered before the age of three years results in severe testicular pathological changes and infertility. Recently, the opposite was reported by Bartoletti et al., who have shown that HCG treatment during the second year of life has no long-term negative side effect on fertility. Importantly, no positive impact from early surgery was found. Thus, the sperm count of the surgical group showed no difference when compared to results obtained with samples from untreated boys
(1). The authors concluded that early prolonged hormonal therapy is advisable in all patients with cryptorchidism, independently of surgical testicular descent into the scrotum. In their study, hormonal therapy is more effective than orchidopexy as far as obtaining adequate sperm quality in adult life is concerned (1).
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