Use of hormonal therapy for undescended testis? Results of a worldwide questionnaire

Abstract

The objective of this study was provide an overview of current practices on hormonal therapy (HT) in children with undescended testes (UDT).

An online questionnaire about HT, referral patterns, and orchidopexy was spread via several (social media) networks involved in pediatric urology.

A total of 283 individuals responded, with 54 countries sampled. The majority (84%) did not prescribe HT for UDT, predominantly due to a paucity of scientific evidence (76%). Among those who use HT, main reason was bilateral UDT (62%). There was no clear preference in administration type (50% intramuscular injection, 50% nasal spray). GnRH was slightly more favoured over HCG (50% vs. 32%). No standardized schedule was used. Most respondents (67%) felt all forms of UDT should be treated by either a pediatric urologist or -surgeon. Eighty-seven percent follow the current guidelines and perform orchidopexy between 6–18 months of age.

Resumen

El objetivo de este estudio era proporcionar una perspectiva global de las prácticas actuales de terapia hormonal (TH) en niños con testículos no descendidos (TND).

Se difundió un cuestionario en línea sobre TH, patrones de derivación y orquidopexia a través de varias redes sociales relacionadas con la urología pediátrica.

En total respondieron 283 personas, proporcionando una muestra de 54 países. La mayoría (84%) no prescribía TH para TND, principalmente debido a la escasez de pruebas científicas (76%). Entre los que utilizaban TH, la razón más común era TND bilateral (62%). No hubo una preferencia clara en el tipo de administración (50% inyección intramuscular, 50% aerosol nasal). La preferencia por GnRH fue ligeramente mayor que la preferencia por HCG (50% frente a 32%). No se utilizó un esquema de tratamiento estandarizado. La mayoría de los encuestados (67%) considera que todas las formas de TND deberían ser tratadas por un urólogo o cirujano pediátrico. El 87% sigue las recomendaciones de las guías actuales y realiza la orquidopexia entre los 6 y los 18 meses de edad

Introduction

Undescended testis (UDT) is the most common congenital anomaly of male genitalia. The incidence in birth cohorts is around 2% of all boys according to the American guidelines,¹ whereas the European guidelines mention an incidence that varies and depends on gestational age, affecting 1.0–4.6% of the full-term and 1.1–45 % of the preterm neonates.² UDT has potential long-term implications: testicular cancer and impaired fertility. Studies have shown that timely correction of the testicular position alone may not be adequate to eliminate some of these consequences, especially in bilateral cases.³ Accordingly, the use of hormonal treatment (HT) has been highlighted since the 1980s.⁴ This is based on the hypothesis that there is a deficiency in the function of the hypothalamic-pituitary-testicular axis which takes place at the end of gestational period or within a couple of months after birth, colloquially described as a “mini-puberty”.⁵ However, most studies on HT have been of poor quality, with heterogeneous and mixed patient populations, testis locations, schedules and dosages of hormonal administration. Additionally, long-term data are almost completely lacking.² Thus, a large variation in administration exists, which is also reflected by a two part round table published recently by our Young Academic Urologists working group in Paediatric Urology (YAU-PU).^6,7

The initiation of human chorionic gonadotrophin (hCG) or gonadotropin releasing hormone (GnRH) or a combination thereof, has demonstrated success rates of up to 20% for promoting testicular descent.⁸

According to both the American Urological Association (AUA) guidelines and the European Association for Urology (EAU) guidelines, the treatment of UDT should begin at six months of age and it should be finalized by 12 months, or 18 months at the latest^1,2,9 Otherwise irreversible effects on spermatogenesis, hormone production and increased risks of tumour development may increase. The AUA guidelines discourages the use of HT as evidence shows low response rates and lack of evidence for long-term efficacy.¹ The EAU guidelines are more liberal, and mention HT can be considered in case of bilateral UDT.² Currently, there are no guidelines for UDT in Iberico-American countries.

Considering the relatively high incidence of the anomaly and the diversity in recommendations, we aimed to investigate the clinical practices regarding the management of UDT around the world via an online survey, with a special emphasis on HT and orchidopexy. We hypothesized that there would be a significant variability in practice and the need for presentation of more robust data on this subject.

Material and methods

The EAU YAU-PU conducted via Delphi consensus an online questionnaire via SurveyMonkey® (Appendix A) that contained questions about basic demographics of the responders, HT, referral and surgery (orchidopexy). As this was an observational study of clinical practice, no interventions, inclusion- or exclusion criteria were reported.The questionnaire is not validated nor did we assess a Pearson coefficient or Cronbach’s alpha co-efficient. A cross-sectional convenience sample of (paediatric) urologists or pediatric surgeons, residents and fellows was used. The questionnaire was spread via several sources including YAU members and their national networks. In addition, the European Society for Paediatric Urology (ESPU) and South-American SIUP (Sociedad Iberoamericana de Urologia Pediatrica) disseminated the questionnaire amongst their members through email and social media platforms, constituting an global group of respondents. The number of people reached out to, and thus the denominator, is unknown.

Due to the descriptive nature of this study, limited statistical analysis were performed.

Results

The questionnaire was distributed between August 2024 and October 2024. There were 290 respondents, with a total of 271 respondants completing all questions (93%). All the answers to all the questions can be found in detail in Table 1. Overall, responders come from 54 countries across the world (Appendix B), with the majority having >10 yrs working experience in their field.

Table 1.

Demographics of the responders n = 290.

	N=	%	Other specified
Profession
- Resident/ in training	18	6%
- Specialist/ consultant	270	94%
- Missing data	2
Speciality
- (Pediatric) urologist	220	76%
- (Pediatric) surgeon	54	19%
- Pediatrician	2	1%
- (Pediatric) endocrinologist	12	4%
- Missing data	2
Type of hospital
- Non-academic hospital	36	13%
- Academic hospital	22727	78%
Private practice		9%
Which country do you currently work, per continent
- Africa (Egypt)	4	1.40%
- Asia	46	15.90%
- Europe	158	54.50%
- North America	34	11.70%
- South America	35	12.00%
- Australia	2	0.70%
- Unknown	11	3.80%
Years of experience
- <5yrs including residents	67	24%
- 5−10 years	41178	14%
- >10 years	4	62%
- Missing data
Do you use HT for UDT?
- Yes	46	16%
- No	239	84%
- Missing data	5
Indications for HT (multiple options)	N = 42		Micropenis n = 1
- Bilateral UDT	28	66%
- Premature babies with (unilateral) UDT	1	2%	Retractile testis n = 1
- Depending on the location of UDT	11	26%
- To improve fertility potential	16	38%	Insufficient length of a. testicularis n = 1
- In case of ambiguous genitals / DSD	3	7%
- Hypogonadotropic Hypogonadism	19	45%	Rarely, not specified n = 1
- Other …	7	17%
- Missing data	4
What do you subscribe when using HT?	N = 43		LH + FSH n = 1
- HCG	14	32%
- GnRH	22	50%	Sustanon in case of micropenis n = 1
- HCG + GnRH combined	4	9%
- FSH	0	0%	HCG + FSH in case of hypogonadotrope hypogonadism n = 1
- Other…	4	9%
- Missing data	3
What form do you prefer	N = 42
- Intra-muscular injection	21	50%
- Nasal spray	21	50%
- Missing data	4
What schedule do you use? (open question)	N=35		Nasal spray: 3 t/d, 4 w n = 15
- Missing data	11		Nasal spray: 2 t/d, 4 w
			LH/FSH: 750/150 1 t/d, 3m
			HCG sc 2x/w, 6 w n = 4
			HCG: 250 IE sc 2x/w, 3m
			HCG: 500 IU hCG s.c. 2x per week (250 IU in young children 1st year of life) if rFSH: 3 x (75-)150 IU s.c/week 2−3x per week
			Unclear medication:
			50 mg every 3 w, 4x
			5mil UI / 72h
			1500UI/w, 6 w
			750 IU 2x/w, 3−4 w
			10 μg 3x/w, 6 m
			4 w
			1x/w, 4 w n=2
			1/w, 3 w
			Nights.
			Depending on body weight
			Postoperative 4 m, unclear what medication
Who subscribes the hormonal therapy? (multiple options)	N = 43
- Pediatric urologist	27	63%
- Pediatrician	3	7%
- Pediatric endocrinologist	18	42%
- Missing data	3
Why do you not use HT? (multiple options) (Fig. 1)	N=238
- Too little scientific evidence	182	76%
- No experience	50	21%
- Too expensive	9	4%
- Potential adverse effects for spermatogenesis	81	34%
- Is prescribed by another physician if necessary	19	8%
- Missing data	52
Until what age do you await spontaneous descending of the testis, and therefore: at what age do you start treatment, and which treatment? Pm does not concern retractile testis (multiple options possible)	N= 271
- Before 3 months + hormonal therapy	2	0.70%
- Between 3−6 months + surgery	20	7%
- Between 3−6 months + hormonal therapy	3	1%
- Between 6−12 months + surgery	172	63%
- Between 6−12 months + therapy	12	4%
- Before 12 months + surgery	70	26%
- Before 12 months + hormonal therapy	3	1%
- Between 1 and 3 years + surgery and/or hormonal therapy	11	4%
- Before puberty + surgery and/or hormonal therapy	1	0.40%
- Missing data	19
When do you think UDT should be managed by paediatric urologist or -surgeon? (multiple options)	N= 272
- Age less than 12 months	88	32%
- Bilateral UDT or non-palpable testis	86	32%
- Relapse/recurrence of cryptorchidism	61	22%
- In case other (non-urological) pathology is present	43	16%
- Always	181	67%
- Missing data	18
In case of bilateral UDT: to whom do you consider the patient should be referred for treatment? (multiple options)	N= 273
- Paediatrician	3	1%
- Paediatric endocrinologist	116	43%
- Paediatric urology / surgery	238	87%
- Missing data	17
In case of bilateral UDT: at what age do you consider the patient should be referred for surgery?	N= 272
- As soon as possible	52	19%
- <6 m	68	25%
- <12m	152	56%
- Missing data	18

HT = hormonal therapy; t/d = times per day; UDT = undescended testis.

Hormonal therapy

Most of the respondents, 84% (239/285), did not use HT for the treatment of UDT. Respondents selected reasons for not using HT are illustrated in Fig. 1. Main reason is lack of scientific evidence.

Figure 1.

Reasons why not to use hormonal therapy for undescended testis according to responders (n = 234).

Amongst the cohort, 46 physicians (16%) stated that they were in favour of using HT for UDT, for which they provided multiple indications. The most common indications included bilateral UDT (66%), hypogonadotropic hypogonadism (45%) and a presumptive improvement in fertility potential (38%). They all shared details. The product of choice was most often GnRH (50%), followed by hCG (32%). There was no clear preference for the administration type: 50% preferred intramuscular injections and 50% nasal spray. Administration was most often performed by pediatric urologists (63%) or pediatric endocrinologists (42%). Treatment schedules were markedly different in dose, frequency and also in duration: from four weeks to four months. Most often mentioned was nasal spray three times per day, for four weeks.

Surgical treatment and referral

A total of 271 responders completed the questions about surgical treatment. Almost all (96%) preferred perform surgery before the age of 12 months (with or without HT). Four percent would wait until age 1–3 yrs with or without HT, and 0.4% would wait until puberty.

When asked which specialty physician should ideally be responsible for the management of UDT, 67% of the responders remarked that any form of UDT should be managed by a pediatric urologist or -surgeon. Other reasons for management by a pediatric urologist or -surgeon where: bilateral UDT or non-palpable testes (32%), age <12 months (32%), cryptorchism recurrence (22%), and when other (non-urological) pathologies were present (16%).

Two questions specifically addressed the management of bilateral UDT. The majority of respondents (87%) preferred an initial referral to a pediatric urologist or -surgeon over a pediatric endocrinologist. Correspondingly, responders stated that the age of referral in cases of bilateral UDT should be within 12 months for 56% respondents, while 25% indicated <6 months of age, and 19% as soon as possible.

Discussion

Hormonal treatment: disadvantages

The result of our survey indicated that the majority of the 290 respondents (84%) did not use HT for UDT claiming reasons of scientific evidence scarcity. This is also the reason the AUA guidelines oppose the use of HT for UDT.¹ HT may have negative effects on the germ cells in the short term, with Heiskanen et al. finding a temporary increase in germ cell apoptosis both in normal and cryptorchid testes one month after treatment with hCG.¹⁰ Other potential negative effects of HT on spermatogenesis were also described by Cortes et al.¹¹ who found that in 72 boys, 19 (26%) were treated with neo-adjuvant treatment with GnRH, eight received neo-adjuvant treatment with hCG and 45 did not receive HT. All boys underwent inguinal orchidopexy combined with a testicular biopsy to analyse the number of spermatogonia per tubule. The results showed lower number of spermatogonia after HT (either GnRH or hCG) compared to no HT. This difference could not be explained by age as the average age in all three groups was around three years.

There is a dearth of long-term outcomes following treatment with HT. However, Dunkel et al. reported that hCG treatment seemed to lead to an increase in germ cell apoptosis after 20 years, which in turn was associated with smaller testis volume and higher follicle-stimulating hormone (FSH) levels in adulthood.¹²

These studies all have a number of limitations including their retrospective nature, and the low numbers of patients included. There was also evidence of confounding in providing HT prior to surgery: testes were more likely in a higher position, which is also an innate potential reason for decreased numbers of spermatogonia. Furthermore, Cortes et al.¹¹ have described using HT between the ages of 1–3 years, whereas recommendations suggest not commencing HT after 12 months of age. Finally, HT can have temporary side effects such as pubic hair, scrotal erythema, scrotal pigmentation and behavioural changes, which according to the AUA guidelines, can occur in up to 75% of the boys.¹

Hormonal treatment: advantages

HT for UDT can be considered for the putative potential to increase fertility. Most of the studies on this subject have been published by Hadziselimovic et al. They repeatedly state that abnormal germ cell development in cryptorchidism is not a result of a congenital dysgenesis but is preceded by a hormone imbalance and perturbation in germ cell-specific gene expression during abrogated mini-puberty. Hence, they suggested a four-step-approach for treatment of UDT, including hormones pre- and post-surgery.¹³ Furthermore, Schwentner et al. performed a prospective randomized trial including 21 boys receiving neo-adjuvant GnRH followed by orchidopexy and testicular biopsy, compared with 21 boys who only underwent orchidopexy and biopsy.¹⁴ They found that after neo-adjuvant treatment the number of adult spermatogonia per tubule in at least 80 tubules (‘fertility index’) significantly improved, especially if they were treated before the age of 24 months. These results contrast from guidelines recommendations and other studies, and may be related to the product of choice (hCG versus GnRH). Other causes could be differences in size, the levels of pre-existing atrophy, or differences in the pre-operative testicular position. Due to results such as these studies the AUA guidelines state “This improvement in germ cell count and maturation may eventually reflect a better prognosis for fertility. It is still unclear if this effect on testis histology persists into adulthood improving fertility and paternity potential or disappears once the hormonal stimulus is removed.”¹

One of the reasons to consider using HT for UDT is bilateral cryptorchidism. This was also the main reason (66%) for the 46 responders who do use HT for UDT. This is in line with a recent survey on management of UDT amongst pediatric surgeons by Aubert et al.¹⁵ who reported that 10% of the respondends recommended HT in bilateral UDT, with the main proponent being to improve fertility potential.

The EAU guidelines panel recommends the use of HT with GnRH for boys with bilateral UDT in an attempt to preserve fertility potential.² However, the level of evidence is low and the strength of this recommendation is weak. The AUA guidelines do not advise on bilateral UDT.

Hormonal treatment: product and schedule

In the event of HT two options exist: hCG and GnRH. hCG can only be given as an intramuscular (IM) injection, while GnRH can be administered either IM or as a nasal spray. The latter is more child-friendly and thus, it is not surprising that the respondents who use HT prefer GnRH over hCG. Moreover, hCG may have long-term adverse effects as described above, although these studies are limited by retrospective nature and small numbers.

GnRH might have more favourable effects. One of the very few prospective trials involving GnRH demonstrated positive results in 21 boys treated with neo-adjuvant GnRH, in which they found no adverse effect on penile growth or testicular volume, and hormonal levels from mini-puberty to the time of orchidopexy were comparable with boys without stimulation.¹⁶ GnRH has also been reported to have longer-term benefits¹⁷: semen analyses of 30 boys with unilateral UDT carried out after puberty showed a significant increase in sperm concentration. In this study, all men who underwent orchidopexy without HT (n = 15/30) had severe oligospermia and 20% of them were azoospermic, whereas in the HT group (n = 15/30) 86% had sperm concentrations within the normal range.¹⁷

In an attempt to empower the data, several systematic reviews and meta-analyses have been carried out, and most conclude that there is too much bias to draw any definitive conclusions around HT for UDT.^18–21 For obvious reasons, the number of high-quality studies with long term follow up investigating HT for UDT is limited which leads to the limited use of it in the clinical setting. Given the lack of high-quality data, guidelines have reluctant stance on the use of HT.^1,2 As may be expected, this limitation affects the clinical use that has been shown in various papers. Firstly, Aubert et al. who investigated the adherence of pediatric surgeons to the EAU/ESPU guidelines, has shown that only 11% of pediatric surgeons would offer HT in bilateral UDT, solely.¹⁵ More recently, our group published a roundtable discussion series where we have shown that there is a huge discrepancy among authors all around the world when it comes to the use of HT regardless of the scenario.^6,7 However, these studies were looking from a more general aspect whereas in this current study, we tried to focus on the use of HT to understand the global variations and similarities. The results revealed in a bigger and wider scale that the current data is far from being convincing clinicians to use HT in UDT.

Referral and surgical treatment

Referral for UDT can be made to a pediatric endocrinologist or to a surgeon (pediatric urologist or pediatric surgeon) according to regional practice patterns. According to our respondents, this depends on the laterality of the problem (uni- or bilateral) as 87% of respondents would refer bilateral UDT to pediatric urologist or -surgeon instead of pediatric endocrinologist. In case of bilateral UDT, respondents are very pro-active: 19% prefer to see the patient as soon as possible, and 25% before the age of six months. The remaining 56% request an appointment before age of 12 months.

The timing of orchidopexy is well studied. According to both the EAU- and AUA-guidelines, management of UDT should start at the age of six months and should be finished by the age of 12 months, or 18 months at the latest.^1,2 Otherwise irreversible effects on spermatogenesis, hormone production and increased risks of tumour development may occur. Most of the respondents recognize this risk, and 94% try to perform surgery before 12 months of age. On a related note, there is no information on treatment of UDT within the SIUP. Trends in timing of orchidopexy was also the topic of investigation for Aubert et al.,¹⁵ in which 157 pediatric surgeons were asked about their policy regarding surgery: 46% performs orchidopexy before age 12 months and 44% before 18 months. Unawareness of guidelines was the most common reason cited for nonadherence. Sondermann et al. analysed a German cohort of 124.741 cases operated on between 2006 and 2020. They found an increase in surgeries within the first 12 months of live over time, but still a significant number of patients who received later treatment.²² The same conclusion of too often delayed surgery was found by Von Cube et al., in their retrospective analysis of a cohort of 1843 German boys with congenital UDT.²³ Main reasons were late referral and comorbidity. This suggests a gap in knowledge about this condition with e.g. pediatricians, which is confirmed in a Brazilian cross sectional observational study by Lima Monte et al.: only 56% knew that age six months is the correct age for referral for treatment of congenital UDT, and only 47% knew the ideal age for surgery.²⁴ The international guidelines do not make a distinction between the timing for uni- or bilateral orchidopexy.^1,2 One could argue whether this is appropriate, as bilateral UDT has been associated with lesser sperm quality,²⁵ and thus time-critical. This is shown by Tasian et al., who described an increase in germ cell loss of 2% per month, and Leydig cell depletion of 1% risk per month for each month a testis remains undescended.²⁶ However, there was no long-term follow-up of these patients Furthermore, in a population-based study from Australia comprising 350,835 boys followed up until adulthood, a 5% increase of use of assisted reproductive technologies was linked to every six month delay of orchidopexy for UDT.²⁷

Limitations

The questionnaire, which was not validated nor tested for reliability,was spread among persons and societies (ESPU, EAU YAU, SIUP) connected specifically to pediatric urologists and -surgeons, and online via several social media channels. Therefore, it is a convenience, non-scientifically controlled sample. The number of people reached out to, and thus the denominator, is unknown. Furthermore, this is the reason for the inclusion of more pediatric urologists and -surgeons compared to pediatric endocrinologists as respondents.

Future research

It is clear that the role of HT for UDT is still an open question. The lack of well-designed randomized clinical trials remains a challenge. In an ideal world, a prospective randomized clinical trial comparing GnRH to hCG and to no HT at all with testes at a similar position, followed by orchidopexy, with long-term follow-up (up to 30 years) to check for long term effects would be optimal. However, this would be highly expensive as it requires high numbers of participants and a long running database with a risk of losing patients to follow-up, and agreement on the exact schedule of dose and duration. Thus, at this juncture, it is unlikely such a study will ever be conducted. Meta-analysis with collection of raw data from all studies done on this topic seems to be more feasible, however this brings a high likelihood of heterogeneity as mentioned by authors of all ready published systematic reviews.^18–20 Also combining long-term results, such as effects in adulthood, from institutions that have used HT for UDT could be an option, but inevitable this is retrospective data. A wide spread collecting database such as now used for rare diseases in the European Reference Network would help with collecting data, and could be our next best thing to answer the long-existing question as to the optimal usage for HT in UDT.

Conclusions

The results of this international questionnaire with 290 respondents from all over the world showed that 84% of the responders feel there is no role for HT in case of UDT. Among the 16% of clinicians who use HT in their clinical practice, different strategies for indication and prescription prevail. This reflects the lack of clear guidelines based on solid underlying data.

The majority of the respondents share the opinion that pediatric urologists and -surgeons should treat all forms of UDT, and surgery should be completed before the age of 18 months, which is in concordance with the current international guidelines.

Funding

None.