The difficulty, the authors argue, is that paediatric varicoceles are not a single entity. They vary enormously in severity, in the side affected, in the age at which they appear, and in the degree to which the affected testicle lags behind its partner in size. Most adolescents with a varicocele are entirely asymptomatic and will never experience fertility problems, which makes aggressive intervention for everyone hard to justify. At the same time, a minority of patients do sustain progressive testicular damage, and the available evidence has never been strong enough to identify them reliably in advance. The result has been wide practice variation, with some surgeons repairing nearly every varicocele they see and others reserving surgery for extreme cases.

Understanding why a varicocele can harm the testicle requires a look at the underlying anatomy and physiology. The internal spermatic veins, which drain blood from the testis back toward the major abdominal vessels, lack effective valves in many individuals. On the left side, the vein takes a longer, more vertical course and empties into the left renal vein at a right angle, creating a column of blood under higher hydrostatic pressure — a configuration that explains why roughly 90 percent of varicoceles occur on the left. When venous drainage stalls, blood pools and flows backwards, or retrogradely, into the pampiniform plexus. Animal studies dating back to the 1980s showed that this reversal of flow raises intratesticular temperature and disrupts the countercurrent heat-exchange system that normally keeps the testis a few degrees cooler than body core temperature, a condition essential for spermatogenesis.

The downstream cellular consequences form a cascade that the review maps out in detail. Venous congestion produces relative hypoxia within the testicular tissue, stabilising hypoxia-inducible factor-1 alpha, a transcription factor that in turn upregulates vascular endothelial growth factor and drives abnormal angiogenesis. At the same time, impaired clearance of reactive metabolites promotes oxidative stress, which damages sperm DNA and membranes, while excess nitric oxide produced within the testis further dilates the spermatic veins in a self-reinforcing loop and interferes with steroidogenesis in the Leydig cells, the factories of testosterone. The net effect is a gradual decline in sperm production, rising germ-cell apoptosis and, in some patients, measurable shrinkage of the affected testis relative to the normal side.

That shrinkage — testicular volume asymmetry — is the single most important clinical warning sign. The review highlights evidence that adolescents with a volume difference greater than 20 percent between the two testes are at substantially higher risk of progressive gonadal dysfunction, whereas asymmetry below 10 percent is generally reassuring. Measurement matters here: ultrasound has largely displaced the Prader orchidometer because it provides reproducible, norm-referenced volumes across childhood and puberty, allowing clinicians to track catch-up growth or deterioration over serial visits. Interestingly, some degree of asynchronous testicular growth during puberty is transient in many boys, and studies of non-operative management have documented spontaneous catch-up growth without surgery, reinforcing the case for careful surveillance in milder presentations.

Doppler ultrasonography adds a second, more technical dimension to risk assessment. Beyond confirming the dilated veins, duplex scanning can quantify peak retrograde flow velocity — the speed at which blood flows backwards through the spermatic vein during a Valsalva manoeuvre. The review identifies a peak retrograde flow above 38 centimetres per second as a threshold associated with persistent, progressive or new-onset testicular asymmetry, and later work has linked high retrograde flow to elevated sperm DNA fragmentation in young adults. A low-flow, low-grade varicocele with minimal asymmetry and normal hormonal markers sits firmly in the observation camp; a high-flow, high-grade lesion with measurable testicular loss pushes decisively toward intervention.

Laboratory markers complete the risk picture. Serum inhibin B, secreted by Sertoli cells, reflects the health of the seminiferous tubules, while follicle-stimulating hormone, luteinising hormone and testosterone track the hormonal axis that governs testicular function. In adolescents old enough to produce a semen sample, semen analysis remains the most direct readout of spermatogenesis, and abnormalities in multiple parameters — particularly a reduced total motile sperm count — combined with hormonal changes argue for repair. The authors acknowledge real-world barriers: many teenagers and parents are uncomfortable with semen collection, and attitudes surveys have documented reluctance on all sides. Nevertheless, they argue that in appropriate patients these tests transform an educated guess into a genuinely individualised decision.

When treatment is chosen, the modern options are safer and more refined than the operations of previous generations. Surgical approaches range from the retroperitoneal Palomo procedure, often performed laparoscopically, to microsurgical inguinal and subinguinal techniques that use an operating microscope to spare the testicular artery and lymphatic vessels. Artery and lymphatic preservation matters: large series have shown that accidental arterial ligation can cause testicular atrophy, and that lymphatic-sparing techniques dramatically reduce the most common complication, hydrocele formation. Percutaneous embolisation, in which an interventional radiologist occludes the incompetent vein with coils through a small catheter, offers a minimally invasive alternative with comparable technical success in selected patients. Across modalities, the review concludes that contemporary varicocele repair is safe, technically effective, and likely to confer a modest benefit on testicular volume and future fertility parameters.

Two clinical scenarios deserve special mention. First, pain: although most varicoceles are silent, a minority cause chronic scrotal discomfort, and the evidence summarised in the review indicates that repair is highly effective for appropriately selected patients, with longer duration of preoperative pain predicting better outcomes. Second, bilaterality: while the left side dominates clinically, venographic and fluid-mechanics studies suggest that varicocele is fundamentally a bilateral disease of the venous drainage system, and bilateral or isolated right-sided varicoceles — the latter occasionally signalling an anatomical obstruction that warrants abdominal imaging — carry a higher risk profile and warrant a lower threshold for both investigation and treatment.

The synthesis that emerges is a risk-stratified model rather than a one-size-fits-all rule. Low-grade varicoceles with less than 10 percent volume asymmetry, normal hormone and semen parameters, and low retrograde flow are candidates for observation with periodic reassessment through adolescence. High-grade or bilateral varicoceles, asymmetry exceeding 20 percent, peak retrograde flow above 38 centimetres per second, and multiple abnormalities on semen and hormone testing identify patients likely to benefit from early repair. Crucially, the authors emphasise shared decision-making: because most affected teenagers remain asymptomatic and the long-term fertility stakes are probabilistic rather than certain, patient and family preferences must sit alongside the objective findings. For a condition that has divided paediatric urologists for half a century, the message is neither watch everything nor fix everything, but measure carefully, stratify honestly and let the evidence — and the adolescent — guide the choice.

Subject of Research: Risk-stratified management of paediatric varicocele, weighing observation against surgical repair in adolescents

Article Title: Observation or treatment of paediatric varicoceles: revisiting the evidence

Article References: Buchinsky, D. S., Naelitz, B. D., Siva, J., Vallabhaneni, S., Momtazi-Mar, L., Klock, J., Hannick, J. H., Lundy, S. D., Weaver, J., & Woo, L. (2026). Observation or treatment of paediatric varicoceles: revisiting the evidence. Nature Reviews Urology. https://doi.org/10.1038/s41585-026-01187-y

Image Credits: AI Generated

DOI: 10.1038/s41585-026-01187-y

Keywords: paediatric varicocele, adolescent urology, testicular volume asymmetry, Doppler ultrasonography, peak retrograde flow, varicocelectomy, embolisation, male fertility, sperm DNA fragmentation, inhibin B, shared decision-making, Nature Reviews Urology

The work was led by Isabelle S. van der Meulen and Sabine E. Hannema of Amsterdam University Medical Center, together with colleagues spanning endocrinology, urology, psychology, sexology and gynaecology. This breadth of expertise was deliberate. The authors argue that questions about puberty suppression and sexuality cannot be answered from within a single discipline, because puberty itself is a phenomenon that unfolds simultaneously across the endocrine system, the developing brain, the genital organs and the psychosocial life of an adolescent. The recommendations were further shaped by input from a round table session held at the 2025 conference of the European Professional Association for Transgender Health (EPATH), which brought together clinical and community perspectives on how these conversations should be handled in practice.

At the physiological level, GnRH analogues work by suppressing the hypothalamus–pituitary–gonadal axis, the hormonal cascade that normally drives the physical transformations of puberty. By halting the release of gonadotropins, the medications pause the production of sex steroids and thereby interrupt the development of secondary sexual characteristics such as breast growth, voice deepening, genital development and changes in body composition and distribution. The rationale is to give adolescents with persistent gender incongruence time to explore their identity without the distress of unwanted, and in many cases irreversible, pubertal changes. When treatment is stopped, endogenous puberty resumes; when followed by gender-affirming hormone treatment, a puberty aligned with the adolescent’s gender identity is induced instead.

However, the same sex steroid hormones that drive physical pubertal changes also play roles in genital maturation, neural development and possibly in sexual response and pleasure. Androgens, for example, contribute to clitorophallus growth and penile tissue remodeling, while estrogens influence vaginal and vulvar development. Suppression of these hormones during a critical developmental window therefore raises legitimate biological questions about whether later genital sensitivity, sexual function or capacity for pleasure might be affected. The authors stress that the existing evidence base is too sparse to answer these questions definitively, and that this uncertainty is precisely why structured, evidence- and experience-based counselling is so important for adolescents and their families who are weighing these decisions.

The recommendations generated by the expert group centre on providing developmentally appropriate information about puberty, puberty suppression and sexual development. Clinicians are encouraged to explain, in language suited to the adolescent’s age and cognitive stage, how the hypothalamus–pituitary–gonadal axis works, what GnRH analogues do to it, and what is known and unknown about the consequences for sexual maturation. Importantly, the experts also highlight psychosocial dimensions of sexual development, including the effects of stigma and minority stress, which research in sexual minority populations has shown to be strongly linked to psychological well-being and, by extension, to sexual well-being. Counselling that ignores these social realities, the authors suggest, would present an incomplete picture of what shapes a young person’s sexual development.

Another core recommendation concerns individualized decision making around fertility and future surgical options. Puberty suppression at early pubertal stages limits the development of gametes, complicating options for fertility preservation, and it also affects the tissues available for later gender-affirming genital surgery, such as vaginoplasty. Decisions about when to start suppression, whether to pause treatment to allow sperm or oocyte maturation, and how to counsel about surgical implications must therefore be tailored to each adolescent’s circumstances, values and goals. The experts emphasize shared decision making, in which adolescents, families and clinicians weigh benefits, risks and uncertainties together, supported by decision aids and ethics support tools that have been developed and evaluated in recent years within transgender care.

Equally central is the promotion of positive, open communication about sexuality itself. The authors note that sexuality remains a taboo topic in many clinical settings, including youth mental health care, and that transgender adolescents frequently report wanting their healthcare providers to talk with them about sexuality and gender diversity rather than avoiding the subject. The recommendations call for clinicians to proactively address sexual desire, arousal, pleasure, relationships and masturbation as normal components of adolescent development, rather than treating sexuality purely as a domain of risk or dysfunction. Tools designed to open these conversations with young people, including question-based conversational aids developed for gender-diverse youth, are highlighted as practical resources that can help clinicians overcome their own hesitation and make these discussions routine rather than exceptional.

On the research side, the article identifies major knowledge gaps and sets out priorities for filling them. Longitudinal studies following TGD individuals from the start of puberty suppression well into adulthood are needed, ideally combining quantitative measures with qualitative approaches that capture lived experience. The first exploratory studies in this area have offered a measure of reassurance: they found similar sexual well-being in young adults who received puberty suppression during adolescence and those who received gender-affirming hormone treatment without prior suppression. Research on sexual functioning after vaginoplasty, and on the influence of puberty suppression timing on later sexual function, has begun to map this terrain, but the authors caution that these are early, often small studies that cannot yet support firm causal conclusions. Research frameworks adapted from other fields, such as the target trial framework for observational data, may help strengthen causal inference in this challenging population.

A further priority is the development of TGD-specific instruments to assess sexual development, sexual function and sexual satisfaction. The authors argue that existing sexual health measures, which were largely designed for cisgender populations, fail to capture the diversity and intersectionality of sexual experiences among TGD individuals, including the interplay of gender dysphoria and gender euphoria with desire, pleasure and body satisfaction. Without valid, sensitive measurement tools, the field cannot accurately track outcomes or evaluate whether and how puberty suppression affects sexual well-being over the life course. Genital sensitivity itself, including erogenous sensation in surgically constructed and hormone-influenced genital tissue, is named as an area requiring both psychophysical and patient-reported investigation.

Ultimately, the expert recommendation is framed not as a verdict on puberty suppression but as a framework for honest, compassionate and scientifically grounded care. By integrating evidence where it exists, transparently acknowledging uncertainty where it does not, and centering the voices and experiences of TGD adolescents themselves, the authors aim to support individuals considering puberty suppression, their families and their clinicians in optimizing both care and long-term well-being. The call for longitudinal, interdisciplinary research signals that the scientific conversation is far from over, and that the coming decade of work will be critical in transforming clinical experience into rigorous evidence about how best to support the sexual development and sexual well-being of transgender and gender-diverse young people.

The biological rationale for caution rests on well-established endocrine principles. Sex steroids act not only as activators of sexual response but also as organizers of tissue development during defined windows of maturation, a concept long recognized in classical studies of pubertal staging in boys and girls. Analogies can also be drawn from conditions such as congenital hypogonadotropic hypogonadism, in which individuals experience absent or delayed endogenous puberty and require hormonal induction; research in these populations has examined psychosexual development under long-term treatment and offers a useful comparative lens for understanding how pubertal hormone exposure relates to later sexual function.

The clinical context for these recommendations has been shaped by several prior expert documents. The European Society for Sexual Medicine has issued position statements addressing hormonal management and sexual function in adolescent and adult trans people, as well as sexual well-being after gender-affirming surgery, and a working group of the European Society for Paediatric Endocrinology has published expert opinion on the endocrine management of transgender and gender-diverse adolescents. The new recommendation complements these efforts by focusing specifically on the intersection of puberty suppression and sexuality, an area those documents addressed only briefly.

Conceptual framing also matters. The World Health Organization defines sexuality broadly, encompassing sex, gender identities and roles, sexual orientation, eroticism, pleasure, intimacy and reproduction, and the ICD-11 now classifies gender incongruence outside mental and behavioural disorders. Within this framing, sexual well-being is understood as a positive dimension of health rather than merely the absence of dysfunction, which reinforces the authors’ argument that counselling should address pleasure and satisfaction, not only risk.

The evidence base itself has grown out of decades of longitudinal cohort research, most notably the Amsterdam Cohort of Gender Dysphoria, which has documented diagnostic and treatment trajectories since the earliest days of the Dutch protocol. Recent pilot studies from this tradition have begun comparing sexual function in adults treated with gender-affirming hormones with or without prior pubertal suppression, and examining sexual satisfaction following vaginoplasty in relation to the timing of suppression. Although preliminary, these studies represent the first direct empirical tests of questions that were previously addressed only through theory, and they provide the methodological foundation on which the recommended larger, longitudinal and mixed-methods research programme can now be built.

Subject of Research: The effects of puberty suppression with GnRH analogues on sexual development and sexual well-being in transgender and gender-diverse adolescents

Article Title: Puberty suppression and sexual well-being in transgender and gender-diverse individuals: evidence- and experience-based counselling and future research directions

Article References: van der Meulen, I. S., van den Boogaard, E., Özer, M., Bungener, S. L., Vrouenraets, L. J., & Hannema, S. E. (2026). Puberty suppression and sexual well-being in transgender and gender-diverse individuals: evidence- and experience-based counselling and future research directions. Nature Reviews Urology. https://doi.org/10.1038/s41585-026-01182-3

Image Credits: AI Generated

DOI: 10.1038/s41585-026-01182-3

Keywords: puberty suppression, GnRH analogues, transgender health, gender-diverse adolescents, sexual well-being, sexual development, fertility preservation, shared decision making, gender-affirming care, EPATH, Nature Reviews Urology, expert recommendation