Long-term endocrine sequelae in testicular cancer: clinical manifestations, mechanisms, and follow-up considerations

Abstract

Objective

To describe the main long-term endocrine sequelae in testicular cancer survivors and their clinical relevance.

Material and methods

A narrative review of the clinical literature on the endocrine consequences of curative therapies for TC (orchiectomy, platinum-based chemotherapy, and radiotherapy) was conducted. The impact of these interventions on the hypothalamic-pituitary-gonadal (HPG) axis and other relevant endocrine systems was examined.

Results

The most prevalent endocrine finding was hypergonadotropic hypogonadism (primary testicular dysfunction), characterized by elevated FSH and altered testosterone levels. The etiology is multifactorial, involving the direct deficiency following orchiectomy and the toxicity of chemotherapy/radiotherapy on Leydig cells. Hypogonadism is correlated with adverse effects on quality of life, fertility, bone metabolism, and body composition.

Additionally, an increased risk of osteopenia/osteoporosis and thyroid dysfunction was documented, the latter associated explicitly with mediastinal or cervical irradiation.

Conclusions

CT survivors present a significant and persistent risk of chronic endocrine dysfunction. It is imperative to establish systematic endocrine surveillance, especially for symptomatic patients or those with borderline hormonal parameters, to facilitate early identification and initiate interventions such as hormone replacement therapy. This strategy is crucial for preserving functional health and quality of life in this young population.

Resumen

Objetivo

Describir las principales secuelas endocrinas a largo plazo en los supervivientes de cáncer testicular (CT), así como su relevancia clínica.

Material y métodos

Se realizó una revisión narrativa de la literatura clínica sobre los efectos endocrinos de las terapias curativas para el CT (orquiectomía, quimioterapia basada en platino y radioterapia). Se examinaron los posibles efectos de estas intervenciones sobre el eje hipotálamo-hipófisis-gonadal (HPG), así como en otros sistemas endocrinos relacionados.

Resultados

La alteración endocrina más frecuente fue el hipogonadismo hipergonadotrópico (disfunción testicular primaria), caracterizado por la elevación de la FSH y alteraciones en los niveles de testosterona. Su etiología es multifactorial e implica tanto la deficiencia directa tras la orquiectomía como la toxicidad ejercida por la quimioterapia/radioterapia sobre las células de Leydig. El hipogonadismo se correlaciona con efectos adversos sobre la calidad de vida, la fertilidad, el metabolismo óseo y la composición corporal.

Además, se documentó un mayor riesgo de osteopenia/osteoporosis y disfunción tiroidea, esta última asociada explícitamente con la irradiación mediastínica o cervical.

Conclusiones

Los supervivientes de CT presentan un riesgo significativo y persistente de disfunción endocrina crónica. Es imperativo establecer una vigilancia sistemática de las funciones endocrinas, especialmente en pacientes sintomáticos o aquellos con parámetros hormonales límite, a fin de facilitar la identificación precoz e iniciar intervenciones como la terapia de reemplazo hormonal. Esta estrategia es crucial para preservar la salud funcional y la calidad de vida en esta población joven.

Introduction

Testicular cancer (TC) is one of the solid malignancies with the most favorable prognosis in young men, with cure rates now exceeding 95% owing to advances in diagnosis and therapy, particularly platinum-based chemotherapy and radiotherapy in addition to orchiectomy [1]. This high survivorship has shifted clinical focus toward long-term health outcomes, including the endocrine sequelae of curative treatment, which significantly impacts quality of life beyond oncologic cure [2].

Among endocrine disturbances, hypogonadism and sexual dysfunction are among the most frequently reported long-term complications in testicular cancer survivors, with prevalence estimates ranging from approximately 19–40% depending on treatment modality and follow-up duration [3]. Longitudinal cohort data suggest that treatment intensification, especially with multiple cycles of cisplatin-based chemotherapy, is associated with a higher odd of testosterone deficiency compared to orchiectomy alon. Thatt radiotherapy also confers an elevated risk [4]. In addition, hypogonadism in this population correlates with increased cardiometabolic risk, including metabolic syndrome, obesity, dyslipidemia, and insulin resistance, further compromising long-term health [5]-

Beyond gonadal dysfunction, evidence also points to other endocrine disturbances in long-term TC survivors. For example, reduced bone mineral density (BMD) and increased vertebral fracture prevalence have been documented, with lower BMD observed particularly in hypogonadal survivors [4]. Furthermore, some cohort studies indicate an elevated prevalence of thyroid hypofunction compared with age-matched controls, suggesting broader endocrine system involvement after TC treatment [6,7]

We aimed to describe the main long-term endocrine sequelae in testicular cancer survivors and their clinical relevance. General oncologic aspects are included only to provide essential context, while the primary emphasis remains on endocrine dysfunction, long-term outcomes, and implications for survivorship care.

Methods

A narrative review of the clinical literature was conducted to examine the long-term endocrine consequences of curative therapies used in testicular cancer, including orchiectomy, platinum-based chemotherapy, and radiotherapy. Relevant studies were identified through searches of PubMed/MEDLINE, Scopus, and Web of Science, focusing on publications reporting endocrine outcomes in adult testicular cancer survivors. The review specifically assessed the impact of these interventions on the hypothalamic–pituitary–gonadal axis, including alterations in testosterone, luteinizing hormone, and follicle-stimulating hormone levels, as well as the prevalence of compensated and overt hypogonadism. When available, evidence regone involvement of other endocrine systems, such as bone metabolism and metabolic regulation, was also considered, and findings were synthesized descriptively accbyeatment modality and endocrine domain.

Results and discussion

Testicular cancer

Testicular cancer is a relatively uncommon neoplasm, accounting for approximately 1% of all malignancies in men; however, it represents the most common malignant tumor in males between 15 and 44 years of age. Its incidence has shown a progressive increased progressivelyveloped countries, a phenomenon possibly related to environmental and hormonal factors, as well as alterations in gonadal development. However, its precise etiology has not yet been fully elucidated [8]. According to the EAU Guidelines on Testicular Cancer 2025, testicular cancer should be classified within germ cell tumors (GCTs), which account for 90–95% of cases and are subdivided into seminomas and non-seminomas, each with distinct clinical behavior, therapeutic response, and prognosis [9] (Table 1).

Table 1.

Author’s elaboration.

Stage	Seminoma	Non-seminoma
I	Orchiectomy + surveillance, or one cycle of carboplatin, or radiotherapy.	Orchiectomy + surveillance (low risk), or BEP × 1–2 cycles (high risk).
II	BEP × 3 cycles, or radiotherapy (only in stage IIA)	BEP × 3–4 cycles; RPLND if residual mass.
III	BEP × 3–4 cycles according to IGCCCG + follow-up.	BEP × 4 cycles, VIP × 4 cycles; RPLND if residual mass.

Source: EAU Guidelines on Testicular Cancer 2025.

In Latin America, although the overall incidence is lower compared with Western Europe or North America, a sustained increase has been observed over the past decades, likely influenced by migration, environmental exposures, and improvements in diagnostic access [8]. Despite its low prevalence (approximately 1 case per 100,000 men per year), testicular cancer has an exceptionally high cure rate (>95% in localized stages), making it a model of oncologic success when diagnosed and treated promptly [9].

The best-established risk factors, as recognized by the 2025 EAU Guidelines, include:

• -

  Cryptorchidism (undescended testis): increases the risk 3- to 10-fold, even after early orchidopexy, with the highest risk when the testis is intra-abdominal [10].

• -

  Family history of testicular cancer: particularly in brothers (8- to 10-fold risk) and fathers (4- to 6-fold risk) [11].

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  Genetic syndromes, such as Klinefelter syndrome and gonadal dysgenesis, especially within the spectrum of testicular dysgenesis syndrome (TDS), are associated with both gonadal and extragonadal germ cell tumors [12].

• -

  History of prior testicular cancer: the risk of developing a contralateral tumorrangese from 2 to 5%, underscoring the importance of long-term surveillance [13].

Pathophysiology of testicular cancer

Testicular cancer arises, in most cases, from germ cells that undergo malignant transformation during fetal life or in early postnatal stages. These abnormal germ cells give rise to a precursor lesion known as germ cell neoplasia in situ (GCNIS). This precursor lesion may remain latent for years until activation occurs in adolescence or early adulthood, influenced by hormonal or environmental changes [14].

The most frequent chromosomal abnormalities include:

• -

  Gain of the short arm of chromosome 12 (isochromosome 12p): observed in more than 80% of germ cell tumors [14].

• -

  Aberrant expression of pluripotency markers (such as OCT3/4 and NANOG), which enhances uncontrolled proliferative capacity [14].

Seminomas derive directly from germ cell neoplasia in situ (GCNIS) without significant further differentiation. These cells retain features like primordial germ celofgonocytes), such as the expression oincludingncy markers (OCT3/4, NANOG, PLAP), which reflects their potential to remain undifferentiated. In addition, they exhibit high sensitivity to radiotherapy due to their low proliferation rate and limited mitotic activity. The tumor microenvironment is frequently infiltrated by lymphocytes, which may contribute to a favorable immune response [15].

Non-seminoma tumors also originate from GCNIS but are characterized by divergent differentiation toward multiple cell lineages. These include embryonal carcinoma (general, highly aggressive cells), teratoma (differentiated somatic tissues), yolk sac tumor (with alpha-fetoprotein [AFP] production), and choriocarcinoma (highly vascularized and producing human chorionic gonadotropin [HCG]). This multilineage differentiation results in a more complex and aggressive biological profile, with greater proliferative activity, invasiveness, and a higher risk of early hematogenous dissemination, particularly in the case of choriocarcinoma[lar biopsy should be considered in selected cases of non-obstructive azoospermia, suspected intratesticular germ cell neoplasia, or severe spermatogenic failure with inconclusive hormonal and imaging findings.

Surgical treatment

Radical inguinal orchiectomy is the initial procedure for all patients with suspected testicular tumors. It is performed via an inguinal approach to avoid scrotal dissemination. Its role is both diagnostic and therapeutic in early-stage disease. Testicular biopsy is contraindicated [9].

In non-seminoma tumors with residual retroperitoneal masses ≥1 cm after chemotherapy, retroperitoneal lymph node dissection (RPLND) is indicated. This procedure should be performed in specialized centers due to its technical complexity [9]. Retroperitoneal lymph node dissection (RPLND) may impair ejaculatory function due to sympathetic nerve injury, leading to retrograde ejaculation or anejaculation, particularly with non–nerve-sparing techniques [16].

ChemotVherapy

Systemic chemotherapy represents the standard of care for metastatic disease (stage II–III) and patients at high risk of relapse. Recommended regimens include:

• -

  BEP (bleomycin, etoposide, cisplatin): first-line treatment for most patients (3 cycles for good-risk disease; 4 cycles for intermediate- or poor-risk disease).

• -

  EP (etoposide, cisplatin): an option for patients without pulmonary involvement or with contraindications to bleomycin.

• -

  VIP (etoposide, ifosfamide, cisplatin): second-line therapy or an alternative in cases of relapse [9].

In stage I seminoma with low-risk features, options include active surveillance, radiotherapy, or a single cycle of carboplatin AUC 7, although BEP has demonstrated superior outcomes in more advanced stages [9].

Radiotherapy

The use of radiotherapy has declined in favor of chemotherapy due to the risks of secondary malignancies and endocrine toxicity. Currently, it is reserved for stage I or IIA seminomas, with fields directed to the para-aortic lymph nodes. Typical doses range between 20 and 30 Gy [9].

Endocrine Sequelae — Hypogonadism

Hypogonadism is a principal long-term endocrine sequela in testicular cancer (TC) survivors and may present in primary (hypergonadotr. It mayecondary (hypogonadotropic), or mixed forms depending on the level and mechanism of axis disruption. Primary hypogonadism results from direct testicular injury—most commonly due to orchiectomy or Leydig cell damage from platinum-based chemotherapy—and is frequently observed in TC survivors; large cohort studies report biochemical hypogonadism in approximately 30–38% of survivors, with significantly higher odds in those treated with ≥4 cycles of cisplatin-based chemotherapy or combined chemotherapy and radiotherapy compared with orchiectomy alone [17]. Biochemically, this form is characterized by low total testosterone with compensatory elevation of LH and FSH, indicating impairelevationsular Leydig cell function [4].

Secoonadism, though less common, may occur when the hypothalamic–pituitary axis is affected, d—such as with radiotherapy that exposes infra-diaphragmatic fields or through indirect mechanisms related to systemic therapy, obesity, and chronic stress. In these cases, gonadotropin levels (LH and FSH) may be inappropriately low or normal despite low testosterone [17]. Some survivors exhibit a mixed profile, particularly those receiving multimodal therapy (chemotherapy + radiotherapy) or with metabolic comorbidities (e.g., obesity, metabolic syndrome), where suboptimal central stimulation coexists with testicular dysfunction [6] (Fig. 1).

Figure 1.

Diagnostic algorithm for endocrine sequelae after testicular cancer.

Longitudinal studies indicate that treatment effects on Leydig cell function may persist or worsen over time. For example, prospective follow-up shows low testosterone levels even >5 years after therapy, significantly more common in those receiving combined modalities than in orchiectomy-only cohorts [4]. Furthermore, evidence suggests that cumulative platinum dose and treatment intensity are directly associated wia th higher risk of long-term hypogonadism, and that Leydig cell functional reserve may decline with aging in survivors who have been exposed to cytotoxic therapy [1] (Fig. 2).

Figure 2.

Algorithm for long-term endocrinological follow-up and management.

The clinical impact of hypogonadism in TC survivors extends beyond biochemical abnormalities. It has been linked with erectile dysfunction, reduced libido, fatigue, and adverse quality-of-life outcomes, as well as impaired fertility, since testosterone deficiency is associated with suboptimal spermatogenesis. Additionally, low testosterone contributes to metabolic dysregulation and increased cardiometabolic risk, including obesity, dyslipidemia, insulin resistance, and hypertension—further compromising long-term health [17].

Hypogonadism also negatively influences bone health: TC survivors with persistent testosterone deficiency have been shown to have lower bone mineral density (BMD) and a higher prevalence of osteopenia/osteoporosis compared with eugonadal peers, increasing fracture risk in long-term follow-up [17].

Diagnosis relies on morning fasting serum testosterone, LH, and FSH to distinguish primary from central forms. While equilibrium dialysis remains the gold standard for free testosterone measurement, most clinical practice uses total testosterone with SHBG measurement to estimate free and bioavailable fractions. Fig. 3 illustrates typical hormonal profiles across hypogonadism subtypes.

Figure 3.

Types of hypogonadism. Source: Jacobs LA, Vaughn DJ.

Once confirmed, testosterone replacement therapy (TRT) can improve symptoms and quality of life but must be individualized considering fertility desire, cardiovascular risk, and oncologic context. Table 2 summarizes key strategies for diagnosis and management, including clinical and laboratory monitoring, TRT options (transdermal, intramuscular, and oral), and fertility-preserving alternatives such as gonadotropin therapy or clomiphene citrate, which may be preferred in men desiring future fertility [4,6]

Table 2.

Hormonal profile and fertility outcomes. Author’s elaboration.

Hormonal profile	Probable etiology	Implications for fertility
FSH ↑, LH normal, T normal	Partial Sertoli cell dysfunction	Oligozoospermia → reduced fertility.
FSH ↑, LH ↑, T low	Mixed dysfunction → Leydig + Sertoli	Persistent azoospermia.
FSH normal, LH normal, T low	Central hypogonadism	Inactive spermatogenesis.

Source: Coviello et al., 2005.

Thyroid dysfunction

Thyroid dysfunction is increasingly recognized as a clinically relevant late effect in testicular cancer survivors, with evidence suggesting an approximately two-fold higher prevalence of thyroid hypofunction (both treated and untreated) in long-term survivors compared to population controls, even up to three decades after diagnosis. In a large Norwegian cohort, thyroid hypofunction was present in around 11% of survivors, with a prevalence ratio of 1.9 (95% CI 1.54–2.38), indicating a significantly elevated burden of hypothyroidism in this population relative to the general population. Significantly, in this study, the risk did not differ statistically by treatment modality (surgery alone vs radiotherapy vs cisplatin-based chemotherapy ± radiotherapy), suggesting that factors beyond direct treatment exposure (e.g., shared etiologic influences, long-term systemic effects) may contribute to thyroid dysregulation [18].

Although historically the focus regarding endocrine late effects has centered on gonadal and metabolic dysfunction, emerging data support the need to consider thyroid sequelae more systematically. Radiotherapy, particularly when encompassing supradiaphragmatic fields, has long been associated with direct damage to thyroid tissue in other oncologic settings (e.g., head and neck radiotherapy), with dose-dependent increases in primary hypothyroidism and thyroid nodules that may manifest years to decades post-therapy. While analogous data specific to testicular radiotherapy (often used in stage I seminoma) are limited, studies of secondary malignancies in testicular cancer survivors have demonstrated increased risks of solid tumors, including thyroid carcinomas, associated with both radiotherapy and platinum-based chemotherapy exposure, with risks potentially increasing with cumulative radiation dose and platinum dose intensity [19].

Radiotherapy for seminoma, historically delivered at doses between 30–40 Gy to para-aortic and pelvic fields, may increase incidental scatter to thyroid tissue and predispose to long-term thyroid dysfun,ction including hypothyroidism, autoimmunity, and nodular disease. Although definitive dose–response relationships in testicular cancer cohorts remain to be quantified, radiobiologic studies in other cancer populations consistently demonstrate that radiation doses ≥10–20 Gy to the thyroid significantly increase the risk of hypothyroidism, with cumulative incidence increasing with higher doses and longer follow-up [20].

Chemotherapeutic exposures, particularly cisplatin-based regimens, have been implicated in endothelial and endocrine disruption that may perturb hypothalamic–pituitary–thyroid (HPT) axis integrity, potentially through vascular injury or dysregulated hormonal signaling. While direct causal mechanisms are not fully elucidated, longitudinal analyses of cisplatin-treated cohorts indicate a cumulative effect of multi-cycle cytotoxic therapy on late endocrine outcomes [21].

Given these risks, long-term surveillance of thyroid function (TSH, free T4) should be incorporated into survivorship care, with earlier testing within the first post-treatment year and continued annual or biennial assessments throughout adulthood, particularly in individuals with prior radiotherapy exposure or symptoms suggestive of thyroid dysfunction (e.g., fatigue, weight change, cold intolerance). Although universal screening protocols specific to testicular cancer survivors are not yet established, extrapolation from other cancer survivors supports lifelong monitoring, with additional evaluation (e.g., ultrasound) where clinical suspicion for nodules or carcinoma exists [20].

Management of thyroid dysfunction

Thyroid dysfunction is not considered a primary sequela of testicular cancer; however, it may emerge as a late effect of treatment. It has been observed in patients who underwent radiotherapy involving cervical or supraclavicular regions, as well as in the context of post-treatment autoimmune responses. In addition, some chemotherapy regimens have been associated with subclinical and autoimmune thyroid dysfunction [22].

• -

  Periodic monitoring of thyroid function: A baseline assessment of thyroid function (TSH, free T4, and anti-thyroid antibodies) is recommended following treatment for testicular cancer, particularly in patients presenting with compatible symptoms (fatigue, weight gain, bradycardia, cold intolerance) or risk factors such as prior cervical radiotherapy. In asymptomatic patients, periodic TSH monitoring is reasonable, especially in those who received combined therapy or who have personal or family histories of autoimmune disease [23].

• -

  Overt or subclinical hypothyroidism: In cases of overt hypothyroidism, levothyroxine replacement therapy is indicated to normalize TSH levels and alleviate symptoms. In subclinical hypothyroidism—defined by elevated TSH with normal free T4—treatment decisions should be individualized according to TSH levels (treatment is usually recommended when TSH > 10 mIU/L), symptomatology, age, and cardiovascular risk profile [23].

Given that many patients are young and require long-term follow-up, early recognition and treatment of thyroid dysfunction may help prevent metabolic and cardiovascular complications [23].

Spermatogenic dysfunction and infertility

Male fertility depends on the functional integrity of the hypothalamic-pituitary-gonadal (HPG) axis, which regulates spermatogenesis through hormonal signals that control the activity of Sertoli and Leydig cells. In patients with testicular cancer, this axis can be disrupted by multiple mechanisms, both before and after treatment, contributing significantly to secondary infertility [24].

Spermatogenesis is a complex process tightly regulated by the HPG axis; the integrity of this axis is fundamental for male fertility. Its disruption—common in patients treated for testicular cancer—can lead to infertility of endocrine origin [24]; Spermatogenesis is particularly vulnerable to chemotherapeutic agents such as cisplatin, as well as to testicular or retroperitoneal irradiation. Even unilateral orchiectomy may impair global sperm production due to incomplete compensatory mechanisms. Common sequelae include oligospermia, transient or permanent azoospermia, sperm DNA fragmentation, and alterations in motility and morphology [25].

Although some men recover fertility within 1–2 years, the probability of conception may remain reduced. Sperm cryopreservation should always be recommended before initiating treatment, even in cases of localized disease where surgery alone is an option.

• -

  These alterations can be classified as primary (testicular) or central (hypothalamic/pituitary) [Preexistingisting Testicular Endocrine Dysfunction at Diagnosis]

It has been observed that, even before initiating oncologic treatment, many patients with testicular cancer already exhibit abnormalities in spermatogenic function. Botchan et al. reported that 50% of patients evaluated before treatment had oligozoospermia or azoospermia, suggesting a primary testicular dysfunction potentially related to the testicular dysgenesis syndrome (TDS), a condition that compromises germ cell and endocrine testicular development from embryonic stages [26].

This primary testicular dysfunction is usually manifested by elevated FSH levels, reflecting Sertoli cell damage. It may also be present with normal or low testosterone, indicating partial Leydig cell impairment. The resulting hormonal imbalance creates an unfavorable intratesticular environment for spermatogenesis [27].

• -

  FSH and Sertoli Cell Function

Follicle-stimulating hormone (FSH) is essential for the stimulation of Sertoli celstimulatingstructural and functional support for spermatogenesis. Following oncologic treatment—particularly cisplatin-based chemotherapy—a persistent elevation in FSH may be observed, reflecting Sertoli cell dysfunction and, consequently, impaired or absent spermatogenesis [28].

Elevated FSH strongly correlates with azoospermia or severe oligozoospermia and, in many cases, serves as an indirect marker of irreversible germinal epithelium damage [26].

• -

  LH, Leydig Cells, and Testosterone

• -

  LH stimulates Leydig cells to produce testosterone, which is essential for spermatogenic maturation. If testosterone production is reduced due to damage or reduced testicular tissue, the testicular microenvironment fails. Serum testosterone is an imperfect marker; normal serum levels have been shown to coexist with reduced intratesticular testosterone if LH is suppressed, locally compromising spermatogenesis [29].

In the context of testicular cancer, treatments may induce a decrease in LH secretion or Leydig cell sensitivity, leading to a reduction in intratesticular testosterone and, consequently, disruption of spermatogenesis [29].

• -

  Persistent Spermatogenic Dysfunction

• -

  Many patients exhibit mixed endocrine dysfunction: elevated FSH (Sertoli cell failure), borderline/low testosterone (partial Leydig cell failure), and sometimes LH abnormalities. This hormonal pattern contributes to an unsuitable environment for sperm, causing persistent secondary post-oncological infertility. This infertility is explained by irreversible damage to Sertoli cells, identified by hias evidenceddicaelevated deficient spermatogenic support (a pattern of mixed primary hypogonadism). Thus, infertility results from both physical damage to the germinal epithelium and hormonal imbalance that prevents spermatogenic reactivation [30].

Bone density alterations

Chronic hypogonadism causes progressive bone loss. In stroke survivors, untreated hypogonadism is associated with a higher prevalence of osteopenia and osteoporosis, even in young individuals. This risk is amplified by prolonged corticosteroid use or exposure to radiation therapy, both of which are detrimental to bone metabolism [31,32].

Given the well-documented risk of transient or permanent impairment of spermatogenesis following chemotherapy or radiotherapy, selected patients should be counseled about fertility preservation before treatment initiation. Sperm cryopreservation before oncologic therapy represents a safe, effective, and widely available strategy to preserve future reproductive potential. It should be discussed with all patients of reproductive age, particularly those scheduled to receive cisplatin-based chemotherapy or radiotherapy. Early counseling allows informed decision-making and avoids irreversible loss of fertility [21].

Chronic hypogonadism causes progressive bone loss. In stroke survivors, untreated hypogonadism is associated with a higher prevalence of osteopenia and osteoporosis, even in young individuals. This risk is amplified by prolonged corticosteroid use or exposure to radiation therapy, both of which are detrimental to bone metabolism. [31,33].

More recently, Vrouwe et al. (2022) confirmed that survivors of germ cell tumors face an increased risk of developing osteopenia and osteoporosis. This study underscored the multifactorial nature of bone loss in this context, involving hypogonadism, chemotherapy, lifestyle factors, and genetic predisposition [32].

Overall, approximately 27% of testicular cancer survivors present with osteopenia and 10% with osteoporosis, with a clear association between hypogonadism and reduced BMD. Furthermore, chemotherapy exposure independently increases the risk of bone loss. Alterations in bone metabolism—such as elevated resorption markers and biochemical hypogonadism—reinforce the interplay between endocrine dysfunction and skeletal fragility in this population [31,33].

Bone density loss in testicular cancer survivors remains an underdiagnosed condition with potentially serious consequences, including fragility fractures at a young age. Therefore, systematic surveillance is recommended, encompassing:

• •

  Periodic evaluation of the hormonal profile.

• •

  DEXA scanning in patients with hypogonadism, intensive treatment exposure, or musculoskeletal symptoms.

• •

  Risk factor modification: smoking cessation, promotion of physical activity, and ensuring adequate calcium and vitamin D intake.

Overall, the adverse effects on male gonadal function in testicular cancer survivors reflect a multifactorial impairment that encompasses endocrine dysfunction, spermatogenesis alterations, and compromised bone health. The presenpreexistingisting testicular dysfunction, abnormal FSH and LH levels, and impaired function of Sertoli and Leydig cells contribute to reduced sperm and testosterone production, resulting in infertility and clinical or subclinical hypogonadism [24,27,34–36] (Table 3).

Table 3.

Summary of bone mineral density alterations. Authors’ elaboration.

Aspect	Clinical finding	Clinical recommendation
Low BMD prevalence	Osteopenia/Osteoporosis 50–73%	Perform DEXA at hypogonadism diagnosis.
BMD difference (T-score)	−6% to −8% in hip/spine	Repeat DEXA every 2–3 years or according to risk.
Vertebral fractures	Prevalence up to 40%, independent of BMD	Assess bone structure, not density alone.
Risk factors	Hypogonadism, chemotherapy, and age	Stratify risk and individualize follow-up.
Specific treatment	TRT improves BMD; bisphosphonates for osteoporosis	Combined strategies (supplementation, exercise, TRT if indicated).

Source: Isaksson et al., 2017.

Limitations and endocrine surveillance recommendations

The evidence on long-term endocrine sequelae in testicular cancer survivors is mainly derived from retrospective and observational studies with heterogeneous treatment exposures, incomplete baseline hormonal assessment, and non-standardized outcome definitions, limiting precise risk stratification. Nonetheless, available data consistsupportpports structured endocrine surveillance. A pragmatic follow-up strategy includes annual evaluation of gonadal function (total testosterone, LH, FSH), thyroid function tests (TSH, free T4) every 1–2 years, and periodic metabolic assessment. Bone mineral density assessment using dual-energy X-ray absorptiometry (DEXA) should be considered in patients with hypogonadism, prior chemotherapy, or additional osteoporosis risk factors, with repeat imaging every 2–5 years depending on baseline findings.

Conclusions

As testicular cancer (TC) survival rates improve thanks to therapeutic advances, understanding its long-term endocrine sequelae becomes crucial. Hypogonadism (primary or secondary) is the most prevalent complication, with clinical consequences ranging from persistent infertility to alterations in body composition, bone mineral density, and thyroid function. This dysfunction can result from direct testicular damage, including orchiectomy, chemotherapy, or radiation th, rapy—orpreexistingisting gonadal abnormalities. Studies confirm that, even years after treatment, a significant proportiosurvivors exhibitibits altered hormone levels, highlighting the importance of regular endocrine assessments for proactive clinical management.

Funding

None.

Ethics committee approval

Not applicable.

Conflict of interest

None of the authors have any conflicts of interest.