Discussion

This case represents an unusual presentation of hypogonadotropic hypogonadism, diagnosed incidentally in adulthood during evaluation of acute traumatic injury. Several aspects of this case warrant detailed discussion.

Delayed diagnosis in adulthood

Hypogonadotropic hypogonadism is typically diagnosed during adolescence when patients present with delayed puberty or failure to develop secondary sexual characteristics [5]. The standard diagnostic criterion includes the absence of typical pubertal development by age 18 years [5]. However, in this 26-year-old patient, the condition remained undiagnosed until adulthood--a scenario that, while uncommon, has been reported in medical literature [1]. Possible explanations for delayed diagnosis include limited access to healthcare during adolescence, cultural or social factors affecting medical evaluation, geographic and linguistic barriers (a patient from Vietnam with limited healthcare access), gradual onset minimizing subjective awareness of abnormality, and lack of systematic screening in asymptomatic individuals.

Radiographic findings as a diagnostic clue

Normal skeletal maturation in males involves progressive physeal closure, with most growth plates fusing by late adolescence. The persistence of open growth plates at age 26 is therefore highly unusual and strongly suggestive of longstanding hypogonadism, as adequate sex steroid levels are required for epiphyseal fusion [3]. In this context, unoccluded physes on routine radiographs indicate delayed skeletal maturation and should be recognized as a radiographic clue to underlying endocrine pathology rather than an incidental variant. Persistently open growth plates in adults warrant careful consideration of sex steroid deficiency and other endocrine or systemic disorders that interfere with bone maturation and epiphyseal closure [6,7].

Hormonal pattern and differential diagnoses

The laboratory findings in this case, characterized by consistently low serum testosterone levels in combination with inappropriately low LH and FSH, are typical of secondary (central) hypogonadism rather than primary testicular failure. Primary hypogonadism due to conditions such as Klinefelter syndrome, post-infectious orchitis, or chemotherapy-induced gonadal damage is usually associated with low testosterone in the presence of elevated gonadotropin levels as a consequence of loss of negative feedback. In contrast, secondary hypogonadism is defined by low testosterone together with low or inappropriately normal LH and FSH and reflects impaired hypothalamic-pituitary signalling, as seen in congenital hypogonadotropic hypogonadism, Kallmann syndrome or pituitary lesions [1,6,8,9].

In the present patient, the history of mumps infection at the age of 10 years initially raised concern for post-infectious orchitis and primary testicular damage. However, the hormonal pattern clearly supports central hypogonadism and makes isolated peripheral testicular failure unlikely.

At the same time, the absence of pituitary MRI at the time of trauma care means that structural hypothalamic-pituitary lesions cannot yet be fully excluded, and the presumed diagnosis of isolated GnRH deficiency must be considered provisional pending further imaging and, ideally, genetic testing.

Further diagnostic evaluation would include olfactory testing, as anosmia strongly suggests Kallmann syndrome [2,10,11]. MRI of the hypothalamic-pituitary region is indicated to exclude structural lesions such as pituitary adenomas, craniopharyngiomas, or infiltrative processes, and abnormal findings have been reported in approximately 10-15% of patients with hypogonadotropic hypogonadism [12,13]. In addition, panel-based genetic testing is recommended for comprehensive etiological assessment, as more than 50 genes have been associated with congenital hypogonadotropic hypogonadism and pathogenic variants can be identified in roughly 40-50% of affected individuals [2,12,14], with ANOS1 (Kallmann syndrome 1) representing the most common X-linked form [12].

These investigations are consistent with current clinical recommendations for the evaluation and management of Kallmann syndrome and related forms of congenital hypogonadotropic hypogonadism [15].

Pathophysiology and molecular mechanisms

Recent research has highlighted the complex pathophysiology of hypogonadotropic hypogonadism, extending beyond simple GnRH neuronal dysfunction. Smedlund and Hill [3] demonstrated that non-neuronal cells play crucial roles in the development and function of the hypothalamic-pituitary-gonadal axis. Disruption of supporting glial cells, tanycytes, or vascular elements may contribute to GnRH deficiency even in the absence of primary neuronal pathology [3,16]. Current understanding recognizes both congenital and functional forms of hypogonadotropic hypogonadism, with functional forms potentially reversible following correction of underlying metabolic, nutritional, or psychological stressors [16-18]. Notably, approximately 10-20% of patients with apparent congenital hypogonadotropic hypogonadism experience spontaneous reversal of hypogonadism after testosterone therapy discontinuation, suggesting dynamic plasticity of the reproductive neuroendocrine system [18]. This expanding understanding of disease mechanisms may lead to novel therapeutic approaches, including targeted molecular interventions and personalized treatment strategies based on genetic profiles [2,12,16].

Management considerations

The cornerstone of treatment for hypogonadotropic hypogonadism is hormone replacement therapy. Two principal therapeutic approaches are available. Testosterone replacement therapy directly replaces the deficient hormone, thereby inducing virilization and the development of secondary sexual characteristics. Although this treatment does not restore fertility, it effectively addresses the metabolic, skeletal, and psychosexual consequences of hypogonadism [7,8,19]. Alternatively, gonadotropin therapy or pulsatile GnRH therapy stimulates endogenous testosterone production and may preserve or restore fertility. Human chorionic gonadotropin, administered in combination with recombinant FSH or human menopausal gonadotropin, can induce spermatogenesis in 70-90% of patients, with reported pregnancy rates ranging from 40-70%, depending on baseline testicular size and prior treatment history [10,20,21]. Although more complex and costly than testosterone replacement therapy, this approach remains essential for patients seeking fertility.

For the present patient, testosterone replacement therapy was selected as the initial treatment strategy and was administered as an intramuscular injection every three months. This regimen was chosen because of its convenience through quarterly administration, reliable and predictable pharmacokinetic profile, cost-effectiveness, and ability to achieve adequate virilization. In addition, testosterone replacement therapy has been shown to improve bone mineral density and reduce fracture risk in hypogonadal men [7,19].

A critical question in this case is whether testosterone therapy initiated at the age of 26 years will successfully induce growth plate closure. Despite the delayed onset of treatment, exposure to sex steroids generally promotes physeal fusion through the aromatization of testosterone to estradiol, which represents the primary mediator of epiphyseal closure in males [19]. Nevertheless, the ultimate skeletal outcome remains uncertain and will require long-term radiographic follow-up. Should the patient wish to achieve fertility in the future, a transition from testosterone replacement therapy to gonadotropin-based treatment would be necessary. The success of fertility induction is known to correlate inversely with age at treatment initiation and directly with baseline testicular volume [10,20,21].

Fracture management and bone health considerations

The presence of unoccluded growth plates raised theoretical concerns regarding fracture fixation strategy. Open growth plates in skeletally immature patients typically warrant physeal-sparing fixation techniques to avoid premature closure or growth disturbance. However, in this adult patient with pathological growth plate persistence, growth preservation was not a concern; rather, growth plate closure was desirable. Therefore, standard adult fixation with transphyseal intramedullary nailing was appropriate and successfully performed.

An important consideration in patients with hypogonadotropic hypogonadism is the significantly increased risk of osteoporosis and fragility fractures [7,19]. Studies demonstrate that men with untreated hypogonadotropic hypogonadism have markedly reduced bone mineral density, with up to 50% meeting criteria for osteoporosis at diagnosis [7]. The current trauma case, though resulting from acute injury rather than low-energy fragility fracture, emphasizes the importance of comprehensive bone health assessment in all patients with hypogonadism. Testosterone replacement therapy has been shown to significantly improve bone mineral density and reduce fracture risk over 2-3 years of treatment [15]. However, bone density monitoring via DEXA scanning remains essential, particularly in patients diagnosed in adulthood who have missed critical years of peak bone mass accrual during adolescence and early adulthood [7,19].

Clinical implications and learning points

This case highlights several important clinical considerations. First, a systematic assessment of skeletal maturity should be incorporated into the interpretation of radiographs obtained in young adults. The presence of unoccluded growth plates in adulthood should be regarded as a red flag and warrants further endocrine evaluation [6,8]. In appropriate clinical contexts, physical examination should include assessment of secondary sexual characteristics, as these findings may provide important diagnostic clues. Although hypogonadotropic hypogonadism is most commonly diagnosed during adolescence, delayed diagnosis can occasionally result in presentation during adulthood, particularly in individuals with limited access to healthcare or atypical clinical manifestations [6,8,9,21].

The case also underscores the importance of multidisciplinary collaboration between orthopedic surgeons and endocrinologists to ensure comprehensive evaluation and management. Genetic testing should be considered to establish a definitive etiological diagnosis and to facilitate family counseling where appropriate [2,12,14]. Furthermore, long-term monitoring of bone health is essential because patients with hypogonadism are at increased risk of reduced bone mineral density and fragility fractures [7,19]. Psychological support and assessment of quality of life should likewise be integrated into patient management, as delayed diagnosis and pubertal failure are associated with a substantial psychosocial burden [18].

The psychosocial consequences of delayed diagnosis deserve particular attention. Studies involving adults with congenital hypogonadotropic hypogonadism have demonstrated profound effects on self-esteem, body image, sexual function, and interpersonal relationships, with many patients reporting feelings of isolation and inadequacy during adolescence while their peers underwent normal pubertal development [21]. Web-based needs assessments have further identified unmet needs for peer support, accessible educational resources, and specialized psychological services [21]. Recognition of these psychological dimensions is therefore essential for providing holistic, patient-centered care.

Limitations and future directions

This case report has several limitations. Long-term follow-up data regarding the patient's response to testosterone therapy, growth plate closure, and final skeletal outcome are not yet available. In addition, further diagnostic evaluation, including olfactory testing to assess for Kallmann syndrome [14,15], pituitary MRI to exclude structural lesions [12,13], and comprehensive genetic panel testing [2,14], was not performed. At the time of the initial trauma care, no MRI of the hypothalamic-pituitary region had yet been performed. Therefore, we cannot fully exclude a structural central cause, and the presumed diagnosis of isolated GnRH deficiency remains provisional pending further imaging. These investigations would provide valuable etiological information and may contribute to more accurate prognostic assessment. Moreover, the initial endocrine workup did not include measurement of free T4, morning cortisol, or IGF‑1. As a result, subtle impairment of thyroid, adrenal, or growth hormone axes cannot be definitively excluded, and this incomplete hormonal profiling represents an additional limitation of the present case report. In addition, bone age assessment was not performed, which limits our ability to quantify the degree of skeletal delay and to correlate radiographic findings with the patient’s chronological age.

Future follow-up will address several clinically relevant questions. An important objective will be to determine whether testosterone therapy successfully induces growth plate closure, which is expected to occur within approximately 18-36 months according to published data [19]. The timing of physeal fusion following treatment initiation will also be evaluated. Furthermore, longitudinal assessment will determine whether the patient develops complete secondary sexual characteristics, with gradual virilization anticipated over a period of two to three years [6,8]. Additional follow-up will focus on the effects of treatment on bone mineral density and fracture healing, with DEXA scanning recommended at baseline and at one- to two-year intervals [7,19]. Genetic testing may clarify whether the patient harbors identifiable mutations associated with congenital hypogonadotropic hypogonadism [2,12,14]. Monitoring will also assess the possibility of spontaneous reversibility following treatment, a phenomenon reported in approximately 10-20% of affected individuals [18]. Future management decisions may depend on the patient's reproductive goals, as a desire for fertility would necessitate a transition from testosterone replacement therapy to gonadotropin-based treatment [10,20,21]. Finally, ongoing evaluation of quality of life and psychosocial functioning will be important to assess the broader impact of treatment on patient well-being [11].

Systematic prospective data on patients diagnosed with hypogonadotropic hypogonadism in adulthood remain limited. Consequently, this case contributes valuable information regarding the natural history, treatment response, and clinical outcomes of hypogonadotropic hypogonadism when diagnosis occurs after the expected age of pubertal completion [8,9,17].

Clinical message

In everyday practice, persistently open growth plates on radiographs of adult trauma patients should prompt targeted endocrine evaluation, including assessment of gonadal and pituitary hormone levels, and early referral to an endocrinologist. Systematic radiographic assessment of skeletal maturity in younger adults, combined with clinical examination of secondary sexual characteristics, can prevent missed diagnoses of hypogonadism and other endocrine disorders that present incidentally during orthopedic care. Multidisciplinary collaboration between orthopedic surgeons, radiologists, and endocrinologists is essential to ensure that such abnormal findings lead to appropriate diagnostic workup and long‑term management.