Participation in sports activities has many benefits, not only on physical well-being, but also social, emotional and mental status [1]. As a result, an inevitable increase in sports injuries has been observed. The risk of sports injury is particularly high in contact and high speed sports [2], *[3]. These sports involve lots of jumping, sprinting and pivoting, which can cause injuries [4]. Although head trauma is relatively uncommon, it composes a significant risk in terms of morbidity and mortality [5].

Traumatic brain injury (TBI) is defined as any change in brain function, or the presence of other evidence of brain pathology, such as visual disturbances, neuroradiological or laboratory evidence of brain damage, caused by an external force [6]. Concussion is a clinical picture characterised by a post-traumatic sudden and transient disruption of normal brain function [7]. Concussion is often used synonymously with mild traumatic brain injury (mTBI) and accounts for 70–90 % of all TBIs. It can also occur secondary to TBIs resulting from sports-related injuries [8], [9].

Two types of sports can cause pituitary dysfunction: martial arts, which involve repetitive brain trauma, such as boxing and kickboxing, where an athlete may experience head trauma over 1000 times; and non-combative sports, such as football and ice hockey, which involve single or multiple head trauma [10], *[11]. In this review, the current data on pituitary dysfunction due to sports injuries will be discussed.

The exact annual incidence rate of TBI following sports injuries in the United States is estimated to range from 1.6 to 3.8 million cases [7]. A systematic review was conducted to investigate a total of 4788 TBI following sports injuries in the National Trauma Data Bank of the United States. The data was analysed across five sporting categories. The majority of sports-related TBI were caused by equestrian activities (45.2 %), followed by falls (20.3 %), roller sports (19.0 %), skiing/snowboarding (12.0 %), and water sports (3.5 %). Almost 86 % of all injuries were classified as mTBI [12].

The relationship between TBI and hypopituitarism was initially documented in a case report published in 1918 [13]. Pituitary dysfunction was generally neglected and considered as a rare complication of TBI because the findings of hypopituitarism were similar to those of post-traumatic stress disorder [14], [15]. Following numerous published studies, TBI is now recognised as an important cause of pituitary dysfunction [16]. In a meta-analysis, hypopituitarism was found in 16.8 % of mTBIs, 10.9 % of moderate TBIs and 35.3 % of severe TBIs [17].

In 2004, Kelestimur et al. examined pituitary function in 11 amateur boxers, revealing isolated GH deficiency in 45 % and significantly lower IGF-1 levels compared to controls [18]. Similarly, Tanriverdi et al. found reduced IGF-1 levels in kickboxers, with GH deficiency in 22.7 % and ACTH deficiency in 9.1 %. One-third had at least one anterior pituitary hormone deficiency [19].

In former football players, Kelly et al. reported hypopituitarism in 23.5 %, primarily GH deficiency and hypogonadism [20]. However, Kovacs et al. found no significant increase in these deficiencies, assessing GH axes with only baseline IGF-1 levels [21]. Another study using the glucagon stimulation test similarly found no pituitary hormone deficiencies [22].

Most studies focus on male athletes. One study on female athletes reported menstrual irregularities in 23.5 % of those with a history of concussion, significantly higher than in non-concussed athletes (5 %), though pituitary hormone levels were not assessed [23].

A meta-analysis by Hacioglu et al. reviewing seven epidemiological studies found pituitary dysfunction rates ranging from 15–46.6 %, highlighting variability in diagnostic criteria, hormonal assessments, trauma severity, and evaluation timing [24]. Table 1 summarizes key findings on pituitary dysfunction following sports-related TBI.

The pathophysiology of pituitary dysfunction following TBI is complex and not yet fully understood. Contributing factors include direct trauma to the hypothalamo-pituitary region, diffuse axonal injury, vascular damage, genetic susceptibility, and autoimmunity. Diffuse axonal injury, a key consequence of concussion, disrupts axonal transport, leading to Wallerian degeneration. Due to its microscopic nature, it is often undetectable on CT or conventional MRI, whereas diffusion tensor imaging (DTI) provides greater sensitivity [25], *[26], [27], [28], [29], [30].

The anatomical and vascular features of the hypothalamo-pituitary region predispose it to injury. The anterior pituitary, primarily supplied by the long hypophyseal portal system, is more vulnerable to ischemia, particularly affecting somatotropic and gonadotropic cells. Consequently, GH deficiency is the most common endocrine disorder post-TBI. In contrast, the posterior pituitary, supplied by the inferior hypophyseal artery, is more resistant to vascular damage, though neural disruption can lead to arginine vasopressin (AVP) deficiency (central diabetes insipidus (DI)) [31], *[32]. Permanent AVP deficiency has been linked to fibrosis and neuronal loss in the hypothalamic nuclei [33], [34]. Furthermore, secondary factors, including anaemia, hypotension, hypoxia and compression of the pituitary gland and hypothalamus, can also result in pituitary dysfunction [35].

Pituitary function often improves over time, but in some cases, new-onset hypopituitarism may develop years after TBI [36], [37], [38]. Autoimmunity has been proposed as a mechanism, with increased blood-brain barrier permeability exposing hypothalamo-pituitary antigens to the immune system. Studies have demonstrated the presence of anti-pituitary (APA) and anti-hypothalamic antibodies (AHA) in TBI patients, correlating with higher rates of hypopituitarism, particularly in boxers with repetitive head trauma [39], [40]. Tanriverdi et al. found a significant correlation between APA positivity and pituitary dysfunction after TBI [39]. A similar outcome was observed in a cohort of boxers with a history of repetitive head trauma, 21.3 % of them were positive for AHA, and the prevalence of hypopituitarism was significantly higher in AHA-positive patients (46.2 % in AHA-positive vs. 10.4 % in AHA-negative group) [40].

The variable outcomes observed in individuals with similar severity of head trauma following TBI have been attributed to the presence of genetic polymorphisms in specific genes that may contribute to the underlying pathophysiology. Apolipoprotein E (APO E) is a critical protein that plays a key role in facilitating neuronal repair, enhancing lipid transport and metabolism within the nervous system, and exhibiting particularly high levels of abundance in the hypothalamo-pituitary region. In a prospective study of 96 patients with severe TBI, it is reported that those with the APOE4 polymorphism exhibited poorer outcomes [41]. In another study, it was determined that boxers with an APOE4 allele exhibited greater chronic neurological impairment [42]. On the other hand, the Apo E3/E3 genotype was associated with a lower risk of hypopituitarism after TBI [43]. In consideration of the available evidence, it can be hypothesized that the presence of certain polymorphisms in specific genes might act as a risk factor for the development of permanent neuroendocrine dysfunctions following TBI. Nonetheless, further studies are warranted to substantiate this hypothesis [44].

Emerging evidence also highlights the role of microRNAs (miRNAs) in post-TBI pituitary dysfunction. miRNAs regulate gene expression by targeting mRNA, and altered miRNA profiles following TBI have been linked to pituitary dysfunction, suggesting a potential role in its pathogenesis [45], [46].

Pituitary dysfunction following TBIs may present with non-specific symptoms such as fatigue, decreased quality of life, cognitive disorders and depression [47]. The severity, number and rate of development of pituitary hormone deficiencies determine the clinical symptoms of pituitary dysfunction sometimes leading to life-threatening conditions [48], [49]. The acute phase of TBI develops in the first 2 weeks after the trauma, while the chronic phase begins 3 months later [50]. Hypopituitarism should be considered both in the acute phase of TBI and in the recovery period due to dynamic changes [51].

GH deficiency is the most common pituitary hormone deficiency following sports injury, ranging from 15 % to 46.6 %, which usually occurs in an isolated manner [24]. It is associated with increased visceral and abdominal obesity, dyslipidaemia, insulin resistance, impaired cardiac function, reduced exercise capacity, poorer quality of life and higher morbidity [52]. In a study, including 30 amateur boxers (20 active and 10 retired) waist circumference, total body and abdominal fat mass and fat ratio and serum leptin levels were found to be higher. IGF-I levels were found to be lower in retired boxers than active boxers and healthy controls indicating a risk for cardiovascular complications in retired boxers [53]. In another study, GH deficiency was found in 47 % of 17 retired boxers and 2 % in competing boxers. GH deficiency was associated with decreased pituitary volume and increased body mass index, waist circumference, total and abdominal fat ratio and fat mass [54]. The higher prevalence of GH deficiency in retired boxers, suggests cumulative effects of repeated head trauma. Although altered body composition puts retired boxers at cardiovascular risk, comparative studies evaluating the occurrence of cardiovascular events are lacking.

In addition to the adverse effects on metabolic parameters, cognitive functions are also affected by GH deficiency [55]. In a study including 27 boxers and 14 kickboxers, those with GH deficiency following sports injuries had significantly lower P300 amplitudes than GH-sufficient athletes, indicating cognitive impairment [56]. Kelly et al. reported metabolic syndrome in 50 % of retired football players, which may have contributed to their poor quality of life. GH deficiency (19.1 %) and hypogonadism (8.8 %) were the most common pituitary dysfunctions after TBI in football players [20]. Despite the evidence presented in numerous studies, comprehensive screening studies on a large scale are required to ascertain the true extent of GH deficiency among athletes, both active and retired [57].

In male athletes, low testosterone levels have been linked to a reduction in lean body mass, diminished strength, and an increased risk of fatigue, depression, and memory impairment. In a study, 3409 former professional US-style football players were examined based on their own statements regarding the presence of concussion symptoms during their football playing period and the presence of low testosterone and erectile dysfunction during the subsequent period. The study revealed a statistically significant correlation between the presence of concussion symptoms in the past and subsequent low testosterone and erectile dysfunction [58]. Loursac et al. reported for the first time central hypogonadism after chronic repetitive head trauma in a professional rugby player which was followed by central hypothyroidism 2 years later [59]. In another case report, a kickboxer experienced transient central hypogonadism after an acute bout [60]. In female athletes, although a higher prevalence of menstrual irregularities was reported in athletes with a history of TBI, pituitary functions were not assessed in the participants [23].

The findings of central adrenal insufficiency may be severe, such as hypotension, hypoglycaemia and electrolyte imbalance during the acute period, or subtle, such as fatigue, weakness, and nausea during the chronic period [61]. Two studies have reported a similar prevalence of central adrenal insufficiency among kickboxers and boxers, with a rate of 9.1 % and 8 %, respectively *[19], [54]. A recent case report documented the detection of central adrenal insufficiency in a young man who exhibited unexpectedly severe memory difficulties following a sports-related concussion which improved after treatment [62].

Symptoms of central hypothyroidism may be masked during the early stages of the disease due to long halflife of thyroxine [51]. The symptoms of central hypothyroidism resemble to primary hypothyroidism, but they are less severe. It is rarely observed isolated and is mostly reported in combination with other hormone deficiencies [63]. In a 16-year-old soccer player, four episodes of mTBI, the last diagnosed as a concussion, lead to symptoms of growth failure, deterioration in soccer abilities and physical skills, and reduced energy levels which was found to be caused by hypopituitarism [64].

One of the anterior pituitary hormone changes that develop after sports-related TBI is an alteration in prolactin levels. Since there may be changes in dopamine release in the brain after sports-related TBI, it is reported that prolactin levels may also change. Hypoprolactinemia is usually ignored in endocrine practice, however, a growing body of recent literature suggests a link between prolactin and a wide range of conditions, including metabolic, psychiatric, sexual and cardiovascular diseases [65], [66], [67]. La Fountaine et al. measured prolactin levels in four male athletes at three time points: within 48 hours, on day seven, and day fourteen post-TBI. Prolactin levels significantly increased over two weeks, correlating with symptom improvement and return-to-play decisions. It was hypothesized that an early transient increase in central dopaminergic tone inhibited PRL release, with this inhibition decreasing as dopaminergic tone returned to baseline. The study suggested that prolactin measurements could serve as an indirect marker of post-concussion dopaminergic dysfunction [68].

The development of AVP deficiency predominantly occurs during the acute phase following TBI. The development of AVP deficiency is associated with the severity of head trauma, and permanent AVP deficiency has been linked to elevated mortality rates [69], [70]. Limited data exist on sports-related TBI and the development of AVP deficiency. In one case report, a 24-year-old female swimmer experienced polyuria and increased thirst for four years following a concussion and was later diagnosed with central DI [71]. In another case, a 49-year-old female karate athlete developed central adrenal insufficiency and central DI seven weeks after a head injury [72].

Despite the absence of prospective studies and well-established algorithms for the screening and treatment of pituitary dysfunction following sports injuries, it appears rational to adhere to the recommendations established for pituitary dysfunction following TBIs [24]. In the acute phase, athletes suffering from acute and severe sports-related TBI, and those who are hospitalised, should be evaluated for central adrenal insufficiency with baseline cortisol measurements [73]. Thyroid axis should be evaluated with TSH and free T4. Thyroid hormones should be evaluated in acute phase only when the patient is stable before hospital discharge and then re-evaluated at regular intervals. It is recommended to assess the somatotropic and gonadal axes several months following TBI, given the transient suppression that occurs during the acute phase. Prior to the diagnosis of hypogonadism, it is imperative to exclude the presence of hyperprolactinemia. In case of symptoms that are consistent with GH deficiency in a patient with a history of mTBI, it is recommended to measure basal IGF-1 levels at initial assessment of GH deficiency. In instances where IGF-1 levels are found to be low, a GH stimulation test should be conducted subsequently [74]. Dynamic testing for GH deficiency may be postponed until the 12th month, due to the substantial rate of recovery and the absence of evidence supporting the benefits of early replacement *[26], [75]. In addition, athletes must be informed about pituitary dysfunction and if any suspicious symptoms are experienced, tests should be conducted at that time [24]. The timely diagnosis of pituitary dysfunction is of greatest importance, given that it has the potential to be life-saving and life-changing, with a significant impact on quality of life [76].

The principles of treatment are almost identical to those for classical hypopituitarism. The long-term consequences of replacement therapy in these patients have yet to be elucidated [3]. Central adrenal insufficiency is the most critical condition and must be detected and treated urgently in the acute phase of TBI. However, it is not recommended to replace GH, levothyroxine and sex steroids during the acute phase (generally considered as the first 10 or 14 days after TBI) due to lack of sufficient evidences in improving outcomes. In the chronic phase (defined as at least 3 months after TBI) cortisol and thyroid hormone deficiencies must be replaced in all patients *[17], *[26]. The decision regarding treatment of GH deficiency and hypogonadism should be individualised. Replacement therapy in patients with GH deficiency has been demonstrated to increase lean body mass, bone mineral density and aerobic exercise capacity, whilst decreasing total body fat [77], [78], [79]. A double-blind, placebo-controlled trial of GH-deficient patients demonstrated that treatment with GH therapy resulted in enhanced maximal oxygen uptake, ventilatory threshold, and maximal power output, in comparison with the placebo [80]. A comprehensive meta-analysis has concluded that there is strong evidence to suggest that GH replacement therapy improves exercise capacity in patients with GH deficiency [81]. In a preliminary study, two retired amateur boxers with severe GH deficiency were treated with recombinant GH. After a 6-month treatment period, both patients showed improvements in body composition and lipid parameters [82]. However, larger scale studies are required to investigate the efficacy and long-term outcomes of GH replacement therapy in GH-deficient athletes. On the other hand, the benefits of GH replacement in patients with GH deficiency do not clearly extend to healthy adults. A meta-analysis has reviewed 44 randomized trials (comparing GH treatment vs no treatment) reported that GH can increase the lean body mass, but not the strength. GH can negatively impact exercise capacity and lead to adverse events, such as oedema and fatigue [83]. In one study 56 recreational athletes were randomly divided into 3 treatment groups as placebo, low or high dose of a recombinant human IGF-1/recombinant human IGF binding protein-3 (rhIGF-1/rhIGFBP-3) complex, for a period of 28 days. The results indicated that the rhIGF-1/rhIGFBP-3 complex did not cause any significant changes in body fat mass or lean body mass; however, it did lead to a substantial rise in maximal oxygen consumption [84]. In another study, 96 athletes were randomized to placebo, GH, testosterone or combined treatments. GH supplementation reduced fat mass and increased sprint capacity, but did not significantly improve strength, power or endurance [85]. However, the fact remains that both GH and testosterone are hormones that competing athletes often misuse for the purpose of enhancing performance and they are prohibited by sports leagues. The treatment of an athlete with pituitary dysfunction may necessitate the application of a therapeutic use exemption (TUE) from the league's drug policy [86], [87]. A further key point to emphasise is that, as some hormone deficiencies may improve over time, or new ones may develop, which necessitates reassessment at regular intervals [34].

Despite the existence of numerous publications pertaining to the prevention of sports-related concussion and/or TBI, there is an absence of research focusing on the mitigation of sports-related pituitary dysfunction [88]. It can be considered that the recommendations established for the prevention of sports-related concussion and/or TBI can also be utilised in the context of sports-related pituitary dysfunction. The Centers for Disease Control and Prevention (CDC) have proposed primary and secondary strategies for the prevention of sports-related TBIs. The primary strategies include the use of protective equipment, the instruction of appropriate sport-specific skills, adherence to the rules of play, and the development of strength and conditioning programmes. The secondary strategies encompass the enhancement of awareness regarding the signs and symptoms of TBI, and the implementation of appropriate responses in the event of a suspected TBI [89].

In a recently published meta-analysis, strategies to prevent concussion were analysed under five headings, including personal protective equipment, policy/rule changes, training strategies, environmental targets, and management strategies targeting recurrent concussion. Contradictory findings on sports-related concussion have been reported in studies evaluating the headgear. The utilisation of headgear has been demonstrated to be effective in reducing the incidence of sports-related concussion in the context of a soccer. However, this effect has not been observed in rugby or lacrosse. Further evaluation of the design and materials of headgear is recommended in order to establish the most effective results. Mouthguards have been shown to be an effective method of preventing orofacial injury in a range of sports. Nevertheless, controversy persists regarding their role in preventing concussion in sports. According to the meta-analysis of studies combining ice hockey and rugby, mouthguard use was associated with a 26 % overall reduction in sports-related concussion rates. A number of factors may contribute to a reduction in the effectiveness of head contact policies. These include referral patterns, referee behaviours, surveillance methods, increased media attention and concussion awareness. The metaanalysis that was conducted in order to assess the effectiveness of rule changes that disallow bodychecking in ice hockey showed an overall 58 % reduction in sports-related concussion rates [90].

TBI during sports activities may lead to dysfunction of the pituitary gland. The current literature on sports-related TBI and hypopituitarism is still limited. The pathophysiological mechanism of the development of pituitary dysfunction after TBI is multifactorial including direct trauma to the hypothalamo-pituitary region, diffuse axonal injury, vascular injury, genetic predisposition, and autoimmunity. Pituitary dysfunction after TBI may present with a clinical picture mimicking post-TBI. For this reason, clinicians should be alert to the possibility of hypopituitarism in patients with TBI. GH deficiency is the most common type of pituitary hormone deficiency following a sports injury. Although the deleterious effects of GH deficiency on athletes are well known, the debate continues as to whether active athletes with severe GH deficiency should receive GH replacement therapy. Prevention strategies include the use of personal protective equipment, policy/rule changes and adherence to the rules of the game, training strategies, and management strategies targeting recurrent concussion.Research agenda•

The exact epidemiology of athletic pituitary dysfunction is unknown.

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The underlying pathophysiological mechanism of hypopituitarism after sports-related TBI is not completely understood.

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Further research is needed to develop screening algorithms for pituitary dysfunction in sports-related repetitive head trauma.

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There is a paucity of research on the effects of TBI on female athletes.

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Further studies are required to analyse cardiovascular risk in retired boxers.

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Data on the relationship between posterior pituitary dysfunction and sports related TBI are limited.

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There is no knowledge of whether GH replacement therapy will be given to athletes with GH deficiency and how this will be monitored.

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There is a need for further systematic and large-scale studies on the prevention of sports-related pituitary dysfunction.

Practice points•

Sports-related concussion is a TBI caused by a direct blow to the head, neck or body that results in the transmission of an impulsive force to the brain during sport and exercise.

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TBI during sports activities may cause pituitary dysfunction. Even mTBIs can lead to pituitary dysfunction.

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Pituitary dysfunction following TBI may present with a clinical picture that mimics the post-TBI period. The clinicians should be aware of the risk of hypopituitarism in patients presenting with non-specific symptoms such as fatigue, diminished quality of life, cognitive dysfunction and depression.

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Pituitary functions in the acute phase may improve or deteriorate by time. Therefore, both in the acute phase of TBI and in the recovery period, hypopituitarism should be considered.

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GH deficiency is the most common type of pituitary hormone deficiency following a sports injury.

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In the acute phase, athletes with acute and severe sports-related TBI and those admitted to hospital should be assessed for central adrenal insufficiency with baseline cortisol measurements.

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GH and gonadotropins should not be analysed in the acute phase.

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Dynamic testing for GH deficiency can be delayed until the 12th month.

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Patients must be informed about pituitary dysfunction and its symptoms.