Traumatic Brain-Injury-Induced Hypopituitarism: Clinical Management and New Perspectives

Once being a neglected etiologic factor, traumatic brain injury is now acknowledged as an important risk factor for pituitary dysfunction. The gland might be damaged as a result of primary or secondary injury. The prevalence of pituitary dysfunction is highly variable across studies. The occurrence rate during acute and/or chronic phases was reported up to 69% in some series, while the rate of persistent hypopituitarism decreased to 12% when confirmatory testing was conducted. Growth hormone deficiency emerges as the most prevalent hormone deficiency subsequent to traumatic brain injury, followed by adrenocorticotropic hormone, gonadotropins (follicle-stimulating hormone and luteinizing hormone), and thyroid-stimulating hormone deficiencies. Pituitary function tends to be dynamic following traumatic brain injury; hormone insufficiencies may improve, and new deficiencies may occur during follow-up. The clinical findings of pituitary hormone deficiencies may vary widely from non-specific and subtle symptoms to urgent life-threatening conditions such as hypotension and hyponatremia. Timely diagnosis is of utmost importance, and it requires awareness and a high level of suspicion. Screening algorithms have been developed to guide clinicians on who should be tested for pituitary dysfunction, how, and for how long following traumatic brain injury. However, the rate of routine screening is still low among clinicians. We aimed to review the current literature focusing on the diagnosis and clinical management of pituitary dysfunction following traumatic brain injury

Traumatic brain injury and prolactin

Traumatic brain injury (TBI) is a well-known etiologic factor for pituitary dysfunctions, with a prevalence of 15% during long-term follow-up. The most common hormonal disruption is growth hormone deficiency, followed by central adrenal insufficiency, central hypogonadism, and central hypothyroidism in varying order across studies. The prevalence of serum prolactin disturbances ranged widely from 0 to 85%. Prolactin release is mainly regulated by hypothalamic dopamine inhibition, and mediators such as TRH, serotonin, cytokines, and neurotransmitters have modulatory effects. Many factors, such as hypothalamic and/or pituitary gland injuries, as well as fluctuations in dopaminergic activity and other mediators and stress response, may cause derangements in serum prolactin levels after TBI. Although it is challenging to investigate the direct effects of TBI on serum prolactin levels due to many confounders, basal prolactin measurements and stimulation tests provide insight into the functionality of the hypothalamus and pituitary gland after TBI. Moreover, during the acute phase of TBI, prolactin levels appear to correlate with TBI severity. In contrast, in the chronic phase, hypoprolactinemia may function as an indirect indicator of pituitary dysfunction and reduced pituitary volume. Further investigations are needed to elucidate the pathophysiologic mechanisms underlying the prolactin trend following TBI, its significance, and its associations with other pituitary hormone dysfunctions. In this article, we re-evaluated our patients' TBI data regarding prolactin levels during prospective long-term follow-up, and reviewed the literature regarding the prevalence, pathophysiology, and clinical implications of serum prolactin disturbances during acute and chronic phases following TBI

Neuroendocrine Consequences of Traumatic Brain Injury and Strategies for its Management

Traumatic brain injury (TBI) is a common problem that generally affects the young population. Hypothalamo-pituitary damage may occur as a result of direct damage during trauma or due to secondary insults, such as hypotension or hypoxia that may occur thereafter. The incidence of pituitary dysfunction post-TBI has been reported to range from 5-76.4%. Growth hormone deficiency and central hypogonadism are among the most common hormone deficiencies that occur post-TBI. Patients who develop pituitary dysfunction post-TBI may present with life-threatening hypotension, hyponatremia during the acute phase, or subtle and nonspecific complaints such as fatigue, depression, or cognitive impairments during follow-up. Pituitary dysfunction may recover but new-onset deficiencies may develop over time, mandating routine screening of TBI patients. Several risk factors have been investigated and various screening algorithms have been proposed in recent studies. We aimed to review the recent literature in terms of epidemiology, screening modalities, and clinical perspectives of pituitary dysfunction post-TBI

Pituitary dysfunction due to sports-related traumatic brain injury

PurposeAfter traumatic brain injury was accepted as an important etiologic factor of pituitary dysfunction (PD), awareness of risk of developing PD following sports-related traumatic brain injury (SR-TBI) has also increased. However there are not many studies investigating PD following SR-TBIs yet. We aimed to summarize the data reported so far and to discuss screening algorithms and treatment strategies.MethodsRecent data on pituitary dysfunction after SR-TBIs is reviewed on basis of diagnosis, clinical perspectives, therapy, screening and possible prevention strategies.ResultsPituitary dysfunction is reported to occur in a range of 15-46.6% following SR-TBIs depending on the study design. Growth hormone is the most commonly reported pituitary hormone deficiency in athletes. Pituitary hormone deficiencies may occur during acute phase after head trauma, may improve with time or new deficiencies may develop during follow-up. Central adrenal insufficiency is the only and most critical impairment that requires urgent detection and replacement during acute phase. Decision on replacement of growth hormone and gonadal deficiencies should be individualized. Moreover these two hormones are abused by many athletes and a therapeutic use exemption from the league's drug policy may be required.ConclusionsEven mild and forgotten SR-TBIs may cause PD that may have distressing consequences in some cases if remain undiagnosed. More studies are needed to elucidate epidemiology and pathophysiology of PD after SR-TBIs. Also studies to establish screening algorithms for PD as well as strategies for prevention of SR-TBIs are urgently required

Long-term neuroendocrine consequences of traumatic brain injury and strategies for management

Introduction: Traumatic brain injuries (TBI) are reported to cause neuroendocrine impairment with a prevalence of 15% with confirmatory testing. Pituitary dysfunction (PD) may have detrimental effects on vital parameters as well as on body composition, cardiovascular functions, cognition, and quality of life. Therefore, much effort has been made to identify predictive factors for post-TBI PD and various screening strategies have been offered. Areas covered: We searched PubMed and reviewed the recent data on clinical perspectives and long-term outcomes as well as predictive factors and screening modalities of post-TBI PD. Inconsistencies in the literature are overviewed and new areas of research are discussed. Expert opinion: Studies investigating biomarkers that will accurately predict TBI patients with a high risk of PD are generally pilot studies with a small number of participants. Anti-pituitary and anti-hypothalamic antibodies, neural proteins, micro-RNAs are promising in this field. As severity of TBI has been the most commonly associated risk factor for post-TBI PD, we suggest prospective screening based on severity of head trauma until new evidence emerges. There is also a need for more studies investigating the clinical effects of hormone replacement in TBI patients with PD

Idiopathic hirsutism: Is it really idiopathic or is it misnomer?

Hirsutism, which is characterized by excessive growth of terminal hair in a male pattern, may result from various causes including polycystic ovary syndrome (PCOS), non-classic congenital adrenal hyperplasia, adrenal or ovarian tumors or it may be idiopathic. Idiopathic hirsutism is currently defined as hirsutism associated with normal ovulatory function, normal serum androgen levels and normal ovarian morphology, however, the pathogenesis of idiopathic hirsutism is not clear. The androgens are the main hormones to stimulate growth of body hair, therefore, there should be any form of increased androgen effect irrespective of normal serum androgen levels in any patient with hirsutism. In accordance to this scientific truth, we have previously shown that, although within normal limits, patients with idiopathic hirsutism have relatively higher serum androgen levels (relative hyperandrogenemia) in comparison to healthy subjects which let as to think that is idiopathic hirsutism really idiopathic? In addition to relative hyperandrogenemia, we have previously shown that, in comparison to healthy subjects, women with idiopathic hirsutism demonstrated higher expression of steroid sulphatase and 17-beta hydroxysteroid dehydrogenase mRNA both in the subumbilical region and arm skin, which contributes to local androgen metabolism. Those results support the idea that, in some patients, although the adrenals or ovaries do not secrete increased amount of androgens leading to hyperandrogenemia, pilocebaceous unit locally produce increased amount of androgens leading to hirsutism without ovulatory dysfunction. Upon the demonstration of relative hyperandrogenemia and possible increase in local androgen synthesis in patients with idiopathic hirsutism, we think that idiopathic hirsutism is not idiopathic and it may be named as “normoandrogenic hirsutism”. Furthermore, it may not be a different entity but may be an early stage of hyperandrogenic disorders such as PCOS. Clinically, this can be find out by following-up patients with idiopathic hirsutism prospectively

The stimulatory effects of glucagon on cortisol and GH secretion occur independently from FGF-21.

Purpose Glucagon stimulation test (GST) is used to assess the hypothalamo-pituitary-adrenal (HPA) and growth hormone (GH) axes with an incompletely defined mechanism. We aimed to assess if glucagon acted through fibroblast growth factor-21 (FGF-21) to stimulate cortisol and GH secretion. The secondary outcome was to determine the relationship of FGF-21 with variable GH responses to GST in obesity. Methods: A total of 26 healthy participants; 11 obese (body mass index (BMI) > 30 kg/m(2)) and 15 leans (BMI < 25 kg/m(2)) were included. Basal pituitary and target hormone levels were measured and GST was performed. During GST, glucose, insulin, cortisol, GH, and FGF-21 responses were measured. Results: The mean age of the participants was 26.3 +/- 3.6 years. Glucagon resulted in significant increases in FGF-21, glucose, insulin, cortisol, and GH levels. The levels of basal cortisol, GH, FGF-21, and IGF-1 were similar in the two groups. The peak GH and area under the curve (AUC)((GH)) responses to GST in the obese group were lower than those of the normal-weight group with a different pattern of response. There were no differences between the groups in terms of peak cortisol, AUC((cortisol)), peak insulin, AUC((insulin)), peak FGF-21, and AUC((FGF21)). Obesity was associated with significantly increased glucose and insulin responses and slightly decreased FGF-21 response to glucagon. Conclusion Obesity was associated with blunted and delayed GH, but preserved cortisol responses to GST. This is the first study showing that glucagon stimulates the HPA and GH axis independently from FGF-21. The delayed GH response to GST in obesity does not seem to be related to FGF-21

Comparison of a combination test (1 mu g ACTH test plus glucagon test) versus 1 mu g ACTH test and glucagon test in the evaluation of the hypothalamic-pituitary-adrenal axis in patients with pituitary disorders

Objective:To investigate whether a combination of the low-dose (1 mu g) adrenocorticotropin (ACTH) stimulation test and glucagon stimulation test (GST) could overcome the problem of equivocal results with the GST or ACTH test alone in patients with pituitary disorders. Subjects and methods: The study included 41 adult patients with pituitary disorders and 20 healthy subjects who underwent evaluation of cortisol response to ACTH, GST, and a combination of both tests. Blood samples for cortisol measurement were obtained at baseline and 30, 60, 90, and 120 minutes after intravenous administration of ACTH 1 mu g and 90, 120, 150, 180, 210, and 240 minutes after subcutaneous injection of glucagon 1 mg. The combination test was performed by injecting ACTH 1 mu g at the 180-minute time point of the GST, with blood samples for cortisol measurement obtained at 210 and 240 minutes. Results: Overall, 28 patients with normal cortisol response to both tests also had a normal cortisol response to the combination test. Ten patients with adrenal insufficiency in both tests also had adrenal insufficiency in the combination test, including a patient who had a peak cortisol value of 12.4 mu g/dL (which is the cutoff value for the combination test).Two patients with adrenal insufficiency in the ACTH stimulation test and one patient with adrenal insufficiency in the GST had normal cortisol responses to the combination test. Conclusion: By using an appropriate cutoff value, the combination test may offer additional information in patients with equivocal results in the GST and ACTH stimulation test