Search

This report presents a case of a Sheehan syndrome diagnosed with a delay of 29 years after occurrence of first symptoms, following a laborious birth ended with dead fetus and massive hemorrhage. The 50-year-old patient, with early menopause from the age of 21, is referred to our rheumatology department to investigate the etiology of a myopathic syndrome, which started 2 months before and gradually worsened. The differential diagnosis took into consideration the autoimmune, infectious, paraneoplastic, endocrinological, and drug-induced myopathic syndrome. Paraclinical investigations revealed panhypopituitarism, and cerebral magnetic resonance imaging detected empty-sella. The etiology of a myopathic syndrome is often multifactorial; therefore, it is important to continue the investigations even after identifying one possible etiological factor, especially when it does not seem to fully explain the clinical-paraclinical picture. Usually, the multiple dimensions of panhypopituitarism bring the patient to various medical specialties depending on the dominant symptomatology. Given the rarity of the above-mentioned syndrome in the present, and the long gap between the initial event and the final diagnosis, its identification continues to be a challenge., (© 2023. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Besides the pulmonary manifestations caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), an emerging endocrine phenotype, which can heavily impact on the severity of the syndrome, has been recently associated with coronavirus disease 2019 (COVID-19). Patients with pituitary diseases or the pituitary gland itself may also be involved in COVID-19 clinical presentation and/or severity, causing pituitary apoplexy.Moreover, hypopituitarism is frequently burdened by several metabolic complications, including arterial hypertension, hyperglycemia, obesity and vertebral fractures, which have all been associated with poor outcomes and increased mortality in patients infected by SARS-CoV-2.This review will discuss hypopituitarism as a condition that might have a bidirectional relationship with COVID-19 due to the frequent presence of metabolic comorbidities, to the direct or indirect pituitary damage or being per se a potential risk factor for COVID-19. Finally, we will address the current recommendations for the clinical management of vaccines in patients with hypopituitarism and adrenal insufficiency., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In rare cases, pancytopenia results from hormonal deficiencies that arise in the setting of panhypopituitarism. Here we describe the unusual case of a 60-year-old man who presented with progressive fatigue and polyuria, and whose laboratory workup revealed a deficiency of the five hormones associated with the action of the anterior pituitary (thyroid hormone, testosterone, cortisol, prolactin, and insulin-like growth factor-1). Imaging of the pituitary demonstrated a cystic mass consistent with a pituitary adenoma replacing much of the normal pituitary tissue. His symptoms and hematologic abnormalities rapidly resolved with prednisone and levothyroxine supplementation. While the majority of reported cases of panhypopituitarism with bone marrow suppression are the result of peripartum sepsis or hemorrhage leading to pituitary gland necrosis (Sheehan's syndrome), it is also important to consider the diagnosis of hypopituitarism in patients with hypothyroidism, low cortisol levels, and pancytopenia. The causal relationship between pancytopenia and panhypopituitarism is not well understood, though it does reinforce the important influence of these endocrine hormones on the health of the bone marrow.

Objective: The aim of the study was to evaluate the effect of growth hormone (GH) replacement therapy on the morphological and functional changes in the left ventricle (LV) in patients with GH deficiency (GHD)., Methods: Patients with adult-onset GHD were treated with GH. Transthoracic echocardiography was performed at baseline and after 6 and 12 months of the treatment. Interventricular septal thickness (IVST), posterior wall thickness (PWT), left ventricular end-diastolic diameter (LVEDD), left ventricular end-diastolic volume (LVEDV), left ventricular mass (LVM), stroke volume (SV) and left ventricular ejection fraction (LVEF) were evaluated at echocardiography, and the values at respective time points were compared by a paired t-test. In addition, a gender-stratified analysis was performed., Results: A total of 45 patients (21 men, 24 women; age: 19-61 years) with GHD were included. At 6 months, only increased PWT (+ 0.2 mm; P = 0.044) was significantly changed compared with baseline. At 12 months of the replacement therapy, statistically significant increase in LVM (+ 8.6 g; P = 0.035) and improvement of LVEF (+ 1.4 %; P = 0.005) were seen. In men, significantly higher values of IVST, PWT, LVEDD, LVEDV, SV and LVM were found at 12 months of follow-up, while no such effect was observed in women., Conclusion: A mild increase in LVM and improvement of LVEF accompanies long-term GH replacement therapy. The effect on LV morphology is more pronounced in men than in women.

Background: Systemic Hypertension (SH) is the main cause of left ventricular (LV) hypertrophy in the general population, but only scanty data are available on LV geometric remodeling (LVGR) in hypertensive patients with GH deficiency (GHD)., Aim: We investigated hypertensive LVGR in adult-onset GHD patients, before (T0) and after 55±16 months (T1) of individualized GH replacement therapy (GHRT)., Subjects: Fifty-one patients, aged 45±15 yr, 29 women, were enrolled. Fifteen patients met criteria for SH (group A) whereas 36 were normotensive (group B)., Methods: An echocardiogram was performed on all patients, at least twice (at T0 and T1). LV geometric remodeling as a relationship between LV mass (LVM) index and relative wall thickness (RWT), LV volumes, and ejection fraction were measured., Results: At T0, group A showed higher LV mass and LVM index values than group B; LV hypertrophy was found in 40% and 22% of patients, respectively (p=0.06). At T1, IGF-I levels had increased significantly in both groups. LV hypertrophy rate consistently increased in group A (from 40 to 60%, p<0.05), whereas slightly decreased in group B (from 22 to 19%, ns). Body surface area (p<0.001), age (p<0.05), and systolic blood pressure (p<0.05) were main determinants of LVM at multivariate analysis., Conclusions: Along with body surface area and age, SH was significantly related to abnormal LVGR (LV hypertrophy) in GHD patients. As a result, blood pressure management and caloric intake restrictions are deemed necessary for this subset of patients.

Assessment of coronary calcium deposits (CCD) by coronary computed tomography (CT) was recently introduced for evaluation of risk to develop events related to coronary heart disease (CHD). We investigated occurrence of CCD in 19 hypopituitary patients (patients), 34 healthy (H) subjects (H controls) and 36 patients with a similar rate of diabetes mellitus and hypertension (morbid, M), but without pituitary diseases (M controls). Patients were replaced with L-thyroxine, cortone acetate, sex hormones and/or desmopressin, but never with GH. Unenhanced coronary CT was performed by 16-row multislice scanner. Framingham score (FS) was calculated and CCD were measured by Agatston score (AS) in all subjects. AS>10 indicates increased CHD risk. CCD and AS >10 were detected in 50% and 33% of patients, respectively. Prevalence of CCD and mean AS were higher in patients than in H and M controls. In patients, AS was negatively dependent on IGF-I levels (p<0.01) and IGF-I SD (p<0.05), and AS >10 was associated with occurrence of hypertension (p<0.02) and hyperinsulinism (p<0.05). Men and women showed the same prevalence of AS >10 (25 vs 31%). FS and AS correlated significantly (rs=0.33, p<0.001), but CCD were detected also in 3/11 patients with low FS. In conclusion, 58% of patients were at CHD risk on the basis of increased FS and/or AS, above all if they were hypertensive and/or showed hyperinsulinism. CCD were detected also in patients with low FS. CHD risk is higher in women. Risk of CCD is increased in patients with low IGF-I levels.

Ischemic pituitary necrosis due to severe postpartum haemorrhage called Sheehan's syndrome is a rare cause of hypopituitarism in the western world, but much more common in developing countries. A 45-year-old female patient being a war refugee from Chechnya with severe anaemia and fatigue was diagnosed at our outpatient department with Sheehan's syndrome after severe postpartum haemorrhage and emergency hysterectomy 15 years ago. Panhypopituitarism was adequately treated with substitution of hydrocortisone, thyroxine and transdermal oestrogen which resulted in haemoglobin increase to nearly normal levels and symptoms improved immediately. Severe anaemia caused by panhypopituitarism shows the importance of the hormonal system for erythropoiesis. Clinical and basic scientific evidence indicates thyroidal hormones to be the main cause.

Despite huge advances having been made in some areas of medicine, options for the treatment of GH deficiency (GHD) have remained constant since the introduction of GH in the 1950s. Several initiatives have been introduced to improve the understanding and treatment of GHD with GH, including the long-term Hypopituitary Control and Complications Study (HypoCCS) and the issuance of clinical guidelines. This article considers the impact of these initiatives and considers new treatment options which will potentially provide important future benefits for GHD patients.

GH regulates important physiological processes, including somatic growth and development, and carbohydrate and lipid metabolism. GH deficiency and GH replacement therapy exert opposite effects on body composition and fat accumulation, suggesting that GH may directly regulate adipocyte functions. Multiple studies have shown that in tissues previously deprived of GH, short-term stimulation with GH is able to mimic the actions of insulin, including stimulation of amino-acid and glucose transport, and lipogenesis. However, the antagonistic effects of GH on insulin-mediated metabolic responses are well-documented: GH excess in patients with GH-producing pituitary tumors causes hyperinsulinemia, insulin resistance, and even clinical diabetes mellitus. These apparently contradictory effects may be explained at the molecular level by the complex interplay between GH and insulin signaling. In this review, we examine the consequences of acute and chronic effects of GH on visceral fat and on metabolic responses in adipocytes, and discuss experimental data illustrating the integrated crosstalk between GH and insulin.

It is known that hypopituitarism reduces life expectancy and increases the risk of death for cardio- and cerebrovascular disease. Many studies report this phenomenon due to vascular diseases, and GH deficiency (GHD) seems to significantly contribute to the higher mortality. Aim of this article is to review the relationship between GH and cardiovascular risk factors to evaluate the beneficial effects of therapy in the adult GHD. GH replacement therapy (GHRT) improves insulin sensitivity, and reduces LDL cholesterol and triglyceride levels. Several studies also documented a decrease in the intima-media thickness at major arteries and improvement in microvascular and endothelial function. Other studies showed a decrease of inflammatory markers and the normalization of coagulation parameters. Finally, some authors have reported improvements in cardiac performance as well. These data evidence the positive effects of GHRT in the prevention of premature atherosclerosis in adults with GHD, and encourage the early administration of replacement therapy.

Neurodegenerative diseases are a major focus of scientific and clinical interest because of their increasing medical and social importance. Due to the intimate connections between central nervous and endocrine systems, it is reasonable to suspect that important, and in some cases clinically relevant, endocrine modifications may accompany the progression of neurodegenerative diseases. Data on endocrine modifications in different neurodegenerative diseases have been reported, but results have often been non-conclusive, or conflicting. Accumulating evidence suggests that the GH/IGF-I axis is involved in the regulation of brain growth, development, and metabolism and in the regulation of muscle function. Dysfunctions in GH/IGF-I axis in most of neurodegenerative diseases are therefore reviewed. Alterations of this system could be actors in the complex network leading to (at least some) neurodegenerative diseases. A thorough effort in investigating every possible involvement is warranted, in the light of future therapeutic strategies.

Stroke is one of the main causes of death and disability in the adult population. Changes in pituitary hormone secretion may be observed during the acute phase of stroke, representing part of the adaptive response to injury. However, reduced pituitary hormone secretion, caused by pituitary and/or hypothalamus damage, may also occur. Hypopituitarism has been observed in 19% of patients with ischemic stroke and 47% of patients with subarachnoid hemorrhage, presenting as an isolated deficiency in most cases. Diabetes insipidus is very rare. Low IGF-I levels, during the acute phase of stroke, have been associated with poor outcome and high mortality. During rehabilitation, higher IGF-I levels have been observed in patients with better outcome, suggesting a neuroprotective role of IGF-I. Accurate evaluation and long-term follow-up of all patients with stroke are necessary to define the prevalence of hypopituitarism, and its relationship with type, severity, and outcome from stroke. Discovery and adequate treatment of possible endocrine deficiencies may improve outcome and quality of life of patients with stroke.

Impaired GH secretion usually accompanies Cushing's syndrome and a variable proportion of patients reportedly fail to recover normal GH secretion after successful treatment. We prospectively studied 34 patients (27 females and 7 males, age range 21- 68 yr) formerly affected by Cushing's disease. Patients were studied 2 to 20 yr (median 3.3 yr) following remission of hypercortisolism. All patients had undergone transsphenoidal surgery with the removal of an ACTH-secreting adenoma. None of the patients had undergone radiation therapy. In all subjects, the GH response to GHRH+arginine stimulation was evaluated. Twenty-two patients (65%) in long-term surgical remission presented subnormal GH secretion: partial GHD was found in 11 patients and severe GHD in another 11 patients. Our experience has demonstrated a GHD in a high percentage of patients with Cushing's disease even after long-term remission of hypercortisolism obtained by surgery alone. This finding is significant as it highlights that even the most favorable therapeutical course, i.e. remission achieved by surgery, is often accompanied by impaired GH release. Assessment of GH secretion is therefore recommended in all patients cured from Cushing's disease, even if not submitted to radiotherapy.

Most cases of adult GH deficiency (AGHD) result from hypothalamic-pituitary tumors or their treatment. Some experimental and clinical observations suggest that GH may possess a mitogenic potential, thus raising the question of whether it is a safe treatment in patients with a previous pituitary tumor. Few study results have been reported on this topic. All of them have inevitable methodological flaws that limit their conclusions. However, all studies report that replacement therapy with GH does not seem to increase the risk of tumor progression or recurrence, when compared to historical or matched controls. Considering the slow-growing nature of most of these benign tumors and the absence of conclusive evidence from the available studies, a continuous imaging surveillance and longer follow-up periods are nevertheless mandatory for a definite statement on the safety of GH treatment in patients with previous pituitary tumors.

The Hypopituitary Control and Complications Study (HypoCCS) was set up in 1995 to monitor the long-term efficacy of GH replacement therapy in adult patients with GH deficiency (GHD). The key findings to date have focussed on the diagnosis of GHD, the effects of GH on lean body mass, lipids and bone, and the quality of life benefits. Current guidelines recommend that the diagnosis of adult GHD be proven biochemically. However, these tests are not suitable for all patients, and data from this study suggest that the presence of 3 or more pituitary hormone defects can predict adult GHD with 95% accuracy. The 3-yr efficacy analysis showed that GH replacement therapy in adults is effective in improving body composition, bone mass and lipid profiles, but age is an important factor in determining the response to treatment. Quality of life was improved and maintained during long-term GH replacement therapy in adults. Future results will show if these initial benefits have been sustained.

Obesity is characterized by abnormal GH secretion, with GH levels reduced up to levels that are comparable to those found in adult patients with organic GH deficiency (GHD). Despite the marked GH insufficiency, obese patients with no evidence of pituitary disease have generally normal levels of total IGF-I but increased levels of free IGF-I. Although the mechanism of the low GH in obesity is not completely understood nor is it clear whether its relationship with visceral adiposity is causal, it is widely accepted that the low GH secretory state in obesity is reversible since it is completely reversed by the normalization of body weight. Since overweight and obesity might affect the GH response to all provocative stimuli, particular attention has been recently paid to the confounding effect of body weight on the interpretation of GH stimulating tests and appropriate cut-offs for lean, overweight, and obese subjects must be used in order to avoid false-positive diagnoses of severe GHD in obese adults. As the definition of appropriate criteria for the correct diagnosis of GHD in obesity is still debated, and the beneficial effects of chronic recombinant human GH replacement on obese individuals have not been definitely proved yet, further studies are therefore mandatory to confirm the real effectiveness of GH supplementation in conditions associated with a blunted GH secretion without organic hypopituitarism and to understand the physiological relevance of "functional" GHD on the pathogenesis of the multiple maladaptative endocrine changes involved in the pathogenesis of obesity.

Adult-onset GH deficiency (GHD), mostly due to organic lesions of the pituitary-hypothalamic region, is frequently associated with multiple anterior pituitary deficiencies that need long-term substitutive treatment. The GH-IGF-I axis may play an important role in modulating peripheral metabolism of hormones (adrenal, thyroid, and sex hormones) and these interactions may have clinically significant implications on the phenotypes of adult GHD patients and on the effects of the combined replacement hormonal treatment of this condition. By accelerating the peripheral metabolism of cortisol, GH therapy may precipitate adrenal insufficiency in susceptible hypopituitary patients; estrogen replacement blunts the response to GH in women whereas in men with androgen substitution the responsivity increases over time. Endocrinologists should be mindful of these phenomena when starting patients with hypopituitarism on GH replacement therapy.

Fertility outcomes in hypopituitaric women are about half of those reported in isolated hypogonadotropic hypogonadism; GH deficiency (GHD) is a major contributor to poor pregnancy rate. GH seems to play a physiological role in the control of male sexual maturation and adult reproductive functions. In males, GH regulates gonadal differentiation, steroidogenesis, and gametogenesis, as well as gonadotropin secretion and responsiveness. In females, GH has a role not only as a modulator on gonadotropins, mediated by the property of IGF-I to amplify the action of both LH and FSH on granulosa, but also, through a direct GH action, on follicular maturation. GH treatment seems to play an important role in the sensibilization of ovary responsivity and uterine morpholgy in GHD patients. Since GH, directly or indirectly via IGF-I, regulates reproductive functions at all levels of the hyophyseal-pituitary-gonadal, it should always be tested as a possible cause of unexplained infertility.

Isolated GH deficiency or combined pituitary hormone deficiencies have been associated with mutations in transcription factors encoding genes that control organogenesis or cell differentiation. Among these factors, Hesx1 is essential for the development of the optic nerve and regulates some of the earliest stages in pituitary development and is intimately involved in orchestrating the expression of other factors involved in pituitary organogenesis. Mutations in HESX1 are reported in patients with hypopituitarism either with typical septo-optic dysplasia (SOD) or with neuromorphological abnormalities not included in classical SOD. The present report describes clinical features, biochemical parameters, and characterization of a missense mutation (Gln6His) in exon1 of HESX1 in a pre-pubertal child who progressively developed multiple hypopituitarism, firstly GH and, afterwards, TSH and ACTH deficiencies, in a pluri-malformative syndrome characterized by short stature and anatomical malformations not associated with a classical SOD phenotype. This finding further supports the necessity to stay alert in evaluating a gene that plays a minor role in the pathogenesis of sporadic hypopituitarism, such as HESX1 gene even when the phenotype does not fit in with a classical SOD syndrome.

GH deficiency (GHD) in adults is accompanied by reduced bone mass that may revert only after 2 yr of GH replacement. However, it is unclear whether the gender may modify bone responsiveness to GH replacement in adults. In this study we have evaluated whether bone mineral density (BMD) and turnover improve after GH replacement according to patients' gender. BMD at lumbar spine (LS) and femoral neck (FN), serum osteocalcin (OC), and urinary cross-linked N-telopeptides of type I collagen (Ntx) were assessed in 64 hypopituitaric patients (35 men, 30-50 yr) before and 2 yr after the beginning of GH replacement. Values of IGF-I and BMD at LS and at FN were expressed as Zscores. At study entry, IGF-I and BMD resulted similar among men and women with GHD. During GH replacement, IGF-I levels increased in both men and women without any difference in the percentage of IGF-I increase between the genders (p=0.47). In women receiving estrogen replacement, however, the percentage of IGF-I increase (p<0.05), and the Z IGF-I score (p<0.001) were significant lower than estrogen untreated women, although IGF-I levels were similar in the 2 groups (p=0.53). The GH dose adjusted for body weight required to restore normal age- and sex- matched IGF-I levels was lower in men than in women (p<0.001), and was higher in women receiving than in those not receiving estrogen replacement (p<0.05). In contrast, hypogonadal men treated with testosterone and eugonadal men received a similar GH dose (p=0.97). Also OC, Ntx levels, lumbar and femoral BMD improved (p<0.001) in all patients. Nevertheless, a greater increase in lumbar BMD increase was observed in men than in women (8.0+/-2.1 vs 2.6+/-0.4%; p<0.05). No significant difference was revealed in bone parameters in women treated or untreated with estrogen replacement and in men treated or not with testosterone replacement for concomitant hypogonadism. At the multiple correlation analysis, gender was a stronger predictor for the required GH dose than the age (p<0.001 and p=0.02, respectively). In conclusion, a 2-yr GH replacement normalizes IGF-I levels, increases bone mass and improves bone turnover both in men and in women with GHD without any difference between the 2 groups, provided that the dose of GH was modulated on the basis of IGF-I levels. Women receiving oral estrogens should receive a GH dose approximately doubled, as compared to men and women not receiving oral estrogens, to achieve similar effects on bone density and turnover. In particular, GH replacement dose, to be successful on bone mass and turnover, depends on gender in hypopituitary patients aged below 50 yr.

The authors present the case history of a 52-yr-old male patient with a unique association of combined pituitary hormone deficiency (CPHD) and situs inversus totalis. Except for signs and symptoms of pituitary hormone deficiency, the patient had no dysmorphic features, and hearing impairment, primary mental or neurological defects were also absent. Pituitary magnetic resonance imaging (MRI) scan showed hypoplasia of the anterior lobe of the pituitary gland and an ectopic posterior pituitary lobe. Despite the presence of situs inversus totalis, the patient was right-handed and functional MRI demonstrated left-hemisphere activation during language tests. Kartagener syndrome was considered, but immunofluorescence analysis showed normal localization of the outer dynein arm protein in respiratory epithelial cells obtained from the nasal mucosa. Direct DNA sequencing of all coding exons of the pituitary transcription factor 1 (PIT1) and prophet of PIT1 (PROP1) genes failed to detect disease-causing mutations, suggesting that these genes were not involved in the development of CPHD in our patient. More interestingly, the potential role of the paired like homeodomain transcription factor 2 (PITX2) gene, which has been implicated not only in CPHD, but also in left-right patterning in animal models, was also excluded, as sequencing showed the absence of mutations in coding exons of this gene. To our knowledge, PITX2 gene mutations have not been investigated in CPHD patients who had situs inversus totalis. We conclude that in contrast to animal models, the PITX2 gene is not involved in the development of situs inversus totalis, at least not in our CPHD patient.

Objective: Adrenal insufficiency due to hypopituitarism can lead to severe hyponatremia with potentially fatal consequences. Prompt diagnosis and adequate hormonal replacement therapy are essential to block an otherwise unfavorable course and to re-establish a healthy life. Unfortunately, this condition is often misdiagnosed., Design: Case report., Setting: Intensive Care Unit of a teaching hospital., Patient: A 76-yr-old man with refractory hypotension, acute myocardial infarction, and left ventricular dysfunction, secondary to severe chronic pan-hypopituitarism, associated with severe hyponatremia., Methods and Main Results: The patient underwent mechanical ventilation and continuous venous-venous hemodiafiltration, for severe respiratory and renal insufficiency. A hormonal replacement therapy with T4, hydrocortisone, and nandrolone was started and the patient was discharged to a rehabilitation facility after 31 days of hospitalization., Conclusions: Hypopituitarism with secondary adrenal insufficiency is often misdiagnosed at an early stage and a high degree of suspicion is necessary for early diagnosis. Determination of plasma cortisol level in patients with hyponatremia not explained by other causes should always be obtained.

Although common, anemia associated with hypopituitarism has received little attention. We conducted a retrospective study to elucidate the effect of replacement therapy with hydrocortisone and/or levothyroxine on the decreased hemoglobin (Hb) level. A total of 68 patients who had been suffering from anterior pituitary deficiencies for more than 12 months were studied. The Hb level was significantly lower in patients with hypopituitarism (p=0.0012). Decreased Hb level (<12.0 g/dl) was observed in 22 patients (32.4%). It was related to hypocortisolism (regression weights=0.39), hypothyroidism (0.37), GHD (0.32) and hypogonadism in men (0.17). Among 68 patients, 30 patients had been receiving replacement therapy for at least 12 months. Hydrocortisone and levothyroxine increased the Hb level in 20 patients whose data were available before the replacement (p=0.0002). However, the Hb level was still lower in 30 patients receiving the replacement (p=0.0001). In 13 patients (8 men) with decreased Hb level (<12.0 g/dl) despite the replacement, GH and testosterone were deficient in 12 (92.3%) and 8 (100%) patients, respectively. In conclusion, replacement therapy with hydrocortisone and/or levothyroxine is effective in most patients but is not sufficient, at least in some patients, to improve the decreased Hb level. These results suggest that additional replacement therapy, i.e. with GH and/or androgen, is necessary to obtain further improvement.

Recent studies have demonstrated that hypopituitarism, in particular GH deficiency, is common among survivors of traumatic brain injury (TBI) tested several months or yr following head trauma. We present the results of endocrine, neurological, neuropsychological and psychiatric evaluation in a group of 67 patients who suffered TBI at least one yr ago. Our study shows that decreased endocrine function is either restricted to one or more anterior pituitary hormones and is present in 34% of patients with any pituitary hormone deficit, while multiple pituitary hormone deficiencies are found in 10% of patients. GH/IGF-I axis was evaluated by GHRH+GHRP-6 test and IGF-I measurement. Severe GHD is the most frequent deficiency present in 15% of TBI patients. Gonadotrophin deficiency was present in 9% of patients with TBI, while thyrotroph and corticotroph function seemed more refractory to impairment. Patients with moderate-to-severe trauma are not necessarily more likely to have hypopituitarism than those with mild injury. Neuropsychological testing revealed a significant positive correlation of peak GH levels after GHRH+GHJRP-6 test with verbal learning and verbal short term memory (RAVLT total score p = 0.06, immediate free recall p = 0.02 and delayed free recall p = 0.04). Verbal and visual memory was significantly lower in elderly patients and in males. Visoconstructional abilities (RCF copy) were significantly lower in the elderly (p < 0.01) and undereducated (p = 0.02). Visual memory (free recall of complex figure after 30 min) significantly correlated with lower IGF-I levels (p = 0.01). Gonadotrophins and testosterone correlated significantly with visoconstructional abilities. Simple and complex conceptual tracking (TMT A and B) was significantly more impaired in older TBI patients (p < 0.01) and with longer time from trauma (TMT B only, p = 0.03). The psychiatric evaluation by using two different scales showed depression, phobic anxiety and psychoticism to be more prominent in the TBI group. Paranoid ideation and somatization negatively correlated with the peak GH responses to GHRH+GHRP-6 test (p = 0.04 and p = 0.03, respectively). Depression scale showed that nearly half of patients suffered from mild to moderate depression. The benefits of hormone replacement therapy on cognitive functioning and mental distress in TBI patients are eagerly awaited.

Symptomatic hypoglycemia is described in children with severe GH deficiency (GHD), but is rare in adults with GHD. We describe the case of a 62- yr-old man, referred for recurrent hypoglycemic events. He reported a previous head trauma at the age of 20 yr and a diagnosis of reactive hypoglycemia at the age of 50 yr. In the last months, during a period of job-related stress, the hypoglycemic episodes became more frequent and severe (glucose <2.2 mmol/l), finally requiring hospitalization. On admission, the patient was in good general health, with normal renal and hepatic function. During hospitalization, no hypoglycemic episodes were recorded, also during a 72-h fasting test. Biochemical data and abdominal computed tomography (CT) excluded insulinoma. A tumor-induced hypoglycemia was ruled out. The 4-h oral glucose tolerance test (OGTT) showed an impaired glucose tolerance with a tendency toward asymptomatic hypoglycemia. Hormonal study disclosed low levels of GH (0.2 ng/ml) and IGF-I (51 ng/ml); the response of GH to GHRH plus arginine confirmed a severe GHD (GH peak 2.7 ng/ml). Other pituitary and counterregulation hormones were within the normal range and magnetic resonance imaging (MRI) of the pituitary gland was normal. Replacement therapy with a low dose of rhGH induced an increase of IGF-I up to low-normal values, accompanied by lasting regression of hypoglycemic events. In conclusion, hypoglycemia was the main clinical symptom of isolated adult onset GHD, in the present case. The possible pathogenesis of isolated adult onset GHD and the association of GHD with conditions predisposing to hypoglycemia are considered and discussed.

Hypopituitarism and hyponatremia, especially when severe, are infrequent findings particularly when the cause of hypopituitarism at presentation is unknown and untreated. Interestingly, hyponatremia is usually seen in elderly patients with hypopituitarism due to various causes. We present a case with unrecognized and untreated hypopituitarism due to a large aneurysm of the internal carotid artery in the sellar region causing the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

It is widely accepted that the classical dose of 250.0 microg ACTH (1-24) (tetracosactin) is clearly supra-maximal while 1.0 and 0.03 microg have been shown as the maximal and the lowest stimulatory ACTH doses for cortisol (F) secretion in normal young subjects. Testing with low ACTH dose would better evaluate adrenal sensitivity to corticotropin. The aims of the present study were: a) to clarify the adrenal sensitivity to ACTH in patients with different duration of corticotroph insufficiency by testing with low and very low tetracosactin doses; and b) to evaluate diagnostic implication regarding the ability of ACTH tests to distinguish patients with corticotroph insufficiency from normal subjects. In 24 hypopituitaric patients (HYPOPIT, 15 male and 9 female, age 22-50 yr, BMI: 22-26 kg/m2) with corticotrophin deficiency we studied the F, DHEA and aldosterone (A) responses to challenges with low ACTH doses (0.06 or 0.5 microg iv at 0 min) followed by 250 microg iv (at +60 min). The results in HYPOPIT were compared with those recorded in 12 normal controls (NS, 6 male and 6 female, age 22-34 yr, BMI: 20-25 kg/m2). Basal F and DHEA levels in HYPOPIT were lower than in NS, while A levels were similar in both groups. The F responses to ACTH in HYPOPIT were dose-independent and markedly lower (p < 0.0001) than in NS. After the 0.06 and 0.5 microg ACTH dose, 16% of HYPOPIT patients showed AF peak within the range of normal response. No HYPOPIT showed AF peak within the normal range after 250 microg ACTH. The DHEA responses to ACTH in HYPOPIT were dose-independent and markedly lower than in NS (p < 0.0001). Overlap between individual DHEA responses in HYPOPIT and NS was present after 0.06 microg and 0.5 microg but not after 250 microg tetracosactin. The A responses in HYPOPIT were dose-dependent and overlapped with those in NS. The adrenal responses to ACTH in HYPOPIT were not associated with the duration of the disease. In conclusion, the present study shows that the mean F and DHEA but not the A responses to ACTH (1-24) are markedly impaired in hypopituitaric patients with corticotroph insufficiency independently of the duration of the disease. The impaired F and DHEA response to ACTH is also independent of the dose, suggesting the existence of relatively enhanced sensitivity of the fasciculata and reticularis adrenal zone to ACTH but meantime remarkable impairment of the adrenal function due to corticotrophin deficiency. In the present study, testing with submaximal ACTH doses did not distinguish patients with secondary adrenal insufficiency from normal subjects.

The aim of this study was to evaluate cardiac performance, in particular diastolic function, in adult patients with adulthood onset GH deficiency. The study group was composed of 19 GH deficient adult hypopituitary patients with at-least 3 additional pituitary hormone deficits and 19 age, sex and BMI matched healthy controls. Mean duration of hypopituitarism was 108.6 +/- 77.0 months. None of the patients and controls presented with or had previous diagnosis of concomitant diseases that could affect cardiac function. All hormone deficiencies, except for GH, were appropriately replaced in the patients. Left ventricular function and geometry were evaluated by two-dimensional, M-mode and Doppler echocardiography. Body composition was evaluated by bioelectrical impedance analysis. Not significant differences were observed with respect to left heart dimensions and left ventricular systolic function between patients and controls. Nevertheless 2 of the left ventricular diastolic function parameters, deceleration time and isovolumetric relaxation time, were significantly prolonged in the patients compared with controls (247.88 +/- 70.65 vs 143.26 +/- 31.70 milliseconds (ms) and 122.31 +/- 18.24 vs 89.47 +/- 12.12 ms respectively, p<0.001). Duration of hypopituitarism was significantly correlated with percent body fat mass (r=0.6119, p<0.01) and percent lean body mass (r=-0.5949, p<0.01). It is concluded that in adults affected by hypopituitarism, GH deficiency predominantly impairs diastolic function while systolic function at rest is spared. This observation might indicate a preclinical stage of a cardiomyopathy.

The aim of this study was to clarify the activity of GH/IGF-1 axis as well as the variations of nutritional parameters following a thermal injury in man. To this goal, in 22 patients with burn [BURN, age (mean+/-SE): 46.5+/-3.4 yr, BMI: 25.0+/-0.8 kg/m2, % burn surface area: 26.0+/-3.0%, ROI score: 0.22+/-0.1] we evaluated IGF-1, IGF binding protein (IGFBP-3), GH, GH binding protein (GHBP), pre-albumin (pre-A), albumin (A) and transferrin (TRA) levels on days 1, 3, 7, 14 and 28 after intensive care unit (ICU) admission. IGF-1, IGFBP-3, GH and GHBP levels were also assayed basally in 29 normal subjects (Ns) (Ns, age: 47.5+/-2.8 yr, BMI: 22.0+/-1.4 kg/m2) and in 34 panhypopituitary patients with severe GH deficiency (GHD, age: 42.7+/-2.5 yr, BMI: 25.6+/-0.8 kg/m2). On ICU day 1, IGF-1 and IGFBP-3 in BURN were higher than those in GHD (p<0.05 for both, respectively) and lower than those in Ns (p<0.05) while GH levels in BURN did not differ from those in Ns and higher than GHD (p<0.01). In BURN, IGF-I and IGFBP-3 levels showed a progressive decline (p<0.05) with nadir on day 14, when they overlapped those in GHD, and then an increase on day 28, though persisting lower than in Ns, while GH levels did not vary during ICU stay. IGF-I levels were associated neither to burn extension nor to ROI score. On ICU day 1 pre-A, A and TRA levels were similar to those in Ns, but underwent a progressive decrease with nadir on day 7 (p<0.001) for pre-A and TRA, and later, on day 14 (p<0.05) for A; pre-A and TRA but not A showed a rebound increase (p<0.01) on day 14, though persistingly lower than in Ns. In conclusion, our present data firstly show the time course variation of IGF-I levels in burn patients as function of nutritional and hormonal variables. It has to be emphasized that in the most critical phase after burn injuries, IGF-1 levels are as low as in hypopituitary patients with severe GHD. The physiological basis which leads to the impairment of this endogenous anabolic drive in this phase is, however, not clear yet.

We studied the effect of treatment with recombinant human GH in an anemic patient with panhypopituitarism in which hemoglobin (Hb) concentration remained as low as 11.0 g/dl in spite of appropriate replacement with thyroid and adrenocortical hormones. Recombinant human GH was subcutaneously and constantly infused for 12 months using a portable syringe pump at a rate of 0.25 U/kg/week. After the treatment with human GH plasma erythropoietin (EPO) levels increased from 12.2 to 25.1 mIU/ml, with a concomitant increase of Hb concentration to 13.6 g/dl. When the administration of human GH was interrupted, both plasma EPO levels and Hb concentrations decreased. There was a close correlation between plasma GH and EPO levels before and during the human GH administration (y=2.444x+1 3.423, r=0.641, p<0.05). Plasma GH levels were well correlated with Hb concentrations before and during human GH administration (y=0.529x+11.313, r=0.690, p<0.01). Plasma IGF4 levels were also correlated with Hb concentrations (y=0.007x+10.874, r=0.832, p<0.001), but not with plasma EPO levels. These findings suggest that GH treatment may be useful in anemic patients with panhypopituitarism.

A case of lymphocytic hypophysitis is described in a patients with Graves' disease and diabetes mellitus. The 62-year-old man was admitted to hospital with the complaints compatible with hyperthyroidism in April 1993. His medical history, physical examination, thyroid function tests, thyroid scintigraphy and thyroid ultrasonography revealed Graves' disease. The patient had also suffered from diabetes mellitus for three years. After this, the patient's progress was not monitored for two years. The patient presented himself again in September 1995 with complaints of hypothyroidism, hypogonadism and hypoadrenalism. Hormonal investigation showed panhypopituitarism. A magnetic resonance imaging of the pituitary gland disclosed an enlarged pituitary and a thickened infundibulum. The high intensity signal of the neurohypophysis was absent. Transsphenoidal hypophysectomy was performed which revealed a grey-white, relatively avascular pituitary mass. Histology showed diffuse infiltration of the anterior pituitary by numerous lymphocytes. The neurohypophysis also showed evidence of lymphocytic infiltration. On the basis of these findings we suggest that lymphocytic hypophysitis may be associated with Graves' disease.

We report 4 patients (3 of which were children) with diabetes insipidus and different degrees of hypopituitarism in whom a pituitary stalk enlargement was disclosed on imaging techniques, and in whom radiological and functional recovery was observed during follow-up. Pituitary substitution therapy with desmopressin, thyroxine, hydrocortisone, growth hormone and/or oral contraceptives was prescribed. During follow-up, regression of the stalk lesion was seen which was spontaneous in 2 cases, following a short course of corticosteroids in another and an empirical trial of tuberculostatic drugs in the fourth. A partial recovery of pituitary function was also observed. These cases illustrate that pituitary stalk enlargement and associated hypopituitarism may be reversible; however, this morphological and functional recovery has rarely been described in adults and has not been previously reported in children.

We experienced an unusual combination of painless thyroiditis and Sheehan's syndrome in a single patient. A 29-year-old postpartum woman was referred to us for suspected Sheehan's syndrome. Endocrine tests confirmed the diagnosis, but, unexpectedly, her thyroid hormone levels in the plasma were elevated. Based on the data from various examinations on her thyroid including an extremely low uptake of radioactive iodine and spontaneous alterations of the thyroid function without any therapy for the thyroid, we diagnosed the patient as suffering from Sheehan's syndrome and painless thyroiditis simultaneously. Underlying mechanism(s) whereby painless thyroiditis occurred in our patient may be an immunological rebound after parturition, an immunological alteration induced by secondary hypoadrenocorticism, or a combination of these. The simultaneous occurrence of Sheehan's syndrome and painless thyroiditis is rare, as evidenced by the existence of only one similar case report in the literature. However, since neither Sheehan's syndrome nor painless thyroiditis is a rare endocrine disorder, the thyroid function of patients with postpartum hypopituitarism and previously diagnosed chronic thyroiditis should be carefully evaluated.

To evaluate the relationship between the secretion of cortisol and the activity of adrenal medulla in the secondary adrenocortical insufficiency, the excretion of epinephrine and norepinephrine was documented in 8 patients suffering from panhypopituitarism. Plasma levels and urinary excretion of cortisol were very low in baseline conditions, and the increase in these parameters of cortisol secretion occurring upon ACTH infusion was significantly reduced with respect to the response to ACTH documented in normal subjects. The mean value of urinary epinephrine excretion was at the lower limit of normal values, and a highly significant positive correlation was found between cortisolemia or cortisoluria and urinary epinephrine excretion in these patients. Despite a significant increase in cortisolemia and cortisoluria upon ACTH administration, this acute increase in adrenocortical activity was without any stimulatory effect on epinephrine or norepinephrine excretion. But, as in baseline conditions, a significant correlation was documented for the degree of adrenocortical activity and epinephrine excretion on the day of ACTH administration. It appears, therefore, that in severe secondary adrenocortical insufficiency the excretion of epinephrine is reduced proportionally to the decrease in adrenocortical activity.

Diffuse hypothalamic-hypopituitarism complicating viral meningoencephalitis has been rarely documented. In this report, we describe the syndrome in a 41 yr old male and review the literature. Detailed endocrine studies were performed 1 month after the onset of apparent viral encephalitis. Repeated 08:00 h serum cortisol levels were low, but increased after administration of lysine-vasopressin. Urine 17-hydroxy-corticosteroid (17-OHCS) values rose with prolonged cortrosyn infusion, but failed to respond after administration of metyrapone. Serum thyroxine was decreased; basal levels of serum thyrotropin were low-normal, but there was a prolonged response to tyrotropin (TSH) to thyrotropin releasing hormone (TRH). Basal prolactin was elevated with a minimal response after TRH. Testosterone and gonadotropins were both diminished, and gonadotropins increased (but less than in normal subjects) after injection of gonadotropin releasing hormone (LHRH). The overnight water deprivation test confirmed the presence of diabetes insipidus. In the present context, the abnormal endocrine investigations were strongly supportive of disturbed hypothalamic activity. Hypothalamic-hypopituitarism following viral meningoencephalitis may occur more frequently than previously reported, and thus basal pituitary function should be assessed in all patients with viral meningoencephalitis.