Hypothalamic-pituitary Disease Research Articles

Subclinical central hypothyroidism in patients with hypothalamic-pituitary disease: does it exist?

Central hypothyroidism (CH) is characterized by decreased thyroid hormone production due to insufficient stimulation of an otherwise normal thyroid gland by TSH. In patients with established hypothalamic-pituitary disease, a low FT4 concentration is considered highly specific, although poorly sensitive, for the diagnosis of CH. That would be comparable to diagnosing primary hypothyroidism in patients at risk only when serum FT4 concentrations are below the reference range, missing all patients with subclinical primary hypothyroidism and preventing proper therapy in patients in which thyroxine replacement is clearly beneficial. Cardiac time intervals, especially the isovolumic contraction time (ICT), have been considered the gold standard of peripheral thyroid hormone action. Using Doppler echocardiography, we have previously shown a very high proportion of prolonged ICT in patients with hypothalamic-pituitary disease and serum FT4 levels indistinguishable from controls. As ICT decreased/normalized after thyroxine-induced increases in FT4 concentrations within the normal reference range, prolonged ICT was considered a bona fide diagnostic biomarker of subclinical CH. Those findings challenge the usual interpretation that FT4 concentrations in the mid-reference range exclude hypothyroidism in patients with hypothalamic-pituitary disease. Rather, subclinical central hypothyroidism, a state analogous to subclinical primary hypothyroidism, seems to be frequent in patients with hypothalamic-pituitary disease and normal FT4 levels. They also challenge the notion that thyroid function is usually the least or the last affected in acquired hypopituitarism. The relevance of Doppler echocardiography to correctly diagnose and monitor replacement therapy in both clinical and subclinical forms of CH should improve quality of life and decrease cardiovascular risk, as already demonstrated in patients with clinical and subclinical primary hypothyroidism.

Oxytocin in response to MDMA provocation test in patients with arginine vasopressin deficiency (central diabetes insipidus): a single-centre, case-control study with nested, randomised, double-blind, placebo-controlled crossover trial

Disruptions of the hypothalamic-pituitary axis can cause an arginine vasopressin deficiency, also known as central diabetes insipidus. Patients with this condition are at high risk of additional oxytocin deficiency owing to the close anatomical proximity of oxytocin-producing neurons; however, no conclusive evidence for such a deficiency has been reported. We aimed to use 3,4-methylenedioxymethamphetamine (MDMA, also known as ecstasy), a strong activator of the central oxytocinergic system, as a biochemical and psychoactive provocation test to investigate oxytocin deficiency in patients with arginine vasopressin deficiency (central diabetes insipidus). This single-centre, case-control study with nested, randomised, double-blind, placebo-controlled crossover trial included patients with arginine vasopressin deficiency (central diabetes insipidus) and healthy controls (matched 1:1 by age, sex, and BMI) and was conducted at the University Hospital Basel, Basel, Switzerland. We used block randomisation to assign participants to receive either a single oral dose of MDMA (100 mg) or placebo in the first experimental session; patients received the opposite treatment at the next session, with a wash-out period of at least 2 weeks between the two sessions. Participants and investigators assessing the outcomes were masked to assignment. Oxytocin concentrations were measured at 0, 90, 120, 150, 180, and 300 min after MDMA or placebo. The primary outcome was the area under the plasma oxytocin concentration curve (AUC) after drug intake. The AUC was compared between groups and conditions using a linear mixed-effects model. Subjective drug effects were assessed throughout the study using ten-point visual analogue scales. Acute adverse effects were assessed before and 360 min after drug intake using a 66-item list of complaints. This trial is registered with ClinicalTrials.gov, NCT04648137. Between Feb 1, 2021, and May 1, 2022, we recruited 15 patients with arginine vasopressin deficiency (central diabetes insipidus) and 15 healthy controls. All participants completed the study and were included in the analyses. In healthy controls, median plasma oxytocin concentration was 77 pg/mL (IQR 59-94) at baseline and increased by 659 pg/mL (355-914) in response to MDMA, resulting in an AUC of 102 095 pg/mL (41 782-129 565); in patients, baseline oxytocin concentration was 60 pg/mL (51-74) and only slightly increased by 66 pg/mL (16-94) in response to MDMA, resulting in an AUC of 6446 pg/mL (1291-11 577). The effect of MDMA on oxytocin was significantly different between groups: the AUC for oxytocin was 82% (95% CI 70-186) higher in healthy controls than in patients (difference 85 678 pg/mL [95% CI 63 356-108 000], p<0·0001). The increase in oxytocin in healthy controls was associated with typical strong subjective prosocial, empathic, and anxiolytic effects, whereas only minimal subjective effects were observed in patients, in agreement with the lack of increase in oxytocin concentrations. The most frequently reported adverse effects were fatigue (eight [53%] healthy controls and eight [53%] patients), lack of appetite (ten [67%] healthy controls and eight [53%] patients), lack of concentration (eight [53%] healthy controls and seven [47%] patients), and dry mouth (eight [53%] healthy controls and eight [53%] patients). In addition, two (13%) healthy controls and four (27%) patients developed transient mild hypokalaemia. These findings are highly suggestive of clinically meaningful oxytocin deficiency in patients with arginine vasopressin deficiency (central diabetes insipidus), laying the groundwork for a new hypothalamic-pituitary disease entity. Swiss National Science Foundation, Swiss Academy of Medical Sciences, and the G&J Bangerter-Rhyner Foundation.

GHRH + arginine test and body mass index: do we need to review diagnostic criteria for GH deficiency?

IntroductionThe proportion of patients with low GH response to provocative tests increases with the number of other pituitary hormone deficiencies, reason why in panhypopituitary patients GH stimulation tests may be unnecessary to diagnose GH deficiency (GHD)PurposeTo re-evaluate the diagnostic cut-offs of GH response to GHRH + arginine (ARG) test related to BMI, considering the patients’ pituitary function as the gold standard for the diagnosis of GHD.MethodsThe GH responses to GHRH + ARG were studied in 358 patients with history of hypothalamic-pituitary disease. GHD was defined by the presence of at least 3 other pituitary deficits (n = 223), while a preserved somatotropic function was defined by the lack of other pituitary deficits and an IGF-I SDS ≥ 0 (n = 135). The cut-off with the best sensitivity (SE) and specificity (SP), was identified for each BMI category using the ROC curve analysis. To avoid over-diagnosis of GHD we subsequently searched for the cut-offs with a SP ≥ 95%.ResultsThe best GH cut-off was 8.0 μg/l (SE 95%, SP 100%) in lean, 7.0 μg/l (SE 97.3%, SP 82.8%) in overweight, and 2.8 μg/l (SE 84.3%, SP 91.7%) in obese subjects. The cut-off with a SP ≥ 95% was 2.6 μg/l (SE 68.5%, SP 96.6%) in overweight and 1.75 μg/l (SE 70.0%, SP 97.2%) in obese subjects.ConclusionsThis is the first study that evaluates the diagnostic cut-offs of GH response to GHRH + ARG related to BMI using a clinical definition of GHD as gold standard. Our results suggest that with this new approach, the GHRH + ARG cut-offs should be revised to avoid GHD over-diagnosis.

A survey on the perception of the specialty of Endocrinology and Nutrition among students preparing for the entrance exam for medical specialty training in Spain

Introduction and aimsPrevious studies have shown that there is decreasing interest in E&N among medical students. The aim of our study was to evaluate the perception of E&N among a sample of medical students. Material and methodsWe surveyed 2252 students prior to taking the exam that allows access to specialised training in Spain. ResultsOverall, 9.9% (222 participants) would probably choose E&N. The most positive aspects in includes of the specialty are its logical pathophysiological basis (54%) and that the work is dynamic and varied (27%), while the least attractive aspects are the few interventional techniques. The parts of the specialty that most attract students are hypothalamic–pituitary disease and diabetes mellitus. ConclusionsThe proportion of candidates who want to study E&N as their first choice is adequate in relation to the number of places available.

A survey on the perception of the specialty of Endocrinology and Nutrition among students preparing for the entrance exam for medical specialty training in Spain

Introduction and aimsPrevious studies have shown that there is decreasing interest in E&N among medical students. The aim of our study was to evaluate the perception of E&N among a sample of medical students. Material and methodsWe surveyed 2252 students prior to taking the exam that allows access to specialised training in Spain. ResultsOverall, 9.9% (222 participants) would probably choose E&N. The most positive aspects in includes of the specialty are its logical pathophysiological basis (54%) and that the work is dynamic and varied (27%), while the least attractive aspects are the few interventional techniques. The parts of the specialty that most attract students are hypothalamic–pituitary disease and diabetes mellitus. ConclusionsThe proportion of candidates who want to study E&N as their first choice is adequate in relation to the number of places available.

PMON75 Unilateral Galactorrhea in an Elderly Male

Abstract Introduction/Background Galactorrhea in men is rare, with a reported prevalence of 5.5%. It tends to occur bilaterally rather than unilaterally. Among the etiologies of galactorrhea, pharmacologic agents, pituitary tumors, and hypothalamic and pituitary-stalk lesions tend to account for most cases. Here we describe a rare cause of unilateral galactorrhea due to previous herpes zoster in the T4 dermatome. Clinical Case A 76-year-old male with history of hypertension, Crohn's disease, and chronic migraine headaches presented to the Endocrine clinic for evaluation of intermittent unilateral galactorrhea, which had been ongoing for the past 5 years. The patient had no known precipitating events, but he had noticed that galactorrhea was more pronounced in the spring-summer seasons, during which time he used to work outdoors more. No history of cancer, hypothalamic-pituitary disease, or other endocrinopathies. The patient was a former smoker and denied marijuana or alcohol use. He reported a family history of breast cancer in his maternal grandmother. He had no biological children. Active medications included sumatriptan as needed for migraines. Physical examination was notable for gynecomastia that was more prominent on the left. Tenderness to palpation was noticed over the left breast with no exudate expressed from the nipples. Genital exam revealed decreased testicular volume at approximately 10 ml each. Laboratory evaluation revealed normal renal function, prolactin, estradiol, β-HCG, TSH, and normal male karyotype. Testosterone level was low with elevated LH and FSH, suggesting primary hypogonadism. Mammogram and US of the breast were not concerning for malignancy. MRI brain was without pituitary abnormalities. After a detailed discussion on a subsequent follow-up visit, the patient recalled an episode of herpes zoster infection over his left breast about 5 years ago and since had been experiencing left breast pain and nipple discharge. Discussion and conclusion We present a unique case of post-herpetic galactorrhea in an elderly male patient. In the literature, there are case reports that describe galactorrhea in patients post chest wall injuries or chest surgeries, and there was one case report of galactorrhea in a postmenopausal female post zoster infection. A possible mechanism of galactorrhea is thought to be stimulation of the lactational neural arch, and in our case, possibly stimulated by the zoster infection. Prior herpes zoster infection and post-herpetic neuralgia are likely causes for underlying intermittent unilateral galactorrhea. Albeit rare, clinicians should be aware of this etiology when comprehensively evaluating for galactorrhea. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Growth hormone deficiency in adults with hypopituitarism-What are the risks and can they be eliminated by therapy?

Growth hormone (GH) deficiency develops early in patients with hypothalamic-pituitary disorders and is therefore common among these patients. GH deficiency in adults is associated with increased morbidity, increased body fat mass, abdominal obesity, dyslipidaemia, reduced exercise capacity, impaired cardiac function as well as reduced self-reported well-being and impaired quality of life. Since recombinant human GH became available as replacement therapy more than 25 years ago, randomised controlled trials and long-term studies, together with meta-analyses, have shown improved outcomes in adult patients with hypopituitarism receiving GH. Many of the features associated with GH deficiency in adults improve, or even normalize, and the safety profile is reassuring. The increased interest in GH deficiency in adults with hypothalamic-pituitary disorders has also contributed to the identification of other factors of importance for an outcome such as the replacement of other pituitary hormone deficiencies, and the management of the underlying hypothalamic-pituitary disease, most commonly a pituitary tumour. In this narrative review, we summarize the burden of GH deficiency in adults with hypopituitarism, the impact of GH replacement on the outcome, as well as safety. Based on currently available data, GH replacement should be considered routine management of adults with hypopituitarism.

Prostate-Specific Antigen Concentrations in Response to Testosterone Treatment of Severely Hypogonadal Men.

ContextClinical guidelines recommend measurement of the serum prostate-specific antigen (PSA) concentration during testosterone treatment of hypogonadal men to determine whether the increase is sufficiently high to warrant urologic referral. Prior studies of the effect of testosterone treatment on PSA concentrations have been conducted in men who were mildly to moderately hypogonadal.ObjectiveThe objective of this work is to determine the PSA response to testosterone treatment of men who are severely hypogonadal.Design and SettingThis retrospective cohort study was conducted at a single academic medical center.ParticipantsEighty-five men participated who were severely hypogonadal as a result hypothalamic-pituitary or testicular disease.Main Outcome MeasureChanges in serum PSA concentrations were measured during testosterone treatment for up to 18 months.ResultsTestosterone treatment increased the median serum testosterone concentration from 36 ng/dL (interquartile range [IQR], 20-91 ng/dL) at baseline to 395 ng/dL (IQR, 266-542 ng/dL) at 6 to 18 months. This treatment resulted in a median increment in PSA above baseline of 0.70 ng/mL (IQR, 0.10-1.85 ng/mL) at 6 to 18 months. Apropos current Endocrine Society clinical guidelines, 31% of the men experienced a PSA increase above baseline greater than 1.4 ng/mL, and 13% reached an absolute PSA concentration of greater than 4.0 ng/mL. Four men were diagnosed with prostate cancer.ConclusionsThe PSA response to testosterone replacement in men who are severely hypogonadal as a result of pituitary or testicular disease is greater than that previously reported in men with mild to moderate hypogonadism. These results suggest the magnitude of the PSA response to testosterone replacement is related to the degree of hypogonadism.

Central Diabetes Insipidus in a Patient with Stiff Person Syndrome

Background: Central diabetes insipidus (CDI) is a rare hypothalamic-pituitary disease due to the deficiency of arginine vasopressin (AVP) synthesis of which more than one third of etiologies are unidentified. Autoimmunity is associated with one third of patients with apparently idiopathic CDI. The most common antibody detected in auto immune CDI is autoantibodies to AVP-secreting cells (AVPcAb). Stiff-person syndrome (SPS) is a rare neurological disorder with features of an autoimmune disease. It is characterized by fluctuating muscle rigidity in the trunk and limbs and a heightened sensitivity to stimuli. It is well known that SPS is associated with multiple auto immune endocrinopathy including auto immune diabetes and auto immune thyroid disease. The association between SPS and CDI is not well documented in the literature. Case information: We report a case of 51 year old female who developed CDI while being treated for SPS unmasked by high dose steroids. Result: Anti amphiphysin is the only antibody detected in our patient. Animal studies showed a high expression of amphiphysin in anterior and posterior pituitary gland, data in human are still vague .One theory is that anti-amphiphysin antibodies attack the amphiphysin molecules in the AVP secreting cells and inhibit release of AVP. Conclusion: This antibody could hint towards the autoimmune cause of CDI.

The Cut-off Limits of Growth Hormone Response to the Insulin Tolerance Test Related to Body Mass Index for the Diagnosis of Adult Growth Hormone Deficiency

Introduction: The diagnosis of growth hormone deficiency (GHD) in adults is based on a reduced GH response to provocative tests, such as the insulin tolerance test (ITT) and the GH-releasing hormone (GHRH) + arginine (ARG) test. However, the cut-off limits of peak GH response in lean subjects are not reliable in obese patients; this is noteworthy since adult GHD is often associated with obesity. To date, there are no ITT cut-offs related to body mass index (BMI). Objective: We aimed to evaluate the diagnostic cut-offs of GH response to the ITT in the function of BMI. Methods: The GH response to the ITT was studied in 106 patients with a history of hypothalamic-pituitary disease, a mean age of 48.2 ± 12.4 years, and a mean BMI of 26.8 ± 6.1 kg/m²). Patients were divided into lean, overweight, and obese groups according to their BMI. The lack of GH response to GHRH + ARG test was considered the gold standard for the diagnosis of GHD. The best GH cut-off in the ITT, defined as the one with the best sensitivity (SE) and specificity (SP), was identified using receiver-operating characteristics curve (ROC) analysis. Results: The best GH cut-off in the ITT was 3.5 μg/L in lean subjects (SE 82.1%; SP 85.7%), 1.3 μg/L in overweight subjects (SE 74.1%; SP 85.7%), and 2.2 μg/L in obese subjects (SE 90.0%; SP 50.0%). The diagnostic accuracy was 97.2, 76.5, and 76.7%, respectively. Conclusions: Our data show that the ITT represents a reliable diagnostic tool for the diagnosis of adult GHD in lean subjects if an appropriate cut-off limit is assumed. Overweight and obesity strongly reduce the GH response to the ITT, GH BMI-related cut-off limits, and the diagnostic reliability of the test.

Clinical characteristics of non-alcoholic fatty liver disease in Chinese adult hypopituitary patients.

BACKGROUNDPatients with hypothalamic-pituitary disease have the feature of central obesity, insulin resistance, and dyslipidemia, and there is increased prevalence of liver dysfunction consistent with non-alcoholic fatty liver disease (NAFLD) in this population. The causes of hypopituitarism in the reported studies varied and combined pituitary hormone deficiency including central diabetes insipidus is much common in this population. This retrospective cross-sectional study was performed to analyze the clinical characteristics and related factors with NAFLD and cirrhosis in Chinese adult hypopituitary/panhypopituitary patients.AIMTo analyze the clinical characteristics of and related risk factors for NAFLD in Chinese adult hypopituitary patients.METHODSAdult Chinese patients with hypopituitarism and/or panhypopituitarism were enrolled at the Pituitary Center of Peking Union Medical College Hospital between August 2012 and April 2018. According to abdominal ultrasonography, these patients were divided into an NAFLD (-) group and an NAFLD (+) group, and the latter was further divided into an NAFLD group and a cirrhotic group. The data, such as patient characteristics, diagnosis, and treatment, were extracted from medical records, and statistical analysis was performed.RESULTSA total of 36 male and 14 female adult Chinese patients with hypopituitarism were included in this retrospective study; 43 (87.0%) of these patients exhibited growth hormone (GH) deficiency, and 39 (78.3%) had diabetes insipidus. A total of 27 (54.0%) patients were diagnosed with NAFLD, while seven patients were cirrhotic. No significant differences were noted in serum GH or insulin-like growth factor 1 among patients with cirrhosis, subjects with NAFLD, and those without NAFLD. However, plasma osmolality and serum sodium concentration of the cirrhotic patients were 314.9 mOsm/kgH2O and 151.0 mmol/L, respectively, which were significantly higher than those of the NAFLD patients (P = 0.036 and 0.042, respectively). Overweight/obesity and insulin resistance were common metabolic disorders in this population. The body mass index (BMI) and homeostasis model assessment of insulin resistance parameters of the cirrhotic patients were 27.7 kg/m2 and 9.57, respectively, which were significantly higher than those of the patients without NAFLD (P = 0.011 and 0.044, respectively). A correlation analysis was performed, and fasting insulin concentration was positively associated with plasma osmolality in patients with NAFLD, after adjusting for gender, age, and BMI (r = 0.540, P = 0.046), but no correlation was noted in patients without NAFLD.CONCLUSIONNAFLD is common in patients with hypopituitarism. Plasma osmolality and serum sodium levels of hypopituitary patients with cirrhosis are higher than those of subjects with NAFLD, and fasting insulin concentration is positively associated with plasma osmolality in patients with NAFLD, which suggests that hyperosmolality might be a contributor to the worsening of NAFLD in hypopituitary patients.

Central Diabetes Insipidus in a Patient with Stiff Person Syndrome

Background: Central diabetes insipidus (CDI) is a rare hypothalamic-pituitary disease due to the deficiency of arginine vasopressin (AVP) synthesis of which more than one third of etiologies are unidentified. Autoimmunity is associated with one third of patients with apparently idiopathic CDI. The most common antibody detected in auto immune CDI is autoantibodies to AVP-secreting cells (AVPcAb). Stiff-person syndrome (SPS) is a rare neurological disorder with features of an autoimmune disease. It is characterized by fluctuating muscle rigidity in the trunk and limbs and a heightened sensitivity to stimuli. It is well known that SPS is associated with multiple auto immune endocrinopathy including auto immune diabetes and auto immune thyroid disease. The association between SPS and CDI is not well documented in the literature. Case information: We report a case of 51 year old female who developed CDI while being treated for SPS unmasked by high dose steroids. Result: Anti amphiphysin is the only antibody detected in our patient. Animal studies showed a high expression of amphiphysin in anterior and posterior pituitary gland, data in human are still vague .One theory is that anti-amphiphysin antibodies attack the amphiphysin molecules in the AVP secreting cells and inhibit release of AVP. Conclusion: This antibody could hint towards the autoimmune cause of CDI.

A case of hypothalamic-pituitary disease: who's the deceiving suspect?

A case of hypothalamic-pituitary disease: who's the deceiving suspect?

Hypothyroidism - A New View On An Old Disease

Hypothyroidism is a common disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. Underactivity of thyroid is usually primary, from disease of thyroid, but may be secondary to hypothalamic-pituitary disease (reduced TSH drive). Untreated hypothyroidism can cause a number of health problems, such as obesity, hypertension, dyslipidaemia, infertility. The prevalence increases with age, and is higher in females than in males. Autoimmune thyroid disease is the most common aetiology of hypothyroidism. Clinical symptoms of hypothyroidism are nonspecific and may be subtle, especially in older persons. TSH and FT4 measurement are the laboratory examinations necessary for the diagnosis of hypothyroidism as well as the differential diagnosis between primary (clinical or subclinical) and secondary one. In the majority of patients, alleviation of symptoms can be accomplished through oral administration of synthetic levothyroxine, and most patients will require lifelong therapy.KYAMC Journal Vol. 7, No.-1, Jul 2016, Page 707-713

Growth hormone and cortisol secretion in the elderly evaluated using the glucagon stimulation test.

The glucagon stimulation test is a reliable alternative test to assess growth hormone and cortisol secretion, but has not been widely used in the elderly population. The aim of this study was to evaluate growth hormone and cortisol secretion using the glucagon stimulation test in an elderly population without known hypothalamic-pituitary disease and to correlate growth hormone and cortisol peaks with age (less than or greater than 80 years) and body mass index. Forty-two subjects (67-88 years) from the geriatric ambulatory unit were submitted and 41 subjects completed the glucagon stimulation test. Median growth hormone peak was 5.99 μg/L and median cortisol peak was 21.6 μg/dL. Growth hormone peak was >3 µg/L in 73.2%, and cortisol peak was >18 µg/dL in 65.8% of patients. There was a statistically significant positive correlation between the growth hormone peak and the cortisol peak. The cortisol peak was significantly different between subjects stratified by growth hormone peak of < or >3 μg/L (15.7 and 21.8 μg/dL, respectively). There was a statistically significant difference in cortisol peak according to age < or > 80 years (22.4 and 18.5 µg/dL, respectively). Considering lower cut-offs recently proposed for growth hormone peak (1.0 μg/L for overweight subjects) and cortisol peak (9.1 μg/dL), only two patients had a growth hormone peak below this value, and all patients had preserved cortisol secretion. We did find a positive correlation between growth hormone and cortisol peaks in the glucagon stimulation test in the elderly, confirming the capacity of the glucagon stimulation test to stimulate both axes. According to the new proposed cut-points for growth hormone and cortisol, we had 95% of normal growth hormone and 100% of normal cortisol responses.

Anthropometric factors have significant influence on the outcome of the GHRH-arginine test: establishment of normative data for an automated immunoassay specifically measuring 22 kDa human growth hormone.

Adult growth hormone (GH) deficiency (GHD) is diagnosed by provocative testing of GH secretion. To improve the diagnostic accuracy of GH-releasing hormone (GHRH) plus arginine (GARG) testing, we evaluated the influence of age, BMI and sex and established normative data for an automatic immunoassay specifically measuring 22 kDa human GH. Prospective multicenter study. Eighty-seven patients with hypothalamic-pituitary disease and 200 healthy controls. Patients were classified according to the number of pituitary hormone deficiencies (PHD). GHD was assumed when ≥2 PHD (in addition to GH) were present (n = 51); 36 patients with <2 PHD were considered GH sufficient (GHS). ROC analysis identified cutoffs with ≥95% specificity for GHD. Controls were prospectively stratified for sex, age and BMI. All participants received GHRH and l-arginine. GH was measured by immunoassay (iSYS, IDS). In controls, multiple stepwise regression analysis showed that BMI (21%, P < 0.0001), sex (20%, P < 0.0001) and age (5%, P < 0.001), accounted for 46% of GH peak level variability during GARG. Comparison of peak GH during GARG (GHD vs GHS + controls) revealed an overall cutoff of 3.9 ng/mL (sensitivity 86%, specificity 95%). After adjustment for BMI and sex, optimal cutoffs (male vs female) were 6.5 vs 9.7 ng/mL in lean, 3.5 vs 8.5 ng/mL in overweight and 2.2 vs 4.4 ng/mL in obese subjects respectively. BMI and sex account for most of the variability of peak GH levels during GARG. Consequently, diagnostic accuracy of the GARG test is significantly improved by use of adjusted cutoffs.

Revised GH and cortisol cut-points for the glucagon stimulation test in the evaluation of GH and hypothalamic-pituitary-adrenal axes in adults: results from a prospective randomized multicenter study.

Recent studies suggest using lower GH cut-points for the glucagon stimulation test (GST) in diagnosing adult GH deficiency (GHD), especially in obese patients. There are limited data on evaluating GH and hypothalamic-pituitary-adrenal (HPA) axes using weight-based dosing for the GST. To define GH and cortisol cut-points to diagnose adult GHD and secondary adrenal insufficiency (SAI) using the GST, and to compare fixed-dose (FD: 1 or 1.5mg in patients >90kg) with weight-based dosing (WB: 0.03mg/kg). Response to the insulin tolerance test (ITT) was considered the gold standard, using GH and cortisol cut-points of ≥3ng/ml and ≥18µg/dL, respectively. 28 Patients with hypothalamic-pituitary disease and 1-2 (n=14) or ≥3 (n=14) pituitary hormone deficiencies, and 14 control subjects matched for age, sex, estrogen status and body mass index (BMI) underwent the ITT, FD- and WB-GST in random order. Age, sex ratio and BMI were comparable between the three groups. The best GH cut-point for diagnosis of GHD was 1.0 (92% sensitivity, 100% specificity) and 2.0ng/mL (96% sensitivity and 100% specificity) for FD- and WB-GST, respectively. Age negatively correlated with peak GH during FD-GST (r=-0.32, P=0.04), but not WB-GST. The best cortisol cut-point for diagnosis of SAI was 8.8µg/dL (92% sensitivity, 100% specificity) and 11.2µg/dL (92% sensitivity and 100% specificity) for FD-GST and WB-GST, respectively. Nausea was the most common side effect, and one patient had a seizure during the FD-GST. The GST correctly classified GHD using GH cut-points of 1ng/ml for FD-GST and 2ng/ml for WB-GST, hence using 3ng/ml as the GH cut-point will misclassify some GH-sufficient adults. The GST may also be an acceptable alternative to the ITT for evaluating the HPA axis utilizing cortisol cut-points of 9µg/dL for FD-GST and 11µg/dL for WB-GST.

Secondary Adrenal Insufficiency: Where Is It Hidden and What Does It Look Like?

Adrenal failure secondary to hypothalamic-pituitary disease is a common although underestimated and underdiagnosed condition, with serious consequences. Corticotropin deficiency can be isolated or more frequently occur in association with other pituitary hormones deficiencies. The most frequent endogenous cause of secondary adrenal insufficiency (SAI) is a tumor of the hypothalamic-pituitary region, usually associated with panhypopituitarism secondary to tumor growth or to its treatment with surgery or irradiation. Less commonly, SAI is due to nontumoral disorders including infiltrative lesions, infective processes, vascular alterations, traumatic brain injury, empty sella or genetic disorders. Finally, long-term administration of exogenous glucocorticoids can determine secondary and/or tertiary hypoadrenalism acting at the hypothalamic level and leading to prolonged suppression of the hypothalamic-pituitary-adrenal axis. It is essential to perform validated diagnostic procedures in order to promptly diagnose hypoadrenalism so as to prevent an adrenal crisis. At the same time, diagnosis is complex as no single test has sufficient sensitivity to identify all patients with SAI. Therefore, clinical judgment and follow-up are crucial for the assessment of corticotropin deficiency. Patients with persisting suggestive symptoms and/or a clinical history of higher risk for adrenal insufficiency deserve careful subsequent reassessments.

Pegvisomant-primed glucagon stimulation test in assessing GH reserve and GH/IGF kinetics in adults suspected of GH deficiency.

The accuracy of the glucagon stimulation test(GST) in diagnosing adult GH deficiency (GHD) has recently been questioned. Because pegvisomant (PegV)increases endogenous GH secretion, we hypothesized that priming PegV to the GST (PegV-GST) 72 h beforehand would improve the diagnostic accuracy of this test. This pilot study aimed to prospectively compare PegV-GST to two other diagnostic tests for adult GHD. Adults suspected of GHD underwent PegVGST,GST and insulin tolerance test (ITT) in random order.Growth hormone levels (measured by a PegV insensitive assay) during PegV-GST, GST and ITT were compared,and acute effects of PegV on GH/IGF kinetics were assessed. Ten subjects with hypothalamic-pituitary disease and 1–4 pituitary hormone deficiencies were studied. Basal and peak GH levels with the PegV-GST were comparable to those of the GST and ITT. The five subjects that failed the GST and ITT were the same subjects that failed the PegVGST,using the peak GH cut point of<3 ng/mL for this test. After PegV priming, basal GH and GH binding protein(GHBP) increased (both P<0.01) and total IGF-I and bioactive IGF decreased (both P<0.05), whereas IGF-II and IGFBPs -1, -2 and -3 were unchanged compared to pre-PegV priming. Serum PegV levels correlated positively with basal GH, peak GH, IGFBP-1 and IGFBP-2 levels, and negatively with D bioactive IGF and DGHBP (all P<0.05). Single dose PegV administration in adults suspected of GHD increased basal GH and GHBP, with concomitant rapid fall in IGF-I levels and bioactive IGF. PegV priming did not appear to improve the diagnostic accuracy of the GST. Further studies involving larger subject numbers are needed to verify the clinical utility of PegV-GST in evaluating adult GHD.

Typical and Atypical Pituitary Adenomas: A Single-Center Analysis of Outcome and Prognosis

Background and Objective: In 2004, the World Health Organization defined atypical pituitary adenomas as those with a Ki-67 expression >3%, an excessive p53 expression and increased mitotic activity. As the usefulness of this classification is controversial, we reviewed typical and atypical pituitary adenomas to compare the clinical and prognostic features. Patients and Methods: We retrospectively reviewed 343 consecutive pituitary adenomas. Atypical pituitary adenomas represented 18.7% of cases. All patients were operated on at the Department of Neurosurgery of our institution and were followed up at the Hypothalamic-Pituitary Disease Unit of the same institution. The median follow-up time was 75 months (range 7-345). Results: Younger age at diagnosis as well as immunohistochemical positivity for adrenocorticotropic hormone and prolactin correlated with a higher risk of atypical pituitary adenomas, whereas typical and atypical pituitary adenomas did not differ with regard to gender, tumor size, recurrence risk and disease-free survival time (DFST). Among the 219 patients who underwent radical surgery, a Ki-67 expression ≥1.5% was associated with a higher risk of recurrence and a worse DFST, even after correction for age at diagnosis, gender, immunohistochemical classification, tumor size, invasiveness and Knosp classification [p = 0.01; hazard ratio (HR) 2.572; 95% confidence interval (CI) 1.251-5.285). Pituitary adenomas with a Ki-67 expression ≥1.5% showed a worse DFST as compared to pituitary adenomas with a Ki-67 expression <1.5% (HR 2.166; 95% CI 1.154-4.064). Conclusion: In this series, atypical and typical pituitary adenomas did not differ with regard to recurrence and DFST. Pituitary adenomas with a Ki-67 expression ≥1.5% showed a higher recurrence risk and a worse DFST as compared to those with a Ki-67 expression <1.5%. We suggest that a Ki-67 expression ≥1.5% may be useful as a prognostic marker, though this will need to be confirmed by prospective, multicenter data.