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Objective: Optic nerve hypoplasia (ONH), the congenital underdevelopment of the optic nerve, is an increasing cause of visual impairment and is associated with pituitary dysfunction. Past studies have focused on the relationship between ONH, pituitary deficiencies, and brain imaging. However, recent studies have demonstrated the true risk for hypopituitarism lies with the presence or absence of ONH, irrespective of midline brain findings. This study reviewed the relationship between the health of the optic nerve (visual acuity) and pituitary gland (number and age of development of pituitary deficiencies) as a way to stratify risk, regardless of imaging findings., Design, Patients and Measurements: Retrospective chart review of 197 patients seen at a single center from 2013 to 2022. Visual assessment was defined by distance acuity, and the presence of nystagmus or afferent pupillary defect. Pituitary deficiencies were diagnosed per Endocrine Society guidelines., Results: In children with bilateral ONH (bONH), profound visual impairment was associated with more pituitary deficiencies between 0 and 15 years of age. The odds of having any pituitary deficiency were 4.9 times higher (95% confidence interval [95% CI]: 2.4-10.1) for patients with bONH versus unilateral ONH (uONH). Central hypothyroidism was the most common first presenting pituitary deficiency followed by growth hormone across all patients., Conclusion: This study shows a significant association between severity of visual impairment and increased probability of pituitary deficiencies in children with bONH versus uONH. Children with ONH require urgent endocrine evaluation due to risk of pituitary deficiencies, but risk stratification may also be based on severity of visual impairment., (© 2024 The Author(s). Clinical Endocrinology published by John Wiley & Sons Ltd.)

Objective: Patients with Sheehan syndrome (SS) are predisposed to coronary artery disease (CAD) due to risk factors like abdominal obesity, dyslipidemia and chronic inflammation. In addition to estimate CAD risk enhancers like high sensitive C reactive protein (hsCRP), apolipoprotein B (ApoB) and lipoprotein A [Lp(a)], this study applies Framingham risk score (FRS) and coronary artery calcium (CAC) score to compute a 10-year probability of cardiovascular (CV) events in SS patients., Design: Case-control study Sixty-three SS patients, on a stable hormonal replacement treatment except for growth hormone and 65 age, body mass index and parity-matched controls., Measurements: Measurement of serum hsCRP, ApoB and Lp(a) and estimation of CAC with 16-row multislice computed tomography scanner., Results: The concentrations of hsCRP, ApoB and Lp(a) were significantly higher in SS patients than in controls (p < .01). After calculating FRS, 95.2% of SS patients were classified as low risk, 4.8% as intermediate risk and all controls were classified as low risk for probable CV events. CAC was detected in 50.7% SS patients and 7.6% controls (p = .006). According to the CAC score, 26.9% SS patients were classified as at risk (CAC > 10) for incident CV events as against 1.6% controls. The mean Multi-Ethnic Study of Atherosclerosis (MESA) score was significantly higher in patients with SS than controls. CAC corelated significantly with fasting blood glucose (r = .316), ApoB (r = .549), LP(a) (r = .310) and FRS (r = .294)., Conclusion: Significant number of asymptomatic SS patients have high coronary artery calcium score and are classified at risk for CAD., (© 2022 John Wiley & Sons Ltd.)

Objective: Previous studies have reported recovery of secondary adrenal insufficiency (SAI) in patients with pituitary disorders, generally immediately after pituitary surgery; however, data regarding recovery of long-term SAI are lacking. We conducted a study to assess the longer term recovery rate of SAI in patients with pituitary disorders., Methods: We identified all SAI patients in the Halifax Neuropituitary Database from 1 November 2005 to 30 September 2014, who had required glucocorticoid therapy for ≥3 months, and had a minimum follow-up of 6 months. Patients with ACTH-secreting adenomas, those receiving glucocorticoids only in the routine peri-operative period for pituitary surgery and those on glucocorticoids for nonpituitary conditions were excluded. SAI was defined as either basal serum cortisol < 130 nm and/or a subnormal cortisol response to ACTH-(1-24) stimulation test or insulin tolerance test response., Results: Fifty-one patients fulfilled the criteria. Nine (17·6%) patients had complete recovery of SAI over a median of 20 months (range: 8-51) after initiating glucocorticoid replacement. Patients with smaller tumour size had increased likelihood of hypothalamic-pituitary-adrenal (HPA) axis recovery, whereas those with secondary hypogonadism or growth hormone deficiency were less likely to recover. Those with initial cortisol >175 nm had an almost one in two chance of recovery., Conclusion: Results from our study show that approximately one in six patients with SAI recover adrenal function, even up to 5 years after diagnosis. We recommend that patients with SAI undergo regular testing to assess recovery in order to prevent unnecessary glucocorticoid therapy., (© 2016 John Wiley & Sons Ltd.)

Objective: Nephropathia epidemica (NE) is a haemorrhagic fever with renal syndrome (HFRS) caused by Puumala hantavirus (PUUV). Pituitary haemorrhage and hypopituitarism may complicate recovery from acute NE., Design: Forty-seven of our recent cohort of 58 NE patients volunteered to be re-examined in order to estimate the burden of hormonal deficiency 4 to 8 years after the acute illness. Two patients had suffered from pituitary haemorrhage, but many others exhibited pituitary oedema during their acute infection. In this study, we searched for symptoms of hormonal deficiency, performed hormonal laboratory screening, and most patients underwent pituitary MRI examination., Results: The pituitary size had diminished in all patients in whom MRI was performed (P < 0·001). One patient with acute phase haemorrhage had made a complete recovery while the other continued to require hormonal substitution. In addition, hormonal laboratory abnormalities were observed in nine other patients; these being attributable to several reasons, for example independent peripheral hormonal diseases, side effects of medication or other secondary causes such as obesity. None of them had signs of late-onset pituitary insufficiency caused by their previous NE. Health-related quality of life (mean and median 15D score) of patients was comparable to that of age-standardized general population., Conclusions: None of our patients had developed obvious late-onset hypopituitarism despite of the fact that pituitary gland can be affected during acute NE. We recommend requesting a history of hantavirus infection whenever the possibility of pituitary dysfunction is suspected at least in patients originating from regions with high NE infection rate., (© 2015 John Wiley & Sons Ltd.)

Background: Glucocorticoid replacement therapy in patients with adrenal insufficiency needs to be tailored to the individual patient based on body composition and clinical signs and symptoms as no objective method for assessment of treatment adequacy is available. Current treatment regimens are often not satisfactory, which is shown by the adverse metabolic profile and doubled mortality rates in treated adrenal insufficiency patients. Measurement of cortisol concentrations in hair reflect the long-term systemic cortisol exposure and may be of use in refinement of hydrocortisone treatment., Objective: We aimed to study whether long-term cortisol (hydrocortisone) levels, as measured in scalp hair, are similar in children with adrenal insufficiency and healthy children., Material and Methods: We set up a case control study, measuring anthropometric characteristics and hair cortisol concentrations (HCC) in 54 hydrocortisone substituted children with adrenal insufficiency (AI patients) in the age of 4-18 years and 54 healthy children matched for gender and age., Results: Mean HCC were significantly higher in AI patients compared with healthy controls (mean 13·3 vs 8·2 pg/mg, P = 0·02). AI patients also had a higher BMI (P < 0·001) and waist circumference (WC) (P = 0·02). HCC was significantly associated with BMI (P = 0·002) and WC (P = 0·002). HCC explained 13% of the difference in BMI and 29% of the difference in WC between AI patients and controls., Conclusion: Hydrocortisone-treated AI patients have increased HCC and adverse anthropometric characteristics compared with healthy controls. HCC measurement may be of value in identifying overtreatment and thereby improve hydrocortisone replacement therapy., (© 2014 John Wiley & Sons Ltd.)

Objective: Primary empty sella (PES) is a frequent anatomical condition rarely causing pituitary dysfunction. We assessed cardiovascular risk in a cohort of PES patients referred to Endocrine Units., Design: The study was performed in three Italian tertiary referral centres. We evaluated pituitary function and cardiovascular risk, on the basis of lipid and glucose metabolism parameters and of Framingham score (FS), in 94 consecutive patients with PES diagnosis and in 94 gender, age and BMI matched controls., Patients: Pituitary function was normal in 30 patients (group A), whereas a single or multiple pituitary hormone deficiency was demonstrated in 64 (group B). Growth hormone deficiency (GHD) was diagnosed in 56, central hypothyroidism in 35, hypogonadotropic hypogonadism in 32 and central hypoadrenalism in 24 cases., Results: Framingham score was higher and glucose and lipid profile were worse in PES patients than in controls. Cardiovascular risk parameters were not different between group A and B. In group B, increased cardiovascular risk was associated with hypothyroidism and hypogonadism, but not with GHD. In group A, cardiovascular risk was higher and FT3 and FT4 levels were lower than in controls. Moreover, PES patients stratified for BMI showed a worse glucose and lipid profile and (in the overweight subgroup) higher FS than matched controls., Conclusions: Primary empty sella patients show increased cardiovascular risk, regardless of BMI. A worse lipid and glucose profile and higher FS were associated with secondary hypothyroidism, even subclinical, as well as hypogonadism., (© 2012 John Wiley & Sons Ltd.)

Objective: Addition of dehydroepiandrosterone sulphate (DHEAS) to standard pituitary replacement may improve quality of life and glucose metabolism. Conflicting results from the previous work probably relate to differences in populations studied and assessment techniques used. We examined the effects of DHEAS on insulin action and the quality of life in female patients with hypopituitary hypoadrenalism., Design: Randomized, double-blind, placebo-controlled, crossover design was used. Patients received either DHEAS 50 mg daily or placebo for 12 weeks., Patients: Fourteen hypopituitary females on stable standard replacement therapy and with low DHEAS were enrolled., Measurements: Insulin action by euglycaemic hyperinsulinaemic clamp and extensive quality of life parameters were assessed after each treatment., Results: Serum DHEAS (DHEAS 5·4 ± 0·8 vs placebo <0·8 ± 0·0 μm; P < 0·001) and androstenedione (DHEAS 4·1 ± 0·8 vs placebo 1·3 ± 0·2 nm; P < 0·05) rose to within the normal range after DHEAS 50 mg daily. There were no differences between treatments in testosterone, sex hormone-binding globulin (SHBG) or IGF-1. Quality of life measures were unchanged after DHEAS. There were no differences between treatments in fasting glucose, serum insulin, HbA1c or in insulin action (glucose infusion rates required to maintain euglycaemia; DHEAS 21·9 ± 2·5 vs placebo 24·5 ± 2·1 μmol/kg/min; P = 0·4). Triglyceride concentrations were lower following DHEAS (DHEAS 1·24 ± 0·18 vs placebo 1·41 ± 0·19 mm; P < 0·05) but other lipid parameters remained unchanged., Conclusion: There were no differences compared with placebo in quality of life or insulin action after DHEAS replacement therapy for 12 weeks. These results do not provide evidence for the addition of DHEAS to standard hypopituitary replacement therapy., (© 2012 Blackwell Publishing Ltd.)

Objective: Central diabetes insipidus is a rare clinical condition with a heterogenous aetiology. Up to 40% of cases are classified as idiopathic, although many of these are thought to have an autoimmune basis. Published data have suggested that anterior hypopituitarism is common in childhood-onset idiopathic diabetes insipidus. We aimed to assess the incidence of anterior hypopituitarism in a cohort of adult patients with idiopathic diabetes insipidus., Design and Patients: We performed a retrospective review of the databases of two pituitary investigation units. This identified 39 patients with idiopathic diabetes insipidus. All had undergone magnetic resonance imaging scanning and dynamic pituitary testing (either insulin tolerance testing or GHRH/arginine and short synacthen testing) to assess anterior pituitary function., Results: One patient had partial growth hormone deficiency; no other anterior pituitary hormonal deficits were found. Thirty-three percent had at least one autoimmune disease in addition to central diabetes insipidus., Conclusions: Our data suggest that anterior hypopituitarism is rare in adult idiopathic diabetes insipidus. Routine screening of these patients for anterior hypopituitarism may not, therefore, be indicated. The significant prevalence of autoimmune disease in this cohort supports the hypothesis that idiopathic diabetes insipidus may have an autoimmune aetiology., (© 2012 Blackwell Publishing Ltd.)

Objective: Recent studies have suggested that mutations in genes encoding several hypothalamo-pituitary (H-P) transcription factors result in hypopituitarism [isolated GH deficiency (IGHD) and combined pituitary hormone deficiency (CPHD)], which may in turn be related to the neuroanatomy revealed by magnetic resonance (MR) imaging. Although studies have focused on patients with either optic nerve hypoplasia (ONH) or isolated hypopituitarism with normal optic nerves, few studies have compared the two groups. We aimed to relate the clinical phenotype of a large cohort (n = 170) of children with congenital hypopituitarism including septo-optic dysplasia (SOD) attending a single centre to the neuroradiological and genetic findings., Design: Clinical, biochemical, MR imaging and molecular data were analysed retrospectively in 170 patients with or 'at-risk' (with ONH) of hypopituitarism to determine predictors of hypopituitarism., Results: The presence of ONH was significantly associated with an absent septum pellucidum [odds ratio (OR) 31.5, 95% confidence intervals (CI) 7.3-136.6, P < 0.001], an abnormal corpus callosum (OR 10.5, 95% CI 3.8-28.6, P < 0.001) and stalk abnormalities (OR 2.3, 95% CI 1.2-4.2, P = 0.009). The risk of hypopituitarism was 27.2 times greater in patients with an undescended posterior pituitary (95% CI 3.6-205.1, P < 0.001). Anterior pituitary hypoplasia (OR 3.1, 95% CI 1.3-7.0, P = 0.006) and an absent pituitary stalk (P < 0.001) were also significantly associated with hypopituitarism. With respect to the type or severity of hypopituitarism, CPHD was more often associated with an abnormal corpus callosum (OR 6.1, 95% CI 1.4-27.4, P = 0.008) and stalk abnormalities (OR 2.8, 95% CI 1.3-6.1, P = 0.006). Male to female ratio was significantly greater in patients with normal optic nerves (3.3:1) as compared with those with ONH (1.2:1). The prevalence of diabetes insipidus, thyrotrophin and ACTH deficiencies was significantly greater in patients with ONH as compared with 'idiopathic' hypopituitarism. Mutations in pituitary transcription factors and genes regulating GH secretion were rare (5/170) in this cohort of patients with sporadic hypopituitarism., Conclusion: Our data suggest that individuals presenting with ONH are at high risk for neuroradiologic and endocrine abnormalities. The neuroradiologic features are predictive not only of the presence, but also of the type, of hypopituitarism. The association of midline abnormalities with hypopituitarism in this cohort suggests a common developmental origin for these features, the aetiology of which remains unidentified in the majority of cases.

Introduction: The presence of an ectopic posterior pituitary gland (EPP) on magnetic resonance imaging (MRI) is associated with hypopituitarism with one or more hormone deficiencies. We aimed to identify risk factors for having multiple pituitary hormone deficiency (MPHD) compared to isolated growth hormone deficiency (IGHD) in patients with an EPP., Methods: In 67 patients (45 male) with an EPP on MRI, the site (hypothalamic vs. stalk) and surface area (SA) [ x (maximum diameter/2) x (maximum height/2), mm(2)] of the EPP were recorded and compared in patients with IGHD and MPHD in relation to clinical characteristics., Results: In MPHD (n = 32) compared to IGHD (n = 35) patients: age of presentation was younger (1.4 [0.1-10.7]vs. 4.0 [0.1-11.3] years, P = 0.005), major incidents during pregnancy were increased (47%vs. 20%, P = 0.02) as were admissions to a neonatal intensive care unit (NICU) (60%vs. 26%, P = 0.04), whilst EPP SA was lower (12.3 [2.4-34.6]vs. 25.7 [6.9-48.2] mm(2), P < 0.001). In patients with a hypothalamic (n = 56) compared to a stalk sited EPP (n = 11): prevalence of MPHD was greater (55%vs. 9%,P = 0.05) and EPP surface area was smaller (17.3 [2.4-48.2]vs. 25.3 [11.8-38.5] mm(2), P < 0.001). In regression analysis, after adjusting for age, presence of MPHD was associated with: major incidents during pregnancy (RR 6.8 [95%CI 1.2-37.7]), hypothalamic EPP site (RR 10.9 [1.0-123.9]) and small EPP SA (RR 2.5 [1.0-5.0] for tertiles of SA)., Conclusion: In patients with an EPP, adverse antenatal events, size (small) and position (hypothalamic) of the posterior pituitary gland on MRI were associated with MPHD. These findings suggest that adverse factors during pregnancy may be important for the development of an EPP.

Objective: Pituitary stalk interruption syndrome (PSIS) is a frequent cause of GH deficiency (GHD) and is commonly associated with other PH deficiencies (PHDs). Although previous reports have correlated multiple PHDs with severe anatomical lesions, the status of the gonadotrophic axis has not yet been thoroughly analysed., Methods: We retrospectively reviewed the medical records of 27 patients (15 males, 12 females) with GHD and PSIS defined by MRI findings. The status of the gonadotrophic axis was evaluated in children who were at least 14.5 years (boys) or 13 years (girls)., Results: Out of 27 patients, five displayed spontaneous full pubertal development with normal hormonal values at the final evaluation, whereas 22 of 27 patients (81%) had complete (n = 18) or partial pubertal deficiency. Three girls had primary amenorrhoea with normal gonadotrophin values, raising the possibility of subtle disturbances of gonadotrophin pulsatility. Of the 21 patients with TSH or ACTH deficiency, 17 (81%) had complete gonadotrophin deficiency. Two of our six patients with apparently isolated GHD during childhood had gonadotrophin deficiency. Cryptorchidism was present at birth in six boys (40%). Of these six boys, one had normal pubertal development. Ten of 11 boys with micropenis at birth had gonadotrophin deficiency., Conclusions: Gonadotrophin deficiency is a common finding in adolescents with PSIS and is frequently associated with other PHDs. However its severity is variable, ranging from complete gonadotrophin deficiency to normogonadotrophic amenorrhoea. The occurrence of gonadotrophin deficiency in 33% of children with apparently isolated GHD and PSIS has important implications for the counselling and follow-up of these patients.

Background: The effect of GH replacement on thyroid function in hypopituitary patients has hitherto been studied in small groups of children and adults with conflicting results., Objective: We aimed to define the effect and clinical significance of adult GH replacement on thyroid status in a large cohort of GH-deficient patients., Patients and Method: We studied 243 patients with severe GH deficiency due to various hypothalamo-pituitary disorders. Before GH treatment, 159 patients had treated central hypothyroidism (treated group) while 84 patients were considered euthyroid (untreated group). GH dose was titrated over 3 months to achieve serum IGF-1 concentration in the upper half of the age-adjusted normal range. Serial measurements of serum T4, T3, TSH and quality of life were made at baseline and at 3 and 6 months after commencing GH replacement., Results: In the untreated group, we observed a significant reduction in serum T4 concentration without a significant increase in serum T3 or TSH concentration; 30/84 patients (36%) became hypothyroid and needed initiation of T4 therapy. Similar but lesser changes were seen in the treated group, 25 of whom (16%) required an increase in T4 dose. Patients who became hypothyroid after GH replacement had lower baseline serum T4 concentration, were more likely to have multiple pituitary hormone deficiencies and showed less improvement in quality of life compared with patients who remained euthyroid., Conclusion: GH deficiency masks central hypothyroidism in a significant proportion of hypopituitary patients and this is exposed after GH replacement. We recommend that hypopituitary patients with GH deficiency and low normal serum T4 concentration should be considered for T4 replacement prior to commencement of GH in order to provide a robust baseline from which to judge the clinical effects of GH replacement.

Objective: To describe the effect of T4 replacement in patients with primary and central hypothyroidism on components of the IGF binding protein complex: IGF-I, the acid-labile subunit (ALS) and IGFBP-3., Patients and Methods: We determined IGF-I, ALS and IGFBP-3 (by 125I-IGF-II ligand blots and immunoblots) in serum of 19 patients with primary and 11 patients with central hypothyroidism., Results: Mean (+/- SD) free T4 (fT4) increased from 4.4 +/- 2.4 pmol/l at baseline to 18.6 +/- 5.2 pmol/l following T4 therapy. In patients with primary hypothyroidism, IGF-I concentrations increased from 101 +/- 57 to 158 +/- 60 microg/l (P < 0.001) and ALS from 12.6 +/- 4.7 to 15.6 +/- 5.2 mg/l (P = 0.001). IGFBP-3 levels (in arbitrary units, AU), assessed by 125I-IGF-II ligand blot and by Western blot (the intensity of the 45/42-kDa doublet following T4 replacement defined as 1 AU) increased from 0.74 +/- 0.47 to 1 (P = 0.029) and from 0.76 +/- 0.42 to 1 (P = 0.018), respectively. In patients with hypopituitarism, IGF-I and ALS concentrations increased on T4 therapy from 49 +/- 23 to 97 +/- 36 microg/l (P < 0.001) and from 7.8 +/- 4.1 to 11.0 +/- 2.7 mg/l (P = 0.010), respectively. IGFBP-3 remained unchanged during T4 replacement., Conclusions: T4 replacement increases the serum levels of IGF-I and ALS in patients with primary as well as central hypothyroidism. IGFBP-3 levels increase in response to T4 replacement in patients with primary hypothyroidism but not in those with central hypothyroidism, suggesting that thyroid hormones increase IGF-I and ALS but not IGFBP-3 in patients with GH deficiency.

Objective: To identify possible abnormalities specific for obesity in hypopituitary patients., Study Design: Cross-sectional case-control study. MEASUREMENTS AND STUDY SUBJECTS: Body composition (DEXA) and measurements of fasting plasma levels of glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptides (GLPs), insulin, C-peptide, glucose, leptin and lipids were performed in 25 hypopituitary patients (15 obese, 10 normal weight) and 26 BMI and age-matched healthy controls (16 obese, 10 normal weight). All hypopituitary patients had GH deficiency and received adequate substitution therapy on this and other deficient axes (3 +/- 1)., Results: Fasting GIP-levels were significantly higher in obese hypopituitary patients compared to lean hypopituitary patients (P < 0.01), while the fasting concentrations of GLP-1 and GLP-2 were comparable between obese and lean hypopituitary patients. The same trend was seen in obese healthy controls vs. lean controls. No differences were observed in glucose, insulin or C-peptide between the hypopituitary patients and the controls. Leptin levels were increased in obese hypopituitary patients compared to lean hypopituitary patients when adjusted for gender. At least a 2-fold higher level of leptin was observed in women compared to men in both patient groups and healthy controls. Lean female hypopituitary patients had higher leptin levels than matched controls., Conclusions: Fasting levels of GIP were elevated in obese substituted hypopituitary patients, while fasting concentrations of GLPs were similar. Obese hypopituitary patients had the same degree of hyperinsulinaemia, affected glucose tolerance, dyslipoproteinaemia and central obesity as obese healthy controls. Further studies are required to identify the possible biochemical reasons for obesity in patients with apparently well-substituted hypopituitarism.

Objective: The conventional dosage of hydrocortisone, used for many years in the management of hypopituitarism (30 mg per day), has now been shown to be more than is physiologically necessary. On this conventional corticosteroid therapy studies have demonstrated an increased prevalence of diabetes and impaired glucose tolerance, which may contribute to the increased vascular morbidity and mortality reported in the condition. In these studies no information is available on oral glucose tolerance test (OGTT) timing in relation to administration of oral steroid and variable hydrocortisone doses were employed., Patients: In order to assess glucose tolerance in patients treated with lower, more physiological doses, we performed a 75-g OGTT at least 1 month after hydrocortisone therapy was adjusted to 15 mg at 0800 h and 5 mg at 1700 h in 45 adult onset hypopituitary patients (30 M, 15 F). Mean (+/- SD) duration of hypopituitarism was 12 +/- 10 years, mean age 52 +/- 14 years and BMI 29.3 +/- 5.1 kg/m2. All were on hydrocortisone, 43 on thyroxine, 31 on sex steroids, 9 on desmopressin and 33 had documented growth hormone deficiency. Hydrocortisone 15 mg was taken at 0800 and the OGTT commenced at 0900., Results: Using standard WHO criteria 36 patients (80%) had normal glucose tolerance, 1 (2%) had newly diagnosed diabetes and 8 (18%) had impaired glucose tolerance. Using the recently announced American Diabetes Association criteria for diagnosis 96% had normal glucose tolerance, 2% had diabetes and 2% impaired fasting glucose., Conclusion: The markedly reduced prevalence of diabetes and impaired glucose tolerance on lower hydrocortisone replacement doses in our series of patients with hypopituitarism, not previously known to be diabetic, is of great interest. This lower prevalence may eventually result in reduced vascular complication rates.

Background: While increased sweating is a prominent symptom in patients with active acromegaly, reduced sweating is gaining status as part of the growth hormone deficiency (GHD) syndrome., Design and Subjects: Sweat secretion rate (SSR), as measured by pilocarpine iontophoresis represents the maximal capacity for stimulated sweat secretion in a localized skin area. SSR was studied in 37 patients with a history of acromegaly, 20 adult patients with GHD before and during long-term GH substitution of GHD adults, and 58 control subjects., Results: Acromegaly: Patients with acromegaly had significantly higher SSR than healthy controls (Z-score + 1.9 (+/- 1.1) mean (+/- SD) (P < 0.001)). SSR was increased irrespective of current clinical disease activity. Thus, the SSR Z-scores in 16 clinically inactive patients were + 2.1 (+/- 1.2), in 10 slightly or doubtfully active patients + 1.5 (+/- 0.7) and in 11 active patients + 1.8 (+/- 1.3). There was no correlation between SSR and IGF-I. GHD: Twenty adult patients participated in an 18-month randomised, placebo controlled, double blinded study of physiological dose GH substitution, followed by 18 months of open GH treatment. SSR at baseline was reduced in male but not in female GHD patients. Mean SSR (95% confidence interval) for 11 male patients was 89.0 mg/30 minutes (51.9-126.1) as compared to 133.5 mg/30 minutes (59.2-259.9) (P = 0.01) in 24 male controls, and for 11 female patients 48.2 mg/30 minutes (25.9-70.6) as compared to 49.2 mg/30 minutes (12.6-93. 9) in 34 female controls. GH treatment in physiological substitution doses for up to 36 months had no effect on SSR., Conclusion: We have demonstrated that longstanding GH hypersecretion in patients with acromegaly induces irreversible changes of sweat gland function, with persistently elevated SSR despite treatment and clinical cure. In GHD patients, SSR was reduced in males but not in females, which together with the established gender difference in normal controls emphasises the role of androgen deficiency as a cofactor for reduced sweating in hypopituitary patients. Sweat gland development seems to be more susceptible to lack of hormones in childhood and adolescence than in adulthood, whereas growth hormone excess can modify sweat function later in life.

Objective: The combined pituitary function test is routinely used in the endocrine investigation of short children. The TRH and luteinising hormone-releasing hormone (LHRH) response tests have been shown to be of minimal value in adults. We have evaluated the clinical utility of these tests in the context of combined pituitary function testing in children., Design: A retrospective analysis of basal hormone measurements and pituitary stimulation tests in relation to clinical assessment of pituitary function., Patients: One hundred and twenty-six children, 82 boys and 44 girls, aged 2-17 years, who had undergone pituitary function testing were studied., Results: The TSH response to TRH stimulation correlated directly with basal plasma TSH but not basal plasma total T4. In patients with an impaired response to stimulation, basal TSH concentrations were <2.0 mIU/l and significantly lower than in patients with a normal response (P < 0.0001). An impaired response to TRH stimulation had a positive predictive value of 0.43 and a negative predictive value of 0.90 for the diagnosis of hypopituitarism. A basal TSH concentration of <2.0 mIU/l had a positive predictive value of 0.22 and a negative predictive value of 0.92. A low basal T4 (normal range 60-140 nmol/l) in combination with an inappropriately low or normal basal TSH was always associated with a diagnosis of hypopituitarism. The responses of plasma LH and FSH to LHRH stimulation correlated directly with basal plasma LH and FSH concentrations. Basal gonadotrophin concentrations, basal sex hormone concentrations or response to LHRH stimulation could not distinguish patients with constitutional delay of growth and puberty from those with hypopituitarism. There was no apparent relationship between either basal gonadotrophin concentrations or response to LHRH stimulation and clinical assessment of pituitary function. In patients > or =13 years with constitutional delay of growth and puberty the median and interquartile ranges of basal LH and FSH were 1.4 IU/l (0.7-3.6) and 2.6 IU/l (2.2-5.2) respectively. The three hypopituitary patients in this study with chronological age > or =13 years had undetectable concentrations of both gonadotrophins. The response of LH and FSH to LHRH stimulation was significantly lower in patients > or =13 years with clinical hypopituitarism than in those with intact pituitary function (P <0.02)., Conclusion: TRH and LHRH tests in children with short stature appear to have little value over and above the baseline hormone measurements. An abnormal response to hormone stimulation is not diagnostic of hypothalamic-pituitary disease. We have demonstrated that neither TRH nor LHRH stimulation tests should be routinely used in the investigation of children with short stature.

Objective: Long-term experience of growth hormone (GH) replacement therapy in a large population of hypopituitary adults with GH deficiency (GHD) is limited, and safety surveillance is clearly essential. KIMS, the Pharmacia & Upjohn International Metabolic Database, is a long-term, open, outcomes research programme of hypopituitary adult patients with GHD who are treated in a conventional clinical setting., Patients: The present analysis encompasses data from 1034 hypopituitary adult GHD patients treated with GH for a total of 818 patient years., Results: Prior to GH therapy, the KIMS patient population exhibited an increased prevalence of obesity, diabetes mellitus (in females) and hyperlipidaemia, compared with normal populations described in published studies. Quality of life, assessed using a disease-specific questionnaire (QoL-AGHDA), was also reduced in KIMS patients. The maintenance dose of GH was significantly higher in patients who were receiving GH prior to enrolment into KIMS (non-naive patients) compared with patients who commenced GH at the time of enrolment (naive patients). In addition, dose of GH correlated significantly with body weight in the former group of patients. Analysis of serum levels of IGF-I indicated that overtreatment with GH was markedly more common in non-naive than in naive patients. The frequency of adverse events in KIMS patients was no higher than that reported in patients receiving placebo in previous clinical trials. Recurrence of pituitary or CNS tumours was reported in six patients, a rate consistent with data from control series. Three deaths were reported, none of which was obviously associated with GH treatment., Conclusions: Our data, drawn from a large population of hypopituitary adults treated with GH for a total of more than 800 patient years, confirm previous reports that untreated GHD in hypopituitary adults is associated with a number of important clinical problems. In addition, the results suggest that there has been a shift in recent years from determination of GH dose on the basis of body weight to dose titration of individual patients, and indicate that the latter technique has important advantages. The data provide further evidence that GH replacement therapy is well-tolerated in adults. However, it is possible that some adverse events may not become evident over the time scale covered by the present analysis, and continued surveillance therefore remains mandatory.

Objectives: The commonest side-effects of GH replacement therapy relate to sodium retention but its mechanism is unclear. In rats, GH inhibits renal and hepatic 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) activities. In man, this action might impair inactivation of cortisol to cortisone in the distal nephron thereby allowing cortisol to activate mineralocorticoid receptors. In this study, we examined the effects of GH replacement on cortisol metabolism., Design: A randomized double-blind study comparing 6 months GH replacement with placebo in adults with GH deficiency due to pituitary or hypothalamic disease., Patients: 6 men and 8 women received placebo and 8 men and 9 women received GH., Measurements: Cortisol and its metabolites were measured in overnight urine samples and in a fasting morning plasma sample at baseline and at 6 months., Results: Five patients withdrew from the study, 4 because of adverse effects of GH. Amongst those who completed the study, the effects of GH on cortisol metabolism differed between patients with and without ACTH deficiency. Amongst those receiving hydrocortisone replacement (n = 18), GH had no effect on plasma cortisol/cortisone ratio, or urine tetrahydrocortisols/tetrahydrocortisone ratio, but produced a substantial reduction in total urinary cortisol metabolites (from 1326 +/- 191 to 777 +/- 229 micrograms/mmol creatinine; P < 0.01) and an increase in urinary free cortisol/cortisone ratio (from 0.88 +/- 0.10 to 2.57 +/- 0.74; P < 0.02). By contrast, GH had none of these effects in patients with normal ACTH secretion. There were no changes in blood pressure or plasma electrolytes, aldosterone, or renin activity with GH, and no changes in any variables with placebo., Conclusions: The increase in cortisol/cortisone ratio in urine but not in plasma, and the lack of effect on hepatic cortisol metabolites, suggests that GH inhibits both the conversion of cortisol to cortisone by renal 11 beta-HSD2 and the conversion of cortisone to cortisol by hepatic 11 beta-HSD1. It is unclear why this action of GH only affects patients with ACTH deficiency. The reduction in total cortisol metabolite excretion suggests that GH also affects bioavailability of hydrocortisone tablets. These observations suggest that glucocorticoid replacement therapy may need to be adjusted in hypopituitary patients who are commenced on GH replacement.

Objective: We have investigated plasma potassium changes during insulin-induced hypoglycaemia (IIH) in adult patients with growth hormone deficiency (GHD) who have low total body potassium and may also have a vulnerable myocardium due to an increased prevalence of atherosclerosis., Design: Hypoglycaemia was induced through the administration of intravenous soluble insulin (0.1 U/Kg, i.v.)., Subjects: 23 consecutive adult patients undergoing routine biochemical evaluation for hypopituitarism., Measurements: GH, cortisol glucose, sodium and potassium levels were measured at 0, 30, 60, 90 and 120 min after insulin administration. Pituitary function was also assessed through measurement of TSH, thyroid hormones, LH/FSH, testosterone and 17-oestradiol. IGF-I concentrations were also analysed., Results: All patients achieved adequate hypoglycaemia (nadir glucose < 2 mmol/l). 15 patients had GHD (peak GH < 10 mU/l) either in isolation or as part of a spectrum of pituitary hormone deficiencies. The remaining 8 patients had normal pituitary function. Plasma potassium concentrations (mean +/- SEM) fell from 3.8 +/- 0.3 mmol/l (normals) and 3.8 +/- 0.2 mmol/l (GHDs) to nadir concentrations of 3.0 +/- 0.2 mmol/l and 3.1 +/- 0.3 mmol/l, respectively (P < 0.005). Overt hypokalaemia (< 3.5 mmol/l) occurred in 13/15 GHDs and all normals. There were no significant differences between the groups., Conclusions: Insulin-induced hypoglycaemia causes similar degrees of significant hypokalaemia in patients with normal pituitary function and in those with GH deficiency, either alone or in combination with other pituitary hormone deficiencies. Therefore, insulin-induced hypoglycaemia does not appear to be associated with any greater risk of hypokalaemia in hypopituitary adults with GHD compared to those with normal anterior pituitary function.

Antidiuretic hormone (ADH) function was assessed in a group of 16 patients with Sheehan's syndrome and 17 controls. All patients were on adequate cortisone and thyroxine replacement therapy before testing. During the dehydration test the patients revealed an impairment of ADH function. The maximum urine osmolalities and the urine-plasma osmolality ratios were significantly lower in the patients with Sheehan's syndrome compared to controls (maximum urine osmolalities 633 +/- 38 (SEM) and 873 +/- 29 (SEM) mOsm/kg, respectively, P less than 0.001; urine-plasma osmolality ratios 2.15 +/- 0.14 (SEM) and 3.01 +/- 0.10 (SEM), respectively, P less than 0.001). Plasma osmolalities were significantly higher in the patients (296.1 +/- 1.2 (SEM) and 290 +/- 0.9 (SEM), respectively, P less than 0.001). The patients took a longer period to achieve these maximum urine osmolalities. Three of the patients with Sheehan's syndrome were diagnosed as having diabetes insipidus since their maximum urine osmolalities were below 600 mOsm/kg and following desmopressin all three had an increment in urine osmolality which exceeded 9%. In addition these three patients had a maximum urine-plasma osmolality ratio below 1.9. Thus, it appears the patients with Sheehan's syndrome have an impairment of ADH function which manifests in some as diabetes insipidus.