Immune checkpoint inhibitor-related hypophysitis and endocrine dysfunction: clinical review.

Immune checkpoint inhibitors are a new and effective class of cancer therapy, with ipilimumab being the most established drug in this category. The drugs' mechanism of action includes promoting the effector T cell response to tumours and therefore increased autoimmunity is a predictable side effect. The endocrine effects of these drugs include hypophysitis and thyroid dysfunction, with rare reports of adrenalitis. The overall incidence of hypophysitis with these medications is up to 9%. Primary thyroid dysfunction occurs in up to 15% of patients, with adrenalitis reported in approximately 1%. The mean onset of endocrine side effects is 9 weeks after initiation (range 5-36 weeks). Investigation and/or screening for hypophysitis requires biochemical and radiological assessment. Hypopituitarism is treated with replacement doses of deficient hormones. Since the endocrine effects of immune checkpoint inhibitors are classed as toxic adverse events, most authors recommend both discontinuation of the immune checkpoint inhibiting medication and 'high-dose' glucocorticoid treatment. However, this has been challenged by some authors, particularly if the endocrine effects can be managed (e.g. pituitary hormone deficiency), and the therapy is proving effective as an anticancer agent. This review describes the mechanism of action of immune checkpoint inhibitors and details the key clinical endocrine-related consequences of this novel class of immunotherapies.

Genetic predictors of cardiovascular morbidity in Bardet-Biedl syndrome.

Bardet-Biedl syndrome is a rare ciliopathy characterized by retinal dystrophy, obesity, intellectual disability, polydactyly, hypogonadism and renal impairment. Patients are at high risk of cardiovascular disease. Mutations in BBS1 and BBS10 account for more than half of those with molecular confirmation of the diagnosis. To elucidate genotype-phenotype correlations with respect to cardiovascular risk indicators 50 patients with mutations in BBS1 were compared with 19 patients harbouring BBS10 mutations. All patients had truncating, missense or compound missense/truncating mutations. The effect of genotype and mutation type was analysed. C-reactive protein was higher in those with mutations in BBS10 and homozygous truncating mutations (p = 0.013 and p = 0.002, respectively). Patients with mutations in BBS10 had higher levels of C peptide than those with mutations in BBS1 (p = 0.043). Triglyceride levels were significantly elevated in patients with homozygous truncating mutations (p = 0.048). Gamma glutamyl transferase was higher in patients with homozygous truncating mutations (p = 0.007) and heterozygous missense and truncating mutations (p = 0.002) than those with homozygous missense mutations. The results are compared with clinical cardiovascular risk factors. Patients with missense mutations in BBS1 have lower biochemical cardiovascular disease markers compared with patients with BBS10 and other BBS1 mutations. This could contribute to stratification of the clinical service.

Cerebral cavernoma: an emerging long-term consequence of external beam radiation in childhood.

The long-term effects of cranial external beam radiotherapy are emerging as survival rates for cerebral tumours improve. Cerebral cavernoma are a recognized consequence of cranial irradiation. Endocrinologists managing the life-long complications of hypopituitarism associated with irradiation need to be aware and vigilant of the risks of cavernoma formation, in particular in the population with a history of childhood irradiation. We present three cases of young patients who were diagnosed with cerebral cavernoma many years after childhood irradiation treatment and review the current literature on this condition. We discuss implications for endocrine practice as rising numbers of patients survive childhood cancer and irradiation and are now attending adult endocrine services for long-term management of secondary hypopituitarism.

Factors determining the remission of microprolactinomas after dopamine agonist withdrawal.

BACKGROUND: Withdrawal of dopamine agonist (DA) therapy in the management of microprolactinoma is common practice, but it is unclear which patients are likely to attain long-term remission. OBJECTIVE: To identify predictive factors for long-term remission. DESIGN: Prospective cohort study. PATIENTS: Forty subjects (39 female, aged 24-60 years) with microprolactinoma; all had been normoprolactinaemic on DA therapy for at least 2 years [mean duration of therapy 9 years (range 2-27)]. MEASUREMENTS: A pituitary magnetic resonance imaging (MRI) was performed on 36 (90%) subjects before DA withdrawal. Relapse was defined as prolactin greater than 480 mIU/l (22.8 microg/l) on two occasions. RESULTS: Nine out of 40 (22.5%) subjects were normoprolactinaemic 12 months after DA withdrawal. Amongst the relapse group, 24 of 31 subjects (79.4%) had already relapsed at 3 months. Normalization of MRI prior to DA withdrawal (P = 0.0006) and longer duration of DA treatment (P = 0.032) were significant predictors of remission. Age, pre-treatment prolactin, nadir prolactin, previous failure of DA withdrawal, pregnancy, dose and type of DA were not significant predictors of remission. The nine patients who were in remission at 12 months were then followed up for 58.0 +/- 5.8 months; all remained in remission. CONCLUSIONS: As many as 22.5% of subjects with microprolactinoma remained normoprolactinaemic 12 months after DA withdrawal and these subjects stayed in remission for up to 5 years. Significant predictive factors were normalization of MRI prior to discontinuation, and duration of DA treatment. Our findings support intermittent DA withdrawal after a period of normoprolactinaemia, particularly where MRI appearances have normalized.

IGF-I treatment in adults with type 1 diabetes: effects on glucose and protein metabolism in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp.

Type 1 diabetes is associated with abnormalities of the growth hormone (GH)-IGF-I axis. Such abnormalities include decreased circulating levels of IGF-I. We studied the effects of IGF-I therapy (40 microg x kg(-1) x day(-1)) on protein and glucose metabolism in adults with type 1 diabetes in a randomized placebo-controlled trial. A total of 12 subjects participated, and each subject was studied at baseline and after 7 days of treatment, both in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp. Protein and glucose metabolism were assessed using infusions of [1-13C]leucine and [6-6-2H2]glucose. IGF-I administration resulted in a 51% rise in circulating IGF-I levels (P < 0.005) and a 56% decrease in the mean overnight GH concentration (P < 0.05). After IGF-I treatment, a decrease in the overnight insulin requirement (0.26+/-0.07 vs. 0.17+/-0.06 U/kg, P < 0.05) and an increase in the glucose infusion requirement were observed during the hyperinsulinemic clamp (approximately 67%, P < 0.05). Basal glucose kinetics were unchanged, but an increase in insulin-stimulated peripheral glucose disposal was observed after IGF-I therapy (37+/-6 vs. 52+/-10 micromol x kg(-1) x min(-1), P < 0.05). IGF-I administration increased the basal metabolic clearance rate for leucine (approximately 28%, P < 0.05) and resulted in a net increase in leucine balance, both in the basal state and during the hyperinsulinemic amino acid clamp (-0.17+/-0.03 vs. -0.10+/-0.02, P < 0.01, and 0.25+/-0.08 vs. 0.40+/-0.06, P < 0.05, respectively). No changes in these variables were recorded in the subjects after administration of placebo. These findings demonstrated that IGF-I replacement resulted in significant alterations in glucose and protein metabolism in the basal and insulin-stimulated states. These effects were associated with increased insulin sensitivity, and they underline the major role of IGF-I in protein and glucose metabolism in type 1 diabetes.

rhIGF-I administration reduces insulin requirements, decreases growth hormone secretion, and improves the lipid profile in adults with IDDM.

IDDM is associated with elevated circulating levels of growth hormone (GH) and reduced insulin-like growth factor I (IGF-I). GH antagonizes the action of insulin-increasing insulin requirements in IDDM. The effects of subcutaneously administered rhIGF-I on glycemic control, insulin requirements, and GH secretion were studied in eight adults with IDDM. Patients received either placebo or rhIGF-I (50 microg/kg b.i.d.) for 19 days in a randomized, double-blind, parallel-design, placebo-controlled trial. Overnight GH, plasma glucose, free insulin, IGF-I, fructosamine, and lipid profiles were assessed during this period. rhIGF-I therapy increased IGF-I concentration from 117.1 +/- 14.2 (mean +/- SE) ng/ml (baseline) to 310.5 +/- 40.6 and 257.1 +/- 41.2 ng/ml on day 5 (P < 0.01 vs. baseline) and day 20 (P < 0.01 vs. baseline), respectively. After 19 days of rhIGF-I treatment, fructosamine concentrations were unchanged compared with baseline (439 +/- 32 vs. 429 +/- 35 micromol/l, day -1 vs. day 20, respectively), yet insulin requirements were decreased by approximately 45% (0.67 +/- 0.08 vs. 0.36 +/- 0.07 U x kg(-1) x day(-1), day -1 vs. day 19, respectively, P < 0.005). After 4 days of rhIGF-I therapy, there was a decrease in free insulin levels (8.38 +/- 1.47 vs. 4.98 +/- 0.84 mU/l, P < 0.05), mean overnight GH concentration (12.6 +/- 3.3 vs. 3.8 +/- 2.1 mU/l, P = 0.05), and total cholesterol and triglycerides (4.68 +/- 0.31 vs. 4.25 +/- 0.35 mmol/l, P < 0.05, 1.27 +/- 0.19 vs. 0.95 +/- 0.21 mmol/l, P < 0.001, respectively). There was no change in any variable in the placebo-treated patients. This study demonstrates that subcutaneous administration of rhIGF-I decreases insulin requirements and improves the plasma lipid profile while maintaining glycemic control in adults with IDDM. The excess nocturnal release of GH, characteristic of IDDM, is also decreased by rhIGF-I therapy.

Growth hormone replacement in adults with growth hormone deficiency: assessment of current knowledge.

The recent availability of recombinant human growth hormone (GH) has led to intense investigation of the consequences of adult GH deficiency (GHD) and the effects of GH replacement. These studies have led to the identification of a characteristic syndrome of GHD consisting of decreased mood and well-being, with alterations in body composition and substrate metabolism. In both placebo-controlled and open studies, GH replacement therapy has consistently been shown to reverse or correct these features. Whether long-term GH replacement will result in a reduction of osteoporotic fractures, cardiovascular morbidity and mortality is not yet known. To date, no permanent serious adverse effects have been associated with GH replacement in GHD, and although currently expensive, it is anticipated that GH replacement will become routine in the treatment of the severely hypopituitary adult.

The effect of recombinant human growth hormone on glucose and leucine metabolism in Cushing's syndrome.

Cushing's syndrome is characterized by central obesity and muscle wasting. As GH is anabolic, it may be able to counteract the loss of body protein. To evaluate the potential therapeutic use of GH preoperatively, eight patients with Cushing's syndrome received sc injections of recombinant human GH (0.07 U/kg.day) for 7 days. Whole body leucine and glucose turnover were measured after an infusion of [1-13C]leucine and [6,6-2H2]glucose before (day 0) and after 2 and 7 days of GH treatment. Compared with the value on day 0, there was a significant increase on days 2 and 7 in insulin (P < 0.005 and P < 0.001), C peptide (P < 0.01 and P < 0.005), insulin-like growth factor I (P < 0.001), and glucose concentrations (P < 0.01 and P < 0.005) and a decrease in the leucine concentration (P < 0.005). There was no significant change in glucose production rate, glucose MCR, leucine production rate (a measure of protein degradation), or nonoxidative leucine disappearance rate (a measure of protein synthesis). The leucine MCR was increased after 7 days (P < 0.05), and the clearance of leucine into protein (nonoxidative leucine disappearance rate/leucine concentration) was increased (P < 0.05) after 2 and 7 days of GH treatment. This is consistent with GH stimulating the availability of amino acid transporters. GH may, therefore, have a therapeutic role in the preoperative treatment of Cushing's syndrome.

Comparison of continuation or cessation of growth hormone (GH) therapy on body composition and metabolic status in adolescents with severe GH deficiency at completion of linear growth.

Although GH replacement improves the features of GH deficiency (GHD) in adults, it has yet to be established whether cessation of GH at completion of childhood growth results in adverse consequences for the adolescent with GHD. Effects of continuation or cessation of GH on body composition, insulin sensitivity, and lipid levels were studied in 24 adolescents (13 males, 11 females, aged 17.0 +/- 0.3, yr, mean +/- se, puberty stage 4 or 5) in whom height velocity was less than 2 cm/yr. Provocative testing confirmed severe GHD [peak GH < 9 mU/liter (3 microg/liter)] in all cases and was followed by a lead-in period of 3 months during which the pediatric dose of GH continued unchanged. Baseline investigations were then performed using dual-energy x-ray absorptiometry (body composition), lipid measurements, and assessment of insulin sensitivity by both homeostasis model assessment and a short insulin tolerance test. Twelve patients remained on GH (0.35 U/kg.wk), and 12 patients ceased GH treatment. The groups were followed up in parallel with repeat observations made after 6 and 12 months. No endocrine differences were evident between the groups at baseline. GH cessation resulted in a reduction of serum IGF-I Z score [-1.62 +/- 0.29, baseline vs. -2.52 +/- 0.12, 6 months (P < 0.05) vs. -2.52 +/- 0.10, 12 months (P < 0.01)] but values remained unchanged in those continuing GH replacement. Lean body mass increased by 2.5 +/- 0.5 kg ( approximately 6%) over 12 months in those receiving GH but was unchanged after GH discontinuation. Cessation of GH resulted in increased insulin sensitivity [short insulin tolerance test, 153 +/- 22 micromol/liter.min, baseline vs. 187 +/- 20, 6 months (P < 0.05) vs. 204 +/- 14, 12 months (P = 0.05)], but no significant change was seen during 12 months of GH continuation. Lipid levels remained unaltered in both groups. Continuation of GH at completion of linear growth resulted in ongoing accrual of lean body mass (LBM), whereas skeletal muscle mass remained static after GH cessation in these adolescents with GHD. This divergence of gain in LBM is of potential importance because increases in LBM occur as a feature of healthy late adolescent development. GH is a major mediator of insulin sensitivity, independent of body composition in adolescents. Further studies are required to determine whether discontinuation of GH in the adolescent with severe GHD once linear growth is complete results in long-term irreversible adverse physical and metabolic consequences and to determine conclusively the benefits of continuing GH therapy.

The effect of cessation of growth hormone (GH) therapy on bone mineral accretion in GH-deficient adolescents at the completion of linear growth.

In many countries, treatment of childhood-onset GH deficiency (GHD) with GH ceases when linear growth is complete. Peak bone mass occurs several years after the completion of linear growth. Given that GH has important anabolic actions on bone, discontinuation of GH therapy at the completion of linear growth may have adverse consequences for the attainment of peak bone mass in adolescent GHD patients. In this United Kingdom multicenter study, 24 adolescents (13 males, mean age 17.0 +/- 1.4 yr, SD) with severe GHD were randomized to discontinue or continue GH (0.35 IU/kg x wk) at the completion of linear growth. Whole body bone mineral content (BMC) and lumbar spine bone mineral density were assessed by dual-energy x-ray absorptiometry at baseline and then at 6-month intervals for 1 yr. Markers of bone remodeling (serum bone-specific alkaline phosphatase and urinary deoxypyridinoline) were measured at the same time points. In patients who continued GH (GH+), median BMC increased by 3.8% (interquartile range, 2.6, 5.9, P < 0.001) at 6 months; and by 6.0% (3.7-9.1, P < 0.001) at 12 months. In patients who discontinued GH (GH-) median BMC was unchanged at 6 and 12 months (+1.9%, -0.4-4.2, P = 0.9; and +2.4%, 0.4-4.9, P = 0.5, respectively, median, interquartile range). The differences in median change in BMC between the two groups at 6 and 12 months was marginally significant (P = 0.085 and 0.074, respectively). Mean lumbar spine bone mineral density increased by 4.7 (95% confidence interval, 1.0, 8.2) at 12 months in patients continuing GH (P = 0.01), but the mean change was not statistically significant change in patients who discontinued GH [+2.7% (95% confidence interval, -0.8, +6.2)]. These preliminary data suggest that, in adolescent patients with severe GHD, discontinuation of GH at completion of growth may limit the attainment of peak bone mass in this patient group. This may predispose to clinically significant osteopenia in later adult life.

Treatment with growth hormone and insulin-like growth factor-I in critical illness.

The wider availability of recombinant human growth hormone and insulin-like growth factor-I has resulted in an investigation into the potential benefits of the pharmacological administration of these anabolic peptides in a variety of clinical conditions, characterized by an increase in catabolic rate. The initial studies were small, often uncontrolled open investigations, but investigators have more recently concentrated on larger, controlled multi-centre trials. Studies to date have included patients with cardiac failure, sepsis, burns, cancer cachexia, end-stage renal failure, trauma and AIDS, and those prior to or following major surgery. The authors have in general cautiously interpreted positive effects of treatment with growth hormone and insulin-like growth factor-I, either alone or in combination, on net protein balance, body composition, well-being and performance. Two large, randomized, placebo-controlled European multi-centre studies have recently detailed the effects of growth hormone treatment in critically ill intensive care patients. Major increases in mortality and morbidity were associated with growth hormone treatment. The mechanism(s) accounting for the increased mortality remain poorly understood. These negative findings have led to a decrease in the clinical use of growth hormone and in research activity in the area of anabolic treatment in human illness.

Transitional care of GH deficiency: when to stop GH therapy.

While the benefits of growth hormone (GH) therapy in adult hypopituitary patients with GH deficiency (GHD) are established, the role of continued GH therapy after final height in adolescent GH-deficient patients remains unclear. Preliminary data suggest that cessation of GH on completion of linear growth may be associated with impairment of somatic development and adverse changes in body composition. For the present time, the decision whether to continue GH treatment in adolescent patients with GHD is best made on an individual basis. For such patients, continuity of care is crucial. Children and adults with GHD are usually managed by physicians in separate departments, who may focus on different aspects of treatment and care. Close collaboration between paediatric and adult physicians is essential to ensure smooth transition and to minimize the drop-out rate from follow-up. Given the previous period of treatment during childhood, paediatric physicians should be best placed to discuss the potential benefits of continuing GH therapy and instigate retesting of GH secretion. Many children with isolated idiopathic GHD will produce normal GH responses if retested at adult height. Patients with multiple pituitary hormone deficits are more likely to have ongoing GHD, as are patients who have received CNS irradiation. Quality of life does not appear to be decreased in adolescents with GHD who stop treatment, so achievement of satisfactory bone mass is a major determinant of the decision whether to continue therapy.

The effects of two doses of replacement growth hormone on the biochemical, body composition and psychological profiles of growth hormone-deficient adults.

This study examined the effects of growth hormone (GH) replacement on the insulin-like growth factor-I (IGF-I), body composition and psychological profiles of GH-deficient adults. We assessed whether two doses of GH produced different effects on these variables and whether patients who, at the end of the study chose to remain on long-term GH replacement responded differently to those who chose to abandon therapy. Forty-two adults (aged 42.9 +/- 1.9 years (mean +/- S.E.M.)) with documented GH deficiency entered two studies (24 in study 1, 18 in study 2). Biochemical, body composition and psychological profiles were assessed at baseline, and after 6 months and 1 year. Psychological assessments were performed using well-established, independent, validated 'Quality of Life' questionnaires (Nottingham Health Profile (NHP) and the Psychological General Well-Being Schedule (PGWB)). The study protocols differed only in the doses of growth hormone (0.024 mg/kg per day and 0.012 mg/kg per day respectively). Comparison between studies and between patients eventually continuing and abandoning GH therapy was performed. GH replacement was associated with significant changes in IGF-I levels (P < 0.001), body composition (P < 0.01) and self-perceived well-being (NHP, P < 0.01; PGWB, P < 0.01). The higher dose of GH produced a greater IGF-I response than the lower dosage (44.6 +/- 7.3 vs 26.2 +/- 3.6 nmol/l, P < 0.05), but no better psychological response (NHP, P = 0.22; PGWB, P = 0.23). Those deciding to continue replacement therapy did not respond differently to those choosing to abandon therapy with respect to IGF-I (P = 0.72), body composition (P = 0.38) and psychological assessment (NHP, P = 0.29; PGWB, P = 0.24). GH replacement in GH-deficient adults was associated with significant improvements in self-perceived well-being as well as changes in body composition and other variables. This improvement was similar at two different doses of replacement GH. Those patients electing to continue on long-term replacement did not achieve a demonstrably different psychological, body composition or biochemical benefit to those patients deciding to discontinue replacement.

Safety aspects of pharmacological GH therapy in adults.

The consequences of "pharmacological" growth hormone administration have been studied in a number of conditions, including those characterized by high rates of catabolism. The majority of studies have reported favourable effects on metabolism but recent reports indicate that GH treatment results in increased mortality in critically ill humans. The objective of the study was to assess the safety of large doses of rhGH therapy in human adults. Original trials were identified by searching MEDLINE (1966-March 2000) and the Cochrane database (2000). References of all identified trials were also inspected for more studies. All relevant trials in which GH had been administered to non-GH-deficient (GHD) adult humans were selected from. Outcomes such as death, clinically significant change in function, change in length of hospital stay or need for treatment, and adverse effects were sought. Studies were selected, quality-assessed and passed suitable for inclusion by two independent reviewers. Those studies that were placebo-controlled with satisfactory randomization were considered for inclusion. Twenty-one reports were included in the review. A wide range of patient groups were studied by a variety of investigators, employing a range of doses and duration of GH treatment. The study protocols differed markedly. The majority of studies were small and were designed and/or powered to enable identification of specific effects on nutritional status, protein metabolism, level of function or quality of life. Only two studies were designed to assess safety issues and mortality. In these, GH treatment was associated with a marked increase in mortality in critically ill ICU patients, with a range of diagnoses. Multi-organ failure and the effects of sepsis/infection accounted for most of the excess mortality. In addition morbidity, in terms of length of ICU stay, was increased by GH administration. Other less marked effects were increased fluid retention and hyperglycaemia as a consequence of GH administration. Functional improvement following GH therapy was documented in some studies. There have been few studies assessing the safety aspects of "pharmacological" GH treatment in adult humans. Two well-designed reports indicate that GH administration results in increased morbidity and mortality in a wide variety of critically ill subjects across a spectrum of age ranges. The mechanism(s) of the GH-associated mortality remain poorly understood. Based on current trial evidence, pharmacological GH treatment cannot be recommended for widespread use in critically ill subjects. Well-conducted and reported randomized trials are still needed to inform practice as to whether GH administration will be safe in specific illness categories.

The prevalence and natural history of pituitary hemorrhage in prolactinoma.

CONTEXT: Incidental pituitary hemorrhage, without full pituitary apoplexy, is a recognized radiological finding, but little information exists on its clinical behavior, with most reports describing surgically treated macroprolactinoma or nonfunctioning adenoma. OBJECTIVE: Our aim was to characterize the prevalence, natural history, and risk factors associated with pituitary hemorrhage in a large clinic prolactinoma population. DESIGN: The design consisted of a retrospective analysis of a clinic population. SETTING: The setting was a tertiary endocrine center in a large teaching hospital. PATIENTS: We studied three hundred sixty-eight patients with prolactinoma. The presence of hemorrhage was documented on magnetic resonance imaging. MAIN OUTCOME MEASURE: The main outcome measures were the prevalence, risk factors, and natural history of pituitary hemorrhage. RESULTS: Pituitary hemorrhage was found in 25 patients, giving an overall prevalence of 6.8%, and was significantly higher in macroprolactinoma (20.3%) compared to microprolactinoma (3.1%, P < .0001). Three patients had classical pituitary apoplexy. The majority of patients in the hemorrhage group had macroprolactinomas (16/25 [64%]) and were women (22/25 [88%]). The proportion of women with macroprolactinoma was higher in the hemorrhage group (14/16 macroprolactinomas [87.5%]) than in the nonhemorrhage group (36/63 macroprolactinomas [57.1%], P = .02). The majority of pituitary hemorrhages (92%) were treated conservatively with dopamine agonist therapy for hyperprolactinemia. Eighty-seven percent of patients had complete resolution of their hemorrhage within 26.6 ± 23.3 (mean ± SD) months. The presence of macroprolactinoma (odds ratio 9.00 [95%CI 3.79-23.88], P < .001) and being female (odds ratio 8.03 [95%confidence interval 1.22-52.95], P = .03) were independently associated with hemorrhage. CONCLUSIONS: These data show that incidental hemorrhage in prolactinoma is not uncommon. It is more likely to occur in macroprolactinoma, where 1 in 5 develop hemorrhage, and is particularly common in women with macroprolactinoma. The majority are asymptomatic and resolve spontaneously.

Thomas Addison's disease after 154 years: modern diagnostic perspectives on an old condition.

Thomas Addison was first to describe adrenocortical failure in 1855. Despite advances in the treatment of this condition, the diagnosis is still often delayed and sometimes missed with potentially fatal consequences. From the same institution where Thomas Addison performed his original autopsy studies, we present four recent cases highlighting the wide clinical spectrum and discuss how modern biochemical and immunological tests could be utilized in early diagnosis and aetiological classification.