Andrew A. Toogood

The severity of growth hormone deficiency in adults with pituitary disease is related to the degree of hypopituitarism

OBJECTIVE A number of studies of the effect of GH replacement therapy in adult patients with GH deficlency have been published, but the definition of GH deficiency has varied considerably. In order to define severe GH deficiency more critically we have determined GH status in the context of gonadotrophin, ACTH and TSH secretion in adult patients with pituitary disease.

Outcome of Cushing's Disease following Transsphenoidal Surgery in a Single Center over 20 Years

CONTEXT Historically, Cushings disease (CD) was associated with a 5-yr survival of just 50%. Although advances in CD management have seen mortality rates improve, outcome from transsphenoidal surgery (TSS), the current first-line treatment, varies significantly between centers. OBJECTIVES The aim of the study was to define outcome including mortality in a cohort of CD patients treated with TSS over 20 yr. DESIGN We conducted a retrospective cohort study of 80 patients who underwent TSS to treat CD between 1988 and 2009. In 72 cases, data on clinical features and outcomes were collected from medical records. In eight patients, records were unavailable, but in all cases mortality data were obtained from National Health Service (NHS) registries and recorded as standardized mortality ratio. SETTING The study was conducted in a United Kingdom tertiary referral center. PATIENTS OR OTHER PARTICIPANTS Adult patients confirmed to have CD participated in the study. INTERVENTIONS All patients underwent TSS. MAIN OUTCOME MEASURE Patients were subdivided into groups based on disease response after initial treatment. Mortality according to subgroup was also assessed. RESULTS Median follow-up for clinical data was 4.6 yr. Three outcome groups were identified: cure, 72% (52 of 72); persistent disease, 17% (12 of 72); and disease recurrence, 11% (eight of 72). Median time to recurrence after initial remission was 2.1 yr (interquartile range, 1.3-3.1 yr). Mean follow-up for mortality was 10.9 yr. Thirteen of 80 patients had died: five of 52 in the cure group, two of eight in the disease recurrence group, two of 12 with persistent disease, and four of eight of those followed up by NHS registry search only. Overall, the standardized mortality ratio was 3.17 [95% confidence interval (CI), 1.70-5.43], whereas in the cure group it was 2.47 (95% CI, 0.80-5.77), and it was 4.12 (95% CI, 1.12-10.54) for disease recurrence/persistent disease groups. CONCLUSIONS We report long-term cure rates in excess of 70%. Mortality is increased in CD and may be higher in patients with persistent/recurrent disease compared to patients cured after initial treatment.

Relationship between growth hormone (GH) status, serum leptin and body composition in healthy and GH deficient elderly subjects

Growth hormone (GH) secretion declines with age and is affected by body composition. The signal that mediates the latter relationship remains ill‐defined. Leptin, the protein product of the adipocyte specific ob gene, is thought to accurately reflect fat mass and could therefore be a candidate to influence GH secretion. We have therefore investigated the relationship between GH status, leptin and body composition in normal and GH‐deficient elderly subjects.

The diagnosis of severe growth hormone deficiency in elderly patients with hypothalamic-pituitary disease.

Adults over the age of 60 years with organic disease of the hypothalamic–pituitary axis may be deficient in growth hormone (GH) to a degree that is distinct from the age‐related decline in GH secretion and sufficient to cause perturbations of body composition, serum lipid profile and bone metabolism. In order to determine the best method for detecting GH deficiency in this age group we have compared spontaneous GH secretion, a provocative test of GH secretion, the arginine stimulation test (AST), and basal estimates of circulating insulin‐like growth factors (IGF) and IGF‐binding proteins (IGFBP).

Hypopituitarism: Clinical Features, Diagnosis, and Management

Hypopituitarism is characterized by loss of function of the anterior pituitary gland. It is a rare condition that can present at any age and is caused by pathology of the hypothalamic-pituitary axis or one of many gene mutations. The symptoms and signs of hypopituitarism may evolve over several years and be nonspecific or related to the effects of the underlying disease process or to hormone deficiencies. Investigation of patients requires a combination of basal hormone levels and dynamic function tests; management requires regular monitoring. The goal of physicians managing patients who have hypopituitarism is to improve their health and long-term outcome.

6 Ageing and growth hormone status

Organic growth hormone (GH) deficiency in adults results in many adverse changes similar to the changes which occur in humans with increasing age. The secretion of GH from the anterior pituitary declines with increasing age. This observation, together with the changes in body composition associated with organic GH deficiency in adults, has led to the suggestion that the elderly without hypothalamic-pituitary disease are GH deficient and may benefit from GH therapy. The impact of organic disease of the hypothalamic-pituitary axis in the elderly may result in a reduction in GH secretion of up to 90%. This reduction in GH secretion is sufficient to cause a fall in the serum insulin-like growth factor-1 (IGF-1) concentration, abnormal body composition and abnormal bone turnover, although bone mineral density is unaffected. These changes are distinct from those associated with the hyposomatotropism of the elderly, but are less severe than those seen in younger adults with organic GH deficiency. In this chapter we discuss the effects of organic GH deficiency in elderly subjects and the potential effects of GH replacement therapy. We also examine the potential for GH therapy to correct some of the detrimental effects of the ageing process.

Adrenal suppression in patients taking inhaled glucocorticoids is highly prevalent and management can be guided by morning cortisol

Context Up to 3% of US and UK populations are prescribed glucocorticoids (GC). Suppression of the hypothalamo–pituitary–adrenal axis with the potential risk of adrenal crisis is a recognized complication of therapy. The 250 μg short Synacthen stimulation test (SST) is the most commonly used dynamic assessment to diagnose adrenal insufficiency. There are challenges to the use of the SST in routine clinical practice, including both the staff and time constraints and a significant recent increase in Synacthen cost. Methods We performed a retrospective analysis to determine the prevalence of adrenal suppression due to prescribed GCs and the utility of a morning serum cortisol for rapid assessment of adrenal reserve in the routine clinical setting. Results In total, 2773 patients underwent 3603 SSTs in a large secondary/tertiary centre between 2008 and 2013 and 17.9% (n=496) failed the SST. Of 404 patients taking oral, topical, intranasal or inhaled GC therapy for non-endocrine conditions, 33.2% (n=134) had a subnormal SST response. In patients taking inhaled GCs without additional GC therapy, 20.5% (34/166) failed an SST and suppression of adrenal function increased in a dose-dependent fashion. Using receiver operating characteristic curve analysis in patients currently taking inhaled GCs, a basal cortisol ≥348 nmol/l provided 100% specificity for passing the SST; a cortisol value <34 nmol/l had 100% sensitivity for SST failure. Using these cut-offs, 50% (n=83) of SSTs performed on patients prescribed inhaled GCs were unnecessary. Conclusion Adrenal suppression due to GC treatment, particularly inhaled GCs, is common. A basal serum cortisol concentration has utility in helping determine which patients should undergo dynamic assessment of adrenal function.

The evolution of radiation-induced growth hormone deficiency in adults is determined by the baseline growth hormone status

OBJECTIVE Recent studies of GH replacement have suggested several beneficial effects for GH deficient adults. It would therefore be helpful to predict the time of onset of GH deficiency after external pituitary irradiation. We have studied the evolution of GH deficiency with time In patients irradiated for pituitary adenomas and other hypothalamic pituitary tumours.

A Cross-Sectional Study of the Prevalence of Cardiac Valvular Abnormalities in Hyperprolactinemic Patients Treated With Ergot-Derived Dopamine Agonists

CONTEXT Concern exists in the literature that the long-term use of ergot-derived dopamine agonist drugs for the treatment of hyperprolactinemia may be associated with clinically significant valvular heart disease. OBJECTIVE The aim of the study was to determine the prevalence of valvular heart abnormalities in patients taking dopamine agonists as treatment for lactotrope pituitary tumors and to explore any associations with the cumulative dose of drug used. DESIGN A cross-sectional echocardiographic study was performed in a large group of patients who were receiving dopamine agonist therapy for hyperprolactinemia. Studies were performed in accordance with the British Society of Echocardiography minimum dataset for a standard adult transthoracic echocardiogram. Poisson regression was used to calculate relative risks according to quartiles of dopamine agonist cumulative dose using the lowest cumulative dose quartile as the reference group. SETTING Twenty-eight centers of secondary/tertiary endocrine care across the United Kingdom participated in the study. RESULTS Data from 747 patients (251 males; median age, 42 y; interquartile range [IQR], 34-52 y) were collected. A total of 601 patients had taken cabergoline alone; 36 had been treated with bromocriptine alone; and 110 had received both drugs at some stage. The median cumulative dose for cabergoline was 152 mg (IQR, 50-348 mg), and for bromocriptine it was 7815 mg (IQR, 1764-20 477 mg). A total of 28 cases of moderate valvular stenosis or regurgitation were observed in 24 (3.2%) patients. No associations were observed between cumulative doses of dopamine agonist used and the age-corrected prevalence of any valvular abnormality. CONCLUSION This large UK cross-sectional study does not support a clinically concerning association between the use of dopamine agonists for the treatment of hyperprolactinemia and cardiac valvulopathy.

Health Care Use of Long-Term Survivors of Childhood Cancer: The British Childhood Cancer Survivor Study

PURPOSE Survivors of childhood cancer are at high risk of chronic conditions, but few studies investigated whether this translates into increased health care utilization. We compared health care service utilization between childhood cancer survivors and the general British population and investigated potential risk factors. METHODS We used data from the British Childhood Cancer Survivor Study, a population-based cohort of 17,981 individuals diagnosed with childhood cancer (1940-1991) and surviving ≥ 5 years. Frequency of talks to a doctor, hospital outpatient visits, and day-patient and inpatient hospitalizations were ascertained by questionnaire in 10,483 survivors and were compared with the General Household Survey 2002 data by using logistic regression. RESULTS Among survivors, 16.5% had talked to a doctor in the last 2 weeks, 25.5% had attended the outpatient department of a hospital in the last 3 months, 11.9% had been hospitalized as a day patient in the last 12 months, and 9.8% had been hospitalized as an inpatient in the last 12 months. Survivors had talked slightly more often to a doctor than the general population (odds ratio [OR], 1.2; 95% CI, 1.1 to 1.3) and experienced increased hospital outpatient visits (OR, 2.5; 95% CI, 2.3 to 2.8), day-patient hospitalizations (OR, 1.4; 95% CI, 1.3 to 1.6) and inpatient hospitalizations (OR, 1.9; 95% CI, 1.7 to 2.2). Survivors of Hodgkins lymphoma, neuroblastoma, and Wilms tumor had the highest ORs for day-patient care, whereas survivors of CNS tumors and bone sarcomas had the highest OR for outpatient and inpatient care. The OR of health care use did not vary significantly with age of survivor. CONCLUSION We have quantified how excess morbidity experienced by survivors of childhood cancer translates into increased use of health care facilities.