Les Perry

A single sleeping midnight cortisol has 100% sensitivity for the diagnosis of Cushing's syndrome

OBJECTIVE The diagnosis of Cushings syndrome remains a major challenge in clinical endocrinology. Various screening tests are commonly used to support a biochemical diagnosis in the context of clinical suspicion. The aim of this study was to compare the sensitivity in the diagnosis of Cushings syndrome of a single in‐patient sleeping midnight cortisol to a standard 48‐hour in‐patient low‐dose dexamethasone suppression test (LDDST) during the same admission.

Cardiovascular Risk and Responsivity to Mental Stress: The Influence of Age, Gender and Risk Factors

Background Exaggerated cardiovascular and neuroendocrine responses to mental stress may enhance cardiovascular disease risk, Coronary heart disease and hypertension increase in prevalence with advancing age, whereas the excess male/female ratio declines in later middle age. Psychosocial factors may contribute to these changing risk profiles. The hypothesis that cardiovascular and neuroendocrine stress responses are associated with age and gender differences in cardiovascular disease risk was tested. Method 132 healthy men and women from younger (30–40 years) and older (55–65 years) age bands were selected at random from general practice lists. They performed a series of mental stress tests during which blood pressure, heart rate, cardiovascular baroreflex sensitivity, Cortisol, respiration patterns and electrodermal activity were monitored. A submaximal exercise test was performed and psychological characteristics were assessed by questionnaire. Results At rest, systolic and diastolic blood pressure was higher in men than in women, while cardiac baroreflex sensitivity was greater in younger than in older participants. Blood pressure responses to tasks were substantial, with changes from the baseline averaging 18.6/8.11, 26.0/13.5 and 40.7/19.0 mmHg for computerized problem solving, mirror drawing and speech tasks, respectively. Men and women in the older age band did not differ from each other in blood pressure, heart rate or baroreflex sensitivity responses. Systolic blood pressure responses (mean ± SEM) were larger in older than in younger women (mean peak difference 6.87 ± 2.67 mmHg), and in the younger male compared with the younger female groups (mean peak difference 7.20 ± 2.97 mmHg). Diastolic blood pressure and heart rate responses to mental stress were larger in younger than in older age participants of both sexes. Baroreflex sensitivity was inhibited during behavioural tasks, with significantly greater suppression in younger than in older groups (5.28 ± 0.52 and 2.62 ± 0.35 ms/mmHg, respectively). Cortisol responses were greater in men than in women, but did not vary with age. Across the entire sample, systolic blood pressure responsivity was negatively related to the expression of anger. Among older men, heightened blood pressure responses were associated with elevated fasting low-density lipoprotein cholesterol levels, and with lower concentrations of high-density lipoprotein cholesterol. Conclusions Systolic blood pressure stress responsivity increases with age in women but not in men. Other data do not support the notion that stress responsivity mediates age and gender differences in cardiovascular disease risk. However, in middle-aged men, exaggerated cardiovascular stress responsivity is associated with an unfavourable risk profile.

UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development

It is paramount that any child or adolescent with a suspected disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD. If there is any doubt, the case should be discussed with the regional team. In most cases, particularly in the case of the newborn, the paediatric endocrinologist within the regional DSD team acts as the first point of contact. The underlying pathophysiology of DSD and the strengths and weaknesses of the tests that can be performed should be discussed with the parents and affected young person and tests undertaken in a timely fashion. This clinician should be part of a multidisciplinary team experienced in management of DSD and should ensure that the affected person and parents are as fully informed as possible and have access to specialist psychological support. Finally, in the field of rare conditions, it is imperative that the clinician shares the experience with others through national and international clinical and research collaboration.

Unmasking of central hypothyroidism following growth hormone replacement in adult hypopituitary 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.

Control over work pace, job strain and cardiovascular responses in middle-aged men.

Objective: To assess the effects of control over work pace on cardiovascular stress responses in healthy middle-aged men. Design: The study involved administration in the laboratory of visual matrix and mirror drawing tasks, the pace of tasks being either under the control of the subject (self-paced) or determined externally (externally paced). The work demands in the two conditions were equated. Method: Forty men aged 55-65 years were randomly assigned to self-paced or externally paced conditions. Blood pressure (recorded continuously using the Finapres), heart rate, cardiac baroreflex sensitivity, salivary cortisol, skin conductance and breathing pattern were monitored at rest, during task performance and at recovery following tasks. Results: Blood pressure and heart rate responses were significantly greater under the externally paced than self-paced conditions. The mean increase in blood pressure during the visual matrix task averaged 19.8/9.4 versus 34.1/15.5 mmHg for the self- and externally paced conditions, and 28.2/13.7 versus 41.8/19.5 mmHg in response to mirror drawing, respectively. Performance of the matrix task was less accurate under externally paced than self-paced conditions, but the two groups did not differ in mirror drawing. A reduction in baroreflex sensitivity and increases in cortisol, respiration rate, tidal volume and skin conductance responses were recorded during tasks, but these responses did not distinguish the two groups. Men were divided on the basis of reported job strain associated with their regular work, using the demand—control model. Blood pressure and heart rate responses were particularly pronounced among men reporting high job strain who were allocated to the externally paced condition. Conclusions: Middle-aged men showed greater stress-related cardiovascular responses when they performed tasks at a pace that they could not control. This pattern may be relevant to the mechanisms through which job strain (high demands associated with low control) influences cardiovascular disease risk.

Society for Endocrinology UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development (Revised 2015)

It is paramount that any child or adolescent with a suspected disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD. If there is any doubt, the case should be discussed with the regional DSD team. In most cases, particularly in the case of the newborn, the paediatric endocrinologist within the regional team acts commonly as the first point of contact. This clinician should be part of a multidisciplinary team experienced in management of DSD and should ensure that the affected person and parents have access to specialist psychological support and that their information needs are comprehensively addressed. The underlying pathophysiology of DSD and the strengths and weaknesses of the tests that can be performed should be discussed with the parents and affected young person and tests undertaken in a timely fashion. Finally, in the field of rare conditions, it is imperative that the clinician shares the experience with others through national and international clinical and research collaboration.

The discriminatory value of the low-dose dexamethasone suppression test in the investigation of paediatric Cushing's syndrome.

Background: Low- and high-dose dexamethasone suppression tests (LDDST, HDDST) are used in the investigation of Cushing’s syndrome (CS). In adults with Cushing’s disease (CD), cortisol suppression during LDDST predicts suppression during the HDDST. Methods: We reviewed the results of the LDDST (0.5 mg 6 hourly × 48 h), HDDST (2.0 mg 6 hourly × 48 h) and corticotrophin-releasing hormone (CRH) test in 32 paediatric patients with CS: 24 had CD, 1 ectopic ACTH syndrome, 5 nodular adrenal hyperplasia and 2 adrenocortical tumours. Results: In CD, LDDST suppressed cortisol from 590.7 ± 168.8 (mean ± SD) to 333.7 ± 104.0 nmol/l after 48 h (0 vs. 48 h, p < 0.05; mean suppression, 45.1%; CI (30.8, 59.4%); 16/24 (66%) suppressed >30%; mean suppression 68.1%, CI (58.1, 77.9%)). The HDDST suppressed cortisol from 596.3 ± 174.5 to 47.1 ± 94.8 nmol/l after 48 h (0 vs. 48 h, p < 0.05; mean suppression, 93.5%; CI (88.2, 98.8%) with 17/24 (71%) suppressing to <50 nmol/l and 100% to <50% of baseline). In the LDDST, suppression correlated with that during the HDDST (r = +0.45, p < 0.05) with >30% suppression predicting that in the HDDST and hence CD. CRH increased cortisol by +100.3% (CI 62, 138.5%), 22/24 (91.7%) showing a >20% increase. In the other CS pathologies (n = 8) the LDDST induced no significant decrease in cortisol. Conclusion: The LDDST was of diagnostic value by discriminating between CD and other CS aetiologies. In our view the HDDST is redundant in the investigation of paediatric CS.

The effect of growth hormone replacement therapy on adrenal androgen secretion in adult onset hypopituitarism

objective Growth hormone replacement therapy in GH‐deficient children is associated with enhanced adrenal androgen production, raising the possibility that GH might stimulate adrenocortical hormone secretion. This has not been extensively investigated in adults to date. GH is a potent modulator of the activity of the 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) enzyme and by altering cortisol metabolism can affect the function of the hypothalamo–pituitary–adrenal (HPA) axis and therefore potentially of adrenal androgen secretion. This study examined the effects of GH replacement in GH‐deficient adults on adrenal androgen secretion.

Benefits of Screening in von Hippel-Lindau Disease – Comparison of Morbidity Associated with Initial Tumours in Affected Parents and Children

Von Hippel-Lindau (VHL) is a rare autosomal dominant syndrome characterised by the association of retinal and CNS haemangioblastomas, phaeochromocytoma and renal cell carcinoma. If a child of an affected parent has inherited a VHL mutation or the parent’s mutation cannot be identified, then clinical screening is recommended. We report the clinical features in three parent-offspring pairs where the parents have presented clinically with renal cell carcinoma, phaeochromocytoma, cerebellar haemangioblastoma and retinal haemangioma, and the children have undergone pre-symptomatic screening. During the first screening a 13-year-old boy was diagnosed with bilateral phaeochromocytoma and later developed an endolymphatic sac tumour at 19 years. A right phaeochromocytoma was found in a 12-year-old girl who was screened from the age of 4 years and in a 13-year-old boy screened from 5 years of age. All children were asymptomatic at the time of diagnosis. These families demonstrate that clinical screening of children at risk of VHL can detect tumours before the first symptoms arise with a consequent reduction in morbidity. These observations strongly support the recommendation to undertake screening of the children of VHL patients.

Concurrent secretion of aldosterone and cortisol from an adrenal adenoma - value of MRI in diagnosis.

A 43‐year‐old female with a 24‐years history of hypertension presented for further investigation and management of primary hyperaldosternoism. Postural studies were not conclusive and magnetic resonance (MR) imaging demonstrated a 27 × 18 mm lesion of the right adrenal gland which showed no signal loss during in and out of phase imaging. Although these appearances were considered to be atypical of those seen on MR in patients with aldosterone producing adrenal adenomas the patient underwent an adrenalectomy with removal of a 3 × 3 × 2 cm right adrenal mass. Post‐operatively she became hypotensive and a 0900 hours serum cortisol was undetectable (< 50 nmol/l), consistent with adrenal insufficiency. Following the administration of hydrocortisone there was normalization of the blood pressure and subsequent adrenal stimulation tests confirmed the presence of functioning adrenal tissue albeit with an inadequate response. Cortisol measurement from preoperative samples revealed loss of normal diurnal rhythm whereas DHEAS levels both pre and postoperatively were undetectable, consistent with ACTH supression resulting from autonomous cortisol secretion in addition to aldosterone. Concurrent secretion of cortisol should always be considered in Conns adenomas particularly when atypical radiological features are present.