Approximately 7% of women of reproductive age manifest polycystic ovary syndrome (PCOS) and <0.5% have other causes of hyperandrogenism including congenital adrenal hyperplasia (CAH), androgen-secreting tumour of an ovary or an adrenal gland, Cushing's syndrome or hyperthecosis. The presence of features atypical of PCOS should prompt more extensive evaluation than that usually undertaken. Features atypical of PCOS include the onset of symptoms outside the decade of 15–25 years, rapid progression of symptoms, the development of virilization and a serum testosterone concentration in excess of twice the upper limit of the reference range. Ethnic background, family history and specific clinical findings, e.g. Cushingoid appearance, may inform a focused investigation. Otherwise, patients should have measurement of 17-hydroxyprogesterone (17-OHP) under basal conditions ideally in the early morning, and if abnormal, they should have measurement of 17-OHP one hour after the administration of synthetic ACTH, 250 μg i.v., to screen for CAH, which is present in ∼2% of hyperandrogenic patients. The overnight cortisol suppression test employing 1 mg dexamethasone at midnight is a sensitive test for Cushing's syndrome. Coronal tomographic (CT) scanning of the adrenals and transvaginal ultrasonography of the ovaries are the investigations of choice when screening for tumours in these organs. Less frequently required is catheterization and sampling from both adrenal and ovarian veins, which is a technically demanding procedure with potential complications which may provide definitive diagnostic information not available from other investigations. Illustrative case reports highlight some complexities in the investigation of hyperandrogenic patients presenting with features atypical of PCOS and include only the ninth case report of an androgen-secreting ovarian teratoma.
Michael Conall Dennedy, Diarmuid Smith, Donal O'Shea, and T Joseph McKenna
Lucy-Ann Behan, David Carmody, Bairbre Rogers, Mark J Hannon, Colin Davenport, William Tormey, Diarmuid Smith, Christopher J Thompson, Alice Stanton, and Amar Agha
Increased cardiovascular and cerebrovascular morbidity and mortality in hypopituitary subjects may be linked to inappropriate glucocorticoid exposure; however, the pathophysiology remains unclear. We aimed to examine the effect of three commonly prescribed hydrocortisone (HC) regimens on vascular risk factors.
An open crossover study randomising ten hypopituitary men with severe adrenocorticotrophic hormone deficiency to three HC dose regimens: dose A (20mg mane and 10mg tarde), dose B (10mg mane and 10mg tarde) and dose C (10mg mane and 5mg tarde).
Following 6 weeks on each regimen, participants underwent 24-h serum cortisol sampling, 24-h ambulatory blood pressure (BP) measurements, calculation of the Ambulatory Arterial Stiffness Index (AASI), oral glucose tolerance testing and fasting serum osteoprotegerin (OPG) sampling.
There were no differences in 24-h BP between dose regimens and controls; however, low-dose HC replacement (dose C) was associated with the lowest AASI, indicating a less stiff arterial tree (P<0.05) compared with the other dose regimens. Loss of the physiologic nocturnal BP dip was more common in higher HC replacement regimens, although only significant for dose B compared with dose C (P=0.03). Twenty per cent of patients had abnormal glucose tolerance, but this was unrelated to dose regimen. OPG correlated strongly with 24-h BP in those on dose A only (r=0.65, P=0.04).
Currently prescribed HC replacement doses do not result in significant differences in absolute BP levels or improvements in insulin sensitivity. However, lower HC doses may result in lower arterial stiffness and a more physiological nocturnal BP dip. Long-term studies are required to confirm these findings and evaluate their impact on vascular morbidity in this patient group.
Colin Davenport, Wan A Mahmood, Hannah Forde, David T Ashley, Amar Agha, John McDermott, Seamus Sreenan, Christopher J Thompson, Frank McGrath, Brendan McAdam, Philip M Cummins, and Diarmuid Smith
Vascular calcification (VC) is inhibited by the glycoprotein osteoprotegerin (OPG). It is unclear whether treatments for type 2 diabetes are capable of promoting or inhibiting VC. The present study examined the effects of insulin and liraglutide on i) the production of OPG and ii) the emergence of VC, both in vitro in human aortic smooth muscle cells (HASMCs) and in vivo in type 2 diabetes.
HASMCs were exposed to insulin glargine or liraglutide, after which OPG production, alkaline phosphatase (ALP) activity and levels of Runx2, ALP and bone sialoprotein (BSP) mRNA were measured. A prospective, nonrandomised human subject study was also conducted, in which OPG levels and coronary artery calcification (CAC) were measured in a type 2 diabetes population before and 16 months after the commencement of either insulin or liraglutide treatment and in a control group that took oral hypoglycemics only.
Exposure to insulin glargine, but not liraglutide, was associated with significantly decreased OPG production (11 913±1409 pg/104 cells vs 282±13 pg/104 cells, control vs 10 nmol/l insulin, P<0.0001), increased ALP activity (0.82±0.06 IU/104 cells vs 2.40±0.16 IU/104 cells, control vs 10 nmol/l insulin, P<0.0001) and increased osteogenic gene expression by HASMCs. In the clinical study (n=101), insulin treatment was associated with a significant reduction in OPG levels and, despite not achieving full statistical significance, a trend towards increased CAC in patients.
Exogenous insulin down-regulated OPG in vitro and in vivo and promoted VC in vitro. Although neither insulin nor liraglutide significantly affected CAC in the present pilot study, these data support the establishment of randomised trials to investigate medications and VC in diabetes.
Rosemary Dineen, Julie Martin-Grace, Khalid Mohamed Saeed Ahmed, Isolda Frizelle, Anjuli Gunness, Aoife Garrahy, Anne Marie Hannon, Michael W O’Reilly, Diarmuid Smith, John McDermott, Marie-Louise Healy, Amar Agha, Agnieszka Pazderska, James Gibney, Chris J Thompson, Lucy-Ann Behan, and Mark Sherlock
Adrenal insufficiency (AI) is associated with increased cardiovascular morbidity and mortality and reduced quality of life (QoL). Optimum glucocorticoid (GC) dosing and timing are crucial in the treatment of AI, yet the natural circadian secretion of cortisol is difficult to mimic. The once-daily dual-release hydrocortisone (DR-HC) preparation (Plenadren®), offers a more physiological cortisol profile and may address unmet needs.
An investigator-initiated, prospective, cross-over study in patients with AI. Following baseline assessment of cardiometabolic risk factors and QoL, patients switched from their usual hydrocortisone regimen to a once-daily dose equivalent of DR-HC and were reassessed after 12 weeks of treatment.
Fifty-one patients (21 PAI/30 SAI) completed the study. Mean age was 41.6 years (s.d. 13), and 58% (n = 30) were male. The median daily HC dose before study entry was 20 mg (IQR 15–20 mg). After 3 months on DR-HC, the mean SBP decreased by 5.7 mmHg, P = 0.0019 and DBP decreased by 4.5 mmHg, P = 0.0011. There was also a significant reduction in mean body weight (−1.23 kg, P = 0.006) and BMI (−0.3 kg/m2, P = 0.003). In a sub-analysis, there was a greater reduction in SBP observed in patients with SAI when compared to PAI post-DR-HC. Patients reported significant improvements in QoL using three validated QoL questionnaires, with a greater improvement in PAI.
Dual-release hydrocortisone decreases BP, weight and BMI compared with conventional HC treatment, even at physiological GC replacement doses. Additionally, DR-HC confers significant improvements in QoL compared to immediate-release HC, particularly in patients with PAI, which is also reflected in the patient preference for DR-HC.