Rachel Crowley

Hyperandrogenemia Predicts Metabolic Phenotype in Polycystic Ovary Syndrome: The Utility of Serum Androstenedione

Context: Polycystic ovary syndrome (PCOS) is a triad of anovulation, insulin resistance, and hyperandrogenism. Androgen excess may correlate with metabolic risk and PCOS consensus criteria define androgen excess on the basis of serum T. Here we studied the utility of the androgen precursor serum androstenedione (A) in conjunction with serum T for predicting metabolic dysfunction in PCOS. Patients and Methods: Eighty-six PCOS patients fulfilling Rotterdam diagnostic consensus criteria and 43 age- and body mass index-matched controls underwent measurement of serum androgens by tandem mass spectrometry and an oral glucose tolerance test with homeostatic model assessment of insulin resistance and insulin sensitivity index calculation. We analyzed 24-hour urine androgen excretion by gas chromatography/mass spectrometry. Results: PCOS patients had higher levels of serum androgens and urinary androgen metabolites than controls (all P < .001). Within the PCOS cohort, both serum A and T were positively correlated with the free androgen index (T × 100/SHBG) and total androgen metabolite excretion (all P < .001). All subjects with T above the normal reference range [high T (HT)] also had high A (HA/HT group, n = 56). However, the remaining 30 patients had normal T levels, either in the presence of HA (HA/NT; n = 20) or normal A (NA/NT; n = 10). The groups did not differ in age or BMI. The HA/HT and HA/NT groups had higher total androgen excretion than NA/NT (P < .01 and P < .05, respectively). Multiple linear regression showed a strong negative association between serum androstenedione and insulin sensitivity. The incidence of dysglycemia according to an oral glucose tolerance test increased with the severity of androgen phenotype (NA/NT, 0%; HA/NT, 14%; HA/HT, 25%, P = .03). Conclusion: Simultaneous measurement of serum T and A represents a useful tool for predicting metabolic risk in PCOS women. HA levels are a sensitive indicator of PCOS-related androgen excess.

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.

Longitudinal changes in glucocorticoid metabolism are associated with later development of adverse metabolic phenotype

OBJECTIVE Dysregulation of enzymes that control local tissue steroid metabolism has been implicated in the pathogenesis of obesity and insulin resistance; however, longitudinal changes in glucocorticoid metabolism have not been investigated. This study was performed to evaluate the role of glucocorticoid metabolism in the development of insulin resistance and obesity and to identify biomarkers for future development of metabolic disease. DESIGN This was a prospective longitudinal observation study conducted over 5 years. METHODS A 24-h collection was used to serially analyze urinary glucocorticoid and mineralocorticoid metabolites in 57 obese and overweight patients with no prior diagnosis of diabetes mellitus, recruited from the community. RESULTS Baseline higher 5α-reductase (5αR) activity, but not 11β-hydroxysteroid dehydrogenase type 1 activity, was predictive of increased fasting insulin at final visit (11.4 compared with 7.4 mU/l in subjects with lower 5αR activity, P<0.05), area under the curve insulin response to oral glucose tolerance test (176.7 compared with 89.1 mU/l.h, P<0.01), and homeostasis model assessment (HOMA2-IR; 1.3 compared with 0.8, P<0.01). Higher total glucocorticoid production was associated with abnormal glucose tolerance and increased BMI. During this study, systolic blood pressure increased (equivalent to ∼1 mmHg/year), as did plasma sodium levels; this evidence of increased mineralocorticoid activity was associated with increased aldosterone metabolites and decreased 11β-hydroxysteroid dehydrogenase type 2 activity. CONCLUSIONS Increased 5αR activity and glucocorticoid secretion rate over time are linked with the development of metabolic disease, and may represent targets for therapeutic intervention, which merits further study.

THERAPY OF ENDOCRINE DISEASE: Improvement of cardiovascular risk factors after adrenalectomy in patients with adrenal tumors and subclinical Cushing’s syndrome: a systematic review and meta-analysis

OBJECTIVE Beneficial effects of adrenalectomy on cardiovascular risk factors in patients with subclinical Cushings syndrome (SCS) are uncertain. We sought to conduct a systematic review and meta-analysis with the following objectives: (i) determine the effect of adrenalectomy compared with conservative management on cardiovascular risk factors in patients with SCS and (ii) compare the effect of adrenalectomy on cardiovascular risk factors in patients with SCS vs those with a nonfunctioning (NF) adrenal tumor. METHODS MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE and Cochrane Central Register of Controlled Trial were searched on 17 November 2015. Reviewers extracted data and assessed methodological quality in duplicate. RESULTS We included 26 studies reporting on 584 patients with SCS and 457 patients with NF adrenal tumors. Studies used different definitions of SCS. Patients with SCS undergoing adrenalectomy demonstrated an overall improvement in cardiovascular risk factors (61% for hypertension, 52% for diabetes mellitus, 45% for obesity and 24% for dyslipidemia). When compared with conservative management, patients with SCS undergoing adrenalectomy experienced improvement in hypertension (RR 11, 95% CI: 4.3-27.8) and diabetes mellitus (RR 3.9, 95% CI: 1.5-9.9), but not dyslipidemia (RR 2.6, 95% CI: 0.97-7.2) or obesity (RR 3.4, 95% CI: 0.95-12). Patients with NF adrenal tumors experienced improvement in hypertension (21/54 patients); however, insufficient data exist for comparison to patients with SCS. CONCLUSIONS Available low-to-moderate-quality evidence from heterogeneous studies suggests a beneficial effect of adrenalectomy on cardiovascular risk factors in patients with SCS overall and compared with conservative management.

Supine or sitting? Economic considerations regarding patient position during plasma metanephrine analysis for the exclusion of chromaffin tumours

Dear Editor, We have read the article ‘Biochemical diagnosis of phaeochromocytoma using plasma-free normetanephrine, metanephrine and methoxytyramine: importance of supine sampling under fasting conditions’ by Darr et al. with great interest. We concur with the importance of using reference ranges derived from supine, fasting patients to ensure a high diagnostic sensitivity for the detection of phaeochromocytomas/paragangliomas (PPGL). However, despite the demonstrated improved specificity, we believe that adopting measurement of plasma metanephrines in fasted patients in the supine position as a first-line diagnostic screening approach would not be practical in modern healthcare provision due to its substantial financial implications. We reviewed all plasma metanephrine results from patients requiring exclusion of PPGL due to presentation with a new adrenal lesion (n = 55) who attended our service at the University Hospital Birmingham during 2013. The vast majority of cases were adrenal incidentalomas (n = 48); in the remainder, the lesion was discovered in the context of regular monitoring for succinate dehydrogenase (SDH) or von Hippel–Lindau (VHL) gene mutations (n = 3), work-up for Cushing’s syndrome (n = 2) or postoperative follow-up imaging of previous extra-adrenal malignancy (n = 2). According to our local protocol, these patients are screened for PPGL with one plasma sample for metanephrines taken without special preparation, in the nonfasted state and sitting position on the day of their first clinic attendance. If plasma metanephrines determined under these conditions are elevated, repeat testing in the fasting state and after 30 min in the supine position is arranged by the endocrine specialist nurses. Of the 55 patients tested, seven (13%) had positive test results under sitting/ nonfasting conditions, that is increased above a reference range derived from healthy controls with samples collected in the supine/fasted state. Three of seven with plasma normetanephrine and/or metanephrine values >4-fold of the reference range were conclusively diagnosed with PPGL and not retested. The four remaining patients underwent repeat testing under supine/fasting conditions, revealing persistently increased plasma metanephrines in three of them, eventually diagnosed with phaeochromocytoma. Only one patient with borderline elevated plasma metanephrines in the sitting/nonfasting state was confirmed to have had a falsepositive result on initial screening, with the repeat test under supine/fasting conditions demonstrating normal plasma metanephrines (Table 1). Our screening under sitting/nonfasted conditions yielded a sensitivity of 86% (due to one case of a nonsecreting paraganglioma) and specificity of 98% for diagnosing chromaffin tumours; the overall prevalence of PPGL in our population was 11%. Blood samples for plasma metanephrines in the sitting and nonfasting state can be conveniently collected in the context of the first outpatient clinic visit and incurs a cost of £40 (£38 for biochemical analysis plus £2 phlebotomy costs). Conversely, supine/fasting sampling requires an extra visit to a nurse-led endocrinology outpatient clinic as a hospital day case, which incurs a total cost of £583 (£545 day case cost plus £38 for biochemical analysis). The overall cost of plasma metanephrine testing for the year 2013 in our department amounted to £4532. Adopting supine/fasting sampling as first-line investigation in all patients would inflate the total annual cost to £32 065, accruing an additional expenditure of £27 533. We acknowledge the fact that the cost of supine sampling may vary significantly from centre to centre but it would always exceed the cost of routine phlebotomy carried out in a one-stop approach during the routine clinic visit. Consequently, the strategy we propose will be

How to approach hypercalcaemia

The management of patients with hypercalcaemia should be informed by the patients symptoms and signs, by the degree of elevation of calcium, by the underlying mechanism by which calcium has been elevated and by the disease process underlying the presentation. Regardless of diagnosis, all significantly hypercalcaemic patients should be rendered euvolaemic before any further and more specific treatment is considered. Highly symptomatic patients and those with a calcium level of > 3.5 mmol represent a medical emergency that requires inpatient treatment.

Supine or sitting plasma metanephrine screening? A unifying solution for patients and doctors

Dear Editor, We have read with a great interest the article by Cassar et al. entitled ‘Biomarkers and insulin sensitivity in women with PCOS: Characteristics and predictive capacity’ in which they reported that PAI-1, leptin and ghrelin levels might emerge as relatively accurate predictors of insulin resistance in the general population. Thanks to the authors for their valuable research. However, we want to make some comments on leptin, which was evaluated in their study. Leptin, which is an adipocyte-secreted hormone, regulates homoeostasis, metabolism, energy food intake, immune function and neuroendocrine function. Previous studies showed that some diseases such as chronic liver diseases, major depression, several inflammatory diseases as rheumatoid arthritis, systemic lupus erythematosus, and Helicobacter pylori infection could affect serum leptin levels. The authors mentioned just pregnancy, diabetes and uncontrolled hypertension diseases as exclusion criteria, but above contributing diseases have to be denoted to obtain a robust study group. Previous studies have shown that some types of glucocorticoids, antihypertensive drugs, antipsychotics and antidepressants had effect on serum leptin levels in addition to lipid-lowering, hormonal or insulin-sensitizing medication as authors stated. Besides, dietary food supplements such as linoleic acid, zinc, vitamin D, vitamin E, vitamin A and omega-3 fatty acid could affect plasma leptin levels. Skeie et al. reported that supplement use was reported by 51 0% among men and 65 8% among women in Denmark. In this respect, the authors should define whether the participants use these kinds of drugs and dietary supplements or not. In conclusion, it is important to express these confounding factors. Though this study contributes valuable information to medical literature, the explanation of these concerns will certainly provide a clearer picture when interpreting leptin levels among participants.

When would I use medical therapies for the treatment of primary hyperparathyroidism

Although there may be controversy surrounding the indications for parathyroidectomy in primary hyperparathyroidism, it remains the only accepted definitive therapy. However, even if parathyroidectomy is indicated, some patients refuse surgery, are medically unfit or have residual or recurrent disease inaccessible to further surgery. Some of these patients may be suitable for long‐term observation but others require intervention for management of symptomatic or moderate to severe hypercalcaemia, loss of bone mineral density or renal calculi. The selection of a suitable therapy for each patient should be individualized.

Fear of medication side effects is a barrier to optimal osteoporosis care

Dear Editor, We read with interest the article byMajumdar et al. [1].We are in agreement with the authors’ statement that patients’ knowledge of osteoporosis should lead to higher rates of treatment after fragility fracture and better medication adherence. With this in mind, all patients who are scheduled to start parenteral therapy for osteoporosis at our centre attend a 30-min individual education session with a specialist nurse. An audit of our denosumab patient cohort revealed that 7 out of 104 patients (6/7 previous fragility fractures; median FRAX 10-year probability of major osteoporotic fracture 23 %) refused denosumab therapy after the education session, citing concern about side effects of the drug. The particular area of anxiety for patients was the report of urinary tract symptoms as a common side effect (1–10 %) in the patient information leaflet (Prolia®, Amgen), although the FREEDOM trial reported an equal, lower incidence of urinary infection (UTI) in patients on denosumab (0.7 %) and placebo (0.4 %, p=0.2) [2]. Ninety-seven patients in our centre who proceeded with a course of denosumab received the same education as those who refused; 79/97 had a history of prior fragility fracture and there was no difference between the 2 groups in age (p=0.6) or FRAX score (p=0.4). In the 97 patients who received denosumab, there were 7 reports of UTI, 5 of whom had no history of UTI prior to treatment. In total, 8 patients with a previous history of UTI elected to proceed with denosumab therapy after becoming aware of urinary symptoms as a potential side effect. There was no apparent difference between these 8 patients who would be considered to be at risk of UTI, and those 7 who refused denosumab because of concern about urinary tract side effects. Denosumab therapy was refused by a subset of patients in spite of the fact that this patient group was at higher risk of a major osteoporotic fracture, than of sustaining a UTI. This suggests that fear of side effects outweighed the ‘fear about their condition’ described as a motivator in the Majumdar group who started treatment [1]. The 2013 International Osteoporosis Foundation report on osteoporosis in the European Union described a decline in rates of treatment of at-risk individuals [3]; with this in mind, it is imperative to identify patient and physician barriers to treatment. Fear of side effects is a recognised factor in patient discontinuation of anti-osteoporotic treatment [4], but is less well-recognised as a barrier to starting treatment. Our experience suggests that patient education is of limited effectiveness in providing reassurance in all cases, and those patients who later refuse anti-fracture therapy are not readily identifiable from the larger cohort of patients with osteoporosis. Future research on interventions to modify patients’ attitudes towards osteoporosis treatment would be useful to those conducting education sessions for this cohort.