Clinical characteristics and comorbidities associated with testosterone prescribing in men.

OBJECTIVE: Testosterone replacement therapy (TRT) is recommended for the treatment of symptomatic hypogonadism in men. Data on prescription behaviours are, however, limited and conflicting. The objective of this study was to investigate clinical characteristics associated with the likelihood of being prescribed TRT by general practitioners (GP) in North-West London (NWL). DESIGN: Retrospective cohort study using Discover database of GP-registered patients in NWL between 2015 and 2019. PATIENTS: We identified 20,299 men aged ≥18 years with serum total testosterone measurement (TT) and without prior TRT prescription records. MEASUREMENTS: We determined whether TRT was subsequently commenced, while analysing clinical characteristics related to hypogonadism. RESULTS: Of all men having TT measurement, 19,583 (96.4%) were not commenced on TRT (Group A) and 716 (3.5%) men were commenced on TRT (Group B). Men prescribed TRT (Group B) had higher mean age, body mass index (BMI) and higher risks of hypertension, depression type 2 diabetes and ischaemic heart disease; conversely, men in Group B had lower mean pretreatment TT and were less likely to have prostate cancer. Four-hundred and thirty-six men (24.3%) with TT < 8 nmol/L and symptoms of low libido were not prescribed TRT. CONCLUSIONS: Our study highlights several factors which may influence the decisions made by clinicians when initiating TRT in primary care. Clearer guidance for clinicians may help to improve the consistency of treatment of men with hypogonadism.

Investigating the potential of clinical and biochemical markers to differentiate between functional hypothalamic amenorrhoea and polycystic ovarian syndrome: A retrospective observational study.

OBJECTIVES: Functional hypothalamic amenorrhoea (FHA) is a common cause of amenorrhoea, but diagnosis can be challenging. The aim of this study was to investigate the clinical and biochemical features of FHA, compared to that of polycystic ovarian syndrome (PCOS) and assess the diagnostic performance of the different parameters for differentiating the two conditions. DESIGN AND PATIENTS: This was a retrospective observational study. We analysed clinical and biochemical parameters of women diagnosed with FHA and PCOS following specialist assessment at the reproductive endocrine gynaecology clinic, St Mary's Hospital. RESULTS: Compared with PCOS, women with FHA had significantly lower body mass index (BMI; 20.1 ± 2.9 vs. 31.1 ± 7.8 kg/m2 ; p< .0001) and a thinner endometrium (3.75 ± 2.23 vs. 6.82 ± 3.32 mm; p< .0001). Women with FHA had significantly lower luteinising hormone (LH; 3.46 ± 7.31 vs. 8.79 ± 4.98 IU/L; p< .0001), and lower LH to follicle-stimulating hormone (FSH) ratio, estradiol, thyroid-stimulating hormone, free thyroxine and prolactin levels; there was no significant difference in FSH levels. BMI had the greatest predictive performance for FHA (area under the curve [AUC]: 0.93; p< .001), followed by estradiol (AUC: 0.89; p< .001), LH (AUC: 0.88; p< .001) and LH:FSH ratio (AUC: 0.86; p< .001). CONCLUSIONS: Our data provides quantification for diagnostic accuracy of clinical parameters to differentiate FHA from PCOS, namely low BMI, estradiol, LH and LH:FSH ratio. These data could help clinicians more reliably diagnose FHA in women with secondary amenorrhoea.

Current National and International Guidelines for the Management of Male Hypogonadism: Helping Clinicians to Navigate Variation in Diagnostic Criteria and Treatment Recommendations.

Male hypogonadism-rebadged by some as testosterone deficiency syndrome-is a clinical and biochemical diagnosis of increasing worldwide interest. Organic male hypogonadism-usually permanent-is well-established, but aging men may also exhibit lower serum testosterone levels; principally due to burden of extra-gonadal comorbidities such as obesity, diabetes and metabolic syndrome, but with an underlying intact hypothalamo-pituitary-testicular (HPT) axis capable of springing back into operation once comorbidities are addressed. Despite encouraging observational data and plausible theoretical underpinning, evidence for efficacy and safety of testosterone in this "aging" group of men is lacking; addressing comorbid illnesses remains the key priority instead. Nevertheless, in recent years, accumulation of misleading information online has triggered a global tsunami of testosterone prescriptions. Despite this, many men with organic hypogonadism remain undiagnosed or untreated; many more face a diagnostic odyssey before achieving care by the appropriate specialist. As testosterone therapy is not without risk several clinical practice guidelines have been published specialist societies to guide physicians on best practice. However, these are heterogeneous in key areas, reflecting divergent approaches to the same evidence basis. Herein, we navigate the major clinical practice guidelines on male hypogonadism and test their respective recommendations against current best evidence.

Do Benefits Outweigh Risks for Corticosteroid Therapy in Acute Exacerbation of Chronic Obstructive Pulmonary Disease in People with Diabetes Mellitus?

Chronic obstructive pulmonary disease (COPD) and diabetes mellitus (DM) are chronic health conditions with significant impacts on quality and extent of life. People with COPD and DM appear to have worse outcomes in each of the comorbid conditions. Treatment with corticosteroids in acute exacerbation of COPD (AECOPD) has been shown to reduce treatment failure and exacerbation relapse, and to shorten length of hospital stay, but not to affect the inexorable gradual worsening of lung function. Treatment with corticosteroids can lead to a wide spectrum of side effects and complications, including worsening hyperglycemia and deterioration of diabetes control in those with pre-existing DM. The relationship between COPD and DM is rather complex and accumulating evidence indicates a distinct phenotype of the comorbid state. Several randomized controlled trials on corticosteroid treatment in AECOPD excluded people with DM or did not report on outcomes in this subgroup. As such, the perceived benefits of corticosteroids in AECOPD in people with DM have not been validated. In people with COPD and DM, the detrimental side effects of corticosteroids are guaranteed, while the benefits are not confirmed and only presumed based on extrapolation from the general COPD population. Therefore, the potential for harm when prescribing corticosteroids for AECOPD in people with DM cannot be excluded.

Clinical Presentation and Outcomes of Phaeochromocytomas/Paragangliomas in Neurofibromatosis Type 1.

Introduction: Patients with neurofibromatosis type 1 (NF1) are at risk of developing phaeochromocytomas/paragangliomas (PHAEO/PG). Unlike in other familial PHAEO/PG syndromes, there are no published guidelines regarding screening in asymptomatic or normotensive patients with NF1. This strategy may be associated with preventable morbidities in those patients who ultimately present with symptomatic PHAEO/PG. Objective: To describe the mode of presentation and the incidence of adverse clinical outcomes attributed to PHAEO/PG in NF1. Methods: A retrospective study was performed in a tertiary referral centre in collaboration with a national complex NF1 centre. Hospital records and databases between 1998-2018 were searched. Results: Twenty-seven patients with NF1 and PHAEO/PG were identified. In all but one, PHAEO/PG was diagnosed after NF1. The median age at the time of diagnosis of PHAEO/PG was 43 years (range 22-65) and 21/27 (78%) were females. The diagnosis was mostly incidental in 13/27 (48%) while classical PHAEO/PG symptoms were found in 15/27 (56%), and hypertension was found in 14/27 (52%) of NF1 patients prior to PHAEO/PG diagnosis. No patient had undergone biochemical screening for PHAEO/PG. Metastatic disease was evident in 2/27 patients, 8 suffered potentially avoidable complications attributed to PHAEO/PG (including two deaths). Conclusion: The course of PHAEO/PG in NF1 is associated with an unpredictable presentation and potentially avoidable adverse outcomes. We recommend that routine biochemical screening for PHAEO/PG should be part of the care package offered to all patients with NF1 by regular measurements of plasma free or urinary fractionated metanephrines starting from early adolescence and repeated every 3 years.

A rare ophthalmic condition associated with primary hyperparathyroidism (PHPT): sclerochoroidal calcification (SC)

Summary: An 82-year-old male with a proven diagnosis of primary hyperparathyroidism (PHPT) was found to have bilateral changes in the fundi during a routine eye examination which were consistent with SC. In this report, we discuss the link between SC and PHPT and question the need for prospective observational studies to establish the true association between these conditions. Though screening PHPT patients for SC might not be justified/warranted given the benign course of the latter, patients with SC need to be assessed for PHPT, as the former may be the first clue to an underlying treatable systemic disease. Learning Points: Sclerochoroidal calcifications (SCs), though rare and harmless, could be associated with an underlying systemic disease, such as primary hyperparathyroidism (PHPT). Biochemical screening for hypercalcaemia is a simple, cheap and widely available tool that could facilitate an identification of undiagnosed PHPT in patients with SC. A joint care by endocrinologists and ophthalmologists is warranted for those patients, as thorough investigations and long-term follow-up plans are crucial.

Is calcium supplementation always needed in patients with hypoparathyroidism?

Oral calcium salts are recommended for the treatment of chronic hypoparathyroidism (HypoPT), although dosimetry is variable between individual patients and clinicians. However, patient feedback on calcium salts can be negative, particularly due to gastrointestinal side effects and hypercalciuria-related complications. We begin with a clinical case of a HypoPT patient taking oral calcium salts following thyroid surgery, who requested support in reducing her dose of these with a view to stopping entirely. To evaluate her request, we first describe the usual treatment of HypoPT according to current guidance and then present data from (a) a case note review of a cohort of 24 HypoPT patients managed with a "no calcium" treatment regimen by single physician (b) a comprehensive online survey of HypoPT patients' treatment and experiences (n = 330). The case note review found that target range serum calcium levels were successfully achieved in all 24 patients since transitioning to a "no calcium" regimen, without any breakthrough hypocalcaemia-related symptoms, the development of new renal stones, the occurrence of calcium-related hospital admissions or the finding of significant hypercalciuria. The online survey identified 36% of HypoPT patients who continued to take activated vitamin D, but had discontinued calcium supplements. HypoPT patients not currently taking calcium reported a significantly lower prevalence of adverse effects and outcomes, both compared with their previous experiences whilst taking calcium and also compared with the 64% of patients who continued to take oral calcium. We conclude that, subject to methodological limitations, there are significant issues of tolerability arising from conventional calcium-based treatment regimens for patients with chronic HypoPT. For selected patients, it may be reasonable to facilitate a managed therapeutic transition to "no calcium" regimen, and we also propose that calcium-based regimes be prospectively evaluated against calcium-free (or calcium-low) alternatives.

Phaeochromocytoma/paraganglioma and adverse clinical outcomes in patients with neurofibromatosis-1.

INTRODUCTION: Phaeochromocytomas/paragangliomas (PHAEO/PG) are linked to hereditary syndromes including neurofibromatosis type 1 (NF-1). Current guidelines do not recommend biochemical screening for PHAEO/PG in asymptomatic or normotensive patients with NF-1. This strategy may miss preventable morbidities in those patients who ultimately present with symptomatic PHAEO/PG. Our aim was to review the literature and extract data on mode of presentation and the incidence of reported adverse outcomes. METHODS: PubMed and EMBASE literature search using the keywords "Phaeochromocytoma", "Paraganglioma" and "Neurofibromatosis" was performed looking for reported cases from 2000 to 2018. RESULTS: 73 reports of NF-1 patients with PHAEO/PG were found. Patients were predominately women (n=40) with a median age of 46 years (range 16-82). PHAEO/PG was found incidentally in most patients, 36/73 did not present with typical symptoms while 27 patients were normotensive at diagnosis. 31 patients had adverse outcomes including metastases and death. CONCLUSION: Given the protean presentation of PHAEO/PG, relying on symptomology and blood pressure status as triggers for screening is associated with adverse outcomes. Further studies are required to ascertain whether biochemical screening in asymptomatic and normotensive patients with NF-1 can reduce the rate of adverse outcomes.

Reversible weakness and encephalopathy while on long-term valproate treatment due to carnitine deficiency.

We describe a case of a 35-year-old woman who presented with bilateral leg weakness and encephalopathy while on long-term valproate therapy. She was diagnosed with valproate-induced encephalopathy due to carnitine deficiency. Clinical improvement occurred with oral carnitine supplementation. Our case report highlights the importance of considering carnitine deficiency in patients presenting with unexplained neurological signs while on long-term valproate treatment.