Natural history of non-functioning pituitary microadenomas: results from the UK non-functioning pituitary adenoma consortium.

OBJECTIVE: The optimal approach to the surveillance of non-functioning pituitary microadenomas (micro-NFPAs) is not clearly established. Our aim was to generate evidence on the natural history of micro-NFPAs to support patient care. DESIGN: Multi-centre, retrospective, cohort study involving 23 endocrine departments (UK NFPA consortium). METHODS: Clinical, imaging, and hormonal data of micro-NFPA cases between January, 1, 2008 and December, 21, 2021 were analysed. RESULTS: Data for 459 patients were retrieved [median age at detection 44 years (IQR 31-57)-152 males/307 females]. Four hundred and nineteen patients had more than two magnetic resonance imagings (MRIs) [median imaging monitoring 3.5 years (IQR 1.71-6.1)]. One case developed apoplexy. Cumulative probability of micro-NFPA growth was 7.8% (95% CI, 4.9%-8.1%) and 14.5% (95% CI, 10.2%-18.8%) at 3 and 5 years, respectively, and of reduction 14.1% (95% CI, 10.4%-17.8%) and 21.3% (95% CI, 16.4%-26.2%) at 3 and 5 years, respectively. Median tumour enlargement was 2 mm (IQR 1-3) and 49% of micro-NFPAs that grew became macroadenomas (nearly all >5 mm at detection). Eight (1.9%) patients received surgery (only one had visual compromise with surgery required >3 years after micro-NFPA detection). Sex, age, and size at baseline were not predictors of enlargement/reduction. At the time of detection, 7.2%, 1.7%, and 1.5% patients had secondary hypogonadism, hypothyroidism, and hypoadrenalism, respectively. Two (0.6%) developed hypopituitarism during follow-up (after progression to macroadenoma). CONCLUSIONS: Probability of micro-NFPA growth is low, and the development of new hypopituitarism is rare. Delaying the first follow-up MRI to 3 years and avoiding hormonal re-evaluation in the absence of tumour growth or clinical manifestations is a safe approach for micro-NFPA surveillance.

Rifabutin-Induced SIADH and Leucopenia in a Renal Transplant Recipient with Genitourinary Tract Tuberculosis: A Case Report and Review of the Literature.

Tuberculosis (TB) infection of the genitourinary tract (GU TB) is rare in renal transplant recipients, with only a few published case series. GU TB is difficult to diagnose with or without immunosuppression but must always be suspected in any patient with unexplained sterile pyuria. As GU TB is associated with graft rejection, prompt diagnosis and treatment are vital. Treatment is challenging, as rifampicin, the most effective drug used to treat tuberculosis, is a significant inducer of cytochrome P-450 3A metabolism, with the potential to cause significant reductions in the serum levels of calcineurin inhibitors. For this reason, rifabutin, a weaker cytochrome P-450 3A inducer, with similar efficacy against TB, is sometimes used as an alternative to rifampicin in transplant recipients. We present a renal transplant patient diagnosed with GU TB, treated with a regime containing rifabutin, who subsequently developed profound hyponatremia and leucopenia. Serum and urine biochemistry was consistent with a diagnosis of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Both SIADH and leucopenia resolved with rifabutin cessation. This is the first report of biochemically proven, idiosyncratic SIADH and leucopenia associated with the use of rifabutin in the treatment of GU TB in a renal transplant recipient.

Residual Adrenal Function in Autoimmune Addison's Disease-Effect of Dual Therapy With Rituximab and Depot Tetracosactide.

CONTEXT: In autoimmune Addison's disease (AAD), exogenous glucocorticoid (GC) therapy is an imperfect substitute for physiological GC secretion. Patients on long-term steroid replacement have increased morbidity, reduced life expectancy, and poorer quality of life. OBJECTIVE: The objective of this article is to restore adrenocortical steroidogenic function in recent-onset AAD. DESIGN: An open-label, multicenter trial of immunotherapy and trophic stimulation in new-onset AAD was conducted. Serial measurement of serum and urine corticosteroids at baseline and throughout a 72-week follow-up period was performed. SETTING: This study was conducted at the.endocrine departments and clinical research facilities at 5 UK tertiary centers. PATIENTS: Thirteen participants (9 female, 4 male; age 19-64 years) were included with AAD confirmed by high adrenocorticotropin, low circulating cortisol (basal < 100 nmol/L or post-tetracosactide < 300 nmol/L), and positive serum 21-hydroxylase antibodies. INTERVENTION: All participants received dual therapy with B-lymphocyte-depleting immunotherapy (rituximab 1 g given twice) and repeated depot tetracosactide (1 mg on alternate days for 12 weeks). MAIN OUTCOME MEASURE: Restoration of normal GC secretion (stimulated cortisol > 550 nmol/L) at week 48 was the main outcome measure. RESULTS: Ten of 13 (77%) participants had detectable stimulated serum cortisol (26-265 nmol/L) at trial entry. Following intervention, 7 of 13 (54%) had an increase in stimulated cortisol measurement, with a peak response of 325 nmol/L at week 18 in 1 participant. Increased steroid metabolites, assayed by urine gas chromatography-mass spectrometry at week 12 and week 48, was detected in 8 of 13 (62%) individuals, reflecting an increase in endogenous steroidogenesis. Four of 13 had residual adrenal function at 72 weeks. CONCLUSION: Combined treatment with rituximab and depot tetracosactide did not restore normal adrenal function. Nevertheless, adrenocortical plasticity is demonstrated in some patients, and this has the potential to be exploited to improve adrenal function.

Safety and tolerability of one-year intramuscular testosterone regime to induce puberty in older men with CHH.

We present herein our 20-year experience of pubertal induction in apubertal older (median age 56 years; range 38.4-69.5) men with congenital hypogonadotrophic hypogonadism (n = 7) using a simple fixed-dose and fixed-interval intramuscular testosterone that we originally pioneered in relation to achieving virilisation of natal female transgender men. This regime was effective and well tolerated, resulting in complete virilisation by around 1 year after treatment initiation. No physical or psychological adverse effects were encountered in this group of potentially vulnerable individuals. There were no abnormal excursions of laboratory parameters and extended follow-up beyond the first year of treatment revealed remarkable improvements in bone density. We highlight advantages to both patients and physicians of this regime in testosterone-naïve older men with congenital hypogonadism and discourage the over-rigid application to such patients of treatment algorithms derived from paediatric practice in relation to the evaluation and management in younger teenagers with delayed puberty of uncertain cause.

Clinical Case Seminar: Postmenopausal androgen excess-challenges in diagnostic work-up and management of ovarian thecosis.

Postmenopausal hyperandrogenism can be tumour- or non-tumour-related, with pathology residing either in the ovary or adrenal gland(s). The tempo of investigation is determined by the clinical severity of hyperandrogenism (presence/absence of actual virilisation) and degree of serum testosterone elevation. When clinical or biochemical hyperandrogenism is severe, rapidly developing, or associated with hypercortisolism, screening for adrenocortical or ovarian carcinoma with cross-sectional imaging should be prioritised over detailed biochemical evaluation. Adrenal hyperandrogenism is readily characterised, both biochemically and radiologically. By contrast, even a combination of high-resolution imaging with laboratory evaluation, including dynamic endocrine testing, often cannot distinguish between ovarian hyperthecosis (OH) and virilising ovarian tumour (VOT); a definitive diagnosis usually emerging only after histological examination of excised ovaries. VOTs are typically below the resolution-limit of current imaging modalities and exhibit suppression of gonadotropin-dependent androgen secretion with GnRH-analogue therapy. Thus, for well-characterised ovarian hyperandrogenism, laparoscopic bilateral salpingo-oophorectomy may serve both as a diagnostic and therapeutic procedure. Nevertheless, women unable or unwilling to undergo ovarian surgery can be reassured that malignant VOTs are exceedingly rare and that long-term medical therapy with oral antiandrogens or GnRH-analogues is safe and well-tolerated. OH is strongly associated with insulin-resistance, with hyperinsulinaemia acting synergistically with raised gonadotropin levels to stimulate thecal cell hyperplasia and androgen secretion by the postmenopausal ovary, which lacks granulosa cell aromatase activity and thus cannot convert testosterone to 17 beta estradiol. Thus, features of metabolic syndrome may indicate OH, and significant reductions in androgens can thereby potentially be achieved with lifestyle measures and/or insulin-sensitising drugs.

Non-menopausal endocrine and non-endocrine causes of flushing and sweating.

Hot flushes and generalised sweating are relatively common presenting complaints, with hypogonadism an important differential diagnosis in both sexes and menopause being the most typical cause in females of climacteric age. However, a variety of other conditions do need to be carefully considered in respect of eugonadal individuals and also for those hypogonadal ones where properly dosed sex steroid replacement has failed to control flushing and sweating, or where the presentation is atypical. Alternative aetiologies may be immediately obvious from the history and physical examination, but more unusual conditions may require deeper scrutiny. This clinical review elaborates on the non-menopausal endocrine and non-endocrine causes of flushing and sweating, including both common and rarer conditions.

Challenges in the acute management of profound hyponatremia presenting with severe symptoms.

Currently available guidelines in the acute management of severely symptomatic hypotonic hyponatremia vary in their approach to the use of hypertonic saline. In the acute setting, deciding on when to implement available treatment algorithm using hypertonic saline may be difficult, given that the duration of hyponatremia and potential alternative diagnoses presenting with similar symptoms may be hard to establish promptly. We present the case of a young female with symptomatic profound hyponatremia who subsequently developed osmotic demyelination syndrome due to rapid overcorrection of serum sodium concentration. We discuss the interplay between the dynamic pathophysiological processes responsible for hypotonic hyponatremia in adrenal insufficiency and conduct a detailed analysis of currently available guidelines to highlight the challenges in acute and reactive treatment in clinical practice.

Lesson of the month 2: Catecholamine-induced cardiomyopathy - pitfalls in diagnosis and medical management.

Cardiomyopathy as the initial presentation of phaeochromocytoma (PCA) is uncommon. Diagnostic work-up and perioperative management may be challenging within this context. We report three cases of PCA presenting with cardiomyopathy to illustrate the pitfalls in diagnosis and management. None of the patients had typical adrenergic symptoms and all three were established on beta-blockers prior to diagnosis. Their fractionated plasma catecholamine levels were elevated and the diagnosis of PCA was confirmed with various imaging modalities and post adrenalectomy. Interpretation of fractionated catecholamine levels in the context of established cardiomyopathy is difficult as cardiac failure of any aetiology generates an adrenergic response. Hence screening all patients with idiopathic cardiomyopathy is likely to generate a high false-positive rate. However, a high index of suspicion should prompt further diagnostic work-up in patients with idiopathic cardiomyopathy for occult PCAs. Peer-reviewed guidelines are required to guide the investigation and management of suspected catecholamine-induced cardiomyopathy.

Diagnosis of treponemal co-infection in HIV-infected West Africans.

OBJECTIVES: To evaluate the performance of two enzyme immunoassays (EIA), Murex and ICE, and the Determine TP point-of-care test (POCT) in diagnosing treponemal infection (syphilis or yaws) in patients attending a large HIV clinic in Ghana; to determine the prevalence of treponemal co-infections; and to characterise demographic and clinical features of patients with infection. METHODS: Samples were tested with EIAs and rapid plasma reagin (RPR), then POCT and reference assays for Treponema pallidum to determine prevalence of active and past infection. Sensitivity and specificity of each assay were calculated and demographic and clinical characteristics of patients compared. Data were collected from case notes of patients retrospectively. RESULTS: Overall, 45/284 patient samples (14.8%, 95% CI, 11.1-19.4%) were Treponema pallidum particle agglutination (TPPA) positive, and of these, 27 (64.3%) were RPR positive and 4 (8.9%) were treponemal IgM positive. Both EIAs and Determine TP POCT showed high sensitivities and specificities for identifying infection although RPR was less reliable. Clinical features of syphilis or yaws were rarely identified in TPPA-positive patients suggesting most had previous or late latent infection. Treatment of various intercurrent infections using short courses of antibiotics active against T. pallidum was common in the clinic. CONCLUSIONS: A high proportion of this HIV-infected cohort showed evidence of treponemal infection. Both EIAs as well as the POCT were practical and effective at diagnosing treponemal co-infection in this setting. RPR alone was unreliable at identifying active treponemal co-infection, however might be useful in some settings where treponemal-specific assays are unaffordable.

Short Communication: Low seroprevalence of cryptococcal antigenaemia in patients with advanced HIV infection enrolling in an antiretroviral programme in Ghana.

OBJECTIVES: To determine the prevalence of cryptococcal antigenaemia in a clinic population with advanced HIV infection, with a view to giving antifungal therapy to those testing positive. METHODS: Serum samples from adults with CD4 count <100 cells/mm(3) presenting to a large HIV clinic in Kumasi, Ghana, were tested retrospectively for cryptococcal antigenaemia using a latex agglutination assay, and clinical and demographic data extracted from case notes. RESULTS: Of 92 samples tested, two were positive thus giving a prevalence of 2% (95% CI, 0-5.2%). CONCLUSIONS: The prevalence of cryptococcal antigenaemia in patients with advanced HIV infection enrolling in an antiretroviral programme appears to be low in Kumasi, suggesting that the value of routine testing of outpatients diagnosed with advanced HIV infection may be limited in this population.

How appropriate are cerebrospinal fluid polymerase chain reaction requests for suspected central nervous system infections?

Cerebrospinal fluid (CSF) polymerase chain reaction (PCR) assays have become the main diagnostic tests for central nervous system viral infections in recent years. Previous studies have suggested algorithms based on CSF leukocyte count and total protein levels to determine when CSF PCR assays are indicated. Based on these criteria, 1,469 CSF PCR tests requested over a two-year period were reviewed. A proportion of positive PCR results were found in children with normal CSF, unlike in adults where such occurrences were extremely rare. The results suggest that applying a strategy of screening CSF specimens using leukocyte count, glucose and protein, at least in adults, may have avoided more than half of CSF PCR requests with little detriment to patient care and considerable cost savings. Larger prospective studies are needed to determine whether algorithms using standard CSF parameters and clinical information can optimise the use of CSF PCR assays in clinical practice.