Male hypogonadism: pathogenesis, diagnosis, and management.

Organic male hypogonadism due to irreversible hypothalamic-pituitary-testicular (HPT) pathology is easily diagnosed and treated with testosterone-replacement therapy. However, controversy surrounds the global practice of prescribing testosterone to symptomatic men with low testosterone and non-gonadal factors reducing health status, such as obesity, type 2 diabetes, and ageing (ie, functional hypogonadism), but without identifiable HPT axis pathology. Health optimisation remains the gold-standard management strategy. Nevertheless, in the last decade large clinical trials and an individual patient data meta-analysis of smaller clinical trials confirmed that testosterone therapy induces modest, yet statistically significant, improvements in sexual function without increasing short-term to medium-term cardiovascular or prostate cancer risks in men with functional hypogonadism. Although testosterone improves bone mineral density and insulin sensitivity in these men, trials from the last decade suggest insufficient evidence to determine the safety and effectiveness of use of this hormone for the prevention of fractures or type 2 diabetes. This Review discusses the pathogenesis and diagnosis of male hypogonadism and appraises the evidence underpinning the management of this condition.

Effect of oestrogen modulation on semen parameters in men with secondary hypogonadism: Systematic review and meta-analysis.

BACKGROUND: Selective oestrogen receptor modulators and aromatase inhibitors stimulate endogenous gonadotrophins and testosterone in men with hypogonadism. There are no systematic reviews/meta-analyses assessing the effects of selective oestrogen receptor modulators/aromatase inhibitors on semen parameters in men with secondary hypogonadism. OBJECTIVES: To assess the effect of monotherapy or a combination of selective oestrogen receptor modulators/aromatase inhibitors on sperm parameters and/or fertility in men with secondary hypogonadism. MATERIALS AND METHODS: A systematic search was conducted in PubMed, MEDLINE, Cochrane Library and ClinicalTrials.gov. Study selection and data extraction were performed by two reviewers independently. Randomised controlled trials and non-randomised studies of interventions reporting effects of selective oestrogen receptor modulators and/or aromatase inhibitors on semen parameters or fertility in men with low testosterone with low/normal gonadotrophins were selected. The risk of bias was assessed using ROB-2 and ROBINS-I tools. The results of randomised controlled trials were summarised using vote counting while summarising effect estimates where available. Non-randomised studies of intervention meta-analysis were conducted using the random-effect model. The certainty of evidence was assessed using GRADE. RESULTS: Five non-randomised studies of interventions (n = 105) of selective oestrogen receptor modulators showed an increase in sperm concentration (pooled mean difference 6.64 million/mL; 95% confidence interval 1.54, 11.74, I2  = 0%) and three non-randomised studies of interventions (n = 83) of selective oestrogen receptor modulators showed an increase in total motile sperm count (pooled mean difference 10.52; 95% confidence interval 1.46-19.59, I2  = 0%), with very low certainty of evidence. The mean body mass index of participants was >30 kg/m2 . Four randomised controlled trials (n = 591) comparing selective oestrogen receptor modulators to placebo showed a heterogeneous effect on sperm concentration. Three included men with overweight or obesity. The results were of very low certainty of evidence. Limited pregnancy or live birth data were available. No studies comparing aromatase inhibitors with placebo or testosterone were found. DISCUSSION AND CONCLUSION: Current studies are of limited size and quality but suggest that selective oestrogen receptor modulators may improve semen parameters in those patients, particularly when associated with obesity.

Rathke's cleft cyst discovered with ruptured anterior communicating artery aneurysm: a case report.

INTRODUCTION: Rathke's cleft cysts are thought to have a benign clinical outcome apart from associated hypopituitarism and visual defects. Synchronous central nervous system lesions, including pituitary adenoma and intracerebral aneurysms, are rarely reported. Diagnosis of Rathke's cleft cyst after presenting with a subarachnoid hemorrhage due to a ruptured arterial aneurysm is reported only once before. CASE PRESENTATION: A 33-year-old Sri Lankan female presented with a subarachnoid hemorrhage due to a ruptured anterior communication artery aneurysm. She underwent pterional craniotomy and aneurysm clipping. She was found to have partial cranial diabetes insipidus and hypogonadotropic hypogonadism. She had a cystic lesion occupying enlarged sella turcica with characteristics of a Rathke's cleft cyst. Subsequently, she underwent trans-sphenoidal excision of the sellar lesion. Histology confirmed the diagnosis of Rathke's cleft cyst. CONCLUSIONS: Rare co-occurrence of a Rathke's cleft cyst and an anterior communicating artery aneurysm would have been missed if subtle manifestations atypical for subarachnoid hemorrhage were not further pursued. This could have led to progressive visual deterioration and hypopituitarism.

Primary hyperparathyroidism in an adolescent presenting with genu valgus progressing to extensive bone disease; a case report.

BACKGROUND: Primary hyperparathyroidism which is rare in adolescents presents commonly with non-specific symptoms and systemic complaints. Though there are few reported cases of genu valgus, genu valgus progressing to extensive bone disease despite mildly elevated calcium had not been reported before. CASE PRESENTATION: A 12-year-old male had been evaluated for bilateral (left > right) genu valgus and short stature. Serum calcium and phosphate levels had been normal. X-ray of the femora and pelvic bones had not shown additional abnormalities. Valgus deformity progressed despite left femoral plating, and a left distal femoral medial closed wedge osteotomy had been performed at 15 years. Plain imaging at that time had shown localised osteopaenia. At the age of 17 years, he developed multiple fragility fractures of his left hip rendering him wheelchair-bound. Further evaluation revealed a serum PTH level of 2571 (10-65) pg/mL with calcium of 2.82 (2.2-2.6) mmol/L and inorganic phosphate of 1.7 (2.2-4.7) mg/dL. The lumbar spine DXA scan showed a Z-score of -5.8. A left parathyroid adenoma was localised and there was evidence of hyperparathyroid bone disease including brown tumours. He underwent left parathyroidectomy and left thyroid lobectomy after which his PTH level dropped to 4.03 pg/mL. He developed hypocalcaemia which was managed successfully with calcium and alfacalcidol replacement. CONCLUSIONS: Primary hyperparathyroidism can present with genu valgus in adolescents. Initial normocalcaemia which could be due to concomitant vitamin D deficiency could mask this leading to delayed diagnosis until severe irreversible bone disease ensues.

Postmenopausal hyperandrogenism due to an ovarian sex cord-stromal tumour causing elevated dehydroepiandrosterone sulphate: a case report.

BACKGROUND: The source of excess androgen can be obscure in postmenopausal women with new-onset hyperandrogenism. If serum dehydroepiandrosterone sulphate (DHEAS) is raised, it is presumed to be of adrenal origin because DHEAS is exclusively produced from adrenal cortical cells. This reports an elderly female presenting with new-onset hyperandrogenism due to an ovarian sex cord-stromal tumour, associated with increased serum DHEAS levels. CASE DESCRIPTION: A 76-year-old female with long-standing diabetes and hypertension presented with hirsutism and male type alopecia for six months. She had menopause at 55 years of age. There was a pelvic mass on examination. Total testosterone was 6.106 ng/ml (0.124-0.357) and DHEAS was > 1000 µg/dL (35-430). Contrast-enhanced computed tomography of the abdomen and pelvis showed a heterogeneously enhancing complex mass measuring 11 × 8 cm in the left adnexal region. Adrenal glands were normal. She underwent total abdominal hysterectomy, bilateral salphingo-oophorectomy, and omentectomy. Both testosterone and DHEAS normalised following surgery. Histology revealed a sex cord-stromal tumour, likely a steroid cell tumour with malignant potential. Fluorodeoxyglucose-Positron emission tomography did not show any additional lesions. CONCLUSIONS: Due to the lack of sulfotransferase in ovarian tissue, markedly elevated DHEAS originating from an ovarian neoplasm is unusual. This phenomenon has not been described except in a patient with a steroid cell tumour causing Cushing syndrome and hyperandrogenism. The mechanism of this rare occurrence remains elusive. Knowledge of this unusual presentation would enable the clinicians to be cautious in localising the androgen source in women with hyperandrogenism.

Apoplexy of Crooke cell tumour leading to the diagnosis of severe Cushing disease; a case report.

BACKGROUND: Patients with Crooke cell tumours present with features of Cushing syndrome or mass effect. There are few reports of patients with Crooke cell tumours presenting due to apoplexy. All of them had silent tumours. Patients with Cushing syndrome caused by Crooke cell tumours have not been reported to present with apoplexy. CASE PRESENTATION: A 35-year-old female presented with sudden onset headache and visual loss for 1 week. She had secondary amenorrhoea for 10 years. There were features of Cushing syndrome including central obesity, multiple monomorphic acne, dorso-cervical and supraclavicular fat pads, hypertension, proximal weakness, pigmentation and refractory hypokalaemia. She was found to have markedly elevated serum cortisol, central hypothyroidism and hypogonadotropic hypogonadism. There was a mass in the sellar region (4.7 cm × 1.9 cm × 5.3 cm) suggestive of a pituitary tumour extending to the suprasellar region. Imaging showed evidence of bleeding and compression of the optic chiasm. She underwent urgent trans-sphenoidal excision of the tumour. Histology was compatible with a pituitary neuroendocrine tumour. There was margination of ACTH reactivity to the cell periphery and ring like positivity in most of the cells in the cytokeratin stain. Features were in favour of a Crooke cell tumour. After surgery she improved gradually and became eucortisolaemic. CONCLUSIONS: This is a unique presentation of an apoplexy of Crooke cell tumour causing Cushing syndrome. Delayed health seeking behaviour of this patient despite severe Cushing disease could have led to this presentation which has not been reported before.

Haemopoietic stem cell transplantation in Systemic lupus erythematosus: a systematic review.

Despite advances in treating Systemic lupus erythematosus (SLE), a proportion of patients continue to face significant morbidity and mortality. Haemopoietic stem cell transplant (HSCT) has been recognized as an option for such patients. We analysed the evidence on efficacy and safety of HSCT in patients with SLE. A database search was done for articles on HSCT in SLE up to July 2017 in PUBMED, Cochrane library, LILACS and clinical trial registration databases to select prospective or retrospective studies with 8 or more patients. Of the 732 search results from the PUBMED, Cochrane and LILACS database search, following duplicate removal, 15 studies were eligible for detailed assessment. Findings of an additional trial were obtained from the clinical trial registration database. Data were extracted on study design, patient characteristics, nature of intervention, outcomes, complications and study quality. Case reports and small case series were summarised without detailed qualitative analysis. Most of the studies showed remission in the majority of patients. Relapse of the original disease increased with longer follow-up. Common adverse effects included: infections and secondary autoimmune disorders. Short follow up period and lack of randomised controlled trials were the main limitations restricting the generalizability of study results. A meta-analysis was not performed due to heterogeneity of studies. Although HSCT is a viable option in SLE, its exact clinical utility needs to be further evaluated in well-designed studies.

Effect of Antimicrobial Agents on Inflammatory Cytokines in Acute Leptospirosis.

The aim of this study was to assess the inflammatory cytokine response and possible association with antimicrobial treatment with penicillin, ceftriaxone, and doxycycline in acute leptospirosis. In the early acute stage, interleukin-10 (IL-10) levels were higher in mild cases than in severe cases (P = 0.01). IL-6 and IL-8 levels were low in patients who received >5 antimicrobial doses (P < 0.01). IL-8 levels were negatively correlated with the number of ceftriaxone doses administered (r = -0.315; P = 0.031). Further studies are needed to evaluate the possible downregulation of proinflammatory cytokines by ceftriaxone in leptospirosis.

Evolution into Takayasu arteritis in a patient presenting with acute pulmonary oedema due to severe aortic regurgitation; a case report.

BACKGROUND: Takayasu arteritis is a rare large vessel vasculitis which predominantly affects young Asian females. Aortic regurgitation and heart failure are well described manifestations which are usually preceded by constitutional symptoms, limb claudication, pulse and blood pressure discrepancies, vascular bruits and features of organ ischaemia. CASE PRESENTATION: A 25-year- old Sri Lankan female presented with a three days history of acute shortness of breath, cough and orthopnoea. On examination she had severe aortic regurgitation resulting in high output cardiac failure. There was no evidence of acute coronary ischaemia or infective endocarditis. The only significant investigation finding was an elevated erythrocyte sedimentation rate (ESR) of 114 mm/first hour. The patient was treated for pulmonary oedema and empirically for infective endocarditis. Extensive evaluation for an underlying infection, large vessel vasculitis or malignancy did not reveal any abnormalities. Detailed periodic assessment identified reduced blood pressure in left arm (70/40 mmHg) compared to right (100/70 mmHg) and reduced pulse volume of left arm with left subclavian bruit more than one year after the initial presentation. Digital subtraction angiography revealed significant stenosis at first part of left subclavian and origin of left vertebral arteries. A diagnosis of Takayasu arteritis was made and patient was started on high dose glucocorticoids. CONCLUSIONS: Takayasu arteritis can present initially with isolated cardiac involvement even as acute cardiac manifestations and high degree of suspicion with close follow up would allow early detection of development of other classic features and timely diagnosis.