Summary

Functional hypogonadotropic hypogonadism is a relatively common condition in middle-aged to elderly men that can significantly impair quality of life. Besides lifestyle optimisation, androgen replacement remains the mainstay of treatment; however, its adverse effects on spermatogenesis and testicular atrophy are undesirable. Clomiphene citrate is a selective oestrogen receptor modulator that acts centrally to increase endogenous testosterone without affecting fertility. Although it has demonstrated effectiveness in shorter-duration studies, its longer-term outcomes are less well-documented. In this study, we report the case of a 42-year-old male with functional hypogonadotropic hypogonadism who sustained an excellent dose-dependent, titratable clinical and biochemical response to clomiphene citrate with no known adverse effects for 7 years to date. This case highlights that clomiphene citrate has potential as a safe and titratable longer-term treatment option, and the need for further randomised control trials in therapy options to normalise androgen status.

Learning points

• Functional hypogonadotropic hypogonadism is a relatively common, but likely underdiagnosed, condition in middle-aged to older males.

• Testosterone replacement is the current mainstay of endocrine therapy but can cause sub-fertility and testicular atrophy.

• Clomiphene citrate is a serum oestrogen receptor modulator that acts centrally to increase endogenous testosterone production without affecting fertility.

• It has potential as a safe and efficacious longer-term treatment option that can be titrated to increase testosterone and relieve clinical symptoms in a dose-dependent manner.

• Longitudinal prospective studies as randomised control trials evaluating alternatives to exogenous testosterone are required.

Summary

A 64-year-old man with progressive metastatic castrate-resistant prostate adenocarcinoma presented with recurrent fluid overload, severe hypokalaemia with metabolic alkalosis and loss of glycaemic control. Clinical features were facial plethora, skin bruising and proximal myopathy. Plasma adrenocorticotrophic hormone (ACTH), serum cortisol and 24-h urinary cortisol levels were elevated. Low-dose dexamethasone failed to suppress cortisol. Pituitary MRI was normal and ⁶⁸Gallium-DOTATATE PET–CT scan showed only features of metastatic prostate cancer. He was diagnosed with ectopic ACTH syndrome secondary to treatment-related neuroendocrine prostate cancer differentiation. Medical management was limited by clinical deterioration, accessibility of medications and cancer progression. Ketoconazole and cabergoline were utilised, but cortisol remained uncontrolled. He succumbed 5 months following diagnosis. Treatment-related neuroendocrine differentiation of prostate adenocarcinoma is a rare cause of ectopic ACTH syndrome.

Learning points

• Neuroendocrine differentiation following prostate adenocarcinoma treatment with androgen deprivation has been described.

• Ectopic adrenocorticotrophic hormone (ACTH) syndrome should be considered where patients with metastatic prostate cancer develop acute electrolyte disturbance or fluid overload.

• Ketoconazole interferes with adrenal and gonadal steroidogenesis and can be used in ectopic ACTH syndrome, but the impact may be insufficient. Inhibition of gonadal steroidogenesis is favourable in prostate cancer.

• More data are required to evaluate the use of cabergoline in ectopic ACTH syndrome.

• Ectopic ACTH syndrome requires prompt management and is challenging in the face of metastatic cancer.

Summary

Iron metabolism and markers hereof are altered in anorexia nervosa (AN) but far from completely understood. We report a case of extreme hyperferritinemia in a patient with AN and discuss the possible mechanisms and current knowledge about the association between hyperferritinemia and AN. A 20-year-old woman with a history of AN presented with bradycardia, weariness, and malaise in addition to an incidentally very high ferritin level. The symptoms disappeared spontaneously after a short admission. There were no signs suggestive of systemic, hematological, or malignant disease causing the very high concentration of ferritin. Her body weight was in decline, leading up to admission, but did initially increase after discharge accompanied by declining ferritin concentration. However, a clear association between ferritin dynamics and weight changes or physical activity was not identified and neither were other causes of the hyperferritinemia. Around one in four patients with AN have increased ferritin concentrations. Our case represents the highest ferritin concentration reported in a patient with AN without other underlying causes or comorbidities.

Learning points

• Perturbed iron metabolism is frequent in restrictive type anorexia nervosa but incompletely understood.

• Altered ferritin in anorexia nervosa may be linked to nutritional status.

Summary

Primary thyroid lymphoma (PTL) is a rare malignancy, accounting for less than 5% of all thyroid neoplasms. The follicular subtype is even more rare, accounting for approximately 10% of all PTL cases. We report a case of a 64-year-old woman, who presented with a rapidly growing goitre with mass effect and B symptoms. She had a history of Hashimoto’s thyroiditis and her thyroid ultrasound revealed diffuse goitre with a dominant nodule (56 × 63 × 60 mm) within the right thyroid lobe. Ultrasound-guided percutaneous fine-needle aspiration of the right thyroid nodule was classified as benign, according to Bethesda System, with lymphocytic thyroiditis. A CT scan of the neck showed diffuse enlargement of the thyroid gland extending towards the anterior mediastinum with tracheal deviation and lymphadenopathy within levels VII and right II–IV. The core needle biopsy of the right thyroid nodule revealed a follicular non-Hodgkin’s B cell lymphoma with a Ki67 of 60%. According to the Ann Arbor staging system, she was at stage IIIE. She underwent chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with remarkable clinical improvement and is currently in remission 2 years after the diagnosis. PTL is an extremely rare malignancy that usually arises in a lymphocytic thyroiditis background, presenting as a rapidly enlarging goitre, which can lead to compressive symptoms or airway comprise.

Learning points

• Primary thyroid lymphoma (PTL) is a rare malignancy, accounting for less than 5% of thyroid neoplasms.

• PTL should be suspected when a patient presents with a rapidly enlarging goitre, especially in the setting of Hashimoto’s thyroiditis.

• Fine-needle aspiration has a limited capacity for PTL diagnosis due to similar cytomorphological features of lymphoma with thyroiditis. Therefore, in case of clinical suspicion and if fine needle aspiration fails to diagnose PTL, a tissue biopsy should be performed.

• Treatment is dependent on both the stage and histology of PTL. Chemotherapy and local radiotherapy remain the mainstay treatment for PTL.

Summary

We present a case of a 42-year-old man who developed acute onset severe hypertriglyceridaemia within days of commencing olanzapine therapy. Despite having a family history of metabolic syndrome, he had no personal history of hyperlipidaemia and had normal fasting lipids 1 week prior to treatment initiation. His case is consistent with a diagnosis of multifactorial chylomicronaemia syndrome with a possible undiagnosed underlying genetic lipid metabolism disorder. Our case highlights the difficulty in identifying patients at risk of severe hypertriglyceridaemia prior to the commencement of olanzapine.

Learning points

• Atypical antipsychotic medications, in particular olanzapine and clozapine, are associated with metabolic side effects.

• Olanzapine can precipitate acute onset severe hypertriglyceridaemia consistent with multifactorial chylomicronaemia syndrome.

• It is difficult to predict individuals at risk of olanzapine-induced hypertriglyceridaemia.

• This case demonstrates the importance of metabolic screening prior to the commencement of olanzapine and the possibility of repeating fasting serum lipids soon thereafter.

Summary

This is a report of a rare case of Graves’ hyperthyroidism associated with severe bilateral Graves’ orbitopathy, in a patient with an anophthalmic eye socket. On clinical review her prosthetic eye (left eye) was tilting upwards, along with worsening of Graves’ orbitopathy (GO) in the only seeing eye. As she refused IV glucocorticoids, she was offered rituximab which only caused a transient improvement in the clinical activity score of the eye. She had persistent right upper lid retraction of 6 mm, associated with lagophthalmos. To protect her seeing eye from corneal ulceration, the patient received a botulinum toxin injection to the right upper eyelid to induce blepharoptosis as an interim measure prior to right upper eyelid blepharotomy in April 2021. This patient remains biochemically euthyroid on block and replace therapy and her TRAb level is falling over time. Treatment for active GO is ongoing and the patient required a redo blepharotomy for painful corneal exposure in the right eye.

Learning points

• Graves’ orbitopathy (GO) does not actually primarily affect the eyeball itself but the orbital contents as well.

• Patients with severe GO in an only seeing-eyed patient should be referred early to a multidisciplinary Joint Thyroid Eye clinic for expert review and management.

• Patient outcomes including sight loss are likely to be improved by the extended range of medical and surgical treatment modalities available at specialist clinics treating GO, including the use of immunomodulatory drugs like rituximab or teprotumumab.

Summary

Tumour-induced osteomalacia (TIO) is due to an overproduction of fibroblast growth factor 23 (FGF23) by mesenchymal tumours, causing hypophosphatemia, osteomalacia and muscle weakness. TIO is usually cured by tumour resection, but neoplasms may be unidentifiable and unresectable or the patient may refuse surgery. In these cases, medical treatment with oral phosphate and calcitriol is mandatory, but it is not fully effective and it is associated with low compliance. Burosumab, a human MAB against FGF23 employed to treat X-linked hypophosphatemia (XLH), has recently been approved for TIO in the USA. Maximum burosumab dose in XLH is 90 mg administered for 2 weeks; there are no data on clinical efficacy and safety of this dose in TIO. We reported the case of a 73 years old male with multiple non-traumatic fractures, low bone mineral density, pain and reduced independence of activities of daily living. Biochemical evaluation showed hypophosphatemia, high alkaline phosphatase (ALP) and C-terminal telopeptide (CTX) and normal albumin-corrected total calcium and parathyroid hormone. Tubular phosphate reabsorption was low (80%), whereas C-terminal tail of FGF23 (cFGF23) was elevated. A ⁶⁸Ga-DOTATOC PET was performed, identifying a lesion in the first left rib. The patient refused surgery; therefore, burosumab therapy was started. After 18 months of treatment (maximum dose: 60 mg administered for 2 weeks), plasma phosphate normalized and ALP levels improved (138 U/L). Patient clinical symptoms as well as pain severity and fatigue improved. Neither adverse events nor tumour progression was reported during follow-up except for a painless fracture of the second right rib.

Learning points

• Our case shows efficacy and safety of burosumab treatment administered every 2 weeks in a tumour-induced osteomalacia (TIO) patient.

• After 18 months of treatment at a maximum dose of 60 mg every 2 weeks, we found plasma phosphate normalization and ALP reduction as well as improvement in clinical symptoms and fatigue.

• Neither adverse events nor tumour progression was reported during follow-up, except for a painless fracture of the second right rib.

Summary

The spectrum of endocrine-related complications of COVID-19 infection is expanding; one of the most concerning of which is adrenal haemorrhage due to the risk of catastrophic adrenal crisis. In this study, we present a case that highlights the challenging management of a large, indeterminate unilateral adrenal mass during pregnancy and draws attention to a rare yet probably underestimated complication of COVID-19. During hospitalization for severe COVID-19 pneumonia, a 26-year-old woman was incidentally found to have a 12.5 cm heterogeneous left adrenal mass. Soon after the discovery, she became pregnant and upon referral, she was in the seventh week of gestation, without clinical or biochemical features of hormonal excess. The uncertainty of the diagnosis and the risks of malignancy and surgical intervention were discussed with the patient, and a period of radiological surveillance was agreed upon. An MRI scan performed 3 months later showed a size reduction of the adrenal lesion to 7.9 cm, which was against malignancy. A Doppler ultrasound showed a non-vascular, well-defined round lesion consistent with an adrenal haematoma, likely a complication of the recent COVID-19 infection. The multidisciplinary team recommended further radiological follow-up. The patient then spontaneously had miscarriage at 12 weeks gestation. Subsequent radiological surveillance showed a further size reduction of the adrenal lesion to 5.5 cm. The patient conceived again during follow-up, and the repeated Doppler ultrasound showed stable appearances of the adrenal mass, and thus, it was agreed to continue radiological monitoring after delivery. The pregnancy was uneventful, and the patient delivered a healthy baby. An MRI scan performed after delivery showed a stable but persistent lesion consistent with a likely underlying adrenal lesion.

Learning points

• Unilateral adrenal haemorrhage can occur as a complication of COVID-19 and should be considered in the differential diagnosis of heterogeneous adrenal masses if there is a history of recent infection.

• Management of large indeterminate adrenal masses during pregnancy poses several challenges and should be led by an experienced multidisciplinary team.

• Underlying adrenal tumours may trigger non-traumatic haemorrhages, especially if exacerbated by stressful illness.

Summary

Large-cell neuroendocrine carcinoma (LCNEC) is a rare neuroendocrine prostatic malignancy. It usually arises after androgen deprivation therapy (ADT), while de novo cases are even more infrequent, with only six cases described. The patient was a 78-year-old man with no history of ADT who presented with cervical lymphadenopathy. Diagnostic approaches included PET/CT, MRI, CT scans, ultrasonography, biopsies, and cytological and immunohistochemical evaluations. Results showed a poorly differentiated carcinoma in the thyroid gland accompanied by cervical lymph node enlargement. Thyroid surgery revealed LCNEC metastasis to the thyroid gland. Additional metastases were identified in both the adrenal glands. Despite appropriate treatment, the patient died of the disease. De novo LCNEC of the prostate is a rare, highly aggressive tumor with a poor prognosis. It is resistant to most therapeutic agents, has a high metastatic potential, and is usually diagnosed at an advanced stage. Further studies are required to characterize this tumor.

Learning points

• De novo LCNECs of the prostate gland can metastasize almost anywhere in the body, including the thyroid and adrenal glands.

• LCNECs of the prostate are usually associated with androgen-depriving therapy, but de novo cases are also notable and should be accounted for.

• Further studies are required to fully understand and treat LCNECs more effectively.

Summary

Depot medroxyprogesterone acetate, also known as Depo-Provera, is a progesterone-only contraceptive that is administered by injection to patients every three months. We describe the case of a 19-year-old female who was diagnosed with central diabetes insipidus following the administration of the contraceptive injection Depo-Provera. The patient was diagnosed with polycystic ovarian syndrome at age 16 and was originally prescribed oral contraceptives to restore menstrual regularity. Three years later, Depo-Provera was substituted for convenience, and symptoms of polyuria and polydipsia appeared one month after initiating the progesterone-only regimen. We are proposing that central diabetes insipidus may be a possible adverse effect of Depo-Provera in women with polycystic ovarian syndrome who receive the progesterone-only contraception, due to the interference of their arginine vasopressin mechanism through the alteration of estrogen levels. We review potential mechanisms through the presentation of previously completed research in polycystic ovarian syndrome.

Learning points

• We propose that although rare, the decrease in estrogen that is experienced during the administration of Depo-Provera can interfere with arginine vasopressin release in patients with polycystic ovarian syndrome (PCOS).

• Increased awareness of possible lasting adverse effects on fluid balance with unopposed progesterone administration in PCOS is important, as this case of the development of diabetes insipidus suggests.

• Discussion of such potential side effects is important when considering contraceptive options for the regulation of menses in patients with PCOS.