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Katta Sai Department of Internal Medicine, Saint Vincent Hospital at Worcester Medical Center, Worcester, Massachusetts, USA

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Amos Lal Department of Internal Medicine, Saint Vincent Hospital at Worcester Medical Center, Worcester, Massachusetts, USA

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Jhansi Lakshmi Maradana Department of Internal Medicine, Saint Vincent Hospital at Worcester Medical Center, Worcester, Massachusetts, USA

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Pruthvi Raj Velamala Department of Internal Medicine, Saint Vincent Hospital at Worcester Medical Center, Worcester, Massachusetts, USA

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Trivedi Nitin Department of Endocrinology, Diabetes, and Metabolism, Saint Vincent Hospital at Worcester Medical Center, Worcester, Massachusetts, USA

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Summary

Mifepristone is a promising option for the management of hypercortisolism associated with hyperglycemia. However, its use may result in serious electrolyte imbalances, especially during dose escalation. In our patient with adrenocorticotropic hormone-independent macro-nodular adrenal hyperplasia, unilateral adrenalectomy resulted in biochemical and clinical improvement, but subclinical hypercortisolism persisted following adrenalectomy. She was started on mifepristone. Unfortunately, she missed her follow-up appointments following dosage escalation and required hospitalization at an intensive care level for severe refractory hypokalemia.

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Elke Thijs Internal Medicine, University Hospital, Ghent, Belgium

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Katrien Wierckx Endocrinology, OLV Hospital, Aalst, Belgium

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Stefaan Vandecasteele Nephrology – Infectious Diseases, A.Z.-Sint Jan, Bruges, Belgium

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Annick Van den Bruel Endocrinology, A.Z.-Sint Jan, Bruges, Belgium

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Summary

A 42-year-old man with complaints of muscle soreness and an increased pigmentation of the skin was referred because of a suspicion of adrenal insufficiency. His adrenocorticotropic hormone and cortisol levels indicated a primary adrenal insufficiency (PAI) and treatment with hydrocortisone and fludrocortisone was initiated. An etiological workup, including an assessment for anti-adrenal antibodies, very long-chain fatty acids, 17-OH progesterone levels and catecholamine secretion, showed no abnormalities. 18Fluorodeoxyglucose positron emission tomography/CT showed bilateral enlargement of the adrenal glands and bilateral presence of an adrenal nodule, with 18fluorodeoxyglucose accumulation. A positive tuberculin test and positive family history of tuberculosis were found, and tuberculostatic drugs were initiated. During the treatment with the tuberculostatic drugs the patient again developed complaints of adrenal insufficiency, due to insufficient dosage of hydrocortisone because of increased metabolism of hydrocortisone.

Learning points:

  • Shrinkage of the adrenal nodules following tuberculostatic treatment supports adrenal tuberculosis being the common aetiology.

  • The tuberculostatic drug rifampicin is a CYP3A4 inducer, increasing the metabolism of hydrocortisone. Increase the hydrocortisone dosage upon initiation of rifampicin in case of (adrenal) tuberculosis.

  • A notification on the Addison’s emergency pass could be considered to heighten physician’s and patients awareness of hydrocortisone drug interactions.

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Diana Oliveira Endocrinology, Diabetes and Metabolism Department, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal

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Mara Ventura Endocrinology, Diabetes and Metabolism Department, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal

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Miguel Melo Endocrinology, Diabetes and Metabolism Department, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal

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Sandra Paiva Endocrinology, Diabetes and Metabolism Department, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal

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Francisco Carrilho Endocrinology, Diabetes and Metabolism Department, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal

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Summary

Addison’s disease (AD) is the most common endocrine manifestation of antiphospholipid syndrome (APS), but it remains a very rare complication of the syndrome. It is caused by adrenal venous thrombosis and consequent hemorrhagic infarction or by spontaneous (without thrombosis) adrenal hemorrhage, usually occurring after surgery or anticoagulant therapy. We present a clinical case of a 36-year-old female patient with a previous diagnosis of APS. She presented with multiple thrombotic events, including spontaneous abortions. During evaluation by the third episode of abortion, a CT imaging revealed an adrenal hematoma, but the patient was discharged without further investigation. A few weeks later, she presented in the emergency department with manifestations suggestive of adrenal insufficiency. Based on that assumption, she started therapy with glucocorticoids, with significant clinical improvement. After stabilization, additional investigation confirmed AD and excluded other etiologies; she also started mineralocorticoid replacement. This case illustrates a rare complication of APS that, if misdiagnosed, may be life threatening. A high index of suspicion is necessary for its diagnosis, and prompt treatment is crucial to reduce the morbidity and mortality potentially associated.

Learning points:

  • AD is a rare but life-threatening complication of APS.

  • It is important to look for AD in patients with APS and a suggestive clinical scenario.

  • APS must be excluded in patients with primary adrenal insufficiency and adrenal imaging revealing thrombosis/hemorrhage.

  • Glucocorticoid therapy should be promptly initiated when AD is suspected.

  • Mineralocorticoid replacement must be started when there is confirmed aldosterone deficiency.

  • Hypertension is a common feature of APS; in patients with APS and AD, replacement therapy with glucocorticoids and mineralocorticoids may jeopardize hypertension management.

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E Bahaeldein Endocrinology, South Tipperary General Hospital, Clonmel, Ireland

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M J Brassill Endocrinology, South Tipperary General Hospital, Clonmel, Ireland

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Summary

Postmenopausal hyperandrogenism is a relatively rare diagnosis resulting from excess androgen production from the adrenals or ovaries. The exclusion of malignant causes is a priority. Laboratory tests and imaging are utilised to help differentiate the source of excess androgens. We report two cases of postmenopausal hyperandrogenism in women aged 75 and 67 years. Both cases presented with clinical features suggestive of hyperandrogenism which had developed gradually over the previous 2 years. Laboratory investigations confirmed a significant elevation in their serum testosterone levels. In both cases, imaging did not reveal any abnormality of the adrenals or ovaries. To help differentiate an adrenal vs ovarian source a single-dose GnRH analogue was given with measurement of testosterone and gonadotrophin levels pre and post. The reduction in gonadotrophins achieved by the GnRH analogue resulted in suppression of testosterone levels which suggested an ovarian source. Both patients proceeded to bilateral oophorectomy. Histology revealed a benign hilus cell tumour in one case and a benign Leydig cell tumour in the other.

Learning points:

  • A key part of the work-up of postmenopausal hyperandrogenism is to differentiate between an adrenal or an ovarian source of excess androgens;

  • Imaging may not identify small ovarian tumours or hyperthecosis and may also identify incidental adrenal masses which are non-functioning;

  • Current guidelines suggest ovarian and adrenal venous sampling when imaging is inconclusive but this requires technical expertise and has a high failure rate;

  • GnRH analogue use can successfully confirm ovarian source and should be considered as a diagnostic tool in this setting.

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Philip D Oddie Medical School, University of Oxford, Oxford, UK

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Benjamin B Albert Liggins Institute, University of Auckland, Auckland, New Zealand

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Paul L Hofman Liggins Institute, University of Auckland, Auckland, New Zealand
Starship Children’s Health, Auckland District Health Board, Auckland, New Zealand

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Craig Jefferies Starship Children’s Health, Auckland District Health Board, Auckland, New Zealand
Starship Children’s Health, Auckland District Health Board, Auckland, New Zealand

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Stephen Laughton Starship Children’s Health, Auckland District Health Board, Auckland, New Zealand

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Philippa J Carter Starship Children’s Health, Auckland District Health Board, Auckland, New Zealand

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Summary

Adrenocortical carcinoma (ACC) during childhood is a rare malignant tumor that frequently results in glucocorticoid and/or androgen excess. When there are signs of microscopic or macroscopic residual disease, adjuvant therapy is recommended with mitotane, an adrenolytic and cytotoxic drug. In addition to the anticipated side effect of adrenal insufficiency, mitotane is known to cause gynecomastia and hypothyroidism in adults. It has never been reported to cause precocious puberty. A 4-year-old girl presented with a 6-week history of virilization and elevated androgen levels and 1-year advancement in bone age. Imaging revealed a right adrenal mass, which was subsequently surgically excised. Histology revealed ACC with multiple unfavorable features, including high mitotic index, capsular invasion and atypical mitoses. Adjuvant chemotherapy was started with mitotane, cisplatin, etoposide and doxorubicin. She experienced severe gastrointestinal side effects and symptomatic adrenal insufficiency, which occurred despite physiological-dose corticosteroid replacement. She also developed hypothyroidism that responded to treatment with levothyroxine and peripheral precocious puberty (PPP) with progressive breast development and rapidly advancing bone age. Five months after discontinuing mitotane, her adrenal insufficiency persisted and she developed secondary central precocious puberty (CPP). This case demonstrates the diverse endocrine complications associated with mitotane therapy, which contrast with the presentation of ACC itself. It also provides the first evidence that the known estrogenic effect of mitotane can manifest as PPP.

Learning points:

  • Adrenocortical carcinoma is an important differential diagnosis for virilization in young children

  • Mitotane is a chemotherapeutic agent that is used to treat adrenocortical carcinoma and causes adrenal necrosis

  • Mitotane is an endocrine disruptor. In addition to the intended effect of adrenal insufficiency, it can cause hypothyroidism, with gynecomastia also reported in adults.

  • Patients taking mitotane require very high doses of hydrocortisone replacement therapy because mitotane interferes with steroid metabolism. This effect persists after mitotane therapy is completed

  • In our case, mitotane caused peripheral precocious puberty, possibly through its estrogenic effect.

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Khaled Aljenaee Department of Endocrinology, Royal College of Surgeons in Ireland, Connolly Hospital Blanchardstown, Dublin, Ireland

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Sulaiman Ali Departments of Endocrinology

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Seong Keat Cheah Department of Endocrinology, Royal College of Surgeons in Ireland, Connolly Hospital Blanchardstown, Dublin, Ireland

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Owen MacEneaney Histopathology, Mater Misericordiae University Hospital, Dublin, Ireland

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Niall Mulligan Histopathology, Mater Misericordiae University Hospital, Dublin, Ireland

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Neil Hickey Department of Radiology, Connolly Hospital Blanchardstown, Dublin, Ireland

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Tommy Kyaw Tun Department of Endocrinology, Royal College of Surgeons in Ireland, Connolly Hospital Blanchardstown, Dublin, Ireland

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Seamus Sreenan Department of Endocrinology, Royal College of Surgeons in Ireland, Connolly Hospital Blanchardstown, Dublin, Ireland

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John H McDermott Department of Endocrinology, Royal College of Surgeons in Ireland, Connolly Hospital Blanchardstown, Dublin, Ireland

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Markedly elevated androgen levels can lead to clinical virilization in females. Clinical features of virilization in a female patient, in association with biochemical hyperandrogenism, should prompt a search for an androgen-producing tumor, especially of ovarian or adrenal origin. We herein report the case of a 60-year-old woman of Pakistani origin who presented with the incidental finding of male pattern baldness and hirsutism. Her serum testosterone level was markedly elevated at 21 nmol/L (normal range: 0.4–1.7 nmol/L), while her DHEAS level was normal, indicating a likely ovarian source of her elevated testosterone. Subsequently, a CT abdomen-pelvis was performed, which revealed a bulky right ovary, confirmed on MRI of the pelvis as an enlarged right ovary, measuring 2.9 × 2.2 cm transaxially. A laparoscopic bilateral salpingo-oophorectomy was performed, and histopathological examination and immunohistochemistry confirmed the diagnosis of a Leydig cell tumor, a rare tumor accounting for 0.1% of ovarian tumors. Surgical resection led to normalization of testosterone levels.

Learning points:

  • Hirsutism in postmenopausal women should trigger suspicion of androgen-secreting tumor

  • Extremely elevated testosterone level plus normal DHEAS level point toward ovarian source

  • Leydig cell tumor is extremely rare cause of hyperandrogenicity

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Bronwen E Warner Departments of Paediatric Endocrinology and Diabetes

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Carol D Inward Departments of Paediatric Nephrology, Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust, Bristol, UK

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Christine P Burren Departments of Paediatric Endocrinology and Diabetes
NIHR Biomedical Research Unit in Nutrition, Diet & Lifestyle, University Hospitals Bristol NHS Foundation Trust, Education Centre, Bristol, UK

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Summary

This case, presenting with bilateral impalpable testes, illustrates the relevance of a broad differential disorders of sex development case management. It provides new insights on hypothalamic–pituitary–gonadal (HPG) axis and testicular function abnormalities in the multisystem disorder of Lowe syndrome. Lowe syndrome, also known as oculocerebrorenal syndrome, is a rare disorder characterised by eye abnormalities, central nervous system involvement and proximal renal tubular acidosis. There are a handful of reports of pubertal delay, infertility and cryptorchidism in Lowe syndrome. Biochemistry aged 72 h: testosterone 6.4 nmol/L, LH <0.5 IU/L and FSH <0.5 IU/L. Gonadotropin-releasing hormone stimulation test identified significantly raised baseline LH = 45.4 IU/L (contrasts with earlier undetectable LH), with a 20% increase on stimulation, while baseline FSH = 4.3 IU/L with no increase on stimulation. Day 14 HCG stimulation test produced an acceptable 50% increase in testosterone. The constellation of further abnormalities suggested Lowe syndrome: hypotonia, bilateral cataracts (surgical extraction and intraocular lens implantation) and renal tubular acidosis (microscopic haematuria, hypercalciuria, proteinuria, generalised aminoaciduria, hypophosphataemia and metabolic acidosis). DNA sequencing identified de novo hemizygous frameshift mutation OCRL c.2409_2410delCT in exon 22. Interpretation of initial and repeat GnRH and HCG testing indicates the likelihood of testicular failure. Partial testicular descent occurred but left orchidopexy was required. Improving long-term gonadal function in Lowe syndrome assumes increased importance for current cohorts as advances in renal replacement therapy have greatly improved life expectancy. Noting HPG axis abnormalities in Lowe syndrome in infancy can identify cases requiring increased surveillance of pubertal progress for earlier detection and management.

Learning points:

  • Clinical endocrine problems in Lowe syndrome has been reported, but has focused on abnormalities in adolescence and young adulthood: pubertal delay and infertility.

  • We present an infant with isolated LH elevation at baseline and on GnRH stimulation testing who also had bilateral impalpable testes.

  • Early testing of the HPG axis in patients with Lowe syndrome may help predict gonadal abnormalities from a younger age, which will enhance the overall case management into adolescence.

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Anil Piya Laboratory of Biochemistry, Mercer University School of Medicine, Savannah, Georgia, USA
Division of Pediatric Endocrinology, Memorial University Medical Center, Savannah, Georgia, USA

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Jasmeet Kaur Laboratory of Biochemistry, Mercer University School of Medicine, Savannah, Georgia, USA
Anderson Cancer Institute, Memorial University Medical Center, Savannah, Georgia, USA

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Alan M Rice Division of Pediatric Endocrinology, Memorial University Medical Center, Savannah, Georgia, USA
Augusta University School of Medicine, Augusta, Georgia, USA

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Himangshu S Bose Laboratory of Biochemistry, Mercer University School of Medicine, Savannah, Georgia, USA
Anderson Cancer Institute, Memorial University Medical Center, Savannah, Georgia, USA

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Summary

Cholesterol transport into the mitochondria is required for synthesis of the first steroid, pregnenolone. Cholesterol is transported by the steroidogenic acute regulatory protein (STAR), which acts at the outer mitochondrial membrane prior to its import. Mutations in the STAR protein result in lipoid congenital adrenal hyperplasia (CAH). Although the STAR protein consists of seven exons, biochemical analysis in nonsteroidogenic COS-1 cells showed that the first two were not essential for pregnenolone synthesis. Here, we present a patient with ambiguous genitalia, salt-lossing crisis within two weeks after birth and low cortisol levels. Sequence analysis of the STAR, including the exon–intron boundaries, showed the complete deletion of exon 1 as well as more than 50 nucleotides upstream of STAR promoter. Mitochondrial protein import with the translated protein through synthesis cassette of the mutant STAR lacking exon 1 showed protein translation, but it is less likely to have synthesized without a promoter in our patient. Thus, a full-length STAR gene is necessary for physiological mitochondrial cholesterol transport in vivo.

Learning points:

  • STAR exon 1 deletion caused lipoid CAH.

  • Exon 1 substitution does not affect biochemical activity.

  • StAR promoter is responsible for gonadal development.

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Asma Deeb Paediatric Endocrinology Department, Mafraq Hospital, Abu Dhabi, UAE

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Hana Al Suwaidi Paediatric Endocrinology Department, Mafraq Hospital, Abu Dhabi, UAE

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Salima Attia Paediatric Endocrinology Department, Mafraq Hospital, Abu Dhabi, UAE

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Ahlam Al Ameri Paediatric Endocrinology Department, Mafraq Hospital, Abu Dhabi, UAE

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Summary

Combined17α-hydroxylase/17,20-lyase deficiency is a rare cause of congenital adrenal hyperplasia and hypogonadism. Hypertension and hypokalemia are essential presenting features. We report an Arab family with four affected XX siblings. The eldest presented with abdominal pain and was diagnosed with a retroperitoneal malignant mixed germ cell tumour. She was hypertensive and hypogonadal. One sibling presented with headache due to hypertension while the other two siblings were diagnosed with hypertension on a routine school check. A homozygous R96Q missense mutation in P450c17 was detected in the index case who had primary amenorrhea and lack of secondary sexual characters at 17 years. The middle two siblings were identical twins and had no secondary sexual characters at the age of 14. All siblings had hypokalemia, very low level of adrenal androgens, high ACTH and high levels of aldosterone substrates. Treatment was commenced with steroid replacement and puberty induction with estradiol. The index case had surgical tumor resection and chemotherapy. All siblings required antihypertensive treatment and the oldest remained on two antihypertensive medications 12 years after diagnosis. Her breast development remained poor despite adequate hormonal replacement. Combined 17α-hydroxylase/17,20-lyase deficiency is a rare condition but might be underdiagnosed. It should be considered in young patients presenting with hypertension, particularly if there is a family history of consanguinity and with more than one affected sibling. Antihypertensive medication might continue to be required despite adequate steroid replacement. Breast development may remain poor in mutations causing complete form of the disease.

Learning points

  • Endocrine hypertension due to rarer forms of CAH should be considered in children and adolescents, particularly if more than one sibling is affected and in the presence of consanguinity.

  • 17α-hydroxylase/17,20-lyase deficiency is a rare form of CAH but might be underdiagnosed.

  • Blood pressure measurement should be carried out in all females presenting with hypogonadism.

  • Anti-hypertensive medications might be required despite adequate steroid replacement.

  • Initial presenting features might vary within affected members of the same family.

  • Adverse breast development might be seen in the complete enzyme deficiency forms of the disease.

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Maura Bucciarelli Department of Medicine, Lehigh Valley Health Network, Allentown, Pennsylvania, 18103, USA

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Ya-Yu Lee Division of Endocrinology, Department of Medicine, Lehigh Valley Health Network, Allentown, Pennsylvania, 18103, USA

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Vasudev Magaji Division of Endocrinology, Department of Medicine, Lehigh Valley Health Network, Allentown, Pennsylvania, 18103, USA

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Summary

Ectopic ACTH secretion from breast cancer is extremely rare. We report a case of a 30-year-old woman with a history of breast cancer, who presented with psychosis and paranoid behaviour. CT of the head showed white matter disease consistent with posterior reversible encephalopathy syndrome (PRES). Despite using mifepristone with multiple antihypertensives including lisinopril, spironolactone and metoprolol, she was hypertensive. Transaminitis did not allow mifepristone dose escalation and ketoconazole utilization. Etomidate infusion at a non-sedating dose in the intensive care unit controlled her hypertension and cortisol levels. She was transitioned to metyrapone and spironolactone. She was discharged from the hospital on metyrapone with spironolactone and underwent chemotherapy. She died 9 months later after she rapidly redeveloped Cushing's syndrome and had progressive metastatic breast cancer involving multiple bones, liver and lungs causing respiratory failure.

Learning points

  • Cushing's syndrome from ectopic ACTH secreting breast cancer is extremely rare.

  • Cushing's syndrome causing psychosis could be multifactorial including hypercortisolism and PRES.

  • Etomidate at non-sedating doses in intensive care setting can be effective to reduce cortisol production followed by transition to oral metyrapone.

Open access