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Sydney Medical School (Central), University of Sydney, Sydney, NSW, Australia
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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
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Functional hypogonadotropic hypogonadism is a relatively common, but likely underdiagnosed, condition in middle-aged to older males.
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Testosterone replacement is the current mainstay of endocrine therapy but can cause sub-fertility and testicular atrophy.
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Clomiphene citrate is a serum oestrogen receptor modulator that acts centrally to increase endogenous testosterone production without affecting fertility.
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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.
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Longitudinal prospective studies as randomised control trials evaluating alternatives to exogenous testosterone are required.
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School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia
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Surgical Services, John Hunter Hospital, Newcastle, New South Wales, Australia
University of Newcastle, Newcastle, New South Wales, Australia
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Department of Endocrinology, John Hunter Hospital, Newcastle, New South Wales, Australia
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Summary
We report concurrent metastatic prostatic adenocarcinoma (PC) and functioning androgen-secreting adrenocortical carcinoma (ACC) in a 77-year-old man. The failure to achieve adequate biochemical castration via androgen deprivation therapy (ADT) as treatment for PC metastases, together with elevated DHEA-S, androstenedione, and discordant adrenal tracer uptake on FDG-PET and PSMA-PET, suggested the presence of a concurrent functional primary adrenal malignancy. On histopathological analysis, scant foci of PC were present throughout the ACC specimen. Castration was achieved post adrenalectomy with concurrent drop in prostate-specific antigen. We outline the literature regarding failure of testosterone suppression on ADT and salient points regarding diagnostic workup of functioning adrenal malignancies.
Learning points
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Failure to achieve castration with androgen deprivation therapy is rare and should prompt careful review to identify the underlying cause.
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All adrenal lesions should be evaluated for hormone production, as well as assessed for risk of malignancy (either primary or secondary).
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Adrenocortical carcinomas are commonly functional, and can secrete steroid hormones or their precursors (androgens, progestogens, glucocorticoids and mineralocorticoids).
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In this case, a co-incident, androgen-producing adrenocortical carcinoma was the cause of failure of testosterone suppression from androgen deprivation therapy as treatment for metastatic prostate cancer. Pathological adrenal androgen production contributed to the progression of prostate cancer.
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Summary
Complete androgen-insensitivity syndrome (CAIS), a disorder of sex development (46,XY DSD), is caused primarily by mutations in the androgen receptor (AR). Gonadectomy is recommended due to the increased risk of gonadoblastoma, however, surgical intervention is often followed by loss of libido. We present a 26-year-old patient with CAIS who underwent gonadectomy followed by a significant decrease in libido, which was improved with testosterone treatment but not with estradiol. Genetic testing was performed and followed by molecular characterization. We found that this patient carried a previously unidentified start loss mutation in the androgen receptor. This variant resulted in an N-terminal truncated protein with an intact DNA binding domain and was confirmed to be loss-of-function in vitro. This unique CAIS case and detailed functional studies raise intriguing questions regarding the relative roles of testosterone and estrogen in libido, and in particular, the potential non-genomic actions of androgens.
Learning points
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N-terminal truncation of androgen receptor can cause androgen-insensitivity syndrome.
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Surgical removal of testosterone-producing gonads can result in loss of libido.
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Libido may be improved with testosterone treatment but not with estradiol in some forms of CAIS.
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A previously unreported AR mutation – p.Glu2_Met190del (c.2T>C) – is found in a CAIS patient and results in blunted AR transcriptional activity under testosterone treatment.
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Summary
Beta-human chorionic gonadotropin (βhCG) is normally produced by syncytiotrophoblasts of the placenta during pregnancy and aids embryo implantation. However, it is also secreted in varying amounts in non-pregnant conditions commonly heralding a neoplastic process. We present a case of 50-year-old man, who presented with bilateral gynaecomastia with elevated testosterone, oestradiol, suppressed gonadotropins with progressively increasing levels of human chorionic gonadotropin (hCG). Biochemical and radiological investigations including ultrasonography of testes, breast tissue, MRI pituitary and CT scan full body did not identify the source of hCG. FDG PET scan revealed a large mediastinal mass with lung metastasis. Immunostaining and histological analysis confirmed the diagnosis of primary choriocarcinoma of the mediastinum. It is highly aggressive and malignant tumor with poor prognosis. Early diagnosis and management are essential for the best outcome.
Learning points:
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High βhCG in a male patient or a non-pregnant female suggests a paraneoplastic syndrome.
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In the case of persistently positive serum hCG, exclude immunoassay interference by doing the urine hCG as heterophilic antibodies are not present in the urine.
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Non-gestational choriocarcinoma is an extremely rare trophoblastic tumor and should be considered in young men presenting with gynaecomastia and high concentration of hCG with normal gonads.
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A high index of suspicion and extensive investigations are required to establish an early diagnosis of extra-gonadal choriocarcinoma.
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Early diagnosis is crucial to formulate optimal management strategy and to minimize widespread metastasis for best clinical outcome.
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Institute of Genetic Medicine, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, UK
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Hypogonadal men may experience intense vasomotor symptoms, and vasomotor sweating can occasionally be associated with profound fluid losses. We describe a 37-year-old male, who exhibited persistent hypovolaemic hypernatraemia that was challenging to treat despite a continuous high fluid input (>4–5 L/day). He was noted to have drenching sweats and normochromic anaemia. He had recent traumatic head injury, which resulted in neurocognitive dysfunction, so pituitary function tests were done which showed primary hypogonadism. After exclusion of all other possible causes of excess sweating, hypernatraemia and anaemia, a trial of testosterone therapy was instituted. Sweating dramatically ceased within hours of his first testosterone injection, hydration status normalised within days and anaemia and neurocognitive function progressively improved with continued testosterone replacement. This case demonstrates how, in a susceptible individual, hypovolaemic hypernatraemia can arise from insensible cutaneous fluid loss through eccrine sweating, mediated by vasomotor symptoms of untreated hypogonadism. Although this scenario has not been described in the literature, we felt it needed to be shared with the wider medical community because of how the diagnosis and treatment utterly transformed this patient’s functional status and outcome.
Learning points:
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Hypogonadal men may experience intense vasomotor symptoms and vasomotor sweating can occasionally be associated with profound fluid losses.
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Whether or not there is also hyperosmolar hypernatraemia, clinicians should always consider the possibility of underlying hypogonadism in men with normocytic anaemia and excessive sweating.
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Androgen (testosterone) replacement in hypogonadal men can have a dramatic effect on vasomotor sweating and hot flushes.
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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:
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Hirsutism in postmenopausal women should trigger suspicion of androgen-secreting tumor
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Extremely elevated testosterone level plus normal DHEAS level point toward ovarian source
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Leydig cell tumor is extremely rare cause of hyperandrogenicity
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Australian National University Medical School, Canberra, ACT, Australia
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Australian National University Medical School, Canberra, ACT, Australia
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Klinefelter syndrome (KS) is a chromosomal disorder affecting males, with the typical karyotype of 47,XXY due to a supernumerary X chromosome, which causes progressive testicular failure resulting in androgen deficiency and infertility. Despite it being the most common sex chromosomal disorder, its diagnosis is easily missed. In addition to its classical clinical features of tall stature, gynaecomastia, small testes, and symptoms and signs of hypogonadism including infertility, KS is also often associated with neurocognitive, behavioural and psychiatric disorders.
We present a 44-year-old man with KS who, despite having erectile dysfunction, paradoxically had increased libido. He used sildenafil to overcome his erectile dysfunction. Hypersexuality was manifested by very frequent masturbation, multiple sexual partners most of whom were casual, and a sexual offence conviction at the age of 17 years.
Discussion focuses on the frequent failure of clinicians to diagnose KS, the neurocognitive, behavioural and psychiatric aspects of KS, this unusual presentation of hypersexuality in a man with KS, and the challenges of medical management of hypogonadism in a man with a history of a sexual offence.
Learning points:
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Klinefelter syndrome (KS) is common in men (about 1 in 600 males), but the diagnosis is very often missed.
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In addition to classic features of hypogonadism, patients with KS can often have associated neurocognitive, behavioural and/or psychiatric disorders.
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More awareness of the association between KS and difficulties related to verbal skills in boys could improve rates of early diagnosis and prevent longer-term psychosocial disability.
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Hypersexuality in the context of hypogonadism raises the possibility of sex steroid independent mechanistic pathways for libido.
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Testosterone replacement therapy in KS with hypersexuality should be undertaken with caution using a multidisciplinary team approach.
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Summary
We report the case of a 19-year-old boy, presenting several congenital malformations (facial dysmorphisms, cardiac and musculoskeletal abnormalities), mental retardation, recurrent respiratory infections during growth and delayed puberty. Although previously hospitalised in other medical centres, only psychological support had been recommended for this patient. In our department, genetic, biochemical/hormonal and ultrasound examinations were undertaken. The karyotype was 49,XXXXY, a rare aneuploidy with an incidence of 1/85 000–100 000, characterised by the presence of three extra X chromosomes in phenotypically male subjects. The hormonal/biochemical profile showed hypergonadotropic hypogonadism, insulin resistance and vitamin D deficiency. The patient was then treated with testosterone replacement therapy. After 12 months of treatment, we observed the normalisation of testosterone levels. There was also an increase in pubic hair growth, testicular volume and penis size, weight loss, homeostatic model assessment index reduction and the normalisation of vitamin D values. Moreover, the patient showed greater interaction with the social environment and context.
Learning points
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In cases of plurimalformative syndrome, cognitive impairment, recurrent infections during growth and, primarily, delayed puberty, it is necessary to ascertain as soon as possible whether the patient is suffering from hypogonadism or metabolic disorders due to genetic causes. In our case, the diagnosis of hypogonadism, and then of 49,XXXXY syndrome, was unfortunately made only at the age of 19 years.
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The testosterone replacement treatment, even though delayed, induced positive effects on: i) development of the reproductive system, ii) regulation of the metabolic profile and iii) interaction with the social environment and context.
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However, earlier and timely hormonal replacement treatment could probably have improved the quality of life of this subject and his family.
Concord Clinical School, The University of Sydney, Sydney, New South Wales, 2139, Australia
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Concord Clinical School, The University of Sydney, Sydney, New South Wales, 2139, Australia
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Concord Clinical School, The University of Sydney, Sydney, New South Wales, 2139, Australia
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Summary
X-linked adrenoleukodystrophy (X-ALD) is a rare genetic condition caused by mutations in the ABCD1 gene that result in accumulation of very long chain fatty acids (VLCFAs) in various tissues. This leads to demyelination in the CNS and impaired steroidogenesis in the adrenal cortex and testes. A 57-year-old gentleman was referred for the assessment of bilateral gynaecomastia of 6 months duration. He had skin hyperpigmentation since 4 years of age and spastic paraparesis for the past 15 years. Physical examination findings included generalised hyperpigmentation (including skin, buccal mucosa and palmar creases), blood pressure of 90/60 mmHg, non-tender gynaecomastia and bilateral hypoplastic testes. Lower limb findings were those of a profoundly ataxic gait associated with significant paraparesis and sensory loss. Primary adrenal insufficiency was confirmed and investigations for gynaecomastia revealed normal testosterone with mildly elevated luteinising hormone level and normal prolactin. The combination of primary adrenal insufficiency (likely childhood onset), partial testicular failure (leading to gynaecomastia) and spastic paraparesis suggested X-ALD as a unifying diagnosis. A serum VLCFA panel was consistent with X-ALD. Subsequent genetic testing confirmed the diagnosis. Treatment with replacement doses of corticosteroid resulted in improvement in blood pressure and increased energy levels. We have reported the case of a 57-year-old man with a very late diagnosis of X-ALD manifested by childhood onset of primary adrenal insufficiency followed by paraparesis and primary hypogonadism in adulthood. Thus, X-ALD should be considered as a possibility in a patient with non-autoimmune primary adrenal insufficiency and neurological abnormalities.
Learning points
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Adult patients with X-ALD may be misdiagnosed as having multiple sclerosis or idiopathic spastic paraparesis for many years before the correct diagnosis is identified.
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Screening for X-ALD with a VLCFA panel should be strongly considered in male children with primary adrenal insufficiency and in male adults presenting with non-autoimmune primary adrenal insufficiency.
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Confirmation of a genetic diagnosis of X-ALD can be very useful for a patient's family as genetic testing enables detection of pre-symptomatic female heterozygotes who can then be offered pre-natal testing to avoid transmission of the disease to male offsprings.
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Summary
Madelung's disease is a rare fat metabolism disorder characterised by benign multiple symmetric, encapsulated lipomatosis. The exact cause of the disease is unknown; it may be associated with chronic alcoholism and mutations in mitochondrial DNA (A8344G), but there have been cases without these factors reported in the literature. A 29-year-old man with a 6-year history of diabetes mellitus was admitted to our hospital for poorly regulated diabetes and decreased libido. He was not an alcohol consumer. His family history was unremarkable. Physical examination revealed that he had a eunuchoid body shape. There was a symmetric excess fat accumulation in his submandibular, deltoid, nuchal, suprapubic and inguinal areas. He was diagnosed with Madelung's disease, and imaging studies supported the diagnosis. Hormonal evaluation revealed a hypergonadotropic hypogonadism. Karyotype analysis revealed a 47,XXY mutation. Genetic research showed no mitochondrial DNA mutation. Metabolic disorders, such as diabetes mellitus, hyperlipidaemia, hyperuricaemia and liver disease, endocrine gland diseases, such as hypothyroidism, and neurological diseases, such as polyneuropathy and cognitive disorders, may accompany Madelung's disease. The present study represents the first reported case of Madelung's disease accompanied by Klinefelter's syndrome.
Learning points
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Madelung's disease is a rare fat metabolism disorder characterised by benign multiple symmetric and encapsulated lipid accumulation.
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The exact cause of the disease is unknown.
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Metabolic disorders, such as diabetes mellitus, hyperlipidaemia, hyperuricaemia and liver disease, endocrine gland diseases, such as hypothyroidism, and neurological diseases, such as polyneuropathy and cognitive disorders, may accompany Madelung's disease.
