Clinical Overview > Gland/Organ > Testes
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Search for other papers by Tetsuji Wakabayashi in
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Search for other papers by Kenta Okada in
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Search for other papers by Ken Ebihara in
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Search for other papers by Shun Ishibashi in
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Summary
The underlying genetic drivers of Kallmann syndrome, a rare genetic disorder characterized by anosmia and hypogonadotropic hypogonadism due to impairment in the development of olfactory axons and in the migration of gonadotropin-releasing hormone (GNRH)-producing neurons during embryonic development, remain largely unknown. SOX10, a key transcription factor involved in the development of neural crest cells and established as one of the causative genes of Waardenburg syndrome, has been shown to be a causative gene of Kallmann syndrome. A 17-year-old male patient, who was diagnosed with Waardenburg syndrome on the basis of a hearing impairment and hypopigmented iris at childhood, was referred to our department because of anosmia and delayed puberty. As clinical examination revealed an aplastic olfactory bulb and hypogonadotropic hypogonadism, we diagnosed him as having Kallmann syndrome. Incidentally, we elucidated that he also presented with subclinical hypothyroidism without evidence of autoimmune thyroiditis. Direct sequence analysis detected a nonsense SOX10 mutation (c.373C>T, p.Glu125X) in this patient. Since this nonsense mutation has never been published as a germline variant, the SOX10 substitution is a novel mutation that results in Kallmann syndrome and Waardenburg syndrome. This case substantiates the significance of SOX10 as a genetic cause of Kallmann syndrome and Waardenburg syndrome, which possibly share a common pathway in the development of neural crest cells.
Learning points
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Kallmann syndrome and Waardenburg syndrome possibly share a common pathway during neural crest cell development.
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SOX10, a key transcription factor involved in the development of neural crest cells, is a common causative gene of Kallmann syndrome and Waardenburg syndrome.
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Careful evaluation about various phenotypic features may reveal the unknown genetic drivers of Kallmann syndrome.
Search for other papers by Eriselda Profka in
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Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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Search for other papers by Alfredo Berrettini in
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Search for other papers by Valeria Daccò in
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Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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Search for other papers by Carla Colombo in
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Summary
An 8-year-old boy with cystic fibrosis came to our attention for an empty scrotum. General physical examination showed a normal penis and hypoplastic scrotum with non-palpable testes bilaterally. Routine blood investigations showed low levels of LH, testosterone, inhibin B and antiMullerian hormone and elevated levels of FSH. Karyotype was normal. An abdominal ultrasound confirmed the absence of the testes into the scrotum, in the inguinal region and abdomen. At laparoscopy were noted bilaterally hypotrophic spermatic vessels, absence of the vas deferens and a closed inner ring. Inguinal exploration found out a small residual testis and histological examination showed fibrotic tissue. This is the first case of testicular atrophy associated to CFTR mutation described. The process that led to bilateral testicular and vas deferens atrophy remains unexplained, a possible influence of CFTR dysfunction cannot be ruled out, although it is possible that these conditions are independently associated.
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Cystic fibrosis produces a multisystemic disease which can affect also the reproductive tract.
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Nearly 97–98% of male patients are infertile because of congenital bilateral absence of vas deferens.
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A correlation between cystic fibrosis and bilateral testicular atrophy could be possible.
Search for other papers by Tejhmal Rehman in
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Search for other papers by Ali Hameed in
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Search for other papers by Nigel Beharry in
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Search for other papers by J Du Parcq in
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Search for other papers by Gul Bano in
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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.
Memorial University Medical Center, Savannah, Georgia, USA
Search for other papers by Himangshu S Bose in
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Pediatric Endocrinology and Diabetes Center, Kalispell Regional Medical Center, Kalispell, Montana, USA
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Laboratory of Pathology, Memorial University Medical Center, Savannah, Georgia, USA
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Search for other papers by Elizabeth W Perry in
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Summary
Steroid hormones are essential for the survival of all mammals. In adrenal glands and gonads, cytochrome P450 side chain cleavage enzyme (SCC or CYP11A1), catalyzes conversion of cholesterol to pregnenolone. We studied a patient with ambiguous genitalia by the absence of Müllerian ducts and the presence of an incompletely formed vagina, who had extremely high adrenocorticotropic hormone (ACTH) and reduced pregnenolone levels with enlarged adrenal glands. The testes revealed seminiferous tubules, stroma, rete testis with interstitial fibrosis and reduced number of germ cells. Electron microscopy showed that the patient’s testicular mitochondrial size was small with little SCC expression within the mitochondria. The mitochondria were not close to the mitochondria-associated ER membrane (MAM), and cells were filled with the microfilaments. Our result revealed that absence of pregnenolone is associated with organelle stress, leading to altered protein organization that likely created steric hindrance in testicular cells.
Learning points:
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Testes revealed seminiferous tubules, stroma, rete testis with interstitial fibrosis and reduced number of germ cells;
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Testicular mitochondrial size was small with little SCC expression within the mitochondria;
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Absence of pregnenolone is associated with organelle stress.
Search for other papers by Priya Vaidyanathan in
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Search for other papers by Paul Kaplowitz in
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Summary
Pubertal gynecomastia is common, can be seen in 65% of the adolescent boys and is considered physiological. It is thought to be due to transient imbalance between the ratio of testosterone and estradiol in the early stages of puberty. It resolves in 1–2 years and requires no treatment. However, more persistent and severe pubertal gynecomastia is less common and can be associated with pathological disorders. These can be due to diminished androgen production, increased estrogen production or androgen resistance. We report a case of persistent pubertal gynecomastia due to partial androgen insensitivity syndrome (PAIS), classical hormone findings and a novel mutation in the androgen receptor (AR) gene.
Learning points:
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Laboratory testing of follicle-stimulating hormone (FSH), leutinizing hormone (LH) and testosterone for pubertal gynecomastia is most helpful in the setting of undervirization.
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The hormonal finding of very high testosterone, elevated LH and estradiol and relatively normal FSH are classical findings of PAIS.
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Gynecomastia due to PAIS will not resolve and surgery for breast reduction should be recommended.
Search for other papers by M A Shehab in
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Search for other papers by Tahseen Mahmood in
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Search for other papers by M A Hasanat in
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Search for other papers by Md Fariduddin in
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Search for other papers by Sharmin Jahan in
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Summary
Congenital adrenal hyperplasia (CAH) due to the three-beta-hydroxysteroid-dehydrogenase (3β-HSD) enzyme deficiency is a rare autosomal recessive disorder presenting with sexual precocity in a phenotypic male. Klinefelter syndrome (KS) is the most common sex chromosome aneuploidy presenting with hypergonadotropic hypogonadism in a male. However, only a handful of cases of mosaic KS have been described in the literature. The co-existence of mosaic KS with CAH due to 3β-HSD enzyme deficiency portrays a unique diagnostic paradox where features of gonadal androgen deficiency are masked by simultaneous adrenal androgen excess. Here, we report a 7-year-old phenotypic male boy who, at birth presented with ambiguous genitalia, probably a microphallus with penoscrotal hypospadias. Later on, he developed accelerated growth with advanced bone age, premature pubarche, phallic enlargement and hyperpigmentation. Biochemically, the patient was proven to have CAH due to 3β-HSD deficiency. However, the co-existence of bilateral cryptorchidism made us to consider the possibility of hypogonadism as well, and it was further explained by concurrent existence of mosaic KS (47,XXY/46,XX). He was started on glucocorticoid and mineralocorticoid replacement and underwent right-sided orchidopexy on a later date. He showed significant clinical and biochemical improvement on subsequent follow-up. However, the declining value of serum testosterone was accompanied by rising level of FSH thereby unmasking hypergonadotropic hypogonadism due to mosaic KS. In future, we are planning to place him on androgen replacement as well.
Learning points:
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Ambiguous genitalia with subsequent development of sexual precocity in a phenotypic male points towards some unusual varieties of CAH.
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High level of serum testosterone, adrenal androgen, plasma ACTH and low basal cortisol are proof of CAH, whereas elevated level of 17-OH pregnenolone is biochemical marker of 3β-HSD enzyme deficiency.
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Final diagnosis can be obtained with sequencing of HSD3B2 gene showing various mutations.
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Presence of bilateral cryptorchidism in such a patient may be due to underlying hypogonadism.
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Karyotyping in such patient may rarely show mosaic KS (47,XXY/46,XX) and there might be unmasking of hypergonadotropic hypogonadism resulting from adrenal androgen suppression from glucocorticoid treatment.
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Search for other papers by Vikram Lal in
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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.
Search for other papers by Ahmad Haider in
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Search for other papers by Karim S Haider in
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Research Department, Gulf Medical University, Ajman, UAE
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Summary
In daily practice, clinicians are often confronted with obese type 2 diabetes mellitus (T2DM) patients for whom the treatment plan fails and who show an inadequate glycemic control and/or no sustainable weight loss. Untreated hypogonadism can be the reason for such treatment failure. This case describes the profound impact testosterone therapy can have on a male hypogonadal patient with metabolic syndrome, resulting in a substantial and sustained loss of body weight, pronounced improvement of all critical laboratory values and finally complete remission of diabetes.
Learning points:
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Hypogonadism occurs frequently in men with T2DM.
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In case of pronounced abdominal fat deposition and T2DM, the male patient should be evaluated for testosterone deficiency.
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Untreated hypogonadism can complicate the successful treatment of patients with T2DM.
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Under testosterone therapy, critical laboratory values are facilitated to return back to normal ranges and even complete remission of diabetes can be achieved.
Search for other papers by Kingsley Okolie in
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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.
Search for other papers by Bronwen E Warner in
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Search for other papers by Carol D Inward in
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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:
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Clinical endocrine problems in Lowe syndrome has been reported, but has focused on abnormalities in adolescence and young adulthood: pubertal delay and infertility.
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We present an infant with isolated LH elevation at baseline and on GnRH stimulation testing who also had bilateral impalpable testes.
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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.
