Hyperandrogenism: Clinical Aspects, Investigation and Treatment

peer reviewedAndrogen excess (AE) is one of the most common endocrine disorders, affecting 10% of adult women before the menopause. The clinical picture varies widely depending on the etiology of AE. Most of these women are suffering from hirsutism, acne, menstrual disturbances, anovulation and obesity. Virilization is unusual, except in patients with ovary or adrenal cancer. Polycystic ovary syndrome (PCOS) and idiopathic hirsutism (IH) are the most frequent causes of androgen excess, accounting for more than 90% of the cases. The pathogenesis of PCOS is still an unresolved problem. A hereditary predisposition has been suggested. Enzymatic deficiency is a less frequent cause of AE, the most common deficiency being the non classic 21-OH deficiency (NCAH). AE has been implicated as a side effect of many drugs. Ovary and adrenal tumours are unusual, however, they must be considered especially in case of severe hirsutism or virilization. Complementary investigations are selected based on the result of clinical examination. Pharmacologic therapy, usually with anti-androgens, is the most widely used treatment for PCOS, IH and NCAH. Surgical therapy should be considered only when there is a particular indication such as Cushing's syndrome, ovary or adrenal tumours.L'hyperandrogénie affecte environ 10 % des femmes en âge de procréer. Elle associe à des degrés divers, hirsutisme, virilisation, obésité, résistance à l'insuline, troubles menstruels et infertilité. Les étiologies les plus fréquentes sont le syndrome des ovaires micropolykystiques (OMPK) et l'hirsutisme idiopathique. Parmi les déficits enzymatiques surrénaliens, c'est la déficience en 21-hydroxylase qui occupe de loin la première place. Rarement, c'est une tumeur maligne de l'ovaire ou de la surrénale, ou encore une maladie de Cushing, qui provoque l'hyperandrogénie. Après un examen clinique soigneux, la mise au point comprendra essentiellement des dosages hormonaux et des examens d'imagerie centrés sur la surrénale et l'ovaire et parfois sur l'hypopbyse. Les traitements sont adaptés à l'étiologie. Ils s'adresseront à la chirurgie dans les cas de tumeurs ovariennes, surrénaliennes ou hypophysaires. Cependant, dans la grande majorité des cas d'hyperandrogénie, c'est bien le traitement médicamenteux qui sera utilisé. Celui-ci concerne notamment le syndrome des OMPK, l'hirsutisme idiopathique et les blocs enzymatiques. Le traitement médical fait principalement appel à trois grandes classes de médicaments, les oestroprogestatifs, les anti-androgènes et les corticoïdes

mTOR-activating mutations in RRAGD are causative for kidney tubulopathy and cardiomyopathy

BACKGROUND: Over the last decade, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, approximately 20% of all tubulopathy patients lack a genetic diagnosis. METHODS: We performed whole-exome and genome sequencings of a patient cohort with a novel inherited salt-losing tubulopathy, hypomagnesemia, and dilated cardiomyopathy. We also conducted subsequent functional analyses in vitro of identified variants of RRAGD, a gene that encodes a small Rag guanosine triphosphatase (GTPase). RESULTS: In eight children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt wasting, and nephrocalcinosis, we identified heterozygous missense variants in RRAGD that mostly occurred de novo Six of these patients also had dilated cardiomyopathy and three underwent heart transplantation. We identified a heterozygous variant in RRAGD that segregated with the phenotype in eight members of a large family with similar kidney manifestations. The GTPase RagD encoded by RRAGD plays a role in mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron included the thick ascending limb and the distal convoluted tubule. The identified RRAGD variants were shown to induce a constitutive activation of mTOR signaling in vitro. CONCLUSIONS: Our findings establish a novel disease, which we call autosomal dominant kidney hypomagnesemia (ADKH-RRAGD), that combines an electrolyte-losing tubulopathy and dilated cardiomyopathy. The condition is caused by variants in the RRAGD gene, which encodes Rag GTPase D; these variants lead to an activation of mTOR signaling, suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function

Neurological Adverse Effects Attributable to β-Lactam Antibiotics: A Literature Review

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