Clinical case seminar - Hypogonadotropic hypogonadism as a presenting feature of late-onset X-linked adrenal hypoplasia congenita

Mutations in the orphan nuclear receptor DAX-1 cause X-linked adrenal hypoplasia congenita. Affected boys usually present with primary adrenal failure in early infancy or childhood. Impaired sexual development because of hypogonadotropic hypogonadism becomes apparent at the time of puberty. We report adult-onset adrenal hypoplasia congenita in a patient who presented with hypogonadism at 28 yr of age. Although he had no clinical evidence of adrenal dysfunction, compensated primary adrenal failure was diagnosed by biochemical testing. Semen analysis showed azoospermia, and he did not achieve fertility after 8 months of treatment with gonadotropins. A novel Y380D DAX-1 missense mutation, which causes partial loss of function in transient gene expression assays, was found in this patient. This case demonstrates that partial loss-of-function mutations in DAX1 can present with hypogonadotropic hypogonadism and covert adrenal failure in adulthood. Further, an important role for DAX-1 in spermatogenesis in humans is confirmed, supporting findings in the Dax1 (Ahch) knockout mouse

How zebrafish research has helped in understanding thyroid diseases

Next-generation sequencing technologies have revolutionized the identification of disease-causing genes, accelerating the discovery of new mutations and new candidate genes for thyroid diseases. To face this flow of novel genetic information, it is important to have suitable animal models to study the mechanisms regulating thyroid development and thyroid hormone availability and activity. Zebrafish ( Danio rerio), with its rapid external embryonic development, has been extensively used in developmental biology. To date, almost all of the components of the zebrafish thyroid axis have been characterized and are structurally and functionally comparable with those of higher vertebrates. The availability of transgenic fluorescent zebrafish lines allows the real-time analysis of thyroid organogenesis and its alterations. Transient morpholino-knockdown is a solution to silence the expression of a gene of interest and promptly obtain insights on its contribution during the development of the zebrafish thyroid axis. The recently available tools for targeted stable gene knockout have further increased the value of zebrafish to the study of thyroid disease. All of the reported zebrafish models can also be used to screen small compounds and to test new drugs and may allow the establishment of experimental proof of concept to plan subsequent clinical trials

ENDO-ERN expert opinion on the differential diagnosis of pubertal delay.

The differential diagnoses of pubertal delay include hypergonadotropic hypogonadism and congenital hypogonadotropic hypogonadism (CHH), as well as constitutional delay of growth and puberty (CDGP). Distinguishing between CDGP and CHH may be challenging, and the scientific community has been struggling to develop diagnostic tests that allow an accurate differential diagnosis. Indeed, an adequate and timely management is critical in order to enable optimal clinical and psychosocial outcomes of the different forms of pubertal delays. In this review, we provide an updated insight on the differential diagnoses of pubertal delay, including the available tests, their meanings and accuracy, as well as some clues to effectively orientate towards either constitutional pubertal delay or pathologic CHH and hypergonadotropic hypogonadism

Standardized ultrasound report for thyroid nodules : the endocrinologist's viewpoint

BACKGROUND: Ultrasonography (US) plays a crucial role in the diagnostic management of thyroid nodules, but its widespread use in clinical practice might generate heterogeneity in ultrasound reports. OBJECTIVES: The aims of the study were to propose (a) a standardized lexicon for description of thyroid nodules in order to reduce US reports of interobserver variability and (b) a US classification system of suspicion for thyroid nodules in order to promote a uniform management of thyroid nodules. METHODS: RELEVANT PUBLISHED ARTICLES WERE IDENTIFIED BY SEARCHING MEDLINE AT PUBMED COMBINING THE FOLLOWING SEARCH TERMS: ultrasonography, thyroid, nodule, malignancy, carcinoma, and classification system. Results were supplemented with our data and experience. RESULTS: A STANDARDIZED US REPORT SHOULD ALWAYS DOCUMENT POSITION, EXTRACAPSULAR RELATIONSHIPS, NUMBER, AND THE FOLLOWING CHARACTERISTICS OF EACH THYROID LESION: shape, internal content, echogenicity, echotexture, presence of calcifications, margins, vascularity, and size. Combining the previous US features, each thyroid nodule can be tentatively classified as: malignant, suspicious for malignancy, borderline, probably benign, and benign. CONCLUSIONS: We propose a standardized US report and a tentative US classification system that may become helpful for endocrinologists dealing with thyroid nodules in their clinical practice. The proposed classification does not allow to bypass the required cytological confirmation, but may become useful in identifying the lesions with a lower risk of neoplasm

GLIS3 and Thyroid: A Pleiotropic Candidate Gene for Congenital Hypothyroidism

Variations in the transcription factor Gli-similar 3 (GLIS3) gene have been associated to variable congenital endocrine defects, including both morphogenetic and functional thyroid alterations. Evidence from Glis3 knockout mice indicates a relevant role for GLIS3 in thyroid hormone biosynthesis and postnatal thyroid gland growth, with a mechanism of action downstream of the TSH/TSHR interaction. However, the pathophysiological role of this transcription factor during the embryonic thyroid development remains unexplored. In this manuscript, we will provide an overview of the current knowledge on GLIS3 function during development. As a perspective, we will present preliminary evidence in the zebrafish model in support of a potential role for this pleiotropic transcription factor in the early stages of thyroid gland development

Publisher Correction: Prokineticin receptor 2 affects GnRH3 neuron ontogeny but not fertility in zebrafish

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Switch to restoration therapy in a testosterone treated central hypogonadism with erythrocytosis

We describe a case of severe erythrocytosis caused by testosterone replacement therapy in a 66-year-old man affected with hypogonadotropic hypogonadism (HH) determining osteoporosis, resolved by switching to restoration therapy with clomiphene citrate. The patient complained fatigue, loss of libido and defective erections and a spontaneous vertebral fracture despite bisphosphonate therapy and vitamin D supplementation. The examinations proved isolated HH and he was therefore treated with testosterone gel with regression of specific manifestations but elevated hemoglobin and hematocrit values. Therefore, it was decided to switch to a restoration therapy with clomiphene citrate 25\u2009mg/die, which resulted in the resolution of symptoms without evident side effects. In a couple of months, the patient showed normalization of testosterone levels and increment of testicular volume. Since secondary hypogonadism is the consequence of an insufficient stimulation of the gonads by hypothalamic-pituitary axis, therapeutic approaches aimed to restore endogenous testosterone production should be considered in alternative to testosterone replacement, particularly if side effects intervene. Among these strategies, clomiphene citrate seems to have a high efficacy and safety profile also in the elderly with isolated HH and no evident pituitary lesion

Targeted Next-Generation Sequencing Indicates a Frequent Oligogenic Involvement in Primary Ovarian Insufficiency Onset

Primary ovarian insufficiency (POI) is one of the major causes of female infertility associated with the premature loss of ovarian function in about 3.7% of women before the age of 40. This disorder is highly heterogeneous and can manifest with a wide range of clinical phenotypes, ranging from ovarian dysgenesis and primary amenorrhea to post-pubertal secondary amenorrhea, with elevated serum gonadotropins and hypoestrogenism. The ovarian defect still remains idiopathic in some cases; however, a strong genetic component has been demonstrated by the next-generation sequencing (NGS) approach of familiar and sporadic POI cases. As recent evidence suggested an oligogenic architecture for POI, we developed a target NGS panel with 295 genes including known candidates and novel genetic determinants potentially involved in POI pathogenesis. Sixty-four patients with early onset POI (range: 10–25 years) of our cohort have been screened with 90% of target coverage at 50×. Here, we report 48 analyzed patients with at least one genetic variant (75%) in the selected candidate genes. In particular, we found the following: 11/64 patients (17%) with two variants, 9/64 (14%) with three variants, 9/64 (14%) with four variants, 3/64 (5%) with five variants, and 2/64 (3%) with six variants. The most severe phenotypes were associated with either the major number of variations or a worse prediction in pathogenicity of variants. Bioinformatic gene ontology analysis identified the following major pathways likely affected by gene variants: 1) cell cycle, meiosis, and DNA repair; 2) extracellular matrix remodeling; 3) reproduction; 4) cell metabolism; 5) cell proliferation; 6) calcium homeostasis; 7) NOTCH signaling; 8) signal transduction; 9) WNT signaling; 10) cell death; and 11) ubiquitin modifications. Consistently, the identified pathways have been described in other studies dissecting the mechanisms of folliculogenesis in animal models of altered fertility. In conclusion, our results contribute to define POI as an oligogenic disease and suggest novel candidates to be investigated in patients with POI

Genetic diagnosis of endocrine diseases by NGS: novel scenarios and unpredictable results and risks

The technological advancements in genetics produced a profound impact on the research and diagnostics of non-communicable diseases. The availability of next-generation sequencing (NGS) allowed the identification of novel candidate genes but also an in-depth modification of the understanding of the architecture of several endocrine diseases. Several different NGS approaches are available allowing the sequencing of several regions of interest or the whole exome or genome (WGS, WES or targeted NGS), with highly variable costs, potentials and limitations that should be clearly known before designing the experiment. Here, we illustrate the NGS scenario, describe the advantages and limitations of the different protocols and review some of the NGS results obtained in different endocrine conditions. We finally give insights on the terminology and requirements for the implementation of NGS in research and diagnostic labs

Defining non-functioning adrenal adenomas on the basis of the occurrence of hypocortisolism after adrenalectomy

Background In patients with adrenal incidentalomas (AI), there is uncertainty on how to rule out hypercortisolism. The occurrence of post-surgical (unilateral adrenalectomy) hypocortisolism (PSH) has been proposed as a proof of the presence of a pre-surgical hypercortisolism in AI patients. The aim of this study was to define the thresholds of cortisol level after 1 mg overnight dexamethasone suppression test (F-1mgDST), urinary free cortisol (UFC), midnight serum cortisol (MSC) and adrenocorticotroph hormone (ACTH) able to predict the absence of PSH in AI patients undergoing surgery. Methods In 60 patients who underwent AI excision, cortisol secretion was assessed by low-dose corticotropin stimulation test or insulin tolerance test, when needed. We searched for the lowest pre-surgical value of F-1mgDST, UFC and MSC and the highest value for ACTH in AI patients with PSH as indexes of normal cortisol secretion. Results the lowest values of F-1mgDST, UFC and MSC and the highest value for ACTH in PSH patients were 1.2 \ub5g/dL (33 nmol/L), 10.4 \ub5g/24h (29 nmol/24h), 1.2 \ub5g/dL (33 nmol/L) and 26.9 pg/ml (6 pmol/L), respectively, but only F-1mgDST <1.2 \ub5g/dL (33 nmol/L) was able to predict the absence of PSH. Among AI patients with F-1mgDST <1.2 \ub5g/dL (33 nmol/L) no subjects had diabetes mellitus and/or metabolic syndrome and these subjects tended to have a better metabolic profile than those with F-1mgDST 651.2 \ub5g/dL (33nmol/L) Conclusion in AI patients a F-1mgDST <1.2 \u3bcg/dL (33 nmol/L) rules out PSH and could be used to exclude hypercortisolism in AI patients