Body composition and myokines in a cohort of patients with Becker muscular dystrophy.

INTRODUCTION/AIMS: Becker muscular dystrophy (BMD) is an X-linked disease leading to muscle wasting and weakness. The decrease in lean body mass (LBM) in Duchenne muscular dystrophy, has shown correlation with loss of muscle function and bone density (BD). Myokines (including irisin) are hormones secreted by skeletal muscle that allow crosstalk between muscle and bone. The present study analyzed body composition and circulating myokine levels in a cohort of BMD patients; moreover, the association between dual energy X-ray absorptiometry (DXA) parameters, functional motor assessments, and myokine levels was investigated. METHODS: All patients underwent DXA, blood samples for myokine assays, and functional motor assessments. A group of healthy controls (HCs) was also included. RESULTS: Thirty BMD patients, median age at evaluation 36.0 y [26.0-41.0], were included. Twenty-nine patients underwent whole-body DXA. Median value of total body Z-score was -0.70. The prevalence of low skeletal muscle mass defined as appendicular skeletal muscle mass index (ASMMI) < 7.59 kg/m2 was 83%. Irisin levels were significantly lower in BMD compared to HCs (p = .03). All DXA parameters showed significant correlation with the functional motor assessments, in particular the h2 -standardized lean mass lower limb index (p = .0006); h2 -standardized total fat mass showed negative correlations with North Star Ambulatory Assessment and 6 min walk test (p = .03). DISCUSSION: DXA is a useful tool to evaluate body composition in BMD patients; the decrease in BD and LBM is associated with a reduction of motor function in BMD.

Central hypogonadism in Klinefelter syndrome: report of two cases and review of the literature.

PURPOSE: Klinefelter syndrome (KS) is characterized by late adolescence/young adulthood onset of primary hypogonadism. Hypogonadotropic hypogonadism (HH), when congenital, is usually associated with absent/incomplete puberty and low/normal gonadotropins. We report the clinical and genetic features of two subjects with KS and an unexpected HH hormone profile. METHODS: Magnetic resonance imaging (MRI) of hypothalamus-pituitary region and next generation sequencing (NGS) of congenital HH-associated genes were obtained. A narrative review of the literature was conducted. RESULTS: Patients were diagnosed with Klinefelter syndrome following karyotype analysis. Nevertheless, they showed unusual features: both had incomplete puberty, low gonadotropins and testosterone levels, and the first one was anosmic. Sellar lesions were excluded by MRI, and NGS was negative in both subjects. Our data add to those of the only 14 similar cases reported so far. Unexplained HH rarely occurs in KS and is variably associated with anosmia, other pituitary hormones deficiencies and heterogeneous karyotypes. However, most cases show an early, pre-pubertal onset of hypogonadism. If the causes behind this gonadotropins defect are largely unknown, hereby we provide the first review of the literature on this topic and propose some pathogenetic hypotheses, including the coexistence of KS and congenital HH as suggested by overlapping clinical features in some of these patients. CONCLUSION: HH is an exceptional occurrence in Klinefelter syndrome and is associated with heterogeneous phenotypes and, probably, aetiologies. Moreover, KS could underlie HH nonresponsive to gonadotropins. An exhaustive diagnostic workup and a tailored clinical management are advisable in these rare forms.

Pubertal delay: the challenge of a timely differential diagnosis between congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty.

Distinguishing between constitutional delay of growth and puberty (CDGP) and congenital hypogonadotropic hypogonadism (CHH) may be challenging. CDGP and CHH appear to belong to the same clinical spectrum (with low sex hormones and low LH and FSH), although one is classically transient and known as a self-limited form of delayed puberty (CDGP) while the other is permanent (CHH). Thus, the clinical history and the outcomes of these two conditions require different approaches, and an adequate and timely management for the patients is mandatory. Since the initial presentation of CDGP and CHH is almost identical and given the similarities of CDGP and partial forms of CHH (i.e. patients with partial and early interrupted pubertal development) the scientific community has been struggling to find some diagnostic tests able to allow an accurate differential diagnosis between these two conditions in delayed puberty. In this review we provide an up to date insight on the tests available, their meanings and accuracy, as well as some clues to effectively differentiate between constitutional pubertal delay and pathologic CHH.

[The management of hypothyroidism during pregnancy.] / La gestione dell'ipotiroidismo in gravidanza.

During pregnancy, the need for thyroid hormone and its production increase: the presence of a concomitant thyroid disease, however, may prevent the maternal thyroid from meeting such increased demands for hormone production, which could lead to - or worsen - a state of hypothyroidism. Hypothyroidism in pregnancy could adversely affect the growth and development of the fetus as well as the course of the pregnancy itself. The present case report involves a 38-year-old woman with autoimmune hypothyroidism, who has been on levothyroxine replacement therapy since adolescence. The patient underwent the transfer of an embryo previously obtained by in vitro fertilization (Fivet), starting with pre-pregnancy TSH levels of 0.5 mU/L. Two weeks after the transfer, despite a preemptive increase in Euthyrox dosage once pregnancy was confirmed, TSH values rose to 7.6 mU/L, which is why the dose of levothyroxine was increased: after another two weeks, a new sampling showed the return of TSH to levels appropriate for pregnancy status (<2.5 mU/L). During the remainder of gestation, thyroid function was monitored regularly, with minor adjustments in levothyroxine dosage according to TSH values, with no further major swings in its levels until the end of pregnancy.

The complications of male hypogonadism: is it just a matter of low testosterone?

The history of diagnosing hypogonadism and hypotestosteronemia shows us the many steps that were necessary to achieve our current knowledge and the ability to improve these patients' well-being. Moreover, so far, criteria for diagnosing hypotestosteronemia varies according to the underlying condition, and according to the consensus or guideline adopted. Furthermore, besides the many signs and symptoms, there are several complications associated with low testosterone levels such as osteoporosis, metabolic alterations, as well as cardiovascular disorders. However, data are often conflicting regarding the severity, timing or even the real clinical relevance of these complications, although these studies often lack essential information such as gonadotropin levels or the underlying cause of hypogonadism. The present review focus on the complications of male hypogonadism according to the cause of testosterone deficiency, highlighting the lack of information found in many studies investigating its effects. We thereby stress the necessity to always perform a complete evaluation of the type of hypogonadism (including at least gonadotropins and secondary causes) when investigating the effects of low testosterone levels.

Genetic architecture of self-limited delayed puberty and congenital hypogonadotropic hypogonadism.

Distinguishing between self limited delayed puberty (SLDP) and congenital hypogonadotropic hypogonadism (CHH) may be tricky as they share clinical and biochemical characteristics. and appear to lie within the same clinical spectrum. However, one is classically transient (SDLP) while the second is typically a lifetime condition (CHH). The natural history and long-term outcomes of these two conditions differ significantly and thus command distinctive approaches and management. Because the first presentation of SDLP and CHH is very similar (delayed puberty with low LH and FSH and low sex hormones), the scientific community is scrambling to identify diagnostic tests that can allow a correct differential diagnosis among these two conditions, without having to rely on the presence or absence of phenotypic red flags for CHH that clinicians anyway seem to find hard to process. Despite the heterogeneity of genetic defects so far reported in DP, genetic analysis through next-generation sequencing technology (NGS) had the potential to contribute to the differential diagnostic process between SLDP and CHH. In this review we will provide an up-to-date overview of the genetic architecture of these two conditions and debate the benefits and the bias of performing genetic analysis seeking to effectively differentiate between these two conditions.

New and Consolidated Therapeutic Options for Pubertal Induction in Hypogonadism: In-depth Review of the Literature.

Delayed puberty (DP) defines a retardation of onset/progression of sexual maturation beyond the expected age from either a lack/delay of the hypothalamo-pituitary-gonadal axis activation or a gonadal failure. DP usually gives rise to concern and uncertainty in patients and their families, potentially affecting their immediate psychosocial well-being and also creating longer term psychosexual sequelae. The most frequent form of DP in younger teenagers is self-limiting and may not need any intervention. Conversely, DP from hypogonadism requires prompt and specific treatment that we summarize in this review. Hormone therapy primarily targets genital maturation, development of secondary sexual characteristics, and the achievement of target height in line with genetic potential, but other key standards of care include body composition and bone mass. Finally, pubertal induction should promote psychosexual development and mitigate both short- and long-term impairments comprising low self-esteem, social withdrawal, depression, and psychosexual difficulties. Different therapeutic options for pubertal induction have been described for both males and females, but we lack the necessary larger randomized trials to define the best approaches for both sexes. We provide an in-depth and updated literature review regarding therapeutic options for inducing puberty in males and females, particularly focusing on recent therapeutic refinements that better encompass the heterogeneity of this population, and underlining key differences in therapeutic timing and goals. We also highlight persistent shortcomings in clinical practice, wherein strategies directed at "the child with delayed puberty of uncertain etiology" risk being misapplied to older adolescents likely to have permanent hypogonadism.

Genetic and phenotypic differences between sexes in congenital hypogonadotropic hypogonadism (CHH): Large cohort analysis from a single tertiary centre.

Background: Congenital hypogonadotropic hypogonadism (CHH) is a condition with a strong genetic background, caused by a deficient production, secretion, or action of gonadotropin-releasing hormone (GnRH). Published data on CHH cohorts indicate a male predominance, although this is not supported by our current understandings. Aims: In order to unravel the possible causes or contributors to such epidemiological sex difference, the aim of our study is to investigate differences in genetic background and clinical presentation between males and females in a large cohort of CHH patients. Materials and methods: We enrolled 338 CHH patients with absent or arrested pubertal development, referred to our Center from 01/2016. Data collection included clinical assessment at diagnosis and genetic analysis performed by next generation sequencing (NGS), employing a custom panel of 28 candidate genes. Results: Among 338 patients 94 were female (F) and 244 male (M), with a ratio of 1:2.6. We found that 36.09% (122/338) of patients harbored potentially pathogenic rare genetic variants (RVs) with no significant differences between sexes; on the other hand, a significantly higher frequency of oligogenicity was observed in females (F 9,57% 9/94 vs M 3,69% 9/244, P = 0.034). The prevalence of non-reproductive phenotypic features was significantly higher (P = 0.01) in males (53/228, 23.2%) than in females (10/93, 10.8%): in particular, kidney abnormalities affected only male patients and midline defects had a significantly higher prevalence in males (P = 0.010). Finally, BMI SDS was -0.04 ± 1.09 in females and 0.69 ± 1.51 in males, with a statistically significant difference between groups (P = <0.001). Conclusion: Our data confirm the male predominance in CHH and identify some differences with regard to the clinical presentation between males and females that could indicate a variable expression of genetic rare variants and a dimorphic modulation of phenotype according to metabolic/behavioral factors, which will need to be substantiated and investigated by further studies.

Protective Effect of Denosumab on Bone in Older Women with Primary Hyperparathyroidism.

OBJECTIVES: To determine the effect of denosumab, which is used in primary osteoporosis (PO), in primary hyperparathyroidism (PHPT)-related osteoporosis. DESIGN: Retrospective, longitudinal study. SETTING: Outpatient osteoporosis clinic. PARTICIPANTS: Older women with PHPT (78.6 ± 5.5) (n = 25) and PO (78.8 ± 5.2) (n = 25) matched on age, body mass index, familial history of hip fracture, femoral bone mineral density (BMD), and personal history of fragility fractures. INTERVENTION: Twenty-four months of denosumab therapy. MEASUREMENTS: We assessed the calcium-phosphorus metabolism parameters; BMD at the lumbar spine (LS), femoral neck (FN), and total hip (TH) using dual X-ray absorptiometry; and morphometric vertebral fractures using radiographs in all subjects at baseline and after 24 months. Changes in BMD and total alkaline phosphatase (ALP) activity were considered significant if they were greater than the least significant change (LS 2.8%, FN 5.9%, TH 4.8%, ALP -22%) and were expressed as percentage difference between end of follow-up and baseline (Δ). RESULTS: After 24 months, women with PHPT had greater ΔALP (-30.6 ± 11.3), ΔFN (5.6 ± 4.8), and ΔTH (4.8 ± 4.4) than those with PO (ΔALP -21.4 ± 13.1, ΔFN 2.9 ± 4.8, ΔTH 1.2 ± 4.1, P < .05 for all comparisons). A significant increase in BMD was more frequent in women with PHPT (92%) than in those with PO (52%, P < .05) and it was 13.4 times as likely in women with PHPT as in those with PO (P = .02), regardless of possible confounders. Two subjects in each group had an incident fracture. CONCLUSIONS: Denosumab therapy is effective in older women with PHPT-related osteoporosis.