Context:
The term pseudohypoparathyroidism (PHP) indicates a group of heterogeneous disorders whose common feature is represented by impaired signaling of various hormones (primarily PTH) that ...activate cAMP-dependent pathways via Gsα protein. The two main subtypes of PHP, PHP type Ia, and Ib (PHP-Ia, PHP-Ib) are caused by molecular alterations within or upstream of the imprinted GNAS gene, which encodes Gsα and other translated and untranslated products.
Evidence acquisition:
A PubMed search was used to identify the available studies (main query terms: pseudohypoparathyroidism; Albright hereditary osteodystrophy; GNAS; GNAS1; progressive osseous heteroplasia). The most relevant studies until February 2011 have been included in the review.
Evidence synthesis and conclusions:
Despite the first description of this disorder dates back to 1942, recent findings indicating complex epigenetic alterations beside classical mutations at the GNAS complex gene, pointed out the limitation of the actual classification of the disease, resulting in incorrect genetic counselling and diagnostic procedures, as well as the gap in our actual knowledge of the pathogenesis of these disorders. This review will focus on PHP type I, in particular its diagnosis, classification, treatment, and underlying molecular alterations.
Pseudohypoparathyroidism (PHP), the first known post-receptorial hormone resistance, derives from a partial deficiency of the α subunit of the stimulatory G protein (Gsα), a key component of the ...PTH/PTHrP signaling pathway. Since its first description, different studies unveiled, beside the molecular basis for PHP, the existence of different subtypes and of diseases in differential diagnosis associated with genetic alterations in other genes of the PTH/PTHrP pathway. The clinical and molecular overlap among PHP subtypes and with different but related disorders make both differential diagnosis and genetic counseling challenging. Recently, a proposal to group all these conditions under the novel term “inactivating PTH/PTHrP signaling disorders (iPPSD)” was promoted and, soon afterwards, the first international consensus statement on the diagnosis and management of these disorders has been published. This review will focus on the major and minor features characterizing PHP/iPPSDs as a group and on the specificities as well as the overlap associated with the most frequent subtypes.
Sommario
L’acromegalia è una malattia sistemica con segni e sintomi caratteristici, tra cui alterazioni delle caratteristiche facciali e ingrossamento delle estremità acrali. Sebbene le alterazioni ...neuropsicologiche non siano storicamente associate a questa malattia, la pratica clinica ha dimostrato che sintomi psicologici possono essere presenti nei pazienti acromegalici e avere un impatto significativo sulla qualità della vita. La qualità della vita nel paziente con acromegalia è un parametro importante per definire il compenso di malattia globale ed è direttamente influenzata, oltre che dalle terapie e dalla sintomatologia clinica, anche dal quadro neuropsicologico. Ad oggi, diversi studi hanno individuato una maggiore incidenza di patologia neuropsicologica nei pazienti affetti da acromegalia; in particolare, i pazienti hanno tassi più elevati di disturbi affettivi come depressione, ansia e disturbi somatici. Inoltre, come intuibile, anche le modificazioni dell’aspetto corporeo contribuiscono a innescare disturbi di percezione del proprio corpo che, oltre ad essere debilitanti di per sé, contribuiscono al mantenimento e all’aggravarsi della patologia psicologica in generale. Inoltre, valutazioni più complete e specialistiche dal punto di vista neurocognitivo hanno dimostrato come i pazienti acromegalici soffrano anche di una diminuzione della performance cognitiva in diversi domini, peggiorando ulteriormente il quadro globale e la qualità di vita. È interessante segnalare come tutte queste problematiche dipendenti dall’effetto di GH sul sistema nervoso centrale creino delle alterazioni a lungo termine, che non regrediscono con il raggiungimento del controllo o della cura di malattia. Per questo motivo, oltre ad auspicare ulteriori studi più approfonditi per meglio comprendere l’impatto di GH e IGF1 sul quadro neuropsicologico, raccomandiamo nella pratica clinica maggiore attenzione a questo aspetto, con un approccio sempre più multidisciplinare, comprendente anche la collaborazione di neuropsicologi, psichiatri e neurologi nel team dedicato al paziente acromegalico.
Abstract
Context
Coronavirus disease 2019 (COVID-19) represents a global health emergency, and infected patients with chronic diseases often present with a severe impairment. Adrenal insufficiency ...(AI) is supposed to be associated with an increased infection risk, which could trigger an adrenal crisis.
Objective
Our primary aim was to evaluate the incidence of COVID-19 symptoms and complications in AI patients.
Design and Setting
We conducted a retrospective case-control study. All patients were on active follow-up and lived in Lombardy, Italy, one of the most affected areas.
Patients
We enrolled 279 patients with primary and secondary AI and 112 controls (patients with benign pituitary lesions without hormonal alterations). All AI patients had been previously trained to modify their replacement therapy on stress doses.
Intervention
By administering a standardized questionnaire by phone, we collected data on COVID-19 suggestive symptoms and consequences.
Results
In February through April 2020, the prevalence of symptomatic patients (complaining at least 1 symptom of viral infection) was similar between the 2 groups (24% in AI and 22.3% in controls, P = 0.79). Highly suggestive COVID-19 symptoms (at least 2 including fever and/or cough) also occurred equally in AI and controls (12.5% in both groups). No patient required hospitalization and no adrenal crisis was reported. Few nasopharyngeal swabs were performed (n = 12), as indicated by sanitary regulations, limiting conclusions on the exact infection rate (2 positive results in AI and none in controls, P = 0.52).
Conclusions
AI patients who are adequately treated and trained seem to display the same incidence of COVID-19-suggestive symptoms and disease severity as controls.
The pharmacological treatment of pituitary tumours is based on the use of stable analogues of somatostatin and dopamine. The analogues bind to somatostatin receptor types 2 and 5 (SST2 and SST5) and ...dopamine receptor type 2 (DRD2), respectively, and generate signal transduction cascades in cancerous pituitary cells that culminate in the inhibition of hormone secretion, cell growth and invasion. Drug resistance occurs in a subset of patients and can involve different steps at different stages, such as following receptor activation by the agonist or during the final biological responses. Although the expression of somatostatin and dopamine receptors in cancer cells is a prerequisite for these drugs to reach a biological effect, their presence does not guarantee the success of the therapy. Successful therapy also requires the proper functioning of the machinery of signal transduction and the finely tuned regulation of receptor desensitization, internalization and intracellular trafficking. The present Review provides an updated overview of the molecular factors underlying the pharmacological resistance of pituitary tumours. The Review discusses the experimental evidence that supports a role for receptors and intracellular proteins in the function of SSTs and DRD2 and their clinical importance.
The plasma membrane tetraspan molecule MS4A4A is selectively expressed by macrophage-lineage cells, but its function is unknown. Here we report that MS4A4A was restricted to murine and human ...mononuclear phagocytes and was induced during monocyte-to-macrophage differentiation in the presence of interleukin 4 or dexamethasone. Human MS4A4A was co-expressed with M2/M2-like molecules in subsets of normal tissue-resident macrophages, infiltrating macrophages from inflamed synovium and tumor-associated macrophages. MS4A4A interacted and colocalized with the β-glucan receptor dectin-1 in lipid rafts. In response to dectin-1 ligands, Ms4a4a-deficient macrophages showed defective signaling and defective production of effector molecules. In experimental models of tumor progression and metastasis, Ms4a4a deficiency in macrophages had no impact on primary tumor growth, but was essential for dectin-1-mediated activation of macrophages and natural killer (NK) cell-mediated metastasis control. Thus, MS4A4A is a tetraspan molecule selectively expressed in macrophages during differentiation and polarization, essential for dectin-1-dependent activation of NK cell-mediated resistance to metastasis.
According to World Health Organization estimates, 5% of the adult population worldwide suffers from depression. In addition to the affective, psychomotor and cognitive symptoms which characterize ...this mood disorder, sexual dysfunction has been frequently reported among men suffering from depression. The most common sexual manifestations are decreased libido, erectile dysfunction and orgasmic disorder. In addition, epidemiological studies have documented a reduction of testosterone concentrations in men with depression and, for these reasons, depressive disorders appear as one possible cause of male functional hypogonadism. Moreover, some largely used antidepressant medications can cause or worsen sexual complaints, thus depression and its treatments rise several andrological-relevant issues. The other way round, men with hypogonadism can manifest depressed mood, anxiety, insomnia, memory impairment which, if mild, may respond to testosterone replacement therapy (TRT). However, the prevalence of functional hypogonadism in depression, and of depressive symptoms in hypogonadal men, is not known. Severe depressive symptoms do not respond to TRT, while the effect of treating major depression on functional hypogonadism, has not been investigated. Overall, the clinical relevance of each condition to the other, as well as the physiopathological underpinnings of their relationship, are still to be clarified. The present review summarizes current evidence on the influence of testosterone on mood and of depression on the hypothalamic-pituitary-testis axis; the clinical association between male hypogonadism and depression; and the reciprocal effects of respective treatments.
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