Endocrines, Volume 2, Issue 1 (March 2021) – 6 articles

Metastatic estrogen receptor α (ERα)-expressing breast cancer (BC) occurs after prolonged patient treatment with endocrine therapy (ET) (e.g., aromatase inhibitors—AI; 4OH-tamoxifen—4OH-Tam). Often these metastatic BCs express a mutated ERα variant (e.g., Y537S), which is transcriptionally hyperactive, sustains uncontrolled proliferation, and renders tumor cells insensitive to ET drugs. Therefore, new molecules blocking hyperactive Y537S ERα mutation transcriptional activity are requested. Here we generated an MCF-7 cell line expressing the Y537S ERα mutation stably expressing an estrogen-responsive element (ERE) promoter, which activity can be monitored in living cells. Characterization of this cell line shows both hyperactive basal transcriptional activity with respect to normal MCF-7 cells, which stably express the same ERE-based promoter and a decreased effect of selective ER downregulators (SERDs) in reducing Y537S ERα mutant transcriptional activity with respect to wild type ERα transcriptional activity. Kinetic profiles of Y537S ERα mutant-based transcription produced by both drugs inducing receptor degradation and siRNA-mediated depletion of specific proteins (e.g., FOXA1 and caveolin1) reveals biphasic dynamics of the inhibition of the receptor-regulated transcriptional effects. Overall, we report a new model where to study the behavior of the Y537S ERα mutant that can be used for the identification of new targets and pathways regulating the Y537S ERα transcriptional activity. Full article

Typically, salivary cortisol is reported as 5–10% of total cortisol, but the stability of this proportion and the effect of exercise on the 24-h profile is unclear. Therefore, this study investigated the circadian rhythm of the proportion of serum cortisol represented by salivary cortisol, and the impact of acute high-intensity exercise. Recreationally trained males (n = 8, age = 25.7 ± 2.4 years, height = 174.7 ± 7.8 cm, mass = 69.8 ± 12.1 kg) completed two 24-h profiles (rest and exercise conditions) for serum (Q60) and salivary (Q120) cortisol. Exercise consisted of 5 × 30 s sprinting intervals on the cycle ergometer. Cortisol was assessed using commercially available assays. The proportion (C_prop) of serum cortisol (C_ser) represented by salivary cortisol (C_sal) was calculated as [C_prop = C_sal/ C_ser × 100]. Multilevel growth models tested for trends across the 24-h profile. The highest relation between C_ser and C_sal was observed at 08:00 AM (r = 0.90). The average C_prop was 5.95% and demonstrated a circadian profile characterized by a cubic model. Acute exercise did not alter C_ser, C_sal, or C_prop. Thus, the proportion of C_ser represented by C_sal changes across a 24-h period and should be accounted for if using salivary cortisol to reflect circadian output of cortisol. Full article

The autosomal dominant familial form of neurohypophyseal diabetes insipidus (adFNDI) is a rare inherited endocrine disorder characterized by hypotonic polyuria, severe thirst and polydipsia, which results from a deficient neurosecretion of the antidiuretic hormone, also known as arginine vasopressin (AVP). To date, adFNDI has been linked to more than 70 different heterozygous point mutations of the 2.5 kb AVP gene, encoding the composite precursor protein of AVP. A minority of disease-causing mutations, such as the common c.55G>A variant, are predicted to affect amino acid residues close to the signal peptide (SP) cleavage site, and result in abnormal post-translational processing and intracellular trafficking of AVP precursors exerting neurotoxic activity on vasopressinergic magnocellular neurons. Generally, SP variants cause a gradual decline in the neurohypophyseal secretion of AVP in small children, although a wide variability in clinical onset and severity of manifestations has been reported. For the first time, we describe a kindred from Calabria (Southern Italy) with adFNDI and document a partial clinical phenotype in one female young adult member of the family. Methods: A young adult woman was subjected to clinical, neuroradiological and genetic assessments for a mild, adolescent-onset, polyuric state at our Endocrinology Unit. Her family medical history revealed an early-onset (<12 years of age) occurrence of polyuria and polydipsia, which was successfully managed with high doses of oral desmopressin, and a typical adFNDI inheritance pattern that was seen over three generations. Results: In the index patient, the extensive hypertonic dehydration during fluid deprivation test elicited a prompt elevation of urine osmolality and diuresis contraction, indicative of a partial adFNDI phenotype. Diagnosis was confirmed by concordant hormonal tests and magnetic resonance imaging (MRI) evidence of a reduced hyperintense signal of the neurohypophysis, which was regarded as compatible with the depletion of the vasopressinergic magnocellular neurons. Direct DNA sequencing and restriction enzyme cleavage analysis revealed that a heterozygous c.55G>A transition, predicting a p.Ala19Thr replacement in the C-terminal region of SP, was the cause of adFNDI in the investigated kindred. Conclusions: The identification of the genetic cause of aFNDI in this Calabrian kindred provides further information and confirms the wide variability of disease onset and severity of manifestations related to SP variants of the AVP gene, supporting the need for genetic testing in all patients with familial occurrence of polyuria, regardless of their clinical and radiological phenotype. Even though sexual differences in the antidiuretic responses are documented, it is unclear whether female gender would attenuate clinical disease progression in the presence of a pathogenic c.55G>A mutation. Full article

Owing to the rarity and the biological and clinical heterogeneity of gastroenteropancreatic neuroendocrine neoplasia (GEP NEN), the management of these patients may be challenging for physicians. This review highlights the specific features of GEP NEN with particular attention on the role of Ki67 heterogeneity, the potential prognostic role of novel radiological techniques, and the clinical usefulness of functional imaging, including 68Ga-DOTA-SST PET/CT and 18F-FDG PET/CT. Understanding these specific features may help to plan proper and tailored follow-up programs and therapeutic approaches. Full article

Advanced maternal age is associated with the natural oocyte depletion, leading to low oocyte yield, high infertility treatment cancellation rates, and eventual decreases in pregnancy rates. Various innovative interventions have been introduced to improve the outcome of infertility treatment for aging patients. Numerous published data demonstrated that early follicle development was regulated by intraovarian growth factors through autocrine or paracrine mechanisms. Platelet-rich plasma (PRP), a plasma fraction of peripheral blood with a high concentration of platelets, has been implemented in regenerative medicine in the last decade. The plasma contains a variety of growth factors that were suggested to be able to enhance angiogenesis regeneration and the cell proliferation process. The initial report showed that an intraovarian injection of PRP improved the hormonal profile and increased the number of retrieved oocytes in patients with diminished ovarian reserve. Subsequently, several studies with larger sample sizes have reported that this approach resulted in several healthy live births with no apparent complications. However, the use of ovarian PRP treatment needs to be fully investigated, because no randomized controlled trial has yet been performed to confirm its efficacy. Full article

Estrogen receptor alpha (ERα) is a modulator of breast cancer maintenance and evolution. Hence, analysis of underlying mechanisms by which ERα operates is of importance for the improvement of the hormonal therapy of the disease. This review focuses on the irreversible character of the mechanism of action of ERα, which also concerns other members of the steroid hormones receptors family. ERα moves in permanence between targets localized especially at the chromatin level to accomplish gene transcriptions imposed by the estrogenic ligands and specific antagonists. Receptor association as at the plasma membrane, where it interacts with other recruitment sites, extends its regulatory potency to growth factors and related peptides through activation of signal transductions pathways. If the latter procedure is suitable for the transcriptions in which the receptor operates as a coregulator of another transcription factor, it is of marginal influence with regard to the direct estrogenic regulation procedure, especially in the context of the present review. Irreversibility of the successive steps of the underlying transcription cycle guarantees maintenance of homeostasis and evolution according to vital necessities. To justify this statement, reported data are essentially described in a holistic view rather than in the context of exhaustive analysis of a molecular event contributing to a specific function as well as in a complementary perspective to elaborate new therapeutic approaches with antagonistic potencies against those tumors promoting ERα properties. Full article