Giorgia Spaggiari

Impairment of sperm DNA methylation in male infertility: a meta-analytic study

Considering the widespread use of assisted reproductive techniques (ART), DNA methylation of specific genes involved in spermatogenesis achieves increasingly clinical relevance, representing a possible explanation of increased incidence of syndromes related to genomic imprinting in medically assisted pregnancies. Several trials suggested a relationship between male sub‐fertility and sperm DNA methylation, although its weight on seminal parameters alteration is still a matter of debate. To evaluate whether aberrant sperm DNA methylation of imprinted genes is associated with impaired sperm parameters. Meta‐analysis of controlled clinical trials evaluating imprinted genes sperm DNA methylation comparing men with idiopathic infertility to fertile controls. Twenty‐four studies were included, allowing a meta‐analytic evaluation for H19, MEST, SNRPN, and LINE‐1. When a high heterogeneity of the results was demonstrated, the random effect model was used. H19 methylation levels resulted significantly lower in 879 infertile compared with 562 fertile men (7.53%, 95% CI: 5.14–9.93%, p < 0.001), suggesting a 9.91‐fold higher risk ratio to show aberrant sperm DNA methylation (95% CI: 5.55–17.70, p < 0.001, I2 = 19%) in infertile men. The mean MEST methylation level was significantly higher in 846 infertile compared with 353 fertile men (3.35%, 95% CI: 1.41–5.29%, p < 0.001), as well as for SNRPN comparing 301 infertile men with 124 controls (3.23%, 95% CI: 0.75–5.72%, p < 0.001). LINE‐1 methylation levels did not differ between 291 infertile men and 198 controls (0.44%, 95% CI: −2.04–1.16%, p = 0.63). The meta‐analytic approach demonstrated that male infertility is associated with altered sperm methylation at H19, MEST, and SNRPN. Although its role in infertility remains unclear, sperm DNA methylation could be associated with the epigenetic risk in ART. In this setting, before proposing this analysis in clinical practice, an accurate identification of the most representative genes and a cost‐effectiveness evaluation should be assessed in ad hoc prospective studies.

Molecular basis of androgen action on human sexual desire

Reproduction is a fundamental process for the species maintenance and the propagation of genetic information. The energy expenditure for mating is overtaken by motivational stimuli, such as orgasm, finely regulated by steroid hormones, gonadotropins, neurotransmitters and molecules acting in the brain and peripheral organs. These functions are often investigated using animal models and translated to humans, where the androgens action is mediated by nuclear and membrane receptors converging in the regulation of both long-term genomic and rapid non-genomic signals. In both sexes, testosterone is a central player of this game and is involved in the regulation of sexual desire and arousal, and, finally, in reproduction through cognitive and peripheral physiological mechanisms which may decline with aging and circadian disruption. Finally, genetic variations impact on reproductive behaviours, resulting in sex-specific effect and different reproductive strategies. In this review, androgen actions on sexual desire are evaluated, focusing on the molecular levels of interaction.

Central hypogonadism due to a giant, “silent” FSH-secreting, atypical pituitary adenoma: effects of adenoma dissection and short-term Leydig cell stimulation by luteinizing hormone (LH) and human chorionic gonadotropin (hCG)

Abstract We present a case report of an atypical giant pituitary adenoma secreting follicle-stimulating hormone (FSH). A 55-year-old patient presented for erectile dysfunction, loss of libido and fatigue. The biochemical evaluation showed very high FSH serum levels in the presence of central hypogonadism. Neither testicular enlargement nor increased sperm count was observed, thus a secretion of FSH with reduced biological activity was supposed. The histological examination after neuro-surgery showed an atypical pituitary adenoma with FSH-positive cells. Hypogonadism persisted and semen analyses impaired until azoospermia in conjunction with the reduction in FSH levels suggesting that, at least in part, this gonadotropin should be biologically active. Thus, we hypothesized a concomitant primary testicular insufficiency. The patient underwent short-term treatment trials with low doses of either recombinant luteinizing hormone (LH) or human chorionic gonadotropin (hCG) in three consecutive treatment schemes, showing an equal efficacy in stimulating testosterone (T) increase. This is the first case of atypical, giant FSH-secreting pituitary adenoma with high FSH serum levels without signs of testicular hyperstimulation, in presence of hypogonadism with plausible combined primary and secondary etiology. Hypophysectomized patients may represent a good model to assess both pharmacodynamics and effective dose of LH and hCG in the male.

The TRHR Gene Is Associated with Hypothalamo-Pituitary Sensitivity to Levothyroxine

Background: Thyroidectomized patients need variable doses of levothyroxine (LT4) to obtain target thyroid-stimulating hormone (TSH) levels. Individual feedback set-points have been hypothesized and the influence of several genes in the regulation of the pituitary-thyroid axis has been demonstrated. Objectives: We hypothesized that genetic variants of the TRHR gene could be associated with a different hypothalamo-pituitary sensitivity to thyroid hormone feedback. Methods: We retrospectively analyzed 84 thyroidectomized patients with no residual thyroid function and undetectable thyroglobulin levels. Patients were evaluated under LT4 resulting in TSH levels detectable but <0.5 μIU/ml. The two SNPs rs3134105 and rs3110040 were identified as informative markers of the TRHR gene. Genotyping was performed using high-resolution melting technology. Genotype distribution was compared between the patients and 99 euthyroid controls. Results: The selected SNPs were in linkage disequilibrium and only rs3134105 was further considered. A significant difference between the three possible genotypes for rs3134105 was found for TSH (p = 0.04) and free thyroxine (fT4)/TSH ratio (p = 0.02). Moreover, despite similar serum concentrations of free triiodothyronine (fT3) and fT4, carriers of at least one A allele of rs3134105 had significantly lower serum TSH levels (p = 0.01) as well as higher fT3/TSH (p = 0.01) and fT4/TSH ratios (p < 0.01). Conclusions: We demonstrated an association between serum TSH levels and discrete alleles of the TRHR gene in totally thyroidectomized patients under LT4 therapy. Therefore, the TRHR gene seems to be a determinant of hypothalamo-pituitary sensitivity to LT4.

Verso la personalizzazione del trattamento con FSH nell’infertilità maschile

SommarioL’infertilità maschile idiopatica rimane ad oggi una sfida terapeutica. I dati relativi al miglioramento della qualità spermatica dopo terapia con gonadotropine sono ancora controversi, nonostante il noto ruolo dell’ormone follicolo-stimolante (FSH) nella spermatogenesi. La ricerca scientifica si sta sempre più focalizzando su possibili fattori predittivi di risposta e schemi di trattamento efficaci, al fine di ottenere terapie personalizzate.

Probiotics Ingestion Does Not Directly Affect Thyroid Hormonal Parameters in Hypothyroid Patients on Levothyroxine Treatment

Purpose The relationship between probiotics and levothyroxine (LT4) requirement has not yet been investigated. The aim of this study was to assess whether a mixture of highly charged Lactobacilli and Bifidobacteria (VSL#3®) is able to influence LT4 metabolism acting on the gut microbiota. Methods A prospective, randomized, single-blind, controlled, investigator-started clinical trial was carried out. Patients with primary hypothyroidism were randomly assigned to the study (VSL#3® + LT4) and the control group (LT4). A 2-month treatment phase was followed by 2 months of follow-up. Clinical examination, blood tests for thyroid function and for peripheral tissue markers of thyroid hormones (PTM) were performed monthly. LT4 dose adjustments were performed when necessary. Results Thirty-nine patients were enrolled in the study group and 41 in the control group. No difference in thyroid function [thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxine (fT4)] and PTM was found between groups and among visits. FT3/fT4 ratio was directly correlated to TSH at each visit in both groups, with the exception of the first evaluation of probiotics-treated subjects (rho = 0.287, p = 0.076). LT4 daily dose adjustments occurred more frequently in the control than in the study group (p = 0.007), despite no differences in the mean LT4 daily dose. In particular, LT4 doses were increased six times in the control group and decreased four times in the study group. Conclusion VSL#3® does not directly alter thyroid functional compensation. A probiotics-mediated influence on thyroid hormones homeostasis is suggested since probiotics supplementation could be able to prevent serum hormonal fluctuations. ClinicalTrials.gov ID Registration number NCT03095963.

Voluminosa cisti paratiroidea cervico-mediastinica di riscontro occasionale in paziente affetto da sindrome di Boerhaave

Un uomo di 67 anni giungeva alla nostra osservazione per riscontro a una TC torace di una voluminosa formazione colloido-cistica, che si approfondava nel mediastino verso sinistra con deviazione tracheale controlaterale. La TC era stata richiesta per controllo post-operatorio dopo terapia chirurgica d’urgenza per sindrome di Boerhaave (rottura completa della parete esofagea in assenza di patologia preesistente che si verifica per un improvviso aumento della pressione intraesofagea, associato a mancato rilassamento dello sfintere esofageo superiore). Una RMN collo-torace confermava la presenza di una raccolta fluida scarsamente vascolarizzata perifericamente e delimitata da esilissima parete di diametro di 60 × 63× 100 mm (Fig. 1). A un successivo controllo ecografico la cisti, interamente anecogena e non vascolarizzata, risultava essere esterna rispetto al tessuto tiroideo, sita inferiormente rispetto al polo inferiore del lobo tiroideo sinistro. Il margine inferiore non era valutabile a causa dell’approfondarsi nel mediastino antero-superiore. L’esame citologico su agoaspirato (eseguito in altra sede) non documentava presenza di cellule e tireoglobulina, calcitonina e paratormone (PTH) risultavano indosabili. Veniva eseguito un successivo agoaspirato presso la nostra Unità Operativa, anche a scopo evacuativo. Venivano aspirati 170 cc di liquido limpido “ad acqua di roccia”, suggestivo per cisti paratiroidea. Al termine dell’agoaspirato la lesione cistica appariva ecograficamente notevolmente ridotta, con diametro di 26,4 × 22,8 mm e interamente sita in regione cervicale. L’esame citologico confermava la natura amorfa del