Francesca Sciarra

Background: Iron overload (IO) disorders, including thalassaemias, hereditary haemochromatosis, and transfusion-dependent anaemias, represent a growing clinical challenge with widespread systemic implications. Reproductive dysfunction remains severely underappreciated despite its high prevalence. Hormonal changes due to iron toxicity are frequently reported, yet are seldom the focus of reproductive medicine, causing fragmented knowledge, inconsistent clinical approaches, and a lack of consensus guidelines. Objective and Rationale: This review synthesizes evidence on the impact of IO on male and female reproductive function, including gonadal dysfunction, impaired fertility, sexual dysfunction, and endocrine-metabolic complications. By addressing gaps in study design, diagnostic criteria, and management, we aim to provide the first comprehensive, expert-driven synthesis on the topic, integrating clinical, translational, and mechanistic insights to establish a structured framework for future research and patient care. Search Methods: A systematic literature search was conducted across PubMed, Scopus, and Web of Science, including studies up to May 2025. Search terms included ‘iron overload’, ‘thalassemia’, ‘hemochromatosis’, ‘hypogonadism’, ‘fertility’, ‘spermatogenesis’, ‘ovarian insufficiency’, and ‘pregnancy’. Quantitative synthesis involved pooling data on prevalence rates of hypogonadism, semen abnormalities, primary and secondary amenorrhoea, age at menarche, and pregnancy outcomes. Outcomes: Gonadal dysfunction primarily arises from iron deposition within the hypothalamic–pituitary–gonadal axis, coupled with oxidative damage to Leydig and Sertoli cells in males, disrupting testosterone synthesis and spermatogenesis, and to ovarian follicles and granulosa cells in females, causing reduced ovarian reserve and altered hormonal signalling. Iron-induced hypogonadism is the most frequent endocrine complication, significantly impacting reproductive health and quality of life. Our analysis of 1201 men and 2134 women indicated hypogonadism, reflecting impaired testicular endocrine function, in 47.0% of men; among those specifically assessed for spermatogenesis, over half presented azoospermia (17.6%) or other sperm abnormalities (37.5%). In women, primary amenorrhoea was reported in 45.7%, secondary amenorrhoea in 20.0%, and the weighted mean age at menarche was delayed (14.4 ± 2.1 years). Sexual dysfunction, notably erectile dysfunction, commonly accompanies hypogonadism, further impairing quality of life. Female sexual health has not been investigated at all. Pregnancy is increasingly achievable, but remains clinically challenging. Across 3536 reviewed pregnancies, ART was required in ∼20%, miscarriage occurred in 11.2%, and caesarean section was used in ∼80%. Mean gestational age at delivery was 37.1 ± 3.1 weeks, and mean birth weight was 2.64 ± 0.68 kg. Besides gonadal damage (direct or pituitary-related), systemic iron-related endocrine and metabolic disturbances, including hypothyroidism, growth hormone deficiency, diabetes mellitus, and cardiovascular disease, further aggravate reproductive impairments. Although effective iron chelation therapy reduces the systemic iron burden and is effective in preventing endocrine complications when initiated early, evidence supporting the reversal of established reproductive dysfunction remains limited, highlighting the need to optimize iron control from a young age to preserve reproductive health. Wider Implications: This review underscores the critical need for standardized gonadal screening to facilitate personalized reproductive care and early intervention in subjects with IO disorders. We propose an integrated clinical framework, combining early endocrine monitoring, fertility preservation protocols, and reproductive counselling. Future multidisciplinary research should prioritize prospective studies with clearly defined reproductive endpoints and explore optimized chelation strategies to safeguard reproductive potential. Addressing these gaps will fundamentally reshape clinical management, bridging haematology, endocrinology, and reproductive medicine.

Phosphodiesterases (PDEs) are a huge superfamily of enzymes that fine-tune the intracellular levels of cyclic nucleotides —cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)—thus playing a pivotal role in the control of many cellular processes. While traditionally studied in the context of cardiovascular and neurological systems, mounting evidences highlight a crucial involvement of PDEs in metabolic homeostasis. This review explores the expanding landscape of PDEs function beyond classical cyclic nucleotide degradation, focusing on their roles in glucose and lipid metabolism and their implications in metabolic disorders, including obesity, type 2 diabetes (T2DM), and metabolic syndrome (MetS). Starting from an overview of the PDE superfamily, this work deeply examines the compartmentalized actions of cAMP-dependent protein kinase A (PKA) and cGMP-dependent protein kinase G (PKG) signaling pathways in key metabolically active tissues integrating PDE activities across different organs and disease states to offer a holistic view of their metabolic relevance. Special attention is given to the therapeutic relevance of PDE inhibitors (PDEi), distinguishing between established applications and emerging strategies targeting specific PDE isoforms in metabolic disease contexts to underscore the evolving concept that PDEs act as dynamic regulators of metabolic signaling networks. Understanding their isoform-specific and tissue-specific actions could thus open new avenues for therapeutic intervention in complex metabolic disorders.

Hemochromatosis (HC) is characterized by the progressive accumulation of iron in the body, resulting in organ damage. Endocrine complications are particularly common, especially when the condition manifests in childhood or adolescence, when HC can adversely affect linear growth or pubertal development, with significant repercussions on quality of life even into adulthood. Therefore, a timely and accurate diagnosis of these disorders is mandatory, but sometimes complex for hematologists without endocrinological support. This is a narrative review focused on puberty and growth disorders during infancy and adolescence aiming to offer guidance for diagnosis, treatment, and proper follow‐up. Additionally, it aims to highlight gaps in the existing literature and emphasizes the importance of collaboration among specialists, which is essential in the era of precision medicine.

Purpose: Human Papillomavirus (HPV) in semen represents a controversial topic. Recent evidence suggests a correlation with poor semen quality, but its detection is still unstandardized in this biological fluid. Thus, the aims of this study were to verify the ability of nested PCR to reveal HPV-DNA in semen; to evaluate association of seminal HPV with sperm parameters and risk factors for infection; to investigate the rate of HPV-DNA positivity in patients with and without risk factors; to assess HPV transcriptional activity. Methods: We enrolled sexually active men and collected clinical and anamnestic data during andrological and sexually transmitted infections (STIs) evaluation. For each patient, we performed semen analysis and nested PCR to detect HPV-DNA in semen. In positive semen samples, we proceeded with genotyping and RNA quantification to detect HPV transcriptional activity. Results: We enrolled 185 men (36.0 ± 8.3 years), of which 85 with (Group A) and 100 without HPV risk factors (Group B). Nested PCR was able to reveal HPV-DNA in semen, discovering a prevalence of 8.6% (11.8% in Group A and 6% in Group B, respectively). We observed no correlation between sperm quality and seminal HPV. Genital warts and previous anogenital infection were significantly associated with the risk of HPV positivity in semen. Moreover, no viral transcriptional activity was detected in positive semen samples. Conclusions: Our study suggests that searching for seminal HPV could be important in patients both with and without risk factors, especially in assisted reproduction where the risk of injecting sperm carrying HPV-DNA is possible.

We present a liquid chromatography tandem mass spectrometry method for the simultaneous analysis of 16 endogenous steroids (androgens, estrogens, glucocorticoids and progestogens) in human serum. Samples (250 μl of matrix) were extracted with t‐butylmethyl ether prior to LC–MS/MS analysis. The chromatographic separation was achieved on a reversed‐phase column using a methanol–water gradient. The HPLC was coupled to a triple quadrupole mass spectrometer equipped with an electrospray ionization source with acquisition in multiple reaction monitoring mode. The method was validated using surrogate matrices and human serum samples. The specificity of the method was confirmed for all of the considered steroids; linearity was also assessed (R² > 0.99, lack‐of‐fit test) in the ranges of concentrations investigated. The lower limits of quantification were in the range 10–400 pg/ml depending on the target steroid. Accuracy was in the range 85–115% for all target steroids except for the lower limit of quantitation levels where it was 80–120%. The extraction recovery was always >65%. No significant matrix effects were observed. To test the reliability of the method, the analysis of serum samples collected from 10 healthy subjects (5 M/5F) was performed. The present method can be used to identify the trajectories of deviation from the concentration normality ranges applied to disorders of the gonadal and adrenal axes.