Iron overload disorders in adults: a comprehensive review of gonadal function, reproductive, and sexual health.

Abstract

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.