Therapeutics · Hormonal Agents
Campello E, Scala A, Bulato C, Benetti A, Faggian G, De Toni L, Simion C, Torresan F, Ferlin A, Simioni P, Garolla A, Gender Incongruence Interdisciplinary Group (GIIG)
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Gender-affirming hormone therapy (GAHT), particularly estrogen-based regimens, is associated with an increased risk of venous thromboembolic events (VTE), which may be exacerbated in individuals with hereditary thrombophilia. Despite this risk, the prevalence and clinical implications of hereditary thrombophilia in transgender individuals remain underexplored.
We screened 114 transgender individuals (54 AMAB, 60 AFAB) at the University Hospital of Padua (Italy) for hereditary thrombophilia, including factor V Leiden (FVL), prothrombin G20210A (PT20210A), antithrombin (AT), protein C (PC), and protein S (PS) deficiencies, as well as antiphospholipid antibodies.
Hereditary thrombophilia was identified in 9.6% of participants, including two cases of severe thrombophilia. No participants tested positive for antiphospholipid antibodies. Individuals with thrombophilia had a higher prevalence of personal and family history of VTE. Three thrombotic events were recorded prior to GAHT: one transgender woman (heterozygous FVL) with unprovoked lower limb VTE, one transgender man (PC deficiency) with neonatal cerebral ischemia, and one transgender man (heterozygous FVL) with subclavian VTE during chemotherapy.
A multidisciplinary approach involving coagulation specialists and endocrinologists was implemented to optimize risk reduction strategies, including tailored GAHT regimens and anticoagulation when necessary. No VTE occurred during a 15-month follow up. These findings highlight the importance of thrombophilia screening to enable individualized care and enhance the safety of GAHT protocols.
Mazzilli R et al., 2026 · Journal of endocrinological investigation
Male factor could contribute, alone or in combination with female factor, to the inability to conceive in a couple in more than half of cases. The effect of male factor infertility (MFI) on embryological assisted reproductive technology (ART) outcomes remains an ongoing discussion. to evaluate the impact of MFI on embryo aneuploidy rates, to better understand the role and possible indication for Preimplantation genetic testing for aneuploidies (PGT-A), considering the role of sperm characteristics, paternal age, sperm DNA fragmentation and sperm aneuploidies. this narrative review included all available articles, published up to January 2026. Available evidence, often based on heterogeneous and old-fashioned methodologies, suggests that MFI may impair embryonic development, particularly in terms of fertilization rate and blastulation rate, more than embryo euploidy; however, a comprehensive evaluation of MFI should be integrated into clinical practice in the context of couple infertility, to also optimize the efficiency and outcomes of ART. Promising results emerged from sperm DNA fragmentation as a tool to predict embryo euploidy, but further investigations involving larger sample sizes and improved standardization are required.
Grande G et al., 2026 · The Journal of clinical endocrinology and metabolism · Free to read
Male factor infertility (MFI) is frequently labelled idiopathic when evaluation relies primarily on semen analysis, potentially overlooking endocrine and pathophysiological mechanisms relevant for targeted management. To phenotypically define MFI and develop a pathophysiology-based classification aimed at reducing idiopathic infertility following comprehensive evaluation. Prospective monocentric cohort study conducted at a tertiary referral academic centre. Eight hundred male partners of infertile couples evaluated between October 2024 and January 2026 after exclusion of isolated female factor infertility. Prevalence of MFI categories, hormonal patterns across phenotypes, and proportion of idiopathic infertility after comprehensive work-up. All patients underwent standardized clinical evaluation, hormonal assessment (total testosterone, FSH, LH), testicular ultrasound, and complete semen analysis. Microbiological testing, transrectal ultrasound, and genetic analyses were performed according to guidelines. Primary spermatogenic failure was the most prevalent category (56.0%), followed by infection/inflammation (22.4%) and hypogonadotropic hypogonadism (8.5%). Idiopathic infertility was identified in only 5.3% of cases. Distinct endocrine profiles were observed, with high-FSH spermatogenic failure representing the dominant phenotype. Comprehensive phenotyping markedly reduces the proportion of patients classified as having idiopathic infertility and identifies clinically relevant subgroups. This prospective study provides validation of a pathophysiology-based classification and supports a shift toward endocrine-integrated diagnostic strategies in male infertility, with potential implications for targeted management.
Ponce MR et al., 2026 · Andrology · Free full text on PubMed Central
Transgender individuals assigned male at birth (AMAB) may choose to preserve their fertility prior to starting gender-affirming hormone therapy (GAHT). However, limited data exist regarding the baseline reproductive and hormonal characteristics of this population before and after GAHT. To characterize semen quality and hormonal profiles in transgender AMAB individuals prior to GAHT and compare findings with cisgender men and with transgender individuals who discontinued GAHT for at least 3 months. This retrospective study included transgender AMAB individuals from two tertiary andrology centers who underwent sperm cryopreservation before GAHT initiation (treatment-naïve group). Clinical evaluation included anthropometric measures, testicular volume assessment, varicocele detection, and sex hormone measures. Semen parameters were analyzed according to WHO criteria and compared with those of cisgender men and previously treated transgender individuals. Thirty-two treatment-naïve transgender AMAB individuals were included. Hormonal parameters were generally within reference ranges. Only 46.9% of treatment-naïve individuals met WHO criteria for normozoospermia, compared with 75.5% of cisgender controls. Compared with nine previously treated individuals, estradiol levels were higher and seminal volume lower. A higher frequency of seminal abnormalities was observed, although not statistically significant. A substantial proportion of treatment-naïve transgender AMAB individuals exhibited impaired semen parameters prior to GAHT initiation. Prior GAHT exposure showed a trend toward poorer semen quality. These findings support early fertility counseling and preservation in transgender individuals prior to GAHT initiation.
Graziani A et al., 2026 · Andrology · Free to read
Besides gonadal involvement (hypogonadism, male factor infertility, and testicular hypotrophy), patients with Klinefelter syndrome (KS) may suffer from several extra-gonadic complications, including neoplastic events. The aim of this review is to summarize all major clinical evidence dealing with the association between KS and neoplastic diseases and provide practical suggestions for the management of patients with KS regarding neoplastic risk. This narrative review was conducted through a comprehensive search of the PubMed database, using combinations of the following keywords: "Klinefelter syndrome," "cancer," "neoplasm," "breast cancer," "germ cell tumor," "lymphoma," and "testosterone replacement therapy". KS is associated with a higher risk of breast cancer and mediastinal germ cell tumors and an apparent higher risk of hematological malignancies, in particular non-Hodgkin lymphoma and leukemia. Evidence on testicular cancer is limited, with no clear increase in risk attributable to KS, while prostate cancer has a lower risk and lower mortality rate. Given the complexity of the syndrome and the limited available evidence, regular clinical follow-up with targeted investigations when clinically indicated may facilitate early diagnosis and management of associated comorbidities.
Scala A et al., 2024 · Minerva endocrinology · Free to read
In transgender individuals assigned female at birth, testosterone therapy is employed for body masculinization. Guidelines recommend close monitoring for potential side effects of hormonal therapy, especially during the first year. Erythrocytosis is a common finding during testosterone therapy and has been associated with a potential risk of thrombotic and cardiovascular events. Currently, the hematologic effects of testosterone therapy are understudied, with existing data primarily derived from the cisgender male population. The aim of this study was to comprehensively examine the hematological changes induced by testosterone therapy in the transgender population. A systematic search was conducted using the electronic database PubMed. Thirty-six manuscripts were retrieved. After screening for original studies, 19 articles were included. Selected articles were published between 2005 and 2023. In our systematic review, the prevalence of erythrocytosis varied from 0% to 29.3%, with severe erythrocytosis ranging from 0.5% to 2.3%. Testosterone therapy was associated with an increase in hemoglobin and hematocrit, particularly within the first year of therapy. Factors such as serum testosterone levels, along with the duration, doses, and formulation of testosterone therapy, were found to be associated with the development of erythrocytosis. Further research is crucial to provide specific recommendations for clinical practice.
Ceolin C et al., 2025 · Journal of endocrinological investigation · Free full text on PubMed Central
Evidence on the skeletal effects of gender-affirming hormone therapy (GAHT) in transgender individuals remains limited, especially across age groups. Individuals assigned male at birth (AMAB) often show reduced bone mineral density (BMD) even before GAHT, whereas findings in those assigned female at birth (AFAB) are more variable. Given the key role of adolescence and early adulthood in peak bone mass, timely skeletal assessment is essential. This study compared BMD before and after one year (1-y) of GAHT to age-matched cisgender controls. Prospective observational study involving 269 adults (162 transgender and 107 cisgender controls) conducted at the University Hospital of Padua (January 2020-November 2024). Dual-energy X-ray absorptiometry (DXA) was performed at baseline and after 1-y of GAHT. After 1-y of GAHT, in AMAB individuals, lumbar spine BMD significantly increased (from 0.97 ± 0.16 to 1.02 ± 0.14 g/cm², p < 0.001), particularly in those under 20 years. AFAB individuals experienced a modest but significant reduction in femoral neck BMD (from 0.81 ± 0.12 to 0.79 ± 0.13, p < 0.05), especially in the 20–30-year age group. Age-stratified analyses revealed that younger participants showed greater BMD improvements, while those over 20 exhibited stable or declining values. Linear regression confirmed age as an independent predictor of BMD change, with older age associated with reduced skeletal responsiveness to GAHT at key femoral sites. GAHT has variable effects on bone health, influenced by age and sex assigned at birth. Early initiation may favor bone accrual, especially in AMAB individuals, while AFAB individuals may require closer monitoring for site-specific bone loss during testosterone therapy.
Ceolin C et al., 2024 · Journal of endocrinological investigation · Free full text on PubMed Central
Preliminary data suggested that bone mineral density (BMD) in transgender adults before initiating gender-affirming hormone therapy (GAHT) is lower when compared to cisgender controls. In this study, we analyzed bone metabolism in a sample of transgender adults before GAHT, and its possible correlation with biochemical profile, body composition and lifestyle habits (i.e., tobacco smoke and physical activity). Medical data, smoking habits, phospho-calcic and hormonal blood tests and densitometric parameters were collected in a sample of 125 transgender adults, 78 Assigned Females At Birth (AFAB) and 47 Assigned Males At Birth (AMAB) before GAHT initiation and 146 cisgender controls (57 females and 89 males) matched by sex assigned at birth and age. 55 transgender and 46 cisgender controls also underwent a complete body composition evaluation and assessment of physical activity using the International Physical Activity Questionnaire (IPAQ). 14.3% of transgender and 6.2% of cisgender sample, respectively, had z-score values < -2 (p = 0.04). We observed only lower vitamin D values in transgender sample regarding biochemical/hormonal profile. AFAB transgender people had more total fat mass, while AMAB transgender individuals had reduced total lean mass as compared to cisgender people (53.94 ± 7.74 vs 58.38 ± 6.91, p < 0.05). AFAB transgender adults were more likely to be active smokers and tend to spend more time indoor. Fat Mass Index (FMI) was correlated with lumbar and femur BMD both in transgender individuals, while no correlations were found between lean mass parameters and BMD in AMAB transgender people. Body composition and lifestyle factors could contribute to low BMD in transgender adults before GAHT.
Phillippe HM et al., 2014 · J Pharm Pract
Thrombophilia alters normal hemostasis, shifting the balance in favor of thrombus formation. Inherited conditions include factor V Leiden (FVL), prothrombin G20210A mutation, deficiencies in natural anticoagulants (antithrombin [AT], protein C, and protein S), hyperhomocysteinemia, and elevations in clotting factors (factors VIII and XI). Although FVL and prothrombin mutation are common disorders, deficiencies in the natural anticoagulants are rare. The risk of initial thrombosis conferred by inherited thrombophilia varies with the highest risk in those homozygous for either FVL or prothrombin mutation, or with AT deficiency. In the nonpregnant patient, the presence of a thrombophilia does not affect treatment of an acute event. Although vitamin B supplementation has been shown to decrease the levels of homocysteine, the treatment has failed to show a benefit in thrombus prevention and is therefore not recommended.