Semen analysis alone cannot diagnose male factor infertility
A semen analysis is the first step in a male workup and cannot give the diagnosis alone. The four authors reviewed the recent research for this expert opinion. They propose six diagnostic groups to guide treatment. They describe follicle-stimulating hormone (FSH) as the best evidence-based treatment option for selected men whose low sperm count or motility has no found cause.
Key Findings
Male factors account for 50% of couple infertility cases. Almost 30% of men with impaired sperm parameters have no identifiable cause, which the paper calls idiopathic male infertility.
One full diagnostic workup covered 1,147 white-European men from couples with primary infertility. The workup identified a causal category for 81% of them.
Despite normal sperm parameters, medical history and physical examination, 15 to 40% of the men are still infertile. The paper calls this unexplained male infertility.
Over 20 clinical trials, summarized in four meta-analyses, have tested FSH in idiopathic male infertility. For one pregnancy, the number needed to treat is 10 to 18 men.
An Italian survey found that 55% of 718 men eligible for FSH under national rules were effectively treated.
Interpretation
The paper is an expert opinion built on a narrative review. The authors ran no systematic review or meta-analysis, and they helped write some of the guidelines they discuss. The FSH evidence comes from earlier trials and meta-analyses. The guidelines they cite rate that evidence as low, while the authors call it strong. Response varies, and reliable markers to predict who will respond are currently lacking. The authors say the suggested FSH threshold rests on normative aspects more than on clinical studies. The paper addresses the evaluation and treatment of the male partner.
RRM Context
The authors want doctors to work up both partners at the same time and to find the cause before treating. They say a guideline that puts intrauterine insemination first for idiopathic infertility leaves no real room to investigate the man. Restorative reproductive medicine also puts finding the cause first.
Our editorial summary of this paper, not the article's abstract.
Abstract
Purpose
Infertility is defined as the inability to conceive after 1 year of unprotected intercourse, affecting approximately 15-20% of couples in Western countries. It is a shared problem within the couple; when the main issue lies with one of the partners, it is preferable to refer to "male factor" or "female factor" infertility rather than simply male or female infertility. Despite male factor infertility accounting for half of all couple infertility cases, the clinical approach to the male partner is not uniformly standardized across international guidelines.
Methods
To provide an expert overview, we have comprehensively reviewed and critically analyzed the most up-to-date literature on this sensitive topic, leading to the development of a proposal for tailored assessment of the diagnostic-therapeutic pathway and preventive strategies. The diagnostic approach also considers that infertile men are objectively less healthy than their fertile counterparts of the same age and ethnicity.
Results
This article discusses the diagnostic flow, the classification of male factor infertility, the definition of idiopathic infertility, the involvement of general health, and treatment recommendations, emphasizing follicle-stimulating hormone treatment in selected groups of patients.
Conclusion
We provide expert opinion on current drawbacks and future perspectives in this field, with practical advice for the clinical practice of general practitioners and expert in reproductive medicine.
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.
Rocca MS et al., 2026·Journal of translational medicine·Free to read
Standard semen analysis has little prognostic value in distinguishing fertile from infertile men. Furthermore, in men with semen parameters within the reference ranges, it cannot distinguish fertile men from infertile men, i.e. partners of couples with idiopathic infertility. Oxidative stress, mitochondrial dysfunction, sperm telomere shortening, and DNA fragmentation have been proposed as contributors to impaired male fertility. However, these biomarkers have not been evaluated as a whole in subjects with normal semen parameters, partners of fertile and infertile couples.
To characterise a multidimensional panel of sperm biomarkers-including sperm telomere length (STL), mitochondrial DNA copy number (mtDNAcn), reactive oxygen species (ROS), lipid peroxidation (LP), sperm chromatin dispersion (SCD), and respiratory control ratio (RCR)-and to identify whether these parameters might discriminate, in men with normal semen parameters, infertile men from fertile controls.
A total of 150 men with semen parameters within the normal ranges were enrolled: 47 male partners of couples with idiopathic infertility and 103 fertile controls. STL and mtDNAcn were quantified by qPCR; ROS were assessed using OxiSperm®II with semiquantitative imaging; LP was measured spectrophotometrically in seminal plasma; SCD was used to determine DNA fragmentation; and mitochondrial function was evaluated by oxygen consumption and RCR. Correlations between biomarkers and semen parameters were analysed using Pearson or Spearman coefficients, and intergroup comparisons were adjusted for age.
Semen parameters did not differ significantly between male partners of fertile and infertile couples. compared to men of fertile couples, men of infertile couples exhibited significantly shorter STL (0.57 ± 0.59 vs 1.21 ± 1.13, p_adj = 0.001) and higher oxidative stress, with both ROS (8300.9 ± 4214.8 vs 6555.3 ± 3394.3, p_adj = 0.027) and LP (88.33 ± 55.50 vs 40.29 ± 46.98, p_adj < 0.001) markedly elevated. mtDNAcn, SCD, and RCR showed no difference between the groups. Across the entire cohort, STL correlated negatively with ROS and LP and positively with RCR. ROS correlated negatively with total sperm count, motility and RCR, and positively with LP. LP displayed the strongest pattern of associations, correlating negatively with concentration, total count, motility, STL and RCR, and positively with age and volume.
Among men with normal semen analysis, partners of couples with idiopathic infertility exhibit a distinct sperm molecular profile characterised by telomere shortening and oxidative imbalance. STL, ROS and LP emerged as age-independent biomarkers associated with infertility status and showed promising discriminatory ability in this cohort, supporting their integration as second-level tests to complement routine semen analysis in cases of normozoospermia.
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.
Delbarba A et al., 2026·Reviews in endocrine & metabolic disorders·Free full text on PubMed Central
Male hypogonadism is associated with significant alterations in body composition, including reduced lean body mass (LBM), increased fat body mass (FBM), particularly visceral adiposity, and impaired muscle function, contributing to frailty and cardiometabolic risk. These changes reflect the disruption of a complex endocrine crosstalk among bone, muscle, and adipose tissue, mediated by cytokines such as osteokines, myokines, and adipokines. This dysregulation promotes the development of osteosarcopenic obesity, a condition characterized by the coexistence of low bone mass, sarcopenia, and excess adiposity. Testosterone (T) plays a central role in maintaining body composition by stimulating muscle protein synthesis, inhibiting adipogenesis, and preserving bone health. Its deficiency, irrespective of etiology, leads to rapid impairment of anabolic pathways, resulting in decreased lean mass and increased fat accumulation. Evidence from clinical and experimental models demonstrates that these alterations are partially reversible with T replacement therapy (TRT), although variability exists depending on the underlying cause of hypogonadism. Dual-energy X-ray absorptiometry (DXA) represents the gold standard for assessing bone mineral density (BMD) and a key tool for evaluating body composition through a three-compartment model. It allows precise quantification of fat and lean mass, as well as their regional distribution, with minimal radiation exposure. In this review, we provide a comprehensive and clinically oriented overview of body composition alterations in male hypogonadism, focusing on underlying pathophysiological mechanisms and the practical application of DXA across different clinical scenarios. We discuss evidence from conditions such as Klinefelter syndrome, Kallmann syndrome, androgen deprivation therapy, HIV infection, and transgender care, aiming to offer a pragmatic framework for integrating body composition assessment into routine practice and improving patient management.
Grande G et al., 2025·Andrology·Free full text on PubMed Central
In infertile couples whose male partner has alterations in semen parameters frequently, a comprehensive andrological approach is lacking and approximately 30-50% are classified as idiopathic infertility. These couples are often directly addressed to assisted reproduction techniques (ARTs). However, several clinical conditions may benefit from medical treatment. By acting on etiology and/or risk factors, this aims at improving seminal parameters and restoring natural fertility. To verify the impact of a comprehensive andrological assessment on the management of infertility (in particular, in couples with isolated male factor infertility) using as the primary outcome the natural pregnancy rate. A multicenter retrospective study was conducted between 2015 and 2022 in 1014 couples with primary infertility seeking natural conception (including 266 couples with previous ART failure). Each couple underwent a multidisciplinary evaluation. This involved: a gynecologist and an andrologist both with expertise in infertility, a psychologist when requested, and a fertility awareness practitioner according to a unique diagnostic and therapeutic multidisciplinary protocol. An isolated male factor was found in 23% of couples. In 45%, it was associated with female factors also. The comprehensive diagnostic approach reduced the proportion of idiopathic infertility to 8% of the couples. Targeted treatment, based on diagnostic categories, was associated with spontaneous pregnancy in 40.9% of the couples. In the 233 cases without female factors, normal semen parameters were observed only in 13% of patients. Male genital tract inflammation was observed in 48.8% of the patients, genital tract infection in 43.1%, and hypospermatogenesis in 16.7%. Patients with infections were treated with antibiotics and probiotics. If further inflammation was documented, this was followed by low-dose corticosteroids and antioxidants. Follicle stimulating hormone (FSH) treatment was used in patients with hypospermatogenesis, and varicocele repair surgery was performed in four patients. Our data underline the efficacy of a comprehensive approach to the diagnostic process of male factor infertility, both in reducing the percentage of idiopathic infertility and in restoring natural fertility based on a targeted treatment.
Mazzilli R et al., 2023·Journal of endocrinological investigation·Free full text on PubMed Central
Infertility, which is defined as the inability to conceive after at least 12 months of regular unprotected sexual intercourses, affects about 15-20% of couples worldwide and a male factor is involved in about half of the cases. The development of assisted reproductive technology (ART) made it possible to conceive also to individuals affected from severe oligospermia or azoospermia. However, the impact of the male factor on embryo development, implantation, prevalence of chromosomal abnormalities, genetic and epigenetic alterations, and clinical and obstetric outcomes is still controversial.
This narrative review examines the indications, minimum access criteria, and outcomes by individual ART technique in relation to the male factor.
Ferlin A et al., 2022·Journal of endocrinological investigation
Infertility affects 15-20% of couples and male factors are present in about half of the cases. For many aspects related to the diagnostic and therapeutic approach of male factor infertility, there is no general consensus, and the clinical approach is not uniform.
In the present document by the Italian Society of Andrology and Sexual Medicine (SIAMS), endorsed by the Italian Society of Embryology, Reproduction, and Research (SIERR), we propose evidence-based recommendations for the diagnosis, treatment, and management of male factor infertility to improve patient and couple care.
Components of the initial evaluation should include at minimum medical history, physical examination, and semen analysis. Semen microbiological examination, endocrine assessment, and imaging are suggested in most men and recommended when specific risk factors for infertility exist or first-step analyses showed abnormalities. Full examination including genetic tests, testicular cytology/histology, or additional tests on sperm is clinically oriented and based on the results of previous investigations. For treatment purposes, the identification of the specific cause and the pathogenetic mechanism is advisable. At least, distinguishing pre-testicular, testicular, and post-testicular forms is essential. Treatment should be couple-oriented, including lifestyle modifications, etiologic therapies, empirical treatments, and ART on the basis of best evidence and with a gradual approach.
These Guidelines are based on two principal aspects: they are couple-oriented and place high value in assessing, preventing, and treating risk factors for infertility. These Guidelines also highlighted that male infertility and in particular testicular function might be a mirror of general health of a man.
Esteves SC et al., 2012·Archives of gynecology and obstetrics
Our article reviews the evolving concepts in the field of male infertility for gynecologists and other health professionals involved in the care of men and women experiencing difficulty in having a child. The increased knowledge will help in the better management and treatment of infertile couples. Review of literature through Pubmed, Science Direct, Online Library. Gynecologists are often the first healthcare providers to assess an infertile couple. Because half of all infertility problems stem from male factors, it is crucial for the gynecologist to remain updated on the main conditions that cause male infertility as well as current diagnostic tools and treatment options, including conventional strategies and assisted reproductive techniques. Extraordinary advances have been achieved in the field of male infertility over the past several years and many old concepts are now challenged. Therefore, it is imperative that male infertility physicians should update the gynecologists about the recent advances in the work-up of infertile men in terms of diagnosis and management. Such convention will help improve the standards of care for the infertile couple and enhance the cooperation between male and female reproductive endocrinologists.
Male Fertility › Male Factor Treatment › Medical Management · Diagnostics › Hormone Testing › Serum Panels · Therapeutics › Hormonal Agents › Gonadotropins
PMID 39804439 39804439 DOI 10.1007/s40618-024-02524-x 10.1007/s40618-024-02524-x Santi et al. 2025, Santi 2025
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