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Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, Padova, Italy.
RRM Academy Synopsis
New Editorial Frames Infertility as a Couple's Issue
About 10 to 15 out of 100 couples worldwide cannot conceive. The 2024 editorial opens a journal's special issue on infertility and sums up four studies and two reviews. The author argues that infertility involves both partners and that research should aim to restore natural fertility.
Key Findings
Roughly 10 to 15% of couples worldwide cannot conceive, and just over half of them, about 56%, ever see a doctor about it, the editorial reports.
As many as 27% of male partners in couples seeking fertility care are not given an andrological evaluation (a workup for male fertility problems), the editorial notes.
Among 77 women with diminished ovarian reserve, a blood marker called SEMA3A ran higher than it did in healthy volunteers, one study found.
In IVF/ICSI cycles (2004 to 2018) with one or two embryos, day-five transfers were linked to more births than day-three, an edge the study suggests appeared mainly under age 36.
Testing cervical mucus samples across a cycle turned up 25 candidate protein markers that could help spot ovulation.
Interpretation
The piece is an editorial. It opens a special issue and sums up six papers in a few sentences each. The editorial does not give full methods or full results. The numbers it reports, group sizes and percentages, come from other researchers' work. Check the original papers before drawing conclusions from them. The editorial's own argument is different: infertility care should look at both partners. The author also calls for more research on restoring natural fertility as an alternative to the overuse of IVF over the last 40 years.
RRM Context
Restorative reproductive medicine already does two things this editorial calls for. Clinicians look at both partners together. They look for the cause of infertility first. The call for research on restoring fertility fits the goal NaProTechnology and other RRM methods already work toward.
Our editorial summary of this paper, not the article's abstract.
Abstract
One of the biggest problems facing modern medicine is infertility [...].
Genetic variability within the follicle-stimulating hormone (FSH)-related genes might contribute to phenotypic heterogeneity in patients with Klinefelter syndrome (KS), yet its clinical impact on sperm retrieval remains unclear.
To investigate the association between FSHB c.211 G > T and FSHR polymorphisms (c.2039 A > G and c.29 G > A) and hormonal parameters, as well as their potential role in predicting sperm retrieval rate (SRR) in patients with KS undergoing testicular sperm extraction (TESE).
A retrospective cohort of patients with KS was analyzed. Only subjects not receiving testosterone replacement therapy were included (n = 417). Hormonal, anthropometric, and clinical variables were compared across genotypes using nonparametric tests. Additive genetic models were applied to evaluate allele-dose effects. Multivariable logistic regression was performed to identify independent predictors of SRR. Predictive performance of clinical and combined clinical-genetic models was assessed using ROC curve analysis.
FSHB and FSHR genes polymorphisms were associated with variations in serum FSH concentrations, confirming a modulatory role of the FSH-related genes. In additive modeling, the FSHR c.29 G > A polymorphism emerged as an independent predictor of SRR (adjusted OR: 0.29; 95% CI, 0.09-0.97), whereas FSHB c.211 G > T showed a nonsignificant trend. The inclusion of genetic variants modestly improved predictive accuracy compared with clinical variables alone, as demonstrated by ROC analysis.
Genetic variants within the genes involved in FSH action might contribute incremental information for the prediction of sperm retrieval in patients with KS. While the overall predictive gain remains moderate, additive genetic modeling highlights a potential allele-dose effect of FSHR c.29 G > A on reproductive outcome, supporting a role for integrated clinical-genetic assessment in this population, although external validation remains required.
Klinefelter syndrome (KS) is characterized by marked phenotypic heterogeneity that might be influenced by genetic modifiers, including androgen receptor (AR) repeat length (CAGn and GGCn). The clinical relevance of these repeat lengths in patients with KS before testosterone replacement therapy (TRT) remains unclear.
To investigate the association between AR repeat length and anthropometric, hormonal, metabolic, and reproductive parameters in a well-characterized cohort of untreated adult patients with KS.
In this cross-sectional single-center study, 214 men with classical 47, XXY karyotype were evaluated prior to TRT. Clinical, biochemical, and reproductive parameters were analyzed according to AR CAGn and GGCn repeat length. Nonparametric tests, multivariable linear and logistic regression models, and interaction terms between CAGn and GGCn were tested. Standardized beta coefficients were used to compare the relative contribution of AR repeat length with major clinical determinants.
In unadjusted analyses, CAG repeat length was associated with estradiol concentrations, whereas GGC repeat length showed associations with hematocrit, platelet count, and total cholesterol. However, most associations were characterized by small effect sizes and did not persist after multivariable adjustment for possible confounders (age, BMI, and total testosterone levels). Moreover, AR repeat length was not associated with sperm retrieval rate. Standardized beta analyses demonstrated that testosterone levels, BMI, and age accounted for the largest proportion of phenotypic variability, whereas CAGn and GGCn repeat length had minimal roles.
In untreated patients with KS, AR repeat length (CAGn and GGCn) appears to have a limited clinical impact compared with classical endocrine and metabolic determinants. These findings suggest that phenotypic variability in KS might be primarily driven by chromosomal aneuploidy and primary testicular dysfunction rather than AR repeat length.
Graziani A et al., 2026·Journal of clinical medicine·Free full text on PubMed Central
Erectile dysfunction (ED) is increasingly recognized as an early manifestation of systemic vascular disease and might represent a window for cardiovascular risk assessment. Dynamic penile colour Doppler ultrasound (PCDU) provides quantitative arterial and venous parameters that could reflect subclinical vascular impairment. We investigated the association between PCDU parameters and estimated cardiovascular risk in men with ED. In this single-center retrospective observational study, 275 men undergoing PCDU for ED were evaluated. Clinical characteristics, biochemical data, and QRISK3 10-year cardiovascular risk scores were collected. Mean peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI) were analyzed. Correlation analyses, logistic regression using a QRISK3 ≥ 10% threshold, linear regression models, age-stratified analyses, and receiver operating characteristic (ROC) curve analyses were performed. Patients with impaired PSV (<35 cm/s) were older and exhibited higher QRISK3 scores and a greater prevalence of diabetes mellitus and previous cardiovascular events. Mean PSV was inversely correlated with QRISK3 (r = -0.203, p < 0.01) and was associated with higher cardiovascular risk categories in unadjusted logistic regression (β = -0.016, p = 0.048), but not after adjustment for age and diabetes mellitus. ROC analysis showed modest discrimination of increased cardiovascular risk (AUC = 0.60). The addition of PSV to a model including age and diabetes resulted in minimal improvement in discrimination (AUC 0.966 vs. 0.968). Age-stratified analysis demonstrated a significant association between lower PSV and higher cardiovascular risk only in patients ≤60 years. A progressive increase in QRISK3 was observed according to the number of abnormal Doppler parameters (p = 0.013). PCDU parameters reflect the overall cardiovascular risk burden in men with ED. Although not independent predictors beyond traditional risk factors, penile Doppler abnormalities might identify a vascular phenotype associated with higher estimated cardiovascular risk, particularly in younger individuals. These findings support the role of comprehensive vascular assessment in selected patients with ED.
Barbato M et al., 2026·Frontiers in Reproductive Health·Free full text on PubMed Central
Couple infertility is a common clinical condition that is too often treated with assisted reproductive techniques (ARTs) without a proper evaluation of both male and female factors. To improve the likelihood of natural conception, fertility awareness methods (FAMs) are widely used. We performed a multicenter prospective study enrolling couples with primary idiopathic infertility who were seeking natural conception. Participants were followed for 12 months using FAMs, and their outcomes were compared with those of couples who only used ARTs. The aim of our study was to evaluate the pregnancy rate after 12 months among couples with idiopathic infertility using FAMs compared with those who immediately pursued ARTs. We evaluated 41 couples in the FAM group and 56 couples in the ART group. In the FAM group, we reported a pregnancy rate (PR) of 51.22%. Among women aged <34 years, we reported a PR of 90.9%, while it decreased to 36.7% among women aged 35-39 years. In the ART group, 10 couples achieved pregnancy (PR 17.8%). Within this group, we reported a PR of 30% among women aged <34 years and 17.4% among women aged 35-39 years. After 12 months of unprotected intercourse without spontaneous conception in women younger than 35 years or after 6 months in women aged 35-39 years, couples should undergo a complete multidisciplinary diagnostic evaluation involving both the male and female partners. If a diagnosis of idiopathic infertility is established at the end of this process, couples (especially younger ones) may be advised to wait an additional 12 months while using FAMs, as no advantage has been observed with direct access to ARTs. They could then be referred to ART if a spontaneous pregnancy is not achieved during this period.
Related research
Thyroid and Metabolic Function · Thyroid Disorders
Thyroid disorders are often ubiquitous and insidious in their presentation. They have been implicated in a broad spectrum of reproductive disorders ranging from abnormal sexual development to menstrual irregularities and infertility. If pregnancy occurs in a patient with thyroid disease, the physician must ensure that therapeutic measures instituted to restore the health of the mother do not adversely affect the developing fetus. This review examines the role of thyroid disease in disorders confronting the obstetrician/gynecologist and provides a theoretical framework upon which to base practical management decisions.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
Infertility is not merely a reproductive inconvenience but frequently signals systemic or hormonal pathology — including polycystic ovarian disease, endometriosis, thyroid dysfunction, and immune abnormalities — each carrying independent health risks beyond failure to conceive. Identifying and treating these underlying conditions reduces long-term morbidity and reframes infertility evaluation as a form of preventive medicine rather than a terminal bypass decision.