Most Italian Female Fertility Supplements Contain Unproven Ingredients
18 of 24 fertility supplements sold in Italy held an ingredient with no proven benefit, a review of trials found. The authors checked each ingredient against randomized trials. Ten products scored higher for expected efficacy, eight scored lower and six scored none.
Key Findings
The 24 supplements combined 38 different ingredients. Thirty of the 38 had no reported efficacy for female infertility in the randomized trials the authors reviewed.
Eighteen of the 24 supplements (75.0%) held at least one ingredient with no evidence of benefit for female reproductive outcomes.
Of the 24 supplements, only one held nothing but ingredients with demonstrated efficacy that also met the minimal effective daily dose (mED).
Ten of the 24 supplements (41.7%) landed in the higher expected efficacy group. Eight landed in the lower group. Six (25.0%) landed in the no expected efficacy group.
Vitamin D3 appeared in about 30% of supplements, and every one of them was underdosed for it.
Interpretation
The authors compared each product's ingredient list with randomized-trial evidence. The efficacy groups come from a scoring formula they adapted from a heart-disease evidence grading system. Each group is an expected efficacy based on ingredients and doses, and the paper reports no pregnancy results for the products. Only trials of single substances, or blends of up to three ingredients, counted. The review covers products on the Italian Ministry of Health register as of 1 June 2021, which the authors name as its main limitation. For vitamin D3, the paper states that effects on female fertility are still unknown.
RRM Context
About a quarter of infertility diagnoses involve ovulatory disorders, the paper reports. Most women who do not ovulate have PCOS (now called polyendocrine metabolic ovarian syndrome, PMOS). Restorative reproductive medicine starts by finding why a couple has not conceived. A supplement label says nothing about that cause. The same group earlier reviewed supplements sold for male infertility and found similar gaps.
Our editorial summary of this paper, not the article's abstract.
Abstract
Infertility is the condition of about 15% of couples that cannot get a conception after one year of unprotected sexual intercourse. In females, the reduced reproductive capacity underlies the most varied causes. Dietary supplements (DS) might be used to improve the pregnancy rate and a wide range of DS are proposed today to support female fertility. Although many authors demonstrated the positive effect of some of these products, the real efficacy of this approach is still debated. In order to evaluate the potential efficacy of DS for female infertility, we analysed the products marketed in Italy, using an original approach. A review of literature was performed to evaluate the effect of nutraceuticals on various female reproductive outcomes and to detect the minimal effective daily dose (mED) able to improve at least one of these. Thereafter, we conceived a formula to classify the expected efficacy of each DS. Each DS was scored and included into three classes of expected efficacy: higher, lower, and none. Ten out of 24 supplements (41.7%) resulted in the higher and 8 (34.3%) in the lower efficacy group, the remaining 6 DS (25.0%) were expected to have no efficacy. DS marketed in Italy are usually blends of many substances that are frequently employed at a negligible dose or without any evidence of efficacy. These findings raise serious doubt about the potential effectiveness of most commercial DS for female infertility.
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.
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.
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.
Meng X et al., 2023·Reproductive biology and endocrinology : RB&E·Free full text on PubMed Central
Low vitamin D status has been associated with an increased risk for infertility. Recent evidence regarding the efficacy of vitamin D supplementation in improving reproductive outcomes is inconsistent. Therefore, this systematic review was conducted to investigate whether vitamin D supplementation could improve the reproductive outcomes of infertile patients and evaluate how the parameters of vitamin D supplementation affected the clinical pregnancy rate. We searched seven electronic databases (CNKI, Cqvip, Wanfang, PubMed, Medline, Embase, and Cochrane Library) up to March 2022. Randomized and cohort studies were collected to assess the reproductive outcomes difference between the intervention (vitamin D) vs. the control (placebo or none). Mantel-Haenszel random effects models were used. Effects were reported as odds ratio (OR) and their 95% confidence interval (CI). PROSPERO database registration number: CRD42022304018. Twelve eligible studies (n = 2352) were included: 9 randomized controlled trials (RCTs, n = 1677) and 3 cohort studies (n = 675). Pooled results indicated that infertile women treated with vitamin D had a significantly increased clinical pregnancy rate compared with the control group (OR: 1.70, 95% CI: 1.24-2.34; I2 = 63%, P = 0.001). However, the implantation, biochemical pregnancy, miscarriage, and multiple pregnancy rates had no significant difference (OR: 1.86, 95% CI: 1.00-3.47; I2 = 85%, P = 0.05; OR: 1.49; 0.98-2.26; I2 = 63%, P = 0.06; OR: 0.98, 95% CI: 0.63-1.53; I2 = 0%, P = 0.94 and OR: 3.64, 95% CI: 0.58-11.98; I2 = 68%, P = 0.21). The improvement of clinical pregnancy rate in the intervention group was influenced by the vitamin D level of patients, drug type, the total vitamin D dosage, the duration, administration frequency, and daily dosage of vitamin D supplementation. The infertile women (vitamin D level < 30 ng/mL) treated with the multicomponent drugs including vitamin D (10,000-50,000 IU or 50,000-500,000 IU), or got vitamin D 1000-10,000 IU daily, lasting for 30-60 days could achieve better pregnancy outcome. To the best of our knowledge, this is the first meta-analysis systematically investigated that moderate daily dosing of vitamin D supplementation could improve the clinical pregnancy rate of infertile women and reported the effects of vitamin D supplementation parameters on pregnancy outcomes. A larger sample size and high-quality RCTs are necessary to optimize the parameters of vitamin D supplementation to help more infertile patients benefit from this therapy.
Skoracka K et al., 2021·Advances in nutrition (Bethesda, Md.)·Free full text on PubMed Central
Infertility is an increasing problem that affects couples attempting pregnancy. A growing body of evidence points to a link between diet and female fertility. In fact, data show that a diet high in trans fats, refined carbohydrates, and added sugars can negatively affect fertility. Conversely, a diet based on the Mediterranean dietary patterns, i.e., rich in dietary fiber, omega-3 (ɷ-3) fatty acids, plant-based protein, and vitamins and minerals, has a positive impact on female fertility. An unhealthy diet can disrupt microbiota composition, and it is worth investigating whether the composition of the gut microbiota correlates with the frequency of infertility. There is a lack of evidence to exclude gluten from the diet of every woman trying to become pregnant in the absence of celiac disease. Furthermore, there are no data concerning adverse effects of alcohol on female fertility, and caffeine consumption in the recommended amounts also does not seem to affect fertility. On the other hand, phytoestrogens presumably have a positive influence on female fertility. Nevertheless, there are many unanswered questions with regard to supplementation in order to enhance fertility. It has been established that women of childbearing age should supplement folic acid. Moreover, most people experience vitamin D and iodine deficiency; thus, it is vital to control their blood concentrations and consider supplementation if necessary. Therefore, since diet and lifestyle seem to be significant factors influencing fertility, it is valid to expand knowledge in this area.
Alesi S et al., 2022·Nutrients·Free full text on PubMed Central
Infertility is a global health concern affecting 48 million couples and 186 million individuals worldwide. Infertility creates a significant economic and social burden for couples who wish to conceive and has been associated with suboptimal lifestyle factors, including poor diet and physical inactivity. Modifying preconception nutrition to better adhere with Food-Based Dietary Guidelines (FBDGs) is a non-invasive and potentially effective means for improving fertility outcomes. While several dietary patterns have been associated with fertility outcomes, the mechanistic links between diet and infertility remain unclear. A key mechanism outlined in the literature relates to the adverse effects of inflammation on fertility, potentially contributing to irregular menstrual cyclicity, implantation failure, and other negative reproductive sequelae. Therefore, dietary interventions which act to reduce inflammation may improve fertility outcomes. This review consistently shows that adherence to anti-inflammatory diets such as the Mediterranean diet (specifically, increased intake of monounsaturated and n-3 polyunsaturated fatty acids, flavonoids, and reduced intake of red and processed meat) improves fertility, assisted reproductive technology (ART) success, and sperm quality in men. Therefore, integration of anti-inflammatory dietary patterns as low-risk adjunctive fertility treatments may improve fertility partially or fully and reduce the need for prolonged or intensive pharmacological or surgical interventions.
Chavarro JE et al., 2007·Obstetrics and gynecology
To evaluate the relation of a dietary pattern and other lifestyle practices to risk of ovulatory disorder infertility. We followed a cohort of 17,544 women without a history of infertility for 8 years as they tried to become pregnant or became pregnant. A dietary score based on factors previously related to lower ovulatory disorder infertility (higher consumption of monounsaturated rather than trans fats, vegetable rather than animal protein sources, low glycemic carbohydrates, high fat dairy, multivitamins, and iron from plants and supplements) and other lifestyle information was prospectively related to the incidence of infertility. Increasing adherence to a "fertility diet" pattern was associated with a lower risk of ovulatory disorder infertility. The multivariable-adjusted relative risk of ovulatory disorder infertility comparing women in the highest with women in the lowest quintile of the "fertility diet" pattern score was 0.34 (95% confidence interval 0.23-0.48; P for trend<.001). This inverse relation was similar in subgroups defined by women's age, parity, and body weight. A combination of five or more low-risk lifestyle factors, including diet, weight control, and physical activity was associated with a 69% lower risk of ovulatory disorder infertility and an estimated population attributable risk of 66% (95% confidence interval 29-86%). Following a "fertility diet" pattern may favorably influence fertility in otherwise healthy women. Further, the majority of infertility cases due to ovulation disorders may be preventable through modifications of diet and lifestyle. II.
Lifestyle and Environment › Nutrition and Metabolic Health › Dietary Patterns · Research Methods › Evidence Synthesis › Systematic Reviews · Therapeutics › Supplements and Botanicals › Vitamins and Minerals
Amerigo Vitagliano, Gabriel Cosmin Petre, Francesco Francini-Pesenti, L De Toni, A Di Nisio
A Vitagliano, G Petre, F Francini-Pesenti
PMID 34684554 34684554 DOI 10.3390/nu13103552 10.3390/nu13103552 Vitagliano et al. 2021, Vitagliano 2021
00240q980