Reproductive Endocrinology · Ovarian Hormones
Foresta C, Caretta N, Lana A, De Toni L, Biagioli A, Ferlin A, Garolla A
Endothelial dysfunction seems to be the first step of the atherosclerotic process. In the past few years, it has been demonstrated that injured endothelial monolayer is restored by a premature pool of circulating progenitor cells (PCs) and a more mature one of circulating endothelial PCs (EPCs). Even though there is increasing evidence that estrogens play a beneficial role on EPCs and, even if debated, on the cardiovascular system, less is known about androgens.
Our objective was to evaluate the levels of circulating PCs and EPCs in men with hypogonadotropic hypogonadism (HH) and the effect of prolonged testosterone (T) replacement therapy on these cells.
We conducted a prospective study on males with HH at a university andrological center.
The study included 10 young HH patients (28.6 +/- 3.1 yr) and 25 age-matched controls.
Idiopathic HH patients were treated with T gel therapy, 50 mg/d for 6 months.
We assessed circulating PC and EPC concentrations and immunocytochemistry for androgen receptor expression on cultured EPCs.
At baseline, HH patients showed a significant reduction of both PCs and EPCs with respect to controls. T replacement therapy induced a significant increase of these cells with respect to baseline. Immunocytochemistry on cultured EPCs showed strong expression of the androgen receptor.
Hypotestosteronemia is associated with a low number of circulating PCs and EPCs in young HH subjects. T treatment is able to induce an increase in these cells through a possible direct effect on the bone marrow.
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.
Mastorakos G et al., 2002 · Fertil Steril
To compare the effects of cyproterone acetate and desogestrel, as part of combined oral contraceptives, on lipid metabolism and hirsutism of adolescents with polycystic ovary syndrome (PCOS). Prospective randomized clinical trial. Outpatient gynecology clinic (referral center) of a university. PATIENT(S): Twenty-eight adolescent girls with clinical and biological hyperandrogenism and six or less menses during the past 12 months. INTERVENTION(S): Group A (n = 14) received 0.15 mg of desogestrel plus 0.030 mg of ethinyl estradiol daily. Group B (n = 14) received 2 mg of cyproterone acetate plus 0.035 mg of ethinyl estradiol daily. Treatment was given for 21 days followed by a 7-day rest for a period of 12 months. MAIN OUTCOME MEASURE(S): Hirsutism and lipid profile were evaluated before initiation and at 3, 6, 9, and 12 months of treatment. Androgen profile was evaluated before and at 12 months of treatment. RESULT(S): A significant decline of the Ferriman-Gallway hirsutism score was observed from the sixth month of therapy in both groups. During therapy, the levels of testosterone, free testosterone, Delta(4)-androstenedione, and 17OH-progesterone decreased significantly, whereas sex hormone-binding globulin (SHBG) increased significantly in both groups. The level of total cholesterol and low density lipoprotein (LDL) cholesterol increased significantly, whereas high density lipoprotein (HDL) cholesterol and apolipoprotein A-I increased significantly from the third month of therapy in both groups. Total cholesterol/HDL cholesterol and LDL cholesterol/HDL cholesterol ratios remained unchanged. The levels of triglycerides increased significantly in the cyproterone acetate-treated group after the third month. CONCLUSION(S): Treatment of adolescent girls with PCOS with the two studied formulations is comparably effective in decreasing hirsutism and androgen levels. Both combined oral contraceptives are associated with an increase of total cholesterol, LDL cholesterol, and HDL cholesterol levels and no change of the total cholesterol/HDL cholesterol and LDL cholesterol/HDL cholesterol ratios. Treatment with the cyproterone acetate combined oral contraceptive is associated with a tendency toward increasing the levels of triglycerides.
Foresta C et al., 2009 · Clinical endocrinology
Endothelial progenitor cells (EPCs) are bone marrow-derived cells required for endothelial repair. Circulating EPC concentration is low in conditions characterized by endothelial dysfunction but their number can be increased by treatment with phosphodiesterase-5 (PDE5) inhibitors. EPCs are also reduced in hypogonadal men and testosterone (T) treatment restores their concentration. To evaluate the relationship between the effect of PDE5 inhibitors and T on EPCs, we analysed the acute effect of vardenafil on the number of EPCs in hypogonadotrophic hypogonadal (HH) patients, before and after T treatment. A case-control study at a university andrology centre. Fifteen HH subjects and 25 aged-matched controls. The number of circulating EPCs and progenitor cells (PCs) in HH patients was evaluated after acute vardenafil administration at baseline and after 6 months of T supplementation. At baseline, HH men had significantly lower numbers of PCs and EPCs with respect to controls and vardenafil administration had no effect on the number of these cells. After 6 months of T treatment, all HH patients were eugonadal. With respect to baseline, PCs and EPCs were significantly higher and reached the levels observed in controls. Vardenafil administration in HH men at the end of T treatment induced a significant increase in PCs and EPCs in a manner similar to that in controls. This study showed that normal T levels are necessary to restore the responsiveness of EPCs to PDE5 inhibitors, suggesting that T positively modulates PDE5 in bone marrow.
Caretta N et al., 2005 · Journal of endocrinological investigation
Aging in men is accompanied by a decrease in libido and sexual activity. Recently, it has been demonstrated that a significant proportion of men >60 yr of age has biochemical hypogonadism. Hypoandrogenism, which is associated with other conditions that negatively influence erectile activity, may be an important cofactor in the induction of erectile dysfunction and in the response to phosphodiesterase type 5 (PDE5) inhibitors in aging. In these patients, administration of 50 mg sildenafil or 3 mg apomorphine has no influence on erectile function. Recently we showed that, in hypogonadal subjects, testosterone treatment might stimulate endothelial and neuronal production of vasoactive substances like nitric oxide (NO). Furthermore it can improve endothelial repair mechanisms by increasing bone marrow-derived endothelial progenitor cell (EPC) number in the peripheral circulation. Finally, the normal response to pharmacological stimulation with apomorphine or sildenafil, observed in hypogonadal men treated with testosterone, indicates a positive role of this hormone in the central and peripheral control of erection, confirming the possible positive influence on endothelial function and PDE5 expression. Therefore, we suggest measuring plasma testosterone levels in aged men with erectile dysfunction and recommend treating them barring clinical contraindications. Testosterone plus PDE5 inhibitors may be beneficial in improving erectile function in hypogonadal men with erectile dysfunction who were unresponsive to PDE5 inhibitors alone.
Lincoff AM et al., 2023 · The New England journal of medicine
The cardiovascular safety of testosterone-replacement therapy in middle-aged and older men with hypogonadism has not been determined. In a multicenter, randomized, double-blind, placebo-controlled, noninferiority trial, we enrolled 5246 men 45 to 80 years of age who had preexisting or a high risk of cardiovascular disease and who reported symptoms of hypogonadism and had two fasting testosterone levels of less than 300 ng per deciliter. Patients were randomly assigned to receive daily transdermal 1.62% testosterone gel (dose adjusted to maintain testosterone levels between 350 and 750 ng per deciliter) or placebo gel. The primary cardiovascular safety end point was the first occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, assessed in a time-to-event analysis. A secondary cardiovascular end point was the first occurrence of any component of the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization, assessed in a time-to-event analysis. Noninferiority required an upper limit of less than 1.5 for the 95% confidence interval of the hazard ratio among patients receiving at least one dose of testosterone or placebo. The mean (±SD) duration of treatment was 21.7±14.1 months, and the mean follow-up was 33.0±12.1 months. A primary cardiovascular end-point event occurred in 182 patients (7.0%) in the testosterone group and in 190 patients (7.3%) in the placebo group (hazard ratio, 0.96; 95% confidence interval, 0.78 to 1.17; P<0.001 for noninferiority). Similar findings were observed in sensitivity analyses in which data on events were censored at various times after discontinuation of testosterone or placebo. The incidence of secondary end-point events or of each of the events of the composite primary cardiovascular end point appeared to be similar in the two groups. A higher incidence of atrial fibrillation, of acute kidney injury, and of pulmonary embolism was observed in the testosterone group. In men with hypogonadism and preexisting or a high risk of cardiovascular disease, testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events. (Funded by AbbVie and others; TRAVERSE ClinicalTrials.gov number, NCT03518034.).
