Impact of age at first visit on glycolipid metabolism, bone metabolism, and fertility potential in patients with Klinefelter syndrome

Giordana Ferraioli; Andrea Graziani; Noemi Sagone; Andrea Di Nisio; Massimo Iafrate; Fabrizio Dal Moro; Alberto Ferlin; Andrea Garolla

doi:10.1111/andr.70033

Bone Health · Bone Mineral Density

Impact of age at first visit on glycolipid metabolism, bone metabolism, and fertility potential in patients with Klinefelter syndrome

Ferraioli G, Graziani A, Sagone N, Di Nisio A, Iafrate M, Moro FD, Ferlin A, Garolla A

Published January 2026 Andrology

DOI 10.1111/andr.70033 PMID 40191911 PMC PMC12670481

RRM Academy Synopsis

Later Klinefelter first visits are linked to worse metabolic health

A retrospective study of 445 men with Klinefelter syndrome found that older age at first visit was associated with worse metabolic and bone measures. Among men who had a testicular biopsy, sperm were found in about 5 out of 10 first seen under 26 and about 3 out of 10 first seen at 35 or older.

Key Findings

Older age at first visit correlated with higher waist circumference, BMI, blood glucose, LDL cholesterol and triglycerides, and with lower testosterone, vitamin D and lumbar Z-score (all p < 0.05).
Increased abdominal circumference, overweight and obesity, and hypercholesterolemia were more frequent from age 26 onward at first visit (p < 0.001).
Of 199 men who had testicular biopsy, 72 had sperm retrieved and frozen (36.2%). Age at first visit was the only variable predicting successful retrieval in logistic regression (p = 0.04).
Sperm retrieval was 46.0% (29 of 63) under 26, 35.9% (28 of 78) at 26 to 34, and 25.9% (15 of 58) at 35 or older.
Only the under 26 and 35 or older groups differed in sperm retrieval (p = 0.02).

Interpretation

Classic Klinefelter syndrome (47, XXY) means a male has one extra X chromosome. This cross-sectional retrospective study measured 445 men once, at their first visit to one university clinic in Padua, so the results show association. The study did not follow men over time or test whether earlier diagnosis changes later health. Sperm retrieval figures come from the 199 men who had a biopsy, all done by the conventional method. Biopsy was recommended to men with no sperm in the semen who wanted to father a child.

RRM Context

Restorative reproductive medicine is couple-centered and looks for the cause of infertility before treatment, so the male partner is evaluated too. The authors say Klinefelter syndrome is most often found in adulthood because of infertility. They cite it in 2% of infertile men and 10% of men with no sperm in the semen. A man's infertility work-up can find a chromosomal condition that also carries metabolic and bone risks.

Our editorial summary of this paper, not the article's abstract.

Abstract

Background

Classic Klinefelter syndrome (KS) is characterized by one extra X chromosome (47, XXY), leading to hypergonadotropic hypogonadism and higher risk of alterations in glycolipid homeostasis, cardiovascular diseases, and low bone mineral density. Most frequently, KS is diagnosed in adulthood because of infertility.

Objectives

To investigate the potential association between the age at first visit and the presence of comorbidities in patients with KS.

Materials and Methods

In this cross-sectional retrospective study, we analyzed the data from 445 patients affected by non-mosaic 47, XXY KS and aged less than 50 years. Anthropometric measurements, biochemical and hormonal tests, semen analysis, scrotal echo-color Doppler, and dual energy X-ray absorptiometry (DXA) were performed on the patients. A subset of patients underwent testicular sperm extraction (TESE).

Results

Age at first visit significantly correlated positively with waist circumference (WC), body mass index (BMI), blood glucose, glycated hemoglobin, total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, and negatively with total testosterone (TT), calculated free testosterone (cFT), calcium, phosphorus, vitamin D, and lumbar Z-score. Age at the first visit >26 years was associated with higher frequency of increased WC, BMI, and hypercholesterolemia. Among the 199 patients who underwent testicular biopsy, the mean retrieval rate was 36.2% and was higher in the younger group (<26 years).

Discussion and Conclusions

Early diagnosis and management of KS is important for preventing or reducing comorbidities later in life. In particular, glycemic, lipid, and phospho-calcium metabolism worsen with advancing age at first visit. Furthermore, early management of the patient seems to be associated with a higher probability of recovering spermatozoa through TESE.

Topics

Bone Health › Bone Mineral Density › Measurement · Longevity and Reproductive Aging › Age and Fertility › Male Age and Fertility · Male Fertility › Male Endocrine and Genetic Factors › Genetic Causes of Male Infertility

Giordana Ferraioli, Andrea Graziani, Noemi Sagone, Andrea Di Nisio, Massimo Iafrate, Fabrizio Dal Moro, Alberto Ferlin, Andrea Garolla

G Ferraioli, A Graziani, N Sagone, A Nisio, M Iafrate, F Moro, A Ferlin, A Garolla

PMID 40191911 40191911 DOI 10.1111/andr.70033 10.1111/andr.70033 Ferraioli et al. 2026, Ferraioli 2026

Impact of age at first visit on glycolipid metabolism, bone metabolism, and fertility potential in patients with Klinefelter syndrome

Later Klinefelter first visits are linked to worse metabolic health

Key Findings

Interpretation

RRM Context

Abstract

Topics

By this author

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