Age-related presence of spermatogonia in patients with Klinefelter syndrome: a systematic review and meta-analysis

Abstract

BACKGROUND Klinefelter syndrome (KS) has been defined by sex chromosome aneuploidies (classically 47, XXY) in the male patient. The peripubertal timeframe in KS patients has been associated with the initiation of progressive testicular fibrosis, loss of spermatogonial stem cells (SSC), hypogonadism and impaired fertility. Less than half of KS patients are positive for spermatozoa in the ejaculate or testis via semen analysis or testicular sperm extraction, respectively. However, the chance of finding spermatogonia including a sub-population of SSCs in KS testes has not been well defined. Given the recent demonstration of successful cell culture for mouse and human SSCs, it could be feasible to isolate and propagate SSCs and transplant the cells back to the patient or to differentiate them in vitro to haploid cells. OBJECTIVE AND RATIONALE The main objective of this study was to meta-analyse the currently available data from KS patients to identify the prevalence of KS patients with spermatogonia on testicular biopsy across four age groups (year): fetal/infantile (age ≤ 1), prepubertal (age 1 ≤ x ≤ 10), peripubertal/adolescent (age 10 < x < 18) and adult (age ≥ 18) ages. Additionally, the association of endocrine parameters with presence or absence of spermatogonia was tested to obtain a more powered analysis of whether FSH, LH, testosterone and inhibin B can serve as predictive markers for successful spermatogonia retrieval. SEARCH METHODS A thorough Medline/PubMed search was conducted using the following search terms: ‘Klinefelter, germ cells, spermatogenesis and spermatogonia’, yielding results from 1 October 1965 to 3 February 2019. Relevant articles were added from the bibliographies of selected articles. Exclusion criteria included non-English language, abstracts only, non-human data and review papers. OUTCOMES A total of 751 papers were identified with independent review returning 36 papers with relevant information for meta-analysis on 386 patients. For the most part, articles were case reports, case-controlled series and cohort studies (level IV-VI evidence). Spermatogonial cells were present in all of the fetal/infantile and 83% of the prepubertal patients’ testes, and in 42.7% and 48.5% of the peripubertal and adult groups, respectively were positive for spermatogonia. Additionally, 26 of the 56 (46.4%) peripubertal/adolescent and 37 of the 152 (24.3%) adult patients negative for spermatozoa were positive for spermatogonia (P < 0.05). In peripubertal/adolescent patients, the mean ± SEM level for FSH was 12.88 ± 3.13 IU/L for spermatogonia positive patients and 30.42 ± 4.05 IU/L for spermatogonia negative patients (P = 0.001); the mean ± SEM level LH levels were 4.36 ± 1.31 and 11.43 ± 1.68 IU/L for spermatogonia positive and negative, respectively (P < 0.01); the mean ± SEM level for testosterone levels were 5.04 ± 1.37 and 9.05 ± 0.94 nmol/L (equal to 145 ± 40 and 261 ± 27 and ng/dl) for the spermatogonia positive and negative groups, respectively (P < 0.05), while the difference in means for inhibin B was not statistically significant (P > 0.05). A similar analysis in the adult group showed the FSH levels in spermatogonia positive and negative patients to be 25.77 ± 2.78 and 36.12 ± 2.90 IU/L, respectively (mean ± SEM level, P < 0.05). All other hormone measurements were not statistically significantly different between groups. WIDER IMPLICATIONS While azoospermia is a common finding in the KS patient population, many patients are positive for spermatogonia. Recent advances in SSC in vitro propagation, transplantation and differentiation open new avenues for these patients for fertility preservation. This would offer a new subset of KS patients a chance of biological paternity. Data surrounding the hormonal profiles of KS patients and their relation to fertility should be interpreted with caution as a paucity of adequately powered data exists. Future work is needed to clarify the utility of FSH, LH, testosterone and inhibin B as biomarkers for successful retrieval of spermatogonia.

Disorders of Sex Development—Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation

“…Pure 45,X monosomy is associated with a more severe phenotype of severe short stature, gonadal dysgenesis, and dysmorphic features compared to mosaic genotypes who may enter puberty spontaneously before developing primary ovarian failure, premature loss of oocytes, and infertility. Klinefelter syndrome is characterized by the presence of a 47,XXY cell line and clinical features include tall stature, small testes, gynecomastia, primary gonadal failure, progressive germ cell loss, and infertility [20]. 46,XX/46,XY mosaicism and 46,XX/46,XY chimerism are associated with dysgenetic gonads, infertility, and a highly variable phenotype which may present with ambiguous genitalia at birth [21].…”

“…The testicular phenotype of KS involves a progressive loss of spermatogonial stem cells (SSC) beginning in prepuberty, with testicular fibrosis occurring in (peri)pubertal and adult patients [135]. A meta-analysis of the presence of spermatogonia in individuals with KS demonstrated spermatogonia in the testes of all fetal/infantile samples, 83% of those obtained from prepubertal patients, and in 40-50% of adolescent/adult individuals [20].…”

Disorders of Sex Development: Classification, Review, and Impact on Fertility

“…Van Saen et al [69] reported that there is a progressive loss of spermatogonial stem cells that begins at prepubertal time, with frequent testicular fibrosis by adulthood. A meta-analysis of the presence of spermatogonia in individuals with KS demonstrated their presence in the testes of all fetal/infant samples, in 83% of those obtained from prepubertal patients, and in 40-50% of adolescents/adults [70]. Thus, the options for fertility preservation in individuals with KS depend on the age of the patient.…”

European academy of andrology guidelines on Klinefelter Syndrome Endorsing Organization: European Society of Endocrinology

“…It is still debated whether the chances to find foci within the testes with remnant intact spermatogenesis decrease with advancing age in KS [132][133][134]. Fertility in KS may also be linked to their Leydig cell functionality 106.…”