Reproduction in Men with Klinefelter Syndrome: The Past, the Present, and the Future

Department of Urology and Reproductive Medicine, Weill Medical College of Cornell University, New York, New York 10065, USA.
Seminars in Reproductive Medicine (Impact Factor: 2.35). 04/2009; 27(2):137-48. DOI: 10.1055/s-0029-1202302
Source: PubMed


Klinefelter syndrome (KS) is the most common chromosomal aberration in men. There are approximately 250,000 men with KS in the United States, and the prevalence of KS in male reproductive practices is 3 to 4%; however, most men are never diagnosed. KS has an effect on normal development, growth, social interactions, bone structure, and sexual and reproductive function, thus a multidisciplinary approach to men with KS is important in providing state of the art care to children and men with KS. Over the last 10 years, with advancements in artificial reproductive techniques and the successful delivery of healthy children from men with KS, the involvement of reproductive endocrinologists and urologists in the care of patients with KS is becoming commonplace. The new areas of intense research investigate optimal methods of hormonal manipulations, preservation of fertility in adolescents, and development of universal early screening programs for KS. This review provides the latest update in our understanding of the pathophysiology, natural history, and evolving paradigms of therapy in adolescents and men with KS.

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    • "Several pathological conditions known to cause subfertility and infertility are characterized by severe hormonal deregulation [23] [24]. We have previously shown that 17␤-estradiol (E2) and 5␣-dihydrotestosterone (DHT) are modulators of SCs metabolism [25] [26] and there is a close relationship between metabolism and apoptosis, being the mitochondria the central organelle [27], thus we hypothesized that sex steroid hormones could have a role on the regulation of mitochondria related pro-apoptotic factors. "
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    ABSTRACT: Apoptosis is an important regulatory event in testicular homeostasis and optimization of sperm production. Sertoli cells (SCs) form the blood-testis barrier creating a special microenvironment where germ cells develop and are under strict hormonal control. Estrogens and androgens are known to play critical roles in SCs functioning, improving their in vitro survival by preventing apoptotic progression. Herein, we studied the influence of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT) on the apoptotic signaling pathways of immature rat cultured SCs. For that we chose key points of the apoptotic pathway that interact with the mitochondria and evaluated the mRNA expression and/or protein levels of several apoptotic markers such as p53, the anti-apoptotic protein Bcl2, the pro-apoptotic Bcl2 family member Bax, the apoptosis-inducing factor (AIF) and caspase-3 and 9. Caspase-3 activity and DNA fragmentation were also evaluated as endpoint markers of apoptosis. E2 and DHT down-regulated the mRNA transcript levels of p53, Bax, caspase-9 and caspase-3. The protein levels of AIF were reduced after DHT treatment while E2-treated cells presented decreased levels of cleaved caspase-9 protein. Moreover, Bax/Bcl2 ratio is significantly decreased in E2-treated cells. The apoptotic endpoints caspase-3 activity and DNA fragmentation presented significant decreased levels after hormonal treatment. Taken together, these results show that E2 and DHT act as apoptotic signaling modulators in in vitro immature rat SCs suggesting that androgens and estrogens may be capable of modulating independent pathways of the apoptotic event by regulating different pro-apoptotic factors.
    The Journal of steroid biochemistry and molecular biology 05/2013; DOI:10.1016/j.jsbmb.2012.11.019 · 3.63 Impact Factor
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    • "Early diagnosis of 47, XXY and proactive testosterone replacement along with multidisciplinary approach for physical, speech, behavioral, and occupational therapy promotes effective developmental , social, and academic progress [Paduch et al., 2009; Radicioni et al., 2010]. It is important to remember that most descriptions of the phenotype and associated comorbidities are derived from studies of older patients who were not treated during puberty and early adulthood. "
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    ABSTRACT: 47, XXY or Klinefelter syndrome (KS), the most common chromosomal aberration in males, is characterized by either absolute or relative hypogonadism with frequent decline in serum testosterone (T) following the onset of puberty. Decreased T levels are the result of testicular dysfunction with decrease in size of Leydig cells, and loss of germs and Sertoli cells leading to tubular hyalinization. Increase in estradiol results from over-expression of aromatase CYP19. Deficient androgen production and observed varied response of end-organs to T leads to delayed progression of puberty with decreased facial/body hair, poor muscle development, osteoporosis, and gynecomastia. It is possible that hypogonadism and excessive estradiol production contribute to emotional and social immaturity, and specific learning disabilities in KS. Based on the authors' experience and literature review, early fertility preservation and hormonal supplementation may normalize pubertal development, prevent metabolic sequelae of hypogonadism, and have a positive effect on academic and social development. No randomized clinical trials are available studying the effects of T supplementation on reproductive or cognitive issues in KS. Aggressive T supplementation (topical gel) and selective use of aromatase inhibitors may be considered at the onset of puberty with careful follow-up and titration to reach age-specific high-normal physiologic serum values. The decision to institute hormonal therapy should be part of a multidisciplinary approach including physical, speech, behavioral, and occupational therapy. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 02/2013; 163C(1). DOI:10.1002/ajmg.c.31350 · 3.91 Impact Factor
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    • "We confirmed male sex by PCR analysis of the X and Y chromosomes. This also excludes Klinefelter syndrome (47, XXY), which could theoretically explain a phenotype associated with the female sex in a male patient [19]. The TLR of female carriers of XLRP is considered to be specific for this condition, and has not, to the best of our knowledge, been previously described in a male. "
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    ABSTRACT: To report on the retinal function and structure in a 37-year-old male who presented with a tapetal-like reflex (TLR) indistinguishable from that seen in female carriers of X-linked retinitis pigmentosa (XLRP). Clinical examination included dark adaptometry, full-field electroretinography (ERG), multifocal ERG, optical coherence tomography, and fundus autofluorescence photography. Molecular genetic testing included screening for known mutations in autosomal dominant, autosomal recessive, and X linked retinitis pigmentosa (RP) genes with a commercially available chip, and sequencing analysis of retinitis pigmentosa GTPase regulator (RPGR)-open reading frame 15 (ORF15). Fundus examination revealed a bilateral TLR, which is typical of female carriers of XLRP. Imaging studies and electrophysiological testing was unremarkable, except for a significant increase in full-field ERG amplitudes after prolonged dark adaptation as compared to after standard dark adaptation. Mutation screening was negative. TLR was found for the first time, to the best of our knowledge, in a male subject. There were no definitive signs of retinal degeneration, suggesting that this reflex in itself is not necessarily a precursor of the retinal degeneration that can be seen in female carriers of XLRP.
    Molecular vision 05/2012; 18:1147-55. · 1.99 Impact Factor
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