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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    • "The successful delivery of healthy children using sperms from men with KS has led to the involvement of reproductive endocrinologists and urologists in the care of patients with KS becoming commonplace. The new areas of research include the investigation of optimal methods of hormonal manipulations, preservation of fertility in adolescents, and development of universal early screening programs for KS (Paduch et al., 2009). Preventive care is to be provided from the time of diagnosis, preferentially using a multidisciplinary approach, including that from an endocrinologist, clinical psychologist or psychiatrist, neurologist, urologist, geneticist, sexologist, and a fertility team (Gies et al., 2014). "
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    ABSTRACT: Klinefelter syndrome (KS) is the most common genetic cause of male infertility. Widespread development in assisted reproductive technology has provided non-mosaic KS patients with the opportunity of having biological children. Testosterone replacement therapy and micro-dissection testicular sperm extraction are effective sperm retrieval techniques for KS patients. Despite the success of sperm retrieval and intracytoplasmic sperm injection (ICSI), some areas of early aggressive hormonal spermatogenesis and appropriate management of KS remain controversial. Androgenotherapy, a common treatment for KS, carries a risk of decreasing focal spermatogenesis by lowering the gonadotropin content. Inadequately treated hypogonadism increases psychosocial morbidity in KS patients. Preventive care must be provided from the time of diagnosis, preferentially through a multidisciplinary approach. This indicates the need for improved genetic counseling of KS patients. The aim of this study was to report the prevalence of non-mosaic KS in a Chinese infertile male population. The rate of early diagnosis was lower in KS patients; most of these were diagnosed after rising concerns of reproductive capacity. The mean age of patients with sperm or germ cells was significantly lower, while the semen volume of these patients was significantly higher. However, the semen volume was negatively correlated with the age and ratio of luteinizing hormone/testosterone content in KS patients. Therefore, genetic counseling of KS patients should focus on early diagnosis and timely treatment, in addition to improving the quality of life of all KS patients. The use of testosterone replacement therapy and/ or micro-dissection testicular sperm extraction should be preferentially considered for fertility preservation.
    Preview · Article · Sep 2015 · Genetics and molecular research: GMR
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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.
    Full-text · Article · May 2013 · The Journal of steroid biochemistry and molecular biology
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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.
    Full-text · Article · Feb 2013 · American Journal of Medical Genetics Part C Seminars in Medical Genetics
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