The natural history of endocrine function and spermatogenesis in Klinefelter syndrome: What the data show

School of Medicine, Boston University, Boston, Massachusetts, USA.
Fertility and sterility (Impact Factor: 4.59). 08/2012; 98(2):266-73. DOI: 10.1016/j.fertnstert.2012.06.024
Source: PubMed


Once thought to be a chromosomal aberration associated with absolute sterility, Klinefelter syndrome may now be potentially treatable by testicular sperm retrieval coupled with intracytoplasmic sperm injection. With these therapeutic advances, azoospermic 47,XXY men now may have an opportunity for biological paternity. However, our knowledge of the basic mechanisms underlying germ cell loss and Leydig cell compromise is lagging, and is just now beginning to evolve and provide answers to some of the field's most vexing questions: how to maximize and preserve fertility in Klinefelter males many years or even decades before they wish to actively pursue fatherhood. This article reviews the development of the androgenic and spermatogenic compartments of the Klinefelter testis through puberty, and recommends that it is only with a clear understanding of the basic facts that a rational, considered approach to fertility optimization and preservation can be determined.

8 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Klinefelter syndrome is commonly encountered by the physician dealing with male infertility. Despite the success of sperm retrieval and ICSI, there remain many areas of controversy about the mechanisms and natural history of spermatogenesis, as well as the appropriate management of these patients. This collection of articles provides a state of the art review of what is known and what is unknown about this syndrome and reports a variety of managment approaches to these patients. (Fertil Steril (R) 2012;98:251-2. (C) 2012 by American Society for Reproductive Medicine.)
    Fertility and sterility 06/2012; 98(2):251-2. DOI:10.1016/j.fertnstert.2012.05.011 · 4.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: STUDY QUESTION: Does the health status of infants fathered by nonmosaic Klinefelter syndrome (KS) patients whose partners underwent ICSI with sperm obtained from testicular dissection reveal any genetic risk for the offspring?. SUMMARY ANSWER: KS patients undergoing testicular sperm extraction (TESE) are capable of conceiving healthy children. WHAT IS KNOWN ALREADY: Paternity has been successfully achieved in nonmosaic KS patients (47,XXY karyotype) by ICSI using either ejaculated or testicular spermatozoa. A crucial concern is the potential transmission of genetic abnormalities to the offspring. Some studies reported that 47,XXY spermatogonia are capable of completing spermatogenesis leading to the production of mature spermatozoa with increased aneuploidies. Other authors showed that where focal spermatogenesis is present in nonmosaic KS males, it originates from euploid germ cells and, therefore, produces normal mature gametes. In support of this finding, at present, the great majority of children born from nonmosaic KS patients are chromosomally normal. STUDY DESIGN, SIZE, DURATION: From April 2004 to June 2010, 38 azoospermic patients with nonmosaic KS were examined for the presence of testicular spermatozoa. Spermatozoa were retrieved from 15 patients and 26 ICSI cycles were done (16 with cryopreserved sperm). There were 15 pregnancies leading to the birth of 16 babies who were karyotyped at amniocentesis and after birth. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were recruited from couples attending the European Hospital, Rome, and Clinica MAR&Gen, Granada, for infertility treatment. Both the European Hospital and Clinica MAR&Gen are private clinics. Testicular tissue was extracted with TESE or micro-TESE. After retrieval, fresh sperm was used for ICSI or it was cryopreserved for future use. MAIN RESULTS AND THE ROLE OF CHANCE: Spermatozoa were retrieved from 15 patients (14 TESE and 1 micro-TESE) out of 38 (39.5%). A total of 26 ICSI cycles were performed: 10 with fresh and 16 with cryopreserved-thawed sperm. Mean ages (y) of patients with positive and negative sperm retrieval were, respectively, 34.8 ± 1.72 and 35.6 ± 4.08 (NS, nonsignificant). Comparing ICSI cycles performed with fresh sperm (n = 10) to those performed with frozen-thawed sperm (n = 16): Fertilization rates per injected oocyte were 53.0% (44 of 83) and 47.8% (32 of 67), respectively (NS). The cleavage rate per injected oocyte was 90.6% (29 of 32) versus 68.2% (30 of 44); P = 0.026. Clinical outcomes were not significantly different between the fresh and the frozen-thawed sperm group: clinical pregnancy rates were 7 of 10 (70.0%) and 8 of 16 (50.0%); implanted embryos (per transferred embryo) were 8 of 23 (34.8%) and 8 of 29 (27.6%); delivery rates were 6 of 10 (60.0%) and 5 of 16 (31.3%). Sixteen babies were born, all of them are healthy with a normal karyotype, eight from the fresh sperm group and eight from the frozen-thawed sperm group. LIMITATIONS, REASONS FOR CAUTIONS: The small numbers available for study mean that only common problems can be excluded. WIDER IMPLICATIONS OF THE FINDINGS: This study provides further reassurance that KS men can father healthy children and that pre-implantation genetic diagnosis on embryos conceived with their sperm is not strongly indicated. However, until conclusive information is available, such couples should be offered extensive genetic counseling. STUDY FUNDING/COMPETING INTEREST(S): No external funding was obtained for the present study. None of the authors has any conflict of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable.
    Human Reproduction 03/2013; 28(5). DOI:10.1093/humrep/det046 · 4.57 Impact Factor
Show more