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INTRODUCTION AND OBJECTIVE:Klinefelter Syndrome (KS) is defined by chromosomal aneuploidy (typically 47, XXY). KS is associated with progressive testicular fibrosis, loss of spermatogonial stem cel...

INTRODUCTION AND OBJECTIVE:Men with Klinefelter syndrome (KS) classically have testicular failure and are at risk for both testosterone (T) deficiency and infertility. T replacement therapy (TRT) o...

INTRODUCTION AND OBJECTIVE:Klinefelter Syndrome (KS) is the most prevalent chromosomal disorder in men, defined by having 1 or more extra X chromosome. Literature suggest that there is an increased...

INTRODUCTION AND OBJECTIVE:The recent guidelines from European Academy of Andrology recommend increasing knowledge of Klinefelter Syndrome and creating multidisciplinary teams to care for affected ...

INTRODUCTION AND OBJECTIVES:Klinefelter Syndrome (KS) is defined by aneuploidy (most frequently 47,XXY) in the male patient. The onset of puberty in KS patients is associated with testicular fibros...

INTRODUCTION AND OBJECTIVES:The prevalence of Klinefelter syndrome (KS) (ranging from 0.1 to 0.2% in newborn male infants) rises up to 3-4% among infertile males and 10-12% in azoospermic patients....

We investigated the safety and tolerability of testosterone replacement therapy in adolescents with Klinefelter syndrome.We reviewed the medical records of all consecutive adolescents with Klinefelter syndrome evaluated between 2007 and 2012. Patients receiving testosterone replacement and aromatase inhibitor therapy were identified. Data on demographics, physical characteristics, medical history and serum hormone concentrations were collected for each patient. We evaluated longitudinal changes in serum testosterone, luteinizing hormone and follicle-stimulating hormone as well as changes in body mass index after the initiation of testosterone replacement therapy.We identified 151 adolescents with Klinefelter syndrome. Mean age at presentation was 11.6 years. Testosterone replacement therapy and aromatase inhibitors were initiated in 110 and 75 patients, respectively, at an average age of 13 to 14 years. Topical testosterone replacement therapy was used in 95% of patients with good clinical efficacy and compliance based on serial serum testosterone values. After the initiation of testosterone replacement therapy average serum testosterone improved from 240 to 650 ng/ml. Serum luteinizing hormone and follicle-stimulating hormone increased with the progression of puberty from 2.6 to 16.6 and 7 to 42 mIU/ml, respectively. No adverse outcomes related to testosterone replacement therapy were reported.Hormone supplementation with testosterone and aromatase inhibitors in adolescents with Klinefelter syndrome appears to be safe and effective for maintaining serum testosterone within the normal range. Compliance with topical formulations is high. Topical testosterone replacement therapy is not associated with the suppression of endogenous serum luteinizing hormone or follicle-stimulating hormone.

We developed an artificial neural network and nomogram using readily available clinical features to model the chance of identifying sperm with microdissection testicular sperm extraction by readily available preoperative clinical parameters for men with nonobstructive azoospermia.We reviewed the records of 1,026 men who underwent microdissection testicular sperm extraction. Patient age, follicle-stimulating hormone level, testicular volume, history of cryptorchidism, Klinefelter syndrome and presence of varicocele were included in the models. For the artificial neural network the data set was divided randomly into a training set (75%) and a test set (25%) with n1/n2 cross validation used to evaluate model accuracy, and then modeled with a neural computational system. In addition, a nomogram with calibration plots was developed to predict sperm retrieval with microdissection testicular sperm extraction. We compared these models to logistic regression.The ROC area for the neural computational system in the test set was 0.641. The neural network correctly predicted the outcome in 152 of the 256 test set patients (59.4%). The nomogram AUC was 0.59 and adequately calibrated. Multivariable logistic regression demonstrated patient age, history of Klinefelter syndrome and cryptorchidism to be significant predictors of sperm retrieval (p0.05). However, follicle-stimulating hormone and testicular volume were not significant by internal validation.We modeled a combination of well described preoperative clinical parameters to predict sperm retrieval using a neural computational system and nomogram with acceptable predictive values. The generalizability of these findings requires external validation.

genetic counseling, Klinefelter syndrome (3.6%) who underwent testicular sperm extraction (no men with Klinefelter syndrome had a positive YCM assay), and men with chromosomal abnormalities of the Y chromosome (1.9%) who chose donor sperm or adoption. Sequential testing for karyotype first and then YCM, results in 9.8% of men savings of $500. This reduces the average cost of testing to $1,250.69 per patient, a savings of 3.8%. CONCLUSIONS: The probability of having both a karyotype abnormality and YCM in men with testicular failure is extremely rare. Sequential performance of karyotype, followed by YCM assay if there are no abnormal karyotype findings results in demonstrable financial savings.

The causes of male infertility are heterogeneous but more than 50% of cases have a genetic basis. Specific genetic defects have been identified in less than 20% of infertile males and, thus, most causes remain to be elucidated. The most common cytogenetic defects associated with nonobstructive azoospermia are numerical and structural chromosome abnormalities, including Klinefelter syndrome (47,XXY) and Y chromosome microdeletions. To refine the incidence and nature of chromosomal aberrations in males with infertility we reviewed cytogenetic results in 668 infertile men with oligozoospermia and azoospermia.High resolution Giemsa banding chromosome analysis and/or fluorescence in situ hybridization were done in 668 infertile males referred for routine cytogenetic analysis between January 2004 and March 2009.The overall incidence of chromosomal abnormalities was about 8.2%. Of the 55 patients with abnormal cytogenetic findings sex chromosome aneuploidies were observed in 29 (53%), including Klinefelter syndrome in 27 (49%). Structural chromosome abnormalities involving autosomes (29%) and sex chromosomes (18%) were detected in 26 infertile men. Abnormal cytogenetic findings were observed in 35 of 264 patients (13.3%) with azoospermia and 19 of 365 (5.2%) with oligozoospermia.Structural chromosomal defects and low level sex chromosome mosaicism are common in oligozoospermia cases. Extensive cytogenetic assessment and fluorescence in situ hybridization may improve the detection rate in males with oligozoospermia. These findings highlight the need for efficient genetic testing in infertile men so that couples may make informed decisions on assisted reproductive technologies to achieve parenthood.

We examined preoperative factors that could predict successful microdissection testicular sperm extraction in men with azoospermia and nonmosaic Klinefelter's syndrome. We also analyzed the influence of preoperative hormonal therapy on the sperm retrieval rate.A total of 91 microdissection testicular sperm extraction attempts were done in 68 men with nonmosaic Klinefelter's syndrome. Men with serum testosterone less than 300 ng/dl received medical therapy with aromatase inhibitors, clomiphene or human chorionic gonadotropin before microdissection testicular sperm extraction. Preoperative factors of patient age and endocrinological data were compared in those in whom the procedure was and was not successful. The sperm retrieval rate was the main outcome. Clinical pregnancy (pregnancy with heartbeat) and the live birth rate were also calculated.Testicular spermatozoa were successfully retrieved in 45 men (66%), representing 62 (68%) attempts. Increasing male age was associated with a trend toward a lower sperm retrieval rate (p = 0.05). The various types of preoperative hormonal therapies did not have different sperm retrieval rates but men with normal baseline testosterone had the best sperm retrieval rate of 86%. Patients who required medical therapy and responded to that treatment with a resultant testosterone of 250 ng/dl or higher had a higher sperm retrieval rate than men in whom posttreatment testosterone was less than 250 ng/dl (77% vs 55%). For in vitro fertilization attempts in which sperm were retrieved the clinical pregnancy and live birth rates were 57% and 45%, respectively.Microdissection testicular sperm extraction is an effective sperm retrieval technique in men with Klinefelter's syndrome. Men with hypogonadism who respond to medical therapy may have a better chance of sperm retrieval.

INTRODUCTION AND OBJECTIVES: Men with mosaic Klinefelter Syndrome (mKS) are considered to be better androgenized and less likely to be azoospermic compared to men with non-mosaic Klinefelter’s Syndrome (nmKS). We evaluated the relative sperm retrieval rates for azoospermic men with mosaic vs. non-mosaic Klinefelter syndrome using microdissection testicular sperm extraction (micro-TESE). METHODS: We reviewed the records of 1,421 men with nonobstructive azoospermia who underwent micro-TESE followed by intracytoplasmic sperm injection. One-hundred and eleven men (7.8%) had karyotypes confirming Klinefelter syndrome. Patient characteristics, micro-TESE and pregnancy outcomes at each time point, and overall trend of pregnancy outcomes were compared between mosaic and nonmosaic Klinefelter patients with Student’s t-test, Fisher’s exact test, and CochraneManteleHaenszel test, respectively. RESULTS: Nine (8%) men were mosaic, with the percentage of 47 XXY cells ranging from 6-98%. Men with mKS and nmKS had similar clinical and hormonal characteristics (Table). Men with mKS and nmKS had similar sperm retrieval rates, at 78 and 65%, respectively (Figure). Men with had similar outcomes (embryo transfer, biochemical, and clinical pregnancy) relative to men with nmKS. Neither the differences at each stage toward delivery, nor the overall trend in outcomes (p1⁄40.181) were statistically significant. CONCLUSIONS: Although mosaic Klinefelter men are traditionally considered to have better androgenization, the mosaic Klinefelter men who are azoospermic have very similar fertility measures (sperm retrieval, chance of pregnancy) as azoospermic non-mosaic Klinefelter patients. Fertility counseling for azoospermic Klinefelter men should not be affected by the presence of mosaicism. Clinical Characteristics of Men with Mosiac and Non-mosaic Klinefelter’s Syndrome

INTRODUCTION AND OBJECTIVES: The diagnosis of Klinefelter Syndrome (KS) is made using peripheral blood, which may not reflect genetic aberrations in the gonads. Thus far, exome sequencing has not been successful in the diagnosis of male infertility. MicroRNAs (miRs) are short RNAs that are often differentially expressed in different tissues and disease states. Our objective was to profile miR expression in testicular tissue from patients undergoing microdissection testicular sperm extraction (microTESE) or testis biopsy in order to characterize expression patterns across different karyotypes and stages of spermatogenesis and to develop new testing modalities for male infertility. METHODS: RNA was extracted from testicular tissue from five patients with KS and nonobstructive azoospermia (NOA) as well as from patients with normal male karyotypes, including four patients with obstructive azoospermia and normal testis histology, five patients with NOA and Sertoli cell only syndrome (SCO), and four patients with NOA and early maturation arrest (eMA). MiR profiling was performed using a custom panel (Exiqon) of 22 testis-specific miRs to compare expression across karyotypes. Quantitative polymerase chain reaction was used to generate miR profiles; data analysis was performed using MultiD GenEx software. RESULTS: MicroRNA profile analysis using the 22 miR panel reliably differentiated KS patients from those with normal karyotype. The panel also differentiated patients with normal testis histology from those with SCO, but patients with eMA clustered both with patients with normal histology and SCO patients (dendrogram). CONCLUSIONS: Profiling the pattern of testicular miR expression in patients with NOA is a novel method for diagnosing KS, and may also provide information about likelihood of spermatogenesis. The differential expression of the miRs in this panel shows a strong correlation with testicular histology and further work may reveal the role of miRs as novel regulatory factors of mRNA.

vival. While no histologic differences were seen in the xenografted testis, there were dramatic changes in expression profiles with downregulation of genes involved in germ line specific and the MAPK/ERK pathway, involved in gonadotropin signaling. Methylation status corresponded with expression changes, suggesting a mechanism for CPP induced gonadotoxicity. Using CPP as an example, we have an excellent model for examining the multi-dimensional (survival, histology, epigenetic, gene expression) effects of other gonadotoxins on human germ cells.

Primary yolk sac (endodermal sinus) tumor of the prostate is extremely rare with only 2 cases reported in the literature. We describe a case of primary yolk sac tumor of the prostate in a man with Klinefelter's syndrome. Treatment included 4 courses of combination chemotherapy followed by retroperitoneal lymph node dissection, cystoprostatectomy and ileal conduit urinary diversion. We review the association of Klinefelter's syndrome with extragonadal germ cell tumor along with the management of this rare disease. The existence and pathogenesis of extragonadal germ cell tumor have been well established since the first report in 1927 by Prym.' Lachman et al reported a 30 to 40 times greater incidence of Klinefelter's syndrome among patients with mediastinal germ cell tumors than the incidence of Klinefelter's syndrome in the general population.' Yolk sac (endodermal sinus) tumor is a rare type of extragonadal germ cell tumor that was first recognized in 1959 by Teilum? Two cases of primary yolk sac tumor of the prostate gland have been described in the To our knowledge we report the first case of primary yolk sac tumor of the prostate in a patient with Klinefelter's syndrome. CASE REPORT

We report a case of adenocarcinoma of the prostate in a 41-year-old man with 47XXY karyotype (Klinefelter’s syndrome) and chronic lymphocytic leukemia. The increased incidence of malignancy in individuals with Klinefelter’s syndrome has been well documented for certain neoplasms. Adenocarcinoma of the prostate has not been reported previously in a patient with Klinefelter’s syndrome and a 47XXY karyotype. Absence of mosaicism was confirmed by peripheral lymphocyte, skin fibroblast, bone marrow cell and spleen stroma fibroblast cultures. Chronic lymphocyte leukemia, especially the T-cell cytotoxic/suppressive variant, may additionally add to an immunological deficit. Since carcinoma of the prostate, Klinefelter’s syndrome and chronic lymphocytic leukemia are common, the lack of a previous report is interesting. Etiological aspects are discussed.

Although breast cancer, germ cell tumors and other neoplasms are known to occur in patients with Klinefelter’s syndrome, adrenal carcinoma has not yet been reported in such patients. We describe a rare case of severe primary aldosteronism as the unique manifestation of a large adrenocortical carcinoma in a patient with Klinefelter’s syndrome. Complete biological and hormonal evaluation was performed. Surgical treatment was successful and the patient remained asymptomatic with normal biological and hormonal values after 1 year of followup.

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?.KS patients undergoing testicular sperm extraction (TESE) are capable of conceiving healthy children.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.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 were recruited from couples attending the European Hospital, Rome, and Clinica MARGen, Granada, for infertility treatment. Both the European Hospital and Clinica MARGen 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.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.The small numbers available for study mean that only common problems can be excluded.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.No external funding was obtained for the present study. None of the authors has any conflict of interest to declare.Not applicable.

Persistent mullerian duct syndrome (PMDS) is a rare form of male pseudohermaphroditism characterized by the retention of mullerian derivatives in an otherwise normally virilized male. Approximately 50% of the cases of PMDS can be attributed to mutations in the mullerian inhibitory substance gene. The remaining cases are primarily the result of a deletion in the type II receptor of mullerian inhibitory substance.1 Karyotypes are obtained in patients with PMDS at the discretion of the physician, to confirm a normal 46,XY chromosomal genotype. To date, PMDS has not been identified with any additional genetic or syndromic findings.

Patients with Klinefelter’s syndrome have an increased incidence of mediastinal germ cell tumors1 but testicular tumors are rare.* We describe testicular teratoma in a man with the xx/xxy mosaic Klinefelter syndrome. To our knowledge our case represents the first report of )(x/xxy mosaic Klinefelter’s syndrome associated with testicular teratoma. CASE REPORT A 62-year-old man was referred to our hospital for painless enlargement in the right scrotum. Medical and familial histories were unremarkable. He was well developed, weighing 61 kg., and was 170 cm. tall. A female type distribution of pubic hair was noted. Neither malformations nor gynecomastia was seen. The right testis was enlarged (about 30 ml. in volume) and firm but not tender. Scrota1 skin, epididymides, spermatic cord and inguinal region were normal. The left testis was atrophic and about 1 ml. in volume. Laboratory investigations, including hemogram, blood chemistry studies and urine cytology, were within normal limits. Plasma levels of P-subunit human chorionic gonadotropin, a-fetoprotein and carcinoembryonic antigen were also within normal ranges. Plasma luteinizing hormone, folliclestimulating hormone and testosterone were 27 mIU/ml. (normal 1.8 to 5.2), 69 mIU/ml. (normal 2.9 to 8.2) and 48 ng./dl. (normal 250 to 1,000), respectively. Chromosomal analysis revealed a 46,XX/47,XXY pattern, diagnostic of Klinefelter’s mosaicism (fig. 1). Abdominal computerized tomography did not show enlargement of para-aortic lymph nodes. At high orchiectomy the right testis appeared yellow-white and well circumscribed, approximately 55 X 40 X 40 mm. When the testis was incised hair was noted (fig. 2). Histologically the tumor was classified as a mature teratoma with multiple well differentiated tissue. The patient is alive and apparently tumor-free 10 months postoperatively. DISCUSSION

Editorial Comment: These 2 articles provide insight into the potential for testosterone to increase the risk of prostate cancer. This topic is of great interest because of the recent marketing of testosterone replacement as the “fountain of youth” for many of our elderly patients. Although there has been no consensus on the relationship between testosterone levels and prostate cancer risks, Parsons et al point out that virtually all prior studies used single measurements. Instead, in this study from the Baltimore Longitudinal Study of Aging they evaluated serial androgen measurements over a period as long as 40 years and were able to show that high circulating levels of free testosterone were associated with a significant increase in the risk of prostate cancer. Furthermore, they showed that men with low testosterone levels had a decreased risk. This observation is confirmed in the study by Swerdlow et al that looked at men with Klinefelter syndrome, a condition in which men are exposed to low levels of androgen throughout their life. This study showed that their risk of developing prostate cancer was reduced by 80%. These observations raise concerns about the safety of using testosterone replacement. Until true benefits have been demonstrated in elderly men this practice should be avoided, or if undertaken in men who are clearly hypogonadal, they should undergo a prostate biopsy before treatment to make certain they don’t have cancer, and after therapy is initiated testosterone levels should be carefully monitored.

Testicular tumors associated with Klinefelter’s syndrome are rare. We report a benign testicular epidermal cyst that was diagnosed in a patient with Klinefelter’s syndrome. The association between testicular tumors and Klinefelter’s syndrome, and management of a testicular epidermal cyst are discussed.

Evaluation of 48 cases of male infertility included testicular biopsy. The histologic classification included normal spermatogenesis (normal or abnormal supporting tissue, maturation arrest (spermatocyte or spermatid stage), hypospermatogenesis, Klinefelter's syndrome and Sertoli-cell-only syndrome. No diagnostic advantage was found in bilateral over unilateral testicular biopsies. Clinical presentation of the patient was correlated with histologic classification: 1) 4 of 13 azoospermic cases had normal spermatogenesis, suggesting post-testicular obstruction, 2) severe oligospermic cases (1 X 10(6) sperm per ml.) had spermatogenic abnormalities and 3) only 1 of 8 mild oligospermic cases (10 to 20 X 10(6) per ml.) had abnormalities of spermatogenesis. The histologic pattern in patients with varicocele seemed consistent with hypospermatogenesis in 9 of 13 cases studied. Testicular biopsy may be useful in the diagnosis of reversible post-testicular obstruction in some azoospermic patients. In addition, some patients with severe oligospermia may find an advantage of increased accuracy of diagnostic counseling based on histologic information. Testicular biopsy in cases of moderate oligospermia may be useful as investigational information in determining histologic patterns that may be responsive to certain modes of therapy. Histologic information obtained in cases of mild oligospermia was not sufficient to provide indication for testicular biopsy in mild oligospermic patients.