Prognostic value of the clinical and laboratory evaluation in patients with nonmosaic Klinefelter syndrome who are receiving assisted reproductive therapy

Objective: To characterize clinical and laboratory findings in nonmosaic 47,XXY patients that may help to predict spermatogenetic activity in their testicles.

Design: Prospective study.

Setting: Assisted reproductive technology program.

Patient(s): Twenty patients with nonmosaic Klinefelter syndrome who underwent testicular sperm retrieval for IVF.

Main Outcome Measure(s): The correlation between basal FSH, LH and testosterone levels, mean testicular volume, and results of the hCG test and presence or absence of sperm after testicular sperm extraction (TESE).

Result(s): Sperm was found in nine patients (45%). The mean testicular volume was 7.8 ± 2.5 mL in men with sperm after TESE and 5.6 ± 1.2 mL in those without sperm after TESE; corresponding testosterone levels were 3.5 ± 1.2 ng/mL and 1.7 ± 0.8 ng/mL. Serum levels of FSH and LH did not significantly differ between groups. After the hCG test, the mean serum testosterone level was 16.0 ± 6.3 ng/mL in men with sperm after TESE and 6.7 ± 5.6 ng/mL in those without sperm.

Conclusion(s): Testicular volume, testosterone levels, and results of the hCG test are important predictive factors of spermatogenesis in patients with nonmosaic Klinefelter syndrome.     

Testicular sonography in men with Klinefelter syndrome shows irregular echogenicity and blood flow of high resistance

Purpose : Klinefelter syndrome is the most common chromosomal aberration among azoospermic men. We wanted to compare testicular echogenicity and intratesticular arterial blood in men with this syndrome versus men with normal sperm parameters. Methods : Testicular sonography including Doppler imaging, was performed as part of the infertility workup in 26 men with Klinefelter syndrome as well as in 26 men with normal sperm parameters. Results : In men with Klinefelter syndrome, sonography of the testicular parenchyma revealed a heterogenous irregular pattern with spread hyper- and hypoechoic foci. Doppler sonography resulted in waveforms of high impedance patterns, reflecting intratesticular blood flow of a high resistance. In men with normal sperm parameters testicular echogenicity was of an almost homogenous regular pattern. In these men, intratesticular blood flow typically exhibited a pattern of low vascular resistance. Conclusions : The study demonstrates that testicular echogenicity as well as intratesticular blood flow are different in men with Klinefelter syndrome versus men with normal sperm parameters.     

Partners of men with Klinefelter syndrome can benefit from assisted reproductive technologies

OBJECTIVE: To report the birth of a healthy female infant from a father with nonmosaic Klinefelter syndrome (KS) and document the experience of men with KS undergoing assisted conception. DESIGN: Retrospective. SETTING: Private IVF center. PATIENT(S): Twelve couples with male factor infertility due to Klinefelter syndrome undergoing assisted reproduction treatment. INTERVENTION(S): Controlled ovarian hyperstimulation, testicular sperm extraction, intracytoplasmic sperm injection (ICSI), round spermatid injection (ROSI), and preimplantation genetic diagnosis. MAIN OUTCOME MEASURE(S): Testicular sperm retrieval rate, fertilization rate, and pregnancy outcome. RESULT(S): There was a sufficient amount of motile sperm for injection into mature oocytes in 6 of the 11 testicular biopsies (54.5%). Fertilization rates for ICSI and ROSI cases were 54.2% and 41.6%, respectively. The pregnancy rate per ET was 27.2%. None of the ROSI cases resulted in pregnancy. Two patients had spontaneous abortions at 8 and 18 weeks of gestation, respectively. Only one patient delivered a healthy female baby after 36 weeks of an uneventful pregnancy. CONCLUSION(S): Men with KS can benefit from assisted reproductive technologies, and the testicular sperm retrieval rate among them is promising. Although sex chromosome aberrations among the embryos from men with KS are not common, couples can be offered preimplantation genetic diagnosis before ET.     

Intratesticular Doppler flow, seminal plasma nitrites/nitrates, and nonobstructive sperm extraction from patients with obstructive and nonobstructive azoospermia

Objective: To prospectively evaluate the role of intratesticular vascular flow in modulating sperm function in men with obstructive and nonobstructive azoospermia. The correlation of testicular Doppler values with nitric oxide and testicular sperm extraction was further evaluated.

Design: Prospective study.

Setting: Assisted reproduction unit at a university center.

Patient(s): Twenty-eight men with azoospermia undergoing sperm extraction for intracytoplasmic sperm injection.

Intervention(s): Ultrasound and color Doppler scanning of the testes. Testicular sperm retrieval and nitrite/nitrate assay.

Main Outcome Measure(s): Doppler analysis of testicular transmediastinal artery, plasma and seminal plasma nitrite/nitrate values, and sperm extraction histopathology.

Result(s): The pulsatility index (PI) of the transmediastinal artery was higher in patients with nonobstructive azoospermia (PI = 1.40 ± 0.13) than in those with obstructive azoospermia (PI = 1.09 ± 0.15; P=.011). Seminal plasma nitrite/nitrate concentrations were more elevated in cases of obstructive azoospermia than in gonadal failure. Unsuccessful sperm recovery was observed in four patients who showed the worst indices of gonadal failure. In this subgroup, a transmediastinal PI value >1.50 was always observed.

Conclusion(s): Doppler analysis of the transmediastinal artery and nitrite/nitrate seminal plasma concentrations are useful for distinguishing between obstructive and nonobstructive azoospermia and allow the identification of the presence of spermatozoa within the testes.     

Assisted reproductive techniques in patients with Klinefelter syndrome: a critical review

OBJECTIVE: To summarize the existing experience with the use and success rate of assisted reproductive techniques (ART), in particular testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI), in Klinefelter patients. DESIGN: A systematic review of the literature, including all published case reports to date. PATIENT(S): Thirty-nine reported successful pregnancies fathered by nonmosaic Klinefelter patients. MAIN OUTCOME MEASURE(S): The overall risk of transmitting a chromosomal abnormality to the offspring of Klinefelter patients. RESULT(S): In nonmosaic and mosaic Klinefelter patients, chromosomally normal sperm cells can be extracted from testicular tissue and used for ICSI. CONCLUSION(S): The application of ART to Klinefelter patients can be recommended as a method to achieve reproduction in this selected infertility patient cohort.     

Serum testosterone levels in patients with nonmosaic Klinefelter syndrome after testicular sperm extraction for intracytoplasmic sperm injection

We measured testosterone levels in 24 patients with nonmosaic Klinefelter syndrome before and at 6 and 12 months after conventional or microdissection testicular sperm extraction. Testosterone levels decreased after surgery by either technique, and they did not recover to baseline concentrations, even when using less invasive microdissection techniques.     

A comparison of the morphology of testicular, epididymal, and ejaculated sperm from fertile men and men with obstructive azoospermia

Objective: To assess the morphology of testicular, epididymal, and ejaculated sperm.

Design: Morphology of the three types of sperm was assessed by using Tygerberg strict criteria.

Setting: The Regional Fertility Center, Royal Maternity Hospital, Belfast, Northern Ireland, United Kingdom.

Patient(s): Thirty-two men with obstructive azoospermia and 10 fertile men.

Intervention(s): Trucut needle testicular biopsy and percutaneous epididymal sperm aspiration under local anesthetic.

Main Outcome Measure(s): Percentages of normal sperm and sperm with head, midpiece, and tail defects for testicular, epididymal, and ejaculated sperm. Testicular sperm morphology in men with obstructive azoospermia was compared with that of fertile men.

Result(s): The percentage of normal testicular sperm (4.3%) differed significantly from the percentages of normal epididymal (10.8%) and ejaculated sperm (9.6%). Testicular sperm morphology in men with obstructive azoospermia did not differ from that in fertile men.

Conclusion(s): Tygerberg strict criteria are not suitable for the assessment of testicular sperm morphology.     

Serum levels of inhibin B and follicle-stimulating hormone may predict successful sperm retrieval in men with azoospermia who are undergoing testicular sperm extraction

To evaluate the predictive power for sperm retrieval in testicular sperm extraction of inhibin B and FSH levels in the peripheral blood in association with the testicular histology.Clinical study.Departments of andrology and urology at a university hospital.Fifty-two patients with azoospermia.Determination of serum levels of FSH and inhibin B in men with azoospermia. Testicular incision and histological investigation as well as testicular sperm extraction (TESE) followed by intracytoplasmic sperm injection were performed.Comparison of hormone levels with different histological features of seminiferous tubules (normospermatogenesis, hypospermatogenesis, and Sertoli cell-only syndrome) and TESE outcome.With respect to the histological proof of spermatozoa, the sensitivity of the FSH levels >10 mU/mL was 82%, and of inhibin B levels, <79 pg/mL, 78%; the specificity was 80% for both hormone levels. With respect to the successful sperm extraction in the TESE procedure, the sensitivity of the FSH levels was 58% and the specificity was 50%; and the sensitivity of inhibin B levels was 52.5% and the specificity was 60%.Inhibin B and FSH levels are correlated with spermatogenetic activity. The combination of the two parameters is currently the best predictor for the presence of sperm, which may be found in TESE. However, the prediction is not absolutely reliable: TESE can be also successful when both hormone levels are outside the threshold levels.     

Birth of twin males with normal karyotype after intracytoplasmic sperm injection with use of testicular spermatozoa from a nonmosaic patient with Klinefelter’s syndrome

Objective: To report the birth of healthy twin males after the use of testicular spermatozoa from a nonmosaic patient with Klinefelter’s syndrome.

Design: Case report.

Setting: Private reproduction center with university affiliation.

Patient(s): A couple undergoing intracytoplasmic sperm injection (ICSI) combined with testicular sperm extraction because of the husband’s secretory azoospermia and a nonmosaic 47,XXY peripheral blood karyotype. The wife, a healthy female, presented with a history of oligomenorrhea.

Intervention(s): ICSI was performed using testicular spermatozoa; 3 mM pentoxifylline solution was used to induce sperm motility because the spermatozoa recovered were all immotile.

Main Outcome Measure(s): Normal fertilization, embryo cleavage, pregnancy outcome, and peripheral blood karyotype of the newborns.

Result(s): Thirteen metaphase II oocytes were injected. Seven of them fertilized normally and six did not fertilize. Three good-quality embryos (4-cell stage class III) were transferred, and four were cryopreserved at the two-cell and four-cell stages using a slow freezing protocol. Twelve days after ET, a β-hCG determination was positive. Ultrasonographic examination revealed three intrauterine fetal sacs, but one of them showed a fetal pole without cardiac activity and vanished in subsequent ultrasonographic examinations. The patient delivered twins with normal male peripheral blood karyotypes.

Conclusion(s): Normal outcome after the use of testicular sperm extraction and ICSI in a nonmosaic patient with Klinefelter’s syndrome reaffirms the notion of low transmission risk of this gonosomal aneuploidy.     

Birth of healthy neonates after intracytoplasmic injection of ejaculated or testicular spermatozoa from men with nonmosaic Klinefelter's syndrome: a report of 2 cases

BACKGROUND: Klinefelter's syndrome is one of the major causes of azoospermia, cryptozoospermia and severe oligozoospermia with either a nonmosaic (47,XXY) or mosaic (47,XXY/46,XY) ICSI treatment with cryopreserved testicular spermatozoa failed, but after the third attempt, 6 of 8 oocytes injected with cryopreserved sperm were fertilized and karyotype. Men with Klinefelter's syndrome generally have difficulty having children. CASES: Patient 1 had motile spermatozoa in the ejaculate, which were injected into 3 oocytes, resulting in fertilization and cleavage. Two good-quality embryos were transferred into his wife's uterine cavity. She conceived and, following a normal pregnancy, delivered a healthy female infant. Two years later she conceived for the second time with motile spermatozoa in the ejaculate and delivered a healthy male infant uneventfully. To our knowledge, this was the first case in which a nonmosaic Kleinefelter's syndrome patient fathered 2 children through intracytoplasmic sperm injection (ICSI) using motile spermatozoa in the ejaculate. Patient 2, with azoospermia, was subjected to testicular biopsy to collect spermatozoa. The first 2 attempts at ICSI treatment with cryopreserved testicular spermatozoa failed, but after the third attempt, 6 of 8 oocytes injected with cryopreserved sperm were fertilized and cleaved. Two of these embryos were transferred into the wife's uterine cavity. She conceived and, following a normal pregnancy, delivered a healthy male infant. In all cases, amniocentesis followed by genetic analysis showed a normal karyotype. CONCLUSION: Two infertile men with nonmosaic Klinefelter's syndrome successfully fathered normal children after intracytoplasmic injection of ejaculated or testicular spermatozoa.     

Testicular sperm extraction with intracytoplasmic sperm injection for male infertility

Background and Aims: Testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI) is an effective procedure for the treatment of male infertility, obstructive and non-obstructive azoospermia. We have reviewed our experience to investigate the correlation of TESE-ICSI with morphological, biophysical and endocrine profiles in 27 men.
Results:  Testicular spermatozoa could be retrieved in 25 of 27 patients who underwent TESE. In two cases, testicular spermatozoa could not be recovered and their serum follicle-stimulating hormone (FSH) levels were significantly higher than those of the former group. However, spermatozoa could be retrieved in sufficient numbers for ICSI, even in the patient with the highest FSH concentration. Johnsen scores evaluated by diagnostic pre-TESE open biopsies were significantly higher in the cases with viable testicular spermatozoa than those in the cases without spermatozoa. However, even in the patient whose Johnsen score was 2.1, testicular spermatozoa could be retrieved with TESE, and pregnancy was achieved by ICSI.
Conclusions:  The serum FSH levels and the histological findings of the testes were strong predictors for successful TESE and provided useful information for consultation and making treatment decisions on an individual case. However, whether a patient has enough spermatozoa so that an IVF procedure with ICSI is possible can only be answered by a trial TESE. (Reprod Med Biol 2003; 2 : 31–35)     

Seminal plasma inhibin-B level is a useful predictor of the success of conventional testicular sperm extraction in patients with non-obstructive azoospermia

AIM: The value of serum inhibin-B as a predictor of the presence of testicular spermatozoa is still controversial. The purpose of this study is to evaluate the predictive value of the seminal plasma inhibin-B level, which might more directly reflect the secretion by Sertoli cells, and to discriminate between successful and failed testicular sperm extraction (TESE) in non-obstructive azoospermia. METHODS: Sixty-two patients with non-obstructive azoospermia were examined at the Department of Obstetrics and Gynecology at Niigata University Hospital, Niigata, Japan. The level of inhibin-B was measured using a two-site enzyme-linked immunoassay. RESULTS: Testicular sperm were successfully retrieved in 17 of 62 patients (27.4%). The serum levels of follicle-stimulating hormone (FSH) were significantly lower and the serum and seminal inhibin-B concentrations were significantly higher in the successful TESE group compared with the failed TESE group. According to the receiver operating characteristics (ROC) curve analysis, the best discriminating seminal plasma inhibin-B level was 27.0 pg/mL (sensitivity 88.2%, specificity 93.3%). The best discriminating serum inhibin-B level was 34.0 pg/mL (sensitivity 70.6%, specificity 95.6%). The area under the ROC curve for seminal plasma inhibin-B was significantly larger than that for FSH and testicular volume. Using multivariate logistic regression analysis, only seminal plasma inhibin-B was an independent predictor of the presence of spermatozoa on TESE. CONCLUSION: Seminal plasma inhibin-B level is a useful predictor of the presence of testicular sperm in men with non-obstructive azoospermia.     

Predictive indicators of successful varicocele repair in men with infertility

OBJECTIVE: We sought predictive indicators of functionally successful repair in 168 infertile Japanese males who underwent high ligation of a varicocele via a retroperitoneal approach. METHODS: Possible indicators evaluated included age at marriage, duration of infertility, testicular volume, varicocele grade, seminal analysis findings, and serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), and testosterone. All patients had palpable or visible unilateral left varicoceles. Success in conception was evaluated in all subjects 1 year after varicocele repair. RESULTS: No associations were observed between outcome and mean age at marriage, infertility duration, varicocele grade, seminal volume, or serum PRL and testosterone concentrations, but testicular volume, sperm count, percentage of motile sperm, and serum FSH and LH concentrations were significantly associated with outcome. Multiple regression analysis of dependence of outcome revealed testicular volume and serum FSH concentrations to be independent predictors. CONCLUSIONS: Varicocele repair is likely to accomplish fertility in patients with a combined testicular volume of at least 30 mL or serum FSH concentrations lower than 11.7 mIU/mL.     

Testicular Sperm Extraction (TESE) and Intracytoplasmic Sperm Injection (ICSI) in Hypogonadotropic Hypogonadism with Persistent Azoospermia After Hormonal Therapy

PURPOSE: We aimed to retrieve testicular sperm to be employed on intracytoplasmic sperm injection (ICSI) cycles on a male affected of hypogonadotropic hypogonadism (HH) that remained azoospermic after long-time hormonal treatment. METHODS: Design. We initially performed hormonal therapy using gonadotropins to achieve spermatogenesis. After several semen analyses, we weighed the possibility of looking for testicular spermatozoa for ICSI. Setting. A private university-affiliated setting. Patient. A 30-years-old man diagnosed 10 years ago to suffer from idiopathic, prepubertal HH. Interventions. Gonadotrophin treatment was initiated with hCG and follicle stimulating hormone (FSH). Testicular sperm extraction was carried out when repeated spermiograms were negative. Motile testicular spermatozoa were cryopreserved and were subsequently employed for ICSI. Multiple follicular development was stimulated with gonadotropins after a downregulation with gonadotropin-releasing hormone (GnRH) antagonists in the woman. Main Outcome Measures. Seminal analyses were performed after 3, 6, and 12 months of treatment and serum FSH, luteinizing hormone (LH) and testosterone levels were also measured. RESULTS: Seminal analysis showed always azoospermia. Serum FSH was 2.9 mIU/mL, serum LH >1 mIU/mL and serum testosterone 7.9 ng/mL (12 months after treatment). Nine oocytes were collected by ultrasound-guided transvaginal route and eight of them were microinjected with motile, frozen-thawed testicular spermatozoa. Four oocytes were fertilized. Three embryos were transferred without pregnancy. CONCLUSIONS: The case report here presented shows that the currently available assisted reproduction techniques may be of value in patients with HH not responding to conventional hormonal treatments.     

Birth of a healthy male after frozen thawed blastocyst transfer following intracytoplasmic injection of frozen thawed testicular spermatozoa from a man with nonmosaic Klinefelter's syndrome

We here report on a birth of a male, with normal karyotype, after frozen thawed blastocyst transfer following intracytoplasmic injection of frozen thawed testicular spermatozoa from an azoospermic 27-year-old man with nonmosaic Klinerfelter's syndrome. Testicular sperm were retrieved by percutaneous needle biopsy.     

Testicular regression syndrome. A case report

Testicular regression syndrome occurred in a 20-year-old, white, phenotypic female with a 46,XY karyotype. The basal levels of serum gonadotropins were elevated, while the testosterone was in the normal range. Estrogens were undetectable. At laparotomy no gonadal rudiments or müllerian or wolffian derivatives were found. The logical diagnosis was late embryonic testicular regression with a specific testicular insult 62-63 days after fertilization.     

Identification of seminiferous tubule aberrations and a low incidence of testicular microliths associated with the development of azoospermia.

OBJECTIVE: To evaluate the use of percutaneous testicular sperm aspiration in the assessment of azoospermia and its association with seminiferous tubule microliths. DESIGN: Case report. SETTING: Tertiary care fertility center in a university hospital. PATIENT(S): Male undergoing infertility evaluation. INTERVENTION(S): Testicular biopsy and percutaneous testicular aspiration. MAIN OUTCOME MEASURE(S): Serum hormone analysis, sperm concentration in semen, spermatogenesis in samples from testicular biopsies and aspirations, and microlith composition. RESULT(S): A patient presented for infertility evaluation with a history of severe oligospermia that progressed to azoospermia. The serum testosterone concentration (357 ng/dL) and LH concentration (9.2 mIU/mL) were normal and the serum FSH concentration (18.3 mIU/mL) was elevated. Testicular biopsy results indicated spermatogenic hypoplasia with limited spermatozoa. Seminiferous tubules obtained by percutaneous testicular aspiration were structurally aberrant, with multiple diverticula. Microliths averaging 120 microm in diameter were observed within and blocking the seminiferous tubules. The microliths were composed of calcium phosphate (hydroxyapatite) in both the core and peripheral regions. Electron microscopy revealed a high degree of collagen-like material within the peripheral zone. CONCLUSION(S): The presence of seminiferous tubule microliths is associated with the development of azoospermia. In patients with a low incidence of seminiferous tubule microliths and aberrant seminiferous tubule architecture, percutaneous testicular aspiration may provide a diagnostic advantage over testicular biopsy.     

Serum inhibin B and anti-Müllerian hormone are not superior to follicle-stimulating hormone as predictors of the presence of sperm in testicular fine-needle aspiration in men with azoospermia

OBJECTIVE: To compare FSH, inhibin B (INHB), and anti-Müllerian hormone (AMH) as predictors of the recovery of sperm in testicular fine-needle aspiration biopsy (FNA) performed in men with azoospermia. DESIGN: Cross-sectional, clinical study. SETTING: Academic Unit of Reproductive Endocrinology. PATIENT(S): Fifty-one men with azoospermia and 31 controls. INTERVENTION(S): Testicular FNA. MAIN OUTCOME MEASURE(S): Serum FSH, INHB, and AMH levels. RESULT(S): Clinical diagnoses in men with azoospermia were idiopathic nonobstructive azoospermia (n = 34, 67%), cryptorchidism (n = 4, 8%), varicocele (n = 3, 6%), and other diagnoses (n = 10, 16%). In pairwise comparison of receiver operating characteristic curves, none of FSH (area under curve 0.716), INHB (0.610), AMH (0.565), or volume of the larger testis (0.693) was proved to be superior to the others as predictor of sperm retrieval during an FNA procedure. Similarly, in a logistic regression analysis, none of FSH, AMH, INHB, or volume of the larger testis could predict presence of sperm in FNA. CONCLUSION(S): Serum INHB and AMH, as well as their combination, are not superior to FSH as predictors of the presence of sperm in testicular FNA in men with azoospermia and should not be used for this purpose.     

FSH levels and testicular volumes are associated with the severity of testicular histopathology in men with non-obstructive azoospermia

Purpose

The purpose of this study is to assess a potential association between FSH levels and testicular volumes with the severity of testicular histopathology on testicular biopsy in men with non-obstructive azoospermia (NOA) undergoing microdissection testicular sperm extraction (microTESE).

Methods

A retrospective chart review was performed from the electronic health records of men who underwent microTESE with NOA.

Results

Eighty-six men with NOA underwent microTESE with concomitant testicular biopsy for permanent section to assess the testicular cellular architecture. The histopathological patterns were categorized by severity indicating the odds of sperm retrieval into 2 categories. The unfavorable category included Sertoli cell only pattern and early maturation arrest (n?=?50) and the favorable category included late maturation arrest and hypospermatogenesis patterns (n?=?36). In the men with unfavorable histopathologic patterns, the mean FSH level was 22.9?±?16.6 IU/L, and the mean testicular volume was 10.4?±?6.0 cc. This was in comparison to men with favorable histopathologic patterns revealing a mean FSH level of FSH 13.3?±?12.0 with a mean testicular volume of 13.3?±?5.9 cc. There was a statistically significant higher FSH level in men with unfavorable histopathology than favorable (p?=?0.004) as well as a significant smaller mean testicular volume in men with unfavorable histopathology (p?=?0.029).

Conclusions

Higher serum FSH levels and smaller testicular volumes are associated with more severe testicular histopathological patterns in men with NOA.