Hormonal therapy for non‐obstructive azoospermia: basic and clinical perspectives

Microdissection testicular sperm extraction (micro‐TESE) combined with intracytoplasmic sperm injection is a standard therapeutic option for patients with non‐obstructive azoospermia (NOA). Hormonal treatment has been believed to be ineffective for NOA because of high gonadotropin levels; however, several studies have stimulated spermatogenesis before or after micro‐TESE by using anti‐estrogens, aromatase inhibitors, and gonadotropins. These results remain controversial; however, it is obvious that some of the patients showed a distinct improvement in sperm retrieval by micro‐TESE, and sperm was observed in the ejaculates of a small number of NOA patients. One potential way to improve spermatogenesis is by optimizing the intratesticular testosterone (ITT) levels. ITT has been shown to be increased after hCG‐based hormonal therapy. The androgen receptor that is located on Sertoli cells plays a major role in spermatogenesis, and other hormonal and non‐hormonal factors may also be involved. Before establishing a new hormonal treatment protocol to stimulate spermatogenesis in NOA patients, further basic investigations regarding the pathophysiology of spermatogenic impairment are needed. Gaining a better understanding of this issue will allow us to tailor a specific treatment for each patient.     

Testicular sperm extraction using microdissection for non-obstructive azoospermia

Background : Men presenting with non-obstructive azoospermia (NOA) caused by germinal failure can now be treated in some cases using testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI). However, TESE is a blind procedure that does not identify the focal sperm-producing areas until excision of the testicular tissue. Microdissection TESE, which is the only method available for obtaining excised dilated seminiferous tubules under the operating microscope, improves sperm yield with minimal tissue excision in NOA patients.
Methods and Results : We performed this procedure on 16 NOA patients. All subjects underwent a microdissection TESE on the right testis, and triple biopsy on the left testis in consecutive fashion in order to compare the efficacy of microdissection TESE with that of a standard biopsy. Although dilated seminiferous tubules were presented in all patients, spermatozoa were retrieved in only a single patient by microdissection TESE. Furthermore, spermatozoa could not be identified by standard biopsies.
Conclusion : In this series, microdissection TESE did not contribute to spermatozoa recovery in NOA patients. Further study is needed in order to arrive at a reliable assessment of microdissection TESE relative to a standard multiple biopsy in cases of NOA. (Reprod Med Biol 2002; 1 : 31–34)     

Azoospermie et tétrasomie 48,XXYY : quelle prise en charge de l’infertilité ?

48,XXYY syndrome is a rare form of sex chromosomal aneuploidy. Usually considered as a variant of Klinefelter syndrome because of shared features (azoospermia, tall stature, hypergonadotropic hypogonadism), it is a separate entity because diagnostic is currently made in prepubertal boy with neuro-psychological disorders. We here report the case of a 48,XXYY patient consulting for adult infertility and the indication to perform testicular sperm extraction is discussed.     

The development of surgical sperm extraction and new challenges to improve the outcome

Surgical sperm extraction with intracytoplasmic sperm injection has become widespread worldwide and is regarded as the sole option for patients with azoospermia. However, the sperm retrieval rate remains unsatisfactorily low, particularly for men with non-obstructive azoospermia (NOA). Therefore, the technical challenges associated with improving the sperm retrieval rate for men with NOA are being addressed. The most successful method developed to date is microdissection testicular sperm extraction (micro-TESE), which is rapidly becoming recognized as a useful technique due to its relatively high sperm retrieval rate and low complication rate. However, even with micro-TESE, the sperm retrieval rate for men with NOA remains at 30–60 %, with an even lower birth rate. The technical challenges associated with improving the outcomes of surgical sperm extraction are being approached through the use of ultrasound and optimal surgical devices such as narrow band imaging, multiphoton microscopy, and optical coherent tomography. In addition to the difficulties related to searching for sperm, medical treatments that induce spermatogenesis remain controversial. For example, varicocele repair prior to surgical sperm extraction and hormonal therapy before and after TESE have been extensively examined. We herein briefly summarized the development process in surgical sperm extraction up to the present and technical challenges to improve the outcomes of surgical sperm extraction.     

Chromosomal abnormalities in patients with oligozoospermia and non-obstructive azoospermia

Purpose

To assess the frequency and types of chromosomal abnormalities in 204 Ukrainian patients with non-obstructive azoospermia and oligozoospermia and 87 men with normozoospermia.

Methods

Cytogenetic studies were performed on peripheral blood lymphocyte samples of 164 men with oligozoospermia, 40 men with non-obstructive azoospermia and 87 men with normozoospermia attending infertility clinic.

Results

Chromosomal abnormalities were detected in 17 % of patients with sperm disorders: in 35 % of men with azoospermia and in 12.7 % of men with oligozoospermia. The frequency of chromosomal abnormalities in patients with sperm disorders was significantly higher, than in patients with normozoospermia (P = 0.0001). An increase in the incidence of chromosomal abnormalities with the decrease of sperm count was observed. Chromosomal abnormalities were detected in 1.1 % of patients with normozoospermia, 6.5 % of patients with mild oligozoospermia (sperm count 5–15 × 10⁶/ml), 18.4 % of patients with severe oligozoospermia (sperm count <5 × 10⁶/ml) and 35 % of patients with azoospermia. A significant increase in the frequency of chromosomal abnormalities in patients with severe oligozoospermia was observed when compared to mild oligozoospermia (P = 0.01). A statistically significant association (P = 0.02) of chromosomal abnormalities and sex chromosome abnormalities (P = 0.0001) with azoospermia when compared to oligozoospermia was observed.

Conclusions

Our results highlight the importance of cytogenetic studies in patients with oligozoospermia (both mild and severe) and non-obstructive azoospermia. The presence of chromosomal abnormalities influences significantly the fertility treatment protocols, as well as provides a definite diagnosis to couples suffering from infertility.     

A rational approach to the management of varicocele-associated nonobstructive azoospermia

A consensus needs to be reached on a rational approach to infertile men with varicocele-associated nonobstructive azoospermia. Future studies are warranted to understand the mechanism behind the variable influence of varicocele on testicular function, which causes partial or complete damage of spermatogenesis in some cases and leaves it unaltered in others.     

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.     

The role of varicocele repair in nonobstructive azoospermia must be evaluated with controlled trials rather than observational studies

Certainly, varicoceles can have a substantive effect on sperm production in infertile males. In addition, varicocele repair may optimize sperm production. However, additional studies and evaluation of the role of varicocele repair in men with this condition (nonobstructive azoospermia) are warranted.     

Cytogenetic abnormalities detected in patients with non-obstructive azoospermia and severe oligozoospermia

Purpose  

To find the frequency and types of major chromosomal abnormalities with nonobstructive azoospermia and severe oligozoospermia to give appropriate genetic counseling before assisted reproduction techniques in Isparta (South of Turkey), and to investigate the general characteristics in this infertile male population.     

不同精子参数及来源与ICSI结局的相关性研究

目的:探讨不同精子参数及来源与单精子卵胞浆内注射(ICSI)治疗结局的相关性.方法:回顾分析2010年6月至2011年12月在武汉大学人民医院生殖医学中心行ICSI助孕治疗的413个周期,根据精子质量及来源分为4组,非严重少弱的新鲜射出精子组(A1组,244个周期)、严重少弱的新鲜射出精子组(A2组,61个周期)、睾丸精子组(B组,86个周期)、冻融的射出精子组(C组,22个周期).比较4组的ICSI治疗结局.结果:4组患者的受精率、正常受精率、卵裂率、优胚率、临床妊娠率、胚胎种植率和早期流产率均无显著差异(P＞0.05).结论:精子的质量及来源不影响ICSI治疗的受精及早期妊娠结局.     

Percutaneous epididymal sperm aspiration and short time insemination in the treatment of men with obstructive azoospermia

Objective

To study the efficacy of percutaneous epididymal sperm aspiration (PESA) in combination with short time insemination to treat infertile men with obstructive azoospermia (OA).

Design

Paired randomized controlled trial in which each couple’s cohort of oocytes was divided into two equal groups.

Setting

Center for reproductive care.

Patients

Twenty men with OA.

Interventions

Motile spermatozoa were collected using PESA. Half of the oocytes were used for intracytoplasmic sperm injection (ICSI). The rest were inseminated briefly with PESA sperm in vitro fertilization (IVF). After 4–5 h, the remaining cumulus cells were removed mechanically for second polar body observation to decide whether to apply “rescue” ICSI (RE-ICSI).

Main outcome measures

Rates of oocyte maturation, fertilization, cleavage, and good quality embryos. Numbers of available embryos and good quality embryos were compared between PESA-IVF (using a short incubation protocol + rescue ICSI) group and PESA-ICSI group.

Results

In the short time insemination group, cumulus cells were dispersed by PESA spermatozoa. No second polar bodies were found, so RE-ICSI was done. PESA-IVF + RE-ICSI and PESA-ICSI outcomes were comparable in terms of fertilization rates, 2PN cleavage rate and good quality embryo rates with no statistically significant differences.

Conclusions

PESA sperm without centrifugation could disperse the cumulus cells but were infertile and therefore could substitute for synthetic hyaluronidase. The outcomes of PESA-IVF with rescue ICSI were equivalent to PESA-ICSI. Using spermatozoa obtained by PESA and IVF before RE-ICIS is a viable treatment for men with OA.     

Genetic analysis of three polymorphic sites of the luteinizing hormone beta-subunit gene in infertile Korean men with nonobstructive azoospermia

OBJECTIVE: To investigate the genetic background of nonobstructive male factor infertility. DESIGN: Clinical and controlled study. PATIENT(S): Ninety-five nonobstructive male infertile patients (75 with azoospermia, 18 with oligoasthenoteratozoospermia, and two with oligozoospermia) and 200 healthy fertile control men. INTERVENTION(S): Patients were investigated for genetic background including karyotype, Yq chromosome deletion, and three polymorphisms of the LH beta-subunit gene (Trp8Arg, Ile15Thr, and Gly102Ser). MAIN OUTCOME MEASURE(S): To determine three polymorphisms of the LH beta-subunit gene. RESULT(S): An abnormal karyotype was found in 11 of the 75 patients with azoospermia and one of the 18 patients with oligoasthenoteratozoospermia. Eleven (12%) had one or more deleted sites at 13 loci on Yq. The Gly102Ser variant of the LH beta-subunit gene was not detected at all. The frequency of double Trp8Arg and Ile15Thr heterozygotes was similar between the fertile (14.5%, n = 200) and infertile (12.6%, n = 95) groups, with the exception of one homozygous mutation (Arg8 and Thr15) from patient with azoospermia. CONCLUSION(S): Three variants of the LH beta-subunit gene (Trp8Arg, Ile15Thr, and Gly102Ser) may not be associated with male factor infertility. We found one homozygous Arg8 and Thr15 mutation in a patient with azoospermia with normal hormone levels (FSH, LH, PRL, T), a normal karyotype, and no Yq microdeletions.     

Genetic study of Hormad1 and Hormad2 with non-obstructive azoospermia patients in the male Chinese population

Purpose

To evaluate the association of the Hormad1 and Hormad2 single nucleotide polymorphisms (SNPs) variants with non-obstructive azoospermia (NOA) in the Chinese population.

Methods

In the present study, we assessed 10 single nucleotide polymorphisms (SNPs) of Hormad1 and Hormad2 using Sequenom iplex technology in 361 NOA cases and 368 normal controls from Chinese population.

Results

We observed no statistical differences in the distribution of allele frequencies. Further genetic model analysis and haplotype analysis also showed no significant difference between the two groups. However, we found that genotype distribution of rs718772 of Hormad2 was significantly different between the larger testis group (average testis volume ≥10 ml) and the small testis group (average testis volume <10 ml) in the NOA patients (P = 0.035).

Conclusions

In conclusion, Hormad1 and Hormad2 might not be the susceptible genes for the non-obstructive azoospermia in our study population. However, rs718772 of Hormad2 variant might be associated with testis development in NOA patients.

Electronic supplementary material

The online version of this article (doi:10.1007/s10815-014-0244-x) contains supplementary material, which is available to authorized users.     

Percutaneous vasal sperm aspiration and intrauterine insemination in the treatment of obstructive azoospermia

Objective: To treat obstructive azoospermia by using sperm recovered from percutaneous vasal sperm aspiration in IUI.

Design: Clinical study.

Setting: Institutional clinic in Jinan.

Patient(s): Six men with obstructive azoospermia, three of whom were treated with percutaneous vasal sperm aspiration and IUI; sperm recovered from this procedure were used for IUIs.

Intervention(s): Spermatozoa used for intrauterine injection were retrieved by percutaneous vasal sperm aspiration and incubated at 37°C for 40 to 60 minutes.

Main Outcome Measure(s): Normal pregnancy.

Result(s): Intrauterine insemination was performed in three patients for one or two cycles, with motile spermatozoa. There was one successful term delivery.

Conclusion(s): Percutaneous vasal sperm aspiration can be used successfully to recover sperm in men with obstructive azoospermia for use in IUI. The technique is simple and less traumatic than an open surgical procedure.