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Update on the Management of Non-Obstructive Azoospermia: Current Evidence and...
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Update on the Management of Non-Obstructive Azoospermia: Current Evidence and Unmet Needs

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Reproductive Medicine & Andrology".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 55136

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Giovanni M. Colpi

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Guest Editor
Andrology and IVF Center, Next Fertility Procrea, Lugano, Switzerland
Interests: azoospermia (non-obstructive and obstructive); surgical sperm retrieval for ICSI; epididymis pathology in male infertility; seminal tract surgery; severe male infertility (all kinds); sperm DNA fragmentation in clinical practice; varicocele
Special Issues, Collections and Topics in MDPI journals
Dr. Ettore Caroppo

E-Mail
Guest Editor
Department of Maternal and Child Health, Reproductive and IVF Unit, Asl Bari, Conversano, Italy
Interests: male infertility; non-obstructive azoospermia; hormonal treatment of male infertility; epigenetic factors; infertility
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Azoospermia affects about 1% of male population and up to 15% of infertile male subjects. In most azoospermic patients, the absence of sperm in the ejaculate is due to spermatogenic dysfunction (the so-called non-obstructive azoospermia - NOA); since these patients may be still able to father their own genetically children if viable sperm are found in their testes, much effort have been spent in order to individuate the best surgical technique to retrieve testicular sperm, the most reliable predictive factors of successful sperm retrieval, and the optimal management of these patients. Although there is great consensus about the role of microdissection testicular sperm extraction (microTESE) as the gold standard surgical technique to retrieve testicular sperm in patients with NOA, conventional TESE is still being used in many IVF centres, although this may significantly limit the reproductive chances of these patients.

In this Special Issue, we will publish reviews and original research that provide new insights into the management of patients with NOA. Articles about the surgical approach to sperm retrieval and the hormonal treatment of patients with NOA will be particularly welcome.

Prof. Dr. Giovanni M. Colpi
Dr. Ettore Caroppo
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Differential diagnosis of azoospermia
  • Prediction of sperm retrieval
  • MicroTESE vs TESE
  • Testis histology
  • Hormonal treatment of men with NOA
  • Sperm retrieval in Klinefelter patients
  • New methods to improve the sperm yield from testicular specimens

Published Papers (11 papers)

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Editorial

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3 pages, 162 KiB  
Editorial
Update on the Management of Non-Obstructive Azoospermia: Current Evidence and Unmet Needs
by Ettore Caroppo and Giovanni M. Colpi
J. Clin. Med. 2022, 11(1), 62; https://doi.org/10.3390/jcm11010062 - 23 Dec 2021
Cited by 7 | Viewed by 2348
Abstract
Azoospermia, defined as the absence of sperm in the ejaculate after examination of the centrifuged specimens, affects about 1% of the male population and 10–15% of infertile men [...] Full article
(This article belongs to the Special Issue Update on the Management of Non-Obstructive Azoospermia: Current Evidence and Unmet Needs)

Review

Jump to: Editorial

10 pages, 260 KiB  
Review
Prediction Models for Successful Sperm Retrieval in Patients with Non-Obstructive Azoospermia Undergoing Microdissection Testicular Sperm Extraction: Is There Any Room for Further Studies?
by Ettore Caroppo and Giovanni Maria Colpi
J. Clin. Med. 2021, 10(23), 5538; https://doi.org/10.3390/jcm10235538 - 26 Nov 2021
Cited by 14 | Viewed by 2474
Abstract
Several prediction models for successful sperm retrieval (SSR) in patients with azoospermia due to spermatogenic dysfunction (also termed non-obstructive azoospermia—NOA) have been developed and published in the past years, however their resulting prediction accuracy has never been strong enough to translate their results [...] Read more.
Several prediction models for successful sperm retrieval (SSR) in patients with azoospermia due to spermatogenic dysfunction (also termed non-obstructive azoospermia—NOA) have been developed and published in the past years, however their resulting prediction accuracy has never been strong enough to translate their results in the clinical practice. This notwithstanding, the number of prediction models being proposed in this field is growing. We have reviewed the available evidence and found that, although patients with complete AZFc deletion or a history of cryptorchidism may have better probability of SSR compared to those with idiopathic NOA, no clinical or laboratory marker is able to determine whether a patient with NOA should or should not undergo microdissection testicular sperm extraction (mTESE) to have his testicular sperm retrieved. Further research is warranted to confirm the utility of evaluating the expression of noncoding RNAs in the seminal plasma, to individuate patients with NOA with higher probability of SSR. Full article
(This article belongs to the Special Issue Update on the Management of Non-Obstructive Azoospermia: Current Evidence and Unmet Needs)
13 pages, 4261 KiB  
Review
Performing Microdissection Testicular Sperm Extraction: Surgical Pearls from a High-Volume Infertility Center
by Giovanni M. Colpi and Ettore Caroppo
J. Clin. Med. 2021, 10(19), 4296; https://doi.org/10.3390/jcm10194296 - 22 Sep 2021
Cited by 10 | Viewed by 3263
Abstract
Microdissection testicular sperm extraction (mTESE) has been demonstrated to be the gold-standard surgical technique for retrieving testicular sperm in patients with non-obstructive azoospermia (NOA) as it enables the exploration of the whole testicular parenchyma at a high magnification, allowing the identification of the [...] Read more.
Microdissection testicular sperm extraction (mTESE) has been demonstrated to be the gold-standard surgical technique for retrieving testicular sperm in patients with non-obstructive azoospermia (NOA) as it enables the exploration of the whole testicular parenchyma at a high magnification, allowing the identification of the rare dilated seminipherous tubules that may contain sperm, usually surrounded by thinner or atrophic tubules. MTESE requires a skilled and experienced surgeon whose learning curve may greatly affect the sperm retrieval rate, as demonstrated in previous reports. The present review is intended to offer a precise and detailed description of the mTESE surgical procedure, accompanied by an extensive iconography, to provide urologists with valuable information to be translated into clinical practice. Advice about the pre-surgical and post-surgical management of patients is also offered. Full article
(This article belongs to the Special Issue Update on the Management of Non-Obstructive Azoospermia: Current Evidence and Unmet Needs)
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18 pages, 755 KiB  
Review
Genetic Factors of Non-Obstructive Azoospermia: Consequences on Patients’ and Offspring Health
by Csilla Krausz and Francesca Cioppi
J. Clin. Med. 2021, 10(17), 4009; https://doi.org/10.3390/jcm10174009 - 05 Sep 2021
Cited by 21 | Viewed by 5233
Abstract
Non-Obstructive Azoospermia (NOA) affects about 1% of men in the general population and is characterized by clinical heterogeneity implying the involvement of several different acquired and genetic factors. NOA men are at higher risk to be carriers of known genetic anomalies such as [...] Read more.
Non-Obstructive Azoospermia (NOA) affects about 1% of men in the general population and is characterized by clinical heterogeneity implying the involvement of several different acquired and genetic factors. NOA men are at higher risk to be carriers of known genetic anomalies such as karyotype abnormalities and Y-chromosome microdeletions in respect to oligo-normozoospermic men. In recent years, a growing number of novel monogenic causes have been identified through Whole Exome Sequencing (WES). Genetic testing is useful for diagnostic and pre-TESE prognostic purposes as well as for its potential relevance for general health. Several epidemiological observations show a link between azoospermia and higher morbidity and mortality rate, suggesting a common etiology for NOA and some chronic diseases, including cancer. Since on average 50% of NOA patients has a positive TESE outcome, the identification of genetic factors in NOA patients has relevance also to the offspring’s health. Although still debated, the observed increased risk of certain neurodevelopmental disorders, as well as impaired cardiometabolic and reproductive health profile in children conceived with ICSI from NOA fathers may indicate the involvement of transmissible genetic factors. This review provides an update on the reproductive and general health consequences of known genetic factors causing NOA, including offspring’s health. Full article
(This article belongs to the Special Issue Update on the Management of Non-Obstructive Azoospermia: Current Evidence and Unmet Needs)
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9 pages, 1831 KiB  
Review
Microfluidic Systems for Isolation of Spermatozoa from Testicular Specimens of Non-Obstructive Azoospermic Men: Does/Can It Improve Sperm Yield?
by Gary D. Smith, Clementina Cantatore and Dana A. Ohl
J. Clin. Med. 2021, 10(16), 3667; https://doi.org/10.3390/jcm10163667 - 19 Aug 2021
Cited by 5 | Viewed by 2154
Abstract
Intracytoplasmic sperm injection (ICSI) has allowed reproduction options through assisted reproductive technologies (ARTs) for men with no spermatozoa within the ejaculate (azoospermia). In men with non-obstructive azoospermia (NOA), the options for spermatozoa retrieval are testicular sperm extraction (TESE), testicular sperm aspiration (TESA), or [...] Read more.
Intracytoplasmic sperm injection (ICSI) has allowed reproduction options through assisted reproductive technologies (ARTs) for men with no spermatozoa within the ejaculate (azoospermia). In men with non-obstructive azoospermia (NOA), the options for spermatozoa retrieval are testicular sperm extraction (TESE), testicular sperm aspiration (TESA), or micro-surgical sperm extraction (microTESE). At the initial time of spermatozoa removal from the testis, spermatozoa are immobile. Independent of the means of spermatozoa retrieval, the subsequent steps of removing spermatozoa from seminiferous tubules, determining spermatozoa viability, identifying enough spermatozoa for oocyte injections, and isolating viable spermatozoa for injection are currently performed manually by laboratory microscopic dissection and collection. These laboratory techniques are highly labor-intensive, with yield unknown, have an unpredictable efficiency and/or success rate, and are subject to inter-laboratory personnel and intra-laboratory variability. Here, we consider the potential utility, benefits, and shortcomings of developing technologies such as motility induction/stimulants, microfluidics, dielectrophoresis, and cell sorting as andrological laboratory add-ons to reduce the technical burdens and variabilities in viable spermatozoa isolation from testicular samples in men with NOA. Full article
(This article belongs to the Special Issue Update on the Management of Non-Obstructive Azoospermia: Current Evidence and Unmet Needs)
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7 pages, 218 KiB  
Review
Endocrine Follow-Up of Men with Non-Obstructive Azoospermia Following Testicular Sperm Extraction
by Evangelia Billa, George A. Kanakis and Dimitrios G. Goulis
J. Clin. Med. 2021, 10(15), 3323; https://doi.org/10.3390/jcm10153323 - 28 Jul 2021
Cited by 8 | Viewed by 2008
Abstract
Testicular sperm extraction (TESE) is a surgical procedure which, combined with intracytoplasmic sperm injection, constitutes the main treatment for achieving biological parenthood for patients with infertility due to non-obstructive azoospermia (NOA). Although it is effective, TESE procedures might cause structural testicular damage leading [...] Read more.
Testicular sperm extraction (TESE) is a surgical procedure which, combined with intracytoplasmic sperm injection, constitutes the main treatment for achieving biological parenthood for patients with infertility due to non-obstructive azoospermia (NOA). Although it is effective, TESE procedures might cause structural testicular damage leading to Leydig cell dysfunction and, consequently, temporary or even permanent hypogonadism with long-term health consequences. To a lesser extent, the same complications have been reported for microdissection TESE, which is considered less invasive. The resulting hypogonadism is more profound and of longer duration in patients with Klinefelter syndrome compared with other NOA causes. Most studies on serum follicle-stimulating hormone and luteinizing hormone concentrations negatively correlate with total testosterone concentrations, which depends on the underlying histology. As hypogonadism is usually temporary, and a watchful waiting approach for about 12 months postoperative is suggested. In cases where replacement therapy with testosterone is indicated, temporary discontinuation of treatment may promote the expected recovery of testosterone secretion and revise the decision for long-term treatment. Full article
(This article belongs to the Special Issue Update on the Management of Non-Obstructive Azoospermia: Current Evidence and Unmet Needs)
20 pages, 1335 KiB  
Review
Differential Diagnosis of Azoospermia in Men with Infertility
by Danilo L. Andrade, Marina C. Viana and Sandro C. Esteves
J. Clin. Med. 2021, 10(14), 3144; https://doi.org/10.3390/jcm10143144 - 16 Jul 2021
Cited by 30 | Viewed by 15998
Abstract
The differential diagnosis between obstructive and nonobstructive azoospermia is the first step in the clinical management of azoospermic patients with infertility. It includes a detailed medical history and physical examination, semen analysis, hormonal assessment, genetic tests, and imaging studies. A testicular biopsy is [...] Read more.
The differential diagnosis between obstructive and nonobstructive azoospermia is the first step in the clinical management of azoospermic patients with infertility. It includes a detailed medical history and physical examination, semen analysis, hormonal assessment, genetic tests, and imaging studies. A testicular biopsy is reserved for the cases of doubt, mainly in patients whose history, physical examination, and endocrine analysis are inconclusive. The latter should be combined with sperm extraction for possible sperm cryopreservation. We present a detailed analysis on how to make the azoospermia differential diagnosis and discuss three clinical cases where the differential diagnosis was challenging. A coordinated effort involving reproductive urologists/andrologists, geneticists, pathologists, and embryologists will offer the best diagnostic path for men with azoospermia. Full article
(This article belongs to the Special Issue Update on the Management of Non-Obstructive Azoospermia: Current Evidence and Unmet Needs)
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31 pages, 487 KiB  
Review
Sperm Selection Procedures for Optimizing the Outcome of ICSI in Patients with NOA
by Kaan Aydos and Oya Sena Aydos
J. Clin. Med. 2021, 10(12), 2687; https://doi.org/10.3390/jcm10122687 - 18 Jun 2021
Cited by 11 | Viewed by 3856
Abstract
Retrieving spermatozoa from the testicles has been a great hope for patients with non-obstructive azoospermia (NOA), but relevant methods have not yet been developed to the level necessary to provide resolutions for all cases of NOA. Although performing testicular sperm extraction under microscopic [...] Read more.
Retrieving spermatozoa from the testicles has been a great hope for patients with non-obstructive azoospermia (NOA), but relevant methods have not yet been developed to the level necessary to provide resolutions for all cases of NOA. Although performing testicular sperm extraction under microscopic magnification has increased sperm retrieval rates, in vitro selection and processing of quality sperm plays an essential role in the success of in vitro fertilization. Moreover, sperm cryopreservation is widely used in assisted reproductive technologies, whether for therapeutic purposes or for future fertility preservation. In recent years, there have been new developments using advanced technologies to freeze and preserve even very small numbers of sperm for which conventional techniques are inadequate. The present review provides an up-to-date summary of current strategies for maximizing sperm recovery from surgically obtained testicular samples and, as an extension, optimization of in vitro sperm processing techniques in the management of NOA. Full article
(This article belongs to the Special Issue Update on the Management of Non-Obstructive Azoospermia: Current Evidence and Unmet Needs)
18 pages, 357 KiB  
Review
Reproductive Chances of Men with Azoospermia Due to Spermatogenic Dysfunction
by Caroline Kang, Nahid Punjani and Peter N. Schlegel
J. Clin. Med. 2021, 10(7), 1400; https://doi.org/10.3390/jcm10071400 - 31 Mar 2021
Cited by 17 | Viewed by 5152
Abstract
Non-obstructive azoospermia (NOA), or lack of sperm in the ejaculate due to spermatogenic dysfunction, is the most severe form of infertility. Men with this form of infertility should be evaluated prior to treatment, as there are various underlying etiologies for NOA. While a [...] Read more.
Non-obstructive azoospermia (NOA), or lack of sperm in the ejaculate due to spermatogenic dysfunction, is the most severe form of infertility. Men with this form of infertility should be evaluated prior to treatment, as there are various underlying etiologies for NOA. While a significant proportion of NOA men have idiopathic spermatogenic dysfunction, known etiologies including genetic disorders, hormonal anomalies, structural abnormalities, chemotherapy or radiation treatment, infection and inflammation may substantively affect the prognosis for successful treatment. Despite the underlying etiology for NOA, most of these infertile men are candidates for surgical sperm retrieval and subsequent use in intracytoplasmic sperm injection (ICSI). In this review, we describe common etiologies of NOA and clinical outcomes following surgical sperm retrieval and ICSI. Full article
(This article belongs to the Special Issue Update on the Management of Non-Obstructive Azoospermia: Current Evidence and Unmet Needs)
10 pages, 941 KiB  
Review
Two Decades from the Introduction of Microdissection Testicular Sperm Extraction: How This Surgical Technique Has Improved the Management of NOA
by Nahid Punjani, Caroline Kang and Peter N. Schlegel
J. Clin. Med. 2021, 10(7), 1374; https://doi.org/10.3390/jcm10071374 - 29 Mar 2021
Cited by 14 | Viewed by 4458
Abstract
The treatment of men with non-obstructive azoospermia (NOA) has improved greatly over the past two decades. This is in part due to the discovery of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), but also significantly due to improvements in surgical sperm [...] Read more.
The treatment of men with non-obstructive azoospermia (NOA) has improved greatly over the past two decades. This is in part due to the discovery of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), but also significantly due to improvements in surgical sperm retrieval methods, namely the development of microdissection testicular sperm extraction (mTESE). This procedure has revolutionized the field by allowing for identification of favorable seminiferous tubules while simultaneously limiting the amount of testicular tissue removed. Improving sperm retrieval rates is imperative in this cohort of infertile men as there are a limited number of factors that are predictive of successful sperm retrieval. Currently, sperm retrieval in NOA men remains dependent on surgeon experience, preoperative patient optimization and teamwork with laboratory personnel. In this review, we discuss the evolution of surgical sperm retrieval methods, review predictors of sperm retrieval success, compare and contrast the data of conventional versus mTESE, share tips for optimizing sperm retrieval outcomes, and discuss the future of sperm retrieval in men with NOA. Full article
(This article belongs to the Special Issue Update on the Management of Non-Obstructive Azoospermia: Current Evidence and Unmet Needs)
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13 pages, 453 KiB  
Review
Hormonal Treatment of Men with Nonobstructive Azoospermia: What Does the Evidence Suggest?
by Ettore Caroppo and Giovanni M. Colpi
J. Clin. Med. 2021, 10(3), 387; https://doi.org/10.3390/jcm10030387 - 20 Jan 2021
Cited by 24 | Viewed by 4989
Abstract
Hormonal stimulation of spermatogenesis prior to surgery has been tested by some authors to maximize the sperm retrieval yield in patients with nonobstructive azoospermia. Although the rationale of such an approach is theoretically sound, studies have provided conflicting results, and there are unmet [...] Read more.
Hormonal stimulation of spermatogenesis prior to surgery has been tested by some authors to maximize the sperm retrieval yield in patients with nonobstructive azoospermia. Although the rationale of such an approach is theoretically sound, studies have provided conflicting results, and there are unmet questions that need to be addressed. In the present narrative review, we reviewed the current knowledge about the hormonal control of spermatogenesis, the relationship between presurgical serum hormones levels and sperm retrieval rates, and the results of studies investigating the effect of hormonal treatments prior to microdissection testicular sperm extraction. We pooled the available data about sperm retrieval rate in patients with low vs. normal testosterone levels, and found that patients with normal testosterone levels had a significantly higher chance of successful sperm retrieval compared to those with subnormal T levels (OR 1.63, 95% CI 1.08–2.45, p = 0.02). These data suggest that hormonal treatment may be justified in patients with hypogonadism; on the other hand, the available evidence is insufficient to recommend hormonal therapy as standard clinical practice to improve the sperm retrieval rate in patients with nonobstructive azoospermia. Full article
(This article belongs to the Special Issue Update on the Management of Non-Obstructive Azoospermia: Current Evidence and Unmet Needs)
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