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Biological Therapy for Non-Obstructive Azoospermia Sarah C

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Biological Therapy for Non-Obstructive Azoospermia Sarah C EXPERT OPINION ON BIOLOGICAL THERAPY, 2018 VOL. 18, NO. 1, 19–23 https://doi.org/10.1080/14712598.2018.1380622 REVIEW Biological therapy for non-obstructive azoospermia Sarah C. Vija, Edmund Sabanegh Jrb and Ashok Agarwalc aGlickman Urologic and Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH, USA; bDepartment of Urology, Glickman Urologic and Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH, USA; cAndrology Laboratory, Glickman Urologic and Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH, USA ABSTRACT ARTICLE HISTORY Introduction: Most male patients with non-obstructive azoospermia (NOA) have no therapeutic options Received 26 June 2017 outside of assisted reproductive techniques to conceive a biological child. If mature sperm cannot be Accepted 13 September 2017 obtained from the testes, these patients must rely on options of donor sperm or adoption. Several KEYWORDS techniques are in the experimental stage to provide this patient population alternatives for conceiving. Gene therapy; Areas covered: This review discusses three of the experimental techniques for restoring fertility in men non-obstructive with NOA: spermatogonial stem cell transplantation, the use of adult and embryonic stem cells to azoospermia; develop mature gametes and gene therapy. After this discussion, the authors give their expert opinion spermatogonial stem cell and provide the reader with their perspectives for the future. transplantation; pluripotent Expert opinion: Several limitations, both technical and ethical, exist for spermatogonial stem cell stem cell transplantation, the use of stem cells and gene therapy. Well-defined reproducible protocols are necessary. Furthermore, several technical barriers exist for all protocols. And while success has been achieved in animal models, future research is still required in human models. 1. Introduction Secondary testis failure is caused by impaired pituitary secre- tion of gonadotropins, which leads to insufficient stimulation of Infertility affects approximately 15% of couples of reproduc- the Sertoli and Leydig cells in the testis. Kallmann syndrome tive age. Male factor infertility plays a role in 50% of these results from a lack of hypothalamic Gonadotropic Releasing cases. Among patients with male factor infertility, approxi- Hormone (GnRH) secretion, which leads to insufficient produc- mately 10–15% have azoospermia [1]. Azoospermia is defined tion of LH and FSH. This subsequently leads to secondary as the absence of spermatozoa in the ejaculate. This condition testicular failure as the Sertoli cells are unable to support sper- is typically classified as obstructive azoospermia (OA) or non- matogenesis and the Leydig cells are insufficiently stimulated to obstructive azoospermia (NOA). After confirmation of NOA provide local testosterone secretion for spermatogenesis. Men with a second semen analysis, the workup of azoospermia who take supplemental testosterone will also develop second- involves a detailed history and physical examination along ary testicular failure because the supplemental circulating tes- with hormonal and genetic testing. Testicular biopsy allows tosterone suppresses FSH and LH production. for a histologic diagnosis although the underlying cause of the Men with NOA have limited options for reproduction. azoospermia may never be determined. OA is characterized by Testicular sperm extraction with Intracytoplasmic Sperm Downloaded by [New York University] at 10:52 20 December 2017 an obstructed flow of spermatozoa at any point along the Injection (ICSI) is possible in these patients, but it is expensive male genital tract. Spermatogenesis in the testis is usually and associated with high morbidity in the female partner. If normal in these patients. The etiology of NOA is more varied. sperm cannot be retrieved by testicular sperm extraction, Normal spermatogenesis requires intact and functioning semi- there are no current options to maintain the reproductive niferous tubules as well as functioning Leydig cells for hormo- potential of these individuals. Therefore, there is significant nal support of spermatogenesis by producing testosterone. clinical demand for alternate therapies for NOA that would NOA can be broadly classified into primary testicular failure allow the production of mature spermatozoa either using and secondary testicular failure. Primary testicular failure refers stem cells or by gene therapy for patients with idiopathic to pathology localized to the testis resulting in elevated causes of infertility. Such a technique might allow for natural Follicle Stimulating Hormone (FSH) and Luteinizing Hormone conception in a population that is otherwise relegated to (LH). Known genetic causes of infertility such as Klinefelter’s assisted reproductive techniques. This review will cover three syndrome and Y chromosome microdeletion will cause pri- experimental approaches for restoring fertility in men with mary testis failure. Local effects from chemotherapy or radia- NOA: spermatogonial stem cell (SSC) transplantation, in vitro tion can also cause primary testis failure and result in NOA. A spermatogenesis using adult or embryonic pluripotent stem significant proportion of primary testicular failure cases are cells, and gene therapy. diagnosed as idiopathic, which limits therapeutic options. CONTACT Sarah C. Vij [email protected] Cleveland Clinic Foundation, Cleveland, OH, USA © 2017 Informa UK Limited, trading as Taylor & Francis Group 20 S. C. VIJ ET AL. relevant: the transfer of the tissue back into the patient post- Article highlights pubertally with successful regeneration of spermatogenesis. Testicular tissue grafting can be performed in several loca- ● Existing therapeutics for non-obstructive azoospermia (NOA) are lim- ited and depend on the ability to harvest mature sperm from the tions. The ideal location for graft transplantation is the scrotum testis for ICSI because its temperature is lower than that in other sites that ● Spermatogonial stem cell transplantation is a promising option to have been applied in animal models such as the peritoneum or repopulate the germinal epithelium in men with NOA ● The use of embryonic and adult stem cells to develop mature male under the skin on the back [9]. Grafting in ectopic sites also gametes may provide patients with an alternative therapeutic option. requires that the patient use Assisted Reproductive Techniques ● At present, a complete understanding of the stem cell niche is still (ART) for conception. Some authors recommend grafting to lacking ● For cases of NOA caused by a to a mutation at a single gene locus, several sites to optimize yield [10]. Timing of grafting, prepuber- gene therapy may be a definitive treatment for infertility. tal versus postpubertal, has also been debated. High FSH and LH This box summarizes key points contained in the article. concentrations are required for successful proliferation of the graft; therefore, the peri-pubertal period may be an ideal target time, but this has not been explored. Because prepubertal boys do not yet make enough FSH and LH to support spermatogen- esis, the ideal timing for grafting may be after patients have reached sexual maturity [10]. 2. SSC transplantation Schlatt et al. performed a grafting procedure in neonatal SSCs are precursors to mature spermatids that reside in the mouse model after castration to maintain high levels of FSH basal compartment of the seminiferous tubules of the testis. and LH [11]. This method, of course, cannot be replicated in SSCs have the capability to self-renew and enter into meiosis humans, but it provides evidence that high levels of gonado- to become a spermatocyte [2]. The spermatocytes then differ- tropins are necessary for successful grafting. entiate into haploid spermatids, which are transformed into SSC injection is the other method of transfer to the recipi- mature spermatozoa. The SSC population is therefore critical ent. The rete testis, efferent ducts, or the seminiferous tubules in the production of sperm. have been identified as injection targets for SSCs in several Sertoli cells surround the SSCs and provide signaling mole- species [12]. Upon injection, the SSCs migrate to the basement cules and factors to support both the self-renewal and differ- membrane of seminiferous tubules and subsequently self- entiation process. This microenvironment is referred to as the renew and differentiate to establish spermatogenesis in the stem cell niche [3]. Recreating the SSC niche in the laboratory recipient. This process should theoretically allow for concep- setting is a critical step in the development of SSC transplan- tion without the requirement of assisted reproductive techni- tation. The concept of transplanting SSCs to enable normal ques, which is a major advantage. Hermann et al. injected spermatogenesis in an otherwise sterile individual has promis- adult rhesus monkey SSCs into the rete testes of recipient ing clinical applications in men with NOA. prepubertal rhesus monkeys and showed that mature sperma- Transplantation of SSCs was first described by Brinster and tozoa were present in the ejaculate when they reached matur- Zimmerman in 1994 when suspensions of testicular cells from ity. These spermatozoa demonstrated fertilizing capabilities fertile mice were transplanted into infertile mice resulting in when used with ICSI [13]. fertility restoration and progeny [4]. Subsequently, it has been At present, SSC transplantation is experimental and has not shown that cryopreservation
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