Interest of Clomiphene Citrate (CC) Associated With a Second Testicular Sperm Extraction (TESE) in Patients With Non-obstructive Azoospermia (NOA) After Failure of a First TESE, on the Quantity of Sperm Cells Available for Intracytoplasmic Sperm Injection (ICSI). Randomized Double Blind Trial Versus Placebo.

In the absence of sperm in the semen (azoospermia), there is no chance of natural paternity. It is found in about 1% of men and is either due to an obstruction of the seminal tracks (obstructive azoospermia (OA)) in 1/3 of the cases, or a spermatogenic failure (non-obstructive azoospermia (NOA)) in 2/3 of the cases. To date, no medical treatment had proved its efficiency to induce spermatogenesis in case of NOA.
The development of Intracytoplasmic sperm injection (ICSI) in 1992 allowed to obtain pregnancies from a small number of spermatozoa. The next year, testicular sperms were extracted from testicular tissue obtained surgically in cases of OA , allowing paternity for azoospermic men. In case of NOA, TESE allowed to obtain few sperms in an unexpected number of cases. It was shown that spermatogenesis remains active in rare portions of seminiferous tubules, a phenomenon called focal spermatogenesis, which allows to extract testicular sperms with an average SRR of 50%, and to obtain pregnancy by ICSI. Thus, TESE-ICSI revolutionized the prognosis of NOA, however, half of the cases of NOA had no sperm extracted and remained sterile . Since sperm donation and adoption are unacceptable for several of these couples, there is a real demand for additional treatment.
Two ways to improve chances of paternity in case of NOA are currently discussed:
Proceed to a second attempt of TESE. Since the first attempt could have missed a focus of active spermatogenesis, the chance for a positive second TESE is not null even. Reviewing the few articles published on this issue , the SRR for the second attempt, after a first negative attempt averaged 25%.
Based upon the decrease of testosterone production within the testis in case of NOA and the potential increased of the focal spermatogenesis by gonadotropins, few reports of hormonal therapy in case of NOA have been published and suggested a positive effect of hormonal therapy.
This prompted us to develop this clinical trial to investigate the effect of Clomiphene Citrate versus placebo on the results of a second TESE in NOA.
Results of hormonal therapy in case of NOA were heterogeneous and of poor methodological quality, none was randomized versus placebo: Anti-aromatases or Gonadotropins administered before the first TESE or the second TESE gave positive results. Hussein at al in 2013, suggested a positive effect of Clomiphene citrate (CC), administrated before the first TESE (57% of the CC treated group versus 33.6% in not treated group) but with drop out of patient positive to sperm analysis. However, in these positive studies, sample sizes were small or selected patients on hormonal status or histology criteria suggesting subgroup of favourable NOA. Thus, there is no strong evaluation of the interest of hormonal treatment in NOA, after a negative first TESE.
The investigators decided to evaluate the effect of the CC, the most convincing and convenient hormonal treatment, in patients with negative first TESE for NOA. It is of main interest to known if CC could enhance the SRR of a second TESE, that is the ultimate possibility to have their own child for these patients.

Start Date01 Jan 2023

Sponsor / Collaborator

Hospices Civils de Lyon

100 Clinical Results associated with Azoospermia

100 Translational Medicine associated with Azoospermia

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6,208

Literatures (Medical) associated with Azoospermia

01 Jan 2025·Clinica Chimica Acta

A retrospective analysis of 1600 infertility patients with azoospermia and severe oligozoospermia

Article

Author: Yi Zhou, Bing ; Tang, Jia ; Gu, Heng ; Ting Fu, Wen ; Bin Zhong, Xiao ; Zhen Li, Ming

OBJECTIVEThis study aimed to investigate the genetic etiology of male infertility patients.METHODA total of 1600 male patients with infertility, including 1300 cases of azoospermia and 300 cases of severe oligozoospermia, underwent routine semen analysis, chromosomal karyotype analysis and sex hormone level testing. The Azoospermia factor (AZF) on the Y chromosome was detected using the multiple fluorescence quantitative PCR technique. Additionally, copy number variation (CNV) analysis was performed on patients with Sertoli-cell-only syndrome who had a normal karyotype and AZF.RESULTChromosomal abnormalities were found in 334 cases (20.88 %) of the 1600 male infertility patients. The most common type of abnormality was sex chromosome abnormalities (18.94 %), with 47, XXY being the most frequent abnormal karyotype. The rates of chromosomal abnormalities were significantly different between the azoospermia group and the severe oligospermia group (23.69 % and 8.67 %, respectively; P<0.05). AZF microdeletions were detected in 155 cases (9.69 %), with various deletion types and AZFc region microdeletion being the most prevalent. The rates of AZF microdeletions were not significantly different between the azoospermia group and the severe oligospermia group (9.15 % and 12 %, respectively; P=0.133). In 92 patients with Sertoli-cell-only syndrome who had a normal karyotype and AZF, the detection rate of CNV was 16.3 %. Compared to the severe oligospermia group, the azoospermia group had higher levels of FSH and LH and lower levels of T and E2, and the differences were statistically significant (P<0.05).CONCLUSIONSMale infertility is a complex multifactorial disease, with chromosomal abnormalities and Y chromosome microdeletions being important genetic factors leading to the disease. Initial genetic testing of infertile men should include karyotyping and Y chromosome microdeletions. If necessary, CNV testing should be performed to establish a clinical diagnosis and provide individualized treatment for male infertility.

31 Dec 2024·Systems Biology in Reproductive Medicine

Correlation between sperm DNA fragmentation and methylation in male partners of couples with idiopathic recurrent pregnancy loss

Article

Author: Balasinor, Nafisa ; Patil, Anushree ; Bansal, Vandana ; Tandon, Deepti ; Irani, Delna ; Singh, Dipty

With ∼50% recurrent pregnancy loss cases being termed idiopathic (iRPL), understanding of contribution of male factors to iRPL is still lacking. Higher prevalence of sperm DNA fragmentation index (DFI) and lower sperm 5-methylcytosine (5-mC) levels have been previously reported in male partners of iRPL couples and shed light on importance of the male gamete in maintenance of a successful pregnancy. The present study aimed to determine the serum sex steroid hormone levels, sperm DFI and 5-mC and correlation between them in male partners of fertile and iRPL couples. Further, correlation between sperm DFI and 5-mC with semen parameters and paternal age in both groups were determined. 36 male partners of fertile couples and 45 male partners of women experiencing iRPL were enrolled for this study and semen and blood samples were collected. Serum testosterone and estradiol levels were measured by ELISA; sperm DFI and global 5-mC were determined by TUNEL assay and ELISA respectively. Significantly higher serum testosterone levels were noted in the iRPL group (p = 0.028). Incidence of sperm DNA fragmentation was found to be higher in the iRPL study group but with no significance difference. No significant differences in sperm 5-mC values were noted. Upon correlation analysis within both groups, strong significant negative correlation of sperm DFI % and 5-mC % was observed in the control group (p < 0.001) but not the iRPL group (p = 0.249). Hence, we infer that with lower 5-mC levels in sperm genome, there is a higher incidence of sperm DFI in fertile men. However, this trend is not noted in men of iRPL group which could possibly be due to other underlying epigenetic alterations in genomic regions probably unsusceptible to fragmentation. On the other hand, no significant correlations of semen parameters, testosterone, estradiol and paternal age with sperm DFI and 5-mC were noted in both groups.

01 Dec 2024·Molecular Aspects of Medicine

Advances in human In vitro spermatogenesis: A review

Review

Author: Julian, Sania ; Flannigan, Ryan ; Nguyen, Anna-Lisa V ; Weng, Ninglu

Recent advances surrounding in vitro spermatogenesis (IVS) have shown potential in creating a new paradigm of regenerative medicine in the future of fertility treatments for males experiencing non-obstructive azoospermia (NOA). Male infertility is a common condition affecting approximately 15% of couples, with azoospermia being present in 15% of infertile males (Cocuzza et al., 2013; Esteves et al., 2011a). Treatment for patients with NOA has primarily been limited to surgical sperm retrieval combined with in vitro fertilization intracytoplasmic sperm injection (IVF-ICSI); however, sperm retrieval is successful in only half of these patients, and live birth rates typically range between 10 and 25% (Aljubran et al., 2022). Therefore, a significant need exists for regenerative therapies in this patient population. IVS has been considered as a model for further understanding the molecular and cellular processes of spermatogenesis and as a potential regenerative therapeutic approach. While 2D cell cultures using human testicular cells have been attempted in previous research, lack of proper spatial arrangement limits germ cell differentiation and maturation, posing challenges for clinical application. Recent research suggests that 3D technology may have advantages for IVS due to mimicry of the native cytoarchitecture of human testicular tissue along with cell-cell communication directly or indirectly. 3D organotypic cultures, scaffolds, organoids, microfluidics, testis-on-a-chip, and bioprinting techniques have all shown potential to contribute to the technology of regenerative treatment strategies, including in vitro fertilization (IVF). Although promising, further work is needed to develop technology for successful, replicable, and safe IVS for humans. The intersection between tissue engineering, molecular biology, and reproductive medicine in IVS development allows for multidisciplinary involvement, where challenges can be overcome to realize regenerative therapies as a viable option.

News (Medical) associated with Azoospermia

26 Apr 2023

·www.biospace.com

Contraline Announces Acceptance of Abstracts to be Presented at 2023 American Urology Association and European Association of Urology Annual Meetings

CHARLOTTESVILLE, Va.--(BUSINESS WIRE)-- Contraline, Inc., a clinical-stage medical device company announced the acceptance of abstracts detailing the initial results from the company’s first in human clinical trial of ADAM, a hydrogel-based, long-lasting, non-hormonal, and non-permanent male contraceptive. The abstracts were written and submitted by investigators leading the study, and were accepted for presentation at the two largest, annual international urology meetings, the European Association of Urology (EAU) and the American Urological Association (AUA). Contraline’s first-in-human clinical trial, “The ADAM Study”, began implanting its first patients in September 2022 and is being led by principal investigator Nathan Lawrentschuk, PhD, MBBS, FRACS, Professor of Urology at The Royal Melbourne Hospital and Epworth Hospital, and co-investigator Paul Anderson, MBBS, FRACS. The ADAM System consists of a patented hydrogel, which is implanted into the vas deferens of patients via a minimally invasive procedure, and a delivery device that automates the delivery of the hydrogel. ADAM is the first hydrogel designed to occlude sperm passage through the vas deferens for a predefined period, degrading without intervention and thus offering a non-permanent contraceptive option for men, in contrast to vasectomy, which is considered permanent. The podium presentations by Nathan Lawrentschuk at AUA and Paul Anderson at EAU highlight the early research findings on the ADAM System. The first-in-human clinical trial is focused on defining the safety of the ADAM System, while evaluating the preliminary efficacy in inducing azoospermia in study participants. “The early findings of The ADAM Study support an excellent safety pro the ADAM System, with most adverse events being minor and related to the procedure, which is similar to a no-scalpel vasectomy, rather than as a result of the implant; no patients to date have experienced any serious adverse events. The preliminary efficacy data have demonstrated that azoospermia has been induced in all men implanted with ADAM. These initial data are very exciting and we are eager to continue enrolling patients into the study. This study enables us to optimize the dose of ADAM while continually improving the implantation procedure, opening to the door to conduct a pivotal trial,” said Nathan Lawrentschuk. “Even the early data from The ADAM Study support the vas-occlusive hydrogel being a potential game changer in reproductive medicine, with men and couples being able to take even more control over family planning than ever before,” said Alexander Pastuszak, MD, PhD, Chief Medical Officer of Contraline. Contraline is currently expanding the number of sites for its first in human study in Australia, with the eventual goal of opening a larger study in the United States. About Contraline Contraline, Inc. is a venture-backed medical device company devoted to providing men and couples with long-lasting, safe, and effective contraception. The company is developing ADAMTM, the world’s first injectable hydrogel designed to provide long-lasting, reversible contraception for men. The company was founded in 2015 by Kevin Eisenfrats and Dr. John Herr, and is headquartered in Charlottesville, Virginia. To learn more, visit

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