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AUA2023 BEST POSTERS Epigenetic-based Test to Accurately Predict Successful Microscopic Testicular Sperm Extraction Outcomes

By: Kristin Brogaard, PhD, Inherent Biosciences Inc, Salt Lake City, Utah; Tim Jenkins, PhD, Brigham Young University, Provo, Utah; Larry I. Lipshultz, MD, Baylor College of Medicine, Houston, Texas | Posted on: 30 Aug 2023

Male infertility is a growing concern in the United States, affecting an estimated 7 million men and playing a causative role in nearly 50% of infertility cases.1 However, despite the size of the global fertility market, estimated at $26 billion, there remain few diagnostic tests related to male fertility. The lack of testing and innovation in the male fertility space has several negative consequences, including men being underdiagnosed for infertility and leading to the female partners undergoing unnecessary invasive procedures, costing these couples both money and time.2 Additionally, it has been shown that poor male reproductive health, as evidenced by impaired semen parameters, is highly associated with the poor overall health of men, including increased metabolic diseases, cancers, cardiovascular disease, and shorter lifespans.3,4 There has been a fundamental lack of research and funding to better understand this association of morbidities and the role of semen as a substrate for men’s health screening.5

A particularly undersupported and underresearched subset of infertile men are those with nonobstructive azoospermia (NOA), or no visible sperm in the semen with no identifiable obstruction of the urogenital tract. NOA affects approximately 1% of men worldwide or about 39.7 million men.

In the cases where men present with NOA, a procedure called microscopic testicular sperm extraction (mTESE) can be utilized for isolating sperm directly from the testes, which can then be used in in vitro fertilization, giving these men a chance to use their own sperm to conceive. mTESE is a highly invasive surgery where a man’s testicles are opened and microscopically searched for pockets of sperm. Despite being an extraordinary advancement in reproductive technology, mTESE procedures have very high costs for patients (average $12,000 out of pocket), are highly invasive, and physicians fail to find any sperm in 40%-50% of mTESE procedures.4 Currently, there are limited tools to assess if a patient will have sperm in their testes, and if they are a good candidate for the mTESE procedure. The lack of technology to predict mTESE success has led to unsuccessful procedures, poor outcomes, and significant medical bills. New technology is needed to better assess the treatment paradigm for using mTESE.

In the data presented at the AUA, we described the initial research of a new, noninvasive, semen-based technique to predict presence or absence of sperm in the NOA testicle. The goal of this research is to lead to a novel semen assessment to predict mTESE success.

This new technique identifies sperm-derived cell-free DNA by identifying specific DNA methylation patterns in testicular tissue or semen that are only found on sperm. The methylation patterns are interrogated using a Nanopore MinION DNA sequencer. We initially analyzed 18 testicular biopsy samples with varying underlying histopathology. We found in men with <0.25% sperm-derived DNA there was no sperm observed in the testicular tissue. In comparison, in men with >50% sperm-derived DNA in testicular tissue, 100% had sperm found in the testicles (Figure 1).

Figure 1. Sperm-derived DNA percentages from testicular biopsies of nonobstructive azoospermia patients and surgical sperm extraction procedure results.

To assess if we could have the same predictability from seminal plasma, we analyzed 14 blinded semen samples from men with varying testicular sperm extraction results. In this cohort of patients with <5% sperm-derived DNA in the seminal plasma, there was a 0% success rate of sperm extraction (N=4). Furthermore, patients with >25% sperm-derived DNA in the seminal plasma were found to have a 60% success rate with sperm extraction (N=5; Figure 2). These data suggest men with <5% sperm-derived DNA in the seminal plasma should not undergo a sperm extraction procedure.

Figure 2. Sperm-derived DNA percentages from semen samples of nonobstructive azoospermia patients and surgical sperm extraction procedure results.

More samples are needed for continued analysis; however, these data show semen as a promising analyte for predicting success of sperm extraction and ultimately saving patients both unnecessary physical and economic hardship.

  1. Zion Market Research. Fertility Services Market Size, Trends & Growth Opportunities (2022-2028). Accessed June 23, 2022.
  2. Turner KA, Rambhatla A, Schon S, et al. Male infertility is a women’s health issue—research and clinical evaluation of male infertility is needed. Cells. 2020;9(4):990.
  3. Ahrenfeldt LJ, Möller S, Wensink MJ, et al. Impaired fecundity as a marker of health and survival: a Danish twin cohort study. Hum Reprod Oxf Engl. 2021;36(8):2309-2320.
  4. Tharakan T, Luo R, Jayasena CN, Minhas S. Non-obstructive azoospermia: current and future perspectives. Fac Rev. 2021;10:7.
  5. De Jonge C, Barratt CLR. The present crisis in male reproductive health: an urgent need for a political, social, and research roadmap. Andrology. 2019;7(6):762-768.