Expert approach to severe oligospermia in a patient with prior cryptorchidism and in vitro fertilization failure

Case Presentation.

A 33-year-old male with a history of unilateral cryptorchidism, corrected by orchidopexy at age 2, presents with severe oligospermia. Semen analysis shows a concentration of 2 million/mL, poor motility, and 1% normal morphology. His partner has undergone two failed in vitro fertilization/intracytoplasmic sperm injection cycles, each yielding only one viable embryo despite adequate oocyte yield. Hormonal evaluation reveals borderline abnormalities suggestive of impaired spermatogenesis, and genetic testing is pending. Scrotal ultrasound shows no varicocele. The couple seeks guidance to optimize assisted reproductive technology outcomes.

Clinical Question.

In men with a history of cryptorchidism and persistent severe oligospermia, what diagnostic and therapeutic strategies can improve assisted reproductive technology outcomes? Should testicular sperm be preferred over ejaculated sperm in this context?

Expert approach

Diagnostic workup

Cryptorchidism is a condition in which one or both testes fail to descend to the scrotum before birth. If persistent at 6 months of age, current American Urological Association guidelines recommend orchidopexy (1). Despite timely surgical intervention, these patients remain at risk for infertility later in life and may require assisted reproduction technology to conceive (1, 2). Because of this known association, a thorough evaluation by a reproductive urologist is critical to optimize fertility outcomes, as well as the patient’s health. Moreover, the increased risk of testicular malignancy associated with cryptorchid testes underscores the importance of a thorough physical examination and emphasizes the need for continued self-monitoring through regular testicular self-examinations (3). Even if the physical examination is unremarkable, a more thorough evaluation of the testicular anatomy should be considered. A scrotal ultrasound may be useful for a patient with an abnormal semen analysis and a history of cryptorchidism to evaluate for microlithiasis or nonpalpable testicular masses. Although testicular microlithiasis alone is not considered a major risk factor for malignancy, a history of cryptorchidism may alter the risk profile.

Attributing severe male factor infertility solely to a history of cryptorchidism without a full evaluation for other additional contributing factors would neglect a valuable avenue to diagnose and treat the myriad of conditions known to impair male fertility. Lifestyle factors and medical comorbidities such as substance abuse, sleep apnea, and obesity may independently impair spermatogenesis and exacerbate the decreased germ cell development present in these patients (2). Some men with a history of cryptorchidism, especially those with bilateral cases or delayed surgical correction, are more likely to exhibit primary hypogonadism. Therefore, in hypogonadal men with a history of cryptorchidism, evaluation and management of other potential strategies to address hypogonadism is essential. Genetic studies, including a karyotype and Y chromosome microdeletion, are also an important part of the evaluation of men with severe oligospermia, as conditions like Klinefelter syndrome are more common in men with a history of cryptorchidism (4). A comprehensive evaluation strategy for men with infertility is critical for those with a history of cryptorchidism.

Fertility preservation and risk of progression

Despite lifestyle improvements and hormone optimization, many patients with cryptorchidism may have persistent severe oligospermia. For these patients, consider sperm cryopreservation before assisted reproductive technology (ART). Cryopreservation can serve as a backup sample for in vitro fertilization (IVF) as well as for fertility preservation for the future. Patients with severe oligospermia are at increased risk of progression to nonobstructive azoospermia (NOA). One study found that 21.1% of men with a sperm concentration <1 million/mL became azoospermic over 3- to 5-year period, with the rate increasing to 32% at 5 years (5). This risk may result from a natural decline in testicular function with age, or more abruptly from an acute testicular insult, such as an infection or systemic illness. If a patient were to progress to azoospermia, their only path to biological paternity would be with a microdissection testicular sperm extraction (microTESE). One study reported a 46% successful sperm retrieval from microTESE in patients with NOA and a history of bilateral orchidopexy (6). Thus, although semen cryopreservation offers an important safeguard to ensure sperm availability at the time of oocyte retrieval, microTESE provides an avenue to success with IVF/ICSI for those men with a history of cryptorchidism who have since progressed from oligospermia to NOA.

Deoxyribonucleic acid fragmentation testing and the role of testicular sperm

Sperm deoxyribonucleic acid (DNA) fragmentation testing is a valuable tool to inform treatment decisions in men with cryptorchidism and oligospermia. This advanced semen diagnostic study assesses the integrity of sperm DNA, which plays a critical role in fertilization, embryo development, and pregnancy outcomes. Elevated sperm DNA fragmentation has been associated with reduced fertility, recurrent pregnancy loss, and poor IVF outcomes (7). Further, cryptorchidism has been linked to elevated sperm DNA fragmentation (8). One study found an increased risk of elevated DNA fragmentation in 18% of men with a prior orchidopexy compared with controls with known fertility, and this increased to 43% among men with a history of bilateral orchiopexy (8). Testicular sperm have lower DNA fragmentation, and their use for IVF/ICSI after failed IVF cycles characterized by poor fertilization, blastulation, and increased aneuploidy has been associated with improved IVF outcomes (9). Indeed, the use of testicular sperm with IVF/ICSI for couples with elevated sperm DNA fragmentation is supported by the current American Urological Association/American Society for Reproductive Medicine (ASRM) Male Infertility Guidelines (4). Thus, for those couples in which there is a history of cryptorchidism and prior IVF failure, sperm DNA fragmentation testing should be obtained, along with strong consideration given to the use of testicular sperm for future cycles. Contemporary office-based testicular sperm extraction (TESE) offers minimal discomfort and swift recovery. Both percutaneous and open sperm retrieval techniques would likely be successful for a patient with sperm in the ejaculate, but these investigators would recommend a conventional open TESE in this scenario to enable cryopreservation of multiple vials of testicular sperm for future use. One additional consideration clinicians often face is the decision of fresh or cryopreserved testicular sperm for IVF/ICSI. A meta-analysis of this topic found no difference between fresh or frozen testicular sperm in IVF/ICSI outcomes, including fertilization, clinical pregnancy, and live birth rates (10). Involving a reproductive urologist in the decision-making for these couples becomes critical to appropriately counsel and guide treatment.

ART strategy and reproductive urology involvement

In summary, optimal management of the initial case presented would include many of the tools introduced here. A thorough history would evaluate for additional modifiable risk factors for male factor infertility, and a physical examination would be performed to evaluate for testicular size, symmetry, and the presence or absence of varicoceles. A scrotal ultrasound would be obtained to further assess internal testicular anatomy and evaluate for testicular masses or microlithiasis. Assuming a 46,XY karyotype and a negative Y-chromosome microdeletion test, these investigators would perform a sperm DNA fragmentation assay and counsel the patient on sperm cryopreservation. Further, pending the sperm DNA fragmentation result, we would likely recommend a frozen TESE for upcoming IVF/ICSI cycles, as well as long-term fertility preservation. For a case with unilateral cryptorchidism like the one presented here, retrieval of testicular sperm from the larger, healthier testis, which is typically the noncryptorchid testis, would be preferred. Further, it is the opinion of the investigators that sperm retrieved from the healthier of the two testes, particularly when there is a considerable size discrepancy, could provide a benefit over ejaculated sperm, which arise from both testes. Despite the prior failed IVF/ICSI cycles, there are a variety of ways to improve subsequent cycle outcomes through optimization of male factor infertility or changing the sperm source from ejaculated to testicular sperm.

Learning points

• •All men with abnormal semen analysis and history of cryptorchidism should be referred to a reproductive urologist for evaluation.
• •Men with a history of cryptorchidism are at increased risk for impaired testicular function, including infertility, decreased testosterone, and increased risk of testicular cancer.
• •Optimization of the male before ART can lead to improved outcomes even in cases requiring IVF/ICSI.
• •Recommend sperm banking for men with severe oligospermia and total motile sperm counts below 1 million.
• •Testicular sperm extraction should be considered for men with elevated sperm DNA fragmentation and/or prior poor IVF outcomes.

Conclusion

Men with a history of cryptorchidism require a complete and individualized fertility evaluation, even when orchidopexy occurs early. Persistent testicular dysfunction, hypogonadism, and genetic abnormalities must be assessed alongside semen quality. For men with severe oligospermia and a history of ART failure, sperm cryopreservation and DNA fragmentation testing offer proactive tools to guide treatment. Where elevated DNA fragmentation is present, the use of testicular sperm may significantly enhance ART success. A tailored approach by reproductive urologists can maximize the potential for genetic paternity in this at-risk population.

CRediT Authorship Contribution Statement

Jacob A. Brems: Writing – original draft. Robert M. Coward: Writing – original draft.

Declaration of Interests

J.A.B. has nothing to disclose. R.M.C. reports consulting fees from Tegus; honorarium from American Society for Reproductive Medicine (ASRM); payment for expert testimony from Northwell Health; travel support from ASRM and AUA; Maximus Advisory Board; leadership roles in the Society for Male Reproduction and Urology, the Society for the Study of Male Reproduction, and ASRM; and Maximus stock options.