A 46-year-old man presented with secondary infertility of 12 months’ duration.
The man had two children conceived naturally with a previous partner during his early twenties. His current partner was 36 years old and had not undergone a fertility evaluation. They had been having properly timed and unprotected intercourse for 12 months. He denied any sexual dysfunction. He had no past medical history, never had surgery, and did not take any medications. He denied smoking or using illicit drugs and had no relevant family history. He worked in the finance industry and denied genital trauma or exposure to toxic or radioactive agents.
The patient had a normal masculine hair distribution. His BMI was 25.4. No gynecomastia was present. Testes bilaterally were soft and approximately 8 cc (normal volume ≥18 cc). He had a grade 3 left varicocele and a grade 2 right varicocele. His epididymis and vas deferens were normal bilaterally.
The patient had two semen analyses that showed severe oligoasthenoteratospermia (Table 1). He also underwent an endocrine evaluation that demonstrated biochemical hypogonadism with a morning total serum testosterone of 240 ng/dL (normal, 300-890 ng/dL). He underwent a genetic evaluation that resulted in no Y chromosome microdeletions detected and a 46,XY karyotype.
His wife was referred to a reproductive endocrinologist, and her evaluation was normal. The couple was counseled on their options, which included proceeding with assisted reproductive technology with in vitro fertilization with intracytoplasmic sperm injection (IVF-ICSI), empiric medical therapy with clomiphene citrate, and varicocelectomy. He elected to undergo bilateral microsurgical sub-inguinal varicocelectomy. Five months postoperatively, his semen analysis had improved significantly. Eighteen months postoperatively he reported that his wife had given birth.
Varicocele is an abnormal dilation of the pampiniform venous plexus of the spermatic cord. It is a clinical diagnosis made using a grading scale described by NYU physicians Lawrence Dubin and Richard Amelar almost 50 years ago.1 Grade 1 varicoceles are only palpable when the patient performs a Valsalva maneuver, grade 2 varicoceles are palpable without Valsalva maneuver, and grade 3 varicoceles are visible through the scrotal wall. Varicoceles are present in approximately 15% of young men, and compared with men without a varicocele, men with varicoceles have lower sperm concentration, motility, and morphology.2 Varicocele is present in approximately 40% of men who present with primary infertility (lack of first conception after 12 months of unprotected intercourse), and up to 80% of men with secondary infertility (infertility after previous fertility).3,4
According to best practice statements by both the American Urological Association and the American Society for Reproductive Medicine, treatment of a varicocele should be offered to men in couples who are infertile, have a clinically palpable varicocele, have abnormal semen parameters, and have a partner with normal evaluation or reversible cause for female infertility.5,6 Treatment of varicocele in men who meet these criteria improves the odds ratio of pregnancy 2.4 times that of men who undergo observation.7
Although repairing a varicocele improves semen parameters and pregnancy rates, many couples will elect an assisted reproductive technology as part of their treatment course. Assisted reproductive technologies often come at significant out-of-pocket expense, as few states mandate insurance coverage for female infertility treatments, and even fewer states mandate coverage for male infertility treatments.8,9 The cost of these assisted reproductive technologies varies per center but is correlated with the invasiveness of each technique. Intrauterine insemination (IUI) is the least invasive and carries a median out-of-pocket expense of $2623 per cycle.10 Couples with severe oligospermia often require IVF-ICSI, which carries a median out-of-pocket cost of $19,234 for the first cycle. Given the significant increase in out-of-pocket expenses between IUI and IVF-ICSI, semen analysis improvements can translate to thousands of dollars in terms of patient out-of- pocket expenses.
Although the decision to recommend IUI or IVF-ICSI is nuanced, a common parameter guiding this decision is the total motile sperm count (TMSC). The TMSC is the multiple of the semen volume, concentration, and motile fraction. Thresholds of TMSC used to recommend IUI vary from 1 million to 10 million.11,12 Regardless of the threshold used, this patient’s initial TMSC was less than 1 million and would have required IVF-ICSI. After his varicocele repair, his TMSC improved to 11 million, a number sufficient for IUI.
In a retrospective review of 373 men undergoing varicocelecetomy, Samplaski and colleagues used a threshold of TMSC >5 million for IUI to evaluate the benefit of varicocele repair on upgrading semen parameters.13 The authors reported that men with a baseline TMSC <5 million improved from a mean TMSC of 2.32 million to 15.97 million. Of the 139 men with baseline TMSC <5 million, 58.8% of men improved to the point that they no longer needed IVF-ICSI. Couples faced with the expenses of IVF-ICSI may find this likelihood of requiring a less invasive form of assisted reproductive technology appealing.
Even though varicocele repair improves semen analysis parameters, many men with severe oligospermia at baseline will require IVF-ICSI afterward. Additionally, there are couples in which the wife will require IVF-ICSI due to female factors. If IVF-ICSI is planned for a couple, one might question the utility in repairing a man’s varicocele.
In a systematic review and meta-analysis of men with varicocele and oligospermia, Kirby and colleagues evaluated the effect of varicocele repair on assisted reproductive technology outcomes.14 Compared with men who did not have their varicocele repaired, varicocelecetomy had an odds ratio of live birth rate of 1.699. This improved live birth rate is significant, given that the delivery rate per single cycle of IVF-ICSI is only 19%.15 Although many factors influence delivery rates after IVF-ICSI, many couples will require multiple cycles to achieve a live birth. Given that every IVF-ICSI cycle exposes the couple to financial and health burdens, optimizing the chance of live birth by repairing a varicocele makes sense for many individuals.
Couples seeking treatment for infertility are often focused on one goal: a live birth. However, the evaluation of an infertile male is often one of the earliest encounters an adult man will have with the health care system. Urologists who treat this population are able to identify and address health conditions that may not impact these men for years to come. Infertile men with a varicocele should always be counseled that their testicles have both a reproductive and an endocrine function.
In a study of over 7000 men with an average age of 19 years, men with varicocele had similar serum testosterone levels as men without varicocele.2 However, the ratio of luteinizing hormone to testosterone was significantly lower for men without a varicocele, indicating that by their early twenties, the pituitary glands of men with varicoceles are starting to compensate for a degree of testicular impairment. Our 46-year-old patient had low levels of total testosterone on two separate morning blood draws. Fortunately, he was not symptomatic, and thus did not meet the criteria for testosterone deficiency syndrome. However, given his age and testosterone levels, there is a fair chance he will develop symptoms of testosterone deficiency.16
The impact of varicocele repair on serum total testosterone levels has been evaluated in multiple studies. A meta-analysis of these studies demonstrates that varicocelectomy in hypogonadal men improves serum total testosterone by a mean of 106 ng/dL.17 Additionally, some men report improved ejaculatory and erectile function after varicocele repair.18 Although the clinical significance of these improvements in serum testosterone is unclear, it can be reassuring to men considering varicocelectomy for fertility reasons to know that their gonadal function is improved in multiple ways.
Assisted reproductive technologies like IVF-ICSI enable many infertile couples with severe male factor infertility to achieve pregnancy. However, varicocelectomy in men with severe oligospermia has multiple benefits that should also be considered. Varicocele repair may upgrade semen analysis parameters to the point that the couple may undergo IUI, a less invasive and more affordable technique than IVF-ICSI. Varicocelectomy also increases the live birth rate in couples who do undergo IVF-ICSI. Finally, varicocelectomy improves the testicular endocrine function of men with testosterone deficiency. Practitioners should consider these factors when counseling men with severe oligospermia and clinical varicocele.