The Impact of Male Infertility on Men's Health: Is There a Relationship?
Jay Sandlow, MD, Professor and Vice-Chair, Director of Male Infertility, The Medical College of Wisconsin
Male factor infertility impacts approximately 50 percent of couples who experience difficulty conceiving. The most common cause is varicocele, which is present in up to 40 percent of cases. Other causes, such as obstruction, hormonal dysfunction and genetic factors, account for another significant portion. However, it has become apparent that male infertility may be a harbinger of underlying issues, such as cancer and cardiovascular disease. The following is a short description of the potential health issues that may present with male factor infertility.
Studies have demonstrated that up to 1 percent of men with significant male factor infertility may have an underlying serious illness.1 Although this does not sound like much, when one considers the following, it affects a significant number of men. There are approximately 5 million men between the ages of 20-45 (what most consider reproductive age) in the United States. It is felt that 20 percent of couples in this age group have fertility problems and half of these will have a male factor involved. This would mean that approximately 10 million men are potentially subfertile. Of these, if 1 percent had a serious underlying illness presenting as infertility, this would mean approximately 100,000 men could be affected. This does not include men urologists see for vasectomy.
Underlying problems include pituitary tumors, which cause hypogonadism (secondary to high prolactin levels which inhibit GnRH release), prostate tumors, which can cause partial blockage of SV/ED, testis tumors, which can have direct impact on spermatogenesis, as well as indirect via hormone (HCG) production. Diabetes can impact erectile and ejaculatory function, which can then impact fertility. Genetic defects, such as cystic fibrosis and PCKD, as well as chromosomal anomalies such as Klinefelter’s syndrome (KS, 47 XXY), can have associated health problems, and can be passed to offspring. More recently, there is evidence that men with fertility problems may have higher incidence of cardiovascular disease.2
Testis cancer impacts approximately 4/100,000 men, with highest prevalence between the ages of 18-40. This happens to be the same age group that typically will present with infertility. There is evidence that infertile men have a higher incidence of testis cancer.3 This is felt to be multi-factorial, including increased awareness and screening in the infertile population, as well as underlying dysgenesis that most likely impacts fertility and testicular dysgenesis. Although most studies have demonstrated that routine scrotal ultrasound is not warranted in subfertile men, those with risk factors, e.g., history of cryptorchidism or significant testicular asymmetry, may benefit from a scrotal ultrasound.
Pituitary tumors are rare, but men who have tumors due to prolactinoma may present with infertility, erectile dysfunction, or both. This is typically due to the high prolactin levels that are seen. Prolactin inhibits GnRH, which leads to low LH and FSH, with subsequent hypogonadism. Interestingly, many of these men have reasonable semen parameters; however, their testosterone levels are quite low. Treatment with cabergoline or bromocriptine will typically normalize prolactin and testosterone levels, and rarely, men will need pituitary surgery.
Genetic mutations can alter fertility, directly or indirectly.4 Mutations, such as deletion of one or more of the AZF genes (azoospermia factor) on the Y chromosome, are seen in up to 10 percent to 14 percent of men with azoospermia/severe oligospermia. Although it is now possible to retrieve sperm from many of these men, any male offspring will also carry this mutation. Furthermore, men with deletion in the AZF A or B region do not make mature sperm and to date, no successful sperm retrievals have been documented. Therefore, testing is essential to prevent unnecessary testing and treatment.
Mutations of the cystic fibrosis transmembrane receptor gene (CFTR) are extremely common, particularly in Caucasians of northern European ancestry. This can lead to congenital bilateral absence of the vas deferens (CBAVD), an uncorrectable obstruction. Although sperm acquisition is possible, it is essential that the patient’s partner be adequately screened, as female carriers are typically asymptomatic and an unrecognized carrier would lead to a 50:50 chance of having a child with clinical cystic fibrosis. It is thought that men with CBAVD carry two mutations, although at least one is often an atypical mutation.4
Klinefelter’s syndrome (KS) is the most common chromosomal anomaly seen in men, with an incidence of approximately 1:500. Many men with KS present with infertility, as they are always azoospermic. Typically, these men have low-normal to normal testosterone levels, as the men with KS who have significantly low testosterone will usually present earlier with delayed puberty. It has been shown that men with KS have a higher incidence of breast cancer, extragonadal germ cell tumors, as well as infertility. These men must be made aware of this, and offered long term testosterone replacement.
Finally, there is newer evidence that men with fertility problems may have a higher incidence of cardiovascular disease.2 In a recent presentation at the annual AUA meeting, data demonstrated that childless men had a 17 percent (Hazard Ratio 1.17; 95 percent CI 1.03-1.32) increased risk of cardiovascular death after adjusting for sociodemographic and lifestyle factors, and this elevated risk appeared to also extend to men with only one child. Childless men also had a slightly higher risk of all-cause mortality compared to fathers (7 percent, 95 percent CI 0-13 percent). If cardiovascular deaths were eliminated from the analysis, no significant difference in all-cause mortality based on fatherhood was noted. Although this is by no means a cause and effect scenario, it brings up interesting issues regarding the underlying factors that impact male fertility. In conjunction with the strong evidence that connects men with erectile dysfunction to early cardiovascular disease, there appears to be yet another reason for men with fertility problems to be evaluated.
As Dr. See pointed out in his introductory remarks, the urologist is often the only physician a man will see. It is not uncommon for men with infertility to have underlying disorders that may not only impact their fertility, but their overall health, as well. It is often said that a man’s fertility is the “canary in the coal mine” of his health, with altered fertility being the early warning signs of more dire underlying problems. It is up to us as urologists to educate men and other physicians to identify and treat these problems early.
Jarow JP. Life-threatening conditions associated with male infertility. Urol Clin North Am 21:409-415,1994.
Eisenberg M, Park Y, Hollenbeck A, et al. Fatherhood and the risk of cardiovascular mortality in U.S. men. J Urol Abstract 2178, 2011.
Raman JD, Nobert CF, Goldstein M. increased incidence of testicular cancer in men presenting with infertility and abnormal semen analysis. J Urol 174:1819-22, 2005.
The Evaluation of the Azoospermic Male, AUA Best Practice Statement, 2010.