Male infertility, a growing problem throughout the Western world, threatens our civilization.

I admit this statement seems a touch dramatic at first blush. But, remember our economy and social programs require a constant pipeline of new consumers and exponential population growth. This demographic crisis is apparent in many American towns: Pediatrician offices and schools are closing because so few children are born. The US birth rate has fallen 25% in the past 25 years to a rate comparable to China’s.1,2 Notably, Puerto Rico would have the fifth-lowest birth rate in the world (just ahead of Japan) if independent.

The reasons for this looming population collapse include social problems, delayed childbearing, and increasing infertility. A particularly interesting example of low nationwide male fecundity is the emergence of "grass eaters" (soshokukei danshi) in the wake of the continuing 20-year-long Japanese economic impotency. These are men who are uninterested in sex or reproduction. They supposedly lack adequate testosterone. 

Particularly in the past 5 to 10 years, physicians have pushed off-label low testosterone as a panacea for age-related mental and physical changes. But what degree of fading testosterone is a healthy part of aging? Other causes of male infertility include cytotoxic chemotherapy or occupational exposure, endocrine disorders, and substance abuse. But could something as common, and seemingly benign, as ibuprofen contribute to male infertility?

The discovery that ibuprofen as a nonsteroidal anti-inflammatory drug COX-1 inhibitor has fetal endocrine effects and reduces prostaglandin E2 production has spurred further study.3 Past study has linked ibuprofen to 2 birth defects: hypospadias (a type of penile malformation) and idiopathic cryptorchidism (undescended testicles). Both birth defects are associated with low testosterone levels in utero. A 2017 Scientific Reports article found that ibuprofen reduces steroidogenic enzymes, testosterone synthesis, and Leydig cell function in 8-to-9-week-gestation-age testicular tissue.3 The testosterone response was absent in tissue from other-aged first and second trimester fetuses. Critically, the susceptible fetus is at a gestation age early enough for a mother to be unaware of her pregnancy. Accidental exposure to such a widely available OTC medication is difficult to avoid, because half of pregnancies are unintentional.

Ibuprofen produces a state of compensated hypogonadism characterized by high luteinizing hormone levels with normal testosterone levels. Patients with overt hypogonadism develop symptoms, including decreased sex drive, depression, fatigue, and reduced lean muscle mass. These symptoms are consistent with Japanese "grass eaters" behavior. Bisphenol A and phthalates, known antiandrogen compounds, and ibuprofen act detrimentally on Leydig and Sertoli cells. Leydig cells produce testosterone, and Sertoli cells are critical to spermatid production in the testicle. Ibuprofen downregulates peritubular cell (the smooth muscle surrounding the sites of spermatid production) gene expression as well. In clinical practice, male analgesic (primarily aspirin) use is associated with increased time to pregnancy in female partners.

The journal Proceedings of the National Academy of Sciences of the United States of America published a study in January 2018 showing that ibuprofen causes compensated hypogonadism by suppressing testicular endocrine function.4 The study researchers conducted a randomized double-blinded placebo-controlled trial with 1200-mg daily ibuprofen doses for 6 weeks. This dose is at the upper end of the OTC labeling, and the duration is subacute. The trial participants were age, height, and weight-matched 18-to-35-year-old white biological males. Researchers excluded participants with a body mass index above 30, knee injuries, kidney or liver dysfunction, peptic ulcers, or regular physical activity (except cycling for transport).

Total testosterone, 17β-estradiol (a testosterone metabolite), and sex hormone-binding globulin levels were unchanged after 14 and 44 days of daily ibuprofen use. However, the study found that luteinizing hormone levels changed after 14 and 44 days of ibuprofen exposure. Leydig cells secrete testosterone when signaled by luteinizing hormone. The testosterone/luteinizing hormone ratio decreased in the ibuprofen study arm. This change is consistent with compensated hypogonadism. Ibuprofen had no effect on luteinizing hormone or follicle-stimulating hormone receptor expression. This isolates the mechanisms of action to those involved in testosterone synthesis downregulation.

Sertoli cells release inhibin, which inhibits pituitary gland function, and anti-Müllerian hormone, which prevents early puberty by suppressing sex hormone production, upon follicle-stimulating hormone stimulation. Unusually elevated anti-Müllerian hormone levels in-utero could cause the birth defects (hypospadias and idiopathic cryptorchidism) mentioned above. However, ibuprofen decreased both inhibin and anti-Müllerian hormone levels. Prior research has associated low anti-Müllerian hormone levels with azoospermia. Sertoli cells’ other functions include releasing androgen binding protein (critical to maintain sufficient androgen levels near spermatogenesis) and forming the blood-testis barrier (protecting developing spermatids from the immune system).

The study researchers conducted experiments on testicular explants to isolate ibuprofen’s direct effect on the gland tissue itself. Ibuprofen reduced testosterone production in a dose-dependent manner through transcriptional repression. This means that ibuprofen acts on the Leydig cell’s ability to produce the needed proteins for testosterone production. This is consistent with the compensated hypogonadism seen in the human subjects. Uncoupling the testicles from the rest of the hypothalamic-pituitary axis unmasks the reduction in testosterone. Ibuprofen directly decreases testosterone levels, but the pituitary gland upregulates production (normalizing serum levels) by releasing more luteinizing hormone. Ibuprofen also suppresses testosterone through enzymes, including cytochrome P450, involved in steroid production. This ex vivo testing found no direct harm to spermatogenesis (splitting of testicular cells, meiosis, to produce sperm cells). However, low testosterone levels interfere with healthy sexual behavior.

Most patients may continue using ibuprofen as needed without concern. Yet, chronic high-dose users, such as athletes, are at higher risk for adverse endocrine effects. Patients complaining of symptoms consistent with hypogonadism (eg, decreased sex drive, depression, fatigue, and reduced lean muscle mass) may find relief from avoiding ibuprofen. Ibuprofen’s impact on the male reproductive system is a class effect shared with other NSAIDs. Interested patients, such as men attempting to father children, may use acetaminophen as an alternative for mild pain.

References

1. Birth rate in the United States from 1990 to 2016 (per 1,000 of population). Statista website. statista.com/statistics/195943/birth-rate-in-the-united-states-since-1990. Accessed March 9, 2018.
2. The World Factbook. Central Intelligence Agency website. cia.gov/library/publications/the-world-factbook/rankorder/2054rank.html. Accessed March 9, 2018.
3. Maamar MB, Lesné L, Hennig K, et al. Ibuprofen results in alterations of human fetal testis development. Sci Rep. 2017; 7. doi:10.1038/srep44184.
4. Kristensen DM, Desdoits-Lethimonier C, Mackey AL, et al. Ibuprofen alters human testicular physiology to produce a state of compensated hypogonadism. Proc Natl Acad Sci USA. 2018; 115(4): E715-724. doi: 10.1073/pnas.1715035115.