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CHICAGO -- Men who smoked marijuana had significantly degraded sperm quality and testicular function, worse than tobacco users and comparable to men with diagnosed infertility, according to a long-term Brazilian study.

As compared with smokers, marijuana users had lower median values for sperm concentration, motility, and morphology (P<0.01). Marijuana use also was associated with reduced testicular volume and an increased rate of nonobstructive azoospermia, clinical features often found in male infertility.

Marijuana's deleterious effects on reproductive parameters resulted from increased production of reactive oxygen species (ROS), as seminal ROS concentrations were 20 times higher in marijuana users as compared with smokers, reported Jorge Hallak, MD, of the University of Sao Paulo, at the American Urological Association (AUA )annual meeting.

"Overall, the marijuana group had semen quality equivalent to the infertile group, with the exception of higher ROS and DNA damage than infertile men," Hallak said during an AUA press briefing. "DNA damage is higher in all groups (marijuana users, smokers, and infertile men) as compared to controls, but higher levels were found in the marijuana group and infertile men. Basic semen parameters are not sufficient to identify changes of magnitude in sperm cell function."

A second study summarized at the press briefing provided the first reported evidence of an association between marijuana use and development of benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS).

A showed a consistent and statistically significant decline in sperm quality (count and motility) over the past 40 years. The explanation for the decline remains elusive, but multiple factors have been proposed: environmental exposures, poor nutrition, genetics, and social/behavioral factors.

Over the past 2 decades, technologic advances allowed more detailed examination of sperm. Showed that sperm are , which has been implicated in a multitude of major human diseases and disorders. Subfertility and infertility almost almost always arise as a consequence of oxidative stress, said Hallak.

The rationale for evaluating marijuana's effect on male fertility parameters included a lack of information on the topic and the worldwide use of the drug. With an estimated 200 million users worldwide, marijuana is the most widely used psychoactive drug, including more than 20 million regular users in the U.S.

Since 2000, Hallak and colleagues have studied the effects of marijuana and tobacco on spermatozoa and testicular function and relationships with male infertility, hypogonadism, and sexual dysfunction. Each study participant has two comprehensive semen analyses that go well beyond usual lab assessments and include ROS, sperm DNA integrity, creatinine kinase activity, and antisperm antibodies.

Unlike many prior studies, enrollment was limited to users of cannabis and excluded use of cannabinoid-containing products. The study population comprised 125 men with diagnosed infertility, 144 tobacco smokers, 74 marijuana users, and a control group of 279 men (prevasectomy with no clinical factors for testicular dysfunction).

Current marijuana use was ascertained by self-report at the time of enrollment. Median age at first use of marijuana was 18.6, and median duration of marijuana use was 8 years.

Clinical characteristics of the infertile men included increased levels of prolactin; decreased sperm concentration, motility, and morphology; and increased seminal pH and ROS. Tobacco smokers had decreased follicle-stimulating hormone, luteinizing hormone, and prolactin; decreased testicular volume; and decreased seminal volume.

Marijuana users had a significantly lower median estradiol level (10.04 ng/dL) as compared with all the other groups (P<0.001). Marijuana use was associated with the highest median seminal ROS: 14.31 x 104 cpm/20 x 10⁶ versus 5.66 for infertile men, 0.70 for smokers, and 0.68 for the fertile control group. Hallak noted that marijuana induces production of intracellular ROS whereas tobacco smoke creates extracellular oxidative stress.

The study of marijuana use and BPH/LUTS included 20,548 men (age >45) who had prescriptions for finasteride and or a super-selective alpha blocker during the period from January 2011 to October 2018. The primary objective was to identify factors significantly associated with BPH/LUTS, said Granville Lloyd, MD, of the University of Colorado Anschutz School of Medicine in Aurora.

A multivariable analysis identified marijuana use as a statistically significant player in the development of BPH/LUTS (odds ratio 1.253, P<0.001). Other significant predictors were depression (OR 2.015), erectile dysfunction (OR 1.847), metabolic syndrome/obesity (OR 1.586), hypertension (OR 1.576), hypogonadism (OR 1.392), and diabetes (OR 1.280, P<0.001 for all). Alcohol use did not have a significant association with BPH/LUTS (OR 0.982).

Noting that BPH/LUTS etiology is poorly understood, Lloyd said, "From this analysis we can conclude that BPH is associated with systemic diseases, depression, and marijuana use but not alcohol."

"Men who use marijuana are more likely to be treated for BPH," he stated. "This is a novel finding. Cannabinoids are pharmacologically active and influence voiding, which raises the question of whether marijuana is a risk factor or self-treatment?"

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