Sickle Cell Disease and Its Effects on Male Fertility

The inflammation and lack of adequate blood flow associated with SCD can damage the testes, and abnormal semen analyses have been observed in men with the disease who aren't receiving therapy for it. Research documenting low sperm counts, or oligospermia, in men with SCD has existed for a while.

Vaso-occlusion, or blockage of the blood vessels, and the consequent oxygen deprivation of the vascular system that supplies the genitals can disrupt the hypothalamic-pituitary-adrenal (HPA) axis. In turn, this can cause hypogonadism in men with SCD, according to a 2020 article in the peer-reviewed Transplantation and Cellular Therapy journal. The article, co-written by Mishkin, states that hypogonadism can decrease testosterone production, libido and fertility, and cause erectile dysfunction, another culprit responsible for degraded fertility. Zinc deficiency due to SCD can cause similar problems.

Researchers have identified a high prevalence of compensated (subclinical) hypogonadism in men with SCD. The condition is capable of becoming full-fledged hypogonadism with age, further predisposing SCD patients to infertility.

"A sickle cell crisis just means that blood flow is interrupted somewhere," Mishkin said. "Depending on where it is, different things happen. If it happens to [your bones], you can mess up your bones permanently. If it happens to an organ, you can have a stroke, you can have a heart attack, right? This is dangerous. It can happen to the penis and it's called priapism."

Men who experience priapism as a result of a sickle cell crisis can experience erections lasting three or four hours, which might require the blood to be drained with a syringe. Plus, the entire region could be affected if it happens multiple times, Mishkin said. Priapism could result in poor oxygen delivery to the testes, which can negatively affect sperm. Likewise, the discomfort and sexual dysfunction that accompany priapism pose additional barriers to conception.

A common medication approved by the Food and Drug Administration can help patients with SCD by increasing their levels of fetal hemoglobin, the kind of blood cell that's better at transporting oxygen throughout the body. The medication is called hydroxyurea, which was initially used to treat cancer. However, the drug may have negative effects on sperm parameters.

"Hydroxyurea can reduce sperm counts; stopping the drug allows recovery of the counts," said Cage Johnson, M.D., a professor emeritus of medicine in the division of hematology at the University of Southern California Keck School of Medicine in Los Angeles and a past director of the Sickle Cell Center there.

A study conducted by researchers in India confirmed that even low-dose treatment with hydroxyurea (for example, 10 milligrams per kilogram per day) can produce abnormal sperm parameters.

"Therefore, treatment with hydroxyurea in adolescent and adult male sickle cell disease patients should be preceded by routine assessment of seminal fluid parameters and followed up regularly every three months for any change in seminal fluid parameters for evidence of hydroxyurea toxicity," wrote the authors of the paper, which was published in 2017.

A retrospective study undertaken to assess the effects of hydroxyurea therapy on a few men with SCD found the drug affected all sperm parameters. Researchers found no cases of azoospermia (an absence of sperm in the ejaculate) in the five patients who provided samples in this period. What they did find was a marked decrease in sperm density when they compared semen before and during treatment. They found the adverse effects occurred with less than six months of treatment before reaching a plateau.

However, a study published in 2021 found no significant differences in semen volume, sperm concentration, total sperm count or spermatozoa motility, morphology and vitality between a group of male patients exposed to hydroxyurea treatment before puberty and a group that was about to start hydroxyurea treatment. Researchers compared 26 sperm samples from 15 patients who first received hydroxyurea at a median age of 6 for a median duration of four years with 46 samples from 23 patients, ages 16 to 24, who weren't treated with hydroxyurea.

Given these findings, the drug's effectiveness for SCD and the chance it won't negatively affect fertility may outweigh potential drawbacks of treatment.

On the other hand, azoospermia was reported in a 2007 case study of a 35-year-old man with SCD who received hydroxyurea. A semen analysis after he stopped the treatment showed he had a gradual return to normal spermatogenesis over the course of about six months, and his wife conceived within four months of him stopping treatment.

Mishkin said six months seems to be the approximate amount of time SCD patients often need to go without receiving hydroxyurea treatment in order for sperm to recover. This span of time is not insignificant, however, for many men who suffer from SCD and the recurrent crises it provokes.

"Six months without hydroxyurea, [it's not], 'Oh, just wait six months,'" she said. "You could have a stroke and die."

Researchers who composed a 2022 comprehensive review article for the Journal of Clinical Medicine confirmed that various studies have shown discontinuing the use of hydroxyurea leads to improvements in the sperm counts of some men, though not all.

"We know that a lot of hematologists don't exactly warn people starting hydroxyurea that there may be permanent fertility effects," Mishkin said, adding that men and boys with SCD often aren't even aware that hydroxyurea treatment for some males precludes impregnating a partner later on.

Regular blood transfusions to treat men with SCD can cause iron overload, which can damage the gonadal and endocrine systems, and lead to infertility. Transfusions have, however, been shown to be beneficial, at least in the short term, for semen quality, according to a 2017 review article about reproductive issues in men with sickle cell anemia, a common type of SCD.

Provided they do not result in iron overload, transfusions of red blood cells have been shown to increase sperm count and motility. They can also help address and prevent complications that stem from SCD while lowering the risk of stroke. In transfused SCD patients, chelation therapy can be used to treat the overaccumulation of iron in cells that, sans treatment, could produce hypogonadism and engender or exacerbate infertility.

A comparative study published in 2006 showed patients who received hematopoietic cell transplantation (HCT) were 36 times less likely to conceive than their siblings. HCT, considered the only known potential cure for SCD, exposes patients to alkylating agents and radiation that can cause infertility, as Mishkin and colleagues observed in their Transplantation and Cellular Therapy article from 2020.

Given SCD's possible link to abnormal or significantly absent sperm and increased chances of developing ED, the cryopreservation of sperm is an option to overcome the effects of sickle cell disease and male fertility. It is one modality to preserve fertility in males who are past puberty, prior to any further debilitation of the reproductive system due to SCD (and attributable to treatments for it), according to authors of the 2022 review article in the Journal of Clinical Medicine mentioned previously.

Knowing that many men with SCD have abnormal sperm counts, multiple collections at a sperm bank might be necessary to help ensure optimal fertility outcomes, especially if patients are going to receive stem cell transplants.

"The rates of natural procreation after stem cell transplant are extremely low, to the extent that we tell patients getting transplants that they should freeze," Mishkin said. "That is the blanket recommendation."

Cryopreservation can be quite cost-prohibitive, however.

"The cost of cryopreservation for patients already burdened with significant medical costs—from chronic SCD and the costs associated with transplantation—can become an insurmountable barrier to future fertility," Mishkin and colleagues explained in their Transplantation and Cellular Therapy paper from 2020.

In a 2018 opinion piece Mishkin co-authored for the Annals of Internal Medicine, she and her collaborators noted only about 30 percent of states in the U.S. require some insurance coverage for assisted reproductive technology (ART), and most impose serious limits on available services.

"As members of the HSCT [Hematopoietic Stem Cell Transplantation] program at our institution, we have worked with the Columbia University Fertility Center to secure equivalent discounts for our HSCT patients with SCD," they wrote. "In addition to negotiating such discounts at their own institutions, physicians can improve counseling about infertility for patients considering transplant. Even more important in this era, we can mitigate disparities by lobbying via physician organizations for mandatory insurance coverage of ART for any patient anticipating iatrogenic sterility, especially minors."