By following, since last year, male patients who had Covid-19, andrologist Jorge Hallak, professor at the Faculty of Medicine of University of Sao Paulo, began noticing that their fertility and hormonal test results remain altered for many months after they recover from the disease.
Despite being an initial test and not being able to diagnose fertility or infertility, the sperm count of several patients has indicated, for example, that sperm motility – the ability of sperm to move and fertilize the egg, whose normal index is above 50% – dropped to between 8% and 12% and remained at that level almost a year after being infected with SARS-CoV-2. Hormonal tests indicate that the testosterone levels of many of them also plummeted after the illness. While the normal level of this hormone is 300 to 500 nanograms per deciliter of blood (ng/dL), in patients who had covid-19 this index ranged below 200 and often stayed between 70 and 80 ng/dL
“We have seen, increasingly, prolonged changes in the quality of semen and hormones in patients who had covid-19, even in those who had a mild or asymptomatic condition,” says Hallak to the FAPESP Agency.
Some studies carried out by the researcher in collaboration with colleagues from the Department of Pathology at FM-USP, published in recent months, have helped to elucidate these observations made in clinical practice. The researchers found that SARS-CoV-2 also infects the testes, impairing the ability of male gonads to produce sperm and hormones.
“It is very worrying how the new coronavirus affects the testicles, even in asymptomatic or mildly symptomatic cases of the disease. Among all the testicle-damaging agents I’ve studied to date, SARS-CoV-2 seems to be very active,” says Hallak. “Each pathology has particularities that practice and experience show us. SARS-CoV-2 has the characteristic of affecting spermatogenesis in ways that we are discovering now, such as persistently very low progressive motility, without significant change in sperm concentration”, he says.
In a study of 26 patients who had covid-19, researchers found through ultrasound exams that more than half of them had severe inflammation in the epididymis – the structure responsible for storing sperm and where they acquire the ability to move.
The patients have an average age of 33 years and are treated at the Hospital das Clínicas of the USP Medical School and at the Androscience Institute. The results of the study, supported by FAPESP (Foundation for Research Support of the State of São Paulo), were published in the journal Andrology.
“Unlike a classic bacterial infection or by other viruses, such as mumps, which causes swelling and pain in the testicles in one third of those affected, epididymitis caused by the new coronavirus is painless and cannot be diagnosed by palpation (physical exam) or with the naked eye,” explains Hallak.
Therefore, according to him, it would be interesting to teach the self-examination of the testicles as a public health policy in the post-pandemic. “It is ideal that adolescents, young adults and men of age or with reproductive desire, after being infected with SARS-CoV-2, seek a urologist or andrologist and make an appointment with measurement of testicular volume, measurement of testosterone and other hormones , in addition to semen analysis with sperm function tests, followed by an ultrasound examination with color Doppler, to check for any type of testicular involvement that can affect fertility and hormone production”, suggests Hallak.
“These individuals must be followed up for one to two years after the infection, at least, as we still don’t know how the disease evolves”, he points out.
Testicular cell invasion
Another study recently published by the same group of researchers and also supported by FAPESP indicated that SARS-CoV-2 invades all types of testicular cells, causing lesions that can impair hormonal function and male fertility. Through a project coordinated by professors from the Faculty of Medicine of USP Paulo Saldiva and Marisa Dolhnikoff, minimally invasive autopsy techniques were used to extract testicular tissue samples from 11 men, aged between 32 and 88 years, who died at Hospital das Clinics of the Faculty of Medicine of USP due to severe covid-19.
The results of the analyzes indicated a series of testicular lesions that can be attributed to inflammatory alterations that reduce the production of sperm (spermatogenesis) and hormones. “What immediately caught our attention in these patients who died from covid-19 was the drastic decrease in spermatogenesis. Even the youngest, of childbearing age, had practically no sperm,” says Amaro Nunes Duarte Neto, an infectious disease specialist and pathologist at the USP Medical School and the Adolfo Lutz Institute and coordinator of the study.
According to the researcher, some of the probable causes of the decrease in spermatogenesis in these patients were lesions caused by the virus in the testicular parenchyma vessels, with the presence of thrombi, which led to hypoxia – lack of oxygenation in the tissues –, in addition to fibrosis that obstruct the tubules seminiferous, where sperm are produced.
One of the probable reasons for the hormonal decrease is the loss of Leydig cells, which are found between the seminiferous tubules and produce testosterone. “The functions of the testes to produce sperm and male sex hormones are independent, but there is an interconnection between them. If the production of hormones by Leydig cells is impaired, fertility will also be reduced”, says Duarte Neto.
Some of the symptoms of testosterone deficiency (hypogonadism) are muscle loss, tiredness, irritability, memory loss, and weight gain, which can be mistaken for the long-term effects of covid-19. “An important part of this clinical picture is surely related to a low testicular function. But this has not yet been addressed because patients do not have pain and it is not usual to measure hormones or analyze sperm after they recover from covid-19”, warns Hallak.
The researchers plan to conduct a follow-up study of male patients who have had the disease to assess how long it takes for testicular damage caused by SARS-CoV-2 to be reversed naturally or through drug administration. “We still don’t know if these testicular injuries can be reversed and how long it will take for them to happen,” says Hallak.
The researcher’s main concerns are in relation to men of reproductive age, adolescents and prepubescents, for whom there is still no data on testicular lesions caused by covid-19. It is not known what the impacts will be on puberty in relation to the fertile capacity, whether hormone production will be affected in a transient, prolonged or definitive way, and what is the degree of irreversible residual damage.
As there are no SARS-CoV-2 pre-infection data for each individual, prospective studies should include a control group for comparison purposes, suggests Hallak. “These individuals may have infertility problems and hormonal changes in the future and not know that this could have been caused by the covid-19 infection, because they had mild symptoms or were asymptomatic”, he ponders.
Increased male infertility
The researcher estimates that covid-19 could cause an increase in male infertility. Currently, between 15% and 18% of couples face difficulties in conceiving – due to male problems in 52% of cases.
This scenario can trigger a greater search for assisted reproduction techniques which, according to him, is sometimes rushed in Brazil for male causes, without adequate and standardized initial assessment and often without establishing the causative diagnosis initial and without enough time to propose approaches based on the best cost-benefit and the application of specific treatments that can cure the cause or restore the natural fertile capacity.
“We will have to be very careful with post-pandemic assisted reproduction of covid-19, as the consequences of this in the months following the infection are not known,” says Hallak.
Since SARS-CoV-2 has been detected in all testicular cell types, which participate in all stages of spermatogenesis, it is not known whether the virus may also be present in sperm from patients who had covid-19 months after they have recovered from the illness.
These spermatozoa may have been affected by the virus and, ideally, at least one spermatogenesis cycle should be waited in advance – around 90 days – so that a new andrological investigative evaluation can be carried out, says Hallak. “We have seen very high DNA damage caused by the new coronavirus, around 80%, while the normal is up to 25% and, acceptable, up to 30%”, he compares.
Another concern of the researcher is the replacement of testosterone in these patients who had covid-19 and hormonal decline, which, according to him, is an unnecessary measure. “Testosterone replacement in an already affected patient will further inhibit testicular function. The testes have repair mechanisms to produce hormones again, and there are drug treatments that increase the natural production of steroid hormones, progressively restoring the individual’s intrinsic testicular function. This will also depend on whether Leydig cells were injured and to what degree, which is something we don’t know yet”, he ponders.