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Collateral damage

Medication used to treat lupus jeopardizes fertilization

LAURA DAVIÑAPediatric rheumatologist Clovis Artur Almeida da Silva remembers the day in detail, in 2002, when 16-year old Maria das Flores (not her real name) went to see him at the Children’s Institute (ICr) of the Hospital das Clínicas de São Paulo hospital to tell him that her mother had found the condom she was carrying in her handbag. Months later, the then 17- year old Maria das Flores went back to see Almeida, to tell him that she had had intercourse for the first time in her life and that he was the first person to hear the news. She also told him that she had remembered to use a condom. This example of doctor-patient trust is very special for Almeida. Maria das Flores was one of the patients with systemic lupus erythematosus who had come for treatment at the Rheumatology Outpatient Clinic of the ICr. Caused by a dysfunction of the immune system, triggered by genetic defects, hormone alterations, viral infections and other factors, lupus affects one out of every 100 thousand people (90 percent of whom are women). It is four times more common among adults than among children and damages tissues in various parts of the body; it affects the joints, causes skin rashes and scaly skin and, in more serious cases, can affect the central nervous system and the kidneys.

More efficient drugs discovered in the last 15 years have allowed people with lupus to live longer and with a better quality of life. They can also date, get married, and have children. With the aim of keeping up with the changes in the age bracket, Almeida decided to learn more about how this autoimmune disease – for which no cure has been found yet – influences the lives of adolescent boys and girls from the ages of 12 to 18, who represent nearly 20 percent of the people with lupus. In the last 10 years, Almeida and researchers from other institutions in the states of São Paulo, Rio de Janeiro, Minas Gerais, and Bahia analyzed the sexual development of nearly 400 children, adolescents and young adults with lupus. The study revealed that people with lupus achieve sexual maturity later on in life and are generally less fertile. The researchers found signs of even more important information: most of the late sexual maturity and the drop in fertility are not consequences of the disease, but of the medication used to control it.

“We discovered major effects caused by the medication in both males and females,” says Almeida. One of the effects of the medication is the late onset of menarche, the first menstrual cycle, which is the beginning of the female’s fertile life. Almeida compared the ages at which 30 adolescent girls with lupus first menstruated with the ages of 30 adolescent girls without this condition. In the first group, the onset of menarche was at about 13 years of age, nearly two years later than in the case of the healthy girls, according to an article published in 2009 in Lupus medical journal. “Corticosteroids (anti-inflammatory drugs) are the villains in this story. These drugs, used for treating lupus, delay female sexual maturity,” explains the researcher from the ICr.

Interested in expanding and probing this investigation, Almeida partnered with teams from 11 universities in the states of São Paulo, Rio de Janeiro, Minas Gerais and Bahia to evaluate 298 adolescents with lupus. He then compared the results with those of a previous study conducted with 2,500 healthy girls. The comparison showed that 12 percent of the girls had had amenorrhea, the sudden absence of menstruation; this condition normally lasted from four to seven months. Two factors explain the dysfunction: the seriousness of the disease itself and the collateral effects of the medication. “In lupus, the antibodies produced by the body can cause inflammation of the ovaries and alter sexual hormone levels,” says Almeida. Coupled with this effect, high doses of corticosteroids reduce the function of the pituitary gland, located at the base of the brain, which in turn reduces the secretion of the follicle stimulating hormone (FSH) and of the luteinizing hormone (LH), responsible for the maturing of the ova.

The study also showed that another medication used to control lupus – the immunosuppressant cyclophosphamide, which reduces the inflammatory activity of the disease – increases the risk of abortion. The likely explanation for this effect – observed among girls who became pregnant during treatment, despite the recommendation that they use contraceptives – is that cyclophosphamide inhibits cell division and interferes with the development of the embryo. Almeida noticed that even without the use of the immunosuppressant, adolescents with lupus have fewer ova than healthy adolescents. Published in the Lupus medical journal in 2007, the study was the topic of an editorial in the Journal of Rheumatology, by Miriam Kaufman, one of the world’s leading experts in adolescent medicine. “The [Brazilian] authors pointed out these youngsters’ need to get guidance on their decisions about their sex lives,” Miriam wrote.

Another undesired effect of cyclophosphamide was the increase of fungal infections, namely vaginal candidiasis, identified in 14 percent of the girls with lupus. “Candidiasis has to be treated because it can spread throughout the body,” says Almeida.

Concurrently with the research study on the girls, the team from the Children’s Institute and from the Rheumatology Discipline of the University of São Paulo evaluated the fertility and sexual maturity of male adolescents and young adults. One of the effects, possibly associated with the use of the medications, is a reduction in the size of the penis. Pediatric rheumatologist Ana Paula Vecchi, a member of Almeida’s team, evaluated the penis length of 25 young adults with lupus and noticed that, on average, their penises were two centimeters shorter than those of healthy males. The smaller size was even more pronounced in males with an early onset of lupus, before the age of 13.

Ana Paula believes that in these cases treatment had begun early on, before the sex organs had fully developed. “Corticosteroids affect the pituitary gland, which leads to reduced production of hormones,” says the rheumatologist. “And with less testosterone, the penis also grows less. In spite of this problem, which bothers many men a lot, the young adults in the study reported that they had no difficulty having sexual intercourse, did not feel their libido was low, and did not have low self-esteem.

Penis size is not the only problem among men with lupus, as they are also less fertile than healthy men, in general. From 2002 to 2006, Almeida’s team monitored 35 men aged 15 to 45; except for lupus, they suffered from no other conditions and were neither smokers nor heavy drinkers. Sperm analysis revealed that 60 percent of the men with lupus had fertility problems, ranging from a low sperm count and reduced sperm mobility to total absence of male reproductive cells.

The testicles of these men were also smaller than those of healthy men. In addition, their FSH levels were high (FSH is the hormone that regulates sperm production). The group from ICr observed that the factor responsible for sperm alterations was the use of cyclophosphamide, which adversely affects the development of the sexual glands (gonads). Indeed, the effect of the medication was so strong that the sperm of these men remained in an altered state five years after the end of treatment.

Blood marker
The fact that damage to sperm in this case is always associated with alterations in the levels of two hormones – FSH and inhibin B; the latter is produced by the testicles and regulates the production of FSH – led pediatric rheumatologist Ricardo Maisse Suehiro, from Almeida’s team, to develop a possible marker of the deformation of male reproductive cells. “There is a direct relation between the levels of the two hormones,” says Suehiro. “When the level of FSH goes up, because of the cyclophosphamide, the testicles produce less inhibin B, which impairs the quality of the sperm.” If these results are confirmed by further studies, inhibin B levels in the blood may become a marker indicating sperm alterations, which would eliminate the need for lupus patients to undergo spermograms.

Almeida believes that the group’s findings in the last few years will help to refine the treatment of people with lupus and improve their quality of life. At present, at the invitation of a US institution, Almeida is working on the development of a compound – triptorelin – that might help to protect the ovaries of women who take cyclophosphamide. For the males, Almeida suggests that sperm banks be created to freeze healthy sperm before lupus treatment begins.

The projects
1. Evaluation of gonad function in males with systemic lupus erythematosus (nº 2004/07832-2); Type Regular Research Awards; Coordinator Clovis Artur Almeida da Silva – Instituto da Criança; Investment R$ 17,431.08 (FAPESP).
2. Evaluation of gonad function in males with dermatomyositis and polymyositis (nº 2005/56482-7); Type Regular Research Awards; Coordinator: Clovis Artur Almeida da Silva – Instituto da Criança; Investment: R$ 9,730.37 (FAPESP)

Scientific articles
SOARES, P. M. et al. Gonad evaluation in male systemic lupus erythematosus. Arthritis Rheum. v. 56, p. 2.352-61. Jul. 2007.
SUEHIRO, R. M. et al. Testicular Sertoli cell function in male systemic lupus erythematosus. Rheumatology. v. 47, p. 1.692-97. Nov. 2008.
SILVA, C. A. et al. Maintenance of fertility in patients with rheumatic diseases needing anti-inflammatory and immunosuppressive drugs. Arthritis Care and Research. 26 Aug. 2010 (online).