Alan Pappe/Corbis/Corbis (DC)/LatinstockThe hustle and bustle of city life goes hand in hand with stress. Between work, traffic, family, household chores and leisure, tasks succeed each other and the hours of sleep that one’s body insistently demands become an increasingly rare luxury. Moreover, it is not only the body that withstands the tension and the lack of rest with difficulty: one’s sex drive and performance are also affected, according to recent studies. Besides sabotaging a pleasurable and vital activity, reducing desire and causing impotence, stress may also lead to female infertility, hence the difficulty in having children faced by many couples. “Sex is essential for preserving the species”, sums up the biomedical professional Monica Anderson, a sleep expert, from the Psychobiology Department of the Federal University of São Paulo (Unifesp), to explain her scientific interest in the subject.
In the early morning, when going to Unifesp on weekends, Monica goes past youths leaving bars in the São Paulo City district of Vila Mariana. She just cannot overlook the possible impact of often swapping day for night on their days off. Sleepless nights – the most common form of stress that modern city life impinges upon the organism – affect memory, diminish one’s capability of focusing, cause hypertension and incite hunger, along with the specific need to consume calorie-rich foods, leading to undue weight gain, among other undesirable consequences. In the last few months, the Unifesp group led by physician Sergio Tufik, who heads the Sleep Institute, which is one of the 11 Cepids (Research, Innovation and Dissemination Centers) financed by FAPESP, has been demonstrating an even more worrying consequence of sleep deprivation for men than the ills that put one’s life at risk: sleeping poorly can cause impotence.
This was the result of the Episono (Episleep) epidemiological survey, which analyzed the quality of sleep of more the 1,000 São Paulo City inhabitants aged 20 to 80. Conducted at the Sleep Institute, this study had already revealed that one third of São Paulo women suffer from insomnia and one third of the city’s inhabitants have sleep apnea, the breathing interruptions that cause one to awaken for a split second (see Pesquisa FAPESP no 158). Now, it is bringing into the limelight the damage that sleep deprivation casts upon sexual health.
During the Episono study, Monica asked 467 men a number of questions about their sexual performance and desire. One of the questions, in particular, determined whether the man suffered from erectile dysfunction. “How would you describe your capacity to get and to maintain an erection suitable for satisfactory intercourse?” To her surprise, 17% of the respondents stated that they only managed it “sometimes”, or “never”. This rate, which is very high, rises further after the age of 50, when 63% of the men complained about erectile dysfunction, as the Unifesp team explains in detail in an article soon to be published in Sleep Medicine. From the ages of 20 to 29, the problem is less common: 7% of young men complain about their own sexual performance. Nevertheless, this is a completely unexpected percentage for this age group.
Age is the main risk factor for erectile dysfunction – after the age of 40, the risk increases. When assessing the health and the questionnaires of the survey participants along with the results of their polysonographies (the most complete exam for assessing sleep quality), Monica found that nights of poor sleep pose a real threat to erections. However, what she showed in relation to men had already been observed years ago among mice by American researcher David Gozal, from the University of Chicago, one of the world’s greatest experts in the field, who was in São Paulo in November for the 3rd International Congress of Sleep Medicine.
The damaging effect of sleep deprivation on erections should not come as a surprise. After all, to function well, the penis depends on an efficient circulatory system, something that is atypical among people with sleep disturbances. In their quest for genetic markers connected with an inclination to develop erectile problems, the Unifesp team corroborated the complexity of the physiology of erections. According to an article soon to be published in the Journal of Sexual Medicine, the best-known journal in this field of research, erectile dysfunction seems to be associated with diabetes, hypertension, the severity of sleep apnea, age and BMI (body mass index, the chief measure of obesity). All these health problems are also linked, in a way, to sleep disturbances, which makes it difficult to separate them. The group researched variations in the genetic sequence responsible for producing eNOS (endothelial nitric oxide synthase), the enzyme responsible for the production of nitric oxide, a neurotransmitter that plays a key function in erection. This gene, at first, looked as if it might be a good candidate in helping to prevent erectile dysfunction risks, but it now seems it is not, after all. At least among the populations of São Paulo and Germany. “Perhaps because these populations are more inclined to obesity”, speculates Monica. Risk factors such as excess weight might mask the association between gene alterations and impotence detected in studies conducted in Mexico, Taiwan and Turkey. Despite these results, however, the sleep and sex expert did not give up and has already identified another gene that looks as if it may be a promising indicator of erectile dysfunction, described in an article not yet published.
The basis for understanding what happens with humans comes from a substantial body of research with rats. Placed on islets surrounded by water, the rats were able to take naps during the experiments, but were deprived of REM sleep, which is when dreams occur. During this phase of sleep, the brain deactivates the muscles, causing the rats’ muzzle to drop and touch the water. This in turn woke them up, like a person who sleeps on a bus leaning his or her head on the shoulder of an unknown stranger. The effect is similar: a jolt that interrupts REM sleep. “After four days of sleep deprivation”, the researcher tells us, “half of the rats get erections alone in their cage”. The experiments’ videos leave no room for doubt. The rats have erections, masturbate and even ejaculate. “Lack of sleep releases something that increases their sex drive”, Monica tells us. At least part of the explanation of this effect – which researchers have named hypersexuality (see Pesquisa FAPESP nº 110) – involves hormones. The levels of testosterone, a hormone largely associated with masculinity, drop enormously among the sleep deprived rats, whereas the levels of progesterone, another sex hormone, rise fivefold, according to Monica.
The results seem to clash with the erectile problems observed among men with sleep disturbances. Monica, however, reminds us that erection and ejaculation are reflexes, but sex is far more than this. She showed that when a receptive female appears on the scene, a sleep deprived male rat has more difficulty achieving suitable performance. In an article published this year in Behavioural Brain Research, Tathiana Alvarenga, from Monica’s team, shows that such a male closes in on the female and makes several attempts to mount her, which is normal. However, he has to rehearse many more times than the well-rested rats. The problem involves both penetration and ejaculation, which become much more difficult. This is a source of concern, because sleep deprivation does not only affect youths who spend their night reveling. “In the past, people went to bed with the chicks; now they spend the night on the Internet”, compares Monica.
Today, work takes up a substantial part of one’s time and if one does not give up leisure, family and social life, then what ends up abandoned is one’s pillow. Women, who tend to accumulate a profession plus the mother and home keeper functions, may also be at risk and are often unable to sleep at night, while they organize their agenda or revisit the day’s events in their mind. Although Monica’s team is yet to find out what the impact of insomnia on fertility is, studies with female rats provide some clues. Female rats are considered a good model for the human female reproductive system, since their neurological and hormonal systems are very similar to those of women, the chief difference being that the female rats’ cycle last five days while women’s last 28, as an article soon to be published in the Journal of Sexual Medicine explains. The Unifesp group deprived female rats of REM sleep for four days during different phases of their hormonal cycle. When the deprivation ends in the phase of the hormonal cycle during which the female rats are receptive, and after they rest, they promptly try to find a male, as sleep deprivation seems to heighten their sexuality. They run around their cage and jump vertically; their ears shake and they arch their backs much more, to expose their genital region, all of which are signs of strong sexual soliciting, rather than of receptiveness. The contrary occurs when sleep deprivation begins in the non-receptive stage, which corresponds to women’s pre-menstrual syndrome period (PMS). After catching up on their sleep, the females make their aversion to males that try to seduce them very clear. They squeal, rise up on their hind paws and attack their suitor with their front paws, like little boxers. When they are on their four legs, they curve their back in the shape of an inverted U. After a few tries, the males see no alternative other than giving up.
Analyses of the hormonal levels of these female rats showed that, as in the males, lack of sleep affects their levels of progesterone. This had different consequences depending on their cycle phase. Physiologist Janete Franci, from the University of São Paulo (USP) in Ribeirão Preto, studies the effect of hormones in the reproductive system of female rats and has shown that stress can unleash ovulation or inhibit it. In the post-menstrual phase, which lasts for a variable amount of time, estrogen and progesterone progressively prepare the body for ovulation. Janete’s team discovered that sudden, short-duration stress during this phase can trigger early ovulation. This would explain what are, by now, indications of long standing that women who have been raped are more likely to become pregnant that those who have had voluntary intercourse.
To simulate sexual violence, the researchers used a glass stick to stimulate the female rats’ cervix delicately. As this procedure is not comparable to the sexual aggression that many women suffer throughout the world, they simulated fear by keeping a cat in full view of the rodents while conducting this experiment. “We witnessed a higher than normal progesterone peak appear earlier than expected”, Janete tells us. As the progesterone discharge that precedes ovulation was brought forward, the researcher believes that the release of the ovum may also have been brought forward. As she explains, stress activates the adrenal glands, which secrete adrenaline, the main hormone that induces reactions to emergencies and the release of the progesterone and testosterone hormones. The progesterone peak unleashed by fear, in turn, increases the concentration of the luteinizing hormone (LH), bringing about earlier than normal ovulation.
All of this only happens in the post-menstrual phase, when estrogen is preparing the body for ovulation. Outside this phase, Janete observed the opposite reaction under the same experimental circumstances: LH levels may even drop under stress. “We must now study the viability of the fetuses generated as a result of untimely ovulation”, warns Janete. We are yet to find out the consequences of fertilizing an ovum that is not fully mature.
Just as a major fright can unleash a storm of reproductive hormones among women, chronic stress may lead to infertility. Among female rats, the USP group showed that ongoing stress might underlie the chief reason for infertility, the polycystic ovary syndrome, which afflicts one out of every ten women of reproductive age. It is still a mystery why, among these women, the ovum gets trapped within the ovarian follicle, whose walls become progressively thicker until they form a cyst. The outcome is erratic ovulation, which might happen, for instance, twice a year, and on unforeseeable occasions, rendering pregnancy rather unlikely. “Many of these women are anxious people”, Janete tells us – a clue that indicates that stress may be part of the source of the problem. “It is common for them to give up becoming pregnant, to adopt a child and, once the tension has disappeared, to become pregnant promptly thereafter”.
Female rats exposed to long stress periods (three hours a day inside a refrigerator, at 4o C, for eight weeks) developed the polycystic ovary syndrome, according to an article published by the Ribeirão Preto team in 2008 in Endocrinology. Janete’s group found an excess of noradrenaline in these rats’ ovaries, particularly after four weeks of stress. With more than four weeks, it is as if exhaustion of the capacity to produce hormones sets in, making hormones scarcer. “We showed, for the first time, that stress can cause infertility”, tells us the researcher, who describes how the syndrome sets in among women. “If during puberty the level of a girl’s noradrenaline is higher than normal, the syndrome may be triggered. Afterwards, even if the amount of released noradrenaline decreases, there is no treatment for it”. The article, published last year and part of the doctoral work of Marcelo Bernuci, also showed the involvement of a region of the brain called the locus coeruleus in the bombardment of the ovaries with noradrenaline: when its neurons (blue) are damaged, female rats do not develop polycystic ovaries during the eight weeks of the experiment. Bernuci is now testing propanolol, an anti-hypertensive drug used to prevent infarctions, to block the action of noradrenaline in the ovaries – which may become a weapon in the fight against polycystic ovaries.
In the cradle
Janete also found that the effects of stress upon sex are not limited to youths and adults that are overly busy with obligations and leisure. Traumatic events soon after birth may affect the brain’s development and have a lasting effect, as is shown by the work conducted in collaboration with physiologist Aldo Lucion from the Behavioral Neuroendocrinology area of the Federal University of Rio Grande do Sul (UFRGS). In female rats that were repeatedly separated from their mother as newborns, the number of neurons fell by half in the medial preoptic area of the brain, which is involved with ovulation control, as an article published this year in Brain Research demonstrated.
According to Lucion, the separations were brief and caused no problems other than anguish at the rupture of the bond between the pups and their mothers. During the pups’ first ten days of life, the researchers removed them once a day from their nest, all at the same time, held them in their hand for about one minute, and then placed them back in the nest with their mother. This quick separation sufficed to reduce not only the number but also the size of the cells in the medial preoptic area. Furthermore, this was a lasting change, as shown by the analyses of the brains of the female rats at 11 days, soon after the experiment, and at 90 days, which corresponds roughly to women aged 30.
The changes in the brain seem to explain the observations published last year in Neuroendocrinology: female rats handled in their infancy later present major changes in their sexual behavior and reproductive physiology. The differences were striking when females aged 90 to 110 days during their receptive period were introduced to males. Those that had been separated from their mother in infancy produced fewer ova and seemed less inclined to exhibit the arching of the back that indicates sexual receptiveness.
What appeared to take place is that, atrophied by uncertainties in infancy, the medial preoptic area was unable to stimulate the production of the hormone peaks that ovulation and sexual behavior demand. During the fertile period, the females in the experiment had a lower than expected level of noradrenaline and of nitric oxide. The latter, besides stimulating erections, is involved in ovulation and in the maturing of ova. Consequently, the levels of three sexual hormones, namely, estradiol (a type of estrogen), the follicle-stimulating hormone (FSH) and the luteinizing hormone (LH), were lower than they should have been, failing to reach the concentration peaks required to unleash ovulation and sexual behavior. The next step will be to understand the molecular and biochemical part of how stress affects brain development. “We are studying neuronal growth factors”, the physiologists tell us. The results of the group from Rio Grande do Sul highlight the importance of a close and constant relation between a mother and her offspring. The same applies to humans, warns us the UFRGS researcher: “The mother may be present, but it is the quality of the relationshiip that matters to the child”. An unpublished article by his group showed that the blood of the children of women who had postnatal depression have increased levels of cortisol, a hormone typical of stress. “The mothers with postnatal depression are present, they breastfeed their children and look after them, but they don’t look at their children much, but eye contact is very important”, tells us Lucion. The babies’ stress reaction surprised the researcher, used to the notion that this mechanism was not yet formed in newborns, whose nervous and hormonal systems are not fully developed. “The mother doesn’t need to be present all the time”, Lucion explains, “but children need a stable caretaker that they can rely on”. Together, the São Paulo and Rio Grande do Sul studies make it clear that environmental conditions have significant effects on the neurophysiology of sex. Too much stress may diminish fertility and sexual desire, which can be a problem for those who want to have children, besides standing in the way of one of life’s pleasures. Achieving a better understanding of how this works might eventually lead to therapeutic paths, but even now a clear prescription for a fulfilling sex life is to make sure one has good nights of sleep and avoids too much stress. It is well worth it. Back in the sixteenth century, the French poet Pierre de Ronsard already stated: “To live with no voluptuousness is to live beneath the earth”.
1. Sleep Studies Center; Modality Cepid – Research, Innovation and Dissemination Centers; Coordinator Sergio Tufik – Unifesp; Investment R$61,891.76 (FAPESP).
2. Neuroendocrinal regulation and the effects of stress on the female reproductive function (04/09638-9); Modality Theme Project; Coordinator Janete Aparecida Anselmo Franci – USP-RP; Investment R$1,077,666.13 (FAPESP)
ANDERSEN, M. L. et al. Prevalence of erectile dysfunction complaints associated with sleep disturbances in São Paulo, Brazil: a population-based survey. Sleep Medicine, in press.
ANDERSEN, M. L. et al. Paradoxical sleep deprivation influences sexual behavior in female rats. Journal of Sexual Medicine, in press.
BERNUCI, M. P. et al. Locus coeruleus mediates cold stress-induced polycystic ovary in rats. Endocrinology. V. 149, n. 6. p. 2907-16. June 2008.
CAMOZZATO, T. S. C. et al. Neonatal handling reduces the number of cells in the medial preoptic area of female rats. Brain Research. V. 1247, p. 92-9. Jan. 2009.