OUTLOOK WOMEN’S HEALTH SEXUAL AROUSAL Sex matters Research on women’s sexual desire and satisfaction lags behind that on men’s, but scientists and drug companies are trying to close the gap. BY ANNA PETHERICK or owning a home,” says Sheryl Kingsberg, a clinical psychologist at University Hospitals hen it comes to sex, women are Cleveland Medical Center in Ohio. The bur- faced with a lack of hard facts. Con- den of its absence is “equivalent to things like sider the existence of an anatomical chronic back pain or diabetes”, she adds. Warea known as the Gräfenberg spot (G-spot). Kingsberg is referring to the findings of a Eleventh-century Indian texts and Cosmopoli- study3 that measured the quality-of-life impact tan magazine seem sure it exists, and imaging of hypoactive sexual desire disorder (HSDD), studies of blood flow support its existence1, but which is defined as the distressing absence other studies find little evidence for it2. of sexual appetite. Studies of women’s sexual Similarly, some evolutionary biologists desire are biased towards cultures in which ask- studying the link between antidepressants and think that the female orgasm has been influen- ing about such things is not considered taboo, sexual desire and arousal. It took ten years to tial in natural selection, helping sperm to travel but HSDD is thought to be the most common gather enough evidence and support to start upstream. But others view it as more like the form of sexual dysfunction in women, affect- a serious prevalence study, she says. By that male nipple — something that owes its exist- ing about 9% of women before the menopause point, pharmaceutical companies were inter- ence to strong selective forces acting only on and 12% after it. “Desire does decrease after the ested, particularly when her study implied the opposite sex. menopause, but the other aspect of HSDD — that sexual dysfunction explained a lot of Researchers still lack a consensus on even the distress about low desire — is higher in younger non-adherence to serotonin-specific reuptake most basic questions: does a woman’s sexual women,” says Anita Clayton, a psychiatrist at inhibitors (SSRIs), especially among men. desire exist independently of arousal, or is desire the University of Virginia in Charlottesville. just the conscious awareness of physiological Other problems, such as pain during sex, PILL TALK readiness for sex? vaginal atrophy and anorgasmia (the inabil- The medicine that could be having the biggest But there is one thing that scientists do agree ity to experience orgasm), are less common effect on women’s sex drive, however, is the on: research into women’s psychological and but often interact, says Annamaria Giraldi, a oral contraceptive (‘the pill’), a connec- physiological experiences of sex, and associ- researcher in clinical sexology at the University tion that is rarely studied. The US Food and ated problems, has played second fiddle to of Copenhagen Hospital in Denmark. Drug Administration (FDA) has never asked equivalent work in men. Although a few other Another study4 found that women with whether this is a problem with hormonal areas of biology and medicine also give women HSDD have medical costs that are about 17% contraceptives, points out Kim Wallen, a short shrift (see page S18), the difference in sex higher than those of women of the same age behavioural endocrinologist at Emory Col- research is compounded by cultural uneasiness without this complaint. This finding does lege of Arts and Sciences in Atlanta, Georgia. at the idea of a woman’s sexuality being dis- not imply that low desire is causing illness, “Drug companies aren’t into it because they tinct from her fertility. It has not helped that however. It is more likely to be the other way don’t want to find out that their drugs have women lack an arousal marker that is as simple round, as any medical issue that affects energy long-term negative side-effects,” he adds. to measure as a penile erection. levels or self-image can have an effect on sexual By using eye-tracking techniques, Wallen Some progress has been made, helped by desire and arousal. Some neurological diseases, has found that women in the third week of ERIC BROUSSEAU committed individuals including Richard von such as depression, can make orgasm more Krafft-Ebing in the late nineteenth century, difficult to achieve, for example. A few studies and William Masters and Virginia Johnson in suggest that diabetes can have the same effect. the 1960s. It has been known for some time Hypothyroidism is also linked to low desire, that women’s sexual desire and arousal can be but this can usually be resolved by thyroid- shaped by early life experiences, various com- hormone supplements. mon maladies, and several widely prescribed Among the medical treatments known to medications. But rigorous exploration of the affect sex drive are breast-cancer drugs, which mechanisms underlying these associations — often reduce oestrogen levels and so decrease and how, therefore, women’s sex lives might be desire. A few drugs, such as the dopamine improved — has only recently begun. agonists used to treat Parkinson’s disease, have the opposite effect. “Some Parkinson’s DRUGS AND DESIRE patients — both men and women — get com- This lack of knowledge is a major problem pletely hypersexual,” says Clayton, who recalls given the importance that women place on one male patient she knew whose prescrip- healthy sexual functioning. “It’s equivalent to tion stimulated him to do a striptease on other really important things in life — more the Internet. Photoplethysmographs measure vaginal and important to women than financial success Clayton has spent about three decades clitoral blood flow to gauge sexual responses. S2 | NATURE | VOL 550 | 5 OCTOBER©20 201717 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. ©2017 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. WOMEN’S HEALTH OUTLOOK someone is in the moment, but not their gen- eral level of appetite over the past few weeks.” A fresh trial measured desire retrospectively by recording levels over the previous month, as well as counting ‘satisfying sexual events’. This time, both endpoints were significantly different from placebo, but the FDA was unhappy with the degree of change, and again rejected flibanserin. It was finally approved in 2015 after an advisory committee considered an appeal. Approval was accompanied by a risk evalu- ation and mitigation strategy (REMS), which stipulated that women must access the drug from a specially trained provider and must sign a document to say they would not drink alcohol while taking it. The alcohol test that led to the REMS involved 23 men and 2 women knocking back shots early in the morning on an empty stomach. A larger and more realistic study has since found no alcohol-related prob- lems. “The REMS makes people unnecessar- ily worried about what would otherwise be a a four-week pill cycle (which is associated paintbrushes and understand the neural physi- really nice option for them,” says Kingsberg. with a particular hormonal profile) avoid ology of female sexual arousal in rats. That’s Unlike its handling of erectile-dysfunction looking at images of fellatio, and also rate ridiculously recent for such basic science.” drugs, the FDA has discouraged direct-to- ZARA PICKEN them as unattractive, unlike women in other His lab has either discovered or added to consumer advertising for flibanserin. stages and naturally knowledge about the effects of the neurotrans- More drugs to treat HSDD are in the cycling women. When “Some mitters dopamine, melanocortin, oxytocin, pipeline, including bremelanotide — a he gave a subcutane- Parkinson’s vasopressin and adrenaline, which all help peptide-based injectable drug from Palatin ous con traceptive to to ramp up sexual excitation. Conversely, Technologies in Cranbury, New Jersey, that macaques, they also lost patients — serotonin is involved in sexual satiation — it increases melanocortin. Success in phase III interest in sex. both men and dampens desire, as do endogenous opioids trials was based on increased desire and a Other studies have women — get and endocannabinoids. Most of the drugs cur- decrease in distress. A company called Emo- tried to explain the link completely rently being developed to improve women’s tional Brain in Almere, the Netherlands, is between oral contra- hypersexual.” sexual desire have been through Pfaus’s lab at looking at a more personalized approach, says ceptives and decreased some point. chief executive Adriaan Tuiten, developing arousal. A blood protein called sex hormone- separate drugs that either increase activity in a binding globulin (SHBG) mops up testoster- BOOSTING THE LIBIDO woman’s excitatory brain circuits or reduce the one that would otherwise increase sex drive. There is currently only one drug available to activity of inhibitory circuits — the choice of Taking the contraceptive pill increases the boost women’s libido: flibanserin (marketed agent depends on the woman’s genetics. level of SHBG, decreasing the available tes- as Addyi by Valeant Pharmaceuticals of Laval, Talking therapies can also be effective. This tosterone. “For some women, even when they Canada), which is sold only in the United explains the large placebo effects in all of these go off birth control, their SHBG levels stay States. It works by temporarily increasing the trials — just talking about their issues with the pretty high, and they just don’t get everything levels of dopamine and adrenaline, and limit- investigators helps a lot of women. And some of back,” says Clayton. “It’s a small percentage of ing the amount of serotonin, in areas of the the most promising research currently under women, but it’s worrisome to clinicians.” brain responsible for processing sexual reward way involves combining drugs with various For other women, oral contraceptives can and motivation.