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.
When it comes to sex, women are faced with a lack of hard facts. Consider the existence of an anatomical area known as the Gräfenberg spot (G-spot). Eleventh-century Indian texts and Cosmopolitan magazine seem sure it exists, and imaging studies of blood flow support its existence1, but other studies find little evidence for it2.
Similarly, some evolutionary biologists think that the female orgasm has been influential in natural selection, helping sperm to travel upstream. But others view it as more like the male nipple — something that owes its existence to strong selective forces acting only on the opposite sex.
Researchers still lack a consensus on even the most basic questions: does a woman's sexual desire exist independently of arousal, or is desire just the conscious awareness of physiological readiness for sex?
But there is one thing that scientists do agree on: research into women's psychological and physiological experiences of sex, and associated problems, has played second fiddle to equivalent work in men. Although a few other areas of biology and medicine also give women short shrift (see page S18), the difference in sex research is compounded by cultural uneasiness at the idea of a woman's sexuality being distinct from her fertility. It has not helped that women lack an arousal marker that is as simple to measure as a penile erection.
Some progress has been made, helped by committed individuals including Richard von Krafft-Ebing in the late nineteenth century, and William Masters and Virginia Johnson in the 1960s. It has been known for some time that women's sexual desire and arousal can be shaped by early life experiences, various common maladies, and several widely prescribed medications. But rigorous exploration of the mechanisms underlying these associations — and how, therefore, women's sex lives might be improved — has only recently begun.
Drugs and desire
This lack of knowledge is a major problem given the importance that women place on healthy sexual functioning. “It's equivalent to other really important things in life — more important to women than financial success or owning a home,” says Sheryl Kingsberg, a clinical psychologist at University Hospitals Cleveland Medical Center in Ohio. The burden of its absence is “equivalent to things like chronic back pain or diabetes”, she adds.
Kingsberg is referring to the findings of a study3 that measured the quality-of-life impact of hypoactive sexual desire disorder (HSDD), which is defined as the distressing absence of sexual appetite. Studies of women's sexual desire are biased towards cultures in which asking about such things is not considered taboo, but HSDD is thought to be the most common form of sexual dysfunction in women, affecting about 9% of women before the menopause and 12% after it. “Desire does decrease after the menopause, but the other aspect of HSDD — distress about low desire — is higher in younger women,” says Anita Clayton, a psychiatrist at the University of Virginia in Charlottesville.
Other problems, such as pain during sex, vaginal atrophy and anorgasmia (the inability to experience orgasm), are less common but often interact, says Annamaria Giraldi, a researcher in clinical sexology at the University of Copenhagen Hospital in Denmark.
Another study4 found that women with HSDD have medical costs that are about 17% higher than those of women of the same age without this complaint. This finding does not imply that low desire is causing illness, however. It is more likely to be the other way round, as any medical issue that affects energy levels or self-image can have an effect on sexual desire and arousal. Some neurological diseases, such as depression, can make orgasm more difficult to achieve, for example. A few studies suggest that diabetes can have the same effect. Hypothyroidism is also linked to low desire, but this can usually be resolved by thyroid-hormone supplements.
Among the medical treatments known to affect sex drive are breast-cancer drugs, which often reduce oestrogen levels and so decrease desire. A few drugs, such as the dopamine agonists used to treat Parkinson's disease, have the opposite effect. “Some Parkinson's patients — both men and women — get completely hypersexual,” says Clayton, who recalls one male patient she knew whose prescription stimulated him to do a striptease on the Internet.
Clayton has spent about three decades studying the link between antidepressants and sexual desire and arousal. It took ten years to gather enough evidence and support to start a serious prevalence study, she says. By that point, pharmaceutical companies were interested, particularly when her study implied that sexual dysfunction explained a lot of non-adherence to serotonin-specific reuptake inhibitors (SSRIs), especially among men.
The medicine that could be having the biggest effect on women's sex drive, however, is the oral contraceptive ('the pill'), a connection that is rarely studied. The US Food and Drug Administration (FDA) has never asked whether this is a problem with hormonal contraceptives, points out Kim Wallen, a behavioural endocrinologist at Emory College of Arts and Sciences in Atlanta, Georgia. “Drug companies aren't into it because they don't want to find out that their drugs have long-term negative side-effects,” he adds. By using eye-tracking techniques, Wallen has found that women in the third week of a four-week pill cycle (which is associated with a particular hormonal profile) avoid looking at images of fellatio, and also rate them as unattractive, unlike women in other stages and naturally cycling women. When he gave a subcutaneous contraceptive to macaques, they also lost interest in sex.
Other studies have tried to explain the link between oral contraceptives and decreased arousal. A blood protein called sex hormone-binding globulin (SHBG) mops up testosterone that would otherwise increase sex drive. Taking the contraceptive pill increases the level of SHBG, decreasing the available testosterone. “For some women, even when they go off birth control, their SHBG levels stay pretty high, and they just don't get everything back,” says Clayton. “It's a small percentage of women, but it's worrisome to clinicians.”
For other women, oral contraceptives can worsen the effect of antidepressants on desire. These women, who have a deletion in a serotonin-transporter gene, are eight times more likely to be diagnosed with a sexual dysfunction than are women without this genetic marker5.
Many details of the excitatory and inhibitory mechanisms in the brain that underpin the effects of hormones and drugs on female sexual desire have been uncovered by neuroendocrinologist Jim Pfaus and his colleagues at Concordia University in Montreal, Canada. He works mostly on rats, but the basic neural biochemistry is similar to that in humans.
Pfaus is frustrated by how long it has taken scientists to study the biology of female sexual experiences. “It was ten years ago that we started to stimulate rat clitorises with paintbrushes and understand the neural physiology of female sexual arousal in rats. That's ridiculously recent for such basic science.”
His lab has either discovered or added to knowledge about the effects of the neurotransmitters dopamine, melanocortin, oxytocin, vasopressin and adrenaline, which all help to ramp up sexual excitation. Conversely, serotonin is involved in sexual satiation — it dampens desire, as do endogenous opioids and endocannabinoids. Most of the drugs currently being developed to improve women's sexual desire have been through Pfaus's lab at some point.
Boosting the libido
There is currently only one drug available to boost women's libido: flibanserin (marketed as Addyi by Valeant Pharmaceuticals of Laval, Canada), which is sold only in the United States. It works by temporarily increasing the levels of dopamine and adrenaline, and limiting the amount of serotonin, in areas of the brain responsible for processing sexual reward and motivation. Originally conceived as an antidepressant, flibanserin failed to reduce depression in clinical trials. But the developer, the German company Boehringer Ingelheim, knew that antidepressants sometimes had sexual effects and had been monitoring for changes, so they repurposed the drug as a treatment for HSDD.
Flibanserin's progress was far from straightforward, however. Its first final-stage clinical trial sought an improvement in 'satisfying sexual events', an ill-defined endpoint that was nonetheless achieved. But the trial also required participants to record their daily level of sexual desire, which did not improve, and in 2010 the FDA rejected flibanserin. The problem, says Kingsberg, was the measurement, not the drug. “Desire is like appetite — if you probe on a daily basis, you get how hungry someone is in the moment, but not their general 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 evaluation 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 problems. “The REMS makes people unnecessarily worried about what would otherwise be a really nice option for them,” says Kingsberg. Unlike its handling of erectile-dysfunction drugs, the FDA has discouraged direct-to-consumer advertising for flibanserin.
More drugs to treat HSDD are in the pipeline, including bremelanotide — a peptide-based injectable drug from Palatin Technologies in Cranbury, New Jersey, that increases melanocortin. Success in phase III trials was based on increased desire and a decrease in distress. A company called Emotional Brain in Almere, the Netherlands, is looking at a more personalized approach, says chief executive Adriaan Tuiten, developing separate drugs that either increase activity in a woman's excitatory brain circuits or reduce the activity of inhibitory circuits — the choice of agent depends on the woman's genetics.
Talking therapies can also be effective. This explains the large placebo effects in all of these trials — just talking about their issues with the investigators helps a lot of women. And some of the most promising research currently under way involves combining drugs with various types of cognitive therapy.
Where does all this leave women who have sexual problems? For those with HSDD, there is some hope for treatment. But for less common problems, such as anorgasmia, science does not yet have much to offer. Interest and awareness are growing, however, as taboos and myths about women's sexual desire and arousal are gradually being broken down.