Joan is a 50-year-old diabetic patient from the Caribbean who works as a home health aide. At a visit last year, she looked down at her shoes and asked in a soft, embarrassed voice if I had something to help her with her "nature." Her desire for sex was gone and she wanted something to bring it back. She is married and satisfied with her relationship; she and her husband live with their son who is in his 20s. She had previously enjoyed her sex life, but things have begun to change as she approaches menopause. She did not have any specific gynecologic concerns or pain, but she was beginning to miss her periods. I have occasionally given her treatments for vaginal candidiasis, particularly at times when her diabetes was less controlled. There did not seem to be any particular medical or relationship issues that would explain her lack of desire.
Her request came around the time that Procter & Gamble were (unsuccessfully) seeking US Food and Drug Administration (FDA) approval for Intrinsa, a testosterone patch for hypoactive sexual desire disorder (HSDD). Her request posed 2 questions: Is lack of sexual desire really a disease? And is Intrinsa "the pink Viagra"?
Within my own clinical practice, my patients express a variety of reactions to decreased sexual desire. Some patients, like Joan, seem bothered by lack of sexual desire and seek treatment from me. Others note their lack of desire with indifference. Or, their concern is not for themselves but for their partners, and the impact their decreased desire has on them. There are those who see lack of sexual desire as a welcome liberation. This is not just true of women. Men have also commented to me on the advantages of lessened sexual desire. One noted: "If I'd had this problem when I was younger, I would have been so much more productive."
Given this diversity, it is not surprising that defining the problem of decreased sexual desire is problematic. Standard definitions can be found in International Classification of Diseases (ICD)-10, Diagnostic and Statistical Manual (DSM)-IV and the American Foundation for Urologic Disease (AFUD), all of which recognize lack of sexual desire as a subset of sexual dysfunction. All of their definitions incorporate personal distress as part of the diagnosis; in other words, lack of desire that is not distressful to a patient is not pathologic. Here is the definition of HSDD used in the Procter & Gamble FDA application:
Hypoactive sexual desire disorder (HSDD) is the persistent or recurrent deficiency or absence of sexual thoughts, fantasies, and/or desire for or receptivity for sexual activity, which causes personal distress or interpersonal difficulties. Low sexual desire may be associated with low sexual activity, sexual arousal problems or orgasm difficulty." [1]
This particular conceptualization sticks closely to the Masters and Johnson Human Sexual Response Model. Masters and Johnson categorized sexual activity in 4 consecutive stages: excitement, plateau, orgasm, and resolution. Each of these stages had physiologic correlates, reflecting a rather biological view of sexuality.
This model and the definitions derived from it are now the subject of intense debate. Rosemary Basson and her colleagues[2]have emphasized that the linear model proposed by Masters and Johnson may not well reflect the actual experience of women. Instead, they conceptualize women's sexual experience as one of "overlapping phases of variable order," a series of circles rather than a line. They have emphasized the need to understand the context of arousal disorders and the fact that "[in] the absence of distress, a disruption of sexual response or lack of interest may have epidemiological but not clinical importance."
A more radical departure from the current medical model is found in the New View of Female Sexuality, recently discussed in a Medscape CME program.[3] The New View questions the Human Sexual Response model, pointing out that it was derived from a select population and has not been validated in population-based studies. Rather than starting with specific symptoms, the New View classifies problems on the basis of their etiology: those due to sociocultural, political, or economic factors; those relating to partner and relationship; those due to psychological factors; and those due to medical factors. The New View emphasizes education (including bibliotherapy). Proponents of the New View have campaigned actively against the medicalization of female sexuality and against Intrinsa. (See their Web site at https://www.fsd-alert.org.)
The debate over defining the problem is muddied considerably by the overpowering role of the pharmaceutical industry in the genesis of female sexual dysfunction as a diagnosis. Roy Moynihan, writing in the British Medical Journal over the past several years, has chronicled how Procter & Gamble (and investigators closely associated with the company) have promoted female sexual dysfunction and Intrinsa to the medical and lay communities.[4] To quote Moynihan:
[Procter & Gamble] sponsored key scientific meetings in sexual medicine, hired leading sex researchers as consultants, funded continuing medical education activities, produced a reporter's guide to testosterone, and created a publicly accessible website. It has worked with agents from three public relations companies and at least one major advertising firm to promote awareness of both the "disease" and the drug.
Even if there are patients who experience distress over lack of sexual desire (as it seems to me there are), will not the very existence of a highly promoted pink-pill–equivalent to the "little blue pill" create its own market? Will not a massive "health education campaign" actually change expectations and create a "dis-ease" in women who would otherwise not experience distress?
If we accept that hypoactive sexual desire is a true disorder, what is the evidence that testosterone is a valid treatment?
We know that testosterone improves sexual function in hypogonadal men. It is also marketed to older men for a putative "male menopause" despite the fact that it is a known stimulant of prostate cancer. In women there are conflicting data on the correlation between testosterone levels and sexual desire. And testosterone is prescribed by some gynecologists to their patients even in the absence of FDA approval.[5]
This is the background to the Procter & Gamble submission to the FDA for approval of Intrinsa in June 2004. Intrinsa is a transdermal patch that delivers 300 microg/day of testosterone. It is meant to be worn continuously and changed twice a week. Two of the major studies cited in the FDA solicitation were published this year, one in May in Obstetrics and Gynecology (Buster and colleagues[6]) and the other in June in the Annals of Internal Medicine (Braunstein and colleagues[7]). Both studies were quite similar, and a review of them allows us to cover the basic efficacy issues raised before the FDA:
The studies examined women who had undergone surgical hysterectomy and bilateral oophorectomy, were concurrently taking estrogen, and had hypoactive sexual desire disorder. It was for treatment only in this group of women that Procter & Gamble sought approval.
Both were randomized controlled trials involving comparison of a placebo patch with either a 300 microg/day testosterone patch[6] or testosterone patches in 3 strengths (110 microg/day, 300 microg/day, and 450 microg/day[7]).
Both studies involved several hundred women (539 women[6] and 447 women[7]); the Buster study involved 3 treatment arms so only 110 women were randomized to the 300 microg/day arm. Thus, it had less power to detect significant differences.
Three measures were used for efficacy: a Sexual Activity Log (SAL), a Profile of Female Sexual Function (PFSF), and a Personal Distress Scale (PDS). These 3 measures were developed by Procter & Gamble specifically to measure response to treatment of HSDD. The SAL measured satisfactory sexual activity (with or without intercourse) in the prior 7 days. The PFSF looked at 7 "domains of sexual function" over the previous 30 days; in the clinical trials it was the desire scale that served as an end point. The PDS measured how distressed a woman felt about her lack of interest in sex over the previous 30 days. Conceptually, the 3 measures covered the basic components of the HSDD definition: desire (PFSF), activity (SAL), and distress (PDS).
Both studies were supported by Procter & Gamble and involved either Procter & Gamble consultants or employees as authors. Procter & Gamble assisted in the statistical analysis and writing of the Buster paper.
The primary end point for the FDA (and also the primary end point in both published papers) was improvement in the SAL. Both studies reported statistically significant improvements in sexual activity with the Intrinsa patch. I have tried to summarize their findings in the Table . Curiously, given the fact that the SAL was the primary endpoint, neither study reported on baseline or post-treatment values and neither study reported on the absolute size of the benefit attributable to treatment. To find out the actual values, it is necessary to turn to the FDA's Medical Review, available on the Internet.[1] The FDA medical review helps put the benefits of Intrinsa in context.
What was the absolute increase above placebo in women taking the transdermal testosterone (TTS)? ". . . the mean observed difference between the increase in the TTS arm and the increase in the placebo arm was an approximate difference of one more event per 4 weeks in the TTS arm." One event a month does not seem impressive.
In evaluating whether or not this is meaningful, it is useful to consider the context of how serious HSDD is. The FDA Medical Review also includes the following description of the patients diagnosed with HSDD:
Data collected by the Applicant [ie, Procter and Gamble] early in the development program in 2000 during the time of the initial 3 instrument validation studies showed on average 3-4 total satisfying sexual episodes (SSEs) per 4 weeks in women with HSDD [N= 347] in Europe, the US and Canada compared with "normal" age-matched controls [N= 260] who reported 10-12+ SSEs per 4 weeks. [1]
In short, women who have "lost their nature" had a deficit of about 7-9 "episodes" a month. Intrinsa fills that deficit by 1 episode.
Both studies reported improvements in sexual desire (as measured by the PFSF) and decreases in personal distress because of lack of interest in sex. FDA reviewers again questioned whether the small absolute improvements found in the studies were clinically meaningful. But it seems to me that if the drug fails on the primary end point, it cannot be rescued by the secondary end points.
The FDA advisory committee, however, found all of these differences to be clinically meaningful. On the other hand, the Advisory Committee felt that Procter and Gamble had not provided sufficient evidence of the long-term safety of Intrinsa. Given concerns over the long-term cardiovascular effects of estrogen and testosterone treatment, the committee recommended that further safety studies be undertaken. This conclusion was heavily influenced by the results of the Women's Health Initiative.
It is interesting to contrast the results with Intrinsa to those that led to the approval of Viagra. Those studies involved 3000 men and were summarized as follows in the Medical Letter:
In 4 fixed-dose trials, improvement in erections was reported by 63% of 214 patients taking 25 mg, 74% of 391 taking 50 mg, and 82% of 380 taking 100 mg of the drug, and in 24% of 463 taking placebo. The effect was detectable as soon as 30 minutes after taking the drug and for as long as 4 hours. Some patients have reported increased erectile activity the next day. The manufacturer reports statistically significant improvement in subgroups with cardiovascular disease, diabetes, transurethral prostatectomy, spinal cord injury and in those taking antidepressants, antihypertensives or antipsychotic drugs. [8]
Not only does Viagra seem to be a far more effective drug, but it is taken only when needed and had been tested before marketing in the broad variety of patients who would be likely to use it. Intrinsa falls short on all of these points.
There is something sad about the Intrinsa story. Clearly, Procter & Gamble spent enormous time and resources on a drug with, at best, marginal efficacy. It's too bad that the result was not a safe and truly effective medicine. But maybe there is no magic pill.
This brings me back to my patient, Joan. I sense her distress and that she has come to me for help. Would Intrinsa, if it were available, be an option for her?
She is not a woman who has undergone surgical menopause and thus is not a candidate for Intrinsa. Is it possible that if the drug were approved she might request it? Certainly, particularly if it is marketed aggressively. But, as someone with diabetes (and thus at increased cardiovascular risk), she would probably be a very poor candidate for any such "off label" use. She would, like the women in the Procter & Gamble trial, have to start taking estrogen therapy. But she would also have to take a progesterone as she has an intact uterus. The drug would not give her back "her nature" in the sense of "curing" her lack of desire. For this, education and counseling may be a gentler and more effective approach.
Medscape's article on the New View suggests referring patients to The Complete Idiot's Guide to Sensual Massage.[9] It's probably available at the local library, can't be associated with too many adverse outcomes, and sounds a good deal more inviting than a testosterone patch.
Medscape Ob/Gyn. 2005;10(2) © 2005 Medscape
Cite this: Is Lack of Sexual Desire a Disease? Is Testosterone the Cure? - Medscape - Sep 14, 2005.
Comments