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01-31-2020, 11:44 AM
Testosterone for Women: Waiting for the Female Aphrodisiac

In December 2004 a U.S. Food and Drug Administration (FDA) Advisory Committee for Reproductive Health Drugs refused to recommend Procter & Gamble’s Intrinsa testosterone patch for female sexual dysfunction (FSD) in surgically menopausal women whose ovaries had been removed. The FDA panel found that administering testosterone to these patients would produce an average of one extra sexual encounter a month, a benefit that in the panel’s view did not justify exposing women to the risk of heart attacks and strokes. (1)

This decision surprised executives at both Procter & Gamble and at BioSante Pharmaceuticals, Inc., its principal rival in the race to develop a mass-marketed male hormone sex stimulant for women. BioSante had been rooting for P& G’s application because it believed its own testosterone delivery systems – gels, creams, nasal sprays, and pills – would outperform the Intrinsa transdermal testosterone patch both as drug delivery vehicles and thus in the marketplace. (2)

The decision to bar the use of sexually therapeutic testosterone in the absence of long-term safety studies did not demoralize the leadership at either company. On the contrary, Proctor & Gamble announced that it would eventually resubmit the Intrinsa application once it had carried out studies on naturally menopausal women, a much larger potential market than the estimated 10 million women who have had their ovaries removed. The president and CEO of BioSante, Stephen M. Simes, emphasized the positive by saying that he was “gratified that the panel agreed that FSD is an indication worthy of treatment with testosterone.” He added that he looked forward to getting “the FDA’s advice on what additional safety data will be required.” Sidney Wolfe, director of Public Citizen’s Health Research Group, had already told the panel that P & G’s skin patches could increase testosterone levels by a factor of four and thereby double the risk of breast cancer. (1) Given the current momentum that is driving public interest in the use of androgenic drugs to boost libido, it is unlikely that this sort of medical caution will prevail against the further expansion of the testosterone market that is targeting the sexual needs of both men and women.

The current campaign to market testosterone devices such as the Intrinsa patch and LibiGel ointment for the treatment of “female sexual dysfunction” should be seen in its larger historical context. Given the short memory spans of our major media, it is not surprising that the history of this hormone therapy has been absent from virtually all of the coverage it has received. But knowing something about the history of testosterone for women is essential to assessing the potential benefits and hazards that today’s physicians and drug companies claim to understand. What is more, a familiarity with the history of attitudes toward giving male hormones to “frigid” women offers important lessons in how and why we came to evaluate intimate sexual experiences in ostensibly scientific ways.

The more recent context for the promotion of “female sexual dysfunction” as a treatable disorder takes us back to the introduction of Viagra for “erectile dysfunction” (ED) in 1998. The spectacular success of Viagra raised a gender equity issue: If aging men were entitled to a sex drug, then aging women were entitled to nothing less than an equivalent therapy. The inevitable clinical trials that administered Viagra to women proved disappointing, thereby confronting researchers and patients alike with the stubborn (yet also reassuring) fact that female sexual response was more complicated than the essentially hydraulic process that produces an erection. (The fact that male sexual response is also more complex than erectile functioning appears to have been lost on many consumers of the famous blue pills.) The beckoning market for a female sex stimulant prompted doctors and scientists to acknowledge how little they knew about the anatomy of the female sex organs and how these organs reacted to various forms of stimulation. This encounter with the complexity of human sexual response did little, however, to discredit the idea that a pharmacological fix for low libido was waiting to be found.

The topic of female sexual disorders received additional publicity less than a year after the launching of the Viagra boom when an article titled “Sexual Dysfunction in the United States” appeared in the Journal of the American Medical Association (JAMA). This widely publicized study reported that “sexual dysfunctions are highly prevalent in both sexes, ranging from 10% to 52% of men and 25% to 63% of women.” (3) The fact that these authors never mentioned drug therapies for sexual dysfunction, and that they emphasized the importance of “health-related and psychosocial factors,” was not what registered among drug company executives looking for new markets. What did resonate throughout the media was the finding that “43% of American women” had sexual problems that needed fixing. It seemed as though American society had suddenly found itself burdened with yet another public health crisis that required a medical solution. But how novel was this diagnosis? And why were women assigned the principal role in a problem that clearly involved an equal number of men?

The idea that women are the principal cause of sexual problems in marriage has been a staple of medical folklore for more than a century. Men were assumed to have a stronger sexual impulse than women. Over the many years the term was in circulation, the medical literature always assigned sexual “frigidity” exclusively to women. (4) The disorder once known as male “impotence,” and that was eventually rechristened “erectile dysfunction,” never carried the same stigma of emotional deficiency and personal inadequacy. Impotence was an unfortunate physiological problem, while “frigidity” signaled a defective personality and a failure to live up to a wife’s marital obligations. Some (male) doctors knew perfectly well that a great deal of the “frigidity” displayed by wives was the direct result of sexually ignorant or indifferent husbands. A 1931 JAMA editorial, for example, argues that most female “frigidity” is caused by the emotional disinterest of husbands who had “obtained their premarital knowledge of the sexual act from intercourse with prostitutes” whose sexual gratification was of no interest to the paying customer. (5)

The medical literature offered various cures for female “frigidity.” During the 1930s and 1940s these included the use of electricity to sensitize the vaginal mucous membrane: “The treatment consists in inserting a large vaginal electrode into the vagina, connecting it with the negative pole, while the positive pole is connected with a wet abdominal electrode, the galvanic current is allowed to pass for about ten minutes. Without disturbing the electrodes, we now give the sinusoidal-galvanic current for another ten minutes. No pain must be caused by the treatment.” (6) Other commentators, as noted, recommended sexual education for the many husbands who appeared to know nothing about female sexual anatomy or psychology. It was during the 1930s that proposals to use hormonal substances to boost female sex drive began to appear with increasing frequency in the medical literature.

Testosterone was first synthesized in 1935. By the end of that decade synthetic testosterone propionate and methyltestosterone had become, in effect, experimental drugs that were being used for various (and, in retrospect, usually mistaken) clinical purposes. Megadoses sometimes amounting to thousands of milligrams that were intended to neutralize estrogen-driven breast cancers were one application. One of the unofficial dogmas of this early period was that the male hormone would sexually stimulate men and that estrogens would have a similar effect on women. Androgens were sometimes applied to the penis, while estrogens were applied to the clitoris. (7) The discovery that testosterone sexually stimulated females thus came as a shock to the physicians who observed this effect. A 1941 paper reports the author’s reaction to this phenomenon in both young and old women: “My attention was first drawn to it by several elderly women who found the resurgence of libido distressing. The phenomenon is equally as striking among young women. A number of married women, who had considered themselves frigid, stated that after receiving the testosterone propionate injections they experienced a marked increase in coital gratification, culminating in an orgasm.” (8)

Another physician later recalled the discovery of inadvertent androgenic stimulation of women during this early period in the case of a patient being treated for uterine bleeding: “Her physicians were amazed that testosterone, the so-called male hormone, could accentuate libido in the female to the degree experienced.” Just as significant were the measures taken by these male doctors to keep this newly intensified sexual appetite under control: “When the patient returned for further evaluation, it was decided that, despite the benefit the treatment had had on her uterine bleeding, it would be better to discontinue it in order to reverse her libidinous tendency. Testosterone was discontinued, and therapy with progesterone was instituted. Within a short time her libido decreased markedly.” Such regulation of female libido by male doctors was deeply embedded in the mores of twentieth-century medicine. At the same time, there was no doubt about the stimulating effect of these androgens: When female patients being treated for gynecological disorders report intensified sex drive, he says, “we have unbiased evidence on the effect of androgens in increasing libido in the female.” (9) Since 1938, one paper reported a decade later, “the effect of androgens in increasing libido in women” had become “an almost universal observation.” (10) Yet the fact is that, over the next half-century, the use of testosterone for this purpose fell off the medical agenda and did not reappear until the testosterone boom that began during the mid-1990s.

The promotion of testosterone as a female aphrodisiac was delayed for 50 years because the social conservatism of American physicians and of the society as a whole during the 1940s and 1950s could not accommodate public encouragement of sexual fulfillment as a therapeutic goal for all adults. It is seldom noted that the work of the pioneering sexologists of the first half of the twentieth century, including that of the controversial Alfred Kinsey, was intended to save marriages that were imperiled by sexual frustration. The most ardent testosterone therapist of the early 1940s, a University of Georgia gynecologist named Robert B. Greenblatt, implanted testosterone propionate pellets into women for precisely this purpose. As he described this strategy in 1943: “Many married women volunteered the information that their loss of sexual desire led to marital discord. Following pellet implantation there was a return of coital pleasure which often terminated in orgasm. A reawakened interest on the part of the husband usually followed and husband and wife once more fell in love.” (11)

Over the half-century that followed these successful experiments, the discussion in the medical literature of androgens for sexual stimulation fell off sharply. Androgen therapy for “frigidity,” one author writes in 1962, “is usually of little or no avail.” (12) “There is no treatment for frigidity as such,” a (female) British doctor writes in 1967. (13) “A good meal, a bottle of wine, and a good film of her choice, are often excellent aphrodisiacs,” says a South African physician who, writing in 1976, says not a word about androgens. (14) A 1978 report in the British Journal of Psychiatry offers androgens a qualified role in sex therapy (15), but a 1989 report in the British Journal of Clinical Psychology concludes that “testosterone has very limited value and offers no obvious advantage when combined with sexual counselling.” (16)

The socially sanctioned return of testosterone for women has occurred in the context of the growing acceptance of hormone replacement as an “anti-aging” therapy for that segment of the adult population that is willing to pay for it and accept the risks of what amounts to an uncontrolled experiment. The lifestyle demands of the aging Baby Boomer generation include a presumed entitlement to lifelong sexual fulfillment. In the absence of cultural restraints that might oppose this ambition, testosterone therapy for “female sexual dysfunction” – a questionable diagnostic category at best (17) – awaits only that crucial meeting between the drug companies and the FDA that will put to rest the medical safety issue once and for all.

(1) “‘Female Viagra’ fails to win FDA panel’s approval,” [http://www.usatoday.com/news/health/2004-12-02-female-hormone-patch_x.htm (December 2, 2004; accessed June 30, 2005).
(2) See http://www.drugs.com/nda/intrinsa_041203.html (December 3, 2004; accessed June 30, 2005).; “BioSante Plans FDA Meeting on Female Sexual Dysfunction Gel,” TheStreet.com/_forbes/stocks/biotech/10200668.html (December 23, 2004; accessed June 30, 2005).
BioSante produces testosterone products to treat low testosterone levels in both males and females: ” Bio-T Gel’ (male testosterone gel) is being developed as a once daily transdermal gel for treatment of hypogonadism (low testosterone levels) in men. The symptoms of hypogonadism inlcude impotence, lack of sex drive, muscle weakness and osteoporosis. LibiGel (female testosterone gel) and LibiGel E/T’ (estradiol + testosterone gel) are being developed as once daily transdermal gels for treatment of female sexual dysfunction (FSD). The symptoms for FSD include lack of sexual desire, arousal or pleasure; low energy, reduced sense of well-being, osteoporosis. See http://biosantepharma.org/products/testosterone.html (accessed July 4, 2005).
(3) Edward O. Laumann, Anthony Paik, and Raymond C. Rosen, “Sexual Dysfunction in the United States,” Journal of the American Medical Association 281 (February 10, 1999): 537.
(4) The only exception to this rule I have encountered is found in “Treatment of Sexual Impotence,” JAMA (September 25, 1926): 1066.
(5) “Treatment of Frigidity,” JAMA 96 (January 3, 1931): 62.
(6) Max Huhner, The Diagnosis and Treatment of Sexual Disorders in the Male and Female (Philadelphia: F.A. Davis Company, 1942): 407.
(7) See, for example, Local Application of Sex Hormones,” JAMA 117 (September 9, 1941): 473.
(8) Udall J. Salmon, “Rationale for Androgen Therapy in Gynecology,” Journal of Clinical Endocrinology 1 (1941): 167-168.
(9) Herbert S. Kupperman, “Hormonal Aspects of Frigidity,” Quarterly Review of Surgery, Obstetrics and Gynecology 16 (1959): 255.
(10) Anne C. Carter, Eugene J. Cohen, and Ephraim Shorr, “The Use of Androgens in Women,” Vitamins and Hormones 5 (1947): 363.
(11) Robert B. Greenblatt, “Testosterone Propionate Pellet Implantation in Gynecic Disorders,” JAMA 121 (January 2, 1943): 20.
(12) E.C. Mann, “Frigidity,” The Journal of the Michigan State Medical Society 61 (1962): 762.
(13) Jean Pasmore, “The Frigid Female,” The Practitioner 198 (May 1967): 733.
(14) B.A. Michaelides, “Treatment of Frigidity in General Practice,” South African Medical Journal (August 7, 1976): 1339.
(15) Anthony Carney, John Bancroft, and Andrew Mathews, “Combination of Hormonal and Psychological Treatment for Female Sexual Unresponsiveness: A Comparative Study,” British Journal of Psychiatry 132 (1978): 339-346.
(16) Michael G.T. Dow and James Gallagher, “A controlled study of combined hormonal and psychological treatment for sexual unresponsiveness in women,” British Journal of Clinical Psychology 28 (1989): 210.
(17) See, for example, Ray Moynihan, “The marketing of a disease: female sexual dysfunction,” BMJ 330 (January 22, 2005): 192-194.