Testosterone in Female Hypoactive Sexual Desire Disorder
Condition: Hypoactive Sexual Desire Disorder
MeSH terms: Hypokinesia; Sexual Dysfunctions, Psychological
Study type: Interventional
Phase: Phase 3

Summary: 
      The success of sildenafil in the treatment of erectile dysfunction has led to efforts to find
      similar treatments for prevalent disorders of female sexual dysfunction. Daily transdermal
      testosterone has been shown to improve sexual function in women after oophorectomy (Shifren
      et al, Transdermal testosterone treatment in women with impaired sexual function after
      oophorectomy, New England Journal of Medicine, 343; 682-8, 2000). In laboratory measures of
      sexual arousal, a single application of transdermal testosterone enhanced vaginal blood and
      increased erotic fantasy in normal volunteer women in the laboratory setting, four hours
      after application (Tuiten et al, Can sublingual testosterone increase subjective and
      physiological measures of laboratory-induced sexual arousal?, Arch Gen Psychiatry,
      59;465,2002). We therefore planned a study of transdermal testosterone (25mg) marketed as
      Androgel in female hypoactive sexual desire disorder. Patients are recruited from the
      sexology clinics at Soroka Hospital and the Beersheva Mental Health Center. They are
      randomized to Androgel or placebo and given 10 packets and instructed on application to the
      abdomen and shoulders, four hours before planned intercourse. Patients unable to discuss
      planned intercourse with their partner are offered psychosexual counseling and those still
      unable after three sessions are excluded. After one month patients on active Androgel are
      crossed over to placebo or vice versa. Patients self-rate sexual response after each
      intercourse using the Brief Index of Sexual Functioning for Women, and Arizona Sexual
      Experiences Scale (ASEX)-Female and are rated in interview at the end of each month of
      treatment using the Sexual Function Questionnaire (SFQ-V1). Our prn technique avoids the
      androgenizing side effects of continuous daily treatment.
    

Detailed description: 
      The role of androgens in addition to estrogens in female sexual health has been known for
      several decades [Davis and Tran 2001]. Recently methods of delivering testosterone other than
      by injection have made the use of androgens in treatment more available. Testosterone gel is
      absorbed well [Wang, et al. 2000] and has been shown to be effective in the treatment of
      hypogonadal men. Doses of 100 mg gel rubbed into skin increased testosterone levels to 30-40
      nmoles/L within 8-20 hours. Levels returned to baseline in this study within 1-2 days after
      cessation of chronic treatment although return to baseline after a single application was not
      studied.

      A recent study [Shifren, et al. 2000] has shown that transdermal continuous patch
      testosterone dose 150micro g or 300micro g vs. placebo daily during the 12 week study
      improved sexual health including desire, arousal, and orgasm frequency in women with
      surgically induced menopause after oophorectomy. Blood levels reached 3.0nmoles/L (5x
      baseline). Shrifren et al [2000] found no significant side effects with transdermal sustained
      testosterone treatment. Another study [Goldstat, et al. 2003] looked at transdermal
      testosterone given in gel, 10mg a day given for 12 weeks in a double-blind design for 31
      pre-menopausal women with a mean age of 40 years. The women entered the study presenting with
      low sexual desire. Testosterone treatment resulted in a significant improvement in
      psychological general well being and sexual self rating scale. No adverse effects were
      reported. Blood levels of testosterone increase about 2.5 times baseline to 2.6nmoles/L.

      Despite the absence of side effects reported in the small studies for relatively short
      periods of time done up till now in women with testosterone treatment, in the treatment of a
      long term disorder such as diminished sexual desire it is reasonable to be concerned with
      androgenizing side effects. Therefore, it would be extremely useful if testosterone could be
      given on a prn (as needed) basis before sexual intercourse. Recently Tuiten et al [2000]
      studied normal volunteer women with vaginal flow measures using photoplethysmography in
      addition to questionnaire data on sexual arousal after exposure to erotic movies with pre
      treatment of sublingual testosterone vs. placebo in a single dose sublingually of 0.5mg.
      Testosterone significantly enhanced vaginal blood flow response to the erotic movies and also
      the subjective sexual interest, desire and arousal to the movies. The psychophysiological
      effect was maximal 4 hours after the sublingual testosterone. Blood levels of 25nmol/L
      testosterone, 10 times baseline, were maximal 10 minutes after sublingual delivery and
      returned to baseline within 90 minutes.

      This study suggested that it may be possible to give transdermal testosterone 4-8 hours
      before intercourse in couples where the female partner suffers from low sexual interest or
      desire and /or difficulties in arousal, but where the couple is able to plan intercourse
      several hours in advance, which is possible in many couples, based on our clinical
      experience. In such couples androgen could be given on a prn basis and the possibility of
      side effects with long term use greatly reduced. We therefore propose such a study.

      Methods The study will be done as a double-blind randomized crossover study. Women entering
      the study will be pre-menopausal ages 21-40 with a diagnosis of hypo-active sexual disorder
      by an experienced sexologist diplomate of the Israel Society for Sexual Therapy. Patients
      will be accepted for study only if they can plan intercourse with their partner. Patients
      unable to do so will be offered 3 sessions of counseling about sexual communication and those
      still unable to plan intercourse after those 3 sessions will be excluded from the study.
      Patients accepted for the study after written informed consent will be given 8 packets of
      Testosteron Gel (Androgel) 50mg and shown how to spread the gel on the skin of the lower
      abdomen or upper shoulders. They will be told that they can use the gel up to twice weekly
      for one month. Patients will be instructed to spread the gel 4-8 hours before planned
      intercourse. The patients will be instructed to shower to remove any remaining gel after
      intercourse. After each intercourse they will fill out the Arizona Sexual Experiences Scale
      (ASEX)- Female [McGahuey, et al. 2000]. At baseline and at the end of the month they will be
      interviewed and rated for the month as a whole using the Sexual Function Questionnaire
      (SFQ-V1) [Quirk, et al. 2002]. They will then be given a package of 8 placebo gels with the
      same instruction and invited back after a month for another rating. Half of the women will be
      given placebo and then switched over to active androgen.

      We request permission to advertise on the internet and/or in newspapers for symptomatic
      volunteers for the study.

      Possible (but improbable due to the low doses and the prn use) side effects include: Increase
      in total cholesterol, high density lipoprotein cholesterol, low density lipoprotein
      cholesterol, triglycerides, fasting glucose and insulin; changes in blood counts and changes
      in liver function tests (serum aspartate aminotransferase, serum glutamyltransferase, serum
      albumin); hirsutism and acne, increase in facial hair or loss of hair; diarrhea, nipple and
      breast enlargement or breast pains; headache; elevation of blood pressure, changes in mood or
      aggressiveness. Slight local skin irritation or dryness of skin. However, as stated before,
      these side effects are unlikely using prn treatment.

      Dose: The recent study of Shifren et al [2000] used continuous transdermal patch and reached
      blood levels of 3.0nmoles/L (5x baseline) in post-menopausal women, with no side effects over
      12 weeks. Goldstat et al [2003] looked at transdermal gel 10mg, which is applied daily but
      washes off as the day wears on, for 12 weeks with no side effects in pre-menopausal women.
      They reached blood levels of 2.6nmoles/L (2.5x baseline). Tuiten et al [2000] used sublingual
      one time dose of 0.5mg, reaching a peak blood level of 25nmoles/L (10x baseline) at 10
      minutes which returned to baseline within 90 minutes. We propose to minimize side effects and
      maximize benefit by single application use of 50mg testosterone in transdermal gel to be used
      only up to twice a week. Blood levels from this dose from Wang et al [2000] should be about
      20nmoles/L. Since patients are instructed to shower after intercourse, these blood levels
      should exist for only 4-8 hours twice a week. Based on Tuiten et al [2000] a short pulse of
      testosterone up to these levels is necessary to achieve psychophysiological effects, and thus
      we request permission to use a dose of 50mg Androgel which would be too high if used daily
      chronically in women.
    

Intervention name(s): testosterone gel (Androgel)
Intervention type(s): Drug
Intervention MeSH terms: Testosterone
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double
Primary purpose: Treatment
Keywords: androgel; female sexuale dysfunction; controlled double-blind; testosterone