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Safety and Efficacy of a Testosterone Metered-Dose Transdermal Spray for Treating Decreased Sexual Satisfaction in Premenopausal Women: A Randomized Trial

Susan Davis, MD, PhD; Mary-Anne Papalia, MD; Robert J. Norman, MD; Sheila O'Neill, MD; Margaret Redelman, MD; Margaret Williamson, MD; Bronwyn G.A. Stuckey, MD; John Wlodarczyk, PhD; Karen Gard'ner, MSc; and Andrew Humberstone, PhD
[+] Article and Author Information

From Monash University, Alfred Hospital, Prahran, Victoria, Australia; Research Centre for Reproductive Health, University of Adelaide, School of Paediatrics and Reproductive Health, Adelaide, South Australia, Australia; Royal Hospital for Women, Randwick, New South Wales, Australia; Sydney Centre for Sexual and Relationship Therapy and John Wlodarczyk Consultancy Services, Sydney, New South Wales, Australia; Princess Alexandra Hospital, Brisbane, Queensland, Australia; Sir Charles Gairdner Hospital, University of Western Australia, Perth, Western Australia, Australia; and Acrux Limited, Melbourne, Victoria, Australia.


Australian Clinical Trials Registry number: ACTRN012605000481673.

Reproducible Research Statement:Study protocol, statistical code, and data set: Available to approved individuals through written agreements with research sponsor (Acrux Limited).

Potential Financial Conflicts of Interest:Employment: K. Gard'ner (Acrux Limited), A. Humberstone (Acrux Limited). Consultancies: S. Davis (Acrux Limited), J. Wlodarczyk (John Wlodarczyk Consultancy Services). Stock ownership or options (other than mutual funds): K. Gard'ner (Acrux Limited), A. Humberstone (Acrux Limited). Receipt of payment for manuscript preparation: J. Wlodarczyk (Acrux Limited).

Requests for Single Reprints: Susan Davis, MD, PhD, Women's Health Program, Department of Medicine, Monash University, Alfred Hospital, Commercial Road, Prahran, Victoria 3181, Australia; e-mail, susan.davis@med.monash.edu.au.

Current Author Addresses: Drs. Davis and Papalia: Women's Health Program, Department of Medicine, Monash University, Alfred Hospital, Commercial Road, Prahran, Victoria 3181, Australia.

Dr. Norman: Research Centre for Reproductive Health, University of Adelaide, School of Paediatrics and Reproductive Health, Level 6, Medical School North, Frome Road, Adelaide, South Australia 5005, Australia.

Dr. O'Neill: Royal Hospital for Women, Locked Bag 2000, Randwick, New South Wales 2031, Australia.

Dr. Redelman: 35 Spring Street, Bondi Junction, New South Wales 2022, Australia.

Dr. Williamson: Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Queensland, 4102, Australia.

Dr. Stuckey: Department of Medicine, Sir Charles Gairdner Hospital, Hospital Avenue Nedlands, Perth, Western Australia 6009, Australia.

Dr. Wlodarczyk: John Wlodarczyk Consultancy Services, 12 Mirral Crescent, New Lambton Heights, New South Wales 2305, Australia.

Ms. Gard'ner and Dr. Humberstone: Nucleus Network, 5th Floor, Burnet Tower, AMREP Precinct, 89 Commercial Road, Melbourne, Victoria 3004, Australia.

Author Contributions: Conception and design: S. Davis, M.A. Papalia, J. Wlodarczyk, A. Humberstone.

Analysis and interpretation of the data: S. Davis, R.J. Norman, J. Wlodarczyk, A. Humberstone.

Drafting of the article: S. Davis, J. Wlodarczyk, A. Humberstone.

Critical revision of the article for important intellectual content: S. Davis, R.J. Norman, S. O'Neill, M. Redelman, B.G.A. Stuckey, J. Wlodarczyk, K. Gard'ner, A. Humberstone.

Final approval of the article: S. Davis, R.J. Norman, M. Williamson, J. Wlodarczyk, K. Gard'ner.

Provision of study materials or patients: S. Davis, M.A. Papalia, R.J. Norman, S. O'Neill, B.G.A. Stuckey, A. Humberstone.

Statistical expertise: S. Davis, J. Wlodarczyk.

Obtaining of funding: S. Davis, A. Humberstone.

Administrative, technical, or logistic support: S. Davis, M.A. Papalia, K. Gard'ner, A. Humberstone.

Collection and assembly of data: S. Davis, S. O'Neill, M. Redelman, B.G.A. Stuckey, K. Gard'ner, A. Humberstone.


Ann Intern Med. 2008;148(8):569-577. doi:10.7326/0003-4819-148-8-200804150-00001
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Of the 480 women screened at 6 study sites, 168 were ineligible, primarily because their screening free testosterone level was greater than 3.8 pmol/L (>1.1 pg/mL) (Figure 1). Two hundred sixty-one women were randomly assigned and received study medication. At baseline, the treatment groups were well balanced in terms of race, age, body weight, and BMI (Table 1); 98.9% were white. The proportion of women using oral contraception at baseline varied across the treatment groups from 34% of the one 90-μL group to 19% of the two 90-μL group (Table 1).

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Figures

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Appendix Figure.
Sabbatsberg Sexual Self-Rating Scale.

Reproduced with permission from Acta Obstet Gynecol Scand Suppl. 1977;64:1-91.

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Figure 1.
Study flow diagram.

CIN 1 = cervical intraepithelial neoplasia (mild); ITT = intention-to-treat. *Dyspareunia. †More than 3 satisfactory sexual events per month at baseline.

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Figure 2.
Mean monthly number of satisfactory sexual events, by treatment group.

*Least-squares means from negative binomial model of mean satisfactory sexual events during treatment, adjusted for baseline satisfactory sexual event and site.

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Figure 3.
Risk ratios for monthly number of satisfactory sexual events versus placebo, by treatment group.

*Estimates from negative binomial model of mean sexual satisfactory events during treatment, adjusted for baseline sexual satisfactory events, site, age, and body mass index.

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Figure 4.
Free testosterone levels, by month and treatment group.

The testosterone levels at baseline exceed the levels used as an inclusion criterion (<3.8 pmol/L [<1 pg/mL]) because the authors used a different, more sensitive testosterone assay than that used to screen women for eligibility.

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References

Letters

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Comments

Submit a Comment
Should you replace Testosterone in Premenopausal females?
Posted on April 15, 2008
Hari KVS Kumar
Medwin Hospitals, Hyderabad, India
Conflict of Interest: None Declared

To The Editor Annals of Internal Medicine We have some comments regarding the study of testosterone replacement in Premenopausal Women by Dr Davis and colleagues (1).

1) The inclusion criteria specified for the study participants was early morning free testosterone level of 3.8 pmol/L or less. However, the mean free testosterone level at baseline as shown in Table 3 is more than 6 pmol/L in all the study groups. This appears contrary to the defined inclusion criteria.

2) Out of the 480 symptomatic, screened woman initially, 168 (35%) were ineligible because of free testosterone level above the cutoff value (3.8 pmol/L). This highlights the fact that androgen levels are not related to the sexual dysfunction in women as reported earlier (2).

3) Use of oral contraceptive pills result in suppression of free and total testosterone level and may contribute to decreased libido (3). In the study, the maximum benefit is seen in the group using daily 90 µL dose of transdermal testosterone. Baseline characteristics show that more number of patients of the same group was using oral contraceptives in relation to others (34% vs 2% in placebo).Could this be the contributing factor behind the observed benefit in this group?

References: 1) Davis S, Papalia MA, Norman RJ et al. Safety and efficacy of a Testosterone Metered-Dose Transdermal spray for treating Decreased Sexual Satisfaction in Premenopausal Women. Annals Intern Med 2008; 148: 569-577.

2) Santoro N, Torrens J, Crawford S et al. Correlates of circulating androgens in mid-life women: the study of women's health across the nation. J Clin Endocrinol Metab. 2005; 90 : 4836-4845.

3) Martin-Loeches M, Orti RM, Monfort M, Ortega E, Rius J. A comparative analysis of the modification of sexual desire of users of oral hormonal contraceptives and intrauterine contraceptive devices. Eur J Contracept Reprod Health Care 2003; 8: 129-134.

Conflict of Interest:

None declared

Effect of partner and environment on the sexual satisfaction in premenopausal women
Posted on April 26, 2008
Liu Hong
Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, China
Conflict of Interest: None Declared

To the editor:

We read with interest the article by Davis and colleagues [1]. They clearly show that a daily 90-ul dose of transdermal testosterone improves self-reported sexual satisfaction for premenopausal women with reduced libido and low serum-free testosterone levels.

The report evaluates many factors associated with the sexual satisfaction of women, such as age, premenopausal status, body mass index, sexual activity, depression, testosterone level, pregnancy, relationship problems, medication, and so on. However, they don't clearly show the factors affecting their partners. If the sexual activity is with a partner, clinicians will need to know the effect of partner on the sexual satisfaction in premenopausal women. The readers will strongly suggest a more detailed follow-up. For example, does the partner keep the same one? What about the health and relationship activity of the partner? Could the authors comment on the sexual satisfaction of a woman whose partner is always sitting in the office, as compared to one whose partner is keeping doing physical exercises?

The placebo effect is strong, indicating more factors should be considered in the evaluation. The environment also affects the sexual satisfaction in premenopausal women. It is assumed to be different for a novel place, as compared to the same bed. Could the authors comment on the potential effect of environment on the sexual satisfaction in premenopausal women?

References:

1. Davis S, Papalia MA, Norman RJ et al. Safety and efficacy of a testosterone metered-dose transdermal spray for treating decreased sexual satisfaction in premenopausal women: a randomized trial. Annals Intern Med 2008; 148: 569-577.

Conflict of Interest:

None declared

To the Editor Annals of Internal Medicine
Posted on June 9, 2008
Susan R Davis
Monash University
Conflict of Interest: None Declared

We wish to address readers' comments regarding our paper reporting the effects of transdermal testosterone for premenopausal women 1. As described in the on line appendix, the discrepancy between screening testosterone at baseline and the data presented, is due to the former being measured by a free testosterone kit assay to achieve quick turn- around at the time of recruitment and the latter being measured using a validated sensitive assay at Esoterix Inc., Calabasas Hills, California, USA. The primary reason for setting a screening blood testosterone level was to exclude women with high testosterone levels to minimize the likelihood of androgenisation. We agree that there is no level of testosterone that correlates with low self-reported sexual wellbeing2. Although the maximal benefit appeared to be in the women receiving one 90 -µL dose per day, when we looked at all of the data across the study rather than just the final month there was a much stronger signal and results were significant for both the 1x 90-µL dose and 2x 90 -µL dose . We are in agreement that sexual function is extremely complex. However to undertake a study that takes into account all the major influences on sexual wellbeing and satisfaction would be extremely ambitious. That we demonstrated an effect of testosterone therapy, albeit modest, over and above the inherent background "˜noise' in this study indicates that testosterone independently influences female sexual function.

1. Davis SR, Papalia MA, Norman RJ, et al. Safety and Efficacy of a Testosterone Metered-Dose Transdermal Spray for treatment of decreased sexual satisfaction in Premenopausal Women: A Placebo-Controlled Randomized, Dose-Ranging Study. . Annals Internal Med. 2008;148:569-577.

2. Davis SR, Davison SL, Donath S, Bell RJ. Circulating androgen levels and self-reported sexual function in women. JAMA. Jul 6 2005;294(1):91-96.

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