16 June, 2014:

The steady-state pharmacokinetics of two doses of a transdermal testosterone cream: 5 and 10 mg was investigated after daily application for 21 days by Fooladi and colleagues in a two-way, cross-over study conducted for 6 weeks [1]. Seven healthy postmenopausal women (mean age 59.3 years) were randomly allocated to 5 or 10 mg of transdermal testosterone cream applied daily to the upper arm. Serum total testosterone (TT), free testosterone (fT), sex hormone binding globulin, and metabolite concentrations were measured. Baseline-corrected and uncorrected serum TT and fT pharmacokinetic parameters (AUC0-24, Cavg, Cmax, and Tmax) were calculated using a standard model-independent approach. After the single-dose application of 5 mg of the transdermal testosterone cream on day 22, the median uncorrected TT Cavg was found to be 0.54 ng/ml (range 0.43–1.31 ng/ml), and the median uncorrected fT Cavg was found to be 4.14 pg/ml (range 2.41–9.72 pg/ml). Doubling of the dose only resulted in a 30% increase in baseline-corrected TT Cavg (0.52 vs. 0.69 ng/ml for 5 and 10 mg, respectively) and a 31% increase in baseline-corrected fT Cavg (4.75 vs. 6.24 pg/ml for 5 and 10 mg, respectively). Neither dose resulted in any meaningful variation in dihydrotestosterone, estrone, estradiol, or sex hormone binding globulin across the post-dose sampling period. It was concluded that the 5-mg dose of transdermal testosterone cream restores TT and fT levels to levels above and within the reference range, respectively, for premenopausal women. 

Comment

Treatment of women who suffer from sexual dysfunction with testosterone leads to improved libido and other relevant sexual parameters. Beneficial effects in other areas such as IVF, cardiovascular disease, the musculoskeletal system, vaginal health and cognition are possible or even likely. The metabolic syndrome appears non-aggravated while the promotion of hormone-dependent breast cancer remains undecided [2]. In fact, one wonders why not give testosterone to all postmenopausal women, sexual dysfunction or not. Transdermal or intravaginal routes of administration have been recently preferred to the oral route because of the obvious advantages of bypassing the liver. The introduction of new formulations of non-oral testosterone has been very slow, allowing the widespread off-label use of preparations for hypogonadism in men, while in the meantime 'female-dosed' formulations have great difficulty to obtain approval [2]. This uphill battle is made difficult because of several issues such as: endpoint definition (subjective), different laboratory techniques (various assays and statistics, making inter-trial results hard to compare), clinical trial-related matters such as small sample sizes and the concomitant use of estrogens [3,4], and finally the need to monitor serum testosterone levels during treatment, which can be a costly affair, let alone a bother. Most of all, however, there is the lack of long-term safety data, a prime requirement to any regulator. And this against the background of the Nurses' Health Study on the increase of breast cancer incidence [5], and the general hormonophobia that still rules 12 years after the first WHI publication.

Although the circulating levels of testosterone do not seem to correlate with tissue effects [2], these levels are nevertheless keenly monitored for safety reasons. In this context it is always noted whether the concentrations exceed the 'physiological' level. Endogenous testosterone decreases with age in men and women and, since a fairly large population study, we have age-decade-specific data that provide us with the levels for postmenopausal women [6]. I could not find data on possible differences in testosterone levels in postmenopausal women with or without sexual dysfunction. Such a difference might help define a deficiency. Clinically effective doses of transdermal or intravaginal testosterone are seen to exceed the 'physiological' levels but what this means is unsure. The present, very small study tested the steady-state levels of total testosterone, free testosterone, sex hormone binding globulin and other hormonal parameters in an elegant design. Two doses were compared, 5 and 10 mg cream (the one used in practice) and the double dose led to a 30% increase, probably unexpectedly, although a previous study with 150 and 300 µg testosterone suggested a similar outcome, but this time with concomitant estrogen use. In the regulator’s mind, this might stir up the question of why not use 5 mg, knowing that this dose stays within physiological range (but might not be effective?). Or else, testosterone levels might not be overly useful as secondary treatment target.

Frits Riphagen

Brussels, Belgium

References

1. Fooladi E, Reuter SE, Bell RJ, et al. Pharmacokinetics of a transdermal testosterone cream in healthy postmenopausal women. Menopause 2014, May 19. Epub ahead of print http://www.ncbi.nlm.nih.gov/pubmed/24845394

2. Davis SR. Androgen therapy in women, beyond libido. Climacteric 2013;16(Suppl l):18-24. http://www.ncbi.nlm.nih.gov/pubmed/23647457

3. El Hage G, Eden JA, Manga RZ. A double-blind, randomized, placebo-controlled trial of the effect of testosterone cream on the sexual motivation of menopausal hysterectomized women with hypoactive sexual desire disorder. Climacteric 2007;10:335-43 http://www.ncbi.nlm.nih.gov/pubmed/17653960

4. Shifren JL, Braunstein GD, Simon JA, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 2000;343:682-8. http://www.ncbi.nlm.nih.gov/pubmed/10974131

5. Tamimi RM, Hankinson SE, Chen WY, et al. Combined estrogen and testosterone use and risk of breast cancer in postmenopausal women. Arch Intern Med 2006;166:1483-9. http://www.ncbi.nlm.nih.gov/pubmed/16864758

6. Haring R, Hannemann A, Ulrich J, et al. Age-specific reference ranges for serum testosterone and androstenedione concentration in women measured by liquid chromatography-tandem mass spectrometry. J Clin Endocrinol Metab 2012;97;408-15. http://www.ncbi.nlm.nih.gov/pubmed/22162468