A Systematic Review of Intravaginal Testosterone for the Treatment of Vulvovaginal Atrophy

Robin J. Bell, MBBS, PhD, MPH, FAFPHM; Farwa Rizvi, MBBS, MPH; Rakabul M. Islam, MPH, PhD; Susan R. Davis, MBBS, PhD, FRACP

Disclosures

Menopause. 2018;25(6):704-709.

Conclusions

Although intravaginal therapy appears to be a promising treatment alternative for VVA, the available clinical trial data are insufficient to support this approach in clinical practice. Future double-blind, placebo-controlled clinical trials of intravaginal testosterone therapy need to include both objective clinical outcome measures and measurement of serum sex steroids by LCMS, and to be sufficiently powered, to establish both efficacy and safety.

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Funding/support
SRD is an National Health and Medical Research Council Principal Research Fellow (Grant no. 1041853).

Table 1. Designs of included studies
First author (y), design	Participants	Intervention	Treatment duration
Study of premenopausal women
Apperloo (2006), double-blind crossover RCT	n=10, 20–41 y, premenopausal women	2000 mcg T propionate or identical placebo	Single dose
Studies of postmenopausal women
Raghunandan (2010), three-arm RCT not blinded	n=75, 40–65 y, UGA and sexual dysfunction, 3 groups of 25	CEE 0.625mg cream; CEE 0.625mg plus T 0.5 g 2% cream daily for 2 wks then 2×/wk lubricant gel (control)	12 wks
Fernandes (2014, 2016), four-arm RCT not blinded	n=80, 40–70 y, vulvovaginal atrophy, 4 groups of 20	Polyacrylic acid cream; CEE cream 0.625 mg/dose; testosterone cream 300 μg/dose; lubricant gel 3× per wk	12 wks
Studies of postmenopausal women with breast cancer taking an aromatase inhibitor
Witherby (2011), two-arm CT not blinded	n=20, 45–69 y, vulvovaginal atrophy, 2 groups of 10	150 or 300 μg T propionate in cream base applied daily	4 wks
Dahir (2014), single-group	n =13, 50–69 y, symptoms of sexual dysfunction	300 μg T cream base applied daily	4 wks
Melisko (2017); two-arm RCT not blinded	n=76, 37–78 y, vaginal dryness, dyspareunia, or decreased libido, 40 estradiol ring, 36 T cream	Intravaginal ring releasing 7.5 μg estradiol/24 h; 0.5 g of a 1% T cream (5000 mcg) daily for 2 wks, then 3× weekly	12 wks

CEE, conjugated equine estrogen; RCT, randomized controlled trial; T, testosterone; UGA, urogenital atrophy.

Table 2. Summary of treatment effects of intravaginal testosterone in women without breast cancer
Outcome parameter	First author (y)	Treatment	Baseline	12 wks
Vaginal maturation index	Raghunandan (2010)	CEE 0.625mg cream, n =25	46.10±5.26	52.98±5.84
		CEE 0.625mg+T 0.5 g 2% cream, n=25	45.74±6.16	53.2±5.68
		Lubricant gel, n =25	46.78±5.69	47.98±5 77
	Fernandes (2016)	Polyacrylic acid cream, n =19	No change vs lubricant
		T 300 μg cream, n =19	No change vs lubricant
		CEE 0.625mg cream, n =18	Improved vs lubricant (P<0.001)
pH ≤5 (%)	Fernandes (2016)	Polyacrylic acid cream, n =19	30%	32%
		T 300 μg, n=19	5%	68%
		CEE 0.625mg cream, n =18	10%	94%
Vaginal health score	Raghunandan (2010)	CEE 0.625mg cream, n=25	13.12±2.52	18.96±2.32
		CEE 0.625mg+T 0.5 g 2% cream, n=25	13.24±1.61	20.12±1.72
		Lubricant gel, n =25	13.32±2.32	15.84±2.59
Vaginal health score ≥15 (%)	Fernandes (2016)	Polyacrylic acid cream, n =19	45%	58%
		T 300 μg cream, n =20	25%	89%
		CEE 0.625mg cream, n =20	20%	100%
		Lubricant gel, n =20	45%	45%
Mod/large amount of lactobacilli (% of women)	Fernandes (2016)	Polyacrilic acid cream, n =20	12%	11%
		T 300 μg cream, n =20	11%	32%
		CEE 0.625mg cream, n =20	15%	33%
		Lubricant gel, n =20	21%	5%
Sexuality score	Raghunandan (2010)	CEE 0.625mg cream, n =25	4.24±1.51	6.04±1.81
		CEE 0.625mg+T 0.5 g 2% cream, n=25	4.32±1.41	10.68±2.69
		Lubricant gel, n =25	4.92±1.53	5.84±1.37
FSFI Lubrication domain	Fernandes (2014)	Polyacrilic acid cream, n =19	2.9±2.2	4.4±2.4
		T 300 μg cream, n=19	1.6±1.6	3.9±2.7
		CEE 0.625mg cream, n =18	1.5±2.0	2.8±2.9
		Lubricant gel, n =20	1.9±1.6	2.88±2.2
FSFI pain domain	Fernandes (2014)	Polyacrilic acid cream, n =19	2.6±2.1	4.3±2.6
		T 300 μg cream, n=19	1.5±1.6	4.3±2.6
		CEE 0.625mg cream, n =18	1.3±2.0	3.0±2.9
		Lubricant gel, n =20	2.1±2.1	3.1±2.4
Estradiol, pg/mL	Raghunandan (2010)	CEE 0.625mg cream, n =25	27.62±15.5	45.89±18.98
		CEE 0.625mg+T 0.5 g 2% cream, n=25	34.39±21.85	58.16±29.09
		Lubricant gel, n =25	25.80±9.53	27.46±6.9
Change in estradiol from baseline (n)	Fernandes (2016)	Polyacrilic acid cream, n =20		0/19
		T 300 μg cream, n =20		0/19
		CEE 0.625mg cream, n =20		3/18
		Lubricant gel, n =20		0/20
Free T, pg/mL	Raghunandan (2010)	CEE 0.625mg cream	0.684±0.34	0.685±0.34
		CEE 0.625mg +T 0.5 g 2% cream, n =25	0.58±0.38	1.49±1.22
		Lubricant gel, n =25	0.68±0.36	0.61±0.33
			Baseline	Peak level
Total T, nmol/L	Apperloo (2006)	T, n=10	2.76	7.71
Free T, nmol/L		Placebo, n =10	2.71	2.99
		T, n=10	0.03	0.12
		Placebo, n =10	0.03	0.04
Estradiol, nmol/L		T, n=10	0.24	0.65
Estradiol, nmol/L		Placebo, n =10	0.29	0.64

Raghunandan et al—Vaginal maturation index: the change in both CEE only and CEE+T groups was greater than in the lubricant group (P<0.01). Vaginal health score: the change in both the CEE only and CEE+T groups was greater than in the lubricant group (P<0.01). Sexuality score: the change in all groups was significant, but the change in the CEE+T group was greater than in either the CEE only or lubricant groups (P<0.01).
Estradiol: there was a change in both the CEE only and CEE+T groups (P<0.01). Free T: there was an increase in the CEE +T group only (P<0.01). Fernandes et al—Vaginal maturation index: an improvement in CEE versus lubricant only (P<0.001). pH ≤5 (%): the change in the CEE and T groups was significantly different from the lubricant group (P<0.02). Vaginal health score ≥15 (%): the change in the CEE and T groups was significantly different from the lubricant group (P<0.01). Mod/large amount of lactobacilli (% of women): the change in the CEE and T groups was significant at P <0.05. FSFI lubrication domain: there was a significant change seen in all groups (P<0.05). The scores at 12 weeks in the T and PA groups were different from the lubricant group (P<0.05), but there was no adjustment for baseline differences. FSFI pain domain: there was a significant change seen in T, E, and PA groups (P<0.03). The scores at 12 weeks in the T and PA groups were different from the lubricant group (P<0.01), but there was no adjustment for baseline differences.
Apperloo et al—Total T: the peak mean level in the T group was different from placebo (P<0.005). Free T: the peak mean level in the T group was different from placebo (P<0.005).
CEE, conjugated equine estrogens; FSFI, Female Sexual Function Index; PA, polyacrylic acid; T, testosterone.

Table 3. Summary of treatment effects of intravaginal testosterone in women taking an aromatase inhibitor
Outcome parameter	First author (y)	Treatment	Baseline	28 d (Dahir and Witherby); (Melisko 12 wks)
Vaginal maturation index (% mature)	Witherby (2011)	150 μg T cream, n=10	20%	40%; 0/10 >50%
Vaginal maturation index (% mature)	Witherby (2011)	300 μg T cream, n=10	0%	60%; 9/10 >50%
pH (mean)	Witherby (2011)	150 μg T cream, n=10	5.4	5.5
pH (mean)	Witherby (2011)	300 μg T cream, n=10	5.1	4.6
Total symptom score (mean)	Witherby (2011)	150 μg T cream, n=10	6.2±1.48	Change −0.8
Total symptom score (mean)	Witherby (2011)	300 μg T cream, n=10	5.5±2.27	Change −1.3
Total FSFI score	Dahir (2014)	300 μg T cream, n=13	8.69±3.80	18.78±7.05
Sexual interest^a	Melisko (2017)	Estradiol vaginal ring, n =35	1.2±0.9	0.9±0.7
Sexual interest^a	Melisko (2017)	5,000 mcg T cream	1.4±0.8	1.0±0.6
Dysfunction^a	Melisko (2017)	Estradiol vaginal ring, n =35	2.9±1.1	2.0±1.1
Dysfunction^a	Melisko (2017)	5000 mcg T cream, n =33	2.9±0.8	1.9±1.1
Satisfaction	Melisko (2017)	Estradiol vaginal ring, n =35	2.5±1.6	4.0±1.5
Satisfaction	Melisko (2017)	5,000 mcg T cream, n =33	3.2±1.6	4.0±1.5
Estradiol, pg/mL (median)	Witherby (2011)	150 mcg T cream, n =10	<5 pg/mL	<5 pg/mL in 18/20 women
Estradiol, pg/mL (median)	Witherby (2011)	300 mcg T cream, n =10	<5 pg/mL
Estradiol pg/ml (mean)	Melisko (2017)	Estradiol vaginal ring, n =35	26.8 (95% CI 14.5–39.1)	Elevated in 2/35 women
Estradiol pg/ml (mean)	Melisko (2017)	5000 mcg T cream, n =33	9.0 (95% CI 5.1–12.9)	Elevated in 1/33 women
Total T ng/dL	Witherby (2011)	150 mcg T cream, n=10	<21 ng/dL	<42 ng/dL in 19/20
Total T ng/dL	Witherby (2011)	300 mcg T cream, n =10	<21 ng/dL
Total T ng/dL (mean)	Melisko (2017)	5000 mcg T cream, n =33	33 ng/dL	171 ng/dL

Witherby et al—Vaginal maturation index (% mature): the change was significantly greater in the 300 versus the 150-mcg groups (P=0.005). pH (mean): the reduction in pH in the 300-mcg group was greater than that seen in the 150-mcg group, although the difference did not achieve statistical significance (P=0.09). Total symptom score: the change in scores in the two groups was not different (P=0.37).
Melisko et al—Sexual interest: there was a significant change in both groups (P=0.02). Dysfunction: there was significant change in both groups (P<0.001). Satisfaction: only the change in the E group was significant (P=0.004).
Dahir and Travers-Gustafson—The change in the total FSFI was significant (P<0.001).
CEE, conjugated equine estrogens; FSFI, Female Sexual Function Index; T, testosterone.
^aLower score is better.

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