Beneficial effects of testosterone therapy on menopause symptoms and quality of life

Testosterone levels in women decline steeply with age during the reproductive years; by the time women reach their late 40, their blood testosterone levels are approximately half what they were in their 20s.[1, 2] 
 
Symptoms of androgen deficiency, including a reduced sense of well-being, dysphoric mood (sadness, depression, anxiety, and irritability), fatigue, decreased libido, hot flashes, bone loss, decreased muscle mass and strength, changes in cognition and memory, and insomnia may occur prior to cessation of menses.[3] Pre-menopausal women frequently report "menopausal symptoms", most of which are not related to estradiol levels.[4]
 
In the past, post-menopausal women with menopausal symptoms have been treated with estrogen, and more recently with bio-identical estrogen. However, new research shows that menopausal symptoms can be treated safely and effectively with testosterone.[5] It has even been shown that testosterone therapy may be more effective than estrogen therapy for treating menopausal symptoms and improving wellbeing.[6] This is great news for women with a family history of breast or emdometrial cancer, who fear taking estrogen.
 
A notable study "Beneficial effects of testosterone therapy in women measured by the validated Menopause Rating Scale" investigated the effectiveness of a 3 month continuous testosterone therapy, delivered by subcutaneous implant, on the relief of somatic, psychological and urogenital symptoms in both pre- and post-menopausal women.[5] This study also investigated long-term efficacy and safety in a sub-group of women who were treated for 2-3 years.
 
STUDY DESIGN:
300 pre- and post-menopausal women with symptoms of androgen deficiency, were asked to self-administer the 11-item Menopause Rating Scale at baseline and 3 months after their first insertion of a subcutaneous testosterone implant. 
 
The mean age of the women was 52 years. 36.0% were pre-menopausal, 35.3% reported non-surgical, spontaneous menopause (last menstrual cycle greater than 12 months), 19.0% were surgical-menopausal (bilateral oophorectomy with or without hysterectomy), and 9.6% had a hysterectomy with one or both ovaries intact.
 
Baseline hormone measurements, menopausal status and BMI were assessed to determine correlation with symptoms and clinical outcome.
 
TESTOSTERONE THERAPY:
The mean dose of subcutaneous testosterone implanted at the first visit was 121 mg. The range was between 75mg and 160mg. The initial testosterone dose was partially based on weight with a higher dose being used in more obese women. The study authors report that an initial testosterone dose in mg of twice a patient's weight in kg has been successfully used in their clinical practice.
 
MAIN OUTCOME MEASUREMENTS:
Changes related to therapy were determined. Total Menopause Rating Scale scores as well as psychological, somatic and urogenital sub-scale scores were compared prior to therapy and following testosterone pellet implant therapy.
 
The Menopause Rating Scale is shown below; it comprises 11 symptom categories with severity scale. Details on this open access MRS may be found at www.menopause-rating-scale.info
 

RESULTS: [5, 7]

At baseline before start of testosterone therapy, 87% of the women had free testosterone levels in the lower third of the reference range, 11% of the women had free testosterone in the middle third, and only 2% had free testosterone in the upper third. There was no significant difference in total and free testosterone levels between pre- and post-menopausal patients.
 
Testosterone levels achieved 4 weeks after testosterone pellet implantation
4 weeks after subcutaneous testosterone implantation the mean total testosterone level was 300 ng/dL (range 101–633 ng/dL). See commentary below.
 
Testosterone levels when patient’s symptoms returned 
153 women had testosterone levels measured when their symptoms of androgen deficiency returned, prior to pellet re-implantation (see commentary below):
)
* The mean testosterone level was 185 ng/dl (range 47–461 ng/dL).
 
* The mean free testosterone level was 19 pg/mL (range 1.1–74.8 pg/mL).
 
Symptoms 
Pre-menopausal and post-menopausal women reported similar hormone deficiency symptoms. Both groups demonstrated similar improvement in total score, as well as psychological, somatic and urogenital subscale scores with testosterone therapy. Better effect was noted in women with more severe complaints. Higher doses of testosterone correlated with greater improvement in symptoms.
 
In most individual Menopause Rating Scale symptom categories, higher doses of testosterone correlated with greater clinical improvement. In addition, after adjusting for dosage based on total body weight, greater improvement in hot flashes, sweating (1), heart discomfort (2), sleep problems (3), depressive mood (4), physical and mental exhaustion (7), sexual problems (8) and joint and muscular discomfort (11) correlated with higher testosterone dose. 
 
In post-menopausal patients, higher testosterone doses correlated with greater improvement in the Menopause Rating Scale total score and all three sub-scores: somatic, psychological and urogenital.
 
In pre-menopausal patients, higher testosterone doses correlated with greater improvement in Menopause Rating Scale total score and urogenital sub-score. 
 
Over 90% of patients reported less irritability (feeling nervous, inner tension, feeling aggressive) on testosterone therapy. This refutes the common concern regarding testosterone's potential to increase aggression and irritability.
 
Side effects
Known androgenic side effects include a possible increase in facial hair and mild acne. Some women reported a slight increase in facial hair, but no patient discontinued therapy for that reason. Only three patients discontinued testosterone therapy due to "lack of effect" (which might have been an indication that the dose was too low). 
 
85.7% of women reported a mild to moderate increase in facial hair, 11.2% reported a moderate increase in acne, half of who had a prior history of adult acne. Surprisingly, 50% of women reported skin improvement on therapy (e.g., moister skin, softer skin and fewer wrinkles).
 
Long-term safety
A group of 285 patients continued to be treated for over one year (mean 28.1 +/- 10.4 months) with testosterone implants. Mean testosterone implant dose was 133.3 mg, range 55–240 mg. Dosing was based on weight and adjusted based on clinical response to therapy. Mean interval of insertion was 13.8 + 3.8 weeks. No adverse effects were seen on blood sugar, insulin resistance, diabetes, or lipid profiles in follow-up of women for over 2 years.
 
CONCLUSION
This study shows for the first time that adequate doses of continuous testosterone alone, delivered by subcutaneous implant, was effective therapy for physical, psychological and urogenital symptoms in both pre- and post-menopausal women. This suggests that testosterone has a physiologic function for women's health. Along with a growing body of research data, this study underscores that testosterone administration improves quality of life in both pre- and postmenopausal women.
 

Commentary

This study demonstrates several important and surprising findings. 
 
Testosterone levels for clinical symptomatic improvement
Higher doses of testosterone correlated with greater improvement in symptoms. The mean total testosterone level achieved 4 weeks after first pellet insertion was 300 ng/dL (range 101–633 ng/dL). This is 4-8 times the upper limit of the normal female total testosterone reference range, which is around 20–75 ng/dL.[2, 8] 
 
When symptoms returned, the mean total testosterone was 184 ng/dL (range 47–461 ng/dL). This is still  over 2-6 times the upper limit of the female total testosterone reference range.
 
When symptoms returned, the mean free testosterone level was 19 pg/mL (range 1.1–74.8 pg/mL). The average free testosterone prior to pellet re-implantation was still over the upper limit of the normal female free testosterone reference range, which is around 0.6–17 pg/mL.[2, 8] 
 
This indicates that the female testosterone reference is not optimal and should not be used to guide testosterone treatment. As shown in this study, a woman can greatly benefit from testosterone therapy even if her testosterone levels are in the high end of the reference range. This also explains that women who have tried testosterone therapy and did not experience any therapeutic effect most likely did not get a testosterone dose high enough to bring their testosterone levels into the therapeutic range, which for many women exceeds the "normal" reference range threshold. This is supported by another study showing that 300 microgram of testosterone per day (delivered by patch) for 24 weeks significantly increased frequency of satisfying sexual episodes compared to the placebo group, but no change was seen in the group receiving 150 microgram per day compared to placebo.[9]
 
Androgenic side effects 
In this study, while some women experienced acne and minor facial hair growth, surprisingly, 50% of women reported skin improvements while on testosterone therapy; moister skin, softer skin and fewer wrinkles. It is well known that testosterone side effects are dose-dependent.[10] Thus, it is important to find the optimal point for each individual woman.
 
Safety aspects
This study found no adverse effects on blood sugar, insulin resistance, diabetes, or lipid profiles in women who continued to receive treatment for over 2 years. This is in line with previous research showing that testosterone supplementation in both pre- and post-menopausal women is safe, even in higher doses.[11, 12] On study in women aged 22-44 yr who were treated with testosterone for severe pre-menstrual syndrome or loss of libido found that elevating testosterone levels from 37 ng/dL to 205 ng/dL did not affect the menstrual cycle.[13] 
 
Testosterone is increasingly used as part of postmenopausal HRT (hormone replacement therapy) regimens.[14] However, the study reported here clearly demonstrates that mono-therapy with testosterone alone is highly effective, and a previous study has shown that testosterone therapy may be more effective than estrogen therapy for treating menopausal symptoms and improving wellbeing.[6] Because estrogen may increase risk of breast cancer [15], especially in women who have a family history of breast cancer, many women who suffer are not taking conventional estrogen HRT. For these women, testosterone supplementation is the ideal treatment.
 
Regarding breast cancer, new research is showing that testosterone therapy in women may also protect against breast cancer. I will cover this in an upcoming article. Stay tuned!
 
 
References:

1.            Zumoff, B., et al., Twenty-four-hour mean plasma testosterone concentration declines with age in normal premenopausal women. J Clin Endocrinol Metab, 1995. 80(4): p. 1429-30.

2.            Davison, S.L., et al., Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab, 2005. 90(7): p. 3847-53.

3.            Lobo, R.A., Androgens in postmenopausal women: production, possible role, and replacement options. Obstet Gynecol Surv, 2001. 56(6): p. 361-76.

4.            Dennerstein, L., et al., A prospective population-based study of menopausal symptoms. Obstet Gynecol, 2000. 96(3): p. 351-8.

5.            Glaser, R., A.E. York, and C. Dimitrakakis, Beneficial effects of testosterone therapy in women measured by the validated Menopause Rating Scale (MRS). Maturitas, 2011. 68(4): p. 355-61.

6.            Sherwin, B.B. and M.M. Gelfand, Differential symptom response to parenteral estrogen and/or androgen administration in the surgical menopause. Am J Obstet Gynecol, 1985. 151(2): p. 153-60.

7.            Glaser, R., S. Kalantaridou, and C. Dimitrakakis, Testosterone implants in women: pharmacological dosing for a physiologic effect. Maturitas, 2013. 74(2): p. 179-84.

8.            Burger, H.G., et al., A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition. J Clin Endocrinol Metab, 2000. 85(8): p. 2832-8.

9.            Davis, S.R., et al., Testosterone for low libido in postmenopausal women not taking estrogen. N Engl J Med, 2008. 359(19): p. 2005-17.

10.          Koyama, Y., et al., Reconstruction of bone fenestration on mandiblar by the guided bone regeneration methods with beta-TCP/PLGC membranes. J Nanosci Nanotechnol, 2007. 7(3): p. 859-61.

11.          Braunstein, G.D., Management of female sexual dysfunction in postmenopausal women by testosterone administration: safety issues and controversies. J Sex Med, 2007. 4(4 Pt 1): p. 859-66.

12.          Traish, A.M. and L.J. Gooren, Safety of physiological testosterone therapy in women: lessons from female-to-male transsexuals (FMT) treated with pharmacological testosterone therapy. J Sex Med, 2010. 7(11): p. 3758-64.

13.          Dewis, P., et al., Does testosterone affect the normal menstrual cycle? Clin Endocrinol (Oxf), 1986. 24(5): p. 515-21.

14.          Maclaran, K. and N. Panay, The safety of postmenopausal testosterone therapy. Womens Health (Lond Engl), 2012. 8(3): p. 263-75.

15.          Travis, R.C. and T.J. Key, Oestrogen exposure and breast cancer risk. Breast Cancer Res, 2003. 5(5): p. 239-47.

Last modified on Saturday, 26 July 2014 22:44
Monica Mollica

Medical Writer & Nutritionist

MSc in Nutrition

University of Stockholm & Karolinska Institute, Sweden 

   Baylor University, TX, USA

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