Women’s Health Update

by Tori Hudson, ND

Testosterone Therapy in Postmenopausal Women

The use of testosterone therapy in the clinical management of postmenopausal women is an area of menopause with insufficient data regarding safety and efficacy, and inadequate ability to utilize accurate laboratory assays to make decisions. Testosterone therapy has been studied for several endpoints in women, but most of the evidence is from clinical trials that relates to management of sexual function, especially sexual desire.

The majority of women treated with estrogen replacement have resolution of their menopausal symptoms. For those who do not, and especially for those women complaining of a loss of libido, estrogen with testosterone may be beneficial.

One study of early postmenopausal women (both physiological menopause and surgical) who were switched from estrogen alone to estrogen/testosterone therapy found overall symptom relief was superior to estrogen-only therapy. Sexual drive and satisfaction both increased.¹

A double-blind study of women dissatisfied with their hormone replacement therapy (HRT) regimen showed that sexual desire, satisfaction, and frequency of sexual activity were increased when they used the estrogen/testosterone combination.² Other studies have shown that the combination of 1.25 mg of esterified estrogen and 2.5 mg of methyltestosterone given daily for two years after surgical menopause significantly reduce the intensity of hot flashes and vaginal dryness in 81% and 73% of women, respectively.³

In the largest testosterone trial to date, in postmenopausal women, a randomized clinical trial of 814 women with hypoactive sexual desire revealed that a 300 μg testosterone patch improved the frequency of satisfying sexual episodes and decreased distress in postmenopausal women.⁴ In this study, the women were not treated with estrogen or progesterone. Three excess cases of breast cancer were detected but not statistically significant in the study. The most frequent adverse event was unwanted hair growth. Upon examination of the Women’s Health Initiative (WHI) data, there was a slight but not statistically significant increase in invasive breast cancer at the 3-year visit when testosterone was used with conjugated equine estrogens (CEE).

Another group examined breast cancer and testosterone results and calculated the risk of breast cancer in women using estrogen plus testosterone to be 2.5 times greater than that in women not using hormones.

Women’s circulating testosterone levels reflect both production and clearance rates, and only 1%

t Ttound to either sex hormone binding globulin (SHBG) or albumin. The ovaries are responsible for approximately one-third of the circulating testosterone, and the other two-thirds comes from peripheral conversion of precursors from the ovary and the adrenal gland such that, in total, 50% of the circulating testosterone directly or indirectly comes from the ovaries.

While the adrenal glands do not produce testosterone, a large percentage of the circulating testosterone is derived from the adrenal gland precursors. Bilateral oophorectomy, even if it is done after menopause, results in significant decreases in testosterone levels. There are many variables that affect free testosterone concentrations. Women who are on oral estrogen therapy or systemic glucocorticoid therapy, HIV-positive women with significant weight loss, and women with hypopituitarism/hyperthyroidism/chronic illness (anorexia nervosa, clinical depression, advanced cancer, and burn trauma) have lower levels of endogenous free testosterone. Obesity and hypothyroidism can increase free testosterone levels. Women of different ages have vastly different testosterone levels. One cross-sectional study of healthy premenopausal women aged 21 to 51 found that women’s levels declined significantly with aged such that women in their 40s had approximately half the circulating testosterone than a woman in her early 20s.⁵ A Norwegian study reported a 15% decrease in testosterone postmenopause.⁶ However, in the Melbourne Women’s Midlife Health Project, a study of women aged 45 to 55, average testosterone levels did not vary in those few years before or after menopause.⁷ In another Australian study of women aged 18 to 75 years, total and free testosterone levels did significantly decline with age, starting early in their reproductive years.⁸

Although not all studies agree, in general, the postmenopausal ovary continues to produce some testosterone, but postmenopausal women have lower testosterone levels than premenopausal women, and the decline is gradual and results from both normal aging ovarian and adrenal function. This is likely a function of aging rather than specifically menopause.

Therapeutic Use of Testosterone in Postmenopausal Women

There is no current government approved testosterone product for use in treating symptoms of sexual dysfunction in women Past prescription formulations that have been available but are no longer available from pharmaceutical companies have included something called Estratest. Two generic prescriptions are currently available to women, which contain either 1.25 or 0.625 esterified estrogens, combined with either 2.5 or 1.25 mg of methyltestosterone, respectively. At present, other testosterone options for women include methyltestosterone or bioidentical testosterone, and these can only be obtained from a compounding pharmacy either alone or in combination with other hormones. Testosterone prescriptions in doses for men are available in the form of topical applications of Testim or Androgel or the patches: Androderm and Testoderm, Striant, a buccal delivery, or various injections.

It is estimated that postmenopausal women have approximately 1-10th the amount of free testosterone as men. A dose of oral 0.625 mg of methyl testosterone is approximately equivalent to 4 to 6mg of bioidentical oral testosterone and is generally formulated alone or together with the biestrogen or triestrogen formulation and then with progesterone, especially if the patient still has a uterus. Compounded testosterone is available in capsules, sublingual troches, cream, or gel. For local arousal/orgasmic response, testosterone cream can be applied to the genital region ½ to 1 gm right before sex and up to twice per week (in order to avoid clitoral enlargement), and commonly in doses 1 mg to 4 mg/gm.

Common prescriptions for systemic application of creams are from 1 mg to 10 mg per gram of cream. The cream is applied to the palms/inner upper arms once per day. The North American Menopause Society (NAMS) concluded, “Postmenopausal women with decreased sexual desire who have no cause other than being postmenopausal, may be candidates for testosterone treatment.” Other causes of low libido should be ruled out and laboratory testing of testosterone levels should be used to monitor for supraphysiologic levels before and during therapy, although not used to diagnose testosterone insufficiency. Customary serum testing and even salivary testing are problematic in terms of accuracy/reliability. The simplest and most reliable method of testing is testosterone is to order a free androgen index, which is calculated from total testosterone and SHBG. Another method is the Sodergard equation for free testosterone, which requires total testosterone, SHBG, and albumin.

average reaction time may also occur in women on estrogen-testosterone vs. estrogen alone.¹⁴

The NAMS asserts that testosterone therapy is contraindicated in women with breast or uterine cancer, or cardiovascular or liver disease. Before initiating testosterone treatment, baseline profiles for serum lipids and liver function should be acquired and then retested at 3 months and then annually if stable. Testosterone should be given at the lowest dose for the shortest time that meets treatment objectives (North American Menopause Society 2010).

Counseling for the potential risks and benefits of any testosterone recommendation should be provided before starting therapy. The potential adverse effects include some common side effects such as acne, excess facial hair, and anger/aggression. Higher levels of testosterone therapy could cause lowering of the voice, clitoral enlargement, excess body hair, edema, erythrocytosis, and liver dysfunction. For more information on the evidence-based role of exogenous testosterone in postmenopausal women, a full report on the position statement of the NAMS is available.¹⁸

Notes

1. Dobay B, Balos R, Willard N. Improved menopausal symptom relief with estrogen androgen therapy. Presented at: Annual Conference of the North American Menopause Society. Chicago, IL; September 1996.

2. Sarrel P, Dobay B, Wiita B. Sexual behavior and neuroendocrine responses to estrogen and estrogen-androgen in postmenopausal women dissatisfied with estrogen-only therapy. J Reprod Med. 1998;43(10):847–856.

3. Watts N, Notelovitz M, Timmons M, et al. Comparison of oral estrogens and estrogens plus androgen on bone mineral density, menopausal symptoms, andlipid-lipoprotein profiles in surgical menopause. Obstet Gynecol. 1995;85:529–537.

4. Davis SR, Moreau M, Kroll R, et al. APHRODITE Study Team. Testosterone for low libido in postmenopausal women not taking estrogen. NEJM. 2008;359(19):2005–2017

5. Zumoff B, Strain G, Miller L, Rosner W. Twenty-four hour mean plasma testosterone concentration declines with age in normal premenopausal women. J Clin Endocrinol Metab. 1995;80:1429–1430.

6. Overlie I, Moen M, Morkrid L, et al. The endocrine transition around menopause: a five-year prospective study with profiles of gonadotropins, estrogens, androgens and SHBG among healthy women. Acta Obstet Gynecol Scand. 1999;78:642–647.

7. Burger H, Dudley E, Cui J, 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;85:2832–2838.

8. Davisno S, Bell R, Donath S, et al. Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab. 2005;90:3847–3853.

9. Davis S, McCloud P, Strauss B, Burger H. Testosterone enhances estradiol’s effects on postmenopausal bone density and sexuality. Maturitas. 1995;21:227–236.

10. Miller B, De Souza M, Slade K, Lucciano A. Sublingual administration of micronized estradiol and progesterone, with and without micronized testosterone: effect on biochemical markers of bone metabolism and bone mineral density. Menopause. 20000;7:318–326.

11. Watts B, Notelovitz M, Timmons M, et al. Comparison of oral estrogens and estrogens plus androgen on bone mineral density, menopausal symptoms, and lipid-lipoprotein profiles in surgical menopause. Obstet Gynecol. 1995;85:529–537.

12. Folter A, Nathorst-Boos J, Carlstrom K, von Schoultz B. Addition of testosterone to estrogen replacement therapy in oophorectomized women: effects on sexuality and well-being. Climacteric. 2002;5:357–365.

13. Montgomery J, Appleby L, Brincat M, et al. Effect of oestrogen and testosterone implants on psychological disorders in the climacteric. Lancet. 1987;1:297–299.

14. Regestein Q, Friebely J, Shifren J, Schiff I. Neuropsychological effects on methyltestosterone in women using menopausal hormone replacement. J Womens Health Gend Based Med. 2001;10:671–676.

15. Sherwin B, Gelfand M. Differential symptom response to parenteral estrogen and/or androgen administration in the surgical menopause. Am J Obstet Gynecol. 1985;151:153–160.

16. Shifren J, Braunstein G, Simon J, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. NEJM. 2000;343:682–688.

17. Wisniewski A, Nguyen T, Dobs A. Evaluation of high-dose estrogen and high-dose estrogen plus methyltestosterone treatment on cognitive task performance in postmenopausal women. Horm Res. 2002;58:150–155.

18. Expert review committee. The role of testosterone therapy in postmenopausal women: position statement of the North American Menopause Society. Menopause. 2005;12(5):497–511.

Dr. Tori Hudson graduated from the National College of Naturopathic Medicine (NCNM) in 1984 and has served the college in many capacities over the last 25 years. She is currently a clinical professor at NCNM and Bastyr University; has been in practice for 25 years; and is the medical director of the clinic A Woman’s Time in Portland, OR, and director of research and development for Vitanica, a supplement company for women. She is also a nationally recognized author, speaker, educator, researcher, and clinician.