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Menopause Matters

Estrogen-Androgen Therapy

Tori Hudson, ND

A growing body of literature is focusing on the role of estrogen-androgen therapy in maintaining women's health and emotional well-being during midlife and beyond.

Physiology
Both the ovaries and adrenal glands secrete androgens, and production decreases as women age. After bilateral oophorectomy, serum androgen levels may drop by 50%.¹ A similar decline occurs in women who reach menopause spontaneously, although it usually takes more time-about 1 to 2 years.²

In women, estrogen-androgen therapy primarily affects motivational or libidinal aspects of sexual behavior, such as desire and fantasies. It also has beneficial effects on bone mineral density and hot flashes. Moreover, recent evidence suggests that androgen may have neuroprotective effects.³ Androgen's effect on lipids depends on the route of administration: Oral formulations have a variable effect that is not seen with the injectable or transdermal (patch or gel) formulations.

Evidence
Although clinical trials have not conclusively established that exogenous androgen improves sexual health in postmenopausal women using estrogen, the following studies support a potential link:

• Injectable estrogen-testosterone recipients, as compared with estrogen-alone recipients, experienced heightened energy, libido, and sense of well-being.⁴

• Compared with oral estrogen alone, oral estrogen-testosterone increased sexual desire and sexual satisfaction in postmenopausal women.⁵

• Adding testosterone (subcutaneous pellet) to estrogen significantly improved parameters of sexual functioning (ie, sexual activity, satisfaction, pleasure, orgasm frequency).⁶

• Transdermal testosterone combined with oral estrogen improved sexual function and psychological well-being in women with impaired sexual function.⁷

Clinical Role
Candidates for estrogen-androgen therapy should be evaluated carefully; clinicians should rule out medical disorders and consider psychosocial issues before assuming that androgen deficiency is the cause of the loss of libido. In the context of surgical menopause, however, the cause of androgen deficiency is known. In women whose loss of libido occurs in tandem with menopause and in whom estrogen therapy has not improved symptoms, a trial of estrogen-androgen therapy may be justified. In contrast, women with a lifelong lack of libido may need other types of interventions.

The US Food and Drug Administration has not approved any androgen therapies to increase female libido. The agency has approved one androgen-containing product for women: a combination of esterified estrogens and methyltestosterone (a synthetic, orally absorbable androgen), marketed as Estratest HS. This product is indicated for the treatment of moderate to severe vasomotor symptoms unresponsive to estrogen, although some women have reported increased sex drive while taking it.

Micronized testosterone USP formulations are available from custom-compounding pharmacists, although no trial data have documented their efficacy and safety. Transdermal patch and gel formulations of testosterone for women are in development.

Androgen therapy is appropriate for women only when used concomitantly with estrogen. The usual dose is 1.25 mg of methyltestosterone. Higher doses, which some women self-administer in the hope of achieving greater libido enhancement, have been linked to masculinizing effects such as deepening of the voice, acne, and increases in growth of facial and body hair.⁸ Moreover, high doses may not provide the desired improvement in libido. High doses may also adversely affect lipid profiles,⁹ although more studies are needed to clarify this effect.

Estrogen and androgen dosages must be tailored to produce normal serum values. Patients' hormone levels should be measured annually (every 6 months if values are abnormal). Some experts advise measuring free or bioavailable testosterone before initiating estrogen-androgen replacement therapy. Clinicians need to know the normal values used by their laboratory, and stay within those parameters. Monitoring blood lipids is also recommended.

As androgen therapy does not protect the endometrium, women with an intact uterus who are receiving estrogen-androgen therapy must also use a progestogen. It is not known whether exogenous estrogen-androgen therapy alters breast cancer risk. According to Estratest labeling, the only contraindication for methyltestosterone use in postmenopausal women is the presence of severe liver disease.

Available data suggest that estrogen-androgen therapy can enhance libido. Although promising, the evidence does not support routine administration of androgen with estrogen as part of postmenopausal hormone therapy. However, women who have undergone bilateral oophorectomy may be good candidates for such therapy.¹⁰ If serum androgen levels are low, then the decision to initiate estrogen-androgen therapy depends on a thorough clinician-patient discussion of the pros and cons of such an intervention.

References

1. Judd HL, Lucas WE, Yen SSC. Effect of oophorectomy on circulating testosterone and androsterone levels in patients with endometrial cancer. Am J Obstet Gynecol. 1974;118:793-798.
   
2. Longcope C. Hormone dynamics at the menopause. Ann N Y Acad Sci. 1990;592:21-30.
   
3. Hammond J, Le Q, Goodyear C, Gelfand MM, et al. Testosterone-mediated neuroprotection through the androgen receptor in human primary neurons. J Neurochem. 2001;77: 1319-1326.
   
4. Sherwin BB, Gelfand MM. The role of androgen in the maintenance of sexual functioning in oophorectomized women. Psychoso Med. 1987; 49:397-409.
   
5. Sarrel P, Dobay B, Wiita B. Estrogen and estrogen-androgen replacement in postmenopausal women dissatisfied with estrogen-only therapy: sexual behavior and neuroendocrine responses. J Reprod Med. 1998;43:847-856.
   
6. Davis SR, McCloud P, Strauss BJ, Burger H. Testosterone enhances estradiol's effects on postmenopausal bone density and sexuality. Maturitas. 1995;21:227-236.
   
7. Shifren JL, Braunstein GD, Simon JA, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med. 2000;343:682-688.
   
8. Gelfand MM, Wiita B. Androgen and estrogen-androgen hormone replacement therapy: a review of the safety literature, 1941 to 1996. Clin Ther. 1997; 19:383-404.
   
9. Watts NB, Notelovitz M, Timmons MC, et al. Comparison of oral estrogen and estrogens plus androgen on bone mineral density, menopausal symptoms, and lipid-lipoprotein profiles in surgical menopause. Obstet Gynecol. 1995;85:529-537.
   
10. Gelfand MM. Role of androgens in surgical menopause. Am J Obstet Gynecol. 1999;16:1473-1480.

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