testosterone HRT for women

PERIMENOPAUSE UPDATE
Objectives

Describe changes in androgens in aging, menopause, and following oophorectomy.
Define patients who might be appropriate for testosterone therapy.
Discuss alternative medical therapy versus prescription medical therapy.
WOMEN AND LIBIDO-IS THERE A ROLE FOR TESTOSTERONE?
Testosterone is an important metabolic and sex hormone produced by the ovary throughout a woman's lifetime, with levels changing at different times of life and under certain medical conditions. The variable reduction in testosterone production during the perimenopause is sometimes associated with a syndrome of specific changes in sexual desire and sexual response.1 Estrogen deficiency also impairs sexual response, but its replacement will not improve and might exacerbate sexual symptoms from androgen loss.2

Decreasing testosterone may be one of many possible causes of decreasing sexual desire; however, disorders of desire are complex and require careful, non-judgmental history taking. Testosterone replacement/supplementation may be appropriate in a small percentage of women who complain of decreased desire.3 Many women experiencing the clinical symptoms of androgen deficiency and low free testosterone levels respond well to testosterone replacement therapy.

Androgen Production
There is very little androgen action in the female fetus-the placenta has absorbed all the mother's androgens and although fetal adrenal glands produce a high level of weak androgens, the female usually is not virilized in humans. Androgens remain relatively low until adrenarche, when dehydroepiandrosterone sulfate (DHEAS) develops. During puberty, the adrenal gland makes higher levels of weak androgens-DHEAS is very high during puberty into the early twenties. The adrenal and ovarian androgen production from puberty to menopause is relatively high, although there is a decline of adrenal production after the early twenties while ovarian production continues until well after menopause. The predominant symptom of women with androgen deficiency is loss of sexual desire.4 This is not limited to women experiencing a surgical menopause but may also be a feature of women who have either undergone premature or natural menopause.

Blood Production Rates of Steroids
(Mg / day) Reproductive Age Postmenopausal Oopherectomized
Androstenedione 2-3 0.5-1.0 0.4-0.8
Dehydroepiandrosterone (DHEA) 6-8 1.5-4.0 1.5-4.0
Dehydroepiandrosterone sulphate (DHEAS) 8-16 4-9 4-9
Testosterone 0.2-0.25 0.05-0.1 0.02-0.07
Estrogen 0.350 0.045 0.045

Menopause and Disorders of Desire
Sexuality and sexual function involve more than just physical ability; psychological factors are just as important. The aging process involves many normal physical changes, some of which naturally affect sexuality. There is a gradual slowing of response, but women do not ordinarily lose their capacity for orgasm.5,6 During menopause, women may experience a variety of conditions that cause changes in sexual function. These changes include diminished sexual responsiveness, dyspareunia (painful intercourse related to estrogen deficiency), decreased sexual activity, decreased desire, a dysfunctional male partner, or lack of a partner.7 When assessing disorders of desire, answers to the following questions will provide important clues:

What is the nature of the patient's current sexual activity?
Is there an identifiable event associated with loss of desire?
How much disparity is there between the patient's desire and her partner's?
It is the issues surrounding a woman's autoerotic behavior, her own sexual thoughts, dreams and fantasies, and masturbation, which define a woman's libido that need to be examined. Is the problem really lack of interest or is it anger, fear of rejection, or negative messages partners give to one another? Is the lack of desire selective? Is the underlying effort to remain sexually aloof a way to punish or control the partner? Have there been attempts to solve the problem?

It is important to determine if there is a surgical event connected to loss of desire. Women who can clearly define their sexual drive through issues of fantasy and desire, and who can say there was a specific drop associated with a specific medical event, are very likely to respond to androgen therapy.8

There are a number of medical causes of decreased libido. These include acute and chronic illness, fatigue, malnutrition, alcohol, drugs, stroke, pituitary disease, renal disease, depression, and testosterone and estrogen deficiency. Traumatic deliveries can also result in chronic dyspareunia and incontinence, both affecting sexual relations and satisfaction.

Possible Medical Causes of
Decreased Libido
Illnesses Virtually any illness (genital or general; physical, emotional, or both): liver, renal, cardiac or hormonal disease, cystitis, anemia, hypertension, stroke, cancer, neurologic disease, colostomy, neostomy, bladder surgery, incontinence, herpes virus or HIV infection, gonorrhea, venereal warts.

Medications Antihypertensives, antineoplastic drugs, some antidepressants, (including selective serotonin reuptake inhibitors), major or minor tranquilizers (depending on dose), diuretics, antihistamines.

Treatments Major surgery (hysterectomy, mastectomy, cardiac bypass, organ transplant), dialysis, radiotherapy, chemotherapy.

There are also interpersonal causes of disorders of desire. These include reduced sexual attractiveness of patient or partner, boring sexual routines, situational disturbances, and marital adjustment problems. Contrary to popular belief, marriages do not increase in emotional intimacy with time.9 It is not uncommon for a couple who were very sexually active in their twenties to lack emotional intimacy in their forties. The kind of emotional intimacy that leads to desire is often lacking in long-term married relationships.

In disorders of desire, 90 percent of it has to do with the relationship. However, 10 percent of it may be related to decreasing levels of testosterone. The biggest question to ask in evaluating disorder is whether the patient has had desire in the past, including autoerotic behavior and fantasies.

Androgen Therapy
Changes in the circulating levels of androgens play an important role in psychologic and sexual changes that occur after menopause. The effects of short-term estrogen therapy in improving psychologic symptoms, maintaining vaginal lubrication, decreasing vaginal atrophy, and increasing pelvic blood flow in postmenopausal women are well documented; however, some patients require more than estrogen alone to improve psychologic dysfunction, decreased sexual desire, or other sexual problems associated with menopause. Results from clinical studies show that hormone replacement therapy with estrogen plus androgens provides greater improvement in psychologic (e.g., lack of concentration, depression, and fatigue) and sexual (e.g., decreased libido and inability to have an orgasm) symptoms than does estrogen alone in naturally and surgically menopausal women.10

For menopausal women who have never had much sexual desire, or who experience no change in libido, testosterone would probably not be the right therapy. But for those women who have felt sexual desire and wonder where it went, testosterone may be helpful.

During menopause, low estrogen levels lead to vulvar and vaginal atrophy,11 which can cause discomfort. This can have a dampening effect on libido, although lubricants can help. Estrogen replacement therapy can increase vulvar sensation and decrease dyspareunia, but it does not do anything for desire.12

Non-androgenic progestins in oral contraceptives, with the addition of ethinyl estradiol, can drive free testosterone to very low levels. This will eliminate the mid-cycle surge of androgens and accompanying surge of autoerotic and sex-seeking behavior in humans related to ovulation.

There is no convincing evidence that adding physiologic doses of androgens consistently enhances libido in menstruating women. Naturally menopausal women over 50 still produce a fair amount of androgens, for at least five to 10 years. For 35- to 60-year-old women who have had oophorectomies, there may be an increase in libido with the addition of androgens.13 Evidence that this is the case comes from a study, comparing estrogen-only, estrogen-testosterone, and placebo therapy in women who have had oopherectomies.14 The levels of testosterone used in the study were, however, superphysiologic, sometimes four to five times the average in males.

Testosterone and estrogen combined may increase bone density more than estrogen alone.15 Recent studies have also shown estrogen-androgen therapy to contribute to the prevention of osteoporosis and reduce serum levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol.16,17 Finally, there appears to be some connection between testosterone and an elevated sense of well being in some patients, although this is difficult to assess given the powerful placebo effect.18

For women who might be candidates, there are a number of androgen therapies available: combined oral conjugated estrogens, injectables, subcutaneous testosterone pellets, transdermal patches (in development), and creams and gels.

Androgens and Estrogens

Oral Dosages
Diethylstilbestol (DES) amd Methyltestosterone
0.25 mg DES/5 mg methyltestosterone
1x day for 21 days (7 days off)
Dosage may be decreased to 0.125 mg DES/2.5 mg methyltestosterone

Conjugated Estrogens and Methyltestosterone
1.25 mg conjugated estrogens/10 mg methyltestosterone
1x day for 21 days (7 days off)

Esterfied Estrogens and Methyltestosterone
0.625 to 2.5 mg esterfied estrogens and 1.25 to 5 mg methyltestosterone
1x day for 21 days (7 days off)

Fluoxymesterone and Ethinyl Estradiol
1 to 2 mg fluoxymesterone and 0.02 to 0.04 mg ethinyl estradiol
2x day for 21 days (7 days off)

Injection Dosages
(not recommended or commonly used in the United States)
Testosterone Cypionate and Estradiol Cypionate
50 mg testosterone cypionate/2 mg estradiol cypionate
1x every 4 weeks

Testosterone Enanthate and Estradiol Valerate
90 mg testosterone enanthate/4 mg estradiol valerate
1x evey 4 weeks

Testosterone Enanthate Benzilic Acid Hydrazone, Estradiol Dienanthate, and Estradiol Benzoate
150 mg testosterone enenthate benzilic acid hydrazone/7.5 mg estradiol dienanthate/
1 mg estradiol benzoate
1x every 4 to 8 weeks or less

Oral preparations are difficult to evaluate because their androgen delivery cannot be measured; only secondary effects can be measured. So it is hard to tell whether patients are receiving a lot or not enough testosterone. Transdermal preparations can vary in application effectiveness and dosing, but can achieve very high testosterone levels.

Androgen therapy does have side effects. These include hirsutism, increased facial oiliness, acne, deepening voice, hostility, weight gain, alopecia,19 elevated liver functions, lower HDL levels, and (rarely) epedicellular carcinoma.20 Finding the right balance that will help women with their libido without causing adverse side effects is very difficult. How much is too much or too little testosterone has yet to be determined.

Other potential indications for androgen therapy in women are currently being evaluated. These include use in women with premature ovarian failure, premenopausal androgen deficiency symptoms, postmenopausal and glucocorticosteroid-related bone loss, alleviation of wasting syndrome secondary to human immunodeficiency virus infection, and management of premenstrual syndrome.21

REFERENCES
1 Davis SR. Androgen replacement in women: a commentary. J Clin Endocrinol Metab. 1999 Jun;84(6):1886-91.

2 DeCherney AH. Hormone receptors and sexuality in the human female. J Womens Health Gend Based Med. 2000;9 Suppl 1:S9-13.

3 Sarrel PM. Effects of hormone replacement therapy on sexual psychophysiology and behavior in postmenopause. J Womens Health Gend Based Med. 2000;9 Suppl 1:S25-32.

4 Davis SR. The therapeutic use of androgens in women. J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):177-84.

5 Masters WH. Sex and aging - expectations and reality. Hospital Practice. August 15, 1986. 175-198.

6 Meston CM. Aging and sexuality. West J Med. 1997 Oct;167(4):285-90.

7 Kingsberg SA. Postmenopausal sexual functioning: a case study. Int J Fertil Womens Med. 1998 Mar-Apr;43(2):122-8

8 Myers CS, et al. Effect of estrogen, androgen, and progestin on sexual psychophysiology and behavior in post-menopausal women. J Endocrinol Metab 1990;70(4): 1124-1131.

9 Greer R. et al. Aspects of geriatric sexuality. Family Practice Recertification. Vol 13:No 6: 57-73.

10 Sarrel PM. Psychosexual effects of menopause: role of androgens. Am J Obstet Gynecol. 1999 Mar;180(3 Pt 2):319-14.

11 Cutson TM, Meuleman E. Managing menopause. Am Fam Physician. 2000 Mar 1;61(5):1391-400, 1405-6.

12 Naftolin F, et al. The cellular effects of estrogens on neuroendocrine tissues. J Steroids Biochem 1988;Vol 30:195-107.

13 Myers CS, et al. Effect of estrogen, androgen, and progestin on sexual psychophysiology and behavior in post-menopausal women. J Endocrinol Metab 1990;70(4): 1124-1131.

14 Sherwin BB, Gelfand MM. Differential symptom response to parenteral estrogen and/or androgen administration in the surgical menopause. Am J Obstet Gynecol 1995;151: 153-160.

15 Shoupe D. Androgens and bone: clinical implications for menopausal women. Am J Obstet Gynecol 1999 Mar;80 (3 pt 2):329-333.

16 Bachmann GA. Androgen cotherapy in menopause: evolving benefits and challenges. Am J Obstet Gynecol. 1999 Mar;180(3 Pt 2):308-11. 17 Hoeger KM, Guzick DA. The use of androgens in menopause. Clin Obstet Gynecol. 1999 Dec;42(4):883-94.

18 Sherwin BB, Gelfand MM. Differential symptom response to parenteral estrogen and/or androgen administration in the surgical menopause. Am J Obstet Gynecol 1995;151: 153-160.

19 Redmond GP. Hormones and sexual function. Int J Fertil Womens Med. 1999 Jun-Aug;44(4):193-7.

20 Hoeger KM, Guzick DS. The use of androgens in menopause. Clin Obstet Gynecol. 1999 Dec;42(4):883-94.

21 Davis S. Androgen replacement in women: a commentary. J Clin Endocrinol Metab. 1999 Jun;84(6):1886-91.