- Email: [email protected]
Androgen Replacement Therapy and Women’s Health
, , , , , ,
GYNAECOLOGY
, , , , , ,
ANDROGEN REPLACEMENT THERAPY AND WOMEN'S HEALTH Olufemi A. Olatunbosun, MD,FRCSC, Associate Professor, Department of Obstetrics and Gynaecology, College of Medicine, University of Saskatchewan
ABSTRACT
Although androgen replacement has been in use far several decades far various gynaecological disarders, it has had few adherents in women's health because of misconceptions that it is unphysiological and a male harmane. The potential role of androgens in the pharmacological management of menopausal harmane deficiency states remains to be firmly defined, but there has recently been renewed interest in the addition of low-dose androgen to the traditional estrogen replacement therapy. This is a welcome development because not all menopausal symptoms are adequately controlled with estrogen ar estrogen/progestin therapy. Weight gain, increase in body hair and slight enlargement of the clitoris constitute the most important side effects experienced by androgen users. The purpose of this review is to discuss the role of androgens as an adjuvant to estrogen/progestin replacement therapy with the hope that the clinician wiU evaluate its incorparation into menopausal women's health care. RESUME Mhne si le traiternent substitutif aux androgenes sert depuis plusieurs decennies d traiter divers troubles gynecologiques, il a peu d' adeptes dans le domaine de Ia sante des femmes parce qu' on connalt malle role physiologique des androgenes et parce qu'il s' agit d' harmanes masculines. Le role potentiel des androgenes dans le traiternent pharmacologique des etats de deficit hormonal de Ia minopause reste d preciser , mais on a recemment constate un regain d'interet pour I' ajaut de faibles doses d' androgenes d I' oestrogenotherapie substitutive classique. Ce progres est souhaiwble parce que les sympt6mes de Ia minopause ne sont pas taus supprimes par le traitement aux oestrogenes au par le traitement aux oestrogenes et aux progestatifs. Un gain ponderal, une pilosite accrue et une /egere hypertrophie du clitoris sont les effets secondaires les plus importants chez les utilisatrices d' androgenes. Cet examen vise d discuter du role des androgenes comme traitement d' appoint au traiternent substitutif aux oestrogenes et (au) aux progestatifs, en souhaitant que le clinicien evalue leur integration aux soins de sante des femmes minopausees. J soc OBSTET GYNAECOL CAN 1998;20(9):837·43
KEYWORDS
Menopause, harmane replacement therapy, androgens. Received on September 19th, 1997. Revised and accepted on October 10th, 1997.
JOURNAL SOGC
837
AUGUST 1998
, , , decreased with aging. 4 Although many women are concerned about having a low sex drive, only a few admit or discuss this with their physicians. 4 The level of comfort in discussing issues relating to human sexuality is crucially important in women's health, especially when sexual harassment and sexual abuse concerns are at record highs. Although non-menopausal aspects of sexual relationships are important causes of sexual dysfunction, hormone replacement therapy has been shown to have beneficial effects on sexual desire. While estrogen replacement effectively reverses the atrophic changes in the sexual organs associated with hypo-estrogenic states,5 data are accumulating in support of testosterone as the hormone responsible for sexual drive in womenY The libido is not increased by estrogen therapy but may be improved by testosterone administration. Prospective studies of menopausal women treated with combined subcutaneous implants of estradiol and testosterone showed marked improvement in sexual drive, enjoyment of sex and general well-being. 5This beneficial effect is particularly dramatic in biologically premenopausal women who have had a bilateral oophorectomy.8 Besides the improvement in a woman's motivation and desire for sex, androgen replacement in the menopause increases the frequency of intercourse and sexual response during intercourse, and enhances continuing sexual activity which has been found to protect against vaginal dryness and dyspareunia. Several decades of use have produced compelling evidence of the efficacy of androgens in enhancing human sexual function in menopausal women. The real challenge is to make clinicians consider supplementary androgen therapy when estrogen/progestin have not provided adequate relief from sexual dysfunction. Sexual dysfunction in the menopause is an important component of women's health that is worthy of new therapeutic considerations.
INTRODUCTION
Estrogen therapy, either alone or in combination with a progestin, has been and will probably continue to be the mainstay of treatment for hypo-estrogenic symptoms of the menopause, and for reducing the risk of coronary heart disease and osteoporosis. Nevertheless, many women have menopausal symptoms which are not alleviated by estrogen alone. 1,2 For example, psychological and sexual symptoms persist in some hypogonadal women despite adequate estrogen replacement.) It is becoming clear that, in these instances, androgen replacement therapy should be considered a valuable adjunct to estrogen therapy. New formulations of androgens for hormone replacement are currently available for clinical use or are at various stages of development. Therefore, clinicians need to be aware of new clinical indications for existing compounds and tailor the mode of therapy to the needs of the individual patient. Androgens, traditionally considered to be male hormones, are normally present in women and are essential components in the steroid biosynthetic pathway to estrogen. The ovaries and adrenal glands both contribute to androgen production. The primary circulating androgen is testosterone. In premenopausal women, androgens are involved in follicular development and atresia. They also contribute to the maintenance of bone architecture. The purpose of this article is to discuss the importance of androgen replacement therapy in the menopause and to review the current literature on androgen therapy. I hope that this review will sufficiently demystify androgen replacement, and help the clinician to evaluate the appropriateness of its incorporation into menopausal women's health care. ANDROGENS AND SEXUAL FUNCTION
Sexuality-related problems are important concerns in women's health, although not often freely discussed in clinical settings. Sexual desire and function in women are dependent on a complex interplay of psychological, environmental and biological factors. Urogenital symptoms associated with estrogen deficiency are most common during the menopause. Atrophic changes in the vagina can lead to lack of lubrication, vaginal soreness, dyspareunia, vaginismus and post-coital bleeding. Several studies have found that the overall frequency of sexual fantasy, foreplay, oral sex and vaginal intercourse
JOURNAL SOGC
ANDROGEN REPLACEMENT THERAPY AND COGNITIVE FUNCTION
The menopause has been suggested to be an important modifier of psychological function in women, although such health promoting activities as regular exercise, smoking cessation and dietary discretion may be effective in achieving psychological well-being. Estrogen exerts favourable effects on cognitive function and prevention of senile dementia through neurochemical effects, direct effects on vasculature and effects on the generation of free
838
AUGUST 1998
, , , and psychological symptoms. 16 Thus, the most compelling reason for considering androgen replacement therapy in women is the hormone's efficacy in ameliorating the sudden onset of symptoms associated with surgical menopause. The decision to continue on long-term estrogen-androgen replacement afrer an initial six-month period, or to switch to estrogen alone, will require careful consideration of each woman's situation, well-being and risk profile.
radicals! A growing body of clinical research is emerging strongly supporting the view that androgen therapy may act synergistically with estrogen in relieving symptoms of depression, nervous tension, palpitations, headaches and insomnia. Women who have undergone a surgical menopause show improved cognitive function and feelings of well-being following hormonal replacement with combined estrogen-androgen preparations. lO Sherwin11,12 found higher scores in tests of short-term and long-term memory in postoperative users of combined estrogenandrogen preparations than in users of estrogen alone. In the aggregate, this finding suggests that there are important additional benefits associated with the addition of androgens to estrogen replacement therapy. While the precise mechanism of the action of androgens in improving cognitive function is unclear, it is suggested that the effects may be modulated by various neurochemical factors. 9,lo
SKELETAL SYSTEM
Osteoporosis is a major public health problem in Canada, and fractures of the vertebral spine, hip and wrist are the cause of much of the mortality and morbidity associated with the disease, with an annual age-adjusted incidence of fractures per 100,000 of3Z.7 in males and 89.8 in females. 17 The annual cost of all fracture treatment in Canada is about one billion dollars.ls There is sparse clinical and experimental evidence of the role of combined estrogen-androgen therapy for osteoporosis prevention. Despite initial optimism regarding the possible use of androgens for reducing the risk for menopausal osteoporosis, studies are evenly divided as to whether or not there is an increase in bone mass in women receiving estrogen-androgen versus estrogen replacement therapy.19,2o The cohort study of Watts and colleagues l4
SURGICAL MENOPAUSE AND HORMONE REPLACEMENT
Oophorectomy is increasingly being undertaken in the management of benign gynaecological conditions including endometriosis, chronic pelvic pain and intractable premenstrual syndrome. There also has been a renewed interest in prophylactic oophorectomy at the time of routine hysterectomy in an attempt to reduce the subsequent risk of ovarian cancer.13 Following iatrogenic menopause, there is a rapid fall in serum sex hormone levels which leads to immediate vasomotor and psychological symptoms. Premature menopause due to surgical removal of the ovaries must be managed effectively by hormone replacement therapy to avoid such long-term health sequelae as increased risks of osteoporosis and cardiovascular disease. Although estrogen therapy alone can help to alleviate some of the hypo-estrogenic symptoms, those that receive estrogen-androgen combination therapy are reported to have greater relief from their symptoms. Clearly, surgical menopause continues to be the leading indication for initiating primary estrogen and androgen therapy. Much of the published literature describing the role of estrogen-androgen therapy following surgical menopause is from Canadian investigators/,ll,l2 and is growing. 14 There have been several clinical trials of combined estrogen and androgen replacement versus estrogen alone in oophorectomized women. 14-16 Those that received estrogen-androgen combination therapy were reported to have greater improvement of their vasomotor
JOURNAL SOGC
found a small but non-significant increase in the spinal bone density of patients who received estrogen only compared to those taking an oral combination containing estrogens and methyltestosterone. A large prospective European studyl9 indicated that the bone density at the lumbar spine and neck of the femur remained unchanged in women who continued to use oral estrogen therapy alone, while those that changed to subcutaneous estradiol and testosterone replacement demonstrated increased bone density at those sites. Overall, there is some encouraging evidence that physiological doses of androgens may act in synergism with estrogens in either preventing bone loss or in reversing some of the postmenopausal bone loss that may have occurred. 19,20 Hormone replacement combining estrogen and androgen seems to be a favourable therapy for selected patients. OTHER BENEFITS FROM ANDROGEN THERAPY
The effect of androgens in several auto-immune and growth disorders is little understood and extremely interesting. 21 Auto-immune diseases like systemic lupus
839
AUGUST 1998
NVP=SUFFERINC How much Nausea and Vomiting
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she can take before receiving
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Delayed release tablets ,,~mbinaMn of D~'II/.mine Suc(;inatc \.'.'i th P'irldcXl!lE H'I'J(cchloridel It can be prescribed as soon as symptoms appear up to the end of the pregnancy.
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As stated in an article in The New Eng/and Journal of Medicine. Diclectin is the drug of choice for NVP. - Koren, Pastuza~ and lto Drugs in Pregnancy New England Journal of Medicine,Apn116, 1998, Vol. 338 (160 1128i
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, , , erythematosus and rheumatoid arthritis are more common in women than in men. It has been suggested that women with these diseases have lower plasma androgen levels than control women. 21,22 The efficacy shown by danazol, an isoxazol derivative of 17 a-ethanol testosterone, in the treatment of young women with rheumatoid arthritis,22 supports the theory that low androgen levels may playa role in auto-immune disorders. A novel aspect of treatment with androgen regimens is the use of such weak adrenal androgens as dehydroepiandrosterone and DHEA-sulphate in the management of auto-immune diseases. Supporting evidence is provided by results from clinical studies, and a small series of cases, that low-dose adrenal androgen replacement may improve age-related decline in cognitive ability,23 enhance rapid eye movement (REM) sleep24 and offer cardioprotection by reducing platelet aggregation,25 as well as acting as an insulin-sensitizing and anti-obesity agent. 26 The use of androgens as adjuncts in the treatment of these disorders will require sound clinical trials. If further studies confirm that androgens do have beneficial effects in auto-immune and age-related disorders, it would be a major development in menopausal hormone replacement therapy.
TABLE 1 FORMULATIONS FOR ANDROGEN THERAPY Preparation and dosage
Intramuscular Testosterone enanthate (200 mg/mL) Delatestryl (Squibb) (100 mg every 4 weeks) Testosterone enanthate 150 mg/mL, Climacteron (Sabex) estradiol dienanthate 7.S mg/mL and estradiol benzoate 1 mg/mL (1 mL every 4-8 weeks) Testosterone cypionate 100 mg/mL (1 mL every 4 weeks)
Depo Testosterone Cypionate (Pharmacia & Upjohn)
Oral Testosterone undecanoate 40 mg (40 mg alternate days)
Andriol (Organon)
Fluoxymesterone 5 mg (5 mg alternate days)
Halotestin (Pharmacia & Upjohn)
Methyltestosterone 10 mg/20 mg (Dosage individualized)
Metandren (Novartis)
Methyltestosterone 1.25 mg/2.5 mg and esterified estrogens 0.625 mg (One tablet daily)
Estratest* (Solvay)
local formulations Ointment Testosterone propionate or cypionate (Local pharmacy preparation) 2%, in petrolatum jelly • Not available in C anada
Canada), licensed for replacement therapy in males for conditions associated with symptoms of deficiency or absence of endogenous testosterone, and for male climacteric symptoms. The dose of oral preparations should be low initially to reduce the potential for side effects. Andriol, available as 4O-mg soft gel capsules, is being used as supplementary therapy to estrogen, on a daily or alternate day basis. This dosage regimen is relatively arbitrary and can be altered to the specific therapeutic goals of each patient. Combined oral estrogen and androgen preparations are currently being developed in Canada and, as newer formulations of these agents become available, it is likely that they will play an increasingly important role in the clinical management of the menopause. Existing data are insufficient to recommend a prolonged duration of androgen replacement in the menopausal woman. The available literature regarding a carefully planned, brief duration of therapy is encouraging and all options should be presented to the patient.
REGIMENS OF ANDROGEN REPLACEMENT THERAPY
Androgens are available in a number of formulations (Table 1), presented in various delivery systems and applied at varying dose levels. Androgens are usually administered either as intramuscular injections, subcutaneous implants, oral tablets or as local ointments, according to the needs of the patient. The usual dose suggested is monthly intramuscular injections of 75 to 150 mg testosterone enanthate. 12 It is feasible to administer intramuscular and subcutaneous preparations for prolonged periods of treatment. However, because of peaks and nadirs and variable blood levels, problems of dosing may be disadvantageous for the patient. An oral estrogen-androgen preparation marketed as Estratest (esterified estrogens, 0.625 mg, and methyltestosterone 1.25 or 2.5 mg daily; Solvay Pharmaceuticals) has been available in the United States for some time. Oral androgen preparations currently in use in Canada are testosterone undecanoate (Andriol; Organon, Canada), methyltestosterone (Metandren; Novartis, Canada) and fluoxymesterone (Halotestin; Pharmacia and Upjohn
JOURNAL SOGe
Proprietary names (manufacturer)
PRECAUTIONS
Androgen monotherapy should not be practised for menopausal hormone replacement except for specific
841
AUGUST 1998
, , , age-related vulvo-vaginallesions. Androgen treatment in menopausal patients with intact uteri should be an adjunct to combined estrogen/progestin therapy, rather than a substitute for progestins, in order to prevent the development of endometrial hyperplasia and carcinoma. Androgens are contra-indicated in patients with breast cancer, in those with hepatic or renal dysfunction and those with, or at risk for hypercalcaemia or with hypersensitivity to androgens.
dose androgen to the traditional estrogen replacement therapy. This is a welcome development because not all menopausal symptoms are adequately controlled with estrogen or estrogen/progestin therapy. Given the compelling evidence that androgen lack is involved in mediating some of the symptoms of menopause, it is reasonable to advocate replacement. The availability of a wide range of pharmacological agents enables physicians to tailor the management of the menopause to the individual needs of their patients. The use of estrogen therapy with or without an androgen should be an informed joint decision of physician and patient that must be re-evaluated regularly as new information becomes available.
POTENTIAL SIDE EFFECTS
The decision to use androgen replacement therapy rests with the patient following counselling. In this situation, not only the benefits but also the risks and safety considerations are important items for discussion. Most of the side effects of androgens are of mild or moderate intensity, and include increase in body hair, deepening of the voice and weight gain. Slight enlargement of the clitoris could be a concern for some women, although most do not seem to be bothered by this phenomenon. In general, most of the side effects associated with androgens tend to be well tolerated by women and are reversible following discontinuation of therapy. Androgens like most drugs produce biological effects that are dose dependent. There is a suggestion that serum lipid profiles are elevated in women using 2.5 or five mg per day of methyltestosterone,14 but this has not been observed in other studies. 27 Androgen replacement in low doses, given as transdermal patch28 or as oral testosterone undecanoate (which is absorbed via the lymphatic system, thereby escaping hepatic first passage) does not appear to affect lipoprotein concentrations adversely. In general, only a short-term application of androgens is necessary for its adjuvant role in hormone replacement. During such a short course of therapy hyperlipidaemia is not a concern. However, the safety of long-term androgen therapy deserves careful study.
REFERENCES 1.
Barrett-Connor E, Timmons C, Young R, Wi ita B, Estratest Working Group. Interim safety analysis of a two-year study comparing oral estrogen-androgen and conjugated estrogens in surgically menopausal women. J Women's Health 1996;5:593-602. 2. Casson PR, Carson SA. Androgen replacement therapy in women: myths and realities. Int J Fertil Menopausal Stud 1996;41 (4):412-22. 3. Burger HG, Hailes J, Menclaus M, Nelson, J, Hudson B, Balaz N. The management of persistent menopausal symptoms with oestradiol-testosterone implants: clinical, lipid and hormonal results. Maturitas 1984;6(4):351-8. 4 Rosen RG, Taylor JF, Leiblun SR, Bachmann GA. Prevalence of sexual dysfunction in women: results of a survey study of 329 women in an outpatient gynecologic clinic. Sex Ther 1993;19:172-88. 5 Leiblum SR, Bachmann GA, Kemmann E, Colbourn D, Swartzman L. Vaginal atrophy in the postmenopausal woman: the importance of sexual activity and hormones. JAMA 1993;249:2195-8. 6. Burger H, Hailes J, Nelson J, Menelaus M. Effect of combined implants of oestradiol and testosterone on libido in postmenopausal women. BMJ (Clin Res Ed) 1987; 294:936-7. 7. Sherwin BB, Gelfand MM, BrenderW. Androgen enhances sexual motivation in females: a prospective crossover study of sex steroid administration in the surgical menopause. Psychosom Med 1985;47:339-51. 8. Lindgren R, Berg G, Hammar M, Zuccon E. Hormonal replacement therapy and sexuality in a population of Swedish postmenopausal women. Acta Obstet Gynecol Scand 1993;72:292-7. 9. Fillit H. Future therapeutic developments of estrogen use. J Clin Pharmacol 1995;35(9 Suppl):25S-28S. 10. Whiteford GM. Alzheimer's disease and serotonin: a review. Neuropsychobiology 1986;15:1-10.
SUMMARY
Although androgen replacement therapy has been in use for several decades for various gynaecological disorders, it has had few adherents in women's health because of misconceptions that it is unphysiological and a male hormone. The potential role of androgens in the pharmacological management of menopausal hormone deficiency states remains to be defined firmly, but there has recently been renewed interest in the addition oflow
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AUGUST 1998
, , , 11. Sherwin BB. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology 1988;13(4):345-57. 12. Sherwin BB. Affective changes with estrogen and androgen replacement therapy in surgically menopausal women. J Affect Disord 1988;14:177-87. 13. Rozario D. Brown I, Fung MF, Temple L. Is prophylactic oophorectomy an acceptable means to reduce the incidence of ovarian cancer? Am J Surg 1997;173(6):495-8. 14. Watts NB, Notelovitz M, Timmons MC et al. Comparison of oral estrogens and estrogen plus androgen on bone mineral density, menopausal symptoms, and lipidlipoprotein profiles in surgical menopause. Obstet Gynecol 1995;85:529-37. 15. Sherwin BB, Gelfand MM. The role of androgen in maintenance of sexual functioning in oophorectomized women. Psychosom Med 1987;49:397-409. 16. Sherwin BB. Sex hormones and psychological functioning in postmenopausal women. Exp Gerontol 1994;29:423-30. 17. Canadian Task Force on the Periodic Health Examination. The periodic health examination: 2.1987 update. Can Med Assoc J 1988;138:618-26. 18. Hanley DA, Josse RG. Prevention and management of osteoporosis: consensus statements from the Scientific Advisory Board of the Osteoporosis Society of Canada. 1. Introduction. Can Med Assoc J 1996;155(7):921-3. 19. Sawas M, Studd JW, Norman S, Leather AT, Garnet TJ, Fogelman I. Increase in bone mass after one year of percutaneous estradiol and testosterone implants in postmenopausal women who have previously received long-term oral estrogens. Br J Obstet Gynaecol 1992;99:7 57 -60. 20. Raisz L, Wiita B, Artis A et a/. Comparison of the effects of estrogen alone and estrogen plus androgen on biochemical markers of bone formation and resorption in postmenopausal women. J Clin Endocrinol Metab 1996;81 :37-43. 21. Lahita RG. The connective tissue diseases and the overall influence of gender. Int J Fertil Menopausal Stud 1996;41 (2): 156-65. 22. Van Vollenhoven RF, McGuire JL. Estrogen, progesterone, and testosterone: can they be used to treat autoimmune diseases? Cleve Clin J Med 1994;61 (4):276-84. 23. Morales AJ, Nolan JJ, Nelson JC et al. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol Metab 1994;78:1360-7. 24. Friess E, Trachsel L, Guldner J et al. DHEA administration increases rapid eye movement sleep and EEG power in the sigma frequency range. Am J PhysioI1995;268:E1 07 -E113. 25. Lesse RL. The effects of DHEA on atherogenesis and platelet function. Ann NY Acad Sci 1995;774:281-91. 26. Bates GW, Egerman RS, Umstot ES et al. Dehydroepiandrosterone attenuates study-induced declines in insulin sensitivity in postmenopausal women. Ann NY Acad Sci 1995;774:291-3.
JOURNAL SOGe
27. Sherwin BB, Gelfand MM, Schucher R, Gabor J. Postmenopausal estrogen-androgen replacement and lipoprotein lipid concentrations. Am J Obstet Gynecol 1987;156(2):414-9. 28. Kaunitz AM. The role of androgens in menopausal hormonal replacement. Endocrinol Metab Clin North Am 1997;26(2):391-7.
843
AUGUST 1998
GYNAECOLOGY
, , , , , ,
ANDROGEN REPLACEMENT THERAPY AND WOMEN'S HEALTH Olufemi A. Olatunbosun, MD,FRCSC, Associate Professor, Department of Obstetrics and Gynaecology, College of Medicine, University of Saskatchewan
ABSTRACT
Although androgen replacement has been in use far several decades far various gynaecological disarders, it has had few adherents in women's health because of misconceptions that it is unphysiological and a male harmane. The potential role of androgens in the pharmacological management of menopausal harmane deficiency states remains to be firmly defined, but there has recently been renewed interest in the addition of low-dose androgen to the traditional estrogen replacement therapy. This is a welcome development because not all menopausal symptoms are adequately controlled with estrogen ar estrogen/progestin therapy. Weight gain, increase in body hair and slight enlargement of the clitoris constitute the most important side effects experienced by androgen users. The purpose of this review is to discuss the role of androgens as an adjuvant to estrogen/progestin replacement therapy with the hope that the clinician wiU evaluate its incorparation into menopausal women's health care. RESUME Mhne si le traiternent substitutif aux androgenes sert depuis plusieurs decennies d traiter divers troubles gynecologiques, il a peu d' adeptes dans le domaine de Ia sante des femmes parce qu' on connalt malle role physiologique des androgenes et parce qu'il s' agit d' harmanes masculines. Le role potentiel des androgenes dans le traiternent pharmacologique des etats de deficit hormonal de Ia minopause reste d preciser , mais on a recemment constate un regain d'interet pour I' ajaut de faibles doses d' androgenes d I' oestrogenotherapie substitutive classique. Ce progres est souhaiwble parce que les sympt6mes de Ia minopause ne sont pas taus supprimes par le traitement aux oestrogenes au par le traitement aux oestrogenes et aux progestatifs. Un gain ponderal, une pilosite accrue et une /egere hypertrophie du clitoris sont les effets secondaires les plus importants chez les utilisatrices d' androgenes. Cet examen vise d discuter du role des androgenes comme traitement d' appoint au traiternent substitutif aux oestrogenes et (au) aux progestatifs, en souhaitant que le clinicien evalue leur integration aux soins de sante des femmes minopausees. J soc OBSTET GYNAECOL CAN 1998;20(9):837·43
KEYWORDS
Menopause, harmane replacement therapy, androgens. Received on September 19th, 1997. Revised and accepted on October 10th, 1997.
JOURNAL SOGC
837
AUGUST 1998
, , , decreased with aging. 4 Although many women are concerned about having a low sex drive, only a few admit or discuss this with their physicians. 4 The level of comfort in discussing issues relating to human sexuality is crucially important in women's health, especially when sexual harassment and sexual abuse concerns are at record highs. Although non-menopausal aspects of sexual relationships are important causes of sexual dysfunction, hormone replacement therapy has been shown to have beneficial effects on sexual desire. While estrogen replacement effectively reverses the atrophic changes in the sexual organs associated with hypo-estrogenic states,5 data are accumulating in support of testosterone as the hormone responsible for sexual drive in womenY The libido is not increased by estrogen therapy but may be improved by testosterone administration. Prospective studies of menopausal women treated with combined subcutaneous implants of estradiol and testosterone showed marked improvement in sexual drive, enjoyment of sex and general well-being. 5This beneficial effect is particularly dramatic in biologically premenopausal women who have had a bilateral oophorectomy.8 Besides the improvement in a woman's motivation and desire for sex, androgen replacement in the menopause increases the frequency of intercourse and sexual response during intercourse, and enhances continuing sexual activity which has been found to protect against vaginal dryness and dyspareunia. Several decades of use have produced compelling evidence of the efficacy of androgens in enhancing human sexual function in menopausal women. The real challenge is to make clinicians consider supplementary androgen therapy when estrogen/progestin have not provided adequate relief from sexual dysfunction. Sexual dysfunction in the menopause is an important component of women's health that is worthy of new therapeutic considerations.
INTRODUCTION
Estrogen therapy, either alone or in combination with a progestin, has been and will probably continue to be the mainstay of treatment for hypo-estrogenic symptoms of the menopause, and for reducing the risk of coronary heart disease and osteoporosis. Nevertheless, many women have menopausal symptoms which are not alleviated by estrogen alone. 1,2 For example, psychological and sexual symptoms persist in some hypogonadal women despite adequate estrogen replacement.) It is becoming clear that, in these instances, androgen replacement therapy should be considered a valuable adjunct to estrogen therapy. New formulations of androgens for hormone replacement are currently available for clinical use or are at various stages of development. Therefore, clinicians need to be aware of new clinical indications for existing compounds and tailor the mode of therapy to the needs of the individual patient. Androgens, traditionally considered to be male hormones, are normally present in women and are essential components in the steroid biosynthetic pathway to estrogen. The ovaries and adrenal glands both contribute to androgen production. The primary circulating androgen is testosterone. In premenopausal women, androgens are involved in follicular development and atresia. They also contribute to the maintenance of bone architecture. The purpose of this article is to discuss the importance of androgen replacement therapy in the menopause and to review the current literature on androgen therapy. I hope that this review will sufficiently demystify androgen replacement, and help the clinician to evaluate the appropriateness of its incorporation into menopausal women's health care. ANDROGENS AND SEXUAL FUNCTION
Sexuality-related problems are important concerns in women's health, although not often freely discussed in clinical settings. Sexual desire and function in women are dependent on a complex interplay of psychological, environmental and biological factors. Urogenital symptoms associated with estrogen deficiency are most common during the menopause. Atrophic changes in the vagina can lead to lack of lubrication, vaginal soreness, dyspareunia, vaginismus and post-coital bleeding. Several studies have found that the overall frequency of sexual fantasy, foreplay, oral sex and vaginal intercourse
JOURNAL SOGC
ANDROGEN REPLACEMENT THERAPY AND COGNITIVE FUNCTION
The menopause has been suggested to be an important modifier of psychological function in women, although such health promoting activities as regular exercise, smoking cessation and dietary discretion may be effective in achieving psychological well-being. Estrogen exerts favourable effects on cognitive function and prevention of senile dementia through neurochemical effects, direct effects on vasculature and effects on the generation of free
838
AUGUST 1998
, , , and psychological symptoms. 16 Thus, the most compelling reason for considering androgen replacement therapy in women is the hormone's efficacy in ameliorating the sudden onset of symptoms associated with surgical menopause. The decision to continue on long-term estrogen-androgen replacement afrer an initial six-month period, or to switch to estrogen alone, will require careful consideration of each woman's situation, well-being and risk profile.
radicals! A growing body of clinical research is emerging strongly supporting the view that androgen therapy may act synergistically with estrogen in relieving symptoms of depression, nervous tension, palpitations, headaches and insomnia. Women who have undergone a surgical menopause show improved cognitive function and feelings of well-being following hormonal replacement with combined estrogen-androgen preparations. lO Sherwin11,12 found higher scores in tests of short-term and long-term memory in postoperative users of combined estrogenandrogen preparations than in users of estrogen alone. In the aggregate, this finding suggests that there are important additional benefits associated with the addition of androgens to estrogen replacement therapy. While the precise mechanism of the action of androgens in improving cognitive function is unclear, it is suggested that the effects may be modulated by various neurochemical factors. 9,lo
SKELETAL SYSTEM
Osteoporosis is a major public health problem in Canada, and fractures of the vertebral spine, hip and wrist are the cause of much of the mortality and morbidity associated with the disease, with an annual age-adjusted incidence of fractures per 100,000 of3Z.7 in males and 89.8 in females. 17 The annual cost of all fracture treatment in Canada is about one billion dollars.ls There is sparse clinical and experimental evidence of the role of combined estrogen-androgen therapy for osteoporosis prevention. Despite initial optimism regarding the possible use of androgens for reducing the risk for menopausal osteoporosis, studies are evenly divided as to whether or not there is an increase in bone mass in women receiving estrogen-androgen versus estrogen replacement therapy.19,2o The cohort study of Watts and colleagues l4
SURGICAL MENOPAUSE AND HORMONE REPLACEMENT
Oophorectomy is increasingly being undertaken in the management of benign gynaecological conditions including endometriosis, chronic pelvic pain and intractable premenstrual syndrome. There also has been a renewed interest in prophylactic oophorectomy at the time of routine hysterectomy in an attempt to reduce the subsequent risk of ovarian cancer.13 Following iatrogenic menopause, there is a rapid fall in serum sex hormone levels which leads to immediate vasomotor and psychological symptoms. Premature menopause due to surgical removal of the ovaries must be managed effectively by hormone replacement therapy to avoid such long-term health sequelae as increased risks of osteoporosis and cardiovascular disease. Although estrogen therapy alone can help to alleviate some of the hypo-estrogenic symptoms, those that receive estrogen-androgen combination therapy are reported to have greater relief from their symptoms. Clearly, surgical menopause continues to be the leading indication for initiating primary estrogen and androgen therapy. Much of the published literature describing the role of estrogen-androgen therapy following surgical menopause is from Canadian investigators/,ll,l2 and is growing. 14 There have been several clinical trials of combined estrogen and androgen replacement versus estrogen alone in oophorectomized women. 14-16 Those that received estrogen-androgen combination therapy were reported to have greater improvement of their vasomotor
JOURNAL SOGC
found a small but non-significant increase in the spinal bone density of patients who received estrogen only compared to those taking an oral combination containing estrogens and methyltestosterone. A large prospective European studyl9 indicated that the bone density at the lumbar spine and neck of the femur remained unchanged in women who continued to use oral estrogen therapy alone, while those that changed to subcutaneous estradiol and testosterone replacement demonstrated increased bone density at those sites. Overall, there is some encouraging evidence that physiological doses of androgens may act in synergism with estrogens in either preventing bone loss or in reversing some of the postmenopausal bone loss that may have occurred. 19,20 Hormone replacement combining estrogen and androgen seems to be a favourable therapy for selected patients. OTHER BENEFITS FROM ANDROGEN THERAPY
The effect of androgens in several auto-immune and growth disorders is little understood and extremely interesting. 21 Auto-immune diseases like systemic lupus
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AUGUST 1998
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, , , erythematosus and rheumatoid arthritis are more common in women than in men. It has been suggested that women with these diseases have lower plasma androgen levels than control women. 21,22 The efficacy shown by danazol, an isoxazol derivative of 17 a-ethanol testosterone, in the treatment of young women with rheumatoid arthritis,22 supports the theory that low androgen levels may playa role in auto-immune disorders. A novel aspect of treatment with androgen regimens is the use of such weak adrenal androgens as dehydroepiandrosterone and DHEA-sulphate in the management of auto-immune diseases. Supporting evidence is provided by results from clinical studies, and a small series of cases, that low-dose adrenal androgen replacement may improve age-related decline in cognitive ability,23 enhance rapid eye movement (REM) sleep24 and offer cardioprotection by reducing platelet aggregation,25 as well as acting as an insulin-sensitizing and anti-obesity agent. 26 The use of androgens as adjuncts in the treatment of these disorders will require sound clinical trials. If further studies confirm that androgens do have beneficial effects in auto-immune and age-related disorders, it would be a major development in menopausal hormone replacement therapy.
TABLE 1 FORMULATIONS FOR ANDROGEN THERAPY Preparation and dosage
Intramuscular Testosterone enanthate (200 mg/mL) Delatestryl (Squibb) (100 mg every 4 weeks) Testosterone enanthate 150 mg/mL, Climacteron (Sabex) estradiol dienanthate 7.S mg/mL and estradiol benzoate 1 mg/mL (1 mL every 4-8 weeks) Testosterone cypionate 100 mg/mL (1 mL every 4 weeks)
Depo Testosterone Cypionate (Pharmacia & Upjohn)
Oral Testosterone undecanoate 40 mg (40 mg alternate days)
Andriol (Organon)
Fluoxymesterone 5 mg (5 mg alternate days)
Halotestin (Pharmacia & Upjohn)
Methyltestosterone 10 mg/20 mg (Dosage individualized)
Metandren (Novartis)
Methyltestosterone 1.25 mg/2.5 mg and esterified estrogens 0.625 mg (One tablet daily)
Estratest* (Solvay)
local formulations Ointment Testosterone propionate or cypionate (Local pharmacy preparation) 2%, in petrolatum jelly • Not available in C anada
Canada), licensed for replacement therapy in males for conditions associated with symptoms of deficiency or absence of endogenous testosterone, and for male climacteric symptoms. The dose of oral preparations should be low initially to reduce the potential for side effects. Andriol, available as 4O-mg soft gel capsules, is being used as supplementary therapy to estrogen, on a daily or alternate day basis. This dosage regimen is relatively arbitrary and can be altered to the specific therapeutic goals of each patient. Combined oral estrogen and androgen preparations are currently being developed in Canada and, as newer formulations of these agents become available, it is likely that they will play an increasingly important role in the clinical management of the menopause. Existing data are insufficient to recommend a prolonged duration of androgen replacement in the menopausal woman. The available literature regarding a carefully planned, brief duration of therapy is encouraging and all options should be presented to the patient.
REGIMENS OF ANDROGEN REPLACEMENT THERAPY
Androgens are available in a number of formulations (Table 1), presented in various delivery systems and applied at varying dose levels. Androgens are usually administered either as intramuscular injections, subcutaneous implants, oral tablets or as local ointments, according to the needs of the patient. The usual dose suggested is monthly intramuscular injections of 75 to 150 mg testosterone enanthate. 12 It is feasible to administer intramuscular and subcutaneous preparations for prolonged periods of treatment. However, because of peaks and nadirs and variable blood levels, problems of dosing may be disadvantageous for the patient. An oral estrogen-androgen preparation marketed as Estratest (esterified estrogens, 0.625 mg, and methyltestosterone 1.25 or 2.5 mg daily; Solvay Pharmaceuticals) has been available in the United States for some time. Oral androgen preparations currently in use in Canada are testosterone undecanoate (Andriol; Organon, Canada), methyltestosterone (Metandren; Novartis, Canada) and fluoxymesterone (Halotestin; Pharmacia and Upjohn
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Proprietary names (manufacturer)
PRECAUTIONS
Androgen monotherapy should not be practised for menopausal hormone replacement except for specific
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, , , age-related vulvo-vaginallesions. Androgen treatment in menopausal patients with intact uteri should be an adjunct to combined estrogen/progestin therapy, rather than a substitute for progestins, in order to prevent the development of endometrial hyperplasia and carcinoma. Androgens are contra-indicated in patients with breast cancer, in those with hepatic or renal dysfunction and those with, or at risk for hypercalcaemia or with hypersensitivity to androgens.
dose androgen to the traditional estrogen replacement therapy. This is a welcome development because not all menopausal symptoms are adequately controlled with estrogen or estrogen/progestin therapy. Given the compelling evidence that androgen lack is involved in mediating some of the symptoms of menopause, it is reasonable to advocate replacement. The availability of a wide range of pharmacological agents enables physicians to tailor the management of the menopause to the individual needs of their patients. The use of estrogen therapy with or without an androgen should be an informed joint decision of physician and patient that must be re-evaluated regularly as new information becomes available.
POTENTIAL SIDE EFFECTS
The decision to use androgen replacement therapy rests with the patient following counselling. In this situation, not only the benefits but also the risks and safety considerations are important items for discussion. Most of the side effects of androgens are of mild or moderate intensity, and include increase in body hair, deepening of the voice and weight gain. Slight enlargement of the clitoris could be a concern for some women, although most do not seem to be bothered by this phenomenon. In general, most of the side effects associated with androgens tend to be well tolerated by women and are reversible following discontinuation of therapy. Androgens like most drugs produce biological effects that are dose dependent. There is a suggestion that serum lipid profiles are elevated in women using 2.5 or five mg per day of methyltestosterone,14 but this has not been observed in other studies. 27 Androgen replacement in low doses, given as transdermal patch28 or as oral testosterone undecanoate (which is absorbed via the lymphatic system, thereby escaping hepatic first passage) does not appear to affect lipoprotein concentrations adversely. In general, only a short-term application of androgens is necessary for its adjuvant role in hormone replacement. During such a short course of therapy hyperlipidaemia is not a concern. However, the safety of long-term androgen therapy deserves careful study.
REFERENCES 1.
Barrett-Connor E, Timmons C, Young R, Wi ita B, Estratest Working Group. Interim safety analysis of a two-year study comparing oral estrogen-androgen and conjugated estrogens in surgically menopausal women. J Women's Health 1996;5:593-602. 2. Casson PR, Carson SA. Androgen replacement therapy in women: myths and realities. Int J Fertil Menopausal Stud 1996;41 (4):412-22. 3. Burger HG, Hailes J, Menclaus M, Nelson, J, Hudson B, Balaz N. The management of persistent menopausal symptoms with oestradiol-testosterone implants: clinical, lipid and hormonal results. Maturitas 1984;6(4):351-8. 4 Rosen RG, Taylor JF, Leiblun SR, Bachmann GA. Prevalence of sexual dysfunction in women: results of a survey study of 329 women in an outpatient gynecologic clinic. Sex Ther 1993;19:172-88. 5 Leiblum SR, Bachmann GA, Kemmann E, Colbourn D, Swartzman L. Vaginal atrophy in the postmenopausal woman: the importance of sexual activity and hormones. JAMA 1993;249:2195-8. 6. Burger H, Hailes J, Nelson J, Menelaus M. Effect of combined implants of oestradiol and testosterone on libido in postmenopausal women. BMJ (Clin Res Ed) 1987; 294:936-7. 7. Sherwin BB, Gelfand MM, BrenderW. Androgen enhances sexual motivation in females: a prospective crossover study of sex steroid administration in the surgical menopause. Psychosom Med 1985;47:339-51. 8. Lindgren R, Berg G, Hammar M, Zuccon E. Hormonal replacement therapy and sexuality in a population of Swedish postmenopausal women. Acta Obstet Gynecol Scand 1993;72:292-7. 9. Fillit H. Future therapeutic developments of estrogen use. J Clin Pharmacol 1995;35(9 Suppl):25S-28S. 10. Whiteford GM. Alzheimer's disease and serotonin: a review. Neuropsychobiology 1986;15:1-10.
SUMMARY
Although androgen replacement therapy has been in use for several decades for various gynaecological disorders, it has had few adherents in women's health because of misconceptions that it is unphysiological and a male hormone. The potential role of androgens in the pharmacological management of menopausal hormone deficiency states remains to be defined firmly, but there has recently been renewed interest in the addition oflow
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, , , 11. Sherwin BB. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology 1988;13(4):345-57. 12. Sherwin BB. Affective changes with estrogen and androgen replacement therapy in surgically menopausal women. J Affect Disord 1988;14:177-87. 13. Rozario D. Brown I, Fung MF, Temple L. Is prophylactic oophorectomy an acceptable means to reduce the incidence of ovarian cancer? Am J Surg 1997;173(6):495-8. 14. Watts NB, Notelovitz M, Timmons MC et al. Comparison of oral estrogens and estrogen plus androgen on bone mineral density, menopausal symptoms, and lipidlipoprotein profiles in surgical menopause. Obstet Gynecol 1995;85:529-37. 15. Sherwin BB, Gelfand MM. The role of androgen in maintenance of sexual functioning in oophorectomized women. Psychosom Med 1987;49:397-409. 16. Sherwin BB. Sex hormones and psychological functioning in postmenopausal women. Exp Gerontol 1994;29:423-30. 17. Canadian Task Force on the Periodic Health Examination. The periodic health examination: 2.1987 update. Can Med Assoc J 1988;138:618-26. 18. Hanley DA, Josse RG. Prevention and management of osteoporosis: consensus statements from the Scientific Advisory Board of the Osteoporosis Society of Canada. 1. Introduction. Can Med Assoc J 1996;155(7):921-3. 19. Sawas M, Studd JW, Norman S, Leather AT, Garnet TJ, Fogelman I. Increase in bone mass after one year of percutaneous estradiol and testosterone implants in postmenopausal women who have previously received long-term oral estrogens. Br J Obstet Gynaecol 1992;99:7 57 -60. 20. Raisz L, Wiita B, Artis A et a/. Comparison of the effects of estrogen alone and estrogen plus androgen on biochemical markers of bone formation and resorption in postmenopausal women. J Clin Endocrinol Metab 1996;81 :37-43. 21. Lahita RG. The connective tissue diseases and the overall influence of gender. Int J Fertil Menopausal Stud 1996;41 (2): 156-65. 22. Van Vollenhoven RF, McGuire JL. Estrogen, progesterone, and testosterone: can they be used to treat autoimmune diseases? Cleve Clin J Med 1994;61 (4):276-84. 23. Morales AJ, Nolan JJ, Nelson JC et al. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol Metab 1994;78:1360-7. 24. Friess E, Trachsel L, Guldner J et al. DHEA administration increases rapid eye movement sleep and EEG power in the sigma frequency range. Am J PhysioI1995;268:E1 07 -E113. 25. Lesse RL. The effects of DHEA on atherogenesis and platelet function. Ann NY Acad Sci 1995;774:281-91. 26. Bates GW, Egerman RS, Umstot ES et al. Dehydroepiandrosterone attenuates study-induced declines in insulin sensitivity in postmenopausal women. Ann NY Acad Sci 1995;774:291-3.
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27. Sherwin BB, Gelfand MM, Schucher R, Gabor J. Postmenopausal estrogen-androgen replacement and lipoprotein lipid concentrations. Am J Obstet Gynecol 1987;156(2):414-9. 28. Kaunitz AM. The role of androgens in menopausal hormonal replacement. Endocrinol Metab Clin North Am 1997;26(2):391-7.
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