SUSAN DAVIS

The Jean Hailes Foundation, Clayton, Victoria 3168, Australia

Dr. Susan Davis, The Jean Hailes Foundation, 173 Carinish Road, Clayton, Victoria 3168, Australia; E-mail: suedavis@netlink.com.au.

Abstract

There is increasing evidence to suggest that many postmenopausal women experience symptoms alleviated by androgen therapy and that such symptoms may be secondary to androgen deficiency. Affected women complain of fatigue, low libido, and diminished wellbeing, symptoms easily and frequently attributed to psychosocial and environmental factors. When such symptoms occur in the setting of low circulating bioavailable testosterone, testosterone replacement results in significant improvement in symptomatology and, hence, quality of life for the majority of women. Whether the apparent therapeutic effects of testosterone replacement are mediated by testosterone and its metabolite 5α- dihydrotestosterone or are a consequence of aromatization to estrogen is not known. Despite the paucity of data regarding its effects, inclusion of testosterone in postmenopausal hormone replacement regimens is not uncommon and is likely to become more widespread with the availability of preparations developed specifically for women.

Other novel and even more controversial 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 glucocorticoste- roid-related bone loss, alleviation of wasting syndrome secondary to human immunodeficiency virus infection, and management of premenstrual syndrome.

The aim of this commentary is to very briefly review the rationale for the use of testosterone in women, create awareness of some of the therapeutic options available in various countries, and stimulate discussion of this important aspect of women’s health.

Introduction

The therapeutic use of testosterone in women, although con-troversial, is becoming more widespread. Unfortunately, the data to support this practice are relatively limited, as only a few randomized studies have been conducted. Androgen replacement for women has been previously reviewed in this journal (1) and more recently and more extensively elsewhere (2, 3). This commentary is focused on the evidence to support the use of testosterone therapy in women and potential novel indications, and highlights the need for further research in this area.

Androgens have important physiological actions in women that are poorly understood. Furthermore, there is no consensus on either the clinical or biochemical definition of androgen deficiency in women. The latter has been hampered by the insensitivity of most assays for testosterone at the lower end of the normal reproductive female range. Clearly a working definition of androgen deficiency in women is needed for consistency of ongoing research in this area and as a foundation for clinical guidelines for the use of testosterone in women to prevent its inappropriate use.

It is the cumulative experience of this author and others working in this field (3a) that the clinical profile that char-acterizes the woman most likely to respond to androgen therapy, and therefore possibly female androgen deficiency, includes persistent inexplicable fatigue, blunted motivation, low libido, and diminished well-being in a woman who is estrogen replete with low circulating bioavailable testosterone (either total testosterone/sex hormone-binding globulin (SHBG) ratio or free testosterone in the lower third of the female reproductive range). Indisputably, the basis of each of these symptoms is potentially multifactorial; therefore, it is essential that the treating physician endeavors to discern the extent to which other factors contribute to these symptoms. Although this may be time consuming and complex, it is essential that the treating physician does so and manages any identifiable factors. This may involve commencement of es-trogen therapy for vaginal atrophy or referral to a counselor, psychiatrist or sex therapist. The impact of any intervention should be reviewed before recommending testosterone replacement.

Causes of hypoandrogenism in women

Circulating androgen levels [total testosterone, free tes-tosterone, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEA-S)] in women fall continuously with age (4, 5). This is a consequence of the age-related decline in adrenal androgen production and loss of the midcycle increase in ovarian testosterone secretion in the late reproductive years (6). After ovariectomy, both testosterone and androstenedi- one (A) fall acutely by approximately 50% (7). Other causes of suppression of circulating androgen levels include chemical ovariectomy with either chemotherapy or GnRH antagonists, radiotherapy, and the administration of exogenous estrogens and glucocorticosteroids. In general, there is a fall in circulating free testosterone in women using the combined oral contraceptive pill or oral estrogen replacement therapy (8, 9). The latter a result of increased SHBG combined with suppression of LH production by the pituitary, and hence less stimulus for the ovarian stromal production of testosterone. These effects are amplified in older women, whose overall androgen production is declining (8, 9). Treatment with oral glucocorticosteroids results in ACTH suppression and therefore reduced adrenal androgen production (10). This appears to contribute in part to the pathogenesis of osteopenia and osteoporosis associated with glucocortico- steroid treatment in both women and men. Hypothalamic amenorrhea and hyperprolactinemia may also be character-ized by low testosterone and bone loss. Similarly, women with premature ovarian failure have been reported to suffer significant bone loss despite apparently adequate standard estrogen-progestin therapy (l1). Therefore, it may be that some women with either ongoing hypothalamic amenorrhea or premature ovarian failure require testosterone replacement to fully protect their bones.

In women, the mechanisms of androgen action are not well understood. Androgens may act directly via the androgen receptor or as precursor hormones for estrogen production in the ovaries and extragonadal tissues, importantly bone, adipose tissue, and brain. Thus, the maintenance of physi-ological circulating androgen levels in women ensures an adequate supply of precursor hormone for estrogen biosyn-thesis in extragonadal sites in which high estrogen tissue concentrations may be required physiologically (for example, maintenance of bone mineralization and prevention of bone loss). Corroborative data for this hypothesis are that total and bioavailable testosterone and DHEA-S are the greatest predictors of bone mineral density (BMD), with low free testosterone being most highly correlated with premeno-pausal hip bone loss (12,13); androgen levels are consistently and positively associated with BMD in postmenopausal women (14, 15); and abundant aromatase activity has been reported in fetal osteoblasts and cell lines of osteoclastic origin (16). With respect to the central nervous system, regions of high aromatase activity in animals correlate with regions of the brain in women with the highest concentrations of testosterone (17, 18). However, in these regions, namely the preoptic area, substantia nigra, and hypothalamus, the levels of measurable testosterone greatly exceed those of estradiol in samples from female cadavers taken acutely postmortum (17).

In summary, the extent to which androgens act directly in women or as prehormones for estrogen production, or per-haps by lowering SHBG and increasing free circulating levels of estradiol and other sex steroids, is not known. It is possible that all of these effects are important to varying degrees in different tissues.

Clinical indications for androgen therapy in women

Androgens appear to be important in female sexuality, with reduced androgen levels in the late reproductive years and beyond contributing to the decline in sexual interest experienced by many women. Standard estrogen replacement therapy has little effect on libido in women not troubled by vaginal dryness and dyspareunia (19-21). In a study of sexagenarian women, the only hormone positively correlated with sexual desire was circulating free testosterone (22). We and others have demonstrated improvement in several aspects of sexuality in postmenopausal women treated with testosterone over and above the effects of estrogen replace-ment alone (19-21, 23-27). Sustained improvement in intensity of sexual drive, arousal, frequency of sexual fantasies, sat-isfaction, pleasure, and relevancy to daily life were observed in a cohort of postmenopausal women (Fig. 1). Enhancing effects have been reported with both oral methyl testosterone and parenteral testosterone administration. Enhanced sexuality, as observed in these studies, is subtle. Notably increased sexual activity in women is a poor index of response to therapy, as the frequency of intercourse is often dictated by established patterns and interest of the partner. Our results (25) may differ from other reports because we conducted one of the very few blinded randomized studies designed specifically to address the effects of testosterone on sexuality, plus it involved a 2-yr protocol with six monthly evaluations to minimize the confounding effects of a placebo response.

Figure 1. Summary graph showing the grand mean (i.e. means of 6, 12, 18, and 24 months) for each sexuality parameter adjusted for baseline as a covariate. O, Estradiol implants alone; ■, estradiol plus testosterone implants. Error bars represent the SE for each mean. If the error bars do not overlap for a single parameter, the difference is significant at P < 0.05 (25).

Testosterone replacement should also be considered as part of the management of young women with premature menopause, particularly Turner's syndrome. Women who are sexually active when they develop premature ovarian failure often suffer a great deal as a consequence of their diminished libido. Alternatively, young women who have not become sexually active, who have either primary or secondary premature ovarian failure, should be fully informed about the option of androgen replacement or, perhaps, in some instances offered low dose androgen replacement as a component of their hormone replacement regimen.

Whether premenopausal women who complain of loss of libido who have low bioavailable testosterone levels should be offered androgen replacement is more controversial. In general, management of such women needs to be very open- minded, and therapy completely individualized. It is the clinical experience of the author that a subset of premeno-pausal women with sexual dysfunction and reduced circulating androgen levels significantly benefits from judicious parenteral testosterone replacement. However, testosterone replacement is unlikely to benefit women at any age in whom other factors play a dominant role in their sexual dysfunction. Therefore, a thorough psychosocial and sexual history is essential when evaluating the appropriateness of testosterone therapy in a woman.

Prevention and treatment of bone loss

Studies of both oral and parenteral estrogen plus testos-terone therapy in postmenopausal women have shown ben-eficial effects of testosterone replacement on BMD (25,28,29). Oral esterified estrogen in combination with methyltestos-terone therapy not only increases spinal BMD, but also sup-presses biochemical markers of bone reabsorption, with an increase in markers of bone formation over 2 yr (29, 30). Combined estradiol-testosterone replacement with sc implant pellets increases bone mass in postmenopausal women, with the effects in the hip and spine greater than those with estradiol implants alone (Figs. 2 and 3) (25,28,31). Androgen replacement to prevent bone loss should also be considered for women with premature ovarian failure. Despite adequate standard estrogen-progestin therapy, two thirds of such women have significantly reduced BMD to levels associated with increased hip fracture risk. Of these, 47% have reductions in BMD within 18 months of their diagnosis (11).

Effects on body composition

Testosterone levels are frequently lower in human immu-nodeficiency virus (HIV)-positive premenopausal women, and testosterone replacement is associated with an increase in fat-free mass and body cell mass in HIV-positive men. Augmentation of testosterone levels in HIV-positive pre-menopausal women using a transdermal patch is associated with overall increased mean body weight and body mass index as well as improved quality of life (32). We have re-ported an increase in fat-free mass and a reduced fat mass to fat-free mass ratio in postmenopausal women treated with concurrent estrogen-testosterone therapy (25). A gain in fat free mass probably reflects increased muscle mass, and as aging is associated with loss of muscle mass, this is a beneficial effect of testosterone therapy in the older woman. However, administration of testosterone attenuates the reduction in centralized body fat achieved with estrogen replacement alone (25).

Figure 2. The effects of hormonal implants on BMD (grams per cm²), lumbar spine (L1-L4), and femoral trochanter (troc). E, Estradiol; E&T, estradiol plus testosterone. Error bars represent the SE. Inner error bars are used to compare means between times for the same treatment. The comparison between the treatment groups is made with the outer error bars. If error bars do not overlap, that is differ by more than 2 SE, the means are significantly different by at least P < 0.05 (25).

Testosterone and the premenstrual syndrome

Recent studies indicate that premenstrual syndrome (PMS) represents individual vulnerability to the effects of circulating steroids. Variations in testosterone levels during the menstrual cycle may influence behavioral changes such as those seen in PMS, and significantly lower levels of tes-tosterone throughout the menstrual cycle have been reported in women who suffer from PMS compared with controls (33, 34). Testosterone replacement is used in the management of PMS in some clinical centers in the United Kingdom and Australia (35). Randomized trials evaluating such therapy are nearing completion, and positive outcomes from these are necessary before testosterone therapy for PMS can be recommended for widespread use.

Testosterone and autoimmune disease

Immunogenetic factors are the major determinants of the development of immune-mediated diseases; however, gender and age also play a role. Androgens appear to suppress both cell-mediated and humeral immune responses, and it has been proposed that higher testosterone levels, as seen in men, maybe protective against autoimmune disease (36-38). The direct administration of testosterone replacement may result in symptomatic improvement in postmenopausal women with rheumatoid arthritis (39), and reduced disease activity has been reported in both pre- and postmenopausal women treated with DHEA associated with increases in levels of circulating DHEA, DHEA-S, and testosterone (40). Further evaluation of potential beneficial effects of testosterone administration in women with autoimmune arthritis is warranted in view of the favorable preliminary studies, the positive effects of this therapy on lean body mass and bone density, and the adverse effects of glucocorticosteroids on these parameters.

Figure 3.

Administering testosterone to women

The majority of available testosterone preparations for human use have been formulated for use in men. Furthermore, few countries have officially approved the use of testosterone for hormone replacement therapy in women, and clinical guidelines for safe use are lacking. Testosterone is available as oral methyltestosterone in the United States, and testosterone implants have been approved for replacement therapy for women in the United Kingdom. It is our clinical experience that even for postmenopausal women, testosterone levels often need to be restored to at least the upper end of the normal physiological range for young ovulating women to achieve a good therapeutic response in terms of improved libido. The dose of testosterone administered, however, should result in circulating levels as close to physiological as possible to avoid adverse side-effects.

Of the available oral preparations, methyltestosterone in combination with esterified estrogen (EE; either 0.625 mg EE plus 1.25 mg methyltestosterone or 1.25 mg EE plus 2.5 mg methyltestosterone) has been the most studied and in the currently available doses in North America offers therapeutic benefits, but has occasional side-effects. Although long term therapy with large doses of this compound has adverse hepatic effects, this has not been seen with lower doses (41). This oral therapy does, however, negate some of the beneficial lipid effects of estrogen, with reductions in high density lipoprotein cholesterol and apolipoprotein A1 with 0.625 mg EE plus 1.25 mg methyltestosterone (41). This combined therapy does not appear to attenuate the favorable effects of EE on vascular reactivity (42) and is associated with reduced concentrations of apolipoprotein B (41, 43) and increased total body low density lipoprotein cholesterol catabolism (43). Physicians should be aware that androgenic side-effects may occur with the EE/methyltestosterone preparations (41) and should warn patients of this possibility and monitor for androgenic side-effects. As this compound cannot be measured in serum in a clinical setting, it is impossible to recommend biochemical treatment guidelines.

Testosterone undecanoate has been less well studied; how-ever, a recent pharmacokinetic study indicates undesirable supraphysiological peaks of circulating testosterone with doses of testosterone undecanoate as low as 20 mg (44). Therefore, with the limited data available, its use in women cannot be recommended.

Subcutaneous testosterone implants have been used for many years in postmenopausal women. These implants are fused crystalline implants 4.5 mm in diameter containing testosterone BP (British Pharmacopoeia) as the active ingre-dient. Our clinical experience, verified by published data, is that a dose of 50 mg is extremely effective in enhancing libido and improving BMD without unwanted virilizing side- effects (24, 25, 27). The 50-mg implant, which is inserted under local anesthesia, sc, usually in the lower anterior abdominal wall, is effective for between 3-6 months. There is, however, marked individual variation in this period; therefore, testosterone levels should be carefully monitored, and serum testosterone measured before the administration of each subsequent implant. Rarely are testosterone implants of 100 mg necessary to achieve adequate therapeutic effects. Indeed, Buckler and others reported circulating testosterone levels approximately 3 times the upper limit of normal 4 weeks after insertion of a 100-mg testosterone pellet (44). Unfortunately, the impact of these levels on sexuality and other clinical parameters was not reported. In contrast, 6 weeks after insertion of a 50-mg testosterone implant, mean circulating testosterone levels are just above the upper limit of the normal range for ovulating women (27).

Mixed testosterone esters (50-100 mg) are occasionally administered every 4-6 weeks as an im injection to women with androgen deficiency symptoms, although there are no published data to support this practice. Clinically, this therapy results in a more rapid onset of effects, such that women report enhanced libido within 2-3 days of treatment. In contrast, women generally report a delay in restoration of libido 10-14 days after insertion of a testosterone implant. The pharmacokinetics of mixed testosterone esters administered im to women have not been studied; however, many women report increased acne and occasional cliteromegaly with this therapy.

The recent development of a transdermal testosterone ma-trix patch intended specifically for use in women will provide a new therapeutic option for androgen replacement. The patch, which is now undergoing clinical trials, is designed to deliver 150 pg testosterone/day with a twice a week application. This results in an average increase in circulating testosterone levels of approximately 25 ng/dL (~1 nmol/L). The availability of such a patch will have some obvious advantages over both oral and implant therapy; however, some women may experience skin irritation or simply prefer a less conspicuous mode of therapy. Much higher dose transdermal patches in women have been reported to produce supraphysiological circulating testosterone levels in women, and their use cannot be advocated (44).

Nandrolone decanoate is a very weakly aromatizable an-drogen that is available in some countries for the treatment of postmenopausal osteoporosis and is administered im. The dose should not exceed 50 mg, and although the recommen-dation is for this to be give monthly, androgenic side-effects may be encountered but can be avoided with every 8 week administration, or even less frequently in very petite women. In the majority of women, treatment with nandrolone de-canoate results in cessation of bone loss over time, and in some women, it produces an absolute increase in BMD (45).

Other alternatives, not currently generally available but still in widespread use, are transdermal testosterone as a cream or gel, or delivery by a transvaginal ring. Such prep-arations may be regionally available on specific prescription from compounding pharmacists; however, to date, there are no pharmocokinetic data available or published clinical ex-perience regarding the use of such preparations.

As a general rule, testosterone replacement should not be administered to postmenopausal women who are not re-ceiving concurrent estrogen replacement therapy. In the first instance, estrogen alone may improve other postmenopausal symptoms, alleviate vaginal dryness, and enhance sexuality, obviating the need for androgen therapy. Furthermore, sup-pression of SHBG with testosterone alone may increase the possibility of adverse side-effects, although this may be less relevant for methyltestosterone, which binds poorly to SHBG (41). The exception to this practice would be the use of nan- drolone decanoate in the more elderly woman, hence the need for vigilant monitoring for virilizing side-effects with this preparation used alone.

Relatively strong contraindications to testosterone therapy include moderate to severe acne, clinical hirsutism, androgenic alopecia, and circumstances in which enhanced libido would be undesirable. Absolute contraindications include pregnancy and lactation as well as known or suspected an-drogen-dependent neoplasia.

Side-effects from excessive dosage include virilization, fluid retention, and potentially adverse lipoprotein-lipid effects, which are more likely with oral administration.

Clinical data indicate that parenteral testosterone therapy that results in testosterone levels close to and within the normal physiological range for women has no undesirable metabolic consequences (25, 31). It is not known whether there is any relationship between exogenous androgen therapy and the incidence of breast cancer, as epidemiological studies have shown both positive and negative associations between endogenous androgen levels and breast cancer risk. Androgen receptors are found in over 50% of breast tumors (46) and are associated with longer survival in women with operable breast cancer and a favorable response to hormone treatment in advanced disease (47). There are also some data to suggest that the mechanism by which high dose medroxyprogesterone acetate has a therapeutic effect on breast cancer is mediated via the androgen receptor (48).

Conclusions

It is increasingly being accepted that androgen deficiency in women underpins a variety of symptoms and pathophys-iological conditions and that in certain subsets of women, androgen replacement therapy is of clinical benefit. The in-clusion of testosterone therapy in postmenopausal hormone therapy regimens is increasing, but is still limited by the lack of availability of preparations and formulations designed specifically for use in women. Although more controversial, premenopausal women with either spontaneous or iatrogenic androgen deficiency also warrant consideration for androgen replacement, as do women experiencing glucocor- ticosteroid-induced bone loss and possibly premenopausal bone loss. The role of androgen therapy in the premenstrual syndrome should be further elucidated by results from ran-domized placebo-controlled studies which are currently underway.

Many women are not comfortable discussing their loss of sexual desire, particularly those who have undergone che-motherapy, and often comment that they feel the issue will be viewed by their physician as trivial relative to their recovery or remission. Also, the symptoms of iatrogenic menopause can easily be attributed to side-effects of chemotherapy or to other psychosocial factors in premenopausal women or in those who have undergone premature menopause. Therefore it is the treating physician's responsibility to facilitate discussion of sexuality in all at risk women, and the possibility of low circulating androgen levels as an underlying cause for those with positive symptomatology should be evaluated.

References

Davis SR, Burger H. 1996 Andgrogens and postmenopausal women. J Clin Endocrinol Metab. 81:2759-2763. 

Davis SR, Burger HG. The rationale for physiological testosterone replacement in women. Bailliere Clin Endocrinol Metab. In press. 

Davis SR. 1998 The clinical use of androgens in female sexual disorders. J Sex Marital Ther. 24:153-163. 

Australasian Menopause Society Council. Consensus of the Australasian Menopause Society Council, 1999. In press. 

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

Zumoff B, Rosenfeld RS, Strain GW. 1980 Sex differences in the 24 hour mean plasma concentrations of dehydroisoandrosterone (DHA) and dehydroisoan- drosterone sulfate (DHAS) and the DHA to DHAS ratio in normal adults. J Clin Endocrinol Metab. 51:330-334. 

Mushayandebvu T, Castracane DV, Gimpel T, Adel T, Santoro N. 1996 Evidence for diminished midcycle ovarian androgen production in older reproductive aged women. Fertil Steril. 65:721-723. 

Judd HL. 1976 Hormonal dynamics associated with the menopause. Clin Obstet Gynecol. 19:775-788. 

Mathur RS, Landgreve SC, Moody LO, Semmens JP, Williamson HO. 1985 The effect of estrogen treatment on plasma concentrations of steroid hormones, gonadotropins, prolactin and sex hormone-binding globulin in post-menopausal women. Maturitas. 7:129-133. 

Krug R, Psych D, Pietrowsky R, Fehm HL, Born J. 1994 Selective influence of menstrual cycle on perception of stimuli with reproductive significance. Psychosom Med. 56:410-417. 

Abraham GE. 1974 Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle. J Clin Endocrinol Metab. 39:340 -346. 

Anasti JN, Kalantaridou SN, Kimzey LM, et al. 1998 Bone loss in young women with karotypically normal spontaneous premature ovarian failure. Obstet Gynecol. 91:12-15. 

Simberg N, Titinen A, Silfrast A, Viinikka L, Ylikorkala O. 1995 High bone density in hyperandrogenic women: effect of gonadotropin-releasing hormone agonist alone or in conjunction with estrogen-progestin replacement. J Clin Endocrinol Metab. 81:646-651. 

Slemenda C, Longcope C, Peacock M, Hui S, Johnston CC. 1996 Sex steroids, bone mass, and bone loss. A prospective study of pre-, peri- and postmenopausal women. J Clin Invest. 97:14-21. 

Ettinger B, PressmanA, Sklarin P, Bauer DC,CauleyJA,Cummings SR. 1998 Associations between low levels of serum estradiol, bone density, and fractures among elderly women: the study of osteoporotic fractures. J Clin Endocrinol Metab. 83:2239-2243. 

Khosla S, Melton LJ, Atkinson EJ, O'Fallon WM, Klee GG, Riggs BL. 1998 

Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. J Clin Endocrinol Metab. 83:2266-2274. 

Shozu M, Simpson ER. 1998 Aromatase expression of human osteoblast-like cells. Mol Cell Endocrinol. 139:117-129. 

Bixo M, Backstrom T, Winblad B, Andersson A. 1995 Estradiol and testosterone in specific regions of the human female brain in different endocrine states. J Steroid Biochem Mol Biol. 55:297-303. 

Roselli CE, Resko JA. 1993 Aromatase activity in the rat brain: hormone regulation and sex differences. J Steroid Biochem Mol Biol. 44:499-508. 

Utian WH. 1972 The true clinical features of postmenopausal oophorectomy and their response to estrogen replacement therapy. S Afr Med J. 46:732-737. 

Campbell S, Whitehead M. 1977 Oestrogen therapy and the menopausal syndrome. Clin Obstet Gynecol. 4:31-47.  

Sherwin BN, Gelfand MM, Brender W. 1997 Androgen enhances sexual motivation in females: a prespective, crossover study of sex steroid administration in surgical menopause. Psychosom Med. 47:339-351. 

Bachmann GA, Leiblum SR. 1991 Sexuality in sexagenarian women. Matu- ritas. 13:45-50. 

Studd JWW, Colins WP, Chakravarti S. plants in the treatment of psychosexual problems in postmenopausal women. Br J Obstet Gynaecol. 84:314-315. 

Burger HG, Hailes J, Nelson J, Menelaus M. 1987 Effect of combined implants of estradiol and testosterone on libido in postmenopausal women. Br Med J. 294:936-937. 

Davis SR, McCloud PI, Strauss BJG, Burger HG. 1995 Testosterone enhances estradiol's effects on postmenopausal bone density and sexuality. Maturitas. 21:227-236. 

Studd JWW, Chakravarti S, Oram D. 1977 The climacteric. Clin Obstet Gynecol. 4:3-29. 

Burger HG, Hailes J, Menelaus M. 1984 The management of persistent symptoms with estradiol-testosterone implants: clinical, lipid and hormonal results. Maturitas. 6:351-358. 

Savvas M, Studd JWW, Fogelman I, Dooley M, MontgomeryJ, Murby B. 1988 Skeletal effects of oral estrogen compared with subcutaneous oestrogen and testosterone in postmenopausal women. Br Med J. 297:331-333. 

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

Raisz LG, Witta B, Artis A, et al. 1995 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. 81:37-43. 

Savvas M, Studd JWW, Norman S, Leather AT, Garnett TJ. 1992 Increase in bone mass after one year of percutaneous oestradiol and testosterone implants in post menopausal women who have previously received long-term oral oestrogens. Br J Obstet Gynaecol. 99:757-760. 

Miller K, Corcoran C, Armstrong C, et al. 1998 Transdermal testosterone administration in women with acquired immunodeficiency syndrome wasting: a pilot study. J Clin Endocrinol Metab. 83:2717-2725. 

Bloch M, Schmidt PJ, Su T-P, Tobin MB, Rubinow DR. 1998 Pituitary-adrenal hormones, and testosterone across the menstrual cycle in women with premenstrual syndrome and controls. Biol Psychiatry. 43:897-903. 

Rubinow DR, Roy-Byrne P. 1984 Premenstrual syndromes: overview from a methodological perspective. Am J Psychol. 141:163-172. 

Burger H, Davis SR. 1998 Should women be treated with testosterone. Clin Endocrinol (Oxf). 49:159-160. 

Cutolo M, Seriolo B, Sulli A, Accardo S. 1995 Androgens in rheumatoid arthritis. In: Bijlsma JWJ, Linden S van der Barnes CG, eds. Rheumatology highlights 1995. Rheumatol Eur. 24:211-214. 

Masi AT, Feigenbaum SL, Chatterton RT. 1995 Hormonal and pregnancy relationships to rheumatoid arthritis: convergent effects with immunological and microvascular systems. Semin Arthritis Rheum. 25:1-27. 

Wilder RL. 1996 Adrenal and gonadal steroid hormone deficiency in the pathogenesis of rheumatoid arthritis. J Rheumatol. 44(Suppl):10 -12. 

Booij A, Biewenga-Booij CM, Huber-Bruning O, Cornelis C, Jacobs JWG, Bijlsma JWJ. 1996 Androgens as adjuvant treatment in postmenopausal female patients with rheumatoid arthritis. Ann Rheum Dis. 55:811-886. 

van Vollenhoven RF, Morabito LM, Engleman EG, McGuire JL. 1998 Treatment of systemic lupus erythematosus with dehydroepiandrosterone: 50 patients treated up to 12 months. J Rheumatol. 25:285-289. 

Hickok LR, Toomey C, Speroff L. 1993 A comparison of esterified estrogens with and without methyltestosterone: effects on endometrial histology and serum lipoproteins in postmenopausal women. Obstet Gynecol. 82:919-924. 

Honore EK, Williams JK, Adams MR, Ackerman DM, Wagner JD. 1996 Methyltestosterone does not diminish the beneficial effects of estrogen replacement therapy on coronary arter reactivity in cynomolgus monkeys. Menopause J North Am Menopause Soc. 3:20-26. 

Wagner JD, Zhang L, Williams JK, et al.. 1996 Esterified estrogens with and without methyltesterone decrease arterial LDL metabolism in cynomolgus monekys. Arterioscler Thromb Vasc Biol. 16:1473-1479. 

Buckler HM, Robertson WR, Wu FCW. 1998 Which androgen replacement therapy for women? J Clin Endocrinol Metab. 83:3920-3924. 

Need GA, Horowitz M, Bridges A, Morris H, Nordin C. 1998 Effects of nandrolone decanoate and antiresorptive therapy on vertebral density in os-teoporotic postmenopausal women. Arch Intern Med. 149:57-60. 

Recchione C, Venturelli E, Manzari A, Cavalteri A, Martinetti A, Secreto G. 1995 Testosterone, dihydrotestosterone, and oestradiol levels in postmenopausal breast cancer tissues. J Steroid Biochem Mol Biol. 52:541-546. 

Bryan RM, Mercer RJ, Rennie GC, Lie TH, Morgan FJ. 1984 Androgen receptors in breast cancer. Cancer. 54:2436-2440. 

Birrell SN, Roder DM, Horsfall DJ, Bentel JM, Tilley WD. 1995 Medroxy-progesterone acetate therapy in advanced breast cancer: the predictive value of androgen receptor expression. J Clin Oncol. 13:1572-1577.