Testosterone Therapy in Premenopausal Women

ABSTRACT

Testosterone therapy for postmenopausal women and women with surgical menopause, albeit controversial, is becoming more widespread. However, only limited data are available to support its use in premenopausal women. Androgens have important biological roles in young women, influencing bone and muscle mass, mood and well-being, and libido. Pathophysiological states affecting ovarian and adrenal function or both may result in androgen deficiency in premenopausal women. Young women with hypothalamic amenorrhea, premature ovarian failure, oophorectomy, premenstrual syndrome, acquired immunodeficiency wasting syndrome, adrenal insufficiency, and hypopituitarism may have testosterone deficiency. Young women with loss of libido may also have testosterone deficiency. Medications that may lead to testosterone insufficiency include oral estrogen, oral contraceptives, and corticosteroids. Testosterone deficiency in young women may be underdiagnosed because the symptoms generally are nonspecific and the measurement of total and free testosterone is inaccurate with commonly used techniques. Only a few studies investigating the effects of testosterone therapy have been performed thus far in premenopausal women. Long-term trials evaluating safety and effectiveness of testosterone therapy in premenopausal women are lacking. Common adverse effects include hirsutism and acne, which reverse with discontinuation of treatment. The availability of testosterone regimens specifically designed for women is expected to help maintain testosterone levels within the normal range and clarify whether the apparent beneficial effects of testosterone therapy are physiological or pharmacological.

KEYWORDS

Premenopausal women - androgen insufficiency - testosterone therapy

REFERENCES

• 1 Davis S. Androgen replacement in women: a commentary.  J Clin Endocrinol Metab. 1999;  84 1886-1891
• 2 Abraham G E. Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle.  J Clin Endocrinol Metab. 1974;  39 340-346
• 3 Judd H L, Lucas W E, Yen SS. Effect of oophorectomy on circulating testosterone and androstenedione levels in patients with endometrial cancer.  Am J Obstet Gynecol. 1974;  118 793-798
• 4 Burger H G. Androgen production in women.  Fertil Steril. 2002;  4(suppl) 53-55
• 5 Mushayandebvu T, Castracane V D, Gimpel T, Adel T, Santoro N. Evidence for diminished midcycle ovarian androgen production in older reproductive aged women.  Fertil Steril. 1996;  65 721-723
• 6 Zumoff B, Strain G W, Miller L K, Rosner W. Twenty-four hour mean plasma testosterone concentration declines with age in normal premenopausal women.  J Clin Endocrinol Metab. 1995;  80 1429-1430
• 7 Davison S L, Bell R, Donath S, Montalto J G, Davis S R. Androgen levels in adult females: changes with age, menopause and oophorectomy.  J Clin Endocrinol Metab. 2005;  90 3847-3853
• 8 Rainey W E, Carr B R, Sasano H, Suzuki T, Mason J I. Dissecting human adrenal androgen production.  Trends Endocrinol Metab. 2002;  13 234-239
• 9 Orentreich N, Brind J L, Rizer R L, Vogelman J H. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood.  J Clin Endocrinol Metab. 1989;  59 551-555
• 10 Notelovitz M. Androgen effects on bone and muscle.  Fertil Steril. 2002;  4(suppl 4) 534-541
• 11 McGriff-Lee N, Kalantaridou S N, Pucino F, Calis K A. Effects of androgens on bone in men and women.  Clin Rev Bone Min Metab. 2005;  3 51-65
• 12 Slemenda C, Longcope C, Peacock M, Hui S, Johnston C C. Sex steroids, bone mass, and bone loss: a prospective study of pre-, peri-, and postmenopausal women.  J Clin Invest. 1996;  97 14-21
• 13 Anasti J N, Kalantaridou S N, Kimzey L M, Defensor R A, Nelson L M. Bone loss in young women with karyotypically normal spontaneous premature ovarian failure.  Obstet Gynecol. 1998;  91 12-15
• 14 Sherwin B B, Gelfand M M, Brender W. Androgen enhances sexual motivation in females: a prospective, crossover study of sex steroid administration in the surgical menopause.  Pscychosom Med. 1985;  47 339-351
• 15 Davis S R, Tran J. Testosterone influences libido and well being in women.  Trends Endocrinol Metab. 2001;  12 33-37
• 16 Morris N M, Udry J R, Khan-Dawood F, Dawood M Y. Marital sexual frequency and mid-cycle female testosterone.  Arch Sex Behav. 1987;  16 27-37
• 17 Tutten A, Laan E, Panhuysen G et al.. Discrepancies between genital responses and subjective sexual function during testosterone substitution in women with hypothalamic amenorrhea.  Psychosom Med. 1996;  58 234-241
• 18 Nathorst-Boos J, von Schoultz B. Psychological reactions and sexual life after hysterectomy with and without oophorectomy.  Gynecol Obstet Invest. 1992;  34 97-101
• 19 Nathorst-Boos J, von Schoultz B, Carlstrom K. Elective ovarian removal and estrogen replacement therapy-effects on sexual life, psychological well-being and androgen status.  J Psychosom Obstet Gynaecol. 1993;  14 283-293
• 20 Zussman L, Zussman S, Sunley R, Bjornson E. Sexual response after hysterectomy-oophorectomy: recent indices and reconsideration of psychogenesis.  Am J Obstet Gynecol. 1981;  140 725-729
• 21 Davis S R, Davison S L, Donath S, Bell R J. Circulating androgen levels and self-reported sexual function in women.  JAMA. 2005;  294 91-96
• 22 Santoro N, Torrens J, Crawford S et al.. Correlates of circulating androgens in mid-life women: the study of Women's Health Across the Nation.  J Clin Endocrinol Metab. 2005;  90 4836-4845
• 23 Kalantaridou S N, Calis K A, Vanderhoof V H et al.. Transdermal estradiol therapy significantly reduces serum free testosterone levels in young women with spontaneous premature ovarian failure. Abstract presented at: Annual Endocrine Society Meeting June 4-7, 2005 San Diego, CA;
• 24 Bermudez J A, Moran C, Herrera J, Barahona E, Perez M C, Zarate A. Determination of the steroidogenic capacity in premature ovarian failure.  Fertil Steril. 1993;  60 668-671
• 25 Doldi N, Belvisi L, Bassan M, Fusi F M, Ferrari A. Premature ovarian failure: steroid synthesis and autoimmunity.  Gynecol Endocrinol. 1998;  12 23-28
• 26 Miller K K, Sesmilo G, Schiller A, Schoenfeld D, Burton S, Klibanski A. Androgen deficiency in women with hypopituitarism.  J Clin Endocrinol Metab. 2001;  86 561-567
• 27 Bloch M, Schmidt P J, Su T P, Tobin M B, Rubinow D R. Pituitary-adrenal hormones and testosterone across the menstrual cycle in women with premenstrual syndrome and controls.  Biol Psychiatry. 1998;  43 897-903
• 28 Dor J, Bider D, Shulman A et al.. Effects of gonadotropin-releasing hormone agonists on human ovarian steroid secretion in vivo and in vitro - results of a prospective, randomized in-vitro fertilization study.  Hum Reprod. 2000;  15 1225-1230
• 29 Casson P R, Elkind-Hirsch K E, Buster J E, Hornsby P J, Carson S A, Snabes M C. Effect of postmenopausal estrogen replacement on circulating androgens.  Obstet Gynecol. 1997;  90 995-998
• 30 Bancroft J, Sherwin B B, Alexander G M, Davidson D W, Walker A. Oral contraceptives, androgens, and the sexuality of young women: II. The role of androgens.  Arch Sex Behav. 1991;  20 121-134
• 31 Grinspoon S, Corcoran C, Stanley T et al.. Mechanisms of androgen deficiency in human immunodeficiency virus-infected women with the wasting syndrome.  J Clin Endocrinol Metab. 2001;  86 4120-4126
• 32 Rosner W. The functions of corticosteroid-binding globulin and sex-hormone binding globulin: recent advances.  Endocr Rev. 1990;  11 80-89
• 33 Bolour S, Braunstein G. Testosterone therapy in women: a review.  Int J Impot Res. 2005;  17 399-408
• 34 Artl W, Callies F, van Vlijmen J et al.. Dehydroepiandrosterone replacement in women with adrenal insufficiency.  N Engl J Med. 1999;  341 1013-1020
• 35 Kim M, Rosenfield R, Dupon C. The effects of dexamethasone on plasma free androgens during the normal menstrual cycle.  Am J Obstet Gynecol. 1976;  126 982-986
• 36 Zumoff B, Walsh B, Katz J et al.. Subnormal plasma dehydroepiandrosterone to cortisol ratio in anorexia nervosa: a second hormone parameter of ontogenic regression.  J Clin Endocrinol Metab. 1983;  56 668-672
• 37 Cunningham S K, McKenna T J. Dissociation of adrenal androgens and cortisol secretion in Cushing's syndrome.  Clin Endocrinol (Oxf). 1994;  41 795-800
• 38 Goldstat R, Briganti E, Tran J, Wolfe R, Davis S R. Transdermal testosterone therapy improves well-being, mood, and sexual function in premenopausal women.  Menopause. 2003;  10 390-398
• 39 Wilder R L. Adrenal and gonadal steroid hormone deficiency in the pathogenesis of rheumatoid arthritis.  J Rheumatol Suppl. 1996;  44 10-12
• 40 Bachmann G, Bancroft J, Braunstein G et al.. Female androgen deficiency: the Princeton consensus statement on definition, classification, and assessment.  Fertil Steril. 2002;  77 660-665
• 41 Guay A T. Screening for androgen deficiency in women: methodological and interpretive issues.  Fertil Steril. 2002;  77(suppl 4) 83-88
• 42 Davis S R. When to suspect androgen deficiency other than at menopause.  Fertil Steril. 2002;  77(suppl 4) 568-571
• 43 Miller K K, Rosner W, Lee H et al.. Measurement of free testosterone in normal women and women with androgen deficiency: Comparison of methods.  J Clin Endocrinol Metab. 2004;  89 525-533
• 44 Braunstein G D, Sundwall D A, Katz M et al.. Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial.  Arch Intern Med. 2005;  165 1582-1589
• 45 Davis S R, McCloud P I, Strauss B JG, Burger H G. Testosterone enhances estradiol's effects on postmenopausal bone density and sexuality.  Maturitas. 1995;  21 227-236
• 46 Lobo R A, Rosen R C, Yang H M, Block B, Van Der Hoop R G. Comparative effects of oral esterified estrogens with and without methyltestosterone on endocrine profiles and dimensions of sexual function in postmenopausal women with hypoactive sexual desire.  Fertil Steril. 2003;  79 1341-1352
• 47 Raisz L G, Witta B, Artis A et al.. 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
• 48 Sarrel P, Dobay B, Wiita B. Estrogen and estrogen-androgen replacement in postmenopausal women dissatisfied with estrogen-only therapy. Sexual behavior and neuroendocrine responses.  J Reprod Med. 1998;  43 847-856
• 49 Sherwin B B, Gelfand M M. The role of androgen in the maintenance of sexual functioning in oophorectomized women.  Pscychosom Med. 1987;  49 397-409
• 50 Shifren J L, Braunstein G, Simon J et al.. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy.  N Engl J Med. 2000;  343 682-688
• 51 Simon J, Braunstein G, Nachtigall L et al.. Testosterone patch increases sexual activity and desire in surgically menopausal women with hypoactive sexual desire disorder.  J Clin Endocrinol Metab. 2005;  90 5226-5233
• 52 Kalantaridou S N, Calis K A, Mazer N A, Godoy H, Nelson L M. A pilot study of an investigational transdermal testosterone patch system in young women with spontaneous premature ovarian failure.  J Clin Endocrinol Metab. 2005;  90 6549-6552
• 53 Miller K, Corcoran C, Armstrong C et al.. Transdermal testosterone administration in women with aquired immunodeficiency syndrome wasting: a pilot study.  J Clin Endocrinol Metab. 1998;  83 2717-2725
• 54 Dolan S, Wilkie S, Aliabadi N et al.. Effects of testosterone administration in human immunodeficiency virus-infected women with low weight. A randomized placebo-controlled study.  Arch Intern Med. 2004;  164 897-904
• 55 Javanbakht M, Singh A B, Mazer N A et al.. Pharmacokinetics of a novel testosterone matrix transdermal system in healthy, premenopausal women and women infected with the human immunodeficiency virus.  J Clin Endocrinol Metab. 2000;  85 2395-2401
• 56 Burger H, Davis S R. Should women be treated with testosterone.  Clin Endocrinol (Oxf). 1998;  49 159-160
• 57 Kalantaridou S N, Davis S R, Nelson L M. Premature ovarian failure.  Endocrinol Metab Clin North Am. 1998;  27 989-1006
• 58 Worboys S, Kotsopoulos D, Teede H, McGrath B, Davis S R. Evidence that parenteral testosterone therapy may improve endothelium-dependent and -independent vasodilation in postmenopausal women already receiving estrogen.  J Clin Endocrinol Metab. 2001;  86 158-161
• 59 Kravariti M, Naka K K, Kalantaridou S N et al.. Predictors of endothelial dysfunction in young women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 2005;  90 5088-5095
• 60 Sutton-Tyrrell K, Wildman R P, Matthews K A et al.. SWAN Investigators. Sex hormone-binding globulin and the free androgen index are related to cardiovascular risk factors in multiethnic premenopausal and perimenopausal women enrolled in the Study of Women Across the Nation (SWAN).  Circulation. 2005;  111 1242-1249
• 61 Kaaks R, Berrino F, Key T et al.. Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC).  J Natl Cancer Inst. 2005;  97 755-765
• 62 Somboonporn W, Davis S R. Testosterone effects on breast: implications for testosterone therapy for women.  Endocr Rev. 2004;  25 374-388
• 63 Tuckerman E M, Okon M A, Li T C, Laird S M. Do androgens have a direct inhibitory effect on endometrial function? An in vitro study.  Fertil Steril. 2000;  74 771-779
• 64 Hickok L R, Toomey C, Speroff L. A comparison of esterified estrogens with and without methyltestosterone: effects on endometrial histology and serum lipoproteins in postmenopausal women.  Obstet Gynecol. 1993;  82 919-924