Testosterone Therapy in Women-Dr Shahjada Selim

1. Testosterone Therapy in Women Dr Shahjada Selim Associate Professor Department of Endocrinology Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh General Secretary, Bangladesh Endocrine Society (BES)

2. Disclosure I’ve nothing to disclose

3. Background • Testosterone is a critical but enigmatic female hormone. It acts directly as an androgen in addition to being an obligatory precursor for biosynthesis of oestradiol.1 • Control of testosterone production in women is not well understood because no feedback loop governing its production has been described. • Testosterone is considered to be the main hormone underlying sexual desire in both men and women. 1. Simpson ER, Davis SR. Minireview: aromatase and the regulation of estrogen biosynthesis—some new perspectives. Endocrinology 2001; 142: 4589–94.

4. ▪ There is a steady decline in testosterone levels from the 20s through menopause. By the time women are in their late 40's their testosterone level has fallen to about half of what it was in their 20’s. ▪ There is no further change in testosterone as women go through natural menopause, but levels do slowly decline with increasing age. ▪ With surgical menopause, the level of testosterone drops precipitously. 1. Kaplan HS, Owett T. The female androgen deficiency syndrome. J Sex Marital Ther 1993;19:3-24.

5. 1. Kaplan HS, Owett T. The female androgen deficiency syndrome. J Sex Marital Ther 1993;19:3-24.

6. Causes of low testosterone in women 1.Susan R Davis. September 8, 2015 http://dx.doi.org/10.1016/ S2213-8587(15)00284-3

7. Symptoms, signs & conditions indicative of testosterone deficiency1 1. Meliegy et al 2017. Systemic review of hormone replacement therapy in the infertile man. Arab Journal of Urology. 16. 10.1016/j.aju.2017.11.011.

8. Diagnosis testosterone deficiency1 Endocrine Society Clinical Practice Guideline Task Force recommends against making a clinical diagnosis of androgen deficiency syndrome in healthy women because there is a lack of a well- defined syndrome, and data correlating androgen levels with specific signs or symptoms are unavailable 1. Margaret E et al. The Journal of Clinical Endocrinology & Metabolism, Volume 99, Issue 10, 1 October 2014, Pages 3489– 3510, https://doi.org/10.1210/jc.2014-2260

9. Diagnosis testosterone deficiency1 D/D • Hypothyroidism • Iron deficiency anemia • Autoimmune disease (SLE, RA etc) • Depression

10. Diagnosis testosterone deficiency1 Assays for plasma total testosterone is the preferred test the levels are shown to decrease with age in women, as they do in men. As serum T levels constantly fluctuates on a daily basis. So, best time to test -8- 11am. If a woman still has her period, she should ideally take the blood testosterone test about 8 to 20 days after her menstrual period starts. According to the Boston University School of Medicine, if a woman’s plasma total T level is <25 ng/dL in women under 50 years old, this is low. T levels <20 ng/dL in women aged 50 and older are considered low. 1. André Guay and Susan R. Davis. World Journal of Urology 2002. 20:106-110

11. Testosterone in women One study found that women with 0 to 10 ng per dL (0 to 0.3 nmol per L) had markedly decreased sexual desire in all situations and absent or markedly decreased orgasms. Because of studies like this, supplemented with anecdotal evidence, many women have been started on testosterone therapy. 1. Kaplan HS, Owett T. The female androgen deficiency syndrome. J Sex Marital Ther 1993;19:3-24.

12. Use of Testosterone in Women Potential uses In December 2004, the FDA voted against approving a new testosterone patch for women because of safety issues. The advisory panel had concerns about the low numbers of women studied and the length of the studies. However, many physicians are prescribing testosterone in other forms. Oral esterified estrogen with methyltestosterone has been used extensively since the 1970s, though it has not been FDA approved. It is marketed for treatment of hot flashes, although there is marginal evidence to support its use for this. 1. Watts NB el 1995. Comparison of oral estrogens and estrogens plus androgen on bone mineral density, menopausal symptoms, and lipid-lipoprotein profiles in surgical menopause:668]. Obstet Gynecol 1995;85:529-37.

13. Use of Testosterone in Women Postmenopausal hormone therapy Most women can expect to spend one third of their lives in the postmenopausal stage. With the new evidence that traditional hormone therapy using estrogen and progesterone can increase the risk of cardiovascular disease as well as uterine and breast cancer,1women with postmenopausal complaints of hot flashes, mood changes, and poor sexual functioning have been more interested in testosterone therapy as an option. Clinical guidelines for the use of androgens for female sexual dysfunction has been developed by the Endocrine Society.2 1. JAMA 2002;288:321-33 2. Accessed online October 19, 2005, at: http:// www.endo-society.org/news/press/2004/androgen-guidelines.cfm.

14. Use of Testosterone in Women Postmenopausal hormone therapy There is little evidence in the literature for the benefit of estrogen plus testosterone over estrogen alone for the treatment of hot flashes. Depression, anger, moodiness, insomnia, and lack of well-being are common complaints of postmenopausal women. A limited number of studies3have shown that psychological symptoms and memory are improved with the addition of testosterone to estrogen. 1. JAMA 2002;288:321-33 2. Accessed online October 19, 2005, at: http:// www.endo-society.org/news/press/2004/androgen-guidelines.cfm. 3. Am J Obstet Gynecol 1985;151:153-60. Horm Res 2002;58:150-5.

15. Use of Testosterone in Women Sexual dysfunction Testosterone replacement is prescribed most commonly to treat problems with libido, sexual enjoyment, and orgasm in patients who are postmenopausal or who have had an oophorectomy. As many as 50 percent of postmenopausal women have sexual dysfunction,1and a low testosterone level has been correlated with reduced coital frequency in these women.1 1. McCoy NL, Davidson JM. A longitudinal study of the effects of menopause on sexuality. Maturitas 1985;7:203-10.

16. Endocrine Society Task Force Recommendations: Testosterone Therapy for Women with HSDD ➢ Endocrine Society Task Force suggested a 3- to 6-month trial of a dose of T for postmenopausal women who request therapy for properly diagnosed HSDD and in whom therapy is not contraindicated resulting in a mid-normal premenopausal value in a reference assay to avoid pharmacological T administration 1. JAMA 2002;288:321-33

17. Endocrine Society Task Force Recommendations: …Testosterone Therapy for Women with HSDD ➢Measuring T levels at baseline [8-11am] and after 3–6 weeks of initial treatment to assess patient overuse ➢In cases of ongoing T therapy, we suggest reviewing T levels every 6 months to monitor for excessive use and signs of androgen excess ➢Cessation of T therapy for women who have not responded to treatment by 6 months. ➢No safety and efficacy data for T therapy are available after 24 months 1. JAMA 2002;288:321-33

18. T Treatment for HSDD: be vigilant • The response to therapy does not correlate with T levels. • Symptoms often recur after discontinuation of therapy, and sexual dysfunction often requires long-term treatment. • Physiological T preparations for clinical use in women are not available in many countries, including the United States, and long- term safety data are lacking. • The criteria for the definition of disordered desire have changed from that used in clinical trials, which could impact response in individual patients.

19. Use of Testosterone in Women Premenopausal treatment Women with diminished sex drive have been shown to have lower free T levels.1 However, physicians are reluctant to use testosterone in premenopausal women because of concerns about masculinization. In a 12-week trial2of 34 women, testosterone therapy (1% cream, 10 mg per day applied to the thigh) improved well-being, mood, and sexual function in premenopausal women with low libido and low testosterone levels. No increase in hirsutism, acne, or voice change occurred. 1. J Sex Marital Ther 2000;26:269-83. 2. Menopause 2003;10:390-8

20. Endocrine Society Task Force Recommendations: ➢ES recommends against the routine treatment of women with low androgen levels due to hypopituitarism, adrenal insufficiency, bilateral oophorectomy, or other conditions associated with low androgen levels because of the lack of adequate data supporting efficacy and/or long- term safety. ➢against routinely measuring T in women for diagnosis, because a correlation between symptoms and T levels has not been established. ➢against the routine use of DHEA therapy in women with adrenal insufficiency because data concerning its effectiveness and safety are limited.

21. Use of Testosterone in Women Bone density • Osteoporosis is a leading cause of morbidity and mortality in older women. Low circulating testosterone is correlated with hip fracture and height loss in postmenopausal women.1 • Estrogen alone has been used to prevent loss of bone mass, but other studies have shown that oral estrogen-androgen hormone therapy promotes bone formation. 2It is not known, however, if this prevents fractures or prolongs life. 1. J Bone Miner Res 1995;10:650-4. 2. Obstet Gynecol 1995;85:529-37. Maturitas 1985;7:203-10. Fertil Steril 2003;79:1341-52.

22. Use of Testosterone in Women Other uses Testosterone is used for women with premature ovarian failure, Turner’s syndrome, HIV infection, or chronic corticosteroid use. More research in the area of chronic illness has been completed in men than in women. Other uses such as the prevention of dementia and depression have been postulated.

23. Benefits of Testosterone Treatment for women* Indication Bone strength Possible Benefit Increase bone mineral density 1 Formulations Oral, supraphysiologic doses Cognitive or psychological Protective of memory, improved sense of well-being 2 Increase desire/interest, frequency 3 Increase frequency, satisfaction, orgasm 4 Increase desire, orgasm 1 Increase frequency and pleasure 2 Physiologic doses Oral Implants Intramuscular, supraphysiologic dose Transdermal Sexual dysfunction *All studies of testosterone supplementation in women use testosterone in combination with estrogen 1. Obstet Gynecol 1995;85:529-37. J Reprod Med 1999; 44:1012-20. Maturitas 1985;7:203-10. 2. Maturitas 1995;21:227-36. N Engl J Med 2000;343:682-8. 3. Fertil Steril 2003;79:1341-52. J Reprod Med 1998;43:847-56. 4. Maturitas 1985;7:203-10. Br Med J 1987;294:936-7.

24. Possible Uses of Testosterone Treatment Indication Poor sexual functioning in postmenopausal women Prevention of osteoporosis Formulation Oral, implant, transdermal Consider if patient is Comment symptomatic Not clear when to use testosterone Safety not ensured at high dosages Oral Women Psychological symptoms such as depression Oral, dehydroepiandrosterone

25. Safety in women The controversy over using testosterone has primarily come from issues involving safety.1 The typical side effects related to the estrogen-testosterone preparations are alopecia, acne, and hirsutism, although these are dose and duration dependent and are not common.2 Controlled studies 3have found low incidence of deep voice, oily skin, acne, and male-pattern hair loss. Virilization is not common, usually is reversible, and typically occurs only with supraphysiologic dosages. 1. J Clin Endocrinol Metab 1997;82:3793-6. J Clin Endocrinol Metab 2000;85:2670-7. Urology 1997; 49:191-6. Am J Physiol Endocrinol Metab 2002;282:E601-7. Diabetes Care 2001;24:2149-51. Am J Med 2001;111:261-9. Obstet Gynecol 1995;85:529-37. Am J Obstet Gynecol 1985;151:153-60. Clin Ther 1997;19:1070-84. Clin Ther 1997;19:383-404. J Reprod Med 1999; 44:1012-20. 2. Clin Ther 1997;19:1070-84. 3. Obstet Gynecol 1995;85:529-37. Clin Ther 1997;19:383-404. N Engl J Med 2000;343:682-8. Menopause 2003;10:390-8.

26. Safety in women An approved non-oral preparation for women (such as a transdermal patch, gel, or cream) if such a treatment is available should be used ❖ Reduced total cholesterol and HDL cholesterol levels have been demonstrated when used in women in addition to estrogen, although the long-term effects on heart disease are not known ❖ Testosterone use in the short term has not been associated with an increase in cardiovascular disease or symptoms. Usual estrogen-testosterone doses in women have not been linked to hepatic damage.4 ❖ 4. Clin Ther 1997;19:383-404.

27. Potential Risks and Side Effects of Testosterone Treatment Risks/side effects Cardiovascular2 Comments No clear effect on these cardiovascular risk factors: total cholesterol, high-density lipoprotein cholesterol, C-reactive protein, or insulin sensitivity Usually does not occur at physiologic doses; oral formulations should be avoided in men for this reason More common in men taking higher doses Men and women: usually dose and duration related Liver toxicity 3 Polycythemia4 Virilization (i.e., alopecia, hirsutism, acne) 5 1. Urology 1997; 49:191-6. Am J Physiol Endocrinol Metab 2002;282:E601-7. Diabetes Care 2001;24:2149-51. 2. Am J Med 2001;111:261-9. Obstet Gynecol 1995;85:529-37. J Reprod Med 1999; 44:1012-20. 3. Clin Ther 1997;19:383-404. 4. J Clin Endocrinol Metab 1997;82:3793-6. J Clin Endocrinol Metab 2000;85:2670-7. 5. Obstet Gynecol 1995;85:529-37. Am J Obstet Gynecol 1985;151:153-60. Clin Ther 1997;19:1070-84. Clin Ther 1997;19:383-404.

28. Testosterone Replacement Modalities For use in women1 Modalities Esterified estrogen/ methyltestosterone Testosterone enanthate/estradiol valerate (Moderate to severe vasomotor symptoms of menopause) Dosage Orally once per day Side effects* Acne, change in voice, nausea 1 mL intramuscularly every four weeks (90 mg/4 mg per mL) Site reaction * These side effects are in addition to those usual for testosterone: in women—acne, hirsutism, and deepening voice 1. Boehringer S. Comparison of testosterone products. Pharmacist’s Letter 2003;19:19-83.

29. Monitoring Patients on Testosterone Therap1,2 Test/examination History and physical Frequency Every six months (including breast examination) 3–6 weeks after initiation of therapy and every 6 months thereafter to assess for patient overuse or signs of androgen excess Annually Annually Annually Annually Comment Watch for virilization in skin, hair, and genitals do Serum T Morning Lipid levels Complete blood cell count Mammography Endometrial ultrasonography 1. Endocr Pract 2002;8:440-56. 2. The Endocrine Society. Endocrine society calls for clinical guidelines on androgens for women. Accessed online October 19, 2005, at: http:// www.endo-society.org/news/press/2004/androgen-guidelines.cfm.

30. Summary and key messages Androgen deficiency is a true medical condition in both pre- and post- menopausal women. Androgen deficiency in women is a controversial concept. Some researchers argue that the condition causes symptoms such as tiredness and loss of sexual interest. Other researchers say that there is not enough evidence to support the existence of the condition. If you choose to have testosterone therapy you will need close and regular monitoring to minimize your risk of side effects.

31. Summary and key messages Treatment should only be with formulations that achieve blood concentrations of testosterone that approximate premenopausal physiological concentrations. As no approved female product is presently approved by a national regulatory body, male formulations can be judiciously used in female doses and blood testosterone concentrations must be monitored regularly. Treatment with androgens has to be monitored carefully because of the possible harmful effects of excessive levels of testosterone.