Clinical use of testosterone and DHEA in the menopausal woman, with or without ET/EPT

Transcription

1 Medicine, Nursing and Health Sciences Instructional course 8: Hormones, menopause and female sexual function: the definitive update. Clinical use of testosterone and DHEA in the menopausal woman, with or without ET/EPT Susan R Davis MBBS FRACP PhD Women s Health Research Program School of Public Health Monash University Melbourne

2 Primary indication for testosterone therapy for women: Treatment of persistent low libido that profoundly impairs quality of life testosterone improves sexual desire, arousal and sexual satisfaction in premenopausal and postmenopausal women presenting with loss of sexual desire NOTE- substantial overlap between desire and arousal in women

3 Who fits this category? Women late reproductive years and beyond who say they have experienced a distinct change they don t like not feeling sexual / interested Women with the following conditions who seek help for loss of libido Surgical menopause Premature ovarian failure Adrenal insufficiency ( including glucocorticosteroid therapy) There is no upper age limit 3

4 Deciding who not to treat Treatment is a TRIAL so rather than exclude women from a trial decide who not to treat Women unlikely to benefit: Young women with normal ovarian function- other issues Women in poor relationships Need to understand if the relationship stress is 1 or 2 to FSD SSRI- associated FSD.? efficacy of testosterone in this setting Women on high dose oral estrogen therapy- high SHBG Women with other sexual difficulties Women who have never experienced satisfactory sexual function 4

5 Contraindications androgenic alopecia/ hirsutism hormone dependent malignancy potential contraindication very low SHBG levels- need to be very judicious in dosing 5

6 Identifying the patient who is a candidate for testosterone therapy Deciding whether to treat or not treat with testosterone Blood tests? How to treat? Oral / transdermal? What are the risks of treatment? Consequences of not treating 6

7 Ovary Androgen production before menopause Adrenal 60% Androstenedione 40% 20% DHEA 50% DHEAS 90% 50%-75% Peripheral conversion 25-35% Testosterone

8 Testosterone acts directly/as an oestrogen Brain bone, adipose, skin, vascular endothelium, vascular smooth muscle, Aromatase ovary, testis placenta Testosterone 5 reductase types 1 & 2 In androgen responsive tissues Oestradiol DHT Davis 2005

9 Total androgen production/day in premenopausal women 9

10 TOTAL testosterone in blood: 60-65% high affinity bound to SHBG 35% loosely to albumin 35%; 1-2% of testosterone circulates unbound in women SHBG binding affinity: DHT > Testosterone > Estradiol > Estrone > DHEA DHEAS IS NOT SHBG BOUND 10

11 ORAL Testosterone Obesity Growth Hormone Glucocorticosteroids Insulin RESISTANCE ORAL ESTROGENS Thyroxine SHBG SHBG Free sex hormones level Free sex hormones level

12 Exogenous estrogen increases SHBG and lowers free testosterone levels in postmenopausal women. Tazuke et al Medicine 1992

13 female androgen insufficiency There is no diagnostic cut off level for any of the androgens that identifies a woman with low sexual function as having female androgen insufficiency syndrome. So why measure an androgen profile at all? To avoid treating women with androgen who have relatively high levels To avoid treating women with elevated SHBG To add caution in treating women with low SHBG

14 Measurement of androgens of interest in women 1. Measurement of testosterone in women only accurate with highly sensitive and specific methodology: Free testosterone kit assays unreliable Measurement of free testosterone by equilibrium dialysis requires accurate measurement of total T BEST OPTION: a reliable total testosterone measure, SHBG and calculation of free testosterone by the Sodergard equation by the lab (or LCMS) 2. Measurement of DHEAS is robust

15 Laboratory investigations WHEN CONSIDERING ANDROGEN THERAPY Fatigue Thyroid function FBE / Iron stores fasting glucose? Androgen profile: Total testosterone SHBG Calculated free T ( by lab) Other as indicated, DHEAS

16 Identifying the patient who is a candidate for testosterone therapy Deciding whether to treat or not treat with testosterone Blood tests? How to treat? Oral / transdermal? What are the risks of treatment? Consequences of not treating 16

17 USE OF DHEA FOR FEMALE SEXUAL DYSFUNCTION 17

18 Authors DHEA RCTs of systemic DHEA for female sexual dysfunction do not support its use Duration (weeks) Dose (mg/day) Participantspostmenopausal n, (age in years) Sexual function Instrument to measure sexual function Mortola and Yen (46-61 y) No change Self-reported 1990 Morales (8 on HT) No change Visual Analog Scale y Wolf (69±1.7) No change Self reported Hackbert & Heiman ( 51-68y) Improvement FES, DSFI, OFQ, self-report, vaginal photoplethysmograph Schmidt Improvement Derogatis Sexual Functioning Inventory Kritz-Silverstein (55-85y) No change Female Sexual Function Index Panjari (40-65y) No change Sabbatsberg Sexual Self- Rating Scale, sexual event diary, MENQOL 18

19 USE OF DHEA FOR HSDD One study demonstrated daily transvaginal DHEA improved vaginal atrophy and dyspareunia and improved sexual satisfaction in PM women with vaginal atrophy Labrie et al Menopause 2009 Needs to be confirmed in an independent study Less frequent application needs to be evaluated Cannot be extrapolated to women without vaginal atrophy 19

20 Clinical Studies of DHEA in women with adrenal compromise 8 studies in women with adrenal insufficiency 6 primary adrenal insufficiency 2 hypopitutism Only 4 assessed sexual function

21 A Systematic Review and Meta-Analysis of Randomized Placebo- Controlled Trials of DHEA Treatment Effects on Quality of Life in Women with Adrenal Insufficiency JCEM 2009 Alkatib et al. 94 (10): 3676 Conclusion: DHEA may improve, in a small and perhaps trivial manner, HRQOL and depression in women with adrenal insufficiency. There was no significant effect of DHEA on anxiety and sexual well-being. The evidence appears insufficient to support the routine use of DHEA in women with adrenal insufficiency. 21

22 USE OF SYSTEMIC TESTOSTERONE FOR TREATMENT OF LOW LIBIDO data from large randomised placebo controlled trials of - surgically postmenopausal women on estrogen - naturally postmenopausal women on estrogen + progestin - postmenopausal women on no hormone therapy - premenopausal women in late reproductive years 22

23 Testosterone for the treatment of FEMALE desire/arousal disorder 23

24 NOT RECOMMENDED TRANSDERMAL MALE FORMULATIONS INJECTABLES TESTOSTERONE UNDECANOATE COMPOUNDED TROCHES (oral) / CREAMS 24

25 Testosterone implants 50mg implants used for decades in Australia and UK to treat women with FSD No adverse effects on body composition/lipids 75mg testosterone implants Usual dose for men 8-10 implants One implant for a woman will last about 6mths Do NOT insert a new implant without first checking testosterone level Side effects are rare with this dose but are common at higher doses. 25

26 Intrinsa (testosterone 3.94 mg per 14 cm² patch; 300 µg/day dose) NO LONGER AVAILABLE Androfeme 1% cream available in Australia can be ordered on line Androfeme 1% cream Starting dose 0.5ml Check blood levels at 3-4 weeks and contact patient if level of total T or free T > LAB UPPER LIMIT FOR YOUNG WOMAN to reduce dose Review patient at 3 months No benefit by 6m STOP therapy. CONTINUE to monitor therapy 6-12monthly as patients do change their habits Libigel testosterone gel for women 26 Research trials

27 TESTOSTERONE LEVELS WILL VARY ACCORDING TO SHBG LEVELS Davis 2011

28 ONSET OF EFFECTS ABOUT 2 WEEKS WITH TE IMPLANT ABOUT 4-6 WEEKS WITH TRANSDERMAL THERAPY 2828th Presentation February 2011 title

29 What are the risks of treatment? Identified Risks Androgenic effects Potential Risks Vascular function Breast Safety

30 Androgenic Adverse Events over 1 year of treatment %patients Placebo TTS 150 TTS 300 p< Acne Alopecia Voice deepening Increased Hair Growth Davis et al N Eng J Med 2008

31 NO ADVERSE EFFECTS OF NON ORAL TE AT DOSES FOR WOMEN ON ENDOMETRIUM INSULIN, GLUCOSE OR CRP LIVER FUNCTION, Hb or COAGULATION 31

32 ROUTE Testosterone patch Testosterone implant Oral testosterone COCHRANE REVIEW Somboonporn et al

33 Cardiovascular events in testosterone patch studies CARDIOVASCULAR EVENTS TREATMENT n Women years of observation MIs Strokes DVTs Total Placebo 1,848 1, All TTP 3,278 2, INCIDENT RATE RATIOS TESOSTERONE VS PLACEBO 95%CI 0.82 (0.21 to 3.81) 80%CI 0.82 (0.31 to 2.30) 9/12/

34 Testosterone and Breast cancer-observational data Davis 2010

35 Invasive breast cancer /100,000 women years in observational studies of testosterone users vs Victorian Cancer Registry Nurses health study (methyl-t) N=550 Victorian cancer registry data Parenteral T N=15489 N=18754 N=508 N=

36 Exogenous testosterone and cognition: Improvements in: Visual and verbal memory and concentration Shah et al Menopause 2006 Davison et al Maturitas 2011 Complex information processing Regestein et al J Womens Health Gend Based Med 2001 Memory Wisniewski et al Horm Res 2002 Visuospatial task performance Aleman et al Psychoneuroendocrinol 2004 Shah et al Menopause 2006 Wisniewski et al Horm Res 2002

37 Testosterone therapy is not assoc with change in mammographic density over 12 months 40 p = p = Baseline Week 52 Percent Dense Area (SE) Placebo TTP 150 TTP 300 N=87 N=84 N=99 Davis et al JCEM 2009

38 Identifying the patient who is a candidate for testosterone therapy Deciding whether to treat or not treat with testosterone Blood tests? How to treat? Oral / transdermal? What are the risks of treatment? Consequences of not treating 38

39 Wellbeing is lower in pre-and postmenopausal women with low sexual satisfaction * * p<0.001 * * * * Davison at J Sex Med 2009

40 The overall effect of HSDD on quality of life is similar in magnitude to that of chronic back pain and urinary incontinence TOTAL SCORE PGWB Index Urquhart Menopause 2009; Botlero Menopause 2009; Davison J Sex Med 2009

41 FSD is a condition that merits assessment and treatment

42 Exogenous testosterone improves brachial FMD, exercise tolerance and muscles strength in women with CCF Metres walked Muscle strength Iellamo et al JACC 2010 isometric maximal voluntary contraction Isokinetic power torque 42