1. Hormone replacement therapy: practical considerations Marco Gambacciani and Nick Panay

2. HRT governing principle HRT should be part of an overall strategy including lifestyle recommendations regarding diet, exercise, smoking and alcohol for maintaining the health of postmenopausal women IMS Updated Recommendations, February 2007

3. The emerging concepts in HRT Timing (window of opportunity) –Early start –Maintenance of estrogenic benefits Patient selection –Avoiding generalized prescribing Personalization –Tailoring dose to patient –Continuation and tapering the dose with age

4. Age-specific HRT use USA 1988–94 SOURCE : CDC/NCHS:NHANES III HRT: Factors Associated with HRT use, NIH, Office of Research of Women’s Health, March 2001 IMS Position Statement, Climacteric 2004;7:333–7 Before< 12–4≥ 5

5. Percentage Menopause-related symptoms Osteoporosis, bone loss, fracture prevention Doctor prescribed it, told me to take it Cardiovascular disease prevention Other Depression, anxiety, emotional distress 0102030405060 Reasons women gave for initiating or continuing HRT Newton KM, et al. J Women’s Health 1997;6:459–65

6. Estrogen deprivation and symptomatic postmenopausal women 75% of women report hot flushes (HF) around menopause 25% remain symptomatic for > 5 years Not all women will experience HF when they become menopausal HF are not just a symptom In postmenopausal women suffering from HF, the brain sensitivity to estrogen depletion is higher The International Menopause Society HRT in climacteric and aging brain, Pisa 15–18 March, 2003

7. Estrogen deprivation and symptomatic postmenopausal women HRT: –Can cure HF and improve sleep, mood and quality of life –May have the potential to prevent/delay cognitive decline, Alzheimer’s disease, Parkinson’s disease, schizophrenia through multiple neuroprotective actions The International Menopause Society HRT in climacteric and aging brain, Pisa 15–18 March, 2003

8. Emerging directions in HRT Early start Patient selection Personalization Lower HRT doses

9. Why lower HRT doses? Continued efficacy with fewer side-effects and possibly fewer risks Potential for greater acceptance by women Improved continuance to achieve potential long-term health benefits Efficacy in prevention of osteoporosis is not compromised

10. Estrogenic side-effects

11. HRT: maximizing efficacy, minimizing problems Estrogenic side-effects HRT: maximizing efficacy, minimizing problems Estrogenic side-effects Problems –Breast tenderness – especially in those over 60 –Fluid retention –Nausea –Heavy withdrawal bleeds –Breakthrough bleeding –Endometrial hyperplasia

12. HRT: maximizing efficacy, minimizing problems Estrogenic side-effects HRT: maximizing efficacy, minimizing problems Estrogenic side-effects Management –Start with low-dose estradiol in most cases –1.0 mg p.o. (0.5 mg)/0.3 mg CEE/25–50 µg t.d./25 mg implant –Warn re possibility of side-effects initially and reassure –Monitor E2 levels if poor response to therapy –Consider local use of estrogens for new/persistent urogenital symptoms, e.g. vaginal dryness, even when systemic therapy has been initiated

13. Mammographic density: comparative data Marchesoni et al. Maturitas 2005 –CEE 0.625 mg/MPA 5 mg, 45% had increase in mammographic density –Tibolone 4% Christodoulakos et al. Maturitas 2006 –CEE 0.625 mg/MPA 5 mg13.2% –E2 2 mg/NETA 1 mg31.8% –E2 1 mg/NETA 0.5 mg12.2%

14. Effect of ultra-low-dose HRT on mammographic breast density Digitized quantification No significant difference between groups ALD 0.1: 0.5 mg 17β-estradiol + 0.1 mg NETA ALD 0.25 : 0.5 mg 17β-estradiol + 0.25 mg NETA Lundström E, et al. Climacteric 2007;10:249–56

15. HRT: maximizing efficacy, minimizing problems Estrogenic side-effects Exceptions to low starting dose of E2 –Premature ovarian failure –Severe osteoporosis –Predominance of psychological problems, e.g. climacteric depression

16. Maintaining benefits Low-dose HRT

17. Dose response to estrogen therapy Number of moderate–severe hot flushes Adapted from Notelovitz M, et al. Obstet Gynecol 2000;95:726–31 Number 80 70 60 50 40 30 20 10 0 0123456789101112 * ******* ****** Placebo 0.25 mg E2 0.5 mg E2 1 mg E2 2 mg E2 Significantly (p < 0.05) different from placebo *

18. 0 2 4 6 8 10 123456789 111213 Cycle Adjusted mean number* 0.625 0.45 0.3 Placebo 0.625/2.5 0.45/2.5 0.45/1.5 0.3/1.5 Placebo CEE/MPACEE Women's HOPE Study Number of hot flushes over 13 cycles Adapted from Utian W, et al. Fertil Steril 2001;75:1065–79 *Adjusted for baseline Mean number of hot flushes at baseline = 12.3 (range 11.3–13.8)

19. Number of hot flushes Modified from Schürmann R, et al. Climacteric 2004;7:189 – 96

20. * * * significantly (p = 0.001) different from placebo * * * * * * * * Panay N, et al. Climacteric 2007;10:120 – 31 CHOICE Trial Number of moderate to severe hot flushes by week

21. CEECEE/MPA Spine BMD: ITT population Lindsay R, et al. JAMA 2002;287:808

22. * * * * Significantly (p < 0.005) different from placebo * * * Lumbar spine Percentage change over placebo after 26 months Effects of oral E2/NETA and E2 alone vs. placebo in prevention of osteoporosis in postmenopausal women (mean age 52.8) Multicenter RCT study Greenwald MW, et al. Menopause 2005;12:741 – 8

23. Progestogenic side-effects Intolerance

24. HRT: maximizing efficacy, minimizing problems Progestogen intolerance: mineralocorticoid effects Symptoms –Edema, weight gain, bloating, migraine Etiology –Competition for mineralocorticoid receptors –Possible effect on renin-angiotensin- aldosterone cascade

25. HRT: maximizing efficacy, minimizing problems Progestogen intolerance: mild androgenic effects Symptoms –Acne, greasy skin, hirsutism, etc. Competition for androgen receptor –Especially C19 nortestosterone- derived progestogens

26. HRT: maximizing efficacy, minimizing problems Progestogen intolerance: CNS effects Stimulation of progesterone receptors in CNS may lead to negative mood effects Mediation by neurotransmitter pathways –GABA receptors stimulated –Serotonin levels reduced –Increased monoamine turnover

27. Progestogen intolerance: minimizing progestogenic side-effects Progestogenic side-effects may resolve after first few weeks Direct treatment –Mild diuretics –Linolenic acid for breast tenderness –?Mifepristone (anti-progesterone)

28. HRT: maximizing efficacy, minimizing problems Minimizing progestogenic side-effects Action –Change progestogen Drospirenone may offer additional benefits –Lower dose and duration (7–10 days) –Switch to: ccHRT, tibolone, intermittent progestogen, LNG-IUS Transvaginal ultrasonography ± endometrial biopsy if bleeding problems

29. Minimizing side-effects Bleeding

30. HRT: maximizing efficacy, minimizing problems Heavy/prolonged bleeding Increase dose/duration of progestogen (13–21 days) Avoid bleeds altogether Continuous combined HRT Tibolone LNG-IUS Panay N, Studd J. Hum Reprod Update 1997;3:159

31. Women’s HOPE Study Cumulative amenorrhea rates: CEE/MPA 0.625/2.5 0.45/2.5 0.45/1.5 0.3/1.5 Placebo Archer DF, et al. Fertil Steril 2001;75:1080–7

32. Clinical efficacy: low-dose c.c. HRT Amenorrhea rates after 1 year 1 mg 17β-estradiol + 2 mg drospirenone Archer D, et al. Menopause 2005;12:716–27

33. CHOICE Trial Amenorrhea rates in women treated with oral E2 0.5 mg with NETA 0.25 (ALD 0.25) and NETA 0.1 mg (ALD 0.1) * * * * * Significantly (p < 0.05) different from placebo * * ** Sturdee D, et al. Climacteric 2008;11:63

34. Unopposed ultra-low-dose transdermal estradiol (14 µg/day) Endometrial effects vs placebo: Proliferation8.5% vs. 1.1%p = 0.6 Bleeding12.4% vs. 8.6%p = 0.3 Atypical hyperplasia × 1 Adenosarcoma × 1 Johnson SR, et al. Obstet Gynecol 2005;105:779–87 Conclusions: “This therapy apparently causes little or no endometrial stimulation”

35. Management of breakthrough bleeding with c.c. HRT/tibolone Usually in women –Recently menopausal – 1-year rule –Early menopause May be due to endogenous E2 production > 6 months breakthrough bleeding: investigate for pathology by ultrasonography (endometrial biopsy if endometrial thickness > 4 mm)

36. HRT indications Vasomotor symptoms Urogenital symptoms Joint and muscle pains, mood swings, sleep disturbances and sexual dysfunction Prevention of osteoporosis and related fractures Prevention of atrophy –Epithelia –Skin –Connective tissue –Intervertebral disks IMS Updated Recommendations, February 2007

37. HRT contraindications I (as specified by regulatory authorities) Current, past or suspected breast cancer Known or suspected estrogen- dependent malignant tumors (e.g. endometrial cancer) Undiagnosed genital bleeding Untreated endometrial hyperplasia Previous idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism) Burger H, et al. Climacteric 2004;7:210–16

38. HRT contraindications II (as specified by regulatory authorities) Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction) Untreated hypertension Active liver disease Known hypersensitivity to the active substances or to any of the excipients Porphyria cutanea tarda (an absolute contraindication) Burger H, et al. Climacteric 2004;7:210–16

39. HRT potential benefits I CVD –HRT improves many aspects of the metabolic syndrome and reduces the risk of diabetes –There is evidence that HT may be cardioprotective if started around the time of menopause and continued long-term (often referred to as the ‘window of opportunity’ concept) –In women less than 60 years old, recently menopausal, without prevalent cardiovascular disease, the initiation of HT does not cause early harm, and may reduce cardiovascular morbidity and mortality IMS Updated Recommendations, February 2007

40. HRT potential benefits II CNS –HRT initiated around the time of menopause or by younger postmenopausal women is associated with a reduced risk of Alzheimer’s disease Combined HRT may reduce the risk of colon cancer IMS Updated Recommendations, February 2007

41. Principles of hormone treatment HRT should not be recommended without there being a clear indication for its use Counselling should convey the benefits and risks of menopausal HT in simple terms, e.g. absolute numbers rather than as percentage changes from a baseline This allows a woman and her physician to make a well-informed decision about HRT IMS Updated Recommendations, February 2007

42. Principles of hormone treatment Women experiencing spontaneous or iatrogenic menopause before the age of 45, and particularly before the age of 40, are at higher risk for cardiovascular disease and osteoporosis They will benefit from hormone replacement, which should be given at least until the normal age of menopause IMS Updated Recommendations, February 2007

43. Principles of hormone treatment Women taking HRT should have at least an annual consultation for a physical examination, update of medical history, relevant laboratory and imaging investigations and a discussion on lifestyle IMS Updated Recommendations, February 2007

44. Principles of hormone treatment Whether or not to continue therapy should be decided at the discretion of the well- informed hormone user and her health professional, dependent upon the specific goals and an objective estimation of benefits and risks There are no reasons to place mandatory limitations on the length of treatment IMS Updated Recommendations, February 2007