Alternative Menopausal Hormone Therapies.pdf

1. Alternative Hormonal Treatments TEVFİK YOLDEMİR MD. BSc. MA. PhD. yoldemirtevfik tevfikyoldemir

2. Effects of selected ERAAs on target tissues in humans TABLE 2. Effects of selected ERAAs on target tissues in humans ERAA Effects on target tissue Endometrium Vagina Breast Bone Ospemifene Partial agonist43<46 Agonist43<46 Neutral (limited data)43<46 Agonist (limited data)47,48 & Up to 52-wk RCT & Up to 52-wk RCT & Up to 52-wk RCT & 3-mo RCT & Slight j in thickness from BL by TVU & SS j in superficial cells & No clinically significant abnormalities by mammography & Positive effects of bone turnover on biomarkers & Generally no histologic changes from BL & SS , in parabasal cells & No reports of cancer during these RCTsa & No reports of cancer & SS , in pH & P G 0.001 for all vs PBO Tamoxifen Agonist49<51 Agonist52 Antagonist51 Agonist53 & Meta-analysis of four trials & Prospective study & Meta-analysis of four trials & 2-y RCT & SS j in cancer (P G 0.001) vs PBO & SS j in MI across 24 mo vs controls (P G 0.0001) & SS , in cancer vs PBO (P G 0.0001) & SS j in lumbar spine BMD vs PBO (P G 0.001) & j in thicknessb & SS , in serum osteocalcin from BL vs PBO (P G 0.001) Raloxifene Neutral or antagonist51,54<58 Neutral54,59 Antagonist51 Agonist60,61 & Meta-analysis of three trials & Up to 6-mo CT & Meta-analysis of five trials & Up to 24-mo RCT & No difference in thickness by TVU and in incidence of bleeding vs controls & No difference in VMV or parabasal, intermediate, or superficial cells by smear vs controls & SS , in all breast cancers (P G 0.0001) & SS j in BMD vs PBO or BL (P G 0.05) & No increase in cancer & SS , in biomarkers of bone turnover vs PBO or BL (P G 0.05) Bazedoxifene (monotherapy) Antagonist62 Antagonist63 Neutral or antagonist 64,65 Agonist66<68 & 7-y RCT & 12-wk RCT & 24-mo RCT & Up to 5-y RCT & No difference in thickness by TVU and in incidence of hyperplasia vs PBO & Little change in superficial cells vs BL; parabasal cells increased; intermediate cells decreasedc & No j in density by mammography vs PBO & SS , in incidence of new vertebral fractures vs PBO (P G 0.05) & SS , in incidence of cancer vs PBO (P = 0.02) & No difference in cancer rates or pain vs PBO & SS j in lumbar spine BMD vs PBO (P e 0.023) & SS , in serum osteocalcin/ CTX vs PBO (P e 0.009) ERAA, estrogen receptor agonist/antagonist; RCT, randomized clinical trial; (j) increase; BL, baseline; (,) decrease; TVU, transvaginal ultrasound; SS, statis- tically significant; PBO, placebo; MI, maturation index; BMD, bone mineral density; CT, clinical trial (randomized or not); VMV, vaginal maturation value; CTX, ARCHER ET AL Menopause 2014: Vol. 22, No. 7, pp. 786-796

3. Tissue selective estrogen complex (TSEC) Menopause 2018 Vol. 25, No. 9, pp. 1033-1045

4. conjugated estrogens/bazedoxifene treatment & vasomotor symptoms JOURNAL OF WOMEN’S HEALTH Volume 25, Number 11, 2016: 1102-1111 Bazedoxifene

5. Mean daily number of hot flashes JOURNAL OF WOMEN’S HEALTH Volume 25, Number 11, 2016: 1102-1111 Bazedoxifene

6. Mean daily hot flash severity score JOURNAL OF WOMEN’S HEALTH Volume 25, Number 11, 2016: 1102-1111 Bazedoxifene

7. Number and severity of hot flash JOURNAL OF WOMEN’S HEALTH Volume 25, Number 11, 2016: 1102-1111 Bazedoxifene

8. Effect of years since menopause JOURNAL OF WOMEN’S HEALTH Volume 25, Number 11, 2016: 1102-1111 Bazedoxifene

9. Menopause-specific quality of life JOURNAL OF WOMEN’S HEALTH Volume 25, Number 11, 2016: 1102-1111 Bazedoxifene

10. Bazedoxifene & BMD & Fracture Clinical Reviews in Bone and Mineral Metabolism (2018) 16:22–32 Bazedoxifene

11. Bazedoxifene & BMD & Fracture Clinical Reviews in Bone and Mineral Metabolism (2018) 16:22–32 Bazedoxifene

12. BZD 20 mg & vertebral / non-vertebral fractures Clinical Reviews in Bone and Mineral Metabolism (2018) 16:22–32 Vertebral fracture Non-vertebral fracture Bazedoxifene

13. SMART trials Maturitas 80 (2015) 435–440 Bazedoxifene

14. Main efficacy results for TSEC from the SMART trials observed with CE/BZA compared with placebo and raloxifene. These effects remained after 2 years of treatment [11]. However, data comparing CE/BZA and other MHT regarding the reduction in hot flashes are not available. Only one study showed a similar efficacy for relieving hot flashes between CE 0.45 mg/BZA 20 mg and CE 0.625 mg/MPA 1.5 mg, but the principal purpose of this included 664 postmenopausal women aged 40–65 years. Women who received CE/BZA exhibited improvement in the percentage of superficial vaginal cells and parabasal cells in week 12 (p < .01 compared with placebo). However, significant differences in the reduction in vaginal pH and improvement in the most bother- some vulvovaginal symptoms (i.e., dyspareunia, vaginal dryness) Table 1. Main efficacy results for TSEC from the SMART trials. Study and trial registration Objective Main results SMART 1 NCT00675688 [11] Effects on menopausal symptoms, metabolic parameters, and overall safety vs. BZA, HT (CE/MPA), and PBO " Reduction of the moderate-severe daily hot flushes (p < .05 vs. PBO) and its severity (p < .001 vs. PBO) " Improvements in sleep parameters (p < .05 vs. PBO) " Improvements in lipid parameters and homocysteine levels, no changes in carbohydrate metabolism, and only minor effects on some coagulation parameters " Endometrial safety " Breast pain and adverse events similar to placebo SMART 2 NCT00234819 [12] Safety and efficacy treating moderate to severe vasomotor symptoms vs. BZA, HT (CE/MPA), and PBO " Reduction in the number and severity of hot flashes (p < .001 vs. PBO) " Improvements in sleep parameters (p < .05 vs. PBO) " Improvements in satisfaction and quality of life (p < .05 vs. PBO) SMART 3 NCT00238732 [13] Efficacy and safety of two doses of TSEC vs. PBO for the treatment of moderate to severe VVA associated with menopause " Increase in superficial and intermediate cells, and decrease in parabasal cells (p < .01 vs. PBO) " Improvements in satisfaction, vasomotor symptoms, sexual function, and quality of life (p < .05 vs. PBO) SMART 4 NCT00242710 [14] Endometrial safety and BMD effects vs. HT (CE/MPA) and PBO " Endometrial safety similar to PBO " Bleeding and breast tenderness lower than HT (p < .05) " Improve lumbar spine and total hip BMD (p < .001 vs. PBO) " Favorable safety/tolerability profile over 1 year SMART 5 NCT00808132 [15] Endometrial safety and BMD effects vs. BZA alone, HT, and PBO " Low endometrial hyperplasia incidence (<1%) in all groups " Cumulative amenorrhea rates similar to PBO and BZA and higher than HT (p < .001) " Improve lumbar spine and total hip BMD (p < .001 vs. PBO) " Breast tenderness similar to PBO and BZA and significantly lower than HT (p < .01) " Adverse event rates were similar among the groups " Serious AEs overall and AE-related discontinuation rates lower than HT BZA: bazedoxifene; CE: conjugated estrogen; HT: hormone therapy; MPA: medroxyprogesterone acetate; PBO: placebo; SMART: Selective estrogens, Menopause, And Response to Therapy; TSEC: tissue-selective estrogen complex; VVA: vulvar/vaginal atrophy. Gynecological Endocrinology, 2018; 34:10, 826-832 Bazedoxifene

15. Safety and Tolerability Maturitas 80 (2015) 435–440 Bazedoxifene

16. Rates of cumulative amenorrhea Maturitas 80 (2015) 435–440 Bazedoxifene

17. Effects of CE/BZD on BMD Therapeutics and Clinical Risk Management 2016:12 549–562 Bazedoxifene

18. Breast pain during treatment Therapeutics and Clinical Risk Management 2016:12 549–562 Bazedoxifene

19. Breast tenderness in daily diaries Therapeutics and Clinical Risk Management 2016:12 549–562 Bazedoxifene

20. Bleeding/ spotting Therapeutics and Clinical Risk Management 2016:12 549–562 Bazedoxifene

21. Strenght of the antagonist and agonist effect of ospemifene compared with other SERMS L. Del Pup European Review for Medical and Pharmacological Sciences 2016; 20: 3934-3944 Ospemifene

22. A non-estrogen selective estrogen receptor modulator Intentiontotreatpopulation perprotocolpopulation Maturitas 78 (2014) 91–98 Ospemifene The intent-to-treat (ITT) population, which consisted of all randomised participants who took at least one dose of the study medication. The per-protocol (PP) population completed at least 10 weeks of treatment, took ≥85% of the study medication and did not have any other major protocol violation, vaginal infection or any other medical condition that would confound the primary efficacy assessment.

23. Intentiontotreatpopulation perprotocolpopulation Maturitas 78 (2014) 91–98 Ospemifene Change from baseline was determined as −3 being a change from ‘severe’ to ‘none’; −2 being either a change from ‘severe’ to ‘mild’ or from ‘moderate’ to ‘none’; −1 being either ‘severe’ to ‘moderate’, ‘moderate’ to ‘mild’, or ‘mild’ to ‘none’, and zero being no change. A change of 1 indicated a change from ‘moderate’ to ‘severe’, ‘mild’ to ‘moderate’, or ‘none’ to ‘mild’.

24. Week1 Week12 Maturitas 78 (2014) 91–98 Ospemifene

25. Total score - Female Sexual Function Index Intentiontotreatpopulation dyspareunia !"#$%&'()#& *+,-./,01*2/**34*5* Ospemifene ITT - all randomized subjects who had received > one dose of the study medication

26. Intention to treat population !"#$%&'()#& *+,-./,01*2/**34*5* Ospemifene

27. dyspareunia !"#$%&'()#& *+,-./,01*2/**34*5* Ospemifene

28. Overall Safety of Ospemifene in Postmenopausal Women from Placebo-Controlled Phase 2 and 3 Trials JOURNAL OF WOMEN’S HEALTH, 2017 Ospemifene

29. JOURNAL OF WOMEN’S HEALTH, 2017 Ospemifene

30. Intravaginal6.5mg(0.50%)DHEA(Prasterone)vs 0.3mgConjugatedEquineEstrogensvs 10μgEstradiol DecreaseofSeverityofDyspareunia Journal of Steroid Biochemistry and Molecular Biology 174 (2017) 1–8 Prasterone

31. Intravaginal6.5mg(0.50%)DHEA(Prasterone)vs 0.3mgConjugatedEquineEstrogensvs 10μgEstradiol vs Placebo ImprovementofDyspareunia Journal of Steroid Biochemistry and Molecular Biology 174 (2017) 1–8 Prasterone

32. Intravaginal6.5mg(0.50%)DHEA(Prasterone)vs 0.3mgConjugatedEquineEstrogensvs 10μgEstradiol DecreaseofSeverityofVaginalDryness Journal of Steroid Biochemistry and Molecular Biology 174 (2017) 1–8 Prasterone

33. EffectofIntravaginal6.5mg(0.50%)DHEA(Prasterone)vs 0.3mgConjugatedEquineEstrogens ImprovementofVaginalDrynessOverPlacebo Journal of Steroid Biochemistry and Molecular Biology 174 (2017) 1–8 Prasterone

34. SerumDHEAremainswellwithinnormalpostmenopausalvalues followingintravaginal0.50%DHEA Journal of Steroid Biochemistry & Molecular Biology 159 (2016) 142–153 Prasterone

35. Serum testosterone shows no biologically significant change following intravaginal 0.50% DHEA Journal of Steroid Biochemistry & Molecular Biology 159 (2016) 142–153 Prasterone

36. Serum estradiol remains well within normal postmenopausal values followingintravaginal 0.50% DHEA Journal of Steroid Biochemistry & Molecular Biology 159 (2016) 142–153 Prasterone

37. Effect of Intravaginal Prasterone on Sexual Dysfunction J Sex Med 2015;12:2401–2412 Prasterone

38. J Sex Med 2015;12:2401–2412 Prasterone

41. Effect of DHEA on vaginal dryness / pain at sexual activity (ITT population) CLIMACTERIC 2015;18:590–607 Prasterone

42. Effect of DHEA on irritation/itching (ITT population) CLIMACTERIC 2015;18:590–607 Prasterone

43. Vaginal dryness Menopause: 2009;Vol. 16, No. 5, pp. 907/922 Prasterone

44. Pain at sexual activity Menopause: 2009;Vol. 16, No. 5, pp. 907/922 Prasterone

45. Effect of prasterone on MS or MBS pain at sexual activity Maturitas 81 (2015) 46–56 Prasterone

46. Effect of prasterone on MS vaginal dryness Maturitas 81 (2015) 46–56 Prasterone

47. Effect of prasterone on MS irritation/itching Maturitas 81 (2015) 46–56 Prasterone

48. Menopause: 2009; Vol. 16, No. 5, pp. 923/931 Prasterone

54. Factors that increase or decrease levels of SHBG in women Your Sexual Medicine Journal (2022) 34:635–641; https://doi.org/10.1038/s41443-022-00613-0

55. Your Sexual Medicine Journal (2022) 34:635–641; https://doi.org/10.1038/s41443-022-00613-0

56. Testosterone therapy and postmenopausal women • Where an appropriate approved female testosterone preparation is not available, off- label, prescribing of an approved male formulation is reasonable, provided hormone concentrations are maintained in the physiologic female range. • Should a trial of testosterone therapy be given for HSDD, a baseline total testosterone and SHBG concentration should be measured before commencement, with a repeat level 6 weeks after treatment initiation. • Evaluation of therapy response should be monitored clinically in terms of improvement of low sexual desire/well-being after 12 weeks of therapy. • Patients should be monitored for their clinical response to treatment and assessed for signs of androgen excess with a serum total testosterone level every 6 months, to screen for overuse. • If no benefit is experienced by 6 months, treatment should be ceased. J Clin Endocrinol Metab, October 2019, 104(10):4660–4666 CLIMACTERIC 2021, VOL. 24, NO. 1, 46–50

57. The Obstetrician & Gynaecologist 2022;24:228–41. https://doi.org/10. 1111/tog.12836

58. The Obstetrician & Gynaecologist 2022;24:228–41. https://doi.org/10. 1111/tog.12836

59. How to apply and follow • Testosterone gel or cream should be used on clean, dry skin on the lower abdomen and upper thighs. Skin contact with others should be avoided until the skin is dry and hands should be washed immediately after application. • Response to therapy usually requires at least 8 weeks to manifest, so treatment should be trialled for a minimum of 3 months. • If there has been no improvement after 6 months, then testosterone should be discontinued. • To assess whether a satisfactory response is maintained, and to identify adverse androgenic events, regular reviews should be undertaken, at least on an annual basis. • The optimal duration of treatment has yet to be ascertained. Research studies predominantly involved 6–12 months of use, so efficacy and safety beyond this period is unclear. The Obstetrician & Gynaecologist 2022;24:228–41. https://doi.org/10. 1111/tog.12836

60. Weak/no evidence • The association between endogenous androgen concentrations and sexual function in women is uncertain, and there is no cut-off level that can be used to differentiate women with or without sexual dysfunction. • Insufficient evidence that testosterone enhances cognitive performance or improves depressed mood. • Insufficient evidence that testosterone improves musculoskeletal outcomes, including bone mineral density. • A nonsignificant trend for increased deep vein thrombosis has been seen with transdermal testosterone; however, this could be associated with estrogen therapy. • Safety data for testosterone therapy beyond 24 months is not available. The Obstetrician & Gynaecologist 2022;24:228–41. https://doi.org/10. 1111/tog.12836

61. Limited Evidence • A baseline total testosterone concentration should be measured before starting treatment and repeated 6 weeks after commencement. Signs of androgen excess can be screened for with 6-monthly levels. • Treatment should be stopped if no benefit after 6 months. Testosterone may improve wellbeing but data are inconclusive. • Available data to date show that short-term transdermal testosterone therapy does not appear to impact breask cancer risk, but RCT data for long-term breast cancer risk is insufficient. The Obstetrician & Gynaecologist 2022;24:228–41. https://doi.org/10. 1111/tog.12836

62. What should be measured • Total testosterone levels provide a more accurate representation of therapeutic response than free testosterone, or the calculated Free Androgen Index (FAI). • In certain circumstances, SHBG levels may be helpful as additional supportive information: — Where SHBG levels are high e.g. due to high dose oral estrogen therapy, especially conjugated estrogens. This may explain lack of therapeutic response to physiological testosterone replacement, despite normal total testosterone levels. — Conversely, when SHBG levels are very low. This may explain why androgenic adverse effects with testosterone replacement have occurred, despite normal total testosterone levels. • When treating low sexual desire /arousal it is also important that urogenital tissues are adequately estrogenised in women with vulvovaginal atrophy / genitourinary syndrome of the menopause e.g. through use of vaginal estrogen, to avoid dyspareunia BRITISH MENOPAUSE SOCIETY Tool for clinicians Testosterone replacement in menopause

63. Take away messages -1 • TSEC is associated with a clinically significant reduction in the number and severity of hot flashes (GRADE 2A). This efficacy is similar to that recorded with MHT. • TSEC is associated with clinically significant improvements in health- and sleep-related quality of life (GRADE 2B). These improvements are similar to those observed with MHT. • TSEC decreases dyspareunia and reduces vaginal dryness compared to placebo. In addition, the use of TSEC involves significant improvements in sexual health. However, isolated VVA is not an approved indication for TSEC. Gynecological Endocrinology, 2018; 34:10, 826-832

64. Take away messages -2 • TSEC is associated with a safe breast profile with the same incidence rates of breast tenderness and effect on mammary density as placebo (GRADE 2A). • TSEC achieves high amenorrhea rates compared with placebo and significantly higher rates compared with MHT (GRADE 2A). • TSEC exhibits a favorable endometrial safety profile with an incidence of hyperplasia similar to that of placebo (GRADE 2A). Gynecological Endocrinology, 2018; 34:10, 826-832

65. Take away messages -3 JAMA October 24/31, 2017 Volume 318, Number 16

66. Duavee®

67. Duavee®

68. Neurokinin-3 receptor (NK3R) antagonists The long-term safety of NK3R antagonists is to be established in phase III trials. Hepatic safety is highlighted as an aspect to be appropriately monitored, particularly following the discontinuation of pavinetant . The relative advantages of long-term treatment with NK3R antagonists versus HT in menopausal women also remain to be determined. NK3R antagonists are not anticipated to elicit the peripheral side effects of hormones; for example, there are no signs of endometrial hyperplasia, to-date, in response to fezolinetant An expanded role for NK3R antagonists may be in the treatment of VMS triggered by hormone deprivation therapy in women treated for estrogen-sensitive cancers (e.g. breast cancer)

69. neurokinin 3 receptor antagonist - (VESTA) Menopause 2020 Vol. 27, No. 12, pp. 1350-1356 DOI: 10.1097/GME.0000000000001621 fezolinetant

70. 0.5 or 1 mg estradiol / 100 mg progesterone 1. Kagan R, Constantine G, Kaunitz AM, Bernick B, Mirkin S. Improvement in sleep outcomes with a 17β-estradiol-progesterone oral capsule (TX-001HR) for postmenopausal women. Menopause. 2018;25(6). doi:10.1097/GME.0000000000001278 2. Lobo RA, Archer DF, Kagan R, et al. A 17β-estradiol-progesterone oral capsule for vasomotor symptoms in postmenopausal women. Obstet Gynecol. 2018;132(1):161-170. 3. Mirkin S. Evidence on the use of progesterone in menopausal hormone therapy. Climacteric. 2018;21(4):346-354. 4. Simon JA, Kaunitz AM, Kroll R, Graham S, Bernick B, Mirkin S. Oral 17β-estradiol/progesterone (TX-001HR) and quality of life in postmenopausal women with vasomotor symptoms. Menopause. 2019;26(5). doi:10.1097/GME.0000000000001271 Bijuva

71. CEE / MPA 0.625 mg/2.5 mg continuous 0.45 mg/1.5 mg continuous 0.625 mg/5 mg continuous 0.3 mg/1.5 mg continuous 0.625 mg/5 mg sequential Prempro & Premphase

72. 1 mg oestradiol (as hemihydrate) and 10mg dydrogesterone. sequential 2 mg oestradiol (as hemihydrate) and 10mg dydrogesterone. sequential 1 mg 17β-estradiol (as hemihydrate) and 5 mg dydrogesterone. continuous 0.5 mg 17β-estradiol (as hemihydrate) and 2.5 mg dydrogesterone. continuous Femoston / Femoston-conti

73. TEVFİK YOLDEMİR MD. BSc. MA. PhD. tevfikyoldemir yoldemirtevfik

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