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Menopausal Harmone Therapy & Indian Gynaecologists Dr Sharda Jain

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Menopausal Harmone Therapy & Indian Gynaecologists Dr Sharda Jain

  1. 1. Menopausal Harmone Therapy & Indian Gynaecologists Dr Sharda Jain Secretary general Delhi Gynaecologist forum MENOPAUSE
  2. 2. All Menopausal Hormone Therapy regimes are not the same Past President IMS TOBIE DE VILLIERS
  3. 3. Symptoms of the Menopausal Journey 3
  4. 4. Signs and symptoms; menopausal transition and beyond Vasomotor Symptoms Sleep Disorders Mood Changes Urogenital Atrophy Dyspareunia Osteoporosis Atherosclerosis Coronary Artery Disease Cerebrovascular Disease 40 yrs 50 yrs Menopause 60 yrs Menstrual Disorders Harlow et al. STRAW+10 Staging Reproductive Aging Climacteric, Fertil Steril, JCEM, Menopause 2012
  5. 5. The History of HRTHRTprescriptionsfilledperyear intheUSA(millions) 20 40 60 80 100 Year 30 40 50 60 70 80 90 2000 2002 2010 CEE marketed Endometrial cancer 90 million prescriptions per year WHI publication Progestins CHD benefits HRT ↓ 32% by 2003 0
  6. 6. Today  We are 1.3 billion Life expectancy 71 years Unni J. J Midlife Health. 2010 Jan-Jun; 1(1): 43–47 Global Age of Menopause 51 yrs Menopause : 47.5 years (Unni) ICMR 49 years
  7. 7. 47.3 46.2 45.5 46.1 47.8 East West North South Centre Mean natural menopause age in different regions of India Avg. age of menopause of an Indian woman is 46.2 yrs Health & Social Work Volume 42, Number 2 May 2017, Ahuja M.J Midlife Health. 2016 Jul-Sep;7(3):126-131. IMS PREVALENCE
  8. 8.  woman's ovaries stop working at a very early age, ranging anywhere from the age of puberty to age 40, and this is known as premature ovarian failure (POF)—1.5 – 20 %. Premature menopause Jadhav A & Bavaskar Y. Int J Community Med Public Health. 2017 Sep;4(9):3088-93
  9. 9. Endocr Rev. The role of estrogens in control of energy balance and glucose homeostasis.2013; 34 (3): 309-338 Detrimental Effects of Estrogen Deficiency on Metabolism Premature Menopause
  10. 10. Premature Menopause & Cardiovascular Disease If menopause occurs early CARDIOPROTECTIVE effect of Oestrogen is gone & increases the risk of CVD
  11. 11. Pre-Menopause & Diabetes – WHI Study • PREMATURE MENOPAUSE INCREASES THE RISK OF *DIABETES *PREDIABETES *METABOLIC SYNDROME • WOMEN WITH LESS THAN 30 YEARS REPRODUCTIVE LIFESPAN HAD 40 % INCREASE THAN WOMEN WITH Reproductive lifespan of 36 to 40 years
  12. 12. MHT & RISKS Breast Cancer ? Venous Thromboembolic Disease Coronary Heart Disease Osteoporosis Memory Loss & Dementia Endometrial Cancer Should be used at lowest dose for shortest time Recommended for Post- menopause only; Not for perimenopause International Journal of Epidemiology, Volume 30, Issue 3, June 2001, Pages 423–426 WHI LESSIONS
  13. 13. Perceptions after WHI (2002) In spite of the beneficial effects of MHT: • Alleviation of vasomotor symptoms (hot flushes) • Improvement of VVA and recurrent urinary tract infections • Fracture protection The following risks outweighed the beneficial effects: • Cardiovascular risk • Risk of thromboembolic disease • Risk of breast cancer • Risk of death HRT was replaced by term MHT It was perceived to be a class effect of all MHT regimes!
  14. 14. Lessons learned from WHI-- applicable to all MHT’s The beneficial effect of MHT on cardiovascular disease is only evident when started before the age of 60 or within 10 years after menopause. All cause mortality is not raised in patients on MHT
  15. 15. THE ADDITION OF MPA (THE PROGESTIN) TO CE (THE ESTROGEN) IN PATIENTS WITH INTACT UTERUS ATTENUATED THE BENEFICIAL EFFECTS SEEN WITH ESTROGEN ALONE IN CHD TOBIE DE VILLIERS (2020 ,talk )
  16. 16. THE RISK OF BREAST CANCER IS LOWERED WITH ESTROGEN ALONE COMPARED TO CE/MPA TOBIE DE VILLIERS ( 2020,talk )
  17. 17. 15-years Post-WHI “The big concern in clinical practice is not the overuse of hormone therapy for prevention of chronic conditions; it's the underutilization and under treatment of women who have hot flashes, night sweats, disruptive sleep, and impaired quality of life and are otherwise appropriate candidates for hormone therapy .” * WHI Chief Investigator, Prof. JoAnn Manson Harvard Medical School, Medscape 1/2018 *TOBIE DE VILLIERS ( 2020 )
  18. 18. Uterus Sequential therapy with tablet break Regular bleeding at end of cycle Options in MHT • Cyclic HRT Haines CJ et al. Hong Kong Med J. 1999;5(2):195–99 Estrogen Continuous Estrogen Estrogen No tablet break No bleeding as no uterus Uterus Sequential therapy without tablet break Regular bleeding at end of cycle Continuous Sequential HRT Estrogen Progestogen Day 14 Continuous Combined HRT Estrogen Progestogen Combined therapy without tablet break No bleeding at end of cycle 7 day tablet break Progestogen Day 14Day 7 Oral or Transdermal
  19. 19. Does the estrogen matter? • Compared to estradiol, certain estrogens in CEEs are more resistant to metabolism, and the medication shows relatively increased effects in certain parts of the body like the liver. • This results in an increased risk of blood clots and cardiovascular disease with CEEs relative to estradiol.[1] 1 H Kuhl. Climacteric2005;8 suppl 1:3-63
  20. 20. HRT Remains the Most Effective Therapy for Vasomotor Symptoms1 No statistically significant efficacy of botanicals in reducing vasomotor symptoms2 1. Baber RJ et al. Climacteric. 2016;19:109–50; 2. Newton KM et al. Ann Intern Med 2006;145:869–79. Reprinted from Annals of Internal Medicine, Newton et al, Treatment of Vasomotor Symptoms of Menopause with Black Cohosh, Multibotanicals, Soy, Hormone Therapy, or Placebo, 145(12):869-879, Copyright (2006) American College of Physicians. All Rights Reserved. Reprinted with the permission of American College of Physicians, Inc. Baseline 3 months 6 months 12 months 0 1 2 3 4 5 6 7 8 Vasomotorsymptomsperday Black Cohosh Multibotanical Multibotanical + soy HRT: CEE +/- MPA Placebo * *p=0.016 multibotanical + soy vs. placebo at 12 months
  21. 21. Risk of stroke is associated with route and dose of administration 0.5 5 High-dose patches: 1.1 (0.8, 1.5) Favors Placebo Favors HRT 1 Low-dose patches: 1.1 (0.8, 1.5) Low-dose oral: 1.1 (0.8, 1.5) High-dose oral: 1.1 (0.8, 1.5) Case-control study from the UK General Practice Research Database • Low-dose transdermal HRT did not appear to increase stroke risk Renoux C et al. BMJ 2010;340:2519
  22. 22. Role of Progestogens in HRT & Endometrial safegaurd Estrogen provides the benefits of HRT on menopausal symptoms. For women who have not had a hysterectomy, the addition of a progestogen to HRT is necessary to protect the endometrium from the stimulatory effects of unopposed estrogen Writing Group for the PEPI Trial. JAMA 1996;275:370–5. Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial: Results of Endometrial Biopsy Conclusion: Adding a progestogen is needed to safeguard the endometrium by causing secretory transformation Placebo CEE alone CEE+MPA sequential CEE+MPA continuous CEE+MP N 119 119 118 120 120 Normal 97.5% 37.8% 94.9%* 99.2%* 95.0%* Simple hyperplasia 0.8% 27.7%** 3.4% 0.8% 4.2% Complex hyperplasia 0.8% 22.7%** 1.7% 0% 0% Atypia 0% 11.8%** 0% 0% 0.8% Adenocarcinoma 0.8% 0% 0% 0% 0% *p=0.16 (normal vs. abnormal) compared with placebo; **p<0.001 vs. placebo
  23. 23. Alternatives to adding a progestogen Tibolone: • A prodrug metabolized to estrogen, progestogen and testosterone Selective estrogen receptor modulator (TSEC) • CE plus Bazedoxifene Levonorgesterel containing IUCD
  24. 24. Classification of progestogens Progesterone Retroprogesterone Progesterone Dydrogesterone Progesterone Derivatives Testosterone Derivatives 17-OH-progesterone Derivates 19-progesterone Derivatives 19-nortestosterone Derivatives Pregnane • Hydroxyprogesterone Caproate • Hydroxyprogesterone Heptanoate • Gestonorone Caproate • Chlormadinone Acetate • Medrogestone • Medroxyprogesterone Acetate • Cyproterone Acetate Nor-Pregnane • Nomegestrole Acetate • Demegestone • Promegestone • Nestorone • Trimegestone Estranes • Lynestrenol • Levonorgestrel • Norethisterone • Norethisterone Acetate • Ethinodiol Diacetate • Norgestrienone • Dienogest Gonanes • Norgestrel • Desogestrel • Gestodene • Norgestimate Spirolactone Derivative Drospirenone Adapted from: Druckmann R. Journal Für Menopause. 2002:1-5. All Progestogens are not same
  25. 25. Progesterone and Dydrogesterone Progesterone2 Micronization is Light technology bends it into performed to make a curved retro-steroid structure Micronized Progesterone Dydrogesterone Dioscorea rootsDioscorea plants 1. Source: http://www.med.nyu.edu/content?ChunkIID=21816 2. Fischer M. Agnew Chem Int Ed Engl 1978; 17: 16-26. Both progesterone and dydrogesterone are produced from the dioscorea plant1 Dydrogesterone, shaped by light, enhances the progestogenic effects
  26. 26. MPA: from hero to zero There is general consensus today that the poor cardiovascular and breast results of the E+P arm of WHI were not a class effect of progestogens, but the result of the specific metabolic effects of MPA TOBIE DE VILLIERS
  27. 27. Choice of progestogen and breast cancer risk: Finnish cohort study 1 1.13 1.64 2.03 2.07 0 0.5 1 1.5 2 2.5 Baseline risk without HRT Estradiol/ dydrogesterone Estradiol/MPA Estradiol/NETA Estradiol/other progestogens Standardincidenceratio,95%CI Risk elevation may not be uniform for all progestogens N=50 210 women >50 years of age, treatment duration 5 years or more Lyytinen H et al. Obst Gyn. 2009;113:65–73
  28. 28. Risk of VTE and different progestogens; Esther case- control study Micronized progesterone and pregnane derivatives appear to have an acceptable thrombotic risk profile 0.1 1 10 100 Adjusted ORs for VTE with oral and transdermal estrogen vs non-users, 95% CI Micronized progesterone: 0.7 (0.3, 1.9) Favors Placebo Favors HRT Oral estrogen: 4.2 (1.5, 11.6) Pregnane derivatives: 0.9 (0.4, 2.3) e.g. Dydrogesterone Norpregnane derivatives: 3.9 (1.5, 10.0) e.g. Nomegestrol acetate 271 consecutive VTE cases (mean age: 61.6 years) and 610 controls (mean age: 61.5 years) Canonico M. Circulation 2007;115:840–845
  29. 29. “Progestogens are not alike with regard to potential adverse metabolic effects, cognitive effects or associated breast cancer risk when combined with systemic estrogen therapy.”
  30. 30. E2/Dydrogesterone formulations and indications approved in India Continuous sequential 1/10 and Continous combined 1/5 • For the treatment of Hormone replacement therapy (HRT) in estrogen deficiency in postmenopausal women with a uterus • Prevention of osteoporosis in postmenopausal women who are intolerant of other products approved for the prevention of osteoporosis Bleeding at end of cycle 17β-estradiol 1 mg/d Dydrogesterone 10 mg/d Day 14 Day 28 17β-estradiol 1 mg/d Dydrogesterone 5 mg/d Day 14 No bleeding Day 28
  31. 31. Benefit/risk profile of MHT: VMS MHT, including tibolone and the combination of conjugated equine estrogens and bazedoxifene (CE/BZA), are the most effective treatments for vasomotor symptoms (VMS) associated with menopause at any age, but benefits are more likely to outweigh risks if initiated for symptomatic women before the age of 60 years or within 10 years after menopause. Revised Global Consensus on MHT De Villiers TJ et al, Climacteric 2016 CC E/D 1/5 improves hot flushes compared to placebo Significant reduction in moderate-to-severe hot flushes versus placebo (n=305) Stevenson JC et al. Maturitas. 2010;67:227–232
  32. 32. Cieraad D et al. Arch Gynecol Obstet 2006;274:74–80. Seq COCP E/D 1/10 decreases hot flushes • In a study of 193 peri- and postmenopausal women: – Mean number of hot flushes per day decreased by 86% – Improvement supported by changes in Greene climacteric symptom score 0 2 4 6 8 10 12 14 16 18 20 22 0 12 24 0 12 24 0 12 24 0 12 24 E/D (1/10) CEE/norgestrel (0.625/0.15) MeanscoresontheGreeneclimacteric symptomscale,SD Week Psychological scale Somatic scale Vasomotor scale Sexual dysfunction
  33. 33. Sequential COCP E/D improved BMD Sequential E/D effective versus placebo in preventing loss of bone mass in the lumbar spine and femoral neck over 2 years (n=595) Lees B, et al. Osteoporos Int 2001;12:251–258 Continuous 1/5, 1/10, and 1/20 significantly increased lumbar vertebrae and hip BMD vs. baseline (n=177) Stevenson J et al. Maturitas 2001;38:197–203 --------------------------------------------------------------------------------------------------------------------------
  34. 34. Benefit/risk profile of MHT: VVA/GSM MHT, including tibolone, is effective in the treatment of vulvovaginal atrophy (VVA) now also considered as a component part of the genitourinary syndrome of menopause (GSM). Revised Global Consensus on MHT De Villiers TJ et al, Climacteric 2016 Sequential OCP E/D 2/10 Reduced Menopausal Symptoms -------------------------------------------------------------------------------------------------------------------------- From: “Femoston®: Effects on bone and quality-of-life”,Amy JJ, Eur Menop J 1995;2(Suppl):16–22. ©1995, Informa Healthcare. Figure reprinted with permission of Informa Healthcare.
  35. 35. Benefit/risk profile of MHT: Cardiovascular • Randomized clinical trials and observational data as well as meta- analyses provide evidence that standard-dose estrogen-alone MHT may decrease the risk of myocardial infarction and all-cause mortality in women younger than 60 years of age and within 10 years of menopause • Data on estrogen plus progestogen MHT initiated in women younger than age 60 years or within 10 years of menopause show a less compelling trend for mortality benefit, and evidence on cardio protection is less robust with inconsistent results compared to the estrogen alone group. Revised Global Consensus on MHT De Villiers TJ et al, Climacteric 2016
  36. 36. Sequential COCP E/D:+ Results • EFFECT on LIPID PROFILE • DIABETES • HYPERTENTION • CV EVENTS
  37. 37. Benefit / Risk profile of MHT: Breast Cancer Revised Global Consensus on MHT De Villiers TJ et al, Climacteric 2016 -------------------------------------------------------------------------------------------------------------------------- Breast Cancer risk with E/D (E2/dydrogesterone) similar to non-users of MHT Schneider C et al. Climacteric 2009;12:514–24
  38. 38. MHT Breast Cancer Endometrial Cancer Coronary Heart Disease Osteoporosis Memory Loss & Dementia Venous Thrombo embolic Disease International Journal of Epidemiology, Volume 30, Issue 3, June 2001, Pages 423–426 Should be used at lowest dose for shortest time Recommended for Post-menopause only; Not for perimenopause
  39. 39.  Individualization of MHT, i.e., the dose, type, route, is according to the need of the individual woman  Use unopposed estrogen only for women who have undergone hysterectomy  Progesterone needs to be added if prescribed for women with an intact uterus  The art of prescribing MHT is to use the minimum effective dose judiciously on indication only ,that too after appropriate counseling Wayahead on MHT….
  40. 40. important issues before deciding on HT • A specific indication for starting HT must be present, and it must be documented • Symptoms which definitely require HT are vasomotor symptoms and symptoms as a result of urogenital atrophy • The main rule for giving HT is to use the “lowest possible dose for shortest possible duration” Take Home Messageson MHT….
  41. 41. Contd…. • For prevention and treatment of Osteoporosis, other modalities (bisphosphonates) should be preferred over estrogens • Assessment of Risk Factors prior to starting HT is an essential prerequisite • LIFESTYLE MODIFICATION is an integral component of managing postmenopausal women Wayahead….
  42. 42. Non-Pharmacological Management: Limitations  Soy isoflavones & Black Cohosh had no statistically significant effects on Menopausal symptoms  Soy iso flavones…no binding with estrogens receptors  Additionally, Black Cohosh products carry a warning statement due to risk of liver damage
  43. 43. • Universal Event – Why treat ? • Protective role of -Give MHT estrogen matters • Proven Safe MHT which works like Anti oxidant √ for well being of a women at menopause ( like calcium ) “I am feeling so much more
  44. 44. Dr Sharda Jain MD, (PGIMER), MAMS , FICOG, FIMSA, DHM, QM & AHO PGDMLS (SYMBIOSIS) Regd. No 11076/ DMC No 2734 ACADEMICIAN & SURGEON PAR EXELLENCE Taught for 2 decades at PGIMER (Chandigarh )+LHMC(Delhi DIRECTOR : Lifecare Centre + Lifecare ABS Lifecare IVF * GLOBAL STEMGEN MEMBER : Ethical Committee of India (MCI) EXPERT : Delhi Medical council for last 12 years FOUNDER & SECRETARY GENERAL : Delhi Gynaecologis Forum FOUNDER & CHAIRPERSON : WOW India CHAIRPERSON : Medico Legal Foundation FORMER NATIONAL CHAIRPERSON : Women Wing , IMA (2004-2007) ADVISOR HEALTH : National Commission For Women (2001-2004) MEMBER : Central / State Sup, Board PNDT Act Ex PRESIDENT: LHMC Alumini Association (2010-2011) CHAIRPERSON : Dept. Obg/ Gynae Pushpanjali Crosslay Hospital (Max Vaishali) (10 yrs) Ex PRESIDENT : A.M.C. Delhi NCR Over 1000 TALKS / Nearly 370 PPT in Slideshare.in/ chapters in books/> 150 Publications Awards :Lifetime Achievement Awards: FOGSI ,DGF.LHMC Alumini,WOW India +many more
  45. 45. USP of Delhi Gynaecologist forum Training of Doctors in - Diploma course in IVF- ICSI- Embryology - Certficate course in A to Z of Male /Female Infertility - Basic Ultrasound course - Colposcopy - PGDMLS (Diploma course in Medico Legal Issues) Website : www.delhigynaecologistforum.com Follow – us on & Head Office : 11 Gagan Vihar , Near Karkari Morh Flyover Delhi -51 Ph : 01122414049 , 8826638849 Presently 8forums of D.G.F in all over Delhi

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