This document discusses menopause and menopausal hormone therapy (MHT). It provides information on: 1) The average age of menopause for Indian women is 46.2 years. Premature menopause, which occurs before age 40, increases risks for cardiovascular disease, diabetes, and metabolic syndrome. 2) Lessons learned from the WHI study show that the risks of MHT depend on factors like age of starting treatment, type of estrogen and progestogen used, and whether the uterus is present. Not all progestogens have the same safety profile. 3) The choice of progestogen is important as some, like medroxyprogesterone acetate (MPA), may

1. Menopausal Harmone Therapy &
Indian Gynaecologists
Dr Sharda Jain
Secretary general
Delhi Gynaecologist forum
MENOPAUSE

2. All Menopausal Hormone Therapy
regimes are not the same
Past President IMS
TOBIE DE VILLIERS

3. Symptoms of the Menopausal Journey
3

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. 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. 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. 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.  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. 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. Premature Menopause &
Cardiovascular Disease
If menopause occurs early
CARDIOPROTECTIVE effect
of Oestrogen is gone &
increases the risk of CVD

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. 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. 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. 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. 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. THE RISK OF BREAST CANCER IS LOWERED WITH
ESTROGEN ALONE COMPARED TO CE/MPA
TOBIE DE VILLIERS ( 2020,talk )

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. “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. 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. 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. 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. 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. 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. 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. Sequential COCP E/D:+ Results
• EFFECT on LIPID PROFILE
• DIABETES
• HYPERTENTION
• CV EVENTS

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. 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.  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. 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. 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. 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. • 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. 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

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