Menopausal Hormone Replacement Therapy by Dr Shahjada Selim

1. MENOPAUSAL HORMONE
THERAPY
Dr Shahjada Selim
Associate Professor
Department of Endocrinology, BSMMU
Faculty in Endocrinology, Texila American University, USA
Website: shahjadaselim.com

2. Definitions
 Menopause is a natural event defined as 12
months of amenorrhea with no obvious pathologic
cause.
 Perimenopause is the lay term encompassing the
menopause transition and the first 12 months after
the final menstrual period (FMP).
 Estrogen Therapy (ET) is unopposed estrogen for
postmenopausal women without a uterus.

3. Definitions
 Estrogen-Progestogen Therapy (EPT) is a combination
of estrogen and progestogen (either progestin or
progesterone).
 Hormone Therapy (HT) encompasses both ET and EPT.
 Bioidentical hormone therapy (BHT): Consists of
hormones chemically identical or very similar to those made
in the body. Available from two sources: 1) FDA-approved
and tested; 2) unapproved and untested from compounding
pharmacies

4.  Menopausal hormone therapy (MHT) is the broad term
used to describe both unopposed estrogen use for women
who have undergone hysterectomy and combined
estrogen-progestin therapy for women with an intact uterus
who need a progestin to prevent estrogen-associated
endometrial hyperplasia [1].
 Hormone therapy (HT) is the only pharmacologic therapy
government approved in US and Canada for treating
menopausal symptoms. HT encompasses both estrogen-
alone and estrogen-progestogen therapies.
What is Menopausal Hormone Therapy?
1.The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of The
North American Menopause Society. Menopause 2017; 24:728.

5. Menopausal hormone therapy (HT) has undergone
major changes during the past 20 years. Prior to
2000, HT was widely used to treat menopausal
symptoms such as hot flushes and vulvovaginal
atrophy.
In the late 1990s, the Women’s Health Initiative (WHI)
trial was undertaken to determine whether HT
provided protection from certain chronic diseases
(e.g. coronary heart disease (CHD) that affect women
after menopause.
Background

6. Interim analyses raised concerns about associated
adverse outcomes, mainly an increased risk of breast
cancer in the combined estrogen + progestin arm
[1], and an increased risk of stroke in the estrogen-
only arm.
Investigators concluded that the risk–benefit profile of
HT did not support its use for primary prevention of
chronic diseases in postmenopausal women and the
study was terminated. Intense media coverage
followed which led to a dramatic and persistent
decline in the use of HT worldwide [2].
1. Rossouw JE et al. JAMA 2002; 288(3): 321–333.
2. Burger HG et al. Climacteric 2012; 15(3): 281–287.

7. • Over the next several years, extensive re-analysis
and assessment of the WHI data cast doubt about
the validity of the original conclusions.
• Notably, age-stratified data indicated that absolute
excess risk of adverse outcomes, including all-
cause mortality, was low in women aged 50–
59 years at the start of treatment [1], and that
benefits in this age group were maintained during a
cumulative follow-up of 18 years.
• Conversely, no beneficial effects were observed in
women aged 60–69 or 70–79 years at the start of
treatment [2].
1. Simon JA. Climacteric 2012; 15(Suppl. 1): 3–10.
2. Manson JE et al. JAMA 2017; 318(10): 927–938.

9. Assessment
• Establish menopause.
• Review symptoms.
• Assess risk for CVD and Osteoporosis.
• Women's view on menopause.
• Patient’s decision clearly recorded.
• Contraception needs.

10. Menopause - Diagnosis
• ? Blood tests: FSH >30IU/L(D3-5)
• NICE no lab tests if 45yr + and symptoms
– Largely unreliable in perimenopause
– Depend on stage of cycle
– Normal levels do not exclude perimenopause as cause of
symptoms
– More helpful when no cycle to monitor e.g. post
hysterectomy / IUS, or to investigate secondary
amenorrhoea
• History and symptoms

11. Evaluating risk factors for hormone therapy in candidate patients
• Age
• Menstruation status
• Menopausal symptoms
• Past and current medical history
• Family history
• Lifestyle factors (e.g. smoking, alcohol use, exercise)
• Concurrent medications
Examinations/investigations to perform:
• Body weight
• Waist circumference
• Blood pressure
• Blood tests if indicated by responses to questioning
• Imaging (e.g. ultrasound, bone density) if indicated by responses to
questioning
• Mammography if not performed within previous year
• Bone densitometry (dual-energy x-ray absorptiometry) if patient at risk for
osteoporosis
• Genetic screening

12. Other history
• Family history of cancers like breast, bowel,
ovarian?
• History of Thrombosis?
• Risk factors for stroke and CVD?
• History of migraines?

13. Management Strategies
• Various preparation available:
– Different strengths.
– Combinations.
– Route of administration.
• “Sequential”.
• “Continuous”.
• Routes: oral, transdermal, subcutaneous, intranasal,
Vaginal.
• Can start HRT before amenorrhea begins.

14. Governing principles according to IMS [1]
 HRT should not be recommended without a clear
indication for its use, i.e. significant symptoms or
physical effects of estrogen deficiency.
 Postmenopausal HRT is not a single regimen given
to a standard woman.
 HRT must be individualized and tailored according
to symptoms and the need for prevention, as well as
personal and family history, results of relevant
investigations, the woman’s preferences and
expectations.
1.DeVilliers TJ et al. Climacteric 2013; 16(3): 316–337.

15. Benefits of HRT [IMS]
 HRT remains the most effective therapy for
vasomotor symptoms and urogenital atrophy.
 Other menopause-related complaints, such as
joint and muscle pains, mood swings, sleep
disturbances and sexual dysfunction (including
reduced libido) may improve during HRT.
 Increased elasticity of the blood vessels,
allowing them to dilate (widen) and let the blood
flow more freely throughout the body.
General

16.  Improved short-term symptoms of menopause such
as hot flashes and mood swings, as well as vaginal
dryness, dry skin, sleeplessness and irritable
bladder symptoms
 Decreased risk of osteoporosis and fractures
(broken bones)
 Decreased incidence of colon cancer
 Possible decreased incidence of Alzheimer’s diseas
 Possible improvement of glucose levels

17. HRT …

18. Table. Estrogen therapy products approved for postmenopausal use in the United States
Oral products
Composition Product name(s) Range of available dose strengths
Conjugated estrogens Premarin 0.3-1.25 mg
Synthetic conjugated estrogens, A* Cenestin 0.3-1.25 mg
Synthetic conjugated estrogens,
B**
Enjuvia 0.3-1.25 mg
Esterified estrogens Menest 0.3-1.25 mg
17β-estradiol Estrace, various generics 0.5-2.0 mg
Estradiol acetate Femtrace 0.45-1.8 mg
Estropipate Ortho-Est 0.625 mg (0.75 mg estropipate, calculated as
sodium estrone sulfate 0.625 mg) to 5.0 mg (6.0 mg)
Transdermal products
Composition Product name(s) Dose details
17β-estradiol matrix patch Alora, Climara, Esclim,
Fempatch, Menostar,
Vivelle, Vivelle-Dot, various
generics
0.014-0.1 mg delivered daily;
applied once or twice weekly
17β-estradiol reservoir patch Estraderm 0.05-0.1 mg delivered daily;
applied twice weekly
17β-estradiol transdermal gel EstroGel, Elestrin, Divigel Applied daily via metered pump or packet
delivering 0.52-0.75 mg of 17β-estradiol in gel
17β-estradiol topical emulsion Estrasorb 2 packets applied daily
17β-estradiol transdermal spray Evamist 1 spray/d, up to 2-3/d if needed
* 9 estrogens
** 10 estrogens

19. Table. Estrogen therapy products approved for postmenopausal use in US (cont’d)
Vaginal products
Composition Product name(s) Dose details
17β-estradiol vaginal cream* Estrace Vaginal Cream Initially 2-4 g/d for 1-2 wk, followed by
maintenance dose of 1 g/d
(0.1 mg active ingredient/g)
Conjugated estrogens cream* Premarin Vaginal Cream For vaginal atrophy: 0.5-2 g/d for 21 d then off 7 d
For dyspareunia: 0.5 g/d for 21 d then off 7 d , or
twice weekly
(0.625 mg active ingredient/g)
17β-estradiol vaginal ring Estring Device containing 2 mg releases
7.5 µg/d for 90 days (for vulvovaginal atrophy)
Estradiol acetate vaginal ring Femring Device containing 12.4 mg or 24. 8 mg estradiol
acetate releases 0.05 mg/d or 0.10 mg/d estradiol
for 90 days (both doses release systemic levels for
treatment of vulvovaginal atrophy and vasomotor
symptoms)
Estradiol hemihydrate vaginal
tablet
Vagifem Initially 1 tablet/d for 2 wk, followed by 1 tablet
twice weekly (tablet 10 µg of estradiol
hemihydrates, equivalent to 10 µg of estradiol; for
vulvovaginal atrophy)
*N.B. Higher doses of vaginal estrogen are systemic, meant to relieve hot flashes as well as vaginal atrophy; the
lower doses are intended for vaginal symptoms only even though a small amount does get absorbed.

20. Table. Combination EPT products comparing estrogen and progestogen doses
Product
name(s)
Standard/low
dose
Estrogen Progestogen
Prempro Standard
Low
0.625 mg conjugated estrogens
0.3 or 0.45 conjugated
estrogens
2.5 or 5 mg medroxyprogesterone acetate
1.5 mg medroxyprogesterone acetate
Femhrt Standard
Low
5 µg ethinyl estradiol
2.5 µg ethinyl estradiol
1 mg norethindrone acetate
0.5 mg norethindrone acetate
Activella Standard
Low
1 mg 17β-estradiol
0.5 mg 17β-estradiol
0.5 mg norethindrone acetate
0.1 mg norethindrone acetate
Angeliq Low
Lower
0.5 mg 17β-estradiol
0.25 mg 17β-estradiol
1 mg drospirenone
0.5 mg drospirenone

21. Non oral route of therapy advantage in
• VTE
• Migraine
• Malabsorption diseases
• Gallstones
• Liver disease.
Less impact on clotting factors
Steady Absorption over 24 hours
Avoids first pass metabolism in liver

22. Estrogen…Is a Miracle Drug
• Estrogen works for hot flashes and vaginal
dryness
• May help with urinary incontinence
• All types and routes of administration equally
effective
• Markedly improves quality of life for younger
postmenopausal women

23. Estrogen and Heart Disease
• A healthy 60 year old female has about a 30%
lifetime risk of dying of heart disease
• Observational studies show a 35 to 50% lower
risk of CAD in estrogen users
• However, results of recent clinical trials conflict
with these findings

24. Tibolone
• Tibolone is a steroid with tissue-specific activities which has
the capacity to exert estrogenic or progestogenic/androgenic
effects, depending on the tissue substrate.
• These tissue-specific properties of tibolone enable it to act in
specific parts of the body like an estrogen:
– Providing effective relief of climacteric symptoms.
– Preventing osteoporotic bone loss.
– Having beneficial androgenic effects on mood and libido.
• Tibolone has the following advantages:
– On the endometrium: It does not act as an estrogen. Therefore
does not stimulate endometrial proliferation. In contrast to
conventional HRT, the use of Tibolone does not require the
addition of a progestogen to induce regular withdrawal bleedings
to limit endometrial proliferation, nor to protect against
endometrial hyperplasia.
– On the breast tissue: It does not act as an estrogen in breast
tissue. This leads to low incidence of breast tenderness and
causes no increased mammographic density.

25. Governing principles [IMS]
 Healthy women younger than 60 years should
not be unduly concerned about the safety
profile of HRT. New data and re-analyses of
older studies by women’s age show that, for
most women, the potential benefits of HRT
given for a clear indication are many and the
risks are few when initiated within a few
years of menopause.
Safety considerations

26. • Hysterectomized women: estrogen only.
• Non Hysterectomized:
– Estrogen and progesterone as sequential
preparations.
– Progesterone added sequentially for 10-14 days
every 4weeks.
– For 14 days every 13 weeks.
– Combined and continuous.

27. • Perimenopausal:
– Monthly or three monthly cyclical regime.
– Continuous not used due to irregular bleeding.
• Post menopausal:
– Predominately combined used and accepted due to lack
of bleeding.
– Other preparation may be used.
– Irregular bleeding can occur in the 1st 4-6months.
– Does not warrant investigation unless bleeding is
heavier, persists beyond 6 months, occurs after
significant amenorrhea.

28. Follow up
• 1st visit after start of treatment in 3months.
• Then after evaluation every 1year.
• BP monitoring every 6/12.
• Contraception:
– Continue contraception for 2 years if women
<50years.
– One year contraception if >50 years.

29. • For vasomotor symptoms: use for/upto 5 years.
• For treatment of osteoporosis: life long
– Delays risk of fracture 5-10 years.
– Some women wish to change to other medication
like raloxifene, biphosphonates.
• Premature menopause: until 52years.
• Local symptoms treated with vaginal estrogen
creams.

30. Adverse effects
• Estrogen related: fluid retention, bloating,
breast tenderness. Nausea, headache, leg
cramps, dyspepsia.
• Progesterone related: migraines, headache,
fluid retention, depression, acne, mood
swings.
• Common to both: weight gain, poor cycle
control.

31. Studies on HRT
• Women`s health initiative and Million women study .
• WHI:
– Risk of breast cancer in estrogen alone group was 23%
lower than placebo group.
– In combined HRT group increase in risk emerged after 3
years of randomisation.
• Million women study:
– Increased risk of breast cancer in all HRT regimen.
– Greatest risk with combined group.
– The pattern of progesterone administration did not change
the risk.

32. Benefits
• Vasomotor symptoms.
• Urogenital symptoms.
• Osteoporosis.
• Colorectal cancer.

33. Added benefits of HRT
HRT reduces the risk of various chronic conditions that
can affect postmenopausal women, including:
•diabetes – taking HRT around the time of menopause
reduces a woman’s risk of developing diabetes
•osteoporosis – HRT prevents further bone density loss,
preserving bone integrity and reducing the risk of
fractures, but it is not usually recommended as the first
choice of treatment for osteoporosis, except in younger
postmenopausal women (under the age of 60)
•bowel cancer – HRT slightly reduces the risk of
colorectal cancer (bowel cancer)
•cardiovascular disease – HRT has been shown to
reduce cardiovascular disease markers when used
around the time of menopause.

34. What If…
• Contraindication to HRT
• Belief that HRT interfere with nature
• Desire to be in control
• Fear of long term effects of HRT
• Fear of adverse effects.
• lack of information about HRT

35. Alternatives…
• Lifestyle Changes
• Dietary changes & supplements
• Complementary therapies
• Drugs

36. Why Alternatives to HRT are requested?
• Contraindication to HRT
• Belief that HRT interfere with nature
• Desire to be in control
• Fear of long term effects of HRT
• Fear of adverse effects.
• Lack of information about HRT

37. !Facts about alternatives for HRT
1.Most treat only a single problem
2.There is potential harm, because of a lack of
efficacy or possible risks
3.There is a lack of evidence to confirm benefits or
possible adverse effects.
4.There is a widespread belief that “natural” means
harmless, but herbs may contain potent
chemicals & should be used with caution.

38. Alternatives to HRT
• Lifestyle Changes
• Dietary changes & supplements
• Complementary therapies
• Drugs

39. Life Style Changes
• Avoidance of Triggers for Vasomotor Changes
• Avoidance of Risk Factors for osteoporosis
• Exercise

40. Multivitamins
• Vit E: 400-1200 IU daily
– Reduces VM symptoms (Kass-Annesse,2000)
– Reduces the risk of CHD (100 IU daily for 2
years)
– Low level of Vit E is a better predictor of CHD
than elevated cholesterol or blood pressure
(Cooper et al,1994)

41. • Vitamin D: 400 IU daily with calcium
significantly reduced fracture risk (Chapuy et
al, 1992)
• Oily fish eaten at least twice a week reduced
mortality from CHD (Daviglus et al, 1997)
• Garlic: reduction of cholesterol is doubtful
(Daviglus et al, 1997)

42. Minerals
• Adequate calcium intake: 1500 mg daily:
reduction of hip fracture (Cumming et al, 1997).
• Adequate intake of magnesium is crucial for
osteoporosis prevention (Kass-Annesse,2000).
• The dietary ratio of calcium to magnesium is best
maintained at 2:1.

43. Natural hormones
A. Phytoestrogens [Derived from plants ]
– Asian women experience fewer menopausal symptoms than
western women & their traditional diet contain high level of
phytoestrogens, about 200 mg daily compared with < 5 mg
daily in western diet.
• Types
– Isoflavones: soya beans (richest source), chick peas, lentils
– Lignans: apples, stone fruits, onion, garlic, seed oils, cereals,
fruit & vegetables.
– Coumestans: clover
• Available in:
– tablet (Klimadynon=cimicifugae)
– food supplements in bread,
– snack bars,
– health drinks.

44. Natural progestagen creams
• Extracted from: plant source, mainly yams
& soya.
• Effects: An improvement in vasomotor
symptoms but no effect on bone

45. Dehydroepiandrosterone (DHEA)
• Available as: a food supplement.
• Effects:
– improved mood, sleep, tiredness & ability to
cope (Thaker & Booher, 1999).
• Adverse effects:
– lowering HDLP, increasing insulin resistance &
raising blood pressure

46. Risk factors for osteoporosis
• Family history.
• Low BMI.
• Early menopause(<45years).
• Cigars smoking.
• Alcohol abuse.
• Sedentary life.
• Steroid intake.
• Malabsorption syndrome.
• Hyperthyroid.
• Hypogonadism.

47. Calcium and Vitamin D
• Check levels in:
• all with confirmed osteoporosis or fracture at
baseline
• if on treatment for osteoporosis and new fracture
• malabsorption
• Vitamin D deficiency common
• Consider Ca and Vit D supplements for :
• Biochemical insufficiency, dietary deficiency, ?all
age >70, nursing home residents, high dose
steroids

48. Avoid factors increasing urinary calcium loss
• High sodium intake
• High phosphorus (soft drinks such as cola)
& may be damaging for young bone (Carey
& Carey, 1999).
• High protein intake, generally in the form of
animal protein (Nordin, 2000).
• High caffeine intake is associated with an
increase in fracture

49. When to treat Osteoporosis
• Be aware of indications for DEXA.
• Assess risk of fracture using FRAX and NOGG,
rather than treating BMD alone.
• Exclude secondary causes.
• Fracture in postmenopausal women aged >75, can
be treated without need for DEXA
• Women with prior fracture have 86% increased risk
further fracture.
• Intervention essential to prevent further fracture.

50. Treatment options
• Bisphosphonates (consider drug holiday)
• HRT – NOS recommend 1st line in women
<age 60 with no c/I to HRT
• Strontium
• Raloxifene
• Denosumab
• Teriparetide
• All should have annual review.

51. HRT and CVD
• Favourable effects on lipids, w/h ratio, lipid clearance,
vascular function, vascular remodelling
• Conflict between studies
• WHI—increased risk in CVD with HRT in Older
women only
• Observational studies, rct and Cochrane reviews 2012
and 2014, women under age 60—benefit of HRT
shown
• Window of opportunity

52. VTE and HRT
• Overall baseline VTE risk 1.0 per 1,000 women per
year
• Oral HRT- additional 1.5 events per 1,000 women per
year, mostly in 1st year
• Risk affected by progestogen type--? Increased with
MPA
• No apparent increase with transdermal HRT
• Offer transdermal if BMI >30
• If risk factors for VTE, no concern re vaginal
estrogen, systemic HRT—discuss and if HRT
indicated, use transdermal

53. Other Medical Issues
• Diabetes—no c/I to HRT, route dictated by lipids (if
increased TGs, use transdermal)
• Asthma – hormonal effect unclear, be prepared to
change/stop HRT if worsens, may improve
• Thyroid – Control may be affected by HRT, (TBG
up) check 3 months after starting HRT
• Migraine – not c/I, use transdermal, may worsen or
improve

54. Gynaecological Cancers
• Endometrial – if very early and surgery considered
cure, HRT can be considered with specialist input,
generally c/I
• Ovarian cancer –caution with HRT after endometrioid
ovarian ca
• Cervical–no c/I to HRT. If treated with radiotherapy,
use continuous combined HRT—possibility of
haematometra if sequential HRT with stenosed cervix
• Vulval, vaginal – no c/I to use of HRT

55.  Menopausal symptoms can be managed with
education, lifestyle changes, support and
hormone replacement therapy (HRT), also
known as menopausal hormone therapy (MHT).
 In the early postmenopausal years, HRT is an
effective therapy for menopausal symptoms. In
most women with moderate to severe
symptoms, the benefits outweigh the small
increases in risk.
Summary

56.  The long-term use of HRT has some benefits,
but also has some risks.
 The current role of HRT is for menopausal
symptom relief, at the lowest effective dose and
for the shortest duration required for the control
of bothersome menopausal symptoms.
 The decision to use HRT, and for how long it
should be used, must be based on individual
assessment and needs.
Summary

57.  The long-term use of HRT has some benefits,
transdermal estrogens are considered part of the
armamentarium of HT: may offer certain benefits
in specific clinical scenarios
 Micronized progesterone may also offer benefits
in bleeding patterns and reduced risk of breast
cancer compared to MPA
Summary

58. www.shahjadaselim.com