femoston vs tibolone hormone replacement therapy 1.5.15

1Copyright © 2014 Paras Hospitals. All rights reserved. 1

Dr Nupur GuptaDepartment of Obstetrics & Gynecology

Paras Hospital

Tackling women's midlife crisis: What's new in Hormone Therapy?


From Menarche to Menopause

Transition


What is Menopause?

Permanent cessation of menstruation resulting from loss of ovarian follicular activity

Perimenopause: from the first features of approaching menopause until up to 1 year after final menstrual period

Burger HG et al. Recent Prog Horm Res 2002;57:257–75.

Years around menopause

Est

rad

iol

(pm

ol/

L)

FS

H (

iu/L

)

0 1 2 3 4 5-1-2-3-4

0

20

40

60

80

100

120

0

50

100

150

200

250

300


The Menopause - Acute Symptoms

Hot flushesHot flushes

Night sweatsNight sweats

HeadachesHeadaches

Panic attacksPanic attacks

Mood swingsMood swings

IndecisivenessIndecisiveness

Insomnia leading to:

irritability

poor short term

memory

difficulty with

concentration


MEDIUM TERM SYMPTOMSMEDIUM TERM SYMPTOMS

Vaginal drynessVaginal dryness

DyspareuniaDyspareunia

Reduced libidoReduced libido

Thinning skin/ hairThinning skin/ hair

Skin formicationSkin formication

Urethral syndrome (frequency, nocturia & urge Urethral syndrome (frequency, nocturia & urge

incontinence)incontinence)


LONG TERM SYMPTOMS

CARDIOVASCULAR DISEASE

OSTEOPOROSIS

CEREBROVASCULAR DISEASE


When is Medical Intervention Required?

Adapted from Bungay G et al. Br Med J 1980;281:181–3; Van Keep PA et al. Maturitas 1990;12:163–70.

Vasomotor SymptomsSleep DisordersMood Changes

Vaginal AtrophyDyspareuniaSkin Atrophy

OsteoporosisAtherosclerosisCoronary Heart DiseaseCerebrovascular Disease

40 yrs 50 yrs

Menopause

60 yrs

Symptoms and Disorders in Relation to Age and Menopause

Menstrual Disorders


Menopausal Symptoms

Total No. of women 1801Asymptomatic 192Symptomatic 1609

Meeta et al Early age of natural menopause in India, a biological marker for early preventive health programs CLIMACTERIC 2012;15:1–6


Attitude of Gynecologists for HT prescription in India

Meherishi S, Khandelwal S; Jr of Midlife Health 2012


Rise in female life expectancy over the last 100 years

0

10

20

30

40

50

60

70

80

90

1850 1900 1950 2000

Lifeexpectancy

Age atmenopause


a. Counseling: Diet; Exercise

b. Common Indications of Hormone therapy - estrogens,

progestogens, combined therapies and tibolone

– Symptom relief (Vasomotor symptoms)

– Urogenital atrophy

– Bone

MANAGEMENT OPTIONS

Meeta, et al.: Guidelines on menopause. Journal of Mid-life Health ¦ Apr-Jun 2013 ¦ Vol 4 ¦ Issue 2


Prescription of HRT: ROUTES

OralOralTransdermal: Transdermal: patch or gelpatch or gel

SubcutaneousSubcutaneous(implant)(implant)

Intramuscular Intramuscular (depot)(depot)

Intra-uterine Intra-uterine (Mirena)(Mirena)

Intra-vaginal Intra-vaginal (tablets, ring (tablets, ring or cream)or cream)


Oestrogen Only HRT (ERT)

women who have had a total hysterectomy

If the hysterectomy was subtotal, then may need to use

progestogens as well (some endometrium may be left behind)

If the hysterectomy was for endometriosis, then progestogens

continuously along with oestrogen should be used at least

initially


Estrogens

Most Potent


Sequential Combined HRT

Sequential oestrogen and progestogen

The addition of the progestogen protects the endometrium and leads to a regular bleed

Oestrogen for 28 days

Progestogen for 14 days


Continuous Combined HRT

This should not be started until 1 year after the LMP

No monthly bleed

Oestrogen combined with progestogen for 28 days


Estrogens Used in MHT

Equivalent dose for bone endpoints*

Estrogen Ultra Low Low Standard High

Conjugated equine estrogens (mg) 0.151 0.3 0.625 1.25

17β-estradiol (mg) 0.52 1 2 4

Estradiol valerate (mg) 1 2

Transdermal 17β-estradiol (μg) 143 25 50 100

*Estrogenic effects may vary for other endpoints

The Estrogen Dose Counts

Note: For many women, low-doses of estrogen provide adequate relief of symptoms with high rates of amenorrhea


Role of Progestogens in HRT For women with intact uterus, the addition of a progestogen

protects the endometrium from the stimulatory effects of unopposed estrogen

PEPI Trial: Results of Endometrial Biopsy

Conclusion: Adding a progestogen is needed to safeguard the endometrium

Placebo CEE alone CEE+MPA sequential

CEE+MPA continuous

N 119 119 118 120

Normal 98% 38% 95% 99%

Simple hyperplasia 1% 28% 3% 1%

Complex hyperplasia 1% 23% 2% 0%

Atypia 0% 12% 0% 0%

Adenocarcinoma 1% 0% 0% 0%


Progestogens: Receptor-binding Activity

ProgestogenProgestog

enicEstroge

nicAndroge

nicAnti-

androgenicGlucocort

icoid

Anti-mineralo-corticoid

Dydrogesterone1 + – – ± – ±

Progesterone1 + – – ± + +

MPA1 + – ± – + –

Norethisterone1 + + + – – –

Drospirenone1 + – – + – +

CPA1 + – – ++ + –

Dienogest1 + ± – + – –

Levonorgestrel1 + – + – – –

Norgestrel1 + – + – – –

Tibolone2 + ± + – – –1. Schindler AE. Maturitas 2003;46(S1):7–16; 2. De Gooyer ME et al. Steroids 2003;68:21–30.

+ Effective; ± Weakly effective; – Not effective.


Guidelineson MHT

(Menopausal Hormone Therapy)


Guidelines Indian Menopause

Society, 2013

International Menopause

Society, 2013

North American

Menopause Society,

2012

Indication • Most effective for Vasomotor symptoms

• For sleep disturbances & urogenital atrophy

Potential

Benefits

• Positive effects on lipid profile

• Metabolic syn (Type 2 DM, abdominal obesity)


Guidelines Indian Menopause

Society, 2013


Society, 2013

North American

Menopause Society,

2012

Age of

Initiation

• Begins within 10 years of menopause or <60 years of age

“Window of opportunity”

Duration

of Use

• Premature menopause: MHT up to natural age of menopause

• 3‑5 years


Guidelines

Indian Menopause

Society, 2013


Society, 2013

North American

Menopause Society,

2012

Monitoring • Pre HT work up (Indian MS)‑ ‑• Initial follow-up at 3 months (NAMS)

• Annual follow up – physical, laboratory/imaging (All)‑• Discussion on lifestyle strategies to prevent or

reduce chronic disease


Guidelines: Safety Profile of MHT Events Indian Menopause

Society, 2013

International

Menopause

Society, 2013

The North American

Menopause Society,

2012/The Endocrine

Society 2010

CVD • No/lower risk in healthy women <60 years of age or within 10

years of menopause

Breast

CancerIt does not

increase risk if

given for <5 yrs

Small increase in

risk (incidence of

<1.0/1000 women

/year of use)

Risk of events in younger

women is lower than that for

older women

Does not increase

breast cancer risk

if given for <5 yrs

Santen R et al. J Clin Endocrinol Metab 2010;95(Suppl1):S1–S66.


MANAGEMENT OF HRT

Initial visitInitial visit

3 months3 months

6 months6 months

Yearly: BP, breast examination and vaginal Yearly: BP, breast examination and vaginal examination (3 yearly smears to age 60 and 3 examination (3 yearly smears to age 60 and 3 yearly mammography aged 50-64)yearly mammography aged 50-64)

Invite earlier visit for specific problemsInvite earlier visit for specific problems


Schematic representation of lifetime changes in bone mass

0

10

20

30

40

50

60

70

80

0 25 40 70

Women

Men

Attainment of Consolidation Age related

peak bone mass bone loss

Climacteric


RISK FACTORS FOR OSTEOPOROSISRISK FACTORS FOR OSTEOPOROSIS

MINOR Cigarette smoking Sedentary lifestyle Low Calcium intake

MODERATE Family history of

osteoporosis Underweight High alcohol consumption

MAJOR Early menopause Prolonged steroid therapy Prolonged amenorrhoea


Benefits and HRT: Osteoporosis

Its beneficial effect on bone Its beneficial effect on bone diminishes soon diminishes soon

after stopping treatmentafter stopping treatment

However HRT remains the treatment of choice However HRT remains the treatment of choice

in women with in women with premature ovarian failurepremature ovarian failure


Hormonal Therapy for OsteoporosisInternational Menopause Society Global Consensus 2013 Statement

MHT is an effective

treatment for the prevention

of fracture (vertebral/hip) in

at-risk women before age

60 years or within 10 years

after the menopause

De Villiers TJ et al. Climacteric 2013;16:316–37.


What’s New in MHT?


Fournier A et al. Breast Cancer Res Treat 2008;107:103–11; Fournier A et al. J Clin Oncol. 2008 ;26:1260–1268.

Choice of Progestogen & Breast Cancer Risk:E3N French Cohort Study: 2007

Risk of breast cancer

N = 80,377 womenDuration = 8.1 years

Risk elevation may not be uniform

for all progestogens

E/D - 17ß-Estradiol + Dydrogesterone


Invasive Breast Cancer associated with Different types & Times since last use of MHT

Mean duration of use

N -169N - 638

N - 931

5.1 yrs 6.1 yrs 6.1 yrs

Fournier A et al. Breast Cancer Res Treat (2014) 145:535–543

78,353 women

Haz

ard

Rat

io


Less Gynecological Risk with (17β-estradiol/dydrogesterone)

Schneider C et al. Climacteric 2009;12:514–24.

Inci

den

ce p

er 1

,000

per

son

-yea

rs

Ovarian cancer

Uterine cancer

Cervical cancer

0.0

0.5

0.23

0.180.22

0.160.12

0.090.13

0.04

0.23

(0.17–0.31)

(0.16–0.30)

No HRTOther HRTE/D HRT

(0.01–0.32)

(0.17–0.31)

(0.10–0.23) (0.03–

0.39)

(0.13–0.25)

(0.07–0.18)

(0.00–0.25)


Risks and HRT: Stroke

In RCT’s HRT In RCT’s HRT increased the risk of stroke increased the risk of stroke (mostly (mostly ischaemic) compared with placeboischaemic) compared with placebo

Older womenOlder women have a greater absolute risk of stroke have a greater absolute risk of stroke

Risk may depend on Risk may depend on oestrogen doseoestrogen dose


No Increased CV Risk Demonstrated with (17β estradiol/dydrogesterone)

Schneider C et al. Climacteric 2009;12:445–53.

0.0

0.2

0.4

0.6

0.8

1.0

1.2

0.58

0.93

0.660.68

1.10

0.95

0.40

0.27 0.31

Myocardial

infarctionStroke

Venous thromboembolism

Inci

den

ce p

er 1

000

per

son

-yea

rs

No MHT

Other MHT

E/D MHT

(0.48–0.70)

(0.57–0.82)

(0.18–0.76)

(0.80–1.07)

(0.95–1.26)

(0.10–0.58)

(0.56–0.79)

(0.82–1.11)

(0.13–0.64)


Risks and HRT: Venous Thromboembolism

Oral HRT has been associated with an increased risk of DVT

and PE in RCT’s and observational studies.

Evidence suggests that it is higher with combined HRT than

oestrogen-only HRT and that these events are more likely in

the first year of use


Risk of Thromboembolism with Different ProgestogensESTHER case-control study 271 consecutive VTE cases (mean age: 61.6 years) and 610 controls (mean age: 61.5 years)

Canonico M. Circulation 2007;115:840–5.

Ad

just

ed O

Rs

(95%

CI)

fo

r V

TE

wit

h o

ral a

nd

tra

nsd

erm

al

estr

og

en v

s. n

on

-use

rs

(e.g. dydrogesterone)

Pregnane derivatives & micronized progesterone appear to have the least thrombotic risk profile

(1.5–11.6)

(0.3–1.9) (0.4–2.3)

(1.5–10.0)


N – 362; Healthy postmenopausal women; 39–74 years

Continuous E/D 1/5 mg vs. CEE/MPA

A.T. de Kraker et al. / Maturitas 49 (2004) 253–263

HDL-C


N = 193; Duration = 24 weekN = 193; Duration = 24 week

E/D - ↑ HDL E/D - ↑ HDL

CEE/N - ↓ CEE/N - ↓ HDLHDL

CEE/N - ↑ incidence, duration & severity of bleedingCEE/N - ↑ incidence, duration & severity of bleeding

Sequential E/D 1/10mg vs. CEE/Norgestrel (0.625/0.15 mg)

Cieraad D et al. Arch Gynecol Obstet 2006;274:74–80.

HDL-C


Sequential E/D1/10 and 2/10: HDL Profile

Stevenson JC, Rioux JE, Komer L, Gelfand M. Climacteric 2005;8:352–9. ©2005 Informa Healthcare. Figure reproduced with permission of Informa Healthcare.

Placebo (n=54)1/5 mg (n=62)1/10 mg (n=74)

Cycle 13 Cycle 26

0

5

10

15

20

25

*

* *

Increase in HDL cholesterol (%)

*p≤0.05 vs. placebo


Low-Dose Sequential E/ D: Blood Glucose and Insulin

• E/D can affect menopausal changes in insulin secretion/elimination

Fasting glucose (mmol/L)

Fasting insulin (mU/L)

0

1

2

3

4

5

6

Baseline Year 1 Year 2

4.14

5.13

3.12* 2.88**

4.96* 4.87**

Mea

n co

ncen

trat

ion

of

gluc

ose

or in

sulin

Godsland IF et al. Clin Endocrinol (Oxf) 2004;60:541–9.


-15

-10

-5

0

5

10

15

0 3 12 months

Am

bu

lato

ry s

ysto

lic B

P

chan

ge

fro

m b

asel

ine

(%)

Estradiol/Dydrogesterone 1/10 (n=14)

No treatment (n=15)

Normotensive women

Van Ittersum FJ et al. Am J Hypertens 1998;11:1147–52.

Sequential E/D 1/10: Decreased Systolic BP During Long-Term Therapy

6 9

*

*

*p<0.05 vs. baseline


Fact - MHT users gain less weight or body fat than nonusers)1

2 years, body fat mass (N=100)2

17β-Estradiol/Dydrogesterone reduced the body fat

mass (↓ –1.2%)

Women not taking MHT (↑ +3.6%)

Transdermal MHT (↑ +4.7%)

Tibolone users (no change)

Is there a risk of weight gain with MHT?

1. Santen RJ et al. J Clin Endocrinol Metab 2010;95(7 Suppl 1):s1–66.2. Hänggi W et al. Clin Endocrinol (Oxf) 1998;48:691–9.


Conclusion

Used by the right woman, at the right dose & right age, Used by the right woman, at the right dose & right age, Femoston:Femoston:

Relieve vasomotor and other menopausal symptomsRelieve vasomotor and other menopausal symptoms

Provide protection against bone loss (second line)Provide protection against bone loss (second line)

Provide acceptable bleeding patternsProvide acceptable bleeding patterns


Tibolone

Dr Rama YadavJunior Consultant,

Dr Nupur GuptaDepartment of Obstetrics & Gynecology

PARAS HOSPITALS


Tibolone

oestrogenic oestrogenic

androgenic androgenic

progestogenic agentprogestogenic agent

STEAR ( Selective Tissue Estrogen Activity STEAR ( Selective Tissue Estrogen Activity

Regulator)Regulator)


Tibolone for Menopausal symptoms

↓ hot flushes

↓ headache, insomnia, fatiguability

Mood changes[increases endorphins]

Increases sexual function[libido]

Improves vaginal atrophy

Improves urogenital symptoms


Tibolone and Bone

↑ BMD 2.6% vs -2.3% in placebo after 2 years

(Gallagher et al,2001; J Clin Endo Metab)

Other RCTs show ↑BMD.

No data from RCT on fracture risk available

Consensus: Tibolone as effective as EPT/ET in preventing bone

loss.

International Tibolone Consensus Group; Maturitas,2005


Tibolone and Cardiovascular system

Favorable effect on lipid profile:

↓Triglyceride- 25%

↓ HDL-C 34%

No effect on LDL and Lipoprotein(a)

No effect- Antithrombin3, Plasminogen, CRP

–J Clin Endo Metab; 2002

Inconclusive evidence on cardiovascular clinical outcomes and

VTE with regard to risk or benefit.



Tibolone and Breast

Inhibits formation of active estrogen in breast

Antiproliferative and antiapoptotic

↓ breast tenderness

↓ mammographic density

Inconclusive evidence on breast cancer incidence. RCTs

awaited.



Tibolone and Endometrium

Prevents endometrial proliferation

(Volker et al,2001; Climacteric)

No increase in size or volume of myomas

Addition of progestogen not required[as progestogenic]

Standard endometrial surveillance not required

(International Tibolone Consensus Group;

Maturitas,2005)


Tibolone or Livial This is an alternative CC HRT

It is a gonadomimetic containing oestrogen, progestogens & androgens

Licensed for vasomotor symptoms and osteoporosis

The risk: benefit ratio similar to HRT in women under 60, but over 60 increased risk of stroke

Slightly increased risk for endometrial cancer

Less risk of breast cancer compared with CCT but increased over ERT

May help libido due to androgen content


Side-effects Leucorrhoea

Abdominal pain

Weight gain

Vaginal bleeding( less than with continuous EPT)

Breast pain( less than with continuous EPT)


Indication

Tibolone may have added value in

Women with low sex drive

Women with mood disorders

Women with risk of accelerated bone loss

Women with premenopausal breast tenderness

Women with high breast density

Women with fibroids

Women with urogenital complaints


Contraindications

Pregnancy n lactation [teratogenic]

Estrogen dependant cancer

Thrombophilic disorders

VTE/CAD

Liver diseases

Porphyria

Known/suspected ca breast/Ovary


Tibolone vs Combined HT: Cochrane 2012

Formoso G, Perrone E,Maltoni S, Balduzzi S, D’Amico R, Bassi C, Basevi V,Marata AM,Magrini N,Maestri E. Short and long term effects of tibolone in postmenopausal women. Cochrane Database of Systematic Reviews 2012, Issue 2

p = .015

p = .0006

Total no. of Events


Tibolone vs 17β-Estradiol/dydrogesterone

Hänggi et al. 1997. British Journal of Obstetrics and Gynaecology. 1997;104:708–17


Long term safety

Symptomatic benefits of tibolone appear

questionable compared to those of combined HT

More concerning is uncertainty about Tibolone’s

risk profile

Tibolone vs Combined HT: Cochrane 2012

Formoso G, Perrone E,Maltoni S, Balduzzi S, D’Amico R, Bassi C, Basevi V,Marata AM,Magrini N,Maestri E. Short and long term effects of tibolone in postmenopausal women. Cochrane Database of Systematic Reviews 2012, Issue 2


Take home message

Better effects than HRT/ERT

LIVIAL 2.5mg starting dose

Best for women with estrogen contraindication

Better improvements in vasomotor symptoms, osteoporosis

No known toxicity

.

femoston vs tibolone hormone replacement therapy 1.5.15

Healthcare

paras hospitals

early age of natural

vaginal tablets

journal of midlife health

midlife crisis

indiameherishi s

ht prescription

prescription of hrt