women’s health day 2 september 2017...2017/09/02 · women’s health day 2 september 2017...

Keogh Institute for Medical Research

Women’s Health Day 2 September 2017

Bronwyn Stuckey Keogh Institute;

Department of Endocrinology and Diabetes Sir Charles Gairdner Hospital; School of Medicine and Pharmacology University of Western Australia


Defining menopause

Menopause

• The final menstrual period (median age 50-52 years)

Peri-menopause

• The transition to the end of a woman’s reproductive life

menstrual cycle begins to change in length and symptoms may begin to occur (takes about a decade; hormonal swings and heightened symptoms)

Post-menopause

• 12 months after the final menstrual period

Early menopause

• Last period between 40 and 45 years

Premature menopause (premature ovarian insufficiency POI)

• Last period before 40 years (spontaneous, surgical or drug-induced)


Harlow JCEM 2012

Stages of Reproductive Aging Workshop


The hot flush

4.00

4.50

5.00

5.50

6.00

6.50

7.00

7.50

8.00

8.50

9.00

36.40

36.42

36.44

36.46

36.48

36.50

-30 -25 -20 -15 -10 -5 0 5 10 15 20 25 30

Me

an S

CL

(μm

ho

)

Me

an C

ore

Bo

dy

T (°

C)

Core body temperature and sternal skin conductance

Mean Body T (° C)

Mean SCL (μmho) Time 0 is the beginning of sternal skin conductance response

Hot flush begins

Molnar. J Appl Physiol 1975;38:499–503

SCL= skin conductance level


Perimenopause


Hormones in the perimenopause

Hale et al., Menopause 2009

In the individual = chaotic and unpredictable Alternating vasomotor symptoms and mastalgia


Contraception in the perimenopause

• Highest rate of unplanned pregnancy is in teenagers

• Second highest is in the over 40s

• When to change over from contraception to MHT is tricky unless the patient is prepared to go off hormones and see if any periods appear

– Blood tests don’t really help

– Menopausal symptoms will not be controlled


Management of the perimenopause

• OCPs with oestradiol rather than ethinyl oestradiol and greater cover over the 4 week cycle may be a useful bridge between oral contraception and HRT – providing both symptom relief and contraception

• Intrauterine progestin with supplementary transdermal oestrogen may be preferred in overweight women

– IUD progestin does not suppress the cycle, which may be a problem with other symptoms like mastalgia

• VTE risk in pregnancy is greater than VTE risk with combined OCPs


The symptoms of menopause

• Central: Hot flushes & night sweats; insomnia; palpitations; mood and memory changes

• Joint aches & muscle pains

• Urogenital: Dry vagina/dyspareunia; urinary frequency, UTI, incontinence

• Skin: Dryness, thinning, loss elasticity, crawling under the skin, acne

• Hair: increased facial hair, thinning scalp & pubic hair

• Loss of libido

• Long term consequences: metabolic, cardiovascular, bone & brain

How long do they last?! •20% have few or no symptoms •60% have 4 - 8 years of symptoms •20% may have severe symptoms that continue into their 60s and 70s


Diagnosing menopause: the history makes the diagnosis

Don’t

• Check FSH, LH, oestradiol or testosterone in a woman at the normal age of menopause

• Indications for intervention are clinical; blood test results will not influence management decisions



Don’t

• Check FSH, LH, oestradiol or testosterone in a woman

at the normal age of menopause

• Indications for intervention are clinical; blood test results will not influence management decisions

Early cessation of menses is an exception to this rule



Do

• Take a good history of menopausal symptoms;

a symptom score card can help

• Consider other causes for symptoms

• Record personal and family history of medical conditions that may influence management

• Menopause is an excellent opportunity to reinforce key preventative health messages

– Do an audit!


Menopause – time for an audit

Menopause is an opportune time to do an audit

For a woman at the age of 50 breast cancer is not her most dangerous enemy

– Fasting glucose +/- OGTT

– Lipids

– Bone density

– BMI

– Assessment of lifestyle factors –

• smoking, alcohol, exercise

– mammogram


HRT: risk and benefit in chronic disease

HRT

CVD

VTE

Breasts Diabetes

Bones


Most women at menopause perceive that breast cancer is their greatest threat

Australian Bureau of Statistics - AusStat

0

1000

2000

3000

4000

5000

6000

7000

55-64 65-74 75-84 85+

Breast cancer

Heart disease

Stroke

Age

Nu

mb

er

of

de

ath

s 2

00

4


Hormone use Person y Cases Age-adjusted risk Multivariate adjusted risk

Never 358,125 662 1.0 1.0

Current 265,203 337 0.54 (0.46-0.62) 0.61 (0.52-0.71)

2-4.9 years 78,928 60 0.47 (0.36-0.61) 0.53 (0.41-0.70)

5-9.9 y 77435 74 0.51 (0.40-0.65) 0.58 (0.45-0.74)

>10 y 69594 107 0.69 (0.56-0.85) 0.74 (0.59-0.91)

Grodstein Annals Int Med 2000

Nurses’ Health Study 1976-1996 risk of major coronary heart disease


Hazard ratio for cardiovascular disease by initiation year since menopause

Rossouw JAMA 2007

-1

-0.5

0.5

1

1.5

2

<10

10-19

>20

HRT Oestrogen Oestrogen + progestin

p = 0.02 p = 0.15 p = 0.05

http://content.nejm.org.ezproxy.library.uwa.edu.au/content/vol356/issue25/images/large/07f1.jpeg



Differential effects of sex steroids in early and late stages of atherosclerosis

Mendelsohn Science 2005


Danish Osteoporosis Prevention Study (DOPS) n = 1006

• Randomised

– HRT

– no treatment

• Open label

• 45-58 years

• CV endpoint composite

– death,

– admission to hospital for myocardial infarction,

– heart failure

Schierbeck BMJ 2012


CV risk in those who start HRT early

Women starting oral HRT within 10 years of the menopause or age before 60 (n = 9629)

• Reduction in all-cause mortality (30%)

• RR 0.70, 95% CI 0.52 to 0.95

• AD: 7 per 1000 women

• Reduction in coronary heart disease (death and MI) (48%)

• RR 0.52, 95% CI 0.29 to 0.96

• AD: 7 per 1000 women,

• No clear evidence of an association with stroke.

Boardman Heart 102(1):9-11,2016



HRT

CVD

VTE

Breasts Diabetes

Bones


The most important legacy of the WHI study - spotlight on the progestin problem

-1

-0.5

0.5

1

1.5

2

<10

10-19

>20

HRT CEE CEE+MPA

Heart disease - progestogen and the timing hypothesis

Breast cancer – risk in the E v E+P group

-60

-40

-20

0

20

40

60

E Alone

E+P




Oestrogen v oestrogen + progestogen

Oestrogen provides • Benefit for menopausal symptoms – flushes and more • Benefit for longterm health (if started early)

Progestogen • Protects the endometrium – nothing more • Attenuates CV benefit • Confers breast cancer risk

Therefore for a woman who has no uterus – no progestogen

and a much easier consultation discussion


E3N prospective cohort study

N = 80,377 postmenopausal women

Average age at start 53.1 years (40-66 years)

Lifetime use of HRT obtained from initial

and follow-up Qs

Followed for 8.1 postmenopausal years (+/- 3.9)

Results for use of

• Differing progestogens,

i.e. progesterone, dydrogesterone or others

Is there a difference between progestogens


Results from E3N study Increased incidence of breast cancer with addition of progestin Influence of type of progestin Note “dose effect” difference between different formulations No differential effect between oestrogen formulations or route

Fournier Breast Cancer Res Treat 2008


In vitro effects on normal breast cells and breast cancer cells

• Normal breast cells (HBE)

• Breast cancer cells (T47-D, MCF-7)

Cell lines as above

E2 P4 MPA E2 + P4 E2 + MPA

E2 + MPA displayed mitogenic and anti-apoptotic effects in HBE (normal) cells Progesterone was able to inhibit the E2 mitogenic effect and to be pro-apoptotic Modulation of the GR pathway genes by MPA may be of importance MPA is known to exhibit a strong relative binding to the GR GR has been reported in 40% of invasive ductal breast cancers

Courtin et al. Breast Cancer Res Treat.2010 DOI 10.1007/s10549-011-1394-5


Conjugated Estrogens (CE)

• Composed of multiple estrogens and are agonists of ER-α and –β2

• Shown to be the most suitable in preclinical studies for pairing with bazedoxifene5-7

Bazedoxifene (BZA)

• Selected for its effects on endometrium in

particular

• Bazedoxifene reduces the risk of endometrial

hyperplasia that occurs with oestrogen alone

Replaces progestogen with a selective oestrogen receptor modulator (SERM) Action of the SERM is to oppose oestrogen effect in certain tissues The SERM and the dose of SERM and oestrogen are chosen for the best efficacy in prevention of endometrial hyperplasia

1. Komm BS, et al. J Cell Physiol. 2013;228:1423–1427; 2. Duavive Data Sheet ;

2. 3. Berrodin TJ, et al. Mol Endocrinol. 2009;23:74-85;

4. Weismiller D. Prim Care Clin Office Pract. 2009;36:199-226;

3. 5. Crabtree J, et al. Mol Cell Endocrinol. 2008;287:404-6;

6. Kharode Y, et al. Endocrinolology. 2008;149:6084-6091; 7. Peano B, et al. Endocrinology 2009;150:1897–

1903.

TSEC – Tissue Selective Estrogen Complex

Advantages - Eliminates need for progestogen Disadvantages – fixed dose, oral preparation only



HRT

CVD

VTE

Breasts Diabetes

Bones


Increasing risk of VTE with age in HRT and placebo

Hazard ratio (95% CI)

Age at screening Placebo Treatment arm

Conjugated equine oestrogen

50-59 years 1.0 1.37 (0.70-2.68)

60-69 years 2.16 (1.20-3.89) 2.82 (1.59-5.01)

70-79 years 2.78 (1.48-5.22) 3.77 (2.07-6.89)

CEE + medroxyprogesterone acetate

50-59 years 1.00 2.27 (1.19-4.33)

60-69 years 2.31 (1.23-7.72) 4.28 (2.38-7.22)

70-79 years 3.37 (1.72-6.60) 7.46 (4.32-14.38)

Additional increase with age, MPA and obesity

Archer Climacteric 2012


Observational studies of oral v transdermal oestrogen and VTE

Canonico BMJ 2008

Pooled OR for oral 2.5 (1.9-3.4), OR for transdermal 1.2 (0.9-1.7)


What is the risk of recurrence after VTE

After VTE

no significant association between recurrent VTE and use of transdermal estrogens (hazard ratio, 1.0; 95% CI, 0.4-2.4), n=1023. [Olie V Menopause. 2011;18(5):488-93]

Thombophilias

increase the risk of a first VTE but, unlike oral MHT, transdermal MHT are not associated with an additional increase in risk [Straczek C Circulation. 2005;112(22):3495-500]

Keogh Institute for Medical Research 2

Risk of VTE with thrombophilic mutations +/- oral or transdermal HRT

Straczek Circulation 2005

No mutation no HRT


Are there any stopping rules?

“Use the lowest dose for the

shortest amount of time

Less than 5 years recommended

with combined therapy”

How long do they last?! •20% have few or no symptoms •60% have 4 - 8 years of symptoms •20% may have severe symptoms that continue into their 60s and 70s

What are the safety data surrounding

longterm therapy?


Global Consensus Statement

HRT is the most effective treatment for moderate to severe menopausal symptoms and is most beneficial before the age of 60 years or within 10 years after menopause.

The dose and duration of HRT should be consistent with treatment goals.

Oestrogen only is appropriate therapy for women after a hysterectomy.

Oestrogen plus a progestogen should be used when the uterus is present.

Topical low dose oestrogen is preferred for those women whose symptoms are limited to vaginal dryness and dyspareunia.

Current safety data do not support the use of MHT in breast cancer survivors.

(Global Consensus Statement. De Villiers et al Climacteric 2016;19:313-315)

(IMS Recommendations. Baber et al Climacteric 2016;19: 109-150)


Should we encourage women to stop HRT?

• 332,202 women in Finland stopped HRT 1994-2009

• data from stopping HRT to death or end of 2009

• 1.97 million women years • 5129 deaths from CVD or stroke • standard mortality ratio • divided into <1 year post HRT

use to >1 year post HRT use • <5 year v >5 year use • started <60y v >60y

Mikkola J Clin Endocrinol Metab 2015


HRT discontinuation and vascular deaths


Higher risk of cardiac death in HRT stoppers compared with continuing HRT • in 1st year SMR (95%CI) 2.30 (2.12-2.50) and • in later years SMR (95%CI) 1.26 (1.21-1.31) Higher risk of stroke in HRT stoppers compared with continuing HRT • in 1st year SMR (95%CI) 2.52 (2.28-2.77) and • in later years SMR (95%CI) 1.25 (1.19-1.31)

SMR= standardised mortality ratio


HRT discontinuation and vascular deaths


Is there a plausible biological explanation for this?

withdrawal of non-genomic vasodilatory effects of oestrogen

reduced oestrogen-induced nitric oxide gene expression

withdrawal of inhibition of endothelin-1

increased sympathetic and decreased parasympathetic activity

associated with the return of hot flushes

return of palpitations and arrythmias associated with oestrogen

withdrawal esp in women with long-QT syndrome


Traffic rules for HRT

Start early – at least within 10 years of LMP

Proceed with caution in the face of some comorbidities e.g. prior DVT, migraine

No stopping rules


Summary

• Perimenopause is chaotic – Requires treatment of both high and low oestrogen

symptoms and contraception

• Other conditions can cause hot flushes • Menopause is an excellent time for an “audit” • Start HRT early • Modify recipe according to patient’s history

– Hysterectomy, VTE, etc

• No stopping rules – “dose and duration according to treatment goals”

women’s health day 2 september 2017...2017/09/02 · women’s health day 2 september 2017...

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