Menopause

Drorith Hochner-Celinkier

Head, Department Obstetrics & Gynecology

Hadassah University Hospital

Mount Scopus, Jerusalem

16/11/2014

Menopauseהמעבר • גילהקלימקטרית • התסמונתבלות•קמלות•האורח • חדלון

Endocrinopathy Physiological event

?

“Nature is unsentimental”

Herbert Spencer, 1848

It is a question of the survival of the fittestIf you are lucky, you reproduce, then you dieOnce you can no longer reproduce, you are evolutionary speaking, deadHow come women, who normally become infertile in their mid-40s, often live on and on ?How come the average life span of women in almost all societies exceeds that of men, who remain fertile well into old age ?

“The Grandmother Hypothesis”Kristen Hawkes, University of Utah, Nature 428:128 March 2004

Hazda hunter-gatherer, Tanzania Grandmothers ensure their grandchildren

survival, boost their daughter’s fertility

Fitness benefits of prolonged post reproductive lifespan in womenMirkka Lahdenpera et al, Nature 428, 178-181, March 2004

The increase in the number of grandchildren is due to physical help / form of advice and not to some genetic effect The average lifespan of postmenopausal Finns was 68, and of Canadian 74. These ages correspond to the points where the matriarch’s children themselves had stopped reproducing At that point, a woman’s fitness falls, as well as her life expectancy

Menopause

Definition The permanent cessation of menstrual periods

following loss of ovarian follicular activity

Perimenopause The 2-8 year period prior to menopause, when the

endocrinological, biological and clinical features of approaching menopause commence, and extending through the first 12 months after cessation of menses

Average age: 50-52 years (51.3) Approximately 25% of women become menopausal

prior to age 45. If it occurs prior to age 40, it is called premature ovarian failure.

What determines the age of menopause?

The Median age at menopause throughout recorded history appears not to have change

Unlike age at menarche, which is related to body mass, age at menopause is genetically predetermined

It is not related to the number of previous ovulations, race, socioeconomic condition, height, weight, or age at menarche

There are several conditions known to decrease the age of menopause: living at high altitude, undernourishment, and history of cigarette smoking, the latter decreasing age of onset by approximately two years.

Demographic features of the Menopause

Life expectancy has dramatically increased. In the 1900’s, it was about 50 years; today, it is close to 80 years

Therefore, the average woman spends 30 years, or 1/3 of her life in the postmenopausal state.

There are about 100 million menopausal women in the U.S

Life Expectancy and Age of Menopause

Menopause: Pacemaker or follicle depletion?

Ovarian Synthesis, Transport and Metabolism of Estrogens

Estrogens are synthesized mainly by the ovary

17ß-estradiol binds to SHBG and albumin in the blood

Free estrogens diffuse into target tissues to exert their specific genomic or nongenomic effects

Lipoidal estrogens are synthesized in the blood and presumably in other tissues but accumulate predominantly in fat

Enzymatic catabolism of estrogens yields the hydroxy and metoxyestrogens

Classic Pathway of Estrogen Signal

Transduction Estrogen binds to ER

ER dissociates from the RAPs

The Hormone-Receptor complex moves to the nucleus

The H-R complex binds to DNA and initiate transcription

Transcription is catalyzed by RNA polymerase ll and various proteins including TATA-box-binding proteins

Activated ERs interacts with several proteins and binds to the ERE through the DNA-binding domain of the receptor and stimulates the transcription

Ligand-Dependent and Ligand-independents

Estrogen-Receptor Activation

The ER can be activated by Estrogen

The ER can be be activated independently of estrogen, the unbound but activated R will exert transcriptional effects.

ER are located in the cell-membrane invaginations, their activity is linked to mitogen-activated protein kinase pathway, resulting in a rapid, nonnuclear effect

השינויים ההורמונאליים בגיל המעבר

Endocrinology of the Menopause

Decrease and eventual cessation of

ovarian follicular activity

Decline in Inhibin B

Rise in FSH (x18) and LH

The ovaries become less responsive

to pituitary gonadotrophins (FSH/LH)

Decrease in Estradiol and Progesterone Predominant menopausal estrogen is E1

Lower androgen levels

Estrogens Production in the Menopause

The rate-limiting step of E synthesis is the transfer of cholesterol from the cytosol to the inner membrane of the mitochondrion, where the cytochrom P450 enzymes that catalyze the cleavage of the side chain of the cholesterol are located

Androstendione and Testosterone are obligatory precursors of estrogens

The P450 aromatase monooxygenase enzyme complex catalyze their conversion to estrogens

Aromatization occurs in fat, liver, kidney and brain.

Consequences of Estrogen Loss

Most signs and symptoms in menopause result from decreased circulating estrogens .

Some patients may have severe and multiple reactions that may be disabling.

However, 20% have no symptoms or only minimal symptoms, which may go unnoticed.

Consequences of Estrogen Loss

??

?

Vasomotor Symptoms

Hot flushes

Night sweating

Palpitations

Headaches

Panic attackFormication: ants crawling under skin

50-80% last more than 1 year

20-25% last more than 5 years

Hot Flushes

Most common climacteric symptom

(Experienced by 65-75% of women)

Debilitating symptom which occurs

without warning

Increase in heart rate

Increase in skin blood flow (x4)

Rise in skin temperature 1-7oC

Usually lasting no more than 3-4 minutes

Frequency is variable, from 2/w to 20/d

Neuropsychiatric Complaints

Depression

Tiredness

Irritability

Loss of energy

Memory loss

Lack of concentration

Anxiety

Decreased libido

Psychological Symptoms

The importance of distinguishing climacteric symptoms from other psychological and somatic complaints has been repeatedly stressed.

However, no detailed guidelines are available to assist the clinician in day to-day management of patients with these types of symptoms.

There is general consensus that hot flashes, night sweats and vaginal changes are associated with menopause.

Postulated Causes of Psychological symptoms

Primary alteration in brain

function in response to changing

steroid levels via interactions with

neurotransmitters

Secondary to disabling vasomotor

and genital symptoms

Secondary to coincidental illness

Postmenopausal changes in the vaginal mucosa

Vagina

Loss of folds

Folds or rugae

Muscular coat

Erectile tissue

Inner mucous liningcontains large

amount glycogen

Loss of inner mucous lining and glandular function

Premenopausal Postmenopausal

Samsioe G, A profile of the Menopause 1995; 49 (Fig. 6.4)

Atrophic Vaginitis

Woman 2 years since naturally menopausal

Not on estrogen replacement therapy

Loss of labial and vulvar fullness

Pallor of urethral and vaginal epithelium

Decreased vaginal moisture

Bachmann GA, Nevadunsky NS. http://www.aafp.org/afp/20000515/3090.html. Accessed May 2004 & October 2006

Increase in vaginal dryness with age

Dryness increased significantly in late perimenopause and postmenopause (p < 0.001)

Dennerstein L et al., Obstet Gynecol. 2000; 96: 351–8

Pre-menopause

(n = 172)

Lateperi-

menopause(n = 106)

Post-menopause

1 year(n = 72)

Post-menopause

2 years(n = 54)

Post-menopause

3 years(n = 31)

Premenopause Perimenopause Postmenopause

51

Urethral mucosa: climacteric changes

UrethraOuter vascular coat

Inner mucous lining

Intermediate spongy tissue containing a plexus of veins

Markedly widenedlumen

Premenopausal Postmenopausal

Samsioe G, A profile of the Menopause 1995; 49 (Fig. 6.4)

Urogenital aging

Late manifestation of the menopause Incidence increases with age Under-recognised, inappropriately treated May take long term replacement therapy (> 1 year) to

reverse the changes

Dudley Robinson © 2005

Menopausal symptoms of lower urinary tract

dysfunction

Nocturia

Incontinence

Urgency

Frequency

Straining

Pain

Age (years)

Report

ing S

ym

pto

ms

(%)

Perry S et al., J Public Health Med 2000; 22:427–434

Urogenital aging :effects on urogenital tract

Reduction in skin collagen content1

Rectus fascia less elastic2

Hydroxyproline content in connective tissue from women with stress incontinence 40% lower then continent controls3

Estrogens have a direct effect on collagen synthesis4

Changes in women with atrophy may be due to alteration in systemic collagenase activity5

Urogenital prolapse associated with reduction in both vaginal and periurethral collagen6

1 Brincat et al., 1985; 2 Landon et al., 1989; 3 Ulmstein et al., 1987; 4 Falconer et al., 1996;5 Kushner et al., 1999; 6 Jackson et al., 1996; James et al., 1999

The Skin in the Menopause

Estrogen deficiency induces a decrease in the collagen level in the skin, leading to:

30% of skin collagen is lost within 5 years

Thinning and drying Thinning and drying WrinklingWrinkling Brittle nailsBrittle nails Loss of hairLoss of hair

Atrophy of Estrogen Dependant Tissues

Breast sags Vagina thin and atrophic Vulva thin and atrophic Trigone of the bladder atrophies General skin atrophy Decrease in pelvic floor support

Osteoporosis

Normal bone Osteoporosis

Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone density and bone quality.

NIH Consensus Conference 2001

Definition of Osteoporosis

NIH Consensus Development Panel on Osteoporosis. JAMA 285 (2001): 785-95

Bone loss by age and sex

Bone mass

Age (years)

Finkelstein. Cecil Textbook of Medicine 1999.Riggs et al. N Engl J Med 1986.Finkelstein. Cecil Textbook of Medicine 1999.Riggs et al. N Engl J Med 1986.

Men

Women

Menopause-associatedbone loss

10 20 30 40 50 60 70 80

Averages 2% per year, perhaps 5% annually in first 5 -10 years post-menopause

50% of bone mass lost by age 70

Trabecular bone (vertebrae, hip) most affected

Osteocytes

Osteoclasts

Reversal

Apoptotic Osteoclasts

Lining Cells

Osteocytes

Activation

Osteocytes

Formation

Osteoblasts

Osteocytes

Resorption

Resting Phase

Osteoclasts

Osteoclasts

Bone Remodeling

Osteoid

Lining Cells

Osteocytes

Preosteoblasts

IL = interleukin; TNF = tumor necrosis factor.Jilka RL. Bone. 1998;23:75-81.

Pathogenesis of Estrogen Deficiency and Bone Loss

– Estrogen loss triggers increases in IL-1, IL-6, and TNF due to:

• Reduced suppression of gene transcription of IL-6 and TNF

• Increased number of monocytes

– Increased cytokines lead to increased osteoclast development and lifespan

OP: Characteristics

ירודה עצם צפיפות שינויים

ארכיטקטורה- במיקרוהעצם של

לשברים בסיכון עליה

Risk Factors for Osteoporosis

Low trauma fracture since age 40

Maternal history of osteoporotic fracture

Age > 65

Thin body build (body weight < 57 kg)

Prolonged amenorrhea

Early menopause

Chronic corticosteroid use (> 6 months)

Disease predisposing to osteoporosis

Meunier PJ et al., Clin Ther 1999; 21: 1025-44

Osteoporosis: The Size of the Problem

Highly prevalent - affects 200 million women worldwide1

1/3 of women aged 60 to 702/3 of women aged 80 or older

Approximately 20-25% of women over the age of 50 have one or more vertebral fractures2

United States: 25%3 Australia: 20%4

Western Europe: 19%5 Denmark: 21%6

Scandinavia: 26%5

1. International Osteoporosis Foundation

2. Melton LJ 3rd et al. Spine 1997;22:2S-11S

3. Ettinger B et al., J Bone Miner Res 1992;7:449-56

4. Jones G et al., Osteoporos Int 1996;6:233-9

5. O'Neill et al., J Bone Miner Res 1996;11:1010-8 6. Jensen GF et al., Clin Orthop 1982;166:75-81

Wasnich RD: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 4th edition, 1999

Incidence Rates for Vertebral, Wrist and Hip Fractures in

Women >50 ys40

30

20

10

50 60 7080

Vertebrae

Wrist

Age (Years)

Hip

Annual incidenc

e per 1000

women

Cooper C, et al. 1993;Am J Epidemiol 137(3):1001

Surv

ival (

%)

Years after Fracture

Effect of Vertebral or Hip Fracture on Survival

100

80

60

40

20

0

100

80

60

40

20

0

0 1 2 3 4 5

Vertebral

Hip

ExpectedObserved

ExpectedObserved

Diagnosis of OP

Bone densityBone markers

Bone formation

markers

Serum - bone specific alkaline phosphatase

Osteocalcin

Bone resorption

markers

Urine - N-tilopeptide cross-linked type 1 collagen (NTX)

Blood cross-laps

Normal: T-score > –1

Low bone mass : T-score between –1 and –2.5

Osteoporosis: T-score ≤–2.5

PMOP: Diagnostic Criteria WHO

Kanis Ja. Et al., J Bone Miner Res, 1994, 9:1137-1141

Normal

LowBoneMassOsteoporosis

Fre

qu

ency

of

Occ

urr

ence

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

Bone Mineral DensityIn Standard Deviation Units (T-Score)

OOOP: classification

BMD and Fracture Rate

BMD T-scores

Fra

ctu

re R

ate

pe

r 1,

00

0 P

ers

on

-Ye

ars

>1.01.0 to 0.5

0.5 to 0.00.0 to –0.5

–0.5 to –1.0–1.0 to –1.5

–1.5 to –2.0–2.0 to –2.5

–2.5 to –3.0–3.0 to –3.5

< –3.5

Adapted from Siris ES, et al. JAMA. 2001;286:2815-22.

Fracture Rate

BMD Distribution

0

10

20

30

40

50

60

Breast cancer

Mortality From Heart Disease

US Women

Kramarow E et al. Health and Aging Chartbook. Health, United States, 1999. National Center for Health Statistics; 1999.

0

1000

2000

3000

4000

5000

6000

7000

25 35 45 55 65 75 85 95

Age

De

ath

s/1

00,0

00Heart disease

0

Hip fractures

Symptoms of CVD in women

Different from those in men

Angina can be mistaken for indigestion or heartburn

MI symptoms can include overwhelming fatigue, shortness of breath, nausea, or indigestion

Alterable CVD risk factors

Smoking Obesity Physical inactivity Stress Hypertension Hypercholesterolemia DM

Unalterable CVD risk factors in women

Age >55 years

Family history of CVD (< 65 ys in females, < 55 in males)

Hereditary dyslipidemia

Premature menopause

Screening for CVD

Blood pressure measurement

Lipid measurements

EKG

Homocysteine (?)

C-reactive protein (?)

Stress echocardiography (?)

Electron beam computed tomography (?)

Measures to reduce risk of CVD

Smoking cessation Weight management Regular exercise Treatment of hypertension Control of diabetes Treatment of dyslipidemia

Proven strategies in men appropriate for women:

RisksBenefits

HT: Risks/Benefits prior to WHI (July 2002)

Based largely on data from observational studies

Menopausal Symptoms Symptoms

Genitourinary Health

Osteoporosis

Vaginal Atrophy

Cognitive Function

Cardiovascular DiseaseBreast Cancer

Gall bladder DiseaseVenous Thromboembolism

Women and CVD

Source: CDC/NCHS and the American Heart Association.

Cardiovascular Disease Mortality Trendsfor Males and Females

520

500

480

460

440

420

200

79 81 83 85 87 89 91 93 95 97

Years

Death

s in

Th

ou

san

ds

Males

Females

United States: 1979-97

WHIWomen’s Health Initiative HRT

study16,608 apparently healthy postmenopausal women

CEE 0.625 mg/d + MPA/d 2.5 mg vs. placeboPrimary endpoints: coronary heart disease and invasive breast cancerMean follow-up of 5.2 years (planned 8.5 ys)

Trial stopped in July of 2002 due to an increased rate of breast cancer and

evidence of risk exceeding benefit for HRT users

0

10

20

30

40

50

1 2 3 4 5 6 andBeyond

WHI: Effect of HT on CHD and

Stroke

0

10

20

30

40

50

1 2 3 4 5 6 andBeyond

Stroke

41%*

CHD

29%* Years of HRT

Num

ber

of

Pati

ents

Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333.

Placebo

HRT

*statistically significant

The Brain and the Menopause

Neurotransmission

Neuroprotection

Neurite BranchingSynaptogenesis

Cerebral Blood Flow

Trophic Factor

Expression

Effects of Estrogen on Neuronal Function

Birge SJ. Menopause Management. 2000;9:13-21

Estrogens exert neuroprotective effects on the

brain: Inhibition of β-amyloid formation Stimulation of cholinergic activity Reduction of oxidative stress related cell damage Protection against vascular risks

Alzheimer’s Disease (AD)

AD prevalence in 1997 in the US is 4 M

Prevalence is expected to quadruple in the next 50 ys to 1 in every Americans

The rate of AD is x2-3 higher in women

Only 2% of woman are aware that ERT could have any impact on AD

Delaying AD admission by 1month could save $1.2 billion annually

0

20

40

60

80

100

65 70 75 80 85 90 95

n = 1093Tang M-X, et al. Lancet. 1996;348:429-32

ET Delays AD Onset in Women

Pe

rce

nta

ge

Fre

e o

f A

D

Age at Onset (years)

>1 Year (n = 58)

<1 Year (n = 67)

Never (n = 968)

Duration of Estrogen Use

Mean Age, 74 Years

Alzheimer’s Disease and ET

Risk of Alzheimer’s among estrogen users was reduced by 50-70% compared to non-users Women who had used estrogen for > 1 yr had a significant reduction in risk Age of onset was significantly later Mechanisms: (poorly understood)

Estrogens increase synapses and neuronal growth Estrogens reduce amount of Amyloid found in Alzheimer’s Disease

Women’s Health Initiative Memory

Study (WHIMS) 4532 women age 64 to 79 years at baseline randomized

to EPT (combined CEE/MPA) vs placebo

40 EPT users vs 21 placebo users diagnosed with probable dementia (20 vs 12 with Alzheimer’s disease)

Dementia HR 2.05 (1.21-3.48) for EPT vs placebo

45 vs 22 cases of dementia per 10,000 women annually

Attributable risk: 23 additional cases per 10,000 EPT users annually

Shumaker et al. JAMA 2003.

Data Source: Legato, MJ, et al., “Women’s Perceptions of Their General Health, with Special Reference to Their Risk of Coronary Artery Disease: Results of a National Telephone Survey,” Journal of Women’s Health, Vol.,VI, No. 2, 1997

Top Priority: Better Health

Percentage Of Women Indicating Areas Percentage Of Women Indicating Areas Of Life They Would Most Like To ImproveOf Life They Would Most Like To Improve

Health and

Fitness

Finances Family Life Personal Relationships

34

25

95

Management of the Menopause

Diagnosis

Consultation

Lifestyle advice

Consider HT

Evaluation of Menopausal Patient

History

Symptoms (vasomotor, urogenital, skin and joint)

Past hx – IHD, fractures, thrombosis, fibroids, liver disease, cancer, hypertension

Family hx –IHD, oesteoporosis, breast CA Social hx – smoking, diet, exercise,

medications

Evaluation of Menopausal Patient

Examination

General (include BMI and BP) Breast Abdomen Pap and PV examination

Evaluation of Menopausal Patient

Investigations

FSH (if diagnosis uncertain) Mammogram Lipid profile, liver function tests US Bone densitometry

Life Style Advice

Moderate weight bearing exercise Maintain normal weight No smoking Minimize caffeine ingestion Decrease alcohol consumption Adequate dietary or supplementary calcium:

1000mg per day on HT 1500mg per day not on HT

Management of the menopausal woman:

Existence of symptoms:

Mood disturbancesHot flushesUrogenital atrophy

Goals• I mprove quality of life• Relieve symptoms• Prevent OP• Prevent CAD• Elongate life

Existence of condit ions or f or: OPCVDCNS disorder (?)

Lifestyle interventions:Normalization of weightDietary intervention

Smoking cessationRegular exerciseControl of hypertension, diabetes, alcohol consumption, and lipid normalization.

Contraindications for HT:Hormone dependent tumors (e.g. breast, endometrium)Severely impaired liver functionThromboembolic phenomenonGall bladder diseaseCoronary Artery Disease

SmokingObesity