Professor Hassan Nasrat FRCS, FRCOG

Professor of Obstetrics and GynecologyFaculty of Medicine

King Abdulaziz University

The Menopausal Woman

Definition and Terminology

Pathphysiology

Do we have a real problem?

Symptoms and Signs (Consequences of E deprivation)

Long Term Risk of E deprivation

Management HRT and The Controversy

The Menopause and The Perimenopause

The Menopause: Permanent cessation of menstruation resulting from the loss of ovarian follicles (WHO). Is a retrospective diagnosis.

Perimenopause: Is the period of time when normal women, usually in their forties, and usually menstruating, experience symptoms of oestrogen deficiency due to declining ovarian function (1-9 years)

This group has been termed the “Sandwich generation” caring for their immediate families, aging parents as well as having career commitment.

The Perimenopause

Gametogenic failure followed by.

Ovarian hormonal failure Cessation of Estrogen.

The Biochemical markers are unreliable in diagnosis of the perimenopause because of irregularity hormonal levels.

Ovarian gametogenic Failure:

• Failure in quantity: Accelerated Loss of

Follicles Decreased Fertility Rate

• Failure in quality:

– Embryonic chromosomal anomalies e.g.

Trisomies.

– Increased spontaneous miscarriage

The Relation Between Age and Follicular # Follicle Depletion Appears to Accelerate in the Decade Preceding

Menopause – In the Menopause There is Almost Complete Cesation of Ovarian Estrogen production

Age In Years

Changes in female life expectancy and age of menopause

Definition and TerminologyPathphysiologyDo we have a real problem?Symptoms and Signs (Consequences of E deprivation)Long Term Risk of E deprivationManagement HRT and The Controversy

Ovarian Hormonal Failure “Cessation of Estrogen Hormones”:

• Change in Menstrual Pattern:

• Vasomotor instability:

• Sleep Disturbances:

• Psychological/cognitive disturbances:

• Atrophic Conditions:

• Somatic Symptoms:

• Long-term problems 2ry to oestrogen deprivation:

Consequences Of Cessation Of Estrogen Production

Hot Flushes

Insomnia

Irritability

Mood disturbances

Sexual Dysfunction

Stress Urinary Incontinence

Connective Tissue Changes

Osteoporosis

CVD

Dementia (AD)

Cancer

Early Symptoms

Late Physical Changes

Later Diseases

Symptoms & Physical Changes of Estrogen Deficiency

Urinary Symptoms

Affect 70 % of Women, Vary in SeverityIs a Form of Thermoregulatory DysfunctionCan Effectively be Treated with Estrogen Cause Sleeplessness, with Serious Mood

Disturbance, Depression and Irritability

Hot Flushes

Sexual Dysfunction

Atrophy of vaginal Epithelium and Dryness Pudendal Nerve Neuropathy

Dyspareunia, Decreased Sexual Desire and Arousal (decreased clitoral sensitivity)

Connective Tissue Changes Reduced Collagen Contents of

Skin (wrinkles) and Bones

Atrophy of urethral and Trigon epithelium

Osteoporosis

‘a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration with a consequent increase in

bone fragility with susceptibility to fracture’

Osteoporosis

Estrogen and The Skeletal System:

With Acute Estrogen Deficiency After The Menopause, There Is Accelerated Bone Loss Which Mounts To About 1-1.5% Loss Of Total Bone Mass/Year.

For The First 20 Years After Cessation Of Menses, Menopause Related Bone Loss Results In 50% Reduction In Trabecular Bone And 30 % Reduction In Cortical Bone.

Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration with a consequent increase in bone fragility with susceptibility to fracture’

Normal…..VS.…Osteoporotic Bone

Normal iliac crest Osteoporotic iliac crest

Oestrogen and The Skeletal System:

The Precise mechanism of action of Oestrogen on the skeletal system is unknown. It seems to acts at different sites:

- Increase efficiency of calcium absorption (enhance availability of Vit. D, 1,25 dihydroxy vit. D)

- Direct action on Osteoblasts- Through stimulation of estrogen dependant

growth factors.- Promote the synthesis of Calcitonin.

Oestrogen and The Skeletal System: Osteoporosis is a major public health problem.

Vertebral 700,000Proximal femur 300,000Distal forearm 200,000Other limb sites 300,000Total 1,500,000

Annual incidence of fracture in the USA due to osteoporosis

The life time risk of hip fracture in white women is 15%. The combined risk of breast, uterine and ovarian cancer.Hip fracture is fatal in 20%. Half the survivors are unable to walk.

Risk Factors for Osteoporosis

•Family history of osteoporosis.•Early natural or surgical menopause.•Previous fragility fracture.•Smoking.•Low body weight.•Medical disorders (e.g thyroid disease) ,steroid therapy

Depending on clinical risk factors alone is inadequate. 30% of women with no risk factors have significant bone loss (Slemenda etal Ann Inter Med, 1990, 112:96-101)

Pathophysiologic factors

Age Race Oestrogen Wt Diseases

Diet Drugs Lifestyle

Low Ca.

Low Vit D

Alcohol

Smoking

SedentaryOsteoporosis

Oestrogen and The Skeletal System:

Peak Bone Mass: determined by Genetic & Non-genetic factors (nutrition, exercise, ..etc)

Rate of bone loss in later life: aging, lifestyle, the menopause, smoking..etc

Measurement of BMD: Most commonly used:- Dual-energy X-ray absorptiomery (DXA).- Quantitative computed tomography (QCT).- Single-photon absorptiometry (SPA)

Newer Technique:- Ultrasound attenuation and velocity.- Magnetic resonance imaging.

Other techniques: - Dual-photon absorptiometry (DPA) - Neutron activation analysis. - Radiogrammetry radiographic densitometry.

Dual Energy X-ray absorptiometry

DXA

- Is the gold standard for BMD measurement. The technique depends on measuring the row bone mineral content (BMC) in a clinically relevant area of the skeleton e.g vertebra or hip (gm ca++). - The BMD is obtained by dividing the BMC by the area scanned (gm Ca++ /CM2).- The result is expressed as : Z score: SD from patient age mean value.

T score: SD from adult standard value.

Osteoporosis:

The diagnosis of osteoporosis is currently based on bone mass measurement:

T score < 1 SD Normal

T score >1 SD Osteopaenia

T score > 2.5 SD Osteoporosis

WHO, 1994

DEXA report:

BMD Measurement using U/S

Oestrogen and the CVS

Deaths from CHD Number of deaths per 10,000

Age band (years) Bush, 1990

1000

10,000

100

1040- 45- 50- 55- 60- 65- 70- 75- 80- 85+

Women

Men

Cardiovascular protective Effect of Estrogen

Action On Lipid Metabolism: Reduction In LDL-C (10%-20%) Raise The HDL-C (10%-30%)

Direct & Indirect Vascular And Hemostatic Actions Augment Vasodilator And Antiplatelets Factors, Nitric Oxide And Prostacycline.

Estrogen Has Antioxidant And Calcium Channel Blocking Properties.

Direct Inotropic Action On The Heart.

Management of the Menopause

• History: – symptoms of Estrogen deficiency– History of relevant medical or surgical

conditions (e.g. diabetes, CVD, Thrombosis, Cancer…etc.) in patient and family.

– History of Relevant medications: e.g. steroid.– Family history of Cancer (breast or ovarian)

• Examination And Investigations:– General:– Local: including Pap Smear– BMD– Mammography

• Counseling and Advice:–Life Style (Diet, exercise…etc.)

• Medications: –HRT–Calcium –Vit. D–SERM–Other specific agents for

osteoporosis

Hot Flashes, Vaginal Dryness, Urinary

Symptoms, And Emotional Liability… etc

Management of Early Consequences of Estrogen Deficiency:

Estrogen Is The Most Effective

Treatment Available For Relief Of

Menopausal Symptoms

Estrogen and Recurrent UTIThe Effect of Intravaginal Estriol Vs. Placebo on the Incidence

of UTI in Postmenopausal Women with Recurrent UTI

Randomized placebo-controlled, prospective study over two years period Oral HRT patients maintained bone mass while placebo-treated women lost significant mas2.3% was seen when HRT was withdrawn.

Effect of HRT in Bone Mass

Estrogen Replacement Therapy“ERT”

•Type of Estrogen:

•Route of Administration:

•Combined Preparation “HRT”

•Duration of treatment:

•Risks of HRT

Oral Oestrogen

Transdermal Oestrogen

Gel Containing oestrogen

Estrogen Implants

Vaginal Oestrogen

Estrogen Replacement Therapy ’ERT’

Combined Preparation “HRT”

- In Women With Intact Uteri Progesterone Preparation

Should be Added.

- It Has Virtually Eliminated The Risk Of Endometrial

Cancer..

Risks Associated with HRT:

General and Metabolic Risks: Venous thrombosis

gallbladder diseases

liver diseases.

Endometrial Neoplasia:

Breast Cancer:

Cumulative number of Deaths for 100 000 female births, in England and Wales, 1995

•One women in 12 will get

Br. Ca. i.e. is cumulative life

time risk by age 85 ys. •Substational proportion of

this risk occur in later life. •Between 30-50 the risk is

2% per 20 ys or 0.1% per y.

Between 50-70 ys. The

annual risk is 2/1000. Or 2%

cumulative risk between 50-

60 years (0.2% per annum)

Breast Cancer Risk and HRT

‘The Obstetrician and Gynecologist, Vol.. 1, October, 1999, No2’

Ostrogen Hormone and Breast Cancer

•There is a small but significant increase in risk beyond 5 years of HRT use. The relative risk is about 1.3 at 15 years. (i.e. in the decade 50-60 the HRT user for 5-15 years may be considered to have an annual risk of 1.3 0.2% per annum of developing breast cancer). •The risk persists for 5 years after the end of therapy but not beyond that.

Analysis of world literature. Collaborative group on hormonal factors in breast cancer, Lancet 350:1997

The Obstetrician and Gynecologist, Vol. 1, 1999, No2

Selective Estrogen Receptors Modulators

‘SERM’

Are group of antiestrogens that possess:

Oestrogen Agonistic activity at desired targets: on bone and on lipoproteins.

And Antagonistic action on the breast and the endometrium

Selective Estrogen Receptors Modulators‘SERM’

Molecular structure ofRaloxifene hydrochloride

The potential benefits of SERM drugs include protection from four diseases:Osteoporosis, coronary heart disease, endometrial and breast cancer.