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26/03/2015

Menopause
Georges El-Kehdy, MD

¾ Definition : period of time marked by irregular menstrual
cycles that precedes menopause (menopause is the
permanent cessation of menses with loss of follicles)
¾ Age of onset: 39-51y (average 46y)
¾ Duration :2-8y (average 5y)
¾ Hormonal changes
• Inhibin is decreased
• FSH is increased(>20mIU/ml), LH is normal
• E2 remains normal or slightly elevated until 6-12months before
menopause

¾ Fertility is reduced because of reduced quality of aging
follicles with < inhibin,>FSH and acceleration of follicular
loss

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26/03/2015

¾Age : 44-56y with a median of 51y
¾Factors that decrease age of menopause
smoking, malnutrition, low BMI. high
altitude, previous hysterectomy or
endometrial ablation
¾Maternal age of menopause:+ correlation
¾Alcohol increases the age of menopause
¾No correlation with age of menarche or
parity

Hormonal Production





Absence of follicles
Decreased ovarian volume
Gonadotropins are increased
Androgens are decreased
Estrogens are decreased
Androgens/estrogens ratio is increased
with increased incidence of hirsutism

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26/03/2015 GONADOTROPINS • • • • FSH is increased 10-20 fold LH is increased 3 fold LH has a shorter half-life than FSH FSH and LH continue to increase for 2 years then a slight and gradual decline • Elevation of gonadotropins has a diagnostic value ANDROGENS ¾ Androstenedione • Production is decreased by 50% • Origin is mainly adrenal with minimal ovarian ¾ DHEA and DHEAS • Production is decreased by 70% • Origin is adrenal ¾ Testosterone • Production is decreased by 25% • Origin is ovarian • Ovarian production is increased compared with premenopausal production • FSH stimulates ovarian stromal tissue 3 .

26/03/2015 ESTROGENS • Estrogen production is decreased • Estrone level is higher than estradiol level E1=30-70pg/ml E2=10-20pg/ml • Origin is from peripheral conversion by aromatization of androstenedione to estrone and than to estradiol Impact of Estrogen Deprivation • • • • • • Vasomotor symptoms Atrophic changes Psychophysiologic effects Cognition and Alzheimer's disease Cardiovascular disease Osteoporosis 4 .

26/03/2015 Symptoms associated with the menopause Acute Intermediate/late • Hot flushes • Dyspareunia • Night sweats • Loss of libido • Insomnia • Urethral syndrome • Anxiety/irritability • Vaginal atrophy • Memory loss • Cardiovascular disease • Poor concentration • Osteoporosis • Mood changes Climacteric complaints By menopausal status Pre Vasomotor symptoms Peri Depressive mood Post Anxiety/fears Sleep problems Sexual problems Cognitive difficulties 0 20 40 60 80 100 Mean percentage of women Hunter. 1988 5 .

Vasomotor Symptoms (VMS) 6 . and  neck.26/03/2015 Vasomotor Symptoms (VMS) • The beginning is a subjective feeling of intense heat. and then the anterior chest: vasodilatory  response to dissipate the heat. • Next is a reddening of the skin. • Next is increase in perspiration. first of the head. • The perception begins in the thermo‐regulatory  center located in the hypothalamus. and  cooling phase. evaporation.

 often associated  with ± profuse sweating – Moderate: perceptible but does not interrupt  activity – Mild: transient redness of the skin 7 .26/03/2015 Temperature in VMS Vasomotor Symptoms (VMS) • Average duration: 2‐3 min • Average frequency: 1 every 2‐3 hours • Intensity: variable – Severe: interferes with activity.

 but in the brain [measured  through its metabolite 3‐methoxy‐4‐ hydroxyphenylglycol (MHPG)] → Adrenergic  Brain receptor (modulated by Estrogen) 8 .26/03/2015 Thermoregulation Endocrinology of VMS • • • • Decrease in Estrogens: + LH pulses: ±? Opioidergic System: ±? Nor‐Epinephrin: +.

and 20% to 30% of those in their 60s and 70s experience VMS Hot Flushes May Continue Years After Menopause Ages 29 to 82 Years 50 Number of Subjects 45 Number of years women report having hot flushes as estimated by a survey of 501 untreated women who experienced hot flushes 40 35 30 25 20 15 10 5 0 0 2 4 6 8 10 12 14 16 18 20 22 24 28 30 36 41 Years Mean age of natural menopause was 49.5 years. 1990. mean age of surgical menopause was 43. Ann NY Acad Sci.592:52-86. 9 . Used with permission. • They peak around the final menstruation • One third of women in late reproductive age.7 years.26/03/2015 Vasomotor Symptoms (VMS) • The prevalence of hot flashes varies with culture and ethnicity. • Some cultures do not have a word to describe VMS • Up to 75% of American women report them and 26% to 60% rate them as severe. Kronenberg F.

26/03/2015 Risk Factors for VMS MENOPAUSE Impact of estrogen deprivation EFFECTS ON COGNITIVE FUNCTION Decreased memory.decreased cognitive function and increased incidence of Alzheimer disease are mainly in relation with aging Estrogen deprivation might have a role because ERT might improve these effects by protection of CNS cells 10 .

26/03/2015 MENOPAUSE Impact of estrogen deprivation PSYCO-PHYSIOLOGIC EFFECTS • Depression is not increased with menopause • Emotional stability is disrupted by poor sleep pattern which gets worse with aging and menopause • HRT is indicated for severe hot flushes MENOPAUSE Impact of estrogen deprivation CARDIOVASCULAR DISEASE ¾ Risk of coronary heart disease • CHD is one of the leading causes of death in women following cancer • Risk of CHD is over 3.5 times in men that of women • With increasing age this advantage is gradually lost (role of estrogen deprivation) ¾ Lipid profile changes • HDL cholesterol is higher in women then in men and does not change with menopause • LDL cholesterol is lower in females than in males but increases after the menopause 11 .

MENOPAUSE Hormonal Replacement Therapy (HRT) TRADITIONAL INDICATIONS OF HORMONAL REPLACEMENT THERAPY ¾ Menopausal symptoms ¾ Prevention of: • Primary and secondary coronary heart disease (CHD) • Osteoporosis • Alzheimer disease 12 .26/03/2015 MENOPAUSE Impact of estrogen deprivation OSTEOPOROSIS ¾ Bone remodeling is a constant process of bone resorption and formation ¾ Osteoporosis is the decreased bone mass with micro architectural deterioration of bone tissue leading to bone fragility ¾ Estrogen deficiency is associated with an increased responsiveness of bone to parathormone then an increased osteoclastic activity leading to osteoporosis ¾ Risk of fracture depends on bone mass reached at maturity(20years) and bone loss after menopause ¾ After menopause there is an acceleration of bone loss.

26/03/2015 MENOPAUSE Hormonal Replacement Therapy (HRT) QUESTIONS ABOUT HRT • How effective in CHD and osteoporosis • What is the risk of breast cancer • What is the risk of thrombo-embolic disease MENOPAUSE Hormonal Replacement Therapy (HRT) PREVIOUS STUDIES ¾ Observational and epidemiologic ¾ Results are conflicting 13 .

26/03/2015 MENOPAUSE Hormonal Replacement Therapy (HRT) RECENT STUDIES ¾Meta-analysis ¾RCT: Randomized Controlled Trials MENOPAUSE Hormonal Replacement Therapy (HRT) UPDATES ON HRT • • • • Protection against CHD Risk of breast cancer Risk of thrombo-embolic events Decisions for HRT 14 .

26/03/2015 MENOPAUSE Hormonal Replacement Therapy (HRT) Protection against CHD ¾Observational epidemiologic ¾Results 50% reduced risk of CHD 37% reduced mortality of CHD MENOPAUSE HRT Protection against CHD Impact of lipid profile LDL-cholesterol decreased HDL-cholesterol increased Triglycerides increased 15 .

7years • Two groups: 1.HRS(1998) • Participants: 2763 women with pre-existing CHD and a mean age of 66.1years Protection against CHD Secondary prevention of CHD HRS: results and conclusions • HRT did not reduce the overall rate of CHD events • HRT increased the CHD events during the first two years • HRT should not be used for secondary prevention of CHD 16 .625mg MPA 2.5mg 2.Placebo group • Duration of the study : 4.26/03/2015 Protection against CHD Secondary prevention of CHD Heart and Estrogen/progestin Replacement Study.Treated group with CEE 0.

8years HRT did not reduce the risk of CHD events in women with preexisting CHD Protection against CHD Primary prevention of CHD Women’s Health Initiative Trial(WHI2002) • Participants: 16608 healthy women.26/03/2015 Protection against CHD Secondary prevention of CHD HRS II (2002) • Participants: same of HERS with additional 2. age 5079 • Two randomized groups: Treated group with CEE0.5 Placebo group 17 .625 and MPA 2.7years follow-up • Objective: to determine if the reduction in CHD events observed in the later years of HERS persisted • Results: after 6.

26/03/2015 Protection against CHD Primary prevention of CHD WHI Trial results • HRT increased the risk of CHD by 29%in healthy menopaused women (37 versus30per 10 000 women) • Absolute risk per 10 000 womenyears=7CHD events • Conclusion: HRT should not be used for primary prevention of CHD Risk of breast cancer Observational and epidemiologic studies • 1990: prospective study from Sweden showed a slightly increased risk of breast cancer • 1995: Iowa Women’s Health Study showed no increased risk of breast cancer 18 .

46) Not decreased Risk of breast cancer Observational and epidemiologic studies Meta-analysis: World’s literature (1997) • Risk of breast cancer is increased in menopaused women on HRT • Risk increases with duration of use : after 5years the RR=1.26/03/2015 Risk of breast cancer Observational and epidemiologic studies The Nurses Health Study (1995) Risk of breast cancer Estrogens in past users Estrogens in current users Progestogens added Not increased Increased (RR=1.35 • Risk of breast cancer is reduced after cessation of HRT and disappears after 5 years 19 .

26/03/2015 Risk of breast cancer Conclusion of previous studies • Results are discordant • Trend: increased risk of breast cancer with HRT • Need for controlled randomized studies Risk of breast cancer WHI study results • HRT increased the risk of breast cancer by 26% (38 versus 30 per 10 000 women ) • Absolute excess risk per 10 000 womenyears: 8 cases of breast cancer • The risk of breast cancer is significantly increased after 4 years of HRT use 20 .

00 5.5 1 0.5 0 4.13 ) • Absolute excess risk per 10 000women per year=8 events • HRT increased the risk of stroke by 41% (29 versus 21 per 10 000) 21 .00 6.00 years RISK OF THROMBOEMBOLIC EVENTS WHI study • HRT increased by 100% the risk of thromboembolism( RR=2.5 2 HERS HERS II 1.26/03/2015 RISK OF THROMBO-EMBOLIC EVENTS 3 relative risk 2.

26/03/2015 CONCLUSIONS Risks of HRT 2.5 TE CHD Breast K 1 0.5 relative risk 2 1.5 0 CONCLUSIONS Benefits of HRT • • • • Treatment of menopausal symptoms Prevention of osteoporosis Decreased risk of colorectal cancer Decreased risk of endometrial cancer 22 .

WHO Division of Mental Health.9:402-10. 1993. 2002.26/03/2015 CONCLUSIONS Decisions for HRT • Don’t start HRT if menopausal symptoms are absent • Start HRT if menopausal symptoms are affection the quality of life • Resume HRT if menopausal symptoms reappear • Discontinue HRT if no menopausal symptoms and use alternatives for osteoporosis prevention or treatment Definition of QOL – Global sense of self-satisfaction – Sense of well-being – Patient’s perception of her interest in life – Maintaining satisfactory interpersonal relationships – Perception of physical and psychological wellness – Satisfaction with position in life in the context of culture and value systems Utian WH. 23 . et al. Menopause.

and black cohosh— no difference compared with placebo ‹ Phytoestrogens ‹ Clonidine (patch or pill) ‹ Megestrol ‹ SSRI/SNRI therapy ‹ Gabapentin SSRI/SNRI = selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor. dong quai. Life Style Modifications • • • • • Core Body Temperature Exercise Body Mass Index Smoking Relaxation Techniques 24 . cool environment ‹ Vitamin E.26/03/2015 Alternative Approaches Used for Vasomotor Symptoms ‹ Lifestyle changes.

) • Safety – – Endometrial cancer Breast cancer • Lack of Adverse Effects Non-Hormonal Treatment • Pharmacological – Antidepressants – Anticonvulsants – Antihypertensive – Vitamin E • Herbal-Nutritional – Black Cohosh – Phytoestrogens • Soy • Red Clover – Dong quai – Ginseng – Evening Primrose – Kava 25 ..g. etc. colon.26/03/2015 Post-Menopausal Treatment • Efficacy – – – – Treats climacteric complaints Prevents postmenopausal bone loss Beneficial effects on cardiovascular parameters Other benefits (cognitive function. reduction in incidence of some cancers e.