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Menopause Drorith Hochner-Celinkier Head, Department Obstetrics & Gynecology Hadassah University Hospital Mount Scopus, Jerusalem 16/11/2014.

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Presentation on theme: "Menopause Drorith Hochner-Celinkier Head, Department Obstetrics & Gynecology Hadassah University Hospital Mount Scopus, Jerusalem 16/11/2014."— Presentation transcript:

1 Menopause Drorith Hochner-Celinkier Head, Department Obstetrics & Gynecology Hadassah University Hospital Mount Scopus, Jerusalem 16/11/2014

2 Menopause גיל המעבר התסמונת הקלימקטרית בלות קמלות חדלון האורח EndocrinopathyPhysiological event ?

3 “Nature is unsentimental” Herbert Spencer, 1848 It is a question of the survival of the fittest If you are lucky, you reproduce, then you die Once you can no longer reproduce, you are evolutionary speaking, dead How 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 ?

4 “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 women Mirkka 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

5 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.

6 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.

7 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

8 Life Expectancy and Age of Menopause

9 Menopause: Pacemaker or follicle depletion ?

10 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

11 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

12 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

13 השינויים ההורמונאליים בגיל המעבר

14 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 E 1 Lower androgen levels

15 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.


17 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.

18 Consequences of Estrogen Loss ? ? ?

19 Vasomotor Symptom s Hot flushes Night sweating Palpitations Headaches Panic attack Formication: ants crawling under skin 50-80% last more than 1 year 20-25% last more than 5 years

20 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 1-7 o C Usually lasting no more than 3-4 minutes Frequency is variable, from 2/w to 20/d

21 Neuropsychiatric Complaints Depression Tiredness Irritability Loss of energy Memory loss Lack of concentration Anxiety Decreased libido

22 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.

23 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

24 Postmenopausal changes in the vaginal mucosa Vagina Loss of folds Folds or rugae Muscular coat Erectile tissue Inner mucous lining contains large amount glycogen Loss of inner mucous lining and glandular function PremenopausalPostmenopausal Samsioe G, A profile of the Menopause 1995; 49 (Fig. 6.4)

25 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. Accessed May 2004 & October 2006

26 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) Late peri- menopause (n = 106) Post- menopause 1 year (n = 72) Post- menopause 2 years (n = 54) Post- menopause 3 years (n = 31) PremenopausePerimenopausePostmenopause 51

27 Urethral mucosa: climacteric changes Urethra Outer vascular coat Inner mucous lining Intermediate spongy tissue containing a plexus of veins Markedly widened lumen PremenopausalPostmenopausal Samsioe G, A profile of the Menopause 1995; 49 (Fig. 6.4)

28 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

29 Menopausal symptoms of lower urinary tract dysfunction Nocturia Incontinence Urgency Frequency Straining Pain Age (years) Reporting Symptoms (%) Perry S et al., J Public Health Med 2000; 22:427 – 434

30 Urogenital aging :effects on urogenital tract  Reduction in skin collagen content 1  Rectus fascia less elastic 2  Hydroxyproline content in connective tissue from women with stress incontinence 40% lower then continent controls 3  Estrogens have a direct effect on collagen synthesis 4  Changes in women with atrophy may be due to alteration in systemic collagenase activity 5  Urogenital prolapse associated with reduction in both vaginal and periurethral collagen 6 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

31 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  Wrinkling  Brittle nails  Loss of hair

32 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

33 Osteoporosis

34 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

35 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-associated bone 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

36 Osteocytes Osteoclasts Reversal Apoptotic Osteoclasts Lining Cells Osteocytes Activation Osteocytes Formation Osteoblasts Osteocytes Resorption Resting Phase Osteoclasts Bone Remodeling Osteoid Lining Cells Osteocytes Preosteoblasts

37 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

38 OP: Characteristics  צפיפות עצם ירודה  שינויים במיקרו - ארכיטקטורה של העצם  עליה בסיכון לשברים

39 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

40 Osteoporosis: The Size of the Problem Highly prevalent - affects 200 million women worldwide 1 1/3 of women aged 60 to 70 2/3 of women aged 80 or older Approximately 20-25% of women over the age of 50 have one or more vertebral fractures 2 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

41 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 ys 40 30 20 10 50607080 Vertebrae Wrist Age (Years) Hip Annual incidence per 1000 women

42 Cooper C, et al. 1993;Am J Epidemiol 137(3):1001 Survival (%) Years after Fracture Effect of Vertebral or Hip Fracture on Survival 100 80 60 40 20 0 100 80 60 40 20 0 012345 Vertebral Hip Expected Observed Expected Observed

43 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

44 Kanis Ja. Et al., J Bone Miner Res, 1994, 9:1137-1141 Normal Low Bone Mass Osteoporosi s Frequency of Occurrence -4-3-20123 Bone Mineral Density In Standard Deviation Units (T-Score) OOOP: classification

45 BMD and Fracture Rate BMD T-scores Fracture Rate per 1,000 Person-Years >1.0 1.0 to 0.5 0.5 to 0.0 0.0 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

46 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 2535455565758595 Age Deaths/100,000 Heart disease 0 Hip fractures

47 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

48 Alterable CVD risk factors  Smoking  Obesity  Physical inactivity  Stress  Hypertension  Hypercholesterolemia  DM

49 Unalterable CVD risk factors in women  Age >55 years  Family history of CVD (< 65 ys in females, < 55 in males)  Hereditary dyslipidemia  Premature menopause

50 Screening for CVD  Blood pressure measurement  Lipid measurements  EKG  Homocysteine (?)  C-reactive protein (?)  Stress echocardiography (?)  Electron beam computed tomography (?)

51 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:

52 Risks Benefits 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 Disease Breast Cancer Gall bladder Disease Venous Thromboembolism

53 Women and CVD Source: CDC/NCHS and the American Heart Association. Cardiovascular Disease Mortality Trends for Males and Females 520 500 480 460 440 420 20 0 79818385878991939597 Years Deaths in Thousands Males Females United States: 1979-97

54 WHI Women’s Health Initiative HRT study 16,608 apparently healthy postmenopausal women CEE 0.625 mg/d + MPA/d 2.5 mg vs. placebo Primary endpoints: coronary heart disease and invasive breast cancer Mean 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

55 WHI: Effect of HT on CHD and Stroke Stroke 41%* CHD 29%* Years of HRT Number of Patients Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333. Placebo HRT *statistically significant

56 The Brain and the Menopause

57 Neurotransmission Neuroprotection Neurite Branching Synaptogenesis 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

58 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

59 n = 1093 Tang M-X, et al. Lancet. 1996;348:429-32 ET Delays AD Onset in Women Percentage Free of AD Age at Onset (years) >1 Year (n = 58) <1 Year (n = 67) Never (n = 968) Duration of Estrogen Use Mean Age, 74 Years

60 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

61 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.

62 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 Of Life They Would Most Like To Improve Health and Fitness FinancesFamily Life Personal Relationships 34 25 9 5

63 Management of the Menopause  Diagnosis  Consultation  Lifestyle advice  Consider HT

64 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

65 Evaluation of Menopausal Patient Examination General (include BMI and BP) Breast Abdomen Pap and PV examination

66 Evaluation of Menopausal Patient Investigations FSH (if diagnosis uncertain) Mammogram Lipid profile, liver function tests US Bone densitometry

67 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


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