Menopause

1. Menopause Dr. Mohammed EL-Shafei Prof. of Ob. & Gyn. Faculty of medicine Mansoura university Egypt

2. Definitions • Climacterium: is a period of transition between a women's childbearing and non-childbearing age. • Menopause (natural): is permanent cessation of menstruation usually 12 months in a woman over 45 years due to an intrinsic ovarian failure resulting in follicular inactivity and reduced production of sex hormones. • Premenopause:is the first phase of menopause covering a period of 5-10 years before the last period. • Postmenopause:is the last phase of menopause. Begins one year after the last period and ends at the age of 65.

3. Age of onset of menopause:ranges from 40 to 55 years, the average age is 51 y. • Types of menopause: 1) Natural menopause :is a retrospective diagnosis established when menstruation stop for 12 months in absence of organic or pathological cause. • If occur before the age of 40 it is referred to premature menopause, premature ov failure before 40 years which may be due to: 1- Genetic, constitutional, familial, metabolic, immunological causes. 2- Autoimmune diseases. 3- Infection. 4- Environmental. 5- Idiopathic • If menstruation continues beyond 55 years it is referred to "delayed menopause" which may be: constitutional, or due to uterine fibroids, DM & estrogenic tumors of the ovary. 2) Induced menopause: may be due to surgical removal of both ovaries or their destruction by radiation or administration of chemotherapy to treat malignant disease.

4. Mode (type) of onset of menopause(uterine bleeding pattern during menopause) menstruation rarely stopped abruptly & may take one or combination of the following 1- Oligomenorrhea: is a common manifestation, the menstrual interval is increasing until menstruation finally ceases. 2- Hypomenorrhea: the normal menstrual blood flow gradually  until it disappears. There may be oligohypomenorrhea. 3- Sudden amenorrhea: rarely occur due to sudden exhaustion of ovarian oocytes with sudden  in estrogen secretion. 4- Abnormal bleeding: e.g. cyclic or periodic excessive bleeding should not be considered a normal feature of menopause until proved otherwise

5. The endocrine (Hormonal) changes associated the menopause: 1- Decrease estradiol blood level due to diminished secretion of the ovaries (depletion of the ovarian follicles) 2- Gradual excessive production of gonadotropins in the perimenopause is a constant feature & results from: a)Lack of -ve feed back of E2 secondary to diminished production & ↑ follicular resistance. b)Lack of inhibin (produced by the ovaries), a main cause for increase of FSH.

7. Morphological changes concomitant to the menopause I) Somatic changes: a- Breasts: shrink & become flat except in obese women in whom they remain large & pendulous, this is because atrophy affects glandular tissue only. b- Hirsutism: hair growth on the upper lip & chin due to  androgens c- Obesity: may be due to deposition of fat in the anterior abdominal wall d- Skeletal system: calcium is lost from bone at rate about 1% per year  oesteoporosis with incidence of fractures particularly in vertebral bodies, distal radius & femoral neck. e- Cardiovascular system:  In postmenopausal women there is in total plasma cholesterol & LDL &  HDL  Ischemic cardiovascular diseases are more common in postmenopausal women than premenopausal of same age which appear to be protected against ischemic heart disease. Hypertension is common in postmenopausal women

8. II) Local (genitourinary) changes: 1) Genital system: Vulva: Labia majorae become flatter, introital narrowing and growth of pubic hair is diminished, however pruritus vulvae is never a symptom of menopause. Vagina: Vaginal mucosa undergo atrophy & loses its rugae & appear pale due to decreased vascularity. Decreased vaginal acidity with liability to infection & dyspareunia. Vaginal fornices are contracted, flushed, cone shaped. Cervix: Shrinks & become flushed with vagina Return of corpus/cervix ratio of 1:1 ( as in childhood) Stenosis of cervical canal. Uterus: Diminish in size and contain less muscle tissue. The endometrium is usually thin, atrophic, but may be proliferative or even hyperplastic (as a result of extra-glandular conversion of androgens to estrone). Fibromyomata usually shrinks but may continue to grow & associated with irregular bleeding during HRT.

9. II) Local (genitourinary) changes(cont.) Fallopian tubes: become short, thick with loss of epithelial plicae. Ovaries: shrink and its surface become wrinkled (small & fibrous). Ligaments & pelvis fascia: undergo atrophy which predispose to prolapse 2) Urinary tract: - The epithelium of the urethra & bladder trigone become thinner - The connective and elastic tissue of urethra & bladder become thinner and the muscle lose their tone. - This may result in frequency, urgency & incontinence.

10. Symptoms of menopause (menopausal syndrome) • The symptoms are collectively known as the menopausal syndrome and are related to estrogen deficiency. • About 50% of women do not develop these symptoms • Duration & severity vary in different women • May occur before, duringor after cessation of menses

11. Symptoms of menopause (menopausal syndrome) (cont) 1) Vasomotor instability: Hot flushes or a wave of heat over the chest, neck and face followed by profuse sweating. Is the most characteristic symptom. It lasts for few seconds up to 30 minutes and may occur at night disturbing sleep. palpitation, headache, dizziness may also occur. 2) Nervous & Psychological symptoms:sleep disturbances, anxiety, irritability, depression, mood changes and lack of concentration 3) Gastrointestinal: constipation, abdominal distension. 4) Urinary: frequency of micturition, dysuria, stress incontinence and predisposition to urinary tract infections. 5) Senile vaginitis , dyspareunia, uterine prolapse. 6) Hirsuitism 7) Non specific symptoms (headache)

12. Health hazards related to the menopause:( Osteoporosis & CV system) I- Osteoporosis:(by the age of 60, 25 % of women develop spinal compression & fracture) • Osteoporosis is a systematic skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture (risks). The most common osteoporotic fractures are vertebral, hip and distal forearm (radius & calcanium). • Primary osteoporosis develops as a result of excessive age-related bone loss. Age and menopause are the two main determinants of osteoporosis. The cessation of ovarian production of estrogen, at the time of the menopause, results in an accelerated rate of bone loss in women. • Other risk factors • Race white women are higher risk • Smoking, high caffine (coffe & tea) • High protein & low calcium diet • Early menopause • Sedentary life • Drugs like heparine or corticosteroids & alcohol intake • Skeletal effect: • curvature of the spine & ↓ hight • fracture neck femur • Osteoporosis is diagnosed by densitometry • Prevention & treatment of osteoporosis: (see treatment of menopause)

13. Health hazards related to the menopause (cont.) II- Increased risk for cardiovascular diseases: (as coronary heart disease, atherosclerosis, hypertension and stroke), due to decrease estrogen which may increase blood cholesterol levels and low density lipoproteins (LDL) and decrease in high density lipoprotein (HDL).

14. How to manage a case of climacteric(Diagnosis) 1- Initial Assessment: includeassessment of • The presenting complaint • Specific menopausal symptoms • Gynecological history: LMP • Previous medical & family history • Hormonal, marital & social circumstances. 2- Examination: • Height, weight, obesity index. • B.P. measurement. • Examination of breasts & abdomen. • Local pelvic examination. • Urinalysis

15. How to manage a case of climacteric(Diagnosis)(cont.) 3- Investigations: • Cervical & vaginal smears ( pap smear ). • Mammogram. • D & C, biopsy if there is vaginal bleeding. • Plasma estrogen. • ↑Serum FSH, if the diagnosis of menopause is in doubt • Biochemistry: - Lipid profile including cholesterol. - Fasting blood glucose. • X-ray of spine, hips & overnight urinary calcium/creatinine ratio. • Pelvic ultrasound ( including note of endometrial thickness ). • Bone densitometry measurement is not a routine screening test. NB: diagnosis is confirmed by check the level of FSH & LH • Persistent high level of FSH (level above 40 miu is diagnostic • Ovarian biopsy is rarely needed (premature menopause) • Determine of bone mineral density & bone mass to exclude osteoporosis

16. Treatment of the menopausal syndrome I- Non Hormonal treatment: (best candidate is hypertensive patient a) Reassurance & education:about the physiological nature of symptoms b) Exercises: are important c) Regulation of diet & bowel activity:byIncreasing calcium intake 1200mg/day & vit D, increasing fat intake, restriction of alcohol, coffee, tea & cola and Chinese herbal tea reduce flushes due to ginseng which is chemically & functionally similar to estrogen. d) Sedatives:mild sedation is given e.g mebropamate bromides & chloral hydrate. e) - adrenergic agonists:as clonidine, lafexidine, veralipride (antidopaminergic drug), bellergal ( a preparation of belladonna alkaloid), ergotamine tartrate & phenobarbital and B-blockers f) Treatment of other medical problems associated with menopause:as obesity, hypertension, diabetes mellitus and osteoarthritis

17. Hormone replacement therapy (HRT( Regimens for HRT: may be 1) Continuous unopposed estrogen. 2) Continuous progestogen. 3) Continuous estrogen / progestogens. 4) Cyclic estrogen / progestogens. N.B. HRT programs for women who have not had a hysterectomy fall into two categories, Cyclic, where progesterone is given for part of the month and continuous combined therapy (CCT), where it is given daily.

18. 1- Estrogens A) Oral: Cheap, convenient, easy to use, well tolerated. However, hepatic first pass reduces their biological activity (by conversion to esterone) and can activate certain liver enzymes. • Types: (conjugated equine estrogen (.625 mg/ day) & Estradiol valerate (1-2mg / day) B) Parentral:Vaginal, Percutaneous, Skin patches "Estraderm" (see figures below) & esterogel and subcutaneous implants: • Advantage: direct absorption and avoid 1st pass effect on the liver.

21. Side effects of estrogen (Risks( 1- Nausea, Mastalgia, Headache & Mood changes. 2- Endometrial neoplasia 3- Ovarian neoplasia 4- Breast neoplasia 5- Gall bladder diseases 6- Thromboembolic disease 7- Hypertension 8- Glucose tolerance 9- Other malignancies 10- Weight gain

22. Contraindications to estrogen therapy A) Absolute contraindication: 1) Known or suspected breast cancer. 2) Endometrial carcinoma. 3) Undiagnosed vaginal bleeding. 4) Active liver disease. 5) Active thromboembolic disease. B) High risk factors : 1) History of thromboembolism (may use transdermal estrogen). 2) Poorly controlled hypertension. 3) Chronic liver dysfunction  impaired metabolism of estrogen  estrogen level. 4) Acute intermittent porphyria may be precipitated. 5) Gall stones. 6) Pre-existing heart disease C) Relative contraindication: 1- Fibroid 2- Endometriosis. The activity of these benign gynecologic conditions may be stimulated & submucous myoma may lead to heavy and/or irregular bleeding may occur during HRT. D) Conditions requiring close observation during therapy: • Obese, diabetic, hypertensive patients. • Heavy smokers • Patients with varicose veins • Patients on phenytoin therapy

23. 2- Progestogens • Synthetic compounds, effective by the oral route and have a progestational activity. • Testosterone derivatives: Norgestrel: 0.05 mgm/day • Norethisterone acetate: 1 mgm/day • Gestodine: 50 micrograms/day • Progesterone derivatives:Micronized progesterone: 200 mgm/day • Medroxyprogesterone acetate: 2.5 mgm/day Side effects • Cyclical bleeding. • Depression. • Premenstrual symptoms (bleeding, fluid retention, mastalgia & headache

24. 3- Estrogen / progestogen( E/P) combinations • Several sequential estrogen / progestogen combination are available. • Drawbacks of combined E/P: a- Withdrawal bleeding, in 90% of cases & may be unacceptable by many women. b- Significant progestin side effects. c- Possible of beneficial effect of estrogen on cholesterol metabolism. • Although easy to use, its main disadvantage is the limited choice of estrogen & progestogen as well as limited dose range.

25. HRT (cont.) 4- Androgens were used tolibido (increase risk of virilization 5- Tibolone :non bleeding regimens  Has estrogenic, progestogenic and androgenic properties  Tissue specific action (endometrial)  Appears to be at least as efficacious for climacteric symptoms as other forms of HRT • No effect on breast 6- Selective estrogen receptor modulators (SERMS as raloxifene  Have been recently marketed for use in P.M. osteoporosis  Appear to function as weak estrogen with antiestrogenic effect in breast & endometrium They offer no symptom control and even exacerbate symptoms such as hot flushes

26. HRT (cont.) 7- Phytoestrogens as klimadynone  Comes from plants, that demonstrate mild estrogenic activity (2% that of estradiol)  May have a role in alleviating menopausal symptoms related to estrogen deficiency • Exhibits no growth in the endometrial thickness 8- Others recently GNRHa by its antigonadotrophic effect is used in treatment of P.M. symptoms

27. Indications of HRT 1) Symptomatic women: • Hot flushes severe enough to cause discomfort • Atrophy of reproductive tract e.g • Dyspareunia due to atrophic vaginitis & vaginal dryness • Recurrent cystitis & urethritis. • Urethral syndrome • Incontinence of urine. • Climacteric depression (may improve after loss of menstruation) as depression is related to the perimenopausal hormonal cycle of E& P. After menopause, no PMT, no menstrual migraine 2) Premature menopause 3) Women with Significant risk factors: • Established osteoporosis. • Combination of osteoporotic risk factors. • Fast bone losers. • Hyperlipidaemia type . 4) All women who understand the issue & requesting hormone replacement therapy.

28. Advantages and benefits of HRT • Relieve menopausal symptoms • Prevent urogenital atrophy • Decrease the risk of developing colonic cancer & Al-zaheimer and C.V.D & osteoporosis

29. Prevention and treatment of osteoporosis • Calcium supplementation 1200 mg//day and exercise are important • HRT: can be used for no more than 5 years, However when HRT is stopped the rate of bone loss increase • Bisphosphonates:e.g. alendronate 5-10 mg, risedronate (5 mg). it inhibits bone resorption. • Raloxiphfene (SERM): 60 mg/day , it has a combined estrogen-like effect (on bone) and antiestrogenic effect ( on breast and uterus). It can be used for osteoporosis if HRT is contraindicated or refused. • If estrogen is contraindicated Calcitonin or Alendronate : nasal spray 200mg / day , it inhibits bone resorption by decreasing osteoclasts activity. • Phytoestrogen: plant substances found in food similar in its action to estrogen e.g. soya • Regular exercise • Stop smoking

30. Long term Risk of HRT • Clinical studies demonstrate that the risk of endometrial cancer increase with long duration of estrogen only HRT. • The increased risk persist for several years after discontinuation. Adding progesterone decrease this risk. • Slight increase risk for breast cancer if HRT is used more than 5 years (relative risk 1.3) • Slight increase risk of thromboembolic diseases during the first year of use. • For these reasons, HRT should not exceed 5 years.

31. How to decrease the risk of HRT • Give the smallest dose of estrogen that minimize the symptoms→for short period (not more than 5 years) • Add cyclic progestagen • Avoid long term use of HRT or use alternative & Phytoestrogen

32. Follow up ofmenopause • Continuous follow-up visits to a special clinic at 3 & 6 months interval during the early years of menopause & every 12 months later. • At each visit, B.P. is measured & breast examination to detect any breast mass , pelvic examination, vaginal & cervical smears & endometrial sampling and/or transvaginal sonography.

33. Thank You