Menopause and role of HRT

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Menopause And Role Of Hormone Replacement Therapy And Other Alternatives Dr. Charul Dhakad Institute of Medical Sciences Banaras Hindu University Varanasi Seminar

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Menopause is not a disease. It is a natural process in women’s life. How a woman faces it depends on how frequent and severe her symptoms are. If viewed as end of youth and sexuality this time will be much difficult than if viewed as next natural phase of life. MENOPAUSE

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DEFINITION WHO defines menopause as permanent cessation of menses for one year following the exhaustion of Graffian follicle and decreased ovarian activity. The word "menopause" literally means the "end of monthly cycles“ from the Greek words pausis (cessation) and the word root men from mensis meaning (month). Menopause can occur spontaneously or following bilateral oopherectomy

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VARIANTS OF MENOPAUSE Natural Menopause Medical / Surgical / Induced Menopause Women will immediately experience an abrupt menopause after hysterectomy or bilateral oopherectomy. Cold –Turkey Menopause Menopause that occurs when HRT is taken off due to diagnosis of estrogen dependent tumors

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Usually - 45-55yrs Premature - <40yrs Delayed - >55yrs AGE OF MENOPAUSE

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Pituitary Hypothalamus GnRH (+) Estradiol Progesterone LH FSH Inhibins Ovary Why does menopause occur? -due to reduced secretion of the ovarian hormones E and P. Hypothalamic-pituitary-ovarian axis

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Hormonal Changes During Menopause Gonadotropins Serum FSH increase to 10-20 times Serum LH increase to 3 fold Gonadotropins reach a maximum level in 1 – 3 years after menopause. Then there is gradual but slight decline. Estrogens Estrogen is not a single hormone. There are 3 types of natural estrogens:- Estrone 10-20% produced by fatty tissue Less potent than estradiol Important after menopause Estradiol 10-20% Produced by ovary Important before menopause Strongest estrogen Decreased in menopause Estriol 60-80% Estrogen predominant during pregnancy Made from combination of components of placenta, fetus and mother

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Progesterone As progesterone production ceases after menopause, an unopposed stimulation of endometrium by estrogen causes endometrial hyperplasia. Shortly after menopause ovary secretes primarily androstenedione and testosterone but major amount of these are derived from adrenals only. Hormonal Changes During Menopause contd… Burger et al. J Clin Endocrinol Metab ,1999.

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HOW MENOPAUSE OCCURS Initially cycles become irregular FSH rises in response to decreased feedback of ovarian hormones Menstrual cycles are missed and ultimately stop Climacteric (Gk: ladder) – old, general, less precise term. It indicates the period of time when a woman passes from the reproductive stage of life through perimenopausal transition and menopause to the post menopausal years.

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PHASES OF TRANSITION Stages of Reproductive Ageing Workshop (STRAW) model Describes seven stages of reproductive ageing. Subdivided into 3 reproductive stages:- regular menstrual cycles menopausal transition stage postmenopausal stage

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FACTORS AFFECTING ONSET OF MENOPAUSE Earlier Menopause Undernourished female Vegetarian Active smoking Low socioeconomic status Early menarche High altitudes Left handed female Growth retardation in late gestation Post hysterectomy female Late menopause Fatty female Alcohol OCP use Increased parity

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Ovaries – shrink in size and become wrinkled Fallopian tube – show features of atrophy - muscle coat becomes thinner - cilia disappear Uterus – becomes smaller Body to cervix ratio 1:1 Endometrium is thin and atrophic Vagina becomes narrow due to loss of elasticity. Endothelium becomes thin. There is no glycogen and pH alkaline Breasts- fat is reabsorbed and glands atrophy. Become flat and pendulous. Loss of muscle tone leads to pelvic relaxation and tendency to prolapse ANATOMICAL CHANGES

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AMENORRHEA Estrogen produced by ovaries is not sufficient enough for endometrial proliferation, absence of cyclic progesterone lead to absence of withdrawal bleed VASOMOTOR SYMPTOMS most common complaint Definition Hot flush is a subjective sensation of heat that is associated with objective signs of cutaneous vasodilatation and a subsequent drop in core temperature. Hot flush may be accompanied by sweating, flushing, palpitations, anxiety, irritability, and even panic, and women may also report night sweats. MENOPAUSAL SYMPTOMS

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Each episode 1-3 minutes Commonly 5 – 10 times per day Recur as many as 30 times per day Avg. duration 1 – 2 years Less episodes in cold environment Women with H/O bilateral oopherectomy tend to have more serious symptoms. Classically hot flushes subside within 5 years of natural menopause in approx. 50%. In 10% symptoms may be as long as 15 years. Hot Flushes contd…

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Low concentration of circulating estrogen Low body weight Little or no exercise Cigarette smoking African-American origin Low socioeconomic status Low educational status Menopause at a young age Abrupt menopause Surgically induced Chemotherapy induced Radiation induced Drug induced Hot Flushes - Risk Factors

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Reassurance Education lifestyle adjustment Preventive measures Hot Flushes Treatment Mild and short term symptoms

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Control BP Intake of antioxidants Exercise (esp. weight bearing) Decrease fat intake Add soy foods in diet Increase Ca2+ intake Skip alcohol and coffee Take Vitamin E Quit smoking Drink plenty of water- 8 glasses per day Prevent dryness of vagina- use water based vaginal lubricants because oil based lubricant does not dissolve as easily in the vagina and therefore trigger infection Lowering of room temperature Preventive measures of Hot Flushes

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Weight bearing exercises Walking, jogging, climbing stair, floor push-ups and wall push-ups, can improve bone strength and are beneficial for osteoporosis patients.

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Estrogens Because of the causal association between hot flushes and estrogen depletion estrogenic preparations are the mainstay of treatment HRT decreases hot flushes by 50–100% Most women will note a return of their hot flushes when HRT is suddenly discontinued Estrogen component should therefore be discontinued gradually over weeks For women who had been treated with hormones increased hazard ratios (HR) were noted coronary heart disease stroke pulmonary embolism Other risks include symptomatic gallbladder disease. Pharmacological Interventions

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Progestagens Transdermal progesterone cream causes 83% reduction in hot flushes. Adverse effects include:- vaginal bleeding thromboembolic events bloating weight gain. Androgens hot flushes are significantly reduced in women who received a combination of estrogen and androgen replacement therapy. (Gelfand M et al . Am J Obstet Gynecol 1999). In these patients, sexual desire, arousal, wellbeing, and energy level were also enhanced by the addition of androgen treatment. However, adverse effects included weight gain, bloating, hirsuitism, and acne Pharmacological Interventions contd…

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Tibolone has a weak estrogenic, progestagenic, and androgenic effect, used as an alternative to HRT to relieve menopausal symptoms. increases bone-mass density and lower cholesterol its effect on breast cancer risk is unknown. Complementary medicine Vitamin E- associated with a 25% reduction in hot flushes compared with 22% with placebo……………..(Barton DL, et al. J Clin Oncol 1998) Soya - Soya contains isoflavone, a main category of naturally occurring plant sterols, phytoestrogens. Pharmacological Interventions contd…

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Vaginal tissue and tissues of urethra and bladder base are known as estrogen sensitive About half of postmenopausal women have symptoms of urogenital atrophy. Vaginal symptoms Dryness Dyspareunia Recurrent vaginal infections Urinary symptoms Dysuria, urgency Recurrent UTIs Stress incontinence may be related to estrogen deficiency. Urethral shortening associated with postmenopausal atrophic changes may result in urinary incontinence. UROGENITAL SYMPTOMS

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Vaginal estrogen treats vaginal dryness and atrophy, and is safe for use by women with a uterus since there is minimum systemic absorption. This preparation can also be used when systemic HRT is contraindicated. HRT does not improve urinary incontinence, and can even make it worse. Oral HRT does not reduce urinary tract infections.* For women with vaginal dryness who wish to avoid hormones, vaginal lubricants such as replens can be helpful, but are not as effective as topical estrogens. However, the Heart and Estrogen /progestin Replacement Study (HERS) randomized trial indicated a worsening of incontinence with hormone therapy for both urge and stress incontinence, and the Nurses’ Health Study also reported a small increase of incontinence in hormone users. *(UTI and effect of HRT in obs and gynae2001&2004) TREATMENT

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NEUROLOGIC AND PSYCHOSOMATIC CHANGES Difficulty in concentration Loss of short term memory Depression Nervousness   Combinations of factors play a role 1 Estrogen deficiency 2 Inherent personality 3 Adverse social circumstances and life events   Estrogen is capable of protecting CNS by multiple mechanisms Protects against neuronal cytotoxicity induced by oxidation. Reduces amyloid P-component which is found in Alzheimer’s neurofibrillary tangles. Estrogen increases synapses and neuronal growth esp. dendritic spine density. Irritability Dizziness Fatigue Dementia

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CARDIOVASCULAR DISEASE CVD is the single largest cause of death in old age. CVD kills 17million women /yr. CHD kills more women than men (AHA2006) Atherosclerosis is the major factor Risk of death from coronary artery disease is at least 3 times as great as for men than for women before menopause, The relative risk for women increases after menopause making risk equal. 80% deaths occur in low and middle socioeconomic status.

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MANAGEMENT Dietary modification Exercises Control of hypertension Cessation of smoking Blood sugar control Role of HRT is controversial RUTH- Raloxifene use for the heart trial

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Metabolic syndrome Approximately 40% of women aged 60 years and older have the metabolic syndrome.   Dyslipidemia Menopause has a negative effect on women’s lipid–lipoprotein profile. Levels of TG≥150 mg/dL and HDLc≤ 50 mg/dL, coupled with an increase in small dense LDL particles, constitute the atherogenic dyslipidemia, which characterizes the metabolic syndromeLevels   Hypertension BP≥140mmHg systolic/≥90mmHg diastolic. Hypertension exposes to a four-fold increase in the risk of CVD in comparison with normotensive women.   Diabetes mellitus—insulin resistance   Obesity Obesity is characterized by a body mass index (BMI) ≥29 kg/m2. Abdominal adiposity is defined as a waist circumference in excess of 88 cm. Obesity is a major risk factor for CVD. CVD RISK FACTORS

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CVD contd… Risk Assessment of CVD   Lipoprotein (a) [Lp (a)] Fasting lipid profile Apolipoprotein B (ApoB) Fasting glucose Renal, liver and thyroid function tests Homocysteine (Hcy) C-reactive protein (CRP) Genetic

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CVD RISK FACTORS Modifiable risk factors Non modifiable risk factors Smoking Age Obesity Family H/O Sedentary life style Medical conditions Diabetes Hypertension Hypercholestremia   Whether HRT causes or prevents cardiovascular disease (CVD) is controversial. An increased risk of CVD was seen in WHI, mainly in the initial year of use of HRT. HRT should not be given for primary or secondary prevention of CVD Should be avoided by those at increased risk of CVD. If there are compelling reasons to use HRT, patients should be counseled about potential cardiovascular risks.

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State of low bone mass and micro architectural deterioration of the skeleton Increased bone fragility and increased risk of fractures. maximal incidence of osteoporosis related fractures occur several decades later Upto 30% of all women older than 90 years will experience hip fracture. Risk of fracture from osteoporosis will depend on bone mass at the time of menopause Estrogens maintain a balance between osteoclastic and osteoblastic activity. In absence of estrogen, osteoclastic activity predominates resulting in bone resorption It increases calcium absorption, active form of vitamin D formation and renal conservation of calcium. OSTEOPOROSIS

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MODIFIABLE RISK FACTORS Inadequate intake of calcium and vitamin D Smoking   Low body weight Excess alcohol use (>2 drinks/day) Sedentary life NON MODIFIABLE RISK FACTORS Age Race ( Caucasian, Asian) Small body frame Early menopause  Prior fracture Family history of osteoporosis ASSOCIATED MEDICAL CONDITIONS Hyperthyroidism Hyperparathyroidism Chronic renal disease Chronic steroid use OSTEOPOROSIS RISK FACTORS

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Back pain Kyphosis Loss of height (Dowager’s hump) Fracture after minor trauma Colle’s fracture Fracture neck of femur Vertebral body compression fracture OSTEOPOROSIS SYMPTOMS

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Radiographic techniques Standard radiograph – usually lumbar spine films. Detects bone losses of > 30 – 40% Single photon absorptiometry – hand Dual energy X-ray absorptiometry – measures radius, hip, spine CT scan   Bone densitometry report interpretation T score – standard deviation between patient and average peak young adult bone mass. The more negative , the greater risk of fracture. Z score – standard deviation between patient and average bone mass for same age and weight. A Z-score lower than -2.0 requires diagnostic evaluation for causes other than postmenopausal bone loss.   Definitions based on mineral density Osteopenia : -1 to -2.5 S.D. Osteoporosis : below -2.5 S.D.

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Exercise: - Load bearing exercise has an additive effect when combined with HRT. Smoking and alcohol consumption to be reduced. Calcium supplementation 1000 mg/ day with HRT. Total requirement: 1500 mg/day. Calcium supplementation is most efficient when single doses do not exceed 500 mg and taken with meals. Vitamin D : Recommended dose 400-800 IU Bisphosphonates: act by inhibiting bone resorption by binding bone mineral content. Alendronate: 10 mg/day, 70 mg weekly Risendronate 5 mg/day , 35 mg weekly Effect of bisphosphonates on bone turnover and bone marrow density will last upto 1 year and perhaps longer , when discontinued after 2 years or more of therapy. OSTEOPOROSIS MANAGEMENT

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Zolendronate once yearly therapy Ibandronate once a month therapy Calcitonin: inhibits bone resorption recombinant salmon calcitonin with intranasal delivery (200 IU /daily). Fluoride : potent stimulator of bone formation. Treatment is recommended for no longer than 4 years to avoid toxic accumulation in bones and teeth. Teriparatide : this is m-RNA produced synthetic human parathormone . It stimulates bone formation. It is reserved for patients with severe osteoporosis who fail to respond to other therapies.

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Asymptomatic women should not use HRT for disease prevention. (cu obs & gynae 2005). HRT is justified for symptomatic women. The Department of Health advises that for the treatment of menopausal symptoms, HRT is beneficial in the short term. The minimum effective dose should be used for the shortest duration. What is ‘the shortest duration’? The Committee on Safety of Medicines advises 2–3 years, whereas others suggest 5 years, but both figures are arbitrary. A consensus conference in 2003 agreed that ‘Women who choose to take HRT for more than 5 years should be counseled about the long-term risks. HORMONE REPLACEMENT THERAPY

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The WISDOM study In the UK, the Medical Research Council accepted impact of menopause and organized a multicentre trial, the Women's International Study of long-Duration estrogen after Menopause (WISDOM). In 2002, after adverse results led to a premature discontinuation of part of the US Women's Health Initiative trial, the Medical Research Council stopped the WISDOM study. The Million Women Study It is a UK cohort study based on the National Health Service Breast Screening Programme, between 1996-2001, which invites all women, aged 50–64 to attend for routine screening every 3 years. From 1996 to 2001, 5 year period, the study recruited 1,084,110 women (hence its eye-catching name) The average follow-up was 2.6 years for analyses of cancer incidence. This study stopped because of over-representation of the ‘worried well’, particularly women who were concerned about breast cancer.

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Estimated cumulative incidence of breast and endometrial cancer per 1000 women in developed countries who never used hormone replacement therapy (HRT) and who used HRT for 10 years, beginning at age 50 years. (Lancet, Million Women Study Collaborators 2003. Breast cancer and hormone-replacement therapy in the Million Women Study.)

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Organized by the US National Institutes of Health1991, was a randomized, double-blind, placebo-controlled trial conducted in 40 US centers. The trial had two arms. One involved combined estrogen–progestogen HRT, and the other estrogen-only treatment—called ‘estrogen replacement therapy’ (ERT) in the USA. The HRT arm recruited 16 608 post-menopausal women aged 50–79 with an intact uterus. After a mean follow-up period of 5.2 years, the trial was stopped because the risks exceeded the benefits, the main risk being that of breast cancer. The ERT arm recruited 10 739 post-menopausal, hysterectomised women aged 50–79 years, randomly allocated to receive either 0.625 mg conjugated equine estrogens or placebo. This arm was discontinued in February 2004. The Women's Health Initiative study

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HRT ERT Mac Lennan AH WHI Climacteric 2004

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Current indications for the use of HRT are more limited than previously. For the treatment of menopausal symptoms where the risk-benefit ratio* is favorable, in fully informed women, in the lowest possible dose to control symptoms and for the shortest duration possible. For women with early menopause (<45 years) until the age of natural menopause (taken as 50 years). HRT should only be used for the prevention of osteoporosis in women unable to use other medicines licensed for this use. *The risk-benefit ratio of HRT differs for every woman, based on her need for treatment, age at outset, duration of use and type of HRT. Accordingly, the Medicines and Healthcare products Regulatory Agency (MHRA) could not provide a universal recommendation for optimum duration of treatment or safe upper-age limit for use of HRT. (HRT safe update MHRA2007) Indications For HRT

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Vasomotor symptoms Urogenital symptoms Prevent osteoporosis Reduce the risk of colorectal cancer Women with premature menopause for prevention and treatment of cardiovascular disease and osteoporosis until 50 years (taken as the age of natural menopause) Reduced libido and sexual function will not be directly affected by HRT. Loss of libido after surgical menopause has been assisted by testosterone therapy. But there are potential adverse effects Benefits Of HRT

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ABSOLUTE Suspected breast or Endometrial cancer Undiagnosed abnormal genital bleeding Active thromboembolic disorder Active liver or gall bladder disease Pregnancy or Breast feeding Contraindications Of Hormone Replacement Therapy RELATIVE Heart disease Migraine headache History of liver or gall bladder disease History of Endometrial cancer History of thromboembolic events

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Blood pressure recording Breast examination Pelvic examination Cervical cytology Blood sugar – fasting and PP Lipid profile Thyroid function tests Liver function tests TVS to measure endometrial thickness(normal < 5 mm) Mammography Evaluation Prior To Starting HRT

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Only estrogen regimens Premarin: - Conjugated equine estrogen- a combination of estrone (50%), equilin(23%), 17-α-dihydroequilin and various other estrogens extracted from urine of pregnant mares. Most commonly used. Dose: - 0.3/0.625/1.25 mg daily. Micronized estradiol:- 1-2 mg/daily Estriol (Evalon):- 1-2 mg/daily Estradiol valerate:- 1-2 mg/daily Esterified estrogen: - 0.625-1.25 mg/daily Estropipate :- 0.625- 1.25 mg/daily Ethinyl estradiol :- 0.02 mg/daily Oral Preparations

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Estrogens alone There is a similar wide evidence base to support the use of unopposed estrogens for the relief of vasomotor symptoms, urogenital symptoms and for improved quality of life in post-hysterectomised women. Evidence for their use in the relief of psychological symptoms is more equivocal. Topical estrogens are widely used (including in women with an intact uterus) to treat urogenital atrophy. Alternative Drug Therapies Contd..

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Estrogen – Progestin sequential regimens Estrogen is given on 1- 25 days of month Progestins are administered for last 12-14 days of cycle using comparable doses of following progestins:- 5 mg medroxy progesterone acetate or 0.7 mg norethindrone or 1.0 mg norethindrone acetate or 200 mg micronized progesterone   Disadvantages Vaginal bleeding Premenstrual symptoms Breast tenderness Oral Preparations Contd..

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Continuous estrogen-progesterone regimes Estrogen given daily 2.5 mg medroxy progesterone acetate daily or 0.35 mg norethindrone or 100 mg micronized progesterone Advantage: - Improved patient compliance as there is no withdrawal bleed but breakthrough irregular bleeding may be a problem. Oral Preparations Contd..

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Transdermal patch Estradiol delivered 25μg/ 50μg/ 75μg/ 100μg per day Estrogen + Progesterone combipatch 50 μg estradiol and 250 μg norethisterone per day Transdermal patches may be preferred to oral administration in some situations: - If there is poor control of symptoms with oral treatment. If there are side-effects such as nausea. There may be a lower risk of VTE with patches. If the woman is taking a liver enzyme-inducing drug. If the woman has a bowel disorder which may affect oral absorption. Steadier hormone levels with patches may be beneficial if there is a history of migraine. Most HRT tablets contain lactose, so patches are preferred if there is lactose sensitivity. Non oral drug delivery systems

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Percutaneous estradiol In form of gel (Estrogel, Estreva) In form of lotion (Estrasorb) To be applied over upper arms and shoulders or abdomen and thighs.   Estradiol implants Pellets of 25/50/75 mg for subcutaneous application twice yearly. Because of first pass metabolism in liver, oral estradiol results in a circulating estrone to estradiol ratio of 3 ; with transdermal application the ratio is 1.

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Vaginal application Estrogen cream : Readily absorbed from vagina with immature atrophic mucosa Dose: 0.3 mg conjugated estrogen 2-3 times/ week.   Vagifem : Tablets containing 25 μg estradiol Dose : 1 tab daily x 2 weeks Then 1 tab twice weekly   Vaginal ring: Femring/ Menoring releases estradiol (50- 100 μg/day) over 3 months time span. Measurement of vaginal pH from lateral vaginal wall (pH < 4.5) correlates well with good estrogen effects. Treatment with vaginal creams longer than 6-12 months requires endometrial surveillance. Non oral drug delivery systems

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Intranasal administration Aerodiol is an aqueous formulation of estradiol given by nasal sprays This method is known as “Pulsed estrogen therapy”   The progestin intra- uterine device A smaller model of MIRENA, the frameless IUD designed for postmenopausal women delivering 14 μg levonorgestrel per 24 hours named as Fibro Plant- LNG. This method minimizes the systemic effects of progesterone Non oral drug delivery systems

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Because adenocarcinoma has been reported in patients with pelvic endometriosis who are treated with unopposed estrogen, the combined regime is advocated in patients with a history of endometriosis. Patients who underwent procedures that have potential to leave residual endometrium like supracervical hysterectomy, endometrial ablation should be treated with a combination regime. The combined estrogen- progesterone approach makes sense for patients previously treated for endometroid tumors of the ovary. Progestins For Hysterectomised Women

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TIBOLONE Tissue specific gonadomimetic which has estrogenic, androgenic and progestogenic action in different tissues. Its 3α hydroxyl metabolite and 3β- hydroxyl metabolite are estrogenic. Δ4 Isomer metabolite is progestogenic and androgenic. Dose: 2.5 mg/day Estrogenic response On urogenital system and vagina Prevents osteoporosis Improves hot flush and vasomotor symptoms Progestogenic response – on endometrium Androgenic response Benefits mood and libido Decrease in SHBG Decrease in total cholesterol and TG and also HDL Recent data from Million Women Study shows that tibolone increases the incidence of both breast cancer and endometrial cancer. Alternative Drug Therapies

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SERM Raloxifen is a selective estrogen receptor modulator that partially mimics the effect of estrogen in bone and cardiovascular system while functioning as antiestrogen in uterus Raloxifen binds with higher affinity to the estrogen receptor α than β.  Effect:- Osteoporosis: Reduces vertebral fracture risk by 30% Lipid profile: Favorably alter the level of LDL and fibrinogen Cardiovascular system: antioxidant role, beneficial lipid effect and reduction in homocysteine level makes it possible that there will be some favourable impact. Alternative Drug Therapies Contd..

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RUTH (Raloxifene Use for The Heart) study results will provide more informations. Raloxifene is antiestrogenic on breast tissue. Study of tamoxifen and raloxifen (STAR) may be able to demonstrate the preventive role of raloxifen on carcinoma breast. The MORE study (Multiple Outcomes of Raloxifen Evaluation) results will give more information in future. Dose: 60 mg/day Drawbacks: Raloxifen does not relieve hot flushes. Alternative Drug Therapies Contd..

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Which preparation - systemic or local; cyclical or continuous? Women with an intact uterus Vasomotor symptoms Perimenopausal: systemic cyclical combined HRT (a 3-monthly regimen can be used for women with infrequent periods or who cannot tolerate progestogens). Postmenopausal: systemic continuous combined HRT or tibolone. Urogenital symptoms Perimenopausal: low-dose vaginal estrogen or systemic cyclical combined HRT. Postmenopausal: low-dose vaginal estrogen or systemic continuous combined HRT. Prescribing HRT

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Women who have had a hysterectomy Vasomotor symptoms: systemic estrogen-only HRT. Urogenital symptoms: low-dose vaginal estrogen or systemic estrogen-only HRT. N.B. if a woman has had a subtotal hysterectomy , there may be a remnant of endometrial tissue. Prescribe three months of cyclical HRT. If withdrawal bleeding occurs, start cyclical HRT, as this confirms the presence of endometrial tissue. If there is no bleeding, estrogen-only HRT may be used.

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Delivery routes include: Continuous or cyclical oral therapy Patches Creams or gels Nasal sprays Local devices such as the progesterone-releasing Mirena® coil The estrogen-releasing vaginal ring Subcutaneous implants The choice of delivery route depends partly on patient preference but there may also be other advantages to certain delivery routes. Which delivery route?

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Indications Moderate-to-severe vasomotor symptoms (systemic HRT) Urogenital symptoms (systemic or vaginal estrogen) Night sweats, insomnia, poor sleep quality (indirectly improving wellbeing and symptoms of depression). Low libido (HRT in combination with androgens; tibolone) General advice • Benefits of treatment should be offset against risks (for otherwise healthy women with moderate-to-severe symptoms, benefits of short-term HRT are likely to outweigh the risks) • Advice should be individualized, and written information provided if possible Lifestyle changes and alternative therapies should be discussed • Treatment should be at the lowest effective dose • Treatment should be reviewed every year, taking into account new knowledge and changing risk factors Evidence-based clinical guidelines for HRT for menopausal symptoms

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Women who choose to take HRT for longer than 5 years should be told about potential risks • The different types and regimens of HRT should not be grouped together as having a class effect   Potential risks Breast cancer • The absolute risk of breast cancer is small • Breast cancer risk probably increases after use of combined HRT for longer than 5 years, • There is no difference in mortality between women who do and do not take HRT • The results of the only major randomised trial of estrogen-only therapy in women who have had a hysterectomy (WHI) showed no increase in risk of invasive breast cancer after 6·8 years • There is no evidence that these effects will differ between doses, mode of administration, or type of estrogen or progestagen

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Coronary heart disease (CHD) • There is no evidence for use of HRT for primary or secondary prevention of CHD • The role of HRT in primary prevention of CHD remains unclear when considered for perimenopausal and early postmenopausal women   Venous thromboembolic events (VTE) • Oral HRT increases the risk of VTE • Transdermal formulations could be beneficial for those at risk of VTE who choose to take HRT Stroke • HRT could increase the risk of ischemic stroke in postmenopausal women • There is no evidence for use of HRT for primary or secondary prevention of stroke

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Dementia • There is no role for HRT in the prevention or treatment of dementia • Combined HRT could increase the risk of dementia in women older than age 65 years   Osteoporosis • HRT cannot be recommended as a first line therapy for the prevention and treatment of osteoporosis, except when treatment is also needed for menopausal symptoms • HRT can be used to reduce the risk of osteoporotic fracture, after weighing up its risks and benefits against those of alternative therapies especially in women with menopausal symptoms Endometrial cancer • Unopposed estrogen is associated with an increased risk of endometrial hyperplasia and cancer; progestagens should be used for endometrial protection • Continuous combined regimens seem to confer no increased risk

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Ovarian cancer • There is insufficient evidence to draw conclusions about the effects of HRT on ovarian cancer   Premature menopause • Women with premature menopause have been encouraged to take HRT until age 50 years. Dr Martha Hickey et al. Lancet 2005.

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Women often use complementary therapies, as they are perceived to be a safe alternative to traditional hormone therapies. However ,efficacy and safety of a number of these preparations are still questionable. COMPLEMENTARY THERAPIES

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Phytoestrogens Are plant substances have effect similar to estrogens Diet high in isoflavones, appear to have lower rates of menopausal vasomotor symptoms, cardiovascular disease, osteoporosis, and breast, colon, endometrial and ovarian cancers. Preparations vary from enriched foods such bread and drinks (soy milk)to more concentrated tablets. Most important gps are called isoflavonones and lignans . Isoflavones are found in soybeans ,chickpeas redclover and other legumes(beans and peas). Lignans are found in oilseeds,cereal brans ,whole cereals vegetables,legumes and fruits Have variety of activites-oestrogenic, antioestogenic ,antiviral , anticarcinogenic , bactricidal , antifungal, antioxidant ,antimutagenic antihypertensive. COMPLEMENTARY THERAPIES contd..

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Soy Effects of soy products on menopausal symptoms were inconsistent across studies. Long-term treatment with soy has raised some concerns from the point of view of a low risk of endometrial hyperplasia.   Red clover (Trifolium pratense) may significantly reduce hot flashes in menopausal women slow bone loss and even boost bone mineral density estrogen-like effect of red clover isoflavones may be involved may have a direct effect by preventing the breakdown of existing bone. prevent heart disease in several ways Doses 40–160 mg duration of treatment -12–16 weeks Complementary therapies contd..

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Black Cohosh, Cimicifuga racemosa Other Names: American Baneberry, Black snakeroot, Bugbane, Bugwort, Cimicifuga, Rattleroot, Rattleweed, Squawroot certified by the German Medicines Control Agency for use in controlling menopausal symptoms for 6 months studies suggest an ‘estrogen-like' activity has shown benefit for vasomotor symptoms no clinical trials assessing the effect of black cohosh on breasts Endometrial thickening has been assessed by ultrasound over 3 months of treatment with 40 mg Evening primrose oil rich in gamma linolenic acid no evidence for efficacy in the menopause. Two small placebo-controlled randomized trials have shown it to be ineffective for treating hot flushes Complementary therapies contd..

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ANGELICA SINENSIS: THE SUPREME WOMAN’S HERB The Chinese name of angelica sinensis is variously spelt as Dong Qui Dong quai Dong quai is a perennial plant native to southwest China commonly used in traditional Chinese medicine has not been found to be superior to placebo in one randomized trial Interaction with warfarin and photosensitization has been reported, due to the presence of coumarins. Agnus Castus (chasteberry)Although there are some data for the benefits of Agnus castus in premenstrual syndrome, no such data exist for menopausal symptoms Complementary therapies contd…

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Ginkgo biloba used widely little evidence to show that it improves menopausal symptoms. Some studies have shown a benefit for relief of anxiety and depression. There are claims for cognitive benefits from some studies in postmenopausal women Ginseng a perennial herb native to Korea and China extensively used in eastern Asia has not been found to be superior to placebo for vasomotor symptoms in a randomized trial, although parameters of well being and depression improved. Case reports have associated ginseng with postmenopausal bleeding and mastalgia Interactions have been observed with warfarin, phenelzine and alcohol. Complementary therapies contd…

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Complementary interventions AcupunctureA small randomized controlled trial of 45 postmenopausal women undergoing shallow acupuncture Electro acupuncture or oral estrogen administration showed a significant reduction in hot flush frequency in all three groups. The degree of symptom reduction was greatest in the estrogen group. Reflexology Relieve stress or treat health conditions through the application of pressure to specific points or areas of the feet used for various conditions, such as pain, anxiety and premenstrual syndrome

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Take Home Message Menopause is not a disease. It is a natural process in every women’s life. Menopausal symptoms are very common and can impair the daily lives of many women. Vasomotor symptoms are the most common. Others are urogenital symptoms, cardiovascular disease, osteoporosis, neurologic and psychosomatic changes. Hormone replacement used to be the corner stone of management of menopausal symptoms. However, the alternative and complementary therapies like , behavior modifications, exercise, naturally occurring substances, and some non-hormonal drugs are increasingly being used. Improved understanding of the menopausal transition, its symptoms, and therapies will permit a better response to the needs of patients .

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