Adobe Systems Meixnerová I., Tvarožek S. Menopause and HRT 2020 Department of Gynecology and Obstetrics Brno University Hospital and Masaryk University, Faculty of Medicine head: doc. MUDr. Vít Weinberger, Ph.D Obstetrics and Gynecology - lectures Adobe Systems Menopause and HRT Key words Perimenopause (climacteric) Menopause Premenopause Postmenopause Induced menopause Senium Hormonal replacement therapy • Adobe Systems Menopause and HRT Definition Perimenopause (Climacteric) •the period of transition between the fertile age of a woman and the onset of senium •physiologically between 45 and 60 years •Premature ovarian failure (insufficiency) – before 40 years Menopause •last menstrual bleeding •defined retrospectively 12 months after the last menstrual bleeding •Typically occurs between 49 and 51 years of age Adobe Systems Menopause and HRT Definition Premenopause •period of time within 12 months before menopause •menstrual cycle (MC) is still preserved •ovarian function is progressively decreasing •symptoms of menopausal syndrome are already appearing •MC can be irregular, decreasing number of ovarian cycles •Decrease in progesterone levels, relative predominance of estrogen Adobe Systems Menopause and HRT Definition Postmenopause •begins 12 months after the last menstrual bleeding •minimal estrogen production – hypergonadotropic hypoestrism •estrogens of extragenital origin (adipose tissue) •constantly elevated FSH level (40 IU/l and more) •LH-FSH ratio <1; elevated LH ( 3-7x ) and FSH level ( 4-10x ) •high levels for 2-5 let, then gradual decrease in gonatropin level •with the end of postmenopause starts the senium – decline of secondary sex characteristics reduction of steroid production in adrenal glands after age of 60 Adobe Systems Menopause and HRT Anatomic changes •caused by estrogen deficiency, depletion of ovarian follicles •termination of ovarian function, atrophy •endometrium - premenopausal hyperproliferation or glandular cystic hyperplasia - postmenopausal atrophy vagina - loss of elasticity, shortening, thinning of the mucosa, disappearance of lactobacilli, atrophy of the uterus, vulva, ligaments and pelvic floor muscles, skin (dry, wrinkled), hirsutism, breast atrophy, change body weight pelvic floor – pelvic organ descensus and prolaps • • • Adobe Systems Menopause and HRT Climacteric syndrome Symptoms associated with climacterium Climacteric (menopausal) syndrome •vegetative •organic •metabolic Adobe Systems Menopause and HRT Climacteric syndrome vegetative vasomotor symptoms •hot flashes •night sweats •palpitation changes in psychic •mood changes, depression, anxiety, mournfulness, exhaustion •memory impairment, loneliness, irritability, •loss of libido, headache, sleep problems, loss of energy Adobe Systems Menopause and HRT Climacteric syndrome organic • • • • • •estrogen deficiency •estrogen receptors are present in the vagina, urethra, bladder trigon and pelvic floor muscles, in the skin •atrophic vulvovaginitis, dyspareunia, pruritus, chronic vaginitis •stress incontinence, urge incontinence •atrophic senile urethritis, hypoestrogenic cystopathy •thinning of the epidermis, faster skin aging, loss of elasticity •decreasing estradiol level causes a decrease in SHBG - an increase in free testosterone levels (hirsutism) • • • • Adobe Systems Menopause and HRT Climacteric syndrome metabolic •osteoporosis loss of bone mass, disorder of bone architecture, •tendency to fractures – compression fractures of the vertebrae, femoral neck and wrist •atherosclerosis •estrogens have a cardioprotective effect (prevents HDL degradation by inhibiting hepatic lipase) •estrogen deficiency - decrease in HDL, increase in LDL, triglycerides • and plasma cholesterol •cardiovascular disease, ischemic heart disease • Adobe Systems Menopause and HRT Osteoporosis •loss of bone density, bone microarchitecture impairment, Increased susceptibility to fractures •in the CR 7 % of population, almost 35% in postmenopausal women •postmenopausal osteoporosis - caused by estrogen deficiency •from the age of 30 begins a loss of bone mass of 0.1 - 1% per year •in early postmenopause 1/3 of women: loss of bone density of up to 7% per year - fast loosers •significant estrogen deficiency in fertile age - after ovariectomy, loss of bone density up to 7% per year •clinically: bone fracture, bone and joints pain • Adobe Systems Menopause and HRT Osteoporosis – risk factors •age, premature menopause, ovariectomy, GnRH analogues •anorexia, malabsorption, low weight •immobility, smoking, alcoholism •long-term use of corticoids •hyperparathyroidism (PTH increases bone resorption) •metabolic syndrome, diabetes, hepatopathy, nephropathy, chronic gastrointestinal inflammation •rheumatoid arthritis • • Adobe Systems Menopause and HRT Osteoporosis - diagnostics •anamnesis - risk factors, family history, the age of menopause, fractures, drugs, diseases •Somatic examination – weigt, loss of height, ability to get up and walking •X-ray examination - side image of Th and LS spine densitometry •Densitometry – measuring of bone mineral density (bone loss) •Quantitative computed tomography (QCT) •Heel ultrasound bone scans – less accurate •Biochemical blood analysis, vitamin D level, markers of bone resorption (carboxy-terminal telopeptide CTx) and bone formation (alkaline phosphatase and osteocalcin) • Adobe Systems Menopause and HRT Densitometry •Principle: X-ray absorption in bone mass •Vertebrae L1 – 4, proximal femur including neck, distal forearm •Degree of decalcification is assessed according to deviation from the average values in healthy young people of the same sex – T-score •normal T-score -1,0 and higher •osteopenia T-score -1,0 to -2,5 •osteoporosis T-score -2,5 and lower •Repeated measurements at intervals of 1-2 years on the same machine •Indicated in women at high risk of osteoporosis – long-term corticoid treatment, age over 65 years, thyreopathy • Adobe Systems Menopause and HRT oc3-mrs oc3-mrh Osteocore Densitometry Adobe Systems Menopause and HRT Osteoporosis - therapy •physical activity, nutrition (dairy products, fish), stop smoking •calcium - the recommended daily calcium intake in postmenopausal women is 1200mg (dairy products) •vitamin D - the target level of vitamin D is 50 -75 nmol/l, dose of 800 IU/day in combination with calcium reduces the risk of fracture •HRT – reduces bone loss, increases the risk of breast cancer • Adobe Systems Menopause and HRT Osteoporosis - therapy •Tibolon – STEARs (selective tissue estrogenic activity regulator), comparable effect to HRT, does not increase breast density, does not stimulate the endometrium to grow •Bisphosphonates - inhibition of osteoclastic resorption •Osteoanabolic treatment – a derivative of PTH hormone Teriparatide •Raloxifen – SERM (Selective estrogen receptor modulator), an estrogen receptor agonist in bone, does not affect the endometrium • Adobe Systems Menopause and HRT Pharmacotherapy in menopause •non-hormonal – phytoestrogens – soy (Estrovone), red clover (Fytofem), Alfalfa (Medicago sativa), cimicifuga (Fytofem), bee products (Sarapis) - SSRIs - antidepressants •hormonal - ovarian hormone replacement HRT - estrogens + progestins ERT - estrogens Tibolon – steroid analogue, does not affect endometrium, the drug of choice in patients with a history of endometriosis, has a protective effect on bone mass (Livial, Ladybon) • Adobe Systems Menopause and HRT HRT indication •menopausal syndrome – vasomotor symptoms – mental problems •estrogen deficiency syndrome – organic (urogenital atrophy) – metabolic (osteoporosis) •anticipated effects of long-term use– prevention of Alzheimer's and Parkinson's disease, prevention of senile macular degeneration, senile blindness, tooth loss and colon cancer (contrary to long-term use) Adobe Systems Menopause and HRT HRT contraindication •breast cancer, estrogen dependent tumors • •endometrial cancer, unclear uterine (vaginal) bleeding • •active hepatopathy, severe liver disease • •thromboembolic disease - pulmonary embolism, phlebothrombosis • •arterial thromboembolism - myocardial infarction, angina pectoris • Adobe Systems Menopause and HRT Examination before HRT •Anamnesis •Gynecological examination, ultrasound •Gynecologic Cancer Prevention •Mammography •Blood pressure and weight check •Densitometry – in women with risk of osteoporosis • Adobe Systems Menopause and HRT HRT side effects •Brest tension and pain, fluid retention • •nausea and headache, lower limb cramps • •thromboembolic complication •uterine bleeding • • • Adobe Systems Menopause and HRT General principles of HRT premenopause •Gestagen substitution, intrauterine hormonal system(IUS) •low-dose monophasic contraception perimenopause •combined sequential estrogen - gestagen therapy •low-dose therapy, if not effective, increase the dose •Period maintenance – according to the patient 's wishes (up to 52 yo) postmenopause •combined continuous estrogen - gestagen therapy • Adobe Systems Menopause and HRT General principles of HRT •In women with uterus – ALWAYS combined substitution with gestagens! - long-term administration of estrogens without gestagens increases the risk of endometrial cancer •In women without uterus (after hysterectomy) only estrogen therapy •HRT should be discontinued 4-6 weeks before surgical procedure •early start - start of treatment no later than 5 years after menopause •duration of therapy 5-10 years •individual approach • Adobe Systems Menopause and HRT HRT therapeutic regimes •cyclic – 3 weeks of application, one week break with withdrawal bleeding •sequential – continuous application of estrogen with the addition of progestin in the second half of the menstrual cycle •continuous – application without break Application forms •oral, transdermal, percutaneous, intramuscular, intranasal, subcutaneous and local (vaginal) • Adobe Systems Menopause and HRT HRT drugs estradiol valerate + levonorgestrel •Klimonorm EV 2mg + LNG 0,15mg cyclic (not available in CR) estradiol valerate + medroxyprogesterone acetate •Divina EV 2mg + MPA 10mg cyclic (not available in CR) •Indivina EV 1mg + MPA 2,5mg, EV 2mg/ MPA 5mg continuous estradiol valerate + cyproterone acetate •Climen 2mg/1mg cyclic, sequential estradiol valerate + dienogest •Velbienne EV 1mg + dienogest 2mg continuous Adobe Systems Menopause and HRT HRT drugs estradiol benzoate + testosterone •Folivirin EB 5mg + T 50mg intramuscular every 4 – 6 weeks estradiol hemihydrate •Estrofem 2mg, 1mg •Estrimax 2mg •Estrahexal skin patch 2mg, 4mg •Dermestril 25, 50 skin patch 2mg, 4mg •Oestrogel – gel •Vagifem – vaginal suppositories •Linoladiol – vaginal cream •Lenzetto – 1,53mg/dose, transdermal spray • Adobe Systems Menopause and HRT HRT drugs estradiol hemihydrate + drospirenone •Angeliq E 1mg + drospirenone 2mg continuous • estradiol hemihydrate + norethisteronacetate •Activelle E 1mg + NETA 0,5mg continuous •Gynovel E 1mg + NETA 0,5mg continuous •Kliogest E 2mg + NETA 1mg continuous •Novofem E 1mg + NETA 1mg sequential continuous, withdrawal bleeding •Trisequens E 2mg 22 days/E 1mg 6 days + NETA 2mg 10 days sequential continuous, withdrawal bleeding Adobe Systems Menopause and HRT Preparáty HRT estradiol hemihydrate + dydrogesterone •Femoston E 1mg, E 1mg + dydrogesteron 10mg sequential continuous •Femoston E 2mg, E 2mg + dydrogesteron 10mg sequential continuous •Femostin conti E 1mg + dydrogesteron 5mg continuous •Femoston conti mini E 0,5mg + 2,5mg dydrogesteron continuous Estriol •Ovestin – 1mg/g vaginal suppositories, 1mg tbl., 0,5mg vag supp Tibolon •Livial 2,5mg •Ladybon 2,5mg Adobe Systems Menopause and HRT HRT risks •long-term use of HRT (over 10 years) increases the risk of breast cancer by 10 - 30% •estrogens can be cancer promoters •increase of breast tissue density by up to 8% - decrease of mammography sensitivity •using unopposed estrogens in women with a uterus: the relative risk of endometrial cancer is 2.3-9.5%, the risk increases with the duration of drug administration •in compliance with the rules of therapy - the benefits outweigh the risks •individual approach Adobe Systems Menopause and HRT Thank you for your attention Adobe Systems Menopause and HRT Questions 1.Menopause A)starts 12 months after the last menstrual bleeding B)is defined 12 months after the last menstrual bleeding C)starts 12 months before the last menstrual bleeding D)is a period of time with irregular menstrual cycles E) 2.Postmenopause is characterised by A)hypergonadotropic hypoestrinism B)hyporgonadotropic hyperestrinism C)hypergonadotropic hyperestrinism D)estrogen overproduction Adobe Systems Menopause and HRT Questions 1.Menopause A)starts 12 months after the last menstrual bleeding B)is defined 12 months after the last menstrual bleeding C)starts 12 months before the last menstrual bleeding D)is a period of time with irregular menstrual cycles E) 2.Postmenopause is characterised by A)hypergonadotropic hypoestrinism B)hyporgonadotropic hyperestrinism C)hypergonadotropic hyperestrinism D)estrogen overproduction Adobe Systems Menopause and HRT Questions 1.Menopause A)starts 12 months after the last menstrual bleeding B)is defined 12 months after the last menstrual bleeding C)starts 12 months before the last menstrual bleeding D)is a period of time with irregular menstrual cycles E) 2.Postmenopause is characterised by A)hypergonadotropic hypoestrinism B)hyporgonadotropic hyperestrinism C)hypergonadotropic hyperestrinism D)estrogen overproduction Adobe Systems Menopause and HRT Questions 3.Climacteric (menopausal) syndrome is not characterised by A)vasomotor disorders B)estrogen deficiency C)atrophic vulvovaginitis D)estrogen overproduction E) 4.HRT is not contraindicated in case of A)breast cancer B)estrogen dependent tumors C)osteoporosis D)arterial thromboembolism Adobe Systems Menopause and HRT Questions 3.Climacteric (menopausal) syndrome in not characterised by A)vasomotor disorders B)estrogen deficiency C)atrophic vulvovaginitis D)estrogen overproduction E) 4.HRT is not contraindicated in case of A)breast cancer B)estrogen dependent tumors C)osteoporosis D)arterial thromboembolism Adobe Systems Menopause and HRT Questions 3.Climacteric (menopausal) syndrome in not characterised by A)vasomotor disorders B)estrogen deficiency C)atrophic vulvovaginitis D)estrogen overproduction E) 4.HRT is not contraindicated in case of A)breast cancer B)estrogen dependent tumors C)osteoporosis D)arterial thromboembolism Adobe Systems Menopause and HRT Questions 5.Principles of HRT A)in women with a uterus, we choose only estrogen therapy B)in women without uterus, we choose only gestagen therapy C)in women with a uterus, we choose combined estrogen-gestagen therapy D)All answers are correct Adobe Systems Menopause and HRT Questions 5.Principles of HRT A)in women with a uterus, we choose only estrogen therapy B)in women without uterus, we choose only gestagen therapy C)in women with a uterus, we choose combined estrogen-gestagen therapy D)All answers are correct