• PERIMENOPAUSE – A period of 3years before menopause & followed by 1 year of amenorrhoea – Assosiated with mild ovarian hormonal deficiency – Leads to anovulation, menorrhagia
• MENOPAUSE – The time of cessation of ovarian function resulting in permenant amenorrhoea – For confirmation: 12 months• CLIMACTERIC: – Phase of waning ovarian activity – 2-3yrs before and 2-5 yrs after menopause
Demography; Indian perspective• 60 million women in India are above 55yrs• Majority of women spend 1/3rd of their life in postmenopausal period
Age • Usual age 45 to 50yrs average being 47yrs. • Premature menopause - before 40 yrs • Late menopause – menstruation beyond 52 yrs
• Delayed menopause – Due to good health and better nutrition. – Also seen in women with uterine fibroids . – Also in women with high risk of endometrial cancer • Menopausal age is directly associated with smoking and genetic disposition. • Smoking induces premature menopause.
Pathophysiology • During climacteric, ovarian activity declines. • Initially, ovulation fails, no corpus luteum forms and no progesterone is secreted by the ovary. • Later, graffian follicle fails to develop, estrogenic activity decreases and endometrial atrophy leading to amenorrhea. • Increased secretion of FSH and LH by anterior pituitary.
• FSH 50 times increase, LH 3-4 times increase. • Menopausal urine has become and important commercial source of gonadotropins. Later gonadotropin activity of anterior pituitary ceases and fall in FSH level eventually occurs.
• Hormone levels• 50% reduction in androgen production and 66% reduction in oestrogen production..• Some estrogen produced by ovary (oestrone, E1)• FSH appears in large concentrations.• Low oestrogen levels(below 20pg/ml) predisposes to osteoporosis and ischemic heart disease.
Risk factors for menopausalrelated problems are as follows:• Early menopause• Surgical menopause or radiation.• Chemotherapy esp alkylating agents.• smoking., caffeine, alcohol.• Family history of menopausal diseases.• Drugs related such as GnRH, heparin, corticosteroids and clomiphene(anti- oestrogen) when given over prolonged peiod can cause oestrogen deficiency.
• Anatomical changes SITE CHANGES Genital organs Atrophy and regression Ovary Shrink,surfaces:grooved , furrowed Tunica albuginea Thickens Size of ovary <2*1.5*1cm in US Plain muscle in fallopian Atrophy tube: Cilia Disappear Uterus Smaller Endometrium As basal layer: deeply stained stroma and a few glands
SITE CHANGESCervix SmallerVaginal fornices DisappearsVagina NarrowEpithelium Pale, thin,and dry: senile vaginitisVulva Atrophy (+narrow vagina:dyspareunia)Skin of labia minora and vestibule Pale,thin,dryLabia majora Reduction in fatPubic hair Reduced and greyBreast More pendulous(fat dep)Glandular tissue <5%Pelvic cellular tissue Becomes laxLigaments supporting the uterus and Lose their tone:prolapse of genitalvagina organs, stress incontinence of urine, and fecal incontinence
Menopausal symptoms• Menstrual – 3 classic ways in which the menstrual period ceases are as follows: • Sudden cessation. • Gradual diminution in the amount of blood loss with each regular period until menstruation stops. • Gradual increase in spacing of periods until they cease for at least a period of one year.
Other symptoms• 60-70% women go through menopausal period without problems• Rest needs guidance and treatment
Hot Flushes• Early and acute symptom of estrogen deficiency.• These are waves of vasodilatation affecting the face and neck and last for 2-5 mins each.• Followed by severe sweating.• Occurring at night may disturb sleep.• Sometimes preceded by headache.• Palpitation and anginal pain maybe felt.• Mental depression due to lack of sleep, irritability and lack of concentration.• With passage of time severity of hot flushes decreases.
Cause of hot flushes •Caused by noradrenalin, which disturbs the thermoregulatory system. •Oestrogen deficiency reduces hypothalamic endorphins, which release more norepinephrine and serotonin. •This leads to inappropriate heat loss mechanism.
Neurological• Vasomotor symptoms and paraesthesia take the form of sensations of pins and needles in the extremities.
Libido• E and androgen deficiency causes urogenital atrophy, which affect sexual function.• Leads to a decline in sexual interest.
• The symptoms which develop a little later are : – Urinary • Dysuria • Stress incontinence and urge • Recurrent infection Genital Dry vagina Dyspareunia Loss of libido Faecal incontinence
Urinary tract• Oestrogen deficiency causes • Urethral caruncle • Dysuria with or without infection • Urge •Stress incontinence( due to poor vascularity and loss of tone of internal urethral sphincter). These symptoms are clubbed together under the term urethral syndrome.
Genital• Atrophic vagina reduces the vaginal secretion, and dry vagina cause dyspareunia.• Loss of libido adds to sexual dysfunction.
COMPLICATIONS or LATE SEQUELAEMenopause is a normal developmentalprocess, but the decline in E can have clinical sequelae.
– Vasomotor symptoms. • HTN– Osteoporosis. • Arthritis • Osteoporosis of vertebral bones, upper end of hip joint,wrist • frature– Cardiovascular disease. • ischaemic heart disease, MI, HTN • Stroke • Cardiac irregularities • Tachycardia
• An incipient slowly progressing skeletal disorder: microarchitectural detirioration of bone mass resulting in increased fragility and predilection to frature in the absence of sig. trauma
Definition by WHOOSTEOPENIA:• As a BMD b/w 1 and 2.5 SD below the young adult mean peakOSTEOPOROSIS:• As BMD which is 2.5 or more below the SD of mean young adult values
Pathophysiology• Bone remodeling : at cellular level osteoclastic and osteoblastic activity• Metabolic : osteocytes and lining cells• Peak bone mass : by 35-40yrs• Then after slow subsequent age related loss of bone mass: 0.4% annually for everyone• Accelelarated rate in women: 2% cortical bone and 5% trabecular bone; estrogen def, Ca def, VitD def
• Bone Ca amts at 40 yo : 1200g; when drops to 750g: frature is liabile• In elderly women : vertebral fraturegibbus formation, bent spine and shortening of height• : hip frature
Family history of osteoporosisLow Ca intake in dietSmoking and excess of caffeine and alcohol intakeEarly menopauseLow weightSurgical menopauseRadiation menopauseThyrotoxicitySedentery life syleWomen on GnRH, heparin, cortico steroids , danazol, clomiphene
CARDIOVASCULAR DISEASE• Estrogen is cardioprotective(antioxidant property also)• After menopause HDL,LDL, total cholesterol ,• Estrogen deficiencyatherosclerosis, ischemic heart disease, MI• Risk factors: obese women with hypertension , previous thromboembolicepisodes
Stroke• Incidence of stroke also increase in menopausal women
Skin changes• Collagen content is reduced, causing skin to wrinkle• The loss of collagen is more rapid in the first few years after menopause• 30% of skin collagen is lost within the first 5 years.• The rate is 2% per year for the first 10 years after menopause.
CNS• ER are abundant in the brain. E have a role in many brain processes, and it’s absence result in physiologic and symptomatic changes.• E is important for – cerebral blood flow – cerebral glucose administration – synaptic activity, neuronal growth – survival of cholinergic neurons – complex functions as cognition.• The role of E deficiency in postmenopausal depression, declining cognitive function, dementia, and Alzheimers disease is not clear.
Pyometra• Years after menopause, women may develop senile pyometra cervical stenosis• Rx : drainage by cervical dialatation under GA
3)Physical examination: The clinical findings vary greatly depending on the time elapsed since menopause and the severity of the estrogen deficiency Skin: thin ,dry Breast loss turgor The labia are small The uterus becomes much smaller The muscles of the pelvic floor are looser in tone and are thin Prolapse may be present
4) Laboratory diagnosis General examination: BP, Palpation of breasts, weight, hirsuitism Pap smear Mammography, pelvic US E2, FSH, LH determination Bone density study: Dual energy X-ray absorptiometry(DEXA) Single or dual photon absorptiometry
Counselling The women often develops pregnancy & cancer phobia. Duty of gynaecologist- exm. &investigation. Pelvic ultrasound-ovarian size, endometrial thickness, mammography & as well as E2 &FSH levels, when HRT is considered.
The advice on contraceptives is necessary. Until the menopause is well established & amenorrhea has lasted for 12 month, couple is advice to use barrier method. Diet: least 1.2g of Ca, Vit A,C,E &400mg of Vit .D & Soya beans are good. Weight bearing exercise delay onset of osteoporosis.
Mild tranquillizers Anti depressants like sulpiride Releives anxiety, depression, sleeplessness
Hormone replacement therapy Not all women require HRT 70-85% of women remain healthy need only good nutrition and healthy life style.
Indications of HRT1) Women having 2) All asymptomatic climacteric high-risk women having symptoms Premature Vasomotor menopause symptoms (surgical / spontaneous) Urinary Family history of symptoms osteoporosis Sexual Thin, small sedentary women dysharmony Poor diet, excess Established alcohol osteoporosis CVD, Alzhemeir’s disease, colonic on x-ray /B.M.D. cancer Measurements Corticosteroid &
Contraindications of HRT Breast cancer, uterine cancer or family history of cancer. Previous history of thromboembolic episode. Liver & gall bladder disease.
DRUGS USED IN HRT Oestrogen Progesterone Other drugs: ◦ Tibolone ◦ Raloxifene ◦ Soya ◦ Bisphosphonates
Estrogen therapy Short term estrogen therapy• 1) To releive symptoms like; hot flush, night sweats, palpitations, disturbed sleep In smallest effective dose for 3-6 months Natural estrogens Oral premarin(Conjugated equine estrogen (CEE): 0.625 mg daily) Ethinyl estradiol(0.01mg),Evalon(1-2mg), micronized oestrogen are effective.
Medroxyprogestrone(10mg) or primolut- N (2.5mg) daily for 10-12d each month. Combined hormone therapy(femet). 2mg 17-β-oestrodiol & 1mg of norethisterone acetate.
◦ 2) for dyspareunia, urethral syndrome and senile vaginitis Local estrogen cream(oestriol: 1/2g- everyday-10-12 days each month for- 3-6 months) Short acting Cyclic progesterone administration is not required. Postmenopausal withdrawal bleeding do not occur. Estring(vaginal ringreleases 5- 10microgram - 3months)
Long term therapy: ◦ For delaying osteoporosis ◦ Reduce the risk of CV disease ◦ Beyond 8-10yr
ESTROGEN: ORAL Advantages. *Easy to take & cheap. *Good control due to short ½ life. Disadvantages. *High dose required. *first pass effect in liver. *daily intake *tablet contain lactose& not suit to women who are allergic to lactose.
ESTROGEN: TRANSDERMAL Advantages. ◦ Low dose, pure estradiol. ◦ Avoids intestine & liver metabolism. ◦ Reduces serum triglyceride & insulin resistance. ◦ No thromboembolic risk or hypertension Disadvantages. ◦ More expensive ◦ Not well tolerated in warm climates ◦ Variable absorption.
ESTROGEN: IMPLANTS Sub cutaneous implant (estradiol): - ◦ 25 / 50 / 100 mg. 6 monthly. Advantages. ◦ Pure estradiol, 6 monthly insertion, high level of estradiol in blood. ◦ Avoids first pass effects ◦ Better response in severe osteoporosis. Disadvantages. ◦ Needs surgical procedure ◦ Unable to control absorption ◦ Difficult to remove pellet
THE RISKS OF HRT Vaginal bleeding Thromboembolism Endometrial cancer if E2 is taken alone Brest cancer due to progestogen if HRT is taken over 5yrs. CHD in a women with CVD.
Progesterone Role in HRT Prevents endometrial hyperplasia and cancer in non-hysterectomised women Implant may replace oestrogen, where estrogen is c/I or sensitive Prevents breast cancer Improves bone mineral density ◦ primolut-N 2.5mg , ◦ medroxyprogestrone & duphaston ◦ Mirena IUCD- levonorgestrel
Tibolone Synthetic derivative of 19-nor-testosterone. Weak oestrogenic, progestogenic, & androgenic action. Endometrial hyperplasia Elevates the mood, relieves the VM symptom, improves sex drive & reduces bone resoption. Cardioprotection(red. TG) SE: wt gain, oedema, tenderness in breast, GI symptom& vaginal bleed.
raloxifene Non steroidal comp., SERM, reduses the risk of fracture by 50%, esp. vertebra by BMD by 2-3%. It causes 10% reduction in total cholesterol & LDL & HDL level. It does not raise the level of triglycerides.so cardio protective for long term. Reduces osteoporosis.
raloxifene Side effects *hot flushes, cramps, venous thrombosis, retinopathy.• Cotraindications *venous thrombosis *should be given with oestrogen *hepatic dysfunction *stop the drug 72 hr before surgery *indomethacin,naproxen,ibuprofen,diazepam.
Bisphosphonates etidronate, tiludronate reduce bone resorption through the inhibition of osteoclastic activity. Elidronate(10mg/Kg f body wt-2W followed by a gap of 2-3M & this course is repeated for 10 such cycles. Not given with Ca.(absorption ) Overdose- hypocalcemia. Milk &antacid - gastric irritation.
alendronate (5mg daily or 35mg weakly) overdose-hypocalcemia. Risedronate (5mg/D or35mg/M)- gastric side effect. Zolendronic acid(once yr i.v 5mg over 15min) SE: osteonecrosis of the jaw & visual dis. Calcitonin-inh. Osteoclast activity *nasal spray(single dose of 200IU daily for 3M)
*NS can cause flushes, rhinitis, allergic reaction &nasal bleeding. * fracture by 30% Subcutaneous inj. Of Calcitonin-GI symptoms ,aneamia &inflammation of joint cause poor compliants so also the high cost. Teriparatide-rec. formation of PIH *abt 20μg once daily SC inj. Ver. Fracture-65% others-50% ,if used <2yr
*nausea, headache are the complication. Strontium ranelate(1-2g daily orally) BMD-50%, very expensive, not easily available. Clonidine- imidazole der. *treat hot flushes *effective in HT *dose 0.2-0.4mg daily.
PREMATURE MENOPAUSE Def: ovarian failure occurring 2 SD in year before the mean menopausal age in the population. Clinically: sec. amenorrhea for at least 3 months with raised FSH/LH & low E2 level in a women under 40 year of age. Inc. 1% -be. 30yr-1:1000 -at 35yr-1:250 -be.40yr-1%
AETIOLOGY1.Genetic disorder chr. abnormalities (10-20%) –X sex chr. AD sex linked inheritance. Ovarian dysgenesis-30%2.Autoimmune disease(30-60%) Mumps, thyroid dys.,hypo parathyroidism, & Addison’s dis. Ovarian biopsy –infiltration of follicle with plasma cells& lymphocytes. CD8 & CD4 autoimmune d. Antiovarian Ab are present.
3.Tuberculosis4.Smoking5.Radiaton & chemotherapy Reversible Radiation up to 400 to 500 rads. restores normal ovarian fun. in 50% cases. Alkalytic agents.6.Hystrectomy Kinking & blockage of ovarian vessels Tubectomy
7.Prolonged GnRH therapy.8.enz.defect-17α-hydroxylase & galactosemia have adverse effect on oocytes – pri. Amenorrhea.9.Resistant ovary Terminology is used less frequently these days. Follicles fail to respond to gonadotropin stimulation.10.Induction of multiple ovulation in infertility.
PATHOPHYSIOLOGY Lack of receptors is explained as the cause of non response of follicle.
C/F Hot flushes Sweating Insomnia Headache Psychological Cancer phobia Pseudocyesis Irritability Depression Lack of conc.
INVESTIGATION FSH level: 40mIU/ml or more. E2 level: 20pg/ml or less Thyroid fun., Ca level, chr. study,& thyroid Ab. Blood sugar. X-ray pituitary fossa for the tumour. BMD study is not always necessary, it is an invasive procedure. Ovarian biopsy. Ultrasound. Prolactin level.
COMPLICATIONS The risks of osteoporosis & cardiovascular diseases increase in premature menopause.
MANAGEMENT1.Cause of premature menopause should be ascertained & the cause treated.2.Ovulation induction or oocyte donation in IVF programme has caused pregnancies to occur in some cases.3.Progestogen challenge test will indicate if menstruation can be induced, provided endometrium is primed with oestrogen.
4.Corticosteroid therapy is effective in autoimmune disease if Ab to sex hormone are present in the blood. Plasmapheresis has also been attempted.5.A women with hypo-oestrogenism may require HRT or other drugs to prevent osteoporosis . oestrogen implant with progestogen or Mirena IUCD offers long-term HRT.
LATE MENOPAUSEDef: cond. in which menstruation cond. beyond 52 year. Late menopause occurs in women with fibroids and is seen in women who develop endometrial cancer. Often it is constitutional. Beyond 52 yr , endometrial biopsy is required to rule out endometrial pathology.
POSTMENOPAUSAL BLEEDINGNormally-1 yr POA –after 40 yr. however, VB –anytime after 6 MOA in menopausal age postmenopausal bleeding & investigated. without amenorrhea / irre. Bleeding , if the women over the age of 52 yr cont. to menstruate, she needs investigation to rule out endometrial hyperplasia & mali. Of genital tract.
AETIOLOGY1.vulva-trauma , vulvitis ,benign & malignant lesions.2.vagina-foreign body such as ring pessary for prolapse, senile vaginitis , vaginal tumour (benign as well as malignant) postradition vaginitis.3.cervix-cervical erosion, cervicitis, polyp, decubitus ulcer in prolapse &cervical malignancy.
7. ovary- benign ovarian tumour such as benner tumour, granulosa & theca cell tumour, & malignant ovarian tumour. 8. Hypertension & blood dyscrasia. 9. Urinary tract- urethral caruncle, papilloma &CA of bladder. May be mistaken for genital tract bleeding. 10.bowel- bleeding from haemorrhoid , anal fissures, & rectal cancer may be misleading.
11.imp. Reason –indiscriminate. Prolonged use of oestrogen unopposed by progestogens, & HRT when applied clinically. Tamoxifen causes endometrial hyperplasia & cancer. 30-50% -PMB –malignancy of genital tract -most common –endometrial cancer , cervical cancer& ovarian tumour. Common benign conditions are endometrial hyperplasia and polypi.
INVESTIGATION Aim: Excluding malignancy1.Blood count & smear- blood dyscrasia.2.Blood sugar level.3.Cervical cytology-cervical lesion.4.Endometrial study.5.Sonosalpingography –endometrial polyp.6.ultrasound- endometrial thickness >4mm indicates the need of endometrial biopsy.
Several methods Dilatation & curettage (D&C) – fractional curettage comprising separate scrap of endometrium &endocervix not only allows the exact site of malignancy if present, but also detect the extent of the tumour & staging. Uterine cavity aspiration & endometrial sampling.
MANAGEMENT1. Treat the cause.2. When no cause is found, & if there has been only one bout of bleeding, the pt should be kept under observation. Abt 80% of cases do not bleed again. If cond. to bleed- laparotomy. An undiagnosed small tumour may be discovered & dealt appropriately. – AH with bilateral oophorectomy histopathological study.