Comprehensive Overview of Menopause and Tibolone Therapy

Comprehensive Overview of Menopause and Tibolone Therapy

• 1.
  Menopause Menopause means “cessationof menstruation”. • It usually refers to period after the last menstrual period in woman’s life. • It precedes complete cessation of ovarian function by several months or years. • Ovarian failure, premature menopause occurs i.e. before the age of 40. • Surgical menopause occurs due to hysterectomy or oophorectomy.
• 3.
  Phases of Menopause Pre-menopause •Regular Cycles Peri-menopause • Irregular cycles, Climacteric complaints transitional phase lasting 1 to 5 yrs Post-menopause • Time period starting 1 year after last menstrual period & lasts for rest of woman’s life • No bleeding, Climacteric and local/urogenital complaints, Osteoporosis, Cardiovascular disease
• 4.
  Biosynthesis of Estrogens Estrogensare derived from cholesterol: • Estrone is formed both in ovaries and fatty tissue via androstenedione. • Estradiol is mainly secreted by the ovaries • Estriol is synthesized from estrone and estradiol Most Potent
• 5.
  Menopausal endocrine changes Increasedlevels of FSH and LH Negligible estradiol production Emergence of estrone as the predominant hormone Increased ovarian secretion of testosterone Relatively greater decrease in total estrogen than in androgen production Positive shift in ratio of androgens to estrogens
• 6.
  Effects of Estrogens Developmentof female characteristics. Development of endometrium & increased cervical mucus production Stimulates changes in vaginal epithelium LDL-C and total cholesterol are lowered & HDL-C is increased Cause development of a soft and usually smooth skin texture firming of facial tissue by Exerting minor oedema Counters loss of bone mass
• 7.
  Menopause: Estrogen Deficiency Syndrome a)Early (Stage I) • Irregular periods, Hot flushes and Night sweats b) Intermediate (Stage II) Psychological problems • Insomnia, Depression, Headache, Apprehension, Irritability, Mood Changes, Frigidity etc. Urogenital problems • Urinary incontinence Other changes are: • Decrease in the size of breasts • Changes in texture especially dryness of hair and skin. c) Late (Stage III) • Osteoporosis and CVD
• 8.
  Sequence of Appearance 40-45years – Menopause First five years after menopause • Vasomotor symptoms and Vaginal atrophy • Skin atrophy and Urogenital symptoms Five to Ten years after menopause • Osteoporosis • Cardiovascular disease
• 9.
  When is MedicalIntervention Required? Adapted from Bungay G et al. Br Med J 1980;281:181–3; Van Keep PA et al. Maturitas 1990;12:163–70. Vasomotor Symptoms Sleep Disorders Mood Changes Vaginal Atrophy Dyspareunia Skin Atrophy Osteoporosis Atherosclerosis Coronary Heart Disease Cerebrovascular Disease 40 yrs 50 yrs Menopause 60 yrs Symptoms and Disorders in Relation to Age and Menopause Menstrual Disorders
• 10.
  Osteoporosis - Postmenopausal boneloss hardly causes any symptoms. - After a number of years, the “silent” bone loss reaches a level where fractures start to occur. - Osteoporosis has been called “The silent Epidemic”. By 70 years of age • 15% women experience Wrist fractures • 25% women experience Vertebral fractures • 15% women experience Hip fractures
• 11.
  Estrogen Therapy Estrogen • Stabilisesbone density by preventing further loss • Decreases rate of bone resorption • Allows normal mineralisation of remodeling units • Maintains equilibrium between resorption & formation • Estrogen has direct action on skeleton • Estrogens do not restore lost bone. HRT reduces risk of osteoporotic fractures by 40%
• 12.
  Sibolone – Aneffective therapy Structure of Tibolone and metabolites Tibolone is a unique molecule that exerts estrogenic as well as progestogenic / androgenic properties. The three metabolites and their receptor binding The activity of Tibolone and its metabolites is selective and tissue specific known as selective, tissue estrogenic activity regulators (STEARs).
• 14.
  Sibolone’s Tissue SelectiveAction • The estrogenic activity of Tibolone offers its beneficial effects on menopausal symptoms and bone loss, but exerts no estrogenic activity in the endometrium or breast. • This leads to low side-effects especially when compared to the usual HRT regimens.
• 15.
  Estrogen metabolism in presenceof Sibolone DHEAS DHEA ANDROSTENEDIONE aromatase sulphatase ESTRONE Sulphotransferase ESTRONE SULPHATE 17 β HSD 17 β HSD (Inactive (Type 1) (Type 2) Estrogen) ESTRADIOL Χ Χ + + DHEAS- Sulphated Dihydroepiandrostenedione DHEA- Dihydroepiandrostenedione HSD-Hydroxy Steroid Dehydrogenase -blocks -stimulates
• 16.
  Enzyme Regulation inBreast Main action by: Enhance formation of inactive estrogens and reduces levels of local estrogens • Blocks sulfatase activity, thereby inhibiting formulation of active estrogens in breast tissue. Reduction is marked and dose- dependent inhibition of sulfatase activity is seen. • Stimulates sulfotransferase, results in formation of inactive estrogens • Tibolone and 4 -isomer blocks 17-HSD (type I) and stimulates 17- HSD (type II),
• 17.
  Tibolone for Menopausalsymptoms ↓ hot flushes ↓ headache, insomnia, fatiguability Mood changes[incr eases endorphins] Increases sexual function[libid o] Improves vaginal atrophy Improves urogenital symptoms
• 18.
  Indication Tibolone may haveadded value in – Women with risk of accelerated bone loss – Women with urogenital complaints – Women with low sex drive – Women with mood disorders – Women with premenopausal breast tenderness – Women with high breast density – Women with fibroids
• 19.
  Tissue-selective metabolism in endometrium Thelevels of locally active estrogens in the endometrium are reduced by keeping them in a sulfated non-receptor activating form and/or estrogenic activity is counteracted by the progestogenic activity of the 4 -isomer and Tibolone. Thus, tibolone does not stimulate the endometrium
• 20.
  Clinical Experience • Sibolonerelieves menopausal symptoms by its estrogenic action • Improves mood & sexual well-being by its androgenic and estrogenic activities. • It also increases levels of beta-endorphin which reduces during menopause, affecting sexual desires • Several trials have confirmed its efficacy in improving the following symptoms: • Hot flushes & Night sweats • Cervical mucus production & dyspareunia • Vaginal atrophy or dryness
• 21.
  Sibolone as add-backtherapy in women on GnRH agonists Beneficial as estrogens are known to increase myoma size Sibolone does not influence size or volume of myomas Makes agonist therapy more acceptable, without affecting its therapeutic benefits Sibolone offers symptomatic relief without adverse effects of Estrogen therapy Symptoms like Hot flushes, bone loss, etc. leads to withdrawal Severe suppression of estrogens leading to temporary EDS (just as in menopause) GnRH agonists used in endometriosis and myomas in pre-menopausal women (long term therapy)
• 22.
  Summing up In theendometrium • Sibolone does not stimulate the endometrium • No histological changes in 90% women, mild proliferation in rest • E+P stimulates endometrium, Sibolone maintains atrophy • Sibolone also has a low incidence of vaginal bleeding Vaginal Bleeding • No co-relation between bleeding & endometrial stimulation as Sibolone does not stimulate endometrium • Endometrial biopsy from women who have bled show normal histology • Mild and transient bleeding : occurs during first 3-6 months • Incidence much lower than EPT, no discontinuation
• 23.
  Summing up In theBreast • Does not stimulate the breast nor increase mammographic density. • Does not interfere breast cancer screening unlike EPT and Raloxifene • Low incidence of enlargement and tenderness • Lower discontinuation rates • Breast pain incidence & intensity much lower than EPT • Patients on EPT-induces breast symptoms when switched over to Sibolone report no breast symptoms or very low rates • True even for women with benign breast disease • No increased risk for breast cancer in comparison to placebo
• 24.
  Sibolone and Cardiovasculardisease • Sibolone therapy has neutral effect on CV disease • Significant decrease in levels of – Total Cholesterol and Triglycerides – HDL-Cl and Lipo-protein (a) • No significant reduction in LDL-C • The drop is in the less effective sub-class of HDL-C and not in effective sub-class • Positive effect of HDL-C is not majorly affected - function not impaired • Decreases levels of small dense LDL-C particles that are most prone to oxidation leading to arthrosclerosis • Does not adversely affect blood clotting • May have beneficial effect of fibrinolysis
• 25.
  Sibolone’s other benefits •Increases blood flow velocity which is reduced in post menopausal women. It however, has no deleterious effect on BP • Prevents increase in body fat mass as well as decreases in the body muscle mass, normally seen in menopausal women • Improves muscle strength in these women Sibolone improves the Quality of Life of menopausal women
• 26.
  Sibolone’s Dosage • Dosageis 2.5mg daily - No dose adjustment for elderly • Taken preferably at same time • In pre-menopausal women (GnRH-a therapy): lowest effective dose for shortest duration Starting Sibolone • Natural menopause - commence at least 12 months after natural bleed • Surgical menopause - commence immediately Switching from sequential or CC-HRT • Sequential HRT- start on day following completion of prior regimen • Continuous-combined HRT- start at any time Missed dose • Take as soon as remembered; if >12 hrs overdue, skip dose, next dose taken at normal time • Missing doses may increase chance of breakthrough bleeding/ spotting
• 27.
  Promoting Sibolone Target Drs •Gynaecologists • Members of the Indian Menopausal Society • Orthopedics • Lady GPs
• 28.
  Handling Objections Weight Gain •Normal for postmenopausal women to gain weight, while on any HRT in absence of proper diet & exercise regime • Comparative trials studying Sibolone v/s HRT have shown no significant difference • As Sibolone improves mood and alleviates depression, appetite improves • The tissue specific activity of Sibolone on muscle mass may also increase body weight • The weight increase gradually decreases with time
• 29.
  Handling Objections Pigmentation • Certainwomen are more prone to have pigmentation, especially on face (cheekbones) and/ or legs, during pregnancy, after they have been on combined OC pills. • These women more prone to hyper-pigmentation, if on either Sibolone or any cc-HRT. • Due to estrogenic as well as progestogenic effect. Both E & P increase levels of MSH (Melanocyte stimulating hormone). • As Sibolone stimulates P receptors, this event may occur, though incidence is very rare. • Some menopausal women, not on HRT also develop such patches • Considering benefits of Sibolone, skin pigmentation is often not considered as serious. • Anti-pigmentation creams will fade the patches.
• 30.
  Sibolone- Competitors COMPANY BRANDPACK PTS PTR MRP Sum of MAT VAL AUG 21 Sum of MAT VAL GR AUG 21 Sum of MAT UNIT AUG 21 Sum of MAT UNIT GR AUG 21 ORGANON LIVIAL 28 1073.57 1192.86 1670 2.3 -8.9 19.4 -16.3 SIIPL SIBOLONE 15 204.69 227.43 318.4 1.4 71.1 61.9 69.1 Total 3.7 10.4 81.4 35.4 Units in Actuals MAT UNITS IN 000'S VALUES IN ACTUALS MAT VALUES IN CRS
• 31.
  SALIENT FEATURES OF Prevents boneloss & increases BMD- Superior to isoflavonones & raloxifene Improves quality of life in menopausal women Excellent safety profile Unique Selective Tissue Estrogenic Activity Regulator Relieves Climacteric symptoms
• 32.
  SALIENT FEATURES OF Positively affectsmood & improves sexual well being Corrects vaginal dryness & cytology Offers benefits of HRT without the menses Most economical
• 38.
  Thank You