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Clinical uses of Oestrogens 1. Hormone Replacement Therapy [ HRT ] For Menopause [OE alone or with a Prog] 2. Oral Contraception [OE with a Prog] 3. Dysmenorrhoea [OE with Prog - most OCs effective] 4. Dysfunctional Uterine Bleeding [DUB] [OE with a Prog -cyclically] 5. Acne [OE with a Prog - cyclically] 6. Evaluation of ovarian function [OE with a Prog - cyclically] 7. Failure Of Ovarian Development /Turner’s Syndrome [OE alone or with a Prog] Other use 8. Prostate Carcinoma [To inhibit Gn Release ] [OE alone] ________________________________________________________________________________ OE = Oestrogen Prog = Progestogen Gn = Gonadotrophin Clinical uses of Progestogens 1 HRT / OCs / Dysmenorrhoea [With OE] 2.Endometriosis [Medroxyprogesterone 2.5 -10 mg or Norethisterone 5-10 mg / day for 6-9months. Long acting medroxyprogesterone injection [effective for 12 wk] also used. 3.Threatened / Habitual abortion [Doubtful efficacy] 4.Evaluation of ovarian function [Used in the past] 5.Pregnancy diagnosis [Used in the past] 6.Inhibition of lactation [Bromocriptine preferred] HRT for Menopause Indications: (a) To relieve: Symptoms of hot flushes, Atrophic vaginitis Pruritis/Kraurosis vulvae Urethritis (b) To prevent: Atherosclerosis [Doubtful] Osteoporosis / Early Bone loss Hysterectomized [Treatment may be started on any day of MC] - OE alone Continuously Intact uterus [4 wk cycle] [a] OE alone [b] OE + Prog. First 14 days OE + Prog Next 14 days [Low doses] continuously -If not menstruating Treatment may be started on any day. -If Menstruating Treatment may be started on day 1 (or 5) of the cycle. [OE alone increases Risk of Endometrial Carcinoma With Prog. Risk but of Breast Carcinoma ] _______________________________________________________________________________________ OE = Oestrogen Prog= Progestogen MC = Menstrual cycle -Hormones taken orally /skin patch but treatment must be started with minimum effective dose. -Treatment given from a few months to few years. -OE or OE+ Prog combined patch is effective for 3- 4 days. Steroids for HRT of Menopause Oestrogens (1)Steroids Natural Oestradiol -17ß, Oestriol Oestrone + Equilin [Conjugated Oestrogens] Synthetic Ethinyloestradiol Mestranol Dehydrostilboestrol [Dienoestrol] Diethylstilboestrol [Stilboestrol] (2)Non-Steroids Given orally / skin patch/ vaginal cream _____________ Progestogens [ All Steroids] Natural Progesterone Synthetic (a)1st Generation* Dehydroprogesterone [Dydrogesterone] Medroxyprogesterone (b) 2nd Generation** Norethisterone Norgestrel ___________________________________________________________________ *Selective but week progestogens ; week androgens **Non-selective but potent ; moderate androgens HRT- Side Effects of Oestrogens/ Progestogens GID, Induce or enhance symptoms of Diabetes mellitus Risk of : -Intravascular coagulation -Endometrial carcinoma [with OE alone] -Breast / Liver carcinoma [with prolonged use] -Carcinoma in children of mothers given OE in pregnancy [Breast, uterus, testis, kidney] Contraindications Pregnancy Undiagnosed Vaginal Bleeding Thromboembolic disease Severe cardiac / hepatic / renal disease Genital tact Malignancy Precautions History of Thromboembolism Inherited Liver disorders [Dubin Johnson / Rotor-Syn.] _____________________________________________________________________ GID = Gastrointestinal disturbances- [nausea, vomiting, epigastric distress /pain] Other agents for HRT/Osteoporosis (a) Gonadomimetic agents (1) Tibolone A steroid with Prog / OE & weak androgenic activity GnRH Release by Stabilising Hypothalamus / Pituitary axis [Helps to reduce menopause related GnRH increase] SE: GID / dizziness / vaginal bleeding / rarely thromboembolism. Other agents for HRT / Osteoporosis [contd.] 2-Selective Oestrogen Receptor Modulator [SERM] - Raloxifene -Selective agonist of OE receptors [ERa] -Non-Significant effect on OE receptors in other body tissues [in bone tissue] [uterus / breast / hypothalamus] Use Prevention and treatment of osteoporosis in Post menopausal women. [given orally ] SE Hot flushes / Leg cramps / Oedema [Not recommended in women of child bearing age] _________________________________________________________________________________________ Other OE receptors [ERb] Ovaries, Prostate, Lungs, CNS, Blood vessels [ERg] Various tissues: Role unknown Methods for oral / long term contraception (a) Oral Contraceptives 1.Combined Pill [Combination Pill / OE + Prog] Monophasic [ same preparation for 21 days] Diphasic [ Prog content Doubled after 1wk and maintained Triphasic [ Prog content increased by 50-60% after 5-7 days and maintained In some preparations OE content is also slightly varied. 2.Sequential OE OE + Prog 1-14 days of M.C 15-21 days of M.C [ up to 16 days] [ up to 20days] 3.Progestogen only [Mini pill] Low dose Prog 4.Post-coital [Vacation Pill] on day 1 of M.C & continued without break. Prog OE OE + Prog Danazol 5.Once a month combined pill [Quinesterol 3 mg + Norethynodrel 12 mg] ________________________________________________ (b) Long Term Parenteral Contraceptives Deep I.M S.C. Implant Intrauterine Medroxyprogesterone Etonogestrel Levonorgestrel ________________________________________________________________________ M.C = S.C = Menstrual cycle Subcutaneous Other Agents For Menopausal Osteoporosis [Agents Preventing Bone Loss] [a] - Bisphonates [Etidronate / Clodronate / Pamidronate/ Risedronate] Act by SE Oteoclast activity GID / Paraesthesia Ca++ PTH in blood Liver function -with Clodronate Lymphocyte Count -with Pamidronate Flue-like symptoms -with Risedronate [b] - Salcatonin [Synthetic Calcitonin] Act by SE Bone Resorption [Counteracts PTH effect & reduces osteoclastic activity] GID / Paraesthesia [c] - Calcium salts / Vitamin D ____________________________________________________________________________________________ GID = Gastrointestinal disturbances [nausea, vomiting, epigastric distress/pain] Commonly used Steroids for Oral Contraception Oestrogens Ethinyloestradiol Mestranol Progestogens I Generation [Selective but week receptor action] Now mainly used for HRT] Dydrogesterone Medroxyprogesterone II Generation [Non-selective but potent receptor action: Moderate androgens] Norethisterone Norgestrel Norgestimate III Generation* [Non-selective but potent receptor action: week androgens] Gestodene Desogestrel Etonogestrel ____________________________________________________________________________________ *Risk of androgen SE reduced but of venous thromboembolism & MI are somewhat increased OCs Possible modes of action OE + Prog Gn Release Ovulation (99%) Interference in Ovum / Blastocyst transport Implantation [Endometrium hypoplastic / out of phase] OE alone Corpus Luteum degeneration FSH secretion Prog. Alone Cervical mucus hostility towards spermatozoa Uterine pH and sperm motility Sperm Capicitation Ovarian endothelial cell activity. Minor Side Effects of Oral Contraceptives (a) High OE / Low Prog GID, Dysmenorrhoea, Menorrhagia, Enlargement of uterus / Breast Chloasma, Telangiectasia Oedema, Visual disturbances Redistribution of Fat (b) Low OE / High Prog Redistribution of fat Irritability, headache, depressed mood, fatigue Dry vagina, Moniliasis / Breakthrough bleeding Breast tenderness, Carbohydrate intolerance Increased appetite / weight Acne, oily scalp, alopecia / CHO- intolerance Cholestatic hepatitis / Increased BP Contraindications / Precautions / Risk factors for OCs Absolute contraindications Pregnancy Thromboembolism, Cerebrovascular /Coronary artery Disease Impaired liver function, Hepatic adenoma Undiagnosed vaginal bleeding Breast or other malignancies Relative contraindications Within 2 wk of pregnancy termination Diastolic pressure >110 / vascular or migraine headaches Cardiac or renal disease / Diabetes mellitus Gall Bladder disease Epilepsy Fibrocytic disease Heavy smokers Planned operation in next 6 wk / patients in leg casts Risk of side effects increased in Smokers >35 Yr Obese History of Preeclampsia Hypertension _______________________________________________________________________ Stop pill 6 weeks prior to major surgery. Prevention Of Pregnancy After Missing A combined Pill < 12 hr > 12 hr Take the missed pill immediately and further pills as normal Take the most recent pill but discard other missed pills If the number of pills [after the most recent pills] is < 7 Start the next packet without break If the number of pills [after the most recent pills] is > 7 Start the next packet after 1 wk break ___________________________________________________________________ Use extra precautions for the next 7 days
