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Hormone Replacement Therapy – Review of Options : 

Hormone Replacement Therapy – Review of Options Dr. Srikanta Sahu, M.B.B.S. Resident. Dr. Surendra Nath Panda, M.S. Professor Dept. of Obstetrics & Gynaecology M.K.C.G.Medical College Berhampur-760004, Orissa, India

Why Hormone Replacement Therapy?: 

Why Hormone Replacement Therapy? With a marked increase in longevity, women now spend 1/3 rd of their lives in the post-menopausal period. It is estimated that 1/3 rd of total female population are in menopause. Therefore they would have to cope with the post menopausal syndrome and face the consequences .HRT relieves the well known symptoms of post menopausal syndrome .Again women are now asking for a quality life after menopause. So HRT is a hot topic in this era as it is no more for symptomatic management for PMS, but for the total management from prophylactic to curative .

Since estrogen deficiency is a major cause of the long-term complications of the menopause, estrogen replacement is the rational treatment to address the cause of the problems after menopause .But as there are limitations of estrogen therapy as HRT, some other drugs are also used besides estrogen : 

Since estrogen deficiency is a major cause of the long-term complications of the menopause, estrogen replacement is the rational treatment to address the cause of the problems after menopause .But as there are limitations of estrogen therapy as HRT, some other drugs are also used besides estrogen What is hormone replacement therapy?


Oral: - Conjugated equine estrogen (CEE): 0.625 mg (Estrone Sulphate + equilin sulphate +17 d dihydro equilin) Estradiol valerate (1, 2, 4 mg). Estrial succinate (1, 2 mg). Transdermal (estradiol): - Patches: 25 micro gm, 50 micro gm / 24 hour twice weekly. Gel : 75 micro gm / 24 hours daily. Sub cutaneous implant (estradiol): - 25 / 50 / 100 mg. 6 monthly. Vaginal: cream. 1) Estrogens- DRUGS USED IN HRT


DRUGS USED IN HRT Oral route –. Norgestrol: 150 mg /day. Micronised progesterone: 200 mg /day. Dydrogesterone: 20 mg / day. Medroxy progesterone acetate: 10mg/day. Norethisterone acetate : 0.7 – 2.5 mg/ day. Hormone releasing intra uterine system –. Levonorgestrel: 20 mcg / day. Progestasert: 65mcg / day. Vaginal - natural progesterone gel / pessary. Transdermal - sequential / continuous patch. 2) Progestins:


DRUGS USED IN HRT Synthetic steroid, tissue specific HRT 2 hydroxy metabolites are estrogenic D 4 isomer binds to progesterone & androgen receptors Addition of progesterone not required 3) Tibolone- 4) Androgen - Oral Tablets Implants-Pellets of 100 mg testosterone


DRUGS USED IN HRT Regimens Estrogen alone: in post hysterectomy cases E + P Cyclic sequential: E on day 1-25; P on day 14 –25 (for climacteric patients with intact uterus ) Continuous sequential: E daily; P for 12 days at 16 days interval (for post menopausal patients with intact uterus) Continuous combined: E + P taken daily Progesterone alone: cyclic / continuous Estrogen + Progesterone + Androgen

Benefits of HRT: 

Vasomotor symptoms: Hot flushes & night sweats resulting from hyperactivity of mid brain-hypothalamic-pituitary axis & characteristic of climacteric are relieved by HRT Sleep disturbances: Early morning awakening and inability to get back to sleep is a frequent complaint in postmenopausal women. Estrogen receptors are present in Reticular Activation System, preoptic area, and hypothalamus. Estrogen replacement improves sleep by acting at these sites. Benefits of HRT

Benefits of HRT: 

Mood & psychological changes: Estrogen replacement appears to have a direct mental tonic effect on the cognitive functions even in the absence of vasomotor symptoms .It over comes anxiety, over sensitivity, tearfulness, irritability, aggression. However if progesterone is also given, it may reduce the beneficial effects of estrogen on libido & mood. Benefits of HRT

Benefits of HRT: 

Benefits of HRT Atrophy of genital tract leading to vaginal dryness & postmenopausal bleeding from atrophic vaginitis / atrophic endometrium respond to estrogen therapy. Dyspareunea due to vaginal dryness is not a problem in menopause, but it is a problem during climacteric. Loss of libido also responds to estrogen replacement. Some also get benefit from testosterone.

Benefits of HRT: 

Benefits of HRT Urinary symptoms: Incontinence –Urethral abnormality, Detrussor instability, Overflow Incontinence Frequency, Urgency, Dysuria Difficulty in voiding Estrogen may produce considerable improvement in these symptoms by increasing Epithelial thickness, vascularity, closing pressure of urethra Adrenergic receptor in bladder urethral muscle Collagen content of connective tissue

Benefits of HRT: 

Benefits of HRT Bone & skeleton: Post menopausal women, due to increased bone resorption, exceeding the rate of new bone formation. Loose 30% of their total bone mass. It leads to osteoporosis, and fracture may occur with minimal / trivial trauma. Estrogens cause stimulation of C cells of thyroid resulting in increased level of calcitonin, which causes inhibition of osteoclastic bone resorption. Progesterone has synergistic action, as it binds competitively with glucocorticoid receptors in bone, thus inhibiting the resorbing effect of cortisone.

Benefits of HRT: 

Benefits of HRT Cardiovascular system : In menopause as there is increased level of plasma total cholesterol & LDL and decreased level of HDL, leading to atherosclerosis, there is increase in cardiovascular diseases. Estrogen causes decreases the incidence & mortality of I.H.D., due to its beneficial effect on the lipid metabolism. Skin, hair, body fat : In postmenopausal women there is decrease in content of collagen in skin .So the skin becomes wrinkled. Estrogen increases the collagen content .It also prevents varicose ulceration.

Benefits of HRT: 

Benefits of HRT Neuroprotection: It reduces the risk of Alzheimer’s disease by reducing  amyloid protein & cholinergic dysfunction in brain. It enhances the proliferation of neuronal cell population within the hippocampus. It regulates the synaptic neurotransmission & increases nerve growth factor. Thus it enhances neuroplasticity, memory, and cognition. It delays the onset of Parkinson’s disease by its action on dopaminergic system in midbrain.

Benefits of HRT: 

Benefits of HRT Other effects: Estrogen prevents tooth loss & periodontal disease. There is substantial decrease in the risk of fatal colon cancer. There is reduction in age related macular degeneration,cataract and severe nuclear sclerosis. In diabetic women there is improvement in glycemic control. Less risk of Osteoarthritis:. Alleviates the worsening symptoms of multiple sclerosis.

Specific actions of TIBOLONE: 

Specific actions of TIBOLONE Tibolone comes closest to being the ideal product for long term HRT because of the specific actions. Brain: - enhances mood, libido. Heart: -beneficial effects on CVS. Breast: -lower incidence of breast tenderness and no effect on mammography. Endometrium: -no proliferation. Urogenital symptoms:- improved. Bone: -prevents bone loss. It induces amenorrhoea. Thus it is a menstruation free HRT, which is most welcome to most women, with an intact uterus.


RISKS OF HRT Continuous use of estrogen can cause endometrial hyperplasia, leading to endometrial carcinoma. Addition of progesterone reduces this risk as it inhibits DNA synthesis, reduces the no. of estrogen receptors, stimulates the enzyme 17alpha dehydrogenase, which converts E2 to E1. Tibolone does not stimulate the endometrium as it exhibits progestogenic & androgenic activities in endometrial tissue. Endometrial risk:


RISKS OF HRT There is increased incidence of breast carcinoma with long-term use of estrogen. Progestogen has no protective effect . So annual breast examination including mammography is necessary. Tibolone & its metabolites are very potent inhibitors of stimulants of breast tumors. Breast neoplasia:


RISKS OF HRT Unopposed estrogen therapy may cause endometroid tumor. So patients need annual pelvic examination. Ovarian neoplasia Venous thromboembolic disease There is little risk of venous thromboembolism with conventional HRT.


Advantages. Easy to take & cheap. Good control due to short ½ life. Disadvantages. High dose required. Wide variation in absorption & metabolism during its first pass through intestine, liver. High incidence of minor side effects. E2: E1 remains same. Increase in free cholesterol pool in hepatic cells. Increases serum triglycerides, worsens glucose tolerance & insulin resistance Advantages & Disadvantages of each preparation: - ESTROGEN: ORAL -


Advantages. Stable compound due to ethinyl group, Minimal dose required 10 –20 microgram. Disadvantages. Passes unchanged to liver, greater metabolic effects on liver results in increased risk of venous & arterial thrombosis, Suppression of F.S.H. & Urinary calcium excretion. Relatively increased incidence of breast carcinoma. Stimulates: hepatic production of renin substrate & angiotensinogen with risk of hypertension, vasoconstriction, platelet aggregation Advantages & Disadvantages of each preparation: - ESTROGEN: ORAL - ETHINYL ESTRADIOL


Very potent, not subject to enzymatic metabolism, low plasma clearance. Stored in fat & released slowly. But in higher doses (1.25 mg /day) this may cause increased plasma level of renin substrate like EE. Advantages & Disadvantages of each preparation: - ESTROGEN: ORAL - CEE.


Short acting as it has only short retention time in the nuclei of endometrial cells .No endometrial proliferation. Cyclic progesterone administration is not required. Postmenopausal withdrawal bleeding do not occur. Particularly effective in the treatment of urogenital symptoms. Advantages & Disadvantages of each preparation: - ESTROGEN: ORAL - Estriol


Low dose, pure estradiol. Avoids intestine & liver metabolism. Physiological E2: E1. Reduces serum triglyceride & insulin resistance. No adverse effect on biliary cholesterol saturation index & biliary salt composition. But more expensive, not well tolerated in warm climates, skin reaction may occur. Variable absorption. Advantages & Disadvantages of each preparation: - ESTROGEN: TRANSDERMAL


Pure estradiol, 6 monthly insertion, high level of estradiol in blood. Avoids first pass effects, physiological E2: E1 ratio, better response in severe osteoporosis. But needs surgical procedure, unable to control absorption, risk of supraphysiological blood levels, difficult to remove pellet, prolonged release of estradiol. Advantages & Disadvantages of each preparation: - ESTROGEN: IMPLANTS


Given with / without combination of systemic therapy to the older women having urogenital symptoms. Natural estrogen preparation avoids significant systemic absorption. Advantages & Disadvantages of each preparation: - ESTROGEN: VAGINAL CREAM


SPECIAL SITUATIONS Hypertension:- non oral estrogens are of choice Thromboembolism:- Transdermal route is preferable Gallbladder disease: - non-oral route Side effects: change to non-oral Poor response: may be due to inadequate absorption from intestine / transdermally: - Implant is beneficial Lactose intolerance: - lactose present in oral preparation, so non-oral route is of choice Choice Of Preparation


INDICATIONS FOR STARTING HRT Women having climacteric symptoms All asymptomatic high-risk women having Premature menopause (surgical / spontaneous) Established osteoporosis on x-ray /B.M.D. Measurements Family history of osteoporosis Thin, small sedentary women Poor diet, excess alcohol Corticosteroid & other medications High urinary calcium / creatinine Low plasma estradiol Asymptomatic women with / without risk factors having no contraindications but who request HRT

Contraindications of conventional HRT: 

Contraindications of conventional HRT Known / suspected breast cancer Estrogen dependent neoplasia Undiagnosed abnormal genital bleeding Active thrombophlebitis Abnormal liver function tests Malignant melanoma Known / suspected pregnancy


SPECIFIC INDICATIONS OF TIBOLONE Breast cancer risk Breast cancer treated Family history Low parity / nulliparity Racial factor Endometrial cancer risk Past H/O endometriosis / fibroid Patients with NIDDM Patients with hypertriglyceridemia & H/O thromboembolic phenomena

Adverse effects of Progestins & their management: 

Adverse effects of Progestins & their management Bleeding problems: heavy / prolonged bleeding on sequential therapy – Select more androgenic type progestogen (LNG & Norethisterone). Physical side effects: edema, weight gain, bloating, migraine - Spironolactone 25 mg O.D. In the last week. Acne, greasy skin - progestogen having no androgenic effect. Head ache - adding a mild diuretic / androgen. Psychological: fatigue, depression, irritability, anxiety, and forgetfulness - switch from oral to non oral treatment. Women having CVS disease / DM: natural progesterone / less androgenic derivative of progesterone is ideal.


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