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Ovulatory Dysfunction in Infertility

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Ovulatory Dysfunction in Infertility Hormone Therapy Review of Options Assoc.Prof.Pawin Puapornpong. Faculty of Medicine Srinakharinwirot University 1 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 . Assoc.Prof.Pawin Puapornpong. 2 What is hormone replacement therapy? 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 Assoc.Prof.Pawin Puapornpong. 3 DRUGS USED IN HRT 1. Estrogens . 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. Assoc.Prof.Pawin Puapornpong. 4 DRUGS USED IN HRT 2. Progestins: . 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. Assoc.Prof.Pawin Puapornpong. 5 DRUGS USED IN HRT 3. Tibolone . Synthetic steroid, tissue specific HRT . 2 hydroxy metabolites are estrogenic . D 4 isomer binds to progesterone & androgen receptors . Addition of progesterone not required 4. Androgen • Oral Tablets • Implants-Pellets of 100 mg testosterone Assoc.Prof.Pawin Puapornpong. 6 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 Assoc.Prof.Pawin Puapornpong. 7 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. Assoc.Prof.Pawin Puapornpong. 8 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. Assoc.Prof.Pawin Puapornpong. 9 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. Assoc.Prof.Pawin Puapornpong. 10 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 Assoc.Prof.Pawin Puapornpong. 11 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. Assoc.Prof.Pawin Puapornpong. 12 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. 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. Assoc.Prof.Pawin Puapornpong. 13 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. Assoc.Prof.Pawin Puapornpong. 14 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. Assoc.Prof.Pawin Puapornpong. 15 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. Assoc.Prof.Pawin Puapornpong. 16 RISKS OF HRT Endometrial risk: . 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. Assoc.Prof.Pawin Puapornpong. 17 RISKS OF HRT Breast neoplasia: . 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. Assoc.Prof.Pawin Puapornpong. 18 RISKS OF HRT Ovarian neoplasia . Unopposed estrogen therapy may cause endometroid tumor. So patients need annual pelvic examination. Venous thromboembolic disease There is little risk of venous thromboembolism with conventional HRT. Assoc.Prof.Pawin Puapornpong. 19 Advantages & Disadvantages of each preparation: - ESTROGEN: ORAL - . 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 Assoc.Prof.Pawin Puapornpong. 20 Advantages & Disadvantages of each preparation: - ESTROGEN: ORAL - ETHINYL ESTRADIOL . 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 Assoc.Prof.Pawin Puapornpong. 21 Advantages & Disadvantages of each preparation: - ESTROGEN: ORAL - CEE. 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. Assoc.Prof.Pawin Puapornpong. 22 Advantages & Disadvantages of each preparation: - ESTROGEN: ORAL - Estriol Short acting as it has only short retention time in the nuclei of endometrial
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