HKCOG Guidelines Guidelines for the Administration of Hormone Replacement Therapy published by The Hong Kong College of Obstetricians and Gynaecologists A Foundation College of Hong Kong Academy of Medicine Number 2 November 1998 1 BENEFITS OF HORMONE REPLACEMENT THERAPY (HRT): (1) Relief of menopausal symptoms (2) Prevention against osteoporosis (3) Prevention against cardiovascular disease The administration of HRT may also reduce the risk of Alzheimer's Disease but there are fewer data to support this1. HRT may be offered to most postmenopausal or symptomatic perimenopausal women, and their decision to use it will rest upon the balance between the advantages and disadvantages of treatment. 1.1 Menopausal symptoms Oestrogen is effective in reducing the severity and frequency of hot flushes and sweating. There is less evidence to show that oestrogen is effective in controlling other acute symptoms attributable to the menopause2. Whilst some Chinese women suffer from severe vasomotor symptoms, these occur less commonly than in Caucasians3,4. These symptoms may therefore be a relatively less important indication for treatment in Chinese women. 1.2. Prevention against Osteoporosis Bone loss after the menopause especially affects the femoral neck and lumbar spine. The administration of oestrogen is effective in preventing osteoporosis and osteoporotic fractures in these sites5. Bone mineral density (BMD) studies can be performed in Hong Kong, and these measurements provide information that may be of benefit in decision making regarding the use of HRT. BMD studies should especially be considered for those women with risk factors for osteoporosis (Appendix 1). The disadvantage of BMD measurements is the cost involved. As far as osteoporosis is concerned, once oestrogen treatment is discontinued, protection against bone loss is largely lost. 1.3. Prevention against Cardiovascular Disease There is indirect evidence to suggest that the administration of oestrogen reduces cardiovascular risk by as much as 50%6. The beneficial actions of oestrogen include an improvement in the lipid profile, a reduction in cholesterol uptake by the vessel wall and an increase in blood flow due to arterial relaxation. Oestrogen is also thought to act as an antioxidant and a calcium antagonist, and it also increases insulin sensitivity. The cardioprotective effect of oestrogen applies to current as well as previous users of HRT. Women who are at increased risk of cardiovascular disease should especially benefit from treatment (Appendix 2). 2 DISADVANTAGES AND RISKS OF HRT The main disadvantage of HRT is the necessity to use one or other of the preparations for a relatively long period of time. In addition, for some women who have not had a hysterectomy, the resumption of menstrual-like bleeding may be considered to be a disadvantage of treatment. The most serious risk attributed to the use of HRT is that of breast cancer. At the present time, the extent of the risk cannot be accurately estimated. Many studies have been performed which suggest that the administration of HRT does not increase the risk of breast cancer, whilst others have suggested a slight increase in risk7. Studies are currently being performed overseas which will more accurately measure this risk. The most common side effects of HRT are breast sensitivity or engorgement and fluid retention. These problems tend to improve within months of initiating treatment, but if necessary the dose of oestrogen may be reduced to a level of comfort. 2.1 Absolute contraindications to the use of HRT Existing breast carcinoma Existing endometrial carcinoma Venous thrombosis Acute liver disease 3 PRESCRIPTION OF HORMONE REPLACEMENT THERAPY For the purpose of hormone replacement, oestrogen may be administered orally, percutaneously, transdermally or in a subcutaneous implant. Vaginal administration of oestrogen is usually reserved for the short term treatment of lower genital tract symptoms. For most women, the route of administration of oestrogen can be chosen according to their preference. Those with medical conditions which can in theory be affected by the hepatic "first pass" effect of oral oestrogens may be better treated with non-oral preparations. This includes women with diabetes mellitus, hypertension, hypertriglyceridaemia and a history of venous thrombosis. 3.1. Unopposed oestrogen Unopposed oestrogen implies the use of oestrogen without a progestogen. In those women who have had a hysterectomy, unopposed oestrogen should be prescribed. For those women who still have a uterus, a progestogen should be given in addition to oestrogen to prevent endometrial hyperplasia and carcinoma8. The prescription of oestrogen as well as a progestogen is referred to as combined HRT, and this combination may be given either cyclically (sequentially) or continuously (see below). 3.2 Combined cyclical (sequential) HRT A cyclical (sequential) regimen implies that a progestogen is given on a cyclical basis (in addition to oestrogen), and this cyclical use of a progestogen usually results in regular withdrawal bleeding at the end of each progestogen cycle. When prescribing HRT at the time of (or soon after) the menopause, a cyclical (sequential) regimen is less likely to cause irregular bleeding than would a continuous combined regimen (see Section 3.3). With a cyclical regimen, oestrogen is usually prescribed for 21 or 28 days whilst the progestogen is given for 10 or 12 days each month. A small percentage of women may become amenorrhoeic during cyclical treatment. 3.3. Continuous combined HRT For women with an established menopause (( 2 years), continuous combined HRT can be given, in which case both the oestrogen and a progestogen are given on a daily basis. On such a regimen, the aim is for these women to remain amenorrhoeic. Spotting is common during the first few months of this treatment. An alternative to continuous combined HRT is the use of tibolone, a synthetic agent which has weak oestrogenic, androgenic and progestogenic properties. This drug can be used under the same circumstances as continuous combined oestrogen and a progestogen. 3.4 Recent data on a new class of drugs referred to as selective estrogen receptor modulators (SERMs) have suggested that these drugs reduce the risk of breast and endometrial cancer9. They have a beneficial effect on lipids and bone, but little or no therapeutic effect on acute menopausal symptoms. These drugs may be desirable for asymptomatic women with a fear of breast cancer or those with risk factor(s) for breast cancer. The SERMs may be prescribed for women with or without a uterus. 3.5. Duration of use of HRT There are no rules regarding the duration of use of HRT. While the treatment continues, the beneficial effects will be maintained. Studies on the risk of breast cancer are ongoing and will provide information on the effect of long term treatment on breast cancer risk. 4 MANAGEMENT OF THE MENOPAUSE Treatment can begin at any time after the menopause, and the type of HRT regimen will be dictated by the duration of the menopause and whether or not a hysterectomy has been performed. Some women develop symptoms of oestrogen deficiency before the menopause occurs, and treatment may begin at this time although irregular bleeding in perimenopausal women may be a problem. Apart from the use of HRT, attention to life style factors which promote good health should be encouraged. These include weight control and regular weight bearing exercise. 4.1. Monitoring of women using HRT Cervical smears should be performed routinely as for all women with a uterus. Compliance with treatment, symptom control, side effects (if any) and the bleeding pattern of those on combined treatment should be noted at each visit. The following examinations and investigations are commonly performed, but there is no universal agreement as to which of these are essential: 4.1.1 At first visit: FSH/LH/E2 to confirm menopause (if inical features atypical) Lipid profile/Liver function tests/Bone biochemistry/TSH Mammography 4.1.2. At each visit: Urinalysis Blood pressure 4.1.3. Every two years: Physical examination Lipid profile/Liver function tests Fasting glucose Mammography 4.1.4 As indicated: Bone mineral density studies 4.2. Management of irregular bleeding on HRT 4.2.1. Women using combined cyclical HRT Some women will be amenorrhoeic on this regimen, and a biopsy is not necessary. Bleeding should occur around the time of progestogen withdrawal. If bleeding occurs at times other than this or is persistently irregular, endometrial biopsy is recommended. 4.2.2. Women using continuous combined HRT Ideally women using continuous combined HRT should achieve amenorrhoea within about 4 months of starting treatment. Spotting in the first few months is common. Endometrial biopsy should be considered in women who develop irregular bleeding who were previously amenorrhoeic on this regimen. 5 EXAMPLES OF PREPARATIONS AVAILABLE IN HK AND NORMAL DOSES (AS OF 1/1/99) (the route of administration, generic name and trade name are separated by a comma) 5.1 Unopposed oestrogen Oral, Conjugated equine oestrogens 0.625mg daily, PREMARIN Oral, Oestradiol 2mg daily, ESTROFEM Oral, Oestradiol valerate 2mg daily, PROGYNOVA Gel, Percutaneous oestradiol gel 2.5g daily, OESTROGEL Patch, Oestradiol 4mg patches (2 patches/week), DERMESTRIL or ESTRODERM TTS 5.2 Combined cyclical (sequential) Oral, Oestradiol 2mg daily + dydrogesterone 10mg 14/28 days, FEMOSTON Oral, Oestradiol 2mg 22 days/1mg 6 days + norethisterone acetate 1mg daily 10/28 days, TRISEQUENS Oral, Oestradiol valerate 2mg 21 days + cyproterone acetate 1mg 10/28 days, CLIMEN Oral, Conjugated equine oestrogens 0.625mg 21/28 days + medrogestone 5mg 10/28 days, PREMPAK Oral, Conjugated equine oestrogens 0.625mg daily + medroxyprogesterone acetate 5mg 14/28 days, PREMELLE CYCLE Patch, Oestradiol 4mg patches (2 patches/week) for 2/52 followed by oestradiol 10mg + norethisterone acetate 30mg patches (2 patches/week) for 2/52, ESTROCOMB TTS 5.3 Continuous combined Oral, Conjugated equine oestrogens 0.625 mg + medroxyprogesterone acetate 2.5mg daily, PREMELLE Oral, Oestradiol 2 mg + norethisterone acetate 1mg daily, KLIOGEST Oral, Tibolone 2.5 mg daily, LIVIAL APPENDAGES: Appendix 1. Risk factors for osteoporosis 1. Prolonged oligomenorrhoea/amenorrhoea or a premature menopause 2. Prolonged immobilization/inactivity 3. Excessive intake of alcohol or caffeine; smoking 4. Those with low BMI, short stature, family history 5. Those taking drugs which predispose to osteoporosis e.g. steroids, thyroxine, anticonvulsants 6. Medical conditions which predispose to osteoporosis Cushing's Syndrome Hyperthyroidism Hyperparathyroidism Chronic diseases - liver or kidney Malabsorptive disorders Gastrectomy Rheumatoid arthritis Appendix 2. Risk factors for cardiovascular disease 1. Existing cardiovascular disease 2. Family history of cardiovascular disease 3. Hypercholesterolaemia 4. Smoking 5. Diabetes mellitus 6. Hypertension 7. Obesity REFERENCES: 1. Paganini-Hill A. Oestrogen replacement therapy and Alzheimer's disease. Br J Obstet Gynaecol 1996;103:80-86 2. Hunter MS. The effects of estrogen on mood and well-being. In: The Modern Management of the Menopause; A perspective for the 21st century. Berg G, Hammar M (eds). Parthenon Publishing, UK. 1994:177-184 3. Haines CJ, Chung TKH, Leung DHY. A prospective study of the frequency of acute menopausal symptoms in Hong Kong Chinese women. Maturitas 1994;18:175-181 4. Tang GWK. Menopausal symptoms. J Hong Kong Med Assoc 1993;45:249-254 5. Lindsay R. The role of estrogen in the prevention of osteoporosis. Endocrinol Metabol Clin North Am 1998; 27:399-409 6. Beale CM, Collins P. The menopause and the cardiovascular system. Baillieres Clin Obstet Gynaecol 1996;10:483-513 7. Burger CW. Kenemans P. Postmenopausal hormone replacement therapy and cancer of the female genital tract and breast. Current Opinion in Obstetrics & Gynecology 1998; 10:41-5 8. Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Pettiti D. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol 1995;85:304-14 9. Baynes KCR, Compston JE. Selective oestrogen receptor modulators: a new paradigm for HRT. Current Opinion in Obstetrics & Gynecology 1998;10:189-92 ACKNOWLEDGEMENT: This document was prepared by Professor CJ Haines, Dr Susan Fan, Professor GWK Tang and Dr LCH Tang and was endorsed by the Council of the Hong Kong College of Obstetricians and Gynaecologists. This guideline was produced by The Hong Kong College of Obstetricians and Gynaecologists as an educational aid and reference for obstetricians and gynaecologists practising in Hong Kong. The guideline does not define a standard of care, nor is it intended to dictate an exclusive course of management. It presents recognised clinical methods and techniques for consideration by practitioners for incorporation into their practice. It is acknowledged that clinical management may vary and must always be responsive to the need of individual patients, resources, and limitations unique to the institution or type of practice. Particular attention is drawn to areas of clinical uncertainty where further research may be indicated. HKCOG GUIDELINES NUMBER 2 (NOVEMBER 1998)