Hormone replacement therapy in young women with karyotypically normal spontaneous premature ovarian failure [protocol]

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1 Página 1 de 7 Hormone replacement therapy in young women with karyotypically normal spontaneous premature ovarian failure [protocol] Kalantaridou SN, Calis KA, Nelson LM. This protocol should be cited as: Kalantaridou SN, Calis KA, Nelson LM.. Hormone replacement therapy in young women with karyotypically normal spontaneous premature ovarian failure (Protocol for a Cochrane Review). In: The Cochrane Library, Issue 2, Oxford: Update Software. Background Present menopausal hormone replacement therapy regimens were designed for women who experience ovarian failure (normal menopause) around age 50. Postmenopausal women who take hormone replacement therapy prolong their exposure to estrogen beyond the average age of completion of their reproductive phase. At least 1% of women, however, experience premature ovarian failure before the age of 40, and optimal hormone replacement therapy regimens should be established for these younger women (Coulam 1986). For example, compared with normal postmenopausal women, women with premature ovarian failure need higher doses of estrogen to control menopausal symptoms. A prospective, randomised, controlled study showed that estrogen replacement therapy prevents bone loss in postmenopausal women (PEPI trial 1996). Furthermore, a prospective cohort study and a case-control study have shown that estrogen replacement decreases the risk for fractures in postmenopausal women (Cauley 1995; Michaelsson 1998). Nonetheless, in a small study, the recognized bone-sparing dose of mg of conjugated estrogen (Lindsay 1984) failed to prevent vertebral bone loss in premenopausal women made estrogen-deficient by gonadotropin-releasing hormone agonist therapy (Sugimoto 1993). Also, available evidence suggests that the usual menopausal hormone replacement therapy is not adequate to protect young women with premature ovarian failure from developing osteoporosis (Anasti 1998). Two-thirds of women with premature ovarian failure have femoral neck bone mineral density more than one standard deviation below the mean of similar age women with normal ovarian function, despite taking estrogen replacement therapy (Anasti 1998). Also, a prospective study has shown (Cummings 1993) that a femoral neck bone mineral density more than one standard deviation below the mean of age-matched controls predicts a 2.6-fold increased risk of hip fracture. The findings of these two studies suggest that two-thirds of women with premature ovarian failure may be at increased risk for hip fracture despite taking estrogen replacement. Premature ovarian failure is a condition that causes amenorrhea, elevated gonadotropins, hypoestrogenemia (Kalantaridou 1998) and hypoandrogenemia (Bermudez 1993). Young women can experience ovarian failure by several mechanisms, including karyotypic abnormalities, autoimmunity, radiation or chemotherapy, and surgical castration. In most cases the cause of premature ovarian failure is unknown (karyotypically normal spontaneous premature ovarian failure). Women with premature ovarian failure are at higher risk for cardiovascular disease compared to naturally menopausal women (Van der Schouw 1996; Jacobsen 1997). Also, women with premature ovarian failure have a nearly twofold agespecific increase in mortality rate compared to naturally menopausal women (Snowdon 1989; Cooper 1998). The aim of this review is to evaluate evidence from randomised controlled trials, if any, that hormone replacement (estrogen/progestin, estrogen/androgen/progestin or other types of hormone replacement strategies, such as for example tibolone) can maintain bone mass of women with spontaneous premature ovarian failure.

2 Página 2 de 7 Objectives To investigate whether the use of hormone replacement therapy can restore bone mass in young women with premature ovarian failure. We will test the hypothesis that "hormone replacement therapy (estrogen/progestin, estrogen/androgen/progestin or other types of hormone replacement strategies, such as for example tibolone) maintains bone of women with spontaneous premature ovarian failure. Secondary hypotheses will include: "hormone replacement therapy (estrogen/progestin, estrogen/androgen/progestin or other types of hormone replacement strategies, such as for example tibolone) can: 1) treat symptoms of sex steroid deficiency (such as hot flashes, night sweats, dyspareunia, e.t.c.), 2) decrease heart disease risk factors, 3) restore sexual function, and 4) restore cognitive function in women with premature ovarian failure". Criteria for considering studies for this review Types of studies Randomised controlled studies will be considered for inclusion in this review if they evaluate the effect of hormone replacement on bone mineral density and/or fractures of women with spontaneous premature ovarian failure. Only double blind randomised controlled studies will be considered suitable for inclusion. Randomised controlled studies evaluating the effect of hormone replacement on symptoms of sex steroid deficiency, heart disease risk factors, sexual or cognitive function in young women with premature ovarian failure will be considered as well. Types of participants Women with spontaneous premature ovarian failure and normal chromosomes receiving hormone replacement therapy. Criteria for karyotypically normal spontaneous premature ovarian failure: 1. Age > 18 and < 40 years 2. Two FSH levels > 40 miu/ml (at least one month apart) 3. Amenorrhea for at least four months 4. No evidence of genetic, metabolic, toxic, or iatrogenic cause of the ovarian failure Types of intervention Randomised controlled studies investigating the effect of hormone replacement (estrogen/progestin/androgen, or other types of hormone replacement strategies, such as for example tibolone; administered by all routes, i.e. orally and/or parenterally) on bone mineral density and/or fractures of women with premature ovarian failure will be considered suitable for inclusion in this review. All the randomised controlled studies with bone densitometry (measured by DEXA, DPA, etc) will be included. Studies investigating the effect of hormone replacement on symptoms of sex steroid deficiency, heart disease risk factors, cognitive or sexual function will be considered as well. One year should be the minimum length of the trials. Groups to be compared: 1. women with spontaneous premature ovarian failure receiving estrogen/progestin (or other types of hormone replacement strategies, such as for example tibolone)

3 Página 3 de 7 replacement compared with women with spontaneous premature ovarian failure receiving estrogen/androgen/progestin replacement 2. women with premature ovarian failure receiving estrogen/progestin (or other types of hormone replacement strategies, such as for example tibolone) replacement compared with women premature ovarian failure receiving placebo (or no treatment) 3. women with premature ovarian failure receiving estrogen/androgen/progestin replacement compared with women with premature ovarian failure receiving placebo (or no treatment). Types of outcome measures Studies will be considered suitable for inclusion in this review if they evaluate any of the following outcome measures in women with spontaneous premature ovarian failure receiving hormone replacement: Spinal bone mineral density (L2-4) and/or hip bone mineral density (femoral neck, trochanter, Ward's triangle, total hip) Vertebral and/or hip fracture rates Symptoms of sex-steroid deficiency (such as hot flashes, night sweats, dyspareunia), Heart disease risk factors (i.e. total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, body composition) Sexual and cognitive function In addition, any other outcome assessed in the trials will be considered as well. Search strategy for identification of studies The literature search will be limited initially to those studies reported in English. Trials reported in a foreign language will be sought over time as resources permit. All publications which describe randomised, controlled trials investigating the effect of hormone replacement on bone mineral density, symptoms of sex-steroid deficiency, heart disease risk factors, sexual and cognitive function of women with premature ovarian failure will be obtained using the search strategy developed by the Menstrual Disorders and Subfertility Group for MEDLINE and handsearching of specialist journals and examination of review articles (see Review Group details for more information). The reviewers will also search the electronic database EMBASE. In addition, the following terms and variations of these terms will be included: premature ovarian failure premature menopause hormone replacement therapy estrogens progestogens androgens tibolone Reference lists of included and excluded studies will be inspected. Investigators conducting randomised controlled trials examining the safety and efficacy of hormone replacement therapy in women with premature ovarian failure will be contacted to obtain study data and details of subsequent journal publication. Methods of the review The selection of trials for inclusion in the review will be undertaken by two reviewers (SNK and KAC) employing the search strategy described above. A third reviewer (LMN) will assess any trials where there will be uncertainty regarding eligibility. All the reviewers are experienced in clinical issues.

4 Página 4 de 7 An assessment of the quality of trials and data extraction will be performed independently by the three reviewers (SNK, KAC, LMN) using forms designed according to the Cochrane guidelines. Any discrepancies will be resolved by discussion. When necessary, additional information on trial methodology or actual original data will be sought from the principal author of any trials that appear to meet the eligibility criteria. Included trials will be analysed for the following quality criteria and methodological details: a) Method of randomizations; blinding; number of patients randomised, excluded, or lost to follow up; reporting of the outcome of all the women enrolled and whether the trial was single or multicentered; the presence of power calculation; duration of the study; sources of any funding. b) Information on the trial participants included age, number of years since the development of ovarian failure, exclusion criteria. c) Interventions used: types of therapeutic agent used, dose, duration, and timing of administration of therapeutic agents used. d) Outcomes: 1. Outcomes relevant to this analysis (e.g. changes in bone mineral density, changes in total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, body composition, sexual and cognitive function). Bone mineral density is the principal outcome measure. 2. Primary outcomes of the trial, which may differ from the outcomes relevant to this analysis 3. Adverse effects due to hormone replacement therapy will be recorded (such as endometrial hyperplasia and breast cancer). Major quality criteria will be given a ranking to enable sensitivity analyses. Results from trials using estrogen/progestin, estrogen/androgen/progestin, tibolone will be analysed separately. Dosages will be broken down for analysis as well. Sensitivity analysis will be performed according to randomizations quality, control group comparison (either placebo or no treatment), equality at baseline, rate of withdrawal and losses to follow-up, intention to treat analysis, and length of treatment period. Statistical analysis will be performed in accordance with the guidelines for statistical analysis developed by the Menstrual Disorders and Subfertility Group as it applies to continuous outcomes. Heterogeneity between the results of different studies will be examined by inspecting the scatter in data points and the overlap in their confidence intervals and by checking the results of the chi-squared tests. If the randomised controlled studies have different length of therapy, subgroup analysis will be performed. We will combine placebo- and no-treatment studies. These studies will be analysed separately as subgroups. This review will include eligible trials that are retrievable as of April Subsequent eligible trials will be included in an update of this review. Acknowledgements Potential conflict of interest None known References Additional references

5 Página 5 de 7 Anasti 1998 Anasti JN, Kalantaridou SN, Kimzey LM, Defensor RA, Nelson LM. Bone loss in young women with karyotypically normal spontaneous premature ovarian failure. Obstetrics and Gynecology 1998;91:12-5. Bermudez 1993 Bermudez JA, Moran C, Herrera J, Barahona E, Perez MC, Zarate A. Determination of the steroidogenic capacity in premature ovarian failure. Fertility and Sterility 1993;60: Cauley 1995 Cauley JA, Seeley DG, Ensrud K, Ettinger B, Black D, Cummings SR. Estrogen replacement therapy and fractures in older women. Study of osteoporotic fractures research group. Annals of Internal Medicine 1995;122:9-16. Cooper 1998 Cooper GS, Sandler DP. Age at natural menopause and mortality. Annals of Epidemiology 1998;8: Coulam 1986 Coulam CB, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstetrics and Gynecology 1986;67: Cummings 1993 Cummings SR, Black DM, Nevitt MC, Browner W, Cauley J, Ensrud K, Genant HK, Palermo L, Scott J, Vogt TM. Bone density at various sites for prediction of hip fractures. The Study of Osteoporotic Fractures Research Group. Lancet 1993;341:72-5. Jacobsen 1997 Jacobsen BK, Nilssen S, Heuch I, Kvale G. Does age at natural menopause affect mortality from ischemic heart disease?. Journal of Clinical Epidemiology 1997;50: Kalantaridou 1998 Kalantaridou SN, Davis SR, Nelson LM. Premature ovarian failure. Endocrinology and Metabolism Clinics of North America 1998;27: Lindsay 1984 Lindsay R, Hart DM, Clark DM. The minimum effective dose of estrogen for prevention of postmenopausal bone loss. Obstetrics and Gynecology 1984;63: Michaelsson 1998 Michaelsson K, Baron JA, Farahmand BY, Johnell O, Magnusson C, Persson PG, Persson I, Ljunghall S. Hormone replacement therapy and risk of hip fracture:

6 Página 6 de 7 population based case control study. The Swedish Hip Fracture Study Group. British Medical Journal 1998;316: PEPI trial 1996 The Writing Group for the PEPI trial. Effects of hormone therapy on bone mineral density. Results from the postmenopausal estrogen/progestin interventions (PEPI) Trial. The Journal of the American Medical Association 1996;276: Snowdon 1989 Snowdon DA, Kane RL, Beeson WL, Burke GL, Sprafka JM, Potter J, Iso H, Jacobs DR Jr, Phillips RL. Is natural menopause a biologic marker of health and aging?. American Journal of Public Health 1989;79: Sugimoto 1993 Sugimoto AK, Hodsman AB, Nisker JA. Long-term gonadotropin-releasing hormone agonist with standard postmenopausal estrogen replacement failed to prevent vertebral bone loss in premenopausal women. Fertility and Sterility 1993;60: Van der Schouw 1996 Van der Schouw YT, Van der Graaf Y, Steyerberg EW, Eijkemans MJC, Banga JD. Age at menopause as a risk for cardiovascular mortality. Lancet 1996;347: Cover sheet Hormone replacement therapy in young women with karyotypically normal spontaneous premature ovarian failure Reviewer(s) Contribution of Reviewer(s) Kalantaridou SN, Calis KA, Nelson LM. Sophia N. Kalantaridou: Took the lead in writing the protocol, developed objectives, selection criteria, methods and background. Karim A. Calis: Contributed to background section. Developed and performed search strategy. Lawrence M. Nelson: Conceptualised and edited the protocol. Issue protocol first published Date of last minor amendment Date of last substantive amendment Most recent changes 2001 issue 4 Information not supplied by reviewer 05 August 2001 Information not supplied by reviewer

7 Página 7 de 7 Review expected to be published in: Contact address Cochrane Library number Editorial group Editorial group code Issue 4, 2003 Ms Sophia Kalantaridou Kosti Palama 3 Ioannini GREECE 5042 Telephone: Facsimile: Kalantas@exchange.nih.gov CD Cochrane Menstrual Disorders and Subfertility Group MENSTR