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Hormone Replacement Therapy

I. A Pharmacoeconomic: Appraisal of its Therapeutic Use in Menopausal Symptoms and Urogenital Estrogen Deficiency

  • Pharmacoeconomic Drug Evaluation
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Abstract

Synopsis

Menopause and the accompanying reduction in estrogen production may cause a number of symptoms in women which include hot flushes, sweating, mood and sleep disturbances, fatigue and urogenital dysfunction. The effectiveness of estrogen-based hormone replacement therapy (HRT) in ameliorating these symptoms, and in preventing long term sequelae such as osteoporosis. is well established. Comparative trials indicate that oral conjugated estrogens O.625mg, oral ethinyl estradiol O.02mg and transdermal estradiol O.05mg have equivalent efficacy in relief of mild to moderate menopausal symptoms and prevention of bone mineral loss. Concomitant progestogen therapy is usually prescribed/or women with intact uteri 10 protect against endometrial hyperplasia and carcinoma. The addition of progestogen maintains and may even enhance the bone-conserving effects of estrogen, and continuous regimens appear to reduce the incidence of irregular menses. Adverse reactions are predominantly local skin irritation with transdermal preparations (14% of patients) and systemic effects common to most forms of HRT including breast tenderness, flushing, headache and irregular bleeding, occurring in ≤ 2% of patients.

Data concerning the effect of HRT on quality of life are limited, but most analyses have assigned utility values of 0.99 for mild and 0.95 for severe menopausal symptoms. However, recent clinical data suggest that these utility values may underestimate the impact of menopausal symptoms on quality of life. The cost benefit and cost effectiveness of HRT in the treatment of menopausal symptoms have not been fully researched, although preliminary results suggest that conjugated estrogens and transdermal estradiol compare well with alternative therapies such as veralipride and Chinese medicines. A Swedish study using a prevalence-based approach estimated that estriol treatment in all women with urinary incontinence aged ≥ 65 years resulted in monetary savings compared with treating 20% of women. Cost-utility data indicated that the change in quality-adjusted life years (QALYs) with HRT was always positive, but the degree of change was determined by the baseline assumptions. Estimated changes in QALYs with HRT ranged from 0.006 for 5 years of treatment with unopposed estrogen in women with intact uteri, to 0.5 for 10 years of the same treatment in women with severe menopausal symptoms following hysterectomy. Compliance with HRT is suboptimal as 5 to 50% of women withdraw from therapy, thereby increasing costs per year of life saved.

Thus, HRT is both medically and economically justified in women with severe menopausal symptoms, whereas compliance is an important factor in determining economic benefit in women with less severe symptoms. During long term therapy the associated beneficial effects on osteoporosis and cardiovascular parameters, and patient monitoring requirements, will assume greater significance.

Treatment Considerations

As women approach the climacteric or have menopause surgically induced. a number of physiological changes occur as a result of decreased estrogen production. Vasomotor instability (hot flushes and sweating), mood and sleep disturbances, fatigue, and difficulties with memory and concentration occur in approximately 80% of women. These symptoms may continue for several years, with more than 15% of women still experiencing vasomotor symptoms after 10 years. Dyspareunia and urinary incontinence occur in approximately 40% of women, caused by atrophy of tissues in the urogenital organs due to estrogen deficiency. While there are many alternative treatments available, estrogen-based hormone replacement therapy (HRT is the only option that has proven efficacy in alleviating symptoms as well as in osteoporosis prevention.

Efficacy, Benefits and Risks

Oral formulations of HRT undergo substantial first-pass metabolism in the liver. This necessitates higher oral dosages compared with non-oral formulations (e.g. transdermal. vaginal, percutaneous, subcutaneous) for equivalent effect and results in a high plasma estrone: estradiol ratio. However. the elevation in plasma estradiol levels induced by therapeutically equivalent dosage regimens results in similar pharmacodynamic effects. Raised levels of follicle-stimulating hormone (FSH) and luteinising hormone (LH) are reduced, and vaginal cytology resembles the premenopausal state.

Comparative clinical trials have demonstrated effective relief from menopausal symptoms with oral and transdermal estrogens. Cyclic administration of concomitant progestogens maintained symptom relief, but resulted in periodic bleeding; this was largely ameliorated by continuous regimens. Intravaginal HRT application effectively relieves urogenital symptoms but does not raise plasma estradiol levels to therapeutic concentrations.

Compliance is a major therapeutic concern with HRT, as prolonged therapy is necessary for most beneficial effects. At present, approximately 10% of postmenopausal women receive HRT. Between 5 and 50% of women withdraw from therapy because of cyclic bleeding episodes, adverse effects, fear of cancer, or lack of effect on symptoms, or on the advice of their doctor.

The predominant adverse effect occurring in women receiving transdermal HRT is local skin irritation. reported in about 14% of patients. Other effects are common to most forms of HRT and include breast tenderness, flushing, headache, fluid retention, nausea and vomiting, irregular bleeding, vaginal discharge and depression. The majority of these symptoms occur in < 2% of patients, and in many cases symptoms may diminish with adjustment of the dosage regimen.

Data concerning quality-of-life changes with HRT are limited, but most pharmacoeconomic studies have assumed that menopausal symptoms reduce quality of life by a utility factor of 0.05 in patients with severe and 0.01 in those with mild symptoms. More recent clinical data indicate that these utility values may have underestimated the impact of menopausal symptoms on well-being. Comparative data concerning quality of life in patients receiving HRT or symptomatic treatment with veralipride for 6 months indicate a clear advantage for HRT.

Pharmacoeconomic Considerations

Cost-effectiveness studies have compared the value of several alternative therapies for menopausal symptoms, determined by the efficacy of each regimen in reducing or eliminating symptoms. Conjugated estrogens and transdermal estradiol were both relatively cost effective compared with symptomatic treatments, although deficiencies in study design suggest that confirmation of these results is desirable. Assuming 100% compliance, cost-utility analyses determined that quality-adjusted life year (QALY) changes with HRT were always positive in women experiencing menopausal symptoms, but concluded that costs per QALY were most advantageous in women with severe symptoms or longer therapy duration, and in women who had undergone hysterectomy. Economic benefits of combined estrogen and progestogen therapy compared with unopposed estrogen therapy in women with intact uteri differed according to baseline assumptions. Sensitivity analyses indicated that decreasing compliance to 50% after 5 years of therapy reduced annual programme costs, but increased the cost per year of life saved (YLS) from £10 800 to £12 600.

Direct costs due to menopausal changes have been assessed for urogenital deficiency. Laundry costs for incontinence have been estimated at between 22 and 26 Swedish kronor per day per patient aged ≥ 65 years. No data are available for women aged between 50 and 65 years. Cost-benefit analysis of estriol treatment of urogenital dysfunction in Swedish women estimated that treatment of all women aged > 65 years would result in cost savings compared with treatment of 20% of women. Savings in sanitary materials, laundry costs and treatment for urinary tract infections offset the increased costs for oral and vaginal estriol.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Ruth Whittington & Diana Faulds

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  1. Ruth Whittington
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Various sections of the manuscript reviewed by: M.M.C. Botelho, Department of Gynaecology and Obstetrics. University Hospital of Santa Maria, Lisbon, Portugal; J.E. Compston, Department of Medicine, Uni versity of Cambridge School of Clinical Medicine, Cambridge, England; E. Daly, Department of Public Heallh and Primary Care, Radcliffe Infinnary, Oxford, England; B. Honsberger. Research Group for Management in Health Services for the University of Gallen, Gallen, Switzerland; J.A. Kanis, Sheffield Metabolic Bone Unit, University of Sheffield, Sheffield, England; S.K. Khoo, Depanmem of Obstetrics and Gynaecology, University of Queensland, Royal Brisbane Hospital, Herston, Queensland, Australia; B. Lindgren, Department of Community Health Sciences, Lund University, Malmo, Sweden; J. Rovira, Asociacion de Economia de la Salud, Barcelona, Spain; J.E. Tieffenberg, Asociación de Investigación y Desarrollo en Salud, Buenos Aires, Argentina; A.N.A. Tosteson, Dartmouth-Hitchcock. Medical Center, Danmouth Medical School, Lebanon, New Hampshire, USA; W.H. Utian, Department of Obstetrics and Gynecology, Universi ty MacDonald Womens Hospital, Cleveland, Ohio. USA; B.G. Wren, Edgecliff, New South Wales, Australia.

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Whittington, R., Faulds, D. Hormone Replacement Therapy. Pharmacoeconomics 5, 419–445 (1994). https://doi.org/10.2165/00019053-199405050-00008

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