New products and regimens

The downturn in the use of hormone replacement therapy since the original publication of the Women’s Health Initiative (2002) and Million Women studies (2003) has now stabilized. New products are now being developed which maintain benefits and minimise risks. However, some useful products have been withdrawn by Pharma companies through profitability decisions; other products will regrettably not be launched despite favorable data. New lowand ultra-low-dose oral preparations (containing 0.3 mg conjugated equine estrogens and 0.5 mg estradiol, respectively) appear to maintain benefits for symptom relief and osteoporosis whilst minimizing sideeffects and risks. A 14 mg transdermal system appears to maintain bone protection without the need for endometrial protection. New progestogens can minimize progestogenic side-effects through antiandrogenic and antimineralocorticoid effects, e.g. drospirenone, bioidentical progesterone and selective progesterone receptor modulators. A new female androgen patch has been licensed in Europe for treatment of low libido causing distress (hypoactive sexual desire disorder) in surgically menopaused women on estrogen therapy. A non-hormonal option, desvenlafaxine succinate (a serotonin and noradrenaline reuptake inhibitor), for vasomotor symptoms is currently in phase-III clinical trial stage and should be launched in the next year. Additionally, a selective estrogen receptor modulator/conjugated equine estrogen preparation combination currently in phase-III clinical trials is showing encouraging data for efficacy/risks and should provide a further option for women using hormone therapy in the future. TRENDS IN HRT USAGE AND DEVELOPMENT As a result of adverse publicity on the purported risks of hormone replacement therapy (HRT) arising from publication of the Women’s Health Initiative (WHI) study and the Million Women Study (MWS) in 2002/2003, there was a significant downturn in HRT usage which dropped by up to 50% in some countries. The last couple of years have seen stabilization of usage, following recent favorable data on cardiovascular and breast cancer risks and life expectancy. Menopause remains a serious issue which most women feel should be treated. Consequently, both clinicians and scientists have started to look at ways in which the benefits of HRT can be maintained whilst side-effects and risks can be minimized. Correspondence: Dr N. Panay, Queen Charlotte’s and Chelsea & Westminster Hospitals, 150 Du Cane Road, London W12 0HS, UK CLIMACTERIC 2007;10(Suppl 2):109–114 a 2007 International Menopause Society DOI: 10.1080/13697130701549301 However, in view of the decline in the HRT market, some pharmaceutical companies have been reluctant to invest time and money in the development and promotion of new HRT products. Some less profitable products, e.g. nasal estrogen, have recently been withdrawn from the market, thus denying some individuals the only HRT which suits them. This paper will examine the different ways in which some formulations have evolved over the last few years in an attempt to achieve the holy grail of symptom relief without compromise. NEW DOSING OF ORAL FORMULATIONS New data suggest that the benefits of HRT can be maintained with lower doses than previously used whilst minimizing risks and possibly side-effects. HRT has evolved from standard-dose through to low-dose regimens, e.g. conjugated equine estrogens 0.3 mg (Wyeth Pharmaceuticals). After initial dose-ranging studies of estradiol confirming efficacy at lower doses than previously thought possible, ultra-low-dose regimens of 0.5 mg estradiol in combination with 0.25 and 0.1 mg norethisterone acetate have been studied. Data from a recent study, The Clinical Study on Hormone Dose Optimization in Climacteric Symptoms Evaluation (CHOICE), showed maintenance of efficacy of symptom relief with high amenorrhea rates, minimal adverse events and neutrality to the breast and metabolism. CHOICE was a randomized, placebo-controlled, prospective, multicenter study of 0.5 mg 17b-estradiolþ 0.1 mg norethisterone acetate (NETA) or 0.5 mg 17b-estradiolþ 0.25 mg NETA (Novo Nordisk FemCare). Statistical significance compared to placebo was reached by week 3 for all primary endpoints, e.g. the reduction in number and severity of moderate to severe hot flushes (Figure 1). Other investigated parameters also showed rapid significant reduction in the active treatment groups compared to placebo, including the hot flush weekly weighted score. The Greene Climacteric Scale scores, particularly ‘difficulty in sleeping’, also achieved rapid statistically significant improvement. Improvements in these outcome measures with these ultra-low-dose combinations were comparable to the benefits previously achieved with higher-dose preparations. Safety data from the CHOICE study indicate that treatment with the ultra-low-dose continuous combined HRT (ccHRT) resulted in extremely favorable amenorrhea rates of 89% from the very outset of the treatment. These amenorrhea rates are higher than those achieved with commonly used standardor low-dose ccHRT. This favorable bleeding profile of the ultra-low-dose ccHRT resulted in a drop-out rate of only 1% for both ultra-low-dose combinations due to bleeding. Data in a subset of women from the CHOICE study (154 subjects) showed that the ultra-lowdose preparations produced no significant difference in mammographic density (visual and digitized) compared to placebo after 24 weeks of therapy (Figure 2). There was also no significant difference between the groups in terms of breast discomfort, pain and tenderness. It is hoped that this dose-response effect could translate to neutrality on the breast with the ultra-low-dose Figure 1 Number of moderate to severe hot flushes per week in the CHOICE trial. ALD 0.1, 0.5 mg 17b-estradiol þ0.1 mg norethisterone acetate (NETA); ALD 0.25, 0.5 mg 17b-estradiolþ 0.25 mg NETA New products and regimens Panay