January 24, 2008
Advances in Hormone Replacement Therapy: Weight Benefits of Drospirenone, a 17[Alpha]-Spirolactone-Derived Progestogen
By Foidart, Jean-Michel Faustmann, Thomas
Abstract Hormone replacement therapy (HRT) remains the most effective treatment for menopausal symptom relief, and may provide cardiovascular benefits in younger women initiating treatment soon after menopause. However, large surveys indicate that many symptomatic women refuse or discontinue HRT prematurely owing to fear of weight gain. A continuous combined HRT containing 17beta- estradiol (E^sub 2^) 1 mg plus drospirenone (DRSP) 2 mg is effective in relieving menopausal symptoms and preventing postmenopausal osteoporosis. DRSP is a unique synthetic progestogen with a pharmacological profile similar to that of natural progesterone, including antialdosterone activity, a property not exhibited by other synthetic progestogens. DRSP can therefore reduce estrogen- related sodium and water retention in postmenopausal women receiving HRT via the renin-angiotensin-aldosterone system, which regulates sodium and water balance. This may translate into weight benefits. Pooled data from two placebo-controlled clinical trials (n = 333) indicated statistically significant weight loss of - 1.5 kg at 6 and 12 months in postmenopausal women receiving E^sub 2^/DRSP vs. placebo (p
Keywords: Drospirenone, hormone replacement therapy, progestogen, body weight, antialdosterone, renin-angiotensin-aldosterone system
The menopause, the permanent cessation of menstruation, is experienced by the majority of women in their early fifties. As life expectancy continues to increase, women are likely to spend more than a third of their lives postmenopause. In 2000, there were an estimated 45.6 million postmenopausal women in the USA alone . These demographic changes are expected to increase the number of menopausal and postmenopausal women to over 1 billion globally in 2030, with approximately 47 million women experiencing the menopause annually . Approximately 80% of women have menopausal symptoms, of whom 45% find the symptoms distressing [3,4].
Hormone replacement therapy (HRT) remains the most effective treatment for the relief of menopausal symptoms [4-6]. Indeed, current European and US menopause society guidelines strongly recommend use of HRT for the relief of menopausal and urogenital symptoms, and for the prevention of bone loss [4,5,7-10]. Menopausal symptoms are varied, ranging from transient, inconvenient and distressing physical and psychological symptoms, such as hot flushes, insomnia and mood changes, to more serious long-term conditions, such as increased risk of fractures due to osteoporosis. Evidence from numerous studies has shown that HRT can relieve vasomotor symptoms, protect against osteoporosis and fractures [1,4- 9,11,12], provide a cardioprotective effect [13-18], preserve cognitive function [19,20] and, ultimately, lead to an improved quality of life for postmenopausal women .
Despite the overwhelming body of evidence for its benefits, some symptomatic postmenopausal women choose not to take HRT, or discontinue therapy at an early stage. Widespread media communication of the results of the Women's Health Initiative (WHI) study and die Heart and Estrogen/progestin Replacement Study (HERS) has contributed to the concerns and uncertainties many women have about HRT [22-30]. Initial reports of data from these large-scale studies did not support the cardioprotective effects of HRT described previously in numerous observational studies of postmenopausal women [13,14], but instead suggested an increased risk for cardiovascular disease. However, recent publication of comprehensive analyses of the data from the WHI and HERS trials, and odier studies, suggest that HRT is cardioprotective in younger (
Unfortunately, since the initial reports of the WHI data in 2002, many postmenopausal women consider HRT to be associated with more risks and fewer benefits than they had previously thought [26-34]. Specific issues cited are increased risk of breast cancer and heart disease. With respect to menopause symptoms, many women cited bleeding disturbance with HRT as a significant issue. Lifestyle issues also affect women's attitudes to HRT, and the potential for weight gain is a significant problem. Fear of gaining weight is frequently given as a reason why many postmenopausal women do not wish to take, or choose to discontinue, HRT [31,33-35].
The present paper reviews women's attitudes to HRT post-WHI, and considers the reasons they choose not take HRT, with a focus on weight gain. The reasons why weight gain is frequently associated with menopause are discussed further, and the possibility that continuous combined HRT products containing new progestogens could contribute to the maintenance of body weight in postmenopausal women is explored.
Perceptions of hormone replacement therapy
Studies in Europe and the USA illustrate the different expectations women have of HRT, depending on their socioeconomic and cultural backgrounds [26,31-34,36-38]. Women questioned also demonstrated differences in their understanding of the changes they were likely to experience during the menopause. Their knowledge of the benefits and risks of HRT also varied considerably. One reason cited by women in all geographical groups for not wanting to use HRT, or for stopping their HRT treatment early, is the potential for weight gain.
In telephone surveys of postmenopausal women in Europe (n = 8012) and the USA (n = 5002), concerns regarding the increased risk of breast cancer and cardiovascular disease were cited as reasons for discontinuing HRT [31,33], but weight gain was also ranked surprisingly high as an unacceptable risk associated with therapy. A further US study found that a higher number of women discontinued HRT due to their worries about weight gain and monthly bleeding associated with initiating therapy than the number of women who actually experienced these side-effects while receiving treatment .
A retrospective pre-WHI study of new HRT users found that early treatment cessation was more frequent in younger women who did not have an obstetrician/gynecologist as their initial HRT prescriber . This finding suggests that a significant number of women will not gain the additional long-term benefits of therapy. An initial consultation that includes a full explanation of the benefits of HRT may therefore encourage a woman to make a more informed choice about her treatment.
Weight gain during the menopause
A range of different factors might contribute to the weight gain often experienced at this time in a woman's life [41-43]. A natural decrease in the basal metabolic rate reduces calorie use, leading to an increase in body weight . Fat mass is typically redistributed, resulting in an increase in the waist-to-hip ratio in menopausal women [42,44,45]. In many cases, this increased adiposity and altered fat distribution appears to be a consequence of both reduced energy expenditure and the decline in endogenous estrogens . Some clinical studies have shown that weight gain and change of fat distribution can be an estrogen-related effect of HRT treatment [47-49], although others report no significant effect of HRT on body weight [50-52]. As the fear of weight gain is often cited as a reason for not taking HRT, women who are confident that HRT will not cause a weight increase are more likely to be receptive to treatment.
Hormone replacement therapy and the renin-angiotensin- aldosterone system
The renin-angiotensin-aldosterone system (RAAS) plays a critical role in the regulation of body fluids, serum sodium, potassium and blood pressure via the angiotensin-mediated stimulation of aldosterone production [53,54] (Figure 1). Aldosterone acts on die kidney to conserve sodium and water, and eliminate potassium. Endogenous and synthetic estrogens increase the synthesis of angiotensinogen (the angiotensin precursor) by the liver. The consequent stimulation of the RAAS leads to increased production of aldosterone. Subsequent sodium and water retention leads to increased plasma volume, water retention symptoms, such as edema and weight gain, and, in susceptible women, to elevation of blood pressure. In premenopausal women, estrogen-induced stimulation of the RAAS is countered by progesterone, which competes with aldosterone at the mineralocorticoid receptor, thereby opposing any estrogen-mediated effects and preventing fluid retention [53,54]. Figure 1. Schematic of the renin-angiotensin-aldosterone system (DRSP, drospirenone).
Oral therapy with natural or synthetic estrogens, such as HRT, can affect the RAAS. Oral estrogens are rapidly absorbed in the gut and then undergo their first pass through the liver at high levels [55,56], excessively stimulating angiotensinogen and, consequently, aldosterone production. The conventional synthetic progestogens used in continuous combined HRT do not exhibit the antimineralocorticoid activity of natural progesterone [53,54]. Many of these progestogens are derived from testosterone, and their progestogenic effects are attributable to their androgenic properties and glucocorticoid effects. Therefore they are unable to block the aldosterone receptor and are consequently unable to counter the estrogen-induced increase in aldosterone levels, leading to fluid retention which is the key to HRT-associated weight gain .
Drospirenone: The ideal progestogen
A synthetic progestogen is primarily used in combined continuous HRT to counter the estrogen-mediated proliferation of the uterine endometrium in women with an intact uterus. The ideal synthetic progestogen would have properties that closely mimic the activity of endogenous progesterone and therefore potentially offer additional benefits. Drospirenone (DRSP), derived from 17alpha-spirolactone, is a novel synthetic progestogen which has activity closer to natural progesterone than other synthetic progestogens [54,57-59]. Indeed, DRSP is the only synthetic progestogen to have significant antialdosterone properties (Table I) [54,57-59]. As a potent aldosterone antagonist, DRSP acts on the mineralocorticoid receptor to prevent sodium retention, and thus reduces estrogen-related water retention associated with HRT. DRSP also has antiandrogenic properties that may counteract the negative effect of androgens on hair growth, lipid changes, insulin and, possibly, body composition in postmenopausal women . Like natural progesterone, DRSP has no effect on either glucocorticoid or estrogen receptors.
Symptoms of premenstrual syndrome (PMS) can have a significant negative effect on quality of life, encompassing mood swings, irritability, water retention, and breast tenderness. In women suffering from premenstrual dysphoric disorder (PMDD), the severity of symptoms entirely disrupts normal functioning in daily life (e.g. relationships, work). The etiology of these disorders is unknown; however, treatment with the aldosterone antagonist, spironolactone, is effective in alleviating some of these symptoms and improving quality of life. As DRSP has antialdosterone activity, it is therefore likely to improve these quality-of-life-affecting somatic symptoms. Indeed, the combination of DRSP and ethinyl estradiol (EE) as an oral contraceptive has shown significant benefits on general well-being and PMS symptoms, especially physical symptoms, and improvements in health-related quality of life in several studies [60-62]. A combination containing DRSP 3 mg and EE 20 [mu]g in a new 24/4 regimen (24 active pills + 4 placebo pills) has demonstrated relief of emotional and physical symptoms of PMDD in large clinical trials [63,64]. The HRT combination of 17beta-estradiol (E^sub 2^) 1 mg plus DRSP 2 mg (Angeliq(R); Bayer Schering Pharma AG, Berlin, Germany) has also shown quality-of-life benefits in postmenopausal women .
In addition, contrary to the commonly held belief that HRT causes weight gain, clinical studies of E2 1 mg plus DRSP 2 mg demonstrated that this combination may actually help maintain or even slightly decrease body weight . It is the unique pharmacological profile of DRSP (Figure 2) that translates into additional clinical benefits for postmenopausal women [53,54,66] and may contribute to improved HRT acceptance and compliance .
Table I. Comparison of drospirenone with other progestins [54,57- 59].
Figure 2. Pharmacological and clinical effects of aldosterone and antialdosterone action of drospirenone [53,54"66] (CNS, central nervous system; PARA, progestogen with aldosterone receptor antagonism).
Drospirenone: Benefits on body weight
Evidence for the benefits of E^sub 2^/DRSP with respect to body weight is increasing as further studies are carried out. A standardized weight measurement is taken as part of the safety assessment in all E^sub 2^/DRSP trials - analysis of these data has demonstrated that the unique pharmacological profile of DRSP translates into clinical benefits in terms of body weight maintenance, as summarized below.
Data from two placebo-controlled studies of E2 1 mg/DRSP 2 mg in postmenopausal women with an intact uterus were pooled to estimate weight change compared with placebo for up to 12 months. These two trials were selected for pooling because they are the only long- term (at least 12 months) placebo-controlled studies conducted with E^sub 2^/ DRSP; both trials used the same criteria for body weight measurement.
The first study was a double-blind, placebo-controlled, 2-year trial enrolling 240 postmenopausal women with an intact uterus, aged 45-65 years . The study was designed to investigate the effects of treatment with different dosages of DRSP in combination with E^sub 2^ 1 mg on bone parameters. Weight measurements were standardized by using the same balance throughout the study: patients removed their shoes and were allowed to wear only light indoor clothing.
The second trial was a 1-year, double-blind, placebo-controlled, parallel-group study assessing die effects of E^sub 2^/DRSP on dermatological parameters (Bayer Schering Pharma AG, data on file). A total of 94 postmenopausal women with an intact uterus were enrolled. In all, 93 women (mean age 58.1 years) were evaluated over thirteen 28-day cycles. Treatment compliance was high throughout the study in both the E^sub 2^/DRSP (n = 47) and placebo groups (n = 46). Weight was measured routinely at every visit; again, the same balance was used throughout, and patients wore only light indoor clothing without shoes.
The pooled data showed a statistically significant weight loss of approximately -1.5 kg at both 6 and 12 months in women treated with E^sub 2^/DRSP vs. placebo (p
A beneficial effect on body weight was also observed in a 1- year, multicenter, double-blind, randomized, parallel-group study of postmenopausal women that was carried out to determine the effect of thirteen 28-day cycles of E^sub 2^/DRSP compared with E^sub 2^ monotherapy . A total of 1147 postmenopausal women with an intact uterus were enrolled in the study, of whom 1142 were evaluated. Mean body weight at baseline was comparable for all treatment groups. Throughout the treatment period, women receiving E^sub 2^ 1 mg combined with DRSP 2 mg registered constant body weight or loss of weight, whereas increases in weight were recorded in those receiving E^sub 2^ 1 mg monotherapy (Figure 3; p
Table II. Estimated change in body weight: estradiol/ drospirenone vs. placebo (kg) in 333 women.
The effect of the E^sub 2^/DRSP combination on amount and distribution of body fat has also been studied in a randomized, double-blind, placebo-controlled trial . A total of 240 healthy postmenopausal women (53-65 years old) were randomized to placebo or E2 plus DRSP for 2 years. Among the main outcome measures were the changes in central (CFM) and peripheral fat mass (PFM). Topographic distribution of body fat was measured using the CFM/PFM ratio. Women receiving E^sub 2^ 1 mg/DRSP 2 mg showed a decrease in CFM from baseline at months 6 (-0.37 kg) and 24 (-0.56 kg). PFM was decreased at 6 months (-0.33 kg) but increased at 24 months (+0.26 kg). At month 24, the CFM/PFM ratio was significandy lower than at baseline (-0.047 kg; p
DRSP in combination with EE as an oral contraceptive has also shown benefits with respect to body weight. A large, multicenter, open-label, randomized trial in Europe compared the efficacy, cycle control and tolerance of the monophasic oral contraceptive EE 30 [mu]g/DRSP 3 mg (Yasmin(R); Bayer Schering Pharma AG) with an oral contraceptive containing EE 30 [mu]g plus desogestrel (DSG) 150 [mu]g (Marvelon(R); Organon, The Netherlands) . Overall, 887 women were randomized to receive treatment over 26 cycles with a 3- mondi follow-up. Body weight measurements without clothing were made at home in the morning, prior to breakfast, using the same scales each time. During the study weight was checked every cycle on the first day of taking the medication, then weekly, always on the same day of the week, including the tablet-free intervals. For the first 35 days of follow-up, weight was checked on the same day, each week.
Figure 3. Change in body weight in postmenopausal women: estradiol (E^sub 2^) 1 mg/drospirenone (DRSP) 2 mg (n = 227) compared with E^sub 2^ (n = 226). Adapted from  with permission from Lippincott Williams & Wilkins.
A significant difference in body weight was seen between the two treatment groups throughout the study. In the EE/DRSP group, mean body weight per cycle remained just under baseline throughout the study (range -0.22 to -0.68 kg), apart from cycles 25 and 26, whereas in the EE/DSG group the mean body weight was above baseline (range +0.02 to +0.89 kg) throughout the study except for cycles 1- 5 (range -0.01 to -0.15 kg). The differences between treatment groups were significant over cycles 1-13 (p = 0.0001) and 14-26 (p = 0.0009). Mean body weight was above baseline in both treatment groups during the follow-up phase . Although overall a decrease was seen in the EE/ DRSP group and an increase was seen in the EE/ DSG group, the majority of women in both groups maintained a stable body weight (within 2 kg of baseline). However, the number of women gaining or losing more than 2 kg did differ between the treatment groups, with more women in the EE/ DRSP cohort losing > 2 kg and more women in the EE/DSG cohort gaining > 2 kg . These findings indicated that overall the EE/DRSP combination has a favorable effect on body weight, and were consistent with another large-scale study comparing these two oral contraceptives over 13 cycles .
HRT remains one of the most effective treatments for the management of vasomotor symptoms during the menopause [4-6]. Among the reasons why women decide against HRT, the fear of weight gain remains one of the most frequently cited [31,33-35]. Compliance with HRT is the result of a complex process that is influenced by perceptions and expectations of HRT, and attitude to the prevention of osteoporosis and cardiovascular disease when treatment is initiated. Individual women's knowledge and expectations regarding HRT treatment should, therefore, be addressed by physicians when prescribing HRT.
Increased efforts are needed to improve HRT compliance through improved education and better treatment options. By helping to maintain or slightly decrease body weight, E2/DRSP may overcome one of the major hurdles to optimal treatment concerning many women with conventional HRT products. Studies in postmenopausal women indicate diat E2/ DRSP is an effective HRT regimen, not only providing quick and effective relief of vasomotor symptoms  and protecting against postmenopausal osteoporosis , but also having benefits regarding weight maintenance and a blood pressure-lowering effect in hypertensive menopausal women that has not been shown with other HRT options [72-74]. These additional beneficial effects are due to the antialdosterone antagonism activity of DRSP, the only synthetic progestogen to exhibit these properties [53,54,57-59,66].
1. Menopause practice: A clinician's guide [Internet]. Cleveland (OH): North American Menopause Society; date unknown [cited 2007 June 7]. Available from: http://www.menopaus. org/edumaterials/ cliniciansguide/cliniciansguidetoc.htm
2. Hill K. The demography of menopause. Maturitas 1996; 23:113- 127.
3. Consensus conference on hormone replacement therapy Final consensus statement [Internet]. Edinburgh: Royal College of Physicians of Edinburgh; October 2003 [cited 2007 June 7]. Available from: http://www.rcpe.ac.uk/education/ standards/consensus/ hrt_03.php
4. National Institutes of Health. National Institutes of Health State-of-the-Science Conference statement: management of menopause- related symptoms. Ann Intern Med 2005; 142:1003-1013.
5. Skouby SO, Al-Azzawi F, Barlow D, Calaf-Alsina Erdogan Ertungealp J, Gompel A, Graziottin A, Hudita D, Pines A, Rozenberg S, et al. European Menopause and Andropause Society. Climacteric medicine: European Menopause and Andropause Society (EMAS) 2004/ 2005 position statements on peri- and postmenopausal hormone replacement therapy. Maturitas 2005;51:8-14.
6. MacLennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev 2004;(4):CD002978.
7. North American Menopause Society. Estrogen and progestogen use in peri- and postmenopausal women: March 2007 position statement of The North American Menopause Society. Menopause 2007;14:168-182.
8. Recommendations on postmenopausal hormone therapy. Update to the original IMS Position Statement in Climacteric 2004;7:8-11 [Internet]. Lancaster (UK): International Menopause Society; 2007 Feb 27 [cited 2007 June 7]. Available from: http:// www.imsociety.org/pdf_files/comments_ and_press_statements/ ims_press_statement_27_02_07.pdf?SE SSID=jbtblkcosb 1 roa 118msar3c220
9. Managing the menopause. British Menopause Society Council consensus statement on hormone replacement therapy [Internet], Marlow, (UK): British Menopause Society; 2006 Jun 10 [cited 2007 June 7]. Available from: http://www.thebms. org.uk/ statementcontent.php?id= 1 #
10. Center for Drug Evaluation and Research. Guidance for industry: Estrogen and estrogen/progestin drug products to treat vasomotor symptoms and vulvar and vaginal atrophy symptoms - recommendations for clinical evaluation. Rockville, (MD): US Department of Health and Human Services, Food and Drug Administration; January 2003.
11. Utian WH. Psychosocial and socioeconomic burden of vasomotor symptoms in menopause: a comprehensive review. Health Qual Life Outcomes 2005;3:47.
12. Torgerson DJ, Bell-Syer SE. Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials. J Am Med Assoc 2001;285:2891-2897.
13. Grady D, Ruben SB, Petitti DB, Fox CS, Black D, Ettinger B, Ernster VL, Cummings SR. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016- 1037.
14. Stampfer MJ, Colditz G. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med 1991;20:47-63.
15. Hsia J, Criqui MH, Herrington DM, Manson JE, Wu L, Heckbert SR, Allison M, McDermott MM, Robinson J, Masaki K; Women's Health Initiative Research Group. Conjugated equine estrogens and coronary heart disease. Arch Intern Med 2006;166:357-365.
16. Grodstein F, Manson JE, Stampfer M. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. J Womens Health 2006;15:35-44.
17. Salpeter SR, Walsh JM, Greyber E, Ormiston TM, Salpeter EE. Mortality associated with hormone replacement therapy in younger and older women: a meta-analysis. J Gen Intern Med 2004;19:791-804.
18. Alexandersen P, Tanko LB, Bagger YZ, Qin G, Christiansen C. The long-term impact of 2-3 years of hormone replacement therapy on cardiovascular mortality and atherosclerosis in healthy women. Climacteric 2006;9:108-118.
19. LeBlanc ES, Janowsky J, Chan BK, Nelson HD. Hormone replacement therapy and cognition: systematic review and meta- analysis. J Am Med Assoc 2001;285:1489-1499.
20. Yaffe K, Sawaya G, lieberburg I, Grady D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. J Am Med Assoc 1998;279:688-695.
21. Gambacciani M, Ciaponi M, Cappagli B, Monteleone P, Benussi C, Bevilacqua G, Genazzani AR. Effects of low-dose, continuous combined estradiol and norethisterone acetate on menopausal quality of life in early postmenopausal women. Maturitas 2003;44:157-163.
22. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, et al. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. J Am Med Assoc 2002;288:321- 333.
23. Anderson GL, Umacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, et al. Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. J Am Med Assoc 2004;291:1701-1712.
24. Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, Trevisan M, Black HR, Heckbert SR, Detrano R, et al. Women's Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:523-534.
25. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, et al. HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). J Am Med Assoc 2002;288:49-57.
26. Hoffmann M, Hammar M, Kjellgren, Lindh-Astrand L, Brynhildsen J. Changes in women's attitudes towards and use of hormone therapy after HERS and WHI. Maturitas 2005;52:11-17.
27. Hersh AL, Stefanick ML, Stafford RS. National use of postmenopausal hormone therapy: annual trends and response to recent evidence. J Am Med Assoc 2004;291:47-53.
28. Ettinger B, Grady D, Tosteson AN, Pressman A, Macer JL. Effect of the Women's Health Initiative on women's decisions to discontinue postmenopausal hormone therapy. Obstet Gynecol 2003;102:1225-1232.
29. Breslau ES, Davis WW, Doner L, Eisner EJ, Goodman NR, Meissner HI, Rimer BK, Rossouw JE. The hormone therapy dilemma: women respond. J Am Med Womens Assoc 2003;58:33-43.
30. Rolnick SJ, Kopher RA, DeFor TA, Kelley ME. Hormone use and patient concerns after the findings of the Women's Health Initiative. Menopause 2005;12:399-404.
31. Strothmann A, Schneider HP. Hormone therapy: the European women's perspective. Climacteric 2003;6:337-346.
32. Genazzani AR, Schneider HP, Panay N, Nijland EA. The European Menopause Survey 2005: women's perceptions on the menopause and postmenopausal hormone therapy. Gynecol Endocrinol 2006;22:369-375.
33. Strothmann A, Schneider HPG, Schaefer M. Hormone therapy: the US women's perspective. Poster presented at the 16th Annual Meeting of the North American Menopause Society, San Diego, California, September 28-October 1, 2005.
34. Bakken K, Eggen AE, Lund E. Side-effects of hormone replacement therapy and influence on pattern of use among women aged 45-64 years. The Norwegian Women and Cancer (NOWAC) study 1997. Acta Obstet Gynecol Scand 2004;83:850-856. 35. van Seumeren I. Weight gain and hormone replacement therapy: are women's fears justified? Maturitas 2000;34(Suppl 1):S3-S8.
36. Clinkingbeard C, Minton BA, Davis J, McDermott K. Women's knowledge about menopause, hormone replacement therapy (HRT), and interactions with healthcare providers: an exploratory study. J Womens Health Gend Based Med 1999;8:1097-1102.
37. Schneider HP. Cross-national study of women's use of hormone replacement therapy (HRT) in Europe. Int J Fertil Womens Med 1997;42(Suppl 2):365-375.
38. Lewin KJ, Sinclair HK, Bond CM. Women's knowledge of and attitudes towards hormone replacement therapy. Fam Pract 2003;20:112- 119.
39. Reynolds RF, Obermeyer CM, Walker AM, Guilbert D. The role of treatment intentions and concerns about side effects in women's decision to discontinue postmenopausal hormone therapy. Maturitas 2002;43:183-194.
40. Faulkner DL, Young C, Hutchins D, McCollam JS. Patient noncompliance with hormone replacement therapy: a nationwide estimate using a large prescription claims database. Menopause 1998;5:226-229.
41. Wing RR, Matthews KA, Kuller LH, Meilahn EN, Plantinga P. Weight gain at the time of menopause. Arch Intern Med 1991;151:97- 102.
42. Pasquali R, Casimirri F, Labate AM, Tortelli O, Pascal G, Anconetani B, Gatto MR, Flamia R, Capelli M, Barbara L. Body weight, fat distribution and the menopausal status in women. Int J Obes Relat Metab Disord 1994;18:614-621.
43. Poehlman ET, Goran MI, Gardner AW, Ades PA, Arciero PJ, Katzman-Rooks SM, Montgomery SM, Toth MJ, Sutherland PT. Determinants of decline in resting metabolic rate in aging females. Am J Physiol 1993;264:E450-E455.
44. Bjorkelund C, Ussner L, Andersson S, Lapidus L, Bengtsson C. Reproductive history in relation to relative weight and fat distribution. Int J Obes Relat Metab Disord 1996;20:213-219.
45. Ley CJ, Lees B, Stevenson JC. Sex- and menopauseassociated changes in body-fat distribution. Am J Clin Nutr 1992;55:950-954.
46. Augoulea A, Mastorakos G, Lambrinoudaki I, Christodoulakos G, Creatsas G. Role of postmenopausal hormone replacement therapy on body fat gain and leptin levels. Gynecol Endocrinol 2005;20:227- 235.
47. Arabi A, Garnero P, Porcher R, Pelissier C, Benhamou CL, Roux C. Changes in body composition during post-menopausal hormone therapy: a 2 year prospective study. Hum Reprod 2003;18:1747-1752.
48. Meeuwsen IB, Samson MM, Duursma SA, Verhaar HJ. The effect of tibolone on fat mass, fat-free mass, and total body water in postmenopausal women. Endocrinology 2001; 142:481-487.
49. Shadoan MK, Anthony MS, Rankin SE, Clarkson TB, Wagner JD. Effects of tibolone and conjugated equine estrogens with or without medroxyprogesterone acetate on body composition and fasting carbohydrate measures in surgically postmenopausal monkeys. Metabolism 2003; 52:1085-1091.
50. Norman RJ, Flight IH, Rees MC. Oestrogen and progestogen hormone replacement therapy for peri-menopausal and postmenopausal women: weight and body fat distribution. Cochrane Database Syst Rev 2000;(2):CD001018.
51. Genazzani AR, Gambacciani M. Effect of climacteric transition and hormone replacement dierapy on body weight and body fat distribution. Gynecol Endocrinol 2006;22:145-150.
52. Espeland MA, Stefanick ML, Kritz-Silverstein D, Fineberg SE, Waclawiw MA, James MK, Greendale GA. Effect of postmenopausal hormone tiierapy on body weight and waist and hip girths. Postmenopausal Estrogen-Progestin Interventions Study Investigators. J Clin Endocrinol Metab 1997; 82:1549-1556.
53. Oelkers W, Foidart JM, Dombrovics N, Welter A, Heithecker R. Effects of new oral contraceptive containing an antimineralocorticoid progestogen, drospirenone, on the renin- angiotensin system, body weight, blood pressure, glucose tolerance and lipid metabolism. J Clin Endocrinol Metab 1995;80: 1816-1821.
54. Oelkers W. Drospirenone, a progesterone with antimineralocorticoid properties: a short review. Mol Cell Endocrinol 2004;217:255-261.
55. Elger W, Schwarz S, Hedden A, Reddersen G, Schneider B. Sulfamates of various estrogens are prodrugs with increased systemic and reduced hepatic estrogenicity at oral application. J Steroid Biochem Mol Biol 1995;55:395-403.
56. Kuhl H. Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 2005;8(Suppl 1):3- 63.
57. Muhn P, Fuhrmann U, Fritzemeier KH, Krattenmacher R, Schillinger E. Drospirenone: a novel progestogen with antimineralocorticoid and antiandrogenic activity. Ann N Y Acad Sci 1995;761:311-335.
58. Pollow K, Juchem M, Elger W, Jacobi N, Hoffman G, Mobus Y. Dihydrospirorenone (ZK30595): a novel synthetic progesterone - characterization of binding to different receptor proteins. Contraception 1992;46:561-574.
59. Krattenmacher R. Drospirenone: pharmacology and pharmacokinetics of a unique progesterone. Contraception 2000;62:29- 38.
60. Borenstein J, Yu HT, Wade S, Chiou CF, Rapkin A. Effect of an oral contraceptive containing ethinyl estradiol and drospirenone on premenstrual symptomatology and health-related quality of life. J Reprod Med 2003;48:79-85.
61. Parsey KS, Pong A. An open-label, multicenter study to evaluate Yasmin, a low-dose combination oral contraceptive containing drospirenone, a new progestogen. Contraception 2000;61:105-111.
62. Apter D, Borsos A, Baumgartner W, Melis GB, VexiauRobert D, Colligs-Hakert A, Palmer M, Kelly S. Effect of an oral contraceptive containing drospirenone and ethinylestradiol on general well-being and fluid-related symptoms. Eur J Contracept Reprod Health Care 2003;8:37-51.
63. Pearlstein TB, Bachmann GA, Zacur HA, Yonkers KA. Treatment of premenstrual dysphoric disorder with a new drospirenone- containing oral contraceptive formulation. Contraception 2005;72:414- 421.
64. Yonkers KA, Brown C, Pearlstein TB, Foegh M, SampsonLanders C, Rapkin A. Efficacy of a new low-dose oral contraceptive with drospirenone in premenstrual dysphoric disorder. Obstet Gynecol 2005;106:492-501.
65. Archer DF, Thorneycroft IH, Foegh M, Hanes V, Giant MD, Bitterman P, Kempson RL. Long-term safety of drospirenone-estradiol for hormone therapy: a randomized, doubleblind, multicenter trial. Menopause 2005;12:716-727.
66. Rubig A. Drospirenone: a new cardiovascular-active progestin with antialdosterone and antiandrogenic properties. Climacteric 2003;6(Suppl 3):49-54.
67. Warming L, Ravn P, Nielsen T, Christiansen C. Safety and efficacy of drospirenone used in a continuous combination with 17beta-estradiol for prevention of postmenopausal osteoporosis. Climacteric 2004;7:103-111.
Tanko LB, Christiansen C. Effects of 17beta-oestradiol plus different doses of drospirenone on adipose tissue, adiponectin and atherogenic metabolites in postmenopausal women. J Intern Med 2005;258:544-553.
69. Foidart JM, Wuttke W, Bouw GM, Gerlinger C, Heithecker R. A comparative investigation of contraceptive reliability, cycle control and tolerance of two monophasic oral contraceptives containing either drospirenone or desogestrel. Eur J Contracept Reprod Health Care 2000;5:124-134.
70. Huber J, Foidart JM, Wuttke W, Merki-Feld GS, The HS, Gerlinger C, Schellschmidt I, Heithecker R. Efficacy and tolerability of a monophasic oral contraceptive containing ethinylestradiol and drospirenone. Eur J Contracept Reprod Health Care 2000;5:25-34.
71. Schurmann R, Holler T, Benda N. Estradiol and drospirenone for climacteric symptoms in postmenopausal women: a double-blind, randomized, placebo-controlled study of the safety and efficacy of three dose regimens. Climacteric 2004;7:189-196.
72. Preston RA, White WB, Pitt B, Bakris G, Norris PM, Hanes V. Effects of drospirenone/17-/? estradiol on blood pressure and potassium balance in hypertensive postmenopausal women. Am J Hypertens 2005;18:797-804.
73. White WB, Pitt B, Preston RA, Hanes V. Antihypertensive effects of drospirenone with 17beta-estradiol, a novel hormone treatment in postmenopausal women with stage 1 hypertension. Circulation 2005;112:1979-1984.
74. White WB, Hanes V, Chauhan V, Pitt B. Effects of a new hormone therapy, drospirenone and 17-beta-estradiol, in postmenopausal women with hypertension. Hypertension 2006;48:246- 253.
JEAN-MICHEL FOIDART1 & THOMAS FAUSTMANN2
1 Hopital de la Citadelle, Liege, Belgium, and 2 Bayer Schering Pharma AG, Berlin, Germany
(Received 19 June 2007; revised 16 July 2007; accepted 18 July 2007)
Correspondence: J.-M. Foidart, Hopital de la Citadelle, Bvd du 12eme de Ligne 1, B-4000 Liege, Belgium. Tel: 32 422 56582. Fax: 32 422 40005. E-mail: [email protected]
Copyright Taylor & Francis Ltd. Dec 2007
(c) 2007 Gynecological Endocrinology. Provided by ProQuest Information and Learning. All rights Reserved.