Sage Journals: Discover world-class research

Abstract

The problems that arise in connection with the menopause have been treated for many years with various hormone-replacement therapy formulations. The spironolactone derivative drospirenone is a novel progestin that, in combination with estradiol, provides a new low-dose, continuous, combined hormone therapy with a broad and safe activity profile. Through its antiandrogenic and antimineralocorticoid properties, drospirenone acts specifically against menopausal symptoms, provides protection of the endometrium, does not counteract the effect of estradiol on bone metabolism and has a beneficial effect on body weight and lipid metabolism. Its effect on blood pressure is particularly relevant: drospirenone blocks the aldosterone receptor and thus has a regulating effect on the renin–angiotensin–aldosterone system and so promotes enhanced sodium/water excretion.

Keywords

aldosterone antagonists blood pressure climacteric symptoms drospirenone estradiol hormone-replacement therapy hyperkalemia hypertension osteoporosis postmenopause

Due to increasing life-expectancy, women today spend more than a third of their life in a post-menopausal phase that is basically characterized by hormone deficiency. It is estimated that 25 million women throughout the world go through the climacteric every year and it is to be expected that the number of women over 50 years of age will increase from approximately 500 million today to over 1 billion by 2030 [1]. As a result of this demographic trend, the health of postmenopausal women has become an important topic. The main aim of menopausal hormone therapy (HT) is to alleviate climacteric symptoms and reduce the risk of postmenopausal osteoporosis. Other potential additional benefits are the prevention of endometrial hyperplasia, a positive effect on plasma lipoproteins and prevention of cardiovascular diseases.

Overview of the market

The symptoms and signs assigned to estrogen deficiency in the menopause are many and varied. Possible consequences are menopausal symptoms such as hot flushes, bouts of sweating, poor concentration, poor memory, insomnia, atrophic urogenital alterations and, in the long term, increased osteoporosis morbidity [2]. All these symptoms directly influence the quality of life of affected women [3]. Intensified research activities and deeper knowledge of the biological processes in the menopause have led to HT that is better suited to the physiological requirements of individual women. It is therefore particularly important to provide new therapeutic solutions with additional advantages directed to the increasing demands of patients and to improvement of compliance. The latest knowledge in the field of HT seems to have shifted the increasingly acrimonious debate regarding hormones and their benefits and risks to a valid scientific discussion with new recommendations and new strategies and products [4 –9].

The recent evaluation by the Nurses Health Study cohort trial showed, among other things, that estrogen-replacement therapy continued for at least up to 15 years is not associated with an increase in the incidence of breast cancer. New evaluations of the Women's Health Initiative (WHI) study revealed that estrogen-replacement therapy does not increase the incidence of the most common forms of breast cancer and may even reduce the risk in certain groups of women [10,11]. However, patients who have stopped HT due to confusing messages from some experts, the media and relevant authorities increasingly complain particularly of a number of severe menopausal symptoms going beyond hot flushes and insomnia. These patients would like to have a HT that both relieves the menopausal symptoms and offers additional benefits on efficacy and safety. These aspects make a new product, a combination of drospirenone 2 mg with estradiol 1 mg (Angeliq®, Schering AG) interesting for HT, especially since older HT products are not having their authorizations renewed in many countries so that fewer and fewer products are available in this field.

Introduction to drospirenone 2 mg/ estradiol 1 mg

Drospirenone/estradiol contains 1 mg of estradiol and 2 mg of drospirenone. Whereas estradiol (chemical name: 1,3,5(10)-estratriene-3,17β-diol hemihydrate (IUPAC) is well-known and characterized in the literature, drospirenone is a new and unique progestogen with antialdosterone and antiandrogenic properties (chemical name: 6β,7β15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17carbolactone [IUPAC]).

This completely novel progestogen, drospirenone, differs totally from other progestins, especially from medroxyprogesterone acetate (MPA), the only progestogen evaluated in the WHI study [12 –17]. Against the background of vascular problems with estrogen monotherapy, and the well-known activation of the renin–angiotensin–aldosterone system (RAAS), drospirenone in combination with estrogen may offer a better alternative due to its antialdosterone effect.

This combination product for continuous once-daily administration now makes available a low-dose HT that leads to amenorrhea in the majority of users. Apart from its effective treatment of menopausal symptoms, the clinically relevant antialdosterone properties of drospirenone provide drospirenone/estradiol with additional activity that improves compliance by users, namely water retention is reduced so that the weight gain attributed to estrogens is balanced and blood pressure is improved [18 –21].

Pharmacokinetics

Following repeated oral administration of drospirenone/estradiol combination tablets, serum estradiol levels show little variation over the 24-h dosing interval. Owing to the large circulating pool of estrogen sulfates and glucuronides, and the enterohepatic recirculation, the terminal half-life of estradiol is a composite parameter, and is in the range of 13–20 h after oral administration.

Within the circulation, estradiol is bound nonspecifically to serum albumin and specifically to sex hormone-binding globulin (SHBG; 38%); only approximately 2–3% of circulating estradiol is present as free steroid. Orally administered drospirenone/estradiol induces SHBG formation, and the resulting increase in SHBG by approximately 20% influences the distribution of estradiol with respect to the plasma proteins. The apparent volume of distribution of estradiol after a single intravenous dose is approximately 1 l/kg.

Estradiol is rapidly metabolized, and apart from estrone and estrone sulfate, a large number of other metabolites and conjugates are formed. Estrone and estriol are pharmacologically active but only estrone occurs at relevant concentrations in plasma [22 –28].

Estrone reaches approximately sixfold higher serum levels than estradiol. The serum levels of estrone conjugates are approximately 26-fold higher than the corresponding free estrone levels. The metabolic clearance of estradiol is 10–30 ml/min/kg. The metabolites are excreted via the urine and bile with a half-life of about 1 day.

Following once-daily oral administration of estradiol/drospirenone combination tablets, estradiol and estrone concentrations reach steady state after about 5 days. Serum estradiol levels accumulate approximately twofold between the first dose and steady state.

Drospirenone is rapidly and almost completely absorbed after oral administration. Peak serum concentrations occur approximately 1 h after oral administration of drospirenone/estradiol. The absolute bioavailability of drospirenone is 76–85%, and is not influenced by food.

After oral administration, serum drospirenone levels decrease, with a mean terminal half-life of approximately 35–39 h. Drospirenone does not bind to SHBG or corticoid-binding globulin, but binds to serum albumin. The free fraction of drospirenone in the plasma is approximately 3–5% [29].

Drospirenone is extensively metabolized after oral or intravenous administration. At least 20 different metabolites have been observed in the urine and feces, but only trace amounts are excreted unchanged. The renally excreted drospirenone metabolites do not exhibit pharmacologic activity. The total clearance of drospirenone is 1.2–1.5 ml/min/kg.

Excretion is nearly complete 10 days after a single dose, and the feces to urine excretion ratio is 1.2–1.4. The excretion half-life in urine and feces is around 40 h, which is similar to the plasma terminal half-life of the drug.

The influence of each active ingredient in drospirenone/estradiol on the pharmacokinetics of the other ingredient was studied at steady state in a population of 36 postmenopausal women. No clinically relevant interaction between drospirenone and estradiol was observed within the dose ranges drospirenone 1–4 mg and estradiol 1–2 mg.

The cytochrome P450 (CYP) system is not involved in the metabolism of drospirenone. Inhibitors of this enzyme system are therefore unlikely to have any clinically relevant influence on drospirenone metabolism [29].

The potential ability of drospirenone to interfere with the metabolism of coadministered drugs was investigated in a clinical drug–drug interaction study using omeprazole as a marker substrate. This study showed no inhibition of CYP2C19- or CYP3A4-mediated omeprazole metabolism by drospirenone. Based on these results and on further in vitro data, it is highly unlikely that drospirenone will influence the CYP-mediated metabolism of coadministered drugs.

Figure 1.

Estradiol and drospirenone.

Endogenous and orally administered estrogens pass through the liver, where they promote the synthesis of numerous proteins. One such protein is angiotensinogen, which increases plasma aldosterone levels via the RAAS [30].

A major function of aldosterone is to retain sodium (and water) within the body by increasing the reabsorption of sodium in the kidney. The net physiological effect of unopposed estrogen action on salt and water balance is therefore to increase sodium and water retention.

In the normal menstrual cycle, progesterone secreted during the luteal phase counteracts the mineralocorticoid effect of endogenous estrogen by competing with aldosterone at its receptor. Postmenopausal women do not secrete sufficient quantities of progesterone to counteract the estrogen-induced sodium retention. Moreover, with just a single exception, synthetic progestogens that have been used in HT do not have the antialdosterone properties of progesterone. Therefore, the tendency for estrogen to cause retention of sodium and water is unopposed, promoting an increase in body weight.

Through its antialdosterone properties, drospirenone (a progestogen with aldosterone receptor antagonism [PARA]) does not have the same drawback and rather induces sodium and water excretion [30 –34].

Drospirenone exerts its PARA properties even in the dose range that inhibits ovulation. A dosage of 2 mg/day for 21 days increases renal sodium excretion, urinary NA⁺/K⁺ ratio, plasma renin activity, plasma aldosterone, and urinary excretion of aldosterone-18-glucuronide. These effects are attributable to competitive antagonism at the aldosterone receptor. The relative potency of drospirenone as a PARA has been evaluated using an intravenous continuous infusion model in healthy volunteers. The aldosterone-antagonistic potency of drospirenone is seven times greater than that of spironolactone, based on NA⁺ (K⁺) ratios in urine fractions obtained 4–8 h after the start of infusion [30].

Clinical efficacy

The clinical efficacy of drospirenone/estradiol has been investigated in various prospective, randomized studies. At all doses studied, the drospirenone/estradiol combination proved to be highly effective in the treatment of menopausal symptoms with a low incidence of bleeding, leading to improvement of the quality of life of users. Thus, vasomotor symptoms such as moderate to severe hot flushes and bouts of sweating were improved and mood swings, insomnia and vaginal atrophy were reduced [36 –38].

In addition to these primary effects, further beneficial actions of this combination on bone density and blood lipid values were observed. An important aim of HT is the treatment of postmenopausal osteoporosis. The known beneficial action of estrogen-replacement therapy on bone density and blood lipid values were demonstrated with combination therapy with drospirenone [37]. The 2-year study by Warming and colleagues with 180 healthy postmenopausal women investigated the effect of continuous combination therapy of different doses of drospirenone and 17β-estradiol for the prevention of postmenopausal osteoporosis. In this study, bone mineral density (BMD) at lumbar spine, hip and total body were measured at regular intervals, as well as markers of bone turnover, serum lipids and endometrial thickness.

After 2 years of treatment, the difference in BMD between the drospirenone/estradiol-treated groups and the placebo group was 7% in the spine, 4% in the hip and 3% in the total body (all p < 0.001). This was reflected in the biochemical markers of bone turnover. Serum osteocalcin (SOC) decreased by 52% and urine C-terminal telopeptide (uCTX) decreased by 75% in the drospirenone/estradiol-treated women compared with baseline (both p < 0.001).

With regard to lipid metabolism parameters, the triglyceride and high-density lipoprotein (HDL)-cholesterol values remained unchanged during the study, whereas the total cholesterol and low-density lipoprotein (LDL)-cholesterol values fell by 8 and 13%, respectively, in the drospirenone/estradiol group.

Estrogen-only replacement therapy can lead to endometrial hyperplasia and an increased risk of endometrial cancer in women with an intact uterus. On the basis of endometrial biopsies before and after 2 years of treatment it could be shown in all women that, in contrast to estrogen-only therapy, combination treatment at all studied doses provided endometrial protection and effectively prevented endometrial hyperplasia; these effects are attributable to the progestogenic properties of drospirenone [29,31 –34].

Endometrial thickness only increased in the drospirenone 1 mg group, but not in the 2 and 3 mg groups, compared with placebo. This information, in conjunction with the endometrial histology, indicates the effectiveness of drospirenone on the inhibition of endometrial growth.

Cardiovascular disease is considered to be the main cause of death and morbidity throughout the world and hypertension is the most important risk factor for cardiovascular disease, responsible for 62% of strokes and 49% of ischemic heart disease death [39,40]. The antimineralocorticoid effect of drospirenone counters water and sodium retention caused by of the activation of the RAAS. This antialdosterone effect of the spirolactone derivative drospirenone is relevant in relation to body weight and blood pressure [12 –15].

The weight gain due to fluid retention during estrogen-only therapy often leads to withdrawal of HT [42]. Studies with drospirenone/estradiol have demonstrated either no weight gain or even weight loss [17,18]. Due to its beneficial effect on sodium and water retention and thus on body weight, the drospirenone in drospirenone/estradiol may lead to improved patient compliance.

The beneficial effect on blood pressure has been demonstrated in several studies. In a double-blind, placebo-controlled study in postmenopausal hypertensive women receiving enalapril as a chronic antihypertensive treatment, drospirenone/estradiol given for 2 weeks demonstrated a significant additive blood pressure (BP)-lowering effect on both systolic and diastolic BP compared with placebo [43]. The effects on BP and potassium balance were investigated in a multicenter study with postmenopausal hypertensive women aged 44–70 years with (n = 82) or without Type 2 diabetes mellitus (n = 148) treated with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-II receptor. In the nondiabetic group, ibuprofen was administered for 5 days to increase the likelihood of unmasking hyperkaliemia. The patients were randomized to 28-day treatment with either drospirenone/estradiol or placebo. The study end points were the number and percentage of subjects who developed hyperkalemia (K ≥ 5.5 mEq/l) and changes from baseline in clinical systolic and diastolic BP.

Compared with placebo, treatment with drospirenone/estradiol did not lead to a statistically higher incidence of hyperkalemia in any of the patient types (with or without Type 2 diabetes) with concomitant therapy with ACE inhibitors, angiotensin receptor antagonists or ibuprofen; in addition, a significant BP-lowering effect on both systolic and diastolic BP was found in this high-risk population (BP reduced by −8.6/-5.8 mmHg in patients receiving drospirenone/estradiol vs −3.7/-2.9 mmHg in those receiving placebo; p < 0.01 for both systolic and diastolic BP) [9].

These results have also been confirmed by other studies in which the BP-lowering efficacy of the drospirenone/estradiol combination (with various drospirenone doses) was compared with estradiol-only therapy or placebo treatment in postmenopausal hypertensive women. In the 8-week study performed by White and colleagues in 750 postmenopausal women aged 45–75 years with stage 1 or 2 hypertension, the drospirenone/estradiol combination produced a marked reduction in BP [19]. There was no evidence of a clinically relevant rise in the serum potassium level.

In a recently published study, Preston and colleagues found a substantial BP-lowering effect of drospirenone/estradiol treatment in postmenopausal women with stage I hypertension maintained on 25 mg hydrochlorothiazide (HCTZ) compared with placebo [44]. The potassium-sparing effect of drospirenone was found to counteract the HCTZ-induced potassium loss.

Safety & tolerability of estradiol with drospirenone

The good tolerability and safety of continuous combination treatment with drospirenone/estradiol in postmenopausal women has been demonstrated in several studies [10,16,33].

In a randomized, double-blind, multicenter study with 225 women, the combination of estradiol (1 mg) and drospirenone (1, 2 or 3 mg) was generally well tolerated. The incidence and type of adverse effects were comparable with the side effects usually occurring in HT, including headaches (3–5%), breast tension (7–18%) and bleeding (3%). The side effects themselves were mild to moderate [33].

The endometrial safety of the combination treatment compared with estrogen-only treatment was also demonstrated in another double-blind, randomized, multicenter, parallel-group study [18]. In this study, the endometrial effects of estradiol (1 mg) were compared with those of drospirenone (0.5, 1, 2 or 3 mg) over 13 cycles of 28 days each. The study involved 1142 postmenopausal women aged 45–75 years. Endometrial biopsies were obtained at the first examination after 7 months (if indicated, i.e., if the endometrium was 5 mm thick or more) and at the concluding examination (13 months).

Endometrial hyperplasia was found in eight patients in the estradiol-only treatment group compared with only one case of simple hyperplasia without atypical features in the drospirenone/estradiol group.

Compared with the placebo group, no significant cardiovascular events (e.g., arrhythmia, bradycardia, dizziness) occurred in the drospirenone/estradiol group in the study by White and colleagues. Here again, the usual side effects were breast tension and bleeding [19].

Based on other safety parameters, the drospirenone/estradiol combination was shown to be safe in postmenopausal women. In addition, drospirenone/estradiol decreased BP among women with elevated BP at baseline, reduced the frequency of hot flushes and mood swings, and improved serum cholesterol and lipid profile parameters.

Regulatory affairs

The combination of 2 mg drospirenone and estradiol 1 mg (Angeliq®, Schering AG, Berlin, Germany) has been approved by the European Health Authorities and is available in 60 countries worldwide, including Asia and Latin America.

Conclusion

With the introduction of the novel progestin drospirenone in combination with estradiol, a HT with a broad spectrum of activity is available that not only treats postmenopausal symptoms but also offers additional health benefits compared with other progestins. The advantages of estradiol (i.e., the control of menopausal symptoms and the beneficial effect on lipids, bone density and vasomotor symptoms) are not impaired by drospirenone. In addition, this new progestin protects the endometrium and, due to its antialdosterone effects, has a beneficial effect on estrogen-induced side effects. Fluid retention, and the resulting weight gain, induced by estrogen is counteracted by drospirenone and, furthermore, it has the potential to reduce cardiovascular risk factors such as high BP.

Estradiol has a dual effect on BP [13,45]. On the one hand it stimulates endothelial nitric oxide synthase, which releases nitrogen monoxide that has a vasodilating effect. On the other hand, through hepatic induction, estradiol stimulates enhanced expression of hypertensively and coagulatively active control proteins in the liver. This may explain vascular adverse effects of HT even in the immediate postmenopausal phase in some patients. The combination of estradiol and drospirenone, due to the antimineralocorticoid and antihypertensive effect of the progestogen, may result in a positive effect and significant benefit for peri- and postmenopausal women at risk for cardiovascular diseases [46,47].

Future perspective

A mistake with HT in the past was its lack of individualization and, as the WHI study has clearly shown, one and the same product was prescribed for many different types of women with different individual characteristics. One message coming out of the WHI study is that the personal constitution of the patient should be taken into account when prescribing HT so it can be individually tailored. A number of new products are therefore required so that this can be done. Drospirenone/estradiol has undoubtedly broadened the range of individualized HTs.

Executive summary

The health of women in the postmenopause is an important topic in healthcare.

The spironolactone derivative drospirenone is a novel progestogen which, combined with estradiol, offers a new low-dose, continuous, combined hormone therapy with a broad and safe spectrum of action.

When combined with estradiol, the clinical efficacy encompasses the treatment of menopausal symptoms and postmenopausal osteoporosis, as well as beneficial effects on lipid metabolism. The combination also provides endometrial protection. Drospirenone counteracts fluid retention and may reduce cardiovascular risks as a result of its antialdosterone properties, which lower blood pressure in hypertensive women.

The safety and tolerability of combination treatment with estradiol and drospirenone has been demonstrated in postmenopausal women.

References

Hill

: The demography of menopause. Maturitas 23, 113–127 (1996).

Kuh

Wadsworth

Hardy

: Women's health in midlife: the influence of the menopause, social factors and health in earlier life. Br. J. Obstet. Gynaecol. 104, 923–933 (1997).

Zesthraeus

Johanesson

Henriksson

: The impact of hormone replacement therapy on quality of life and willingness to pay. Br. J. Obstet. Gynaecol. 104, 1191–1195 (1997).

Hulley

Grady

Bush

: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in post- menopausal women. Heart ans Estrogen/progestin Replacement Study (HERS) Research group. JAMA 280, 605–613 (1998).

Writing Group for Women's Health Initiative: Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women's Health Initiative randomized controlled trial. JAMA 288, 321–333 (2002).

Turgeon

McDonnell

Martin

Wise

: Hormone therapy: physiological complexity belies therapeutic simplicity. Science 304, 1269–1273 (2004).

Ostrzenski

Ostrzenska

: WHI clinical trial revisit: Imprecise scientific methodology disqualifies the study's outcomes. Am. J. Obstet. Gynecol. 193, 1599–1604 (2005).

Dubey

Imthurn

Barton

Jackson

: Vascular consequences of menopause and hormone therapy: Importance of timing and type of estrogen. Cardiovasc. Res. 66, 295–306 (2005).

Position Statement: Estrogen and progesterone use in peri- and postmenopausal women: March 2007 position statement of The North American Menopause Society. Menopause 14, 1–14 (2007).

10.

The Women's Health Initiative Steering Committee: Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA 291, 1701–1712 (2004).

11.

Stefanick

Anderson

Margolis KL et al.; for the WHI Investigators: Effects of conjugated equine estrogens on breat cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 295, 1647–1657 (2006).

12.

Sitruk-Ware

: New progestogens. a review of their effects in perimenopausal and postmenopausal women. Drugs Aging 21(13), 865–882 (2004).

13.

Oelkers

: Drospirenone, a progestogen with antimineralocorticoid properties: a short review. Mol. Cell. Endocrinol. 217, 255–261 (2004).

14.

Oelkers

: Drospirenone in combination with estrogens: for contraception and hormone replacement therapy. Climacteric 8(Suppl3), 19–27 (2005).

15.

Palacios

Foidart

Genazzani

: Advances in hormone replacement therapy with drospirenone, a unique progestogen with aldosterone receptor antagonism. Maturitas 55, 297–307 (2006).

16.

Shulman

: A review of drospirenone for safety and tolerability and effects on endometrial safety and lipid parameters contrasted with medroxyprogesterone acetate, levonorgestrel, and micronized progesterone. Women's Health 15 (5), 584–590 (2006).

17.

Foidart

: Added benefits of drospirenone for compliance. Climacteric (Suppl. 3), 28–34 (2005).

18.

Archer

Thorneycroft

Foegh

: Long-term safety of drospirenone-estradiol for hormone therapy: a randomized, double-blind, multicenter trial. J. North Am. Menopause Soc. 12, 716–727 (2005).

19.

White

Hanes

Chauhan

Pitt

: Effects of a new hormone therapy, drospirenone and 17-β-estradiol, in postmenopausal women with hypertension. Hypertension 48, 246–253 (2006).

20.

Preston

White

Pitt

Bakris

Norris

Hanes

: Effects of drospirenone/17-β-estradiol on blood pressure and potassium balance in hypertensive postmenopausal women. Am. J. Hypertension 18, 797–804 (2005).

21.

Whitehead

: Hormone replacement therapy with estradiol and drospirenone: an overview of the clinical data. J. Br. Menopause Soc. Vol. 12(Suppl. 1), 4–7 (2006).

22.

Lobo

Cassidenti

: Pharmacokinetics of oral 17 β estradiol. J. Reprod. Med. 37, 77–84 (1992).

23.

Düsterberg

Schmidt-Gollwitzer

Hümpel

: Pharmacokinetics and biotransformation of estradiol valerate in ovarectomized women. Horm. Res. 21, 145–154 (1985).

24.

Ball

Knuppen

: Formation, metabolism, and physiologic importance of catecholestrogens. Am. J. Obstet. Gyn. 163, 2163–2170 (1990).

25.

Bolt

: Metabolism of estrogens-natural and synthetic. Pharmacol. Ther. 4, 155–181 (1979).

26.

Dunn

Nisula

Rodbard

: Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J. Endocr. Metab. 53, 58–68 (1981).

27.

Düsterberg

Nishino

: Pharmacokinetic and pharmacological features of oestradiol valerate. Maturitas 4, 315–324 (1982).

28.

Sandberg

Slaunwhite

: Studies of phenolic steroids in human subjects. The metabolic fate and hepatobiliary-enteric circulation of 14C estrogen and 14C-estradiol in women. J. Clin. Invest. 36, 1266–1278 (1957).

29.

Krattenmacher

: Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. Contraception 62, 29–38 (2000).

30.

Oelkers

WKH

: Effects of estrogens and progestogens on the renin–aldosterone system and blood pressure. Steroids 61, 166–171 (1996).

31.

Fuhrmann

Krattenmacher

Slater

: The novel progestin drospirenone and its natural counterpart progesterone: biochemical profile and antiandrogenic potential. Contraception 54, 243–251 (1996).

32.

Pollow

Juchem

Elger

: Dihydrospirorenone. A novel synthetic progestin-characterization of binding to different receptor proteins. Contraception 26, 561–574 (1992).

33.

Muhn

Krattenmacher

Beier

: Drospirenone: a novel progestogen with antimineralocorticoid and antiandrogenic activity. Contraception 51, 99–110 (1995).

34.

Elger

Beier

Pollow

Garfield

Shi

Qing S

Hillisch

: Conception and pharmacodynamic profile of drospirenone. Steroids 68, 891–905 (2003).

35.

Oelkers

Berger

Bolik

: Dihydrodrospirenone – a new progestogen with antimineralcorticoid activity: effects on ovulation, electrolyte excretion and the rennin-aldosterone system in normal women. J. Clin. Endocrinol. Metab. 73, 837–842 (1991).

36.

Schürmann

Höller

Benda

: Estradiol and the drospirenone for climacteric symptoms in postmenopausal women: a double-blind, randomized, placebo-controlled study of the safety and efficacy of three dose regimens. Climacteric 7, 189–196 (2004).

37.

Warming

Ravn

Nielsen

Christiansen

: Safety and efficacy of drospirenone used in a continuous combination with 17-β-estradiol for prevention of postmenopausal osteoporosis. Climacteric 7, 103–111 (2004).

38.

Oelkers

WHK

: Drospirenone in combination with estrogens for contraception and hormone replacement therapy. Climacteric 8(Suppl. 3), 19–27 (2005).

39.

MacGregor

: Importance of controlling blood pressure. Cimacteric 8(Suppl 3), 13–18 (2005).

40.

World Health Report 2002: Reducing risks, promoting healthy life. Geneva, Switzerland (2002).

41.

Stevenson

: A new hormone replacement therapy containing a progestogen with antimineralocorticoid activity. J. Br. Menopause Soc. 12(Suppl. 1), 8–10 (2006).

42.

Strothmann

Schneider

HPG

: Hormone therapy: the European women's perspective. Climacteric 6, 337–346 (2003).

43.

Preston

Alonso

Panzitta

Zhang

Karara

: Additive effect of drospirenone/17-β-estradiol in hypertensive postmenopausal women receiving enalapril. Am. J. Hypertens. 15, 816–822 (2002).

44.

Preston

Norris

Alonso

Hanes

Karara

: Randomized, placebo-controlled trial of drospirenone-estradiol on blood pressure and potassium balance in hypertensive postmenopausal women receiving hydrochlorothiazide. Menopause 14, 1–7 (2007).

45.

Reckelhoff

: Sex steroids, cardiovascular disease, and hypertension. Hypertension 45, 170–174 (2005).

46.

Motivala

Pitt

: Drospirenone for oral contraception and hormone replacement therapy. Drugs 67, 647–655 (2007).

47.

Minkin

: Clinical application of antialdosterone-containing hormone therapy for postmenopausal women. J. Reprod. Med. 52, 165–168 (2007).

Combination of Drospirenone and Estradiol: A New Hormone Therapy in Postmenopausal Women

Abstract

Keywords

Overview of the market

Introduction to drospirenone 2 mg/ estradiol 1 mg

Pharmacokinetics

Clinical efficacy

Safety & tolerability of estradiol with drospirenone

Regulatory affairs

Conclusion

Future perspective

References