Maturitas 55 (2006) 297–307

Advances in hormone replacement therapy with drospirenone,

a unique progestogen with aldosterone receptor antagonism
Santiago Palacios a,∗ , Jean-Michel Foidart b , Andrea R. Genazzani c
a Instituto Palacios, Salud y Medicina de la Mujer, Madrid, Spain
b Department of Obstetrics, Gynecology and Senology at the University of Liege, Belgium
c Department of Obstetrics and Gynecology, University of Pisa, Italy

Received 19 July 2006; accepted 22 July 2006

Abstract

Unlike other currently available progestogens, drospirenone (DRSP) has a pharmacological profile, which closely mimics
that of endogenous progesterone, most notably potent anti-aldosterone and anti-androgenic effects. Consequently, DRSP, when
combined with 17␤-estradiol (E2) as hormone replacement therapy (HRT), offsets E2-related water and sodium retention by
blocking the mineralocorticoid receptor. This review evaluates the potential benefits offered by DRSP as the progestin component
of HRT with respect to its anti-aldosterone activity, which translates into positive effects on body weight and blood pressure in
clinical trials of continuous, combined E2/DRSP in post-menopausal women. In a 1-year, large-scale, randomised, controlled trial,
E2 1 mg/DRSP 2 mg significantly decreased mean body weight by 1.2 kg versus baseline (P < 0.001), whereas patients receiving
E2 1 mg gained weight. E2 1 mg/DRSP 2 mg also significantly lowered mean systolic blood pressure (SBP) by 9.0 mmHg from
baseline (P < 0.05) versus 3.7 mmHg in the E2 1 mg group (P = 0.220) in a sub-group of hypertensive women. In addition,
E2/DRSP was not associated with hyperkalaemia (potassium ≥5.5 meq/L) irrespective of concomitant use of ACE inhibitors,
angiotensin II receptor antagonists or non-steroidal anti-inflammatory drugs, and co-morbid diabetes mellitus. In summary, as
well as effectively treating climacteric symptoms, DRSP 2 mg combined with E2 1 mg has shown positive effects on body weight
and blood pressure in clinical trials, most likely due to DRSP’s anti-aldosterone properties. This combination may therefore offer
an alternative therapeutic option with additional benefits beyond current HRT agents for symptomatic post-menopausal women.
© 2006 Elsevier Ireland Ltd. All rights reserved.

Keywords: Progestogen; Hormone replacement therapy; Drospirenone; Post-menopausal women; Hypertension

1. Introduction

It is estimated that 47 million women per annum

will be menopausal by 2030 [1], and approximately
∗ Corresponding author. Tel.: +34 91 578 20 05; 80% of these women will experience transient or
fax: +34 91 431 99 51. permanent symptoms, related to the loss of estrogens,
E-mail address: [email protected] (S. Palacios). during the menopause stages [2]. The transient

0378-5122/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.maturitas.2006.07.009
298 S. Palacios et al. / Maturitas 55 (2006) 297–307

menopausal symptoms can be vasomotor in origin, i.e. [26–32]. It is possible that differences in measures
hot flushes, night sweats or palpitations, or psycholog- of weight gain, physical activity of responders, HRT
ical, such as insomnia. Permanent symptoms include regimens (e.g. the use of micronized progesterone),
urogenital atrophy and osteoporosis. may account for the differences observed in these tri-
For decades, estrogen, either alone or in combina- als. Some studies indicate that HRT may have positive
tion with progestogens, has been the therapy of choice effects on body fat distribution [25,28–32], for exam-
for the relief of menopausal symptoms, as well as for ple, data from the Post-menopausal Estrogen/Progestin
the long-term prevention of post-menopausal osteo- Interventions (PEPI) trial showed that HRT may reduce
porosis. The inclusion of a progestogen in continu- central adiposity [32], although the current evidence is
ous combined hormone replacement therapy (HRT) inconclusive [26].
decreases the risks of endometrial hyperplasia and can- Nevertheless, weight gain is perceived as a side-
cer associated with unopposed estrogen therapy, and effect and is commonly cited as a reason for not tak-
this approach eliminates regular withdrawal bleeding ing HRT [21,22,33,34]. The Norwegian Woman and
[3,4]. Evidence-based guidelines strongly recommend Cancer (NOWAC) study, which sampled 4996 women
the use of combined estrogen/progestin therapy in (1024 HRT users that experienced side-effects were
women with an intact uterus, using the lowest dose to identified) aged 45–64 years, showed that 56.3% of
relieve symptoms effectively and minimise side-effects women experiencing troublesome side-effects reported
[5–9]. However, the potential benefits of HRT on car- weight gain as a side-effect [33]. Similar findings were
diovascular disease, blood pressure and weight gain observed in another large-scale survey of 816 women
remain controversial, and may depend on the specific (449 responders). This study showed that concerns
regimen used. about weight gain were associated with a significant
Post-menopausal women have a higher prevalence risk (RR = 2.06) for discontinuing HRT [34].
of hypertension than pre-menopausal women [10–12], In contrast to endogenous progesterone, the cur-
and are consequently at an increased risk of cardio- rently available synthetic progestogens lack anti-
vascular disease. High blood pressure is a modifiable aldosterone activity. This may result in HRT-associated
risk factor, as reductions can lower the incidence of water retention and bloating as a consequence of estro-
stroke and coronary heart disease (CHD). Even lower- gen activity on the RAAS, which could contribute to
ing the blood pressure in pre-hypertensive individuals perceived weight gain. This highlights the need for
(systolic blood pressure [SBP] 120–139 mmHg or dias- progestogenic compounds that mimic the effects of
tolic blood pressure [DBP] 80–89 mmHg) may have an endogenous progesterone on the RAAS.
added health benefit [13]. Treatment with conventional Drospirenone (DRSP) is a novel progestogen with
HRT appeared to have no significant effect on blood aldosterone receptor antagonism (PARA). In contrast
pressure in a number of studies [13–18]. The risk of with most synthetic progestogens, DRSP displays
hypertension was increased in current HRT users in a very similar pharmacological profile to endoge-
the WHI study, although this may have been related in nous progesterone [35–37]. Thus, DRSP exhibits
part to the older patient cohort in this study (average anti-aldosterone and anti-androgenic properties, but
62 years) [12]. In some patients, blood pressure may is devoid of any estrogenic, glucocorticoid or anti-
increase due to the water- and sodium-retaining effects glucocorticoid activity [35,36,38–40]. In particular,
of the estrogen in HRT preparations, mediated via the the anti-aldosterone activity of DRSP provides the
renin–angiotensin–aldosterone system (RAAS) [19]. potential for positive effects on body weight and also
Weight changes can occur independently of the on blood pressure due to counterbalancing estrogen-
menopause, although adverse weight changes in body related water retention when used in an HRT prepa-
fat distribution and composition are linked to hormonal ration. Several studies have demonstrated the safety
changes [20]. It is widely perceived that HRT causes and efficacy of the continuous combined HRT, 17␤-
weight gain [21,22], although data from clinical tri- estradiol (E2) 1 mg and DRSP 2 mg (Angeliq® , Scher-
als examining weight gain is inconclusive, in some ing AG, Germany) for the treatment of climacteric
studies showing an increase in overall body weight symptoms and prevention of post-menopausal osteo-
[15,23–25] and others showing no significant effect porosis [41–43]. In this review, the function of the
 S. Palacios et al. / Maturitas 55 (2006) 297–307 299

RAAS, and in particular the effects of estrogen and RAAS is to prevent excessive sodium loss and to reg-
progesterone, on body weight and blood pressure are ulate blood pressure. In addition, aldosterone may be
discussed. The potentially advantageous effects of E2 implicated in the pathogenesis of renal and cardiovas-
1 mg/DRSP 2 mg on body weight and blood pressure cular disease.
in post-menopausal women are also evaluated. Due to The female sex hormones, estrogen and proges-
its unique potent anti-aldosterone activity, DRSP in terone are both known to influence the RAAS. Endoge-
combination with E2, could offer an alternative HRT nous and orally administered estrogens promote the
with a favourable benefit/risk ratio for post-menopausal synthesis of angiotensinogen, leading to increased
women. plasma aldosterone levels via the RAAS [19,44]. The
net physiological effect of unopposed estrogen is
increased sodium and water retention, and decreased
2. The influence of estrogen and progesterone potassium retention. In the natural menstrual cycle,
on the RAAS progesterone counteracts the endogenous estrogen-
induced stimulation of the RAAS by competing with
The RAAS plays a key role in the regulation of aldosterone at the mineralocorticoid receptor [44]. Ide-
body fluids and blood pressure. If there is a sustained ally, synthetic progestogens should be capable of ful-
fall in blood pressure, the kidney releases renin, which filling this role in women treated with exogenous estro-
converts angiotensinogen to angiotensin I (Fig. 1). gens.
This inactive peptide is subsequently converted by
angiotensin-converting enzyme (ACE) to the pharma-
cologically active angiotensin II. Angiotensin II in turn 3. DRSP: a synthetic progestogen with added
stimulates aldosterone secretion, resulting in conserva- benefits
tion of sodium and water, and elimination of potassium
by the kidney [40,44]. In addition, angiotensin II is Progestogenic activity is essential in HRT prepara-
a potent vasoconstrictor, causing acute elevations in tions to counteract the proliferative effects of estrogen
blood pressure. The most important function of the on the uterine endometrium. However, endogenous

Fig. 1. Influence of estrogen and progesterone on the renin-angiotensin-aldosterone system.

300 S. Palacios et al. / Maturitas 55 (2006) 297–307

progesterone has low oral bioavailability and a short that mimic the effects of endogenous progesterone
plasma half-life, rendering the hormone unsuitable for [47].
use in HRT preparations [45,46]. Although micronized DRSP (6␤,7␤,15␤,16␤-dimethylene-3-oxo-17␣-
progesterone is available for use in HRT, and data, pregn-4-ene-21,17-carbolactone), differs from conven-
for example, from the PEPI trial demonstrated that tional progestogens as it is derived from 17␣-
it is effective [18], most HRT combinations contain spironolactone, rather than progesterone, 19-
a synthetic progestogen, commonly derived from 19- nortestosterone or 19-norprogesterone [46,47].
nortestosterone (e.g. norethisterone acetate [NETA]) or The novel chemical structure of DRSP underpins its
17␣-hydroxyprogesterone (e.g. medroxyprogesterone unique receptor binding profile among synthetic pro-
acetate [MPA]) [46–48]. While all conventional pro- gestogens. Moreover, its binding region and biological
gestogens exert progestogenic activity, they exhibit activities are closely akin to those of endogenous
different patterns of binding at other steroid receptors progesterone (Table 1) [35,36,40]. DRSP and pro-
and consequently display diverse biological activities gesterone both exhibit moderate binding affinity to
(Table 1) [40,46–48], which also prevent meaningful progesterone receptors and high binding affinity to
extrapolation of the results for one progestogen to all mineralocorticoid receptors (as antagonists) in the
progestogens as a class, or indeed to all HRT prepara- uterus and kidney [45]. Both DRSP and progesterone
tions. have considerable anti-mineralocorticoid activity in
None of the progestogens currently used in con- transactivation studies of hormone receptors [35,38].
ventional HRT preparations has a similar pharmaco- The anti-androgenic potency of DRSP is reported to
logic profile to that of progesterone, most notably with be 5–10 times greater than that of progesterone and
regard to their lack of anti-mineralocorticoid activity one-third that of cyproterone acetate (CPA). This con-
(Table 1). They are, therefore, unable to adequately trasts with the absence of anti-androgenic activity for
counterbalance the water- and sodium-retaining effects MPA [40,45]. Neither DRSP nor natural progesterone
of the estrogenic component of combined HRT, which display estrogenic, androgenic or glucocorticoid
may contribute to increased blood pressure and weight activity [44,45,47].
gain in susceptible individuals. As such, there is Unlike other progestogens, DRSP has anti-
clearly an unmet clinical need for new, well-tolerated aldosterone activity. The binding affinity of DRSP
progestogenic compounds with improved selectivity at the mineralocorticoid receptor is 2.3- to 5-fold

Table 1
Comparison of the biological activities of progesterone and drospirenone with other progestogens

Clinically relevant activity (+); activity not clinically relevant (±); no activity (−).
 S. Palacios et al. / Maturitas 55 (2006) 297–307 301

higher than that of aldosterone, whereas the affinity showed that the latter group was associated with a
of MPA or NETA is only approximately 3% that of higher incidence of hypertension (≥140/90 mmHg),
aldosterone, and neither display anti-mineralocorticoid which was still evident after adjusting for age and body
activity [45,47]. mass index (BMI) [10]. Although blood pressure mea-
In spontaneously hypertensive rats, SBP and DBP surements were home-based, these results may still be
were decreased or remained unchanged over 27 days subject to the white-coat effect, which is more rele-
of DRSP administration, whereas blood pressure vant in small samples. Another larger survey, which
increased with conventional progestogens, such as CPA reviewed 15 longitudinal and cross-sectional studies,
[45]. In addition, DRSP has been shown to increase found that after adjusting for age and BMI, no sig-
sodium excretion compared with placebo or CPA in nificant correlation was found between menopause
menstruating women [44]. Like progesterone, DRSP and blood pressure. However, this paper did not state
therefore has the potential to counter the increase in whether these subjects were normotensive or hyperten-
sodium and water retention caused by estrogenic stim- sive at baseline, or whether they were receiving HRT
ulation of the RAAS, which may otherwise result or anti-hypertensive therapy [53].
in increased plasma volume, water retention-related The link between post-menopausal estrogen defi-
symptoms and raised blood pressure in susceptible ciency, hypertension and subsequent risk of cardio-
individuals. Thus, in contrast with conventional pro- vascular disease, therefore, remains somewhat unclear.
gestogens, the unique PARA activity of DRSP may A review of blood pressure changes in hypertensive
offer beneficial effects on blood pressure and body post-menopausal women receiving conventional HRT
weight in post-menopausal women. The ratio of pro- agents has revealed a variety of effects, although in
gestogenic to anti-mineralocorticoid activity is similar general, risks of increased blood pressure during ther-
for DRSP and progesterone [44], and DRSP is the apy were low [13–18,53]. A small, observational study
only available progestogen that has significant anti- of 226 normotensive post-menopausal women showed
aldosterone activity at dose levels sufficient to oppose that HRT users had a smaller increase in SBP than
the effects of E2 on the endometrium. DRSP in com- non-users over the 5–6 year follow-up (change in SBP:
bination with E2 has, therefore, been developed as a 8.9 mmHg versus 1.6 mmHg; P = 0.01) [17]. However,
continuous combined HRT, as well as an oral contra- one cannot rule out the possibility of a natural ageing
ceptive with ethinyl estradiol (EE). effect, such as that observed in the Framingham Heart
Study [51], given the absence of a control group or
defined endpoints.
4. The effect of DRSP on blood pressure A number of well-designed trials (see Table 2)
have consistently demonstrated a significant blood
Hypertension, defined by the JNC VII guide- pressure-lowering effect with DRSP plus E2 in post-
lines [13] as stage 1: SBP 140–159 mmHg or DBP menopausal women [43,54–56]. This is consistent with
90–99 mmHg; stage 2: SBP ≥160 mmHg or DBP the potent anti-aldosterone activity of DRSP. In one
≥100 mmHg, is linked to cardiovascular disease study, 24 post-menopausal hypertensive women treated
[49–51], a leading cause of death in the western world with enalapril (baseline blood pressure: 139/82 mmHg)
[52]. In the Framingham Heart Study, a longitudinal 30- were randomised to treatment with E2 1 mg/DRSP
year survey, which examined data from normotensive 3 mg once daily or placebo plus enalapril for 14
and untreated hypertensive subjects, SBP increased days. Blood pressure was measured by 24 h ambula-
linearly with age; if left untreated, elevated SBP can tory monitoring. E2/DRSP significantly reduced 24 h
accelerate large artery stiffness, an independent deter- mean (±S.E.) SBP by 9 mmHg (±1.4) and DBP by
minant of cardiovascular risk [51]. 5 mmHg (±1.2) from baseline (both P < 0.05), whereas
Age-related conditions such as the menopause can no change in blood pressure was observed in the
also have an impact on blood pressure. In a ran- placebo plus enalapril group [54]. These findings show
dom cross-sectional survey of households where blood that E2/DRSP has added benefits on blood pressure
pressure was measured on-site, data from 278 pre- when used in combination with other anti-hypertensive
menopausal women and 184 post-menopausal women agents.
302 S. Palacios et al. / Maturitas 55 (2006) 297–307

Table 2
Summary of trials demonstrating the blood pressure-lowering effects of DRSP
Study Population Design BP definition(s) Outcomes
Preston et al. [54] Post-menopausal women 14-day, double-blind, 24 h ambulatory BP (no Significant additive BP-lowering
(n = 24) treated with PLA-controlled, HTN criteria used) effect of E2/DRSP (mean
E2/DRSP/ENA or randomised, decrease from 139/80 to
PLA/ENA parallel-group study 130/75 mmHg), consistent with
anti-mineralocorticoid effect
Preston et al. [55] Post-menopausal women 28-day, randomised, Changes in clinic BP (no Higher BP reductions for
with T2D (n = 82) or PLA-controlled, definition of HTN but E2/DRSP than PLA (mean
without T2D (n = 148) multicentre study baseline BP was reduction in total group:
treated with E2/DRSP or 132/81 mmHg) −8.6/−5.8 to −3.7/−2.9 mmHg;
PLA P < 0.01). No difference in
hyperkalaemia (K ≥ 5.5 meq/L)
between treatment groups
White et al. [56] Post-menopausal women 12-week, multicentre, Stage 1 HTN defined as Mean clinic BP reductions for
with stage 1 HTN double-blind, randomised, SBP 140–159 and/or DBP E2/DRSP vs. PLA were
(n = 213) treated with PLA-controlled 90–99 mmHg. Endpoints −14.1/−7.9 and −7.1/−4.3
E2/DRSP or PLA were changes in clinic BP mmHg (P < 0.0001). Significant
and 24 h ambulatory BP reductions in mean 24 h SBP
were also observed after
treatment with E2/DRSP
(P = 0.002)
Archer et al. [43] Post-menopausal women Multicentre, double-blind, Endometrial hyperplasia The probability of hyperplasia
(n = 1147) treated with randomised, (primary endpoint); BP was 0.060 for the E2 group
continuous parallel-group study (13, (secondary endpoint) compared with 0.007 for
E2 with/without DRSP (5 28-day treatment cycles) E2/DRSP 2 mg. Significant
regimens in total) reduction in mean BP after
treatment with E2/DRSP 2 mg vs.
E2 (−9.0/−5.7 mmHg vs.
−3.7/−2.7 mmHg)
BP, blood pressure; DBP, diastolic blood pressure; DRSP, drospirenone; E2, 17␤-estradiol; ENA, enalapril maleate; HTN, hypertension; PLA,
placebo; SBP, systolic blood pressure; T2D, Type 2 diabetes mellitus.

In a larger study, 230 post-menopausal hypertensive therapy [56]. The mean clinic blood pressure was
women treated with anti-hypertensive therapy (base- decreased by 14.1/7.9 mmHg (SBP/DBP) from base-
line blood pressure: 132/80 mmHg) were randomised line in patients receiving E2/DRSP compared with
to treatment with E2 1 mg/DRSP 3 mg or placebo only 7.1/4.3 mmHg in the placebo group (P < 0.0001).
for 28 days [55]. The mean decrease in clinic SBP These findings show that the combination of E2
from baseline was greater for E2/DRSP than placebo 1 mg/DRSP 3 mg has a significant effect on blood
(−9.62 ± 1.30 and −2.78 ± 1.02 mmHg, respectively; pressure in untreated hypertensive patients and an addi-
P < 0.001) (Fig. 2A). Corresponding values for tive effect in patients treated with anti-hypertensives.
DBP were −5.74 mmHg (±0.72) and −2.94 mmHg The reductions observed in the placebo group of these
(±0.65), respectively (P < 0.01) (Fig. 2B). A similar trials are consistent with previous findings and were
trend was observed in a sub-group of patients with type not due to any lifestyle interventions. The placebo
2 diabetes mellitus. effect is a well-recognised phenomenon in blood
In post-menopausal women with untreated pressure trials, and is usually more evident with clinic
stage 1 hypertension (SBP 140–159 mmHg; DBP measures than 24 h ambulatory monitoring [57].
90–99 mmHg), treatment with E2 1 mg/DRSP 3 mg In a long-term trial, which evaluated the safety of
decreased both clinic and 24 h ambulatory blood E2 1 mg and four regimens of E2 1 mg/DRSP (0.5,
pressure compared with placebo after 12 weeks of 1, 2 or 3 mg) in 1147 post-menopausal women, the
 S. Palacios et al. / Maturitas 55 (2006) 297–307 303

reduction of blood pressure has implications for these

serious risks.
Nevertheless, these findings show that E2/DRSP
consistently lowers blood pressure, which is most
likely related to the anti-aldosterone activity of DRSP;
aldosterone blockade increases renal sodium excre-
tion, potentially leading to a reduction in SBP and
DBP. Concomitant with the increase in sodium excre-
tion via the RAAS, aldosterone receptor antagonists
may also increase serum potassium concentrations,
particularly in susceptible individuals [19,37]. How-
ever, E2/DRSP has not been associated with hyper-
kalaemia (potassium ≥ 5.5 meq/L), even in high-risk
patients [43,55,56]. When compared with placebo,
treatment with E2 1 mg/DRSP 3 mg did not increase
serum potassium concentrations or the incidence of
hyperkalaemia, irrespective of concomitant use of ACE
inhibitors, angiotensin II receptors antagonists or non-
steroidal anti-inflammatory drugs, and co-morbid dia-
betes mellitus [55]. In addition, there were no clinically
or statistically significant changes in serum potassium
Fig. 2. Mean (±S.E.) SBP (A) and DBP (B) in post-menopausal concentrations in patients with mild renal impairment
women receiving treatment with E2 1 mg/DRSP 3 mg or placebo for and normal renal function when treated with DRSP or
28 days. DBP, diastolic blood pressure; DRSP, drospirenone; E2, placebo [55].
17␤-estradiol; SBP, systolic blood pressure [55].
Overall, E2 1 mg/DRSP 2 or 3 mg lowered SBP
by approximately 7–14 mmHg and DBP by approx-
combination of E2/DRSP was effective in protect- imately 5–8 mmHg in hypertensive post-menopausal
ing against endometrial hyperplasia [43]. Secondary women in these trials. Although these changes may
endpoints included, amongst others, blood pressure appear small, decreases in SBP of only 2–3 mmHg
assessments. Based on a post hoc analysis in 102 have previously been associated with improved cardio-
hypertensive women (SBP ≥140 mmHg and/or DBP vascular outcomes [58–60]. Mean reductions in SBP
≥90 mmHg), there was a significant decrease in mean and DBP of 10 and 4 mmHg, respectively, have been
SBP from baseline in those receiving E2 1 mg/DRSP shown to decrease the risks of stroke and myocardial
2 mg (−9.0 mmHg; P = 0.011; n = 15) whereas the infarction by 30% and 23% [58]. There is also evi-
decrease from baseline was not significant with E2 dence to suggest that across the blood pressure range
monotherapy (−3.7 mmHg; P = 0.220; n = 15) after 13, 115/75–185/115 mmHg, the risk of cardiovascular dis-
28-day treatment cycles. Similarly, the mean DBP ease doubles with each increment of 20/10 mmHg
change from baseline in the E2/DRSP group was in individuals aged 40–70 years [61]. These findings
−5.7 mmHg (P < 0.001) compared with −2.7 mmHg underscore the importance of even small decreases in
in the E2 monotherapy group (P = 0.108), although blood pressure, and concur with recommendations to
inter-treatment comparisons did not reach significance. lower blood pressure by lifestyle changes even in pre-
While this study also demonstrated a beneficial effect hypertensive individuals (i.e. SBP 120–139 mmHg or
of E2/DRSP on total cholesterol and low-density DBP 80–89 mmHg), as they are twice as likely to
lipoprotein cholesterol, there was no actual assessment develop hypertension than individuals with lower blood
of cardiovascular endpoints such as stroke, CHD or pressures [13]. As yet, however, there are no data indi-
myocardial infarction. Long-term studies are needed cating that E2 1 mg/DRSP 2 mg has a role in reducing
to address the effect of E2/DRSP on cardiovascular the risk of stroke or CHD in post-menopausal women
outcomes in order to determine whether the observed with elevated blood pressure.
304 S. Palacios et al. / Maturitas 55 (2006) 297–307

5. The effect of DRSP on body weight

Although women tend to gain weight after the

menopause, regardless of whether or not they are pre-
scribed HRT, particular concern among patients about
weight gain during HRT can deter initiation of treat-
ment and cause poor compliance and/or early discon-
tinuation among users [21,22,33,34]. For instance, one
quarter of former HRT users aged 45–75 years cited
weight gain as a reason to discontinue therapy in a
European study of 8012 women [22].
Fig. 3. Change in body weight (mean ± S.E.) in post-menopausal
As mentioned above, DRSP is a potent aldosterone women receiving HRT with E2 1 mg/DRSP 2 mg or E2 1 mg for 13
antagonist that acts on the mineralocorticoid receptor cycles. * P < 0.001 vs. E2 monotherapy. DRSP, drospirenone; E2,
to decrease sodium reabsorption and water retention. 17␤-estradiol; HRT, hormone replacement therapy; SBP, systolic
The potential benefits offered by this improved phar- blood pressure [43].
macological profile of DRSP have translated into a
positive effect on body weight in clinical trials of an Similar findings have been shown when E2/DRSP
oral contraceptive containing DRSP and EE [62–64] is used as HRT in post-menopausal women [43]. In
(see Table 3). Data from two large, randomised, com- one trial (see Table 2), post-menopausal women receiv-
parative trials show that mean body weight remained ing E2 1 mg/DRSP 2 mg experienced a small decrease
significantly lower in women receiving the oral contra- in body weight, whereas women receiving E2 1 mg
ceptive EE 30 ␮g/DRSP 3 mg than in women receiv- monotherapy tended to gain weight, even after the first
ing EE 30 ␮g/desogestrel 150 ␮g over 13 or 26 cycles treatment cycle (Fig. 3) [43]. At study end (cycle 13),
[63,64]. the mean difference between treatments was 0.9 kg

Table 3
Summary of trials showing the beneficial effects of DSP on weight
Study Population Design Weight assessment Outcomes
Oelkers et al. [62] Healthy women (n = 80), 6-month, randomised trial Body weight measured by Body weight reductions ranging
aged 18–34 years, treated (6 treatment cycles) women on home scales from 0.8 to 1.7 kg in the
with EE/DRSP or every second day DRSP/EE groups compared with
levonorgestrel (control) (unclothed, fasting an increase in the control group
states). Mean weights of 0.7 kg (P < 0.05; DRSP/EE
during a cycle were used groups vs. control)
for calculations
Foidart et al. [63] Healthy women (n = 900), Randomised, open-label, Body weight measured by In the DRSP/EE group, the mean
aged 18–35 years, treated multicentre study (26 women on home scales body weight remained below
with EE/DRSP or treatment cycles; 3-month (unclothed, fasting baseline (−0.11 to −0.68 kg). In
EE/desogestrel follow-up) states). Weight checked the EE/desogestrel group, there
weekly. Mean weights was an increase after cycle 5
during a cycle were used (range: +0.02 to +0.89 kg)
for calculations. Mean
pre-treatment weight was
baseline
Huber et al. [64] Healthy women Randomised, open-label, Body weight measured by Weight loss was significantly
(n = 2069), aged 18–35 multicentre study (13 women on home scales greater in the EE/DRSP group
years, treated with treatment cycles) (unclothed, fasting than EE/desogestrel (−0.46 vs.
EE/DRSP or states). Mean weights −0.19 kg; P < 0.0072)
EE/desogestrel during a cycle were used
for calculations
DRSP, drospirenone; EE, ethinyl estradiol.
 S. Palacios et al. / Maturitas 55 (2006) 297–307 305

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Acknowledgement uation, and Treatment of High Blood Pressure. Hypertension
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This work was supported by Schering AG.
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