CLIMACTERIC 2005;8(Suppl 3):4–12

Pharmacology of different
progestogens: the special case
of drospirenone
R. Sitruk-Ware

Rockefeller University and Population Council, New York, USA

Key words: PROGESTOGENS, 19-NORPROGESTERONES, DROSPIRENONE, YASMIN1, ANGELIQ1, HORMONE REPLACEMENT

THERAPY, ORAL CONTRACEPTIVE, MENOPAUSE
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ABSTRACT
The pharmacological properties of progestins used in contraception and hormone
replacement therapy (HRT) vary, depending upon the molecules from which they are
derived. Very small structural changes may induce considerable differences in
effects. It is unclear if the currently available progestins are able to bind specifically
to the progesterone receptors, PR-A or PR-B. The clinical relevance of more
specific binding to one or the other isoforms of the progesterone receptor is still
For personal use only.

unknown. The development of new generations of progestins, with improved

receptor-selectivity profiles, has been a great challenge. Steroidal and non-steroidal
progesterone agonists have also been synthesized, although these molecules are at a
very early stage of development. Several new progestins have been synthesized in the
past decade, including dienogest, drospirenone, Nestorone, nomegestrol acetate and
trimegestone.
Drospirenone differs from the classic progestins in its derivation from spirolactone.
The major effect of drospirenone is antimineralocorticoid activity. By that property,
drospirenone causes decreased salt and water retention, and thus lowering of blood
pressure. The affinity of drospirenone for the mineralocorticoid receptor is about five
times that of aldosterone, the naturally occurring mineralocorticoid. In addition,
drospirenone has no androgenic effect, but does exhibit partial antiandrogenic
activity; its antiandrogenic potency is about 30% of that of cyproterone acetate, the
progestin with the most potent antiandrogenic activity. This property, shared by
several new progestins, may counteract the negative effect of androgens on hair
growth, lipid changes, insulin and, possibly, body composition in postmenopausal
women.
Drospirenone has a long terminal half-life (about 32 hours), and its bioavailability is
about 76%. Drospirenone, which has pharmacodynamic properties very similar to
those of progesterone, has been developed as a combined oral contraceptive
(30 mg ethinylestradiol/3 mg drospirenone; Yasmin1, Schering AG, Berlin, Germany).
Drospirenone is also available in combination with estradiol as an HRT preparation
(1 mg 17b-estradiol/2 mg drospirenone; Angeliq1, Schering AG).

Correspondence: Professor R. Sitruk-Ware, Population Council and Rockefeller University, 1230 York Avenue, New York,
NY 10021, USA

ª 2005 International Menopause Society

DOI: 10.1080/13697130500330382
 New progestins
INTRODUCTION
The term ‘progestogens’ encompasses the endo-
genous hormone progesterone and the synthetic
steroids that mimic progesterone – progestins. The
pharmacological properties of progestogens (by
definition progestins) used in contraception and
hormone replacement therapy (HRT) vary de-
pending upon the molecules from which they are
derived (either progesterone or testosterone), and
it has been demonstrated that small structural
differences can lead to large differences in the
activity of the derivative1–3.
Recently, the results of the Women’s Health
Initiative – a large, randomized, placebo-
controlled trial investigating the use of combina-
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tion hormone therapy4 – and those of other
observational studies5–7 have raised concerns
about the risks associated with the use of some
older progestins, such as medroxyprogesterone
acetate, norethisterone acetate and levonorgestrel,
in combination with conjugated equine estrogens
or oral estradiol. Inappropriately, since many
progestins differ considerably in structure, these
concerns have been generalized to the entire
progestin class8.
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The effects of progestins are related to interac-
tions not only with the progesterone receptor
(PR), but also with other steroid receptors, such as
the androgen receptor (AR), the estrogen receptor
(ER), the glucocorticoid receptor (GR) and the
mineralocorticoid receptor (MR). Such interac-
tions may either induce transactivation or prevent
activation of the steroid receptor, and may be
responsible for some of the undesirable side-
effects of progestins. For example, many proges-
tins used in contraceptives and HRT are derived
from testosterone, and the commonly cited side-
effects of acne and/or weight gain are related to
the androgenic properties or glucocorticoid effects
of these compounds9.
PHYSIOLOGICAL ACTIONS
OF PROGESTERONE AND
INDICATIONS FOR PROGESTINS
Progesterone has several biological effects. It is
secreted by the corpus luteum after ovulation and
transforms the endometrium into a secretory
tissue, permitting the implantation of a fertilized
ovum. Concomitantly, the antigonadotropic
action of progesterone prevents further ovulation.
In addition, progesterone maintains pregnancy by
preventing contractions of the uterus, via its
antiestrogenic activity8.
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Sitruk-Ware
Progesterone has both antiandrogenic and anti-
mineralocorticoid effects. Through competitive
inhibition, progesterone prevents the conversion
of testosterone into its active metabolite, dihy-
drotestosterone, by the enzyme 5a-reductase9.
Progesterone also binds competitively to the
MR, preventing its transactivation and inhibiting
the mineralocorticoid effect11.
Most of the first- and second-generation pro-
gestins were derived from testosterone and were
designed in the 1960s and 1970s for use in
contraceptives. With this in mind, the major
design target was antigonadotropic activity1.
Although effective in preventing pregnancy, these
progestins were less than ideal due to the presence
of undesirable side-effects, such as acne, a
decrease in high density lipoprotein (HDL) chol-
esterol, water retention and bloating12. Over the
past two decades, several new progestins have
been synthesized, designed to be closer in activity
to physiological progesterone, but to have an
improved receptor-selectivity profile. Thus, newer
progestins have potent progestational and anti-
estrogenic effects on the endometrium, with a
strong antigonadotropic activity. However, unlike
their older counterparts, these new progestins are
largely devoid of any androgenic or glucocorticoid
effects9.
Extensive trials with a variety of oral contra-
ceptives have established that an appropriate
combination of estrogen and a progestin can
provide effective contraception and cycle control.
Progestins have also been approved for the
treatment of irregular and anovulatory menstrual
cycles and, when combined with estrogen, in
postmenopausal HRT regimens. Progestins are
used to prevent endometrial hyperplasia and to
induce regular withdrawal bleeding in perimeno-
pausal women who are still secreting estrogen.
Similarly, for the management of menopausal
symptoms in postmenopausal women with intact
uteri, a combined HRT regimen decreases the risk
of endometrial hyperplasia and cancer, in contrast
to unopposed estrogen therapy13–15.
However, the final effect of any progestin used
in a contraceptive or HRT regimen depends upon
its antiestrogenic activity, the dose and duration of
treatment, and the potency of the estrogen with
which it is combined8.
THE EFFECTS OF PROGESTINS
ON BREAST TISSUE
In addition to the uterus and ovaries, progesterone
acts on several body organs, including the breast.
5
 New progestins
The interpretation of data related to the effects
of progestins used in HRT on breast tissue is
controversial. Most data derive from studies
with older progestins which, when combined
with certain doses of estrogen, may slightly
increase the risk of breast cancer compared
with estrogen alone. However, the type of
progestin used, the dose and the duration of
application may influence the effect, either
proliferative or antiproliferative, on human
breast tissue8.
Studies in animals have shown that estrogen
stimulates the growth of tissues in the breast,
while progesterone acts synergistically to differ-
entiate the tissues16. However, in humans, the
data are less clear-cut, with some recent experi-
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ments suggesting that exposure to progesterone is
associated with a higher proliferation rate in
breast tissue8.
The PR has two isoforms, A and B, that arise
from the alternate splicing of a single gene.
Knock-out models have demonstrated that the
presence of the PR-B isoform is sufficient to
mediate the normal proliferative response to
progesterone and the differentiation of mam-
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mary tissues. In contrast, the PR-A isoform acts
as a dominant repressor of PR-B activity17.
These findings suggest that different progestins
may have different binding affinities for the
PR-A and PR-B receptors and, hence, exert dif-
ferent effects on estrogen-induced proliferative
activity8.
THE EFFECTS OF ESTROGEN AND
PROGESTINS ON THE
RENIN–ANGIOTENSIN–
ALDOSTERONE SYSTEM
Estrogens, when administered orally, pass through
the liver where they promote the synthesis of
numerous proteins, including angiotensinogen
(previously named plasma renin substrate). The
renin–angiotensin–aldosterone system (RAAS) has
a critical role in the regulation of body fluids,
serum sodium and potassium, and blood pressure,
through the angiotensin-mediated stimulation of
aldosterone production, which acts on the kidney
to conserve sodium and potassium18,19. Exogen-
ous estrogens, such as ethinylestradiol, stimulate
the production of angiotensinogen in the liver.
Renin splits its substrate, angiotensinogen, to
produce angiotensin I (AI), a protein with no
known biological effect. In turn, AI is converted to
the active peptide, angiotensin II (AII), by the
angiotensin-converting enzyme (ACE). AII stimu-
6 Climacteric
Sitruk-Ware
lates the production of aldosterone, leading to an
increase in sodium reabsorption in the distal
tubule. This pathway ends with an expansion of
extracellular fluid and blood volume. The increase
in blood volume activates the blood-volume–
renin feedback loop, triggering a decrease in renin
secretion. This feedback loop maintains a perma-
nent equilibrium between renin output and blood
volume.
Unlike natural progesterone and the syn-
thetic progestin, drospirenone or, to a lesser
extent, trimegestone27, most synthetic proges-
tins do not have antimineralocorticoid activity
at the doses used in oral contraceptives and
HRT. The ethinylestradiol-related increase in
angiotensinogen secretion is generally accom-
panied by a decrease in renin secretion, which
limits the risk of developing hypertension.
However, in cases where the feedback loop
between angiotensinogen and renin is absent,
the unopposed ethinylestradiol action may lead
to slight increases in body weight and blood
pressure20.
THE EFFECTS OF ESTROGEN AND
PROGESTINS ON LIPID PROFILES
AND CARBOHYDRATE
METABOLISM
HDL cholesterol is known to reduce the risk of
atherosclerosis, and has a cardiovascular protective
effect, whereas a high level of low density lipopro-
tein (LDL) cholesterol is thought to be a major
contributor to heart disease21. Most studies evalu-
ating the effect of estrogens on lipoproteins have
demonstrated a beneficial increase in HDL : LDL
cholesterol ratios. Co-administration of a progestin
may blunt these changes in serum lipids, particu-
larly if they are derivatives of 19-nortestosterone,
since progestins with androgenic properties par-
tially reverse the HDL cholesterol-raising effect
of estrogen12. However, natural progesterone, the
19-progesterone derivatives and drospirenone do
not affect HDL cholesterol levels12,21,22.
Glucose intolerance and hyperinsulinemia are
well-known risk factors for cardiovascular dis-
ease21. Insulin is a potent stimulus of endothelial
cell growth and also regulates LDL receptor
activity23,24. Studies of combined HRT, as re-
ported by Sitruk-Ware21, have shown variations
in response to oral or intravenous glucose
tolerance tests according to the androgenic or
non-androgenic properties of the progestin used,
with non-androgenic progestins being neutral
toward carbohydrate metabolism.
 New progestins
CLASSIFICATION AND
PHARMACOKINETICS OF
PROGESTINS
Progestins have different pharmacologic proper-
ties, depending on the parent molecule from
which they are derived9.
The 19-norprogesterone derivatives of proges-
terone include Nestorone1, nomegestrol acetate
and trimegestone. They are derived from the
pregnane structure, but have one less carbon,
as they do not have a radical methyl at C-19
(Figure 1)9.
Nestorone has a deletion of the 19-methyl
radical, and the addition of the 16-methylene
substituent, which enhances binding to the PR,
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and contributes to the molecule’s high progesta-
tional activity25. Nestorone is not active when
administered orally, but is active when adminis-
tered continuously via sustained-release implants,
vaginal rings or transdermal systems. As with
progesterone, Nestorone does not bind to sex
hormone binding globulin (SHBG), resulting in a
shorter half-life and higher clearance rates, com-
pared with progestins (which do bind to SHBG)26.
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When taken orally, Nestorone has a bioavailabil-
ity of only 10%; however, the elimination rate of
Nestorone is much slower when used in the
sustained-release subdermal implant8.
Nomegestrol acetate is formed by the addition of
a double-bond between C-6 and C-7 of the
hydroxyprogesterone skeleton, and has a deletion
of the methyl radical at C-19. These structural
Figure 1 19-Norprogesterone derivatives of progesterone include Nestorone1, nomegestrol acetate and
trimegestone
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Sitruk-Ware
changes confer a high progestational potency to
nomegestrol acetate, which has a terminal half-life
of about 50 h8. Trimegestone has a hydroxylated
carbon on the penultimate carbon of the side-chain
(C-17), and is twice as potent as Nestorone in
transforming estrogen-primed endometrium into a
secretory tissue, but is less effective at preventing
ovulation27. This progestin exhibits also a partial
antimineralocorticoid effect27.
Chemically, dienogest (Figure 2) is a derivative
of 19-nortestosterone, but has a cyanomethyl
group at position C-17 instead of an alkyl
group28, and a double-bond between C-9 and
C-10. Dienogest has a high bioavailability
(96.2%), a short terminal half-life (11.6 h) and a
substantial clearance rate of about 31 h28.
Drospirenone differs from the classic progestins
as it is derived from spirolactone and is essentially
an antimineralocorticoid progestin. Drospirenone
has the basic 19-carbon chemical structure of its
parent compound, androstane29, and has two
methylene groups; one attached at C-6 and C-7,
and the other at C-15 and C-16. In addition, a
carbolactone group is attached at C-17. Drospir-
enone has a long terminal half-life (about 32 h)29,
and its bioavailability is about 76%2.
BINDING AFFINITIES
Progestins may be evaluated by comparing their
relative binding affinities (RBAs) to steroid
receptors in relation to those of the physiological
reference hormones (set at 100%). The RBAs
7
 New progestins Sitruk-Ware

of trimegestone, medroxyprogesterone acetate, PR, have a steroid-binding domain and a DNA-

norethisterone, gestodene, levonorgestrel and
drospirenone for the human PR, ER, AR, MR
and GR, compared with the natural ligand of
each receptor (progesterone, estradiol, testo-
sterone, aldosterone and dexamethasone,
respectively), are shown in Table 129–31. The
range of RBAs indicates that there are consider-
able differences in activity among these new
progestin molecules. However, the binding affinity
to the steroid receptors does not always correlate
with the in vivo tests of estrogenic or androgenic
potency.
BINDING TO STEROID RECEPTORS
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binding domain. The binding of hormone to
receptor induces a conformational change, which
transforms the PR to an active dimer and allows it
to bind to specific DNA sequences. This transfor-
mation is accompanied by a loss of associated heat
shock proteins and dimerization of the PR. The
activated PR dimer then associates with transcrip-
tion factors, binding to progesterone response
elements within the promoter region of progester-
one-responsive genes8. This binding results in an
increase in the transcription of new genes, which
alter the metabolism of the cell in a steroid-specific
manner.

Steroid hormones are relatively small, hydropho- IN VIVO BIOASSAYS AND

bic molecules that enter cells by a simple diffusion
process. They are preferentially retained in target
cells as stable complexes bound to intracellular
steroid receptors. Steroid receptors, such as the
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PROGESTIN ACTION
The progestational potencies of progestins are
evaluated using several gold-standard in vivo
bioassays (Table 2). The McPhail Index measures

Figure 2 Dienogest is a derivative of 19-nortestosterone, and drospirenone is derived from spirolactone

Table 1 Binding of progestins with human steroid receptors in vitro. Adapted from Sitruk-Ware9 with data from
references 30 and 31
Relative binding affinity (%)
Receptor TMG MPA NET GES LNG DRSP
Progesterone 588 298 134 864 323 19
Androgen 2.4 36 55 71 58 2
Glucocorticoid 13 58 1.4 38 7.5 3
Mineralocorticoid 42 3.1 2.7 97 17 500
Estrogen 50.02 5 0.02 0.15 5 0.02 5 0.02 5 0.5
TMG, trimegestone; MPA, medroxyprogesterone acetate; NET, norethisterone; GES, gestodene; LNG, levonor-
gestrel; DRSP, drospirenone

8 Climacteric
 New progestins Sitruk-Ware

Table 2 In vivo bioassays for testing progestins9. For full description of the bioassays, see Kumar et al.32
Bioactivity Test Species End points
Progestational McPhail Index immature female rabbits endometrial transformation
Progestational pregnancy maintenance female rats dose able to maintain pregnancy
after ovariectomy
Antiovulatory ovulation inhibition test 4-day cyclic rats dose able to suppress
spontaneous ovulation
Androgenic Hershberger assay immature or castrated growth of prostate and seminal
male rats vesicles
Antiandrogenic Hershberger assay immature or castrated male inhibition of testosterone-
rats treated with induced prostate and seminal
testosterone vesicles growth
Estrogenic/ vaginal cornification/ immature or uterine growth and
antiestrogenic uterotropic ovariectomized vaginal cornification
female rats
Glucocorticoid/ thymolytic assay adrenalectomized male rats growth of thymus
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antiglucocorticoid
Antimineralo- renal function rats Na/K and water excretion
corticoid

the dose of progestin required to transform the

uterine endometrium to a secretory state in Antiovulatory potency
immature, estrogen-primed rabbits. The preg- Nestorone is an extremely potent inhibitor of
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nancy maintenance test measures the progestin
dose required to maintain a pregnancy in ovar-
iectomized female rats. A third assay, the
ovulation inhibition test, is used to compare the
antiovulatory potencies of progestins; this assay
measures the dose of progestin required to inhibit
spontaneous ovulation in female rats with normal-
estrus cycles32,33.
The antiandrogenic activity of progestins is
assessed by the Hershberger test. This test
measures the dose of progestin required to anta-
gonize the androgenic effect of a fixed dose of
testosterone on the weight of the male sex organs
in immature rats32.
The antimineralocorticoid activity of pro-
gestins is assessed by their ability to antagonize
aldosterone activity on the renal function of
adrenalectomized rats29.
Progestational potency
Although trimegestone is twice as potent as
Nestorone, both are extremely potent in trans-
forming uterine endometrium to a secretory state.
Their progestational potencies are in excess of 100
times greater than that of natural progesterone.
Levonorgestrel, nomegestrol acetate, medroxy-
progesterone acetate and drospirenone all have
progestational potencies ranging from six to ten
times greater than that of progesterone9.
ovulation, with about 100 times the potency of
progesterone, while levonorgestrel has about
50 times the potency. Drospirenone can inhibit
ovulation with approximately three to ten times
the potency of progesterone34. The progestagenic
and antiovulatory potencies of older proges-
tins versus newer progestins are illustrated in
Figure 3.
Antiandrogenic potency
Cyproterone acetate is the most potent antiandro-
genic progestin, with an activity over twice that
of dienogest, three times greater than that of
drospirenone and ten times greater than that of
progesterone. Cyproterone acetate, dienogest and
drospirenone are the only progestins that demon-
strate antiandrogenic activity at therapeutic
doses28. Nomegestrol acetate and trimegestone
have a partial antiandrogenic effect (about five
times less than that of cyproterone acetate). The
antiandrogenic potencies of older progestins
versus newer progestins are illustrated in Figure 4.
Antimineralocorticoid potency
Drospirenone has a five-fold greater affinity for
the MR than aldosterone itself, and is two to four
times more potent than progesterone29. Some
conventional progestins, cyproterone acetate,

Climacteric 9
 New progestins
Figure 3 Progestagenic and antiovulatory potencies of
new progestins versus levonorgestrel, medroxyproges-
terone acetate and progesterone. TMG, trimegestone;
NOM Ac, nomegestrol acetate; MPA, medroxyproges-
terone acetate; NES, Nestorone; LNG, levonorgestrel
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For personal use only.
Figure 4 Antiandrogenic potencies of progestins. CPA,
cyproterone acetate; TMG, trimegestone; NOM Ac,
nomegestrol acetate
norethisterone, 3-ketodesogestrel and levonor-
gestrel are unable to exert any aldosterone
antagonistic effects, even at high doses35. The
antimineralocorticoid potencies of older pro-
gestins versus newer progestins are summarized
in Table 3.
DROSPIRENONE
Drospirenone is currently the only progestin that
closely matches the pharmacological profile of
progesterone; this is due to its novel molecular
structure, which is derived from 17a-spirolactone.
Drospirenone binds to the PR with the same
affinity as progesterone. It has a higher antimin-
eralocorticoid potency than progesterone,
cyproterone acetate, norethisterone, 3-ketodeso-
gestrel, levonorgestrel and gestodene (Table 3)29,
and is a more potent antiandrogenic progestin than
progesterone (Figure 4)28. Thus, although drospir-
enone is a weaker progestin, with regard to the
endometrium and ovulation suppression, it has an
unsurpassed antimineralocorticoid potency.
Drospirenone has been developed as a com-
bined oral contraceptive (30 mg ethinylestradiol
10
Sitruk-Ware
Table 3 Antimineralocorticoid potency29
Steroid Dose s.c. (mg/animal)
Progesterone 2
Cyproterone acetate 48
Norethisterone 48
3-Ketodesogestrel 48
Levonorgestrel 48
Gestodene 4
Spironolactone 1
Spirorenone 0.5
Drospirenone 51 (0.25 p.o.)
s.c., subcutaneous; p.o., oral
(EE)/3 mg drospirenone (DRSP); Yasmin1, Scher-
ing AG, Berlin, Germany) and as an HRT
preparation (1 mg 17b-estradiol/2 mg drospire-
none; Angeliq1, Schering AG).
Comparator studies of EE/DRSP and an oral
contraceptive containing 150 mg levonorgestrel
(LNG) and 30 mg EE (Microgynon1, Schering
AG) have shown that EE/DRSP is effective in
preventing pregnancy. However, women receiving
the LNG/EE combination experienced a slight
increase in body weight while those who received
EE/DRSP experienced a slight decrease in weight.
In addition, more women receiving EE/DRSP
displayed a decrease in systolic blood pressure of
10 mmHg or less, and increased levels of HDL
cholesterol, compared with women receiving
LNG/EE12. The weight loss under EE/DRSP was
anticipated to be an indicator of reduced water
retention, as a result of drospirenone’s antiminer-
alocorticoid activity antagonizing the sodium-
retaining effect of ethinylestradiol. The positive
effect on blood pressure was probably the result
of a reduction in extracellular volume, while
the favorable lipid profile, with no evidence of
attenuation of the beneficial effects of ethinyl-
estradiol on HDL cholesterol, was probably due
to drospirenone’s lack of androgenicity.
Studies in postmenopausal women have demon-
strated that treatment with drospirenone in a
combined HRT significantly decreases the mean
number of hot flushes/week within 2–3 weeks of
beginning treatment36,37. No endometrial hyper-
plasia or carcinoma was observed during a study
period of 2 years and more than 90% of women
regained amenorrhea38.
CONCLUSIONS
Progestin molecules are not all the same. There
may be profound differences according to struc-
ture, metabolites and pharmacodynamics. It is
Climacteric
 New progestins
wholly inappropriate to draw conclusions about
the effects of one progestin based on data from
another with a different structure and activity
profile.
In contrast to the older progestins, newer
progestins – developed for use in combined oral
contraception and HRT regimens – have been
designed to bind very specifically to the progester-
one receptor and to exert no androgenic or
estrogenic side-effects3,39,40. Thus, these newer
progestins are associated with the benefits of pro-
gesterone without the undesirable effects of acne,
hirsutism and decreased HDL cholesterol. In
addition, some of these newer progestins possess
antimineralocorticoid activity. These molecules
may neutralize the adverse effects of ethinylestra-
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diol on the RAAS and reduce the incidences of
water retention and bloating, and increases in
blood pressure.
Drospirenone differs from classic progestins, as
it is derived from spirolactone. It is essentially an
antimineralocorticoid that partially counteracts
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ACKNOWLEDGEMENT
I thank Narender Kumar for assistance in pre-
paration of Table 2.
Conflict of interest Nil.
Source of funding Most of the work con-
ducted on other progestins mentioned in this
paper was funded by USAID and the National
Institutes of Health. The author received an
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