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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 Sitruk-Ware

Progesterone has both antiandrogenic and anti-


INTRODUCTION mineralocorticoid effects. Through competitive
The term ‘progestogens’ encompasses the endo- inhibition, progesterone prevents the conversion
genous hormone progesterone and the synthetic of testosterone into its active metabolite, dihy-
steroids that mimic progesterone – progestins. The drotestosterone, by the enzyme 5a-reductase9.
pharmacological properties of progestogens (by Progesterone also binds competitively to the
definition progestins) used in contraception and MR, preventing its transactivation and inhibiting
hormone replacement therapy (HRT) vary de- the mineralocorticoid effect11.
pending upon the molecules from which they are Most of the first- and second-generation pro-
derived (either progesterone or testosterone), and gestins were derived from testosterone and were
it has been demonstrated that small structural designed in the 1960s and 1970s for use in
differences can lead to large differences in the contraceptives. With this in mind, the major
activity of the derivative1–3. design target was antigonadotropic activity1.
Recently, the results of the Women’s Health Although effective in preventing pregnancy, these
Initiative – a large, randomized, placebo- progestins were less than ideal due to the presence
controlled trial investigating the use of combina- of undesirable side-effects, such as acne, a
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tion hormone therapy4 – and those of other decrease in high density lipoprotein (HDL) chol-
observational studies5–7 have raised concerns esterol, water retention and bloating12. Over the
about the risks associated with the use of some past two decades, several new progestins have
older progestins, such as medroxyprogesterone been synthesized, designed to be closer in activity
acetate, norethisterone acetate and levonorgestrel, to physiological progesterone, but to have an
in combination with conjugated equine estrogens improved receptor-selectivity profile. Thus, newer
or oral estradiol. Inappropriately, since many progestins have potent progestational and anti-
progestins differ considerably in structure, these estrogenic effects on the endometrium, with a
concerns have been generalized to the entire strong antigonadotropic activity. However, unlike
progestin class8.
For personal use only.

their older counterparts, these new progestins are


The effects of progestins are related to interac- largely devoid of any androgenic or glucocorticoid
tions not only with the progesterone receptor effects9.
(PR), but also with other steroid receptors, such as Extensive trials with a variety of oral contra-
the androgen receptor (AR), the estrogen receptor ceptives have established that an appropriate
(ER), the glucocorticoid receptor (GR) and the combination of estrogen and a progestin can
mineralocorticoid receptor (MR). Such interac- provide effective contraception and cycle control.
tions may either induce transactivation or prevent Progestins have also been approved for the
activation of the steroid receptor, and may be treatment of irregular and anovulatory menstrual
responsible for some of the undesirable side- cycles and, when combined with estrogen, in
effects of progestins. For example, many proges- postmenopausal HRT regimens. Progestins are
tins used in contraceptives and HRT are derived used to prevent endometrial hyperplasia and to
from testosterone, and the commonly cited side- induce regular withdrawal bleeding in perimeno-
effects of acne and/or weight gain are related to pausal women who are still secreting estrogen.
the androgenic properties or glucocorticoid effects Similarly, for the management of menopausal
of these compounds9. symptoms in postmenopausal women with intact
uteri, a combined HRT regimen decreases the risk
of endometrial hyperplasia and cancer, in contrast
PHYSIOLOGICAL ACTIONS to unopposed estrogen therapy13–15.
OF PROGESTERONE AND However, the final effect of any progestin used
INDICATIONS FOR PROGESTINS in a contraceptive or HRT regimen depends upon
Progesterone has several biological effects. It is its antiestrogenic activity, the dose and duration of
secreted by the corpus luteum after ovulation and treatment, and the potency of the estrogen with
transforms the endometrium into a secretory which it is combined8.
tissue, permitting the implantation of a fertilized
ovum. Concomitantly, the antigonadotropic
action of progesterone prevents further ovulation. THE EFFECTS OF PROGESTINS
In addition, progesterone maintains pregnancy by ON BREAST TISSUE
preventing contractions of the uterus, via its In addition to the uterus and ovaries, progesterone
antiestrogenic activity8. acts on several body organs, including the breast.

Climacteric 5
New progestins Sitruk-Ware

The interpretation of data related to the effects lates the production of aldosterone, leading to an
of progestins used in HRT on breast tissue is increase in sodium reabsorption in the distal
controversial. Most data derive from studies tubule. This pathway ends with an expansion of
with older progestins which, when combined extracellular fluid and blood volume. The increase
with certain doses of estrogen, may slightly in blood volume activates the blood-volume–
increase the risk of breast cancer compared renin feedback loop, triggering a decrease in renin
with estrogen alone. However, the type of secretion. This feedback loop maintains a perma-
progestin used, the dose and the duration of nent equilibrium between renin output and blood
application may influence the effect, either volume.
proliferative or antiproliferative, on human Unlike natural progesterone and the syn-
breast tissue8. thetic progestin, drospirenone or, to a lesser
Studies in animals have shown that estrogen extent, trimegestone27, most synthetic proges-
stimulates the growth of tissues in the breast, tins do not have antimineralocorticoid activity
while progesterone acts synergistically to differ- at the doses used in oral contraceptives and
entiate the tissues16. However, in humans, the HRT. The ethinylestradiol-related increase in
data are less clear-cut, with some recent experi- angiotensinogen secretion is generally accom-
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ments suggesting that exposure to progesterone is panied by a decrease in renin secretion, which
associated with a higher proliferation rate in limits the risk of developing hypertension.
breast tissue8. However, in cases where the feedback loop
The PR has two isoforms, A and B, that arise between angiotensinogen and renin is absent,
from the alternate splicing of a single gene. the unopposed ethinylestradiol action may lead
Knock-out models have demonstrated that the to slight increases in body weight and blood
presence of the PR-B isoform is sufficient to pressure20.
mediate the normal proliferative response to
progesterone and the differentiation of mam-
THE EFFECTS OF ESTROGEN AND
For personal use only.

mary tissues. In contrast, the PR-A isoform acts


as a dominant repressor of PR-B activity17. PROGESTINS ON LIPID PROFILES
These findings suggest that different progestins AND CARBOHYDRATE
may have different binding affinities for the METABOLISM
PR-A and PR-B receptors and, hence, exert dif- HDL cholesterol is known to reduce the risk of
ferent effects on estrogen-induced proliferative atherosclerosis, and has a cardiovascular protective
activity8. 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-
THE EFFECTS OF ESTROGEN AND ating the effect of estrogens on lipoproteins have
PROGESTINS ON THE demonstrated a beneficial increase in HDL : LDL
RENIN–ANGIOTENSIN– cholesterol ratios. Co-administration of a progestin
ALDOSTERONE SYSTEM may blunt these changes in serum lipids, particu-
Estrogens, when administered orally, pass through larly if they are derivatives of 19-nortestosterone,
the liver where they promote the synthesis of since progestins with androgenic properties par-
numerous proteins, including angiotensinogen tially reverse the HDL cholesterol-raising effect
(previously named plasma renin substrate). The of estrogen12. However, natural progesterone, the
renin–angiotensin–aldosterone system (RAAS) has 19-progesterone derivatives and drospirenone do
a critical role in the regulation of body fluids, not affect HDL cholesterol levels12,21,22.
serum sodium and potassium, and blood pressure, Glucose intolerance and hyperinsulinemia are
through the angiotensin-mediated stimulation of well-known risk factors for cardiovascular dis-
aldosterone production, which acts on the kidney ease21. Insulin is a potent stimulus of endothelial
to conserve sodium and potassium18,19. Exogen- cell growth and also regulates LDL receptor
ous estrogens, such as ethinylestradiol, stimulate activity23,24. Studies of combined HRT, as re-
the production of angiotensinogen in the liver. ported by Sitruk-Ware21, have shown variations
Renin splits its substrate, angiotensinogen, to in response to oral or intravenous glucose
produce angiotensin I (AI), a protein with no tolerance tests according to the androgenic or
known biological effect. In turn, AI is converted to non-androgenic properties of the progestin used,
the active peptide, angiotensin II (AII), by the with non-androgenic progestins being neutral
angiotensin-converting enzyme (ACE). AII stimu- toward carbohydrate metabolism.

6 Climacteric
New progestins Sitruk-Ware

changes confer a high progestational potency to


CLASSIFICATION AND nomegestrol acetate, which has a terminal half-life
PHARMACOKINETICS OF of about 50 h8. Trimegestone has a hydroxylated
PROGESTINS carbon on the penultimate carbon of the side-chain
Progestins have different pharmacologic proper- (C-17), and is twice as potent as Nestorone in
ties, depending on the parent molecule from transforming estrogen-primed endometrium into a
which they are derived9. secretory tissue, but is less effective at preventing
The 19-norprogesterone derivatives of proges- ovulation27. This progestin exhibits also a partial
terone include Nestorone1, nomegestrol acetate antimineralocorticoid effect27.
and trimegestone. They are derived from the Chemically, dienogest (Figure 2) is a derivative
pregnane structure, but have one less carbon, of 19-nortestosterone, but has a cyanomethyl
as they do not have a radical methyl at C-19 group at position C-17 instead of an alkyl
(Figure 1)9. group28, and a double-bond between C-9 and
Nestorone has a deletion of the 19-methyl C-10. Dienogest has a high bioavailability
radical, and the addition of the 16-methylene (96.2%), a short terminal half-life (11.6 h) and a
substituent, which enhances binding to the PR, substantial clearance rate of about 31 h28.
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and contributes to the molecule’s high progesta- Drospirenone differs from the classic progestins
tional activity25. Nestorone is not active when as it is derived from spirolactone and is essentially
administered orally, but is active when adminis- an antimineralocorticoid progestin. Drospirenone
tered continuously via sustained-release implants, has the basic 19-carbon chemical structure of its
vaginal rings or transdermal systems. As with parent compound, androstane29, and has two
progesterone, Nestorone does not bind to sex methylene groups; one attached at C-6 and C-7,
hormone binding globulin (SHBG), resulting in a and the other at C-15 and C-16. In addition, a
shorter half-life and higher clearance rates, com- carbolactone group is attached at C-17. Drospir-
pared with progestins (which do bind to SHBG)26. enone has a long terminal half-life (about 32 h)29,
and its bioavailability is about 76%2.
For personal use only.

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. BINDING AFFINITIES
Nomegestrol acetate is formed by the addition of Progestins may be evaluated by comparing their
a double-bond between C-6 and C-7 of the relative binding affinities (RBAs) to steroid
hydroxyprogesterone skeleton, and has a deletion receptors in relation to those of the physiological
of the methyl radical at C-19. These structural reference hormones (set at 100%). The RBAs

Figure 1 19-Norprogesterone derivatives of progesterone include Nestorone1, nomegestrol acetate and


trimegestone

Climacteric 7
New progestins Sitruk-Ware

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


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


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

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
For personal use only.

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

Climacteric 9
New progestins 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
Figure 3 Progestagenic and antiovulatory potencies of Spirorenone 0.5
new progestins versus levonorgestrel, medroxyproges- Drospirenone 51 (0.25 p.o.)
terone acetate and progesterone. TMG, trimegestone; s.c., subcutaneous; p.o., oral
NOM Ac, nomegestrol acetate; MPA, medroxyproges-
terone acetate; NES, Nestorone; LNG, levonorgestrel
(EE)/3 mg drospirenone (DRSP); Yasmin1, Scher-
ing AG, Berlin, Germany) and as an HRT
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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
For personal use only.

EE/DRSP experienced a slight decrease in weight.


Figure 4 Antiandrogenic potencies of progestins. CPA,
In addition, more women receiving EE/DRSP
cyproterone acetate; TMG, trimegestone; NOM Ac,
displayed a decrease in systolic blood pressure of
nomegestrol acetate
10 mmHg or less, and increased levels of HDL
cholesterol, compared with women receiving
norethisterone, 3-ketodesogestrel and levonor-
LNG/EE12. The weight loss under EE/DRSP was
gestrel are unable to exert any aldosterone
anticipated to be an indicator of reduced water
antagonistic effects, even at high doses35. The
retention, as a result of drospirenone’s antiminer-
antimineralocorticoid potencies of older pro-
alocorticoid activity antagonizing the sodium-
gestins versus newer progestins are summarized
retaining effect of ethinylestradiol. The positive
in Table 3.
effect on blood pressure was probably the result
of a reduction in extracellular volume, while
the favorable lipid profile, with no evidence of
DROSPIRENONE attenuation of the beneficial effects of ethinyl-
Drospirenone is currently the only progestin that estradiol on HDL cholesterol, was probably due
closely matches the pharmacological profile of to drospirenone’s lack of androgenicity.
progesterone; this is due to its novel molecular Studies in postmenopausal women have demon-
structure, which is derived from 17a-spirolactone. strated that treatment with drospirenone in a
Drospirenone binds to the PR with the same combined HRT significantly decreases the mean
affinity as progesterone. It has a higher antimin- number of hot flushes/week within 2–3 weeks of
eralocorticoid potency than progesterone, beginning treatment36,37. No endometrial hyper-
cyproterone acetate, norethisterone, 3-ketodeso- plasia or carcinoma was observed during a study
gestrel, levonorgestrel and gestodene (Table 3)29, period of 2 years and more than 90% of women
and is a more potent antiandrogenic progestin than regained amenorrhea38.
progesterone (Figure 4)28. Thus, although drospir-
enone is a weaker progestin, with regard to the
endometrium and ovulation suppression, it has an CONCLUSIONS
unsurpassed antimineralocorticoid potency. Progestin molecules are not all the same. There
Drospirenone has been developed as a com- may be profound differences according to struc-
bined oral contraceptive (30 mg ethinylestradiol ture, metabolites and pharmacodynamics. It is

10 Climacteric
New progestins Sitruk-Ware

wholly inappropriate to draw conclusions about the effects of ethinylestradiol on angiotensinogen


the effects of one progestin based on data from synthesis, but does not blunt the beneficial effects
another with a different structure and activity of estrogen on the lipid profile. Therefore, dros-
profile. pirenone combinations in oral contraceptives and
In contrast to the older progestins, newer HRT regimens have been associated with a
progestins – developed for use in combined oral positive effect on estrogen-related side-effects such
contraception and HRT regimens – have been as water retention and related weight gain.
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- ACKNOWLEDGEMENT
gesterone without the undesirable effects of acne, I thank Narender Kumar for assistance in pre-
hirsutism and decreased HDL cholesterol. In paration of Table 2.
addition, some of these newer progestins possess
antimineralocorticoid activity. These molecules Conflict of interest Nil.
may neutralize the adverse effects of ethinylestra-
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diol on the RAAS and reduce the incidences of Source of funding Most of the work con-
water retention and bloating, and increases in ducted on other progestins mentioned in this
blood pressure. paper was funded by USAID and the National
Drospirenone differs from classic progestins, as Institutes of Health. The author received an
it is derived from spirolactone. It is essentially an honorarium from Schering AG for participating
antimineralocorticoid that partially counteracts in this symposium.

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