Académique Documents
Professionnel Documents
Culture Documents
Pharmacology of different
progestogens: the special case
of drospirenone
R. Sitruk-Ware
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.
Correspondence: Professor R. Sitruk-Ware, Population Council and Rockefeller University, 1230 York Avenue, New York,
NY 10021, USA
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.
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-
Climacteric Downloaded from informahealthcare.com by Bayer Schering Pharma on 04/09/13
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.
6 Climacteric
New progestins Sitruk-Ware
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.
Climacteric 7
New progestins Sitruk-Ware
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
Climacteric Downloaded from informahealthcare.com by Bayer Schering Pharma on 04/09/13
antiglucocorticoid
Antimineralo- renal function rats Na/K and water excretion
corticoid
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
10 Climacteric
New progestins Sitruk-Ware
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.
References
For personal use only.
1. Henzl MR, Edwards JA. Pharmacology of 7. Magnusson C, Baron JA, Correira N, et al.
progestins: 17a-hydroxyprogesterone derivatives Breast cancer risk following long term
and progestins of the first and second generation. oestrogen- and oestrogen–progestin replacement
In Sitruk-Ware R, Mishell Jr DR, eds. Progestins therapy. Int J Cancer 1999;81:339–44
and Antiprogestins in Clinical Practice. New 8. Sitruk-Ware R. New progestogens: a review of
York: Marcel Dekker, 2000:101–32 their effects in perimenopausal and post-
2. Stanczyk FZ. Pharmacokinetics and potency of menopausal women. Drugs Aging 2004;21:
progestins used for hormone replacement ther- 865–83
apy and contraception. Rev Endocrin Metab 9. Sitruk-Ware R. Pharmacological profile of pro-
Disord 2002;3:211–24 gestins. Maturitas 2004;47:277–83
3. Sitruk-Ware R. Progestogens in hormonal repla- 10. Wright F, Giacomini M, Riahi M, et al.
cement therapy: new molecules, risks, and Antihormone activity of progesterone and pro-
benefits. Menopause 2002;9:6–15 gestins. In Bardin CW, Milgröm E, Mauvais-
4. Writing Group for the Women’s Health Initia- Jarvis P, eds. Progesterone and Progestins. New
tive Investigators. Risks and benefits of estrogen York: Raven Press Books, 1983:121–34
plus progestin in healthy postmenopausal 11. Corvol P, Elkik F, Feneant M, et al. Effect of
women. Principal results from the Women’s progesterone and progestins on water and salt
Health Initiative randomized controlled trial. metabolism. In Bardin CW, Milgröm E,
JAMA 2002;288:321–33 Mauvais-Jarvis P, eds. Progesterone and Proges-
5. Schairer C, Lubin J, Troisi R, et al. Menopausal tins. New York: Raven Press Books:179–86
estrogen and estrogen-progestin replacement 12. Oelkers W, Foidart JM, Dombrovicz N, et al.
therapy and breast cancer risk. JAMA 2000; Effects of a new oral contraceptive containing an
283:485–91 antimineralocorticoid progestogen, drospire-
6. Beral V. Million Women Study Collaborators. none, on the renin–aldosterone system, body
Breast cancer and hormone-replacement therapy weight, blood pressure, glucose tolerance, and
in the Million Women Study. Lancet 2003;362: lipid metabolism. J Clin Endocrinol Metab
419–27 1995;80:1816–21
Climacteric 11
New progestins Sitruk-Ware
13. Persson I, Adami H, Bergkvist L, et al. Risk of 28. Teichmann A. Pharmacology of estradiol vale-
endometrial cancer after treatment with estro- rate/dienogest. Climacteric 2003;6(Suppl 2):
gens alone or in conjunction with progestogens: 17–23
Results of a prospective study. Br Med J 29. Elger W, Beier S, Pollow K, et al. Conception
1989;298:147–51 and pharmacodynamic profile of drospirenone.
14. Sitruk-Ware R. Progestins in hormonal replace- Steroids 2003;68:891–905
ment therapy and prevention of endometrial 30. Philibert D, Bouchoux F, Degryse M, et al. The
disease. In Sitruk-Ware R, Mishell Jr DR, eds. pharmacological profile of a novel norpregnane
Progestins and Antiprogestins in Clinical Prac- progestin (trimegestone). Gynecol Endocrinol
tice. New York: Marcel Dekker, 2000:269–77 1999;13:316–26
15. Sturdee DW, Barlow DH, Ulrich LG, et al. Is the 31. Krattenmacher R. Drospirenone: pharmacology
timing of withdrawal bleeding a guide to and pharmacokinetics of a unique progestogen.
endometrial safety during sequential oestro- Contraception 2000;62:29–38
gens/progestagen replacement therapy? UK 32. Kumar N, Koide SS, Tsong YY, et al.
Continuous Combined HRT Study Investiga- Nestorone1: a progestin with a unique pharma-
tors. Lancet 1994;344:979–82 cological profile. Steroids 2000;65:629–36
Climacteric Downloaded from informahealthcare.com by Bayer Schering Pharma on 04/09/13
16. Russo J, Tay LK, Russo IH. Differentiation of 33. Tuba Z, Bardin CW, Dancsi A, et al. Synthesis
the mammary gland and susceptibility to carci- and biological activity of a new progesto-
nogenesis. Breast Cancer Res Treat 1982;2:5–73 gen, 16-methylene-17a-hydroxy-18-methyl-10-
17. Conneely OM, Lydon JP. Progesterone receptors norpregn-4-ene-3,20-dione acetate. Steroids
in reproduction: functional impact of the A and 2000;65:266–74
B isoforms. Steroids 2000;65:571–7 34. Muhn P, Fuhrmann U, Fritzemeier H, et al.
18. Oelkers WK. Effects of estrogens and progesto- Drospirenone: a novel progestogen with anti-
gens on the renin–aldosterone system and blood mineralocorticoid and antiandrogenic activity.
pressure. Steroids 1996;61:166–71 Ann N Y Acad Sci 1995;761:311–35
19. Oelkers W, Helmerhorst FM, Wuttke W, 35. Elger W, Steinbeck H, Schillinger E, et al.
Heithecker R. Effect of an oral contraceptive con- Endocrine-pharmacological profile of gestodene.
For personal use only.
12 Climacteric