CLIMACTERIC 2005;8(Suppl 3):412

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 specically to the progesterone receptors, PR-A or PR-B. The clinical relevance of more specic binding to one or the other isoforms of the progesterone receptor is still unknown. The development of new generations of progestins, with improved receptor-selectivity proles, 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 afnity of drospirenone for the mineralocorticoid receptor is about ve 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

2005 International Menopause Society DOI: 10.1080/13697130500330382

New progestins

Sitruk-Ware Progesterone has both antiandrogenic and antimineralocorticoid effects. Through competitive inhibition, progesterone prevents the conversion of testosterone into its active metabolite, dihydrotestosterone, by the enzyme 5a-reductase9. Progesterone also binds competitively to the MR, preventing its transactivation and inhibiting the mineralocorticoid effect11. Most of the rst- and second-generation progestins 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) cholesterol, 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 prole. Thus, newer progestins have potent progestational and antiestrogenic 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 contraceptives 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 perimenopausal 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 therapy1315. However, the nal 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.

INTRODUCTION
The term progestogens encompasses the endogenous hormone progesterone and the synthetic steroids that mimic progesterone progestins. The pharmacological properties of progestogens (by denition progestins) used in contraception and hormone replacement therapy (HRT) vary depending 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 derivative13. Recently, the results of the Womens Health Initiative a large, randomized, placebocontrolled trial investigating the use of combination hormone therapy4 and those of other observational studies57 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. The effects of progestins are related to interactions 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 interactions may either induce transactivation or prevent activation of the steroid receptor, and may be responsible for some of the undesirable sideeffects of progestins. For example, many progestins used in contraceptives and HRT are derived from testosterone, and the commonly cited sideeffects of acne and/or weight gain are related to the androgenic properties or glucocorticoid effects of these compounds9.

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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.

THE EFFECTS OF PROGESTINS ON BREAST TISSUE

In addition to the uterus and ovaries, progesterone acts on several body organs, including the breast.

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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 inuence 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 differentiate the tissues16. However, in humans, the data are less clear-cut, with some recent experiments 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 sufcient to mediate the normal proliferative response to progesterone and the differentiation of mammary tissues. In contrast, the PR-A isoform acts as a dominant repressor of PR-B activity17. These ndings suggest that different progestins may have different binding afnities for the PR-A and PR-B receptors and, hence, exert different effects on estrogen-induced proliferative activity8.

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 uid 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 permanent equilibrium between renin output and blood volume. Unlike natural progesterone and the synthetic progestin, drospirenone or, to a lesser extent, trimegestone27, most synthetic progestins do not have antimineralocorticoid activity at the doses used in oral contraceptives and HRT. The ethinylestradiol-related increase in angiotensinogen secretion is generally accompanied 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.

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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 lipoprotein (LDL) cholesterol is thought to be a major contributor to heart disease21. Most studies evaluating the effect of estrogens on lipoproteins have demonstrated a benecial increase in HDL : LDL cholesterol ratios. Co-administration of a progestin may blunt these changes in serum lipids, particularly if they are derivatives of 19-nortestosterone, since progestins with androgenic properties partially 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 disease21. Insulin is a potent stimulus of endothelial cell growth and also regulates LDL receptor activity23,24. Studies of combined HRT, as reported 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.

THE EFFECTS OF ESTROGEN AND PROGESTINS ON THE RENINANGIOTENSIN 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 reninangiotensinaldosterone system (RAAS) has a critical role in the regulation of body uids, 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. Exogenous 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-

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New progestins

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. Drospirenone has a long terminal half-life (about 32 h)29, and its bioavailability is about 76%2.

CLASSIFICATION AND PHARMACOKINETICS OF PROGESTINS

Progestins have different pharmacologic properties, depending on the parent molecule from which they are derived9. The 19-norprogesterone derivatives of progesterone 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, and contributes to the molecules high progestational activity25. Nestorone is not active when administered orally, but is active when administered 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, compared with progestins (which do bind to SHBG)26. When taken orally, Nestorone has a bioavailability 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

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BINDING AFFINITIES
Progestins may be evaluated by comparing their relative binding afnities (RBAs) to steroid receptors in relation to those of the physiological reference hormones (set at 100%). The RBAs

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

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New progestins of trimegestone, medroxyprogesterone acetate, norethisterone, gestodene, levonorgestrel and drospirenone for the human PR, ER, AR, MR and GR, compared with the natural ligand of each receptor (progesterone, estradiol, testosterone, aldosterone and dexamethasone, respectively), are shown in Table 12931. The range of RBAs indicates that there are considerable differences in activity among these new progestin molecules. However, the binding afnity to the steroid receptors does not always correlate with the in vivo tests of estrogenic or androgenic potency.

Sitruk-Ware PR, have a steroid-binding domain and a DNAbinding 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 specic DNA sequences. This transformation is accompanied by a loss of associated heat shock proteins and dimerization of the PR. The activated PR dimer then associates with transcription factors, binding to progesterone response elements within the promoter region of progesterone-responsive genes8. This binding results in an increase in the transcription of new genes, which alter the metabolism of the cell in a steroid-specic manner.

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BINDING TO STEROID RECEPTORS

Steroid hormones are relatively small, hydrophobic 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

IN VIVO BIOASSAYS AND 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 afnity (%) Receptor Progesterone Androgen Glucocorticoid Mineralocorticoid Estrogen TMG 588 2.4 13 42 50.02 MPA 298 36 58 3.1 5 0.02 NET 134 55 1.4 2.7 0.15 GES 864 71 38 97 5 0.02 LNG 323 58 7.5 17 5 0.02 DRSP 19 2 3 500 5 0.5

TMG, trimegestone; MPA, medroxyprogesterone acetate; NET, norethisterone; GES, gestodene; LNG, levonorgestrel; DRSP, drospirenone

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New progestins

Sitruk-Ware

Table 2 In vivo bioassays for testing progestins9. For full description of the bioassays, see Kumar et al.32 Bioactivity Progestational Progestational Antiovulatory Androgenic Antiandrogenic Test McPhail Index pregnancy maintenance Species immature female rabbits female rats End points endometrial transformation dose able to maintain pregnancy after ovariectomy dose able to suppress spontaneous ovulation growth of prostate and seminal vesicles inhibition of testosteroneinduced prostate and seminal vesicles growth uterine growth and vaginal cornication growth of thymus Na/K and water excretion

ovulation inhibition test 4-day cyclic rats Hershberger assay Hershberger assay immature or castrated male rats immature or castrated male rats treated with testosterone immature or ovariectomized female rats adrenalectomized male rats rats

Estrogenic/ antiestrogenic
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vaginal cornification/ uterotropic thymolytic assay renal function

Glucocorticoid/ antiglucocorticoid Antimineralocorticoid

the dose of progestin required to transform the uterine endometrium to a secretory state in immature, estrogen-primed rabbits. The pregnancy maintenance test measures the progestin dose required to maintain a pregnancy in ovariectomized 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 normalestrus cycles32,33. The antiandrogenic activity of progestins is assessed by the Hershberger test. This test measures the dose of progestin required to antagonize the androgenic effect of a xed dose of testosterone on the weight of the male sex organs in immature rats32. The antimineralocorticoid activity of progestins is assessed by their ability to antagonize aldosterone activity on the renal function of adrenalectomized rats29.

Antiovulatory potency
Nestorone is an extremely potent inhibitor of 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 progestins versus newer progestins are illustrated in Figure 3.

Antiandrogenic potency
Cyproterone acetate is the most potent antiandrogenic 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 demonstrate antiandrogenic activity at therapeutic doses28. Nomegestrol acetate and trimegestone have a partial antiandrogenic effect (about ve times less than that of cyproterone acetate). The antiandrogenic potencies of older progestins versus newer progestins are illustrated in Figure 4.

Progestational potency
Although trimegestone is twice as potent as Nestorone, both are extremely potent in transforming uterine endometrium to a secretory state. Their progestational potencies are in excess of 100 times greater than that of natural progesterone. Levonorgestrel, nomegestrol acetate, medroxyprogesterone acetate and drospirenone all have progestational potencies ranging from six to ten times greater than that of progesterone9.

Antimineralocorticoid potency
Drospirenone has a ve-fold greater afnity for the MR than aldosterone itself, and is two to four times more potent than progesterone29. Some conventional progestins, cyproterone acetate,

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Table 3 Antimineralocorticoid potency29 Steroid Progesterone Cyproterone acetate Norethisterone 3-Ketodesogestrel Levonorgestrel Gestodene Spironolactone Spirorenone Drospirenone s.c., subcutaneous; p.o., oral

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Dose s.c. (mg/animal) 2 48 48 48 48 4 1 0.5 51 (0.25 p.o.)

Figure 3 Progestagenic and antiovulatory potencies of new progestins versus levonorgestrel, medroxyprogesterone acetate and progesterone. TMG, trimegestone; NOM Ac, nomegestrol acetate; MPA, medroxyprogesterone acetate; NES, Nestorone; LNG, levonorgestrel
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Figure 4 Antiandrogenic potencies of progestins. CPA, cyproterone acetate; TMG, trimegestone; NOM Ac, nomegestrol acetate

norethisterone, 3-ketodesogestrel and levonorgestrel are unable to exert any aldosterone antagonistic effects, even at high doses35. The antimineralocorticoid potencies of older progestins versus newer progestins are summarized in Table 3.

DROSPIRENONE
Drospirenone is currently the only progestin that closely matches the pharmacological prole of progesterone; this is due to its novel molecular structure, which is derived from 17a-spirolactone. Drospirenone binds to the PR with the same afnity as progesterone. It has a higher antimineralocorticoid potency than progesterone, cyproterone acetate, norethisterone, 3-ketodesogestrel, levonorgestrel and gestodene (Table 3)29, and is a more potent antiandrogenic progestin than progesterone (Figure 4)28. Thus, although drospirenone is a weaker progestin, with regard to the endometrium and ovulation suppression, it has an unsurpassed antimineralocorticoid potency. Drospirenone has been developed as a combined oral contraceptive (30 mg ethinylestradiol

(EE)/3 mg drospirenone (DRSP); Yasmin1, Schering AG, Berlin, Germany) and as an HRT preparation (1 mg 17b-estradiol/2 mg drospirenone; 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 drospirenones antimineralocorticoid activity antagonizing the sodiumretaining effect of ethinylestradiol. The positive effect on blood pressure was probably the result of a reduction in extracellular volume, while the favorable lipid prole, with no evidence of attenuation of the benecial effects of ethinylestradiol on HDL cholesterol, was probably due to drospirenones lack of androgenicity. Studies in postmenopausal women have demonstrated that treatment with drospirenone in a combined HRT signicantly decreases the mean number of hot ushes/week within 23 weeks of beginning treatment36,37. No endometrial hyperplasia 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 structure, metabolites and pharmacodynamics. It is

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New progestins wholly inappropriate to draw conclusions about the effects of one progestin based on data from another with a different structure and activity prole. In contrast to the older progestins, newer progestins developed for use in combined oral contraception and HRT regimens have been designed to bind very specically to the progesterone receptor and to exert no androgenic or estrogenic side-effects3,39,40. Thus, these newer progestins are associated with the benets of progesterone 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 ethinylestradiol 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

Sitruk-Ware the effects of ethinylestradiol on angiotensinogen synthesis, but does not blunt the benecial effects of estrogen on the lipid prole. Therefore, drospirenone combinations in oral contraceptives and HRT regimens have been associated with a positive effect on estrogen-related side-effects such as water retention and related weight gain.

ACKNOWLEDGEMENT
I thank Narender Kumar for assistance in preparation of Table 2. Conict of interest Nil.

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Source of funding Most of the work conducted on other progestins mentioned in this paper was funded by USAID and the National Institutes of Health. The author received an honorarium from Schering AG for participating in this symposium.

References
1. Henzl MR, Edwards JA. Pharmacology of progestins: 17a-hydroxyprogesterone derivatives and progestins of the rst and second generation. In Sitruk-Ware R, Mishell Jr DR, eds. Progestins and Antiprogestins in Clinical Practice. New York: Marcel Dekker, 2000:10132 2. Stanczyk FZ. Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception. Rev Endocrin Metab Disord 2002;3:21124 3. Sitruk-Ware R. Progestogens in hormonal replacement therapy: new molecules, risks, and benets. Menopause 2002;9:615 4. Writing Group for the Womens Health Initiative Investigators. Risks and benets of estrogen plus progestin in healthy postmenopausal women. Principal results from the Womens Health Initiative randomized controlled trial. JAMA 2002;288:32133 5. Schairer C, Lubin J, Troisi R, et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000; 283:48591 6. Beral V. Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362: 41927 7. Magnusson C, Baron JA, Correira N, et al. Breast cancer risk following long term oestrogen- and oestrogenprogestin replacement therapy. Int J Cancer 1999;81:33944 8. Sitruk-Ware R. New progestogens: a review of their effects in perimenopausal and postmenopausal women. Drugs Aging 2004;21: 86583 9. Sitruk-Ware R. Pharmacological prole of progestins. Maturitas 2004;47:27783 10. Wright F, Giacomini M, Riahi M, et al. Antihormone activity of progesterone and progestins. In Bardin CW, Milgro m E, MauvaisJarvis P, eds. Progesterone and Progestins. New York: Raven Press Books, 1983:12134 11. Corvol P, Elkik F, Feneant M, et al. Effect of progesterone and progestins on water and salt metabolism. In Bardin CW, Milgro m E, Mauvais-Jarvis P, eds. Progesterone and Progestins. New York: Raven Press Books:17986 12. Oelkers W, Foidart JM, Dombrovicz N, et al. Effects of a new oral contraceptive containing an antimineralocorticoid progestogen, drospirenone, on the reninaldosterone system, body weight, blood pressure, glucose tolerance, and lipid metabolism. J Clin Endocrinol Metab 1995;80:181621

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New progestins
13. Persson I, Adami H, Bergkvist L, et al. Risk of endometrial cancer after treatment with estrogens alone or in conjunction with progestogens: Results of a prospective study. Br Med J 1989;298:14751 14. Sitruk-Ware R. Progestins in hormonal replacement therapy and prevention of endometrial disease. In Sitruk-Ware R, Mishell Jr DR, eds. Progestins and Antiprogestins in Clinical Practice. New York: Marcel Dekker, 2000:26977 15. Sturdee DW, Barlow DH, Ulrich LG, et al. Is the timing of withdrawal bleeding a guide to endometrial safety during sequential oestrogens/progestagen replacement therapy? UK Continuous Combined HRT Study Investigators. Lancet 1994;344:97982 16. Russo J, Tay LK, Russo IH. Differentiation of the mammary gland and susceptibility to carcinogenesis. Breast Cancer Res Treat 1982;2:573 17. Conneely OM, Lydon JP. Progesterone receptors in reproduction: functional impact of the A and B isoforms. Steroids 2000;65:5717 18. Oelkers WK. Effects of estrogens and progestogens on the reninaldosterone system and blood pressure. Steroids 1996;61:16671 19. Oelkers W, Helmerhorst FM, Wuttke W, Heithecker R. Effect of an oral contraceptive containing drospirenone on the reninangiotensin aldosterone system in healthy female volunteers. Gynecol Endocrinol 2000;14:20413 20. Oelkers W. Drospirenone, a progestogen with antimineralocorticoid properties: a short review. Mol Cell Endocrinol 2004;217:25561 21. Sitruk-Ware R. Progestins and cardiovascular risk markers. Steroids 2000;65:6518 22. The Writing Group for the PEPI trial. Effects of androgen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: The Postmenopausal Estrogen/Progestin (PEPI) Trial. JAMA 1995;273:199208 23. Stout RW, Bierman EL, Ross R. Effect of insulin on the proliferation of cultured primate arterial smooth muscle cells. Circ Res 1975;36:31927 24. Chait A, Bierman EL, Albers JJ. Low-density lipoprotein receptor activity in cultured human skin broblasts. Mechanism of insulin-induced stimulation. J Clin Invest 1979;64:130919 25. Sitruk-Ware R, Small M, Kumar N, et al. Nestorone: clinical applications for contraception and HRT. Steroids 2003;68:90713 26. Fotherby K. Interactions with oral contraceptives. Am J Obstet Gynecol 1990;163:21539 27. Winneker RC, Bitran D, Zhang Z. The preclinical biology of a new potent and selective progestin: trimegestone. Steroids 2003;68:91520

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28. Teichmann A. Pharmacology of estradiol valerate/dienogest. Climacteric 2003;6(Suppl 2): 1723 29. Elger W, Beier S, Pollow K, et al. Conception and pharmacodynamic prole of drospirenone. Steroids 2003;68:891905 30. Philibert D, Bouchoux F, Degryse M, et al. The pharmacological prole of a novel norpregnane progestin (trimegestone). Gynecol Endocrinol 1999;13:31626 31. Krattenmacher R. Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. Contraception 2000;62:2938 32. Kumar N, Koide SS, Tsong YY, et al. Nestorone1: a progestin with a unique pharmacological prole. Steroids 2000;65:62936 33. Tuba Z, Bardin CW, Dancsi A, et al. Synthesis and biological activity of a new progestogen, 16-methylene-17a-hydroxy-18-methyl-10norpregn-4-ene-3,20-dione acetate. Steroids 2000;65:26674 34. Muhn P, Fuhrmann U, Fritzemeier H, et al. Drospirenone: a novel progestogen with antimineralocorticoid and antiandrogenic activity. Ann N Y Acad Sci 1995;761:31135 35. Elger W, Steinbeck H, Schillinger E, et al. Endocrine-pharmacological prole of gestodene. In Elstein M, ed. Gestodene. Development of a New Gestodene-containing Low-dose Oral Contraceptive. Carnforth, UK: Parthenon Publishing, 1987:1933 36. Ru big A. Drospirenone: a new cardiovascularactive progestin with antialdosterone and antiandrogenic properties. Climacteric 2003; 6(Suppl 3):4954 37. Schuermann R, Holler T, Brenda N. Estradiol and drospirenone for climacteric symptoms in postmenopausal women: a double-blind, randomized, placebo-controlled study of the safety and efcacy of three dose regimens. Climacteric 2004;7:18996 38. Warming L, Ravn P, Nielsen T, Christiansen C. Safety and efcacy of drospirenone used in a continuous combination with 17b-estradiol for prevention of postmenopausal osteoporosis. Climacteric 2004;7:10311 39. Kuhl H. Effects of progestogens on haemostasis. Maturitas 1996;24:119 40. Schindler AE. Differential effects of progestins on hemostasis. Maturitas 2003;46(Suppl 1): S317 41. Zhang Z, Lundeen SG, Zhu Y, Carver JM, Winneker RC. In vitro characterization of trimegestone: a new potent and selective progestin. Steroids 2000;65:63743

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