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Home , Allylestrenol, Chlormadinone, Chlormadinone acetate, Desogestrel, Gestodene, Levonorgestrel

Contraception 84 (2011) 549–557

Review article inhibition doses of progestins: a systematic review of the available literature and of marketed preparations worldwide☆ ⁎ Jan Endrikata,b, , Christoph Gerlingera, Stephanie Richardc, Peter Rosenbaumb, Bernd Düsterberga aBayer Schering Pharma, Müllerstr. 178, D-13342 Berlin, bUniversitätskliniken des Saarlandes, Frauenklinik, 66421 Homburg/Saar, Germany cUniversité de Montréal, Faculté de pharmacie, 2900, Boulevard Édouard-Montpetit Pavillon Roger-Gaudry, H-401, Montréal, Québec, H3T 1J4 Received 16 September 2010; revised 25 March 2011; accepted 13 April 2011

Abstract

Background: The objective of this analysis was to provide a comprehensive review of ovulation inhibition data of progestins currently available worldwide. This analysis may serve as a reference tool for research on new progestin molecules. Study Design: We used literature search engines to detect data of progestin monotherapies on ovulation inhibition in humans. Only treatments with stable dosing during a cycle were accepted. In a second step, we tried to estimate the 99% ovulation inhibiting doses and their fiducial confidence limits using the probit dose–response model. Finally, we analyzed the progestin doses of combined oral contraceptives currently on the market. Results: We found original data on 29 marketed and nonmarketed progestins in a total of 60 publications, published between 1956 and May 2010. Details on methods used for determining ovulation, number of doses and daily dose of each tested progestin, number of subjects, cycles and ovulations are summarized in a table. We designed one example of a dose–response curve using the statistical model. For most progestins, literature data were insufficient for this purpose. A total of 13 progestins are components of oral contraceptives currently on the market worldwide, five of them in combination with 20 mcg ethinyl (EE). Conclusion: This review provides a comprehensive overview of all progestins ever tested for their ovulation inhibition and a summary of all preparations currently on the world market, including their regimens and their combinations with EE. © 2011 Elsevier Inc. All rights reserved.

Keywords: Progestins; Ovulation inhibition potency

1. Introduction activity under oral contraceptives should be regarded as the best surrogate parameter of the of compounds used Scientists researching and developing innovative for contraceptive purposes [1]. control products need to compare their new compounds to The objective of this analysis was to provide a those already characterized. For , such as pro- comprehensive review of ovulation inhibition data of gestins, one important feature is their ovulation inhibition progestins currently available worldwide. potency, i.e., their effect on suppressing ripening of follicles This analysis may serve as a reference tool for research on in the ovaries and inhibiting ovulation. Since the main new progestin molecules. mechanism of action of oral contraceptives is ovulation inhibition, it is assumed that the degree of residual ovarian 2. Materials and methods

☆ Conflict of interest and financial disclosure: J.E., C.G. and B.D. are We used Medline, Montreal University Archives (Atrium) employees of Bayer Schering Pharma. ⁎ Corresponding author. Bayer Schering Pharma, Müllerstr. 178, and Bayer Schering Pharma's Archive Databases for our D-13342 Berlin Germany. Tel.: +49 468 1 94 306; fax: +49 468 9 94 306. search of original data on potency of progestins to inhibit E-mail address: [email protected] (J. Endrikat). ovulation in humans. Articles in English, French, Spanish

0010-7824/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2011.04.009 550 J. Endrikat et al. / Contraception 84 (2011) 549–557

Table 1 Publications on ovulation inhibition doses of progestins Progestin Reference Method Daily dose (mg) Total number Total number % of ovulation of cycles in of ovulation in in all subjects all subjects all subjects 1,2a-Methylene-6- Nevinny-Stickel Urinary pregnanediol 2.000 1 0 0 dehydro-6-chloro-17a- (1964) [6] 3.000 2 0 0 acetoxy- 4.000 1 0 0 16a-Methyl-6-dehydro-6- 1.000 1 1 100 chloro-17a-acetoxy- 2.000 1 1 100 progesterone 9a-Fluoro-11-hydroxy-16- 1.000 6 2 33 methylene-17a-acetoxy- 2.000 9 3 33 progesterone 3.000 3 1 33 4.000 1 0 0 20.000 6 3 50 25.000 3 0 0 Gueguen (1965) [7] Urinary pregnanediol, 2.000 13 2 15

pregnanetriol, E1+E2,E3, 4.000 27 1 4 1- and 10.000 9 0 0 17-hydroxycorticosteroid Rudel et al. (1965) [8] Urinary pregnanediol 1.000 12 3 25 Chlormadinone Aref et al. (1973) [9] Urinary pregnanediol 0.500 5 5 100 Diczfalusy et al. Urinary pregnanediol 0.500 6 3 50 (1969) [10] Gutiérrez-Najar et al. Culdoscopy was carried 0.500 50 37 74 (1968) [11] out to visualize the ovaries. Heinen et al. BBT 0.500 737 89 12 (1971) [12] Larsson-Cohn et al. BBT; urinary LH and 0.500 18 18 100 (1970) [13] total ; plasma progesterone MacDonald et al. BBT 0.500 1 0 0 (1968) [14] Martinez-Manautou Urinary pregnanediol 0.500 122 33 27 et al. (1966) [15] Nevinny-Stickel Urinary pregnanediol 1.000 3 0 0 (1964) [6] 2.000 10 2 20 3.000 3 0 0 4.000 1 0 0 Pélissier et al. Progesterone 10.000 20 0 0 (1991) [16] Saunders et al. BBT, plasma 0.500 9 3 33 (1971) [17] gonadotrophin, FSH, LH and progesterone Taymor et al. Serum FSH and LH; 0.500 11 3 27 (1971) [18] plasma progestin

Cyproterone acetate Spona et al. (1979) LH, FSH, E2 and 0.125 1 1 100 [19] Spona et al. progesterone 0.250 1 1 100 (1987) [20] 0.500 5 2 40 1.000 5 0 0 Cullberg et al. Serum FSH, LH, 0.015 4 2 50

(1982) [21] unconjugated E2, 0.030 6 1 17 progesterone, 0.060 1 0 0 ceruloplasmin, orosomucoid and ; cervical mucus; BBT Dericks-Tan et al. Progesterone 0.125 6 0 0 (1992) [22] Jackson e t al. Ultrasonography to 0.060 10 0 0 (1994) [23] determine the mean follicular diameter; serum

LH, E2 and progesterone Obruca et al. Ultrasonography; E2, 0.075 13 0 0 (2001) [24] progesterone, FSH and LH J. Endrikat et al. / Contraception 84 (2011) 549–557 551

Table 1 (continued) Progestin Reference Method Daily dose (mg) Total number Total number % of ovulation of cycles in of ovulation in in all subjects all subjects all subjects Skouby (1976) [25] Plasma FSH, LH, 0.060 5 0 0 progesterone and ; BBT Viinikka et al. Serum FSH, LH, 0.030 2 1 50

(1976) [26] progesterone and E2; BBT; 0.060 3 0 0 endometrial biopsy 0.125 2 0 0 Viinikka et al. Serum FSH, LH, 0.015 6 2 33

(1977) [27] progesterone and E2; 0.030 3 0 0 endometrial biopsy; BBT

Dienogest Moore et al. Serum progesterone, E2, 0.500 9 3 33 (1999) [28] LH and FSH 1.000 8 1 13 1.500 8 0 0 2.000 8 0 0

Drospirenone Rosenbaum et al. Serum LH, FSH, E2 and 0.500 11 1 9 (2000) [29] progesterone; follicular 1.000 12 1 8 size assessed by 2.000 12 1 8 ultrasonography (modified 3.000 12 0 0 Hoogland score)

Gestodenee Spona et al. (1979) Serum LH, FSH, E2 0.050 7 0 0 [19] Spona et al. and progesterone 0.040 7 1 14 (1987) [20] Spona 0.010 2 2 100 et al. (1993) [30] 0.020 2 2 100 0.030 12 1 8 Gestovis Swyer (1964) [31] Urinary pregnanediol 20.000 3 0 0 Isopregnenone Bishop et al. Laparotomy 10.000 5 4 80 (1962) [32] 20.000 1 1 100 40.000 6 5 83 Visual inspection of 400.000 3 2 67 ovaries Swyer (1964) [31] Urinary pregnanediol 5.000 2 2 100 20.000 3 3 100 Jackson e t al. Ultrasonography; serum 0.030 10 2 20

(1994) [23] LH, E2 and progesterone Rice et al. (1999) [33] Ultrasonography; serum 0.030 57 16 28 progesterone

Spona et al. (1979) LH, FSH, E2 and 0.030 4 2 50 [19] Spona et al. progesterone 0.050 3 0 0 (1987) [20] 0.100 3 0 0 0.150 2 0 0 Dargent et al. LH 10.000 5 0 0 (1978) [34] Foley et al. Plasma progesterone 0.500 50 20 40 (1973) [35] Schmidt-Elmendorff BBT; urinary estrogens, 0.500 8 5 63 et al. (1969) [36] pregnanediol, FSH and LH

Medrogestone Strauch et al. Plasma LH, FSH, E2 and 10.000 10 0 0 (1994) [37] progesterone; SHBG Eichner (1963) [38] Urinary pregnanediol 10.000 4 0 0 West (1990) [39] Urinary 15.000 38 1 3 pregnanediol/creatinine ratio Medroxyprogesterone Wikström et al. Peripheral plasma 5.000 10 2 20 acetate (MPA) (1984) [40] progesterone Urinary 10.000 10 0 0 pregnanediol/creatinine ratio

Nomegestrol acetate Bazin et al. BBT; plasma E2, FSH, 1.250 3 0 0 (1987) [41] LH and progesterone 2.500 5 0 0 5.000 5 0 0 (continued on next page) 552 J. Endrikat et al. / Contraception 84 (2011) 549–557

Table 1 (continued) Progestin Reference Method Daily dose (mg) Total number Total number % of ovulation of cycles in of ovulation in in all subjects all subjects all subjects

Couzinet et al. Plasma E2, LH, FSH and 5.000 10 0 0 (1999) [42] progesterone; GnRH stimulation the end of each LH pulse analysis; ultrasonography Norethistereone Brown et al. Urinary pregnanediol and 10.000 1 0 0 (norethindrone) (1960) [43] estrogens

Buchholz et al. Urinary E1,E2,E2 and 15.000 0 – (1964) [44] 5β--3α,20α-diol Chitlange et al. Ultrasonography 0.300 16 3 19 (1996) [45] Diczfalusy et al. Urinary pregnanediol 0.100 2 1 50 (1969) [10] 2.500 2 0 0 Elstein et al. Urinary LH and total 0.350 9 4 44 (1976) [46] estrogens; BBT Gueguen (1965) [7] Urinary pregnandiol, 10.000 13 0 0

pregnanetriol, E2,E1+E2 Kim-Björklund et al. Ultrasonography, urinary 0.300 43 –

(1992) [47] LH, E2, progesterone, FSH and LH Larsson-Cohn et al. Plasma progesterone, 0.100 10 10 100 (1972) [48] urinary LH and estrogens, BBT Moghissi (1972) [49] Plasma progesterone 0.350 3 2 67 Pincus (1956) [50] BBT 40.000 5 0 0

Shearman (1964) [51] Urinary pregnanediol, E1, 15.000 0 – E2 and E2 Taymor et al. Urinary pregnanediol; 2.500 12 4 33 (1962) [52] BBT 5.000 12 1 8 West (1990) [39] Urinary pregnanediol and 15.000 0 – total estrogens Brown et al. Urinary pregnanediol; 6.000 1 –

(norethindrone) acetate (1960) [43] gonadotrophins; E1, 12.000 1 0 0 E2 and E2. 12.000 1 0 0 Brown et al. Urinary E1,E2,E2, 6.000 2 1 50 (1962) [53] pregnanediol, 12.000 2 1 50 pregnanetriol and pituitary gonadotrophin (HPG); BBT 9 Garcia et al. Urinary pregnanediol 5.000 9 0 0 (1958) [54] Laparotomy 10.000 6 0 0 Urinary pregnanediol 10.000 20 0 0 Urinary pregnanediol 20.000 32 0 0 Laparotomy 20.000 1 0 0 Urinary pregnanediol 40.000 3 1 33 McCormick et al. Urinary pregnanediol 1.000 5 2 40 (1968) [55] Nevinny-Stickel Urinary pregnanediol; 5.000 1 1 100 (1964) [6] BBT Taymor (1964) [56] Urinary pregnanediol 2.500 2 0 0 5.000 2 0 0 Norethynodrel Garcia et al. Urinary pregnanediol 5.000 3 0 0 (1958) [54] 10.000 26 0 0 20.000 6 0 0 Pincus (1956) [50] BBT; vaginal smear; 20.000 5 0 0 endometrial biopsy Pizarro et al. Plasma LH and 0.350 1 1 100 (1976) [57] progesterone; BBT 0.350 1 0 0 0.500 1 1 100 0.500 1 0 0 0.700 1 0 0 0.700 1 0 0 J. Endrikat et al. / Contraception 84 (2011) 549–557 553

Table 1 (continued) Progestin Reference Method Daily dose (mg) Total number Total number % of ovulation of cycles in of ovulation in in all subjects all subjects all subjects 1.000 1 0 0 Rudel et al. (1965) [8] Urinary pregnanediol 2.500 8 1 13 Foss et al. (1968) [58] Urinary pregnanediol 0.050 22 11 50 Moghissi et al. Serum FSH and LH; 0.075 6 3 50 (1971) [59] plasma progesterone;

urinary E1,E2, total estrogens, pregnanediol, cervical mucus; endometrial biopsy Moghissi (1972) [49] Plasma progesterone. 0.075 4 3 75 Wright et al. Macroscopic examination 0.050 15 13 87 (1970) [60] of ovaries; dissection of corpus luteum for histological examination Progesterone Pincus (1956) [50] Urinary pregnanediol 300.000 61 30 49

Promegestone Rosenbaum Plasma E2, progesterone, 0.500 3 0 0 (1984) [61] TeGB (, 0.500 3 0 0 estradiol binding globulin) 0.500 1 0 0 and in some case, FSH and LH Moghissi et al. FSH, LH and 0.300 5 3 60

(1975) [62] progesterone; urinary E1, E2,E2, total estrogens and pregnanediol; cervical mucus; endometrial biopsy; BBT Moghissi (1972) [49] Examination of ovaries 0.300 4 4 100 during elective , myomectomy or ; plasma progesterone

Tibolone Franchimont et al. Plasma FSH, LH, E2 2.500 16 0 0 (1982) [63] and progesterone

Tomagestin Obruca et al. Ultrasonography, E2, 0.060 14 0 0 (2001) [24] P, FSH and LH 0.120 16 0 0 0.180 16 0 0 0.240 17 0 0 and German that were published until May 2010 were We derived data on oral contraceptives on the world included in our analysis. market from IMS Health, Darmstädter Landstraße 108, We solely assessed progestin monotherapies. Any 60598 Frankfurt/Main, Germany (www.imshealth.de). combination regimens with estrogens or other progestins For each progestin, we aimed to model the probability of were excluded to gauge exclusively the effect of one ovulation inhibition based on the natural logarithm of the molecule. In addition, only treatments with stable dosing doses using a statistical probit model [4]. From these model, during a cycle were assessed. Finally, the volunteers in the we aimed to estimate the ED99, i.e., the dose that has a studies had to be healthy women in their fertile age, devoid probability of 99% to inhibit ovulation, together with its 95% of known ovulation problems. fiducial confidence interval using PROC PROBIT of SAS We accepted four methods for determining ovulation. software [5]. These were with decreasing precision: (1) Hoogland score (ultrasound) [1]; (2) progesterone level increase [2]; (3) visual inspection (laparoscopy, laparotomy); (4) basal body 3. Results temperature (BBT) measurement [3]. We considered endo- metrial biopsy [3] and cervical mucus inspection [3] as We found original data for about 29 marketed and inadequate methods for ovulation detection, as these two nonmarketed progestins in a total of 60 publications, methods use clinical endpoints, which are not directly related published between 1956 and May 2010 (Table 1). The to the inhibition of ovulation. number of publications for one single molecule varied from 554 J. Endrikat et al. / Contraception 84 (2011) 549–557 available. As similar summary articles did before in 1977 [64] and 1988 [65], it may serve as a reference tool for research on new progestin molecules. However, these two manuscripts quoted articles, which in turn referred to other articles. We focused on literature exclusively reporting original data. Moreover, important new progestins such as and were developed in the last two decades. One important limitation of this analysis is the diverse quality of data, which include not only the number and the demographics of volunteers, the number of doses, the number of cycles, the number of criteria to determine ovulation, the quality of laboratory methods and the number Fig. 1. dose–response curve as plotted from literature data (solid line: estimated dose response curve; dashed lines: 95% confidence band). of publications determine the precision of the results but also the method for measuring ovarian activity. The state-of-the- art Hoogland score, which takes advantage of ultrasound 1 (e.g., gestovis, , ) to 12 (norethin- follicle measurement in conjunction with progesterone and drone). Also, the number of doses investigated ranged from estrogen levels [1], was not available before the early one dose (gestovis) to seven doses (norethindrone). nineties. Thus, the less precise methods—used before the The methods to determine ovulation varied widely: introduction of the Hoogland score—had to be reported as simple BBT measurement, visual inspection of ovaries, they are. The particular strength of this summary is the focus mucus inspection, endometrial biopsy, measure- on progestin-only regimen because it allows for comparisons ments (estrogen, progesterone) in or plasma/serum, of the potency of different progestins without possible (leutenizing hormone and follicle-stimulating synergistic effects of other compounds such as estrogens. hormone) measurements and ultrasonography. Any combinations with estrogens hide the genuine progestin Also, the doses applied varied widely: gestodene in a effect, as estrogens also have impact on the hypothalamic– minimal dose of 0.01 mg and isopregnone in a maximum pituitary–ovarian axis. dose of 400 mg. In Fig. 1, we provide one example of a dose–response The number of cycles evaluated in all subjects ranged from curve generated from literature data. However, the confi- one cycle up to a total of 737 cycles (0.5 mg chlormadinone dence bands are quite wide, as the number of doses and the acetate) [12]. Correspondingly, the number of ovulations in all number of subjects was so limited. For the vast majority of subjects varied from zero (gestovis) to 89 (chlormadinone the other progestins, statistical modeling did not provide acetate). A zero in the last but one column of Table 1 indicates the desired results, mostly due to lack of data (e.g., no that this dose inhibited ovulation. ineffective dose has been tested) or due to conflicting results For most progestins, the statistical model of the dose– of different papers (e.g., ). When the response curve could not be established due to lack of statistical modeling was possible, it yielded rather imprecise sufficient data, especially on noneffective doses. For estimates. For example, the ED99 for gestodene is estimated those progestins where the model could be fitted, the to be 0.047 mg, with 95% fiducial confidence limits of confidence bands were rather wide due to the paucity of 0.0366 to 1.531 mg (Fig. 1). More data would be needed to the data (see Fig. 1). estimate the dose–response curve and the ED99 with Of the 29 progestins reported in scientific journals, a meaningful precision. total of 13 are components in oral contraceptives currently on In addition, we summarized the hormonal composition of the world market (Fig. 2). A total of five progestins 13 preparations currently on the world market (Fig. 2). [desogestrel, drospirenone, gestodene, levonorgestrel and Depending on the regimen (monophasic or multiphasic) norethisterone (norethindrone)] are combined with 20 mcg and the EE content, the dosage of the progestin varies ethinyl estradiol (EE) in monophasic preparations. Multi- widely. For most preparations, the progestin dose of the phasic regimens allow for lower progestin doses during the marketed preparation is at the higher end of the dose range first 2 weeks of the cycle compared with monophasic investigated in the studies with the progestin alone, as shown preparations. Only dienogest is combined with natural in Table 1. This strategy was most probably followed to estradiol in a four-phasic regimen. ensure almost complete ovulation inhibition and to avoid contraceptive failures. Only 5 of 13 marketed progestins are combined with 4. Discussion 20 mcg EE in monophasic preparations. These are the three more recent progestins, gestodene, desogestrel and This publication provides an up-to-date comprehensive drospirenone, which were developed to reduce andro- review of ovulation inhibition data of all progestins currently genic activity and/or to add additional noncontraceptive J. Endrikat et al. / Contraception 84 (2011) 549–557 555

Fig. 2. Progestin doses in oral contraceptives currently on the world market. benefits, e.g., antimineralocorticoid activity. In addition, potency and a summary of all preparations currently on the there are two 20-mcg EE preparations containing the older world market, including their regimen and their combina- progestins levonorgestrel and (nor- tions with EE. ethindrone acetate). References 5. Conclusion [1] Hoogland HJ, Skouby SO. Ultrasound evaluation of ovarian activity under oral contraceptives. Contraception 1993;47:583–90. This review provides a comprehensive overview of [2] Tortora GJ, Grabowski SR. Principes d'anatomie et de physiologie. all progestins ever tested for their ovulation inhibition Centre éducatif et culturel (Anjou);1994:1204 pages. 556 J. Endrikat et al. / Contraception 84 (2011) 549–557

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