Editorial Robert L. Barbieri, MD Editor in Chief

Potential for better cycle control In the news, now on the shelf: A novel estradiol-based OC The first birth control pill was sold in the United States in 1960. Fifty years later, oral contraceptives continue to evolve—as Natazia demonstrates.

nnovation over 5 decades has 2) a decrease in some antithrombotic reflects the robust conversion and added options to the medicine proteins. It’s been speculated that us- rapid degradation of orally adminis- Ichest of contraceptives that we ing the natural estrogen, estradiol, in tered estradiol to estrone. can offer to our patients. The US an oral estrogen-progestin contra- Food and Drug Administration ceptive would reduce the magnitude Dienogest: Novel progestin recently approved Natazia (Bayer of the liver protein changes observed This new 19-nortestosterone deriva- HealthCare), a novel four-phase, with ethinyl estradiol. This, in turn, tive has a unique C-17 cyanomethyl estrogen step-down, progestin step- would (again, this is speculation) re- group instead of the usual C-17 ethi- up regimen that contains a new duce the risk of deep-vein thrombo- nyl grouping (Figure 2, page 10). estrogen, estradiol valerate, and the sis, which has been observed among Dienogest binds most avidly to the novel progestin, dienogest. Here is women who use contraceptives that progesterone receptor; it does not bind how this OC is constituted and how contain ethinyl estradiol.1,2 to estrogen, glucocorticoid, or miner- it works. Early attempts to formulate a alocorticoid receptors. It binds weakly monophasic oral estrogen-progestin to the androgen receptor, and report- Why estradiol valerate? contraceptive that contains estradiol edly has antiandrogenic activity. Almost all oral estrogen-progestin and estriol did yield OCs that inhib- When dienogest is taken orally, contraceptives contain the potent ited ovulation, but those products more than 90% of the dose is ab- estrogen ethinyl estradiol. The ethi- were associated with a high rate of ir- sorbed; half-life is approximately 11 nyl group at C17 prevents conversion regular bleeding patterns, including hours. It appears to have unparal- of this highly active estrogen to the amenorrhea and spotting.3 leled potency among oral progestins weak estrogen, estrone, thereby ex- Now, the newly approved estro- when tested in estrogen-primed rab- tending its estrogenic bioactivity. gen-progestin contraceptive, Nata- bit endometrium (McPhail test).4 High estrogenic activity, and zia, which contains estradiol valerate Dienogest is metabolized by limited degradation of oral ethinyl (Figure 1, page 10) appears to over- the cytochrome P-450 CYP3A4 sys- estradiol, may account for its pro- come those unwanted side effects. tem. Concomitant administration of nounced effects on the production of When estradiol valerate is tak- dienogest and CYP3A4 inducers— proteins in the liver, including 1) an en orally, the intestines absorb al- barbiturates, carbamazepine, phe- increase in thrombotic proteins and most all of it. The valerate group is nytoin, primidone, rifampicin—may cleaved within the intestines or in decrease the time needed to clear di- the first pass through the liver—thus enogest. Concurrent administration What do you know about the converting the compound to es- of dienogest and CYP3A4 inhibitors— enzyme CYP3A4 and how it affects the work of some OCs? tradiol and valeric acid. A woman antidepressants, azole antifungals, ci- who takes Natazia has a circulating metidine, grapefruit juice, diltiazem, Take the level of estradiol of approximately macrolides, verapamil—may in- Instant Poll 50 pg/mL and a higher level of es- crease the circulating concentration on page 11 trone (250 pg/mL); this difference of dienogest.

continued on page 10

6 OBG Management | September 2010 | Vol. 22 No. 9 obgmanagement.com Editorial

FIGURE 1 The structure of estradiol valerate FIGURE 2 The structure of dienogest

O CN O CH3 OH CH3

H H

H H H HO O

With absorption, estradiol valerate is metabolized to estradiol. This new 19-nortestosterone derivative has a unique C-17 Estradiol is metabolized to estrone and estrone sulfate. cyanomethyl group, not the usual C-17 ethinyl group.

Estrogen step-down, Comparative study. The clinical ing was observed more often in progestin step-up effect of Natazia was explored in a women taking Natazia than in Natazia is formulated as a four-phase randomized controlled trial in which women taking EE-LNG: With estrogen step-down (from 3 mg to 1 it was compared with a monophasic Natazia, about 19% of cycles mg), progestin step-up (from 2 mg to estrogen–progestin combination of were associated with an absence 3 mg) regimen (Table). A 28-day cy- 20 µg ethinyl estradiol plus 0.1 mg of withdrawal bleeding; with EE- cle has 26 pills containing hormones levonorgestrel (EE-LNG) in a 21-7 LNG, 8% of cycles and two inert pills. Underlying this cycle (a formulation found in the • Approximately 80% of subjects formulation are the theoretical con- brand-name OCs Aviane, Alesse, and in each of the two study groups cepts that: Lutera).5 The findings of that trial? were satisfied with the OC they • estrogen step-down ensures es­ • Both formulations were very were given. trogen dominance in the first effective: No pregnancies in part of the cycle, thus stimulating women who took Natazia, one endometrial proliferation and in- pregnancy in women who took Natazia for menorrhagia creasing endometrial production EE-LNG As I noted, Natazia appears to be as- of progesterone receptors, which, • In the first 90 days of the trial, sociated with 1) fewer days of men- in turn, sensitizes endometrium women taking Natazia reported strual bleeding and 2) more cycles to the action of progestin fewer days of bleeding or spot- without withdrawal bleeding than • progestin step-up ensures the ting than women taking EE-LNG an EE-LNG contraceptive.5 These stability of endometrial stroma (17 days and 22 days, respective- findings suggest that Natazia may be and prevents endometrial hy- ly [P < .0001]) especially useful for treating heavy perplasia. • Absence of withdrawal bleed- menstrual bleeding.

Profile of four-phase Natazia

Day of cycle Pill color Pill count Estradiol valerate Dienogest content content

1, 2 Dark yellow 2 3 mg None

3–7 Medium red 5 2 mg 2 mg

8–24 Light yellow 17 2 mg 3 mg

25, 26 Dark red 2 1 mg None

27, 28 White 2 None None

10 OBG Management | September 2010 | Vol. 22 No. 9 obgmanagement.com Two randomized clinical trials dose ethinyl estradiol on hemostasis parameters. Thromb Haemost. 1989;61(1):65–69. that were reported in abstracts at 2. Wiegratz I, Lee JH, Kutschera E, Winkler UH, Kuhl The major professional meetings have H. Effect of four oral contraceptives on hemostatic next 6,7 parameters. Contraception. 2004;70(2):97–107. tested this hypothesis : 3. Fruzzetti F, Bitzer J. Review of clinical experience Trial #1. 190 women who had heavy with estradiol in combined oral contraceptives. big menstrual bleeding were random- Contraception. 2010;81(1):8–15. 4. Sasagawa S, Shimizu Y, Kami H, et al. thing in ized to Natazia or placebo6: Dienogest is a selective progesterone receptor agonist in transactivation analysis with ObGyn practice • 44% of women who took Natazia potent oral endometrial activity due to its experienced complete improve- efficient pharmacokinetic profile. Steroids. ment in their heavy menstrual 2008;73(2):222–2231. 5. Ahrendt HJ, Makalová D, Parke S, Mellinger U, as a device bleeding Mansour D. Bleeding pattern and cycle control made a differ- • Only 4% of women in the pla- with an estradiol-based oral contraceptive: a seven-cycle, randomized comparative trial Hence in your cebo group experienced such of estradiol valerate/dienogest and ethinyl practice? Or maybe it’s a improvement estradiol/levonorgestrel. Contraception. 2009;80(5):436–444. drug that has simplified • Natazia, but not placebo, was 6. Jensen J, Machlitt A, Mellinger U, Schaefers management of a thorny associated with an elevation in M, Fraser IS. A multicenter, double-blind, randomized, placebo-controlled study of oral condition. Perhaps you hematocrit, hemoglobin con- estradiol valerate/dienogest for the treatment streamlined a common centration, and ferritin level. of heavy and/or prolonged menstrual bleeding. procedure, or simply Fertil Steril. 2009;92(3):S32. Trial #2. In a trial conducted to like- 7. Fraser IS, Zeun S, Machlitt A, Mellinger U. A novel reorganized your records. wise test the efficacy of Natazia for oral contraceptive comprising estradiol valerate/ dienogest for the treatment of heavy and/or heavy menstrual bleeding, the rate of prolonged menstrual bleeding without organic Whatever it is that has complete improvement among wom- cause: a double blind placebo-controlled trial. Int made the biggest dif- en treated with Natazia was 41%; the J Gynecol Obstet. 2009;107(suppl 2):S183. ference in your practice rate was 2% in the placebo group.7 Dr. Barbieri reports no financial rela- over the past 12 months, These studies show that Natazia tionships relevant to this article. we’d like to hear about may be especially useful for women it. We’ll select the most who report heavy menses when intriguing and informative they’ve taken other estrogen-proges- ideas and publish them tin contraceptives. in OBG Management. And Instant Quiz your good thing may become the next big More choices mean thing in ObGyn practice. better tailoring Effective counseling and consistent Send your submission True or false? The use of a contraceptive will reduce (100–150 words) to us at enzyme CYP3A4 the high rate of unintended preg- [email protected], with the metabolizes many words “Next big thing” in nancy in the United States. Having the subject line. Include many contraceptive options avail- synthetic progestins your name and where able helps ensure that each woman and ethinyl estradiol. you practice. We’ll even can find the contraceptive that’s best Grapefruit juice increases accept 1- to 3-minute suited to her. the enzymatic activity of CYP3A4, thus increasing videos. The deadline: degradation and reducing November 1, 2010. the concentrations and

effectiveness of progestins and ethinyl estradiol. [email protected]

References See page 50 for the answer. 1. Lindberg UB, Crona N, Stigenhadl T, Teger- Nielsson AC, Silfverstolpe G. A comparison between effects of estradiol valerate and low

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