Kontrasepsiyonda Güncel Görüşler Doç. Dr. Cavidan Gülerman Zekai Tahir Burak Kadın Hastalıkları Eğitim ve Araştırma Hastanesi Üreme Tıbbında Güncel Gelişmeler Sempozyumu 20-21 Aralık 2008 - Ankara

Kontrasepsiyondaki Yeni Gelişmeler Yeni kombine oral kontraseptif formulasyonları Kontraseptif vaginal halkalar Transdermal kontraseptifler Subkutan yeni implant sistemler Histeroskopik sterilizasyon teknikleri Acil kontrasepsiyon

Yeni Kombine Oral Kontraseptif Formulasyonları 1. Düşük ve ultra düşük dozlu estrojen 2. Daha güvenli olan progestinlerin kullanıma sunulması a) Androjenitesi daha az olan 19-nortestosteron progestinlerin kullanımı b) Nonsteroidal progestin drospirenon 3. Tek başına progestin kontrasepsiyonu Oral kontraseptiflerin kompliansını artırmak için “Quick Start” metodu Uzamış siklus rejimleri 4. Steroid ve nonsteroid progesteron agonistleri Selektif progesteron reseptör modülatörleri (SPRM)

Zaman içerisindeki estrojen dozundaki azalma Estrojen Dozu (mg) İlk kullanım yılı * Mestranol içeren oral kontraseptifler

Progestinlerin Sınıflandırılması

Drospirenon Spironolakton analoğudur. Major; antimineralokortikoid etkilidir. Su ve tuz retansiyonu ¯ Kan basıncı ¯ Parsiyel antiandrojenik etkili (Cyproteron asetatın %30’u) DRSP/EE 3 mg drospirenon içerir, 25 mg spironolaktona eşdeğerdir. 100-200 mg spironolakton ödem ve hirsutism 50-100 mg esansiyel hipertansiyon

Hormon Alınmayan İntervali Kısaltan Rejimler Ticari isim Estrojen dozu Progestin dozu Rejim Seasonale® 30 mg EE 150 mg levonorgestrel 84/7 SeasoniqueTM 84/7* *7 gün 10 mg EE Yaz 20 mg EE 3 mg drospirenone 24/4 Loestrin 24 Fe 1 mg noretindron asetat 24/4* *4 gün demir Lybrel 90 mg levonorgestrel 365 gün (non-siklik kontinü günlük doz) EE = etinil estradiol

Siklus Boyunca Yıkılma Kanaması / Lekelenme Günleri Ortalama Sayısı 84/7 Oral Kontraseptif Uzamış Siklus Rejimlerinde Zaman İçinde Yıkılma Kanaması ve Lekelenmenin Azalması Siklus Boyunca Yıkılma Kanaması / Lekelenme Günleri Ortalama Sayısı Siklus Gün 1-84 92-175 183-266 274-357 *30 mg etinil estradiol / 150 mg levonorgestrel Anderson FD, Hait H. Contraception. 2003;68:89-96.

Hormon Alımında Uzayan Sikluslar 2005, Cochrane Database 17 çalışmanın 6’sı kabul edilmiş 28 günlük ile uzun sikluslar karşılaştırılmış Kontraseptif etkinlik ve güvenlik profilleri benzer Kompliansta farklılık yok Kullanıcılar her iki rejimden de memnun

Mifepristone (RU 486) Ayda bir hap olarak mifepristone kullanımı 200 mg, menstruel siklusun 16. günü Acil kontrasepsiyonda mifepristone kullanımı Glasier ve ark. 1992 800 kadın ve adölesan Tek doz 600 mg RU 486 korunmasız koitus sonrasındaki ilk 72 saat içerisinde verildiğinde %100 etkili bulunmuş WHO 1999 1700 kadın, 10 ve 50 mg RU 486, 600 mg’lık doza eşit etkinlikte bulunmuş (tedavi verilmediği taktirde oluşabilecek gebelikte tahminen %85’i azalmış) Korunmasız koitus sonrasındaki 5 güne kadar etkili Am J Gyn and Obs, 2008 Glasier A. N Engl J Med. 1992; 327:1041-1044. WHO Task Force on Postovulatory Methods of Fertility Regulation. Lancet. 1999;353:697-702.

Kontraseptif Vaginal Halkalar Kontraseptif Vaginal Halka Teknolojisi 1. Vaginal epitelden steroid absorbsiyonu hızlıdır. 2. Vaginal halkalar steroidlerin sabit bir hızla salınımına uygun şekilde dizayn edilebilir. 3. Vaginal halkanın kullanımı, kullanıcı tarafından kolayca kontrol edilebilir. 4. Vaginal halka koitus sırasında yerinde kalabilir ya da maksimum 2 saat süreliğine çıkarılabilir.

Kontraseptif Vaginal Halkalar Her siklus için bir halka Rejim: 3 hafta kullan, 1 hafta ara ver Günlük salınım 15 mg etinil estradiol 120 mg etonogestrel Mensesin ilk 5 günü içinde veya gebelik ekarte edilerek de başlanabilir NuvaRing

Vaginal Kontraseptif: Avantajları Kullanıcı kontrollü Kolayca yerleştirilip çıkartılabilir Aylık metod Her gün dikkat etmeye gerek yok Sabit serum hormon seviyelerini sağlayan kontinü salınım En düşük etinil estradiol dozu Absorbsiyonla ilgili gastrointestinal problemlerden uzak Hepatik “first-pass” etki yok OK ile karşılaştırıldığında genital semptomlarla ilgili aşikar bir farklılık yok Vaginal ıslaklık daha fazla rapor edilmiş (diğer vaginal parametrelerde candida, vaginal pH farklılık yok) Veres S, Miller L, Burington B. Obstet Gynecol. 2004;104:555-63.

Kontraseptif Halka: Etki Mekanizması NuvaRing® ovulasyonu inhibe etmektedir FSH düşük konsantrasyonda bulunmuştur LH surge’ü izlenmemiştir Progesteron seviyeleri düşük bulunmuştur (<2.9 nmol/L) Kullanımın bırakılmasından sonra ovulasyon hızla geri dönmektedir Mulders TM, Dieben TO. Fertil Steril. 2001;75:865-870

Kontraseptif Etkinlik NuvaRing® Avrupa Çalışması Gebelik Siklus Pearl İndeksi %95 Cl 6 12109 0.65 0.24-1.41 Roumen et al. Hum Reprod. 2001;16:469-75

Kontraseptif Halka Tolerabilite: Yan Etkiler Kullanıcı %’si Baş ağrısı 5.8 Vaginitis 5.6 Leukorrhea 4.8 Halkayla ilgili şikayetler 4.4 Kilo alma 4.0 Bulantı 3.2 Akne 2.0 Dieben TO, et al. Obstet Gynecol. 2002;100:585-593

İrregüler Kanama NuvaRing vs. KOK karşılaştırması * İrregüler kanama insidansı (%) * * Siklus */**İstatistiksel olarak anlamlı farklılıklar Scientific communication ESC 2004

NES/EE Şematik Dizaynı Nestorone / Etinil Estradiol (150/15 mg gün) Vaginal Halka Ara yüzey 8.4 mm NES çekirdek NES/EE çekirdek 56 mm Halka 1 yıl süreyle etkili 3 hafta vajinada, 1 hafta kanama olması için çıkarılıyor Population Council, halen Faz III çalışmaları yapılıyor (Haziran 2009, 2300 kadın)

Kontraseptif Vaginal Halkalar Laktasyondaki kadınlar için vaginal halka 1. NES içerenler (6 ay devamlı kullanım) n=180, RCT, doz bulma çalışması NES dozu Devam oranları 50 mg/gün %84.8 75 mg/gün %76.7 100 mg/gün %73.2 Ovulasyon her dozda da inhibe olmuş (p<10nmol/L) Contraception 2001;63:257-61. 2. Naturel progesteron hormonu içerenler Bu halka HRT’de progestin gereken kadınlarda da kullanılacaktır.

Transdermal (TD) Kontraseptifler Kontraseptif patch’ler TD jeller TD spray kontraseptifler

Transdermal Kontraseptif Patch Hormonlar kontinü sistemik dozda salınır 150 µg norelgestromin 20 µg etinil estradiol Kontraseptif hormonal seviyelere patch’in yerleştirilmesinden 48 saat sonra hızla ulaşılır Haftalık kullanım (7 gün) Gastrointestinal sistem by-pass edilir Transdermal Contraceptive Patch Transdermal patches first became available in the 1970s with the introduction of nitroglycerin patches for the prevention of angina. With the introduction of scopolamine and particularly nicotine, patches have become an accepted, mainstream method of drug delivery. The first hormone-containing patches were introduced for estrogen replacement in 1986. Today, patches that deliver both estrogen and progestin for hormone replacement are available. Because transdermal delivery does not rely on gastrointestinal absorption, there is no potential loss of a dose in the event of vomiting or diarrhea. The transdermal contraceptive patch Ortho Evra®, marketed by Ortho-McNeil Pharmaceutical, Inc., delivers a continuous systemic dose of hormones (150 µg norelgestromin and 20 µg ethinyl estradiol) over a 7-day period. Because of the method of delivery, the hormones bypass the gastrointestinal tract and are not lost during gastrointestinal upset. References: Abrams LS, Skee DM, Wong FA, Anderson NJ, Leese PT. Pharmacokinetics of norelgestromin and ethinyl estradiol from two consecutive contraceptive patches. J Clin Pharmacol. 2001;41:1232-1237. Abrams LS, Skee DM, Natarajan J, Wong FA, Leese PT, Creasy GW, Shangold MM. Pharmacokinetics of norelgestromin and ethinyl estradiol delivered by a contraceptive patch (Ortho Evra/Evra) under conditions of heat, humidity, and exercise. J Clin Pharmacol. 2001;41:1301-1309. Abrams LS, Skee DM, Natarajan J, Wong FA, Lasseter KC. Multiple-dose pharmacokinetics of a contraceptive patch in healthy women participants. Contraception. 2001;64:287-294. Creasy GW, Abrams LS, Fisher AC. Transdermal contraception. Semin Reprod Med. 2001;19:373-380. Abrams LS, et al. J Clin Pharmacol. 2001;41:1232-1237, 1301-1309. Abrams LS, et al. Contraception. 2001;64:287-294. Creasy GW, et al. Semin Reprod Med. 2001;19:373-380.

Transdermal Kontraseptif Sistem 3-patch sistem 3 hafta süreyle her hafta 1 patch uygulanır Her bir patch haftanın aynı günü uygulanır 1 hafta patch uygulanmaz Patch #1 Patch #2 Patch #3 Patch Ø Yeni siklus başlanır Transdermal Contraceptive System: Description The transdermal contraceptive system is based on a 28-day (4-week) cycle and the delivery of a continuous dose of estrogen and progestin through the skin and subcutaneous tissue for absorption into the bloodstream. Three patches are used during the 28-day cycle for a total of 21 days. Each patch lasts for seven days; a new patch is applied each week to a unique area (except for the breast) and the old patch is discarded. To maximize effectiveness, each patch should be applied on the same day of the week. During week four, no patch is worn and withdrawal bleeding is expected. References: Abrams LS, Skee DM, Wong FA, Anderson NJ, Leese PT. Pharmacokinetics of norelgestromin and ethinyl estradiol from two consecutive contraceptive patches. J Clin Pharmacol. 2001;41:1232-1237. Abrams LS, Skee DM, Natarajan J, et al. Pharmacokinetics of norelgestromin and ethinyl estradiol delivered by a contraceptive patch (Ortho Evra/Evra) under conditions of heat, humidity, and exercise. J Clin Pharmacol. 2001;41:1301-1309. Abrams LS, Skee DM, Natarajan J, Wong FA, Lasseter KC. Multiple-dose pharmacokinetics of a contraceptive patch in healthy women participants. Contraception. 2001;64:287-294. Creasy GW, Abrams LS, Fisher AC. Transdermal contraception. Semin Reprod Med. 2001;19:373-380. Audet MC, Moreau M, Koltun WD, et al. for the ORTHO EVRA/EVRA 004 Study Group. Evaluation of contraceptive efficacy and cycle control of a transdermal contraceptive patch vs an oral contraceptive: a randomized controlled trial. JAMA. 2001;285:2347-2354. Smallwood GH, Meador ML, Lenihan JP, Shangold GA, Fisher AC, Creasy GW; ORTHO EVRA/EVRA 002 Study Group. Efficacy and safety of a transdermal contraceptive system. Obstet Gynecol. 2001;98(5 Pt 1):799-805. 28 gün siklus 28 gün siklus Hafta 1 Hafta 2 Hafta 3 Hafta 4 Hafta 5 Abrams LS, et al. Contraception. 2001;64:287-294. Creasy GW, et al. Semin Reprod Med. 2001;19:373-380. Smallwood GH, et al. Obstet Gynecol. 2001;98:799-805.

TD Kontraseptif Patch: Uygulamalar Boyut: 20 cm2 3 kattan oluşur: İç kısım uygulama anında çıkarılır Hormonlu adhesive tabaka Dıştaki koruyucu polyester tabaka Kalçaya, kolun üst dış yüzüne, üst abdomen bölgesine, meme dışındaki üst gövde bölgesine uygulanabilir Transdermal Contraceptive Patch: Application The Ortho Evra® contraceptive patch is 20 cm2 and consists of three layers, including a release liner that is removed for application, a medicated adhesive layer, and an outer protective polyester layer. The patch is applied to the buttocks, upper outer arm, lower abdomen, or upper torso (excluding the breast). Each patch should be applied to a unique area, which could be near the site of the last patch. Reference: Keder LM. New developments in contraception. J Pediatr Adolesc Gynecol. 2002;15:179-181. Keder LM. J Pediatr Adolesc Gynecol. 2002;15:179-181.

TD Patch: Avantajları Kullanıcı kontrollü, basit, haftalık uygulama Kontraseptif etkide hızlı reversibilite 3 ay kullanım sonrası düzenli sikluslar Kolay başlama ve sonlandırma Transdermal Contraceptive Patch: Advantages The Ortho Evra® contraceptive patch offers important advantages when compared to other methods of contraception. With typical use, the efficacy of the patch (92.9% to 93.7%) is greater than an oral contraceptive (77.2% to 88.7%). Weekly application encourages consistent and correct use of the patch, and its presence is easily verified. It does not require vaginal insertion like the vaginal ring or some of the barrier methods of contraception (e.g., cervical cap). References: Keder LM. New developments in contraception. J Pediatr Adolesc Gynecol. 2002;15:179-181. Zieman M, Guillebaud J, Weisberg E, Shangold GA, Fisher AC, Creasy GW. Contraceptive efficacy and cycle control with the Ortho Evra/Evra transdermal system: the analysis of pooled data. Fertil Steril. 2002;77(suppl 2):S13-S18.

TD Patch: Dezavantajları Uygulama bölgesinde reaksiyon 90 kilonun üzerindeki hanımlarda çok etkin değil Kullanımın ilk 2 ayında memede ağrı Diğer yan etkiler OK’larda görülenlerle benzer Patch’in dışarıdan görülmesi bazı kullanıcılar tarafından istenmeyebilir HIV veya STD’ye karşı koruyuculuk sağlamaz Transdermal Contraceptive Patch: Disadvantages The Ortho Evra® contraceptive patch has important disadvantages that may result in user discontinuation. The patch may produce application site reactions, its efficacy is decreased in women weighing more than 198 pounds, there is a likelihood of a higher rate of dysmenorrhea and of breast pain during the first two cycles, and privacy may be compromised due to the patch’s visibility. Finally, the patch does not provide protection against sexually transmitted infections or HIV. References: Zieman M, Guillebaud J, Weisberg E, Shangold GA, Fisher AC, Creasy GW. Contraceptive efficacy and cycle control with the Ortho Evra/Evra transdermal system: the analysis of pooled data. Fertil Steril. 2002;77(Suppl 2):S13-S18. Zieman M, et al. Fertil Steril. 2002;77(Suppl 2):S13-S18.

Transdermal Kontraseptif Patch: Etkinlik 22,160 Siklus Gebelik Sayısı Gebelik Olasılığı Metod Başarısızlığı 12 %0.8 3 %0.6 Transdermal Contraceptive Patch: Pooled Analysis of Efficacy Through 13 Cycles These efficacy data were derived from three pivotal clinical trials that investigated the efficacy and safety of the Ortho Evra® transdermal patch. All of the trials were multicenter, used open-label contraceptives, and had similar study designs. There were 12 method-failure pregnancies and 3 user-failure pregnancies in 3,319 women treated for 22,160 cycles. The overall probability of pregnancy through 13 cycles was 0.8%, with a Pearl Index of 0.88. The method failure probability of pregnancy through 13 cycles was 0.6%, with a Pearl Index of 0.70. References: Zieman M, Guillebaud J, Weisberg E, Shangold GA, Fisher AC, Creasy GW. Contraceptive efficacy and cycle control with the Ortho Evra/Evra transdermal system: the analysis of pooled data. Fertil Steril. 2002;77(Suppl 2):S13-S18. Smallwood GH, Meador ML, Lenihan JP, Shangold GA, Fisher AC, Creasy GW. Efficacy and safety of a transdermal contraceptive system. Obstet Gynecol. 2001;98(5 Pt 1):799-805. Audet MC, Moreau M, Koltun WD, et al. for the ORTHO EVRA/EVRA 004 Study Group. Evaluation of contraceptive efficacy and cycle control of a transdermal contraceptive patch vs an oral contraceptive: a randomized controlled trial. JAMA. 2001;285:2347-2354. Hedon B, Helmerhorst FM, Cronje HS, Shangold G, Fisher A, Creasy G. Cronje HS. Comparison of efficacy, cycle control, compliance, and safety in users of a contraceptive patch vs an oral contraceptive [abstract ]. Int J Gynaecol Obstet. 2000:70(suppl 1):78. Zieman M, et al. Fertil Steril. 2002;77(Suppl 2):S13-S18. Smallwood GH, et al. Obstet Gynecol. 2001;98(Pt 1):799-805. Audet MC, et al. JAMA. 2001;285:2347-2354. Hedon B, et al. Int J Gynaecol Obstet. 2000:70(suppl 1):78.

Transdermal Kontraseptif Patch: Yan Etkiler Hasta Sayısı (%) Ortho Evra® Patch (n=812) Triphasil® Oral Kontraseptif (n=605) P Değeri Baş ağrısı 178 (21.9) 134 (22.1) 0.95 Bulantı 166 (20.4) 111 (18.3) 0.34 Uygulama bölgesinde reaksiyon 164 (20.2) – Memede ağrı 152 (18.7) 35 (5.8) <0.001 Üst respiratuar enfeksiyon 108 (13.3) 108 (17.9) 0.02 Dysmenorrhea 58 (9.6) 0.04 Abdominal ağrı 66 (8.1) 51 (8.4) 0.85 Transdermal Contraceptive Patch: Most Common Adverse Events Audet et al. designed a randomized, active control clinical trial to compare the Ortho Evra® transdermal contraceptive patch with Triphasil®, an established oral contraceptive, with regard to efficacy, safety, cycle control, and patient compliance. A total of 1,417 women between the ages of 18 to 45 years were randomized to use the patch (n=812) or the oral contraceptive (n=605) for 6 or 13 cycles. In this study, the adverse events reported by the study participants were similar between the group using the transdermal contraceptive patch and that using the oral contraceptive, with the exception of application-site reactions and breast discomfort. The incidence of breast discomfort was higher for the patch group than for the oral contraceptive group during cycles 1 and 2 (15.4% vs 3.5% in cycle 1 [P<0.001] and 6.6% vs 1.5% in cycle 2 [P<0.001]). For cycles 3 to 13, the by-cycle incidence of breast symptoms was similar between the two treatment groups. The overall incidence of dysmenorrhea among the patch group was also statistically significant (P = 0.04) when compared to the oral contraceptive group, as was the higher percentage of upper respiratory tract infections among the oral contraceptive group. Reference: Audet MC, Moreau M, Koltun WD, et al. for the ORTHO EVRA/EVRA 004 Study Group. Evaluation of contraceptive efficacy and cycle control of a transdermal contraceptive patch vs an oral contraceptive: a randomized controlled trial. JAMA. 2001;285:2347-2354. Audet MC, et al. JAMA. 2001;285:2347-2354.

Estrojen Maruziyeti: Kontraseptif Patch’in OK ve Vaginal Halkayla Karşılaştırılması halka (15 µg EE/gün) Patch (20 µg EE/gün) OK (30 µg EE/gün) * * *P<0.05 vs. patch ve halka *P<0.05 vs. halka ve OK †P<0.05 vs. halka † Estrogen Exposure: Contraceptive Patch Compared to OCs and the Vaginal Ring In an open-label, randomized parallel group trial conducted by van den Heuvel et al., the pharmacokinetics of ethinyl estradiol (EE) from a vaginal ring (15 μg EE/day), the Ortho Evra® transdermal patch (20 μg EE/day), and a combined oral contraceptive (30 μg EE/150 μg levonorgestrel/day) were compared in 24 women between the ages of 18 and 40 years. After two to eight weeks of synchronization by treatment with a combined oral contraceptive, the subjects were randomized to 231 days of treatment with one of the three contraceptives being compared. Analysis of the area under the EE concentration-versus-time curve (AUC) during 21 days of treatment showed that exposure to EE was highest in the patch group and that systemic exposure to estrogen was 60% higher with the patch than with the oral contraceptive (P<0.05 for both comparisons). The highest mean peak concentration (Cmax) was seen in the contraceptive pill group, which was 4.5 times higher than in the vaginal ring group and 1.6 times higher than in the patch group (P<0.05 for both comparisons). The mean Cmax for the patch was 2.8 times greater than that of the vaginal ring (P<0.05). In 2005, the U.S. Food and Drug Administration approved updated labeling information for the Ortho Evra patch to alert healthcare providers and patients about the increased levels of estrogen that users of the patch are exposed to in comparison to oral contraceptive users. Reference: van den Heuvel MW, van Bragt AJ, Alnabawy AK, Kaptein MC. Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive. Contraception. 2005;72:168-174. EE konsantrasyonu vs. zaman (AUC 0-21) (ng.h/mL) En yüksek ortalama pik konsantrasyonu (Cmax) (pg/mL) OK = oral kontraseptif; EE = etinil estradiol van den Heuvel, et al. Contraception. 2005;72:168-174.

Transdermal Kontraseptif Patch: Venöz Tromboembolik Olay Riski Çalışmalar Odds Ratio (95% Confidence Interval) Jick SS, et al., 2006 0.9 (0.5–1.6) Cole JA, et al., 2007 2.4 (1.1–5.5) Transdermal Contraceptive Patch: Risk for Venous Thromboembolic Events As with other methods of hormonal contraception, some users of the Ortho Evra® transdermal patch have had venous thromboembolic events. Although it has been hypothesized that the patch confers an increased risk of these events because it contains a greater amount of estradiol than other hormonal contraceptive methods, studies of transdermal patch usage and risk of venous thromboembolic events have given conflicting results. Two case-control studies used electronic healthcare claims data to compare the risk of venous thromboembolic events in women between the ages of 15 and 44 years who used either the transdermal patch or a norgestimate-containing oral contraceptive. In the study by Jick et al., the overall incidence rates of these events were 52.8 per 100,000 women-years for users of the patch and 41.8 per 100,000 women-years for users of the oral contraceptive. The odds ratio for current users of the patch was 0.9 (95% confidence interval [CI] 0.5-1.6). In the study by Cole et al., which also included a chart review, the incidence rate of venous thromboembolic events was 40.8 per 100,000 women-years for current users of the patch as compared to 18.3 per 100,000 women-years for users of the oral contraceptive. Overall, there was a two-fold increase in the risk of venous thromboembolic events among users of the patch when compared with users of the oral contraceptive (OR 2.4, 95% CI 1.1-5.5). Differences in study design may explain the conflicting results of these studies. For example, the study by Jick et al. relied on insurance claims to determine outcomes of venous thromboembolic events rather than on using a chart review as Cole et al. did. There were also differences in the patient selection processes, which may have influenced the outcomes. The study by Jick et al. included only those patients who had just begun using a study medication. As such, prior users of norgestimate-containing oral contraceptives were excluded from the norgestimate group but were permitted in the transdermal patch group. These participants with past hormonal contraceptive experience may have attenuated the incidence of venous thromboembolic events in the transdermal group since the risk of these events is greatest in the early phases of use. In contrast, participants in the study by Cole et al. were included if they had had at least one dispensing of a study medication. In 2006, the U.S. Food and Drug Administration (FDA) approved updated labeling information for the Ortho Evra patch to alert healthcare providers and patients of these epidemiologic studies. The FDA also recommend that women with risk factors for venous thromboembolic events discuss the use of the Ortho Evra patch with their healthcare provider because it may be associated with an increased risk of these events in some women. Women should be counseled about the risk of venous thromboembolic events that is associated with the use of any combined contraceptive product, and women who have risk factors for these events should consider using nonhormonal contraceptive methods. Women who are immobilized due to surgery or injury should discontinue the Ortho Evra patch because of the associated risk for venous thromboembolic events. References: Jick SS, Kaye JA, Russmann S, Jick H. Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol. Contraception. 2006;73:223-228. Cole JA, Norman H, Doherty M, Walker AM. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Obstet Gynecol. 2007;109:339-346. Ortho Evra® [revised prescribing information]. Raritan, NJ: Ortho-McNeil Pharmaceutical, Inc; September 2006. Jick SS, et al. Contraception. 2006;73:223-228; Cole JA, et al. Obstet Gynecol. 2007;109:339-346.

Transdermal Kontraseptif Patch: Sonuç FDA tavsiyesi: 2006’da 2 epidemiyolojik çalışma sonuçlarına göre bazı kadınlarda artmış venöz tromboembolizm (VTE) olaylarına rastlanmasından dolayı, risk faktörleri olan kadınların patch kullanımlarının tekrar gözden geçirilmesi uygun görülmüştür Etkinlik Oral kontraseptif kullanıcılarıyla karşılaştırıldığında daha yüksek komplians bulunmuştur Transdermal Contraceptive Patch: Conclusions Ortho Evra® is a unique transdermal contraceptive patch based on norelgestromin, the primary active metabolite of norgestimate (the progestin in several oral contraceptives), and ethinyl estradiol, the estrogen most commonly used in combination oral contraceptives. A treatment cycle consists of the consecutive application of three patches for seven days each, followed by a seven-day, patch-free phase. Women who use this method have greater compliance when compared with women who use oral contraceptives. In 2006, the U.S. Food and Drug Administration (FDA) approved updated labeling information for the Ortho Evra patch to alert healthcare providers and patients of two recent epidemiologic studies. Even though the results of the two studies are conflicting, the results of the second epidemiology study support FDA’s concerns regarding the potential for Ortho Evra use to increase the risk of blood clots in some women. The label has recommended and continues to recommend that women with concerns or risk factors for thromboembolic disease talk with their healthcare provider about using Ortho Evra versus other contraceptive options because it may be associated with an increased risk of these events in some women. Women should be counseled about the risk of venous thromboembolic events that is associated with the use of any combined contraceptive product, and women who have risk factors for these events should consider using nonhormonal contraceptive methods. Women who are immobilized due to surgery or injury should discontinue the Ortho Evra patch because of the associated risk for venous thromboembolic events.

Transdermal Kontraseptif Jel Nestorone + Naturel Estradiol Transdermal Kontraseptif Sprey Nestorone + Naturel Estradiol Avantajı: Naturel estradiolün venöz tromboembolizm riski, oral verilime göre 4 kat daha azdır. Sprey teknolojisi relatif olarak düşük maliyetli bir yaklaşımdır.

Progestinli İntrauterin Sistemler Levonorgestrel-Releasing Intrauterine System (LNG-IUS, Mirena®) 24 saatte 20 µg levonorgestrel salgılanır Kullanım süresi: 5 yıl Kullanıcıların %0.1’inde ilk kullanım yılında gebelik görülebilir Servikal müküste kalınlaşma Sperm fonksiyonu inhibisyonu Endometriumda incelme Fertilizasyon inhibisyonu Intrauterine Contraceptives: Mechanisms of Action The primary method of action in intrauterine contraceptives (IUDs) is to prevent the fertilization of ova, which is supported by the low rate of ectopic pregnancies among users. The mechanisms of action of the levonorgestrel-releasing intrauterine system (LNG-IUS, Mirena®) are similar to that of levonorgestrel implants or levonorgestrel-containing mini-pills. The LNG-IUS has several different contraceptive actions: thickening of the cervical mucus; inhibition of sperm capacitation, survival, and motility; suppression of ovulation in some women; endometrial thinning; and stimulation of an inflammatory reaction that may impede sperm function and prevent implantation. A high concentration of levonorgestrel in the endometrium leads to increased endometrial atrophy that, in turn, results in a substantial reduction in menstrual flow or in amenorrhea in some users. The release of copper ions (Cu2+) from the ParaGard® IUD is believed to affect sperm motility and viability which impairs fertilization, and to disrupt the normal division of oocytes and the formation of fertilizable ova. Changes also occur in the endometrium that could interfere with the implantation of a fertilized ovum, which explains why this device is particularly effective as a method for emergency contraception. References: Jonsson B, Landgren BM, Eneroth P. Effects of various IUDs on the composition of cervical mucus. Contraception. 1991;43:447-458. Videla-Rivero L, Etchepareborda JJ, Kesseru E. Early chorionic activity in women bearing inert IUD, copper IUD and levonorgestrel-releasing IUD. Contraception. 1987;36:217-226. Kulier R, Helmerhorst FM, O'Brien P, Usher-Patel M, d'Arcangues C. Copper containing, framed intra-uterine devices for contraception. Cochrane Database Syst Rev. 2006;3:CD005347. Jonsson B, et al. Contraception. 1991;43:447-458. Kulier R, et al. Cochrane Database Syst Rev. 2006;3: CD005347.

Kontraseptif İmplantlar İmplanon Tek çubuk implant (4 cm uzunluk ve 2 mm çapta) Etilen vinyl asetattan yapılmıştır ve 68 mg etonorgestrel (desogestrel’in aktif metaboliti) içerir. Kullanım süresi: 3 yıl Pearl indeks: 0.38 Levonorgestrel: iki çubuklu (Jadelle, 5 yıl) Nestorone (NES): Tek çubuk (Population Council, 2 yıl, Latin Amerika) Elcometrine: Tek çubuk (6 ay) Nomegestrol asetat: Tek çubuk (Uniplant, 1 yıl) Capronor: Biodegredable Levonorgestrel (1 yıl)

Kontraseptif İmplant: Karakteristikler Etonorgestrel’in serum seviyeleri implantın yerleştirilmesinden hemen sonra artar Fertilite çabuk geri döner Menstrual sikluslar 3 ay içinde başlar Estrojen içermez Laktasyondaki kadınlar için 6. postpartum haftadan itibaren uygundur İnsersiyon bölgesi nondominant kolun iç bölgesidir Uygulama ve çıkarma için klinisyene gitme zorunluluğu vardır Croxatto HB. Eur J Contracept Reprod Health 2000; 5 Suppl 2: 21-28.

Kontraseptif İmplant Etkinlik: Etki Mekanizması Ovulasyonu baskılar Servikal müküsün viskozitesini artırır 5629 kadın-yılı kullanımında gebelik rapor edilmemiştir Yan etkiler: Düzensiz kanama (%13) Akne (%14.5) Emosyonel labilite (%14.2) Baş ağrısı (%12.7) Kilo alımı (%12.1) Dismenore (%9.7) İmplant bölgesinde kısa süreli ağrı (<%5) The Implanon US Study Group. Contraception 2005;71:319-326.

Progestin – Only Acil Kontrasepsiyon: Nor-Levo Nor-Levo (Levonorgestrel 0.75 mg) İlk doz: Korunmasız koitus sonrası ilk 72 saat içinde İkinci doz: İlk dozdan 12 saat sonra diğer tablet alınır (Geleneksel iki doz verilimi) Weismiller DG. Am Fam Physician. 2004; 70: 707-714.

Histeroskopik Sterilizasyon Teknikleri Essure: Microinsert (4 cm, superelastik nitinol + çelik sarmalı) Adiana: Tuba uterinaların düşük seviyeli radyofrekans dalgasıyla ablazyonu + proksimale yumuşak silikon matriks yerleştirilmesi Ovion: Tuba uterinaya fibröz ve oklüzyona yol açan metal tüp yerleştirilmesi

Erkekte Hormonal Kontrasepsiyon Bu konuda yapılan çalışmaların amacı FSH’yı baskılayarak azospermi oluşturmaktır.

Erkekte Kontraseptif Metodlar: Hormonal Yaklaşım 1. Androjenler: İnjeksiyonlar: Kısa süreli (3 hafta-3 ay) etkili İmplantlar: 7 alfa metil nortestosteron (MENT) ® 1 yıl Oral: Testosteron undecanoate (TU) (Tek oral aktif sentetik T) 3x1 PO veya 2 ayda bir IM 2. GnRH antagonistleri + androjen replasmanı (Testosterone enanthate 100 mg/hafta) 3. Progestinler + androjen replasmanı GnRH aşıları: Çalışmalar sonuç verici olmamıştır. Araştırma programı durdurulmuştur.

Erkekte Kontraseptif Metodlar: Nonhormonal Yaklaşım Suspensuarlar (İnternal ısı) Eksternal ısı RISUG: Reversible Inhibition of Sperm Under Guidance Hindistan’da Faz III çalışma aşamasında IVD: Intra Vasa Device [Silikon (ABD), ürethan tüp (Çin)] Vasa deferense enjekte edilen poliüretan, silikon tıkaç (Çin) Adjuvan (Lonidamin): Antikanser ajan Bazı antihipertansif ilaçlar Phenoxybenzamin Nifedipine Thioridazine Triptergium Enzim inhibitörleri, genomik ve proteomiklerin tanınması İmmünokontraseptifler

İdeal Kontraseptif Güvenli Etkili Reversibl Kullanımı kolay Ucuz Yeni araştırma alanları; reprodüktif sistemi içine alan: Genler, proteinler, enzimlerle yapılmaktadır Dual protektif etki araştırılmaktadır [STD ve HIV’a karşı mikrobisidlerle (Carraguard) kombine]