Recent advances in contraception

An intensive material on recent advances on contraception including the current contraceptive methods and a brief overview on immunocontraception and contraceptive vaccines

1. Recent advances in contraception Dr. Siddhartha Dutta MAMC, New Delhi

2. Outline

3. Contraception : need of the hour World’s population expected to reach 9 billion by 2050 India accounts for 17% of world’s population 21% of all pregnancies resulting live births are unplanned Around 2/5 th of all pregnancies are unintended If unmet need for contraception was met, we can avoid 55 million unwanted pregnancies(71%) 22 million fewer abortions 90,000 fewer maternal deaths

4. IDEAL CONTRACEPTIVE

5. Temporary methods

6. Hormonal contraception All hormonal birth control measures act via same mechanism Stops ovulation Prevents uterus lining from build up Making the cervical mucous thick to prevent penetration of sperm

7. Oral Contraceptives

8. Monophasic pills Low dose pills EE= 30-35μg Very low dose pills EE= 15-25 μg

9. Yaz 20 μg EE and 3 mg Drosperinone regimen 24 pills with active medication Once daily for 24 days in a row Only COC with reported evidence for and approved indication in the treatment of emotional and physical symptoms of premenstrual dysphoric disorder

10. Multiphasic pills Comparable in efficacy to monophasic pills Introduced with an aim of reducing the total dose of hormones per cycle and to ↓ BTB Better carbohydrate and lipid profile Type Estrogen Progesterone Triphasic EE – 30 ug (D1-6) Levonorgestrel 50 ug EE – 40 ug (D7-11) Levonorgestrel 75 ug EE – 30 ug (D12-21) Levonorgestrel 125 ug

11. 4 phase pills Estrogen-estradiol valarate along with newer progestin ( dienogest -DNG ) is used Step down doses of estrogen and step up doses of progestin preparation is used Qlaira Dosing schedule Days E₂ V DNG E₂ V-DNG 1-2 3mg 3-7 2mg 2mg 8-24 2mg 3mg 25-26 1 mg 27-28 placebo

12. Extended cycle regimen SEASONALE 150µg of LNG + 30µg of EE Taken continuously for 84 days , break for 7 days Fewer periods (4 in a year) Breakthrough bleeding/ spotting – First few cycles CONTINUOUS For 365 days No break 0.09mg LNG+20μg EE Diminished breakthrough bleeding after 8-9 months

13. Advantages of continuous use

14. Disadvantages little information on : Long-term safety (although there are long-term data for comparable total estrogen- progestin doses per month) Slightly higher cost for medications (an extra 3 pill packages per year for a 91-day cycle

15. Adverse effects of OCP

16. Progestin only pills Reducing the dose to the lowest possible without reducing efficacy (10 fold reduction) Dosing schedule- Started on 5 th day of menstruation normally Strict compliance(< 3 hrs window) 21 day of post partum period Soon after abortion lactation Extra precaution for 2 days to be taken

17. Desogestrel Suppress ovulation(97-100%) vs 40% with other pop 0.75 mg Thick mucus plug in the cervix ↑ tubal peristalsis Can be taken within 12 hrs window

18. Pop benefits POPs have no estrogen side effects. POPs do not decrease breast milk production. A woman’s periods may be lighter, shorter and have less cramping. POPs may be used by women: Who are breastfeeding Over 35 years who smoke Have a history of blood clots in the veins Have migraine headaches Have a higher risk of heart attack or stroke S/E- depression, irregular bleeding, headache, migraine, weight gain, ectopic pregnancy

19. Non contraceptives benefits of OCPs

20. Transdermal delivery

21. Ortho evra patch Effectiveness-98-99% 28 day regimen Replaced every week No patch free interval if only LNG 40 μ g is in it 21 day regime Replaced every week 7 day patch free interval if EE 30 μ g + LNG 100 μ g ADV DISADV Once a week dosing- good compliance High cost Avoid first pass metabolism Minor skin reaction Progestin with minimal androgenicity Breakthrough bleeding and mastalgia

22. Gel Nestorone(NES) a progestin is used Applied in dose 2.3 mg/day once for 21 days with 7 free days Nestorone®/Estradiol Transdermal Gel(Phase 3) Adv- -No skin irritation - Regular bleeding pattern maintained -No serious adverse event

23. Spray Metered Dose Transdermal System (MDTS) to administer a pre-set dose of the Nestorone once daily to the skin (forearm) Phase 1 Fast-drying spray & drug is slowly absorbed in the blood over a period of hours Suitable for Breastfeeding mothers Who cannot tolerate contraceptive pills with estrogens Leaves no visible residue & less irritation than patches S/E- bruising at the site, breast tenderness, tiredness, headaches, dizziness

24. Vaginal contraception- Nuva ring Effectiveness- 92-97% NES 150μg + 15μg EE/day 21day/7 day ADV- -reused for a year -reduced cost -excellent bleeding control -rapid return of fertility -no changes in weight DISADV- -feeling of ring on place -difficulty in remembering to reinsert

25. Vaginal gel

26. AG200-15 ( Twirla ™) Transdermal Contraceptive Delivery System (TCDS) Low-dose, once-weekly patch EE + LNG Once weekly for 3 weeks, followed by a week without a patch Minimizes seepage of adhesive around edge of patch & ↓ chance of residue on skin Promote enhanced patient compliance Completed phase 3(FDA approval awaited)

27. IUD: LNG20 Levonova 20mcg/day LNG -- Mirena (52mg) over 5 years It releases 15µg of LNG per day in vivo and is effective for 7-10 years Purpose: ↑ use from 5 to 7 years ↓ cost Study completion ~Dec. ‘18

28. Cyclofem Monthly injectable Pre-filled estradiol cypionate and medroxyprogesterone syringes 25 mg MPA, 5 mg estradiol cypionate 94% to 99% effective at preventing pregnancy Still to be introduced in US India- completed phase 3

29. Nestorone/EE 1 Year Ring (CVR) Nestorone/Ethinyl Estradiol 1-Year Ring (CVR) Releases 150 mcg Nestorone & 15 mcg ethinyl estradiol/day over 3-week period 3 weeks in and 1 week out for 13 cycles Used like NuvaRing Lasts 13 cycles Awaiting FDA approval

30. Male Hormonal Contraception

31. Androgen formulations

32. Intramuscular Testosterone enanthate Dose interval-1–2 wk Overall contraceptive efficacy of 94.7% Potential concern- Delay in onset of full contraceptive action for almost 3-4 months. Injections can be painful, high peak levels Side effects from weekly injections of 200 mg of TE in healthy men include weight gain, a reversible 25% reduction in testicular volume , a 6% increase in hemoglobin, and a 10–15% decrease in serum HDL cholesterol

33. Subcutaneous

34. Transdermal

35. Testosterone buccal system Buccal Manufactured under trade name Straint Applied twice a day Dose interval- Daily S/E-allergic reaction , Liver toxicity

36. Nonhormonal Methods

37. Adjudin

38. RAR Antagonist

39. Indenopyridine

40. Intra VAS device Non hormonal Injectable silicone plugs(Shug) 2 plugs blocks the sperm flow in vas deferens Reversibility not known There are two tested types of injected plugs • Medical-grade polyurethane (MPU) • Medical-grade silicone rubber (MSR) USA- silicon(phase 1) China- Polyurethane stent+ nylon mesh(phase 2) lower efficacy rate when compared to traditional vasectomy

41. RISUG

42. Contraction Inhibitor Pill ―Dry Orgasm When segments of vasa deferentia were exposed to phenoxybenzamine or thioridazine , the longitudinal smooth muscle fibers did not contract The circular smooth muscles did, causes, clamping the vas shut Thioridizine’s side effects were so extreme(hives, difficult breathing, swelling of face) that the manufacturer discontinued it in 2005, the common side effects of phenoxybenzamine are dizziness , fast heartbeat & stuffy nose

43. ORIGAMI Male Condom (OMC) ORIGAMI Male Condom™ ( OMC ) is the first NON-rolled, NON- Latex, silicone condom

44. Targeting sperm motility Catsper blocker Sperm-specific transmembrane proteins-allow Ca++ entry in sperm tail The rise in intracellular calcium mediated by the catspers is directly responsible for the increase in flagellar beat frequency that characterizes sperm hyperactivation

45. IMMUNO-CONTRACEPTION IMMUNO CONTRACEPTION

46. Contraceptive vaccine Safe, effective and acceptable contraceptive vaccines Confer long-term (but not permanent) protection following a single course of immunization Be free of overt pharmacological activity and the metabolic and endocrine disturbances that often accompany other methods of birth control Not require insertion of a device or implant Remain effective without continuous conscious action by the user Be inexpensive to manufacture

47. ANTI-SPERM VACCINES

48. ANTI-OVUM VACCINES

49. ANTI-CONCEPTUS VACCINES

50. HORMONAL PLACENTAL ANTIGENS

51. Conclusion From a global standpoint, there is clearly a desire and need for more contraceptive options Couples desire more choices for fertility control as unplanned pregnancies continue to occur at alarming rates Paucity of research in male hormonal contraceptive control Government and not-for-profit sponsors are needed to devote necessary resources for long-term efficacy studies of newer molecules