Recent advances in contraception
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An intensive material on recent advances on contraception including the current contraceptive methods and a brief overview on immunocontraception and contraceptive vaccines
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Recent advances in contraception
- 1. Recent advances in contraception Dr. Siddhartha Dutta MAMC, New Delhi
- 2. Outline Introduction Contraception types Mechanism Female contraception Male contraception Immuno- contraception Conclusion
- 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 Safe Effective Acceptable Inexpensive Reversible Simple to administer Independent of coitus Long lasting to avoid frequent administration Requiring little or no medical supervision
- 5. Contraception Female/ Male Temporary Barrier Hormonal IUD Permanent Vasectomy Tubectomy
- 6. Temporary methods • Condoms • Diaphragms • Cervical cap Barrier • OCP • Implants • Injectables • Orthoevra patch • Nuvaring Hormonal • Copper T • Progestrasert • Lipple’s loop IUD
- 7. 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
- 10. Monophasic pillsLow dose pills EE= 30-35μg Very low dose pills EE= 15-25 μg
- 11. 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
- 12. 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
- 13. 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
- 14. • DNG- least CVS & metabolic effects • More increase in HDL(8%), LDL ↓(6.5%) • Stability in carbohydrate metabolism • No glucocorticoid, anti-mineralocorticoid or anti estrogenic effects • Reduced breakthrough bleeding • Effective in treatment of heavy menstrual bleeding • Significant improvement in Hb, hematocrit, ferritin levels ADVANTAGES- • VTE ?? • Amenorrhea more common DISADVANTAGES
- 15. 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
- 16. Advantages of continuous use Decreased incidence of: 1. Pelvic pain 2. Headaches 3. Bloating/swelling 4. Breast tenderness for women who experience these symptoms during the pill-free interval Improved control over symptoms of endometriosis and polycystic ovary syndrome Greater convenience due to fewer withdrawal bleeds per year
- 17. 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
- 18. Adverse effects of OCP Mild • E-Nausea, vomiting, breast tenderness, mild edema, migraine • P- increased appetite, wt. gain, acne, hirsutism, decrease in libido, increased body temp. Moderate • E- vertigo, leg & uterine cramps, ppt of DM • P- BTB, monilial vaginitis, amenorrhea Severe • E- TE, cholestatic jaundice, cholelithiasis, hepatic adenoma • P- MI, cerebrovascular thrombosis
- 19. 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 Norethisterone 350μg Norgestrel 75μg PoP LNG 30μg
- 20. 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 Stringent time not necessary No androgenic S/E-Acne No ectopic pregnancy No altered carb/lipid met Failure rate is low
- 22. Ortho evra patch • Effectiveness-98-99% • 28 day regimen Replaced every week No patch free interval if only LNG 40μg is in it • 21 day regime Replaced every week 7 day patch free interval if EE 30μg + LNG 100 μg 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
- 23. 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
- 24. 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
- 25. 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
- 26. Vaginal gel C31G Glyminox 1% Gel(savvy) 50-60% effective Vaginal microbicide(carrageenan, betacyclodextrin) contraceptive along with spermicidal agent(nonoxynol-9) Applied 15 minutes prior to intercourse Prevent from sexually transmitted diseases MOA- • -boost bodies natural defense against infection • -damage and disable disease pathogen • -entry and fusion inhibitors ADV- • -Easy to use • -No serious side effects
- 27. 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)
- 28. 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
- 29. 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
- 30. 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
- 32. Androgen formulations • Dose interval- Oral, twice daily • Potential concern- Twice daily dosing, short and variable duration Testosterone undecanoate • Dose interval- Oral, daily • Potential concern- Liver toxicity 17α-Methyltestosterone
- 33. 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
- 34. Testosterone decanoate • Dose interval- 4–6 wk • Potential concern- Injections can be painful, high peak levels 01 Testosterone undecanoate • Dose interval- 8–12 wk • Potential concern- Injections can be painful • Weight gain, a 9% increase in hemoglobin, and a 14% decrease in HDL 02
- 35. Subcutaneous • Dose interval- 4 months • Dose of 600 mg is usually able to maintain plasma testosterone level within physiological range for 4-5 month • Potential concern- Surgical placement, occasional painful expulsions Testosterone implants • Phase 2 • Dose interval- 6 months • Surgical placement, poor sperm suppression, concern regarding bone effects MENT(7α-methyl-19-nortestosterone) implant
- 36. Transdermal Testosterone patch(non scrotal) • Dose interval- daily • Potential concern- Poor efficacy, high frequency of skin irritation Testosterone gel • Dose interval- daily • Potential concern- Possibility of partner transfer, daily application needed Dihydrotestosterone gel • Dose interval- daily • Potential concern- Poor efficacy
- 37. Testosterone buccal system • Buccal • Manufactured under trade name Straint • Applied twice a day • Dose interval- Daily • S/E-allergic reaction , Liver toxicity
- 39. Adjudin Non hormonal Analogue of lonidamine Phase 2 Disrupt the interaction of spermatid-Sertoli cells Binds to FSH receptor on Sertoli cell As it does not affect spermatogonia themselves the loss of fertility is reversible Inj/ implant/ gel Low oral bioavailability Also know to be a potential anticancer drug
- 40. RAR Antagonist Sperm production needs retinoic acid Failure of spermatids to align and be released into the lumen, and aberrant orientation to the sertoli cells 1 week RAR antagonist t/t– 3 month block 100% effective & reversible in animal models
- 41. Indenopyridine Targets both sertoli cells and germ cell Promising preclinical data for a potential oral, non hormonal male contraceptive MOA • It activates the ERK/MAPK pathway, reduces expression of prosurvival factors • Alters expression of sertoli-germ cell adherens junction proteins disrupts sertoli cell microtubule structure • Induces the proapoptotic factor, fas-result in germ cell loss
- 42. 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
- 43. RISUG Reversible inhibition of sperm under guidance Polymer gel of styrene maleic anhydride+ DMSO Injected into the lumen of the vas deferens using a no-scalpel technique Both partially occlude the vas deferens, while also deactivating the sperm that are able to pass through the partially occluded vas deferens, thereby preventing successful fertilization India- phase 3 Reversible by flushing with NaHCO3 S/E- transient painless scrotal swelling
- 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
- 46. ANTI-SPERM VACCINES 2 types of sperm antigens Functional antigens as the enzymes known to be required for sperm metabolism (lactic dehydrogenase-XLDH-C4) Involved in sperm-egg interactions and the processes leading to fertilization (acrosin and hyaluronidase) Structural antigens- expressed on the sperm cell membrane and which may be involved in gamete interaction and fusion Two sperm antigens identified- SP-10 and PH-20, have been shown to have promising antifertility effects when injected into laboratory animals
- 47. ANTI-OVUM VACCINES Antigen-focused on the surface antigen zona pellucida Causes an inflammatory reaction in the ovary which might be indicative of a risk of acute ovarian disturbances or long-term immunopathology
- 48. ANTI-CONCEPTUS VACCINES PLACENTA-SPECIFIC ANTIGENS/structural antigens Forma a part of the trophoblast cell membrane Pregnancy-specific ß1 glycoprotein (SP-1 ) an antifertility effect was observed when female baboons and cynomolgus monkeys were actively immunized with human SP-1, in the majority of cases (50-80%), this effect was manifested as a late abortion. Placental antigen PP-5,when animal is actively immunized with human PP-5 and a substantial reduction in fertility was shown
- 49. HORMONAL PLACENTAL ANTIGENS Production or function of hCG can be inhibited immunologically, the corpus luteum would regress Type 1- developed by the Population Council in New York and by the National Institute of Immunology (NII) in New Delhi, is based on the whole beta subunit of the hormone (ß-hCG) Type 2- developed with support from the WHO Task Force on Vaccines for Fertility Regulation, is based on a portion (carboxyterminal peptide) of the beta subunit of the hormone (ß-hCG-CTP) All of these anti-hCG vaccines require multiple injections to achieve and maintain levels of immunity that are considered effective
- 50. 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
- 51. THANK YOU
Editor's Notes
- 7.6 billion- world India is the 7th largest country but 2nd populous country in the world--1.32 billion(2016) We should take proper measures to control population other wise we may run out of food and basic facilities Delay the first, postpone the second and prevent the third
- cafeteria choice"
- Most popular effective– 99.5% success MOA- suppress FSH/LH(E effect), Also inhibit LH surge– no ovulation P- ensure withdrwal bleed on stoppage of OCP+ makes mucus thick Combined E+P- - disrupts the pro and sec phase of endomet – decreased chances of nidation Low doses of E and P so that S/E are minimized without affecting the contraceptive efficacy
- Comb pill- suppress the FSH/LH release (E) P- to ensure withdrawl bleeding Disruption of the proliferative and secretory phase
- No phasic inc/ dec in E/P content during 21days start at 5 day –21 days then 7 days pill free period Anovulatory(E) regular cyclical bleeding on withdrawl(P) If missed 2 pills next day. If more than 2 days then use barrier Some newer formulations have 24 days of active hormone pills, followed by 4 days of placebo (examples include Yaz 28 and Loestrin 24 Fe)
- 4 reminder pills (without hormones) at the end of the pack. Take one active pill (with hormones)
- Biphasic and triphasic Mimics the hormonal changes during the menstural cycle as physiologically as possible Biphasic – fixed dose E+ D1-10—D11-21– 2 phases inc doses of P(not in INDIA) Triphasic- bit higher dose of E near midcycle+ Inc dose of P for 3 successive phases Breakthrough bleeding is most commonly caused by an excessively thick endometrium
- new class of birth control pill quadriphasic more physiological since they simulate the woman's natural cycle. Available in India Only Ocp with 17β-estradiol (E2)-same estrogen produced in the female body 26/2 regimen that provides reliable contraception together with a good bleeding profile inc risk of pill-taking errors caused by the array of different color pills, complicated directions for catching up when a pill is missed, and the higher price.
- Step down e2v and step up dng No large trials
- Extended cycle use of COCPs may also be called menstrual suppression used for many years to treat endometriosis, dysmenorrhea, and menstruation-associated symptoms personal preference to avoid menstruation has also become a common reason for use. Available in India -- lupin Pearl index- 0.78 Personal preference is the most common reason extended cycle or continuous use COCPs are prescribed to adolescents
- Women take pill for every day for 84 days (12weeks), and then take hormone –free pills for 7days
- Mild – no need to withdraw Mod- may warrant discontinuation Severe- needs stoppage of OC C/I- px, genital ca, te, renal/ gb dis, brca, dm, htn, porphyria, epilepsy(dec seizure threshold)
- Norethi- 5 mg- 350, Nor-300- 75, LNG- 250/150—30, Place the endometrium prematurely to the secretory phase and inc viscosity of the cervical mucus- unfavorable for sperm penetration S/E- acne, hirsutism, amenorrhoea, depression, ectopic px, functional ovarian cyst
- 3rd gen- strong antiovul, dec antiandrogenic Disadv- DVT, brca, pul embolism, liv dis apart from other pop se
- estrogen and progesterone inhibit prolactin activity during pregnancy. After delivery of the placenta, when estrogen and progesterone levels markedly decrease, prolactin levels increase and milk production is initiated.[4] There is a theoretical concern that giving hormones before 6 weeks postpartum, or before breastfeeding is well established, could interfere with optimal lactation It is hypothesized that hormones ingested by the infant in breast milk may result in circulating levels that are higher than expected because of an immature liver that cannot metabolize the hormones, immature kidneys that may not be able to excrete the hormones, and a plasma-binding capacity that may be low, resulting in higher levels of free and biologically active hormones.
- Pearl Index is sometimes used as a statistical estimation of the number of unintended pregnancies in 100 woman-years of exposure (e.g. 100 women over one year of use, or 10 women over 10 years). It is also sometimes used to compare birth control methods, a lower Pearl index representing a lower chance of getting unintentionally pregnant. S/E:
- Spray delivers drug NES in skin with the aid of safe enhancers forms reservoir in skin Australian biotech company Acrux has come up 3×90μl of with a world’s first — a contraceptive spray for women.
- Amines; Antibacterials; Antivirals; Small molecules; Spermicidal contraceptives; Unsaturated fatty acids Membrane lipid inhibitors Phase 3
- once-weekly prescription contraceptive patch.
- This T shape & device has a collar attached to vertical arm containing 52 mg of levonorgestrel dispersed in poly dimethyl siloxane.
- Combined injectable contraceptives (CICs) also known as Lunelle, Cyclofemina, Feminena, Novafem, Lunella, and Cyclo-Provera).
- silicone elastomer ring with 2 cores. It is left in place for 21 days and removed for seven days, for up to 13 cycles (one-year).
- SC implant: 100-600 mg MENT has been shown to be more potent than testosterone and to be resistant to 5α-reduction.
- Apply to the back, abdomen, thighs, upper arms as directed. Efficacy, safety, acceptibility??
- Testosterone buccal systems only work when applied to the upper gum. Although the systems look like tablets, you should not chew or swallow them. Testosterone buccal systems will soften and mold to the shape of your gum and will gradually release medication. However, they will not dissolve completely in your mouth and must be removed after 12 hours. You may brush your teeth; use mouthwash; use tobacco products; chew gum; eat; and drink alcoholic or nonalcoholic beverages while you are wearing a testosterone buccal system. However, these activities may cause the system to fall off your gum. After you are finished the activity, check
- Can target either sperm production (testicular targets) or sperm motility Theoretically, agents targeted to these processes might be very specific, thus lacking the systemic side effects that plague hormonal method
- weakens the adhesion between the Sertoli cell and maturing sperm leading to a sloughing and loss of the latter. The oral dose effective for contraception is so high that there have been side effects in the muscles and liver properties that inhibit cancer growth by targeting mitochondria and blocking energy metabolism in certain kinds of tumor cells in mice,
- Vitamin A (dietary retinol) is essential for normal spermatogenesis. Defects in spermatogenesis (as a result of RARa knock-out) include. Preclinical phase
- Indenopyridines(CDB4022) with GNRH antagonist preclinical some studies have demonstrated irreversible testicular effects in rodents • longer-term studies in nonhuman primates will likely be necessary before testing in humans
- Fluid passes and sperm traps have similar side effects to vasectomy, such as formation of sperm antibodies, Often used by men in China as a potential alternative to vasectomy The polymer is injected directly into the vasa differentia, Once injected, the polymer solidifies in place, forming a flexible plug
- by coating the inner walls of the vas deferens with the polymer chemical Preclinical and clinical studies have failed to demonstrate reversibility
- Sperm rely on ca for motility and fertilization Blocking catsper – effective birth control Early Development
- may be an attractive addition to the currently available range of family planning methods in that they would:
- PH-20, a sperm surface protein shown to give 100% effective contraception in animal model (guinea pig) (mice and rats ~ 55%, rabbits ~ 70%, and baboons ~ 30%)
- the jelly-like glycoprotein coat surrounding the egg No convincing data have been presented to indicate that it can inhibit fertility without causing an inflammatory reaction in the ovary
- Hcg- acts as a support/ maintains/ fortify the fetus – if we withdraw hcg- fetus/ conceptus dies
- The hormonal approach to male contraception has made significant progress in the last decade in terms of clinical development Unfortunately, over the last few yr, the major pharmaceutical sponsors of male hormonal contraceptive research have withdrawn their support in this area of product development, making it difficult to complete the final phases of clinical development