DR. PRIYANKA KUMAWAT

Pharamcology deptt.

PGIMS, Rohtak

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 2/5th 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◦ 3,90,000 fewer children who would lose their

mothers.

Unawareness Use of traditional methods Side effects High cost Difficult mode of delivery Fear of irreversibility of fertility Length of effctiveness(inconvenience to take pills

daily) Fear of problems associated with amenorroea

Slow the pace of population growth Slow the pace of population growth Decrease abortion related complications and

deaths Cut down maternal care costs Promote better maternal health Improve the health of children through

provision of better nutrition and other care

……..beneficial to the society at large!!! Po

TEMPORARY METHODS

All hormonal birth contol measures act via same mechanism

Stops ovulation Prevents uterus lining from build up Making the cervical mucous thick to prevent

penetration of sperm

Monophasic pills Biphasic pills Triphasic pills Progesterone only pills

Type Estrogen Progestin

Mala N EE 30 ug Norgestrel 300 ug

Mala D EE 30 ug Levonorgestrel 150 ug

Ovral L EE 30 ug Levonorgestrel 150 ug

Ovral G EE 50 ug Levonorgestrel 250 ug

Novelon EE 30 ug Desogestrel 150 ug

Femilon EE 20 ug Desogestrel 150 ug

Loette EE 20 ug Levonorgestrel 100 ug

Yasmin EE 30 ug Drospirenone 3 mg

Yaz EE 20 ug Drospirenone 3 mg

Comparable in efficacy to monophasic pillsComparable in efficacy to monophasic pills It was introduced with an aim of reducing the total It was introduced with an aim of reducing the total

dose of hormones per cycle and to ↓ BTB.dose of hormones per cycle and to ↓ BTB. Better carbohydrate and lipid profile.Better carbohydrate and lipid profile.

Type Estrogen Progesterone

Triphasic-

Triquilar

EE – 30 ug (D1-6)

EE – 40 ug (D7-11)

EE – 30 ug (D12-21)

Levonorgestrel 50 ug

Levonorgestrel 75 ug

Levonorgestrel 125 ug

Reducing the dose to the lowest possible without reducing efficacy (10 fold reduction)

Norethisterone 350μg Norgestrel 75μg Levonorgestrel(LNG) 30μg

Dosing shedule- Started on 5th day of menstruation normally 21 day of post partum period Soon after abortion Extra precaution for 2 days to be taken

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 strokeS/E- depression,irregular

bleeding,headache,migraine,weight gain,ectopic pregnancy.

1. Intermenstrual spotting2. Amenorrhoea3. Lactation suppression4. Decreased libido5. Nausea,vomiting6. Liver adenomas7. Gall stones8. Carbohydrate intolerance9. Abnormal lipid profile10. Headache,depression,irritability,lethargy11. Weight gain12. Vascular thromboembolism

Estrogen-estradiol valarate along with newer progestin (dienogest-DNG) is used.

Step down doses of estrogen and step up doses of progestin preperation is used.

ADV- -fewer spotting days,reduction in mean blood loss -reduced breakthrough bleeding -more increase in HDL(8%) -stability in carbohydrate metabolism -effective in treatment of heavy mensrrual bleeding -significant improvement in Hb,hematocrit,ferritin

levels

COMPOUND

DAYS ESTROGEN PRODESTERONE

E2V-DNG 1-2 3mg 2mg

3-7 2mg 2mg

8-24 2mg 3mg

25-26 1mg 3mg

SEASONALE- 150µg of LNG + 30µg of

EE Taken continuously for 84

days, break for 7 days Fewer periods (4 in a

year) Pearl index- 0.78 Breakthrough bleeding/

spotting – First few cycles

CONTINUOUS- For 365 days No break 0.09mg LNG+20μg EE Less side effects

associated with hormone withdrawl

Diminished breakthrough bleeding after 8-9 months

Decreased incidence of: 1. Pelvic pain, 2. Headaches, 3. Bloating/swelling, and 4. Breast tenderness for women who experience

these symptoms during the pill-free interval; Improved control over symptoms of

endometriosis and polycystic ovary syndrome; and

Greater convenience due to fewer withdrawal bleeds per year.

Include little information on :

1. Long-term safety (although there are long-term data for comparable total estrogen- progestin doses per month)

1. Slightly higher cost for medications (an extra 3 pill packages per year for a 91-day cycle).

These potential disadvantages must be weighed against the likely reduction in the:

1. Cost of sanitary supplies 2. Pain medication 3. Time off work or school 4. More breakthrough bleeding initially 5. Possible delay in the recognition of pregnancy

aa

Carcinoma endometrium – protective !!!◦ Use of COC for 12 months: 50% risk reduction◦ Protection persists 20 yrs after discontinuation

Epithelial ovarian cancers – protective !!!◦ Even 3-6 months use: 40% risk reduction (3 yr use-

notable impact, 10 yr use- 80% risk reduction)◦ protection continues 20 yrs after stopping.

Colon & rectal carcinoma-protective!!! - risk reduction by 37%!!! Indirectly prevents choriocarcinoma by preventing

pregnancy Carcinoma liver-no association!!!

Carcinoma cervix – no definite association !!!◦ Detection bias due to increased screening with pap smear◦ No significant increased risk of invasive carcinoma cervix

Carcinoma breast – controversial, caution !!!◦ Current use: ↑early premenopausal ca breast, detection

bias.◦ Past use: ↓ incidence metastatic postmenopausal ca breast◦ Known case of ca breast: COCs are C/I◦ BRCA1BRCA1 & & BRCA2BRCA2 carrierscarriers –50% 50% risk reduction for ca ovary vary

(baseline risk (baseline risk 45% & 25% in BRCA1BRCA1 & & BRCA2BRCA2 respectively)

Clear the confusion !!! Cancers and COCs

Cycle-related:◦ Irregular cycles, dysmenorrhea, menorrhagia

&anemia◦ Functional ovarian cysts

Prevention of: ◦ Bone loss◦ Fibrocystic/benign breast disease◦ Pelvic inflammatory disease (PID), Ectopic pregnancy

Treatment of:◦ Acne, Hirsuitism ◦ Perimenopausal symptoms

Should include the following:1.Instructions on how to take the combined OC2.Information on potential side-effects3.Non-contraceptive benefits of the combined OC4.Addressing common myths and misconceptions5.Discussing risks and warning signs, including

when to seek medical care6.Discussing what to do if pills are missed7.Emphasizing dual protection (the combined OC

with condom use to prevent STIs and HIV infection)

8.Information about emergency contraception in the event of missed pills

Progestin-only injectables:◦ Depot-medroxyprogesterone acetate (DMPA;

“Depo-provera”; Megestron® 150 mg given IM every three months also SQ formulation, lower dose (104 mg); CBD …

◦ NET-EN: norethindrone (or norethisterone) enanthate, Noristerat®) given every two months

Combined injectable contraceptives (CICs, progestin plus estrogen) — given monthly: ◦ Cyclofem® (MPA, 25mg plus estradiol, 5 mg) ◦ Mesigyna® (50 mg Norethindrone enanthate,

plus 5 m.g. estradiol)

Depo in Uniject

effectiveness-0.1-0.4 preg/HWY reversibility- 6 WKS Injectable sustained released preperation of DMPA

available as uniject Inhibits Ovulation,follicular formation,thicken

cervical mucous 150 mg ,in 3months (14 day grace period) Delayed Ovulation After Discontinuation Main Side-Effects:

◦ Amenorrhea◦ AUB◦ Weight Gain◦ Hair Loss

most suitable for women that require an estrogen free birth control method:◦ women with a known sensitivity (allergic) to

estrogen◦ women over the age of 35 years who smoke◦ women with migraine headaches◦ women who are breastfeeding◦ women who have endometriosis◦ women who have sickle cell disease◦ women taking anti-convulsant (for seizures)

medication

Reliable method of birth control. Reduced risk of endometrial cancer and

Pelvic Inflammatory Disease (PID). Reduced symptoms of endometriosis,

PMS and chronic pelvic pain, Decreased incidence of seizures. Possible decreased number of sickle cell

crisis. Periods may disappear after 9 to 12

months on Depo-Provera. Only need to get injection every 12

weeks.

Contraceptive patch(orth evra) Transdermal gel Transdermal spray

Effectiveness-0.8-1.3 preg/HWY28 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

ADVOnce a week dosing ,good complianceAvoid first pass metabolismProgestin with minimal androgenicity

DISADVPatch is noticebleHigh costMinor skin reactionRoom temperature storage is necessory

Nestorone(NES) a progestin is used Applied in dose 2.3 mg/day once for 21

days with 7 free days Antiovulatory mechanismAdv- -no skin irritation -regular bleeding pattern maintained -No serious adverse events

MDTS-metered dose transdermal system Spray delivers drug in skin with the aid of

safe enhancers forms reservoir in skin drug slowly absorbed in the circulation over

a period of hours Antiovulatory mechanism 3×90μl of NES(norethisterone) daily once

application

S/E- bruising at the site,breast tenderness,tearfullness,tiredness,headaches,dizziness,vagueness.

Norplant®

6 capsules Effective 7 yrs 1-yr failure:

0.05%(1 in 20,000); 5-yr. failure 1.6%

Reg. approval in 62 countries

Insertion time: 4.3 min (0.8-18.0)

Removal time: 10.2 min (1.3-50m)

Cost: $27

Jadelle ®

2 rods Effective 5 years 1-yr failure:

0.05% (1 in 20,000); 5-yr failure 1.1%

Regulatory approval in 11 countries

Insertion time: 2 min

Removal time:4.9 min ± 3.5 minutes

Cost: $29

[Sinoplan: $5]

Implanon®

1 rod Effective 3 years Regulatory approval in in 25 countries Insertion time: 1.1 min (0.03-5.0) Removal time:2.6 min (0.2 – 20.0) Cost: comparable; AID RFA out now

Effectiveness- 92-97% Failure rate- 1.2-1.5 preg/HWY 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

C31G Glyminox 1% Gel(savvy) 50-60% effective 1.2-1.5 preg/HWY Vaginal

microbicide(carrageenan,betacyclodextrin) contraceptive along with spermicidal agent(nonoxynol-9)

Applied 15 minutes prior to intercourse Prevent from sexually transmitted diseasesMOA- -boost bodies natural defense against infection -damage and disable disease pathogen -entry and fusion inhibitors -replication inhibitorsADV- -women can control theselves its use -No serious side effects

Failure rate-0.1-2.5 IUD impregnated with SPRM(selective

progesterone receptor modulator)-ulipristil Act by suppression of ovulation,endometrial

atrophy

ESSURE- a spring like device plugged into fallopian tube

QUINARINE- a chemical compound gel like introduced

The ADINA procedure- a plastic implant is inserted into a lesion in fallopion tube and tissue grows into it and plug the tube

Currently available methods

- Condoms - Gossypol- vasectomy

Suppression of gonadotropin releasing hormone from the hypothalamus and the gonadotropins, LH and FSH, from the pituitary gland.

-Decreased LH-decreased testosterone production from Leydig cells, low intratesticular testosterone level, decreased Sertoli cell function and suppression of spermatogenesis

-Decreased FSH results in Sertoli cell dysfunction and impaired spermatogenesis ,

Decreased in spermatozoa production occurs via: -Decreased proliferation of spermatogonia -accelerated germ cell apoptosis -defective spermiation

HORMONAL APPROACHES-

Testosterone enanthate,testosterone undecanoate wkly injections

testosterone + progestin -TE gel + inj DMPA -TE inj/wk + LNG oral daily -TU inj/8wk + LNG implant -TE pellet(implant) +DMPA GNRH antagonist s.c/day + TE inj/wk S/E- weight gain,HDL suppression,prostatic

hypertrophy SARM-MENT(7α methyl-19-norgesterone) implants -10 fold greater potency than testosterone - additional 5α reductase inhibition

property(minimize prostatic problems)

NON HORMONAL o Target sertoli cell-Indenopyridines(CDB4022)

with GNRH antagonisto Spermatid sertoli cell interaction-Adjudino HE6 epididymal duct specific protein receptoro CRISP-1 preventing initiation of capacitation

during sperm transit and maturationo Catspers –allow Ca++ entry in sperm tailo CAMP-necessory for capacitationo IZUMO-sperm specific membrane protein

responsible for sperm egg fusion

RISUG- a clear gel injected in vas blocks it IVD-intra vas devices

Safe, effective and acceptable contraceptive vaccines may be an attractive addition to the currently available range of family planning methods in that they would:

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.

ANTI-SPERM VACCINES

-Research has focused on two types of sperm antigens:

Functional antigens as the enzymes known to be required for sperm metabolism (lactic dehydrogenase-X) , involved in sperm-egg interactions and the processes leading to fertilization (acrosin and hyaluronidase).

Structural antigens such as the molecules expressed on the sperm cell membrane and which may be involved in gamete interaction and fusion.

ANTI-OVUM VACCINES

antigen-focused on the surface antigen zona pellucida (ZP), the jelly-like glycoprotein coat surrounding the egg.

To date, however, no convincing data have been presented to indicate that it can inhibit fertility without causing an inflammatory reaction in the ovary which might be indicative of a risk of acute ovarian disturbances or long-term immunopathology.

ANTI-CONCEPTUS VACCINES

placenta-specific antigens structural antigens, forming 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.

Another placental antigen PP-5,when animal is actively immunized with human PP-5 and a substantial reduction in fertility was shown.

functional antigens, such as placental hormones, have been evaluated.

HORMONAL PLACENTAL ANTIGENS

human chorionic gonadotrophin (hCG)-production or function of hCG can be inhibited immunologically, the corpus luteum would regress

One type of anti-hCG vaccine, 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) (21,22). The other type of anti-hCG vaccine, developed with support from the WHO Task Force on Vaccines for Fertility Regulation, is based on a portion (the carboxyterminal peptide or CTP) 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.

Endocr Rev. 2008 June; 29(4): 465–493.doi:  10.1210/er.2007-0041

Contraception. 2010 November ; 82(5): 471–475. doi:10.1016/j.contraception.2010.03.010

Home |2008 Archive |July 2008 |Barbieri 93 (7): 2439

Special Programme of Research, Development and Research Training in Human Reproduction,World Health Organization, 1211 Geneva 27, Switzerland

Expert opinion,Emerging Drugs(2011)16(2):373-387

Shaw’s textbook of Gynaecology