Recent advances in

Dr. Siddhartha Dutta

contraception MAMC,
New Delhi
Introduction

Contraception types

Mechanism

Female contraception Outline

Male contraception

Immuno- contraception

Conclusion
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
 IDEAL CONTRACEPTIVE

Safe Effective Acceptable

Simple to
Inexpensive Reversible
administer

Long lasting to Requiring little

Independent
avoid frequent or no medical
of coitus
administration supervision
 Contraception
Female/ Male

Temporary Permanent

Vasectomy
Barrier Hormonal IUD
Tubectomy
 • Condoms
Barrier • Diaphragms
• Cervical cap

• OCP
Temporary Hormonal
• Implants
• Injectables
methods • Orthoevra patch
• Nuvaring

• Copper T
IUD • Progestrasert
• Lipple’s loop
 • All hormonal birth control
measures act via same
mechanism

• Stops ovulation
Hormonal
contraception • Prevents uterus lining from
build up

• Making the cervical mucous

thick to prevent penetration of
sperm
 Monophasic
Biphasic pills
pills
Oral
Contraceptives
Progesterone
Triphasic pills
only pills
Low dose pills
EE= 30-35μg
Monophasic pills Very low dose pills
EE= 15-25 μg
 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
 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

 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
ADVANTAGES-

• 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

DISADVANTAGES

• VTE ??
• Amenorrhea more common
 Extended cycle regimen
SEASONALE CONTINUOUS

• 150µg of LNG + 30µg of EE • For 365 days

• Taken continuously for 84 days, • No break
break for 7 days
• 0.09mg LNG+20μg EE
• Fewer periods (4 in a year)
• Diminished breakthrough
• Breakthrough bleeding/ spotting bleeding after 8-9 months
– First few cycles
Advantages of continuous use
Decreased 1. Pelvic pain
incidence 2. Headaches
of: 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

 • little information on :

• Long-term safety (although there

are long-term data for comparable
total estrogen- progestin doses per
Disadvantages
month)

• Slightly higher cost for medications

(an extra 3 pill packages per year
for a 91-day cycle
 Adverse effects of OCP
Mild Moderate Severe

• E-Nausea, • E- vertigo, leg & • E- TE, cholestatic

vomiting, breast uterine cramps, jaundice,
tenderness, mild ppt of DM cholelithiasis,
edema, migraine hepatic
adenoma
• P- increased • P- BTB, monilial
appetite, wt. vaginitis, • P- MI,
gain, acne, amenorrhea cerebrovascular
hirsutism, thrombosis
decrease in
libido, increased
body temp.
 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 Norethisterone
350μg
• Strict compliance(< 3 hrs window)
• 21 day of post partum period
• Soon after abortion PoP
• lactation
• Extra precaution for LNG
Norgestrel
2 days to be taken 75μg 30μg
 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 No androgenic No ectopic

not necessary S/E-Acne pregnancy

No altered Failure rate is

carb/lipid met low
Transdermal delivery

Contraceptive
patch(orthoevra)

Transdermal gel

Transdermal spray
 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

 • 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 Gel(Phase 3)

• Adv-
-No skin irritation
- Regular bleeding pattern
maintained
-No serious adverse event
• Metered Dose Transdermal System (MDTS) to administer a
Spray
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
 Vaginal contraception- Nuva ring

• Effectiveness- 92-97%

• NES 150μg + 15μg EE/day

• 21day/7 day

• ADV-
-reused for a year
-reduced cost DISADV-
-excellent bleeding control
-rapid return of fertility -feeling of ring on place
-no changes in weight -difficulty in remembering
to reinsert
 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
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)

 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
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

 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

Male
Hormonal
Contraception
Androgen formulations

Testosterone undecanoate

• Dose interval- Oral, twice daily

• Potential concern- Twice daily dosing, short and
variable duration

17α-Methyltestosterone

• Dose interval- Oral, daily

• Potential concern- Liver toxicity
 • 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.
Intramuscular
• 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
01 02
Testosterone Testosterone undecanoate
decanoate
• Dose interval- 8–12 wk
• Dose interval- 4–6 wk • Potential concern- Injections
• Potential concern- can be painful
Injections can be • Weight gain, a 9% increase in
painful, high peak hemoglobin, and a 14%
levels decrease in HDL
 Subcutaneous
Testosterone implants

• 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

MENT(7α-methyl-19-nortestosterone) implant

• Phase 2
• Dose interval- 6 months
• Surgical placement, poor sperm suppression, concern
regarding bone effects
 Transdermal

Testosterone Dihydrotestosterone
Testosterone gel
patch(non scrotal) gel

• Dose interval- daily • Dose interval- daily • Dose interval- daily

• Potential concern- • Potential concern- • Potential concern-

Poor efficacy, high Possibility of Poor efficacy
frequency of skin partner transfer,
irritation daily application
needed
 Testosterone buccal
system
• Buccal
• Manufactured under trade
name Straint

• Applied twice a day

• Dose interval- Daily

• S/E-allergic reaction , Liver

toxicity
Nonhormonal Methods
 Non hormonal

Analogue of lonidamine

Phase 2

Disrupt the interaction of spermatid-Sertoli cells

Adjudin 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

 Failure of
spermatids to align
and be released
Sperm production
into the lumen,
needs retinoic acid
and aberrant
orientation to the
RAR sertoli cells

Antagonist
1 week RAR 100% effective &
antagonist t/t– 3 reversible in
month block animal models
 Targets both sertoli cells and germ cell

Promising preclinical data for a potential

oral, non hormonal male contraceptive

MOA
Indenopyridine
• 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
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
 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

RISUG 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

 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
IMMUNO CONTRACEPTION
IMMUNO-CONTRACEPTION
 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
 Antigen-focused on the
surface antigen zona
pellucida

ANTI-OVUM
VACCINES Causes 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

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
 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
 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
THANK YOU