2. CONTENTS :
Introduction
Need For Anti Fertility Agents
A Brief History
An Ideal Contraceptive Agent
Classification
Hormonal Anti Fertilty Agents :
◦ Female Contraceptive Agents.
◦ Male Contraceptive Agents.
Future Research
Bibliography
3. INTRODUCTION :
Drugs which used
for preventing fertilization
are called as anti fertility
agents.
These are also known as
contraceptive agents and
hence the method of
preventing normal process
of ovulation, fertilization
and ovum implantation
nothing but pregnancy is
known as contraception or
Birth control, also fertility
control.
4. NEED FOR ANTI FERTILITY AGENTS :
To bring down population growth as
mortality rate has declined and birth
rate has increased.
To reduce infant and maternal mortality
rate.
To prevent pregnancies that are too
early, too frequent and too many
5. A BRIEF HISTORY :
IMP. POINTS :-
In 1937, Makepeace and colleagues demonstrated that pure progesterone
blocked ovulation in rabbits, and Astwood and Fevold found a similar
effect in rats in 1939.
In the 1950s, Pincus, Garcia, and Rock found that progesterone and 19-
norprogestins prevented ovulation in women.
Source : en.wikipedia.org
6. One of the compounds used was norethynodrel, and early batches
of this compound were contaminated with a small amount of
mestranol(in figure).
Source :- sigmaldrich.com
When mestranol was removed, it was noted that treatment with
pure norethynodrel led to increased breakthrough bleeding and less-
consistent inhibition of ovulation.
Mestranol was thus reincorporated into the preparation, and this
combination was employed in the first large-scale clinical trial of
combination oral contraceptives.
7. TO BE CONTINUED :
Clinical studies in the 1950s in Puerto Rico and Haiti established the
virtually complete contraceptive success of the norethynodrel
/mestranol combination.
In early 1961, Enovid (norethynodrel plus mestranol; no longer
marketed in the U.S.) was the first “Pill” approved by the FDA for
use as a contraceptive agent in the U.S.;
this was followed in 1962 by approval for Ortho-Novum
(norethindrone plus mestranol).
By 1966, numerous preparations using either mestranol or ethinyl
estradiol with a 19-norprogestin were available.
In the 1960s, the progestin-only minipill and long-acting injectable
preparations were developed and introduced.
A variety of contraceptive formulations are currently available,
including pills, injections, skin patches, subdermal implants, vaginal
rings, and IUDs that release hormones.
8. CHARACTERISTICS OF IDEAL CONTRACEPTIVE
:-
Ideal
Contracep
tive
100%
effective
Acceptable
Inexpensive
Safe
Requires
minimal
motivation,
supervision &
maintenance.
Simple to
use
Totally
reversible
10. HORMONAL ANTI FERTILTY AGENTS
These are hormonal preparations used for reversible suppression
of fertility.
Female Contraceptive Agents
Over 100 million women worldwide are currently using hormonal
contraceptives.
With these drugs, fertility can be suppressed at will, for as long as
desired, with almost 100% confidence and complete return of
fertility on discontinuation.
The efficacy, convenience, low cost and overall safety of oral
contraceptives (OCs) has allowed women to decide if and when they
will become pregnant and to plan their activities.
A variety of oral and parenteral preparations are now available
offering individual choices.
12. ORAL CONTRACEPTIVES :
01) COMBINED ORAL CONTRACEPTIVES :
The most frequently used agents are combination oral contraceptives
containing both an estrogen and a progestin.
variety of formulations and strengths.
Almost all contain ethinyl estradiol as the estrogen and a 17α-alkyl-
19-nortestosterone derivative as the progestin.
theoretical efficacy generally is considered to be 99.9%.
The combination agents are further divided into
Monophasic forms (constant dosage of both components during the
cycle)
Biphasic or Triphasic forms (dosage of one or both components
is changed once or twice during the cycle).
13. MECHANISM OF ACTION :
Combination oral contraceptives act by preventing ovulation.
Direct measurements of plasma hormone levels indicate that
LH and FSH levels are suppressed,
a midcycle surge of LH is absent,
endogenous steroid levels are diminished,
and ovulation does not occur.
Although either component alone can be shown to exert these
effects in certain situations, the combination synergistically
decreases plasma gonadotropin levels and suppresses ovulation more
consistently than either alone.
14.
15. OTHER EFFECTS MAY CONTRIBUTE TO A MINOR
EXTENT TO THE EXTRAORDINARY EFFICACY OF
ORAL CONTRACEPTIVES.
Source :- slideshare.net
16. TIMING OF INITIATION OF COC’S :
One tablet is taken daily for
21 days, starting on the 5th day
of menstruation. The next course
is started after a gap of 7 days in
which bleeding occurs known
as “pill free period”. Thus, a
cycle of 28 days is maintained.
Calendar packs of pills are
available. This is the most
popular and most efficacious
method.
Most branded preparations
provide a packet of 21 tablets
only, others provide a packet of
21+7 extra pills, which either
contain lactose or some iron
preparations.
17. TYPES :
A)MONOPHASIC PILLS :
SAME / CONSTANT AMOUNT OF ESTROGEN & PROGESTIN IN EACH
PILL IN ONE PACKET
SOME POPULAR COMBINATIONS :
18. B) PHASED PILLS :
BIPHASIC PILLS : THEY DELIVER THE SAME AMOUNT OF ESTROGEN
EACH DAY BUT LEVEL OF PROGESTIN IS INCREASED ABOUT HALFWAY
THROUGH CYCLE
19. TRIPHASIC PILLS :
CONTAIN HIGH DOSE OF ESTROGEN IN MIDCYCLE WITH INCREASING DOSES
OF PROGESTIN GIVEN OVER 3 SUCCESSIVE PHASES.
20. ADVERSE EFFECTS :
They may be Mild, Moderate or Severe.
Mild Adverse Effects include:
Estrogenic side effects :-
- Nausea , breast tenderness, breakthrough bleeding
- Headache: Often mild and transient
- Worsening of Migraine
21. Progestogenic side effects :-
- Increase in appetite
- hirsutism
- decrease in libido
- increase of body
temperature
- weight gain
- acne
22. MODERATE ADVERSE EFFECTS :
May require discontinuation of therapy
Estrogenic side effects :-
- vertigo
- leg and uterine cramps
- precipitation of diabetes
Progestogenic effects :-
- Breakthrough bleeding but not with phased regimens.
- Vaginal infections
- Amenorrhea.
Following cessation of administration of oral contraceptives,
24. TO BE CONTINUED :
- GI side effects :
Cholestatic jaundice
Hepatic adenomas
- Depression
- Others :- In addition to the
above effects, a number of other
adverse reactions have been
reported for which a causal
relation has not been established.
These include alopecia,
erythema multiforme, erythema
nodosum, and other skin
disorders.
25. CONTRAINDICATIONS :
The combined oral contraceptive pill is absolutely contraindicated
in:
1. Thromboembolic, coronary and cerebrovascular disease or a
history of it.
2. Moderate-to-severe hypertension;
3. Active liver disease, hepatoma or h/o jaundice during past
pregnancy.
4. Suspected/overt malignancy of genitals/breast.
5. Porphyria.
6. Impending major surgery—to avoid postoperative
thromboembolism.
26. RELATIVE CONTRAINDICATIONS
(requiring avoidance/cautious use under supervision)
1. Diabetes: control may be vitiated.
2. Obesity
3. Smoking
4. Undiagnosed vaginal bleeding
5. Uterine leiomyoma: may enlarge with estrogenic preparations;
progestin only pills can be used.
6. Mentally ill (OC’s decreases epileptic threshold )
7. Age above 35 years
8. Mild hypertension
9. Migraine
10. Gallbladder disease
27. 02) MINIPILLS
It has been devised to eliminate the estrogen, because many of
the long-term risks have been ascribed to this component.
A low-dose progestin only pill is taken daily continuously without
any gap.
The menstrual cycle tends to become irregular and ovulation occurs
in 20–30% women, but other mechanisms contribute to the
contraceptive action.
The efficacy is lower (96–98%) compared to 98–99.9% with
combined pill—look for pregnancy if amenorrhoea of more than 2
months occurs.
This method is less popular.
28. MECHANISM OF ACTION :
Their effectiveness is thought to be due largely to a
Thinning of the endometrial lining that impair implantation
Thickening of the cervical mucus, which decreases sperm
penetration
Slowing ovum transport
Adverse Effects :
The most frequently encountered untoward effect and the major
reason women discontinue use of all types of progestin-only
contraceptives are :-
Episodes of irregular, unpredictable spotting and
breakthrough bleeding
29. 03) EMERGENCY /POSTCOITAL PILL :
Postcoital (or emergency) contraception is indicated for use in cases
of mechanical failure of barrier devices or in circumstances of
unprotected intercourse (Cheng et al., 2008).
Mechanism of Action :-
The mechanisms of action of the postcoital contraceptives are not
fully understood, but their efficacy clearly cannot be accounted for
solely by the inhibition of ovulation.
Other potential mechanisms of action include effects on gamete
function and survival and on implantation. These agents do not
affect established pregnancies.
30. CURRENTLY 3 REGIMENS ARE AVAILABLE :
(a) Levonorgestrel 0.5 mg +
ethinylestradiol 0.1 mg (2
OVRAL tablets) taken as early
as possible but within 72 hours
of unprotected intercourse and
repeated after 12 hours.
Till recently, this regimen
called the ‘Yuzpe method’ has
been the most popular.
It is estimated to prevent 3 out
of 4 possible pregnancies, but
nearly 50% women experience
nausea and 20% vomit.
Source :- mypregnancysolutions.com
31. (b) Mifepristone 600
mg single dose taken
within 72 hours of
intercourse has been used
in China,Europe and few
other countries with high
success and fewer side
effects than Yuzpe
method. Source :-www.zizhu-pharm.com
32. TO BE CONTINUED :
(c) Levonorgestrel alone 0.75 mg
taken twice with 12 hour gap
within 72 hours of intercourse.
Trials conducted globally by the
WHO found this regimen to be
2–3 times more effective and
better tolerated.
Incidence of vomiting is only 6%
and other side effects are also less
The WHO essential drug list
(2001) recommended
replacement of Yuzpe method by
this regimen.
EC2, Pill 72, E-Pill, Norlevo, i
pill (available in India)
Source :- indiamart.com
33.
34. TO BE CONTINUED :
Recently approved in 2010,
ULIPRISTALACETATE
(SPRM) in a single oral dose
of 30mg is more effective if
taken in 120hrs/5days.
If these measures fail,
pregnancy should be
terminated to avoid teratogenic
deformities of fetus.
Source :- indiamart.com
35. 04)CENTCHROMAN (ORMELOXIFENE)
non steroidal contraceptive or
SERM developed at
CDRI,under the brand name
SAHELI.
30 mg of centchroman in each
tablet.
Failure rate of 1–3% has been
recorded.
36. MECHANISM OF ACTION :-
Centchroman is a potent competitive agonist at peripheral estrogen
receptors and suppresses proliferative stage of endometrium.
It also accelerates ovum transport, without affecting ovulation.
Summarily, it desynchronises the event of ovum transport with
endometrial phases of development.
Time of initiation of centchroman :
Unlike hormonal OCs which are taken daily for 21 days followed
by 7 days of pill-free period, centchroman is taken twice in a week
for first three months and then once a week subsequently to be
continued irrespective of the following menstrual cycles, as long as
contraception is desired.
37. TO BE CONTINUED :
The first tablet should be taken on the first day of menstrual cycle
(e.g., Sunday).
Then, the second tablet should be taken on 4th day of the cycle (i.e.,
Wednesday).
Subsequent tablets are to be taken on every Sunday and Wednesday
for first 3 months, followed by once a week on the same day every
week, i.e. Sunday or Wednesday as the case may be.
The missed tablet should be taken as soon as possible and the
normal schedule should then be adhered to.
If the dose is missed by 2 to 7 days, the normal dose schedule is
maintained, but mechanical barrier contraception (e.g. condoms) are
used as preventive measure additionally, till the next menstrual
period.
If the dose is missed for more than 7 days, reinitiate the biweekly
schedule for 3 months and weekly schedule thereafter.
38. TO BE CONTINUED :
Contraceptive effect of centchroman is readily reversible
within 6 months and subsequent pregnancy is normal).
Newborns present normal milestones and have no congenital
abnormalities.
If pregnancy occurs, the treatment should be discontinued and
pregnancy should follow the natural course as there is no risk
of teratogenesis with centchroman.
Adverse Effects :
Occasionally, the menstrual cycle is likely to be prolonged in
about 8% of the users which is of no consequence if tablets
have not been missed.
39. TO BE CONTINUED :
Contraindications :
Contraindications for the use of centchroman are:
- jaundice or hepatic dysfunction - polycystic ovarian disease，
-cervical hyperplasia - tuberculosis renal disease
- hypersensitivity
40. INTERACTIONS OF OC’S :
Contraceptive failure may occur if the following drugs are used
concurrently:
(a) Enzyme inducers: phenytoin, phenobarbitone,primidone,
carbamazepine, rifampin. Metabolism of estrogenic as well as
progestational component is increased.
(b) Suppression of intestinal microflora: tetracyclines, ampicillin,
etc. which may cause problems "by impairing the bacterial
flora responsible for recycling ethinylestradiol from the large
bowel"
With both types of interacting drugs, it is wise to switch over to a
preparation containing 50–80 μg of ethinylestradiol or to use
alternative method of contraception.
41. NON CONTRACEPTIVE BENEFITS OF COC’S :
Improvement in menstrual abnormalities
Protection against cancer:
Endometrial and Ovarian cancer: reduces risk by 40%
Protection against health diseases:
Pelvic Inflammatory Disease
Endometriosis
Fibroid Uterus
Benign breast diseases
Ovarian cyst
42. PARENTERAL CONTRACEPTIVES :
1) INJECTABLES :
These have been developed to obviate need
for daily ingestion of pills.
They are given i.m. as oily solution;
are highly effective;
over 50 million women have used them so
far.
Two types of preparations have been tested:
(i) Long acting progestin alone—injected
once in 2–3 months depending on the
steroid and its amount. Two compounds
have been marketed:
(a) Depot medroxyprogesterone acetate
(DMPA)
(b) Norethindrone (Norethisterone)
enanthate (NEE)
43. TO BE CONTINUED :
It is useful in patients where compliance is a problem or in patients
having heavy menstrual bleeding or in those for whom estrogens are
contraindicated e.g” those suffering from migraine
thromboembolism, oedema, hypertension or diabetes.
Mode of action is same as for minipills.
Side effects include irregular bleeding ending up in amenorrhoea
and anovulation, osteoporosis may occur on prolonged use as Gn
suppression may cause low estrogen levels.
There may be weight gain and increased risk of breast cancer.
If pregnancy occurs, it should be terminated to avoid the risk of
congenital deformities.
45. TO BE CONTINUED :
(ii) Long acting progestin + long acting estrogen —Combined
estrogen-progestin injectable contraceptives:
The most widely used formulation “Number 1” developed in
China. This estradiol valerate 5 mg + 17-hydroxy progesterone
caproate 250 mg to be given IM every month,
The other combination contains estradiol cypionate 5 mg +
DMPA 25 mg to be given intramuscularly once in 2 months.
The advantages of such long-acting injectable contraceptives
are that they provide a single defined and predictable bleeding
every month and have high contraceptive efficacy.
The mechanism of action and side effects resemble
combination pills.
46. 2) IMPLANTS
These are drug delivery systems implanted
under the skin, from which the steroid is
released slowly over a period of 1–5 years.
They consist of either—
(a) Biodegradable polymeric matrices—do
not need to be removed on expiry.
(b) Non-biodegradable rubber
membranes—have to be removed on
expiry.
The contraceptive implant is a small
flexible plastic rod that's placed under
the skin in your upper arm by a doctor or
nurse.
It releases the hormone progestogen into
your bloodstream to prevent pregnancy
and lasts for 3 years.
47. AT A GLANCE: THE IMPLANT
The implant is more than 99% effective.
It can be useful for women who can't use contraception that contains
oestrogen.
It's very useful for women who find it difficult to remember to take a
pill at the same time every day.
The implant can be taken out if side effects occur.
It can removed at any time and natural fertility will return very
quickly.
When it's first put in, some bruising, tenderness or swelling may
occur around the implant.
Periods may become irregular, lighter, heavier or longer.
A common side effect is that amenorrhoea.
49. 03)TRANSDERMAL PATCH :
A contraceptive patch, also known
as "the patch", is a transdermal
patch applied to the skin that
release synthetic estrogen
and progestin hormones to
prevent pregnancy.
They have been shown to be as
effective as the combined oral
contracepive pill with perfect use,
and the patch may be more
effective in typical use.
The only currently available
contraceptive patches are Xulane
(after Ortho Evra)) and Evra
Sites of application :
Buttocks, Upper outer arm, Lower
abdomen, back, upper torso.
50. METHOD OF USE :
A CONTRACEPTIVE PATCH CYCLE CONSISTS OF THREE
PATCHES OVER 21 DAYS FOLLOWED BY 7 PATCH-FREE DAYS.
EACH PATCH IS APPLIED ON THE SAME DAY OF THE WEEK
AND IS WORN FOR 7 FULL DAYS.
51. ADVERSE EFFECTS :
The most frequent adverse events reported while using the Ortho
Evra / Evra patch were:
breast discomfort, engorgement or pain (22%),
headache (21%),
application site reaction (17%),
nausea (17%),
upper respiratory tract infection (10%),
menstrual cramps (10%), and
abdominal pain (9%).
Breakthrough bleeding is also reported.
52. 03)DEVICES :
01 ) INTRAUTERINE INSERTS:
A relatively new intrauterine
contraceptive device releases
levonorgestrel at a rate of 20 mcg per
day into the uterine cavity for a
period of 5 years.
The progestin preparation acts locally
on the endometrium and hence
systemic side effects are minimal.
The return of fertility is immediate
after removal.
53. COMPLICATIONS
Intrauterine devices are generally well tolerated, although
complications related to the device and side effects related to the
progestin can occur.
Expulsion
Uterine Perforation
Irregular bleeding
Pelvic infections
Ectopic pregnancy
Pain
Pregnancy: Failure rate in 1st year- 3%
55. 02)VAGINAL RINGS :
The contraceptive vaginal ring is
a flexible transparent plastic ring.
Its placed in the vagina where it
releases two hormones – estrogen
and progestogen.
The first vaginal contraceptive
ring 'NuvaRing’was approved by
FDA in 2001 & marketed in
2002.
Releases 15ug EE & 120ug
etonogestrel over 24hrs
Used for 21 days followed by 7
day hormone- free interval
completely inhibits ovulation.
ADRs
Vaginitis, Leucorrhoea, Headache
,Expulsion.
56. MALE ANTI FERTILITY AGENTS :
Despite improvement in modern female contraceptive
methods and the ability to rapidly introduce new effective
methods to developing countries, there are unmet needs for
family planning in women 15 to 49 years. Achieving the
desired number of children is beneficial to women, families,
and society.
In order to meet the unmet need for women, countries
need to make available modern contraceptives, provide high
quality services, and improve access to such services. In
addition, development of new methods of contraception
involving men should be a priority.
57. The only way to suppress male fertility by drugs is to inhibit
spermatogenesis. Though considerable effort has been made in this
direction and effective drugs have been found, no satisfactory/
acceptable solution is yet tangible. Reasons are—
1. Complete suppression of spermatogenesis is relatively difficult
without affecting other tissues: millions of spermatozoa are released
at each ejaculation vs a single ovum per month in women.
2. Spermatogenesis takes 64 days. A drug which even completely
inhibited spermatogenesis will take a long latent period to produce
infertility. Similarly, return of fertility will be slow.
3. Gonadotropin suppression inhibits testosterone secretion as well,
resulting in loss of libido and impotence: unacceptable to all men
and to most spouses.
4. Risk of adverse effects.
5. Most importantly—men don’t get pregnant: few would be ready to
bear the contingency of regular medication so that their sexual
partners do not become pregnant.
58. DRUGS AND APPROACHES TRIED ARE—
1. Antiandrogens Act by direct action on testes; cause unacceptable
loss of libido.
2. Estrogens and progestins Act by suppressing Gns— cause
unacceptable feminization.
3. Androgens They inhibit Gns but have poor efficacy; combination
with progestin is more efficacious, preserves libido, but is still not
reliable.
4. Superactive Gn RH analogues They inhibit Gn release after
continued action; also inhibit testosterone secretion— produce
impotence, loss of libido.
5. Cytotoxic drugs Cadmium, nitrofurans and indoles suppress
spermatogenesis, but are toxic, often produce irreversible action.
59. TO BE CONTINUED :
06) Gossypol :- It is a no nsteroidal compound, obtained from cotton
seed; has been studied in China.
It is effective orally
causes suppression of spermatogenesis in 99% men and
reduces sperm motility.
Infertility develops after a couple of months; fertility is restored
several months after discontinuation. However, about 10% men
remain oligozoospermic for long periods after discontinuation.
During treatment serum LH and testosterone levels do not change:
libido and potency are not affected.
It has no hormonal or antihormonal activity.
Mechanism of action is uncertain
60. TO BE CONTINUED :
Suggested dose is 20 mg/day for 2–3 months, followed by 40–60
mg/week.
Most important adverse effect is hypokalaemia (due to renal loss of
K+) with its attendant muscular weakness (even paralysis).
Other side effects are—edema, diarrhoea, breathlessness and
neuritis.
63. FUTURE RESEARCH
Research has been focussing on the non-hormonal aspects of
contraception.
Contraceptive vaccines provide a real opportunity for effective
contraception.
hCG vaccines are of great interest as they are formed by early
embryos, not the pregnant female hence providing the least
side effects when inhibited.
They are the first CV to pass Phase I and II trials successfully.
An immunological approach to contraception remains an
innovative idea and has been proven effective in both
experimental and clinical trials. If ongoing trials remain
successful, CV will mark another progress in the field of mass
contraception and its implementation would hopefully reduce
the current prevalence of unintended pregnancies.
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Goodman & Gillman’s - The pharmacological basis of Therapeutics,
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Essentials of Medical Pharmacology, Sixth Edition By KD
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Basic & Clinical Pharmacology, 14th Edition By Bertram G.
Katzung, Page no. 732-737.
Principles of Pharmacolgy, 3rd Edition By H L Sharma and K K
Sharma,Page no. 590-594.
Review Article - Anti-Fertility Agents- Estrogens By Revathi B1*
and Prashanth K2.
Family planning : A Global Handbook For Providers Available
at :- www.fphandbook.org / comparing tables.
65. Anti fertility agents – Intro and history NCBI
https://www.ncbi.nlm.nih.gov/pubmed/4584283.
Review Article - Transdermal contraception methods: today's
patches and new options on the horizon, By Nelson AL.
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Contraceptive Implants Available at :
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“International Journal of Gynecology & Obstetrics India”.
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Narayanan
66. Review Article The science,medicine and future of
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Available at :-
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