adrew2).pdf

Hormonal
Contraceptives
Presenter-
Dr Nikita Ingale,
JR2
Pharmacology GMCH Nagpur
Guide-
Dr Vijay Motghare
Professor and Head
Pharmacology, GMCH Nagpur

2
Hormonal contraceptives
- As per the Census 2011 Population of India - 1,220,200,000 (1210 million)
- In 2015 population of India – 1311 million ,the second most populous country in the world
- Extremely rapid growth in the last 50 years ( 1901- 238.4 million & in 2011- 1210 million)
- The phenomenal growth is now more appropriately termed as “population explosion”.
Population explosion

3
History of contraception
- Condoms are named after Dr Condum, who started the act to stop illegal Offsprings
[condus – receptacle]
- Pebbles were inserted in the uteri of camels to prevent
pregnancies during long journies in the desert by arabs and turks
- Intrauterine devices were introduced in germany by
Ernst Grafenberg made up of silkworm gut and silver wire
- Rock and Pincus ( 1955) announced the successful use of an oral progestin for contraception

4
Contraception
- By definition, preventive methods to help women avoid unwanted
pregnancies.
- They include all temporary and permanent measures to prevent
pregnancy resulting from coitus.
- Cafeteria approach- method which may be suitable for one group may be unsuitable for another because of
different cultural patterns, religious beliefs and socio-economic milieu.
- offer all methods from which an individual can choose according to his needs and wishes and to promote
family planning as a way of life.

5
Ideal Contraception
- Should be safe
- Effective
- Acceptable
- Reversible
- Simple to administer
- Long lasting enough to obviate frequent administration
- Require no medical supervision
- Affordable

6
Contraceptive methods
Spacing methods Terminal methods
Barrier methods
Intrauterine devices
Post conceptional pills
Miscellaneous
Male sterilization
Female sterilization
- Male and female condoms
- Diaphragms
- Vaginal sponges
- Foams
- Creams, jellies, pastes
- Pessary

8
Intrauterine devices
IUDs inhibit pregnancy, primarily via a spermicidal effect caused by a sterile inflammatory reaction
induced by the presence of a foreign body in the uterine cavity (copper IUDs) or by the release of
progestins (Progestasert, Mirena).
1st generation 3rd generation
2nd generation
- This comprise the inert or non- medicated devices,
usually made of polyethylene, or other polymers.
- Appear in different shapes and sizes loops, spirals, coils,
rings, and bows.
- Lippes Loop is the best known
- metallic copper had a strong anti-fertility effect
- The addition of copper has made it possible to develop
smaller devices which are easier to fit, even in
nulliparous women.

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3rd generation IUD
- The most widely used hormonal device is Progestasert, which is a T-shaped device filled with 38 mg of
progesterone, the natural hormone.
- The hormone is released slowly in the uterus at the rate of 65 mcg daily and should be replaced every year
- It has a direct local effect on the uterine lining, on the cervial mucus and on the sperms. Because the hormone
supply is gradually depleted, regular replacement of the device is necessary.

10
3rd generation IUD
- Another hormonal device LNG-20 (Mirena) is a T-shaped IUD releasing 20 mcg of levonorgestrel (a potent
synthetic steroid)
- It has a low pregnancy rate (0.2 per 100 women) and less number of ectopic pregnancies.
- Long-term clinical experience with levonorgestrel releasing IUD is associated with lower menstrual blood loss
and fewer days of bleeding than the copper devices. The levonorgestrel releasing IUD has an effective life of 10
years

11
3rd generation IUD
Mirena –
T shaped IU device
Effective for 7-10 years.
• ↑ viscosity of cervical mucus prevent sperm from entering the cervix & the endometrium unfavorable to
implantation..
• ↓menstrual blood loss & fewer days of bleeding than Cu devices.

12
Oral
Hormonal
contraceptives

13
- Hormonal contraceptives when properly used are the most effective spacing methods of contraception.
- Oral contraceptives of the combined type are almost 100 per cent effective in preventing pregnancy.
- More than 65 million in the world are estimated to be taking the "pill" of which about 9.52 million are estimated
to be in India.
- It was soon discovered that addition of a small quantity of an estrogen enhanced their efficacy; combined pills
have become the most popular method of contraception, because the hormone content of the pills has been
reduced, minimizing the potential harm and affording other health benefits.

14
Menstrual cycle and mechanism of birth control pills

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Oestrogen
Natural
Oestradiol,
Oestrone,
Oestriol
Oestrogen
Semi-synthetic
Ethinyl estradiol
Synthetic
Steroid:
Mestranol
Non-Steroid:
Diethylstilbesterol(oral)
Dienestrol
Hexestrol (topical)

16
Progesterone derivatives: 19- nortestosterone:
1]Older 1]
Medroxyprogesterone acetate
Dydrogesterone (Duphaston)
Hydroxyprogesterone Caproate/ Acetate
Megestrol
2]Newer: 2]Newer:
Nomegestrol Desogestrel
Norgestimate
Gestodene
Older
Lynestrenol
Levonorgestrel
Allylestrenol
Norethindrone (Norethisterone)
Norethynodrel
Progestins
Androgenic
Antiovulatory

P
Oral Parenteral
Injection
DMPA
NET-EN
Implants
- Norplant
Combined estrogen and
progestin preparation
- Monophasic
- Biphasic
- Triphasic
Progestin – only pill
(Minipill)
- Norethindrone
- Norgestrol
Postcoital
contraceptives
(emergency
contraception)
- Levonorgestrol
- Ulipristal
- Mifepristone
17

18
Combined pills
- The combined pill is one of the major spacing methods of contraception.
- The "original pill" which entered into the market in the early 1960s contained 100-200 mcg of a
synthetic oestrogen and 10 mg of a progestogen.
- Since then, a number of improvements have been made to reduce the undesirable side-effects of
the pill by reducing the dose of both the oestrogen and progestogen.
- At the present time, most formulations of the combined pill contain no more than 30-35 mcg of
a synthetic oestrogen, and 0.5 to 1.0 mg of a progestogen.

19
Combined pills
- Ethinylestradiol 30 μg daily is considered threshold but can be reduced to 20 microgm/day if
progestin with potent antiovulatory action is included.
- The progestin is a 19-nortestosterone because these compounds have potent antiovulatory
action.
- Used alone the ovulation inhibitory dose (per day) of the currently used progestins is estimated
to be- levonorgestrel 60 μg, dcsogestrel 60 μg, norgestimate 200 μg. gestodene 40 μg
- While both estrogens and progestins synergise to inhibit ovulation, the progestin ensures prompt
bleeding at the end of a cycle and blocks the risk of developing endometrial carcinoma due to
the estrogen.

20
Combined pills
- 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. Thus , a cycle of 28 days is maintained.
Calendar packs of pills are available This is the most popular and most efficacious method.
Schedule for use of combined pill
Menstrual cycle
1st day
(day 1 of
bleeding)
1 tablet orally
daily for 21
consecutive days
from 5th day
28th day
Repeat the
course till
required
Efficacy: 99.99%
21st day
Gap of
7 days

21
Combined oc pills

22
Missed combined oc pills….???
Missed COC pill
Less than 12 hours elapsed
Take missed pill and continue regime as
normal.
More than 12 hours elapsed
Where in pill cycle?
1 pill missed from a pack in the cycle
Continue COC
2 or more pills missed at any time in the
cycle
course should be interrupted, alternative
method of contraception used and next
course started on the 5th day or bleeding.

23
Phased pills
- Triphasic regimens have been introduced to permit reduction in total steroid dose without
compromising efficacy by mimicking the normal hormonal pattern in a menstrual cycle.
- The estrogen dose is kept constant (or varied slightly between 30-40 μg), while the amount of
progestin is low in the first phase and progressively higher in the second and third phases.
- Phasic pills are particularly recommended for women over 35 years of age and for those with no
withdrawal bleeding or breakthrough bleeding while on monophasic pill
- No A/E on carbohydrate & lipid metabolism, hence can be given in diabetes.
- Biphasic pills: Eg: Nelova 10/11.
- Triphasic pills: Eg: Orthonovum 7/7/7

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Biphasic pills
Days EE LNG
5th -14th (10) 35 µg 0.05 mg
15th-25th (11) 35 µg 1 mg
• During the first half of the cycle, the progestin/estrogen ratio is lower to allow the endometrium to thicken
as it normally does.
• During the second half of the cycle, the progestin/estrogen ratio is higher to allow for the normal
shedding of the lining of the uterus.
High failure rates
NOT AVAILABLE IN INDIA

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Triphasic pills
Pills Days EE LNG
Red (6) 5th -10th 30 µg 50 µg
White (5) 11th-15th 40 µg 75 µg
Yellow(10) 16th-25th 30 µg 125 µg
Green (7) Inert ingredients
ORTHO NOVUM 7/7/7
Pills Days EE NED*
White 6 5th -10th 35 µg 50 µg
Light Peach 5 11th-15th 35 µg 75 µg
Peach 10 16th-25th 35 µg 100µg
*NED-norethindrone
TRIQUILAR TABLETS

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Phased pills

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Progestin only pills/ mini pills
- 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 an alternative for women in whom an estrogen is contraindicated.They
could be prescribed to older women for whom the combined pill is contraindicated because of cardiovascular
risks. They may also be considered in young women with risk factors for neoplasia
- It is taken daily continuously without any gap.
- The menstrual cycle tends to become irregular and ovulation occurs in 20-30% women
- The efficacy is lower (95- 96%) . Pregnancy should be suspected if amenorrhoea of more than 2 months
occurs.
- The progestogen-only pills never gained widespread use because of poor cycle
control and an increased pregnancy rate
OC PILLS = 99.99%
IUCD= 99.2%

28
Schedule for use of minipills
Menstrual cycle
1st day 1 tablet daily orally without a break 28th day
Continue the
course without a
gap till required
Efficacy: 96%
Minipill (progestin – only pill)
Oestrogen
(mcg)
Progestin (mg)
- Micronor - Norethindrone (0.35)
- Norgest - Norgestrol (0.075)

29
Progestin only pills/ mini pills
Advantages:
• Lack of estrogen induced side effects.
• Older (>40years) women with
cardiovascular risk factors.
• Can be used in patients with
Hypertension, Diabetes , Epilepsy, smoking
Disadvantages:
• Less effective than combined pills
• Irregular bleeding, short bleeding intervals,
spotting & amenorrhoea in 20-30% cases.
• Headache, acne, hirsutism.
• Less reliable than Combined Oral
Contraceptives. Delay even by 3 hours renders no
protection.

30
Progestin only pills

31
Postcoital pills/ emergency pills
- These are for use in a woman not taking any contraceptive who had a sexual intercourse risking
unwanted pregnancy.
The most commonly used and standard regimen is-
- Levonorgestrel 0.75 mg two doses 12 hours apart, or 1.5 mg single dose taken as soon as possible,
but before 72 hours of unprotected intercourse.
- This regimen to be 2-3 times more effective and better tolerated than the earlier 'Yuzpe method'
which used levonorgestrel 0.5 mg + ethinylestradiol 0.1 mg, two doses at 12 hours interval within 72
hours of exposure.
- incidence of nausea and vomiting is 6% compared to 20-50% with the estrogen+progcstin regimen

32
Postcoital pills/ emergency pills
- Recently (2010), a Selective Progesterone Receptor Modulator ulipristal has been approved for
emergency contraception.
- Ulipristal 30 mg single dose as soon as possible, but within 120 hours of intercourse. It is an equally
effective (failure rate 1- 3% compared to levonorgestrel 2- 4%) and equally well tolerated alternative
method
- Another antiprogestin that has been used is- Mifepristone 600 mg single dose taken within 72 hours of intercourse.
- Emergency postcoital contraception should be reserved for unexpected or accidental
exposure (rape, condom rupture) only, because all emergency regimens have higher
failure rate and side effects than regular low-dose combined pill.

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Post coital pills

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Ormeloxifene / centchroman / saheli
- Non-hormonal Selective Estrogen Receptor Modulator.
- Developed at CDRI lucknow, introduced in National Family Welfare Programme
Actions –
- Weak estrogenicity (in bones)
- Potent anti-estrogenicity (uterus, breast)
- Devoid of progestogenic or androgenic activity
Sideeffects-
- return of fertility few months after stoppage.
- Failed to gain popularity for use as contraceptive.
- Side effects are nausea, headache,
Fluid retention, weight gain, rise in BP and prolongation of menstrual cycles

35
Injectable
Hormonal
contraceptives

36
Injectable contraceptives
Three compounds have been marketed:
(a) Depoemedroxyprogesterone acetate (DMPA)
-150mg at 3-month intervals.
-After i.m.injection peak blood levels are reached in 3 weeks and t1⁄2 -50days.
-DEPOT·PROVERA 150 mg in I ml , vial for deep i.m. injection during first 5 days of
menstrual cycle. Repeat every 3 months.
(b) Norethisterone enanthate (NEE)
-200 mg at 2-month intervals.
-NORISTERAT 200 mg in I ml vial for deep i.m. injection during first 5 days of menstrual
cycle. Repeat every 2 months.

37
C] DMPA-SC
- A new lower-dose formulation of DMPA, depo-subQ provera 104
is injected under the skin rather than in the muscle.
- It contains 104 mg of DMPA rather than the 150 mg in the intramuscular
formulation.
- Like the intramuscular formulation, DMPA-SC is given at 3-month intervals.
- DMPA-SC is just as effective as the formulation injected into the muscle, and the patterns of bleeding
changes and amount of weight gain are similar.
- Injections of DMPA-SC are given in the upper thigh or abdomen. DMP A-SC should not be injected
intramuscularly, and the intramuscular formulation should not be injected subcutaneously.

38
Advantages:
-Overcomes the inconvenience of daily administration.
-Good efficacy with pearl index 1.1
-Highly effective, reversible, long lasting effect.
Disadvantages:
-More than 65 % show regular menstruation and abnormal bleeding, amenorrhoea
-Prolonged infertility (6-30 months)
-Not suitable for lactating mothers.
-Bone mineral density may decrease.

40
Implants
- These are drug delivery systems implanted under the skin, from which the steroid is released
slowly over a period of 1-5 year,.
They consist of either-
(a) Biodegradable polymeric matrices-do not need to be removed on expiry.
(b) Nonbiodegradable rubber membranes-have to be removed on expiry.
1] NORPLANT

41
Implants
1] NORPLANT: A set of 6 capsules each containing 36 mg levonorgestrel (total 216 mg) for subcutaneous
implantation is available in some countries. but has been discontinued in the USA.
It works for up to 5 years.

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Transdermal
Patch
contraception

43
Transdermal patch
- A transdermal patch containing a progestin norelgestromin and ethinylestradiol for once weekly
application for 3 weeks followed by one week gap
- A transdermal patch (Estradiol-TTS) is available in 3 sizes, viz. 5, IO and 20 cm2 delivering
0.025 mg, 0.05 mg and 0.1 mg respectively in 24 hours for 3-4 days. The usual dose in
menopause is 0.05 mg/day which produces plasma estradiol levels seen in premenopausal
women in the early or mid follicular phase.
- Cyclic therapy (3 weeks on, I week off) with estradiol-TTS is advised with an oral progestin
added for the last 10-12 days. Beneficial effects of estradiol-TTS on menopausal symptoms,
bone density, vaginal epithelium and plasma Gn levels are comparable to those of oral therapy

44
Transdermal patch
Systemic side effects of estradiol-TTS-
- same as with oral estrogens, but are milder.
- Oral therapy delivers high dose of the hormone to the liver and increases synthesis of several
proteins which may have undesirable consequences. Estradiol-TTS avoids high hepatic delivery:
consequently plasma levels of clotting factors are not elevated- risk of thromboembolic phenomena is
low.
- Recently a combined estradiol 50 microg + norethisterone acctale 0.25 mg patch has become
available in some countries
- A gel formulation of estradiol for application over skin is also available. apply over the arms and
spread to cover a large area once daily  HRT.

46
- Vaginal rings containing levonorgestrel have been found
to be effective.
- The hormone is slowly absorbed through the vaginal mucosa, permitting most of it
to bypass the digestive system and liver, and allowing a potentially lower dose.
- The ring is worn in the vagina for 3 weeks of the cycle and removed for the fourth
week
Vaginal rings

47
Absolute Contraindications
- Thromboembolic diseases (past history)
- Cardiac disease
- Moderate to severe hypertension
- Active liver diseases or H/O jaundice
- Suspected/overt malignancy of breast & genitals
- hyperlipidemia
- Undiagnosed abnormal uterine bleeding

48
Relative contraindications
- Diabetes and obesity
- Smoking
- Mild hypertension
- Age> 40 years
- Chronic renal disease

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Failure?????
Contraceptive failure may occur if the following drugs are used concurrently:
(a) Enzyme inducers: phenytoin, phenobarbitonc, primidone,
carbamazepine, rifampin, ritonavir. Metabolism of estrogenic as
well as progestational component is increased.
(b) Suppression of intestinal microflora : tetracyclines,
ampicillin, etc.

50
Any side effects??
- Nausea/dizziness/vomiting
- Bleeding/spotting/ Amenorrhoea may occur
- Weight gain, acne & increased body hair
- Breast fullness or tenderness (mastalgia)
- Depression (mood change or loss of libido)
- Thromboembolic phenomenon
- Gall stones

51
Limitations??
- User-dependent (require continued motivation and daily use)
- Effectiveness may be lowered when certain drugs are taken
- Forgetfulness increases method failure
- Can delay return to fertility
- Re-supply must be readily and easily available
- Do not protect against STDs (e.g., HBV, HIV)

53
- The search for a male contraceptive began in 1950
- Most of the research is concentrated on interference with spermatogenesis. An ideal male contraceptive
would decrease sperm count while leaving testosterone at normal levels. But hormones that suppress
sperm production tend to lower testosterone and affect potency and libido.
A male pill made of gossypol - a derivative of cotton-seed oil.
- It is effective in producing azoospermia or severe oligospermia, but as many as 10 per cent of men may
be permanently azoospermic after taking it for 6 months.
- gossypol can be toxic. Animal studies show a narrow margin between effective and toxic doses.
Male contraception

54
SUMMARY

55
References
- Goodman, L., Gilman, A. and Brunton, LEllis R. Levin, Wendy S. Vitek, and Stephen R.
Hammes Goodman & Gilman's manual of pharmacology and therapeutics.13th edition.
Estrogens, Progestins, and the Female Reproductive Tract . New York: McGraw-Hill
Medical. P809-830
- Betram G. Katzung Anthony J.Trevor. George p chrousus. Gonadal Hormones and inhibitors.
Basic and Clinical Pharmacology 13th edition.New delhi, Mc Graw Hill Education
Edition;2015.p959-995
- K park. demography and family planning. Park’s Textbook of Preventive and Social
Medicine. 23rd edition. Jabalpur, Brij Mohan Bhanot; 2017.p486.
- Leveno KJ, Alexander JM, Bloom SL, Casey BM, Dashe JS., Roberts SW, et al., editors.
Williams manual of pregnancy. 23rd ed. New York: McGrawHill Medical; 2017

56
P
Next PG activity-
Dr Ashish Gupta
Journal reporting
08/01/19

58
Progesterone
Inhibition of ovulation by suppression of LH
 Counteract the adverse effects of estrogen on the endometrium
 Changes in cervical mucus (thick & viscid)
 Inhibition of sperm capacitation
 Hampered implantation by the production of decidualized endometrium & atrophic
glands

Oestrogen
Inhibition of ovulation by suppression of FSH
Alteration of secretions & cellular structure of endometrium
Better cycle control
Prevent breakthrough bleeding

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