HORMONAL

CONTRACEPTIVE
Anggelia Puspasari
Pharmacology and Theraupetic Dept.
Medical faculty
University of Jambi
Introduction
Estrogensand progestins are endogenous hormones that
produce numerous physiological actions.

Women: developmental effects, neuroendocrine actions involved

in the control of ovulation, the cyclical preparation of the
reproductive tract for fertilization and implantation, and major
actions on mineral, carbohydrate, protein, and lipid metabolism.
Males: effects on bone, spermatogenesis, and behavior.

The most common uses of these agents are menopausal

hormone therapy and contraception in women, but the specific
compounds and dosages used in these two settings differ
substantially.
Estrogens
The most potent naturally occurring estrogen in humans, for both ER a- and b-mediated
actions, is 17b-estradiol, followed by estrone and estriol.

Nonsteroidalcompounds with estrogenic or antiestrogenic activity including flavones,

isoflavones (e.g., genistein), and coumestan derivatives occur in plants and fungi.

Theovaries are the principal source of circulating estrogen in premenopausal women, with
estradiol being the main secretory product.

In
postmenopausal women, the principal source of circulating estrogen is estrone
synthesized from dehydroepiandrosterone secreted by the adrenals.

Inmen, estrogens are produced by the testes, but extragonadal production by aromatization
of circulating C19 steroids (e.g.,androstenedione and dehydroepiandrosterone) accounts for
most circulating estrogens.

Theplacenta uses fetal dehydroepiandrosterone and its 16a-hydroxyl derivative to produce

large amounts of estrone and estriol. Human urine during pregnancy is thus an abundant
source of natural estrogens.

Thus, the level of estrogens is regulated in part by the availability of androgenic precursors
Estrogens
Gonadotropins, acting via receptors that couple to the G s-adenylyl
cyclase-cyclic AMP pathway, increase the activities of aromatase and
the cholesterol side-chain cleavage enzyme and facilitate the transport
of cholesterol (the precursor of all steroids) into the mitochondria of
cells that synthesize steroids.

The ovary contains a form of 17b-hydroxysteroid dehydrogenase (type

I) that favors the production of testosterone and estradiol from
androstenedione and estrone, respectively.

However, in the liver, another form of this enzyme (type II) favors
oxidation of circulating estradiol to estrone , and both of these steroids
are then converted to estriol. All three of these estrogens are excreted
in the urine along with their glucuronide and sulfate conjugates.
Estrogen
Estrogen
Estrogen
Estrogens are largely responsible for pubertal
changes in girls and secondary sexual
characteristics.
In boys, estrogen deficiency diminishes the
pubertal growth spurt and delays skeletal
maturation and epiphyseal closure so that linear
growth continues into adulthood. Estrogen
deficiency in men leads to elevated gonadotropins,
macroorchidism, and increased testosterone levels
and also may affect carbohydrate and lipid
metabolism and fertility in some individuals.
Estrogen
Estrogens and progesterone have important effects on the fallopian
tube, myometrium, and cervix.
In the fallopian tube, estrogens stimulate proliferation and
differentiation, whereas progesterone inhibits these processes.
Estrogens increase and progesterone decreases tubal muscular
contractility, which affects transit time of the ovum to the uterus.
Estrogens increase the amount of cervical mucus and its water content
to facilitate sperm penetration of the cervix, whereas progesterone
generally has opposite effects.
Estrogens favor rhythmic contractions of the uterine myometrium,
while progesterone diminishes contractions.

These effects are physiologically important and may also play a role in
the action of some contraceptives.
Estrogen
The effects of estrogens on selected aspects of mineral,
lipid, carbohydrate, and protein metabolism are
particularly important for understanding their
pharmacological actions.

Estrogens directly regulate osteoblasts and increase the

synthesis of type I collagen, osteocalcin, osteopontin,
osteonectin, alkaline phosphatase, and other markers of
differentiated osteoblasts. Estrogens also increase osteocyte
survival by inhibiting apoptosis. Major effect of estrogens is
to decrease the number and activity of osteoclasts.

Estrogens affect bone growth and epiphyseal closure in

both sexes.
Estrogen
Estrogens slightly elevate serum triglycerides and slightly reduce
total serum cholesterol levels. More important, they increase HDL
levels and decrease the levels of LDL and Lp(a).
Estrogens also alter bile composition by increasing cholesterol
secretion and decreasing bile acid secretion. This leads to increased
saturation of bile with cholesterol and appears to be the basis for
increased gallstone formation in some women receiving estrogens.
Estrogen alone slightly decreases fasting levels of glucose and
insulin but does not have major effects on carbohydrate
metabolism.
Estrogens affect many serum proteins, particularly those involved in
hormone binding and clotting cascades.
Estrogens cause a small increase in coagulation factors II, VII, IX, X,
and XII, and decrease the anticoagulation factors protein C, protein
S, and antithrombin III and decreased levels of plasminogen-
activator inhibitor protein-1 (PAI-1).
Estrogen for menopouse management
Preparation available
Estrogen for menopouse management
Estrogen for menopouse management
Estrogen for menopouse management
Estrogen contraceptive
Estrogen contraceptive
Estrogen

Estrogens also undergo enterohepatic recirculation via (1) sulfate

and glucuronide conjugation in the liver, (2) biliary secretion of
the conjugates into the intestine, and (3) hydrolysis in the gut
(largely by bacterial enzymes) followed by reabsorption.
Many other drugs and environmental agents (e.g., cigarette
smoke) act as inducers or inhibitors of the various enzymes that
metabolize estrogens, and thus have the potential to alter their
clearance.
Ethinyl estradiol is cleared much more slowly than is estradiol
due to decreased hepatic metabolism, and the elimination-phase
half-life in various studies ranges from 13 to 27 hours.
Mestranol, another semisynthetic estrogen and a component of
some combination oral contraceptives, is the 3-methyl ether of
ethinyl estradiol. In the body it undergoes rapid hepatic
demethylation to ethinyl estradiol, which is its active form.
Estrogen

Major concerns about the use of estrogens remain today,

especially regarding cancer, thromboembolic disease,
increased risk of cardiovascular disease, altered cognition,
changes in carbohydrate and lipid metabolism,
hypertension, gallbladder disease, nausea, migraine,
changes in mood, and several lesser side effects.
Nausea and vomiting are an initial reaction to estrogen
therapy in some women, but these effects may disappear
with time and may be minimized by taking estrogens with
food or just prior to sleeping. Fullness and tenderness of the
breasts and edema may occur but sometimes can be
diminished by lowering the dose. A more serious concern is
that estrogens may cause severe migraine in some women.
Estrogens also may reactivate or exacerbate endometriosis
Estrogen
Menopausal Hormone Therapy. The established benefits of estrogen
therapy in postmenopausal women include amelioration of vasomotor
symptoms and the prevention of bone fractures and urogenital atrophy
Vasomotor Symptoms. The characteristic hot flashes may alternate with
chilly sensations, inappropriate sweating, and (less commonly) paresthesias.
Treatment with estrogen is specific and is the most efficacious
pharmacotherapy for these symptoms
Osteoporosis is an indication for estrogen therapy, which clearly is
efficacious in decreasing the incidence of fractures. However, because of the
risks associated with estrogen use, first-line use of other drugs should be
carefully considered
Vaginal Dryness and Urogenital Atrophy. Loss of tissue lining the vagina
or bladder leads to a variety of symptoms in many postmenopausal women
Cardiovascular Disease. The incidence of cardiovascular disease is low in
premenopausal women, rising rapidly after menopause, and epidemiological
studies consistently showed an association between estrogen use and reduced
cardiovascular disease in postmenopausal women. estrogens produce a
favorable lipoprotein profile, promote vasodilation, inhibit the response to
vascular injury, and reduce atherosclerosis
SERMs: Tamoxifen, Raloxifene, and Toremifene.
Selective estrogen receptor modulators, or SERMs, are
compounds with tissue-selective actions. The pharmacological
goal of these drugs is to produce beneficial estrogenic actions
in certain tissues (e.g., bone, brain, and liver) during
postmenopausal hormone therapy, but antagonist activity in
tissues such as breast and endometrium, where estrogenic
actions (e.g., carcinogenesis) might be deleterious.
Currently approved drugs in the United States in this class are
tamoxifen citrate (NOLVADEX, OTHERS), raloxifene
hydrochloride (EVISTA), and toremifene (FARESTON), which is
chemically related and has similar actions to tamoxifen.
Tamoxifen and toremifene are used for treatment of breast
cancer, and raloxifene is used primarily for prevention and
treatment of osteoporosis.
Anti-Estrogens: Clomiphene and Fulvestrant.
These compounds are distinguished from the
SERMs in that they are pure antagonists in all
tissues studied. Clomiphene (CLOMID,
SEROPHENE, others) is approved for the treatment
of infertility in anovulatory women, and fulvestrant
(FASLODEX, ICI 182,780) is used for the treatment
of breast cancer in women with disease
progression after tamoxifen.
Progesterone

Compounds with biological

activities similar to those of
progesterone have been variously
referred to in the literature as
progestins, progestational agents,
progestagens, progestogens,
gestagens, or gestogens.
Medroxyprogesterone acetate
(MPA) and megestrol acetate are
C21 steroids with selective activity
very similar to that of
progesterone itself.
The gonanes are a more recently
developed series of "19-nor"
compounds, containing an ethyl
rather than a methyl substituent
in the 13-position, and they have
diminished androgenic activity.
Progesterone
Progesterone
Neuroendocrine Actions. As discussed previously, progesterone produced in
the luteal phase of the cycle has several physiological effects including
decreasing the frequency of GnRH pulses, which is the major mechanism of
action of progestin-containing contraceptives.
Reproductive Tract.
Progesterone decreases estrogen-driven endometrial proliferation and leads to
the development of a secretory endometrium and the abrupt decline in
progesterone at the end of the cycle is the main determinant of the onset of
menstruation. Progesterone also influences the endocervical glands, and the
abundant watery secretion of the estrogen-stimulated structures is changed to a
scant, viscid material.
Progesterone is very important for the maintenance of pregnancy. Progesterone
suppresses menstruation and uterine contractility, but other effects also may be
important. These effects to maintain pregnancy led to the historical use of
progestins to prevent threatened abortion. However, such treatment is of
questionable benefit, probably because spontaneous abortion infrequently results
from diminished progesterone. Based on a recent report that premature labor in
high-risk mothers was diminished by weekly intramuscular administration of 17-
hydroxyprogesterone (DELALUTIN), this indication is being re-evaluated
Progesterone
Mamamary gland. Development of the mammary gland requires both estrogen and
progesterone. During pregnancy and to a minor degree during the luteal phase of the
cycle, progesterone, acting with estrogen, brings about a proliferation of the acini of
the mammary gland. Toward the end of pregnancy, the acini fill with secretions and
the vasculature of the gland notably increases; however, only after the levels of
estrogen and progesterone decrease at parturition does lactation begin.

CNS Effects. During a normal menstrual cycle, an increase in basal body

temperature of about 0.6C (1F) may be noted at mid-cycle; this correlates with
ovulation. This increase is due to progesterone, but the exact mechanism of this
effect is unknown. Progesterone also increases the ventilatory response of the
respiratory centers to carbon dioxide and leads to reduced arterial and alveolar PCO 2
in the luteal phase of the menstrual cycle and during pregnancy. Progesterone also
may have depressant and hypnotic actions in the CNS, possibly accounting for reports
of drowsiness after hormone administration. This potential untoward effect may be
abrogated by giving progesterone preparations at bedtime, which may even help
some patients sleep.

Progesterone
Metabolic Effects.
Progesterone itself increases basal insulin levels and the rise in insulin after
carbohydrate ingestion, but it does not normally alter glucose tolerance.
However, long-term administration of more potent progestins, such as
norgestrel, may decrease glucose tolerance.
Progesterone stimulates lipoprotein lipase activity and seems to enhance fat
deposition.
Progesterone and analogs such as MPA have been reported to increase LDL and
cause either no effects or modest reductions in serum HDL levels. The 19-
norprogestins may have more pronounced effects on plasma lipids because of
their androgenic activity. In this regard, a large prospective study has shown
that MPA decreases the favorable HDL increase caused by conjugated
estrogens during postmenopausal hormone replacement, but does not
significantly affect the beneficial effect of estrogens to lower LDL. In contrast,
micronized progesterone does not significantly affect beneficial estrogen effects
on either HDL or LDL profiles Progesterone also may diminish the effects of
aldosterone in the renal tubule and cause a decrease in sodium reabsorption
that may increase mineralocorticoid secretion from the adrenal cortex.
Progesterone
Progesterone undergoes rapid first-pass metabolism
Progesterone is bound by albumin and corticosteroid-binding globulin, but is not
appreciably bound to SHBG. 19-Nor compounds, such as norethindrone, norgestrel,
and desogestrel, bind to SHBG and albumin, and esters such as MPA bind primarily
to albumin. Total binding of all these synthetic compounds to plasma proteins is
extensive, 90% or more, but the proteins involved are compound-specific.
The elimination half-life of progesterone is approximately 5 minutes, and the
hormone is metabolized primarily in the liver to hydroxylated metabolites and their
sulfate and glucuronide conjugates, which are eliminated in the urine.
A major metabolite specific for progesterone is pregnane-3a, 20a-diol; its
measurement in urine and plasma is used as an index of endogenous progesterone
secretion.
The synthetic progestins have much longer half-lives, e.g., approximately 7 hours for
norethindrone, 16 hours for norgestrel, 12 hours for gestodene, and 24 hours for
MPA. The metabolism of synthetic progestins is thought to be primarily hepatic, and
elimination is generally via the urine as conjugates and various polar metabolites,
although their metabolism is not as clearly defined as that of progesterone.
Progesterone
The two most frequent uses of progestins are for contraception,
either alone or with an estrogen, and in combination with
estrogen for hormone therapy of postmenopausal women.

Progestins also are used for secondary amenorrhea, abnormal

uterine bleeding in patients without underlying organic
pathology (e.g., fibroids or cancer), luteal-phase support to treat
infertility, and premature labor.

Progesterone can be used diagnostically to test for estrogen

secretion and for responsiveness of the endometrium. After
administration of progesterone to amenorrheic women for 5 to 7
days, withdrawal bleeding will occur if the endometrium has
been stimulated by endogenous estrogens.
Hormonal contraceptive
Combination Oral Contraceptives.
Ethinyl estradiol and mestranol are the two estrogens used (with ethinyl
estradiol being much more frequently used); several progestins currently
are used, with levonorgestrel probably being the most common
worldwide. The progestins are 19-nor compounds in the estrane or
gonane series, and each has varying degrees of androgenic, estrogenic,
and anti-estrogenic activities that may be responsible for some of their
side effects. Compounds such as desogestrel and norgestimate are the
most recently developed and have less androgenic activity than other
19-nor compounds.
Monophasic, biphasic, or triphasic pills are generally provided in 21-day
packs.
Preparations containing 35 mg or less of an estrogen are generally
referred to as "low-dose" or "modern" pills. Progesterone dose 0.4 to 1
mg of norethindrone, 0.1 to 0.15 mg of levonorgestrel, 0.3 to 0.5 mg of
norgestrel, 1 mg of ethynodiol diacetate, 0.25 mg of norgestimate, and
0.15 mg of desogestrel, with slightly different dose ranges in biphasic
and triphasic preparations.
Hormonal contraceptive
Hormonal contraceptive
Progestine only contraceptive
Specific preparations include the "minipill"; low doses of progestins
(e.g., 350 mg of norethindrone [NOR-QD, MICRONOR] or 75 mg of
norgestrel [OVRETTE]) taken daily without interruption; subdermal
implants of 216 mg of norgestrel (NORPLANT II, JADELLE) for slow
release and resultant long-term contraceptive action (e.g., up to 5
years); and crystalline suspensions of medroxyprogesterone
acetate (DEPO-PROVERA) for intramuscular injection of 150 mg of
drug, which provides effective contraception for 3 months.
An intrauterine device (PROGESTASERT) that releases low amounts
of progesterone locally is available for insertion on a yearly basis.
Its effectiveness is considered to be 97% to 98%, and
contraceptive action probably is due to local effects on the
endometrium. Another intrauterine device (MIRENA) releases
levonorgestrel for up to 5 years. It inhibits ovulation in some
women but is thought to act primarily by producing local effects.
Hormonal contraceptive
Progestin-only pills provide an oral alternative for lactating women,
as progestins, unlike combination products, have not been shown
to decrease milk production.
POPs are also good options for women with contraindications or
intolerance to estrogen-containing contraceptives and for women
who would like to become pregnant in the near future, as
progestin-only pills do not stop ovulation.
Strict adherence to timing of daily dosing is necessary with
progestin-only pills due to the decreased effect of the progestin on
the cervical mucosa 22 hours after the dose is taken. A dose that
is three hours late is considered missed and should be taken as
soon as it is remembered. Literature suggests using alternative
means of contraception for two days following late or missed
doses. POPs should be taken continuously with no pill-free interval.
POPs associated with a greater degree of irregular bleeding.
Hormonal contraceptive
Postcoital or Emergency Contraceptives
"minipill" (0.75 mg levonorgestrel per pill)
separated by 12 hours. PREVEN is two 2-pill doses
of a high-dose oral contraceptive (0.25 mg of
levonorgestrel and 0.05 mg of ethinyl estradiol per
pill) separated by 12 hours. This is sometimes
referred to as the "Yuzpe" method.
The first dose of such preparations should be taken
anytime within 72 hours after intercourse, and this
should be followed 12 hours later by a second dose.
This treatment reduces the risk of pregnancy
following unprotected intercourse by approximately
60% for the Yuzpe method and 80% for
levonorgestrel alone.