DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Progestin-Only Contraceptives. Several agents are
available for progestin-only contraception, with theoretical
efficacies of 99%. Specific preparations include
the “minipill”; low doses of progestins (e.g., 350 μg of
norethindrone [NOR-QD, ORTHO MICRONOR, others])
taken daily without interruption; subdermal implants
of 216 mg of norgestrel (NORPLANT II, JADELLE) for
long-term contraceptive action (e.g., up to 5 years) or
68 mg of etonogestrel (IMPLANON) for contraception
lasting 3 years; and crystalline suspensions of medroxyprogesterone
acetate for intramuscular injection of
104 mg (DEPO-SUBQ PROVERA 104) or 150 mg (DEPO-
PROVERA, others) of drug; each provides effective contraception
for 3 months.
An IUD (PROGESTASERT) that releases low amounts of progesterone
locally is available for insertion on a yearly basis. Its effectiveness
is considered to be 97-98%, and contraceptive action
probably is due to local effects on the endometrium. An 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.
Mechanism of Action
Combination Oral Contraceptives. Combination oral
contraceptives act by preventing ovulation (Lobo and
Stanczyk, 1994). Direct measurements of plasma hormone
levels indicate that LH and FSH levels are suppressed,
a mid-cycle 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.
Given the multiple actions of estrogens and progestins on
the hypothalamic-pituitary-ovarian axis during the menstrual cycle
and the extraordinary efficacy of these agents, several effects probably
contribute to the blockade of ovulation.
Hypothalamic actions of steroids play a major role in the
mechanism of oral contraceptive action. Progesterone diminishes the
frequency of GnRH pulses. Because the proper frequency of LH
pulses is essential for ovulation, this effect of progesterone likely
plays a major role in the contraceptive action of these agents. In
monkeys and women with normal menstrual cycles, estrogens do
not affect the frequency of the pulse generator. However, in the prolonged
absence of a menstrual cycle (e.g., in ovariectomized monkeys
and postmenopausal women; Hotchkiss and Knobil, 1994),
estrogens markedly diminish pulse-generator frequency, and progesterone
enhances this effect. In theory, this hypothalamic effect of
estrogens could come into play when oral contraceptives are used
for extended time periods.
Multiple pituitary effects of both estrogen and progestin
components are thus likely to contribute to oral contraceptive
action. Oral contraceptives seem likely to decrease pituitary responsiveness
to GnRH. Estrogens also suppress FSH release from the
pituitary during the follicular phase of the menstrual cycle, and this
effect seems likely to contribute to the lack of follicular development
in oral contraceptive users. The progestin component may also
inhibit the estrogen-induced LH surge at mid-cycle. Other effects
may contribute to a minor extent to the extraordinary efficacy of
oral contraceptives. Transit of sperm, the egg, and fertilized ovum
are important to establish pregnancy, and steroids are likely to affect
transport in the fallopian tube. In the cervix, progestin effects also
are likely to produce a thick viscous mucus to reduce sperm penetration
and in the endometrium to produce a state that is not receptive
to implantation. However, it is difficult to assess quantitatively
the contributions of these effects because the drugs block ovulation
so effectively.
Progestin-Only Contraceptives. Progestin-only pills and
levonorgestrel implants are highly efficacious but block
ovulation in only 60-80% of cycles. Their effectiveness
is thus thought to be due largely to a thickening of cervical
mucus, which decreases sperm penetration, and
to endometrial alterations that impair implantation;
such local effects account for the efficacy of IUDs that
release progestins. Depot injections of MPA are thought
to exert similar effects, but they also yield plasma levels
of drug high enough to prevent ovulation in virtually
all patients, presumably by decreasing the frequency of
GnRH pulses.
Untoward Effects
Combination Oral Contraceptives. Shortly after the
introduction of oral contraceptives, reports of adverse
side effects associated with their use began to appear.
Many of the side effects were found to be dose dependent,
and this led to the development of current low-dose
preparations. Untoward effects of early hormonal contraceptives
fell into several major categories: adverse
cardiovascular effects, including hypertension, myocardial
infarction, hemorrhagic or ischemic stroke, and venous
thrombosis and embolism; breast, hepatocellular, and
cervical cancers; and a number of endocrine and metabolic
effects. The current consensus is that low-dose
preparations pose minimal health risks in women who
have no predisposing risk factors, and these drugs
also provide many beneficial health effects (Burkman
et al., 2004).
Cardiovascular Effects. The question of cardiovascular side effects
has been reexamined for the newer low-dose oral contraceptives
(Burkman et al., 2004; Sherif, 1999). For nonsmokers without other
risk factors such as hypertension or diabetes, there is no significant
increase in the risk of myocardial infarction or stroke. There is a 28%
increase in relative risk for venous thromboembolism, but the estimated
absolute increase is very small because the incidence of these
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CHAPTER 40
ESTROGENS AND PROGESTINS