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

1186 capacity to supply food, energy, and raw materials, and
to absorb the detritus of its human burden. Marine
fisheries are being depleted, forests and aquifers are
disappearing, and the atmosphere is accumulating
greenhouse gases from combustion of the fossil fuels
that provide the energy needs of almost 7 billion people.
Perhaps some of the blame can be laid at the feet of
medical science: Advances in public health and medicine
have led to a significant decline in mortality and an
increased life expectancy. However, medical science
has also begun to assume a portion of the responsibility
for overpopulation and its adverse effects. To this
end, drugs in the form of hormones and their analogs
have been developed to control human fertility.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
History. Around the beginning of the 20th century, a number of
European scientists, including Beard, Prenant, and Loeb, developed
the concept that secretions of the corpus luteum suppressed ovulation
during pregnancy. The Austrian physiologist Haberlandt then
produced temporary sterility in rodents in 1927 by feeding ovarian
and placental extracts—a clear example of an oral contraceptive! 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.
Ironically, this finding grew out of their attempts to treat infertility
with progestins or estrogen-progestin combinations. The initial findings
were that either treatment effectively blocked ovulation in most
women. However, concern about cancer and other possible side
effects of the estrogen they used (i.e., DES) led to the use of a progestin
alone in their studies. One of the compounds used was
norethynodrel, and early batches of this compound were contaminated
with a small amount of mestranol. 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.
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 longacting
injectable preparations were developed and introduced.
Millions of women began using oral contraceptives, and frequent
reports of untoward effects began appearing in the 1970s. The
recognition that these side effects were dose-dependent and the realization
that estrogens and progestins synergistically inhibited ovulation
led to the reduction of doses and the development of so-called
low-dose or second-generation contraceptives. The increasing use
of biphasic and triphasic preparations throughout the 1980s further
reduced steroid dosages; it may be that currently used doses are the
lowest that will provide reliable contraception. In the 1990s, the
“third-generation” oral contraceptives, containing progestins with
reduced androgenic activity (e.g., norgestimate [ORTHO-CYCLEN,
ORTHO TRI-CYCLEN LO, others] and desogestrel [DESOGEN, others]),
became available in the U.S. after being used in Europe. A variety of
contraceptive formulations are currently available, including pills,
injections, skin patches, subdermal implants, vaginal rings, and IUDs
that release hormones.
Types of Hormonal Contraceptives
Combination Oral Contraceptives. The most frequently
used agents in the U.S. are combination oral contraceptives
containing both an estrogen and a progestin. Their
theoretical efficacy generally is considered to be 99.9%.
Combination oral contraceptives are available in many
formulations. Monophasic, biphasic, or triphasic pills
are generally provided in 21-day packs. (Virtually all
preparations come as 28-day packs, with the pills for
the last 7 days containing only inert ingredients.) For
the monophasic agents, fixed amounts of the estrogen
and progestin are present in each pill, which is taken
daily for 21 days, followed by a 7-day “pill-free”
period. The biphasic and triphasic preparations provide
two or three different pills containing varying amounts
of active ingredients, to be taken at different times during
the 21-day cycle. This reduces the total amount of
steroids administered and more closely approximates
the estrogen-to-progestin ratios that occur during the
menstrual cycle. With these preparations, predictable
menstrual bleeding generally occurs during the 7-day
“off” period each month. However, several oral contraceptions
are now available whereby progestin withdrawal
is only induced every 3 months.
The estrogen content of current preparations ranges from 20
to 50 μg; most contain 30-35 μg. Preparations containing ≤35 μg of
an estrogen are generally referred to as “low-dose” or “modern” pills.
The dose of progestin is more variable because of differences in
potency of the compounds used. For example, monophasic pills
currently available in the U.S. contain 0.4-1.5 mg of norethindrone,
0.09-0.15 mg of levonorgestrel, 0.3-0.5 mg of norgestrel, 1 mg of
ethynodiol diacetate, 0.25 mg of norgestimate, or 0.15 mg of desogestrel,
with slightly different dose ranges in biphasic and triphasic
preparations. In contrast, most first-generation preparations (circa
1966) contained 50-100 μg of an estrogen and 2-10 mg of a progestin.
These large differences in doses complicate extrapolation of
data from early epidemiological studies on the side effects of “highdose”
oral contraceptives to the “low-dose” preparations now used.
A transdermal preparation of norelgestromin and ethinyl
estradiol (ORTHO EVRA) is marketed for weekly application to the buttock,
abdomen, upper arm, or torso for the first 3 consecutive weeks
followed by a patch-free week for each 28-day cycle. A similar 3-
week on/1-week off cycle is employed for the intravaginal ring containing
ethinyl estradiol and etonogestrel (NUVARING).