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

Agents Similar to Progesterone (Pregnanes)
O
21CH 3
C O
OAc
20C
O
18
17
11
19
O
6
CH 3
PROGESTERONE MEDROXYPROGESTERONE
ACETATE
Agents Similar to 19-Nortestosterone (Estranes)
O
19-NORTESTOSTERONE
Agents Similar to 19-Norgestrel (Gonanes)
O
3
H 3 C
H 2 C
NORGESTREL
OH
OH
C
O
HON
NORETHINDRONE
NORGESTIMATE
spironolactone (e.g., drospirenone) that have anti-mineralocorticoid
and anti-androgenic properties.
History. Corner and Allen originally isolated a hormone in 1933 from
the corpora lutea of sows and named it “progestin.” The next year,
several European groups independently isolated the crystalline compound
and called it “luteo-sterone,” unaware of the previous name.
This difference in nomenclature was resolved in 1935 at a garden
party in London given by Sir Henry Dale, who helped persuade all
parties that the name “progesterone” was a suitable compromise.
Two major advances overcame the early difficulties and
expense of obtaining progesterone from animal sources. The first
was the synthesis of progesterone by Russel Marker from the plant
product diosgenin in the 1940s, which provided a relatively inexpensive
and highly pure product. The second was the synthesis of
19-nor compounds, the first orally active progestins, in the early
1950s by Carl Djerassi, who synthesized norethindrone at Syntex,
and Frank Colton, who synthesized the isomer norethynodrel at
Searle. These advances led to the development of effective oral
contraceptives.
Chemistry. The structural features of several progestins are shown in
Figure 40–5. Unlike the ER, which requires a phenolic A ring for
CH
OH
CH 3
C
CH
H 3 C
OCOCH
H 3
2 C
C CH
Figure 40–5. Structural features of various progestins.
high-affinity binding, the progesterone receptor (PR) favors a Δ 4 -3-
one A-ring structure in an inverted 1β, 2α-conformation (Duax et al.,
1988). Other steroid hormone receptors also bind this nonphenolic
A-ring structure, although the optimal conformation differs from that
for the PR. Thus, some synthetic progestins (especially the 19-nor
compounds) display limited binding to glucocorticoid, androgen,
and mineralocorticoid receptors, a property that probably accounts
for some of their nonprogestational activities. The spectrum of activities
of these compounds is highly dependent on specific substituent
groups, especially the nature of the C17 substituent in the D ring,
the presence of a C19 methyl group, and the presence of an ethyl
group at position C13.
One major class of agents is similar to progesterone and its
metabolite 17α-hydroxyprogesterone (Figure 40–5). Compounds
such as hydroxyprogesterone caproate have progestational activity
but must be used parenterally due to first-pass hepatic metabolism.
However, further substitutions at the 6-position of the B ring yield
orally active compounds such as medroxyprogesterone acetate and
megestrol acetate with selective progestational activity.
The second major class of agents is 19-nor testosterone derivatives.
These testosterone derivatives, lacking the C19 methyl group,
display primarily progestational rather than androgenic activity. An
ethinyl substituent at C17 decreases hepatic metabolism and yields
orally active 19-nortestosterone analogs such as norethindrone,
norethindrone acetate, norethynodrel, and ethynodiol diacetate. The
activity of the latter three compounds is due primarily to their rapid
in vivo conversion to norethindrone. These compounds are less selective
than the 17α-hydroxyprogesterone derivatives just mentioned
and have varying degrees of androgenic activity and, to a lesser
extent, estrogenic and anti-estrogenic activities.
Replacement of the 13-methyl group of norethindrone with a
13-ethyl substituent yields the gonane norgestrel, which is a more
potent progestin than the parent compound but has less androgenic
activity. Norgestrel is a racemic mixture of an inactive dextrorotatory
isomer and the active levorotatory isomer, levonorgestrel.
Preparations containing half as much levonorgestrel as norgestrel
thus have equivalent pharmacological activity. Other gonanes—
including norgestimate, desogestrel, and gestodene (not available in
the U.S.)—have very little if any androgenic activity at therapeutic
doses.
Other steroidal progestins include the gonane dienogest; 19-norprogestin
derivatives (e.g., nomegestrol, Nestorone, and trimegestone),
which have increased selectivity for the progesterone receptor
and less androgenic activity than estranes; and the spironolactone
derivative drospirenone, which is used in combination with oral contraceptives.
Like spironolactone, drospirenone is also a mineralocorticoid
and androgen receptor antagonist.
Biosynthesis and Secretion. Progesterone is secreted by the
ovary, mainly from the corpus luteum, during the second half of
the menstrual cycle (Figure 40–3). LH, acting via its G proteincoupled
receptor, stimulates progesterone secretion during the
normal cycle.
After fertilization, the trophoblast secretes hCG into the
maternal circulation, which then stimulates the LH receptor to sustain
the corpus luteum and maintain progesterone production.
During the second or third month of pregnancy, the developing placenta
begins to secrete estrogen and progesterone in collaboration
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CHAPTER 40
ESTROGENS AND PROGESTINS