Download Steroids: Estrogen and Progestin

Steroids: Estrogen
and Progestin
Jennifer Kettel
Professor John Buynak
CHEM 5398
March 27, 2007
Introduction
• Estrogens
• Progestins
• Hormone Contraceptives
– Combination Contraceptives
– Progestin-Only Contraceptives
– Emergency Contraceptives
Estrogens and Progestins
• Estrogens and progestins are hormones that produce many physiological
actions
• In women,
– Developmental effects (estrogens are largely responsible for pubertal
changes in girls and secondary sexual characteristics)
– Neuroendocrine actions involved in: Control of ovulation and the
preparation of the reproductive tract for fertilization and implantation
– Major Actions on: Minerals, Carbohydrates, Proteins, and Lipid
Metabolism
• In men, effects:
– Bone
– Spermatogenesis
– Behavior
Estrogens
• A group of steroid hormones that readily diffuse across the
cell membrane
• Inside the cell, they interact with estrogen receptors
D
D
A
A
Estriol
Estradiol
D
A
Estrone
Estrogen Synthesis
• Estrogen is produced primarily by developing follicles in the
ovaries, the corpus luteum, and the placenta
• Follicle-stimulating hormone (FSH) and luteinizing hormone (LH)
stimulate the production of estrogen in the ovaries
• Some estrogens are also produced in smaller amounts by
other tissues such as the liver, adrenal glands, and the breasts
• The ovaries are the principal source of circulating estrogen in
premenopausal women, with estrodiol being the main
secretory product
• In postmenopausal women, the principal circulating estrogen
estrone, which is synthesized from dehydroepiandrosterone
and secreted by the adrenals
Estrogen Synthesis
• The most potent naturally occurring estrogen in humans for
both the Estrogen Receptor alpha- and beta-mediated
actions is 17beta-estradiol, followed by estrone and estriol
• Each estrogen contains a phenolic A ring with a hydroxyl
group at carbon 3 and a beta-OH or ketone in position 17
of ring D
• The phenolic A ring is the principal structural feature
responsible for selective, high-affinity binding to both
receptors
• Synthesis of estrogen begins from the synthesis of
androstenedione from cholesterol
• Androstenedione crosses the basal membrane into
surrounding granulosa cells, where its converted to estrone
or estradiol wither immediately or through testosterone
• The conversion is catalyzed by aromatase
Biosynthetic Pathway
This figure shows the
major metabolic
intermediates in the
usual synthesis of
estrogen, starting
with cholesterol,
proceeding to
pregnenolone, an
androgen, and then
estrogen.
http://www.chemistryexplained.com/Di-Fa/Estrogen.html
Estrogen Receptors
• Estrogens exert their effects by interaction with receptors that are
members of the super family of nuclear receptors
• The two estrogen receptor (ER) genes are located on separate
chromosomes: ESR1 encodes ER-alpha and ESR2 encodes ERbeta
• Both ERs are estrogen-dependent nuclear transcription factors
that have different tissue distributions and transcriptional
regulatory effects on target genes
• Both ERs are ligand-activated transcription factors that increase
or decrease the transcription of target genes
• After entering the cell by passive diffusion through the plasma
membrane, the hormone binds to an ER in the nucleus
• In the nucleus, the ER is present as an inactive monomer bound
to heat-shock proteins, and upon binding estrogen, a change in
ER confirmation dissociates the heat-shock proteins and causes
receptor dimerization, which increases the affinity and the rate of
receptor binding to DNA
Anti-estrogens and SERMs
• Anti-estrogens
– Pure antagonists
– Clomiphene is for
treatment of
infertility in
anovulatory
women
– Fulvestrant is used
for the treatment
of breast cancer
• Selective Estrogen
Receptor Modulators
(SERMs)
– Compounds with
tissue-selective actions
– The goal of these drugs
is to produce
beneficial estrogenic
actions in certain
tissues (ex. Brain, bone,
liver) during
postmenopausal
hormone therapy
– Tamoxifen, Raloxifen,
Toremifine
Progestins
• Progestins include the naturally occurring hormone
progesterone, 17-acetoxyprogesterone derivatives in the
pregnane series, 19-nortestosterone derivatives (estranges), and
norgestrel and related compounds in the gonane series
progesterone
norgestrel
17-acetoxyprogesterone
levonorgestrel
19-nortestosterone
Physcical Actions of Progesterone
• In the reproductive tract, progesterone
decreases estrogen-driven endometrial
proliferation and leads to the development of
a secretory endometrium
• The abrupt decline in progesterone at the end
of the cycle is the main determinant of the
onset of menstruation
• Progesterone is very important for the
maintenance of pregnancy
• It suppresses menstruation and uterine
contractility
The Progestin Receptor
•Unlike the ER receptor, which requires a phenolic ring for
binding, the PR favors a non-phenolic ring structure
•There is a single gene that encodes two isoforms of the
progesterone receptor (PR): PR-A and PR-B
•Since the ligand-binding domains of the two PR isoforms are
identical, there is no difference in ligand binding
•However, the biological activities of PR-A and PR-B are
distinct and depend on the target gene in question
•PR-B mediates the stimulatory activities of progesterone
•PR-A strongly inhibits this action of PR-B
•Upon binding progesterone, the heat-shock proteins
dissociate, and the receptors are phosphorylated and
subsequently form dimers (homo- and hetero-) that bind with
high selectivity to progesterone response elements located on
target genes
Anti-progestins
• Anti-progestin, first discovered in
1981, is mifepristone, used to
terminate pregnancy
• In the presence of
progesterone, mifepristone acts
as a competitive receptor
antagonist for both
progesterone receptors
• When administered in the early
stages of pregnancy,
mifepristone causes decidual
breakdown by blocking uterine
progesterone receptors, which
leads to detachment of the
blastocyst, decreasing hCG
production
Mifepristone
Hormonal
Contraceptives
Brief History
• At the beginning of the 20th
century, European scientists
(Beard, Prenant, and Loeb)
developed the concept
that secretions of the
corpus luteum suppressed
ovulation during
pregnancy
• By the 1930s, scientists had
isolated and determined
the structure of the steroid
hormones and found that
high doses of androgens,
estrogens or progesterone
inhibited ovulation
History cont.
• In June 1957, the FDA
approved Enovid 10mg for
menstrual disorders
• Later, in May 1960, the FDA
approved Enovid for
contraceptive use
• Although the FDA
approved this drug for
contraceptive use, it was
not available to married
women in all states until
1965 and unmarried
women in all states until
1975
Types of
Hormonal
Contraceptives
Combination
Contraceptives
• This type is the most frequently used in the United
States, which contain both an estrogen and a
progestin
• The theoretical efficacy is 99.9%
• Ethinyl estradiol (a synthetic estrogen) and
mestranol are the estrogens most frequently
used
• Levonorgestrel is the most common progestin
used worldwide
• Currently, this type of contraceptives have
lowered doses of estrogen (“low-dose”)
Forms of Combination
Contraceptives
• The Pill
• The Patch
• Vaginal Ring
Combination
Contraceptives
• Mechanism of Action
– Act by preventing ovulation
– Measurements of plasma hormone levels
indicate that LH and FSH levels are suppressed
– The mid-cycle surge of LH is absent
– Endogenous steroid levels are diminished
– Thus, ovulation does not occur
– The multiple actions of estrogens and progestins
on the hypothalamic-pituitary-ovarian axis
during the menstrual cycle and the efficacy of
these agents all contribute to the blockade of
ovulation
Progestin-Only Contraceptives
• They contain progestins only,
termed “mini pills”
• Slightly less effective, with
99% efficacy
• Forms
– Pills
– Injectables
• Their effectiveness is thought
to be due largely to a
thickening of cervical
mucus, which decreases
sperm penetration and
impairs implantation
Emergency Contraceptives
• The FDA has approved two preparations
• PLAN-B includes 2 doses of levonorgestrel separated
by 12 hours (progestin-only)
• PREVEN is a 2 pill dose of a high-dose oral
contraceptive (levonorgestrel and ethinyl estradiol)
separated by 12 hours
• The first dose of these drugs should be taken 72 hours
after intercourse
PLAN B
Emergency Contraceptives
• Multiple mechanisms are likely to contribute to the efficacy of
these agents, however, the exact mechanism is unknown
• These mechanisms include:
– Ovulation is inhibited or delayed, alterations in endometrial
receptivity for implantation
– Interference with functions of the corpus luteum that maintain
pregnancy
– Production of a cervical mucus that decreases sperm
penetration
– Alterations in tubular transport of sperm, egg, or embryo
– Effects on fertilization
• Emergency contraceptives do not interrupt pregnancy after
implantation
Side Effects
• Many side effects were found to be dose
dependent, hence the development of the current
low-dose preparations
• Side effects include:
– Cardiovascular effects (hypertension, myocardial
infarction, hemorrhagic stroke, venous thrombosis)
– Breast, Hepatocellular, and Cervical Cancers
– Endocrine and Metabolic effects
• Currently, its found that the low-dose preparations
pose minimal health risks in women who have no
predisposing risk factors
Male Birth Control?
• Current research and development
is in various stages, some which
include
– A male version of “the pill”
– A male hormonal contraceptive
implanted under the skin
– A drug which interferes with the
maturation of sperm in the epididymis
– Plugs that block the vas deferens