Fox Chapter 11, part of chapters 2, 9, 19, 20
Fig. 2.23 (2.24 in 14th edition)
structures of steroids
Structures of cholesterol, cortisol, testosterone, estradiol
reactions of steroids
shows structures and locations of secretion
Interestingly, Cholesterol -> -> Progersteone (corpus luteum) ->
->Testosterone (Leydig cells) -> estradiol (follicles).
steroid hormone receptor is protein that dimerizes
each receptor binds an HRE (hormone response element) (DNA sequence)
mechanism of hormone action is to activate gene transcription (into mRNA)
Menopause (pause in the menes) ["change of life" at about 50]
- lack of estrogen.
(Some hysterectomy or ovarian cancer surgeries might also deplete because
Many symptoms, hot flashes most obvious short term effect.
Osteoporosis most obvious long term effect.
For me, this site worked with explorer, not netscape - estrogen
(hormone) replacement therapy
Hotly contested (a lot of negative press lately), partly because estrogen
increases chances of breast cancer.
There is a drug, Tamoxifen
that blocks estrogen's effects, differently in different tissues.
J.L.Turgeon, D.P.McDonnell, K.A.Martin & P.M.Wise, Hormone therapy:
Physiological complexity belies theraputic strategy, Science 304, 1269-1273,
Estrogen and progesterone receptors in cardiovascular, neural, immune, gastrointestinal
and musculoskeletal systems.
Menopause (average age 51) vasomotor flashes, vaginal dryness, urinary symptoms,
osteoporosis, CHD (coronary heart disease.
Hence chronic estrogen therapy (ET) for CHD and osteoporosis.
A well intentioned study, WHI (women's health initiative) tested placebo,
estrogen & estrogen-progestin.
Discontinued because of increase in breasst cancer, CHD, stroke and venous
thromboembolism (but they did decrease fractures and colon cancer)
Human ovary: 17beta-estradiol.(E2) AND estrone (E1)
Study used conjugated equine estrogen (CEE) extracted from pregnant horse
urine, many estrogens including sulfated estrogens.
Why this matters is that there are several types of estrogen receptors differentially
activated by different estrogens.
Study used continuous oral administration, and hormone through hepatic portal
system highly activates estrogen receptors in the liver, changing important
proteins like angiotensin precursor.
Transdermal patch would be very different.
Women is study were fatter than usual.
Human progesterone vs study's medoxyprogersteone acetate (MPA), again affecting
different receptors differently, also MPA activates glucocorticoid receptor.
There are several estrogen receptors, alpha and beta. and many ways they
"Antiestrogen" tamoxifen is antagonist in breast but agonist in
bone and uterus, so now called SERM (selective estrogen receptor modulator).
Better SERMs are being found.
Anabolic steroids - muscle growth, bone growth, increased hemoglobin
There is an androgen from the adrenal - DHEA dehydroepiandrosterone
Increased secretion of testosterone at puberty has many obvious effects
including on larynx
Absence of androgens by castration decreases seminal vesicle and prostate
The whitish structure in this figure is the seminal
In this figure, the seminal vesicle of castrated
and normal mice are compared
Interestingly, many of testosterone's effects are mediated by estradiol-17beta,
made by aromatase (in a process called "aromatization," note aromatic
[in the organic chemistry sense] ring).
DHT (and several subsequent metabolites) made by 5alpha-reductase
This step takes place in cells
When I typed "five alpha reductase" or the like into my search
engine, I got hits on hair loss, concerning male pattern hair loss (androgenetic
alopecia) accelerated by DHT and alleviated by a drug, Propecia
Some wierd disorders
deficiency -> "testes-at-twelve" (at puberty, testes descend,
clitoris becomes penis etc when there is enough testosterone to overcome
deficit) There is a pedigree in the
androgen receptor mutation (androgen insensitivity syndrome [AIS])
-> testicular feminization, children think they are females until there
is no menstruation
There are androgens from adrenal, so with Congenital adrenal hyperplasia,
CAH, clitoris is large and behavior is "tomboy"
(From introductory book)
sequence coding for protein (mRNA) is copied from exons with introns spliced
"upstream" of gene, proteins binding promoter and enhancer regulate
Carrier protein, receptor, DNA
Carrier protein-T4, receptor-T3, DNA
involves retinoic acid
Remember signal transduction for G protein coupled receptor
TRANSPARENCY (From introductory book)
integrates the above point with epinephrine evolution of glucose
prostaglandins (mediators of inflammation) are derived from fatty acid (arachidonic
acid, 20:4) using cyclooxygenase (COX)
Prostaglandins have different actions in different places; take platelet
aggregation -- TXA2 stimulates clumping, PGI2 prevents them from sticking
to walls of vessels; it is the TXA2 aspect that is why you take aspirin
to prevent heart attack and should not take aspirin before surgery (etc.).
leukotrienes (mediators of inflammation) ... use lipoxygenase
NSAIDS (non-steroidal anti-inflammtory drugs) aspirin, ibuprofen, inhibit
prostaglandin synthesis by inhibiting cyclooxygenase (COX-1 & 2) nonspecifically,
problems in stomach
Celebrex, Vioxx, Bextra inhibit prostaglandin synthesis by inhibiting cyclooxygenase
(COX-2); popular for arthritus, but Merck pulled Vioxx 10/04 for increasing
cardiovascular problems, and later Bextra was pulled.
Aspirin is anti-inflammatory, anallgesic, antipyretic, anticoagulant, implicated
The Biology department's primary expert on endocrinology is Dr.
Asa who is director of research at the St. Louis Zoo. As an adjunct
Professor in SLU's Biology department, she teaches the popular course, "Introductory
Endocrinology" BL A450-01
Exam questions from 2004 - 2011 relevant to this outline
Progesterone is not only a hormone of its own right, it is also the precursor
of (list one of the three important hormones plus the organ that the hormone
you choose is made.
testosterone leydig cells (interstitial cells) of testes, cortisol (hydrocortisone)
adrenal cortex, estradiol 17 beta follicles of ovary
What effect if any would castration have on the seminal vesicle?
it would be smaller
Upstream of a gene, there is a place where a steroid protein receptor combined
with a steroid hormone binds. What is this area in the DNA called?
a response element
In a rare syndrome, a chromosomally normal female can be masculinized by
androgens. Considering that she does not have testes, where did these androgens
The enzyme 5-alpha-reductase is thought to be involved in androgenic alopecia.
Answer either (1) What is androgenic alopecia? or (2) What product of 5-alpha
reductase might contribute to androgenic alopecia?
baldness in men, dihydrotestosterone
The hormone T4 comes up to a cell's plasmalemma in the company of a carrier
protein. Say something about what else is involved before that hormone might
activate a gene's transcription.
converts to T3, binds receptor protein, that protein binds DNA, in the company
of 9-cis retinoic acid bound to RXR receptor
Answer one of the following: COX-2 inhibitors were greeted with enthusiasm
by medical professionals and patients at first (why?) but eventually there
were problems (why?).
without also inhibiting COX1, there were fewer gastric problems, but, alas,
the incidence of heart attacks increased
Say something about why estrogen replacement therapy for the prevention
of osteoporosis is not universally advised.
increase breast cancer, heart attack and stroke
Lipoxygenase and cyclooxygenase are enzymes that (answer one of the following)
(1) act on what precursor? or (2) make what two general classes of products
arachidonic acid (20:4), leukotrienes and prostaglandins
What female hormone is a precursor of testosterone?
What are the gonadotropins for spermatogenesis and testosterone secretion?
FSH and LH (ICSH)
Triiodothyroxine binds to a receptor that binds to the half site of a response
element. What binds to the receptor that occupies the other half of the
Androgens come from the testes and (where else?).
5alpha-reductase is required for normal function because it makes (what?)
out of (what?) [answer both].
DHT from testosterone
Why were COX-2 inhibitors initially considered to be an important advancement
beyond drugs like ibuprofen in the treatment of arthritis?
Since they did not inhibit COX-1, they helped in arthritis treatment without
Why would a transdermal patch be better than oral administration for estrogen
Less conversion by liver
A steroid hormone binds to a receptor that is located in the cytoplasm of
the cell. State one of the next things that happens with this hormone-receptor
Goes to the nucleus and binds response element, a place in the promoter
What does "20:4" signify when referring to the precursor of prostaglandin?
Arachidonic acid, a fairly long chain fatty acid, is 20 carbons long and
has 4 double bonds
On what kind of molecule would you find a sequence known as a "hormone
response element (HRE)?"
Non-steroidal antiinflammatory drugs (NSAIDs) block converrsion of what
fatty acid to prostaglandins?
In the process where epinephrine causes glucose release from liver, what
enzyme does cAMP activate?
protein kinase A
A receptor (protein) for T3 makes a heterodimer with a receptor for what
Hyperplasia of what gland would androgenize a female?
What syndrome results from 5a-reductase deficiency?
testes at twelve
What treatment has been standard for relief of hot flashes?
estrogen replacement therapy
Name one molecule in the biosynthetic pathway between cholesterol and testosterone.
To mediate many of the effects of testosterone, aromatase converts it to
After the alpha subunit of the heterotrimeric G protein binds GTP, what
does it do to GTP?
breaks it to GDP (and P)
What close relative of retinal (retinene, the part of rhodopsin that absorbs
light) is important in the activation of the hormone response element by
What second messenger activates protein kinase when the beta-adrenergic
receptor of a liver cell binds epinephrine?
Increased testosterone at puberty affect what organ to turn sopranos into
Testosterone is converted to dihydrotestosterone (DHT) by what enzyme?
Tamoxifen used to be called an antiestrogen but might now be better referred
to as a SERM (selective estrogen receptor modulator). Why?
antagonist in some tissues but agonist in others
A heterodimer of receptors for thyroid hormone and retinoic acid (together
with their respective ligands, thyroid hormone and retinoic acid) binds
to what specific location on what molecule?
response element on DNA
Estradiol-17b is made by aromatase from what steroid (the immediate precursor)?
Give a reason why the exact same mixture of hormones might have different
effects in a woman if given orally vs via a transdermal patch.
would go to liver by hepatic portal vessel if taken by mouth
A steroid hormone receptor is famous for binding the hormone as well as
what major macromolecule?
Give the name of a class of molecules produced by enzymes acting on arachidonic
In terms of how they inhibit prostaglandin synthesis, how would a COX2 inhibitor
differ from traditional NSAIDS like aspirin?
aspirin was non-specific (COX1 & 2)
Where is the receptor for steroid hormones?
inside the cell
formation of 1,25-dihydroxyvitamin D3 (increase 1alpha-hydroxylase activity
What famous steroid hormone is an intermediate in the conversion of progesterone
testosterone (also androstenedione)
A DNA-binding domain is a hallmark of what kind of molecule that binds to
a hormone response element?
steroid hormone receptor protein
Testosterone is converted by 5alpha-reductase or by aromatase into (name
one of these steroids)?
How does cAMP activate the kinase?
binds to and removes inhibitory subunit from catalytic subunit
Answer one of the following for the precursor that cyclooxygenase turns
to prostaglandins and lipoxygenase turns into leukotrienes - (1) name it,
or (2) say what kind of molecule it is, or (3) where does it come from?
arachidonic acid ((20:4), fatty acid, from membrane phospholipid
Why would hyperplasia of the adrenal masculinize a female?
adrenal cortex makes anabolic steroids like testosterone, too much if there
Why is the area upstream of a gene's coding sequence relevant to the actions
of retinoic acid, thyroxine and steroid hormones?
this area is the promoter where steroid hormone receptors , retinoic acid
receptors, etc bind
The G protein coupled receptor signals to the next molecule in the cascade,
namely the G protein. Why is it called a G protein?
Describe why the system of the hepatic portal vessel might be relevant in
estrogen replacement therapy.
Any chemicals, if taken orally, might be converted to other things by the
Testosterone gets converted to other steroids for its activity. Tell me
one of the enzymes that effects these conversions.
5-alpha reductase (to 5 alpha DHT) or aromatase (to estradiol-17beta
One part of the retinoid X receptor (RXR) binds 9-cis retinoic acid. What
does the other part of this molecule bind?
DNA (the RARE)
Why doesn't the alpha subunit of the heterotrimeric G protein activate the
adenylate cyclase indefinitely?
it has GTPase activity (etc.)
Why would a selective estrogen receptor modulator (SERM) be so potentially
useful for bone health?
have the beneficial effect on osteoblasts but not promote breast cancer
or cardiovascular problems
Many hormone receptors are on the cell membrane. How can steroid hormone
receptors work when they are inside the cell?
by binding steroid hormones and also binding DNA at hormone response element
Tell me one of several molecules that are precursors for all of these: hydrocortisone,
testosterone, and estradiol-17beta.
cholesterol, pregnenolone, progesterone
"A gene is the coding sequence for a protein." The truth but not
the whole truth. Relative to this, where is the hormone response element?
upstream of the coding sequence
What is the precursor of leukotrienes, and where (in the cell's anatomy)
does it come from?
arachidonic acid, in membrane lipid
Why did COX-2 inhibitors show so much promise, and why were some pulled
from the market?
reliece arthritic inflammation without interfering with gastric mucosa,
increased chance of heart attack
By what mechanism is estrogen good for bones?
it promotes osteoblasts
Why was there the conventional wisdom that estrogen by patch was safer than
Swallowed, the liver could make many other products
Why was the women's health initiative study discontinued?
Increase in breast cancer, coronary heart disease
For "androgenic alopecia" tell me either (1) what these words
mean, or (2) what an enzyme or the hormonal product it catalyses has to
do with that.
Male pattern baldness, 5 alpha reductase makes DHT
Progesterone is the precursor of what two sex steroids?
testosterone and estradiol
Where, specifically, is the hormone response element?
on the DNA upstream of the coding sequence for the protein
Why would a mutation in the receptor that caused insensitivity to androgens
have the effect it has in androgen insensitivity syndrome?
testicular feminization b/c there is no response to hormones like testosterone
Why at the time, was the availability of new COX-2 inhibitors heralded as
such an important development?
arthritis symptoms taken care of without the COX-1 interference with the
The thyroid receptor makes a heterodimer with a receptor for what signaling
Estrogen and thyrocalcitonin (calcitonin) would affect bone, answer either
(1) With what cell type? Or (2) In what way (would they affect bone)?
osteoblasts, put in calcium
Name a precursor of estradiol-17b.
testosterone, progesterone, cholesterol
"Steroid hormones affect transcription of certain genes. How?
bind receptor protein that binds response element
They used to call Tamoxifen an anti-estrogen, now they call it a SERM. Answer
either (1) How does SERM translate? Or (2) Why the change?
selective estrogen receptor modulator, it affects different tissues differently
Just like T4 is converted to T3 for receptor activation, testosterone is
converted. Name (1) one of the two active products of testosterone OR (2)
one of the two enzymes used to make these products from the precursor (testosterone).
dihydrotestosterone (5alpha-reductase) estradiol-17beta (aromatase)
For the precursor of prostaglandins, answer either (1) How many carbons
long? Or (2) How many double bonds?
Why was there such enthusiasm for Vioxx and Bextra and why were they eventually
by selectively blocking COX-2, arthritis could be selectively dosed without
inhibiting COX in the gastric mucosa, thee was increase in heart attacks
Why would osteoporosis become more of a potential problem after menopause?
lack of estrogen (which would have helped osteoblasts build bone calcium)
While estrogen replacement therapy was still widely accepted, the conventional
wisdom was that the transdermal patch was better than oral administration.
What is wrong (with oral administration), assuming the same hormone is in
hepatic portal vein delivers absorbed hormone liver that converts it to
lord knows what
What partners with the T3 (triiodothyroxine) receptor to activate the response
the retinoic acid receptor
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