Hormones2

Fox Chapter 11, part of chapters 2, 9, 19, 20

Steroids, etc

Fig. 2.23 (2.24 in 14th edition)
structures of steroids
Structures of cholesterol, cortisol, testosterone, estradiol

Fig. 11.2
reactions of steroids
shows structures and locations of secretion
Interestingly, Cholesterol -> -> Progersteone (corpus luteum) -> ->Testosterone (Leydig cells) -> estradiol (follicles).

Fig. 11.5
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)

Estrogen

Menopause (pause in the menes) ["change of life" at about 50] - lack of estrogen.
(Some hysterectomy or ovarian cancer surgeries might also deplete because of ovarectomy).
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.

Recent literature

J.L.Turgeon, D.P.McDonnell, K.A.Martin & P.M.Wise, Hormone therapy: Physiological complexity belies theraputic strategy, Science 304, 1269-1273, 2004
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 influence transcription.
"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.

Androgens

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 vesicle
In this figure, the seminal vesicle of castrated and normal mice are compared

Fig. 20.13
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

Fig. 20.7
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

5alpha-reductase 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
Dominican republic

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"

Signal transduction

TRANSPARENCY (From introductory book)
"gene"
sequence coding for protein (mRNA) is copied from exons with introns spliced out
"upstream" of gene, proteins binding promoter and enhancer regulate transcription

Fig. 11.4
steroid hormone
Carrier protein, receptor, DNA

Fig. 11.6
thyroid hormone
Carrier protein-T4, receptor-T3, DNA

Fig. 11.7
thyroid hormone
involves retinoic acid

Fig. 11.8
Remember signal transduction for G protein coupled receptor

TRANSPARENCY (From introductory book)
integrates the above point with epinephrine evolution of glucose

Prostaglandins, etc

Fig. 11.34
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 in Reye's syndrome.

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 come from?

adrenal cortex

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 respectively?

arachidonic acid (20:4), leukotrienes and prostaglandins

What female hormone is a precursor of testosterone?
 
progesterone
 
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 response element?
 
Retinoic acid
 
Androgens come from the testes and (where else?).
 
adrenal cortex
 
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 gastric side-effects

Why would a transdermal patch be better than oral administration for estrogen replacement therapy?
 
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 complex.
 
Goes to the nucleus and binds response element, a place in the promoter on DNA
 
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)?"

DNA

Non-steroidal antiinflammatory drugs (NSAIDs) block converrsion of what fatty acid to prostaglandins?

arachidonic

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 substance?

retinoic acid

Hyperplasia of what gland would androgenize a female?

adrenal

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.

progesterone

To mediate many of the effects of testosterone, aromatase converts it to what?

estradiol

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 triiodothyroxine?

retinoic acid

What second messenger activates protein kinase when the beta-adrenergic receptor of a liver cell binds epinephrine?

cAMP

Increased testosterone at puberty affect what organ to turn sopranos into altos?

larynx

Testosterone is converted to dihydrotestosterone (DHT) by what enzyme?

5-alpha-reductase

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)?

testosterone

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?

DNA

Give the name of a class of molecules produced by enzymes acting on arachidonic acid (20:4).

prostaglandins (leukotrienes)

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 to estradiol-17beta?

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)?

dihydrotestosterone, estradiol-17beta

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 is hyperplasia

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?

binds GTP

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 liver

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 oral administration?

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 gastric mucosa

The thyroid receptor makes a heterodimer with a receptor for what signaling molecule?

retinoic acid

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?

20:4

Why was there such enthusiasm for Vioxx and Bextra and why were they eventually pulled?

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 each.

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 element?

the retinoic acid receptor

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this page was last revised 6/19/15