Download 9-10 (Pillion) - UAB School of Optometry

Endo: 9:00-10:00
Friday, November 10, 2009
Dr. Pillion
Gonadal Hormones
Scribe: Patricia Fulmer
Proof: Sheena Harper
Page 1 of 7
Gonadal Hormones [S1]
a. There are some ways that we can intervene with this system through drugs, and he will cover this, especially
where we actually apply the utilization of chemicals that mimic or antagonize the natural hormones.
II. Gonadotropin [S2] A lot of this material is coming from your textbook…look at the handout online!
a. As we go through this, a lot of material is coming from the textbook. He’s posted a handout on Blackboard we
should look at for the test!
b. So the gonadotropin acts as we’ve seen before. Hypothalmic release of gonadotropin pituitary release of LH
and FSH, stimulating the gonadsproduction of sex steroids
c. Testosterone, progesterone, estrogens feedback and inhibit the cycle
d. Unlike other cycles where we have a single hormone that influences its own feedback, estrogen and
progesterone impact each other in a complex way
e. Throughout the course of a woman’s cycle, she’ll make different levels of different hormones
f. We’ll look at what normally happens and how we intervene.
I.
III. Pathways of steroid biosynthesis [S3]
a. The synthetic pathways have been covered previously when we did the adrenal cortex.
b. Cholesterol is the precursor. It makes pregnenolone, then progesterone.
c. This slide shows that we start off making progesterone, and we can convert that in the adrenal cortex to make
cortisol and aldosterone. We also make testosterone from progesterone. They are very closely related
chemically.
d. They can react with each others’ receptors if present in excess. If you have a lot of testosterone, you might get
some progesterone effects and vise versa.
e. Estrogens come from the metabolism of testosterone.
f. All these compounds are coming down the same chemical tree. The body’s enzymes convert that.
g. If the enzymes that convert one thing to the other get messed up, bad things can happen in terms of your
sexual characteristics.
h. It’s useful to consider the fact that all these chemicals are related and they all have biochemical properties of a
relatively long half- life and not being very soluble in water. They are able to cross the cell membrane and can
bind to receptors inside the cell. The receptor inside the cell goes to the nucleus and produces proteins.
i. When testosterone has an effect on our muscles, it’s because testosterone binds and the nucleus increases
protein synthesis. So do estrogen and progesterone.
j. All the gonadal steroids come from cholesterol and the androgens are precursors.
IV. Summary of the steps in the menstrual cycle [S4]
a. This slide is to remind us of the natural cycle and is necessary for pregnancy to occur.
b. It is helpful to bear this in mind when considering contraception.
c. You have FSH made in the first half of the cycle, LH surges at day 14
d. The FSH stimulates the production of estradiol, which plays a role to prepare for the production and
mechanism of progesterone action
e. All this must take place for conception to occur successfully to get a fertilized egg.
f. If it doesn’t happen, you have the normal menstrual cycle.
g. When you think about what you need for conception, what you need for contraception should make more
sense.
V. Estrogen receptors alpha and beta tissue distribution [S5]
a. The other concept that we will see a revolution in is that when he went to school there was one estrogen
receptor. They didn’t understand why some got different cancers and others didn’t. They just knew it had to
do with the estrogen.
b. Then they discovered there’s more than one estrogen receptor. To just say there’s an alpha and beta is too
simple, but that’s what we need to know for now.
Endo: 9:00-10:00
Friday, November 10, 2009
Dr. Pillion
Gonadal Hormones
Scribe: Patricia Fulmer
Proof: Sheena Harper
Page 2 of 7
c. Some of the molecules we call SERMs (selective estrogen receptor modulators) like tamoxifen and roloxifene
can be used to treat breast cancers. They are called selective because they bind with more affinity to one
receptor than the other.
d. When we talk about treating a prostate cancer with one drug and breast cancer with another, we should
understand that it depends on which receptor is present in the tissue and which chemical stimulates the
receptor in one tissue and might actually inhibit the receptor in another.
e. Think about testosterone. It is a cousin of estrogen and progesterone. It has different effects in different cells.
In a hair follicle cell, it has different effects than in a nerve cell, red cell, or muscle cell.
f. The hair cell can’t be the same as the muscle cell when it comes to testosterone if their reactions are different.
The cells probably share a receptor, but the proteins that bind to the receptor and the area of DNA that the
receptor binds to must be different in the two different places.
g. It’s that difference that allows, if you can make a drug that binds to a testosterone receptor and you piggyback
a group on top of that, the group could make that new molecule work better in one location over another
(work in hair cell, but not in muscle cell). It may even decrease the effect in the other location. Some may work
in both places or block the effect of testosterone in one or both places.
h. If you have a guy whose hair is falling out but whose potency is modest, you don’t want to give him a drug that
grows hair but will remove his potency completely.
i. You want a selective drug. We are getting to a point that we can do that better.
j. We’ve seen there are multiple receptors. Some tissues (like breast and ovary) have both types of receptors
present. It is hard to get selectivity there.
k. Other tissues (the brain and prostate) are much richer in the beta receptors than the alphas. If you had an
inhibitor of betas, you’ll be more effective in those tissues.
l. Typically testosterone causes hair to fall out—male pattern baldness. If you block that effect, you’d prevent
male pattern baldness.
m. You want to block the hair falling out, but not block other jobs of testosterone in other organs.
VI. Pharmacological estrogens [S6]
a. The normal, physiological substrate for the estrogen receptors in most females (not a pregnant one) is
estradiol. It is called this because it has 2 hydroxyl groups. A –triol has three hydroxyl groups.
b. Estradiol is metabolized rapidly to estrone (has double bone O). The activity of the molecule goes way down.
c. If you want to give a lady some estradiol to affect her fertility, we could give her estradiol in a pill.
d. The drawback of that would be that it might mess up her cycle. Also, it probably would get absorbed and
metabolized very quickly. It has a half life of 20 min.
e. You’d be giving the pill every two hours day and night if you want to keep the levels high.
f. Pharmacological changes include putting on a triple bond instead of the regular bond to lengthen the half time
to around 12-24 hours.
g. The business end of the molecule still binds to its receptor. The change prevents it from being broken down.
h. EE (ethinyl estradiol) is an analog of estradiol that has a longer half life of about 4-5 hr.
i. Mestranol has a methyl group on the estradiol, is a prodrug, and a longer half life. It gets demethylated to
become active. The liver is usually the place to the drug is activated, so a patient with impaired liver function
or other problems with the liver, it might mess up the metabolism of mestranol.
j. These two are players in our contraceptive ways because they can be taken once a day.
VII. Two plant estrogens and 17B-estradiol [S7]
a. There are a couple natural estrogens with biologic importance.
b. The first is resveratrol- from red wine. Its structure is similar to estradiol with one more hydroxyl group.
c. Both are non-polar, both could likely enter a cell easily and use the same receptors.
d. Resveratrol is important because the people that drink red wine have different outcomes than those that
don’t. People that drink red wine get less osteoporosis and Alzheimer’s.
e. The current recommendation is for a woman to have one glass of red wine per day. Liver damage will occur
with too much.
Endo: 9:00-10:00
Friday, November 10, 2009
Dr. Pillion
Gonadal Hormones
Scribe: Patricia Fulmer
Proof: Sheena Harper
Page 3 of 7
f. Genistein from soybeans looks like estradiol. Asian women that eat a lot of soy have a lower rate of breast
cancer. With the American diet, breast cancer rate goes up.
g. There’s a study at UAB about giving soy to women before puberty and how that affects breast cancer.
h. We don’t know why soy products help, but you should eat them. They’re good for you.
i. There’s a lot more to go, and chemical companies are trying to improve soy.
VIII.
Hormone Replacement Therapy [S8]
a. Up until about 4 years ago, standard operating procedure was that a woman would reach menopause and she
would be put on hormone replacement therapy—given estrogen and progesterone.
b. This is because the deaths from cardiovascular disease go up after menopause and the creation of estrogen is
the changing factor. Give them estrogen, and it will decrease the number or heart attacks they’ll have. It’s
been a while since that study came out.
c. Those that get hormone replacement therapy have a highest risk.
d. We’ve changed our standard now to hormone replacement therapy to everyone. There are situations where
this is beneficial. A woman who isn’t at a higher risk for breast cancer, who has hot flashes that are
debilitating, who has severe vaginal atrophy or dryness, and osteoporosis.
e. Typically now, a woman is put on this therapy right as she enters menopause. These side effects are lessened
with time. In terms of osteoporosis, an intervention with this therapy at menopause and use for a year or two
is very beneficial.
f. The thought is that a year or two of hormone replacement therapy increases risk of cancer modestly, but the
longer you’re on it the higher your risk is. Risk to benefit ratio is better the less time you use it.
IX. Horse Urine estrogens (premarin) [S9]
a. In the past, up to the 1980’s, this is what they gave.
b. They had no synthetics available and it was hard to make.
c. They used sulfated chemicals from horse urine for hormone replacement therapy. It was not of great benefit.
d. There is a debate over whether a human estrogen is better than the horse estrogen for therapy. There have
been no studies done though.
X. Synthetic estrogens and anti-estrogens [S10]
a. There are some synthetic estrogens and anti-estrogens.
b. One is diethylstilbestrol, which dates back to the fifties and sixties, as an estrogen replacement therapy to
encourage infertile girls to get pregnant.
c. People that got pregnant and still took the drug had a high incidence of birth defects. The drug promoted birth
defects and fertility.
d. Taken off the market long ago.
e. Some are trying to find a therapeutic use for it, like a cancer drug.
f. Chlorotrianistene is another analog that was developed, but it isn’t used much.
g. Tamoxifen is an anti-estrogen. You can see from the structure that it doesn’t look like estrogen. It’s big and
bulky. It’s thought that part of the molecule binds to the estrogen receptor and the other part modulates the
effect of the estrogen receptor. Different effects in different tissues. It’s used as an anti-estrogen in breast
cancer. It will bind to estrogen-receptor positive tumors.
h. You can test to see if the tumor is estrogen receptor positive, which helps the tumor grow. If it is, you can treat
with tamoxifen. It will stop the growth.
i. It can also be used for prophalaxis in people who are at risk for breast cancer, and it tends to diminish the
occurrence of breast cancer.
SQ: If the breast is removed when cancer is discovered, why do they stay on Tamoxifen afterward?
A: probably because of the fear that they tumor had metastasized to other places. It would still have estrogen
receptors, so the drug could still work.
XI. Progestins [S11-12]
a. The other side of the coin is progestins. Obviously the progestins and estrogens are hand and glove.
b. You can take natural progesterone, but they aren’t very bioavailable, aren’t water-soluble, and are quickly
metabolized.
c. Then scientists converted it chemically to give it a longer half life.
Endo: 9:00-10:00
Friday, November 10, 2009
Dr. Pillion
Gonadal Hormones
Scribe: Patricia Fulmer
Proof: Sheena Harper
Page 4 of 7
d. In contraception, it’s used often in combo with estrogen, which primes the system for progesterone because
progesterone usually comes after estrogen in the normal cycle.
e. Here’s progesterone and medroxyprogesterone acetate (MPA) or Provera (don’t need to know trade name)
f. MPA has an acetate group on it that is analogous to the carbon-carbon triple bond in the estrogen. It has a
methyl group that increases its activity. The two chemicals are similar in looks and behavior, but MPA has a
longer half life. It is a progesterone-like molecule.
XII. Synthetic Progestins [S13]
a. These are a couple of other synthetic progestins.
b. They have the carbon-carbon triple bond.
c. We use all three of these synthetic progestins in contraceptives. We should know all three: MPA,
Levonorgestrel, and Norethindrone
XIII. Contraception [S14]
a. The most widely used form contraceptives are the combo pill that are for days 5-25 of the cycle.
b. You take EE or mestranol along with norethindrone or norgestrel
c. The first two are estrogens and the second two are progestins. You take one of one and one of the other.
d. The reason they’re both on the slide is because we have competing drug companies that make different
combos of these drugs.
e. All of the ones in the US have greater than 99% effectiveness at preventing conception. There’s not much
difference in the different ones available, except cost.
f. The combo of estrogen and progestin is important. They have the triphasic version where you take minimal
effective amounts of the two components during the different weeks in the cycle. Each week’s pills are
different.
g. These prevent ovulation.
h. At the end you have sugar pills to the let the system recover.
i. Another option is to take progestin by itself all the time. This prevents ovulation sometimes, but it also
prevents implantation of the fertilized cell.
j. A progestin implant is another version of this except they are norplant silastic tubes that are put under the skin
and are good for up to 5 years.
k. These are good for people going to a 3rd world country or leaving for a long time and couldn’t take a pill every
day.
XIV. Combination contraceptive [S15]
a. He always asks if something is characteristic or the combo drug or the mini pill, either the mechanism of
action or the side effects. We should be able to tell the two apart.
b. With the combo contraceptive, you take estrogen and progesterone, take it orally, block the mid-cycle surge of
FSH and LH, block negative feedback, you have another negative feedback mechanism that blocks the LH surge
on day 14 so the ovum is not released. You take it days 5-25.
c. It used to be one pill you took all the time.
d. They found that you could use the bi-phasic and tri-phasic ones and use less hormone that way.
e. The overriding theme of all these things is that if you take too much estrogen, you increase your cancer risk,
especially if you take it a long time. The less estrogen you take, the better.
f. Progestin by itself is effective 98% of the time, the combo is 99%. You have to weigh that percent with the
associated risk of cancer.
g. The number they used to say was 2% cancer risk for each year used.
h. These aren’t trivial in their use. They play an important role though.
XV.Progestin mini-pill [S16]
a. Ovulation is down 70%, but implantation is down too. The combo of those two effects leads to a 98%
effectiveness.
b. Slightly higher failure rate than the combo pill.
c. The mechanism is thought to be through thickening of the cervical mucus.
d. When you think of the combo, think no ovulation.
Endo: 9:00-10:00
Friday, November 10, 2009
Dr. Pillion
Gonadal Hormones
Scribe: Patricia Fulmer
Proof: Sheena Harper
Page 5 of 7
e. When you think of the mini-pill, ovulation may occur but the cervical mucosal thickening is the reason for no
contraception.
Toxicity of contraceptives [S17]
a. You have weight gain, breast growth, depression, nausea, amenorrhea, breakthrough bleeding, and posttreatment infertility
b. Women who are on this for a long time (5 years or more maybe) may not be able to get pregnant for a few
months after they stop the use.
c. Migraines, risk of stroke, acne, hirsutism
d. cardio side effects: increased risk of thromboembolism, myocardial infarction, and stroke
e. Women on it shouldn’t smoke
f. Liver disease
g. Glucose intolerance
h. Use them with care in people with diabetes because they raise blood sugar
i. Can get good test questions from this.
XVII. Mifepristone (RU-486) [S18]
a. RU-486 or mifepristone (we need to know this name) is an anti-progestin and an anti-glucocorticoid
b. It has part of the molecule that looks like estrogen. The other part gives it a long half life.
c. Another part is what messes up the action of estrogen and cortisol, blocking them both.
d. It can be used orally.
e. Vaginal suppository of prostaglandin E that can be used in abortion. It is 95% effective in terminating
pregnancy if used in the first 7 weeks.
f. It is the morning after pill because it blocks the progestin that comes after the egg is fertilized and therefore
prevents implantation.
XVIII. Review Slide 1 [S19]
a. Test Question: when you take estrogen are you at risk for cancer and what kind? In 1997, they published a
study that said that estrogen in hormone replacement therapy had a 2% increase in breast cancer. So ten year
use gave a 20% risk.
b. Estrogens alone increase endometrial cancer, but we don’t give it alone for this reason.
c. If you see a question that asks about using estrogen alone, you wouldn’t want to because of the endometrial
cancer risk
d. When you combine estrogen and progestin, it lowers the risk
e. The breast cancer risk is the one that is of interest. One study said it increases the risk 5x.
f. We have a love/hate relationship with the estrogen and progestin mini-pill because of this.
XIX.
Postmenopausal Use [S20]
a. Postmenopausally, we want to treat hot flashes that can be severe and debilitating for some. It gradually
diminishes with time, and replacement therapy will help that side effect.
b. Vaginal and urethral atrophy- use a low dose as needed
c. Cognition/dementia- estrogens have the ability to slow Alzheimer’s and help memory. This is controversial
though. No long term data about this.
d. It may be that postmenopausal women that used to make estrogen could have an impact on memory and their
brain.
e. Osteoporosis has an adverse effect, severe in some. Treatment with estrogen early after menopause is the
best way to go. It prevents bone reabsorption.
f. Plant estrogens are alternatives. These are found in soy, red clover, kudzu, and many others are sources of
naturally occurring estrogenic-like compounds that may help. The glass of red wine may help fend of
Alzheimer’s and memory loss.
XX.Dilemma of estrogens [S21]
a. The dilemma of estrogens: good for osteoporosis, no effect for cardiovascular disease, breast cancer is a bad
effect of them, and they have other side effects like feminization, breast tenderness, gallstones, cholestasis,
hypercalcemia, and gynecomastia
XVI.
Endo: 9:00-10:00
Friday, November 10, 2009
Dr. Pillion
Gonadal Hormones
Scribe: Patricia Fulmer
Proof: Sheena Harper
Page 6 of 7
b. It is a love/hate relationship
XXI. Infertility agent [S22]
a. The other drug we use in the estrogen family is clomiphene-used as an infertility agent.
b. One isomer is an agonist of estrogen and one isomer is an antagonist
c. The antagonist blocks the normal feedback loop of estrogen to the hypothalamus and pituitary that would
diminish FSH and LH.
d. If a woman isn’t ovulating, you could increase the amount of LH at day 14 of the cycle.
e. Used to give injections, but not very successful
f. If you give an anti-estrogen drug, then it blocks the estrogen at the pituitary and you end up with more FSH
and LH, which makes a woman more fertile.
g. Sometimes you get multiple eggs released, which is why we end up with sextuplets and octuplets.
h. The mechanism of action is an estrogen antagonist and has the effect of increasing the LH surge at day 14.
XXII. SERMs [S23]
a. Selective Estrogen Receptor Modulators
b. Here’s an example of raloxifene- part looks like estrogen and the other part helps it bind selectively to
estrogen receptors and alters the action of the molecule
c. Other SERMs are tamoxifen and toremifene
d. This list here is growing. Hopefully there will be a lot of selective drugs that can work on different problems
throughout a woman’s life in the future years.
XXIII. SERMs and their mechanisms [S24]
a. They have both agonist and antagonist activity.
b. Tamoxifen is an agonist in the breast, a weak agonist in the endometrium.
c. Raloxifene has high affinity for both alpha and beta receptors. In the bone it is an agonist. Not in the uterus.
d. If you have a situation where you don’t need to affect uterine growth but you need it in the bone, you can use
this. It could increase bone response without increasing uterine response. This is good postmenopausally.
XXIV. Androgens [S25]
a. Estrogens are more utilized than androgens. Most of androgens are abused rather than used.
b. Physiologically, we have the same problems. Can I take testosterone orally and get beneficial effects? Yes, but
it will have a short half life. You’d have to take it every hour.
c. You can take testosterone molecules and make chemical derivatives with longer half life.
d. They have both androgenic effects and anabolic effects, which are to build up muscles. We think they have an
anti-cortisol effect.
e. Cortisol is a cousin of testosterone. It makes glucose for the body. The way it makes glucose is that it
stimulates the breakdown of proteins. Normally our body breaks down proteins for glucose. If you put an anticortisol molecule, we prevent that from happening. This causes muscles to get bigger because we aren’t
breaking them down like normal.
f. The other thing that the steroids, androgens in particularly, do is that they change our mindsets so that we can
train harder (sort of). You go through ups and downs as you go through androgen utilization.
g. We are talking about taking androgens at a level of 1000x more than normal.
h. A normal amount of androgen won’t have an effect on muscle mass, so no benefit if trying to gain weight or
muscle.
i. The androgens used for anabolic effects are modified chemically to have that effect.
j. There is some brain-gonadal axis of feedback control.
k. There are some anti-androgen compounds that are useful for males that have tumors that have androgen
receptors.
XXV. Natural Androgens [S26]
a. The natural androgens look like testosterone. The difference in estradiol and these is that estradiol has two
hydroxyl groups and testosterone has a double-bond O group. It is more like estrone.
b. Testosterone is the active chemical in some organs and not others. Some organs convert it to
dihydrotestosterone.
Endo: 9:00-10:00
Friday, November 10, 2009
Dr. Pillion
Gonadal Hormones
Scribe: Patricia Fulmer
Proof: Sheena Harper
Page 7 of 7
c. The enzyme that creates that is important because some organs (genitalia and hair follicles) have
dihydrotestosterone as the active form. Without the enzyme, it wouldn’t be active. If we inhibit the enzyme,
we block the action of testosterone in those organs only.
d. Inside your cells, some cells have receptors that recognize testosterone and some have a receptor that
recognizes dihydrotestosterone. Some have both receptors (liver). So when testosterone comes along, we
convert some to dihydrotestosterone and some stays as testosterone. The enzyme could be regulated, which
would give you more of one effect or the other.
e. Dihydrotestosterone is the business end of a lot of chemicals.
XXVI. Synthetic Androgens [S27]
a. Methyl testosterone reminds you of the mestronol we looked at earlier. You put a methyl group in there and it
lasts longer.
b. Fluoxymesterone has a methyl group and a fluorine. This is almost the same approach as the adrenal
corticosteroids that we added a fluorine to because the body can’t break it down like usual.
c. The trouble with these is that they are hepatotoxic. If we take them orally, we get liver damage.
XXVII. Anabolic Steroids [S28]
a. The anabolic steroids like 19-nortestosterone are more anabolic.
b. Here’s an example. This must be a modification on the molecule that emphasizes the anabolic effect rather
than the androgenic effect.
c. If we downplay the androgen effect and use the anabolic effect, it downplays the androgen system.
d. If you give them a 1000x amount of this, then they get muscle but diminish the size of gonads and induce liver
damage.
e. Can be used in burn patients, anemia, and people of short stature because increases muscle mass and red
blood cell content.
f. Side effects in men: impotency, liver cancer, liver disease, heart disease, and rage (which is unpredictable).
Sometimes people are happy, other times they’ll get in a fight with anyone.
g. Women’s side effects: lower voice, heart disease, hair growth, baldness
XXVIII. Anti-androgen [S29]
a. This would be helpful in a male with a tumor that is sexually related or disease where blocking the effect of
androgens would be useful.
b. Cyproterone acetate is an example. The acetate increases half life.
c. You can imagine this might fit into the receptor but block the androgen effect.
d. Flutamide can be used in combo with the GnRH inhibitor for hirsutism and baldness.
e. GnRH is the normal hormone released from the hypothalamus that stimulates FSH and LH release in the
pituitary. If someone has testicular cancer or prostate cancer, you can give a GnRH analog that has a long life.
For the first minute, it’ll stimulate FSH and LH, but then it will turn it off. Those molecules are sometimes used
to treat gonadal related tumors in men too because they diminish the amount of testosterone produced.
XXIX. 5-alpha-Reductase Inhibitor [S30]
a. Finasteride is the molecule that inhibits the dihydrotestosterone-reductase. This is the enzyme that changes
testosterone to dihydrotestosterone, so by inhibiting the enzyme, you don’t get the transformation.
b. It is used in prostate cancer patients and for hair growth.
c. Don’t use it in women or children. It can lead to precocious puberty symptoms in children that are exposed to
this.
d. It looks like testosterone but has a chemical group that can’t be converted. So it blocks the enzyme that would
change testosterone to dihydrotestosterone.
[END 46:21]