Transcript ENDOCRINE PHYSIOLOGY AND PATHOPHYSIOLOGY

ENDOCRINE PHYSIOLOGY AND
PATHOPHYSIOLOGY
Barb Bancroft, RN, MSN, PNP
www.barbbancroft.com
[email protected]
General Anatomy
• Limbic system (Temporal lobe)
• Hypothalamus—the “big cheese”
• Pituitary gland—anterior and posterior lobes—”the Master Gland”
TARGET GLANDS
• Thyroid gland
• Parathyroid glands (4)
• Adrenal glands—cortex and medulla
• Endocrine portion of the pancreas—Islets of Langerhans (Insulin,
Glucagon)
• Endocrine portion of the kidney—erythropoietin (EPO)
• Ovaries and testicles
Your NEWEST ENDOCRINE ORGAN?
• BELLY FAT (visceral obesity)
Let’s start at the top…
• Hypothalamus is the link between the brain (temporal
lobe/limbic system) and the “master gland”—the
pituitary gland
• The hypothalamus sends messages to the anterior and
posterior pituitary gland which in turn send their
message to target organs
• Once the target organ receives the message and
performs the appropriate action, it sends a message
BACK to the pituitary and hypothalamus to…
• TURN OFF the message…this is known as “negative
feedback”
Analogy…start at the top…the BIG
CHEESE
• Chief Nursing Officer, Director of Nursing,
Dean of the Nursing School (the
hypothalamus)--Sends her MEMO via EMAIL
to
Analogy…the “Middle woMan”
• The MEMO can be either “DO something” or
“STOP doing something…
• This memo goes to the:
• Heads of the Departments, Nursing
Supervisors (the pituitary gland)—relay the
message to
Analogy…the “worker bee”
• Floor Nurses, student nurses (the TARGET
ORGANS)—that do all of the work
• “Ok, OK, OK…I’ll get it done…”
Enough already!
• When you have performed the required work,
you (the target organ) send a message back to
TURN OFF the messages from the “higher
ups”
• This is known as NEGATIVE feedback
Who are the memos/messengers?
• Releasing factors/hormones (DO IT!) or inhibiting
factors/hormones (STOP DOING IT) from the
hypothalamus via a capillary network to the…
• The anterior pituitary gland which in turn
releases either a stimulating or inhibiting
hormone which in turn interacts with a receptor
on the target organ to perform a certain task
• The hypothalamus sends a direct message via
neuronal axons to the posterior pituitary to
release hormones that interact with target tissues
Example:
• The Hypothalamus sends
thyrotropin (an affinity for)
releasing hormone (TRH) to…
• The anterior pituitary which
in turn sends thyroid
stimulating hormone (TSH) to
• The thyroid. The thyroid
releases thyroxine (T4) and
tri-iodothyronine (T3)
• Once enough T4 and T3 are
released to boost
metabolism…the message
returns to the pituitary and
hypothalamus to TURN OFF
• NEGATIVE FEEDBACK
TRH
Hypothalamus
+
•
•
TSH
Pituitary
+
Thyroid
T3, T4
- negative (off)
--
What if something goes wrong?…
• Let’s start at the bottom with the TARGET
ORGAN, thyroid…hypthyroidism
• Decreased T3, T4 feeds back to the pituitary
gland and hypothalamus…pump out more
TRH and TSH to stimulate a thyroid …as the
thyroid continues to “die” and T3, T4 are not
being produced, the TRH and TSH continue to
rise…
Too much or too little…hyper- or hypo• If the problem is in the TARGET organ—it’s a PRIMARY
disorder—PRIMARY HYPOTHYROIDISM (Hashimoto’s
thyroiditis is an example)
• If the problem is in the pituitary —it’s a SECONDARY
disorder—SECONDARY HYPOTHYROIDISM (removal of
pituitary/radiation)
• If the problem is with the hypothalamus —it’s a
TERTIARY disorder—TERTIARY or CENTRAL
HYPOTHYROIDISM
(Pituitary and hypothalamic dysfunction may also be
referred to as CENTRAL dysfunction)
So, to diagnose thyroid problems…
• If it’s primary hypothyroidism, the thyroid will not
be able to produce thyroid hormones…decreased
circulating T₃, T₄
• This feeds back to the pituitary gland and says…I
NEED A LITTLE HELP…so the pituitary ramps up
the production of TSH and the hypothalamus
ramps up the production of TRH
• TSH and thyroid measurements will show
decreased thyroid hormones and an increased
TSH
So, to diagnose thyroid problems…
• If the problem is in the pituitary, ie. Secondary
hypothyroidism…
• The pituitary will NOT be able to produce TSH
to stimulate the thyroid…so…
• Thyroid hormones will be low or non-existent
AND TSH will be low since the pituitary gland
is NOT WORKING.
Let’s prepare an egg in the ovary for ovulation…eggs
live in follicles, follicles produce estrogen
• The Hypothalamus releases gonadotropin
releasing hormone (GnRH)…message to the
• The Anterior pituitary gland to release follicle
stimulating hormone (FSH)
• FSH stimulates the target organ, the ovary, to
prepare a follicle/ egg/estrogen
• Egg prepared? Estrogen released? Job done.
• Feedback to turn off the system
SO then, what is PRIMARY ovarian
failure—menopause!!
• Over the years the ovaries have a
preprogrammed dropout of eggs /estrogen/and
follicles--less and less estrogen, the negative
feedback to the pituitary gland says…Something
is wrong, I need MORE estrogen
• The pituitary RAMPS up it’s production of
FSH…thinking that will help…more FSH, more FSH
• FSH is a diagnostic marker of menopause…more
later
Historical highlight
• An Italian medical student, Bruno Lunenfeld, in the
early 1960s had an epiphany. At the time, he
recognized that during menopause women’s urine was
likely to contain high levels of the hormones that
stimulate ovulation. Of course, finding a regular source
for of such urine presented a problem. At a conference
in Italy, however, Lunenfeld met the nephew of Pope
Pius and discussed his idea. The nephew of the Pope
responded …how about using the urine of
postmenopausal nuns?
• Buckets of urine were collected from nuns in convents
in Italy…the fertility drug? Clomid (clomiphene)
Let’s get back to the original concept:
Secondary or tertiary ovarian failure?
• Hypopituitarism—something has destroyed
the pituitary gland and FSH can no longer be
produced (low or no FSH, low or no estrogen)
• Causes? Pituitary adenoma, other pituitary
tumors and cysts, sarcoidosis, Sheehan’s
necrosis (hemorrhage during delivery shuts off
blood supply to anterior pituitary)
• Hypothalamic dysfunction—Prader-Willi
Syndrome, Kallman’s syndrome
Prader-Willi* Syndrome
• *First described in 1956 by Andrea Prader (1919–
2001) and Heinrich Willi (1900–1971)
• A rare genetic hypothalamic disorder characterized by
a chronic feeling of hunger that can lead to excessive
eating and life-threatening obesity; incomplete sexual
maturity
• Used to be the “fat lady in the circus”…120 pounds by
age 6; 350 pounds by age 12
• With the recent benefits of early diagnosis and ongoing
interventions, the obesity rate among children with
PWS has decreased to be similar to the typical
population.
So many examples…we’ve talked
about two…
1) HPT—Hypothalamic-anterior Pituitary-Thyroid-axis
2) HPO—Hypothalamic-anterior Pituitary-Ovarian
(gonadal)-axis
BUT THERE ARE OTHERS:
• HPA—Hypothalamic- anterior Pituitary-Adrenal axis
• HPT—Hypothalamic-anterior Pituitary-Testicular
(gonadal)-axis
• HPB—Hypothalamic – anterior Pituitary-Breast
AND MORE:
• Hypothalamus – posterior pituitary –target organ
kidney, breast, uterus
The Hypothalamus (under the
thalamus)
• The hypothalamus is, millimeter for millimeter,
the most powerful subdivision in the brain.
• It weighs about 4 grams, is the size of an almond,
and constitutes no more than 1 percent of total
brain volume
• But it packs a powerful punch
• The critical link between the cerebral cortex, the
limbic system, and the hormonal output of the
“master gland”, the pituitary
The hypothalamus
• Contains numerous clumps of neurons (nuclei)
regulating appetite and satiety, thirst
(osmoreceptors), growth and reproduction,
sex drive and sexual orientation, temperature
regulation, sleep, 24-hour biological clock
Who runs the entire show?
• The suprachiasmatic nucleus (SCN) of the
hypothalamus coordinates all of the activities of the
hypothalamus (appetite and satiety, thirst,
temperature, sexual function, hormonal production,
emotions, and blood pressure)
• The SCN also regulates the activity of the pineal
gland and the secretion of melatonin—the
sleep/wake cycle
How does our “biological clock” work?
• Light hits the retina and specialized cells send the message to
the SCN
• The SCN sends the message to the pineal gland which in turn
influences the secretion of melatonin – sleep/wake cycle
• Quite a few genes are involved with your biological clock
• One is cleverly called the CLOCK gene and is not working
properly in patients with bipolar disease
• Lithium resets the biological clock
• Stops the manic phase and helps the patient re-synchronize to
a 24-hour day
Other nuclei of the hypothalamus…
the appetite and satiety center
• Appetite center and norepinephrine—
Prednisone, Remeron (mirtazapine),
• Satiety center and serotonin (fenphen);
atypical antipsychotics block a specific
serotonin receptor, which in turn stimulates
appetite and weight gain (especially Clozapine
and olanzapine)
Inhibiting and Releasing Hormones
(Factors) from the hypothalamus
• Most of the activities of the hypothalamus are carried
out by inhibiting or releasing hormones
• Thyrotropin Releasing Hormone (TRH)—TSH
(pituitary)—thyroid gland
• Gonadotropin Releasing Hormone (GnRH)—FSH, LH
(pituitary)—ovaries and testicles
• Corticotropin Releasing Hormone (CRH)—ACTH
(pituitary)—adrenal cortex
• Somatropin –GH (pituitary)—lots of tissues
• Prolactin Inhibiting Factor (PIF) and Prolactin Releasing
Factor (PRF)—milk-producing glands of the female
breast
Examples of inhibiting and releasing
factors from the hypothalamus:
• Prolactin-releasing (promote lactation)
hormone (PRH) stimulates the secretion of
prolactin (PRL) from the anterior pituitary
gland (WHEN NECESSARY—lactating mom’s
would be a good reason to release prolactin
releasing hormone)
However, the USUAL message is to INHIBIT the
release of prolactin from the pituitary
• Prolactin-inhibiting factor (PIF) from
the hypothalamus inhibits the secretion
of prolactin from the anterior pituitary
(THANK GOODNESS)
• Who would want to lactate on any given
day WITHOUT a baby to lactate for?
• Wet nurses—
Wet nurse
• A woman can only act as a wet-nurse if she is lactating. It
was once believed that a wet-nurse must have recently
undergone childbirth. This is not necessarily true, as regular
breast suckling can elicit lactation via a neural reflex of
prolactin production and secretion. Some adoptive
mothers have been able to establish lactation using a
breast pump so that they could feed an adopted infant.
• There is no medical reason why women should not lactate
indefinitely (some 3rd world countries breast feed children
up to the age of five) or feed more than one child
simultaneously (known as 'tandem feeding')... some
women could theoretically be able to feed up to five
babies.
Examples of inhibiting and releasing
factors from the hypothalamus:
• Gonadotropin-releasing hormone (GnRH) –
stimulates the pituitary to release LH and FSH
(follicle stimulating hormone) to stimulate the
gonads; triggers hormonal secretion from the
ovaries and testicles and jump starts puberty
in kids
Girls –fat tissue and puberty
• Girls—fat = early puberty
• Aromatase in fat tissue converts testosterone to
estradiol and triggers early puberty
• Leptin (from adipocytes) sends a signal to the
hypothalamus to produce GnRH and says…she’s
READY!
• OPPOSITE problem--Female Athlete Triad—thin
(no adipose tissue) with disordered eating,
amenorrhea /oligomenorrhea, and
osteopenia/porosis
Puberty…in girls…
• When does puberty start?
• Breast development (thelarche) at 10 in Caucasians and
before 9 in African-Americans
• Pubic hair one year later
• Menarche two years after breast development
• 27% of AA girls have breasts at 7; 7% Caucasian girls
• Precocious puberty is under 8 in C girls and under in AA
girls
• B & B Supergrow?
• Diet? Fat, Fat tissue?
• Environmental estrogens? PCBs, PBBs, DDE, phthalates,
BPA
Boys, fat tissue, and delayed puberty
• Boys – fat = delayed puberty
• Aromatase in fat tissue converts testosterone
to estradiol and delays their development
Synthetic GnRH drugs
• We make synthetic drugs that mimic the
functions of GnRH –
• Leuprolide(Lupron, Eligard); nafarelin
(Synarel), goserelin (Zoladex), buserelin
(Suprefact/Suprecor)
• We can use these drugs to boost fertility OR
we can use these drugs to DOWNREGULATE
the function of the ovaries and testicles
Endometriosis of the small bowel
• Use of GnRF drugs to “downregulate” the
gonadal secretion of estrogen
• after 10 days of administering these drugs
hypogonadism develops via downregulation
of receptors
• When used to “downregulate” endometriosis
symptoms, the symptoms will get WORSE
initially, due to the “flare effect” (increase in
LH and FSH)
The GnRH agonists—other uses
• Also used for hormonally-stimulated cancers such as
prostate cancer to downregulate testosterone to
reduce hormonal stimulation of the prostate
(hormonal castration)—
• causes gynecomastia in men (the old days we used
DES—diethylstilbesterol to change the hormonal
environment in men)…
• Downregulate hormonal stimulation in breast cancer
patients (as above)
• Used to delaying puberty in precocious puberty cases
• shrink uterine fibroids
Central precocious puberty
• Histrelin acetate (Supprelin LA)—first and only
implant for the treatment of children with
central precocious puberty
• Steady flow of GnRH actually turns OFF the
system
Congenital deficiency of GnRH
• Kallman’s syndrome
• Anosmia
• amenorrhea
Examples of inhibiting and releasing
factors from the hypothalamus:
• Growth hormone-releasing factor
somatotropin—stimulates the release of
growth hormone from the anterior pituitary
(released at night)
• KIDS GROW AT NIGHT—growing pains
Examples of inhibiting and releasing
factors from the hypothalamus:
• Corticotropin-releasing hormone (CRH)—
stimulates the release of ACTH
(adrenocorticotrophic hormone) from the
pituitary which in turn triggers cortisol release
from the adrenal gland
• Hypothalamic—pituitary—adrenal axis
Let’s move on to the the Pituitary
gland
• Pituitary comes from the Latin pituita, meaning
“phelgm,”, also related to the Greek ptuō,
meaning “I spit.” The Greek word, obviously, is
vividly imitative and is the forerunner of the
expletives “Ptooey!” and “Phooey!”
• The Greeks and Romans believed that the brain
secreted a mucoid substance that was discharged
through the nose (ie, “snot”)
• …this notion was finally nixed in the 17th century
but the name pituitary stuck
You actually have two separate pituitary
glands—the anterior and the posterior
pituitary*
• The posterior pituitary gland is a direct extension
of the hypothalamus via the infundibulum
(pituitary stalk—actually infundibulum means
“funnel”) and therefore is part of the nervous
system
• Neurons in the hypothalamus make and store
hormones secreted by the posterior pituitary
• Oxytocin and ADH (antidiuretic hormone, aka
arginine vasopressin, AVP)
• *lower forms of animals have a middle pituitary
The anterior pituitary
• The anterior pituitary is an embryologic
outpouching of the posterior pharynx / roof of
the mouth (Rathke’s pouch) (GI tract)—backs
up through the craniopharyngeal canal and
“sticks” itself to the posterior pituitary
• the anterior pituitary gland is NOT part of the
nervous system, it’s actually part of the GI
tract
• Craniopharyngioma
Anterior pituitary
• To release hormones from the anterior pituitary, the
hypothalamus has to send it’s releasing or inhibiting
hormones via the capillary system (hypophyseal portal
system)—connects the capillary system of the
hypothalamus with the capillary system of the pituitary
• This capillary network is vulnerable to sudden loss of
blood-• Sheehan’s necrosis of the anterior pituitary gland—
infarction of the anterior pituitary during labor and
delivery (sudden loss of blood via a hemorrhaging
episode in the mom)
Anatomic location of the pituitary
gland
• The entire pituitary gland sits beneath the
optic chiasm in a small bone called the sella
turcica (turkish saddle)
• If the pituitary enlarges (macroadenoma, for
example), it will push up against the optic
chiasm and cause a visual loss known as
bitemporal hemianopsia or “TUNNEL VISION”
• Prolactinoma in a graduate NP student at UVA
(visual fields)
Bitemporal hemianopsia
Hormones of the anterior pituitary released in
response to hypothalamic factors
•
•
•
•
•
•
GH (Growth Hormone) (somatotropin)
FSH (Follicle Stimulating Hormone) (GnRH)
LH (Luteinizing Hormone)(GnRH)
TSH (Thyroid Stimulating Hormone)(TRH)
ACTH (Adrenocorticotropic Hormone)(CRH)
PRL (Prolactin)(PIF)
Hormones of the posterior pituitary
• Oxytocin
• ADH (Anti-diuretic Hormone) also known as
Arginine Vasopressin (AVP)
Hormone of the posterior pituitary—
Oxytocin
• The first peptide ever to be replicated outside the
body was oxytocin (1953). It’s released from the
posterior pituitary gland during childbirth to bind
with receptors in the uterus, where it stimulates
uterine contractions to help “expel” the baby
• Synthetic oxytocin, as we all know, is Pitocin
• HISTORICAL HIGHLIGHT: As early as 1902, people
knew there was something in crude extracts of
farm animal pituitary glands that could be used
by obstetricians to aid women who had been in
labor for a prolonged period
Oxytocin
• Milk let-down response from the mammary
glands for breast feeding
• Uterine contractions during orgasm
What else does oxytocin do?
• The “Tend to and be a friend to” hormone—
bonding hormone; trusting; higher levels in
women
• Helps us to read other’s minds
• Cuddly, touchy-feely, earth-momma hormone;
calming effect
• Estrogen enhances oxytocin
Oxytocin—the hormone of monogamy
• Hormone of monogamy? Inspires trust
• In prairie voles at least…
• Women have two genes for it…men? One
gene and testosterone reduces oxytocin
• Men and the wandering eye syndrome?
HELLO???
• Oxytocin nasal spray
PETS and oxytocin
• Back to oxytocin and bonding
• Oxytocin levels almost double in people and in dogs
when humans talk to and stroke their canine/feline
friends
• Endorphins and dopamine levels also increase with
pets
The second hormone of the posterior
pituitary—anti-diuretic hormone (ADH)
• Also called arginine vasopressin (AVP) because in high
doses it vasocontricts; in low doses it conserves water
• ADH is primarily regulated by osmoreceptors in the
hypothalamus
• HIGHEST ADH levels around 11 p.m. to midnight—
conserve H₂0
• Dehydrated? High serum osmolarity? Produced in the
hypothalamus, stored and released from the posterior
pituitary gland; ADH binds to AVP/ADH receptors on
the distal tubules and collecting ducts of the kidney to
increase water reabsorption to dilute the high serum
osmolarity
Other conditions that boost ADH
• Volume loss of 7-25% (hypovolemic shock),
stress, trauma, pain, nicotine, morphine (one
of the reasons for urinary retention in post-op
patients on morphine)
Booze inhibits ADH
• Especially BEER due to it’s hypotonicity and
the fact that one usually drinks copious
amounts
Other notes on ADH
• ADH may also have something to do with
memories formed during sleep—good sleep?
Good memories? Elderly and sleep patterns and
memory problems? Booze and sleep patterns and
memory problems?
• In older patients (or any patients for that matter)
with chronic renal insufficiency, the kidneys stop
responding to ADH—may result in nocturia/bed
wetting
• Kids with enuresis—immature response to ADH
and problems with bladder sphincter tone
How do you treat enuresis in kids?
• Night time bladder control is usually achieved
by 5 or 6 years of age; if not?
• Moisture alarms
• Desmopressin (DDAVP) intranasally for sleepovers and camp
• Can also use a TCA to tighten the bladder
sphincter (imipramine—Tofranil)
Too much ADH? Too little ADH?
• Too much? The Syndrome of Inappropriate
ADH
• Too little? Diabetes Insipidus
Digression: Diabetes insipidus or
diabetes mellitus?
• What does “diabetes” mean? To siphon…what are you
siphoning? URINE…
• Is it “sweet” or “honeyed”?– mellitus
• Is it “tasteless” ?-- insipid
• Dr. Thomas Willis… “Taste thy patient’s urine, for if it be
sweet…”
• “Nurse, take a swig of that…” —”Oh, that’s so sweet!”
• “Yuck—that doesn’t taste like anything…its insipid”
Too little ADH?
• Diabetes Insipidus—disorder of water balance
caused by the non-osmotic renal loss of water
leading to the excretion of a large volume of
dilute urine
• Up to 18 L per day…4 to 6 L is the lowest
threshold for symptoms; urine specific gravity is
less than 1.005
• Incidence? Rare; most cases occur in adulthood;
nephrogenic and familial forms in kids
Causes of Diabetes Insipidus
• Central DI—complete or partial deficiency of ADH
from the posterior pituitary gland; head trauma,
post-surgical (1 to 6 days after surgery), tumors,
infections (TB, syphilis, toxoplasmosis,
encephalitis, meningitis, sarcoidosis),
cerebrovascular disease
• nephrogenic diabetes insipidus—
unresponsiveness of the ADH/AVP receptors on
the kidney to ADH
• Congenital--rare inherited, X-linked recessive
Diabetes Insipidus (DI)…classification
• Acquired; medications (lithium, amphotercin
B, demeclocycline (Declomycin), cisplatin,
aminoglycosides, rifampin
• Dipsogenic DI—excessive and inappropriate
fluid intake due to a defect in the thirst
mechanism
Lithium
• Inhibits water reabsorption in the collecting duct
through impairment of cyclic AMP and frequently
precipitates a transient polyuria in patients taking
therapeutic doses
• Greater than 25% of patients have a persistent
defect in concentrating capacity 1 year after
discontinuing Lithium
• Demeclocycline (Declomycin) also inhibits cyclic
AMP but the effect is fully reversible (hence, why
it’s used for the Syndrome of Inappropriate ADH)
Too much ADH? Syndrome of
inappropriate ADH (SIADH)
• TOO MUCH water without conserving the appropriate
electrolytes; this causes a DILUTIONAL problem—especially
problematic is the low sodium (hyponatremia)
• CNS w/excess ADH release—bleeding/hemorrhage, CVA,
DTs, GBS, head trauma, hydrocephalus, infections, tumors
• Drugs—bromocriptine, carbamazepine (Tegretol),
cyclophosphamide (Cytoxan), Desmopressin (DDAVP),
ecstasy, haloperidol (Haldol), nicotine, opiates, SSRIs, TCAs,
phenothiazines, vinblastine, vincristine
• Neoplasms (ectopic ADH secretion)—Small cell lung cancer
(SCLC), prostate cancer, duodenal carcinoma,
mesothelioma, lymphoma, pancreatic carcinoma, thymoma
Clinical presentation
• Symptoms are dependent on the degree of
hyponatremia and the rapidity at which it
develops
• At serum levels < 125 mEq/L, patients may
present with muscular weakness, nausea,
headaches, lethargy, ataxia, and psychosis to
cerebral edema, increased ICP, seizures and
coma
Treatment of SIADH
•
•
•
•
Correct the low sodium but NOT TOO FAST
If the onset was rapid, you can correct rapidly
But if onset is not known, go slowly
1-2 mEq/L/hour for the first 3-4 hours; and by no
more than 0.5 mEq/L thereafter, for a maximum
correction of 10 mEq/L per 24 hours
• Fluid restriction
• Check sodium levels and volume status q2 hours
Treatment of SIADH
• Hypertonic saline reserved only for treatment
of acute or symptomatic SIADH
• Oral salt tablets
• Loop diuretics
• Demeclocycline – diminishes responsiveness
of kidneys to ADH, resulting in increased
water secretion
Anterior pituitary dysfunction
• Panhypopituitarism
• Decreased TSH, FSH, LH, ACTH, GH
Pituitary dysfunction
• Too much or too little of a specific hormone—
congenital lack of cells producing specific
hormones, OR…
• Cells that produce one specific hormone can
lose control and produce an excess of that
hormone (functioning pituitary adenoma)
Growth hormone--functions
• Released in response to somatotropin from the hypothalamus
• Produced primarily during sleep; results in saltatory growth (not
linear)
• GH is an anabolic hormone—builds you up by increasing amino acid
uptake to build muscle; stimulates growth of bone, cartilage, soft
tissue; decreases fat tissue
• Human growth hormone and the Black Market—athletes and
endurance sports (Lance Armstrong, Barry Bonds)
• Growth hormone from cadaver pituitary glands was responsible for
CJD (Creutzfeldt-Jakob Disease) in a small number of patients
receiving the injections
• Growth hormone impairs insulin action and is known as a counterregulatory hormone—increased growth hormone = secondary
diabetes
Growth hormone
• Natural decline in growth hormone that
occurs with aging (somatopause); GH
deficiency in adults—decreased muscle mass,
increased body fat around the middle;
decrease exercise capacity; osteopenia,
sarcopenia, diminished well-being
• Sound familiar? 
• About 50% of persons over 65 may be
considered biochemically GH deficient
Growth hormone? Too much, Too
little?
•
•
•
•
Pituitary “dwarf”
Lack of cells (somatotropes) that produce GH
Treatment?
Recombinant GH
The most famous pituitary “dwarf”
• Colonel Tom Thumb (Charles Stratton) and his
lovely wife, Lavinia Stratton (1841-1919)
Growth hormone treatment for kids
with pituitary deficiency of GH
• Used to use extracts from cadaver pituitary glands until
patients developed Creutzfeldt-Jakob dementia and
died from the transfer of the prion in the pituitary
tissue
• Recombinant GH is now used for patients with growth
hormone deficiency
• $52,000 for ~ 5 years of treatment; injections 3x per
week
• May also be used for idiopathic short stature—usually
gain 3-6 cm (about 2.3 inches)
• Black market for athletes; “fountain of youth” for
those who can afford it???
Pituitary adenoma producing too
much growth hormone
•
•
•
•
BEFORE the epiphyseal plates close
GIANTISM, diabetes, soft bone matrix
“I don’t hate little people….
The story of David and Goliath (Goliath was a
pituitary giant…)—loss of peripheral vision;
softening of temporal bones
• David’s slingshot—thwack! Epidural
hematoma felled the GIANT; the little guy
wins in the end…
Tallest man—Alton, Illinois’ claim to
fame
•
•
•
•
Robert Wadlow with his father Harold
1918-1940
8’11”
Alton, Illinois
Pituitary adenoma producing too
much growth hormone
• AFTER the epiphyseal growth plates close—
acromegaly—enlargement of the “acrals” or
small bones; enlargement of soft tissues
• Deep voice
• Hirsutism, diabetes
Prolactinoma
• A benign tumor of the pituitary can produce too much
prolactin (prolactinoma) triggering breast milk
production in NON-lactating females (men almost
never have galactorrhea)
• Other symptoms?
• Location? Headaches/visual field defects (more later)
• Amenorrhea, infertility
• Sexual dysfunction and loss of libido in both males and
females
• Emotional lability—guys cry more; girls cry all of the
time; quivering lip
Dopamine plays a major role
• In the release of pituitary hormones;
• Inverse relationship—low dopamine results in
an increased release whereas increased
dopamine inhibits the release
• Prolactinomas –benign pituitary tumors
producing too much prolactin can be treated
medically by increasing dopamine and
inhibiting prolactin
• Old drug used? Bromocriptine; new drug?
Cabergoline (Dostinex)
• Cabergoline is used to treat different types of
medical problems that occur when too much
of the hormone prolactin is produced.
• It works by inhibiting the production and
release of prolactin from the pituitary gland.
Cabergoline use is usually stopped when
prolactin levels have normalized for 6 months.
It may be prescribed again if symptoms of
excess prolactin return.
Inverse relationship between
dopamine and prolactin
• Bromocriptine/Parolodel used to be
prescribed to increase dopamine in order to
decrease prolactin and subsequent milk
production for moms who did not want to
breast feed—PROBLEM? Boosting both
dopamine receptors in the brain caused
movement disorders (dyskinesias) in the mom
• WHOA!
Follicle stimulating hormone—the
Preparation of an egg…
• Follicle = egg =
estrogen
• FSH (follicle stimulating
hormone prepares the
egg for release from the
ovarian follicle); also
stimulates
spermatogenesis in
males
Hypothalamic-Pituitary-Ovarian axis
and oral contraceptives
• Oral contraceptives “feed back” to the
pituitary gland and the hypothalamus to shut
off the endogenous axis and inhibit ovulation
• Pills in the “60s and 70s” vs. today’s pills
• 80-100 mcg/pill vs. 20-30 mcg/pill
• The early OCs would stop an elephant from
ovulating
• Today’s OCs? The egg is “prepared”…miss a
pill and you ovulate
COCs in perimenopausal women
• Vasomotor symptoms—a COC containing 30
mcg of estrogen per day—90% will have
complete relief of symptoms within 2 months
+ that dose will inhibit ovulation
• (Shargil AA. HRT in perimenopausal women with a
triphasic contraceptive compouns; a three year
prospective study. Int J Fertil 1985; 30:15;18-28)
Adrenocorticotropic hormone
• Released in response to CRH from hypothalamus
• ACTH triggers the release of cortisol from the
adrenal cortex; cortisol is a “catabolic”
hormone—it “breaks down” tissues to give you
energy (in the form of glucose) during times of
stress; known as a glucocorticoid
• Increased ACTH between 2 - 6 a.m. resulting in
the highest cortisol levels between 6 – 8 a.m.
ACTH – the molecule
• Pro-opiomelanocortin—3 substances contained
within this molecule
• Endorphins (opio)
• MSH (melanocyte stimulating hormone)—
humans don’t have MSH per se—lower animals
do—especially those that changes color in
conformity with their environment; the size of
their intermediate lobe positively correlates with
the ability to change color
• Cortin—stimulates cortisol from adrenal cortex
Target Organs
• Thyroid gland
• Parathyroid gland (not under control of the
hypothalamus/pituitary)
• Adrenal gland
• Ovaries
• Testicles
The thyroid gland
• Two lobes composed of multiple follicles with
thyroglobulin in the middle of the follicles; the thyroid
gland is under the influence of TSH from the anterior
pituitary which in turn is under the influence of TRH
from the hypothalamus
• TSH stimulates iodine uptake from the diet and the
thyroid produces T₄ (thyroxine) and T₃ (triiodothyronine); T₄ is the pro-hormone converted to T₃;
20 to 1 ratio of T₄ to T₃
• T3 is the functioning hormone
• Tissues obtain 90% of their T₃ by removing 1 iodine
(deiodinating) T₄
The thyroid gland
• When thyroid hormones are released into the
serum, the majority of both hormones are
tightly bound to TBG (thyroid binding
globulin); the physiologically active forms are
“free” or unbound; When evaluating patients
it is more important to pay attention to “Free
T₄ than total T₄; the unbound or free forms
provide the negative feedback signals to the
pituitary and hypothalamus
Thyroid hormone
• What does thyroid hormone do?
• Thyroid hormone affects most body tissues by increasing
the rate of protein, fat, and glucose metabolism; as a result
it increases heat production and body temperature
• Normal linear growth requires thyroid hormone
• Brain growth in kids requires thyroid hormone—primarily
1st two postnatal years—400 grams at birth (primarily
neurons/gray matter; thyroid hormone stimulates growth
of white matter/myelin to connect the neurons
• Your personality
• Normal periods, fertility
Diagnosis of thyroid dysfunction
• Primary Hypothyroidism—decreased thyroid
hormone (T₄) production results negative
feedback to pituitary and an INCREASED TSH
• Secondary Hypothyroidism (pituitary
dysfunction)—decreased TSH and decreased T₄
• Hyperthyroidism—increased thyroid hormone
production results in a DECREASED TSH with an
increased T₄
• Secondary/tertiary hyperthyroidism—RARE
Too little? Hypothyroidism
• Autoimmune thyroiditis—Hashimoto’s thyroiditis—antibodies
to thyroid peroxidase (TPO) and thyroglobulin antibodies are
present
• Iatrogenic—thyroidectomy, radioiodine therapy
• Thyroiditis—subacute thyroiditis (also known as De Quervain’s
thyroiditis), silent thyroiditis, postpartum thyroiditis
• Drugs—methimazole, PTU, iodine, amiodarone (40% iodine by
weight), lithium, interferons, thalidomide, sunitinib, rifampicin
• Congenital hypothyroidism—thyroid aplasia or hypoplasia,
defective biosythesis or thyroid hormones
• Disorders of the pituitary or hypothalamus (secondary or
tertiary; aka central)
Congenital hypothyroidism
• “cretinism”
• Where does the word “cretin”’ come from?
• 18th century; French crétin, from French
dialectal, deformed and mentally retarded person
commonly found in certain Alpine valleys, from
Vulgar Latin *christinus, Christian, human being,
poor fellow, from Latin Chrstinus, Christian;
see Christian
• “too simple to sin”…
Adult with myxedema (severe
hypothyroidism)
• Ventilator and IV levothyroxine
Hypothyroidism
• Exhaustion, somnolence, lethargy, depression, slow
cognition
• Dry hair, balding, loss of lateral third of eyebrows
(Queen Anne’s eyebrows)
• Bradycardia (thyroid hormone and the number of
receptors on the SA Node)
• Hypercholesterolemia, hyponatremia
• Menstrual disturbances/Menorrhagia
Hypothyroidism
• decreased libido
• dry thin pale skin, vitiligo
• Weight gain (10-15 pounds), constipation (10 to 15
pounds…haha)
• Generalized muscle aches and pains; calf stiffness
• carpal tunnel syndrome; slow relaxing tendon reflexes
• Pericardial and/or pleural effusions; ascites
• Cold intolerance
• Normocytic anemia
• “you’re not dead until you’re warm and dead”…
Who should be screened?
• Patients with Down or Turner syndrome
• Patients taking certain drugs—lithium,
amiodarone, thalidomide, interferons, sunitinib,
rifampicin
• Patients who have received radioiodine
treatment or neck radiation
• Patients who have had a subtotal thyroidectomy
• Patients with type 1 diabetes and autoimmune
Addison’s disease
Classification of hypothyroidism—
based on TSH
• Normal TSH?
• Adults presenting with symptomatic primary
hypothyroidism often have a TSH level in
excess of 10 μU/l, and decreased free T₄
• Mild primary hypothyroidism, aka, subclinical
hypothyroidism, usually presents with a TSH
5-10 μU/l but a free T₄ within reference range
• Secondary/central hypothyroidism—TSH is
low
Treatment of hypothyroidism
• Levothyroxine therapy should be monitored by
following the serum TSH
• Initially, the TSH should be measured every 4 to 6
weeks (reflecting the time required to achieve a
steady state with a medication that has a oneweek half life)
• Patients often feel least symptomatic when the
TSH is on the low end of normal
• Overreplacement can increase the risk of AF and
excessive bone loss (over age 60)
• Monitor TSH every six months after stablization
Patient education
• No supplements within 4 hours—calcium, iron or antacids
w/aluminum hydroxide (interfere with absorption)
• Levothyroxine has a half life of seven days in the
bloodstream and it will take a week or more to start to feel
better; conversely, if one tablet is missed, there will be no
noticeable effect
• If muscle weakness, stiffness or cognitive defects are
present, it may take up to six months to fully resolve
• Levothyroxine should be taken on an empty stomach to
maximize absorption
• Small changes of levothyroxine dosage may be likely over
your lifetime; dose will likely DECREASE with aging
Levothyroxine
• 1.7 μg/kg body weight –approximately 100 μg daily for
an average sized woman (60 kg) and 125 μg (75 kg).
• Start with lower dose for patients over 60 or those with
CAD
• When giving a trial of levothyroxine therapy for
subclinical hypothyroidism, start with a dose close to a
full replacement dose (75 or 100 μg daily), on the basis
that it would be difficult to be sure if the symptoms
might not be caused by hypothyroidism, until a
therapeutic dose of levothyroxine has been tried
Target level
• Dose should be adjusted to make the patient
feel better, duh.
• Usually within the lower half of the reference
range (0.4 to 2.5 μU/l)
• If the patient feels pretty well with a level in
the upper half of the reference range,
adjustment is not necessary
Hypothyroidism and infertility
• Thyroid-related infertility—high levels of TSH,
even though within normal limits, may be too
high for fertility; levels between 1-2 μU/l seem
to be best for makin’ babies)
• Even the presence of anti-thyroid antibodies
WITHOUT clinical disease may cause
reproductive problems
• One of the first tests for infertility should
ALWAYS include thyroid testing
Hyperthyroidism
•
•
•
•
2% of women; 0.2% 0f men
Autoimmune disease --Grave’s disease,
toxic multinodular goiter
Iodine-induced hyperthyroidism—
amiodarone, radioiodine contrast media,
• subacute thyroiditis
• Factitious hyperthyroidism (taking
levothyroxine for weight loss)
Hyperthyroidism
•
•
•
•
•
•
•
•
•
Weight loss despite normal/increased appetite
Diarrhea
Sinus tachycardia, palpitations, atrial fibrillation
Tremor
Fatigue, exhaustion, insomnia
muscle weakness
Hyperreflexia
Sweating, heat intolerance
Exophthalmos, proptosis
Grave’s disease—hyperthyroidism
plus…
• Diffuse symmetrical enlargement (goiter) of
the thyroid gland
• Eyelid retraction
• Corneal ulceration
• Diplopia, papilledema, loss of visual acuity
Diagnosis of hyperthyroidism
•
•
•
•
Low TSH (less than 0.05 μU/L
↓
Free T₄ (FT₄)
↓
High T₄? Primary Hyperthyroidism
Low T₄? Secondary hypothyroidism (pituitary)
Normal T₄? Do a T₃
High T₃? Primary hyperthyroidism (T₃ thyrotoxicosis)
Low/normal T₃? Subclinical hypothyroidism or nonthyroidal illness
Diagnosis
• Thyroid scan using radioactive iodine--¹²³I
(different from ¹³¹Iodine used to Tx
hyperthyroidism to ablate the gland)—high
uptake with Grave’s disease, toxic
multinodular goiter, solitary adenoma
• Antithyroid peroxidase (TPO) antibody is
present in autoimmune thyroid diseases such
as Grave’s disease)
Treatment of hyperthyroidism
Radioactive iodine, antithyroid drugs, surgery
• radioactive iodine, (I¹³¹)—highly effective but
usually requires lifelong replacement therapy
due to total destruction of the gland;
overacting adenomas will take up the RAI and
destroy the adenoma, leaving normal gland
intact; not used in PG due to destruction of
fetal thyroid; one dose—simple. Risk of
hypothyroidism is 90%
Treatment of hyperthyroidism
• propothiouracil (PTU) or methimazole (Tapazole) to
decrease T₄ synthesis; remission rate of 30%-50% in
Grave’s disease; methimazole is QD;
• Major side effects—drug-induced hepatitis;
agranulocytosis (neutropenia)—report any fever or
sore throat
• Thyroidectomy (subtotal)—for patients who fail
medication or RAI or who has an extremely large goiter
causing dysphagia or airway compromise
(complications—recurrent laryngeal nerve paralysis,
hypoparathyroidism leading to hypocalcemia)
Treatment
• Before the antithyroid drugs or RAI kick in, relief
of symptoms (palpitations, tremor) with a beta
blocker is important
• Propranolol (Inderal) can be chosen—20-40mg 2
to 4 times a day, with added benefit of preventing
the conversion of T₄ to T₃ but the inconvenient
dosing schedule of 2-4 times/day
• Atenolol (Tenormin) is a common choice---QD
• In subclinical hyperthyroidism, some advocate
treating the elderly because they are at an
increased risk of atrial fib and osteoporosis
Thyrotoxic storm (thyrotoxicosis)
• IV beta blocker to slow heart rate before heart
failure kicks in
• If febrile, don’t use aspirin to decrease the
temperature…ASA releases more T₄ from
thyroid binding globulin and can make the
thyrotoxicosis worse
• Use acetaminophen for fever in these patients
The Parathyroid Glands
• 4 very small (size of a piece of rice) glands plastered to
the back of the thyroid gland
• Produce PTH (parathyroid hormone) which helps
control serum calcium; serum calcium levels low? PTH
is released to stimulate the resorption of bone and
release calcium into the serum; serum calcium levels
increase, bone matrix calcium levels decrease
• serum calcium levels are tightly regulated; any
deviation, particularly an elevation indicates underlying
pathology and merits a thorough evaluation
• Major function of serum calcium is to exert an
inhibitory control over neuromuscular excitability
Hypoparathyroidism
• normal range of total serum calcium—8.4-10.4
mg/dl (2.1-2.7 mmol/L); adjust total seru calcium
with level of albumin; [PTH] range 15-75
• 50% of total serum calcium is bound to albumin
and is biologically IN-active
• Therefore, if the serum albumin is low, the total
calcium may provide a misleadingly low
indication of free or ionized calcium (the
functioning calcium)
Hypoparathyroidism
• Too little PTH results in low levels of serum
calcium and increased neuromuscular excitability;
also known as tetany
• Calcium levels are below 8.4 mg/dl; patients are
confused, complain of parasthesias of the lips and
fingertips; positive Chvostek’s sign (Cheek), and
Trousseau’s sign
• Causes—autoimmune destruction; surgical
removal during thyroidectomy
• Rx: give calcium IV or orally depending on calcium
levels and patient’s condition
Primary hyperparathyroidism
• Primary hyperparathyroidism is the most
common cause of hypercalcemia and should
be considered in anyone with an elevated
calcium level
• Peaks in 7th decade; 75% are women; men =
women before age 45
• Head and neck irradiation in childhood and
long-term lithium
• Usually caused by a single adenoma
Hyperparathyroidism
• Classic S & S rarely seen in U.S. today because of
early detection of calcium abnormalities on
routine blood tests
• Classic signs—hypercalcemic sx of nephrolithiasis
(kidney stones), overt bone disease (“stone and
bone” disease), neuromuscular symptoms
• Symptoms today—weakness, easy fatiguability,
anxiety, and cognitive impairment; kidney stones
in 4-15%
Secondary hyperparathyroidism
• Chronic renal failure—can’t excrete phosphorus,
need to balance it with calcium so the
parathyroids produce PTH to move calcium out of
the bones to balance phosphorus; vicious cycle
eventually depletes bone
• Malignancy—low or undetectable PHT level rules
out primary hyperparathyroidism and raises the
possibility of cancer-associated hypercalcemia
• Ovarian failure—one of estrogen’s functions is to
inhibit PTH; no estrogen? Unopposed PTH
Adrenal gland—two parts; medulla
(inner) and cortex (outer)
• Adrenal medulla—produces EPINEPHRINE (epi—on
top of, nephros, the kidney) (adrenalin) and
NOREPINEPHRINE (noradrenalin)
• Fight-flight response
• Visit Barb in Chicago at 2 a.m.
• Take a wrong turn, 4 flat tires, transmission falls out
of your car
• What’s going to happen to you?
Fight/Flight response—acute stress
response
•
•
•
•
•
•
•
•
Release of glucose, inhibition of insulin
Pupils dilate
Tachycardia, BP goes up
Bronchodilation—rapid respirations
Vasodilate the large arteries to the arms and legs
Vessels in the skin constrict--pale
Hair on the back of the neck and arms stands up
What do your bowels WANT to do?
“If I have told you once, I have told you
twice…”
• “do NOT go to the emergency room with dirty
underwear…!”
The biggest stress of the day…
• On a day-to-day basis the most stressful part of the day is
GETTING OUT OF BED
• Adrenal glands pump out norepinephrine, epinephrine,
cortisol
• Heart rate goes up, blood pressure goes up, blood glucose
goes up
• The liver releases newly synthesized clotting factors, platelets
are stickier due to glucose ), inflammatory mediators are
highest in a.m.
• Increased risk of heart attacks within two hours of getting out
of bed
• How to avoid a heart attack?
Adrenal gland—the outer cortex
• Corticosteroids—cortisol—role in
carbohydrate metabolism and the chronic
stress response—boosts SUGAR
• Mineralcorticoids—aldosterone—regulates
salt and water homeostasis via
renin/angiotensin—boosts BLOOD PRESSURE
• Adrenal androgens—testosterone,
androstenedione, 17-hydroxyprogesterone,
dehydroepiandosterone (DHEA)
Excess cortisol? Clinical features in
order of frequency
• Plethoric (red face)
• Central obesity—cortisol moves fat toward the
center (Centripetal obesity)—”moon face”
• Catabolic hormone--breaksdown skeletal
muscle—skinny arms and legs;
• Amino acids used for gluconeogenesis and high
blood sugars leading to Impaired glucose
tolerance or frank diabetes
• Aldosterone-like properties—sodium and water
retention, and potassium excretion—
Hypertension and hypokalemia
Excess cortisol
• Menstrual irregularity in women, ED in men
• Osteoporosis—moves calcium out of bone
• Protein breakdown in skin leads to thin skin
over abdomen and purple striae (stretch
marks) particularly over the abdomen and
breasts
TOO MUCH CORTISOL?
• Tendency to bruise easily; Poor wound healing
• Hirsutism and frontal alopecia (male pattern
baldness)
• Interscapular fat pad (“buffalo hump”)
• supraclavicular fullness/fat pads
• Acne
• Depression
• Cortisol is a powerful appetite stimulant—craving
simple carbs—boosting insulin and promotes fat
storage
Hypercortisolism—causes?
• Cushing’s disease—too much ACTH from the
pituitary
• Cushing’s syndrome—adrenal tumor, excess
ingestion of corticosteroids;
• Ectopic hormone production of too much
ACTH—bronchial carcinoid is the #1 cause
Hypercortisolism
• Pituitary tumor? Cushing’s disease; Increased
ACTH triggers an increased production of
cortisol from the adrenal cortex
• Adrenal tumor? Elevated cortisol with
negative feedback to pituitary and decreased
ACTH
• Exogenous administration of Prednisone or
other corticosteroid
Cushing’s syndrome is difficult to
recognize early
• How many obese, mildly hirsute,
hypertensive, glucose intolerant, women with
irregular menstrual periods does the primary
care practitioner see every year?
• Easy test (dexamethasone suppression test)—
give 1 mg of dexamethasone @ 11 p.m.
• Draw an 8 a.m. plasma cortisol level; a level
of less than 5 mg/dl excludes the diagnosis
Treatment?
• Depends on where the problem is…pituitary
adenoma? How big? Is it surgical? Treatment
of choice…
• If can’t treat surgically or don’t find the
source…use inhibitors of steroidogenesis such
as ketoconazole or metyrapone (metopirone)
• Bilateral adrenalectomy if necessary
ADDISON’S DISEASE—primary adrenal
cortical insufficiency--JFK
• Not enough adrenal corticol hormones? Decreased
cortisol, decreased aldosterone, decreased
testosterone
• Feedback to Pituitary –
• Increased production of ACTH
• Big molecule containing:
Proopiocorticomelanin
1) ACTH
2) Melanocyte stimulating hormone—skin darkening
3) Opiods (beta endorphins)—happy
Signs and symptoms
• Low blood sugar due to decreased cortisol—
malaise and weight loss (90%), fatigue, weakness
(90%)
• Decreased aldosterone reduces blood pressure
(low sodium and water) and increased potassium
(hyperkalemia)
• Decreased androgens—decreased libido
• Increased ACTH to try to stimulate a “dead”
adrenal cortex—increased pigmentation of lips,
freckles, buccal mucosa, skin creases (80%)
Addison’s disease
• PRESIDENT John F. Kennedy…OF COURSE HE
WAS ALWAYS “TAN” and HAPPY… why?
Treatment of Adrenal Insufficiency—
replace what’s missing
• Prednisone—low or maintenance dose of 0.1 – 0.25
mg/kg/day; moderate dose 0.5 mg/kg/day ; normal
maintenance dose is 5-7.5 mg per day
• Hydrocortisone—15-20 mg q a.m.; 10-15 between 4-6
p.m.
• Fludrocortisone (Florinef)—dose depends on blood
pressure (orthostatic hypotension), or hyperkalemia;
decrease dose with edema or hypokalemia
• Testosterone
• During times of acute stress, steroids need to be
increased
Acute adrenal insufficiency-emergency
• Usually occurs in someone with chronic adrenal
insufficiency who undergoes some from of
significant stress—MI, surgery , trauma
• Sudden withdrawal of steroids (any patient who
is on larger doses of steroids > 20 mg/day of
Prednisone for example) for 2 weeks or more has
the potential for long-term suppression of the
hypothalamic adrenal axis)
• Unable to mount a stress response
• IV hydrocortisone 100 mg IV; then 50 mg q 6
hours x 4; then oral maintenance
Note about taking corticosteroids
• Greater suppression of the HPA axis occurs when the
doses are taken in the evening
• Morning doses “mimic” the usual biological rhythm
• Recovery of the HPA axis may take from a few months
to a few years
• Weaning off steroids—switch to short-acting
corticosteroids such as Prednisone or hydrocortisone
on a BID basis; Next, wean evening dose, leaving a
solitary morning dose. By this time, hydrocortisone
should be substituted for Prednisone.
Primary hyperaldosteronism—Conn’s
syndrome
• Too much aldosterone (usually due to an
adrenal tumor)
• Aldosterone retains sodium and water and
excretes potassium (potassium-wasting)
• Hypertension and hypokalemia
• Carlotta and PICA
The OVARY
• The hormones of the ovary—estrogen,
progesterone, androgens
• Primary ovarian failure—estrogen and
androgen deprivation
• Androgen deprivation—lower energy, loss of
libido, loss of muscle mass
• Estrogen deprivation—estrogen has over 300
functions—the most noticeable symptoms of
deprivation are the vasomotor symptoms
Digression: just how many
eggs/follicles do we get, ladies?
• At 6 months gestation
________________
• At birth
_____________
• At age 30 ___________
• At age 51.3 __
• NO MORE EGGS
• Primary ovarian failure
Peri-menopause
• Transitional state from reproductive years to
postmenopausal years—length is variable--3
to 10 years
• Ovary is on a roller-coaster ride—estrogen
production is UP and DOWN
• Variable menstrual cycles (greater than 7 days,
different from normal)
• FSH is rising (persistent elevations above 40
IU/L or greater than 50 over 50 or greater
than 30 IU/L with estradiol less than 20 IU/L)
Vasomotor symptoms--Hot flashes
•
•
•
•
Lack of sleep
grouchy
Vaginal dryness
Also calcium is leaving bones at a rapid pace
during first 3-5 years due to unopposed PTH
• Newest info? Start low-dose estrogen
Polycystic Ovary Syndrome
• The most common endocrine disorder
affecting women of reproductive age
• First described in 1922 (2 French MDs) who
wrote a paper called…
• 5-10% of women
Polycystic Ovary Syndrome--diagnosis
• National Institutes of Health Criteria (1990)—
must include
hyperandrogenism/hyperandrogenemia;
anovulation or oligo-ovulation; exclusion of
possible related disorders
• The Rotterdam criteria (2003)—two of three
cardinal abnormalities—including oligo- or
anovulation, androgen excess (hirsutism—face,
chin, pubis), and polycystic ovaries (ultrasound)
• Androgen Excess and PCOS Society (2006)—
hyperandrogenism, ovarian dysfunction, exclusion
of possible related disorders
Polycystic Ovary Syndrome
• Lab Tests: Increased ratio of LH to FSH (3:1)—
results in the ovaries producing an excessive
amount of testosterone leading to the clinical
manifestations of hyperandrogenism.
• The LH:FSH abnormality also results in the
production of estriol, a weakened form of
estrogen, resulting in a positive feedback-induced
LH production. This increased LH production
contributes to the development of ovarian cysts,
anovulation and ovarian theca cell (androgen
producing cells) hyperplasia; hyperplasia
stimulates further androgen production…a
vicious cycle.
PCOS—Clinical presentation
•
•
•
•
•
•
•
Hirsutism—50%
Male pattern alopecia or acne—20%
Oligomenorrhea/amenorrhea—50%
Abnormal uterine bleeding—30%
Polycystic ovaries on ultrasound—75%
Obesity – 50%
Infertility resulting from sporadic ovulation
Complications of PCOS …
• The majority of women with PCOS, regardless of weight,
have a form of insulin resistance that is intrinsic to the
syndrome and is poorly understood
• Obese women with PCOS have insulin resistance of PCOS
AND the insulin resistance of adiposity—a double
whammy!
• T2DM is 10x higher in PCOS; T2DM or impaired GT develops
by age 30 in 30-50% of obese women with PCOS
• Risk of fatal MI is 2x higher with severe oligomenorrhea
• Increased risk of endometrial cancer due to unopposed
estrogen stimulation
Treatment of PCOS
• Do you want to become pregnant? First-line
treatment is clomiphene citrate
• Clomiphene induces ovulation in 75% to 80%
• Metformin (Glucophage, Glumetza, Fortamet)—
produces an increase in menstrual cyclicity and
ovulation rates; reducing insulin levels along with
altering insulin’s effect on ovarian androgen
synthesis allows a return to the ovulatory state;
reduces circulating androgen levels by inhibiting
ovarian gluconeogenesis and androgen synthesis
• FIRST LINE THERAPY
Treatment of PCOS
• Not in the mood to get pregnant?
• Oral contraceptives with anti-androgen
components
• OCs offer endometrial protection from
unopposed estrogen stimulation
• Suppress LH secretion and increase the
synthesis of sex hormone binding globulins;
lower androgen levels and decrease hirsutism
and acne
Metformin
• Use OCs with metformin and/or Actos
DO MEN’S TESTICLES EVER DIE?
• Not often…
Target organs—the testicles
•
•
•
•
•
Testosterone levels are highest in morning
Primary testicular failure (rare)
Secondary testicular failure –the pituitary
Tertiary testicular failure (rare congenital syndromes)
Klinefelter’s syndrome (XXY)—gynecomastia (90%
before age 20); small firm testicles; high rate of suicide
attempts
• Exogenous suppression of testosterone—
anabolic/androgenic hormones for performance
enhancement
How about a male with breasts?
•
•
•
•
•
•
•
•
•
Gynecomastia?
Hmmmm
Could it be grandma from Guatemala? (lavendar)
Could it be a feminizing tumor of the testicle?
Could it be drugs that boost estrogen? Cimetidine (Tagamet),
spironolactone (Aldactone) Ginseng? Female hormones?
(Premarin vaginal cream)
Treatment for prostate cancer with GnRFs
Marijuana
BOOZE?
Obesity
Testosterone replacement
• Androgenic:anabolic ratio of an AAS is an important
factor when determining the clinical application of
these compounds
• Compounds with a high ratio of androgenic to an
anabolic effects are the drug of choice in androgenreplacement therapy (e.g. treating hypogonadism in
males), whereas compounds with a reduced
androgenic:anabolic ratio are preferred for anemia and
osteoporosis, and to reverse protein loss following
trauma, surgery, or prolonged immobilization
• All anabolic steroids have significant androgenic effects
Androgenic/anabolic steroids
• The dose of illegal androgenic/anabolic
steroids is 10 to 100 times higher than the
dose a doctor prescribes for medical problems
(low T…)
Preparations of AAS
•
•
•
•
•
•
Testosterone 1:1 (androgenic:anabolic ratio)
Methyltestosterone – 1:1
Fluoxymesterone – 1:2
Oxymetholone – 1:3
Oxandrolone – 1:3-1:13
Nandrolone decanoate (Deca-Durabolin)–
1:2.5 – 1:4 (Barry Bonds, Roger Clemens,
Marion Jones)
Androgenic/anabolic steroids
• 1938 first described use in a weightlifting/body building magazine
• Used “pharmacologically” by our Olympic
athletes in 1958 but soon discovered that the
testicles atrophied, breasts grew, and
prostates enlarged—YIKES
• Finally banned by IOC in 1976
Androgenic/anabolic steroids
• Kids as young as 10 are using (and not for
medicinal purposes)
• Over 5% of girls and ~7% of boys have used
steroids
• boosting muscle growth and strength; decrease
fat stores; improve energy
• Prematurely stop the lengthening of bones
(premature epiphyseal fusion through increased
levels of estrogen metabolites)—stunted growth
(short stature)
The numbers--steroids
• From 2001 to 2003 the use of steroids in girls
increased 300%; boys 20%
• Why the girls? To look like slender muscular
people seen in movies or body builder
• Boys? Improve athletic performance; big
muscles get the girls
(Youth Risk Behavior Surveillance, 2004, CDC)
Side effects (depends on length of use
and age at exposure)
• Pubertal growth—increased muscle mass; body
weight may increase 2-5 kg as a result of shortterm use
• Sebaceous gland oil production—acne (chest and
back)
• Upper body—thorax, neck, shoulders, and upper
arm are more susceptible for steroid effects than
other body parts because of the predominance of
androgen receptors in the upper body
Side effects (depends on length of use
and age at exposure)
• Virilizing effects in females—enlarged clitoris,
baldness in females, permanent deepening of the
voice, temporary decreases in menstrual cycles
(may confuse with PCOS); androgen –sensitive
hair—increased pubic hair, facial hair, chest hair,
arm hair
• Guys, listen up!! the adult penis does not grow
with steroids; it can actually decrease in size with
exposure to high doses; gynecomastia
Adverse effects
• Decreased sexual function, infertility (temporary),
testicular atrophy (suppression of natural
testosterone levels which inhibits production of
sperm (most of the mass of the testes is
developing sperm)
• Hypertension (check on Red Bull
consumption)(chewing tobacco w/ licorice)
• Increased LDL-cholesterol
• Accelerated CV disease (LVH) and atherosclerosis
(controversial)
• Premature baldness in males
Adverse effects in teens
• “roid rage”– users report greater involvement
in violent behaviors even after controlling for
the effects of previous violent behavior and
drug use
• 600 mg/week significantly increased manic
scores
Side effects
• Effects fade away slowly after drug
withdrawal, but may persist for more than 612 weeks after cessation of use
• Mood swings, extreme fatigue, anorexia, and
craving steroids.
Testing for anabolic steroids
• Elevated creatine levels
• Hair samples
• Urine samples for 19-norandrosterone (2.0
μg/L)
• Hemoglobin and hematocrit (anything above
17 g/dl for hemoglobin and anything about 50
% for hematocrit)
• Difficulty distinguishing pharmaceutical EPO
from natural EPO
Androgen deprivation therapy for
prostate cancer and to prevent PC
• Androgen deprivation therapy used for
metastatic prostate cancer—GnRH drugs
• 5-α reductase inhibitors to prevent the
conversion of testosterone to
dihydrotestosterone (DHT)—a more potent
agonist for prostate growth
The Endocrine Kidney
• Production of endogenous erythropoietin in response to
hypoxemia
• Stimulus? Hypoxemia? Not enough O2 in the blood?
Message sent to kidney to boost RBC production in bone
marrow
• Erythropoietin levels in blood are quite low in the absence
of anemia, at around 10 mU/mL. However, in hypoxic
stress, EPO production may increase a 1000-fold, reaching
10,000 mU/mL of blood.
• Renal failure --Epogen/Procrit (epoetin alfa), NeoRecormon
(epoetin beta), Mircera (epo-beta PEG), and Aranesp
(darbepoetin alfa)—but DON’T correct to full hemoglobin!
Increased risk of thrombosis…
Synthetic EPO
• Synthetic EPO—boosting red blood cell mass
to increase oxygen carrying capacity
(expensive)
• When exogenous EPO is used as a
performance-enhancing drug, it is classified as
an erythropoiesis-stimulating agent (ESA).
• Exogenous EPO can often be detected in
blood, due to slight difference from the
endogenous protein.
The Endocrine Kidney and Vitamin D
• Skin to liver to produce calcidiol or calcifediol
(25-hydroxyvitamin D)(form measured in
blood to determine vitamin D status)
• 25-hydroxyvitamin D is converted by the
kidneys to calcitriol (1, 25
dihydroxycholecalciferol), the biologically
active form of vitamin D
• Major job is to absorb calcium and
phosphorus
The endocrine pancreas
• Alpha and beta cells of the Islets of Langerhans
secrete glucagon (catabolic hormone to break
down stored glycogen) and insulin (anabolic
hormone to use glucose to “build you up”)
• Glucagon and insulin maintain serum glucose in a
steady state
• What can go wrong?
• Diabetes Mellitus
• The evolution of a name…
“sugar diabetes”—a “touch of the
sugar”
•
•
•
•
•
•
•
•
Juvenile Onset Diabetes Mellitus (JODM)
Adult Onset Diabetes Mellitus (AODM)
Insulin Dependent Diabetes Mellitus (IDDM)
Non-insulin Dependent Diabetes Mellitus
(NIDDM)
Type I (Roman numeral used)
Type II (Roman numeral used)
Type 1 (Arabic number)
Type 2 (Arabic number)
Definition of diabetes
• Chronic disorder of carbohydrate, fat and protein
metabolism characterized in its fully expressed
clinical form by an absolute deficiency of insulin
(Type 1 diabetes) or a relative insulin deficiency with
insulin resistance and beta cell dysfunction (Type 2
diabetes)
• Type 1A---autoimmune diabetes; antibodies to islet
cell components
• Type 2—insulin resistance and beta cell dysfunction
(early manifestation as postprandial hyperglycemia)
Treatment—drugs, drugs, and more
drugs
• Replace what’s missing—Insulin
• Boost what’s left—oral drugs (sulfonylureas) +
insulin
• Decrease the breakdown of stored sugars in the
liver and boost insulin receptor sensitivity—
metformin
• Mimic incretins—released from the small
intestine to boost insulin after a meal—incretin
mimetics (Byetta, Bydureon, Victoza)
• Inhibit the enzyme that degrades incretins (the
“gliptins” (sitagliptin, saxagliptin…and more)
Bibliography
• Bolk M. Vosser TJ, et al. Effects of evening vs. morning
thyroxine ingestion on serum thyroid hormone profiles in
hypothyroid patients. Clin Endocrinol (Oxf) 2007;66:43-8.
• Nestler JF. Metformin for the treatment of polycystic ovary
syndrome. N Engl J Med 2008 Jan 3; 358:47-54
• Robertson I. The Ultimate High. New Scientist. July 7, 2012;
28-29.
• Vaidya B, Pearce SHS. Management of hypothyroidism in
adults. British Medical Journal 2008;337:284.
• Yawn V. Polycystic ovary syndrome. ADVANCE for NPs&PAs.
December 2012; 11-14.
Bibliography
• Howard MP. Medical Secrets. 2012. Mosby.
• Krane LS, Patel MN, Hemal AK. Advances and
future directions in management of prostate
cancer. Indian J Surg. 2009;71(6):337-341.
• Marcocci C, Cetani F. Primary
Hyperparathyroidism. N Engl J Med 2011;365
(25):2389-97.
• Roth-Kauffman MM. Prostate Cancer. Clinician
Reviews. 2011 (January);21(1):28-32.
Bibliography
• Young VB, et al. Medicine Blueprints. 2010.
Wolters Kluwer. Philadelphia
• Baransky TJ, Clutter WE, McGill JB.
Endocrinology Subspecialty Consult.
2013.Wolters Kluwer. Philadelphia.