ENDOCRINE PHYSIOLOGY AND PATHOPHYSIOLOGY

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ENDOCRINE PHYSIOLOGY AND PATHOPHYSIOLOGY

• Barb Bancroft, RN, MSN, PNP
• www.barbbancroft.com
• bbancr9271_at_aol.com

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General Anatomy

• Limbic system (Temporal lobe)
• Hypothalamusthe big cheese
• Pituitary glandanterior and posterior lobesthe
  Master Gland
• TARGET GLANDS
• Thyroid gland
• Parathyroid glands (4)
• Adrenal glandscortex and medulla
• Endocrine portion of the pancreasIslets of
  Langerhans (Insulin, Glucagon)
• Endocrine portion of the kidneyerythropoietin
  (EPO)
• Ovaries and testicles
• Your NEWEST ENDOCRINE ORGAN?
• BELLY FAT (visceral obesity)

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Lets start at the top

• Hypothalamus is the link between the brain
  (temporal lobe/limbic system) and the master
  glandthe 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 messagethis is known as negative
  feedback

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Analogystart at the topthe BIG CHEESE

• Chief Nursing Officer, Director of Nursing, Dean
  of the Nursing School (the hypothalamus)--Sends
  her MEMO via EMAIL to

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Analogythe 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

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Analogythe worker bee

• Floor Nurses, student nurses (the TARGET
  ORGANS)that do all of the work
• Ok, OK, OKIll get it done

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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

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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

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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
  metabolismthe message returns to the pituitary
  and hypothalamus to TURN OFF
• NEGATIVE FEEDBACK

• TRH -
• Hypothalamus
• TSH - negative (off)
• Pituitary --
• Thyroid
• T3, T4

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What if something goes wrong?

• Lets start at the bottom with the TARGET ORGAN,
  thyroidhypthyroidism
• Decreased T3, T4 feeds back to the pituitary
  gland and hypothalamuspump 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

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Too much or too littlehyper- or hypo-

• If the problem is in the TARGET organits a
  PRIMARY disorderPRIMARY HYPOTHYROIDISM
  (Hashimotos thyroiditis is an example)
• If the problem is in the pituitary its a
  SECONDARY disorderSECONDARY HYPOTHYROIDISM
  (removal of pituitary/radiation)
• If the problem is with the hypothalamus its a
  TERTIARY disorderTERTIARY or CENTRAL
  HYPOTHYROIDISM
• (Pituitary and hypothalamic dysfunction may also
  be referred to as CENTRAL dysfunction)

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So, to diagnose thyroid problems

• If its primary hypothyroidism, the thyroid will
  not be able to produce thyroid hormonesdecreased
  circulating T3, T4
• This feeds back to the pituitary gland and saysI
  NEED A LITTLE HELPso 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

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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 thyroidso
• Thyroid hormones will be low or non-existent AND
  TSH will be low since the pituitary gland is NOT
  WORKING.

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Lets prepare an egg in the ovary for
ovulationeggs 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

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SO then, what is PRIMARY ovarian
failuremenopause!!

• 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 saysSomething is wrong, I need
  MORE estrogen
• The pituitary RAMPS up its production of
  FSHthinking that will helpmore FSH, more FSH
• FSH is a diagnostic marker of menopausemore later

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Historical highlight

• An Italian medical student, Bruno Lunenfeld, in
  the early 1960s had an epiphany. At the time, he
  recognized that during menopause womens 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 Italythe fertility drug? Clomid
  (clomiphene)

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Lets get back to the original concept Secondary
or tertiary ovarian failure?

• Hypopituitarismsomething 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, Sheehans necrosis
  (hemorrhage during delivery shuts off blood
  supply to anterior pituitary)
• Hypothalamic dysfunctionPrader-Willi Syndrome,
  Kallmans syndrome

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Prader-Willi Syndrome

• First described in 1956 by Andrea Prader
   (19192001) and Heinrich Willi (19001971)
• 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 circus120
  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.

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So many examplesweve talked about two

• HPTHypothalamic-anterior Pituitary-Thyroid-axis
• HPOHypothalamic-anterior Pituitary-Ovarian
  (gonadal)-axis
• BUT THERE ARE OTHERS
• HPAHypothalamic- anterior Pituitary-Adrenal axis
• HPTHypothalamic-anterior Pituitary-Testicular
  (gonadal)-axis
• HPBHypothalamic anterior Pituitary-Breast
• AND MORE
• Hypothalamus posterior pituitary target organ
  kidney, breast, uterus

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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

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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

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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 melatoninthe
  sleep/wake cycle

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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

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Other nuclei of the hypothalamus the appetite
and satiety center

• Appetite center and norepinephrinePrednisone,
  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)

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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

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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
  NECESSARYlactating moms would be a good reason
  to release prolactin releasing hormone)

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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

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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.

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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

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Girls fat tissue and puberty

• Girlsfat 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 saysshes
  READY!
• OPPOSITE problem--Female Athlete Triadthin (no
  adipose tissue) with disordered eating,
  amenorrhea /oligomenorrhea, and osteopenia/porosis

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Pubertyin 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

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Boys, fat tissue, and delayed puberty

• Boys fat delayed puberty
• Aromatase in fat tissue converts testosterone to
  estradiol and delays their development

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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

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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)

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The GnRH agonistsother 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
  DESdiethylstilbesterol 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

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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

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Congenital deficiency of GnRH

• Kallmans syndrome
• Anosmia
• amenorrhea

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Examples of inhibiting and releasing factors from
the hypothalamus

• Growth hormone-releasing factor
  somatotropinstimulates the release of growth
  hormone from the anterior pituitary (released at
  night)
• KIDS GROW AT NIGHTgrowing pains

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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
  
• Hypothalamicpituitaryadrenal axis

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Lets move on to the the Pituitary gland

• Pituitary comes from the Latin pituita, meaning
  phelgm,, also related to the Greek ptuo,
  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

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You actually have two separate pituitary
glandsthe anterior and the posterior pituitary

• The posterior pituitary gland is a direct
  extension of the hypothalamus via the
  infundibulum (pituitary stalkactually
  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

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The anterior pituitary

• The anterior pituitary is an embryologic
  outpouching of the posterior pharynx / roof of
  the mouth (Rathkes 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, its actually part of the GI
  tract
• Craniopharyngioma

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Anterior pituitary

• To release hormones from the anterior pituitary,
  the hypothalamus has to send its 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--
• Sheehans necrosis of the anterior pituitary
  glandinfarction of the anterior pituitary during
  labor and delivery (sudden loss of blood via a
  hemorrhaging episode in the mom)

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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)

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Bitemporal hemianopsia
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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)

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Hormones of the posterior pituitary

• Oxytocin
• ADH (Anti-diuretic Hormone) also known as
  Arginine Vasopressin (AVP)

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Hormone of the posterior pituitaryOxytocin

• The first peptide ever to be replicated outside
  the body was oxytocin (1953). Its 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

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Oxytocin

• Milk let-down response from the mammary glands
  for breast feeding
• Uterine contractions during orgasm

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What else does oxytocin do?

• The Tend to and be a friend to hormonebonding
  hormone trusting higher levels in women
• Helps us to read others minds
• Cuddly, touchy-feely, earth-momma hormone
  calming effect
• Estrogen enhances oxytocin

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Oxytocinthe hormone of monogamy

• Hormone of monogamy? Inspires trust
• In prairie voles at least
• Women have two genes for itmen? One gene and
  testosterone reduces oxytocin
• Men and the wandering eye syndrome? HELLO???
• Oxytocin nasal spray

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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

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The second hormone of the posterior
pituitaryanti-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
  midnightconserve 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

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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)

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Booze inhibits ADH

• Especially BEER due to its hypotonicity and the
  fact that one usually drinks copious amounts

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Other notes on ADH

• ADH may also have something to do with memories
  formed during sleepgood 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 ADHmay result in
  nocturia/bed wetting
• Kids with enuresisimmature response to ADH and
  problems with bladder sphincter tone

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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 sleep-overs
  and camp
• Can also use a TCA to tighten the bladder
  sphincter (imipramineTofranil)

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Too much ADH? Too little ADH?

• Too much? The Syndrome of Inappropriate ADH
• Too little? Diabetes Insipidus

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Digression Diabetes insipidus or diabetes
mellitus?

• What does diabetes mean? To siphonwhat are you
  siphoning? URINE
• Is it sweet or honeyed? mellitus
• Is it tasteless ?-- insipid
• Dr. Thomas Willis Taste thy patients urine,
  for if it be sweet
• Nurse, take a swig of that Oh, thats so
  sweet!
• Yuckthat doesnt taste like anythingits
  insipid

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Too little ADH?

• Diabetes Insipidusdisorder 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 day4 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

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Causes of Diabetes Insipidus

• Central DIcomplete 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 insipidusunresponsiveness
  of the ADH/AVP receptors on the kidney to ADH
• Congenital--rare inherited, X-linked recessive

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Diabetes Insipidus (DI)classification

• Acquired medications (lithium, amphotercin B,
  demeclocycline (Declomycin), cisplatin,
  aminoglycosides, rifampin
• Dipsogenic DIexcessive and inappropriate fluid
  intake due to a defect in the thirst mechanism

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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 its used for the Syndrome of Inappropriate
  ADH)

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Too much ADH? Syndrome of inappropriate ADH
(SIADH)

• TOO MUCH water without conserving the appropriate
  electrolytes this causes a DILUTIONAL
  problemespecially problematic is the low sodium
  (hyponatremia)
• CNS w/excess ADH releasebleeding/hemorrhage,
  CVA, DTs, GBS, head trauma, hydrocephalus,
  infections, tumors
• Drugsbromocriptine, 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

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Clinical presentation

• Symptoms are dependent on the degree of
  hyponatremia and the rapidity at which it
  develops
• At serum levels lt 125 mEq/L, patients may present
  with muscular weakness, nausea, headaches,
  lethargy, ataxia, and psychosis to cerebral
  edema, increased ICP, seizures and coma

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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

67
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

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Anterior pituitary dysfunction

• Panhypopituitarism
• Decreased TSH, FSH, LH, ACTH, GH

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Pituitary dysfunction

• Too much or too little of a specific
  hormonecongenital 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)

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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 hormonebuilds 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
  Marketathletes 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 counter-regulatory hormoneincreased
  growth hormone secondary diabetes

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Growth hormone

• Natural decline in growth hormone that occurs
  with aging (somatopause) GH deficiency in
  adultsdecreased 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

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Growth hormone? Too much, Too little?

• Pituitary dwarf
• Lack of cells (somatotropes) that produce GH
• Treatment?
• Recombinant GH

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The most famous pituitary dwarf

• Colonel Tom Thumb (Charles Stratton) and his
  lovely wife, Lavinia Stratton (1841-1919)

74
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
  statureusually gain 3-6 cm (about 2.3 inches)
• Black market for athletes fountain of youth
  for those who can afford it???

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Pituitary adenoma producing too much growth
hormone

• BEFORE the epiphyseal plates close
• GIANTISM, diabetes, soft bone matrix
• I dont hate little people.
• The story of David and Goliath (Goliath was a
  pituitary giant)loss of peripheral vision
  softening of temporal bones
• Davids slingshotthwack! Epidural hematoma
  felled the GIANT the little guy wins in the end

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Tallest manAlton, Illinois claim to fame

• Robert Wadlow with his father Harold
• 1918-1940
• 811
• Alton, Illinois

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Pituitary adenoma producing too much growth
hormone

• AFTER the epiphyseal growth plates
  closeacromegalyenlargement of the acrals or
  small bones enlargement of soft tissues
• Deep voice
• Hirsutism, diabetes

78
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 labilityguys cry more girls cry all
  of the time quivering lip

79
Dopamine plays a major role

• In the release of pituitary hormones
• Inverse relationshiplow 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?

80
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.

81
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 feedPROBLEM? Boosting both
  dopamine receptors in the brain caused movement
  disorders (dyskinesias) in the mom
• WHOA!

82
Follicle stimulating hormonethe 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

83
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. todays pills
• 80-100 mcg/pill vs. 20-30 mcg/pill
• The early OCs would stop an elephant from
  ovulating
• Todays OCs? The egg is preparedmiss a pill
  and you ovulate

84
COCs in perimenopausal women

• Vasomotor symptomsa COC containing 30 mcg of
  estrogen per day90 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 301518-28)

85
Adrenocorticotropic hormone

• Released in response to CRH from hypothalamus
• ACTH triggers the release of cortisol from the
  adrenal cortex cortisol is a catabolic
  hormoneit 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.

86
ACTH the molecule

• Pro-opiomelanocortin3 substances contained
  within this molecule
• Endorphins (opio)
• MSH (melanocyte stimulating hormone)humans dont
  have MSH per selower animals doespecially those
  that changes color in conformity with their
  environment the size of their intermediate lobe
  positively correlates with the ability to change
  color
• Cortinstimulates cortisol from adrenal cortex

87
Target Organs

• Thyroid gland
• Parathyroid gland (not under control of the
  hypothalamus/pituitary)
• Adrenal gland
• Ovaries
• Testicles

88
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
  (tri-iodothyronine) 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

89
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

90
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
  hormoneprimarily 1st two postnatal years400
  grams at birth (primarily neurons/gray matter
  thyroid hormone stimulates growth of white
  matter/myelin to connect the neurons
• Your personality
• Normal periods, fertility

91
Diagnosis of thyroid dysfunction

• Primary Hypothyroidismdecreased thyroid hormone
  (T4) production results negative feedback to
  pituitary and an INCREASED TSH
• Secondary Hypothyroidism (pituitary
  dysfunction)decreased TSH and decreased T4
• Hyperthyroidismincreased thyroid hormone
  production results in a DECREASED TSH with an
  increased T4
• Secondary/tertiary hyperthyroidismRARE

92
Too little? Hypothyroidism

• Autoimmune thyroiditisHashimotos
  thyroiditisantibodies to thyroid peroxidase
  (TPO) and thyroglobulin antibodies are present
• Iatrogenicthyroidectomy, radioiodine therapy
• Thyroiditissubacute thyroiditis (also known as
  De Quervains thyroiditis), silent thyroiditis,
  postpartum thyroiditis
• Drugsmethimazole, PTU, iodine, amiodarone (40
  iodine by weight), lithium, interferons,
  thalidomide, sunitinib, rifampicin
• Congenital hypothyroidismthyroid aplasia or
  hypoplasia, defective biosythesis or thyroid
  hormones
• Disorders of the pituitary or hypothalamus
  (secondary or tertiary aka central)

93
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

94
Adult with myxedema (severe hypothyroidism)

• Ventilator and IV levothyroxine

95
Hypothyroidism

• Exhaustion, somnolence, lethargy, depression,
  slow cognition
• Dry hair, balding, loss of lateral third of
  eyebrows (Queen Annes eyebrows)
• Bradycardia (thyroid hormone and the number of
  receptors on the SA Node)
• Hypercholesterolemia, hyponatremia
• Menstrual disturbances/Menorrhagia

96
Hypothyroidism

• decreased libido
• dry thin pale skin, vitiligo
• Weight gain (10-15 pounds), constipation (10 to
  15 poundshaha)
• Generalized muscle aches and pains calf
  stiffness
• carpal tunnel syndrome slow relaxing tendon
  reflexes
• Pericardial and/or pleural effusions ascites
• Cold intolerance
• Normocytic anemia
• youre not dead until youre warm and dead

97
Who should be screened?

• Patients with Down or Turner syndrome
• Patients taking certain drugslithium,
  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
  Addisons disease

98
Classification of hypothyroidismbased 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 hypothyroidismTSH is low

99
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
  one-week 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

100
Patient education

• No supplements within 4 hourscalcium, 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

101
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

102
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

103
Hypothyroidism and infertility

• Thyroid-related infertilityhigh 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

104
Hyperthyroidism

• 2 of women 0.2 0f men
• Autoimmune disease --Graves disease,
• toxic multinodular goiter
• Iodine-induced hyperthyroidismamiodarone,
  radioiodine contrast media,
• subacute thyroiditis
• Factitious hyperthyroidism (taking levothyroxine
  for weight loss)

105
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

106
Graves diseasehyperthyroidism plus

• Diffuse symmetrical enlargement (goiter) of the
  thyroid gland
• Eyelid retraction
• Corneal ulceration
• Diplopia, papilledema, loss of visual acuity

107
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
  non-thyroidal illness

108
Diagnosis

• Thyroid scan using radioactive iodine--¹²³I
  (different from ¹³¹Iodine used to Tx
  hyperthyroidism to ablate the gland)high uptake
  with Graves disease, toxic multinodular goiter,
  solitary adenoma
• Antithyroid peroxidase (TPO) antibody is present
  in autoimmune thyroid diseases such as Graves
  disease)

109
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
  dosesimple. Risk of hypothyroidism is 90

110
Treatment of hyperthyroidism

• propothiouracil (PTU) or methimazole (Tapazole)
  to decrease T4 synthesis remission rate of
  30-50 in Graves disease methimazole is QD
• Major side effectsdrug-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
  (complicationsrecurrent laryngeal nerve
  paralysis, hypoparathyroidism leading to
  hypocalcemia)

111
Treatment

• Before the antithyroid drugs or RAI kick in,
  relief of symptoms (palpitations, tremor) with a
  beta blocker is important
• Propranolol (Inderal) can be chosen20-40mg 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

112
Thyrotoxic storm (thyrotoxicosis)

• IV beta blocker to slow heart rate before heart
  failure kicks in
• If febrile, dont use aspirin to decrease the
  temperatureASA releases more T4 from thyroid
  binding globulin and can make the thyrotoxicosis
  worse
• Use acetaminophen for fever in these patients

113
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

114
Hypoparathyroidism

• normal range of total serum calcium8.4-10.4
  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)

115
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 Chvosteks sign (Cheek),
  and Trousseaus sign
• Causesautoimmune destruction surgical removal
  during thyroidectomy
• Rx give calcium IV or orally depending on
  calcium levels and patients condition

116
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

117
Hyperparathyroidism

• Classic S S rarely seen in U.S. today because
  of early detection of calcium abnormalities on
  routine blood tests
• Classic signshypercalcemic sx of nephrolithiasis
  (kidney stones), overt bone disease (stone and
  bone disease), neuromuscular symptoms
• Symptoms todayweakness, easy fatiguability,
  anxiety, and cognitive impairment kidney stones
  in 4-15

118
Secondary hyperparathyroidism

• Chronic renal failurecant 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
• Malignancylow or undetectable PHT level rules
  out primary hyperparathyroidism and raises the
  possibility of cancer-associated hypercalcemia
• Ovarian failureone of estrogens functions is to
  inhibit PTH no estrogen? Unopposed PTH

119
Adrenal glandtwo parts medulla (inner) and
cortex (outer)

• Adrenal medullaproduces EPINEPHRINE (epion 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
• Whats going to happen to you?

120
Fight/Flight responseacute stress response

• Release of glucose, inhibition of insulin
• Pupils dilate
• Tachycardia, BP goes up
• Bronchodilationrapid 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?

121
If I have told you once, I have told you twice

• do NOT go to the emergency room with dirty
  underwear!

122
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?

123
Adrenal glandthe outer cortex

• Corticosteroidscortisolrole in carbohydrate
  metabolism and the chronic stress responseboosts
  SUGAR
• Mineralcorticoidsaldosteroneregulates salt and
  water homeostasis via renin/angiotensinboosts
  BLOOD PRESSURE
• Adrenal androgenstestosterone, androstenedione,
  17-hydroxyprogesterone, dehydroepiandosterone
  (DHEA)

124
Excess cortisol? Clinical features in order of
frequency

• Plethoric (red face)
• Central obesitycortisol moves fat toward the
  center (Centripetal obesity)moon face
• Catabolic hormone--breaksdown skeletal
  muscleskinny arms and legs
• Amino acids used for gluconeogenesis and high
  blood sugars leading to Impaired glucose
  tolerance or frank diabetes
• Aldosterone-like propertiessodium and water
  retention, and potassium excretionHypertension
  and hypokalemia

125
Excess cortisol

• Menstrual irregularity in women, ED in men
• Osteoporosismoves 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

126
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 stimulantcraving
  simple carbsboosting insulin and promotes fat
  storage

127
Hypercortisolismcauses?

• Cushings diseasetoo much ACTH from the
  pituitary
• Cushings syndromeadrenal tumor, excess
  ingestion of corticosteroids
• Ectopic hormone production of too much
  ACTHbronchial carcinoid is the 1 cause

128
Hypercortisolism

• Pituitary tumor? Cushings 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

129
Cushings 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 _at_ 11 p.m.
• Draw an 8 a.m. plasma cortisol level a level of
  less than 5 mg/dl excludes the diagnosis

130
Treatment?

• Depends on where the problem ispituitary
  adenoma? How big? Is it surgical? Treatment of
  choice
• If cant treat surgically or dont find the
  sourceuse inhibitors of steroidogenesis such as
  ketoconazole or metyrapone (metopirone)
• Bilateral adrenalectomy if necessary

131
ADDISONS DISEASEprimary 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 hormoneskin
  darkening
• 3) Opiods (beta endorphins)happy

132
Signs and symptoms

• Low blood sugar due to decreased cortisolmalaise
  and weight loss (90), fatigue, weakness (90)
• Decreased aldosterone reduces blood pressure
  (low sodium and water) and increased potassium
  (hyperkalemia)
• Decreased androgensdecreased libido
• Increased ACTH to try to stimulate a dead
  adrenal cortexincreased pigmentation of lips,
  freckles, buccal mucosa, skin creases (80)

133
Addisons disease

• PRESIDENT John F. KennedyOF COURSE HE WAS ALWAYS
  TAN and HAPPY why?

134
Treatment of Adrenal Insufficiencyreplace whats
missing

• Prednisonelow 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
• Hydrocortisone15-20 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

135
Acute adrenal insufficiency--emergency

• Usually occurs in someone with chronic adrenal
  insufficiency who undergoes some from of
  significant stressMI, surgery , trauma
• Sudden withdrawal of steroids (any patient who is
  on larger doses of steroids gt 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

136
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 steroidsswitch 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.

137
Primary hyperaldosteronismConns 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

138
The OVARY

• The hormones of the ovaryestrogen, progesterone,
  androgens
• Primary ovarian failureestrogen and androgen
  deprivation
• Androgen deprivationlower energy, loss of
  libido, loss of muscle mass
• Estrogen deprivationestrogen has over 300
  functionsthe most noticeable symptoms of
  deprivation are the vasomotor symptoms

139
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

140
Peri-menopause

• Transitional state from reproductive years to
  postmenopausal yearslength is variable--3 to 10
  years
• Ovary is on a roller-coaster rideestrogen
  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)

141
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

142
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

143
Polycystic Ovary Syndrome--diagnosis

• National Institutes of Health Criteria
  (1990)must include hyperandrogenism/hyperandrogen
  emia anovulation or oligo-ovulation exclusion
  of possible related disorders
• The Rotterdam criteria (2003)two of three
  cardinal abnormalitiesincluding oligo- or
  anovulation, androgen excess (hirsutismface,
  chin, pubis), and polycystic ovaries (ultrasound)
• Androgen Excess and PCOS Society
  (2006)hyperandrogenism, ovarian dysfunction,
  exclusion of possible related disorders

144
Polycystic Ovary Syndrome

• Lab Tests Increased ratio of LH to FSH
  (31)results in the ovaries producing an
  excessive amount of testosterone leading to the
  clinical manifestations of hyperandrogenism.
• The LHFSH 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
  productiona vicious cycle.

145
PCOSClinical presentation

• Hirsutism50
• Male pattern alopecia or acne20
• Oligomenorrhea/amenorrhea50
• Abnormal uterine bleeding30
• Polycystic ovaries on ultrasound75
• Obesity 50
• Infertility resulting from sporadic ovulation

146
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 adipositya
  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

147
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 insulins 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

148
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 synthe