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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 testiclesYour 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 - negative (off)• Pituitary -- +
• Thyroid T3, T4
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-axis2) HPO—Hypothalamic-anterior Pituitary-Ovarian
(gonadal)-axisBUT THERE ARE OTHERS:• HPA—Hypothalamic- anterior Pituitary-Adrenal axis• HPT—Hypothalamic-anterior Pituitary-Testicular
(gonadal)-axis• HPB—Hypothalamic – anterior Pituitary-BreastAND 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 sleep-
overs 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 counter-regulatory 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 (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
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 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
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 non-
thyroidal 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 androgen-replacement 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 weight-lifting/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 short-term 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 6-12 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.
