Transcript Dr. Friedman`s PowerPoint on Pituitary Hormone Replacement

Theodore C. Friedman, M.D., Ph.D.
Professor of Medicine-UCLA
Chairman, Department of Internal Medicine
Charles R. Drew University
The Ins and Outs of Pituitary Hormone Replacement
MAGIC Adult Convention
Las Vegas, NV
April 21, 2013
Pituitary Hormone replacement-What’s the
big deal?
• Pituitary disorders are common, but experts in
treating them properly are not!
• Small changes in replacement may make a big
improvement in symptoms.
• Many endocrinologists do not understand how to
properly replace patients with hypopituitarism and
do not understand (or don’t believe in) monitoring
hormone levels.
• We simply see the need to do more!
Hormonal Axes
• Adrenal (corticotropes)=CRH-ACTH-Cortisol
• Thyroid (thyrotropes)= TRH-TSH-T4/T3
• Gonads (gonadotropes)= GnRH-LH/FSHTestosterone/estrogen
• GH (sommatotropes) =GHRH-GH-IGF-1
Causes of Hypopituitarism
• Anywhere along the hypothalamic-stalkpituitary axis
• Microadenomas! (Yuen, et al. Clinical
Endocrinology 69:292-298, 2008
Pituitary Causes of Hypopituitarism
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Pituitary Tumor (macroadenomas vs. microadenomas)
Pituitary Surgery
Pituitary radiation
Sheehan’s syndrome/ pituitary apoplexy
Hypophysitis
Pituitary infiltration
Empty Sella
Malnutrition/critical illness
Head trauma
Stalk/Hypothalamic Causes of
Hypopituitarism
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Craniopharyngioma
CNS malignancy
Surgery/radiation
Head trauma/accidents
Infiltrative diseases (histiocytosis X, hemachromatosis,
sarcoidosis)
• Infection
• Drugs (steroids, dopamine analogues, somatostatin
analogues)
Order of hormone deficiencies
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GH
Gonadotropins (FSH, LH)
TSH
ACTH
Prolactin
Posterior pituitary hormones
Microadenomas and
hypopituitarism (Yuen et al, 2008)
• 38 patients with non-secreting pituitary microadenomas (mean tumor size
4.2 mm) and normal serum IGF-I levels were studied.
• 19 patients (50%) were found to be GH-deficient, and had higher body
mass index (BMI) than those that passed the GHRH-arginine test and
healthy controls.
• 19 patients (50%) had at least one other pituitary hormone deficit.
• We concluded that a substantial number of patients with non-secreting
pituitary microadenomas were GH-deficient despite normal serum IGF-I
levels, and had at least one other pituitary hormone deficit, suggesting that
non-secreting microadenomas may not be clinically harmless.
Microadenomas and
hypopituitarism
• Patients with low IGF-1 and a microadenomas are even more likely to be
growth hormone deficient.
• Many Endocrinologists test for hypopituitarism only if a patient has had
prior surgery or radiation to their pituitary.
• My approach is to measure pituitary hormones first and if it points to
hypopituitarism, then get a pituitary MRI
Glucocorticoid InsufficiencyDiagnosis
• Screen with 8 AM cortisol
• If < 3 mg/dL-clear glucocorticoid
insufficiency
• If > 12 mg/dL and not severe stress,
glucocorticoid insufficiency unlikely
• 3-12 mg/dL-gray zone-do cosyntropin test
(unless acute)
Glucocorticoid Insufficiency
• Needs significant impairment of pituitary function
• Classically, pituitary only affects cortisol, not
mineralocorticoids (salt regulating hormones from
the adrenals)
• Can be life-threatening, but most patients do
surprisingly well
• Fatigue, lethargy, nausea, vomiting, joint pains,
abdominal pain, weight loss, hypoglycemia (rare
in adults), low sodium
Adrenal fatigue
• Under stress, adrenals make more cortisol, not
less.
• Low cortisol needs to be either pituitary
(associated with other pituitary hormone defects)
of adrenal (high ACTH, low aldo, high renin)
• “Adrenal fatigue” with the adrenals “petering out”
makes no sense.
Standard (1 hr) Cosyntropin Test
250 mg of IV cosyntropin (ACTH1-24)
plasma cortisol at time 0, 30 and 60 minutes
any value over 20 mg/dL is normal
if peak response is less than 10 mg/dL, glucocorticoid
replacement is required
• if peak response is between 10 and 20 mg/dL,
glucocorticoid replacement is recommended during
stresses, otherwise replacement needs to be individualized
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1 mg vs. 250 mg cosyntropin test
• 250 mg is supraphysiological, will miss subtle
glucocorticoid insufficiency
• Mild ACTH deficiency, like mild hypothyroidism exists
and the consequences of misdiagnosis may be severe.
• Why do the test?
• My philosophy-I want as many patients to know they have
borderline HPA function and as few patients as possible on
replacement steroids
• Needs better cut-offs, but I use 18 mg/dL for 1 mcg and
mg/dL for 20 mcg
Daily cortisol production rate in man
• Esteban et al. (JCEM, 72: 39, 1991) measured daily
cortisol production rates in normal volunteers with a stable
cortisol isotope method.
• 9.9 +/- 2.7 mg/day, 5.7 mg/m2 day.
• Not all of oral cortisol is absorbed, need to take 12-15
mg/day
• Most glucocorticoid replacement is supraphysiological.
• Leads to osteoporosis, glucose intolerance and increased
infections.
• True physiological replacement is likely to be fairly benign
Glucocorticoid Replacement
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Most patients are over-treated
Earliest manifestation of excess treatment is easy bruising
Weight gain, central obesity, etc.
Earliest manifestation of inadequate treatment is joint pain.
Reasonable to mimic circadian rhythm with most or all
cortisol given first thing in the morning
• Want to avoid nighttime administration as it could lead to
sleep disturbances,
• But, some patients need a bit of cortisol at night to go into
deep sleep (Garcia-Borreguero, D. (2000) J. Clin.
Endocrinol. Metab. 85:4201-4206)
• No studies comparing different treatment regimens
Glucocorticoid Replacement (2)
• My approach is to use hydrocortisone mainly in AM-aim
for dose between 10 and 20 mg/day in a women and
slightly higher in a man.
• Decrease dose slowly until some symptoms develop, then
go back a dose.
• Small changes make a big difference
• Increase dose with illness, short term its better to err on
giving more, long term its better to give less
• Can take a bit more (1.25-2.5 mg before heavy exercise)
Monitoring glucocorticoid replacement
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Signs and symptoms
24 hr urine for 17-hydroxysteroids (17-OHS)
UFC tends to be high during replacement
In replacement, most of UFC excretion occurs right after
taking the cortisol, as high doses are not bound to CBG
and exceeds reabsorption by the kidney.
• 17-OHS (corrected for creatinine excretion in g/day)
reflects cortisol metabolism and is more integrated
throughout the day.
Monitoring glucocorticoid replacement
• LW: Sheehan’s syndrome-very athletic and health
conscious
• HC tapered from 20 mg/day to 17.5 mg/day (12.5 mg in
AM, 5 mg in PM)-less bruising, slight weight loss
• On 17.5 mg a day-UFC 191 mg/day (10-34)
• 17-OHS 4.7 mg/day (2-6)
• 17-OHS/gm Cr 3.5 mg/day (1.6-3.6)
• Went down to 15 mg/day of HC, had an adrenal crisis
when had the flu
Steroid coverage for illnesses or surgery
• Short-term give more, but keep duration short
• Moderate illness in hospital
– 50 mg of hydrocortisone twice a day
• Severe illnesses
– 100 mg of IV hydrocortisone Q 8 hours
• Minor procedures without anesthesia
– No extra coverage
• Moderately stressful procedures (endoscopy or
arteriography
– Single 100 mg IV dose of hydrocortisone prior to procedure
• Major surgery
– 100 mg of IV hydrocortisone before anesthesia and Q 8 hours
Steroid coverage for illnesses or surgery
• Exercise-can add 2.5-5 mg before major exercise.
• Flus and colds-could add 5-10 mg if fever
• Pneumonias, sinus infection, urinary tract infectionsdouble the dose-but for as short as possible
Central Hypothyroidism
• Common, even with small tumors
• Mild cases may be more manifest clinically more than
“subclinical hypothyroidism” due to actual low thyroid
hormones in central hypothyroidism
• Similar signs/symptoms as in primary hypothyroidism.
• Low free T4 in the face of lowish TSH.
• In mild cases, free T4 between 0.7 and 1.0 ng/dL
• Measuring free or total T3 not helpful
Central Hypothyroidism-Confirmation
• TRH test (hard to get)-can show blunted TSH
response to TRH
• nocturnal TSH test (TSH should rise at least 1.5fold between 5 PM and midnight) in normals, but
not in patients with central disease-not easy to get
blood at midnight
• Usually base on baseline free T4 and TSH
Central Hypothyroidism-Treatment
• Thyroid gland makes both T4 and T3.
• T3 is the active hormone, but has a short-half life; T4 has a long half
life
• L-thyroxine in most cases, but just as some patients with primary
hypothyroidism do better on T4/T3 combinations (see next slide, some
patients with central hypothyroidism may also do better on T4/T3
combinations).
• GH deficiency can lead to impaired T4 to T3 conversion, so T3 may be
especially beneficial in central hypothyroidism
• Monitor by aiming for free T4 in upper-normal range (1.5-1.7 ng/dL).
• TSH will be suppressed and is usually not worth measuring after
starting treatment.
• Patients with both primary hypothyroidism and a central component
should also be monitored with free T4 and not TSH measurements.
Central Hypothyroidism-Treatment
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Many options for thyroid hormone replacement.
L-T4 alone (Levothyroxine, Synthroid, Levoxyl, Tirosint, Unithroid)
L-T3 alone
L-T4/L-T3 combinations
Desiccated thyroid (Armour, NaturThroid, Erfa)-from pig thyroid
Desiccated thyroid/L-T4 combinations
Proper treatment needs to be individuals (not one blood pressure
medicine).
• Multiple studies have shown poor quality of life among patients on LT4 replacement
• About 16% of patients have a polymorphisms (change in DNA) in
their type 2 deiodinase that converts T4 to T3 (Panicker et al, JCEM,
2009, 94:1623-1629). These patients did better with T4/T3
combinations.
Central Hypothyroidism-TreatmentArmour
• Armour thyroid is made by Forest Labs and concern about variability of
preparations and lack of standardization are unfounded.
• Armour has a higher T3/T4 ratio than the human thyroid. Most patients on
Armour alone have high fT3, low fT4 and low TSH
• L-T3 has a short half-life and L-T3 or Armour should be given twice a day
• There may be other components of thyroid missing in synthetic preparations.
• I usually give Armour in a twice a day dose with extra L-T4
supplementation, especially in patients with a poor quality of life on L-T4
alone.
• Another option is a higher L-T4 dose with a low Armour dose
• For hypopit patients, I aims for a fT4 and fT3 in upper normal range, with a
suppressed TSH.
• My patients do not have a problem with the “new” formulation of Armour
Central Hypothyroidism-L-T4/L-T3
treatment
• Some but not all studies show a benefit of L-T4/L-T3
treatment over L-T4 alone.
• Large study in Italy (Gullo, PLoS One, 2011, 6:e22552)
found that in patients without a thyroid given L-T4
replacement, 15% had a low serum fT3 level, but normal
TSH levels.
• This suggests that certain patients have a different setpoint
for TSH secretion and that some patients need L-T4/L-T3
treatment to achieve normal freeT3 and freeT4 levels.
• It supports measuring freeT3 and freeT4 in patients on
treatment.
Central Hypothyroidism-L-T4/L-T3
treatment
• Celi et al. (JCEM, 2011, 96:3466-74) found that patients on L-T3
alone had lower weight and better lipid profiles than those on L-T4
alone.
• I often give L-T4/L-T3 combination therapy (or Armour/L-T4) to
patients who don’t do well on L-T4 alone, but these studies suggest
that many patients should be on combination therapy (I recently added
a low dose of Armour twice a day to my L-T4 treatment).
• If give T3 alone, T4 goes to 0, I don’t think that is good to have a
major hormone 0 and it gives no reserve if you miss a dose.
• I usually do not give L-T3 alone treatment as I like the long acting
“reservoir” of the L-T4 along with the shorter acting “boost” L-T3
effect.
Central Hypothyroidism-L-T4/L-T3
treatment
• In general, take thyroid medicine first thing in AM on an
empty stomach
• If on twice a day treatment, take 2nd dose in mid- afternoon
• Avoid taking with
• Iron
• Calcium
• Vitamins with iron or calcium
• Proton pump inhibitors, carafate, oral bisphosponates
(Fosamax), orlistat, cholestyramine
• Minor effect of soy
Central Hypothyroidism-selenium
• Selenium increases T4 to T3 conversion and reduces TPO
antibody levels.
• Patients with untreated GH deficiency have decreased T4
to T3 conversion, so they are likely to benefit from
selenium (but also benefit from GH treatment)
• Selenium appears to increase the rate of diabetes.
• I am cautious about giving selenium in those patients with
prediabetes or diabetes or those with a family history of
diabetes.
Growth Hormone Deficiency
• Patients with hypopituitarism have increased mortality,
suggested, but not proven to be due to GH deficiency
• Growth hormone deficiency in adults results in:
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Decreased bone formation
Increased fat mass (central obesity)
Decreased muscle mass
Lipid abnormalities
Increased thickness of blood vessels
Increased inflammatory markers
Impaired quality of life
Increased number of sick days
Impaired exercise tolerance
• Most symptoms are corrected by treatment
Growth Hormone Deficiency-Diagnosis
• Screen with IGF-I:
– If in top 75% of normal range for age and sex (> 150 ng/mL)-GH
deficiency less likely
– If empty sella, history of head trauma, headache and low blood
pressure after delivery (Sheehan’s syndrome), history of pituitary
surgery or radiation or pituitary tumor (micro or macro
adenoma)=GH deficiency more likely
– If < 75 ng/mL-GH deficiency likely
• Stimulation testing
– Glucagon stimulation test is preferred- GH deficient if GH is < 5
ng/mL (cutoff is unclear)
– ITT- GH deficient if GH (by RIA) is < 5 ng/ml
– I use glucagon unless need to use ITT for adrenal insufficiency
workup
Growth Hormone Deficiency-Diagnosis
• I don’t agree that “mild’ growth hormone deficiency should not be
treated.
• Stimulation tests are non-physiological, but gold-standard, maybe
more important is day to day GH/IGF-I axis than with stimulation.
• Unclear what to do with patient with hypopituitarism and lowish IGF-I
and normal stimulation testing. I often use a supplement called Dtrans-tropin which stimulates the hypothalamus to secrete more GHRH
and is available at compounding pharmacies.
Adult Growth Hormone Treatment
• 10% of dose/body weight than that of children.
• Don’t need to adjust for body weight.
• Women, especially on oral estrogens, need higher doses
than men.
• Start at 0.4 mg/day in women, 0.2 mg/day in men.
• Final dose varies widely and can not be predicted.
• Titrate upwards with IGF-I measurements monthly.
• Aim for IGF-I in upper 1/3 of normal range (200-300
ng/mL).
• Usually not much improvement in symptoms until in this
range.
• Too much GH-joint (hand mainly) swelling and pain.
Estrogen Replacement-Women
• Amenorrhea or oligomenorrhea indicates gonadotropin
deficiency
• Irregular periods may be an early sign of pituitary
dysfunction
• WHI and HERS studies were on post-menopausal women
not previously on estrogen (average age in WHI-63) and
used oral estrogen preparations
• Younger women who are hypogonadal are likely to benefit
from estrogen replacement.
• Young women ‘feel better” on higher estrogen
preparations and may require higher doses than postmenopausal women.
Estrogen Replacement-Women (2)
• Oral, but not transdermal estrogens inhibit the action of GH at
the liver, leading to higher GH and lower IGF-I levels (Wolthers
et al, AJP-Endo, 2001, 281:E1191).-I avoid oral estrogens or
birth control pills for patients on GH.
• I like an estrogen patch (Climara or Vivelle) or estroGel
(cream).
• Titrate dose so that estradiol is in the upper normal range for the
follicular period (50-100 pg/mL).
• Progesterone (Prometrium is my preferred choice) in women
with a uterus and can probably be given every 3 months to
induce a period.
• Give Prometrium at night as it is sedating.
• If a women stops oral estrogens or birth control pills and stays
on the same dose of GH, her IGF-1 will rise dramatically and
she will likely get hand swelling and joint pain
Androgen Replacement-Men
• Symptoms include low libido, erectile dysfunction, fatigue,
decreased muscle mass
• Soft testes may be the earliest sign of gonadotropin
deficiency
• Small testes or gynecomastia may be seen and helpful in
borderline testosterone levels
• Measure free (by equilibrium dialysis) and total
testosterone levels. If total Testosterone < 200 ng/dL,
testosterone deficiency likely.
• If 200-350 ng/dL- borderline result, use clinical judgment
plus free testosterone.
• LH/FSH helpful only to exclude primary hypogonadism.
Androgen Treatment-Men
• Testosterone gel or patch is easier.
• Injections often give better results with erectile dysfunction.
• New option is subcutaneous (in the stomach) shots twice a
week
• HCG is another possibility and making a come-back (does
not cause testicular shrinkage). It is similar to LH from the
pituitary.
• Clomiphene (clomid)-blocks feedback inhibition by
estradiol on the pituitary, which increases LH and
testosterone.
• It’s a pill-50 mg every other day is a good dose-main side
effect is gynecomastia.
• Good short term solution as it stimulates HPG axis
Androgen Treatment-Men
• Aim for total testosterone levels in the upper
normal range.
• Androderm patch 5 mg- may need 2 patches to
achieve appropriate levels-lots of skin irritation
• AndroGel 1% 5 G delivers 5 mg, may also need
higher doses (7.5 or 10 G)
• Testosterone subcut 50 mg twice a week
Androgen Treatment-Women
• Women with hypopituitarism have low
testosterone levels-due to LH (on the ovaries) and
low ACTH (on the adrenals).
• Measuring testosterone (and bioavailable
testosterone) by a good laboratory can be a clue to
hypopituitarism.
• Bioavailable testosterone is more accurate than
free testosterone in women
Androgen Treatment-Women
• Our study (still unpublished) on testosterone levels
in women with hypopituitarism and normal
volunteers found that low testosterone levels were
highly correlated with subjective measures
including low libido, low arousal, low mood,
depression and fatigue
• Objective measures of sexual function including
genital sensation and genital blood flow were not
correlated with testosterone levels.
• However, in a small number of patients treated
with a testosterone gel, these deficiencies did not
improve with treatment.
Androgen Treatment-Women
• Testosterone deficiency in women with
hypopituitarism leads to impairment in subjective,
but not objective sexual function.
• Testosterone more likely affects central (brain)
rather than peripheral processes.
• Genital sensation and genital blood flow are
probably not testosterone-mediated.
Androgen Treatment-Women
• I still recommend testosterone replacement in
women with hypopituitarism with a low total (<
10 ng/dL in a good assay) with testosterone cream.
• Compounding pharmacies (Bellevue Pharmacy)
have reliable and safe preparations.
• In almost all my patients treated with testosterone
cream go from low testosterone levels to highnormal levels with minimal side effects.
• Side effects include acne, extra hair growth, rage,
and oily skin
Diabetes Insipidus
• Excessive urination and thirst
• Mild cases are probably common and worthy of
treatment
• Chronic polyuria may lead to bladder/kidney
problems
• How many times are you waking up at night?
Diabetes Insipidus (2)
• I screen by having the patient collect urine for 24 hours
and measure the volume.
• Greater than 3 L indicates diabetes insipidus is likely
• I confirm with a 12 hour fast (no water!) and collect an 8
AM serum and urine osmolality.
• DI-High serum osmolality (>300 mOsm/kg), low urine
osmolality (<500 mOsm/kg) and low AVP < 1pg/mL).
• Formal water deprivation test probably not needed.
Diabetes Insipidus (3)
• DDAVP pills are probably the best; most
Endocrinologists still recommend nasal puffs.
• Take most of the dose at night to prevent waking
up at night.
• Should have a period of “break-through”
urination.
• Treatment is pretty benign.
What’s the problem?
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Most patients are on :
Too much cortisol
Not enough thyroid medication
Not enough growth hormone
Not on testosterone
Leads to weight gain and depression.
Get your doses adjusted!
Hormonal Interactions
• Treating a patient with adrenal insufficiency and
hypothyroidism with thyroid hormone increases the
breakdown of cortisol and may lead to an adrenal crisis.
• Thyroid hormone may also increase catabolism of other
hormones (GH, testosterone) and lead to increased
requirements when thyroid dose is increased.
• Treating with GH may increase T4 to T3 conversion, so
the dose of T3 (if on T3) may need to be reduced.
Hormonal Interactions (2)
• Oral, but not transdermal estrogens, increase the need for
L-thyroxine in women with hypothyroidism (Arafah, BM,
NEJM, 344:1743).
• Oral, but not transdermal estrogens, increase the need for
GH replacement.
• Stopping oral estrogens leads to an elevated IGF-1 (hand
swelling).
• Patients on GH replacement should probably not be on oral
estrogens.
Hormonal Interactions (3)
• Treating adrenal insufficiency may unmask
diabetes insipidus
• Testosterone raises IGF-1
Hormonal Interactions (4)
• Increased GH/ IGF-I leads to lower levels of cortisol (11HSD1).
• Thus, treating a patient with hypopituitarism with GH will
decrease cortisol levels.
• We had one patient that was over-replaced on
glucocorticoids, under-replaced on thyroid hormone and
not treated with GH.
– We started GH, decreased her glucocorticoids and
increased her L-thyroxine-she went into adrenal crisis.
• Make changes slowly.
• Monitor frequently
Other tricks-ferritin
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Ferritin-low iron stores
Anemia is a late sign of low iron
Most menstruating women have low iron stores
Iron is needed for thyroid hormone synthesis
Low ferritin=low blood volume=not enough blood
to brain=fatigue
• Aim for a ferritin around 70
• See goodhormonehealth.com for article on iron
replacement
Other tricks-aldosterone
• Aldosterone deficiency
• I’m finding that many patients with hypopituitarism have
hyporeninemic hypoaldosteronism (pituitary may make a
factor that regulates renin from the kidney)
• Low aldosterone results in low blood pressure, high pulse,
dizziness on standing, palpations, brain fog, fatigue.
• May want to measure renin, aldosterone.
• In patients with low blood pressure, may want to give
Florinef (synthetic aldosterone), midodrine
(vasoconstrictor) and/or salt
• Licorice, licorice root, grapefruits or grapefruit juice
(careful of interactions with other medicines) all increase
binding to the aldosterone receptor in the kidney and help
correct aldosterone deficiency
Other tricks-vitamin D
• Vitamin D deficiency
• Common, but unclear if it leads to a disease or is a marker
for being ill/not exercising/not enough sun.
• Our study found vitamin D did not prevent progression
from pre-diabetes to diabetes.
• Measure 25-OH vitamin D
• I think its worth optimizing
• Aim for a level between 30 and 40 ng/mL
• Below and above that are ASSOCIATED with poor
outcomes
Other tricks-stimulants
• Patients with pituitary problems have been reported to
have apathetic depression-more lethargy and feeling run
down, rather than blue and sad.
• Respond better to stimulants (ritalin, adderal) than antidepressants.
• Stimulants help with the atypical depression, give more
energy, help with focus and lead to decreased appetite and
weight loss-all desirable benefits in hypopit patients.
• They are controlled substances, but fairly safe and
probably easier to get off of compared to some
antidepressants.
• Side effects include trouble sleeping, hyper, higher blood
pressure and higher pulse.
• I usually use ritalin LA 20 mg a day
Chat rooms (lots)
• Meet patients with similar problems (you
are not alone)
• Get referrals
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Sheehan’s
Empty Sella
Hypopituitarism
Cushing’s
For more information/to schedule an
appointment
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www.goodhormonehealth.com
[email protected]
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