Transcript Everything You Wanted to Know About Pituitary Hormone

Theodore C. Friedman, M.D., Ph.D.
Associate Professor of Medicine - UCLA
Chief, Division of Endocrinology,
Molecular Medicine and Metabolism
Charles R. Drew University
Everything You Wanted to
Know About Pituitary Hormone
Replacement That Your Doctor
Never Told You
MAGIC Foundation Affected Adult Convention
February 11, 2007
Pituitary Hormone Replacement
What’s the Big Deal?
• Pituitary disorders are common, but experts in treating
them 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
– They do not understand (or don’t believe in) monitoring hormone
levels
• We need to do more!
What’s the Big Deal, Doc? (cont.)
• Patients with hypopituitarism that receive
conventional therapy have increased mortality
– This is suggested - but not proven - to be due to GH
deficiency (Rosen and Bengtsson, Lancet, 1990, 336:285; Bates,
et al., JCEM, 1996, 81:1169)
• The quality of life was seen to decrease in patients
with hypopituitarism
– This may be due to suboptimum replacement
of pituitary hormones
Hormonal Axes
• Adrenal (corticotropes)=CRH-ACTH-Cortisol
• Thyroid (thyrotropes)= TRH-TSH-T4/T3
• Gonads (gonadotropes)= GnRH-LH/FSHTestosterone/estrogen
• GH (sommatotropes) =GHRH-GH-IGF1
• Prolactin-sommatomamotropes
• Posterior Pituitary-ADH, oxytocin
Order of Hormone Deficiencies
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•
•
•
•
•
GH
Gonadotropins (FSH, LH)
TSH
ACTH
Prolactin
Posterior pituitary hormones
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
Glucocorticoid Insufficiency
Diagnosis
• 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)
• Stimulation tests need to be performed in a place that
has expertise.
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
One mcg Cosyntropin Test
• 1 mg of IV cosyntropin (ACTH1-24) (diluted in saline)
• Plasma cortisol at time 0 and 30 minutes (action ends after
30 min)
– Any value over 18 mg/dL is normal (?)
• Will pick up more mild cases
– Should they be treated or just covered?
1 mg vs. 250 mg Cosyntropin Test
• 250 mg is supraphysiological
– Will miss subtle glucocorticoid insufficiency
• Mild ACTH deficiency, like mild hypothyroidism exists
– Consequences of misdiagnosis may be severe
• Why do the test?
– My Philosophy
• Want as many patients to know they have borderline HPA function
• Want as few patients as possible on replacement steroids
– True physiological replacement (10-15 mg/day of hydrocortisone),
though, may be relatively benign
– Cutoffs unclear, but I use cortisol of 18 ug/dL for one mcg
and 20 ug/dL for 250 mcg test
ITT/ metyrapone Tests
•
•
•
•
Both can exacerbate glucocorticoid insufficiency
Both are non-physiological
Rarely needed
ITT requires physician supervision, but can also
be used to diagnose GH deficiency
• Patients feel horrible after metyrapone test
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
• Most, but 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 benign
• Cortisol secretion is highly regulated
– Stress, circadian rhythm-doubt we can do as well as mother nature
Glucocorticoid Replacement
• Glucocorticoids can be dangerous
– Should be clear indication for treatment
• Patients with burn out (“adrenal fatigue”) have normal HPA axis
(Mommersteeg et al., Psychoneuroendocrinology 2006)
• Increase stress should activate, not “burn out” the adrenals
• Would be careful about “isocort” or other adrenal extracts
– These contain cortisol plus other bioactive adrenal hormones
– Once you start, hard to get off, so decide careful
Glucocorticoid Replacement (2)
• Most patients are over-treated
• Earliest manifestation of excess treatment is
– Easy bruisability
– 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
• Other studies suggest highest dose in AM, with lower doses
throughout the day
– May mimic cortisol secretion
• Want to avoid large nighttime administration as it could lead to
sleep disturbances
– But some patients need a bit of cortisol to go into deep sleep
Glucocorticoid Replacement (3)
• No studies comparing different treatment regimens
• My approach is to use hydrocortisone mainly in AM
• Aim for dose between 15 and 20 mg/day in a woman
– Slightly higher in a man
• Decrease dose slowly until some symptoms develop, then
go back a dose
• Small changes make a big difference, especially between
15 and 25 mg a day of hydrocortisone
• Increase dose with illness
• Short term: it’s better to err on giving more
• Long term: it’s better to give less
• Can take 5 mg more during heavy exercise
Glucocorticoid Replacement
(Try To Avoid Adrenal Crisis)
• Patients on lower doses of glucocorticoids more likely to have a crisis
– But they still do better long-term
•
•
•
•
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•
Exacerbated by the flu, other illnesses
Less likely in hypopit patients than in those with adrenal disease
Med-alert bracelet
Double glucocorticoid dose first
Then Act-O-vial 100 mg solucortef plus syringe, available for IM
injection
Lots of salt and fluids (Gatorade)
Florinef (synthetic aldosterone)
Lots of anti-nausea meds (zofran, phenergan), pain meds, anxiety
meds (ativan) on hand
Do not be stoic - GO TO ER!
Monitoring Glucocorticoid Replacement
• 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
– High doses are not bound to CBG
• Exceed reabsorption by the kidney
• 17-OHS (corrected for creatinine excretion in g/day) reflects
cortisol metabolism
– More integrated throughout the day
• Other hormones affect glucocorticoid metabolism
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
T3 usually 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 1.5-fold between 5 PM and
midnight in normals
– Not in patients with central disease
– Not easy to get blood at midnight
• Usually base on baseline free T4 and TSH
Central Hypothyroidism
Treatment
• L-thyroxine in most cases
– Some patients with primary hypothyroidism,
though, do better on T4/T3 combinations
(Buneviius et al, NEJM, 1999, 340:424)
– Some patients with central hypothyroidism may do better on T4/T3
or T4/Armour combinations
• GH deficiency can lead to impaired T4 to T3 conversion
– T3 may be especially beneficial in central hypothyroidism
• Treating with GH can decrease FT4 levels and unmask
central hypothyroidism
– Recommended to treat borderline central hyopthyroidism to get full
benefit of GH therapy
Central Hypothyroidism
Treatment (2)
• Thyroid hormone treatment increases cortisol breakdown
– Can put someone with adrenal insufficiency into an adrenal crisis
• Make sure adrenal insufficiency is considered/tested before
starting thyroid hormone
• Monitor by aiming for free T4 in upper-normal range (1.5-1.7
ng/dL)
• TSH will be suppressed
– 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
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
• Microadenomas may cause GH deficiency
Growth Hormone Deficiency
Diagnosis
• Screen with IGF-I
– If in top 75% of normal range for age and sex
(> 150 ng/mL), GH deficiency unlikely
– If < 75 ng/mL, GH deficiency likely
• Stimulation testing
– Arginine-GHRH- GH deficient if GH (by RIA)
is < 9 ng/mL
– (RIA is 2X ICMA; 9 by RIA=4.5 by ICMA)
– ITT- GH deficient if GH (by RIA) is < 5 ng/mL
• I use Arginine-GHRH, unless need to use ITT for adrenal insufficiency
workup
– Blunted response in obesity
– Blunted response in males
Growth Hormone Deficiency
Diagnosis (cont.)
• Stimulation tests are non-physiological
– Day-to-day GH/IGF-I axis more important than with stimulation
• Unclear what to do with patient with hypopituitarism, lowish
IGF-I and normal stimulation testing
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
– 300 ng/mL, but depends on assays
– Usually not much improvement in symptoms until in this range
• Too much GH-joint (hand mainly) swelling and pain
Diabetes Insipidus
• Defect in ADH
– Also called AVP
– Posterior pituitary
• 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, then
measure the volume
– Greater than 3 L indicates diabetes insipidus likely
• I confirm with a 12 hour fast (no water!)
– Collect an 8 AM serum and urine osmolality and ADH level
• DI
– High serum osmolality (>300 mOsm/kg)
– Low urine osmolality (<500 mOsm/kg)
– Low ADH (< 1.5 pg/mL)
• Formal water deprivation test probably not needed
Diabetes Insipidus
(cont.)
• DDAVP pills 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, usually
in the evening.
• Treatment is pretty benign
Abnormalities Of Gonadotropes
• Gonadal Axis
– GnRH-LH/FSH -Testosterone/estrogen/progesterone
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Lack of ovulation
Irregular or no periods
Infertility
Vaginal dryness
Osteoporosis
Decreased libido
Possibly poor sense of well-being
What To Do If You Have
Gonadotropin Dysfunction?
• If trying to get pregnant
– Determine ovulation
– See reproductive endocrinologist
• If not trying to get pregnant
– Replace estrogen
– Testosterone
– Possibly Progesterone
Estrogen Replacement in Women
• Amenorrhea or oligomenorrhea indicates gonadotropin
deficiency
• Irregular periods may be early sign of pituitary dysfunction
• Previous WHI and HERS studies on post-menopausal women
were not on estrogen
– Average age in WHI: 63
• Younger hypogonadal women likely to benefit from estrogen
replacement
• Young women ‘feel better” on higher estrogen preparations
– May require higher doses than post-menopausal women
– Less clear for older women
• Replacement and decision to have periods or not based on
patient preference and age
Estrogen Replacement in Women
• Choices include
(cont.)
– Premarin (pregnant mare urine, “conjugated estrogen”, multiple
estrogenic compounds)
– Oral estrogen compounds (estrace)
– Birth control pills
• Contain relatively high doses progesterone and low doses estrogen
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Estrogen patches (Climara, Vivelle)
Estrogen creams (Estrogel)
Vaginal estrogen (Fem-ring, Estring)
Compounded Estrogen (creams, sublingual drops, pills)
Oral Estrogen Replacement,
But Not Other Routes
• First pass effect in the liver
• Blocks the action of GH at the liver to raise IGF-1
– Leads to high GH and low IGF-1 (both bad)
• Raises sex hormone binding globulin (SHBG)
• Raises total testosterone, but decreases free testosterone
– Low free testosterone may lead to decreased libido (and maybe low
energy, decreased muscle mass)
• Recent study showed that effects of oral estrogens (including
birth control pills) decrease free testosterone levels for at least a
year after discontinuing
Oral Estrogen Replacement,
But Not Other Routes (2)
• Raises thyroid-binding globulin (TBG)
– Can lead to an increase in thyroid hormone requirements
• Raises cortisol-binding globulin (CBG)
– Leads to high levels of total cortisol
– Makes testing for adrenal insufficiency difficult
Oral Estrogen Replacement
• In women with hypopituitarism, avoid it!
What Type of Estrogen is Best?
• Ovaries make estrone (E1), estradiol (E2), estriol (E3)
• Estradiol is most abundant (“bioidentical”)
• Slight evidence that estrone is detrimental (breast cancer) and
estriol is good
• Oral estrogens get converted to estrone
• I use mainly estradiol (Climara or Estrogel)
– Titrate dose so that estradiol is in the upper normal range for the
follicular period (50-100 pg/mL)
• Some compounding pharmacies encourage bi-est (estradiol/
estriol) or tri-est (estrone/ estradiol/ estriol)
• Young hypopit patients should take estrogen daily
Should You Take Estrogen/Progesterone
to Induce A Period?
• Taking 5-10 mg of Provera (synthetic Progestin) or 100-200
mg of Prometrium (progesterone “bioidentical”) for 10 days,
then stopping, will usually induce a period
• Taking 2.5 mg of Provera or 100 mg of Prometrium daily will
usually not induce a period
• I tend to have women less than 40-45 have a monthly period,
older than that not to have a period
• Women with an intake uterus should take a
progesterone
Androgen Replacement - Men
• Symptoms include low libido, impotence, fatigue, decreased
muscle mass
• Soft testes may be the earliest sign of gonadotropin deficiency
• Small testes or gynecomastia may be seen
– Helpful in borderline testosterone levels
• Measure total testosterone levels
– If < 200 ng/dL, testosterone deficiency likely
• If 200-350 ng/dL
– Borderline result, use clinical judgment or
– measure bioavailable testosterone (free plus available) or
– free testosterone by equilibrium dialysis, if possible
• LH/FSH helpful only to exclude primary hypogonadism
Androgen Replacement – Men (2)
• Testosterone gel or patch probably preferable to injections
• HCG is another possibility
– Making a come-back (doesn’t cause testicular shrinkage)
– May be used in combination with other treatments
• 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)
– Comes in a pump
• Graded dosing for all preparations would
be desirable
What’s the Problem?
• Most patients are
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On too much cortisol
On not enough thyroid medication
On not enough growth hormone
Not on testosterone
• These lead 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
– May lead to an adrenal crisis
• Thyroid hormone may also
– increase catabolism of other hormones (GH, testosterone)
– lead to increased requirements when thyroid dose is increased
• Treating with GH may increase T4 to T3 conversion
– Dose of T3 (if on T3) may need to be reduced
• GH may decrease TSH
– Treating with GH may unmask or exacerbate central hypothyroidism
– May need a higher dose of thyroid hormone once GH treatment is started
Hormonal Interactions (2)
• Oral, but not transdermal estrogens, increase the need for Lthyroxine 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
• Treating adrenal insufficiency may unmask Diabetes
Insipidus
Hormonal Interactions (3)
• 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
Testosterone for Women
The Physiologic Role Of Testosterone In
Women Remains Poorly Understood
• Previous studies of testosterone supplementation,
largely in surgically or naturally menopausal
women, have reported improvements in
– subjective measures of sexual function
– sense of well being
– variable changes in markers of bone formation and resorption
Potential Benefits of Androgen
Supplementation in Women
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Improved sexual function
Improved bone mineral density
Improved muscle mass and function
Improved mood and sense of well-being
Improved cognitive function
Amelioration of autoimmune disease
Amelioration of premenstrual syndrome
Improvement in dry eye syndrome
Testosterone in Hypopituitarism
• A recent large study demonstrated that patients with
hypopituitarism have increased mortality
– mainly due to cardiovascular, respiratory, and cerebrovascular events
• Hypopituitarism in women is associated with a number of
symptoms, including
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Obesity
Poor quality of life
Decreased libido
Osteopenia
• These persist in spite of standard hormonal replacement
Severe Androgen Deficiency in
Women with Hypopituitarism
• Women with hypopituitarism
– Have impairment of both the adrenal and ovarian sources
of androgen production
– Have lower T and DHEAS levels than women with
ovarian failure alone
Ref Miller et al., J Clin Endocrinol Metab 2001;86:561-7.
Potential Adverse Effects Associated with
Testosterone Supplementation
• The potential risks of testosterone administration to
women include
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virilization
hirsutism
acne
effects on plasma lipids
effects on behavior
Testosterone Delivery
• Currently, the only FDA-approved drug for testosterone in women
is Estratest
– Contains methyl testosterone
– It is a compound that, when given orally, is associated with liver toxicity
in animals and humans
• DHEA is a considered a prohormone of testosterone
– Most of its actions are probably due to binding to the testosterone receptor
• DHEA (25-50 mg)/day is a reasonable approach in women
• Other possibilities include
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Patches (Procter & Gamble, no FDA approval, 2005)
Gels (compounded or investigational)
Injections
Sublingual
Testosterone in Hypopituitarism
• Miller et al. JCEM 91, 1683-1690, 2006
• Design: This was a 12-month randomized,
placebo-controlled study
• Study Participants: 51 women of reproductive age
with androgen deficiency due to hypopituitarism
participated
• Intervention: Physiologic testosterone
administration using a patch that delivers 300 µg
daily or placebo was administered
Testosterone in Hypopituitarism
• Results: Mean free testosterone increased into the normal
range during T administration.
• Mean hip (P = 0.023) and radius (P = 0.007), bone mineral
density increased in the group receiving testosterone,
compared with placebo,
• In testosterone treated group, fat-free mass (P = 0.040) and
thigh muscle area (P = 0.038) increased, but there was no
change in fat mass.
• Mood (P = 0.029) and sexual function (P = 0.044) improved,
as did some aspects of quality of life, but not cognitive
function.
• Testosterone at physiologic replacement levels was well
tolerated, with few side effects.
Demographic Characteristics of Women with
Hypopituitarism (T < 20 ng/dL)
Name
Patients
A.P.
C.B.
C.O.W.
D.G.
E.S.
J.R.
K.T.
M.R.
M.V.
M.Z.
N.S.
S.G.
Mean
SD
Age
BMI
Ethnicity
Disorder
Surgery
24
41
43
29
28
38
48
31
26
44
50
37
36.6
8.8
28.6
30.5
25.8
34.9
34.6
34.6
22.8
28.1
28.1
21.1
30.2
24.0
28.6
3.6
H
H
H
H
H
C
C
H
H
H
C
H
Acromegaly
Acromegaly
Sheehan's
Non-secreting Macroadenoma
Craniopharygioma
Acromegaly
Cushings
Prolactinoma
Craniopharyn
Sheehans
Hypothalamic-Pituitary Dysfunction
Non-secreting Macroadenoma
Y
Y*
N
Y
Y
Y*
Y
Y
Y
N
N
Y
12 patients completed most of the study
Deficiencies
Go, ADH
Go
Go, GH, TSH
Go, TSH, ADH
Go, GH, TSH, ACTH, ADH
Go,TSH, ACTH, ADH
Go, GH, TSH, ACTH
Go, GH, TSH, ACTH
Go, GH, TSH, ACTH, ADH
Go, TSH
Go, GH, TSH, ACTH
Go, GH, ACTH
GH status
high nl
nl
on gh-now nl
not tested
on gh-now nl
nl
on gh-now nl
on gh-now nl
on gh-now nl
not tested
on gh-now nl
not tested
Testosterone
Testosterone Levels in hypopituitary and Healthy
Volunteers
testosterone levels ng/dL
80.0
70.0
**
60.0
50.0
40.0
30.0
20.0
10.0
0.0
Hypopituitarism
Healthy Volunteers
** P < 0.0001
Cholesterol
Cholesterol
300
*
250
mg/dL
200
150
100
50
0
Hypopituitarism
Healthy Volunteers
* P < 0.005
LdL Cholesterol
LdL
250
200
*
mg/dL
150
100
50
0
Hypopituitarism
Healthy Volunteers
* P < 0.05
HdL Cholesterol
P =NS
HdL
120
100
mg/dL
80
60
40
20
0
Hypopituitarism
Healthy Volunteers
Triglycerides
Triglycerides
300
*
250
mg/dL
200
150
100
50
0
Hypopituitarism
Healthy Volunteers
* P < 0.05
400 m walk
400m Walk
300
*
250
Seconds
200
150
100
50
0
Hypopituitarism
Healthy Volunteers
* P < 0.05
Chest press
Chest Press
50.0
45.0
*
40.0
35.0
kg
30.0
25.0
20.0
15.0
10.0
5.0
0.0
Hypopituitarism
Healthy Volunteers
* P < 0.05
SCL - 90 (higher score worse)
** P < 0.0001
SCL-90R (GSI)
2.50
**
2.00
1.50
1.00
0.50
0.00
Hypopituitarism
Healthy Volunteers
Female Sexual Distress Scale
35
*
score range 0 to 48
30
normal range: <15; abnormal range: 15+
25
20
p < 0.0001
15
10
5
0
Healthy Patients
Hypopituitarism
FSFI-Desire
4.5
4
Levels of Desire
3.5
P<0.0001
3
2.5
*
2
1.5
1
0.5
0
Healthy Volunteers
Hypopituitarism
FSFI-Orgasm
5
Levels of Orgasm
4.5
4
3.5
P<0.0001
3
2.5
2
*
1.5
1
0.5
0
Healthy Volunteers
Hypopituitarism
Less Pain Experienced During Vaginal Penetration
FSFI-Pain
5
4.5
4
P<0.001
3.5
3
*
2.5
2
1.5
1
0.5
0
Healthy Volunteers
Hypopituitarism
FSFI-Lubrication
5
4.5
Level of Lubrication
4
P<0.001
3.5
3
2.5
*
2
*
1.5
1
0.5
0
Healthy Volunteers
Hypopituitarism
FSFI-Arousal
4.5
4
Levels of Arousal
3.5
3
2.5
P<0.001
2
*
1.5
1
0.5
0
Healthy Volunteers
Hypopituitarism
FSFI-Satisfaction
4.5
4
Levels of Satisfaction
3.5
3
P<0.0002
2.5
*
2
1.5
1
0.5
0
Healthy Volunteers
Hypopituitarism
Warm Sensation-Vagina
50
P<0.05
units
*
45
40
Healthy Volunteers
Hypopituitarism
Elevated warm sensation threshold indicates
impairment of C-fiber sensory nerve function
Vibratory Threshold-Vagina
p < 0.05
12
*
10
units
8
6
4
2
0
Healthy Volunteers
Hypopituitarism
Elevated vibratory threshold indicates impairment of
A-beta sensory nerve function
Objective Sexual Function (Blood-flow) Labia-post-stimulation
Blood Flow Labia -Post
100.0
90.0
80.0
cm/sec
70.0
60.0
50.0
40.0
30.0
20.0
10.0
0.0
Healthy Volunteers
4 patients and 2 normals below the cut-off of 30 cm/sec
Hypopituitarism
Objective Sexual Function (Blood-flow) Clitoral-post-stimulation
Blood Flow Clitoris-Post
100.0
90.0
80.0
cm/sec
70.0
60.0
50.0
40.0
30.0
20.0
10.0
0.0
Healthy Volunteers
4 patients and 1 normal below the cut-off of 30 cm/sec
Hypopituitarism
Differences in Pre-Post Clitoral Blood Flow
40
35
P<0.05
cm/sec
30
*
25
20
15
10
5
0
Healthy Volunteers
Hypopituitarism
Conclusions Of Short-Term Studies
•
•
•
•
•
•
•
Low free and total serum testosterone levels in patients
Impaired chest press strength and 400 m walk
High cholesterol, LdL and TG
Very reduced psychological well-being
Impaired vaginal, but not clitoral thresholds
Slightly impaired genital blood flow
Recruitment is ongoing
Testosterone Replacement Study at Drew University
• Funded as part of Reproductive Center Grant
• Now recruiting patients
• 80 women (ages 18 to 50 years) with
testosterone deficiency secondary to hypopituitarism
– Will be randomized to receive either placebo or transdermal
testosterone gel
• Leading to a targeted serum testosterone in the upper range of normal
– Double-blind study of 6 months duration
• All patients will be on stable physiological replacement
regimens for other hormones including
– Growth hormone
– Transdermal estrogen replacement
Criteria for Subjects
•
•
•
•
•
•
Women ages 18 to 55
Pituitary gland problems
Low serum testosterone level (can be tested at study site)
Written informed consent
No other significant medical conditions
Patients must discontinue their current testosterone or
DHEA replacement, if on either of these hormones
Testosterone Replacement Study at Drew
University
• Location
– King/Drew Medical Center in Willowbrook
– UCLA in West Los Angeles
• Patient Compensation
– Up to $1500, plus pituitary hormone medications provided
by the study
• Recruitment ongoing
– Call 323-563-9385 or
– email [email protected]
Study Perks For Patients
• Free growth hormone during
all parts of the study
• Open label period
– All patients would get testosterone
gel for one year following randomization period
• Free hormonal testing including GH testing
• Climara patch and Provera supplied without charge
Conclusion
• Sexual dysfunction in women matters!
• Psychological dysfunction in women matters!
– We hope this study will address these problems
• We expect this study will
– accurately assess the important benefits and deleterious effects of
physiological testosterone replacement in women with
hypopituitarism
• At the conclusion of this study, we expect to
– determine whether it is of benefit to add testosterone to the standard
hormonal replacement for women with hypopituitarism
For More Information and
To Schedule An Appointment With Dr. Friedman
• www.goodhormonehealth.com
• [email protected]
• My book on thyroid diseases
– “ The Everything Health Guide
to Thyroid Disease”
– Published by Adams Media
– Just came out
– Available at Amazon.com
A BIG Thanks!
• To Magic Foundation for inviting me and doing
great work!
• To Dianne Tambourine for hosting a great
conference