Transcript Theodore C. Friedman, M.D., Ph.D. Endocrinology of Fatigue

Theodore C. Friedman, M.D., Ph.D.
Associate Professor of Medicine-UCLA
Chief, Division of Endocrinology, Molecular
Medicine and Metabolism
Charles R. Drew University
Reproductive Health
MAGIC Foundation Affected Adult Convention
February 5, 2006
Hormonal Axes
• Adrenal (corticotropes)=CRH-ACTH-Cortisol
• Thyroid (thyrotropes)= TRH-TSH-T4/T3
• Gonads (gonadotropes)= GnRH-LH/FSHTestosterone/estrogen
• GH (sommatotropes) =GHRH-GH-IGF1
Abnormalities of gonadotropes
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Gonads= GnRH-LH/FSH-Testosterone/estrogen/progesterone
Lack of ovulation
Irregular of no periods
Infertility
Vaginal Dryness
Osteoporosis
Decreased libido
Possibly poor sense of well-being
Menstrual Cycle- hormones, temperature, ovulation
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
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
How to Determine Ovulation
• If not having monthly periods, probably not
ovulating
• If regular periods, probably, but not necessarily
ovulating
o
• Measure basal body temperature, increases by 0.5
C in 2nd half of cycle if ovulating.
• Ovulation kits (measures LH surge)
• Check a progesterone level in the 2nd half of the
cycle and look for a rise.
• Intercourse at the time of ovulation and right after
How to Get Pregnant with
Hypopituitarism
• See a Reproductive Endocrinologist
• Exclude other causes of infertility
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Male
Endometriosis
Tubal Problems
PCOS
Insulin resistance
• Start with Clomiphene (estrogen blocker at the pituitary,
blocks negative feedback
• Ovulation induction with FSH/LH analogues
Estrogen Replacement
• Amenorrhea or oligomenorrhea indicates gonadotropin
deficiency
• Younger women who are hypogonadal are likely to benefit
from estrogen replacement.
• Less clear for older women
• Replacement and decision to have periods or not is based
on patient preference and age
Estrogen Replacement (2)
• Choices include:
• Premarin (pregnant mare urine, “conjugated estrogen”, multiple
estrogenic compounds)
• Oral estrogen compounds (estrace)
• Birth control pills (contain high doses progesterone and low doses
estrogen)
• 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 even after discontinuing.
Oral Estrogen Replacement, but
not other routes (2)
• Raises thyroid-binding globulin (TBG) which can lead to
an increase in thyroid hormone requirements.
• Raises cortisol-binding globulin (CBG) and leads to high
levels of total cortisol which makes testing for adrenal
insufficiency difficult
Oral Estrogen Replacement
• In women with hypopituitarism, probably 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).
• Some compounding pharmacies encourage bi-est
(estradiol/ estriol) or tri-est (estrone estradiol/ estriol).
• Should take estrogen daily.
Should you take estrogen/progesterone
to induce a period?
• Taking 5-10 mg of Provera (synthetic Progestin) or 100200 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 and older than that not to have a period.
Should you take estrogen/progesterone
to induce a period? (2)
• Estrogen without progesterone in a women with a uterus can lead to
uterine cancer.
• Probably enough to take progesterone for 10 days every 4 months.
• Provera, more than estrogen, was responsible for increased breast
cancer in WHI.
• Progesterone may be associated with fluid retention and weight gain.
• Progesterone, if given should be given during the 2nd half of the cycle
when progesterone levels rise.
• I tend to give as little progesterone possible, but in some patients, it
helps.
• Progesterone creams or vaginal progesterone are good options, besides
prometrium.
Should you have estrogen levels
monitored?
• If not on estrogen and having periods, estradiol levels are
probably suffice, if no periods, estradiol levels are
probably low.
• Often helpful to confirm (or with irregular periods) by
measuring estradiol (day 3ish) if having periods.
• A level less than 50 pg/mL (check units) is low for this
time of the cycle.
• If on treatment, aim for a estradiol level of 70-125 pg/mL.
• Some doctors check a mid-cycle estradiol level, I think its
hard because if you are off a day or so, you will have very
different values.
Should you have progesterone levels
monitored?
• Can be done to see if ovulation (check day 22ish) and
compare to luteal values.
• If on replacement progesterone, can look for mid-normal
luteal values.
Physiology of
Testosterone Secretion in Women
Adrenal Glands
Ovaries
Testosterone Precursors
50% = 150 mg/day
DHEA DHEAS
Androstenedione
50% = 150 mg/day
Circulating Testosterone
Daily Secretion Rate = 300 mg/day
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
Plasma Binding Proteins and
Concept of Free and Bioavailable
Testosterone
Unbound or Free
0.5 – 3.0%
Albuminbound
50-68%
SHBGbound
30-45%
MEN
Bioavailable
Testosterone
Albuminbound
25%
SHBGbound
70%
WOMEN
Free T = unbound T
Bioavailable = unbound + albumin bound
Defining Androgen Deficiency in
Women
• Statistical definition:
–Serum total or free T less than the lower limit of normal for healthy
young women (<15 ng/dL)
• Relative Androgen Deficiency
–Lower than the median (30 ng/dL) for young, menstruating women
(Used in clinical trials (Shifren et al, 2000, Miller et al, 1998).
• Definition Based on Clinical Threshold
–Use a testosterone threshold below which high prevalence of “clinical
disorder” (example: osteoporosis, hypercholesterolemia)
Female Androgen Deficiency
Syndrome (FADS)
From the Princeton Conference (June 2001):
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Global loss of sexual desire (low libido)
Decreased sensitivity in the nipples and clitoris
Decreased arousability and capacity for orgasm
Loss of muscle tone
Diminished vital energy (fatigue)
Thinning and loss of pubic hair
Dry skin
Blunted motivation, lack of well-being
Unresolved at Princeton Conference:
• No agreed upon cut-off level for normal range of T
Problems in the Measurement of
Testosterone Concentrations in
Women
• Suboptimal sensitivity to measure T levels in women
• Lack of sufficient precision in the low range
• Paucity of normative data
• Cross-reactivity issues
• Lack of consistency in reagents and assay methods
Padero, Bhasin, Friedman, et al, JAGS 2002
Causes of Androgen Deficiency in Women
• Age-related decline
• Oophorectomy
– Surgical
– Radiation
– Chemical
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Adrenal insufficiency
Panhypopituitarism
Glucocorticoid treatment
Chronic illness such as HIV-infection
Premature ovarian failure
Turner’s syndrome
Testosterone in hypopituitarism
• Acquired hypopituitarism in women is characterized by
central hypogonadism and/or hypoadrenalism and
therefore affects critical sources of androgen production in
women.
• Surprisingly, there have only been a few studies on
testosterone levels in women with hypopituitarism and no
large studies on testosterone replacement in women with
hypopituitarism.
Testosterone in hypopituitarism (2)
• A recent large study demonstrated that patients
with hypopituitarism have increased mortality,
which was mainly due to cardiovascular,
respiratory, and cerebrovascular events.
• Hypopituitarism in women is associated with a
number of symptoms, including obesity, poor
quality of life, decreased libido and osteopenia,
that 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
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 the risk of
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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, which contains methyl testosterone, 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
– Patches (Procter & Gamble, no FDA approval, 2005)
– Gels (compounded or investigational)
– Injections
– Sublingual
Tostrelle
• Cellegy Pharmaceuticals
• Excellent pharmacokinetic data in
surgically-menopausal, testosteronedeficient women on transdermal estrogen.
Short-term study
Hypotheses
• Women with hypopituitarism will have decreased serum
free and total testosterone levels.
• They will have decreased muscle strength and physical
performance, reduced sexual function, decreased lean mass
and impaired psychological performance on the SCL-90R.
• Pharmacokinetic studies giving Tostrelle will raise serum
testosterone levels into the upper-normal range.
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
Demographic Characteristics of Normal
Volunteers
Volunteers
A.H.
E.M.
G.R.
G.S.
J.B.
K.A.
L.W.
L.Z.
S.A.
T.J.
Y.R.
Mean
SD
Age
30
23
32
33
23
49
43
20
24
23
26
29.6
9.2
BMI
22.0
20.3
31.1
22.1
20.3
26.1
27.5
30.9
28.6
20.5
25.6
25.0
4.2
C
C
H
C
C
H
C
H
H
C
H
11 patients completed most of the study
BMI
Body Mass Index
40.0
35.0
30.0
kg/m2
25.0
20.0
15.0
10.0
5.0
0.0
PT
NV
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
NV
PT
** P < 0.0001
Cholesterol
Cholesterol
300
*
250
mg/dL
200
150
100
50
0
PT
NV
* P < 0.005
LDL Cholesterol
LDL
250
200
*
mg/dL
150
100
50
0
PT
NV
* P < 0.05
HDL Cholesterol
P =NS
HDL
120
100
mg/dL
80
60
40
20
0
PT
NV
Triglycerides
Triglycerides
300
*
250
mg/dL
200
150
100
50
0
PT
NV
* P < 0.05
400 m walk
400m Walk
300
*
250
Seconds
200
150
100
50
0
PT
NV
* P < 0.05
Stair climb (lower score is worse)
P=NS
Stair Climb
14.0
12.0
Watts
10.0
8.0
6.0
4.0
2.0
0.0
PT
NV
Chest press
* P < 0.05
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
PT
NV
Leg press
P=NS
Leg Press
350
300
250
kg
200
150
100
50
0
PT
NV
Thigh muscle mass by MRI
Thigh Muscle Mass
140.0
120.0
100.0
CC
80.0
60.0
40.0
20.0
0.0
PT
NV
P=NS
SCL - 90 (higher score worse)
** P < 0.0001
SCL-90R (GSI)
2.50
**
2.00
1.50
1.00
0.50
0.00
PT
NV
SCL - T Score
T Value
80
85
70
75
**
60
%
65
50
40
55
30
45
20
35
10
250
PT
PT
NV
NV
** P < 0.0001
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
Hypopituitary Patients
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
Hypopituitary
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
Hypopituitary
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
Hypopituitary
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
Hypopituitary
Warm Sensation-Vagina
50
P<0.05
units
*
45
40
Volunteers
Patients
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
Volunteers
Patients
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
PT
4 patients and 2 normals below the cut-off of 30 cm/sec
NV
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
PT
4 patients and 1 normal below the cut-off of 30 cm/sec
NV
Differences in Pre-Post Clitoral Blood Flow
40
35
P<0.05
cm/sec
30
*
25
20
15
10
5
0
Healthy Volunteers
Hypopituitary
Clitoral Vibratory Threshold
PS = NS
Vibratory Threshold-Clitoris
18.0
16.0
14.0
microns
12.0
10.0
8.0
6.0
4.0
2.0
0.0
PT
NV
Clitoral Warm Sensation
P = NS
Warm Sensation-Clitoris
49.0
47.0
Degrees C
45.0
43.0
41.0
39.0
37.0
35.0
PT
NV
Vagina Cold Sensation
Cold Sensation-Vagina
33.0
31.0
29.0
Degrees C
27.0
25.0
23.0
21.0
19.0
17.0
15.0
PT
NV
Reduced cold sensation threshold indicates
impairment of C-fiber sensory nerve function.
P = NS
Clitoral Cold Sensation
P = NS
Cold Sensation-Clitoris
40.0
Degrees C
35.0
30.0
25.0
20.0
15.0
PT
NV
Conclusions of short-term studies
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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.
Current Study
• 80 women (ages 18 to 55 years) with testosterone
deficiency secondary to hypopituitarism will be
randomized to receive either placebo or transdermal
testosterone gel (we will start with 12 mg of
testosterone/day, leading to a targeted serum testosterone in
the upper range of normal) in a double-blind study of 6
months duration.
• All patients will be on stable physiological replacement
regimens for other hormones including growth hormone
and transdermal estrogen replacement.
Inclusion Criteria
• A.
Women age 18-55
• B. Hypopituitarism with central adrenal and/or
gonadal deficiencies AND
• C. Serum testosterone level on transdermal estrogen
replacement of ≤ 20 ng/dL or free testosterone <1.5
pg/mL
Inclusion Criteria (2)
• C.
No other significant medical condition
• D.
Able to provide informed consent
• E.
All races and ethnicities
• F.
All patients regardless of marital status and
relationship status.
Study perks for patients
• Free growth hormone during all parts of the study.
• Open label period in which 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
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Sexual dysfunction in women matters!
Psychological dysfunction in women matters!
We hope this study addresses 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.
Testosterone-replacement study at Drew
• Location: King/Drew Medical Center in Willowbrook and UCLA in
West Los Angeles
• Patient Compensation: up to $800, plus pituitary hormone
medications provided by the study.
• Recruitment ongoing-please call 323-563-9385 or email
[email protected]
For more information/to schedule an
appointment
• www.goodhormonehealth.com
• [email protected]
• My book on thyroid diseases “Everyone’s
Guide to Thyroid Disorders” should be out
in Fall 2006
Thanks
• Magic Foundation for inviting me and doing
great work!