theodore c. friedman, m.d., ph.d. associate professor of medicine-ucla chief, division of...
TRANSCRIPT
Theodore C. Friedman, M.D., Ph.D.Associate Professor of Medicine-
UCLAChief, 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/FSH-Testosterone/estrogen
• GH (sommatotropes) =GHRH-GH-IGF1
Abnormalities of gonadotropes
• 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 aTIFF (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
• Measure basal body temperature, increases by 0.5
o 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
– 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 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 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.
Testosterone PrecursorsTestosterone Precursors
DHEADHEA DHEASDHEAS AndrostenedioneAndrostenedione
Circulating TestosteroneDaily Secretion Rate = 300 g/day
Circulating TestosteroneDaily Secretion Rate = 300 g/day
50% = 150 g/day50% = 150 g/day
50% = 150 g/day50% = 150 g/day
Physiology of Testosterone Secretion
in WomenOvaries Adrenal Glands
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• 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
MEN WOMEN
Free T = unbound TBioavailable = unbound + albumin bound
Unbound or Free0.5 – 3.0%
Albumin-bound
50-68%
Albumin-bound25%
SHBG-bound
30-45%
SHBG-bound70%
BioavailableTestosterone
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):• 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
• 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– 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, testosterone-deficient women on transdermal estrogen.
Short-term studyHypotheses
• 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 Age BMI Ethnicity Disorder Surgery Deficiencies GH status
PatientsA.P. 24 28.6 H Acromegaly Y Go, ADH high nlC.B. 41 30.5 H Acromegaly Y* Go nlC.O.W. 43 25.8 H Sheehan's N Go, GH, TSH on gh-now nlD.G. 29 34.9 H Non-secreting Macroadenoma Y Go, TSH, ADH not testedE.S. 28 34.6 H Craniopharygioma Y Go, GH, TSH, ACTH, ADH on gh-now nlJ.R. 38 34.6 C Acromegaly Y* Go,TSH, ACTH, ADH nlK.T. 48 22.8 C Cushings Y Go, GH, TSH, ACTH on gh-now nlM.R. 31 28.1 H Prolactinoma Y Go, GH, TSH, ACTH on gh-now nlM.V. 26 28.1 H Craniopharyn Y Go, GH, TSH, ACTH, ADH on gh-now nlM.Z. 44 21.1 H Sheehans N Go, TSH not testedN.S. 50 30.2 C Hypothalamic-Pituitary DysfunctionN Go, GH, TSH, ACTH on gh-now nlS.G. 37 24.0 H Non-secreting Macroadenoma Y Go, GH, ACTH not testedMean 36.6 28.6SD 8.8 3.6
12 patients completed most of the study
Demographic Characteristics of Normal Volunteers
VolunteersA.H. 30 22.0 CE.M. 23 20.3 CG.R. 32 31.1 HG.S. 33 22.1 CJ.B. 23 20.3 CK.A. 49 26.1 HL.W. 43 27.5 CL.Z. 20 30.9 HS.A. 24 28.6 HT.J. 23 20.5 CY.R. 26 25.6 HMean 29.6 25.0SD 9.2 4.2
Age BMI
11 patients completed most of the study
BMI
Body Mass Index
0.0
5.0
10.0
15.0
20.0
25.0
30.0
35.0
40.0
PT NV
kg/m2
Testosterone ** P < 0.0001Testosterone Levels in hypopituitary and Healthy
Volunteers
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
testosterone levels ng/dL
NV PT
**
Cholesterol
Cholesterol
0
50
100
150
200
250
300
mg/dL
NVPT
* P < 0.005
*
LDL Cholesterol
LDL
0
50
100
150
200
250
mg/dL
NVPT
* P < 0.05
*
HDL Cholesterol
HDL
0
20
40
60
80
100
120
mg/dL
NVPT
P =NS
Triglycerides
Triglycerides
0
50
100
150
200
250
300mg/dL
NVPT
* P < 0.05
*
400 m walk
400m Walk
0
50
100
150
200
250
300
Seconds
NVPT
* P < 0.05
*
Stair climb (lower score is worse)
Stair Climb
0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
Watts
NVPT
P=NS
Chest pressChest Press
0.0
5.0
10.0
15.0
20.0
25.0
30.0
35.0
40.0
45.0
50.0
kg
NVPT
* P < 0.05
*
Leg press
Leg Press
0
50
100
150
200
250
300
350
kg
NVPT
P=NS
Thigh Muscle Mass
0.0
20.0
40.0
60.0
80.0
100.0
120.0
140.0CC
NVPT
P=NSThigh muscle mass by MRI
SCL-90R (GSI)
0.00
0.50
1.00
1.50
2.00
2.50
PT NV
SCL - 90 (higher score worse)
**
** P < 0.0001
T Value
0
10
20
30
40
50
60
70
80
%
SCL - T Score
PT NV
T Value
25
35
45
55
65
75
85
PT NV
%
**
** P < 0.0001
0
5
10
15
20
25
30
35
Healthy Patients Hypopituitary Patients
score range 0 to 48
normal range: <15; abnormal range: 15+
p < 0.0001
*
Female Sexual Distress Scale
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Healthy Volunteers hypopituitarism
Levels of Desire
P<0.0001
*
FSFI-Desire
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
Healthy Volunteers Hypopituitary
Levels of Orgasm
P<0.0001
*
FSFI-Orgasm
**
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
Healthy Volunteers Hypopituitary
Less Pain Experienced During Vaginal Penetration
P<0.001
*
FSFI-Pain
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
Healthy Volunteers Hypopituitary
Level of Lubrication
*
FSFI-Lubrication
P<0.001
*
FSFI-Arousal
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Healthy Volunteers hypopituitarism
Levels of Arousal
P<0.001
*
FSFI-Satisfaction
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Healthy Volunteers Hypopituitary
Levels of Satisfaction
P<0.0002
*
Warm Sensation-Vagina
40
45
50
Volunteers Patients
units
P<0.05
*
Elevated warm sensation threshold indicatesimpairment of C-fiber sensory nerve function
Vibratory Threshold-Vagina
0
2
4
6
8
10
12
Volunteers Patients
units
p < 0.05
*
Elevated vibratory threshold indicates impairment ofA-beta sensory nerve function
Objective Sexual Function (Blood-flow) -Labia-post-
stimulation
4 patients and 2 normals below the cut-off of 30 cm/sec
Blood Flow Labia -Post
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0
cm/sec
NVPT
Objective Sexual Function (Blood-flow) -Clitoral-post-
stimulation
4 patients and 1 normal below the cut-off of 30 cm/sec
Blood Flow Clitoris-Post
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0cm/sec
NVPT
Differences in Pre-Post Clitoral Blood Flow
0
5
10
15
20
25
30
35
40
Healthy Volunteers Hypopituitary
cm/sec
P<0.05
*
Vibratory Threshold-Clitoris
0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
16.0
18.0
PT NV
microns
Clitoral Vibratory ThresholdPS = NS
Clitoral Warm Sensation
Warm Sensation-Clitoris
35.0
37.0
39.0
41.0
43.0
45.0
47.0
49.0
PT NV
Degrees C
P = NS
Vagina Cold Sensation
Cold Sensation-Vagina
15.0
17.0
19.0
21.0
23.0
25.0
27.0
29.0
31.0
33.0
PT NV
Degrees C
P = NS
Reduced cold sensation threshold indicatesimpairment of C-fiber sensory nerve function.
Clitoral Cold Sensation
Cold Sensation-Clitoris
15.0
20.0
25.0
30.0
35.0
40.0
PT NV
Degrees C
P = NS
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.
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• 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!