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

1
Theodore C. Friedman, M.D., Ph.D.Associate
Professor of Medicine-UCLAChief, Division of
Endocrinology, Molecular Medicine and
MetabolismCharles R. Drew UniversityReproductiv
e HealthMAGIC Foundation Affected Adult
Convention February 5, 2006
2
Hormonal Axes

• Adrenal (corticotropes)CRH-ACTH-Cortisol
• Thyroid (thyrotropes) TRH-TSH-T4/T3
• Gonads (gonadotropes) GnRH-LH/FSH-Testosterone/es
  trogen
• GH (sommatotropes) GHRH-GH-IGF1

3
Abnormalities of gonadotropes

• Gonads GnRH-LH/FSH-Testosterone/estrogen/progeste
  rone
• Lack of ovulation
• Irregular of no periods
• Infertility
• Vaginal Dryness
• Osteoporosis
• Decreased libido
• Possibly poor sense of well-being

4
Menstrual Cycle- hormones, temperature, ovulation
5
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

6
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 0.5o
  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

7
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

8
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

9
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)

10
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.

11
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

12
Oral Estrogen Replacement

• In women with hypopituitarism, probably avoid it!

13
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.

14
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.

15
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.

16
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.

17
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.

18
Physiology of Testosterone Secretion in Women
Adrenal Glands
Ovaries
50 150 mg/day
50 150 mg/day
Circulating Testosterone Daily Secretion Rate
300 mg/day
19
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.

20
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

21
Plasma Binding Proteins and Concept of Free and
Bioavailable Testosterone
Unbound or Free 0.5 3.0
Albumin- bound 25
Albumin- bound 50-68
Bioavailable Testosterone
SHBG- bound 70
SHBG- bound 30-45
MEN
WOMEN
Free T unbound T Bioavailable unbound
albumin bound
22
Defining Androgen Deficiency in Women

• Statistical definition
• Serum total or free T less than the lower limit
  of normal for healthy young women (lt15 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)

23
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

24
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

25
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
• Turners syndrome

26
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.

27
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.

28
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
  200186561-7.

29
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

30
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

31
Tostrelle

• Cellegy Pharmaceuticals
• Excellent pharmacokinetic data in
  surgically-menopausal, testosterone-deficient
  women on transdermal estrogen.

32
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.

33
Demographic Characteristics of Women with
Hypopituitarism (T lt 20 ng/dL)
Name
Age
BMI
Ethnicity
Disorder
Surgery
Deficiencies
GH status
Patients
A.P.
24
28.6
H
Acromegaly
Y
Go, ADH
high nl
C.B.
41
30.5
H
Acromegaly
Y
Go
nl
C.O.W.
43
25.8
H
Sheehan's
N
Go, GH, TSH
on gh-now nl
D.G.
29
34.9
H
Non-secreting Macroadenoma
Y
Go, TSH, ADH
not tested
E.S.
28
34.6
H
Craniopharygioma
Y
Go, GH, TSH, ACTH, ADH
on gh-now nl
J.R.
38
34.6
C
Acromegaly
Y
Go,TSH, ACTH, ADH
nl
K.T.
48
22.8
C
Cushings
Y
Go, GH, TSH, ACTH
on gh-now nl
M.R.
31
28.1
H
Prolactinoma
Y
Go, GH, TSH, ACTH
on gh-now nl
M.V.
26
28.1
H
Craniopharyn
Y
Go, GH, TSH, ACTH, ADH
on gh-now nl
M.Z.
44
21.1
H
Sheehans
N
Go, TSH
not tested
N.S.
50
30.2
C
Hypothalamic-Pituitary Dysfunction
N
Go, GH, TSH, ACTH
on gh-now nl
S.G.
37
24.0
H
Non-secreting Macroadenoma
Y
Go, GH, ACTH
not tested
Mean
36.6
28.6
SD
8.8
3.6
12 patients completed most of the study
34
Demographic Characteristics of Normal Volunteers
BMI
Age
Volunteers
A.H.
30
22.0
C
E.M.
23
20.3
C
G.R.
32
31.1
H
G.S.
33
22.1
C
J.B.
23
20.3
C
K.A.
49
26.1
H
L.W.
43
27.5
C
L.Z.
20
30.9
H
S.A.
24
28.6
H
T.J.
23
20.5
C
Y.R.
26
25.6
H
Mean
29.6
25.0
SD
9.2
4.2
11 patients completed most of the study
35
BMI
Body Mass Index
40.0
35.0
30.0
25.0
kg/m2
20.0
15.0
10.0
5.0
0.0
PT
NV
36
Testosterone
P lt 0.0001
Testosterone Levels in hypopituitary and Healthy
Volunteers
80.0
70.0

60.0
50.0
testosterone levels ng/dL
40.0
30.0
20.0
10.0
0.0
PT
NV
37
Cholesterol
P lt 0.005
Cholesterol

300
250
200
150
mg/dL
100
50
0
NV
PT
38
LDL Cholesterol
P lt 0.05
LDL
250

200
150
mg/dL
100
50
0
NV
PT
39
HDL Cholesterol
P NS
HDL
120
100
80
mg/dL
60
40
20
0
NV
PT
40
Triglycerides
P lt 0.05
Triglycerides
300

250
200
150
mg/dL
100
50
0
PT
NV
41
400 m walk
P lt 0.05
400m Walk

300
250
200
Seconds
150
100
50
0
NV
PT
42
Stair climb (lower score is worse)
PNS
Stair Climb
14.0
12.0
10.0
8.0
Watts
6.0
4.0
2.0
0.0
NV
PT
43
Chest press
P lt 0.05
Chest Press
50.0

45.0
40.0
35.0
30.0
kg
25.0
20.0
15.0
10.0
5.0
0.0
NV
PT
44
Leg press
PNS
Leg Press
350
300
250
200
kg
150
100
50
0
NV
PT
45
Thigh muscle mass by MRI
PNS
Thigh Muscle Mass
140.0
120.0
100.0
80.0
CC
60.0
40.0
20.0
0.0
NV
PT
46
SCL - 90 (higher score worse)
P lt 0.0001
SCL-90R (GSI)
2.50

2.00
1.50
1.00
0.50
0.00

PT
NV
47
SCL - T Score
P lt 0.0001
T Value
T Value
80
85

70
75
60
65
50


40
55
30
45
20
35
10
0
25
PT
NV
PT
NV
48
Female Sexual Distress Scale
35

30
normal range lt15 abnormal range 15
25
20
score range 0 to 48
p lt 0.0001
15
10
5
0
Healthy Patients
Hypopituitary Patients
49
FSFI-Desire
4.5
4
3.5
Plt0.0001
3
2.5
Levels of Desire

2
1.5
1
0.5
0
Healthy Volunteers
hypopituitarism
50
FSFI-Orgasm
5
4.5
4
3.5
Plt0.0001
3
Levels of Orgasm

2.5
2

1.5
1
0.5
0
Healthy Volunteers
Hypopituitary
51
FSFI-Pain
5
4.5
4
Plt0.001
3.5
3
Less Pain Experienced During Vaginal Penetration

2.5
2
1.5
1
0.5
0
Healthy Volunteers
Hypopituitary
52
FSFI-Lubrication
5
4.5
4
Plt0.001
3.5
3
Level of Lubrication
2.5

2

1.5
1
0.5
0
Healthy Volunteers
Hypopituitary
53
FSFI-Arousal
4.5
4
3.5
3
2.5
Levels of Arousal
Plt0.001
2

1.5
1
0.5
0
Healthy Volunteers
hypopituitarism
54
FSFI-Satisfaction
4.5
4
3.5
3
Plt0.0002
2.5
Levels of Satisfaction

2
1.5
1
0.5
0
Healthy Volunteers
Hypopituitary
55
Warm Sensation-Vagina
50
Plt0.05

units
45
40
Volunteers
Patients
56
Vibratory Threshold-Vagina
p lt 0.05
12

10
8
units
6
4
2
0
Volunteers
Patients
57
Objective Sexual Function (Blood-flow)
-Labia-post-stimulation
Blood Flow Labia -Post
100.0
90.0
80.0
70.0
60.0
cm/sec
50.0
40.0
30.0
20.0
10.0
0.0
NV
PT
58
Objective Sexual Function (Blood-flow)
-Clitoral-post-stimulation
Blood Flow Clitoris-Post
100.0
90.0
80.0
70.0
60.0
cm/sec
50.0
40.0
30.0
20.0
10.0
0.0
NV
PT
59
Differences in Pre-Post Clitoral Blood Flow
40
35
Plt0.05
30

25
cm/sec
20
15
10
5
0
Healthy Volunteers
Hypopituitary
60
Clitoral Vibratory Threshold
PS NS
Vibratory Threshold-Clitoris
18.0
16.0
14.0
12.0
10.0
microns
8.0
6.0
4.0
2.0
0.0
PT
NV
61
Clitoral Warm Sensation
P NS
Warm Sensation-Clitoris
49.0
47.0
45.0
43.0
Degrees C
41.0
39.0
37.0
35.0
PT
NV
62
Vagina Cold Sensation
P NS
Cold Sensation-Vagina
33.0
31.0
29.0
27.0
25.0
Degrees C
23.0
21.0
19.0
17.0
15.0
PT
NV
63
Clitoral Cold Sensation
P NS
Cold Sensation-Clitoris
40.0
35.0
30.0
Degrees C
25.0
20.0
15.0
PT
NV
64
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.

65
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.

66
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 lt1.5 pg/mL

67
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.

68
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.

69
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.

70
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 study_at_goodhormonehealth.com

71
For more information/to schedule an appointment

• www.goodhormonehealth.com
• Mail_at_goodhormonehealth.com
• My book on thyroid diseases Everyones Guide to
  Thyroid Disorders should be out in Fall 2006

72
Thanks

• Magic Foundation for inviting me and doing great
  work!