Volume 6, Issue 2, Winter 2000
Articles in this issue:
Deficiency in Women with Hypopituitarism
by Karen K. Miller, M.D.
of low testosterone levels in men have been well understood
for some time and include a decrease in libido, bone density
and muscle mass (1,2). Circulating androgen levels in
healthy young women are a fraction of those found in men, with
testosterone levels approximately one tenth of male levels,
and it is not known whether relative androgen deficiency has
similar clinical implications for women as for men.
the androgens testosterone and androstenedione are secreted
by the ovaries and adrenal glands (3,4). In contrast,
DHEAS is secreted almost exclusively by the adrenals.
Because hypopituitarism often results in reduced ovarian and/or
adrenal function, researchers here at the Neuroendocrine Unit
at Massachusetts General Hospital hypothesized that women with
hypopituitarism might have reduced androgen levels. Therefore,
fasting testosterone, free testosterone, androstenedione and
DHEAS levels were measured at 8:00 am on three days during one
month in 55 women with hypopituitarism, defined as secondary
hypogonadism and/or hypoadrenalism. Four subsets of hypopituitary
women were studied, including women of reproductive and post-menopausal
age and those receiving or not receiving estrogen therapy.
The majority of patients studied had a history of a pituitary
tumor and had undergone either surgery or radiation therapy,
while the etiology of the hypopituitarism in other patients
included craniopharyngiomas, brain tumors and hypophysitis.
Four subsets of women with normal pituitary function were also
recruited to serve as appropriate controls for the four subsets
of women with hypopituitarism. Healthy women of reproductive
age not taking estrogen were studied in the early follicular
phase, midcyle and mid-luteal phase of the menstrual cycle.
data suggest that androgen levels are markedly decreased in
women with hypopituitarism compared with women who have normally
functioning pituitary glands (5). In all subsets of hypopituitary
women, all androgens studied - testosterone, free testosterone,
androstenedione and DHEAS - were markedly reduced, regardless
of age or estrogen therapy. In addition, the midcycle
increases seen in testosterone, free testosterone and androstenedione
in women with normal pituitary and ovarian function were absent
in the women with hypopituitarism. Furthermore, androgen
levels in many women with hypopituitarism were undetectable
by current assays for at least one androgen for the majority
of women. Figure 1 shows free testosterone levels in 18
women of reproductive age and 18 controls matched for age and
body mass index (BMI).
The clinical implications of the hypoandrogenemia detected in
women with hypopituitarism and indications, if any, for therapy
at this time have not been established. However,
many women with hypopituitarism suffer from osteopenia, obesity
and decreased libido (6-8). In hypogonadal men, androgen
replacement has been well documented to result in an increase
in bone density, decrease in fat mass and an increase in libido
(1,9,10). Therefore, androgen replacement therapy may
prove efficacious in women with hypopituitarism. However,
physiologic androgen replacement doses for women would be significantly
lower than those administered safely to men, and no such preparation
is yet commercially available.
of androgen therapy in women thus far have used supraphysiologic
androgen doses or have not been randomized, controlled trials.
However, a few cross-sectional studies demonstrate correlations
between androgen levels and bone density or libido in women.
Results from the few randomized, controlled studies are
promising in terms of effects of androgens on bone formation
and bone density (11-15). Further study is needed to determine
whether low doses of androgens would result in similar benefits
to libido, bone mineral density and body composition in women
L, Finkelstein J, Schoenfeld D, Rosenthal D, Anderson E, Klibanski
A. 1996 Increase in bone density and lean body mass during testosterone
administration in men with acquired hypogonadism. J Clin Endocrinol
C, Heiman J, Rivier J, Bremner W. 1994 Effects of endogenous
testosterone and estradiol on sexual behavior in normal young
men. J Clin Endocrinol Metab. 78:711-716.
3. Judd H.
1976 Hormonal dynamics associated with the menopause. Clin Obstet
MA, Bardin CW. 1972 Androgen production and metabolism in normal
and virilized women. Metabolism. 21:667-688.
K, Sesmilo G, Schiller A, Burton S, Klibanski A. 2000 Abstract
#2173: Androgen deficiency in women with hypopituitarism.
The Endocrine Society's 82nd Annual Meeting, Toronto, Canada.
C, Slenczka E, Ziegler R. 1991 Erhohte pravalenz von osteoporose
und arteriosklerose bei konventionell substituierter hypophysenvorderlappeninsuffizienz:
bedarf einer zusatzlichen wachstumshormonsubstitution?
Klin Wochenschr. 69:769-773.
7. Rosen T,
Wilhelmsen L, Landin-Wilhelmsen K, Lappas G, Bengtsson B. 1997
Increased fracture frequency in adult patients with hypopituitarism
and GH deficiency. European J Endocrinology. 137:240-245.
V, Beshyah S, Fisher C, Sharp P, Nicolaides A, Johnston D. 1992
Detection of premature atherosclerosis by high-resolution ultrasonography
in symptom-free hypopituitary adults. Lancet. 340:1188-92.
9. Behre H,
Kliesch S, Leifke E, Link T, Nieschlage. 1997 Long-term effect
of testosterone therapy on bone mineral density in hypogonadal
men. J Clin Endocrinol Metab. 82:2386-2390.
J, Bancroft J, Davidson D, Warner P. 1981 Androgen replacement
with oral testosterone undecanoate in hypogonadal men:
a double-blind controlled study. Clin Endo (opxf). 14:49-61.
SR, McCloud P, Strauss BJG, Burger H. 1995 Testosterone enhances
estradiol's effects on postmenopausal bone density and sexuality.
LG, Wiita B, Artis A, Bowen A, Schwartz S, Trahiotis M, Shoukri
K, Smith J. 1996 Comparison of the effects of estrogen alone
and estrogen plus androgen on biochemical markers of bone formation
and resorption in postmenopausal women. J Clin Endocrinol Metab.
C, Longcope C, Peacock M, Hui S, Johnston C. 1996 Sex steroids,
bone mass, and bone loss. A prospective study of pre-,
peri- and postmenopausal women. J Clin Invest. 97:14-21.
KK, Freni-titulaer LW, DePuey EG, Miller DT, Sgoutas DS, Coralli
CH, Phillips DL, Rogers TN, Clark RV. 1989 Sex steroids and
bone density in premenopausal and perimenopausal women. J Clin
Endocrinol Metab. 69:533-539.
G, Leiblum S. 1991 Sexuality in sexagenarian women. Maturitas.
Therapy in Men: An Update
by Laurence Katznelson, M.D.
deficiency in men is manifested typically by symptoms of hypogonadism,
including decreases in erectile function and libido.
Testosterone also has an important role in the regulation
of normal growth, bone metabolism and body composition.
Specifically, testosterone deficiency is an important
risk factor for osteoporosis and fractures in men.
In men older than 65 years of age, the incidence of hip
fracture is 4-5/1000 and approximately 30% of all hip fractures
occur in men. Men
with testosterone deficiency have significant decreases in bone
density, particularly in the trabecular bone compartment.
Testosterone deficiency has been reported in over half
of elderly men with a history of hip fracture.
Men with testosterone deficiency also have alterations
in body composition that include an increase in body fat. Using
quantitative CT scans to assess fat distribution, we have shown
that testosterone deficiency is associated with an alteration
in site-specific adipose deposition with increased deposits
in all areas, particularly in the subcutaneous and muscle areas.
Because truncal fat correlates with glucose intolerance and
cardiovascular risk, hypogonadism may have important implications
with regard to overall health and mortality.
In one study, the alteration in skeletal
muscle composition was associated with a decrease in muscle
testosterone deficiency is associated with an enhanced risk
for osteoporosis, altered body composition including increases
in truncal fat, and, possibly, decreases in muscle performance.
of adequate testosterone replacement therapy leads to improvements
in libido and erectile function.
Following testosterone replacement, men note an increase
in energy and mood, which may reflect either direct behavioral
effects of androgens, and/or, an elevation of hematocrit due
to rising testosterone levels.
Testosterone therapy also leads to important beneficial
effects on the skeleton and lean tissue mass.
Testosterone replacement increases bone density in hypogonadal
men with the most dramatic effects seen in the trabecular bone
effects may be seen as early as 6 months following initiation
of testosterone therapy.
In one recent study of the long-term benefits of testosterone
therapy, the greatest benefits in trabecular bone were seen
in the first several years of therapy. With regard to body composition, testosterone replacement therapy
results in a dramatic reduction in adipose content, with the
greatest effects seen in the subcutaneous and skeletal muscle
areas. Androgen therapy leads to a significant increase in lean skeletal
muscle mass and strength.
Therefore, there are beneficial effects of testosterone
replacement on body composition and bone mineral density in
adult hypogonadal men that may serve as indications for therapy
in addition to libido and sexual function.
levels decline with age, and aging is accompanied by body changes
including loss of muscle and increases in fat, there is great
interest in the potential benefits of testosterone administration
in elderly men. In
a recent study, Snyder et al. (1999) administered testosterone
via a scrotal patch in a randomized, placebo-controlled trial
to 108 elderly men for 3 years.
As shown in Figure 2, testosterone administration resulted
in beneficial effects on lean and fat mass.
Therefore, there may be a role for androgens in
improving body composition and function in elderly men.
||Figure 2. Mean
change from baseline in
total body mass, fat mass, and lean mass,
as determined by DEXA, in 108 men over
65 yr of age. The decrease in fat mass
(P < 0.005)
and the increase in lean
mass (P <
0.001) in the testosterone-treated
subjects were significantly different from
those in the placebo-treated subjects at
36 months. (Reproduced with permission
from The Endocrine Society Snyder PJ,
et al: The Journal of Clinical Endocrinology
& Metabolism 1999; 84:2647-2653).
several modes of administration available for testosterone replacement.
Until recently, the traditional form of testosterone
therapy consisted of intramuscular injections of testosterone
esters given at 2 to 4 week intervals.
This mode of therapy leads to an increase in testosterone
levels, but there are marked oscillations in serum testosterone
levels with an early peak, often to supraphysiologic levels,
followed by levels that fall in the subtherapeutic range.
Therefore, men may note an improvement in sexual function
only in the immediate period following the injection.
Also, men may describe mood swings and behavioral alterations
that may reflect these changing testosterone levels.
advances have led to the development of novel delivery systems
for androgens such as transdermal preparations of testosterone.
These systems provide more physiologic testosterone replacement,
with serum testosterone levels in the normal range throughout
the day. Therefore,
transdermal systems are considered the first line therapy for
men with hypogonadism.
There are several patches currently available.
There are two non-scrotal transdermal systems, Testoderm
TTS and Androderm. Both
of these patch systems are placed on the skin daily, Testoderm
TTS in the morning and Androderm at night.
Use of the patches leads to normal testosterone values,
but Androderm in particular may be associated with local skin
TTS has an advantage because of a low incidence of skin irritation.
The typical dose is 5 mg applied daily.
A newly available
non-patch, transdermal testosterone delivery system is Androgel. Androgel comes as 2.5 or 5.0 gm testosterone packets, applied
daily. Normal testosterone
levels are usually achieved with 5.0 gm and there is a low incidence
of skin irritation. This
system therefore is another option for
testosterone replacement therapy for men.
Further studies are needed to assess long-term compliance
and efficacy of this form of replacement therapy.
several possible adverse effects of testosterone administration
that need to be closely monitored, including clinically significant
benign prostatic hypertrophy (BPH) and prostate cancer.
Despite the theoretical considerations that androgens
will augment prostate size, there is no evidence that androgen
replacement in elderly men will lead to the development of hyperplasia
or aggravate its clinical status.
There is also a concern that prostate cancer may develop
during androgen therapy.
There are no data available as to whether androgen therapy
will enhance the progression of preclinical to clinical cancer.
However, androgens may stimulate the growth of already
existing prostate cancer.
Therefore, prior to testosterone initiation, patients
should be screened for BPH and prostate cancer with a clinical
history, digital exam, and PSA (prostate specific antigen) level.
Because androgens may stimulate erythropoiesis and precipitate
sleep-related breathing disorders, a cbc should be followed
and subjects queried for the presence of sleep apnea.
To assess efficacy of replacement therapy using a transdermal
system, a serum testosterone level should be obtained.
L, Finkelstein JS, Schoenfeld DA, Rosenthal DI, Anderson EJ,
Klibanski A. 1996 Increase in bone density and lean body mass
during testosterone administration in men with acquired hypogonadism.
J Clin Endocrinol Metab. 81:4358-65.
2. Simon D,
Charles M, Nahoul K, et al. 1997 Association between plasma
total testosterone and cardiovascular risk factors in healthy
adult men: the Telecom study. J Clin Endocrinol Metab. 82:682-5.
RS, Wang C. 1993 Androgen deficiency and aging in men. West
J Med. 159:579-585.
PJ et al. 1999 Effect of Testosterone Treatment on Body Composition
and Muscle Strength in Men Over 65 Years of Age. J Clin Endocrinol
5. Wang C
et al. 2000 Transdermal testosterone gel improves sexual function,
mood, muscle strength, and body composition parameters in healthy
men. J Clin Endocrinol Metab. 85:2839-53.
by Beverly M.K. Biller, M.D.
controversy regarding patients with acromegaly has been whether
they are at increased risk of neoplasia, particularly of the
large bowel. A
number of studies have reported an increase in the prevalence
of adenomatous polyps of the colon, although others have not.
Many of the early studies were retrospective and recommendations
regarding screening colonoscopy in patients with acromegaly
are still debated. Two
interesting papers from the United Kingdom published in the
September 2000 issue of the Journal of Clinical Endocrinology
and Metabolism address this topic.
entitled "Insulin-Like Growth Factor-I and the Development
of Colorectal Neoplasia in Acromegaly" is by Jenkins et
al. In this study,
66 patients with biochemically proven acromegaly, ages 42 to
85 years (mean 63.3 years) underwent prospective colonoscopic
key aspect in the design of this study is that all patients
had previously undergone colonoscopic removal of all visible
then returned for a follow-up colonoscopy 3 to 76 months later
(mean 32.7 months). At
the second colonoscopy, 25 patients (38 percent) had one or
more polyps detected, the majority of which were hyperplastic.
Nine patients (14 percent) had at least one adenoma on
a follow-up colonoscopy, which is particularly important because
these lesions, in contrast with polyps, can undergo malignant
of the 66 patients had an elevated serum IGF-I level at the
second colonoscopy. While
an elevation of IGF-I level was not associated with an increased
risk of polyps, it was highly associated with the risk of new
adenoma formation as shown in Figure 3. All but one of the new adenomas which formed occurred in patients
with elevated IGF-I levels at the time of colonoscopy.
The relative risk of developing a new adenoma was 10.3
for patients with IGF-I levels above the upper limit of the
age corrected normal range.
The authors conclude their study by suggesting annual
colonoscopies for patients over 35 who have an elevated IGF-I
or a previous finding of an adenoma.
|Figure 3. The mean
(±SEM) serum IGF-I at the second colonoscopy
in 66 patients with acromegaly with colorectal adenomas,
polyps, or normal colon.
(Reproduced with permission from The
Endocrine Society Jenkins PJ, et al: The Journal
Endocrinology & Metabolism 2000; 85:3218-3221).
by Renehan et al. entitled "The Prevalence and Characteristics
of Colorectal Neoplasia in Acromegaly" in the same journal
issue reaches a different conclusion.
This was a two center prospective screening study in
which colonoscopies were conducted in 122 acromegalics aged
25 to 82 years (mean 54.8).
Data were shown for the 115 patients who were able to
undergo complete exams.
The prevalence of neoplasia was compared with results
from a literature review in a group of autopsy studies and in
a group of screening colonoscopy studies in subjects without
of undiagnosed adenocarcinoma which was detected by colonoscopy
in the acromegalic patients was 2.6 percent. Adenomas were detected
in 11 patients (10 %).
In comparison, the autopsy series were quoted as showing
a rate of 2.3 percent for detection of new cancer and of 0.9
percent from the screening studies.
Both of these are reported as showing no statistically
significant difference in the prevalence of adenocarcinomas
between acromegalics and the general population. The authors of this study conclude that an aggressive approach
of colonoscopic screening in acromegalic patients may not be
It is interesting
that these two new prospective colonoscopy studies do not settle
the controversy as to whether acromegaly is associated with
an increased incidence of colonic neoplasia.
One possible explanation for their different findings
is that the study showing an increased risk of adenoma associated
with elevated IGF-I levels included a population that was nearly
a decade older than the study which showed no clear increased
risk. Even the latter study indicates that the prevalence of adenomas
increase with age. Therefore,
a study with a younger population may have a lower rate of adenoma
higher risk of new adenoma formation in the Jenkins study is
concerning, and at the very least, should encourage us to maximize
all treatment modalities (surgical, medical, radiation) for
all patients. These
conflicting data raise the question as to what we should advise
our patients with acromegaly.
The conservative approach would be to continue to advise
screening colonoscopy for patients with persistent IGF-I elevations,
until further data are available.
et al. Insulin-Like
Growth Factor-I and the Development of Colorectal Neoplasia
in Acromegaly. J Clin Endocrinol Metab.
et al. The Prevalence
and Characteristics of Colorectal Neoplasia in Acromegaly.
J Clin Endocrinol Metab.
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