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Neuroendocrine Bulletin Archive

Bulletin Volume 6, Issue 2, Winter 2000

Articles in this issue:

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Androgen Deficiency in Women with Hypopituitarism
by Karen K. Miller, M.D.

Introduction

The effects 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.  

In women, 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.

Results

Preliminary 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). 

wpe19.jpg (17480 bytes)
Figure 1.  Free testosterone levels in 18 women of reproductive age with hypopituitarism compared
with 18 age- and BMI-matched controls studied in the early follicular (EF), midcycle (MC) and
mid-luteal (ML) phases of the menstrual cycle , women with hypopituitarism. , controls. *, p<0.05.


Discussion

            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.

Most studies 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 with hypopituitarism.

References

1. Katznelson 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 Metab. 81:4358-4365.

2. Bagatell 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 Gynecol. 19:775-788.

4. Kirschner MA, Bardin CW. 1972 Androgen production and metabolism in normal and virilized women. Metabolism. 21:667-688.

5. Miller 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.

6. Wuster 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.

8. Markussis 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.

10. Skakkebaek 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.

11. Davis SR, McCloud P, Strauss BJG, Burger H. 1995 Testosterone enhances estradiol's effects on postmenopausal bone density and sexuality. Maturitas. 21:227-236.

12. Raisz 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. 81:37-43.

13. Slemenda 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.

14. Steinberg 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.

15. Bachmann G, Leiblum S. 1991 Sexuality in sexagenarian women. Maturitas. 13:43-50.

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Testosterone Therapy in Men: An Update
by Laurence Katznelson, M.D.

Testosterone 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 strength.  Therefore, testosterone deficiency is associated with an enhanced risk for osteoporosis, altered body composition including increases in truncal fat, and, possibly, decreases in muscle performance.  

Administration 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 compartment.  These 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.

Because testosterone 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.

wpe1A.jpg (20328 bytes) 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).

There are 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. 

More recent 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 irritation.  Testoderm 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.

There are 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. 

References       

1. Katznelson 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.

3. Swerdloff RS, Wang C. 1993 Androgen deficiency and aging in men. West J Med. 159:579-585.

4. Snyder PJ et al. 1999 Effect of Testosterone Treatment on Body Composition and Muscle Strength in Men Over 65 Years of Age. J Clin Endocrinol Metab.  84:2647-53.

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.

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Journal Club

Colonoscopy in Acromegaly
by Beverly M.K. Biller, M.D. 

A longstanding 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.

The first, 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 evaluation.   A key aspect in the design of this study is that all patients had previously undergone colonoscopic removal of all visible polyps.   Patients 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 transformation.

Twenty-six 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.

wpe14.jpg (9794 bytes)
Figure 3. The mean (SEM) serum IGF-I at the second colonoscopy
in 66 patients with acromegaly with colorectal adenomas, hyperplastic
polyps, or normal colon.  (Reproduced with permission from The
Endocrine Society – Jenkins PJ, et al: The Journal of Clinical
Endocrinology & Metabolism 2000; 85:3218-3221).

The study 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 acromegaly.

The prevalence 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 warranted.

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 formation.

The ten-fold 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.

References       

1. Jenkins et al.  Insulin-Like Growth Factor-I and the Development of Colorectal Neoplasia in Acromegaly.   J Clin Endocrinol Metab.  2000.  85:3218-21.

2. Renehan et al.  The Prevalence and Characteristics of Colorectal Neoplasia in Acromegaly.   J Clin Endocrinol Metab.  2000.  85:3417-24.

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