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Hormone DeficienciesCentral HypothyroidismAndrogen DeficiencyAndrogen DeficiencyTestosterone Therapy
Growth Hormone Deficiency

Androgen Deficiency in Women with Hypopituitarism

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 body mass index (BMI).

The black bars show women with hypopituitarism. The white bars show controls. *

Figure 1. 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.

  1. References
    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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