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From the Clinical Research Centers |
Neuroendocrine Unit, Department of Medicine, Clinical Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Anne Klibanski, M.D., Neuroendocrine Unit, Bulfinch 457B, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: aklibanski{at}partners.org
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Abstract |
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 Top Abstract IntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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Dehydroepiandrosterone sulfate (DHEAS) levels clearly decrease with age (11). However, the effects of age on testosterone and androstenedione levels are controversial (12, 13, 14, 15). Large cross-sectional population studies do not support a decrease in these levels over time (13), but typically do not consider the age-associated waning of the midcycle testosterone peak (16, 17, 18). Reduced ovarian function due to oophorectomy (19), GnRH agonist administration (20), and estrogen therapy (21) has been associated with androgen deficiency in women, as has reduced adrenal function secondary to adrenal insufficiency or glucocorticoid administration (22, 23).
Acquired hypopituitarism secondary to radiation, surgery, neoplasm, or infiltrative disease is unique in that it is characterized by both hypogonadism and/or hypoadrenalism, which may affect two critical sources of androgen production in women. We therefore performed a comprehensive investigation into whether serum androgen levels are significantly decreased in women with hypopituitarism with central hypogonadism and/or hypoadrenalism compared with estrogen-depleted or -replete controls at three time points in a month.
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Experimental Subjects |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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Fifty-five women with hypopituitarism were studied. Four subgroups of women were as follows: 1) less than 50 yr old not receiving estrogen (n = 14), 2) less than 50 yr old receiving estrogen (n = 17), 3) more than 50 yr old not receiving estrogen (n = 12), and 4) more than 50 yr old receiving estrogen (n = 12). The diagnoses of hypogonadism and hypoadrenalism were confirmed by clinical diagnoses made by each subject’s endocrinologist. Subjects considered to have central hypogonadism had all been amenorrheic for at least 1 yr and had serum FSH levels in the premenopausal range or lower if of postmenopausal age. The diagnosis of hypoadrenalism was based on insulin tolerance tests or co-syntropin stimulation tests and signs and symptoms of hypoadrenalism. Subjects with active acromegaly, Cushing’s disease, or receiving supraphysiological replacement doses of glucocorticoids were excluded as were patients with untreated hyperprolactinemia.
Estrogen preparations included oral contraceptives and hormone
replacement therapy in the form of an estrogen and progestogen. The
majority of subjects with hypopituitarism had pituitary adenomas
(n = 40). Diagnoses and treatment with surgery and/or radiation
therapy are shown in Table 1
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Ninety-two healthy controls were studied. Four subgroups of healthy controls were recruited for comparison with the four subgroups of women with hypopituitarism. This included women 1) with regular menses not receiving estrogen (n = 40), 2) premenopausal with a history of regular menses receiving oral contraceptives (n = 18), 3) postmenopausal not receiving estrogen (n = 18), and 4) postmenopausal receiving estrogen replacement therapy (n = 16). All premenopausal women receiving estrogen took oral contraceptives. Estrogen replacement therapy in postmenopausal women included conjugated equine estrogen plus medroxyprogesterone and estradiol patches plus progesterone gel. All control subjects had normal serum TSH levels. None was taking androgens. All premenopausal control subjects had histories of regular menstrual cycles since menarche. Confirmation of ovulatory function in premenopausal controls not receiving estrogen was documented with a serum progesterone of more than 5 ng/mL at visit 3.
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Materials and Methods |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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Subjects were admitted to the General Clinical Research Center at the Massachusetts General Hospital fasting or had blood drawn at an out-patient lab at 0800 h after an overnight fast. Height and weight were obtained. All subjects completed a detailed medical questionnaire, which included questions about medication use.
Hormonal assessment
Fasting 0800 h total serum testosterone levels were measured by RIA after extraction and column chromatography (Endocrine Sciences, Inc., Calabasas Hills, CA) with an intraassay coefficient of variation of 2.9–18.8 and a sensitivity of 3 ng/dL. Free serum testosterone levels were measured by equilibrium dialysis (Endocrine Sciences, Inc., Calabasas Hills, CA) with an intraassay coefficient of variation of 6.6–9.4% and a sensitivity of 0.1%. Androstenedione and DHEAS concentrations were measured by RIA (Diagnostics Systems Laboratories, Inc., Webster, TX) with intraassay coefficients of variation of 2.8–5.6% and 3.8–5.3%, respectively. The sensitivities of the androstenedione and DHEAS assays are 0.03 ng/mL and 1.1 µg/dL, respectively. Progesterone, glucose, insulin, TSH, and free T4 index were measured by previously described methods (24). Samples from each individual were measured in duplicate and run in the same assay. IRHOMA was calculated as insulin x glucose/22.5 (25).
Statistical analysis
Data were analyzed using a repeated measures analysis of covariance (PROC MIXED) with age and body mass index (BMI) as covariates. The pairwise comparisons of the means are least squared means adjusted for age and BMI. Undetectable values were set at values just below the limit of detection (26). We report the proportion of undetectable values in every group. The effect of this is that the mean values of groups with large numbers of undetectable values will be overestimated, differences with groups without undetectable levels will be underestimated, and the variance in patient values for groups with undetectable levels will be underestimated. Given the sample size, the statistical tests are valid.
Partial correlation coefficients were calculated between the mean androgen levels and the values of insulin-like growth factor I (IGF-I), insulin, glucose, IRHOMA, age, and BMI for women with hypopituitarism. The coefficients were controlled for estrogen usage, premenopausal or postmenopausal age, and hypopituitary status. Thus, they represent within group correlations.
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Results |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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Women less than 50 yr of age with hypopituitarism not receiving
estrogen were compared with healthy controls with regular menstrual
cycles at three time points in a month. Serum androgen levels were
markedly decreased in women with hypopituitarism compared with controls
at all time points (
Figs. 1–4).
Means over the three visits in a month were also compared. Serum
testosterone (mean over three visits, 6.8 ± 2.6 vs.
24.8 ± 1.7 ng/dL; P < 0.0001), free testosterone
(mean over three visits, 0.8 ± 0.3 vs. 2.7 ± 0.2
pg/mL; P < 0.0001), androstenedione (mean over three
visits, 0.4 ± 0.1 vs. 1.3 ± 0.1 ng/mL;
P < 0.0001), and DHEAS (24 ± 14 vs.
127 ± 9 µg/dL; P < 0.0001) levels were
markedly decreased in the women with hypopituitarism compared with
controls. Testosterone, free testosterone, androstenedione, and DHEAS
levels were detectable in all normal controls, but were undetectable at
at least one visit for 6 (43%), 7 (50%), 1 (7%), and 2 (14%) women
with hypopituitarism, respectively. Six women had undetectable
testosterone and free testosterone levels at all three visits. Of these
six, five (83%) had panhypopituitarism. All androgen levels were
detectable at all time points in the normal controls.
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). Women of reproductive age receiving estrogen
Women less than 50 yr of age with hypopituitarism receiving
estrogen therapy were compared with healthy premenopausal women
receiving oral contraceptives at 3 time points in a month. Serum
androgen levels were markedly decreased in women with
hypopituitarism compared with controls at all time points (
Figs. 1–4). Means over the 3 visits in a month were also compared. Serum
testosterone (mean over 3 visits, 4.4 ± 2.3 vs.
25.8 ± 2.5 ng/dL; P < 0.0001), free testosterone
(mean over 3 visits, 0.2 ± 0.3 vs. 1.6 ± 0.3
pg/mL; P < 0.0001), androstenedione (mean over 3
visits, 0.3 ± 0.1 vs. 1.03 ± 0.1 ng/mL;
P < 0.0001), and DHEAS (8 ± 13 vs.
122 ± 14 µg/dL; P < 0.0001) levels were
markedly decreased in the women with hypopituitarism compared with
controls. Testosterone and free testosterone levels were undetectable
in 11 hypo-pituitary women (65%) at all 3 time points during the
month. In 2 hypopituitary women, androstenedione levels were
undetectable and in 8 hypopituitary women, DHEAS levels were
undetectable at at least 1 time point during the month. All androgen
levels were detectable at all time points in the normal controls.
Postmenopausal women not receiving estrogen
Women greater than 50 yr of age with hypopituitarism not receiving
estrogen were compared with postmenopausal controls at three time
points in a month. Serum androgen levels were markedly decreased in
women with hypopituitarism compared with controls at all time points
(
Figs. 1–4). Means over the three visits in a month were also
compared. Serum testosterone (mean over three visits, 8.4 ± 3.1
vs. 26.1 ± 2.5 ng/dL; P < 0.0001),
free testosterone (mean over three visits, 1.2 ± 0.3
vs. 3.2 ± 0.3 pg/mL; P < 0.0001),
androstenedione (mean over three visits, 0.8 ± 0.1 vs.
1.1 ± 0.1 ng/mL; P = 0.014), and DHEAS (47
± 17 vs. 134 ± 14 µg/dL; P <
0.0001) levels were markedly decreased in the women with
hypopituitarism compared with controls. Testosterone and free
testosterone levels were undetectable in eight hypopituitary women
(67%) at all three time points during the month. In seven
hypopituitary women (58%), DHEAS levels were undetectable at at least
one time point during the month. All androgen levels were detectable at
all time points in the normal controls.
Postmenopausal women receiving estrogen
Women more than 50 yr of age with hypopituitarism receiving
estrogen replacement therapy were compared with healthy postmenopausal
women receiving estrogen replacement therapy at three time points in a
month. Serum androgen levels were markedly decreased in women with
hypo-pituitarism compared with controls at all time points (
Figs. 1–4). Means over the three visits in a month were also compared. Serum
testosterone (mean over three visits, 7.2 ± 3.0 vs.
22.8 ± 2.5 ng/dL; P < 0.0001), free testosterone
(mean over three visits, 0.6 ± 0.3 vs. 1.8 ± 0.3
pg/mL; P = 0.004), androstenedione (mean over three
visits: 0.5 ± 0.1 vs. 0.9 ± 0.1 ng/mL;
P = 0.016), and DHEAS (40 ± 16 vs.
101 ± 14 µg/dL; P = 0.002) levels were markedly
decreased in the women with hypopituitarism compared with the
controls. Testosterone and free testosterone levels were undetectable
in nine hypopituitary women (75%) at least at one time point during
the month. In one hypopituitary woman, androstenedione levels were
undetectable and in six hypopituitary women, DHEAS levels were
undetectable at at least one time point during the month. All androgen
levels were detectable at all time points in the normal controls.
Effect of type of pituitary hormone deficiency on androgen levels
Mean serum testosterone, free testosterone, and androstenedione
levels were lower in hypopituitary women with both hypogonadism and
hypoadrenalism compared with hypogonadism [testosterone, 3.1 ±
0.8 vs. 11.3 ± 1.1 ng/dL (P <
0.0001); free testosterone, 0.4 ± 0.1 vs. 1.4 ±
0.2 pg/mL (P < 0.0001); androstenedione, 0.2 ±
0.5 vs. 0.9 ± 0.8 ng/mL (P <
0.0001)] or hypoadrenalism [testosterone, 3.1 ± 0.8
vs. 7.7 ± 1.6 ng/dL (P = 0.013); free
testosterone, 0.4 ± 0.1 vs. 1.0 ± 0.2 pg/mL
(P = 0.025); androstenedione, 0.2 ± 0.5
vs. 0.5 ± 0.1 ng/mL (P = 0.018)]
alone. Mean serum DHEAS levels were decreased in hypopituitary women
with both hypogonadism and hypoadrenalism compared with hypogonadism
alone (10.0 ± 4.7 vs. 54.7 ± 6.6 µg/dL;
P < 0.0001). However, there was no difference in DHEAS
levels in hypopituitary women with both hypogonadism and hypoadrenalism
compared with hypoadrenalism alone (10.0 ± 4.7 vs.
21.8 ± 9.1 µg/dL; P > 0.05; Table 2).
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Among the women with hypopituitarism, there were significant correlations between testosterone and IGF-I (r = 0.28; P = 0.046), free testosterone and age (r = -0.29; P = 0.033), and DHEAS and age (r = -0.33; P = 0.017).
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Discussion |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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Because we sampled hypopituitary women at three times during the month to mimic the timing of blood samples taken in the early follicular, midcycle, and midluteal phases of the normal menstrual cycle, we were able to demonstrate static low levels of androgens in such patients. This is in contrast to the increases in testosterone, free testosterone, and androstenedione seen in normal cycling women. Given the loss of critical sources of androgen production in hypopituitary women of reproductive age, particularly at midcycle (17, 18), decreased serum androgen levels might be anticipated. However, we demonstrated that the degree of androgen deficiency is severe, such that testosterone, free testosterone, androstenedione, and DHEAS are all markedly reduced in women of all ages. In addition, at least one androgen level was undetectable in the majority women with hypopituitarism, whereas androgen levels were easily detectable in all normal controls. We assigned values just below the levels of detection for serum androgen levels in patients with undetectable levels. Therefore, the mean serum androgen levels we reported for hypopituitary women are overestimates, and the true differences between the groups are even greater than we report. Although we documented significant androgen deficiency in women with hypopituitarism, limitations in androgen assay sensitivity probably resulted in an underestimation of the severity of androgen deficiency in such women.
Direct ovarian secretion and conversion of ovarian precursors account for more than 50% of testosterone production in healthy premenopausal women and approximately 50% in healthy postmenopausal women, with the remainder attributable to conversion of the adrenal precursors DHEA and androstenedione (19). Similarly, about half of androstenedione production in women is derived from the ovary, and half is from adrenal origins (19). However, over 90% of DHEAS is derived from the adrenal glands (23). The degree of androgen deficiency was most marked in women with panhypopituitarism, probably reflecting the contributions of both the ovaries and adrenals to androgen levels. Consistent with this paradigm, women with hypogonadism alone did not demonstrate significantly reduced levels of DHEAS.
Our study confirms previous reports showing that testosterone, free testosterone, and androstenedione levels are increased at midcycle in healthy controls with regular menstrual cycles (17, 18). An advantage of our study design is that we assessed serum androgen levels at 3 time points during the menstrual cycle in normal women and at 3 comparable time intervals in the hypopituitary women. In contrast to normal cycling women, women with hypopituitarism demonstrated no variation in androgen levels over the course of a month. One study published in 1979 of 18 women, 21–84 yr old, with hypopituitarism found a decrease in total testosterone levels at a single time point (27). DHEAS levels have been demonstrated to be reduced in children with ACTH deficiency (28, 29, 30, 31) and in groups of hypopituitary men and women combined (32, 33). However, no study has examined testosterone, free testosterone, androstenedione, and DHEAS in both estrogen-depleted and -replete women compared at 3 time points to provide a more integrated assessment of androgens during a month. We demonstrated that comparisons of androgen levels in hypopituitary women using only early follicular phase normal ranges underestimate the severity of the hypoandrogenemia by failing to consider a more integrated androgen measurement.
We found a significant correlation between testosterone and IGF-I levels in women with hypopituitarism. This is consistent with the possible stimulatory effects of GH on ovarian androgen production (34). Although no causality can be inferred from this cross-sectional study, the potential contribution of GH deficiency to the hypoandrogenemia seen in this population merits investigation. Hypoandrogenemia may also contribute to GH deficiency given the stimulatory effects of androgens on GH secretion (35). Men with isolated hypogonadotropic hypogonadism exhibit decreased GH pulse amplitude compared with eugonadal men, and testosterone replacement is associated with an increase in 24-h serum GH levels, GH pulse amplitude, and serum IGF-I levels (35). These effects may be partly dependent on aromatization of testosterone to estradiol, as tamoxifen reduces GH secretion in these men (35). The possible interaction between androgens and GH secretion in women remains to be determined, particularly in the setting of gonadotropin insufficiency.
Hypoandrogenemia has profound consequences in men, including increases in fat mass (1) and total and low density lipoprotein cholesterol (36) and decreases in libido (2). However, the syndrome of androgen deficiency in women is not well characterized. Studies have demonstrated correlations between androgens and bone mineral density in premenopausal women and libido in postmenopausal women (37, 38, 39). Unfortunately, most trials of androgen replacement in women have administered supraphysiological doses or have not been randomized or controlled. However, the few randomized placebo-controlled trials investigating the effects of testosterone on bone and libido have been positive. In a randomized study, Raisz et al. administered 1.25 mg esterified estrogens plus 2.5 mg methyltestosterone or conjugated equine estrogens to 28 postmenopausal women for 9 weeks and found significant increases in markers of bone formation, including osteocalcin, bone-specific alkaline phosphatase, and C-terminal procollagen peptide as early as 3 weeks in women receiving estrogen plus androgen therapy compared with estrogen therapy alone (40). These results are consistent with the observation that osteoblasts have androgen receptors and that androgens stimulate osteoblast differentiation in vitro (41, 42, 43). Davis et al. randomized 34 postmenopausal women to receive estradiol implants (50 mg) or estradiol (50 mg) plus testosterone (50 mg) for 2 yr (44). This single blind study demonstrated significant increases in bone mineral density at 2 yr in the women receiving estrogen plus testosterone compared with estrogen alone. These data suggest that relative hypoandrogenemia in other populations of women may have clinically significant consequences, including alterations in bone metabolism and libido, which may improve with androgen replacement therapy.
This is the first comprehensive study to demonstrate profound hypoandrogenemia in women with hypopituitarism compared with estrogen-depleted or -replete controls studied at three time points in a month. The effects of androgen deficiency and androgen replacement therapy on bone density, body composition, and libido in this population should be determined.
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Acknowledgments |
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Footnotes |
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Received August 25, 2000.
Revised October 25, 2000.
Accepted October 29, 2000.
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References |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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, Women with
hypopituitarism; 
, healthy controls; EF, early follicular phase; MC,
midcycle; ML, mid-luteal phase. P 
0.0003 for all
comparisons between women with hypopituitarism and controls.
