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Centre for Clinical Endocrinology, William Harvey Research Institute, St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom
Address all correspondence and requests for reprints to: Professor J. P. Monson, Department of Endocrinology, St. Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, United Kingdom. E-mail: j.p.monson{at}qmul.ac.uk.
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Abstract |
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Objective: Our objective was to determine the effect of DHEA administration on mood in hypopituitary adults on established GH replacement with a constant serum IGF-I.
Design: A double-blind, placebo-controlled trial was conducted over an initial 6 months followed by an open phase of 6 months of DHEA.
Setting: The study was conducted at a tertiary referral endocrinology unit.
Patients: Thirty female and 21 male hypopituitary patients enrolled. Data from 26 females and 18 males were analyzed after patient withdrawal.
Interventions: DHEA (50 mg) was added to maintenance replacement including GH.
Main Outcome Measures: The primary outcome objective was the effect on QoL and libido assessed by QoL assessment in GH deficiency in adults, Short Form 36, General Health Questionnaire, EuroQol, and sexual self-efficacy scale.
Results: Patients had impaired QoL at baseline compared with the age-matched British population. Females showed improvement in QoL assessment in GH deficiency in adults score (–2.9 ± 2.8 DHEA vs.–0.53 ± 3 placebo; P < 0.05), in Short Form 36 social functioning (14.6 ± 23.1 DHEA vs.–4.7 ± 25 placebo; P = 0.047), and general health perception (9.6 ± 14.2 DHEA vs.–1.2 ± 11.6 placebo; P = 0.036) after 6 months of DHEA. Men showed improvement in self-esteem (–1.3 ± 1.7 DHEA vs. 0.5 ± 1.5 placebo; P = 0.03) and depression (–1.6 ± 2.2 DHEA vs. 1.2 ± 2.4 placebo, P = 0.02) domains of the General Health Questionnaire after 6 months of DHEA.
Conclusions: DHEA replacement leads to modest improvement in psychological well-being in female and minor psychological improvement in male hypopituitary patients on GH replacement.
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Introduction |
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Hypopituitarism is associated with profound androgen deficiency, even in patients who are ACTH replete (10, 11). The most abundant adrenal androgen is dehydroepiandrosterone (DHEA). DHEA has been shown to have a beneficial effect on well-being and mood in female patients with adrenal failure (12), with some benefit seen in female patients with secondary adrenal failure (13, 14), but this effect has not been universal (15). Men have rarely been studied (15, 16); one study in hypopituitarism showed no psychological benefit for men (15), whereas another study in primary adrenal failure suggested a benefit, although there was no separation by gender in the analysis (16). Although the effects of DHEA in men have so far appeared to be limited, it cannot be assumed that all effects of DHEA are testosterone related. Furthermore, QoL of men on GH replacement is not always normalized to that of the general population.
We hypothesized that DHEA may provide additional benefit to the known effects of GH on psychological well-being in both male and female patients with hypopituitarism. To further elucidate this, a double-blind, placebo-controlled trial was conducted, adding 50 mg DHEA into standard replacement of hypopituitary patients, including GH, over an initial 6 months, followed by an open phase of 6 months of replacement with DHEA. The primary end point was the effect on QoL and libido.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Thirty female and 21 male patients were enrolled in a single-center, two-stage, double-blind, placebo-controlled trial. All patients had severe GHD and were on hormone replacement for all additional deficiencies. GHD was defined as a peak on insulin stimulation testing (or glucagon) of less than 9 mU/liter (3 ng/ml). Exclusion criteria included age less than 18 yr or greater than 65 yr, active malignancy, liver disease, or pregnancy. Of those enrolled, two failed to attend the initial assessment or could not attend monthly appointments and four withdrew because of side effects (two on DHEA, two on placebo). Two patients had adjustment of GH dose for clinical reasons in the first 6 months and were therefore excluded from the analysis. One patient completed the initial 6-month double-blind phase but did not continue to the open phase. For clinical reasons, one patient had dose adjustments made in the open phase and was therefore not included in the open analysis. Thus, 14 female placebo, 12 female DHEA, 10 male placebo, and eight male DHEA patients’ results were analyzed from the initial double-blind trial.
The patients had a similar mean and age range and similar duration of disease and number of pituitary deficiencies (Table 1
). All but two patients were on hydrocortisone replacement, and all were on stable doses of GH replacement, designed to achieve a serum IGF-I between the median and upper part of the age-related reference range, for at least 3 months before entry into the study. All but one female patient had gonadotropin deficiency (mode of replacement shown in Table 1).
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The study was conducted in two stages: an initial 6-month double-blind trial of 50 mg DHEA or placebo followed by a 6-month open phase of DHEA replacement. If patients had found DHEA of benefit, they were then invited to continue on a named patient basis outside the trial setting. Randomization was stratified by age (<50 and >50 yr) and gender and performed prospectively by an independent statistician. Patient allocation details were kept confidential until after the initial 6-month blind study.
Micronized DHEA and placebo tablets were obtained from McPherson Laboratories (Stafford, TX). The capsules were bottled and labeled by the pharmacy department at St. Bartholomew’s Hospital. The 50-mg DHEA dose has previously been shown to achieve serum DHEA sulfate (DHEAS) concentrations in the normal age-related reference range (17, 18). Steady state is achieved after 8 d in elderly men and women (19). Patients were free to reduce their dose of DHEA if androgenic side effects were experienced. Two patients reduced their dose to 25 mg and two patients to 37.5 mg. These dose reductions were confined to female patients over 47 yr. One patient on placebo reduced the dose to half. Patients took their trial tablets in the morning and were evaluated in the morning (before taking their tablets). Serum levels of DHEAS, tablet counting, and direct questioning were used to assess compliance. Compliance with GH replacement was determined by serum IGF-I measurement.
Patients were seen every 4 wk and had serum IGF-I, DHEA, and hepatic and renal function measured. Male patients on i.m. testosterone were seen immediately before their injections. Serum IGF-I was measured monthly and the dose of GH adjusted if there was a greater than 15% change from baseline. This achieved a constant serum IGF-I throughout the placebo-controlled study. The results on biochemical parameters and GH dosing have been reported separately (Brooke, A. M., L. A. Kalingag, F. Miraki-Moud, C. Camacho-Hübner, K. T. Maher, D. M. Walker, J. P. Hinson, and J. P. Monson, submitted for publication).
Biochemistry
All samples were stored at –30 C until analyzed. All measurements were made in duplicate, and each patient’s samples were measured within one assay. DHEAS, androstenedione, and testosterone were measured using ELISA kits (DRG International, Mountainside, NJ). The assay detection limits were 0.052 µmol/liter (DHEAS), 0.15 nmol/liter (androstenedione), and 0.29 nmol/liter (testosterone). All intra- and interassay coefficients of variation were less than 10% within the male and female concentration range. Serum IGF-I was measured using an in-house RIA after formic-acetone extraction of binding proteins as previously described (20); the mean intra- and interassay coefficients of variation were 7.2 and 10.4%, respectively.
Psychological questionnaires
Patients completed questionnaires on site at 0, 3, 6, 9, and 12 months.
QoL assessment in GHD in adults (QoL-AGHDA) is a sensitive measure of QoL in adult patients with GHD (21). Lower scores out of 25 reflect better QoL. Short form 36 (SF-36) covers 36 items recording general well-being during the previous 30 d marked out of 100 with eight subcategories (22). Higher scores reflect better QoL (23). The General Health Questionnaire (GHQ) comprises five subscales together with a total score. Lower scores reflect better QoL. The comparisons with normative data are marked out of 30 with "not at all" and "no more than usual" receiving zero marks and "rather more than usual" and "much more than usual" receiving one mark. All other data are marked out of 90 with scores 0, 1, 2, and 3 representing progressively worse health states. Normative data for the British population were available for comparison in QoL-AGHDA (24), SF-36 (25), and GHQ (26, 27).
EuroQol (EQ-5D) is a descriptive system of health-related QoL states consisting of five dimensions compared with a standard set of values derived from the United Kingdom population (28) and a visual analog thermometer score (29).
Libido was assessed using the sexual self-efficacy scale (30, 31), which is a questionnaire representing the degree of confidence in various sexual activities. In addition, patients answered direct questions about libido (any increase in sexual thoughts, increase in attention to partner, partner commented on a difference, and more satisfied during intimacy) and benefits of treatment (energy, ability to handle situations or initiative, alertness, self-esteem, and body image) at 6 and 12 months, marked out of 3, with 0 representing no benefit and 3 a strong improvement.
Side effects
These were recorded in a standardized form and rated as none, mild, moderate, severe, or noticed but considered it a benefit.
Statistics
All descriptive results are presented as the mean ± SD. Statistical significance was considered to be obtained if P < 0.05. Data comparisons were made across time using ANOVA, and then comparisons were made between the placebo and DHEA groups using the unpaired Student’s t test and within the groups by the paired Student’s t test. Trends for subjective benefits, side effects, and libido were assessed using a 
2 test and Fisher’s exact test.
The primary outcome objective was psychological well-being. All patients gave full written informed consent according to the standards set out by the East London and the City Health Authority (ELCHA) Ethics Committee.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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All patients had subnormal serum DHEAS concentrations at baseline. Replacement with 50 mg DHEA restored the values into the median to upper part of the physiological reference range for a young adult over 6 months (females, 5.14 ± 2.56 µmol/liter, mean ± SD; males, 6.09 ± 3.53 µmol/liter) (Table 2) with no accumulation effect over 12 months and no difference according to age. Concentrations returned to baseline after the trial period.
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). Serum testosterone did not alter significantly in males, but androstenedione normalized (Table 2). IGF-I
Serum IGF-I concentrations were the same in the placebo and DHEA groups in females at baseline (263 ± 60 ng/ml placebo vs. 258 ± 10 ng/ml DHEA), 6 months (245 ± 53 ng/ml placebo vs. 254 ± 17 ng/ml DHEA), and 12 months (242 ± 55 ng/ml placebo vs. 252 ± 19 ng/ml DHEA) months. In male patients, serum IGF-I was similar at baseline (246 ± 43 ng/ml placebo vs. 263 ± 24 ng/ml DHEA) and at 6 months (241 ± 50 ng/ml placebo vs. 263 ± 39 ng/ml DHEA) and decreased similarly in both groups at 12 months (235 ± 36 ng/ml placebo vs. 210 ± 59 ng/ml DHEA).
Psychological well-being
QoL-AGHDA. Mean QoL-AGHDA score at baseline in the DHEA group was 9.5 ± 5.5 (mean ± SD) in females and 12.0 ± 6.0 in males compared with a better average of 7.4 ± 6.7 in females and 5.8 ± 6.0 in males in an age-matched normal British population and 16.7 ± 6.9 in females and 13.9 ± 6.9 in males in an age-matched British population with untreated GHD (24).
Females showed an improvement in QoL-AGHDA score from baseline (9.3 ± 5.2) after 6 months of DHEA (6.4 ± 3.9) (Fig. 1). This was not significant at 3 months (8.2 ± 5.1). Excluding females who were estrogen deficient, but not on replacement, a similar trend was observed (DHEA –3.0 ± 3.1 vs. placebo –0.3 ± 3.0) but failed to reach significance [P = 0.066; 95% confidence interval (CI), –0.1993 to 5.699]. There was no additional change in the open phase of the study in either the DHEA group (6.6 ± 5.1 at 12 months) or the initial placebo group. There was no significant change in QoL-AGHDA scores in the men.
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Study participants had a lower (worse) baseline score than the British normative values (22, 25) (Table 3). Females demonstrated an improvement in social functioning over 6 months, equivalent to normal age-matched population scores (Table 3). This improvement was still evident after excluding females who were estrogen deficient but not on replacement (DHEA 18.8 ± 24.1 vs. placebo –4.2 ± 20.9; P = 0.036; 95% CI, –44.2 to –1.6). There was no significant improvement at 3 months. However, there was also a significant improvement in well-being in the female placebo group during DHEA replacement in the open phase (–4.7 ± 25 to 19.5 ± 24.1; P = 0.0053; 95% CI, 6.93–37.3). The social functioning score in the DHEA group fell in the second 6 months but did not return to baseline (Table 3).
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), which was maintained to 12 months (61.2 ± 24.6). A significant improvement was still evident after excluding females who were estrogen deficient but not on replacement (DHEA 11.3 ± 10.3 vs. placebo –1.6 ± 14.2; P = 0.041; 95% CI, –25.1 to –0.6). Again, the placebo group had a positive improvement during the open-phase replacement with DHEA (–0.25 ± 13.3 to 11.7 ± 16.9; P = 0.046; 95% CI, –23.6 to –0.2). The trend to improvement in other categories did not reach significance (Table 3).
There was no significant improvement in men with DHEA (Table 3). However, the basal DHEA and placebo scores were significantly different at baseline in social functioning (P = 0.007; 95% CI, 7.1–39.1), physical limitations (P = 0.048; 95% CI, 0.26–52.24), mental health (P = 0.04; 95% CI, 0.6–38.8), energy and vitality (P = 0.008; 95% CI, 9.2–51.3), and general health perception (P = 0.02, 95% CI, 4.6–49.4) (Table 3).
GHQ-30
The basal scores were higher (worse) than normative data from British adults (aged 45–54 yr) (26, 27) (Table 4). In females, there was a nonsignificant trend to improvement with DHEA (Table 5).
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), which was not evident at 3 months (3.4 ± 3.2) and no different from baseline by 12 months (2.9 ± 2.5). There was also an improvement in male self-esteem over 6 months (Table 5) not evident at 3 months (4.3 ± 1.3), but by 12 months, this had deteriorated (3.7 ± 0.8), albeit not back to baseline scores. There was no significant improvement in male coping ability in the initial placebo-controlled study. However, when comparing the placebo group at 6 months with the scores of all patients after 6 months of DHEA (the initial DHEA group and the placebo group in open phase on DHEA), there was a small but significant improvement in scores during DHEA replacement (–0.9 ± 2.0) compared with placebo (0.9 ± 2.4) (P = 0.04; 95% CI, –3.61 to –0.07). There was no difference in the other male subcategories. EuroQol (EQ-5D)
There was no significant improvement in either gender (data not shown).
Libido
The response rate to the sexual self-efficacy scale questionnaire was poor, with 11 of 28 women (six DHEA and five placebo) and 12 of 18 men (four DHEA and eight placebo) respondents. Patients found it either irrelevant or too personal. There was no difference seen in either gender.
On direct questioning, females on DHEA for 12 months noticed an increase in sexual thoughts, with seven of nine respondents in the DHEA group compared with five of 14 in the placebo group reporting an improvement (P = 0.048).
Subjective benefits
After 6 months, there was a subjective moderate or strong improvement in self-esteem among the female DHEA group (P = 0.0497; 95% CI, 0.058–0.734) and in initiative (P = 0.0497; 95% CI, 0.058–0.734) compared with placebo. There was also a significant improvement in the scores for initiative when the placebo group had open-phase DHEA (P = 0.04; 95% CI, –0.02 to –1.35). The males reported no significant benefits.
Side effects
Two patients on DHEA (one female with greasy skin, one man with diarrhea) and two on placebo (one female with increased frequency of seizures, one male with muscle aches) withdrew because of side effects. Four females (over 47 yr) reduced their dose of DHEA (two to 25 mg, two to 37.5 mg). One patient on placebo reduced the dose to half. Over 6 months, four females reported moderate or severe side effects of greasy skin and hair compared with none in the placebo group (P < 0.05; 95% CI, 0.064–0.596). This did not significantly change between 6 and 12 months, except for a significant increase in body sweat (P < 0.05; 95% CI, –0.199 to –1.255). Five women over the trial period commented on cutaneous androgenic effects being beneficial. There were no significant side effects in the men.
Perceptions of replacement
Before unblinding the trial, 75% of the females in the DHEA group and 63% in the placebo group reported they thought they were on the DHEA tablets. In males, 50% in the DHEA group and 60% of the placebo group thought they were on DHEA.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The improvement seen in QoL-AGHDA is important. Patients are used to completing this questionnaire, and the scores are highly reproducible over time. Although there has been a substantial amount of longitudinal data using QoL-AGHDA, this is the first positive QoL data obtained in a placebo-controlled study using this instrument. Although other questionnaires used in this study failed to meet significance, they nevertheless showed a trend to improvement in females. The number of patients recruited and the wide variance in patient scores may have contributed to a lack of statistical power. The starting scores using EuroQol were excellent at baseline, allowing little room for improvement. The improvements seen in females remained significant even after excluding those without estrogen replacement, indicating that is there was additional benefit from DHEA in patients on estrogen replacement. The marginal improvements seen in men were in similar categories to those seen in other trials (12, 13). We hypothesize that some effects of DHEA seen in women occur by virtue of restoring circulating androgen levels but that other effects are specifically related to DHEA, and it is only the latter that is evident in males. DHEA has previously been shown to act as an antidepressant (32), and this study adds weight to the view that DHEA may be of direct benefit to men as well as women. Males and females had improvements in different subcategories of questionnaires. This variability is probably because of the subjective nature of the questionnaires. This is well recognized using generic QoL instruments and supports the use of several generic scores.
There were baseline differences in the male SF-36 and QoL-AGDHA scores between the DHEA and placebo group. The men in the placebo group described better well-being in several subcategories, and this may have masked a placebo effect because there was little room for them to improve. We can only speculate as to the cause of the clear placebo effect in females. The females start with a reported worse QoL than males and may feel they have more to gain from a treatment that has previously been shown to have a beneficial effect in females.
After 12 months on DHEA, women also expressed an increase in sexual thoughts on directed questioning but not using validated questionnaires. The mean age in the women in the study was 47 yr. Over half did not have a regular partner, and the response to the questionnaires was poor. Other studies have shown a beneficial effect on libido (12, 14), and this cannot be excluded by the present study. All men were on testosterone replacement, and no effect of DHEA on libido was noted.
The improvement in the psychological well-being in men suggests that DHEA acts directly rather than by conversion to androgens. It supports the evidence that there may be a neurosteroidal action of DHEA (33). DHEA has been shown in vitro to act as an antagonist of the 
-aminobutyric acid receptor (34) and an agonist of the N-methyl-D-aspartate receptor (35). It has previously been suggested that any improvement in well-being may result from an increase in serum IGF-I (19, 36, 37). However, in the present study, serum IGF-I was kept constant, and therefore this cannot be the explanation for our findings.
In the normal population, there are wide variations in DHEAS concentrations. The three females who reduced the dose of DHEA in the first 6 months all demonstrated physiological serum DHEAS levels. One woman reduced her dose at 6 months when her serum DHEAS was just above the reference range. All four women who reduced their dose were over 47 yr old. This suggests that women may respond differently to similar physiological serum concentrations of DHEA and that postmenopausal women may benefit from a reduced dose. The androgenic side effects were of benefit to those women who had experienced dry skin and hair associated with hypopituitarism. It might be suggested that the relatively high prevalence of side effects may have allowed patients to recognize the treatment, thereby unblinding the study. However, despite side effects, 75% women in the DHEA group and 63% of women in the placebo group thought they were on the DHEA replacement.
There is considerable variability in the reporting of side effects in previous studies over similar trial periods. Some studies using 50 mg have reported no significant side effects (16) or minor side effects in a small proportion of patients (13). Other studies have demonstrated significant androgenic effects (12), even at lower doses of DHEA (14). The one trial that continued for 9 months with low-dose DHEA documented a high incidence of side effects, but there was also a high proportion of side effects in the placebo group (38). Half the patients in our trial continued on DHEA for 12 months, yet the number and severity of side effects were small. This was probably influenced by the fact that those patients noticing side effects were allowed to reduce their dose. It is also possible that there may be national differences in the perception of adverse effects of DHEA administration, but this is speculative. The benefits of DHEA in females were exemplified by the fact that 71% of women chose to continue replacement, in comparison with 48% of men.
At present, many women are taking DHEA as a supplement without medical supervision. This cannot be supported because the long-term effects of DHEA are not yet established. However, our study indicates that, under supervision, the addition of DHEA replacement to conventional hormone replacement may have significant QoL benefits in hypopituitary adults.
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Acknowledgments |
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Footnotes |
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Disclosure statement: The authors have nothing to disclose.
First Published Online July 18, 2006
Abbreviations: CI, Confidence interval; DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate; GHD, GH deficiency; GHQ, General Health Questionnaire; QoL, quality of life; QoL-AGHDA, QoL assessment in GHD in adults; SF-36, Short Form 36.
Received February 10, 2006.
Accepted July 10, 2006.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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