Treatment with DHEA clinical studies

19.5.1 Patients with adrenal insufficiency

The classical approach to study the physiological role of a hormone in humans is to analyze the effect of a hormonal deficit and the changes induced by replacement of the missing hormone. Thus adrenal insufficiency is the most useful model disease to understand the clinical activity of DHEA. As in adrenal insufficiency (AI) not only DHEA but also cortisol and (in primary AI) aldosterone is lacking, one might speculate that replacement of cortisol and aldosterone alone is not sufficient to fully restore wellbeing in AI. Intriguingly, it has only recently been clearly demonstrated that replacement of glucocorticoids (GC) and mineralocorticoids (MC) alone is indeed not sufficient to fully compensate the impairment of health induced by AI.

Testosterone (nmol/L)

Dex + 100 mg DHEA

Dex + Placebo

10

Fig. 19.4 Lasting increases of serum testosterone in healthy dexamethasone-suppressed women after oral administration of 100 mg DHEA versus placebo (Arlt etal. 1998).

Lovas et al. (2002) have demonstrated in 88 patients with primary AI receiving GC and MC impaired self-perception of general health and vitality. In addition, the overall scores for fatigue clearly indicated more fatigue in this patient population. These findings were confirmed by Gurnell et al. (2002) in a population of patients with primary AI demonstrating similar changes in health-related quality of life, indicating that conventionally treated AI is associated with a specific pattern of chronic disability. Jakobi et al. (2001) have provided some more insight into the mechanism of increased fatigue in conventionally treated patients with AI. Muscle function (twitch tension, central activation) was reduced and patients self-terminated a submaximal fatigue protocol significantly earlier than controls (5 ± 1 vs 10 ± 1 min, p = 0.006) (Jakobi etal. 2001).

For replacement of DHEA(S) in AI an oral dose of 25-50 mg DHEA per day has consistently been found to restore circulating DHEA(S) into the normal range of young adults (Arlt etal. 1999a; Hunt etal. 2000; Young etal. 1997). Owingto the long half-life of DHEAS and the interconversion of DHEA and DHEAS a single dose is sufficient to maintain normal DHEA(S) levels over 24 hours. Due to the downstream bioconversion lasting increases in circulating androgens have been demonstrated in women (Arlt et al. 1998; 1999a). In fact, the superior pharmacokinetics of oral DHEA make it a promising tool for androgen replacement in women (Fig. 19.4) with the additional potential advantage of a DHEA-specific neurosteroidal effect (see also Chapter 17).

To date there are four published randomized double blind trials on DHEA treatment in patients with adrenal insufficiency (Arlt et al. 1999a; Hunt et al. 2000; Johannsson et al. 2002; Lovas et al. 2003). A fifth large trial has recently been completed in England; however, up to now the results have only been presented in abstract form (Gurnell et al. 2002). Three of the trials studied women only (Arlt et al. 1999a; Johannsson et al. 2002; Lovas et al. 2003), whereas the other two trials included both men and women (Hunt et al. 2000; Gurnell et al. 2002). In the first double-blind study (Arlt et al. 1999a) 24 women with adrenal insufficiency received in random order 50 mg of DHEA orally each morning for four months and placebo for four months with a one-month washout period. Treatment with DHEA raised the initially low concentrations of DHEA(S), androstenedione, and testosterone into the normal range. Serum concentrations of sex hormone-binding globulin (SHBG), total cholesterol and high-density lipoprotein (HDL) cholesterol decreased significantly. DHEA improved wellbeing and sexuality: compared to placebo DHEA resulted in a decrease in the scores for depression (p = 0.02), anxiety (p = 0.01) as well as for a global severity index (p = 0.02). Scores on all three subscales of the Multidimensional Mood Questionnaire also significantly improved after treatment with DHEA. Beneficial effects of DHEA treatment on anxiety (p = 0.04) and depression (p = 0.01) were also observed for the Hospital Anxiety and Depression Scale. A reduction in fatigue was evident from the Giessen Complaint List (p = 0.03). Treatment with DHEA resulted in significant increases in the initially low scores of all four visual-analogue scales for sexuality. DHEA did not affect fasting serum glucose, insulin and parameters of body composition (Callies et al. 2001). Using an incremental cycling test maximum workload was 95.8 ± 20.4 W after DHEA compared to 91.7 ± 24.1 W after placebo (p = 0.057). DHEA induced a significant decrease in serum leptin (p = 0.01) and an increase in serum osteocalcin (p = 0.02) compared to placebo. Androgenic skin effects of DHEA treatment were reported in 19 out of the 24 women but were mostly mild and transient (Arlt et al. 1999a).

Improvement in mood and fatigue was also observed after DHEA replacement in Addison's disease in the trial reported by Hunt etal. (2000). In this double blind trial 39 patients (24 women, 15 men) received either 50 mg oral DHEA for 12 weeks followed by a four-weekwashout period, then 12 weeks of placebo or vice versa. The hormonal changes induced by DHEA in females were virtually identical to those reported by Arlt etal. (1999a) with increases in serum DHEA(S), androstenedione, and testosterone into normal range for women. In males, serum testosterone and SHBG did not change. Hunt etal. (2000) found a significant increase in self-esteem after DHEA substitution (p < 0.001). Using a Profile of Mood State Questionnaire it was demonstrated that evening mood (p = 0.018) and evening fatigue (p = 0.002) was improved by DHEA. No changes in BMD, body mass index, serum cholesterol or insulin sensitivity were observed after DHEA treatment. Adverse events of DHEA replacement were few and mild (facial acne in nine patients vs. five patients receiving placebo). As the beneficial effects in this study were also observed in male patients who exhibited no change in testosterone, it was concluded that DHEA acts directly at the central nervous system rather than via peripheral conversion to androgens (Hunt et al. 2000). The same group followed up on these results and performed a study in patients with primary adrenal insufficiency (n = 106) who received 12 months of DHEA replacement (50 mg/day) or placebo in a parallel group study design (Gurnell etal. 2002). Preliminary results of this phase III trial demonstrated significant improvement in health-related quality of life during DHEA replacement at three and six months of treatment. An attenuation of this effect after 12 months was observed. However, after withdrawal of DHEA, well-being scores significantly worsened. In addition they found significant beneficial effects of DHEA replacement on femoral neck bone mineral density as assessed by dual energy x-ray absorptiometry (DXA). Body composition analysis by DXA also revealed a significant increase in lean body mass while fat mass remained the same (Gurnell etal. 2002).

In a recent study DHEA (20-30 mg/day) was used in 38 women with secondary AI due to hypopituitarism (Johannsson etal. 2002). DHEA or placebo was given for six months in a randomized, placebo-controlled double blind study, followed by a six-months open treatment period. DHEA(S) increased into the normal range during DHEA administration, whereas androstenedione and testosterone rose only to subnormal levels. The percentage of partners of the patients who reported improved alertness, stamina, and initiative by their spouses were 70%, 64%, and 55%, respectively, in the DHEA group and 11%, 6%, and 11%, respectively, in the placebo group (p < 0.05) Sexual relations tended to improve (p = 0.06). An increase in or the reappearance of axillary and/or pubic hair was seen in all women given 30 mg DHEA and in 69% of women receiving 20 mg DHEA but was not found in women receiving placebo. Glucose metabolism and lipoproteins remained unaffected by DHEA with the exception of transient decrease in HDL cholesterol. Interestingly, based on age-adjusted reference values the study group had 79 ± 20% and 67 ± 23% of predicted values for peak and mean handgrip strength over 10 seconds. These values had significantly increased at 12 months (p < 0.05). Bone markers and BMD remained unchanged. Androgenic skin effects were again more often seen during DHEA treatment.

In contrast, the most recent study using 25 mg DHEA in 39 patients with primary AI in a parallel group design failed to detect a benefit for subjective health status and sexuality (Lovas et al. 2003). The reason for the negative result is most likely the fact that the study was grossly underpowered to detect significant changes. This trial, therefore, is a good example that inadequately designed studies can cause more harm than provide benefits in the development of new treatment strategies (Arlt and Allolio 2003b).

Besides the results of these randomized trials, evidence from case reports (Kim and Brody 2001; Wit et al. 2001) in AI is available. Kim and Brody (2001) have described a 24 year-old female with Addison's disease and the complaint of neither axillary nor pubic hair growth. DHEA was added to the conventional replacement therapy. Serum DHEAS and testosterone levels increased. Pubic hair growth changed from Tanner stage I to Tanner stage III within two years of receiving DHEA at a final dose of 25 mg daily. Similarly, Wit etal. (2001) used oral DHEAS (15 mg/m2) for atrichia pubis in four female adolescents with panhypopituitarism (n = 2) or 17-hydroxylase deficiency (n = 2). They found DHEAS an efficacious treatment leading from atrichia pubis to Tanner stage 4-5 pubic hair.

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