Progesterone derivatives

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Weight gain and appetite stimulation are now recognized as secondary effects of treatment for hormone-sensitive cancers using progesterone derivatives (Gregory et al. 1985; Tchekmedyian et al. 1987). Randomized controlled trials have been conducted to evaluate the efficacy of megestrol acetate (MA) and medroxyprogesterone (MPA) (Downer et al. 1993) as appetite stimulants (Simons et al. 1996). In some studies weight gain seems to be related to a gain in fat mass (Lambert et al. 2002; Engelson et al. 1999; Loprinzi et al. 1993) and, to a lesser extent, fluid retention, whilst others found no weight gain but instead an improvement in QOL related to increased appetite (Beller et al. 1997). The data on improvements in QOL are equivocal (Simons et al. 1996; Jatoi et al. 2000; Rowland et al. 1996), although this may reflect the differing measures used to assess it.

The exact mechanism of action of these agents remains to be elucidated. It has been postulated that central appetite stimulation effect (probably mediated by NPY) (Engelson et al. 1999; McCarthy et al. 1994), reduction of serotonin and cytokine release (Mantovani et al. 1997, 1998), and a corticosteroid-like effect (Beller et al. 1997), suppressing baseline cortisol levels, suggest an impact on the HPA axis (Oster et al. 1994). MA inhibits secretion of LH and follicle-stimulating hormone (FSH) in males and females (Engelson et al. 1999) and reduces testosterone levels (Engelson et al. 1999; Venner et al. 1988). In vitro studies have identified that MA enhances the differentiation of pre-adipocyte mouse fibroblasts to adipocytes (Engelson et al. 1999) which suggests that MA increases not only cell size, but also cell number (Neuenschwander and Bruera 1998). Data are contradictory on the possible down-regulation of IL-6 levels by MA (Mantovani 2002; Jatoi et al. 2002). The effect of these drugs on lean body mass is controversial. In patients with AIDS administering MA 800 mg/day was associated with a gain in fat mass (not a shift in water content) but not in lean body mass (Oster et al. 1994). Thus it has been suggested that one of the possible antianabolic muscle effects of progestagens is decreased testosterone levels. MA seems to induce suppression of androgens, both testicular and adrenal, and impairs their intracellular metabolism (Venner et al. 1988). However, in a recent study on aging-related weight loss and sarcopenia, testosterone in conjunction with MA was unable to demonstrate enhanced gains in muscle mass. The combination of these with resistance exercise appears to bring about gains in muscle mass (Lambert et al. 2002). Well-conducted randomized controlled clinical trials have shown these drugs to be a reasonable option when anorexia and body image are major matters of concern. Evidence on this antian-abolic effect requires further clarification in a cancer population.

MA has shown a dose-related effect on appetite (Jatoi et al. 2002), weight gain, and feelings of well-being (Mantovani et al. 1998) in a dose range of 160-1600 mg. However, the related side-effects also increase with dose (peripheral oedema, hypertension, Cushing syndrome, thromboembolic disease, and adrenal insufficiency with abrupt cessation) (Bruera et al. 1990; Straisser and Bruera 2002). The suggested starting dose is 160 mg/day (Loprinzi et al. 1993), and this is titrated according to the balance between clinical response and side-effects. MPA is used at a dose of 1000 mg/day orally (equivalent to MA 160 mg/day) (Mantovani et al. 2001).

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