Adrenal function under long-term raloxifene administration

Abstract

The aim of the present study was to evaluate the effect of long-term (12 months) administration of raloxifene hydrochloride (60 mg/day) on the steroid production of the adrenal cortex and on the hypothalamic-pituitary-adrenal axis in postmenopausal women. We performed a basal evaluation, a corticotropin releasing factor (CRF) (100 microg i.v. bolus) test and a dexamethasone (DXM) (0.25 mg) suppression-adrenocorticotropic hormone (ACTH) (10 microg i.v. bolus) stimulation test in 11 postmenopausal women, before and after 3, 6 and 12 months of raloxifene treatment. Raloxifene administration significantly modified circulating levels of adrenal steroids, decreasing cortisol (-24%), dehydroepiandrosterone (DHEA) (-36%), and its sulfate (DHEAS) (-41%), and androstenedione (-29%), and increasing circulating allopregnanolone (+39%) levels. Progesterone and 17OH-progesterone levels remained unmodified, while estradiol and estrone levels showed a significant decrease (-51% for estradiol and -61% for estrone). We also observed an increase in circulating ACTH (+58%) and beta-endorphin (+120%). No modifications in the hormonal responses to CRF were observed during the treatment. DXM significantly suppressed circulating steroids at any time with a lower suppression of cortisol from the third month and a higher suppression of DHEA at 12 months. ACTH administration was associated with a significantly blunted cortisol response from the sixth month and a significantly increased response of allopregnanolone from the third month. The present data exclude a raloxifene effect on pituitary sensitivity to CRF and demonstrate a reduced adrenal sensitivity to ACTH, sustained by the opposite changes in basal cortisol and Delta5 androgens, which were reduced, and in ACTH and beta-endorphin, which were increased, as well by the reduced response of cortisol to the direct ACTH stimulus. The reduction of circulating cortisol levels and cortisol response to the ACTH challenge suggests that raloxifene protects against the neurotoxic effects of endogenous glucocorticoids. Furthermore, the progressive increase in basal allopregnanolone and its increased response to ACTH indicate that chronic raloxifene administration exerts direct effects on the pattern of adrenal enzymes, leading to specific changes in the circulating levels of this anxiolytic progesterone metabolite. The important reduction in the circulating levels of estradiol and estrone under long-term raloxifene administration may represent a further mechanism by which this molecule may exert a protective effect against breast and endometrial malignancies.

Effects of raloxifene on sex steroid hormones and C-telopeptide in postmenopausal women with primary breast cancer

“…Apparently raloxifene tended to decrease DHEA-S as compared to placebo, but this trend did not reach statistical significance. Genazzani and colleagues [23] previously reported a similar behavior.…”

“…This decrease is not easy to explain, but emphasizes the importance of a placebo-controlled group. Two previous studies of longer periods of raloxifene treatment have shown either a reduction in estrogens [23], or no modulation at all [24]. The former study lacked a control group and only 11 women were included, while the latter was a randomized, placebo-controlled trial.…”

Stimulatory Adrenocortical Effects of a Selective Estrogen Receptor Modulator in Ovariectomized Female Macaques

“…Conversely, male ER-a knockout mice display elevated androgen synthesis and CYP17 activity in Leydig cells (Akingbemi et al 2003), and CYP17 upregulation in the ovary has been reported in rats treated with various SERMs (Harris et al 2008). The observed SERM effects could also be mediated indirectly through increased ACTH, as reported in one prior study of postmenopausal women receiving raloxifene (Genazzani et al 2003). However, this latter study, as in the macaque tamoxifen study (Wilson et al 2003), found decreased adrenal responsiveness to ACTH challenge, supporting the idea that SERM effects are due at least in part to direct alteration of adrenocortical steroidogenesis.…”

“…In studies of postmenopausal women with breast cancer, tamoxifen has been reported to increase Cort and DHEA-S (Rossi et al 2009) and to increase Cort and decrease DHEA-S (Löfgren et al 2004). In contrast, raloxifene treatment was shown to have no effect on the androgen profile in a cross-sectional study (Christodoulakos et al 2005) and to reduce Cort, DHEA-S, and A4 in a 12-mo trial (Genazzani et al 2003), suggesting that adrenal effects may vary for different SERMs. Adrenocortical cells express ERs and respond to changes in ER activity (de Cremoux et al 1998), suggesting that SERMs may directly affect adrenal function via ERs.…”

Drugs and HPA axis

“…This effect is more apparent with oral estrogen preparations and might be insignificant with transdermal patches [128]. Conversely, long-term administration of the selective estrogen receptor modulator raloxifene is reported to decrease cortisol levels and increase ACTH levels in postmenopausal women [129]. Interestingly, the cholecystokinin 8-like peptide ceruletide, used for paralytic ileus and pancreatic malfunction, stimulates ACTH and cortisol secretion [130] as does the antidepressant herb mixture Hypericum perforatum (St. John's Wort) [131].…”