Brain-Selective Estrogen Therapy Prevents Androgen Deprivation-Associated Hot Flushes in a Rat Model

Abstract

Hot flushes are best-known for affecting menopausal women, but men who undergo life-saving castration due to androgen-sensitive prostate cancer also suffer from these vasomotor symptoms. Estrogen deficiency in these patients is a direct consequence of androgen deprivation, because estrogens (notably 17β-estradiol, E2) are produced from testosterone. Although estrogens alleviate hot flushes in these patients, they also cause adverse systemic side effects. Because only estrogens can provide mitigation of hot flushes on the basis of current clinical practices, there is an unmet need for an effective and safe pharmacotherapeutic intervention that would also greatly enhance patient adherence. To this end, we evaluated treatment of orchidectomized (ORDX) rats with 10β, 17β-dihydroxyestra-1,4-dien-3-one (DHED), a brain-selective bioprecursor prodrug of E2. A pilot pharmacokinetic study using oral administration of DHED to these animals revealed the formation of E2 in the brain without the appearance of the hormone in the circulation. Therefore, DHED treatment alleviated androgen deprivation-associated hot flushes without peripheral impact in the ORDX rat model. Concomitantly, we showed that DHED-derived E2 induced progesterone receptor gene expression in the hypothalamus without stimulating galanin expression in the anterior pituitary, further indicating the lack of systemic estrogen exposure upon oral treatment with DHED.

The impact of 17β-estradiol on the estrogen-deficient female brain: from mechanisms to therapy with hot flushes as target symptoms

“…Therefore, confining E2 into the brain also is critical for these patients. Using orchiectomized rats in the same model of morphine-dependent hot flushes as for the female animals, we have also shown the beneficial TST lowering effect of the DHED-derived E2 ( Figure 3 ) in male animals lacking gonadal E2 source ( 108 ).…”

10β-Hydroxyestra-1,4-diene-3,17-dione Does Not Bind to the Nuclear Estrogen Receptor α

“…Through an extensive series of supporting and multidisciplinary experiments as well as validated bioanalytical assays (e.g., Prokai et al, 2003Prokai et al, , 2015Prokai-Tatrai et al, 2018, 2021Merchenthaler et al, 2016Merchenthaler et al, , 2020, metabolism of these steroidal para-quinol bioprecursor prodrugs (HEDD, DHED and αDHED) to the corresponding estrogen (E1, E2 and 17-estradiol [E2], respectively) has been unequivocally demonstrated to occur in the CNS (Figure 1A) without peripheral hormonal effects. Specifically, these experiments explicitly revealed that estrogen-sensitive organs such as the uterus, seminal vesicle and anterior pituitary were not stimulated by HEDD, DHED or αDHED treatments, even after chronic dosing.…”

A Green Blue LED-Driven Two-Liquid-Phase One-Pot Procedure for the Synthesis of Estrogen-Related Quinol Prodrugs

“…As reported in Table 5, quinols 3a and 3c-d were obtained ranging from acceptable to high yield (Table 5, entry 1 and entries 3-4). Quinols 3a (DHED) and 3c (HEDD) are well recognized pro-drugs in Hormone Replacement Therapy [9][10][11][12][13][14]. The reaction was performed solubilizing 1b (0.2 mmol) and meso-TPP (1.0 mol%) in 2-MeTHF (3.2 mL), followed by the addition of PBS (0.1 M, pH 6) and of PPh3 (0.3 mmol) at different reaction times.…”

“…As reported in Table 5, quinols 3a and 3c-d were obtained ranging from acceptable to high yield (Table 5, entry 1 and entries 3-4). Quinols 3a (DHED) and 3c (HEDD) are well recognized pro-drugs in Hormone Replacement Therapy [9][10][11][12][13][14].…”

“…In this framework, 10β, 17β-dihydroxyestra-1,4-dien-3-one (DHED), received a particular attention as an alternative to 17β-estradiol. In vitro and in vivo studies showed that DHED has the potential to treat menopausal symptoms [9], ocular neurodegenerations (including glaucoma) [10,11], androgen deprivation-associated hot flushes [12], and Alzheimer's [13] and Parkinson's neurological disorders [14]. Estrogen-related quinols are synthesized by the oxygenation of the phenolic A-ring of the molecule [15][16][17][18][19][20][21], the procedure being limited by the use of stoichiometric oxidants (e.g., oxone [22], hypervalent iodine [23,24], and excess of hydrogen peroxide H 2 O 2 [25]).…”