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

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.

[1]  K. Zaman,et al.  Retina-Targeted Delivery of 17β-Estradiol by the Topically Applied DHED Prodrug , 2020, Pharmaceutics.

[2]  H. Urbanski,et al.  Establishment of a non-human primate model for menopausal hot flushes. , 2020, EC gynaecology.

[3]  L. Prokai,et al.  A Novel Prodrug Approach for Central Nervous System-Selective Estrogen Therapy , 2019, Molecules.

[4]  M. Grossmann,et al.  MECHANISMS IN ENDOCRINOLOGY: Estradiol as a male hormone. , 2019, European journal of endocrinology.

[5]  Russell Estradiol as a male hormone , 2019 .

[6]  O. Kah,et al.  Steroid Transport, Local Synthesis, and Signaling within the Brain: Roles in Neurogenesis, Neuroprotection, and Sexual Behaviors , 2018, Front. Neurosci..

[7]  G. Prins,et al.  Estrogens in Male Physiology. , 2017, Physiological reviews.

[8]  P. Maki,et al.  The menopausal hot flush: a review , 2017, Climacteric : the journal of the International Menopause Society.

[9]  L. Prokai,et al.  Treatment with an orally bioavailable prodrug of 17β-estradiol alleviates hot flushes without hormonal effects in the periphery , 2016, Scientific Reports.

[10]  J. Finkelstein,et al.  Effects of Testosterone and Estradiol Deficiency on Vasomotor Symptoms in Hypogonadal Men. , 2016, The Journal of clinical endocrinology and metabolism.

[11]  C. Epperson,et al.  Menopausal Symptoms and Their Management. , 2015, Endocrinology and metabolism clinics of North America.

[12]  T. Gould,et al.  The prodrug DHED selectively delivers 17β-estradiol to the brain for treating estrogen-responsive disorders , 2015, Science Translational Medicine.

[13]  M. Dimopoulos,et al.  Aromatase inhibitors in male breast cancer: a pooled analysis , 2015, Breast Cancer Research and Treatment.

[14]  A. Sciarra,et al.  Oral ethinylestradiol in castration‐resistant prostate cancer: A 10‐year experience , 2015, International journal of urology : official journal of the Japanese Urological Association.

[15]  L. Prokai,et al.  Separation of dansylated 17β-estradiol, 17α-estradiol, and estrone on a single HPLC column for simultaneous quantitation by LC–MS/MS , 2013, Analytical and Bioanalytical Chemistry.

[16]  F. H. Jong,et al.  Aromatase inhibitors in men: effects and therapeutic options , 2011 .

[17]  P. Schellhammer,et al.  Role of estrogen in normal male function: clinical implications for patients with prostate cancer on androgen deprivation therapy. , 2011, The Journal of urology.

[18]  N. Rance,et al.  An improved method for recording tail skin temperature in the rat reveals changes during the estrous cycle and effects of ovarian steroids. , 2010, Endocrinology.

[19]  D. C. Skinner,et al.  A novel animal model to study hot flashes: no effect of gonadotropin-releasing hormone , 2009, Menopause.

[20]  J. Eastham,et al.  Androgen deprivation therapy and estrogen deficiency induced adverse effects in the treatment of prostate cancer , 2009, Prostate Cancer and Prostatic Diseases.

[21]  I. Merchenthaler The effect of estrogens and antiestrogens in rat models of hot flush , 2005 .

[22]  M. Hammar,et al.  Hot flushes in a male population aged 55, 65, and 75 years, living in the community of Linköping, Sweden , 2003, Menopause.

[23]  B. McEwen Invited review: Estrogens effects on the brain: multiple sites and molecular mechanisms. , 2001, Journal of applied physiology.

[24]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[25]  R R Freedman,et al.  Physiology of hot flashes , 2001, American journal of human biology : the official journal of the Human Biology Council.

[26]  S. Davis,et al.  The Role of Local Estrogen Biosynthesis in Males and Females , 2000, Trends in Endocrinology & Metabolism.

[27]  G. Zagaja,et al.  Transdermal estrogen in the treatment of hot flushes in men with prostate cancer. , 2000, Urology.

[28]  R. Winneker,et al.  The effect of estrogens and antiestrogens in a rat model for hot flush. , 1998, Maturitas.

[29]  I. Merchenthaler,et al.  Regulation of progesterone receptor messenger ribonucleic acid in the rat medial preoptic nucleus by estrogenic and antiestrogenic compounds: an in situ hybridization study. , 1997, Endocrinology.

[30]  J. B. Martin,et al.  Galanin is an estrogen-inducible, secretory product of the rat anterior pituitary. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[31]  D. Dierschke Temperature Changes Suggestive of Hot Flushes in Rhesus Monkeys: Preliminary Observations , 1985, Journal of medical primatology.

[32]  P. Lomax,et al.  A primate model of human postmenopausal hot flushes. , 1984, The Journal of clinical endocrinology and metabolism.