Short-term effects of transdermal estradiol in men undergoing androgen deprivation therapy for prostate cancer: a randomized placebo-controlled trial

Russell, Nicholas; Hoermann, Rudolf; Cheung, Ada S; Ching, Michael S.; Zajac, Jeffrey D; Handelsman, David J.; Grossmann, Mathis

doi:10.1530/eje-17-1072

Cited by 17 publications

(22 citation statements)

References 50 publications

(59 reference statements)

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“…In Finkelstein's study (discussed above) (54), 16 weeks of induced hypogonadism in healthy younger men caused elevations in serum beta carboxyl-terminal type 1 collagen telopeptide (CTX) and declines in BMD by quantitative computed tomography which were greater in men who received AI at each active testosterone replacement dose (103). In another 4-week RCT enrolling men rendered chronically hypogonadal with GnRH analogs for prostate cancer, transdermal E2 add-back reduced serum CTX and increased P1NP, consistent with short-term anti-resorptive and pro-osteoblastic effects (104). These studies suggest that the high remodeling rate and bone loss that occurs in male hypogonadism is primarily due to E2 deficiency.…”

Section: E2 and Bone Loss In Older Men And In Models Of Hypogonadismmentioning

confidence: 76%

“…In a preliminary report of an ongoing RCT comparing two modes of ADT for prostate cancer, highdose transdermal E2 versus standard GnRH analog therapy, men in the E2 arm had a lower incidence of hot flushes at 6 months (8 vs 46%) (53). Finally, in a 4-week RCT, low-dose transdermal E2 add-back in men receiving GnRH analog therapy, reduced hot flush frequency-severity scores (104).…”

Section: Vasomotor Stabilitymentioning

confidence: 97%

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MECHANISMS IN ENDOCRINOLOGY: Estradiol as a male hormone

Russell

Grossmann

2019

European Journal of Endocrinology

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103

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Evidence has been accumulating that, in men, some of the biological actions traditionally attributed to testosterone acting via the androgen receptor may in fact be dependent on its aromatization to estradiol (E2). In men, E2 circulates at concentrations exceeding those of postmenopausal women, and estrogen receptors are expressed in many male reproductive and somatic tissues. Human studies contributing evidence for the role of E2 in men comprise rare case reports of men lacking aromatase or a functional estrogen receptor alpha, short-term experiments manipulating sex steroid milieu in healthy men, men with organic hypogonadism or men with prostate cancer treated with androgen deprivation therapy (ADT) and from observational studies in community-dwelling men. The collective evidence suggests that, in men, E2 is an important hormone for hypothalamic–pituitary–testicular axis regulation, reproductive function, growth hormone insulin-like growth factor-1 axis regulation, bone growth and maintenance of skeletal health, body composition and glucose metabolism and vasomotor stability. In other tissues, particularly brain, elucidation of the clinical relevance of E2 actions requires further research. From a clinical perspective, the current evidence supports the use of testosterone as the treatment of choice in male hypogonadism, rather than aromatase inhibitors (which raise testosterone and lower E2), selective androgen receptor modulators and selective estrogen receptor modulators (with insufficiently understood tissue-specific estrogenic effects). Finally, E2 treatment, either as add-back to conventional ADT or as sole mode of ADT could be a useful strategy for men with prostate cancer.

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Section: E2 and Bone Loss In Older Men And In Models Of Hypogonadismmentioning

confidence: 76%

Section: Vasomotor Stabilitymentioning

confidence: 97%

MECHANISMS IN ENDOCRINOLOGY: Estradiol as a male hormone

Russell

Grossmann

2019

European Journal of Endocrinology

Self Cite

103

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“…On the other hand, any currently approved estrogen or estrogen + progestin therapy for MHT produces significant circulating estrogen levels, leading to the unwanted peripheral hormonal liability described above, independently of the type of hormones, dosage form and duration of treatment. Feminization, including gynecomastia in men [24,25], is also a serious drawback of estrogen therapy for a certain population of prostate cancer patients who suffer from similar symptoms (hot flushes, cognitive decline, depression, etc.) as postmenopausal women.…”

Section: Introductionmentioning

confidence: 99%

A Novel Prodrug Approach for Central Nervous System-Selective Estrogen Therapy

Prókai-Tátrai

Prókai

2019

Molecules

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Beneficial effects of estrogens in the central nervous system (CNS) results from the synergistic combination of their well-orchestrated genomic and non-genomic actions, making them potential broad-spectrum neurotherapeutic agents. However, owing to unwanted peripheral hormonal burdens by any currently known non-invasive drug administrations, the development of estrogens as safe pharmacotherapeutic modalities cannot be realized until they are confined specifically and selectively to the site of action. We have developed small-molecule bioprecursor prodrugs carrying the para-quinol scaffold on the steroidal A-ring that are preferentially metabolized in the CNS to the corresponding estrogens. Here, we give an overview of our discovery of these prodrugs. Selected examples are shown to illustrate that, independently of the route of administrations and duration of treatments, these agents produce high concentration of estrogens only in the CNS without peripheral hormonal liability. 10β,17β-Dihydroxyestra-1,4-dien-3-one (DHED) has been the best-studied representative of this novel type of prodrugs for brain and retina health. Specific applications in preclinical animal models of centrally-regulated and estrogen-responsive human diseases, including neurodegeneration, menopausal symptoms, cognitive decline and depression, are discussed to demonstrate the translational potential of our prodrug approach for CNS-selective and gender-independent estrogen therapy with inherent therapeutic safety.

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“…No SERMs have yet been approved to treat bone loss in men. More recently, a study which examined treatment with low‐dose oestradiol in men receiving ADT for prostate cancer demonstrated that topical oestradiol significantly reduced serum levels of the bone resorption marker CTX relative to placebo . Given the short study duration, however, no efforts to assess changes in BMD or fracture risk were undertaken.…”

Section: Prostate Cancermentioning

confidence: 99%

The skeletal impact of cancer therapies

Bedatsova

Drake

2019

Brit J Clinical Pharma

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Both cancer and therapies used in the treatment of cancer can have significant deleterious effects on the skeleton, increasing the risks for both bone loss and fracture development. While advancements in cancer therapies have resulted in enhanced cancer survivorship for patients with many types of malignancies, it is increasingly recognized that efforts to reduce bone loss and limit fractures must be considered for nearly all patients undergoing cancer therapy in order to diminish the anticipated future skeletal consequences. To date, most studies examining the impact of cancer therapies on skeletal outcomes have focused on endocrine-associated cancers of the breast and prostate, with more recent advances in our understanding of bone loss and fracture risk in other malignancies. Pharmacologic efforts to limit the adverse effects of cancer therapies on bone have nearly universally employed anti-resorptive approaches, although studies have frequently relied on surrogate outcomes such as changes in bone mineral density or bone turnover markers, rather than on fractures or other skeletal-related events, as primary study endpoints. Compounding current deficiencies for the provision of optimal care is the recognition that despite clearly written and straightforward society-based guidelines, vulnerable eligible patients are very often neither identified nor provided with appropriate treatments to limit the skeletal impact of their cancer therapies. KEYWORDS androgen deprivation therapy, aromatase inhibitor, bone loss, breast cancer, myeloma, prostate cancer

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Short-term effects of transdermal estradiol in men undergoing androgen deprivation therapy for prostate cancer: a randomized placebo-controlled trial

Cited by 17 publications

References 50 publications

MECHANISMS IN ENDOCRINOLOGY: Estradiol as a male hormone

MECHANISMS IN ENDOCRINOLOGY: Estradiol as a male hormone

A Novel Prodrug Approach for Central Nervous System-Selective Estrogen Therapy

The skeletal impact of cancer therapies

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