Testosterone replacement therapy and prostate cancer: A Word of Caution

Brand, Timothy C.; Canby-Hagino, Edith; Thompson, Ian M.

doi:10.1007/s11918-008-0003-5

Cited by 8 publications

(9 citation statements)

References 63 publications

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“…Regardless of a clear benefit for bone, use of native sex steroids risks inappropriate gene activation in other tissues. The possibility of breast, cardiovascular, and prostate disease that can occur in this context (17)(18)(19) has driven the search for sex hormone receptor modulators with tissue-or function-restricted effects. However, the value of agents like these may be complicated by steroid and precursor metabolizing enzymes expressed by osteoblasts (3,20,21).…”

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confidence: 99%

Expression of an estrogen receptor agonist in differentiating osteoblast cultures

McCarthy

Clough²,

Gundberg³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Osteoblasts respond in direct and indirect ways to estrogens, and age-dependent changes in hormone levels and bone health can be limited by focused hormone replacement therapy. In this study, we report the release and isolation of an estrogen receptor agonist from osteoblast cultures. This entity reprises many aspects of estradiol activity in isolated osteoblasts, but differs from authentic estradiol by several biochemical and physical criteria. At levels that occur in conditioned medium from differentiating osteoblast cultures, the agonist directly drives gene expression through estrogen-sensitive response elements, activates the obligate osteoblast transcription factor Runx2, and potently enhances Smad-dependent gene expression in response to TGF-␤, but exhibits relatively lesser suppressive effects on gene expression through C/EBP and AP-1-binding protein transcription factors. Estrogen receptor agonist activity is resistant to heating at 100°C and separable from the bulk of the remaining alcohol-and hexane-soluble molecules by C18 chromatography. MS and molecular fragmentation analyses predict a Mr of 415.2 to 437.2. Therefore, in addition to earlier studies showing that osteoblasts readily respond to and metabolize various sex steroid-like substrates, we find that they also generate a potent estrogen receptor agonist during differentiation in vitro. Changes in the availability of a molecule like this within bone may relate to differences in skeletal integrity with aging or metabolic disease.intracrine ͉ selective estrogen receptor modulator ͉ steroid S ex steroids cause direct genomic transcriptional effects through specific receptors that contain ligand binding, dimerization, DNA binding, and gene transactivation domains. They also cause indirect stimulatory or inhibitory effects through complexes composed of activated hormone receptor and other transcription factors or through variations in the activation potential of other transcriptional components (1-6) The skeleton is a well recognized target for sex steroids. Bone fragility is notable when sex steroid levels fall in women after menopause, in elderly males, or after sex organ ablation (7-11). In such cases, bone loss follows a release from native constraints on bone resorption that largely result from changes in growth regulators expressed by osteoblasts and from opposing effects on osteoblast and osteoclast activation and apoptosis, leading to an overall increase in bone remodeling (12-16). Importantly, imbalances in bone remodeling are restored by sex hormone replacement therapy. Regardless of a clear benefit for bone, use of native sex steroids risks inappropriate gene activation in other tissues. The possibility of breast, cardiovascular, and prostate disease that can occur in this context (17-19) has driven the search for sex hormone receptor modulators with tissue-or function-restricted effects. However, the value of agents like these may be complicated by steroid and precursor metabolizing enzymes expressed by osteoblasts (3,20,21).Many cells u...

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confidence: 99%

Expression of an estrogen receptor agonist in differentiating osteoblast cultures

McCarthy

Clough²,

Gundberg³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…This was approximately twofold higher than the reported epidemiological rates for that age group; however, since this long‐term study had no control group, it is difficult to ascertain whether the prostate cancer was detected as a result of frequent testing or whether topical testosterone therapy for long durations poses a real increase in risk. Brand and colleagues [33] recommended to exercise caution when prescribing testosterone therapy, because reliable data is lacking on testosterone and prostate cancer risk. In addition to the stable PSA values observed in this study, two other points regarding the safety of testosterone with regard to prostate health are worth making.…”

Section: Discussionmentioning

confidence: 99%

Absorption of Testosterone Gel 1% (Testim) from Three Different Application Sites

Guay

Smith²,

Offutt³

2009

The Journal of Sexual Medicine

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Introduction A popular treatment choice for male hypogonadism is topical testosterone gel. Two proprietary formulations, Testim Gel 1% (Auxilium Pharmaceuticals, Malvern, PA, USA) and AndroGel 1% (Solvay Pharmaceuticals, Marietta, GA, USA), are available. The recommended Testim application site is limited to the arms/shoulders, whereas AndroGel may be applied to the abdomen, shoulders, and upper arms. Aim To compare absorption variability when applying Testim to various body sites. Main Outcome Measures Total testosterone (TT) and calculated free testosterone (CTfree). Methods Hypogonadal men (TT < 300 ng/mL) applied Testim to three distinct anatomical sites for 1 month per site: arms/shoulders (A), chest/abdomen (C), and calves/legs (L). Pretreatment TT and CTfree were compared with end-of-month measurements. Safety was assessed with prostate-specific antigen (PSA) and hemoglobin (Hb) measurements. Results Twenty-one hypogonadal men (age 56.9 ± 9.0) naïve to prior testosterone therapy and otherwise in good health participated. Three groups of seven applied Testim in the sequence ACL, CLA, and LAC. Overall TT and CTfree increased significantly over pretreatment levels (P < 0.0001) into the normal range. Application sites differed with regard to TT levels achieved, A > C ≥ L (P = 0.011). No significant sequence effects were observed, however, the ACL group achieved the highest levels. CTfree correlated well with TT in all men (R2 = 0.87) and by application site (R2 = 0.91, 0.85, and 0.86 for A, C, L, respectively). Pre- and post-treatment PSAs were similar; mean pretreatment Hb increased from 14.7 ± 1.47 to 15.5 ± 1.3 g/dL at month 3. Hemoglobin corrected to normal in four subjects with anemia at enrollment (Hb < 13.5 g/dL). Conclusions Testim Gel 1% applied to various anatomical sites increases TT and CTfree into the normal range; the best levels are achieved with arms/shoulder application. Flexibility in the application site of Testim is possible if TT or CTfree is monitored to ensure adequate therapeutic levels. Anemia, possibly associated with testosterone deficiency, was an incidental finding in several men and was corrected with topical testosterone replacement.

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“…Suplementaciju ovim hormonom trebalo bi primenjivati u dozi koja otklanja simptome hipogonadizma, ali ne i u dozama koje su veće, jer se na taj način povećava rizik od hipertrofije i karcinoma prostate. Zato se preporučuje i praćenje antigena specifičnog za prostatu (27), hemoglobina, hematokrita i pokazatelja funkcije jetre (14).…”

Section: Terapijski Pristup Opiad Sindromuunclassified

Opioid-induced androgen deficiency in males (OPIAD syndrome)

Miljković¹,

Konstantinovic²,

Rančić³

et al. 2015

Medicinski casopis

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UVODS obzirom na sve veću učestalost malignih bolesti širom sveta u terapiji kancerskog bola povećana je upotreba analgetika iz grupe opioida. Prema podacima Svetske zdravstvene organizacije 2012. godine je zabeleženo 14,1 miliona novodijagnostikovanih i 8,2 miliona umrlih pacijenata od maligne bolesti (1). Dugotrajna upotreba opioida udružena je sa endokrinopatijom koja se, između ostalog, manifestuje androgenom deficijencijom. Androgena deficijencija izazvana opioidima (OPIAD sindrom ili opioid-induced androgen deficiency syndrome) nastaje kao posledica niskih vrednosti folikulostimulirajućeg (FSH) i lutenizirajućeg (LH) hormona u serumu, što je i uzrok neadekvatne produkcije polnih hormona (testosterona i estrogena) i nastanka hipogonadizma (2, 3).Simptomi i znaci hipogonadizma uključuju gubitak libida, erektilnu disfunkciju, sterilitet, depresiju i anksioznost, poremećaj spavanja, normocitnu normohromnu anemiju, smanjenje mišićne mase, osećaj premora i slabosti, noćno znojenje i valunge, iregularnost menstrualnog ciklusa, galaktoreju, smanjenu maljavost i smanjenje mineralne gustine kostiju, što za posledicu ima osteoporozu (4-6). OPIAD sindrom se javlja kod pacijenata obolelih od maligne bolesti, kod kojih se u terapiji bola koriste opioidi, bez obzira na vrstu i lokalizaciju maligniteta (2, 3). PREGLED LITERATURE SAŽETAK

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Testosterone replacement therapy and prostate cancer: A Word of Caution

Cited by 8 publications

References 63 publications

Expression of an estrogen receptor agonist in differentiating osteoblast cultures

Expression of an estrogen receptor agonist in differentiating osteoblast cultures

Absorption of Testosterone Gel 1% (Testim) from Three Different Application Sites

Opioid-induced androgen deficiency in males (OPIAD syndrome)

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