Dr. Ron’s Research Review – July 20, 2011

This week’s research review focuses on oxytocin.

Oxytocin is involved in a wide variety of physiological and pathological functions such as sexual activity, penile erection, ejaculation, pregnancy, uterus contraction, milk ejection, maternal behavior, osteoporosis, diabetes, cancer, social bonding, and stress. (Viero, Shibuya et al. 2010)

Oxytocin is implicated in regulating prostate growth. Concentrations are increased in benign, and decreased in malignant prostate disease. (Whittington, Connors et al. 2007)

Oxytocin increases 5alpha-reductase activity of human prostate epithelial cells, but not stromal cells. (Assinder 2008)

Dr. Ron


Articles

REVIEW: Oxytocin: Crossing the bridge between basic science and pharmacotherapy

            (Viero, Shibuya et al. 2010) Download

Is oxytocin the hormone of happiness? Probably not. However, this small nine amino acid peptide is involved in a wide variety of physiological and pathological functions such as sexual activity, penile erection, ejaculation, pregnancy, uterus contraction, milk ejection, maternal behavior, osteoporosis, diabetes, cancer, social bonding, and stress, which makes oxytocin and its receptor potential candidates as targets for drug therapy. In this review, we address the issues of drug design and specificity and focus our discussion on recent findings on oxytocin and its heterotrimeric G protein-coupled receptor OTR. In this regard, we will highlight the following topics: (i) the role of oxytocin in behavior and affectivity, (ii) the relationship between oxytocin and stress with emphasis on the hypothalamo-pituitary-adrenal axis, (iii) the involvement of oxytocin in pain regulation and nociception, (iv) the specific action mechanisms of oxytocin on intracellular Ca(2)(+) in the hypothalamo neurohypophysial system (HNS) cell bodies, (v) newly generated transgenic rats tagged by a visible fluorescent protein to study the physiology of vasopressin and oxytocin, and (vi) the action of the neurohypophysial hormone outside the central nervous system, including the myometrium, heart and peripheral nervous system. As a short nine amino acid peptide, closely related to its partner peptide vasopressin, oxytocin appears to be ideal for the design of agonists and antagonists of its receptor. In addition, not only the hormone itself and its binding to OTR, but also its synthesis, storage and release can be endogenously and exogenously regulated to counteract pathophysiological states. Understanding the fundamental physiopharmacology of the effects of oxytocin is an important and necessary approach for developing a potential pharmacotherapy.

The effect of oxytocin on cell proliferation in the human prostate is modulated by gonadal steroids: implications for benign prostatic hyperplasia and carcinoma of the prostate

            (Whittington, Connors et al. 2007) Download

BACKGROUND: Oxytocin (OT) is implicated in regulating prostate growth. OT concentrations are increased in benign, and decreased in malignant prostate disease. This study investigated whether the altered concentrations of OT present in prostate disease affect the proliferation of malignant and non-malignant human prostate cells. METHODS: The effects of varying concentrations of OT and gonadal steroids on cell proliferation of non-malignant prostatic epithelial (PrEC) and stromal (PrSC) cells and androgen dependent (LNCaP) and independent (PC-3) malignant cell lines were assessed. RESULTS: OT (>0.5 nmol . L(-1)) had no effect on PrEC proliferation when cells were cultured alone. When co-cultured with PrSC and gonadal steroids, OT inhibited epithelial cell proliferation. OT inhibited PrSC proliferation, when cells were cultured alone. When PrSC were co-cultured in the presence of estrogen physiological concentrations of OT were inhibitory. No effect on cell proliferation was observed with higher concentrations of OT. OT did not affect the proliferation of malignant cell lines in the absence of androgens but, in the presence of testosterone, low concentrations of OT (<1 nmol . L(-1)) stimulated proliferation of PC-3 cells. Disruption of caveolae in the plasma membrane removed the inhibitory effect of OT on PrSC proliferation but did not affect the stimulatory effect of OT on PC-3 cells cultured in the presence of androgens. CONCLUSIONS: Changes in prostatic concentrations of OT that occur with aging and malignant disease may act to facilitate cell proliferation. The localization of the OT receptor within the plasma membrane modulates OT's proliferative response in the prostate.

Oxytocin increases 5alpha-reductase activity of human prostate epithelial cells, but not stromal cells

            (Assinder 2008) Download

BACKGROUND: Oxytocin is known to modulate 5-alpha-reductase expression and has, therefore, been implicated in the etiology and novel pharmacological treatments of benign prostatic hyperplasia (BPH). These suggestions have been made in the absence of any direct evidence that oxytocin regulates expression or activity of 5-alpha-reductase isoenzymes in the human prostate. This study evaluated the effects of oxytocin on the activity and expression of 5-alpha-reductase isoenzymes I and II of human prostate stromal (PrSC; primary site of BPH development) and epithelial (PrEC) cells. METHODS: Cell cultures were incubated with oxytocin, or oxytocin plus a specific oxytocin antagonist for 24 hr, and conversion of (3)H-Testosterone to dihydrotestosterone used to estimate total 5-alpha-reductase activity and to determine activity of both type I and type II isoenzymes. Fully quantitative real-time RT-PCR determined levels of expression of both isoenzymes following treatments. RESULTS: Oxytocin significantly increased the total 5-alpha-reductase activity of PrEC but not of PrSC. 5-alpha-Reductase I gene expression and enzyme activity were also increased (P<0.05) in PrEC by oxytocin. Oxytocin significantly increased type II activity, but not expression, in PrEC. Oxytocin did not significantly affect 5-alpha-reductase activity or expression in PrSC. CONCLUSION: Both 5-alpha-reductase I and II are expressed in normal human prostate stromal and epithelial cells. Only 5-alpha-reductase isoenzymes of prostate epithelium are modulated by oxytocin.


References

Assinder, S. J. (2008). "Oxytocin increases 5alpha-reductase activity of human prostate epithelial cells, but not stromal cells." Prostate 68(2): 115-21.

Viero, C., I. Shibuya, et al. (2010). "REVIEW: Oxytocin: Crossing the bridge between basic science and pharmacotherapy." CNS Neurosci Ther 16(5): e138-56.

Whittington, K., B. Connors, et al. (2007). "The effect of oxytocin on cell proliferation in the human prostate is modulated by gonadal steroids: implications for benign prostatic hyperplasia and carcinoma of the prostate." Prostate 67(10): 1132-42.