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Eleftherios E Deiktakis Laboratory of Clinical Chemistry, School of Medicine, University of Crete, Heraklion, Greece

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Eleftheria Ieronymaki Laboratory of Clinical Chemistry, School of Medicine, University of Crete, Heraklion, Greece

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Peter Zarén Department of Translational Medicine, Lund University, Malmö, Sweden

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Agnes Hagsund Department of Translational Medicine, Lund University, Malmö, Sweden

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Elin Wirestrand Department of Translational Medicine, Lund University, Malmö, Sweden

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Johan Malm Department of Translational Medicine, Lund University, Malmö, Sweden

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Christos Tsatsanis Laboratory of Clinical Chemistry, School of Medicine, University of Crete, Heraklion, Greece

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Ilpo T Huhtaniemi Department of Translational Medicine, Lund University, Malmö, Sweden
Imperial College London, Institute of Reproductive and Developmental Biology, London, UK

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Aleksander Giwercman Department of Translational Medicine, Lund University, Malmö, Sweden
Malmö University Hospital, Reproductive Medicine Center, Malmö, Sweden

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Yvonne Lundberg Giwercman Department of Translational Medicine, Lund University, Malmö, Sweden

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Objective

During androgen ablation in prostate cancer by the standard gonadotropin-releasing hormone (GnRH) agonist treatment, only luteinizing hormone (LH) is permanently suppressed while circulating follicle-stimulating hormone (FSH) rebounds. We explored direct prostatic effects of add-back FSH, after androgen ablation with GnRH antagonist, permanently suppressing both gonadotropins.

Methods

The effects of recombinant human (rFSH) were examined in mice treated with vehicle (controls), GnRH antagonist degarelix (dgx), dgx + rFSH, dgx + flutamide, or dgx + rFSH + flutamide for 4 weeks. Prostates and testes size and expression of prostate-specific and/or androgen-responsive genes were measured. Additionally, 33 young men underwent dgx-treatment. Seventeen were supplemented with rFSH (weeks 1–5), and all with testosterone (weeks 4–5). Testosterone, gondotropins, prostate-specific antigen (PSA), and inhibin B were measured.

Results

In dgx and dgx + flutamide treated mice, prostate weight/body weight was 91% lower than in controls, but 41 and 11%, respectively, was regained by rFSH treatment (P = 0.02). The levels of seminal vesicle secretion 6, Pbsn, Nkx3.1, beta-microseminoprotein, and inhibin b were elevated in dgx + rFSH-treated animals compared with only dgx treated (all P < 0.05). In men, serum inhibin B rose after dgx treatment but was subsequently suppressed by testosterone. rFSH add-back had no effect on PSA levels.

Conclusions

These data provide novel evidence for the direct effects of FSH on prostate size and gene expression in chemically castrated mice. However, in chemically castrated men, FSH had no effect on PSA production. Whether FSH effects on the prostate in humans also require suppression of the residual adrenal-derived androgens and/or a longer period of rFSH stimulation, remains to be explored.

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Vita Birzniece School of Medicine, Western Sydney University, New South Wales, Australia
Department of Diabetes and Endocrinology, Blacktown Hospital, New South Wales, Australia
Garvan Institute of Medical Research, New South Wales, Australia
School of Medical Sciences, University of New South Wales, New South Wales, Australia

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Teresa Lam School of Medicine, Western Sydney University, New South Wales, Australia
Department of Diabetes and Endocrinology, Blacktown Hospital, New South Wales, Australia
Department of Diabetes and Endocrinology, Westmead Hospital, New South Wales, Australia

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Mark McLean School of Medicine, Western Sydney University, New South Wales, Australia
Department of Diabetes and Endocrinology, Blacktown Hospital, New South Wales, Australia

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Navneeta Reddy Department of Diabetes and Endocrinology, Blacktown Hospital, New South Wales, Australia

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Haleh Shahidipour School of Medicine, Western Sydney University, New South Wales, Australia
Department of Diabetes and Endocrinology, Blacktown Hospital, New South Wales, Australia

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Amy Hayden School of Medicine, Western Sydney University, New South Wales, Australia
Faculty of Medicine, Health and Human Sciences, Macquarie University, New South Wales, Australia
Crown Princess Mary Cancer Centre, Westmead Hospital, New South Wales, Australia

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Howard Gurney Crown Princess Mary Cancer Centre, Westmead Hospital, New South Wales, Australia

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Glenn Stone School of Computing, Engineering and Mathematics, Western Sydney University, New South Wales, Australia

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Rikke Hjortebjerg Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
Endocrine Research Unit, Department of Endocrinology, Odense University Hospital & Department of Clinical Research, Faculty of Health, University of Southern Denmark, Odense, Denmark
Steno Diabetes Center Odense, Odense University Hospital & Department of Clinical Research, Faculty of Health, University of Southern Denmark, Odense, Denmark

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Jan Frystyk Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
Endocrine Research Unit, Department of Endocrinology, Odense University Hospital & Department of Clinical Research, Faculty of Health, University of Southern Denmark, Odense, Denmark

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Objective

Androgen deprivation therapy (ADT), a principal therapy in patients with prostate cancer, is associated with the development of obesity, insulin resistance, and hyperinsulinemia. Recent evidence indicates that metformin may slow cancer progression and improves survival in prostate cancer patients, but the mechanism is not well understood. Circulating insulin-like growth factors (IGFs) are bound to high-affinity binding proteins, which not only modulate the bioavailability and signalling of IGFs but also have independent actions on cell growth and survival. The aim of this study was to investigate whether metformin modulates IGFs, IGF-binding proteins (IGFBPs), and the pregnancy-associated plasma protein A (PAPP-A) – stanniocalcin 2 (STC2) axis.

Design and methods

In a blinded, randomised, cross-over design, 15 patients with prostate cancer on stable ADT received metformin and placebo treatment for 6 weeks each. Glucose metabolism along with circulating IGFs and IGFBPs was assessed.

Results

Metformin significantly reduced the homeostasis model assessment as an index of insulin resistance (HOMA IR) and hepatic insulin resistance. Metformin also reduced circulating IGF-2 (P  < 0.05) and IGFBP-3 (P  < 0.01) but increased IGF bioactivity (P  < 0.05). At baseline, IGF-2 correlated significantly with the hepatic insulin resistance (r2= 0.28, P  < 0.05). PAPP-A remained unchanged but STC2 declined significantly (P  < 0.05) following metformin administration. During metformin treatment, change in HOMA IR correlated with the change in STC2 (r2= 0.35, P  < 0.05).

Conclusion

Metformin administration alters many components of the circulating IGF system, either directly or indirectly via improved insulin sensitivity. Reduction in IGF-2 and STC2 may provide a novel mechanism for a potential metformin-induced antineoplastic effect.

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