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J Clin Oncol. 2016 August 10; 34(23): 2800.
Published online 2016 June 13. doi:  10.1200/JCO.2015.66.3997
PMCID: PMC5019750

Not All Androgen Deprivation Therapies Are Created Equal: Leuprolide and the Decreased Risk of Developing Alzheimer's Disease

Richard L. Bowencorresponding author
Medical University of South Carolina, Charleston, SC
Tracy Butler
New York University School of Medicine, New York, NY

Nead et al1 report that androgen deprivation therapy (ADT) used for the treatment of prostate cancer increases the risk of developing Alzheimer's disease (AD). Whereas testosterone signaling likely plays a major role in maintaining normal brain health, other hormones of the hypothalamic-pituitary-gonadal (HPG) axis may be just as important if not more so.2 The fact that different ADTs operate via different mechanisms, with different effects on HPG hormones, seems not to have been taken into account by Nead et al1; this likely explains why the conclusion is inconsistent with previous studies.

In particular, the findings of Nead et al1 are in direct opposition to those from a study by D’Amico et al3 that was not cited. The study by D’Amico et al3 compared risk of death from AD in men with prostate cancer who underwent brachytherapy with (n = 1,700) versus without (n = 4,947) a gonadotropin-releasing hormone (GnRH) agonist. Risk of death as a result of AD was significantly decreased in those who received a GnRH agonist (adjusted hazard ratio, 0.45 [95% CI, 0.25 to 0.83]; P = .01).

The most likely cause for these conflicting results is that the article by Nead et al1 considers all ADTs to be equivalent. ADT refers to a large number of different therapies with the overall end effect of suppression of testosterone signaling. For example, the 29 ADT medications queried by the authors in the generation of their data set have different mechanisms of action and heterogeneous effects on other HPG axis hormones. The primary HPG axis hormones affected include GnRH, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogen, progesterone, follistatin, inhibins, and activins. For instance, GnRH agonists suppress circulating levels of LH, FSH, and sex steroids.4 Flutamide causes an increase in all of these hormones.5 Bicalutamide increases LH and FSH, but leaves testosterone levels unchanged.6 Ketoconazole has been shown to stimulate FSH and LH production and suppress estradiol production, but leave levels of prolactin, testosterone, and progesterone unchanged.7

Unfortunately, the risk of AD was not analyzed according to the type of ADT an individual received. Reanalysis of these results might be expected to demonstrate a decreased risk of AD with ADTs that decrease LH and an even greater risk of AD with ADTs that decrease testosterone but increase LH.

Although we agree with Nead et al1 and others2 that, overall, lower testosterone signaling may be associated with increased risk of neurodegeneration, it is critically important to understand that other hormones also affect risk of AD. In particular, there is a large body of preclinical research that indicates that LH promotes AD pathology8 and that treatments that lower LH, including GnRH agonists such as leuprolide acetate, decrease AD pathology (reviewed in Bowen et al8). Leuprolide acetate is an ADT proven to be effective against prostate cancer that may also slow progression of AD in humans.9,10

It is important that readers of the report by Nead et al1 not be left with the impression that men faced with prostate cancer must choose between risk of cancer and risk of AD. Leuprolide acetate and other LH-lowering therapies may be effective against both devastating diseases.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Not All Androgen Deprivation Therapies Are Created Equal: Leuprolide and the Decreased Risk of Developing Alzheimer's Disease

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.

Richard L. Bowen

Employment: Patiently, Health First

Leadership: Patiently

Honoraria: Patiently, Health First

Patents, Royalties, Other Intellectual Property: US Patent No. 6242421, methods for preventing and treating Alzheimer's disease

Tracy Butler

Research Funding: AVID Radiopharmaceuticals (Inst)

Craig S. Atwood

Stock or Other Ownership: JangoBio

Patents, Royalties, Other Intellectual Property: Patent pending

REFERENCES

1. Nead KT, Gaskin G, Chester C, et al. Androgen deprivation therapy and future Alzheimer’s disease risk. J Clin Oncol. 2016;34:566–571. [PMC free article] [PubMed]
2. Barron AM, Fuller SJ, Verdile G, et al. Reproductive hormones modulate oxidative stress in Alzheimer's disease. Antioxid Redox Signal. 2006;8:2047–2059. [PubMed]
3. D’Amico AV, Braccioforte MH, Moran BJ, et al. Luteinizing-hormone releasing hormone therapy and the risk of death from Alzheimer disease. Alzheimer Dis Assoc Disord. 2010;24:85–89. [PubMed]
4. Conn PM, Crowley WF., Jr Gonadotropin-releasing hormone and its analogs. Annu Rev Med. 1994;45:391–405. [PubMed]
5. Sardañons ML, de las Heras MA, Calandra RS, et al. Effect of the antiandrogen flutamide on pituitary LH content and release. Neuroendocrinology. 1989;50:211–216. [PubMed]
6. Verhelst J, Denis L, Van Vliet P, et al. Endocrine profiles during administration of the new non-steroidal anti-androgen Casodex in prostate cancer. Clin Endocrinol (Oxf) 1994;41:525–530. [PubMed]
7. Glass AR. Ketoconazole-induced stimulation of gonadotropin output in men: Basis for a potential test of gonadotropin reserve. J Clin Endocrinol Metab. 1986;63:1121–1125. [PubMed]
8. Bowen RL, Verdile G, Liu T, et al. Luteinizing hormone, a reproductive regulator that modulates the processing of amyloid-β precursor protein and amyloid-β deposition. J Biol Chem. 2004;279:20539–20545. [PubMed]
9. Nedelec C, Ragot S, Irani J, et al. Effects by androgen suppression with luteinizing hormone on cognitive functions in men treated for cancer of prostate [in French] Prog Urol. 2009;19:47–53. [PubMed]
10. Bowen RL, Perry G, Xiong C, et al. A clinical study of lupron depot in the treatment of women with Alzheimer’s disease: Preservation of cognitive function in patients taking an acetylcholinesterase inhibitor and treated with high dose lupron over 48 weeks. J Alzheimers Dis. 2015;44:549–560. [PubMed]

Articles from Journal of Clinical Oncology are provided here courtesy of American Society of Clinical Oncology