Oestrogens: a novel therapy for neurodegenerative conditions?

WHEN we think about oestrogen, it is natural to immediately think that it’s a female ovarian hormone central to the female reproductive system and secondary sex characteristics. Oestrogen, however, is also a neurosteroid that is made locally in the central nervous system by cells such as neurons and glia. Further, evidence suggests that there are few, if any, sex differences in the brain’s ability to make its own oestrogen. Although the body produces three types of oestrogens (oestrone, oestradiol, and oestriol), oestradiol is the most widespread and, therefore, the word oestrogen is often used to capture oestradiol specifically.

At the cellular level, oestrogen binds to oestrogen receptors. These oestrogen-oestrogen receptor complexes lead to cellular changes via modifying DNA transcription or recruitment of downstream signaling and second messenger protein pathways (usually protein kinases). Importantly, as we discuss in our recent review (published on bioRxiv and yet to be peer reviewed), these cellular changes include recruitment of known neuroprotective molecules and pathways, such as hypoxia-inducible factor 1 (HIF-1), and the dampening of pro-inflammatory responses, such as interleukin-17 (IL-17).

The cellular effects of oestrogen suggest that it may be harnessed as a viable therapeutic strategy for neurodegenerative conditions. Pre-clinical studies (here, here and here) in cell culture, mice and rats show that oestrogen protects against myriad neurodegenerative diseases, including dementia, stroke, and Parkinson’s disease.

Our preprint review evaluated 57 pre-clinical research papers on oestrogen and neuroprotection in pre-clinical models and concluded there is significant evidence that oestrogen can protect against the effects of spinal cord injury. Oestrogen appeared to limit lesion size, post-injury inflammation and cell death, and can improve functional recovery. Despite the substantial pre-clinical evidence that oestrogen is a viable treatment for spinal cord injury, there have been no clinical trials thus far. In other neurodegenerative conditions, however, clinical trials of oestrogen therapy have shown promising effects. This includes ameliorating the cognitive symptoms of dementia such as Alzheimer’s disease (here, here and here) and, in the Women’s Estrogen for Stroke Trial (WEST), mitigating cognitive decline in women after stroke.

Although oestrogen is neuroprotective, oestrogen treatment is not without risk. Oestrogen therapies are well documented for increasing the risk of breast and endometrial cancers and, as shown by the large Women’s Health Initiative trial, stroke (here, here and here). In men, oestrogen therapies are clinically known to carry the risk of increased feminisation. One solution is to use oestrogen on a short term basis. With respect to spinal cord injury, the evidence suggests that even one to two doses of oestrogen conferred neuroprotective benefits. The other solution is to look to the class of drugs known as the selective oestrogen receptor modulators (SERMs).

SERMs are unique oestrogen analogs that act as either oestrogen agonists or antagonists depending on the type of tissue and relative distribution of oestrogen receptors. Multiple SERMs have already been approved for use by the Therapeutic Goods Association (TGA). These include the first generation SERM tamoxifen (tradename Nolvadex/Nolvadex-D, AstraZeneca) in 1998, second generation SERM raloxifene (EVISTA, Eli Lilly) in 1999, and more recently, the third generation SERM bazedoxifene (Duavive, Pfizer) in 2016. The clinical indications for these SERMs include hormone receptor-positive and invasive breast cancers, osteoporosis in postmenopausal women, and menopausal vasomotor symptoms.

Of the three SERMs, tamoxifen has been the most studied with respect to neuroprotection. Tamoxifen can readily cross both the blood brain barrier and the blood spinal cord barrier. Further, tamoxifen and its active metabolites have 100–1000-fold higher selectivity for oestrogen receptors than oestrogen, suggesting that it is a viable oestrogen-based therapeutic strategy. Our review found evidence that, like oestrogen, tamoxifen was neuroprotective against the effects of spinal cord injury in pre-clinical models and was able to improve functional outcomes, including locomotion and balance.

Again, despite substantial pre-clinical evidence that tamoxifen is a viable treatment for spinal cord injury, there have been no clinical trials to date.

With respect to other neurodegenerative conditions, tamoxifen has been shown to reduce the impact of a cholinergic challenge on memory in some women at high risk of developing Alzheimer’s disease. It has also shown positive effects in patients with amyotrophic lateral sclerosis (ALS). People with ALS have ongoing degeneration of motor neurons in the spinal cord. There are currently no, or minimally, efficacious treatments for ALS, and phase 2 trials of tamoxifen significantly prolonged patient survival. Neurodegenerative disorders are characterised by many common molecular and cellular mechanisms, such as neuroinflammation. Given that tamoxifen conferred clinical benefit to these patients, it may similarly improve outcomes in those with spinal cord injuries.

Although tamoxifen, and the other SERMs, have a higher benefit-to-risk ratio than oestrogen, and are not associated with increased risk of cancers and feminisation, there is some risk of side effects. Like oestrogen, chronic (years) of tamoxifen use can increase the risk of stroke (here and here). As such, it may be similarly beneficial to use tamoxifen on a short term basis to avoid the risks associated with chronic use. In line with this, our review did find evidence that in pre-clinical rat and mouse models, even a single dose of tamoxifen can improve spinal cord injury outcomes, such as locomotion, and recruit neuroprotective molecules.

In light of the growing evidence, both pre-clinically and, in some cases, clinically, that oestrogens are neuroprotective, further clinical trials are needed. This is an important next step to determine the viability of oestrogen and SERMs as therapeutic interventions for neurodegenerative diseases. Clearly, we need to identify an ideal dosing regimen that balances neuroprotective benefits and risk of side effects.

Dr Caitlin Finney is a postdoctoral research fellow and neuroscientist at the Westmead Institute for Medical Research and the University of Sydney.

Dr Artur Shvetcov is a postdoctoral research fellow and bioinformatician at the Black Dog Institute.

Professor David Brown is a clinical immunologist and immunopathologist. He is the director of NSW Health Pathology-ICPMR and co-director of the Centre for Immunology and Allergy Research at the Westmead Institute for Medical Research.

The statements or opinions expressed in this article reflect the views of the authors and do not necessarily represent the official policy of the AMA, the MJA or InSight+ unless so stated.

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