Could “Brain-Only” Estrogen Treat Symptoms of Menopause?

Hot flashes, mood swings, and insomnia are just a few of the troubling symptoms of menopause, and all of them are caused by a lack of estrogen in the brain. Women can take hormone replacement therapy to ease these tortures, but the drugs carry health risks. Now, researchers may have a fix. They have developed a small molecule, DHED, that is converted into estrogen by an enzyme that resides solely in the brain. As reported in Science Translational Medicine on July 22, DHED protected rats without ovaries from stroke damage, depression, cognitive decline, and even rodent hot flashes. The researchers, led by Laszlo Prokai of the University of North Texas Health Science Center in Fort Worth, plan to initially test the drug as a treatment for menopause symptoms, but imagine that DHED might attenuate cognitive decline associated with neurodegenerative diseases such as Alzheimer’s.

The ovaries produce the bulk of the body’s 17β-estradiol (also known as E2), and when these egg-bearing organs close up shop during menopause or are removed surgically to hedge cancer risk, the body can struggle. Some organs, including the brain, make their own localized supply of estrogen, but loss of the ovarian supply still takes its toll. Estrogen replacement therapy can alleviate some postmenopausal symptoms, and it also reportedly has neuroprotective properties (see Sep 2007 news). However, the hormones increase the risk of breast cancer in some women, and also elevate dementia risk when given to women over the age of 65 (see Rocca et al., 2012, and May 2003 news). 

Prokai and colleagues have worked for more than a decade to find an estrogen compound active only in the brain. In their studies of mechanisms of estrogen neuroprotection, they stumbled upon a short-chain, NADPH-dependent dehydrogenase/reductase (SDR) that detoxifies compounds that cause oxidative damage. More than 70 similar enzymes exist throughout the body, but SDR is primarily active in the brain. As part of the oxidation process that occurs throughout the body, E2 is oxidized into DHED (10β,17β-dihydroxyestra-1,4-dien-3-one). In the brain, SDR then reduces DHED back to E2, Prokai said. The researchers synthesized DHED and tested it as a brain-specific “prodrug.”

Estrogen Unleashed.

SDR, a reductase, converts DHED into estrogen. [Courtesy of Prokai et al., Science Translational Medicine, 2015.]

In keeping with SDR’s brain activity, the researchers found, via mass spectrometry, that only brain extracts converted DHED into estrogen, with the cortex and hippocampus being most active. No conversion of DHED occurred in uterine extracts. Injected intravenously into ovariectomized (OVX) rats, DHED rapidly disappeared from the blood, while E2 concentrations shot up in the brain. The same scenario played out when the researchers injected the rats subcutaneously or fed them DHED. When the compound was given to transgenic mice that systemically express luciferase under control of estrogen receptors, only brain slices lit up. In contrast, estrogen activated the luciferase in multiple organs, including the liver. Furthermore, injecting or feeding rats with DHED promoted no uterine weight gain, which is a common consequence of estrogen therapy. 

Unlike E2, DHED did not cause estrogen receptor α (ERα) transactivation, a known cancer-promoting effect, in cultured human breast cells, nor did the drug promote human breast cancer growth in immunocompromised mice injected with the cells.

To measure DHED’s neuroprotective effects, the researchers turned to transient middle cerebral artery occlusion (tMCAO), a commonly used rat stroke model. They injected E2 or one of several doses of DHED subcutaneously one hour before initiating a stroke in OVX rats, and found that the compound reduced the area damaged by the stroke and reduced neurological deficits in a dose-dependent manner. It took 10 times more E2 to provide the same level of protection. The researchers also found that DHED reduced damage even when injected two hours after the stroke. 

Damage Control.

In ovariectimized rats, stroke triggered massive damage (white areas, left panel). Treatment with E2 (center) or DHED (right) offered some protection. [Courtesy of Prokai et al., Science Translational Medicine 2015].

The researchers challenged OVX rats in the forced-swim test to measure depression. Animals given daily injections of DHED for five days prior to the test performed better than untreated mice and slightly better than those given the same regimen of E2. These benefits disappeared when the animals were treated with an estrogen receptor antagonist. DHED also headed off other menopausal symptoms: Treatment with the drug blunted tail temperature rise in a rat model of hot flashes, and boosted working memory in middle-aged OVX rats. The treatment also promoted molecular and cellular effects, including a boost in the number of dendritic spines on CA1 neurons in the hippocampus. 

Rena Li of the Roskamp Institute in Sarasota, Florida, commented that DHED treatment was a promising approach to estrogen-replacement therapy. However, she wondered whether SDR’s expression and activity would remain stable in aged or Alzheimer’s-diseased brains. “If this is truly brain-specific in humans, and if the enzyme is active in aged and/or AD brains, then it could be useful,” she said.

Prokai said that the lab is currently testing the drug in neurodegenerative disease models. In the clinic, the group plans to first test DHED in women who have undergone early, rapid menopause due to surgical removal of their ovaries. “In these women, menopause symptoms manifest rapidly and severely following surgery, so they would greatly benefit from a safe estrogen therapy,” he said. Prokai and co-senior author  Katalin Prokai-Tatrai founded Agypharma in Mansfield, Texas, with the goal of initiating clinical trials, and plan to use hot flashes as the primary therapeutic measure.—Jessica Shugart

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References

News Citations

  1. Estrogen and Neuroprotection: A Matter of Time?
  2. Dementia Risk Increases, at Least in Those Who Start Hormone Therapy Late

Paper Citations

  1. Rocca WA, Grossardt BR, Miller VM, Shuster LT, Brown RD Jr. Premature menopause or early menopause and risk of ischemic stroke. Menopause. 2012 Mar;19(3):272-7. PubMed.

Further Reading

Papers

  1. Li R, Cui J, Shen Y. Brain sex matters: estrogen in cognition and Alzheimer's disease. Mol Cell Endocrinol. 2014 May 25;389(1-2):13-21. Epub 2014 Jan 11 PubMed.

Primary Papers

  1. Prokai L, Nguyen V, Szarka S, Garg P, Sabnis G, Bimonte-Nelson HA, McLaughlin KJ, Talboom JS, Conrad CD, Shughrue PJ, Gould TD, Brodie A, Merchenthaler I, Koulen P, Prokai-Tatrai K. The prodrug DHED selectively delivers 17β-estradiol to the brain for treating estrogen-responsive disorders. Sci Transl Med. 2015 Jul 22;7(297):297ra113. PubMed.

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