Atherosclerosis, the accumulation of plaque in arteries, is a leading cause of death in the U.S., and almost always occurs in women after menopause. Cognitive concerns such as memory loss, dementia and Alzheimer’s disease are dramatically more common in postmenopausal than premenopausal women.

Now, Keck Medicine of USC has launched a clinical trial to study the effect of a novel hormone replacement therapy on postmenopausal cardiovascular disease and cognitive decline.

“Data supports the concept that estrogen, a hormone that the ovaries stop producing after menopause, protects both the heart and brain from damage,” said Howard N. Hodis, MD, director of the USC Atherosclerosis Research Unit, internal medicine specialist with Keck Medicine and lead researcher of the study. “Our study seeks to determine whether estrogen-containing hormone therapy can prevent or slow atherosclerosis progression and cognitive impairment in women after menopause.”

A key aspect of the study is that it is designed for women who are postmenopausal for six years or less.

“We have studied previous data and conducted clinical trials showing that the timing of when a woman starts hormone therapy is crucial,” said Hodis, who is also a professor of medicine and population and public health sciences at the Keck School of Medicine of USC. “There appears to be a limited window of time wherein women benefit from hormone replacement therapy. Beyond six years of menopause, prevention appears to be too late.”

Improving standard hormone replacement therapies

The hormone therapy being studied has been approved by the Food and Drug Administration since 2013 and consists of estrogen paired with a non-hormone drug known as bazedoxifene.

Traditional hormone replacement therapy combines estrogen with progesterone, or more commonly with progestin, a synthetic progesterone. Estrogen alone can cause the lining of the uterus to thicken, causing bleeding and other health issues, which the progesterone or progestin prevents.

However, progestin/progesterone combined with estrogen has been associated with cancer risks. Bazedoxifene prevents the uterine lining from thickening while appearing not to present the same risks, said Hodis.

Trial eligibility and protocols

The clinical trial, titled Advancing Postmenopausal Preventive Therapy, is open to healthy women six years or less post-menopause, who have a uterus, are 45-59 years of age and do not have cardiovascular disease. Upon enrollment, trial participants:

• Receive an ultrasound of their neck artery that is used as a non-invasive baseline measure of atherosclerosis.
• Undergo several tests to gauge their baseline cognitive function and memory.

Every six months, participants have an ultrasound of the neck artery to monitor any progression of atherosclerosis. They also have electrocardiograms to check for different heart conditions, which are done yearly.

At the end of the study, which lasts approximately three years, women retake the cognitive and memory tests so researchers can determine whether there has been any change since enrollment.

The clinical trial is a double-blinded, placebo-controlled trial, meaning neither participants nor the researchers know who is receiving hormone replacement or a placebo. When the clinical trial is completed, researchers will compare results between the therapy and placebo recipients, and participants will be informed which option they received.

So far, some 260 women are participating in the trial; researchers are looking for 100 more women to enroll. Those interested in participating should contact the USC Atherosclerosis Research Unit at (323) 442-2257 or visit aru.usc.edu.

“Our ultimate goal is to help women and their physicians make informed decisions to promote good health post-menopause,” said Hodis.

The trial is funded by the National Institute on Aging (grant R01-AG058691), part of the U.S. National Institutes of Health (NIH). 

Donna Shoupe, MD, a reproductive endocrinologist specialist with Keck Medicine and professor of obstetrics and gynecology at the Keck School of Medicine and Wendy J. Mack, PhD, a professor of population and public health sciences with the Keck School of Medicine, are co-investigators of the clinical trial.

One of these potential therapies treats the lesions associated with cervical dysplasia and vulvar dysplasia, conditions in which abnormal cells grow along the lining of the cervix or vulva. These conditions are strongly associated with human papillomavirus (HPV) infection and carry a high risk of becoming cancer when left untreated. Additionally, current methods for treating cervical and vulvar dysplasia can address the lesions but not the underlying viral infection, leaving these women at a lifelong increased risk for cervical or vulvar cancer. The investigational treatment involves an injection directly into the lesions to boost the patient’s immune response against HPV and hopefully help the patient clear the HPV from her body.

“Our hope is that this method will improve a patient’s overall immune response to HPV,” said Lynda Roman, MD, associate professor of obstetrics and gynecology and division chief of gynecologic oncology at the Keck School of Medicine of USC. Roman is also the principal investigator of the study. “Many women are infected with HPV but do not develop cervical or vulvar dysplasia, and we suspect that improving the body’s immune response to the virus is the key to halting the development of cervical and vulvar cancer.”

The second trial examines the efficacy of an immunotherapy for women with advanced or recurrent cervical cancer for whom chemotherapy and radiation has been ineffective. Currently, there are few viable treatment options for this subset of cervical cancer patients. The treatment involves T-cell therapy, a promising new approach, combined with chemotherapy to regulate the immune system. The clinical trial is supported by the National Cancer Institute, where the initial trial showing some success with this approach was done.

“If successful, this treatment could change the standard of care for women with advanced cervical cancer and potentially save lives,” said Roman, who is the principal investigator for this trial, as well. “Clinical trials are the method through which we push cancer treatment forward, and we are proud to be a part of this effort.”

Those interested in participating in either of these trials can visit clinicaltrials.keckmedicine.org for more information.

The American Cancer Society estimates that more than 13,200 women will be diagnosed with cervical cancer this year and that more than 4,000 women will die from the disease. The mortality rate has dropped significantly over the past few years due to improved screening, but populations with low access to gynecologic care are still very much at risk for the disease.

— Mary Dacuma