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Progesterone may have a protective effect against the impact of mild traumatic brain injury (mTBI) in female athletes when the injury takes place during the phase of the menstrual cycle (MC), when progesterone levels are highest, early research suggests.

“Our findings suggest being in the luteal phase (right after ovulation) of the menstrual cycle when progesterone is highest — or being on contraceptives, which artificially increase progesterone — may mean athletes won’t have as severe symptoms when they have a concussion injury,” study investigator Amy Herrold, PhD, where to buy generic orlistat uk no prescription research assistant professor of psychiatry and behavioral sciences, Northwestern University Feinberg School of Medicine, said in a press release.

The study was published online February 24 in the Journal of Neurotrauma.

Research Gap

“Our group has been working together toward looking at neuroimaging and potential biomarkers for mTBI or concussion in athletes,” Herrold told Medscape Medical News.

“When we started looking at the literature, we began to see a real gap to be filled, specifically studying female athletes, since a lot of concussion sports literature focused on males and also didn’t focus on female-specific factors such as hormonal menstrual cycle levels or hormonal contraceptives,” she added

College athletics are divided into two categories — varsity and club — and, although there are many more club than varsity athletes (> 2 million vs 460,000), most research has been conducted in varsity athletes.

“This is important because the sports participation of club athletes is less tightly regulated, compared to varsity athletes,” she said.

In addition, previous research suggests gonadal hormones, in particular progesterone, have “widespread non-reproductive functions in the central nervous system (CNS) and have neuroprotective effects in various disorders,” including TBI, the authors write.

“These putative neuroprotective effects emphasize the importance of considering MC phase when mTBI occurs,” the authors note.

In addition, some research has suggested that users of hormonal contraceptives (HC) have lower postconcussive symptom severity, compared to non-HC users — in particular, better cognitive performance after injury.

“We wanted to test whether CBF [cerebral blood flow] mediates the relationship between progesterone serum levels and postinjury symptoms,” lead investigator Yufen Chen, research assistant professor, Department of Radiology, Northwestern University Feinberg School of Medicine, told Medscape Medical News.

If that were the case, it might support a hypothesis that progesterone plays a role in neuroprotection, she said.

Academic Stress

The researchers studied 20-year-old club athletes at Northwestern University (n = 13). These athletes participated in soccer, ultimate Frisbee, crew, triathlon, lacrosse, women’s rugby, and tennis clubs. Study visits were scheduled within 3 to 10 days postconcussion.

On day 1, study subjects completed assessments that included the Perceived Stress Scale (PSS), the Post-Concussive Symptoms Scale (PCSS), and the Beck Depression Inventory-II (BDI-II). The researchers also assessed alcohol and cannabis use.

Blood sampling and MRI occurred on day 2, after which participants were matched with 13 healthy controls recruited from noncollision college sports teams, who were matched for age, ethnicity, handedness, and stage in the menstrual cycle or use or hormonal contraceptives.

Subjects who had sustained a concussion had a higher total on assessments of stress, post-concussive symptoms, depression, and a composite score of these symptoms.

Score mTBI Control P Value
PCSS 21 ± 15> 4 ± 4 .003
PSS 15 ± 6 8 ± 5 .0002
BDI-II 4 ± 6 1 ± 1 Not significant
Symptom composite (Z-score) 2.59 ± 2.02 0 ± .0 .008

“We first looked at the relationship between progesterone levels and the various symptom scores we collected in these subjects and found a relationship between these symptom scores and [higher] progesterone levels, particularly in the PSS,” said Chen.

“Our next step was to look at brain blood flow data to see what areas of the brain had blood flow levels that might be correlated with progesterone levels and perceived stress scores,” she added.

The researchers found a significant three-way relationship between progesterone level, CBF, and perceived stress score in the mTBI group, with the left medial temporal gyrus particularly implicated.

“Higher progesterone was associated with lower (more normative) PSS, as well as higher (more normative) CBF,” the authors report, adding that CBF mediates 100% of the relationship between progesterone and PSS (Sobel P value = .017).

“Because this area has been shown in other studies to be associated with social anxiety disorder and is implicated in face processing, we think this area is somewhat related to stress,” Chen suggested.

Herrold noted that stress is a serious problem for college students who have sustained a concussion because during the recovery period, they may miss classes and fall behind academically. “Trying to keep up with coursework and making up for lost time is extremely stressful,” she said.

Promising Findings

Commenting on the study for Medscape Medical News, David Wright, MD, professor and chair, Department of Emergency Medicine, Emory University School of Medicine, called the finding “interesting but not robust, given the small number of participants — 13 in each group — you really need a lot more patients to validate the finding.”

Wright, who was not involved with the study, said the take-home message is that a prospective study should be conducted to “determine if this effect is real.”

The next step might be to conduct a larger observational study and then “see if the association holds true and, if so, perhaps give progesterone to subjects after a concussion,” Wright suggested.

Chen said, “We think these results are promising and we’re looking forward to replicating these findings in larger scale studies, hopefully with more complicated designs, to look at recovery [from mTBI] over time.”

Funding was provided in part by the Eleanor Wood-Prince Grant Initiative: A Project of the Woman’s Board of Northwestern Memorial Hospital and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NIH). Funding for scanning was supplied by the Warren Wright Adolescent Center (WWAC), Northwestern Memorial Hospital. The authors and Wright have disclosed no relevant financial relationships.

J Neurotrauma. Published online February 24, 2021. Abstract

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