According To A Recent Animal Study, Estrogen Enables Females To Respond Better To Stress

Dr. Enrique Jacome

The idea that females are more resilient than males in responding to stress is a popular view, and now University at Buffalo researchers have found a scientific explanation. The paper describing their study is published online in the high-impact journal, Molecular Psychiatry.

"We have examined the molecular mechanism underlying gender-specific effects of stress," says senior author Zhen Yan, PhD, a professor in the Department of Physiology and Biophysics in the UB School of Medicine and Biomedical Sciences. "Previous studies have found that females are more resilient to chronic stress and now our research has found the reason why."

The research shows that in rats exposed to repeated episodes of stress, females respond better than males because of the protective effect of estrogen. In the UB study, young female rats exposed to one week of periodic physical restraint stress showed no impairment in their ability to remember and recognize objects they had previously been shown. In contrast, young males exposed to the same stress were impaired in their short-term memory.

An impairment in the ability to correctly remember a familiar object signifies some disturbance in the signaling ability of the glutamate receptor in the prefrontal cortex, the brain region that controls working memory, attention, decision-making, emotion and other high-level "executive" processes.

Last year, Yan and UB colleagues published in Neuron a paper showing that repeated stress results in loss of the glutamate receptor in the prefrontal cortex of young males.

The current paper shows that the glutamate receptor in the prefrontal cortex of stressed females is intact. The findings provide more support for a growing body of research demonstrating that the glutamate receptor is the molecular target of stress, which mediates the stress response. The stressors used in the experiments mimic challenging and stressful, but not dangerous, experiences that humans face, such as those causing frustration and feelings of being under pressure, Yan says.

By manipulating the amount of estrogen produced in the brain, the UB researchers were able to make the males respond to stress more like females and the females respond more like males.

"When estrogen signaling in the brains of females was blocked, stress exhibited detrimental effects on them," explains Yan. "When estrogen signaling was activated in males, the detrimental effects of stress were blocked.

"We still found the protective effect of estrogen in female rats whose ovaries were removed," says Yan. "It suggests that it might be estrogen produced in the brain that protects against the detrimental effects of stress." In the current study, Yan and her colleagues found that the enzyme aromatase, which produces estradiol, an estrogen hormone, in the brain, is responsible for female stress resilience. They found that aromatase levels are significantly higher in the prefrontal cortex of female rats.

"If we could find compounds similar to estrogen that could be administered without causing hormonal side effects, they could prove to be a very effective treatment for stress-related problems in males," she says. She notes that while stress itself is not a psychiatric disorder, it can be a trigger for the development of psychiatric disorders in vulnerable individuals.

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Study Shows Estrogen-Only Therapy After Hysterectomy May Be A Lifesaver

Dr. Enrique Jacome

The widespread rejection of estrogen therapy after the 2002 Women's Health Initiative (WHI) study has most likely led to almost 50,000 unnecessary deaths over the last 10 years among women aged 50 to 69 who have had a hysterectomy, Yale School of Medicine researchers reveal in a study published in the American Journal of Public Health.

Led by Philip Sarrel, M.D., emeritus professor in the Departments of Obstetrics, Gynecology & Reproductive Sciences, and Psychiatry, the researchers analyzed United States census data, hysterectomy rates, and estimates of decline in hormone use in women aged 50 to 59 between 2002 and 2011.

Before 2002, it was standard practice for doctors to recommend estrogen therapy for this slice of the population, and more than 90% of these women used it to treat symptoms such as hot flashes, and to prevent osteoporosis and other diseases related to menopausal hormone deficiency. Today, about 10% of these women use estrogen.

This sharp decline in estrogen usage was linked to results from one part of the large, federally funded WHI study in 2002. Women and their doctors became frightened of the dangers of post-menopausal hormones. But according to Sarrel and his colleagues, this was a report about women with a uterus, who took pills that combined estrogen and a progestin. Women who have a uterus must take a second hormone (a progestin) to avoid a risk of uterine cancer. But these results did not apply to women with no uterus who use estrogen-only therapy.

"Sadly, the media, women, and health care providers did not appreciate the difference between the two kinds of hormone therapy," Sarrel said. "As a result, the use of all forms of FDA-approved menopausal hormone therapy declined precipitously."

Sarrel added that for the women taking combined hormone therapy (at least the particular drug, Prempro, used in the WHI study), it was probably a good decision to avoid it because the WHI study showed a significant increase in breast cancer, heart disease, stroke, and blood clots in women who used this drug compared to placebo. However, for the women taking estrogen-only therapy, avoiding treatment does not appear to have been a good decision.

Results from the second part of the WHI study, which followed women who had no uterus and who took either estrogen-only or placebo, were very different. A series of papers published by the WHI between 2004 and 2012 showed that estrogen-only therapy had mostly positive health outcomes. For example, in 2011 and 2012 the WHI reported that women who received estrogen compared to those who received placebo had fewer deaths each year for 10 years and were less likely to develop breast cancer and heart disease. For each of the 10 years the death rate among those not taking estrogen was 13 more per 10,000. Most of these women died from heart disease while breast cancer accounted for almost all the other deaths.

"Estrogen avoidance has resulted in a real cost in women's lives every year for the last 10 years - and the deaths continue," said Sarrel. "We hope this article will stir an overdue debate and raise consciousness about the health benefits of estrogen-only therapy for women in their 50s with no uterus."

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Analysis Shows Calcium And Vitamin D Help Hormones Aid Bones After Menopause

Dr. Enrique Jacome

Should women take calcium and vitamin D supplements after menopause for bone health? Recommendations conflict, and opinions are strong. But now, an analysis from the major Women's Health Initiative (WHI) trial throws weight on the supplement side - at least for women taking hormones after menopause. The analysis was published online in Menopause, the journal of The North American Menopause Society.

Among the nearly 30,000 postmenopausal women in the hormone trial, some 8,000 took supplemental calcium (1,000 mg/day) and vitamin D (400 mg/day), and some 8,000 took look-alike placebos. These women came from all the hormone groups in the study - those who took estrogen plus a progestogen (required for women with a uterus), those who took estrogen alone, and those who took the hormone look-alike placebos. The researchers looked at how the rates of hip fracture differed among women who took hormones and supplements, those who took hormones alone, and those who took neither. 

The supplements and hormones had a synergistic effect. Women using both therapies had much greater protection against hip fractures than with either therapy alone. Taking supplements alone wasn't significantly better than taking no supplements and no hormones. The benefit of hormone therapy was strong in women who had a total calcium intake (supplements plus diet) greater than 1,200 mg/day. Similarly, the benefit was strong in women who had higher intakes of vitamin D, but the individual effect of each one could not be determined because the two supplements were given together. 

The effects translated into 11 hip fractures per 10,000 women per year among the women who took both hormones and supplements compared with 18 per 10,000 women per year among those who took hormones only, 25 per 10,000 women per year among those who took supplements alone, and 22 among those who got neither therapy. 

These results suggest, said the authors, that women taking postmenopausal hormone therapy should also take supplemental calcium and vitamin D. Although they couldn't specify how much, they noted that the benefits seem to increase with increasing total intake of calcium and vitamin D. The dose will depend on keeping side effects, such as constipation from too much calcium, to a minimum, they said. 

That differs from the recommendation of the US Preventive Services Task Force (USPSTF), made earlier this year. USPSTF stated there was no basis for recommending calcium and vitamin D supplements to prevent fractures. But now, with this study, there may well be.

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Study Shows Hormone Levels Are Linked To Female Psychological Disorders

Dr. Enrique Jacome

Women are more susceptible to some of the psychological effects linked to stressful experiences at specific stages in their monthly menstrual cycle, scientists from University College London reported in Neurobiology of Learning and Memory.

The authors believe common mental health problems that develop in women might be prevented if specific dates during the menstrual cycle are targeted. They say their study is the first to demonstrate a possible association between psychological vulnerability and a specific moment during the menstrual cycle - which in this case was ovulation.

Repetitive and undesirable thoughts

Repetitive and unwanted thoughts are common symptoms of mood and anxiety disorders. These intrusive thoughts typically occur after a stressful experience; sometimes for a few days, and even weeks or longer.

Dr Sunjeev Kamboj and team set out to determine how vulnerable women are to a stressful event during different stages of their menstrual cycle. The study involved 41 females aged from 18 to 35 years. They all had regular menstrual cycles, and none of them were on the contraceptive pill.

Each participant was asked to watch a 14-minute "stressful" movie which contained death or injury. Saliva samples were taken immediately afterwards so that their hormone levels could be assessed. They were then asked to write down whether they had unwanted thoughts about the video over the next few days, when they had them, and how often.

Intrusive thoughts more common during the early Luteal phase

Sunjeev Kamboj said:

"We found that women in the 'early luteal' phase, which falls roughly 16 to 20 days after the start of their period, had more than three times as many intrusive thoughts as those who watched the video in other phases of their menstrual cycle. This indicates that there is actually a fairly narrow window within the menstrual cycle when women may be particularly vulnerable to experiencing distressing symptoms after a stressful event."

The researchers say that their findings may influence how health care professionals deal with mental health problems in females, especially those who have suffered trauma.

Dr Kamboj said:

"Asking women who have experienced a traumatic event about the time since their last period might help identify those at greatest risk of developing recurring symptoms similar to those seen in psychological disorders such as depression and post-traumatic stress disorder (PTSD).

This work might have identified a useful line of enquiry for doctors, helping them to identify potentially vulnerable women who could be offered preventative therapies.

However, this is only a first step. Although we found large effects in healthy women after they experienced a relatively mild stressful event, we now need to see if the same pattern is found in women who have experienced a real traumatic event. We also need further research to investigate how using the contraceptive pill affects this whole process."

Studies have linked phases of the menstrual cycle to several mental and physical issues, including:

• Severity of respiratory symptoms - researchers from Norway reported in the American Journal of Respiratory and Critical Care Medicine that a female's respiratory symptoms may be affected by her menstrual cycle, including asthma symptoms. They tend to get worse during the mid-luteal to mid-follicular phases.


• Premenstrual syndrome - symptoms of PMS (premenstrual syndrome) are usually worse for women who feel stressed early on during their menstrual cycle, a team from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the University of Massachusetts-Amherst, and the State University of New York, Buffalo, reported in the Journal of Women's Health.


• Knee injuries - researchers from the University of Texas-Austin, and the University of North Carolina-Chapel Hill, suggest that changes across the menstrual cycle in nerves that control muscle activity make female athletes more susceptible to knee injuries, especially anterior cruciate ligament tears and chronic pain. They believe knee injuries are closely linked to the menstrual cycle.


• Impulsive spending - as their monthly period approaches, women's spending tends to become more impulsive and less controlled. A team from the University of Hertfordshire, England, reported at the British Psychological Society Annual Conference (April 2009) that hormonal fluctuations may lead to women spending more than they can afford, buying stuff they do not really want, and feeling out of control with money.

www.vivenaturalhormones.com