Research Efforts Focus on Link Between Hormonal Contraceptives and HIV Infection

Source: Brigham and Women's - On a Mission
Date: 02/20/2019
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According to the World Health Organization, more than half of all married or in-union women of reproductive age use some form of contraception. Additionally, the number of women around the globe who either use contraception or have an unmet need for family planning is expected to grow by more than 900 million over the next decade.

One popular form of birth control is injectable hormonal contraceptives, predominantly the progestin-only form known as depot medroxyprogesterone acetate (DMPA, Depo-Provera®). Yet growing evidence has linked this form of contraception to an increased risk of HIV acquisition and transmission. Researchers at Brigham and Women’s Hospital are focused on determining the underlying causes for this connection and getting the word out about this important public health issue, which affects both women and men.

“This situation is particularly concerning because DMPA is the most commonly used contraceptive method in sub-Saharan Africa, the region that bears an estimated 70 percent of the global HIV infection burden,” said director of the Laboratory of Genital Tract Biology at Brigham and Women’s Hospital and Harvard University. “Our research provides a biologic explanation for the risks and variations in vulnerability to the potential adverse effects of hormonal contraception.”

Work coming out of Dr. Fichorova’s lab also has contributed to the understanding of inflammation and dysbiosis in women and newborns. Other research has looked at how bacteria, protozoan parasites and viruses act in concert to modify human host immunity. In 2018, Dr. Fichorova’s team received an Innovation Award from the Brigham Research Institute to translate their research and recently filed inventions into a novel live biotherapeutic for treatment of vaginal dysbiosis to prevent these conditions.

For the past five years, much of Dr. Fichorova’s research has focused on understanding how and why certain types of hormonal contraceptives change a woman’s biological defenses against infections—and HIV infection in particular. “If we can unveil the molecular pathways that lead to a predisposition to infection, we can discover novel drug targets for preventive medicine,” she said. “At the same time, we hope to lift a significant barrier to the rational design of new, safer contraceptive technologies.”

In one study, Dr. Fichorova and her colleagues analyzed cervical swabs and other data taken from more than 800 women enrolled in family planning clinics in Uganda and Zimbabwe. A major finding was that DMPA was associated with cervical immune imbalance and biomarkers of inflammation that were also associated with higher risk of HIV seroconversion in these women in the next three months.

The team also found higher shedding of HIV in those who seroconverted, thus suggesting pathways for both higher acquisition and transmission of the virus. They showed that DMPA had even broader immune-suppressive effects when acting on the background of abnormal vaginal microbiota characterized by lower abundance of lactobacilli and overgrowth of potentially pathogenic residential bacteria, a condition most often diagnosed as bacterial vaginosis. The data suggested that not only sexually transmitted infections such as herpes but also non-sexually transmitted reproductive tract infections and dysbiosis can make women more vulnerable to the side effects of DMPA.

To a lesser extent, changes in the cervical immune environment were also found in women taking a type of oral contraceptive where another synthetic progestin (levonorgestrel) was combined with synthetic estrogen.

Dr. Fichorova’s lab also has brought to the spotlight the fact that certain species of lactobacilli act as a sentinel of good health in the female reproductive tract, emphasizing the importance of treating conditions that are not sexually transmitted, such as bacterial vaginosis and yeast infections. Non-sexually transmitted vaginal bacteria prevalent in bacterial vaginosis can ascend to the uterus and cause placental epigenetic changes and systemic perinatal inflammation, leading to serious adverse reproductive and child health outcomes.

“Research enabling the design of safer contraceptive technologies is urgently needed. Women of reproductive age should not have to face impossible choices between preventing an unplanned pregnancy and preventing a devastating infection,” Dr. Fichorova concluded. “Understanding, properly diagnosing and treating non-sexually transmitted vaginal dysbiosis should be promoted as a powerful tool for prevention of contraceptives’ side effects as well as adverse pregnancy outcomes.”

Guidelines on Perimenopausal Depression Recognize Vulnerable Time in Women’s Lives

Source: Brigham and Women's Hospital - On a Mission
Date: 02/07/2019
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Perimenopausal mood changes and depression are experienced in some form by about one-fourth of women undergoing the transition to menopause. Yet until recently, there was no formal direction for healthcare providers in identifying and treating this condition. That changed in September 2018, when a panel led by the National Network of Depression Centers with the support of the North American Menopause Society published the first-ever guidelines.

“The three main hormonally linked mood conditions in women are postpartum depression (PPD), premenstrual syndrome (PMS) and perimenopausal depression,” said Hadine Joffe, MD, MSc, a psychiatrist and executive director of the Connors Center for Women’s Health and Gender Biology and vice chair of psychiatry research in the Department of Psychiatry at Brigham and Women’s Hospital. Dr. Joffe also served on the task force that developed the new guidelines. “PPD and PMS have been well-studied, but much less is known about perimenopausal depression than the other two,” she added. “Until now, there hasn’t been any guidance for clinicians in recognizing this as a vulnerable period in a woman’s life.”

Dr. Joffe explained that one reason for difficulty in identifying perimenopausal depression is that the period of risk usually stretches over several years and may not be immediately recognized, in comparison to a regular, cyclical event such as PMS or the distinct experience of giving birth. “Perimenopause is more nebulous,” said Dr. Joffe, who also is director of the Women’s Hormone and Aging Research Program. “Perimenopause lasts on average about four years. It’s hard to be able to pinpoint depression that arises during this time and say, ‘Aha, this is definitely hormonally linked.’”

Dr. Joffe’s research focuses on whether perimenopausal depression is a result of changes in reproductive hormones and/or common menopause symptoms such as hot flashes and insomnia. She also studies how to treat menopause-related symptoms, including the efficacy of hormonal and nonhormonal interventions for this constellation of symptoms. Last year, she co-authored the JAMA Psychiatry editorial, Should Hormone Therapy Be Used to Prevent Depressive Symptoms During the Menopause Transition?

The new guidelines for perimenopausal depression aim to help by providing information for healthcare providers. They focused on five main areas:

  • Epidemiology of depressive symptoms and depressive disorders
  • Clinical presentation of depression
  • Therapeutic effects of antidepressant medications
  • Effects of hormone therapy
  • Efficacy of other therapies, such as psychotherapy, exercise and natural health products

As members of the Brigham’s Women’s Mental Health Division, Dr. Joffe and colleagues focus on addressing the needs of women with depression and other mental health problems related to pregnancy, postpartum, PMS, perimenopause and other hormonal changes. These guidelines will be incorporated into their clinical practices and their teaching of medical students and psychiatry residents, many of whom are interested in women’s mental health and seek this expert knowledge for their future practices.

This Brigham team also trains others through a one-year dedicated Women’s Mental Health Fellowship. Working with Dr. Joffe, trainees are taught to recognize and treat perimenopausal depression. This training is part of a unique fellowship that provides highly expert and comprehensive training across the field of women’s mental health. Dr. Joffe also lectures on the topic at national meetings and local continuing medical education courses.

The most common symptoms of perimenopause are hot flashes and sleeping difficulties — not depression. But Dr. Joffe’s research has shown that women who experience the former issues are more susceptible to developing mild symptoms of depression, especially because lack of sleep can contribute to mood disorders.

Most women with mood changes during perimenopause have milder symptoms that do not constitute a full-blown mood disorder episode. However, a smaller group develops major depression during perimenopause. Those women generally have a history of depression, Dr. Joffe said. For these women, she added, it’s important to recognize perimenopause as a period of vulnerability for recurrence. Furthermore, physicians who treat these patients should monitor them more closely during perimenopause and should be careful about withdrawing treatment when women may be more vulnerable.

Dr. Joffe emphasized another important reason for creating guidelines: offering relief for those who are suffering. “The good news is that this condition is hugely treatable, once we recognize that it’s happening. It’s also important to recognize that this is a limited period of vulnerability and that the need for treatment passes once the woman passes through menopause and all the hormone changes settle down in postmenopause.”

For mild depression that is related to the hot flashes and sleep problems caused by hormone fluctuations, the task force noted that hormone therapy may be a beneficial approach for many women, particularly those with concomitant vasomotor symptoms, although estrogen therapy is not approved for this use. “If the depression is more severe or a recurrence of an earlier incident of depression,” Dr. Joffe concluded, “the best treatment is likely to be more traditional approaches, such as antidepressants and psychotherapy.”