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Could your hormonal contraceptive be affecting your anxiety treatment?

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Kay Harrison
Kay Harrison,

Contraception that suppresses female sex hormones may reduce the success of therapy for conditions like spider phobia and claustrophobia, says a psychology researcher from UNSW Sydney.

A UNSW psychologist has launched a clinical trial that will examine how responses to treatment for claustrophobia vary in women using hormonal contraception. The trial builds on earlier research that found women taking hormonal contraceptives predicted a poorer response to treatment for spider phobia.

“Women are almost twice as likely to develop anxiety as men; they experience more severe and long-lasting symptoms, yet we know little about what drives this sex imbalance,” says Professor Bronwyn Graham from the Faculty of Science. “My research points to the strong biological role for sex hormones.”

Anxiety disorders are the most common class of mental illness in Australia. Anxiety disorders, such as panic attacks, phobias and post-traumatic stress, cause worry, fear and avoidance that interferes with daily activities. More than one in three Australian women and one in five men will experience an anxiety disorder in their lifetimes.

Women’s increased prevalence seems to emerge after puberty and cease post-menopause, says the award-winning researcher. “There are also notable increases [of occurrence] during periods of hormonal fluctuation [such as following childbirth] that indicate a relationship between sex hormones and the development and management of anxiety disorders,” she says.

The study in claustrophobia, funded by the Liptember Foundation, will compare the treatment responses of women cycling naturally with women taking different hormonal contraceptives. Participants will undergo one hour of exposure therapy – “for phobias, we have good evidence that ultra-brief treatments are just as effective” – then attend a follow-up one month later to test the treatment’s longevity.

Sex hormones fluctuate across a woman’s menstrual cycle and her reproductive lifespan. Additionally, more than 26 per cent of reproductive-age women (15-49 years old) – more than 248 million women globally – use hormonal contraceptives that alter their natural sex hormone levels. These hormones play a significant role in both regulating our emotions and in the neural processes involved in exposure therapy, the number one psychological treatment for anxiety, Prof. Graham says.

Exposure therapy, the gradual exposure to things, situations and activities that cause fear, relies on our ability to form ‘fear extinction memories’, or memories in which our feared outcome doesn’t eventuate.

“Anxiety occurs because people over-predict both the likelihood and the cost of danger. Exposure therapy helps people learn new beliefs and form new memories that, in fact, when they are in these anxiety-provoking situations, they're quite safe, and they cope quite well,” she says. “The molecular machinery that the brain requires to lay down a new memory, including extinction memories, depends on [the hormone] estradiol.”

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Everything we know about the way that the brain processes anxiety and how the brain works to control that anxiety comes from the male brain. Despite the increased prevalence of anxiety disorders in women, most clinical trials do not conduct even a cursory examination of differences in male and female responses to anxiety treatment for safety or efficacy.
Prof. Bronwyn Graham

Estradiol is the main form of estrogen during a woman’s reproductive years. It’s made naturally in the ovaries and is crucial to regulating the menstrual cycle, cardiovascular system, neurologic system, skeletal system and the vascular system. Research with rats and early clinical research with humans is also examining how it helps regulate emotions.

“Studies with female rats have shown they are dependent on estradiol to regulate fear,” she says. High levels of estradiol have been associated with reduced activity in the amygdala, the place where our emotions are processed, and linked to other brain abilities, including memories and learning, Prof. Graham says.

“[These high levels] are increasing activity in the pre-frontal cortex, which is that part of the brain that is really important for top-down emotional regulation. That’s the part of the brain that we need to be engaged if we are to have control over our emotions and our behaviours.”

Both broad classes of hormonal contraception suppress estradiol to some degree. The combined oral contraceptive pill, or ‘the pill’, uses synthetic estrogen and progesterone to chronically suppress the sex hormones to prevent ovulation. Progestin-only contraceptives, such as the mini-pill, intrauterine devices (IUDs) and implants (Nexplanon or Implanon), use synthetic progesterone to thicken the mucus lining the cervix, making it impenetrable.

“While women taking progestin-only contraceptives have significantly higher levels of estrogen and progesterone relative to women on the pill, progestin-only contraceptives can also interfere with ovulation, affecting hormone levels – just in a less consistent way,” she says.

Women on hormonal contraception experience poorer response to treatment for spider phobia

Prof. Graham’s earlier research found that, compared to women cycling naturally, women on hormonal contraception had a reduced response to treatment for spider phobia. While they did experience some decline in symptoms, “they were declining at a slower rate and over time they showed more [propensity to] relapse”.  

Participants took part in a single session of exposure therapy, building from interacting with a baby St Andrew’s Cross spider – catching it in a jar, touching it, having it walk on their arm – to an adult Huntsman. “We call the spiders-on-the-face [option] overlearning. You don't have to do it. But for people who feel like they can, and they want to challenge themselves, they do that, and typically feel a huge sense of accomplishment,” she says.

The study did not differentiate between types of hormonal contraceptives and effectiveness – however, a post-hoc analysis comparing the pill, IUD and implants suggested women on the pill performed the worst.

“[By contrast,] women who received treatment during phases of peak estradiol, such as ovulation, showed faster rates of symptom decline and less long-term relapse than women who received treatment during low estradiol phases, such as during menstruation,” she says. Increased levels of estradiol during treatment may also improve our ability to recall fear extinction memories.

The upcoming study in claustrophobia, with its larger sample size, will determine whether these findings are applicable to anxiety treatment more broadly. This would help optimise treatment outcomes: by timing treatment during peak estradiol periods (for women cycling naturally); and by ascertaining which hormonal contraceptives are more compatible with treatment (for women taking hormonal contraceptives).

A lack of female animals in medical research affects treatment efficacy and safety

Medicine is based on animal models; the vast majority of non-human animal research on the brain uses male animals. “Everything we know about the way that the brain processes anxiety and how the brain works to control that anxiety comes from the male brain,” Prof. Graham says. “Despite the increased prevalence of anxiety disorders in women, most clinical trials do not conduct even a cursory examination of differences in male and female responses to anxiety treatment for safety or efficacy.”

Prof. Graham says this ongoing historical bias is based on the assumption there are no sex differences – and the belief that you can study conditions in males and the findings will equally apply to females. Reproductively mature female animals are also avoided in research because they introduce additional variables – or “noise” – into the data due to what she calls the “big black hole of the menstrual cycle” that make findings more difficult to interpret, she says.

“However, there has been a lot of research published to suggest males are just as variable as females. Males have hormones too. Male hormones also fluctuate daily.”

The result is that many treatments are not effective for women. Women are 1.5 times more likely to experience adverse reactions to drugs and vaccines than men. Eight out of 10 drugs removed from the market are due to the adverse reactions of women. These include many drugs that worked well for men.

“Developing sex-specific models of the causes, consequences and accompanying conditions of anxiety disorders will improve the safety and efficacy of treatment for both women and men. This would help reduce the prevalence of this common and costly disorder,” she says.

If you are interested in participating in the study on claustrophobia, please contact Prof. Graham.