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Why hormone replacement therapy is a boon for brain fog, depression and anxiety

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A flawed study into the use of HRT for menopausal women led to unjustified fears, but now hormones are being used to help reduce midlife brain fog, depression and anxiety.

Some days, when the words she wanted wouldn’t come, Helen Yarrow privately wondered if she was in the early stages of dementia. She’d just turned 50 and the medical receptionist found herself struggling to name even familiar objects. “If I was trying to think of a bench seat, say, I’d be calling it ‘that seat without a back to it’.”

She was too embarrassed to talk to anyone about it, even at work, but she was finally motivated to see her doctor when, at the end of last year, she began waking each day feeling as if she was nursing a terrible hangover even though she doesn’t drink. “I was nauseous and dizzy all morning and felt as if I hadn’t slept at all. I was irritable and grumpy. I just felt lousy. I tried to hide it, but I realised it wasn’t right.”

“It feels hormonal,” she told Dr Mona Ponnen, a women’s health specialist at a South Auckland medical clinic. She was right. Three weeks after starting hormone replacement therapy (HRT) – usually prescribed to treat the physical symptoms of menopause, such as hot flushes and night sweats – her brain fog lifted, along with her mood.

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Yarrow is one of an increasing number of women benefiting from a resurgence in the use of HRT (now called menopausal hormone therapy), after it was wrongly demonised by a poorly reported study from the US Women’s Health Initiative (WHI) in 2002, which linked it with an increased risk of breast cancer and heart attacks.

A lead investigator of the study later admitted the initial results were misleading and distorted for publicity and overstated the harms – generalising results from women over 60 to younger women. It’s now accepted that the treatment is safe and effective for healthy but symptomatic women within 10 years of menopause. In the WHI study, participants were older – in their sixties and seventies – and 90% had no menopausal symptoms.

But specialists say that message is taking longer to get through to women – and primary-care doctors who sometimes persuade women not to have hormone therapy. Ponnen and other specialists say hormone therapy should be used more often by GPs to treat women who have not only the well-recognised symptoms of menopause, but also hormone-linked depression, confusion and anxiety. “They are reluctant to use hormones because they think you are fiddling with nature,” says Ponnen.


A first resort

Auckland reproductive endocrinologist Stella Milsom says that although reanalysis and further data have made it clear that menopausal hormone therapy is “not the devil’s juice”, many primary-care doctors are still too frightened to use it.

“If women are brave enough to see someone, they often don’t get a hearing about it; they are dismissed. One GP says ‘just put up with it’, the next one says ‘it’s dangerous’ and the next one says ‘the symptoms are only going to last a few months’. For symptomatic women, hormone therapy is far and away the most effective treatment, so it should be the first option considered, not the alternatives like painkillers, antidepressants or supplements. There are not many things I do that a woman will come back and say, ‘Thank goodness we did this.’”

She describes the writing and reporting of the WHI paper as “almost negligence”.

“To my mind, it’s the worst thing that’s happened in women’s health over the past couple of decades. The treatment is associated with a very slight risk of breast cancer – but only one extra case for every 1200 women treated each year – no greater than the risk from drinking alcohol or being overweight.

“It’s a very rare risk, but that is not the perception in primary care. The study should have gone to ground years ago, but erroneous messages are still hanging around 17 years later and therefore health professionals need to update themselves with current guidelines so that hormone therapy is not withheld unnecessarily.

“It’s important that women and health professionals understand that, for healthy women with symptoms who are under 60 and within 10 years of menopause, the risks are very small and the benefits are significant. It’s a really miserable business when I see a woman who has taken herself to three different GPs and has been told, ‘No, it’s not for you.’ Hormone therapy can and should be prescribed in primary care and the great majority of women who have symptoms affecting their quality of life are going to get significant benefits, and the risks and short-term side effects (bleeding and breast tenderness) are relatively uncommon and minor.”

Lifting the brain fog: Dr Mona Ponnen, left, and Helen Yarrow. Photo/Rebekah Robinson/Listener


Talking about the issue

On the other hand, Milsom says, hormone therapy is not for all women. It’s not essential, it’s not anti-ageing, it doesn’t need to go in the water supply. There are other options for symptoms if a woman doesn’t want hormones or has contraindications. 

Early in March, researchers from the University of Helsinki published a study in the British Medical Journal that concluded women who used HRT long-term might have a small increased risk of Alzheimer’s disease. They compared the records of 85,000 women who developed Alzheimer’s with the same number of women who did not. Risk varied between a 9% and 17% increase depending on the type and extent of therapy used.

However, some experts pointed out the research could show only possible associations, not cause and effect, and contained no biomarkers or other important clinical or genetic details. They said all HRT guidelines are clear about not starting HRT late in life (for example, after the age of 60), but within 10 years of the transitional perimenopause phase, and that the therapy is safe and effective for most women.

Milsom says the number of referrals she gets from psychiatrists of women seeking help for menopause-related depression and anxiety has significantly increased in recent years. It’s not uncommon for women to have their first serious episode of depression around menopause, or to have existing conditions exacerbated by the reduction in oestrogen levels. Confusion and “brain fog” are also common. Mood symptoms predominate in about 30% of the cases she sees. “Very high-powered women who are used to using their brain in their work every day often find it’s taking them a lot longer to do things, they’re not able to look at accounts or analyse data in the way they once could.”

Although all women will have some changes in hormones, not all women will be symptomatic. “Some will have an absolutely terrible time, others no symptoms at all, and others will be in the middle. It’s like pregnancy, where hormone changes are similar in all women, but the symptoms can be very variable, and we don’t quite understand why that should be.”

Reproductive endocrinologist Stella Milsom. Photo/Supplied

There is no maximum time for women to be on hormone treatment, and when to stop is a consensus between doctor and patient. “Every two or three years I will suggest a patient weans off it and the usual response is, ‘No, thank you, I love being on it and don’t want to stop,’ and I say, ‘Fine’, and I’ll review it again in another year or two. Obviously, if the woman has developed contraindications, I will push the discussion and suggest a non-hormone alternative.”

Auckland psychiatrist Rob Shieff says about 80% of his patients have depression, and a significant majority are women. “It could just be that women have to put up with men … But almost certainly it’s got something to do with circulating hormones; it’s just difficult to know to what degree. But, if you look at complaints of depression across the female life cycle, there’s a spike at puberty, there’s premenstrual dysphoric disorder (PMDD), which obviously has some hormonal contribution, there’s a spike after childbirth, which probably has something to do with hormonal variability, and there’s another significant spike with menopause. So, if you look at the times when hormone flux is likely to happen, they overlap with the periods of greater risk for depression and it’s certainly being noticed more and more.”

Hormonal contributors should be considered early when doctors treat menopausal women, he says. He refers patients to a GP or endocrinologist if they have a lot of perimenopausal symptoms or haven’t responded to the usual treatments. “Some people don’t want to see their GP because they’ve had conversations about HRT that haven’t gone the way they wanted – they’ve been told to avoid it.”

He’s seen patients who have had marked improvement in their symptoms with HRT, although often it’s used alongside psychotherapy or antidepressants. “There’s an awful lot more to menopause than hormone change. It’s a major life step.”

It’s important for women to acknowledge and talk about the issue. “I think some women still feel a degree of embarrassment, humiliation and shame about menopause, as being part of getting old and losing their biological function, so it’s really important for them to feel confident enough to talk about their treatment options, to be clear about their concerns and not having them brushed to one side. If they don’t feel they’ve had appropriate advice, they should see a different health professional.”

Auckland psychiatrist Rob Shieff. Photo/Rebekah Robinson/Listener

Hormone spikes and depression

Professor of psychiatry Jayashri Kulkarni, who founded and directs the Monash Alfred Psychiatry Research Centre in Melbourne, is at the forefront of international research into the effectiveness of hormones in mental-health treatment.

Hormones such as oestrogen, progesterone and testosterone are not just important for reproduction, but are vital brain chemistry drivers, she tells the Listener. “In our clinic, we have many dreadful stories of middle-aged women who have been perfectly healthy, perfectly fine and handling everything well and have had no particular crisis, suddenly developing severe depression and anxiety that doesn’t respond to standard antidepressant therapy.”

She has trialled different hormone strategies at the clinic, and last April she published a paper showing that mid-life women with depression, treated with the menopausal hormone therapy Tibolone for 12 weeks, showed significant improvement. “The use of hormone therapies provides exciting innovations for the treatment of depression during the menopause transition,” she concluded.

In a large-scale trial, published in 2014, Kulkarni’s team showed the oestrogen therapy Estradiol was clinically useful as an adjunct therapy for women with treatment-resistant schizophrenia.

“It’s been really heartening to know that we can actually help women with depression and other [mental-health] conditions by doing hormone treatments rather than going straight to antidepressants. The gonadal hormones – oestrogen, progesterone and testosterone – are critical to good mental health in women because they are potent brain chemicals.”

In women with clear perimenopausal-related depression, it makes sense for doctors to go straight to hormone therapy. “If she says, ‘I was perfectly all right, then I got to 45 and everything fell apart,’ with no other precipitating factors, you’d have to think that this has a hormonal cause. But it doesn’t happen that way because mental-health experts don’t think of hormones. This is the problem with medicine – it depends on the speciality of the person you go to see. A psychiatrist will use antidepressants and other treatments before they think of hormones because that’s an endocrine speciality.”

She urges doctors to “listen to their female patients, because they are often very intuitive about things such as premenstrual depression or the onset of perimenopause – they are very good at picking up even a slight change in function”.

Professor Jayashri Kulkarni. Photo/Supplied

Asked if the hormonal fluctuations that can give rise to mental-health issues may give employers an excuse not to hire women, Kulkarni says women actually have an advantage because oestrogen is a powerful neuroprotective agent, and testosterone is not. “Oestrogen functions in the brain in all kinds of different areas and it also promotes neurocircuit growth, which is important for new learning and memory. Progesterone is important because it can cause depression; it’s the antithesis of oestrogen.

“The women I see are incredible. They are saying, ‘I am functioning at 150mph and it has dropped down to 130mph. I want to get back to my 150, but my male colleagues are probably running at 90.’ It’s almost like performance enhancing, to get her back to where she wants to be. Where the feminists have missed the point is to take the advantage that women have in effective hormone manipulation and run with it.”

 Kulkarni is now focusing on early-life trauma, investigating possible links between hormone disruptions and depression. “We want to know how we can intervene to prevent someone from having a lifetime of depression, and, if she already has depression, how do we optimise her outcomes?”

Early and prolonged exposure to stress and trauma can “prime the pump” of the body’s stress-response system, leaving the flight-or-fight reaction consistently set to “on”.

“She is functioning with usually very high levels of cortisol, because she is constantly chronically stressed. That then kicks on to the gonadal or reproductive hormone axis, because they are very closely tied,” says Kulkarni. “This is the girl who, as she grows older, is very likely to have terrible premenstrual depression, not just a little bit of bloating and discomfort but full-on depression. She is also very likely to have postnatal depression and then perimenopausal depression. The violence done to her becomes integrated into her neurobiology. It doesn’t mean it’s set in concrete, though, because a whole lot of factors affect the neurobiology, including the positive effects of other experiences and her own resilience and good relationships.”

Several studies are under way at Monash into the use of a particular brand of a contraceptive pill as a hormone treatment in women with premenstrual depression and PMDD and early-life trauma.

Here, the use of the pill to treat young women with those conditions is still regarded as a controversial area. Although PMS (premenstrual syndrome) has been recognised for more than 50 years, the more severe PMDD was added to the Diagnostic and Statistical Manual of Mental Disorders only in 2013. Although 20-40% of women will have symptoms of PMS, PMDD is far less common – it’s estimated to occur in less than 6% of women.

Ponnen says she’s seen young women whose PMDD is so bad they almost sequester themselves at home because of their anxiety, low mood, bloating and pain. “They have real dysfunction, as opposed to disorder. They’re tearful, jittery and anxious a lot of the time. If you measured their level of hormones and the next person’s, they would be the same, but they are wired differently so their sensitivity to those hormonal changes is heightened.”

But Milsom says she and many of her colleagues in New Zealand have given up trying to manipulate hormones in women with PMDD and PMS because of the very low success rate. She says many younger women believe their mood swings are related to their period and hormones, but it is not as clear-cut as this. They may be seeing cyclical mood changes that are not related to hormones or periods, and a menstrual diary is a good way of trying to establish if mood relates to the timing of periods.

Manage stress: mental-health nurse practitioner Anna Elders. Photo/Rebekah Robinson/Listener

Hormones driving behaviour

Auckland cognitive behavioural therapist and mental-health nurse practitioner Anna Elders, 39, says she, along with her mother and sister, falls into just this category. “I wouldn’t be surprised if, genetically, a lot of females in my family aren’t predisposed to potentially being more sensitive to hormonal changes. We all recognise that the luteal phase, the two weeks leading up to our periods, was more challenging for all of us. I started to notice challenges when stress really hit, around the time I bought my first home with my husband and life started to get real. I remember talking to my husband and offloading and he didn’t have the emotional comeback that I hoped and I just lost it. I felt extremely upset, extremely irritated and I almost had an out-of-body experience. Looking back now, I can almost guarantee where I would have been in my cycle.”

She’s diagnosed herself with PMDD after tracking her cycles for some time. “I have no doubt that if I saw a clinician about it, they would agree.” She believes about half the women she treats for mental-health issues have a “hormonal component”. They’re having painful, irregular or a lack of periods or have noticeable deterioration in their moods, coupled with anxiety and irritability in the two weeks beforehand.

“One lovely woman came to see me as she was experiencing guilt and shame at her behaviour during her luteal phase. She cried and hugged me when I told her there was a specific condition that she had that explained the Jekyll and Hyde behaviour. That saddens me, because that woman wasn’t young – around my age – and she had spoken to clinicians before and no one had dug enough to identify what she was going through. It was such a relief to her to think it wasn’t something wrong with her personality and that it was hormones driving some of this behaviour.”

One of the cornerstones of Elders’ therapy is stress management. “Women are spinning more plates, and the more plates we spin, the more we put strain on our bodies. We know we can prescribe oral contraceptives and antidepressants to women struggling with mood changes and stress, but they are not necessarily fixes that are going to support women longer term. It’s about looking at lifestyles, diet, gut health, stress levels, life balance and self-esteem.”

Women’s hormonal symptoms are often normalised by doctors, she says. “If PMS or PMDD were conditions that men had, we would have found a successful treatment for them by now, but they’re only just being recognised as significant or abnormal. How often have women been told that cramping, heavy periods or mood changes are normal? It has meant it hasn’t been taken seriously and women have had to suffer.”

Lost in a foreign land

Personal coach Megan Van Lieshout, who runs courses on women’s mind health in South Auckland, many of which attract mid-life “empty nesters”, says hormones play a big part in their challenges around that age. Perimenopausal women make up about 70% of her clientele.

“A lot of the time when we hit pre-menopause, we think we are going crazy and we have no idea what’s happening. When you open up to other women and say you feel like you’re on a roller coaster of all kinds of emotions and physical symptoms, they’ll say, ‘Thank God I’m not the only one suffering all these crazy hormonal changes.’ They feel stuck or lost or they’ve fallen out with their friends. They say they feel as if they’ve turned into this person in a foreign land, that they don’t understand themselves any more because they’ve become a hormonal mess.” She invited Mona Ponnen to speak at some of her workshops. “I realised how many women out there were freaking out because they are too scared to ask [for help].”

Helen Yarrow, just a few months on from the medical consultation that changed her life, is thrilled with how she feels now, thanks to the tiny, transparent – and fully funded – oestrogen patch on her bikini line. Like many other women, she was alarmed at first about the thought of hormone therapy. “I thought it was this big no-no, the cancer-causing thing, but Mona said that was disproved years ago. It’s simply oestrogen and when you think about it, you’re just replacing what’s dropped off in your body and I thought, ‘How can it be bad?’ The change was big and quick. For me, there is no downside – I just love it. I feel normal, my head is clear, and words don’t escape me.”

This article was first published in the March 23, 2019 issue of the New Zealand Listener.