Hormonal contraception and mood disorders

And I just think if we even get that message across, then we've done a lot to actually help women who have been saying for a long time, it's my hormones doc and not really being heard. And I think that's a really critical factor here.

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There is an almost dizzying array of different formulations of hormonal contraception that are available for use in Australia. They contain either progestogen alone or a combination of both oestrogen and a progestogen. Of the combined products, the most popular is an oral pill, commonly called the pill, but there's also an intravaginal ring available. The progestogen-only options are a bit more broad and we've got more choice. They include oral pills, IUDs, a subcutaneous implant, or an IM injection. Hormonal contraception is highly effective and can also bring non-contraceptive benefits for patients who use them. But as with any medication, those benefits need to be weighed against any potential adverse effects. And when it comes to hormonal contraception, one of these considerations is the effects the hormones involved may have on mood. My name is Dr Laura Beaton, and I'm a GP in Melbourne and your host for this episode. I am delighted today to be joined by Professor Jayashri Kulkarni to discuss her recent article in Australian Prescriber, titled ‘Hormonal Contraception and Mood Disorders’. Professor Kulkarni is the Director of the Monash Alfred Psychiatry research center. Jayashri, welcome to the Australian Prescriber Podcast.

Thank you for inviting me.

Jayashri, I was wondering if you could briefly explain to our listeners what effects oestrogen and progesterone have on mood?

What we've known for some time from our animal studies and so on is that oestrogen, progesterone, testosterone and their precursors are very, very potent neurosteroids. They influence neurochemistry brain function and brain circuitry, and the way that people can behave, the mood, cognition, all the emotional gamut of things, in a very, very significant way. So it really is important to consider that body and brain are all working together. So it does mean that we've got special considerations of the roles that oestrogen and progesterone, for example, play on the neurotransmitters that we are aware of that are particularly significant in the development of depression and other mood disorders, such as dopamine, gamma-aminobutyric acid, serotonin and other systems.

And when we look at where in the brain the oestrogen receptors are, they're widely distributed. I'm saying oestrogen because we do tend to know a little bit more about oestrogen than we do progesterone at this point. But nonetheless, both of those hormones and testosterone very, very widely spread receptor systems. So in the hypothalamus, the hippocampus, the amygdala in the brain stem, all the particularly potent brain regions that have influence in governing mood, cognition and behaviour, we can particularly understand that the very rich network of oestrogen and progesterone are going to interact strongly with the neurotransmitters and therefore influence cognition, emotion and behaviour.

Can you explain how the effects on mood might be different when say an oestrogen or progesterone are given exogenously like for contraception compared to the physiological changes that happen?

Millions of women around the world use hormones, and they're particularly estradiol or oestrogen compounds and the progestin compounds, for contraception, and then also as they get older for menopause symptom management. So while the particular oral and other types of delivery systems of these hormones is very, very important in enabling women to have control over their fertility and therefore family planning, what we have not been good at until more recently is actually understanding the full effects of the different types of oestrogen, the different types of progestins, on mood, behaviour and cognition. It's been a bit of a miss in terms of clinical trials, which of course focused on the safety of the hormone and also the dosing and the delivery types. And of course, the efficacy for ceasing ovulation or making implantation not possible.

However, there's this whole other area, which when we think about the brain effects of these potent neurosteroids, we need to be very careful because there are different effects. We talk about the pill as if it's one thing, which it certainly is not. There's lots and lots of different types. Contraception is now available in intrauterine device formats, and also as implanted devices under the skin and so on. So with all this vast array, I just make a plea that when we have a patient in front of us, particularly somebody who's vulnerable for mental health issues, that is she's already had depression or something else to disturb her mental health, or she has a strong family history, or she's had experiences of changes in her mental health, when she's taken various compounds for contraception, that we listen to all of that and factor that into our consideration for her next contraceptive prescription.

I agree, a lot of these conversations, they take a really long time and the more time we spend with the patient understanding them, their goals, and also their history means we probably have a much better chance of giving them options to choose from that are much more likely to suit them. And I guess I was interested that you mentioned, we probably understand a little bit more about the role that oestrogen's playing in the brain compared to maybe the synthetic progestins. Why do we know more about the oestrogen components than the progestins?

Well, first of all, I mean, I think that the whole area needs a lot more research. So we're sort of still behind in more understanding of this and certainly behind with clinical trials. So the whole area is really ripe for more research. But the animal research and also perhaps the clinical imaging researchers have focused more on estradiol because it's a little bit easier to understand the impact in the dosing that estradiol is usually used in clinical practice. There's not that much variation. With the progestins or the progestogens, there's a lot more variation in the impact on the various neurotransmitter systems, depending on the dose of the synthetic compound. And there is a lot more variation in the types of progestins that are out there, either in the so-called mini pill, which is the progestin-only preparation, or even in the different types of oral contraceptives with the combined oestrogenic and progestin compounds.

And by and large, most people in the neuroscience field would give you a blanket statement that oestrogens appear to be neuroprotective. Clinically the premenstrual phase when women have lower oestrogen and then also the menopause transition, when eventually there's a decrease in the circulating estradiol in the brain, seem to be worse for vulnerable women in terms of their emotionality, cognition and behaviour.

This is a minority we are talking about. And by and large, if we're going to be very simplistic, oestrogen seems to be neuroprotective. The progestins we have to be careful with and we do worry about some of the older progestins, norethisterone, levonorgestrel appear to not be as protective or in fact can actually, in some situations, again in the vulnerable woman, worsen depressive conditions. We have been searching in our other studies for what is a better progestin for the mental health of women. And so far nomegestrol acetate appears to be quite a good one. And of course there are new products coming on the market which need to be investigated.

I certainly love that you mentioned that for many of these recommendations, we're talking about subsections of a population and women are not a homogenous group of people.

Yeah, absolutely. I'm proud of the fact that many women are very, very good at knowing their own bodies. And so when somebody says to me, look, when I was on this pill, I really felt just not right. I just couldn't experience anything great in life. I couldn't experience the highs and I was really irritable and I was cranky, but when I went off it, wow, I came back to being myself. Then I want to urge the psychiatrists out there, it's important to actually ask the younger woman who's of reproductive age, if she's changed her contraception recently, or what has she noticed, as another factor in the presentation for a major depressive illness.

And on that, when taking a history of somebody, I wonder when you're trying to differentiate the sort of the different cohorts of women who are in front of you, and because for many people, hormonal contraception may be mood neutral. It may in fact, precipitate a depressive episode or anxiety symptoms and it worsens mood. What are the key questions that you ask to try to determine apriori whether or not hormonal contraception is more likely to be neutral, beneficial, or potentially likely to cause some side effects in a woman?

I think that the key factors that we really look for in our clinical work is to ask about the history of depression, to ask about a particular history of depression when the person has taken a particular type of contraceptive or hormone contraceptive. And also we ask very carefully about a history of premenstrual depression, or cyclical depression. So we take that into account because what that's telling us is there's a sensitivity in this woman to the fluctuations in her cycle. We also look for, if there's been a history of postnatal depression or postnatal mental health changes.

And the other factor which we are finding more and more in clinical practice is the presence of early life trauma. And what we look for is the story of emotional deprivation or emotional abuse or cold, rejecting early life experiences for the woman by her primary carers, then any history of physical abuse or sexual abuse in early life and later life. Because we are hypothesising and working on what is happening in the brain of this young girl who has this kind of early life trauma leading to brain chemistry and brain hormone changes from an early stage with a cascade down from the cortisol and hypothalamic pituitary adrenal axis into the hypothalamic pituitary gonadal axis and so on.

For women who have had a pregnancy before, do you ever find that it's helpful to understand, some people have found that, many of their menstrual mood symptoms were completely gone during pregnancy and for others, that was a very vulnerable time. Do you ever include their experiences of pregnancy or breastfeeding as part of your history?

We go into all of these areas because I'm looking for hormonal clues and pregnancy's a big one, of course. I do find a very interesting phenomenon of the kind of sudden onset premenstrual depression in women who are at post baby number three. Haven't had any hormonal problems up to there and then all of a sudden things sort of seem to go a bit pear shaped and then there's a resettling of the HPG axis after about six months to a year. I've seen that pattern a lot. We have some interesting patterns that are emerging, but it's fascinating to think that the gonadal hormonal axis is a critical one in mental health. And I just think if we even get that message across, then we've done a lot to actually help women who have been saying for a long time, it's my hormones doc and not really being heard. And I think that's a really critical factor here.

And I guess with that in mind, you mentioned also that some of the difficulties of understanding this area include that there are lots of extraneous factors happening in women's lives around the times that they're also seeking contraception. And so I wondered, when thinking about a patient who maybe has come to you with a very clear mood change associated with starting a particular hormonal contraception, and the decision might be made to swap it, to change to something else, if it was kind of a causal effect of that particular contraception, how long would you expect any of those mood disturbances to settle after ceasing?

One thing about working with hormones is that they tend to be rapidly acting. I have seen many patients who describe that there's an insidious onset of the mood disturbance. It's not a classic sort of crashing major depression as we would normally see a major depression, but what happens is many women describe an insidious loss of pleasure, insidious irritation that gets worse and worse. And that grey feeling as one of my patients described, just not quite having the highs and the loss of perspective. So she felt like in any argument, she couldn't see the other side, which was very unlike her and so on and so on. But then when she stopped that particular pill, within 72 hours, she said she suddenly sort of woke up, was her word, she felt very, very different and then of course was quite reluctant to try another type of pill. So I see that pattern a lot.

I think you can take somebody's prescription and change it and then get them back in a week to see what has happened. But people are complex and there's relationship difficulties or work difficulties or other things going on as well that just might also be playing out and therefore more difficult to tease apart. But if it is the hormone contraception, you should be able to see that factor resolve fairly quickly after that particular pill or whatever is changed.

It's wonderful to think about these clinical pearls and how we can really troubleshoot with patients, particularly with the combined products, if there's a significant temporary related mood change and you stop and it goes away, what's our next step? Do we think it's probably the oestrogen or the progestogen component that's maybe been the most potent? Do I try a different oestrogen, maybe one of the newer more physiological ones. Do I try changing the progestin, or do I just completely avoid combined contraception entirely and try a non-hormonal option?

I'm a little sort of pro oestrogen, anti progestin, just because of what I've seen with the variations in the types and doses of the progestins. But let's say all things being equal, I'm not particularly fussed with the oestrogen component, but I do worry a lot about the progestins because there are some ones that I've seen really dreadful reactions to different progestins, the older ones in particular, the dosing is an issue, but the type is an issue as well. And I'm more confident with the nomegestrol acetate in one of the pill preparations, because I have not seen a lot of depression with that particular combination. It seems to be the nicest one in terms of depression that we have at the moment. Of course, people are different, but by and large, that's been the average picture. The difficulties with the progestin-only seem to be the most depressive-creating contraceptive agents.

I stay away from progestin-only products, but for someone who has that depression, it's the estradiol neuroprotective component that probably is missing in that equation, and that's maybe making a more difficult situation for the woman.

Also, again, we need to be careful of the introuterine devices as well. As we know it doesn't take much, so let's not assume that just because it's an IUD or because it's a subcutaneous delivery system that it's not going to get into the CNS and create the issues. A lot of concerns have been raised about the IUDs from women, again who are vulnerable, because there is no oestrogen component to that. It is a progestin synthetic that is produced.

In general practice, we have some competing priorities and the long-acting reversible contraception, which tend to be the subcutaneous progestin-only implant or the IUDs, can have significant benefits for people's reproductive goals. And I do want to draw you out a little bit on the mood effects of the progestins, and certainly with something like a depo injection or the subcutaneous implant, where the mechanism of action is significant systemic absorption compared to the IUDs where the proportion of systemic absorption is a lot lower, compared to the other options.

When it comes to the most commonly used IUD, the one that’s been around for a long time, the 52 mg levonorgestrel IUD, we often explain to women that the mode of action is locally acting and that the minimal systemic absorption isn't suppressing the access or ovulation. And I guess it sounds like you think we need to rethink that assertion.

In the vulnerable population we do know that in some women there is enough circulating synthetic levonorgestrel in this instance that does influence, and we think that the plausible links are particularly through the GABA-induced inhibition of the glutamate transmission and also their impact on the monoamine oxidase. So resulting in decreased serotonin. But of course, that's in the woman who is vulnerable for small doses, if you like, of the synthetic progestin, creating that environment in the CNS. Many women are not. Again, it's this group of vulnerable women who are vulnerable to small shifts in the gonadal hormones, in the CNS, creating an environment of depression, which can happen even with the lower doses that are coming across from an IUD.

I guess I just want to sort of remind people to think that everybody is one whole. And so what happens in one part of the body will affect the brain and other parts of the body as well.

I wonder we do have the newer low-dose 19.5 mg levonorgestrel IUD that's just been on the PBS since 2020. Do you think that we're going to see an appreciable difference in mood side effects compared to the 52 mg device, because that lower dose, in fact, it isn't licensed for really anything beyond contraception because there's such minimal systemic absorption that it's really just only for contraception. What are your thoughts on what we expect to see with this new lower dose?

Because it's new, I don't have the personal experience with my patients, but I have spoken to Terri Foran and others who are experts in the contraceptive area. And she is very pleased with the results that she's seeing with her patients on the lower dose IUD. The only thing is, she said, that there's breakthrough bleeding. For a very, very long time, the whole mood and measurement of mood and irritability and anxiety, and all these things, was not done in the actual clinical trials in development of contraception. I'm doing it because I'm interested in research, but this is small numbers, but it doesn't seem to have become part and parcel of the rating scales and so on that are done in order to determine the impact of the new contraceptives. I mean, a lot of other things are measured, but it is important in the development of the new contraceptives that right from square one in the early trials, that the mental health of the women is also considered an important factor in the drug development itself.

We've spent a fair bit of time talking about some of the potential negative mood side effects of hormonal contraception, but we also have touched briefly on a few cases where in fact, we can actually use hormonal contraception to our benefit for some people's mood, particularly the benefit of some of the combined contraceptive pills, especially with continuous use that can have on premenstrual dysphoric disorder. Can you explain how it's useful, particularly for PMDD, and maybe then we can talk about a few other kind of case examples of where it's useful?

In those women who have premenstrual depression, it is a cyclical depression, and it is very clearly related to menstrual cycle, gonadal hormone shifts. And so in this group, it makes a lot of sense to trial a hormone strategy for what appears to be a hormone-induced problem. The very blunt sort of approach is to say, okay, let's try to minimise or decrease significantly the fluctuations in the actual end product of the HPG axis or even higher up. And so using synthetic estradiol and synthetic progestin is a way of controlling the fluctuations. That's one of the things that we have found very, very useful. But here again is the importance of using a synthetic progestin that is not going to then trigger the depressive episodes by the GABA and glutamate system changes.

And what we have discovered is one particular compound with nomegestrol acetate combined with 17-beta estradiol. And we have prescribed that now, we've published this for women who really do describe cyclical depression. And so the idea here is you are actually trying to minimise that fluctuation. But also I think, what we are also doing is then sort of using the estradiol to particularly enhance some of the neuroprotective effects. And it's important to understand that these particular hormone combinations have a huge number of different ways that they interact with the serotonin receptor system as well in regulating the cerebral blood flow in the amygdala, working in the dorsolateral prefrontal cortex and many other areas that are involved with depression.

For those of you in clinical practice, you'll know that that nomegestrol estradiol pill is not subsidised by the PBS, but it is actually quite expensive, probably around a dollar a day. Many people could argue that a dollar a day for better mental health is an okay price to pay, but for some women that isn't going to be possible. But I take your point and I wonder, are you advocating for this pill to be subsidised at all?

Yes, absolutely.

Excellent. Can I ask you also around that PMDD? And it sounds like mechanistically it's that second half of the cycle's relative lower oestrogen state that might be the more potent effect on mood, balanced with needing to make sure that you are supporting progestin, that isn't likely to cause significant mental decline. And I wonder whether or not this might be a little bit advanced use and a kind of a bit beyond standard clinical practice, but what do you think about the combination of something like a levonorgestrel IUD, even at the 52 mg, with minimal systemic absorption, and something like two weeks of estradiol given even transdermally, it's something I will do commonly in perimenopause and menopause. What do you think about using strategies like this in younger women, particularly in the PMDD group?

Yes, we certainly do. And this is one of the good things about hormones. As long as you are watching the breast health, cervical screening, blood pressure, all the good health measures are fine and the woman doesn't have any of the risk factors in her physical health, there are many very important things that can be used in combination. So commonly, we would start with this particular preparation, the nomegestrol plus the 17-beta estradiol and then what usually happens is we ask the person to take this without the sugar pills or the placebo pills, so that you get a kind of continuous estradiol plus the nomegestrol presentation to the CNS. And then after doing that without the sugar pills for about three months, I'll ask her to take the sugar pills, she'll have an artificial bleed, and you can start the thing again.

If she comes back and says, I'm about 50% improved or 60% improved in the PMDD symptoms, then you know that you're on the right track with a hormonal treatment, but you may not have had enough estradiol to actually change some of the neurochemistry.

So in that instance, we will try to add some more estradiol and it could be the form of a transdermal pure estradiol. So again, you see here, it's a similar situation to what you're talking about, or it could be that if she has the IUD, then you can do an on-off with the transdermal estradiol. I think it's very useful to work with your patient in this way, because what you are doing is together, you are on a journey of understanding and listening to what she's saying she's experiencing.

It is easier I believe to do this than if you get into the standard treatments of PMDD, premenstrual depression would be with antidepressants and they are of course effective, but SSRIs and the SNRIs, they're, the common antidepressants, are not quite hitting the mark here. And so we might end up using a combination of some hormonal preparation with if she's already on that antidepressant, because as you know, it's harder to change and shift antidepressants because of the withdrawal symptoms. They're very difficult. Whereas withdrawal from a hormonal contraceptive is usually you get a menstrual bleed, that's out of sync, but not really much else. So it's easier to change hormonal preparations than to change antidepressants.

And I will say as a GP, I also have found that there's a small subset that I also find a lot of benefit in. And these are my trans male patients who I use hormonal contraception for menstrual suppression. And that really does help with cyclical, gender dysphoria associated with menstruation. And that's another case use that I have found really I can harness the benefits of hormonal contraception in that situation for mood.

Absolutely. And I have a similar response too. So again, it's very rewarding working with your patient and going on a journey together.

Our listeners can hear, it's not all bad news when it comes to hormonal contraception and mood and that these discussions about contraception, they are really nuanced. And I think our conversation today really reinforces that it pays to take the time, take a thorough history from your patient, work with them to find the method that works best for them. Be open and curious and listen to them. Thank you very much for your article. I agree, we need more research in this area, so please keep up the good work I look forward to seeing what is to come and thank you so much for your time today.

My pleasure.

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Professor Kulkarni's full article is available online in the June edition of Australian Prescriber. The views of the host and the guest on this podcast are their own and may not represent Australian Prescriber or NPS MedicineWise.