ADHD, PMDD, Mid Cycle Crash and Hormone Interactions

How we think and feel, at core, is based on our neurotransmitters, the biological chemicals that our brains use to transmit electrochemical signals. These can be affected by life circumstances, neurological conditions, medications, illness and our hormones. Important to both PMT (pre-menstrual tension) and PMDD (Pre-Menstrual Dysphoric Disorder) are how sex hormones affect our neurotransmitters. This affects our mood, thinking and how we feel about ourselves.

In a nutshell, Oestrogen and Progesterone both break down to become Oestradiol, which strongly affects how much neuronal Dopamine is produced and buffered, which then affects how much neuronal Noradrenaline and Adrenaline is used to prop up our basic functionality. Dopamine is used to help us think, understand, predict, solve and recall information in a complex process called the Executive Function. Noradrenaline helps us assess our safety, regulate our mood and initiate tasks. Adrenaline helps us to do physical actions and manage crises. When thinking, feeling and actions are not working effectively, it can seriously negatively impact our experience of this modern world. People with functioning ovaries experience a spectrum of PMT, from minimal effects to PMDD. This is mediated by Oestradiol and the effect is has on Dopamine production.

We will be specifically talking about how ovaries affect people. This can affect both Cis Women and Trans Men. People who have had a hysterectomy, are using a chemical equivalent to still the ovary process, are prepubescent or are post-menopausal will generally find that most of this article doesn’t apply. We will specifically talk about those components further down.

In this article, when we are talking about the effects to the person, we are referring to the part of the population that has ovaries.

Contents

General Practitioner Doctors are not Specialists

Most GPs, unless they have done extra study, will have only a rudimentary knowledge about the reproductive system. Surveys have shown that most GPs downplay any abdominal related pain or discomfort in people who present female or are AFAB (Assigned Female at Birth [on their birth certificate]).

If your GP is not taking your experience seriously, then ask for a referral to a gynaecologist. If your GP doesn’t do so, see a new GP.

Understanding Oestradiol, Dopamine, ADHD and Mental Health

Note: American’s will call some of these chemicals by different names.

Oestrogen = estrogen

Oestradiol = estradiol

Noradrenaline = norepinephrine

Adrenaline = epinephrine

Dopamine is a fundamental neurotransmitter that we use to run our Executive Function – understanding, solving, remembering pertinent temporary information, and thinking clearly. From Dopamine we make two more neurotransmitters, Noradrenaline to work out if we are safe and start tasks, and Adrenaline to complete tasks and handle crises. These neurotransmitters need to be in a Goldilocks Zone of “good” – not too high, not too low – for us to have good mental health.

ADHD is a condition where your brain is struggling to make or retain enough Dopamine in your prefrontal cortex, the bit of brain behind your forehead, to run the Executive Function. This can get much worse if your Oestradiol is low, and is the leading candidate of PMDD, where both conditions are minimising Dopamine at once.

We don’t just make Dopamine from nothing. To synthesis (make) Dopamine in our brain, we need to eat protein that contains the right amino acid, Tyrosine (and or phenylalanine). We extract these amino acids using Vitamin B6 (from food) and Oestradiol (from Oestrogen and Progesterone or from Testosterone), which then converts the extracted Tyrosine into Levodopa (L-Dopa). The final step is to turn the L-Dopa into Dopamine within the brain with the help of Iron from our Ferritin and Vitamin C. Your brain tries to keep the production of Dopamine within that good Goldilocks Zone – if you are low, it makes more, if you are high it slows or stops production. This is called homeostasis.

Your brain’s defines of the “good” zone is strongly, directly (mathematically), controlled by Oestradiol. That is, if your Oestradiol is low, the “good zone” is low, so your production of Dopamine is low. If Oestradiol is higher you can make more, if you have the base ingredients.

From Dopamine, we then make Noradrenaline and from Noradrenaline we make Adrenaline. All three of these chemicals are used as neurotransmitters do regulate brain functions.

If you want to learn more about this, we have a dedicated section for Dopamine [LINK].

If you want to understand reference ranges from your Oestrogen pathology results (Australia) Monash Pathology [External LINK – PDF], but please note that the type of test you get may have a different reference range eg LCMS Serum vs Immanossay Serum. Different countries have different reference ranges for poorly understood reasons.

Menstrual Phase Oestradiol Range, Australia (via Monash Pathology) LCMS Serum:

Follicular 110 – 370 pmol/L

Preovulatory 370 – 1470 pmol/L

Luteal 185 – 550 pmol/L

Postmenopausal 10 – 80 pmol/L

Whew. That’s quite a lot of tiny details with lots of words. The upshot is, you need to eat the right food to have the base building blocks, and you need to have high enough levels of the primary sex hormones to have enough Oestradiol to make Dopamine for your brain. For women that is Oestrogen and or Progesterone, for men it is testosterone.

You can see from the graph above, for women there are two times when Oestradiol is very low. The bit on the far right hand side of the graph, labelled PMT/ PMDD, and the middle, labelled the Mid Cycle Crash.

People can also struggle with insufficient Oestradiol during and after menopause, or if their trans medication is insufficient. Take a look further down for specific Trans information.

Understanding PMDD (Pre-Menstrual Dysphoric Disorder)

PMDD is a somewhat controversial diagnosis. It is well known that most women experience PMT (Premenstrual Tension) during the week prior to menses (blood flow). Some women continue for a few days into menstrual flow. This PMT (sometimes referred to as PMS, Pre-Menstrual Stress) is often experienced as some Executive Function difficulties such as brain fog, forgetfulness, difficulties concentrating and initiating tasks, and some mood dysregulation such as increased anxiety or aggression. This is considered to be normal.

When these aren’t mild experiences, they can be quite life affecting. Doctors would often notice the significant dysregulation of this cohort of menstruating teens and prescribe contraceptive medication to help regulate the sex hormones oestrogen and progesterone to minimise the strength of the dysregulation. Although doctors did not have a formal name prior to 2013, they frequently recognised the cause and had a treatment plan.

PMDD is a recent addition to the DSM 5 (American Diagnostic and Statistics Manual of Mental Disorders 5, 2013), and later to the ICD 11 (International Classification of Diseases, World Health Organisation, 2022). It was a controversial addition, with many patients and psychiatrists advocating FOR the addition, while psychologists and some feminist scholars campaigning against its addition. The fear was that the condition would be over diagnosed to invalidate women’s health and silence women.

Another criticism levelled against PMDD was that the pharmaceutical companies were investing in the meeting and definition discussion for PMDD. This resulted in pharmaceuticals being approved for the treatment of PMDD, which led to arguments suggesting that the diagnosis was merely a profit making ploy.

I think the critics are wrong. Enough of my clients have a level of reaction to the time of their menstrual cycle that clearly is an order of magnitude more severe than what is described by PMT. PMDD helps to differentiate between the two experiences and helps us to consider therapeutic strategies to address PMDD.

In my opinion, the consequences of PMDD on people’s lives has been glossed over and trivialised because of the controversy, leading to many women being ignored when seeking help, admitted to psych ward, misdiagnosed with Bipolar Affective Disorder [External LINK], Psychosis, Substance Use Disorder, Schizophrenia, Borderline Personality Disorder amongst others.

We covered the effect of Oestrogen and Progesterone levels on the production of Oestradiol and how that has a direct regulating effect on Dopamine Synthesis above in Understanding Oestradiol. In people who naturally have a sufficiency of preFrontal Cortex Dopamine, this fluctuation in Oestradiol will create some of distress and dysregulation . That does beg the question, what if you normally struggle with Dopamine, how much worse is it this fluctuation going to be?

As would be expected, the prevalence of ADHD in a cohort of people diagnosed with PMDD was quite high. In a study of 209 participants diagnosed with PMDD, 143 participants took medication for ADHD. That is 68.4% of the participants in this particular study [“Prevalence of hormone-related mood disorder symptoms in women with ADHD”, 2021, external LINK]. The background expected prevalence of ADHD in women is expected to be between 2-5%, indicating a strong connection between ADHD and PMDD. While we cannot definitively say that the two are the same thing, if you appear to be experiencing PMDD symptoms, and you do not have a diagnosis for ADHD, we feel it is a good idea for you to do an assessment for ADHD. If you have a diagnosis for ADHD, then it is likely you will experience PMDD, so learning about this may help.

Expand to read the Diagnostic Criteria for PMDD (PreMenstrual Dysphoric Disorder) according the DSM 5 TR

Where you experience at least 5 of the following symptoms, on average, in the last week prior to menses (menstrual flow) and clear up within a few days of the onset of menses, at least 1 from Part A and at least 1 from Part B:

Part A

Marked affective lability (e.g. – mood swings, feeling suddenly sad or tearful, or increased sensitivity to rejection)
Marked irritability or anger or increased interpersonal conflicts
Marked depressed mood, feelings of hopelessness, or self-deprecating thoughts
Marked anxiety, tension, and/or feelings of being keyed up or on edge

Part B

Decreased interest in usual activities (e.g. – work, school, friends, hobbies).
Subjective difficulty in concentration
Lethargy, easy fatiguability, or marked lack of energy
Marked change in appetite; overeating; or specific food cravings
Hypersomnia or insomnia
A sense of being overwhelmed or out of control
Physical symptoms such as breast tenderness or swelling, joint or muscle pain, a sensation of “bloating,” or weight gain

Understanding the Mid Cycle Crash

The Mid Cycle Crash is generally felt around 3 days after ovulation should have occurred. Research on the Mid Cycle Crash is sparse. Most people experience a drop in mood insignificant enough to shrug off and ignore, but some find that they experience 24 to 48 hours of marked decrease in mood, heightened mood reactivity and a decrease in cognition.

An examination of mood across a menstrual cycle of 62 participants noted the expected PMT difficulties with mood. This particular study found that differences existed between cycles with ovulation and cycles without ovulation in these participants. Generally, participants who ovulated in a cycle felt more positive in mood with a relatively flat mood graph, while participants who did not ovulate felt generally worse with greater variability between good and bad compared to participants who ovulated. Importantly, around 3 days after when ovulation should occur, participants who did not ovulate felt about as bad as their worst PMT feeling. This is a small study, and we couldn’t find much research on the Mid Cycle Crash. [“Ovulation disturbances and mood across the menstrual cycles of healthy women”, 2009, external LINK]

The above Figure is from the link just above it. It shows how the people who did not actually ovulate have a stronger mood cycle, often with a Mid Cycle Crash 3 days after they would have ovulated, or in other words, the switch to the Luteal Phase without ovulation occurring.

When an egg is released during ovulation, the follicle that the egg was attached to curls up into itself and becomes a corpus luteum, a temporary endocrine gland that produces additional Oestrogen and Progesterone, which helps to buffer the levels of Oestrogen and Progesterone promoting embryo implantation towards early pregnancy should egg fertilisation occur. Either way, the additional Oestrogen and Progesterone facilitate Oestradiol which helps to buffer neuronal Dopamine production, which helps maintain and stabilise mood.[“The significance of estradiol metabolites in human corpus luteum physiology”, 2017 external LINK]

When ovulation does not occur, the follicle does not become a corpus luteum, which means no additional Oestrogen and Progesterone production occurs. This leads to the Mid Cycle Crash 3 days later, lasting between 1 to 2 days on average for those who experience it. This also leads to poorer support during the PMT/PMDD part of the menstrual cycle, which exacerbates those symptoms.

Bipolar Affective Disorder (BPAD) and Oestrogen

The common wisdom in mental health is that BPAD is equally prevalent in men and women. Growing evidence shows that BPAD is not only more commonly diagnosed in women, but Major Depressive Disorder is frequently attributed to women where the diagnostic criteria indicate that the MDD should probably have been BPAD.

If BPAD is more common in women, is this hormone related?

It is well recognised that BPAD rapid mood cycling, depressive polarity and suicide attempts is more common in women [Source LINK]. Research into women experiencing BPAD indicate that Oestrogen levels and mood were correlated, and two different trials using Tamoxifen were successful in producing antimanic effects [Source External LINK]. Low levels of Oestradiol have been implicated with mania, psychosis, and mood dysregulation [Source External LINK].

Tamoxifen is a selective Oestrogen receptor modulator; a modulator is a medication that props up low levels of a biochemical and suppresses high levels of that biochemical (this is simplified). That means that Oestrogen won’t go too low, and neither will it go too high. Tamoxifen is not currently listed as a medication for BPAD or MDD in Australia. It is usually used as a preventative for breast cancer.

This won’t be an effective treatment for all women who experience BPAD. If your BPAD is treated by Lithium medication, then likely this won’t work. The research into Oestrogen modification for BPAD is still early.

Postpartum and Postnatal Depression

During pregnancy and post birth, hormone levels can fluctuate quite a lot. This can sometimes help ADHDers with their mood and managing well, but can also cause Postnatal Depression (PD). Various studies have shown that after giving birth, Oestrogen levels often significantly drop for a few months, which seems to be the primary contributor to PD.

There are some good early studies showing that treating PD with an increase of Oestrogen for a few months via hormone treatment not only effectively treated the depression, with better results than standard antidepressants, but follow ups 2 years later showed that the PD had not returned either [Source, External LINK].

We discuss this in more detail here [LINK].

Transgender and Hormones

This section will focus on Transgender people who are taking hormones therapies as part of their Gender Affirming Medications. The hormone therapies effectively switch the source of hormones that create Oestradiol. That is, Trans Women will switch from Testosterone to Oestrogen and Progesterone (often with a testosterone blocker), and Trans Men will switch from Oestrogen and Progesterone to Testosterone.

Transmen

Trans Men take Testosterone. This frequently will deepen your voice, roughen your skin, increase body hair growth and increase your muscle growth. Most people do not notice much change to their chest tissue. Some people find that careful placement of Gel Testosterone can be used to shape body parts to a more masculine look. In the presence of high Testosterone, Progesterone and Oestrogen decrease levels commonly found in Cis Men. As stated above, it is important to ensure that your body Testosterone level is high enough to produce sufficient Oestradiol to sustain Executive Function and Mood.

Transmen generally find that their menstrual cycle becomes lighter and generally stops. It is still possible to become pregnant though, so be careful.

For more information, check out https://transcare.ucsf.edu/article/information-testosterone-hormone-therapy.

Transwomen

Trans Women take Oestrogen, Progesterone and may take Testosterone blockers if they still have active testicles. The Oestrogen is primarily responsible for the rise in pitch of your voice, increasing body curvature, softening your skin and reducing your body hair growth. Testosterone blocker is needed to stop the natural creation of Testosterone, while Trans Women do not need to take any blocker. Oestrogen and Progesterone need to be high enough in your body so when they break down into Oestradiol, it triggers a sufficient release of Dopamine to support your Executive Function and Mood.

Oestradiol, 1 of the 6 forms of Oestrogen, is what Oestrogen and Progesterone break down into. This can be measured via a blood test by your pathologist. Oestradiol has a direct link to Dopamine production amongst other neurotransmitters. Low Oestradiol can cause loss of focus, low libido, low or irregular mood, loss of appetite and several other mental health issues. While it is not well understood what the common lowest amount of safe Oestradiol is, this paper [External LINK, “Oestrogen and anti-androgen therapy for transgender women”] recommends that it is relatively safe to go as high as 400 pg/mL. If you are struggling with thinking/cognition, feeling, appetite and or libido, it is is worth talking to your specialist about gettings your Oestradiol levels tested and trialling raising them if your levels are significantly below 400 (perhaps lower than 300). All bodies are different, so your case may not fit this, and the cause of mental confusion may not be related to Oestradiol.

A note on getting a hormone test. Pathologists will list your chromosome sex, which can mean that pathology may test your testosterone instead, or will give you reference ranges that are fit for a cis man. When you talk to your doctor about getting your hormone levels checked, ensure that they write in the “extra information” box that you are a trans woman and you need the Oestradiol and Progesterone levels tested with a reference range for cis-women. While not guaranteed that the pathology labs will read this box, it does increase your odds of a more useful outcome.

Transwomen do not have any menstrual reproductive organs, so the sections above referring to ovaries and periods doesn’t apply.

Prepubescents

Prior to puberty, sex hormones are relatively low. This means that the amount of Oestradiol is lower and thus Dopamine production is lower. Generally, this is not a problem as the prefrontal cortex is not fully developed (it is there, but the density of neurons is lower), which means not as much Dopamine is needed. With puberty, the sex hormones increase, people with ovaries will begin to menstruate and the prefrontal cortex will transition from smooth to wrinkled as the density of this part of the brain increases. Our brains switch from being mostly emotion and present circumstances triggered behaviours to deeper thinking and future seeking. Or put another way, from midbrain survival to cognitive humans.

This cognition needs a great deal more Dopamine to work, which is handy as puberty releases higher levels of sex hormones, which break down into Oestradiol, which as we described earlier, is directly involved in modulating the amount of Dopamine synthesised in the brain. Unfortunately, in people with ADHD, the production of Dopamine can be insufficient leading to odd behaviours.

In short, prepubescent people generally do not experience PMDD or the Mid Cycle Crash as their brain is not relying on a higher level of Dopamine to function. While ADHDers will often struggle at this age, they won’t experience PMDD.

There is an exception to this. For many, the year prior to their first menses is a transition period where the body has started to cycle through the hormone shifts but may not have reached a level to trigger menses. This can lead to PMDD and Mid Cycle Crashes prior to external signs of menstruation. Often you will start to notice that some of the shape features can be coming in, such as narrowing hips, growing of breasts etc, which can indicate an early puberty. Checking the history of when menstruation began with immediate older family members will help to predict roughly when this is happening for the premenstrual child.

Menopause

When the Ovaries have released all the eggs that they are going to release, the body transitions to menopause. This can be rapid or take a few years. Menopausal people have lower levels of Oestrogen and Progesterone, which leads to lower levels of Oestradiol, and thus lower levels of Dopamine. In neurotypical people, this isn’t too significant. For ADHDers, this can be very problematic, but not necessarily for all ADHDers.

During the transition through menopause, ADHDers can experience wild mood swings, depression, and long lasting behaviour difficulties akin to a very long PMDD experience. This can easily be resolved with some HRT (Hormone Replacement Therapy) if the GP and relevant experts recognise that this is happening. Often doctors will mistake the symptoms for mental illness and try to treat you for that instead. SSRI medication will not significantly affect your mental health symptoms when the problem is low Oestradiol.

Once menopause has completed, you may find that you are struggling to feel happy or motivated. A hormone test to see if your hormones have settled into a safe level of Oestrogen and Progesterone can be done and weak HRT can help improve your mood, thinking and life experience. It can be difficult to convince a doctor to do a hormone test to confirm this.

During the PMT phase of your old cycle, the expected LCMS Serum range is 110 to 370, where ADHDers will often feel strongly symptomatic below 200. For post menopausal women, the range is usually 10 to 80, where ADHDers may feel symptomatic as low as 70.