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What Is PMDD & What Causes It?

Updated: 2 days ago

Imagine feeling emotionally and physically drained for 1-2 weeks every month, struggling to function normally in daily life and literally not feeling like yourself, and then spending the following 2 weeks wondering: 'what is wrong with me?' and having to repair relationships, make up for lost study/work productivity.


This is a reality for many women/people assigned female at birth suffering from Premenstrual Dysphoric Disorder (PMDD). Unlike typical premenstrual syndrome (PMS), PMDD is a severe form of PMS that causes extreme mood shifts, irritability, and physical discomfort and significantly impairs quality of life.


Join us as we explore the complex interplay of factors that contribute to PMDD.


sad woman by a window with rain, she has PMDD


Is Premenstrual Dysphoric Disorder (PMDD) a hormone imbalance?


The simple answer is no.


So What is PMDD?


Premenstrual Dysphoric Disorder (PMDD) is a complex neuro-endocrine condition causing  physical, cognitive and mood symptoms in the luteal phase of the menstrual cycle that resolve with menstruation.


PMDD symptoms include the following:


  • Extreme mood swings

  • Irritability

  • Anger and rage

  • Depression and severe anxiety

  • Changes in appetite such as food cravings

  • Physical symptoms such as bloating, breast tenderness, and headaches.

  • In severe PMDD, women experience cyclical premenstrual suicidal thoughts.



It is well established in the research that women with PMDD experience atypical mood and cognitive responses to normal menstrual cycle hormonal fluctuations during the luteal phase of the menstrual cycle and first few days of the period  (Schmidt et al., 1998). 


The typical hormonal fluctuations that occur in the luteal phase of the menstrual cycle have a different response in the brains of women with PMDD and these hormone changes trigger symptoms in women with PMDD.


Hormonal Fluctuations During The Typical Menstrual Cycle


In a typical menstrual cycle, estrogen levels begin low during the period and rise over the first 2 weeks (follicular phase) till it peaks at ovulation. Estrogen then reduces, has a smaller peak and then falls to its lowest levels during the luteal phase.


Progesterone levels sharply increase during the luteal phase after ovulation. The levels decline during the week prior to the menstrual period.


The female brain experiences a monthly hormonal cycle each month due to the variations in these ovarian hormones which impacts brain function and mood states.


hormonal changes of the menstrual cycle

The Role of Hormones in PMDD


For women who experience PMDD, the hormonal changes - particularly of the luteal phase - produce symptoms that can begin with the rise in progesterone and estrogen levels during the luteal phase, which occurs after ovulation.


The symptoms are typically worse in the late luteal phase when hormone levels fall, and end or resolve when menstruation begins (or shortly thereafter) (Cunningham et al., 2009, O’Brien et al., 2011).


This phase of the menstrual cycle is a time of hormonal vulnerability for the brain of women impacted by PMDD.  It is considered a neuro-endocrine condition.


PMDD is associated with ovulatory cycles (cycles where an egg is released from the ovary). 


There are no symptoms of PMDD in anovulatory cycles (Hammarbäck et al., 1991). During anovulatory cycles, estrogen levels do peak high enough to trigger ovulation. Therefore there are no large falls in estrogen and progesterone to trigger cyclical emotional and physical symptoms.


A related but more severe condition is pre-menstrual psychosis.


Where the cyclicity of symptoms is not connected with the hormonal changes of the menstrual cycle, some women can be misdiagnosed as having bipolar disorder.


PMS vs PMDD: What's The Difference?


Premenstrual symptoms are really common. Up to 75 percent of women experience a combination of physical or emotional symptoms during the late luteal phase of their menstrual cycle. Premenstrual Syndrome (PMS) affects approximately 12 percent of women.


What differentiates premenstrual syndrome from premenstrual dysphoric disorder is the severity and quantitiy of symptoms that occur in PMDD.


In PMS there are at least 1 cognitive and 1 physical symptom that occurs in the 5 days perior to the period starting and this occurs during each cycle.


In PMDD there needs to be at least 1 mood/cognitive symptom and 1 physical symptom, but there has to be at least 5 symptoms in total and these symptoms have significant impact on the quality of life and functioning during the luteal phase of the cycle.


What Causes of PMDD?


The causes of PMDD are multifactorial and the condition is polymorphic, i.e. each individual may have a unique set of contributing factors. This seems to be why responses to different treatments are varied between women.


1. Genetic Susceptibility to PMDD


Premenstrual Dysphoric Disorder (PMDD) has a heritability range between 30% and 80%, as shown by family and twin studies, suggesting heritable neurobiological factors. Specific genetic studies highlight several key points:


Estrogen Receptor Alpha (ESR1) Gene:


A variation in the estrogen receptor alpha (ESR1) gene is associated with PMDD.

It is thought that polymorphisms of the ESR1 could contribute to differences in estrogenic impact in the brain that contributes to mood and cognitive symptoms in women with PMDD.


Estrogen Receptor 2 ESR2 gene:


Estrogen Receptor 2 Gene is involved with calcium influx into neuro and cellular excitability. Studies indicate there are polymorphisms of the ESR2 gene that could be implicated in PMDD (Ca2+ Homeostasis and PMDD).


Serotonin Receptor Function:


One study found an increase in serotonin receptors in the midbrain (involved in mood and emotion) during the luteal phase of the menstrual cycle when estradiol and progesterone (and allo) are falling (Serotonin Receptor and PMDD).


2. Progesterone and Allopregnanolone (ALLO) in PMDD


Progesterone, a hormone released after ovulation, transforms into a metabolite called allopregnanolone (ALLO). ALLO interacts with brain receptors responsible for mood regulation.


Research suggests that in women with PMDD, this rise and fall in ALLO doesn't happen smoothly, leading to mood swings and anxiety. Understanding this hormone's role can provide insight into why PMDD is so challenging to manage.


ALLO and Its Effects


ALLO acts much like alcohol or benzodiazepines as a potent positive modulator of GABA-A receptors, offering sedative, anesthetic, and anxiolytic properties. During acute stress, increased levels of ALLO can provide relief. ALLO is typically more abundant in the luteal phase of the menstrual cycle.


ALLO Levels in PMDD


Some animal and clinical studies indicate that changes in ALLO levels alters the GABA-A receptor sensitivity, reducing the calming effects of ALLO on the brain during the luteal phase (ALLO and GABA-A receptor in PMDD 2023). 


SSRIs and PMDD


Selective serotonin reuptake inhibitors (SSRIs) are effective in treating PMDD in some women (around 60 percent). One of the mechanisms by which they are thought to help PMDD is by increasing conversion of progesterone to ALLO and by increasing the GABA-A receptor to ALLO. 


This reduced sensitivity to ALLO in conjunction with falling estradiol levels seems to play a key role in PMDD.


3. Estrogen, Neurotransmitters, and Brain-Derived Neurotrophic Factor (BDNF)


As estrogen levels fluctuate throughout the menstrual cycle, it affects neuro-transmitter production including serotonin, dopamine and norepinephrine which are important in regulation of mood, cognition, sleep, and eating.


Rapid changes in these neurotransmitters in brains that are more sensitive to hormonal and neurotransmitter fluctuations can lead to depressive symptoms, changes in appetite, and fatigue.


Additionally, brain-derived neurotrophic factor (BDNF) is linked to estrogen levels and likely plays an important role in PMDD. BDNF is important for growth of neurons and is especially important in areas of the brain responsible for learning and memory. Women with PMDD often have lower BDNF levels, which may contribute to their symptoms.


In both PMDD and perimenopausal depression BDNF levels appear to be elevated which is a different pattern seen in women with major depressive disorder, reflecting the fact that they are both hormonally mediated mood and cognitive conditions (BDNF and Mood 2021).


4. Brain Structural and Functional Differences


Research has shown that women with PMDD may have structural and functional differences in their brains. These changes affect areas of the amygdala and prefrontal cortex that are involved in emotional regulation and stress responses.


These changes are likely influenced by the hormonal fluctuations outlined above.


5. Hypothalamic–Pituitary–Adrenal (HPA) Axis Hypothalamic–Pituitary–Gonadal (HPG) Axis, Trauma & Stress


The hypothalamic-pituitary-gonadal axis regulates ovarian hormone production which impacts brain function in a cyclical manner.


The hypothalamic-pituitary-adrenal axis regulates stress hormone production by the adrenal glands.


Both these neuro-endocrine systems impact each other. Anything that dysregulates stress such as a history of trauma or chronic stress can impact ovarian hormonal production and sensitivity to these in the brain.


A history of trauma is a well established risk factor for PMDD. This and chronic stress can alter the sensitivity of the brain to fluctuating hormone levels and neurotransmitter levels.


So What Are The Implications Of All This When It Comes To PMDD Treatment?


All of these mechanisms combined suggest the experience of PMDD is the result of cyclical

neuro-steroid withdrawal in the brain. PMDD should ideally be treated primarily by stabilizing these neurosteroids.


A multi-disciplinary approach can be most beneficial.


PMDD can and should be treated. It is NOT a result of a woman being emotional, is NOT a personality flaw and it is NOT hysteria.


Hormone Therapy for PMDD


Hormonal support is my number 1 treatment of choice for PMDD. Some women respond well to oral birth control pills, and this can be helpful if contraception is also needed.


Others respond better to topping up estrogen with constant dosing of estradiol across the cycle via estradiol patches and using a progestogen (norethisterone), micronized progesterone or leveornogestrel via mirena alongside that. 


Supporting stability of hormones has a flow-on effect in supporting stability of neurotransmitters, resulting in more stable moods and cognitive function.


Medications


Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), are commonly prescribed to manage PMDD. If hormone support is not suitable or sufficient then serotonin-reuptake inhibitors may be a helpful alternative or medication to use in addition to hormone support.


Therapy for PMDD


Anyone with a history of trauma or ongoing stress would be supported by a therapist who can work with them to develop resiliency skills and techniques to support brain and emotional health.


Cognitive-behavioural therapy (CBT) and other forms of counseling can provide valuable cognitive strategies. Mindfulness practices and relaxation techniques can further reduce stress and improve emotional well-being.


This can also be important to get some emotional support. It can be really hard to deal with the emotional ups and downs of your hormones. You can also get help with your relationships as these can be impacted by the symptoms you experience from PMDD.


Lifestyle Changes


Regular exercise, a balanced diet, and stress management techniques can help alleviate


PMDD symptoms. Reducing smoking, caffeine, alcohol, and sugar intake may also be beneficial.


Both smoking and obesity are risk factors associated with PMDD (Smoking and PMDD 2008).

Lifestyle change always helps our health and wellbeing and often with the right hormone support women feel in control and organized enough to pursue their goals.



The Future of PMDD Research and Treatment


It is an exciting time in the field of PMDD. The research is ongoing, with increased recognition of PMDD as having very real underlying neuro-endocrine mechanisms.


Often the rate limiting factor is the translation of research into clinical practice. But the current International Association for PMDD Guidelines give many options based on these current understandings of the neuro-endocrine physiology of PMDD.


The Takeaways: The causes of PMDD


There are 5 main areas linked to the mechanisms causing PMDD:


  1. Genetic susceptibility due to estrogen/serotonin receptor polymorphisms

  2. Responses of GABA-A receptor to allopregnanolone

  3. Sensitivity to declining estrogen levels and an association with BDNF

  4. Structural/functional differences in amygdala and prefrontal cortex

  5. Impact of trauma, stress on HPA & HPG axis and interaction with cyclical hormonal changes in the brain


PMDD can be a challenging disorder to live with, but understanding its causes, symptoms, and treatment options and working with your health provider to find the right approach for you, can significantly improve your wellbeing and daily functioning.


If you or someone you know is struggling with PMDD, especially where suicidal thoughts are occuring, seek professional help and explore the available treatment options.


Dr Deb Brunt @ Ōtepoti Integrative Health would love to support you explore the best option to treat PMDD.


Dr Deb Brunt is a women's health and menopause specialist in Dunedin, New Zealand and also provides health coaching internationally to support optimal health habits so you can live your best life.



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References



Harder JA, Fichorova RN, Srivastava A, et al. Brain-derived neurotrophic factor and mood in perimenopausal depression. J Affect Disord. 2022 Mar 1;300:145-149. 


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