The PMDD Puzzle: Evaluation, Etiology, and Management of a Complex Condition

Dr. Bethany Mattson, ND

The PMDD Puzzle: Evaluation, etiology, and management of a complex condition

Many patients report symptoms of premenstrual syndrome (PMS), including bloating, breast tenderness, cramping, and mood changes before the start of a menstrual cycle. Although these symptoms are common, they are not always normal, and comprehensive evaluation for underlying menstrual disorders is important. When there are profound mood changes after ovulation, premenstrual dysphoric disorder (PMDD) should be considered. PMDD is a serious and complex condition with a hallmark feature of cyclic severe depression that begins after ovulation and resolves with the onset of menses.

EVALUATION

When PMDD is suspected, a comprehensive evaluation typically involves following the DSM-5 diagnostic criteria, prospective symptom and cycle tracking, and laboratory evaluation to rule out underlying endocrine disorders and other psychiatric comorbidities. Close monitoring for increased suicidal ideation is also indicated and should be discussed frequently with the patient. 

The summary of the DSM-5 criteria includes:

  • Presence of cyclic symptoms starting the week before menses which improve during menses and resolve in the week after menses. 
  • At least 5 symptoms reported, such as affective lability, irritability, depressed mood, anxiety, decreased interest in daily activities, difficulty concentrating, lethargy, appetite changes, sleep disturbance, and physical symptoms (breast tenderness, bloating, etc.) 
  • The symptoms are severe enough to cause distress.
  • Presence of symptoms for at least 2 consecutive cycles
  • Exclusion of other psychiatric or medical explanations. 

The timing of symptom onset is key for PMDD evaluation. This can help distinguish between different hormonal patterns and early versus late luteal phase onset. Body literacy and cycle-tracking education are important because knowledge of ovarian activity is required to accurately diagnose PMDD. Although many patients can tell when ovulation may have occurred based on the start of mood changes, some patients do not experience PMDD symptoms until later in the luteal phase, 1-2 weeks after ovulation has occurred. 

The basics of cycle tracking for ovulation include tracking for total cycle length, basal body temperature (BBT), and cervical fluid changes. Basal body temperature increases after ovulation due to the production of progesterone. Patients will be able to track a sustained rise in BBT that persists throughout the luteal phase and can confirm the presence of ovulation and length of the luteal phase, which in turn can provide insights into progesterone production and balance with estrogen levels. A sustained temperature rise is defined as a tenth of a degree above the highest of the last six temperatures for at least 4 days. Cervical fluid is made by estrogen and is present only in the follicular phase before ovulation occurs. After ovulation, cervical fluid dries up and the absence of peak fertile fluid (often egg-white consistency) should correlate with the BBT rise to further confirm ovulation. 

Lab evaluation of PMDD should include serum testing to rule out underlying endocrine, menstrual, or mood disorders such as:

  • Perimenopause
  • Primary ovarian insufficiency
  • Thyroid imbalance including Hashimoto’s Thyroiditis 
  • Anemia
  • Vitamin D deficiency 
  • Vitamin B12 deficiency 

A comprehensive lab order should include a full thyroid panel, iron and ferritin, vitamin B12, vitamin D, prolactin, and cycle day 3 hormone testing including estradiol, FSH, LH, and AMH. Serum cycle day 3 labs can be normal in PMDD. In these cases, a deeper hormone evaluation such as the DUTCH test can help provide clues such as hormone metabolite breakdown and abnormal enzymatic activity. In addition to hormone metabolite testing, important information regarding the hypothalamic pituitary adrenal (HPA) axis can be evaluated with the DUTCH test including 24-hour cortisol levels and adrenal gland functioning. HPA-axis dysregulation is a component of the proposed etiology for PMDD. 

ETIOLOGY

The etiology of PMDD is complex, with multiple current proposed mechanisms, although many are rooted in the interactions between sex hormones, neurotransmitters, and psycho-social factors. There may not be one set mechanism for PMDD development. Often in the clinical setting, what helps one patient with PMDD may exacerbate symptoms for another patient. Progesterone is an example of this, with some patients responding well to supplementation while others experience exacerbation of symptoms with both progesterone and progestin use. Because of these variances in patient response, it is vital to perform a proper evaluation and aim treatment choices toward the root cause identified to enhance treatment efficacy and avoid potential exacerbations. 

Key risk factors for PMDD include history of trauma, tobacco product use, and obesity. There are also genetic links to changes in serotonergic and estrogen receptors that may play a role as well.

Key proposed etiologies currently include: 

  • Heightened sensitivity to normal/expected hormonal fluctuations. 
  • Increased sensitivity to allopregnanolone (a neurosteroid metabolite of progesterone) and altered GABA-a receptor activity in the brain. Although allopregnanolone and GABA can both have a calming action, in some patients with PMDD, increased activity leads to severe exacerbation of symptoms. 
  • Differences in the GABA-A receptor subunit structure have been observed, with hypersensitivity to allopregnanolone as a result. 
  • Serotonergic receptor 5HT1A genetic polymorphisms have been shown to reduce serotonin activity in patients with PMDD, specifically in the luteal phase. This mechanism explains why SSRIs are such an effective treatment option for some patients, with additional benefit seen with cyclic SSRI dosing as opposed to continuous dosing.    
  •  HPA-Axis dysregulation may play a role in increased sensitivity to stress and abnormal cortisol and norepinephrine changes. 
  • Increased sensitivity to glutamate activity, an excitatory neurotransmitter counterbalanced by GABA. Abnormal glutamate activity has been found in a variety of mood disorders, including major depression and anxiety disorder. 
  • Late-luteal phase onset may be linked to falling progesterone levels and could see benefit with progesterone supplementation or progesterone-supporting herbs. However, early luteal phase onset symptoms do not match this pattern, and progesterone supplementation may be less effective in these cases.

Understanding the complex etiology of PMDD can help guide treatment decisions and may initially include trial and error to determine which type of intervention is best for each individual patient. Properly identifying the root cause of dysfunction may aid in minimizing failed interventions and a quicker path to resolution. A detailed history can offer important insights, including past reactions to conventional management such as OCPs and SSRIs.

MANAGEMENT

While the conventional approach to PMDD include medications such as SSRIs and combined OCPs,  an integrative approach to treatment often includes nutritional supplementation and dietary interventions, with or without pharmaceutical management. Education around prospective symptom tracking for a minimum of three cycles once treatment is initiated can guide treatment efficacy. 

Nutrition: 

Dietary changes can be a supportive addition to a PMDD plan and should be focused on finding an ideal individualized diet for the patient. The dietary approach includes maintaining adequate carbohydrate intake and finding each patient’s most balanced diet, with no deficiency or excess in any macronutrient category. A 2019 study found that patients who consumed carbohydrates as whole grains instead of refined grains had a significant reduction in both somatic and emotional symptoms. Low protein, high carbohydrate diets have also been found to be beneficial in mitigating symptoms.  

Supplementation:

In the pursuit of alleviating PMDD symptoms, a personalized approach targeting the root cause proves most effective. Remember to consider any imbalances seen during the initial evaluation and begin there. Among the well-studied supplements for PMDD, Vitex and calcium stand out. Vitex has been found to be as effective as fluoxetine in managing somatic symptoms of PMDD. Patients with PMDD often have lower calcium levels, and daily calcium carbonate supplementation has been found to significantly reduce PMS/PMDD symptoms. Vitamin B6 is also commonly used for PMDD management, but due to the complex etiology of PMDD, the research surrounding its efficacy is mixed and inconclusive. Regardless of supplement choice, patient education surrounding the length of time to see a positive treatment result is important. Ideally, a trial of three full cycles of supplementation should be used to determine whether a supplement regimen is working for that individual. 

Although PMDD is a complex condition to research and treat, there is promising evidence in the literature and clinical setting that integrative evaluation and intervention personalized to the patients unique needs can reduce symptoms and increase quality of life for patients.  


References
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