Premenstrual Dysphoric Disorder

Etiology

The exact etiology of PMS/PMDD is not known. There are, however, risk factors associated with the development of PMS/PMDD, some of which are well-established while others are speculative.

Proven Risk Factors

• Past traumatic events: Traumatic events and preexisting anxiety disorders are risk factors for the development of PMDD. The underlying mechanisms are unknown, making further investigation necessary.[3]
• Cigarette smoking: There is a strong association of moderate-to-severe forms of PMS with current smoking status compared to non-smokers (relative risk [RR] 2.1). The risk is elevated even for former smokers (RR 1.8), and the risk of incident PMS tends to increase with the quantity of cigarette smoking (RR of 1.93 for 20 pack-years). Further, the risk of PMDD is significantly higher for women who began smoking during adolescence.[4]
• Obesity: There is a strong linear relationship between BMI at baseline and risk of incident PMS (p003). For each 1 kg/m2 increase, there was a significant associated increase (3%). The risk of PMS rose significantly in women with BMI at or higher than 27.5 compared with women with a BMI of less than 20.0 kg/m2. RR in women with a BMI of 35.0 kg/m2 was 1.66.[5]

Speculative Risk Factor

• Genetics: Twin studies have implicated heritable factors in the development of PMS/PMDD. Recent studies have provided support for the involvement of the gene that codes for the serotonergic 5HT1A receptor[6] and allelic variants of the estrogen receptor alpha gene (ESR1) in the development of PMS/PMDD.[7]

Epidemiology

Premenstrual symptoms can affect all women of reproductive age, ranging from menarche to menopause.[8] Premenstrual symptoms are a common problem for women in the reproductive age group. In the United States, approximately 70 to 90% of women in the reproductive age group report at least some premenstrual discomfort. Approximately one-third of these women have symptoms that are bothersome enough to qualify for the diagnosis of PMS. The most severe form of premenstrual symptom complex, PMDD, has been noted in 3 to 8% of these PMS cases. Transgender individuals can have premenstrual dysphoric disorder. Anyone with ovaries can have symptoms.

In a study by Halbreich et al., women in the U.S. have about 481 menstrual cycles during this lifespan. Taking into account the 22 months for two pregnancies and postpartum periods, many women roughly experience 459 cycles during their childbearing years. Also, US women with PMDD experience an average of 6.4 days of severe symptoms per menstrual cycle[9]; this is approximately equivalent to 8 years of debilitating symptoms throughout the menstrual cycle. Examining the numbers leads one to the certainty that PMS or PMDD can cause distress and functional impairment over a significant duration of a patient's lifetime, making it an important health problem.

Pathophysiology

Recent evidence from research studies suggests that reproductive hormone release patterns are normal in women with PMS/PMDD, but they have a heightened sensitivity to cyclical variations in levels of reproductive hormones, which predisposes them to experience mood, behavioral, and somatic symptoms.[10] 

Role of Sex Steroids

Progesterone

Many scientists have postulated that PMS/PMDD symptoms develop because of a decline of progesterone in the late luteal phase that causes CNS changes in gamma-aminobutyric acid (GABA) and progesterone metabolites that interact with the GABA-A receptor complex. However, there are other sets of scientists who argue against this hypothesis by stating that many symptoms can begin at ovulation and the early luteal phase before the fall in the level of progesterone. To further corroborate, some studies showed that the hormonal cyclicity was suppressed by treatment with Gonadotropin-releasing hormone, and re-exposure to progesterone reproduced symptoms even when the hormone concentrations were stable. Also, if the above theory of decline in the late luteal phase indicating progesterone as the precipitating factor were to be believed, then administration of progesterone during this phase would have been an effective treatment which is not.[11]

Allopregnanolone

Allopregnanolone is a metabolite of progesterone, and like progesterone, levels of this metabolite also fluctuate during the menstrual cycle. As mentioned, progesterone metabolites interact with the GABA-A receptor complex and allopregnanolone specifically potentiates inhibitory responses to GABA-A receptor agonists. Some studies suggest that women with PMS/PMDD have diminished functional sensitivity of the GABA-A receptor due to deficient allopregnanolone response to stress.[12]

Estrogen

An alternative hypothesis suggests that preovulatory peak in estradiol, postovulatory increase in progesterone, or both trigger symptoms of PMS/PMDD[13]; however, a shortcoming of this theory is its failure to explain why symptoms start with ovulation for some, but in late luteal phase for others. It has also been reported that estrogen is as efficacious as progesterone in provoking PMS-like complaints, and the estrogen component of hormone replacement therapy can amplify progesterone-induced dysphoria.[14] Besides, the administration of estrogen in the luteal phase has been reported to provoke premenstrual symptoms[15], and giving estrogen antagonists in the luteal phase decreases premenstrual mastalgia.[16] 

Testosterone

Transgender men experience improvements in social functioning and reduced anxiety and depression once testosterone therapy is begun.

Role of Central Neurotransmitters

Serotonin

Serotonin is a central neurotransmitter that is well-proven to be involved in mood and behavior regulation. Sex steroids may affect behavior by exerting their effects on serotonergic transmission. Three proofs authenticate this theory. First, premenstrual symptoms are diminished by selective serotonin reuptake inhibitors (SSRIs) and other treatments that boost serotonin levels, like serotonin-releasing agents.[17][18][19] Second, contrary to the first point, a decrease in serotonergic transmission achieved by a tryptophan-free diet[20] or by treatment with a serotonin-receptor antagonist[21] can give rise to PMS/PMDD symptoms. Third, women with PMS/PMDD have atypical serotonergic transmission and a lower density of serotonin transporter receptors than typical women. In addition, they have a higher level of serotonergic responsiveness in the follicular than in the luteal phase, which is different from that observed in women without PMS/PMDD.[22][23][24]

Gamma-aminobutyric acid

GABA is an inhibitory neurotransmitter, and some imaging studies suggest the possible role of GABA in the pathophysiology of PMS/PMDD based on the fact that some progesterone metabolites interact with GABA A receptors [25][26] and that symptomatic women have different responsiveness of this receptor complex as compared to asymptomatic women.[27] Another noteworthy fact is that GABAergic and serotonergic neurons have meaningful interactions, and thus the role of GABA in the pathophysiology of PMS/PMDD is in keeping with the serotonin hypothesis. Additionally, SRIs also strongly influence enzymes involved in creating progesterone metabolites which in turn modulate GABA A receptors.[28][29][30][31]

Glutamate

Glutamate is an excitatory neurotransmitter, and there is a cyclical fluctuation in its levels during the menstrual cycle for all women (symptomatic and asymptomatic), but symptomatic women seem to have an increased sensitivity to these cyclical changes.[32]

Beta Endorphins

Studies have shown that women with PMDD have lower levels of cortisol and beta-endorphins during both the follicular and luteal phases.[33] These observations suggest abnormalities in the hypothalamic-pituitary-gonadal axis in PMDD which is congruent with the findings of HPA-axis dysregulation in mood disorders.[34][35]

History and Physical

Three Heads of PMDD Symptomatology

1. Mood

• Feeling sad, depressed, hopeless, worthless
• Marked mood lability like mood swings; suddenly feeling sad or tearful
• Increased irritability and or anger; frequent conflicts with family members or at work
• Increased anxiety or the feeling of being on edge all the time

    2.  Behavioral

• Lack of energy, fatigability
• Decreased interest in normal activities
• Problems with concentration
• Changes in appetite, either overeating or craving a specific food
• Changes in sleep pattern, either hypersomnia or insomnia
• Feeling overwhelmed or out of control

    3.  Somatic

• Breast swelling or tenderness
• Joint or muscle aches
• A sensation of bloating or weight gain
• Headaches

Symptom Expression Pattern 

The length of time for which the women experience symptoms of PMDD varies from a few days to 2 weeks. For most symptomatic women, symptoms intensify 6 days before and are the most severe 2 days before the menses.[36][37] Of all the symptoms mentioned, anger and irritability are the most distressing and are experienced slightly before the other symptoms.[36]

As discussed, according to DSM-5, symptoms should be directly related to the menstrual cycle and must not merely represent an exacerbation of the symptoms of another disorder, such as major depressive disorder, panic disorder, dysthymic disorder, or a personality disorder (although the symptoms may be superimposed on those of these disorders). Prospective daily ratings must confirm symptoms during at least 2 consecutive symptomatic menstrual cycles. However, a provisional diagnosis may be made before this confirmation.

Evaluation

PMDD Assessment Scales

1. Premenstrual Symptom Screening Tool (PSST): A questionnaire used to diagnose PMDD with 19 items that allow the patient to rate the severity of their symptoms.[38]
2. Calendar of Premenstrual Experiences (COPE): Includes 22 symptoms grouped into 4 categories: mood reactivity, autonomic/ cognitive, appetitive, and related to fluid retention.[39]
3. Visual Analogue Scale (VAS): Steiner et al. used this scale in 1999 to rate each of the 4 core symptoms of PMDD: mood swings, irritability, tension, and depression. The scale consisted of a 100 mm vertical line labeled 0 or “no symptom” at the left end and 100 or “severe” at the right.[38]
4. Daily Record of Severity of Problems (DRSP): This scale consists of 24 items, out of which 21 items are grouped into 11 distinct symptoms and 3 functional impairment items. The items are rated from 1 (not at all) to 6 (extreme).
5. Patient Reported Outcomes Measurement Information System (PROMIS): Deorte et al. used PROMIS computerized adaptive testing (PROMIS CAT) to detect premenstrual symptoms of depression, anxiety, and fatigue; the results of the study provided encouraging evidence for the utility of PROMIS instruments for the measurement of effective premenstrual symptoms.[40]

Treatment / Management

Treatment modalities for PMDD can be divided into 2 categories:

1. Non-Pharmacological Methods

• Exercise: Improves symptoms through elevation of beta-endorphin levels; however, the evidence is not based on randomized controlled trials.

• Dietary modifications: Increased intake of complex carbohydrates or proteins ("slow-burning fuels") is believed to increase tryptophan availability, leading to increased serotonin levels. Randomized controlled trials have demonstrated the superiority of calcium in improving emotional and physical symptoms over placebo. Meta-analysis has demonstrated some benefits of vitamin B6 over placebo. Chaster-berry/Vitex agnus-castus also has been shown to be somewhat efficacious by exerting some dopaminergic effect.

• Stress management: Relaxation/ meditation/ yoga/ breathing techniques.

     2. Pharmacological Methods

• Psychotropic agents
  • Serotonin Reuptake Inhibitors (SRIs): SRIs have been proven to be effective in the treatment of severe mood and somatic symptoms of PMDD. The ones that have been particularly linked with the relief of symptoms are Clomipramine (a tricyclic antidepressant),[41][42][41] Selective serotonin reuptake inhibitors like citalopram,[43][44] escitalopram, fluoxetine, paroxetine and sertraline, and noradrenaline reuptake inhibitor venlafaxine. Antidepressants that predominantly affect noradrenergic transmission are not as effective for PMDD as SRIs, which means that the effect of SRIs in PMDD is not just an antidepressant effect.[45][46] This is supported by the fact that the beneficial effect of SRIs begins rapidly in PMDD, whereas antidepressant effect takes several weeks. Thus, clinicians can use SRIs intermittently from mid-cycle to menses to treat symptoms of PMDD as opposed to continuous treatment[47]. Side effects of SRIs are usually mild. Nausea is the most common adverse effect, but it usually wears off in a couple of days after starting the therapy and doesn’t reappear even if the therapy is intermittent. Reduced libido and anorgasmia are other common adverse effects, but they are absent in drug-free intervals.
  • Benzodiazepines (BZDs): BZDs like alprazolam have been found to be effective only in women with severe anxiety and premenstrual insomnia. However, since there is a risk of dependence, careful monitoring is required, especially in cases with reported prior substance abuse.[48][49]
• Suppression of Ovulation
  • Hormonal therapies: For very severe symptoms, clinicians can use hormonal therapies to provide relief. The aim of hormonal therapy is to inhibit the hypothalamic-gonadal cycle; however, this causes medical menopause and leads to hot flashes and an increased risk of osteoporosis. Thus, to prevent these adverse effects, patients are also started back on estrogen and gestagen (a hormone with progesterone-like activity). Some patient reports suggesting recurrence of symptoms with the add-back gestagen therapy. Hence, as an alternative, clinicians can combine GnRH agonist with tibolone (a synthetic steroid with weak estrogenic, progestogenic, and androgenic activity).
  • Danazol: This is a synthetic partial androgen agonist/ antagonist and gonadotropin inhibitor that has also been shown to be efficacious in treating PMDD by inhibiting ovulation. However, it is associated with hirsutism and teratogenicity and thus not preferred as an initial agent.
  • Oral contraceptive pills (OCPs): Although widely used in clinical practice, their efficacy in treating PMDD has not been strongly supported by evidence. Women on OCP experience more hormone-related symptoms on hormone-free days, and hence OCP treatment with fewer hormone-free days might be beneficial to these women. Drospirenone (a gestagen) was particularly found to be effective in treating PMDD symptoms because of its anti-aldosterone and anti-androgenic effects.
(A1)

Differential Diagnosis

The symptoms of PMDD can overlap with other psychiatric disorders, most importantly major depression, and it is imperative to rule out another existing disorder before making the diagnosis of PMS/PMDD. The key factor in making the diagnosis is the temporal association of symptoms with the menstrual cycle. Some common differentials include:

1. Major depressive disorder: Depression symptoms include low mood, low energy, anhedonia, appetite change, sleep disturbance, difficulty concentrating, and thoughts of suicide. Roughly half the cases of PMS/PMDD can have a coexisting diagnosis of depression.[50] A diagnosis of PMS or PMDD may predate a diagnosis of depression or depression and PMDD may coexist. Criteria for the diagnosis of these disorders are different but not exclusive.
2. Thyroid disease (hyperthyroid or hypothyroid):
   • Hypothyroid symptoms and signs include weight gain, constipation, cold intolerance, depression, dry skin, and delayed deep tendon reflexes.
   • Hyperthyroid signs and symptoms include weight loss, poor sleep, heat intolerance, heart rhythm disturbance such as atrial fibrillation, and hyperreflexia.
3. Generalized anxiety disorder Symptoms of anxiety include palpitations and feelings of fear. Triggers may be identified for anxiety attacks, and the patient shows avoidance of these triggers. Chronic or situational anxiety does not vary with the menstrual cycle. Generalized anxiety disorder and PMDD may coexist. Criteria are different but not exclusive.
4. Mastalgia: Symptoms of mastalgia may be limited to just breast tenderness and swelling, and mastalgia may be present at times other than during the luteal phase but worsen during the luteal phase.