ETIOLOGY AND PATHOPHYSIOLOGY
While many studies have focused on the predisposing factors related to premenstrual dysphoric disorder, the relative contributions to this disorder are unclear. Small studies of monozygotic twins have suggested a hereditary link to premenstrual symptoms. Other considerations include a patient’s onset of menses. Onset at a young age (i.e., less than 11 years old) has been found to be an increased risk factor for many gynecological disorders such as breast cancer, endometriosis, and of importance to this article, premenstrual symptoms. In addition to the genetic and developmental factors that may contribute to the risk of PMDD, research has shown that a history of major depressive disorder, bipolar disorder, postpartum depression, and family history of mood disorders of premenstrual depression may increase a woman’s risk for premenstrual dysphoric disorder. Studies have also indicated that women with PMDD are at a higher risk for lifetime history of depression compared to women without premenstrual dysphoric disorder (30% to 76% vs. only 15%, respectively).
The ACOG has indicated that PMDD symptoms should occur during the late luteal phase of the menstrual cycle, resolve within the onset of menses, and then be absent during menses. This pattern helps in the differential diagnosis. The occurrence of symptoms during the late luteal phase is also important to note when administering certain medications (as discussed later in this article).
Although the pathophysiology of premenstrual dysphoric disorder is not entirely understood, many hypotheses have been proposed to explain the mechanism by which symptoms of PMDD occur. The first and most common hypothesis is an abnormality that exists in the patient’s serotonergic neurotransmitters triggered by normal hormonal changes during the luteal phase of menses. Other hypotheses include deficiencies in hormonal production and nutritional deficiencies and excesses. The first hypothesis suggests a close link between PMDD symptoms and serotonin. The latter describes the use of nutritional and hormonal supplements for the relief of symptoms.
These hypotheses are associated with the pathophysiology of the menstrual cycle. The rise and fall of particular hormones and the biological changes that occur during the cycle provide a logical explanation for most of the symptoms women experience with premenstrual dysphoric disorder. The menstrual cycle involves the hypothalamic-pituitary axis (HPA). Key elements of this process include gonadotropin-releasing hormones (GnRHs), gonadotropins, ovarian hormones, neurotransmitters, and neuropeptides. The HPA is responsible for the secretion and regulation of hormones that control ovulation. The hypothalamus produces GnRH, which in turn regulates the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. The two main phases in the menstrual cycle are the follicular phase (days 1 to 14) and luteal phase (days 15 to 28). The follicular phase occurs when estrogen levels are low, which then stimulates the release of FSH and LH. The rising FSH and LH levels cause ovarian follicular growth that leads to a positive feedback, resulting in increased estrogen production. High estrogen levels cause an LH surge, finally leading to ovulation (around day 14). After ovulation, the mature follicle becomes the corpus luteum, which increases estrogen and progesterone levels. This marks the beginning of the luteal phase. The corpus luteum ultimately degenerates, at which time estrogen and progesterone levels decrease. The degeneration of the corpus luteum causes the uterine lining to break down. This breakdown marks the onset of menstruation. Figure 1 depicts and summarizes the menstrual cycle.
Figure 1. Summary of the Menstrual Cycle
Understanding the phases of the menstrual cycle is crucial, as many studies have strongly supported that ovarian hormones are linked to symptoms of premenstrual dysphoric disorder. Symptoms have been shown to decline with an inhibition of ovulation, surgical ovariectomy, or menopause. Thus, these conclusions lead to current treatment options such as ovulation suppressors. Research suggests that low estrogen levels in the brain during the luteal phase play a role in PMDD symptoms and also that declines in serotonin levels may lead to irritability, decreased energy, and mood changes. This evidence explains the use of selective serotonin reuptake inhibitors (SSRIs) to treat PMDD. Treatment based on the pathophysiology of premenstrual dysphoric disorder is discussed later in this article.