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Menstrual Cycle–Influenced Disorders
Clinical Keys for this Chapter
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Premenstrual syndrome (PMS) and its more severe form, premenstrual dysphoric disorder (PMDD) are the quintessential menstrual cycle–influenced disorders. A common feature of these disorders is the inability to distinguish between affected women and normal controls by routine measurement of the traditional hypothalamic-pituitary-ovarian (HPO) hormones. Interestingly, in many cases, dramatic relief from the symptoms can be obtained by intentionally disrupting or abolishing regular menstrual function.
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Eight out of ten women with ovulatory cycles will have mild symptoms just before and during menses. This is referred to as molimina and should not be diagnosed as PMS. PMS causing moderate to severe symptoms that affect daily activities and relationships is reported by 5-10% of ovulatory women, and PMDD by less than 5%.
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The causative factors in these menstrual cycle–influenced disorders are not abnormal concentrations of the hormones of the HPO axis, but rather are atypical end organ responses to normal levels of gonadotropins and sex steroids. With the exception of recent evidence showing disruption of serotonin regulation in women with PMDD, alterations in hormone levels have been inconsistently documented.
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Because of the unclear and variable symptomatology associated with PMS/PMDD, an initial diagnostic tool is to have affected women keep a daily menstrual diary. This is done to establish the relationship between the symptoms and the luteal phase of the menstrual cycle. Once this relationship has been established, a number of effective treatments may be initiated.
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Other disorders that have been reported consistently to be influenced by the menstrual cycle include migraine headache, epilepsy, asthma, diabetes, rheumatoid arthritis, and irritable bowel syndrome. Less well studied problems include acne flare-ups, multiple sclerosis, glaucoma, and hereditary angioedema.
The human menstrual cycle is unique as a physiologic process in that it involves mechanisms that change on a daily basis rather than remaining stable. This process of change is carried out through the many intricate hormonal interactions between the hypothalamic region of the brain, the pituitary gland, the ovaries, and to some extent, the adrenal glands and the pancreatic islets of Langerhans (see Chapter 4 ).
The classic disorders that appear to be directly influenced by hormonal changes that occur during the menstrual cycle are premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). Common symptoms reported by women with PMS and PMDD include significant bloating, mood changes, depression, and emotional lability that affect their daily activities. There is a second group of menstrual cycle–associated disorders, the hallmark of which is regular ovulatory cycles, that causes cyclical dysfunction of other organ systems.
Premenstrual Syndrome and Premenstrual Dysphoric Disorder
The acronyms PMS for premenstrual syndrome and PMDD for premenstrual dysphoric disorder refer to the same pathologic process at opposite ends of the symptom spectrum ( Figure 36-1 ). In both PMS and PMDD, patients experience adverse physical, psychological, and behavioral symptoms during the luteal phase of the menstrual cycle. There is a crescendo of symptom intensity up to the time that menses begin, with quick resolution thereafter. Some patients have a brief surge of symptoms at the time of ovulation in midcycle.
As many as 80% of regularly ovulating women will experience some degree of physical and psychological premenstrual symptomatology. These mild “moliminal” symptoms are normal, and characteristic of ovulatory cycles. About 5-10% of these women have moderate symptoms that are disruptive to daily activities and are said to have PMS. In less than 5% of women, these symptoms are so severe that they seriously interfere with usual daily functioning and personal relationships. When these women meet the criteria outlined in Box 36-1 , they may be diagnosed with PMDD.
Box 36-1
From Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association for PMDD.
Criteria for Premenstrual Dysphoric Disorder
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Symptoms seriously interfere with usual functioning/relationships
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Premenstrual timing confirmed by menstrual calendar in two consecutive cycles
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Symptoms resolve after the onset of menses
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Symptoms are not an exacerbation of another disorder
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At least 5 premenstrual symptoms:
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At least one of the following:
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Depressed mood
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Marked anxiety
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Marked affective lability
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Marked irritability
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Other possible symptoms:
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Decreased interest in regular activities
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Difficulty concentrating
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Lethargy/fatigue
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Appetite change/food cravings
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Sleep disturbance
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Feelings of being overwhelmed
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Physical symptoms (breast swelling and tenderness, bloating, weight gain, edema, or headache)
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Common symptoms reported by patients include depressed mood, anxiety, affective lability and irritability, decreased interest in regular activities, difficulty concentrating, fatigue, change of appetite, sleep disturbance, and feelings of being overwhelmed. Physical symptoms include breast swelling and tenderness, bloating (a sense of abdominal swelling), weight gain, edema, and headache. The diagnosis of these disorders is confirmed by the predominant occurrence of symptoms in the luteal phase, as documented on a menstrual calendar of two consecutive cycles.
A formal set of diagnostic criteria has been proposed in the fourth edition of The Diagnostic and Statistical Manual (DSM-IV) of the American Psychiatric Association for PMDD (see Box 36-1 ). Although the DSM-IV definition of PMDD specifies that this is not just an exacerbation of another disorder, the dividing line between PMDD and other neuropsychiatric disorders is not so clear cut. For example, 46% of PMDD patients have a history of a prior major depressive episode. Moreover, patients with PMDD and clinical depression share similar alterations on a sleep electroencephalogram (EEG), and they are both responsive to the selective serotonin reuptake inhibitor (SSRI) antidepressants.
Although PMS/PMDD patients and controls do not differ in their average cyclic levels of sex steroids, gonadotropins, prolactin, or cortisol, there exists a strong basis to believe that these disorders have a hormonal rather than a purely psychologic basis. First, abolition of the menstrual cycle with gonadotropin-releasing hormone (GnRH) agonists, pregnancy, menopause, or spontaneous anovulation, provides symptomatic relief, whereas sequential ovarian hormonal therapy in hypogonadal patients can induce PMS/PMDD symptoms. Second, cycles with higher luteal phase levels of estradiol are associated with more severe symptoms.
The physiologic mechanism that results in the occurrence of PMS/PMDD is not well understood. Evidence exists that the phenomenon arises, in part, from atypical metabolism of progesterone that results in lower levels of the steroid allopregnanolone within the central nervous system. In turn, allopregnanolone interacts with the γ-aminobutyric acid (GABA) and serotonin neurons to influence the regions of the brain responsible for emotion and subjective perception. In addition, the GABA and serotoninergic neurons may be inherently dysfunctional in PMS/PMDD patients, especially in those with severe depressive symptoms, hence the overlap between PMDD and clinical depression. Major depressive disorder (MDD) persists, however, on a daily basis for weeks without a relationship to the menstrual cycle. MDD may be exacerbated during the luteal phase of the menstrual cycle and can even coexist with PMDD in some women. In such cases both PMDD and MDD need to be treated ( Table 36-1 ).
TABLE 36-1
Distinguishing Premenstrual Dysphoric Disorder from Premenstrual Syndrome and Major Depressive Disorder
| Predominant Mood Symptoms | Premenstrual Physical Symptoms | Marked Social Impairment | Monthly Cyclicity | |
|---|---|---|---|---|
| Premenstrual syndrome | −/+ | + | − | Yes |
| Premenstrual dysphoric disorder | + | + | + | Yes |
| Major depressive disorder | + | − | + | No |
Research performed to determine the best therapy for this disorder is problematic, because of the subjective nature of the condition, as well as the wide variation in the severity of the symptoms from one cycle to the next. In addition, external influences at work and at home may affect the severity of the symptoms. Finally, placebo interventions produce significant initial benefits in most PMS/PMDD studies. All of these considerations necessitate prolonged studies, which are expensive and infrequently performed.
Because of the lack of clarity and consistency of symptomatology, the initial clinical approach to PMS/PMDD should be to obtain self-reported documentation that the symptoms only (or predominately) occur in the luteal phase of the menstrual cycle. A detailed menstrual diary should be kept on a daily basis and reviewed for at least two cycles. A number of paper-based and electronic tools (easy to use applications or apps) exist for keeping these diaries. When a major depressive disorder is suspected, the patient should be referred urgently for psychiatric care.
Treatment
The majority of women who could be characterized as having PMS should be treated individually and conservatively, with reassurance and mild diuretics for symptoms such as bloating. Aerobic exercise, reducing processed foods, refined sugars and trans-fats are reasonable lifestyle changes to recommend although studies do not show consistent improvement in PMS symptoms. The mild anxiety that frequently occurs with PMS may be treated with agents such as buspirone. At present, the most effective therapy studied for women with PMDD is the SSRI class of antidepressants. Fluoxetine taken at dosages of 20 to 60 mg per day during the luteal phase of the cycle provides significant symptomatic improvement in 50-60% of patients. Sertraline at 50 to 150 mg per day is equally effective. Side effects of the SSRIs are usually self-limited and include insomnia and sexual dysfunction.
Other preparations have been effective in at least one randomized controlled trial. They include calcium carbonate, 1200 mg per day, for control of mood and behavioral symptoms; spironolactone, 100 mg per day, for mood and bloating; and buspirone, 25 to 60 mg per day, for premenstrual anxiety. Danocrine and bromocriptine are effective for the treatment of cyclic mastalgia. Pyridoxine (vitamin B6), 50 to 100 mg a day, has demonstrated mixed results in clinical trials.
GnRH agonists, used with estrogen and progestin “add back” to minimize hot flashes, are effective in eliminating PMS/PMDD symptoms. However, this is an expensive therapeutic approach.
Treatments that have been demonstrated to be ineffective in randomized controlled trials include oral or vaginal progesterone and conventional use of combined oral contraceptives. With the latter, patients have PMS-like symptoms during the placebo week.
Recent studies have shown benefit from the continuous use, or 24 out of 28 day use, of an oral contraceptive containing the progestin drospirenone.
Other Menstrual Cycle–Influenced Disorders
Menstrual Migrane Headaches
Migraine headaches, which are believed to result from sequential intracranial vasoconstriction and vasodilation, are known to be influenced by menstrual cycling. They are two to three times more common in women than in men. They improve in approximately 80% of patients during pregnancy but recur postpartum. Usually, migraines resolve following the onset of the menopause. Sixty percent of women who suffer migraine link the occurrence of their attacks to the menstrual cycle, and 7% exclusively have migraines on the 2 days before or after the onset of menstruation. Menstrual migraines usually occur without a preceding aura and are more long-lasting and resistant to treatment than migraines occurring at other times in the menstrual cycle.
The link between migraine headaches and the hormonal changes of the menstrual cycle is believed to be the phenomenon of estrogen withdrawal. Evidence for this derives from several observations: first, a small proportion of women with menstrual migraine have an upsurge in headache frequency following the preovulatory estradiol surge; second, exogenous estrogen reduces the incidence of migraines; and third, exogenous progesterone may delay the onset of menstruation without preventing the migraine attacks.
Several mechanisms have been proposed to explain why estrogen withdrawal produces migraine headaches. They include abnormal platelet aggregation, central nervous system endogenous opioid dysregulation, and stimulation of increased synthesis of prostaglandin in the central nervous system.
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