This chapter deals primarily with APGO Educational Topic Area:
TOPIC 49 PREMENSTRUAL SYNDROME AND PREMENSTRUAL DYSPHORIC DISORDER
Students should be able to list diagnostic criteria and appropriate treatments for premenstrual syndrome and premenstrual dysphoric disorder, attuned to differences between the two.
Clinical Case
A 32-year-old patient comes to you because her friends have noticed that recently she has become very moody and irritable, particularly before her menstrual period. They have told her they think she has premenstrual syndrome. She reports that, additionally, she is having trouble concentrating, feels anxious, and has trouble sleeping.
Premenstrual syndrome (PMS) is a group of physical, moodrelated, and behavioral changes that occur in a regular, cyclic relationship to the luteal phase of the menstrual cycle and that interfere with some aspect of the patient’s life. These symptoms occur in most cycles, resolving usually with onset of menses but certainly by cessation of menses. This cyclic symptom complex varies both in severity and in the degree of disruption of the patient’s work, home, and/or leisure life. The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), lists the diagnostic criteria for premenstrual dysphoric disorder (PMDD) as a specific set of at least 5 of 11 possible symptoms, with at least 1 core symptom—specifically, depressed mood, anxiety or tension, irritability, or decreased interest in activities (anhedonia). These symptoms occur regularly during the luteal phase of the menstrual cycle.
The pathophysiology of both entities is not well elucidated. Neither condition should be confused with molimina, normal cyclic symptoms associated with ovulation, which do not interfere with the patient’s daily routine.
INCIDENCE
Premenstrual symptoms occur in approximately 75% to 85% of women. PMS that causes significant disruption of daily life occurs in approximately 5% to 10% of women. PMDD, rigorously diagnosed as outlined in the DSM-IV, affects only 3% to 5% of women. PMS and PMDD can begin with menarche but can also present later in life, even in a woman’s forties, although this is often a reflection of the hesitancy of women to seek medical help for their symptoms. The expression or symptom dominance of these disorders differs depending on ethnicity and culture. There is some evidence that the incidence of PMDD varies across cultures as well, with high rates in Mediterranean cultures and the Middle East and low rates in Asia. Twin studies also demonstrate concordance, implying a genetic contribution to the development of these disorders.
SYMPTOMS
Over 200 symptoms have been attributed to PMS. Each patient presents with her own constellation of symptoms, thus making specific symptoms less important than the cyclic occurrence of the symptoms. Somatic symptoms that are most common include abdominal bloating and fatigue. Other symptoms include breast swelling and pain (mastodynia), headache, acne, digestive upset, dizziness, sensitivity to external stimuli, and hot flushes. The most common behavioral symptom is emotional lability. Other behavioral symptoms include irritability, depressed mood, anxiety, hostility, tearfulness, increased appetite, difficulty concentrating, and changes in libido. Box 43.1 lists the diagnostic criteria for PMS. Box 43.2 presents the diagnostic criteria for PMDD as described in the DSM-IV. The criteria for the diagnosis of PMDD are more rigorous than those of PMS and emphasize the existence of mood-related symptoms. PMS can be diagnosed on the basis of either mood or physical symptoms.
BOX 43.1 Diagnostic Criteria for Premenstrual Syndrome
1. Premenstrual syndrome can be diagnosed if the patient reports at least one of the following affective and somatic symptoms during the 5 days before menses in each of three menstrual cycles:
Affective Symptoms
Depression
Angry outbursts
Irritability
Anxiety
Confusion
Social withdrawal
Somatic Symptoms
Breast tenderness
Abdominal bloating
Headache
Swelling of extremities
2. These symptoms are relieved within 4 days of the onset of menses, without recurrence until at least cycle day 13. The symptoms are present in the absence of any pharmacologic therapy, hormone ingestion, or drug or alcohol use. The symptoms occur reproducibly during two cycles of prospective recording. The patient suffers from identifiable dysfunction in social or economic performance.
Adapted with permission from Mortola JF, Girton L, Yen SS. Depressive episodes in premenstrual syndrome. Am J Obstet Gynecol. 1989; 161(1 pt 1):1682–1687.
Etiology
Many theories have been proposed to explain PMS, including altered levels of estrogen, progesterone, endorphins, catecholamines, vitamins, and minerals, but none provides a single, unified explanation that accounts for all the variations that are seen. No compelling variations in any of these substances have been found in women who have symptoms compared with women without symptoms, with the exception of some preliminary studies on serotonin. Although it has been proposed that a low luteal-phase progesterone level is the cause of what is now recognized as PMS and PMDD, measurement of serum progesterone values and clinical results of progesterone supplementation have not supported this theory.
BOX 43.2 Diagnostic Criteria for Premenstrual Dysphoric Disorder
A. In most menstrual cycles during the past year, five or more of the following were present most of the time during the last week of the luteal phase, began to remit within a few days of menses onset, and were absent in the week postmenses, with at least one of the symptoms being items 1, 2, 3, or 4 (“core symptoms”) listed below:
1. Markedly depressed mood, feelings of hopelessness, self-deprecation
2. Marked anxiety, tension, feelings of being “keyed up” or “on edge”
3. Suddenly feeling sad or tearful, with increased sensitivity to personal rejection
4. Persistent and marked irritability, anger, or increased interpersonal conflicts
5. Decreased interest in usual activities
6. Subjective sense of having difficulty in concentrating
7. Lethargy, fatigue, or marked lack of energy
8. Marked change in appetite and cravings for certain foods
9. Hypersomnia or insomnia
10. Feeling overwhelmed or out of control
11. Other physical symptoms, such as breast tenderness or swelling, headaches, joint or muscle pain, a sensation of “bloating,” or weight gain, and pain
B. The disturbance markedly interferes with work or school, or with usual social activities and relationships with others
C. The disturbance is not merely an exacerbation of the symptoms of another disorder, although it may be superimposed on one
D. Criteria A, B, and C must be confirmed by prospective daily ratings during at least two consecutive symptomatic cycles (the diagnosis may be made provisionally prior to this confirmation)
Reprinted with permission from American Psychiatric Association. The Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Revision. (DSM-IV-TR). Arlington, VA: American Psychiatric Association; 2000.
Currently, the data support a theory of serotoninergic dysregulation as the basis for PMDD. Normal cyclic hormonal fluctuations can trigger an abnormal serotonin response. Monoamine oxidase reduces serotonin availability, progesterone potentiates monoamine oxidase, and estrogen potentiates monoamine oxidase inhibitors. Thus, the availability of serotonin is decreased in the progesterone-dominant luteal phase. However, the interaction must be more complex, because replacement of progesterone alone does not ameliorate symptoms. Absolute levels of progesterone have not been found to be different in women with PMDD and those without, and monoamine oxidase inhibitors do not improve symptoms in these patients. More recent data implicate γ-aminobutyric acid as an important factor in decreasing levels of allopregnanolone, a progesterone metabolite.
Diagnosis
Virtually any condition that results in mood or physical changes in any cyclic fashion may be included in the differential diagnosis of PMS (Box 43.3). Studies have shown that a patient’s recall of symptoms and timing of symptoms is often biased and thus inaccurate, because of widespread societal expectations and cultural prominence of “the PMS.” The majority of patients who present for treatment of PMS do not actually demonstrate symptoms restricted to the luteal phase; thus, the diagnosis of PMS and PMDD should be rigorously established using the criteria outlined.
The physician must remain open minded at the outset, and not prematurely exclude the primary problem. In the differential diagnosis, the physician should consider medical problems, psychiatric disorders, and premenstrual exacerbations of medical and/or psychiatric conditions. Perimenopause can also present with similar symptoms (see Chapter 41).
Menstrual Diary
Because the etiology of PMS and PMDD is not clear, no definitive physical examination or laboratory markers are available to aid in diagnosis. At present, the definitive diagnosis of PMS and PMDD hinges on documentation of the relationship of the patient’s symptoms to the luteal phase. Prospective documentation of symptoms can be accomplished using a menstrual diary in two or more consecutive menstrual cycles. The patient is asked to monitor her symptoms and the pattern of menstrual bleeding for two or more cycles. For PMS, she needs only to have one of the listed symptoms but must have a symptom-free interval. For PMDD, the patient is asked to also monitor the severity of symptoms. She must demonstrate 5 of the listed 11 symptoms (see Box 43.2), one of which must be a core symptom. She must also demonstrate a symptom-free follicular phase. If her symptoms persist during the follicular phase but are less severe, luteal phase worsening of a different disorder (sometimes called entrainment) should be considered.
Many physical and psychiatric disorders are known to worsen in the luteal phase, including irritable bowel syndrome and major depressive disorder (MDD). It is important to distinguish these disorders from PMDD. It is particularly important to distinguish MDD and PMDD because of the risk of suicide in patients with MDD. A variety of diagnostic tools exist to assist patients with keeping their menstrual diaries. Figure 43.1 shows one such tool called “Daily Record of Severity of Problems.”
BOX 43.3 Differential Diagnosis of Premenstrual Syndrome
Allergy
Breast disorders (fibrocystic change)
Chronic fatigue states
Anemia
Chronic cytomegalovirus infection
Lyme disease
Connective tissue disease (lupus erythematosus)
Drug and substance abuse
Endocrinologic disorders
Adrenal disorders (Cushing syndrome and hypoadrenalism)
Adrenocorticotropic hormone–mediated disorders Hyperandrogenism
Hyperprolactinemia
Panhypopituitarism
Pheochromocytoma
Thyroid disorders (hypothyroidism and hyperthyroidism)
Family, marital, and social stress (physical or sexual abuse)
Gastrointestinal conditions
Inflammatory bowel disease (Crohn disease and ulcerative colitis)
Irritable bowel syndrome
Gynecologic disorders
Dysmenorrhea
Endometriosis
Pelvic inflammatory disease
Perimenopause
Uterine leiomyomata
Idiopathic edema
Neurologic disorders
Migraine
Seizure disorders
Psychiatric and psychological disorders
Anxiety neurosis
Bulimia
Personality disorders
Psychosis
Somatoform disorders
Unipolar and bipolar affective disorders
From Smith RP. Gynecology in Primary Care. Baltimore, MD: Lippincott Williams & Wilkins; 1996:434.
Diagnostic Tests
Patients with PMDD should be evaluated to rule out specific pathology, although it is also important to understand that no specific physical findings are diagnostic of PMDD. It is reasonable to perform a complete blood count and evaluate the thyroid-stimulating hormone level, because thyroid disease and anemia are quite common in young menstruating women; however, there is no evidence that anemia and thyroid disease occur more frequently in patients who present for treatment of PMS or PMDD.
FIGURE 43.1. Daily Record of Severity of Problems. © 1977 Jean Endicott, PhD, and Wilma Harrison, MD.
TREATMENT
The prospective charting of symptoms not only documents the cyclic or noncyclical nature of the patient’s symptoms but also allows her to play a key role in the diagnostic and management team. This will allow her to regain some control of her symptoms. For some women, providing a diagnostic label helps relieve the fear that they are “going crazy.” A patient’s symptoms may become more bearable as she gains insight. The symptom calendar is usually continued during the treatment phase to monitor the effectiveness of treatment and to suggest the need for further focused therapy.
Nonpharmacologic Treatment
Diet recommendations emphasize eating fresh rather than processed foods. The patient is encouraged to eat more fruits and vegetables and minimize the intake of refined sugars and fats. Minimizing salt intake may help with bloating, and eliminating caffeine and alcohol from the diet can reduce nervousness and anxiety. None of these therapies have shown statistically significant improvements in PMS and PMDD, but they are reasonable; benign; a good part of general health improvement; and, in some studies, have demonstrated trends toward improvement. Clearly, these interventions yield low risks and are generally healthful behaviors.
Lifestyle interventions that have demonstrated significant improvement in symptoms include aerobic exercise and calcium carbonate and magnesium supplementation. Aerobic exercise, as opposed to static (e.g., weightlifting) exercise, has been found to be helpful in some patients, possibly by increasing endogenous production of endorphins. Calcium decreases water retention, food cravings, pain, and negative affect compared with placebo.
Other interventions have been studied but demonstrate conflicting results. These include vitamins E and D and chaste tree berry extract as well as relaxation therapy, cognitive therapy, and light therapy. Many of these therapies have no untoward side effects and can be considered for certain patients. Studies have shown that vitamin B6 supplementation has limited clinical benefit. Patients should be cautioned that dosages in excess of 100 mg/day may cause medical harm, including peripheral neuropathy. Studies of evening primrose oil demonstrate no benefit. Alternative therapies include meditation, aromatherapy, reflexology, acupuncture, acupressure, and yoga. Further research is warranted in these areas.
Pharmacologic Treatment
In addition to lifestyle changes, behavioral therapies, and dietary supplementation, some pharmacologic agents have been shown to provide symptomatic relief. Nonsteroidal anti-inflammatory agents have been found in controlled trials to be useful in PMS patients with dysmenorrhea, breast pain, and leg edema but not useful in treating other aspects of PMS. This effect is possibly related to prostaglandin production in various sites in the body. Spironolactone decreases bloating but does not relieve other symptoms.
Ovulation Suppression
Because the underlying mechanism appears to be normal hormone fluctuations triggering an abnormal serotonin response, it would seem that medications to induce anovulation should be beneficial in the treatment of PMS/ PMDD; however, ovulation suppression does not seem to help patients with PMDD. The research on PMS/PMDD has been fraught with multiple challenges because the strict criteria for diagnosis of PMS/PMDD have only recently been established and standardized, many previous studies suffered from poor methodology, and the placebo effect (30%–70%) in patients with PMS/PMDD is significant. Because symptoms are associated with ovulatory cycles, suppressing ovulation is beneficial for some patients with PMS and can be accomplished by using oral contraceptives, danazol, or gonadotropin-releasing hormone (GnRH) agonists. Oral contraceptives are a logical first choice for patients who also require contraception. Some patients, however, find that their symptoms worsen when taking oral contraceptives.
Selective Serotonin Reuptake Inhibitors
The medical treatment of PMDD differs from that of PMS. In patients who have been diagnosed with PMDD using the strict criteria, the gold standard of treatment is the SSRIs.
Though many medications have been studied, only four are U.S. Food and Drug Administration approved for the treatment of PMDD: fluoxetine, sertraline, paroxetine controlled release, and drospirenone/ethinyl estradiol. In a Cochrane Database Review, 15 randomized placebo-controlled trials demonstrated benefit with SSRIs. The combination of drospirenone and ethinyl estradiol is the only oral contraceptive regimen that has demonstrated benefit and is the newest therapeutic choice for the treatment of PMDD. SSRIs are effective when dosed continuously (daily dosage) or dosed intermittently (taken only during the luteal phase [14 days prior to the onset of menses]). Patients often report improvement with their first cycle of use, lending credence to the idea that the pathophysiology of PMDD is different from that of MDD, in which treatment can take weeks to demonstrate improvement. Side effects of SSRIs include gastrointestinal upset, insomnia, sexual dysfunction, weight gain, anxiety, hot flushes, and nervousness.
Other Treatments
The use of danazol and GnRH agonists has been demonstrated to be beneficial in short-term studies, but long-term effects of such drugs for PMS/PMDD have not been fully evaluated, and these medications are associated with significant, often prohibitive, side effects. The use of either constitutes a “medical oophorectomy” and may be used as a trial before surgical oophorectomy is undertaken. Oophorectomy should be reserved for those severely affected patients who meet strict diagnostic criteria and who do not respond to any potentially effective therapy other than GnRH agonists.
Clinical Follow-Up
After filling out 2 months, worth of prospective daily ratings, the data demonstrate she meets the criteria for premenstrual dysphoric disorder and does not meet criteria for major depressive disorder. She starts taking an selective serotonin reuptake inhibitor and feels better within a month. She plans to continue this for at least a couple of years after which point she will reassess with her physician.
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