Adolescent Health Care: A Practical Guide

Chapter 50

Dysmenorrhea and Premenstrual Syndrome

Paula K. Braverman

More than 50% of female adolescents experience menstrual dysfunction, including dysfunctional uterine bleeding, amenorrhea, dysmenorrhea, and the premenstrual syndrome. Many of the problems are minor, including mild dysmenorrhea and minor variations in cycle length or amount of flow. However, the dysfunction can become more severe when amenorrhea, debilitating dysmenorrhea, or severe dysfunctional bleeding occurs. This chapter and the next several chapters deal with the evaluation of common adolescent menstrual dysfunctions. Dysmenorrhea, the most prevalent of these, is considered first.

Dysmenorrhea

The term primary dysmenorrhea refers to pain associated with the menstrual flow, with no evidence of organic pelvic disease. Secondary dysmenorrhea refers to pain associated with menses secondary to organic disease such as endometriosis, outflow tract obstruction, or pelvic inflammatory disease.

Etiology

Psychological Factors

Psychosocial factors may play a role in dysmenorrhea.

1. One study of college students found an association between dysmenorrhea and anxiety, depression, and a loss of social support networks (Alonso and Coe, 2001).
2. A study of adolescents taking naproxen therapy for dysmenorrhea found that those with more severe symptoms had lower self-concept (DuRant et al., 1985).

Myometrial Factors

Pain is caused by myometrial contractions induced by prostaglandins from the secretory endometrium.

1. Uterine pressure during menses can exceed contraction pressures found during labor.
2. In patients with dysmenorrhea, contractions have been noted to have high frequency, amplitude, and resting tone.
3. When comparing more severe primary dysmenorrhea to mild symptoms, there may be higher intrauterine pressure and more vasoconstriction in smaller branches of the uterine artery (Alvin and Litt, 1982; Dmitrovic et al., 2003).

Prostaglandins

Prostaglandins are formed in the secretory endometrium. Phospholipids from cell membranes are converted into arachidonic acid, the fatty acid precursor for prostaglandin synthesis. Prostaglandin E₂ (PGE₂) and PGF_2α are the key prostaglandins involved in dysmenorrhea, although PGF_2α is considered the most important. They are formed through the cyclooxygenase pathway, which also produces thromboxanes and prostacyclin. PGF_2α induces myometrial contractions, vasoconstriction, and ischemia and mediates pain sensation, whereas PGE₂ causes vasodilation and platelet disaggregation. There are two enzymes in the cyclooxygenase system. The COX-1 enzyme has homeostatic functions including gastrointestinal mucosal integrity, renal and platelet function, and vascular hemostasis. COX-2 is induced by inflammation. It has been noted that:

1. Locally, prostaglandins cause uterine contractions, but they enter the systemic circulation and cause associated symptoms such as headache, nausea, vomiting, backache, diarrhea, dizziness, and fatigue.
2. Exogenous injection of PGE₂and PGF_2α produce myometrial contractions and pain similar to dysmenorrhea, although PGE₂ also inhibit contractions in the nonpregnant uterus.
3. Anovulatory cycles are associated with lower prostaglandin levels in the menstrual fluid and usually no dysmenorrhea. Because many cycles in the first 2 years after menarche are anovulatory, many adolescents do not experience dysmenorrhea from the outset. Rather it occurs more frequently 1 to 3 years after menarche.
4. Patients with dysmenorrhea have higher levels of prostaglandins in the endometrium.
5. Most of the prostaglandins are released in the first 48 hours of menstruation, correlating with the most severe symptoms.
6. Prostaglandin inhibitors decrease dysmenorrhea.

From this evidence it has been presumed that primary dysmenorrhea is related to prostaglandins released during menses, which seems to be increased during ovulatory cycles. It is postulated that women with dysmenorrhea may be more sensitive to prostaglandins. Prostaglandin levels have also been shown to be locally elevated in cases

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of secondary dysmenorrhea such as endometriosis (Koike et al., 1992).

Epidemiology

Dysmenorrhea is the greatest single cause of lost work and school hours in females, with>140 million hours lost per year (Ylikorkala and Dawood, 1978). Various studies worldwide have shown the following:

1. Forty-three percent to 93% of all postpubescent females have some degree of dysmenorrhea; between 5% and 42% of these females describe the pain as severe and are incapacitated for 1 to 3 days per month.
2. Reports of school absence increase with more severe symptoms.
3. Ethnicity and cultural factors may also influence responses to pain.
4. In a study utilizing a cross-sectional national probability sample of 12- to 17-year olds from the National Center for Health Statistics, black adolescents in the United States were more likely to miss school because of dysmenorrhea (23.6%) than whites (12.3%) despite having the same rates of dysmenorrhea (Klein and Litt, 1981).
5. A more recent study of 706 Hispanic adolescents surveyed in a high school showed that they were even more likely to report missing school (38%) (Banikarim et al., 2000).

The prevalence of dysmenorrhea increases with age and pubertal stage.

1. In the study by Klein and Litt (1981), the prevalence of dysmenorrhea rose from 39% of 12-year-old girls to 72% of 17-year-old girls and 38% at SMR 3 to 66% at SMR 5 (Klein and Litt, 1981).
2. Pedron-Nuevo et al. (1998) found rates of 52.1% for those younger than 15 years and 63.8% for those 15- to 19-years old.
3. Teperi and Rimpela (1989) found dysmenorrhea among 48% of 12-year-old postmenarchal girls and among 79% of 18-year olds.

Clinical Manifestations

Primary dysmenorrhea usually begins within 1 to 3 years of menarche and is associated with the establishment of ovulatory cycles. Although the pain usually begins within a few hours of starting menses, it may also start several days before the onset of menses. Local symptoms include pain that is spasmodic in nature and is strongest in the lower abdomen, with radiation to the back and anterior aspects of the thighs. In most cases, the pain resolves within 24 to 48 hours but sometimes the symptoms may persist further into the menstrual cycle. Associated systemic symptoms can include nausea or vomiting, fatigue, mood change, dizziness, diarrhea, backache, and headache.

It may be useful to grade dysmenorrhea as follows:

1. Grade I: Mild dysmenorrhea that does not interfere with the adolescent's participation in everyday activity
2. Grade II: Moderate dysmenorrhea that may interfere in the adolescent's participation in some activities; minimal, if any, systemic symptoms
3. Grade III: Severe discomfort; adolescent restricted from activities for several days; often associated with systemic symptoms

Differential Diagnosis

Gynecological Causes

1. Endometriosis: Endometriosis is characterized by the presence of endometrial glands and stroma outside of the uterus. These implants are commonly located in various locations throughout the pelvis. This condition is not as rare in adolescents as previously thought. In addition to being the most common pathological condition in adolescents with chronic pelvic pain (Laufer and Goldstein, 2005), it is considered a progressive disease that increases in prevalence and severity with age (American College of Obstetrics and Gynecology, 2005). Endometriosis has been diagnosed as follows:
2. By laparoscopy in 19% to 73% of adolescents being evaluated for chronic pelvic pain
3. In premenarchal girls at the initial stages of puberty and as young as age 8 (Laufer et al., 2003).
4. By laparoscopy in 50% to 70% of adolescents with chronic pelvic pain not responsive to oral contraceptive pills (OCP) and nonsteroidal anti-inflammatory drugs (NSAIDs).

The symptoms of endometriosis in adolescents include chronic pelvic pain, which may be cyclic or acyclic. Cyclic pain alone is found in only 9.4% of adolescents (American College of Obstetrics and Gynecology, 2005). This is in contrast to adults who are more likely to have cyclic pain. Other associated symptoms can include dyspareunia; irregular menses; bowel symptoms such as rectal pain, nausea, constipation, diarrhea, and pain on defecation; and urinary symptoms such as dysuria, urgency, and frequency.

On examination, a tender or nodular cul-de-sac or tender uterosacral ligaments may be found. However, adolescents may not have the classic thickened nodular sacrouterine ligaments. Ovarian endometriomas are not usually found before the mid-twenties. Goldstein et al. (1980) found pelvic tenderness in 76% of adolescents with endometriosis whereasReese et al. (1996) found diffuse tenderness in 95% of patients and localized tenderness in 77.6%.

Endometriosis should by considered in patients with dysmenorrhea who do not respond to a combination of OCP and NSAID, as well as those with associated bowel or urinary function symptoms. This diagnosis is also more common when there is a positive family history for endometriosis.

2. Pelvic inflammatory disease
3. Benign uterine tumors: Fibroids
4. Intrauterine device
5. Anatomical abnormalities: Congenital obstructive müllerian malformations, outflow obstruction. Obstructive müllerian abnormalities predispose the patient to endometriosis.
6. Pelvic adhesions
7. Ovarian cyst or mass

Nongynecological Causes

1. Gastrointestinal disorders: Inflammatory bowel disease, irritable bowel syndrome, constipation, lactose intolerance

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2. Musculoskeletal pain: Inflammatory process, trauma, tumor
3. Genitourinary abnormalities: Cystitis, ureteral obstruction, calculi
4. Psychogenic disorders: History of abuse, trauma, psychogenic complaints

Diagnosis

History

1. Menstrual history: Primary dysmenorrhea usually starts 1 to 3 years after menarche, most commonly begins between the ages of 14 and 15 years, and peaks at age 17 or 18. It usually decreases during the twenties and thirties. Secondary dysmenorrhea should be considered if the pain starts with the onset of menarche or after the age of 20 years. Adolescents should be asked about the degree of pain and the amount of impairment in school and other activities. Any previous use of therapeutic modalities and their effectiveness should be ascertained.
2. Prior sexually transmitted diseases and sexual history: This information helps to eliminate infection as a cause.
3. Gastrointestinal and genitourinary systems history: This information helps to eliminate gastrointestinal or genitourinary problems (e.g., cystitis, irritable bowel syndrome) as a cause of pain.
4. Musculoskeletal history: This reveals bone or joint problems including trauma or possible tumor.
5. Psychosocial history: Evaluate for stressors, substance abuse, and sexual abuse. Cigarette smoking, especially heavy smoking, has been found to be associated with dysmenorrhea (Hornsby et al., 1998).

Physical Examination

Examine the pelvis for evidence of endometriosis, endometritis, fibroids, uterine or cervical abnormalities, or adnexal masses and tenderness. However, if the teen is not sexually active and the history is typical for dysmenorrhea, a pelvic examination is indicated only if the symptoms do not respond to standard medical therapy. Examination limited to a cotton swab inserted into the vagina can help rule out a hymenal abnormality or vaginal septum without performing a speculum examination. The musculoskeletal examination should focus on range of motion of the hips and spine to assess for tenderness and limitation in motion.

Laboratory Tests

A complete blood count and a determination of the erythrocyte sedimentation rate should be done if pelvic inflammatory disease or inflammatory bowel disease is suspected. Sexually active adolescents should be tested for sexually transmitted diseases and pregnancy. A urinalysis and urine culture will help diagnose urinary tract problems. If a müllerian abnormality is suspected, ultrasonography or magnetic resonance imaging will define the anatomy. If evaluation of the genitourinary, gastrointestinal, and musculoskeletal systems fail to reveal a cause of the pain and if the pain is severe and intractable despite treatment with antiprostaglandins and oral contraceptives, laparoscopy should be considered.

Therapy

The two most effective treatments for primary dysmenorrhea are with NSAIDs and oral contraceptives.

Education

The patient should be educated and reassured that the problem is physiological and can be helped. The importance of education has been demonstrated repeatedly in studies demonstrating that adolescents have a knowledge deficit about available treatment modalities and how to use them most effectively (Johnson, 1988; Wilson and Keye, 1989;Campbell and McGrath, 1997; Hillen et al., 1999).

Nonsteroidal Anti-inflammatory Drugs

NSAIDs are the primary modality of therapy; 80% of dysmenorrhea can be relieved with these medications. Because much of primary dysmenorrhea is secondary to prostaglandin-mediated uterine hyperactivity, prostaglandin inhibitors can alleviate menstrual cramps and associated systemic symptoms. Many NSAIDs have been found effective in alleviating menstrual cramps. They are divided into two classes—carboxylic acids and enolic acids. Carboxylic acids are more widely used and are divided into four subgroups: (a) salicylic acids (aspirin), (b) acetic acids (indomethacin), and the two most useful sub-groups—(c) propionic acids such as ibuprofen (Motrin), naproxen (Naprosyn), and naproxen sodium (Anaprox), and the (d) fenamates such as mefenamic acid (Ponstel). Of the propionic acids, naproxen sodium may have a shorter onset of action because it is more rapidly absorbed. Mefenamic acid has an additional mechanism of action: It competes with prostaglandin-binding sites and antagonizes existing prostaglandins in addition to inhibiting prostaglandin synthesis. Some of these drugs and their typical doses are as follows:

Drug (Trade Name) Initial Dose (mg) Following Dose (mg) Propionic acids Ibuprofen (Motrin) 400 400 q4–6h Naproxen (Naprosyn) 500 250 q6–8h Naproxen sodium (Anaprox) 550 275 q6–8h Fenamates 500 250 q6h Mefenamic acid (Ponstel) 500 250 q6h

Over-the-counter ibuprofen is available in preparations such as Advil and Nuprin. Naproxen is available as Aleve. Because these over-the-counter medications come in lower doses than the prescription formulations, a larger number of tablets may be needed for effectiveness. The medications should be started either as soon as possible when the symptoms of dysmenorrhea occur or to coincide with the first sign of menstruation. It is not necessary to start before the onset of menses. Usually, these medications are needed only for 1 to 3 days. After one of the NSAIDs is started, it should be tried for two or three menstrual cycles before being judged ineffective. At that time, a trial of a different prostaglandin inhibitor should be performed with a minimum trial of at least 6 months for this mode of therapy.

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With the outlined doses used for short periods, side effects are usually minimal, but they include the following in more than 1% of patients:

1. Gastrointestinal: Nausea, epigastric pain, vomiting, constipation
2. Central nervous system (CNS): Dizziness, headache
3. Skin: Rash
4. Cardiovascular: Edema, palpitations
5. Other: Tinnitus

The NSAIDs discussed in the preceding text inhibit both the COX-1 and COX-2 enzymes. However, selective COX-2 inhibitors will have less gastrointestinal side effects and may also be preferred in patients with coagulation disorders related to platelet function. Multiple studies have evaluated various drugs in this class and have found that they are equivalent to naproxen in relieving dysmenorrhea symptoms. Because of recent drug recalls, the only COX-2 inhibitor available at the time of this printing is celecoxib. The dosing is 400 mg as a loading dose followed by 200 mg every 12 hours (Harel, 2005). These medications are more expensive, potentially more toxic and not necessarily superior in efficacy to less expensive, nonselective NSAIDs.

Hormonal Therapies

If the patient wishes contraception or the pain is severe and not responsive to NSAIDs, oral contraceptives can be tried. The maximal effect may not become apparent for several months.

1. Combined oral contraceptives inhibit ovulation and lead to an atrophic decidualized endometrium resulting in decreased menstrual flow and prostaglandin release.
2. Oral contraceptives decrease symptoms in>90% of patients with primary dysmenorrhea.
3. OCPs are also useful to treat endometriosis because they decrease endometrial proliferation and thereby decrease total local prostaglandin production.

A 2001 Cochrane review (Proctor et al., 2001) conducted a meta-analysis of randomized clinical trials and concluded that OCPs with older first and second generation progestins and higher hormone doses than current OCPs were more effective than placebo for primary dysmenorrhea. However, they commented on the small size of the studies and poor quality. Two more recent studies address this knowledge deficit:

1. A randomized, double-blind, placebo-controlled study of a low-dose OCP containing 20 µg of ethinyl estradiol and 150 µg of desogestrel has shown a significant decrease in primary dysmenorrhea (Hendrix and Alexander, 2002).
2. A randomized, double-blind, placebo-controlled study in 76 adolescents with moderate to severe dysmenorrhea showed that a modern low-dose OCP containing 20 µgof ethinyl estradiol and 100 µg of levonorgestrel was more effective than placebo (Davis et al., 2005).

If cyclic hormonal contraception is ineffective then continuous combination hormonal therapy can be tried. Monophasic OCPs can be used by skipping the placebo pills. An extended cycling OCP, Seasonale, is currently available as a 91-pill regimen containing 84 hormonal pills before the week of placebo with 30 µg of ethinyl estradiol and 150 µg of levonorgestrel. Extended cycling may be particularly helpful in endometriosis (American College of Obstetrics and Gynecology, 2005; Vercellini et al., 2003a; Sulak et al., 2002). Theoretically, the contraceptive patch and vaginal ring could be used in the same manner. However, one study showed that cycling with OCPs provided better relief of dysmenorrhea than cycling with the patch (Audet et al., 2001). Injectable depot medroxyprogesterone acetate has also been effective.

Other Hormonal Modalities

1. Gonadotropin-releasing hormone (GnRH) agonists with utilization of add-back therapy to prevent side effects related to hypoestrogenic state (including bone loss) have been tried in severe cases of endometriosis unresponsive to other modalities. Caution should be utilized in patients younger than 16 years because of concerns about compromised bone density accrual (American College of Obstetrics and Gynecology, 2005).
2. Danazol is equivalent to GnRH agonists, but it less utilized because of androgenic side effects (American College of Obstetrics and Gynecology, 2005).
3. Levonorgestrel-releasing intrauterine system has been effective for dysmenorrhea and endometriosis. The current brand marketed is Mirena (Baldaszti et al., 2003; Vercellini et al., 2003b).

Other Nonhormonal Modalities

Likely to be beneficial

1. Vitamin B₁(Proctor and Farquhar, 2004)
2. Magnesium (Proctor and Farquhar, 2004)
3. Vitamin E (Proctor and Farquhar, 2004)
4. Transcutaneous nerve stimulation (Dawood and Ramos, 1990; Kaplan et al., 1997; Proctor and Farquhar, 2004)

Unclear benefit

• 5. Dietary supplementation with ω-3 fatty acids (Harel et al., 1996; Proctor and Farquhar, 2004)
• 6. Acupuncture (Helms, 1987; National Institutes of Health, 1998; Proctor and Farquhar, 2004)

Premenstrual Syndrome

The term premenstrual syndrome (PMS) is used to describe an array of predictable physical, cognitive, affective, and behavioral symptoms that occur cyclically during the luteal phase of the menstrual cycle and resolve quickly at or near the onset of menstruation. It is characterized by a broad spectrum of symptoms and until recently had confusing definitions. The etiology of PMS is currently unknown, but there is some evidence that reduced serotonergic function during the luteal phase and alterations in the γ aminobutyric acid (GABA) receptor complex response, may be responsible, among other mechanisms (Johnson, 2004; Freeman et al., 2004).

In the mid 1980s, more specific criteria were defined, and studies evaluating both the pathophysiology and treatment modalities were designed according to strict scientific standards. Evidence is accumulating that PMS is not a single condition but a set of interrelated symptom complexes, with multiple phenotypes of subtypes, and pathophysiological events that begin with ovulation (Johnson, 2004; Halbreich, 2004).

In the mental health field, criteria have been developed to define a syndrome called premenstrual dysphoric disorder (PMDD) as a distinct clinical entity. Although the PMS and PMDD overlap, in PMDD the focus is more on problems

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with mood and symptoms are more severe. There is a higher level of dysfunction before the onset of menses. Both Johnson (2004); Speroff and Fritz (2005) conclude that it is not useful to differentiate PMS from PMDD, and agree that there is a broad spectrum of severity. Johnson suggests characterizing PMDD as severe PMS with impairment.

Epidemiology

The exact prevalence is unknown, but estimates are that up to 85% of menstruating women have some degree of symptoms before menses, and that 3% to 8% are so severely afflicted that daily activities are hindered. This smaller subset of women meet criteria for PMDD (Chakmakjian, 1983; Singh et al., 1998; American College of Obstetrics and Gynecology, 2000;Grady-Weliky, 2003). As noted by Johnson (2004), approximately 50% of women have only a few mild symptoms for several days during the luteal phase and probably should not be diagnosed as having PMS. Some selected studies in adolescents have shown the following:

1. In one longitudinal study of 384 15-year-old adolescent girls, Raja et al. (1992) found a 14% prevalence of PMS symptoms.
2. In a survey study of 207 adolescents, 89% reported at least one PMS symptom that the teens considered moderately severe, 59% reported at least one symptom considered severe, and 43% had at least one symptom considered extreme (Fisher et al., 1989).
3. A more recent study of 10- to 17-year-old menstruating females attending an Adolescent Outpatient Clinic found that 61.4% had PMS symptoms, with 49.5% having mild symptoms, 37.1% reporting moderate symptoms, and
4. 13.4% with severe symptoms; 71% with dysmenorrhea also had PMS (Derman et al., 2004).

Risk Factors

Risk factors for PMS include advancing age (beyond 30 years) and genetic factors. Some studies suggest that women whose mothers report PMS are more likely to develop PMS (70%, versus 37% of daughters of unaffected mothers) (Van der Akker et al., 1987; Dalton, 1987). In addition, concordance rates for PMS are significantly higher in monozygotic twins (93%) compared with dizygotic twins (44%) (Dalton, 1987). There are no significant differences in personality profile or level of stress in women with PMS compared with asymptomatic women. However, women with PMS may not handle stress as well. One recent article prospectively evaluating a community cohort of 1,488 women aged 14 to 24 over a 42-month period found that traumatic events such as a physical threat, childhood sexual abuse, and severe accidents increased the odds of developing PMDD (Perkonigg et al., 2004).

Pathophysiology

The exact mechanism of PMS is unknown, but is probably the result of an interaction between sex steroids and central neurotransmitters (Mortola, 1998).

1. Alterations in neurotransmitters: Endorphins, GABA, and serotonin have been implicated (Steiner and Pearlstein, 2000).
2. There is inconsistent evidence for differences (e.g., a drop) in circulating endorphins in symptomatic patients.
3. Women with PMS and PMDD have reduced GABA receptor sensitivity and reduced plasma GABA during the luteal phase.
4. Serotonergic dysregulation is the most plausible theory, although not all women respond to selective serotonin reuptake inhibitors (SSRIs), implying that other factors must be involved (Halbreich, 2004).
5. Hormonal factors: Women with PMS/PMDD are felt to be more sensitive to normal cyclical hormonal fluctuations.
6. The levels of sex steroids, estrogen, progesterone, and testosterone are normal, but women with PMS may be more vulnerable to normal fluctuations. This vulnerability may be in part related to serotonin (Steiner and Pearlstein, 2000). Further evidence for the lack of abnormal hormonal changes in the luteal phase comes from the following:

• In a study utilizing the progesterone-antagonist mifepristone to induce menses, there was no relationship between the induction of menses and the timing or severity of PMS symptoms (Schmidt et al., 1991).
• A placebo-controlled study of women with PMS who had ovarian suppression with a GnRH agonist were found to have recurrence of PMS symptoms when given estrogen and progesterone compared to a lack of mood change in the placebo group (Schmidt et al., 1998). These data strongly suggest an abnormal response to normal hormonal changes.

1. Other hormones: There is no proof of a relationship between PMS and prolactin, growth hormone, thyroid hormone, adrenal activity, luteinizing hormone (LH), follicle-stimulating hormone (FSH), antidiuretic hormone, insulin, aldosterone, renin-angiotensin, or cortisol.
2. Vitamin deficiencies: Zinc, vitamin A, vitamin E, thiamine, magnesium, and pyridoxine (vitamin B₆) have been implicated, but not documented. No significant differences have been found, and the data show inconsistent scientific evidence.

Clinical Manifestations

More than 150 symptoms have been described in literature, ranging from mild symptoms to those severe enough to interfere with normal activities.

1. Emotional symptoms
2. Irritability
3. Depression
4. Fatigue or lethargy
5. Anger/argumentative
6. Insomnia or hypersomnia
7. Mood lability
8. Anxiety
9. Poor concentration
10. Confusion
11. Tearfulness
12. Social withdrawal
13. Physical symptoms
14. Headaches
15. Swelling: Legs or breasts/breast tenderness
16. Increased appetite

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1. Food cravings
2. Weight gain
3. Sense of abdominal bloating
4. Fatigue
5. Muscle and joint aches and pain
6. Hot flashes

Diagnosis

The diagnosis relies on the history of cyclic symptoms. No specific physical findings or laboratory tests have proved useful. Although there are no universally accepted specific diagnostic criteria among the various sources defining PMS including the World Health Organization's International Classification of Diseases, ACOG, the National Institute of Mental Health, and the Diagnostic and Statistical Manual of Mental Disorders, (Halbreich, 2004), three important findings are usually needed to make a diagnosis of PMS:

1. Symptoms must occur in the luteal phase and resolve within a few days of onset of menstruation. Symptoms should not be present in the follicular phase.
2. The symptoms must be documented over several menstrual cycles and not caused by other physical or psychological problems.
3. Symptoms must be recurrent and severe enough to disrupt normal activities.

A calendar such as the one shown in Figure 50.1 can be helpful in the diagnosis and in monitoring teens after the start of any therapy. Prospective recording should be done for at least 2 to 3 months to document that symptoms are occurring cyclically in the luteal phase. Other assessment tools include the Self-Assessment Disk (Magos and Studd, 1988), the Premenstrual Assessment Form (Halbreich et al., 1982), Calendar of Premenstrual Experience (COPE) (Mortola et al., 1990), the Prospective Record of the Impact and Severity of Menstrual Symptoms (PRISM) (Reid, 1985), Premenstrual Syndrome Diary (Thys-Jacobs et al., 1995), Daily Record of Severity of Problems (Endicott and Harrison, 1990), and the Penn Daily Symptom Rating (Freeman et al., 1996).

The National Institute of Mental Health (NIMH) criteria require a change of 30% in intensity of symptoms, as measured with the use of an instrument, comparing days 5 through 10 of the cycle with the 6 days before menses. These changes must be documented for at least two consecutive cycles (American College of Obstetrics and Gynecology, 2000).

The Diagnostic and Statistical Manual of Mental Health Disorders, 4th edition text revision (American Psychiatric Association, 2000) lists similar criteria for PMDD (Table 50.1). It is important to remember that the symptoms cannot represent exacerbation of an existing disorder such as major depression, anxiety disorders, panic, dysthymic disorder, or personality disorder, but they may be superimposed on one of these psychiatric disorders. Women may have psychiatric disorders that become exacerbated during menstruation (menstrual magnification). Certain medical disorders can also become worse during menses, including seizures, migraine headaches, irritable bowel syndrome, asthma, and allergies.

Therapy

No single treatment is universally accepted as effective. Studies have yielded conflicting results with most therapies, and most trials have not been well controlled. Treatments include the following:

1. Lifestyle changes: Although lifestyle changes have not been definitively proved in controlled studies, establishing good exercise and stress management practices can improve overall feelings of well being.
2. Education: The teen should be educated regarding menstrual physiology and the relationship of changing hormones to symptoms. A small study of college students with PMS demonstrated a decrease in perimenstrual symptoms with a health promotion intervention in a peer group setting that positively reframed menstrual cycle perceptions (Morse, 1999).
3. Stress management: The teen can be taught or referred for techniques to manage stress (e.g., biofeedback, self-hypnosis, relaxation exercises). If symptoms of stress are more significant, psychological counseling including cognitive-behavioral therapy or group therapy may be helpful (Girman et al., 2003; Johnson, 2004). Studies have demonstrated improvement in PMS with cognitive-behavior therapy (Kirkby, 1994; Christensen and Oei, 1995; Blake et al., 1998).
4. Exercise: Regular aerobic exercise has been reported to help some women with PMS (Prior et al., 1987; Steege and Blumenthal, 1993; Scully et al., 1998).
5. Vitamin, mineral supplementation, herbal preparations, and dietary manipulation: There have been some positive outcomes for these complementary and alternative therapies. However, although some show promise, more research needs to be carried out to recommend definitively any of these therapies (American College of Obstetrics and Gynecology, 2000; Pearlstein and Steiner, 2000; Stevinson and Ernst, 2001; Girman et al., 2003; Johnson, 2004).
6. Calcium (1,200 mg/day) in the form of calcium carbonate was reported to reduce physical and emotional symptoms in a well-designed, multi-center study (Thys-Jacobs et al., 1998; American College of Obstetrics and Gynecology, 2000; Girman et al., 2003; Johnson, 2004). Further evidence for a role for calcium was found in a recent case–control study, nested in the Nurses' Health Study II, which prospectively evaluated women initially free from PMS and followed them up three times between 1991 and 1999. The results showed that high intake of calcium and vitamin D was associated with a reduced risk of developing PMS (Bertone-Johnson et al., 2005).
7. Magnesium (200 to 400 mg/day) has been noted to reduce negative mood and to reduce water retention and appears to be more effective than placebo in some studies. The mechanism of action is not fully understood and usage not well studied (Facchinetti et al., 1991; Walker et al., 1998; American College of Obstetrics and Gynecology, 2000;Girman et al., 2003).
8. Pyridoxine (vitamin B₆) has been used extensively in the past, particularly in treating the emotional symptomatology of PMS. However, a review of the literature yields conflicting results, and this vitamin is considered to be of limited benefit. The other concern is that peripheral neuropathy can develop with doses>100 mg/day (Wyatt et al., 1999; American College of Obstetrics and Gynecology, 2000

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; Girman et al., 2003; Johnson, 2004).

FIGURE 50.1 Premenstrual symptom calendar.

TABLE 50.1 Diagnosis of Premenstrual Dysphoric Disorder (DSM-IV-TR Criteria)

Adapted from American Psychiatric Association. Diagnostic and statistical manual of mental disorders text revision,4th ed. Washington, DC: American Psychiatric Press, 2000. 1. In most menstrual cycles in the last year at least 5 of these symptoms (including at least one of the symptoms in category A) were present for most of the time 1 wk before menses, began to remit within a few days after the onset of the follicular phase (menses), and were absent in the week after menses. 1. 1. Markedly depressed mood, feelings of hopelessness or self-deprecating thoughts 2. Marked anxiety, tension 3. Marked affective lability (i.e., feeling suddenly sad or tearful) 4. Persistent and marked anger or irritability or increased interpersonal conflicts 2. Other symptoms 1. Decreased interest in usual activities such as friends and hobbies 2. Subjective sense of difficulty in concentrating 3. Lethargy, easy fatigability, or marked lack of energy 4. Marked change in appetite, overeating, or specific food cravings 5. Hypersomnia or insomnia 6. A subjective sense of being overwhelmed or out of control 7. Other physical symptoms (e.g., breast tenderness, bloating, weight gain, headache, joint or muscle pain) 2. The symptoms markedly interfere with work, school, usual activities, or relationships with others. 3. Symptoms are not merely an exacerbation of another disorder, such as major depressive disorder, panic disorder, dysthymic disorder, or a personality disorder (although it may be superimposed on any of these disorders). 4. Criteria I, II, and III are confirmed by prospective daily ratings for at least two consecutive symptomatic menstrual cycles.

1. Vitamin E (400 IU/day) was found to improve somatic and affective symptoms. However, there is limited evidence of its effectiveness (London et al., 1987; American College of Obstetrics and Gynecology, 2000; Stevinson and Ernst, 2001).
2. Vitex agnus-castus(chasteberry) has been found to be superior to placebo in reducing PMS symptoms in some studies. Long-term randomized trials are needed. Chasteberry extracts can potentially affect gonadotropins, as well as estrogen, progesterone, and prolactin. It may also have agonistic effects at dopamine receptors. It should be avoided in pregnancy and breast-feeding (Berger et al., 2000; Schellenberg, 2001; Stevinson and Ernst, 2001; Atmaca et al., 2003; Girman et al., 2003; Johnson, 2004).
3. Ginkgo biloba(ginkgo leaf extract) has been shown to improve breast tenderness, fluid retention, and mood in a placebo-controlled study. The dose is 80 mg twice a day from day 16 of the menstrual cycle through day 5 of menses. Ginkgo inhibits platelet activating factor and may increase bleeding risks. It also interacts with the CYP 450 enzymes and may not be appropriate for individuals on certain medications. Finally, there is concern about increasing the risk of seizures (Girman et al., 2003; Johnson, 2004).
4. Carbohydrate supplements: Mood and carbohydrate food craving improved in randomized trials evaluating the intake of simple and complex carbohydrates. Carbohydrates may increase tryptophan, which is a precursor to serotonin (Sayegh et al., 1995; Stevinson and Ernst, 2001; Johnson, 2004).
5. Other dietary recommendations: Recommendations have been made based on observations that included eliminating high-sodium foods and caffeine, as well as consuming a low-fat, high-fiber diet, and eliminating refined and processed carbohydrates. However, these have not been adequately studied to date to assess efficacy for PMS (Girman et al., 2003; Johnson, 2004).
6. Primrose oil: This method does not appear to be effective.
7. Suppression of ovulation: Because PMS appears to be a cyclic disorder of menses occurring in the luteal phase, suppression of ovulation has been used as a therapy.
8. Combination oral contraceptives: Some authorities consider OCPs to be first-line medications. However, data on their effectiveness is mixed. Symptoms in some individuals with PMS worsen with use of oral contraceptives (Joffe et al., 2003). A newer double-blind placebo-controlled study of an OCP containing drospirenone and 30 µg of ethinyl estradiol was conducted for PMDD (Freeman et al., 2001). Drospirenone has spironolactone antimineralocorticoid and antiandrogenic properties. Statistically significant improvement with this OCP was limited to appetite, acne, and food cravings. However, a more recent multi-center, double-blind, randomized study using 24/4 formulation OCP containing drospirenone and 20 µgofethinyl estradiol demonstrated improvement in both mood and physical symptom scores in subjects with PMDD.

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Possible reasons for efficacy of this new formulation include the lower estrogen dose, as well as improved follicular suppression. The maintenance of a more stable hormonal environment due to the longer number of days on hormone may also be helpful (e.g., 24 rather than 21 days) (Yonkers et al., 2005). The current thinking is that OCP should be considered if the symptoms are primarily physical and not mood related because they appear to be better for the physical symptoms. However, the 24/4 formulation OCP appears to be effective for both types of symptoms.

• Medroxyprogesterone acetate (Depo-Provera) is an alternative contraceptive to suppress ovulation.
• Continuous hormonal therapy with combined hormonal contraceptives can also be considered to suppress cyclic changes and endogenous sex hormone variability (Johnson, 2004; Speroff and Fritz, 2005; Laufer and Goldstein, 2005).

1. GnRH: Most studies have shown benefit from the use of GnRH, but the hypoestrogenic effects with loss of bone density is concerning, especially for adolescents, and therefore limit its use. GnRH with add-back therapy with estrogen and progesterone can be considered when other modalities have failed (Freeman et al., 1997; American College of Obstetrics and Gynecology, 2000; Johnson, 2004; Laufer and Goldstein, 2005). However, add-back regimens may cause a recurrence in PMS/PMDD symptoms. Some have used progestin-only add-back therapy with norethindrone (Johnson, 2004)
2. Bilateral salpingo-oophorectomy would not be considered in adolescents.
3. Natural progesterones: Double-blind, crossover, placebo-controlled trials of vaginal suppositories and oral micronized progesterone have failed to show any benefit.
4. Medications to suppress symptoms
5. Prostaglandin inhibitors: NSAIDs have been used to treat PMS, particularly for the physical symptoms. These have included naproxen sodium, naproxen, or mefenamic acid during the luteal phase. Therapy is stopped after menses begins.
6. Spironolactone, 100 mg/day on days 15 through 28, has been shown to have some positive effects on somatic and affective symptoms, but the results are not conclusive. Spironolactone may be helpful in patients with breast tenderness, bloating, or weight gain from fluid retention (Grady-Weliky, 2003; Johnson, 2004; Laufer and Goldstein, 2005). Other diuretics are not effective (Wang et al., 1995; American College of Obstetrics and Gynecology, 2000).
7. SSRIs: SSRIs are the drugs of choice and first-line therapy for severe PMS/PMDD (Dimmock et al., 2000). Placebo-controlled studies have shown that they are effective for severe PMS and PMDD and improve both physical symptoms and mood (Wyatt et al., 2005). Fluoxetine, sertraline, paroxetine, citalopram, and escitalopram are all effective (Freeman, 2004; Freeman et al., 2005). Venlafaxine inhibits both serotonin and norepinephrine uptake and has been effective for PMDD (Freeman et al., 2001; Freeman, 2004; Johnson, 2004).
8. Studies have shown that using these drugs intermittently only during the luteal phase (i.e., 14 days before onset of menses) rather than continuously is equally effective for symptom reduction.
9. Unlike treatment for depression, symptoms improve within 24 to 48 hours of initiating therapy and there are no reports of discontinuation symptoms when SSRIs are used intermittently for PMDD.
10. Low doses are usually effective (Table 50.2).
11. The most common adverse effects include insomnia, gastrointestinal disturbances, and fatigue. Other side effects include dizziness, sweating, and sexual function disturbances, but these medications are usually well tolerated (Wyatt et al., 2005).
12. Medications to suppress psychological symptoms: Studies have shown some positive effects on somatic and affective symptoms. Suggested therapies have included anxiolytics and other antidepressants such as benzodiazepines (especially alprazolam), clomipramine, and buspirone. These medications can be given in the luteal phase rather than continuously (Smith et al., 1987; Harrison et al., 1990; Freeman et al., 1995; Landen et al., 2001).
13. Buspirone is a partial serotonin receptor agonist.
14. Clomipramine, a tricyclic antidepressant is a nonselective inhibitor of serotonin reuptake.
15. Alprazolam affects the GABA receptor complex. None of these medications would be recommended for routine use in adolescents, but only for use in selected adolescents with severe symptoms unresponsive to other treatment modalities.

TABLE 50.2 Doses of Commonly Used Medications for Premenstrual Dysphoric Disorder

Name of Drug Dose Schedule a Preliminary study Freeman EW, Sondheimer SJ, Sammel MD, et al. A preliminary study of luteal phase versus symptom-onset dosing with escitalopram for premenstrual dysphoric disorder. J Clin Psychiatry 2005;66:789. b Intermittent dosing with just preliminary data, Cohen LS, Soares CN, Lyster A, et al. Efficacy and tolerability of premenstrual use of venlafaxine (flexible dose) in the treatment of premenstrual dysphoric disorder. J Clin Psychopharmacol 2004;24:540; Freeman EW, Rickels K, Yonkers KA, et al. Venlafaxine in the treatment of premenstrual dysphoric disorder. Obstet Gynecol2001;98:737. Adapted from Grady-Weliky TA. Premenstrual dysphoric disorder. N Engl J Med 2003;348:433; Johnson SR. Premenstrual syndrome, premenstrual dysphoric disorder, and beyond: a clinical primer for practitioners. Obstet Gynecol 2004;104:845; Freeman EW, Rickels K, Sondheimer SJ, et al. Continuous or intermittent dosing with sertraline for patients with severe premenstrual syndrome or premenstrual dysphoric disorder. Am J Psychiatry 2004;161:343. Fluoxetine 20 mg/d Intermittent Sertraline 50–100 mg/d Intermittent Citalopram 20–30 mg/d Intermittent Paroxetine 20–30 mg/d Intermittent Escitalopram 10–20 mg/d Intermittenta Venlafaxine 50–200 mg/d Continuousb Clopramine 50–77 mg/d Intermittent Alprazolam 1.25–2.25 mg/d Intermittent Buspirone 5–30 mg twice a d Intermittent

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Summary: Steps in the Treatment of Symptoms of Premenstrual Syndrome

The following successive steps were outlined in an American College of Obstetrics and Gynecology (2000) and in a recent review by Johnson (2004):

• Step 1:

1. If mild/moderate symptoms: Supportive therapy with good nutrition, complex carbohydrates, aerobic exercise, calcium supplements, and possibly magnesium or chasteberry fruit.
2. If physical symptoms predominate: Spironolactone, NSAIDs, or hormonal suppression with OCPs or medroxyprogesterone acetate.

• Step 2: When mood symptoms predominate: SSRI therapy.
• An anxiolytic can be used for specific symptoms not relieved by the SSRI medication.
• Step 3: If not responsive to steps 1 or 2: GnRH agonists.

Web Sites

For Teenagers and Parents

http://kidshealth.org/teen/sexual_health/girls/menstruation.html. Teen site on dysmenorrhea.

http://www.aafp.org/afp/990800ap/489.html. American Academy of Family Physicians (AAFP) article on primary dysmenorrhea.

http://www.obgyn.upenn.edu/mudd/PMSarticle.html. Information on PMS from University of Pennsylvania Obstetrics and Gynecology Department.

http://www.youngwomenshealth.org/menstrual.html. Information from Children's Hospital Boston on dysmenorrhea and PMS.

http://www.nlm.nih.gov/medlineplus/ency/article/001505. htm. Medical encyclopedia from the U.S. National Library of Medicine and National Institutes of Health. Information on PMS and dysmenorrhea.

For Health Professionals

http://www.emedicine.com/emerg/topic156.htm. E-medicine site on dysmenorrhea.

http://vh.org/navigation/vh/topics/menstruation.html. Information from the University of Iowa on dysmenorrhea and PMS.

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