AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Premenstrual syndrome (PMS) is a recurrent luteal phase condition characterized by physical, psychological, and behavioral changes of sufficient severity to result in deterioration of interpersonal relationships and normal activity. Premenstrual dysphoric disorder (PMDD) is considered a severe form of PMS.

Pathophysiology

Incorrect older theories about the causes of PMS include an estrogen excess, estrogen withdrawal, progesterone deficiency, pyridoxine (vitamin B-6) deficiency, alteration of glucose metabolism, and fluid-electrolyte imbalances. Current research provides some evidence supporting the following etiologies:

• Serotonin deficiency is postulated because patients who are most affected by PMS have differences in serotonin levels. The symptoms of PMS can respond to selective serotonin reuptake inhibitors (SSRIs), ie, medications that increase the amount of circulating serotonin.
• Magnesium and calcium deficiencies are postulated as nutritional causes of PMS. Studies evaluating supplementation show improvement in physical and emotional symptoms.
• Women with PMS often have an exaggerated response to normal hormonal changes. Although their levels of estrogen and progesterone are similar to women without PMS, rapid shifts in levels of these hormones promote pronounced emotional and physical responses.
• Other theories under investigation include increased endorphins, alterations in the gamma-aminobutyric system (GABA), and hypoprolactinemia.

Frequency

United States

Symptoms of PMS have been reported to affect as many as 75% of women of reproductive age sometime during their lives. Nearly 30% of women experience PMS; approximately 10% are affected severely. Recent studies indicate that 14-88% of adolescent girls have moderate-to-severe symptoms. Another 3-5% of women meet the criteria for premenstrual dysphoric disorder (PDD). PMDD is reported to affect 3-8% of women of reproductive age.

Mortality/Morbidity

Inability to maintain normal activities is part of the definition of this disease; hence, morbidity is related to loss of function.

Sex

By definition, females are affected.

Age

PMS affects women with ovulatory cycles. Older adolescents tend to have more severe symptoms than younger adolescents. Women in their fourth decade of life tend to be affected most severely. PMS resolves completely at menopause.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Elicit from the patient a description of cyclic symptoms occurring before the menstrual period that resolve with menses.

  To establish the diagnosis, instruct patients to chart symptoms daily for 2 cycles. This usually demonstrates symptoms clustering around the luteal phase of ovulation, with resolution when menses begins.

  Advise the patient to use a numeric scoring system (1 for mild, 2 for moderate, 3 for severe) when recording symptoms (Table 1). Ask the patient bring her lists to the next appointment.

  Table 1. Table 1. PMS Symptoms Grouped by Type (Instruct the patient to rate the symptoms in each category on a chart (1 for mild, 2 for moderate, 3 for severe.)

  Category	Symptoms
  PMS-A, anxiety	Difficulty sleeping, tense feelings, irritability, clumsiness, mood swings
  PMS-C, craving	Headache, cravings for sweet foods, cravings for salty foods, cravings for other types of food
  PMS-D, depression	Depression, angry feelings for no reason, feelings that are easily upset, poor concentration or memory, feelings of low self-worth, violent feelings
  PMS-H, hydration	Weight gain, abdominal bloating, breast tenderness, swelling of extremities
  PMS-O, other	Dysmenorrhea, change in bowel habits, frequent urination, hot flashes or cold sweats, general aches or pains, nausea, acne, allergic reactions, upper respiratory infections

Physical

• Usually, no physical findings are specifically helpful in establishing the diagnosis of PMS. If the adolescent presents during the luteal phase, she may have mastalgia or edema of the breasts or legs.

Causes

• The definitive cause of PMS is unknown.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Depression
Premenstrual dysphoric disorder
Dysmenorrhea

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• No laboratory studies currently exist to reliably assist in the diagnosis of PMS.

Imaging Studies

• Imaging studies are not needed to make the diagnosis, but they may be helpful to exclude other etiologies.

Other Tests

• If depression is a concern, consider using a depression inventory to assess the patient.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Medical care is primarily pharmacological and behavioral, with an emphasis on relief of symptoms.

Surgical Care

In women who are affected severely, a total hysterectomy with bilateral oophorectomy has been effective to alleviate symptoms. For obvious reasons, this therapy is not recommended for adolescents and young women.

Diet

Despite a lack of evidence that diet changes can definitively change PMS symptoms, healthy lifestyle recommendations benefit the patient overall, as well as give her a sense of control.

• Eating 4-6 smaller meals per day during the premenstrual period may be of benefit to reduce symptoms or food cravings.
• One study has shown that women with PMS typically consume more dairy products, refined sugar, and high-sodium foods than women without PMS. Therefore, many clinicians recommend reducing or eliminating these foods from the diet. Avoidance of salt, caffeine, alcohol, chocolate, and/or simple carbohydrates may improve symptoms.
• A written sheet with foods to avoid (cola, coffee, hot dogs, potato chips, canned goods) and foods to encourage (fruits, vegetables, milk, complex carbohydrates, high-fiber foods, low-fat meats) may help assist patients in food choices.

Activity

Benefits of exercise include physical improvements as well as stress reduction.

• Regular aerobic exercise has been shown to decrease symptoms in some adolescents and young women.
• Preliminary studies suggest that yoga may also alleviate symptoms in some women.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

No single treatment is universally effective, and studies with all therapies have not produced consistent results. Current recommendations in the literature regarding oral contraceptive pills are conflicting.

Drug Category: Gonadotropin-releasing hormone (GnRH) agonists

These drugs act as potent inhibitors of gonadotropin secretion by binding competitively on GnRH receptors. They cause suppression, or down-regulation, of gonadotropins and, consequently, suppress ovarian and testicular steroidogenesis. This results in a hypoestrogenic state. The effects are reversible with discontinuation of drug therapy. GnRH agonists are not recommended for use in adolescents because of unknown effects on adolescent bone density.

Drug Category: Pituitary-ovarian axis suppressants

These synthetic steroids probably work by a combination of depressed hypothalamic-pituitary response to lowered estrogen production, the alteration of sex steroid metabolism, and the interaction of the drug with sex hormone receptors. Depresses the output of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Not recommended for use in adolescents.

Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs)

These agents are useful for managing the general aches, pains, and dysmenorrhea associated with PMS.

Drug Name	Ibuprofen (Motrin), naproxen (Naprosyn, Anaprox), ketoprofen (Orudis)
Description	Propionic acid NSAID derivatives. Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclooxygenase, which, in turn, decreases formation of prostaglandin precursors.
Adult Dose	Ibuprofen (Motrin): 400 mg PO q6-8h Naproxen (Naprosyn): 500 mg PO once, then 250 mg PO q6-8h Naproxen sodium (Anaprox): 550 mg PO once, then 275 mg PO q 6-8h Ketoprofen (Orudis): 75 mg PO tid
Pediatric Dose	Ibuprofen (Motrin): 5-10 mg/kg/d PO divided q6-8h Naproxen: 2.5-10 mg/kg/dose PO q8-12h Ketoprofen (Orudis): 0.5-1 mg/kg PO q6-8h Adolescents: Administer as in adults
Contraindications	Documented hypersensitivity (eg, swelling, asthma, hives, urticaria or any forms of angioedema); active GI bleed or active ulcer; cross allergenicity to aspirin
Interactions	Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors Concomitant administration of low-dose aspirin with NSAIDs may result in an increased rate of GI ulceration or other complications, compared to use of NSAIDs alone Clinical studies and postmarketing observations show that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients; this response has been attributed to inhibition of renal prostaglandin synthesis May elevate lithium levels and reduce renal lithium clearance May increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding) may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Category D in third trimester of pregnancy; acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; low white blood cell counts occur rarely and usually return to normal with ongoing therapy; discontinuation of therapy may be necessary if persistent leukopenia, granulocytopenia, or thrombocytopenia is present

Drug Name	Mefenamic acid (Ponstel), meclofenamate (Meclomen)
Description	Fenamate NSAID derivatives. Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclooxygenase, which, in turn, decreases formation of prostaglandin precursors.
Adult Dose	Mefenamic acid (Ponstel): 500 mg PO once, then 250 mg PO q4-6h, alternatively, start with 250 mg PO q8hr on 16 d of cycle, increase to 500 mg PO on 19 d of the cycle Meclofenamate (Meclomen): 100 mg PO once, then 50-100 mg PO q6h
Pediatric Dose	Adolescents: Administer as in adults
Contraindications	Documented hypersensitivity (eg, swelling, asthma, hives, urticaria or any forms of angioedema); active GI bleed or active ulcer; cross allergenicity to aspirin
Interactions	Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors Concomitant administration of low-dose aspirin with NSAIDs may result in an increased rate of GI ulceration or other complications, compared to use of NSAIDs alone Clinical studies and postmarketing observations show that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients; this response has been attributed to inhibition of renal prostaglandin synthesis May elevate lithium levels and reduce renal lithium clearance May increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding) may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Category D in third trimester of pregnancy; acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; low white blood cell counts occur rarely and usually return to normal with ongoing therapy; discontinuation of therapy may be necessary if persistent leukopenia, granulocytopenia, or thrombocytopenia occurs

Drug Category: Cyclooxygenase-2 (COX-2) inhibitors

These drugs are alternatives to standard NSAIDS and work by inhibiting prostaglandin synthesis via inhibition of COX-2.

Drug Category: Diuretics

These agents are used for edema, bloating, weight fluctuations, and mastalgia of PMS.

Drug Category: Dopamine agonists

Bromocriptine may be helpful in the treatment of severe mastalgia not responsive to NSAIDs.

Drug Category: Antidepressants

The SSRIs, fluoxetine (Prozac) and sertraline (Zoloft), are the first-line drugs for severe emotional symptoms. They work best when taken throughout the month. Clomipramine (Anafranil) given for the full cycle or half-cycle has been effective in treatment of emotional symptoms. Nefazodone, an antidepressant that blocks serotonergic and noradrenergic uptake, recently was shown to be effective in relieving symptoms.

SSRIs are greatly preferred over the other classes of antidepressants. Because the adverse effect profile of SSRIs is less prominent, improved compliance is promoted. SSRIs do not have the cardiac arrhythmia risk associated with tricyclic antidepressants. Arrhythmia risk is especially pertinent in overdose, and suicide risk must always be considered when treating a child or adolescent with mood disorder.

Physicians are advised to be aware of the following information and use appropriate caution when considering treatment with SSRIs in the pediatric population.

In December 2003, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) issued an advisory that most SSRIs are not suitable for use by persons younger than 18 years for treatment of "depressive illness." After review, this agency decided that the risks to pediatric patients outweigh the benefits of treatment with SSRIs, except fluoxetine (Prozac), which appears to have a positive risk-benefit ratio in the treatment of depressive illness in patients younger than 18 years.

In October 2003, the US Food and Drug Administration (FDA) issued a public health advisory regarding reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder. This advisory reported suicidality (both ideation and attempts) in clinical trials of various antidepressant drugs in pediatric patients. The FDA has asked that additional studies be performed because suicidality occurred in both treated and untreated patients with major depression and thus could not be definitively linked to drug treatment.

However, a recent study of more than 65,000 children and adults treated for depression between 1992 and 2002 by the Group Health Cooperative in Seattle found that suicide risk declines, not rises, with the use of antidepressants. This is the largest study to date to address this issue.

Currently, evidence does not exist to associate obsessive-compulsive disorder (OCD) and other anxiety disorders treated with SSRIs with an increased risk of suicide.

Drug Name	Clomipramine (Anafranil)
Description	A tricyclic antidepressant. Affects serotonin uptake while its metabolite desmethylclomipramine affects norepinephrine uptake.
Adult Dose	25-75 mg PO qd, given for the full cycle or half-cycle
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; recent myocardial infarction; use of MAOIs within 14 d of initiating treatment
Interactions	Barbiturates, phenytoin, and carbamazepine, decrease effects of clomipramine; clomipramine increases effects of anticholinergics, neuroleptic agents, sympathomimetics, alcohol and CNS depressants; toxicity of MAOIs increases with clomipramine; may partially depend on CYP3A4 for metabolism, caution with coadministration of inhibitors or inducers of this pathway
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Myocardial infarction; nonspecific ECG changes and changes in AV conduction; heart block; arrhythmia; hypotension, particularly orthostatic hypotension; syncope; hypertension; tachycardia; palpitation have been reported Caution in severe cardiopulmonary or renal impairment and inability to metabolize sorbitol

Drug Name	Nefazodone (Serzone)
Description	Antidepressant unrelated to the other antidepressant classes. Antagonist at the 5-HT2 receptor and inhibits the reuptake of 5-HT. Also has negligible affinity for cholinergic and histaminergic receptors.
Adult Dose	100-150 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; use of MAOIs within 14 d of initiating treatment
Interactions	Coadministration with buspirone resulted in marked increases in plasma buspirone concentrations, thus, a low dose of buspirone (ie, 2.5 mg bid) is recommended; decreases effects of anticoagulants, oral hypoglycemics, diuretics, clonidine, methyldopa; increases effects of digoxin, carbamazepine, and MAOIs
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in cardiac disease, cerebrovascular disease or seizures; discontinue therapy and reevaluate if priapism occurs; liver failure resulting in transplantation or death have occurred rarely

Drug Category: Antianxiety agents

Alprazolam (Xanax) and buspirone (BuSpar) have been effective in helping the anxiety-related symptoms of PMS.

Drug Name	Buspirone (BuSpar)
Description	An antianxiety agent not chemically or pharmacologically related to the benzodiazepines, barbiturates, or other sedative or anxiolytic drugs. A 5-HT1 agonist with serotonergic neurotransmission and some dopaminergic effects in CNS. Has anxiolytic effect but may take up to 2-3 wk for full efficacy.
Adult Dose	7.5 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; use of MAOIs within 14 d of initiating treatment
Interactions	Coadministration with nefazodone, erythromycin, or itraconazole increase serum levels of buspirone (use low dose not exceeding 2.5 mg bid) May cause hypertensive crisis with coadministration of MAOIs; toxicity increased with phenothiazines and CNS depressants; increases toxicity of digoxin and haloperidol
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Interferes with motor performance; caution in hepatic or renal impairment

Drug Category: Nutritional supplements

Recent studies have shown that calcium and magnesium deficiency may play a role in PMS; therefore, supplementation is suggested.

Drug Name	Magnesium (Almora, Magonate)
Description	Selectively causes a depletion of brain dopamine, which may alter mood. The most common adverse effect is diarrhea. May use other oral supplements, including magnesium oxide or magnesium hydroxide.
Adult Dose	27 mg (as elemental magnesium) PO qd
Pediatric Dose	Adolescents: Administer as adults
Contraindications	Documented hypersensitivity; heart block; Addison disease; myocardial damage; severe hepatitis
Interactions	Concurrent use with nifedipine may cause hypotension and neuromuscular blockade; also may worsen neuromuscular blockade observed with aminoglycosides, tubocurarine, vecuronium, and succinylcholine; magnesium may increase CNS effects and toxicity of CNS depressants, betamethasone, and ritodrine
Pregnancy	A - Safe in pregnancy
Precautions	May alter cardiac conduction, leading to heart block in digitalized patients; monitor respiratory rate, deep tendon reflex, and renal function when administered parenterally; caution when administering magnesium dose because may produce significant hypotension or asystole

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Outpatient management primarily involves monitoring, a 2-month symptom diary and instituting further therapy as the symptoms warrant. PMS is a very difficult condition to treat and cannot be completely eradicated by any single therapy. It is hoped that continued research in this area will lead to better treatment.
• Because of the difficulty in treating PMS and the variations in response to treatments experienced by patients, alternative strategies have been explored for patients with PMS. These include the following:
• • Relaxation response: This technique consists of quiet sitting, progressive muscle relaxation, and the repetition of a constant stimulus, such as the word "one" during each inhale and exhale. Patients are recommended to practice for 10-20 minutes daily.
  • Biofeedback and guided imagery
  • Cognitive behavioral therapy and group therapy
  • Light therapy: Bright-light therapy uses 10,000 lx cool-white flourescent light daily for 30 minutes.
  • Massage
  • Chiropractic therapy
  • Homeopathy

Complications

• School absence
• Behavior problems

Prognosis

• Most PMS symptoms worsen with the patient's age until menopause; thus, little good news can be given to severely affected adolescents.

Patient Education

• Because PMS may cause major morbidity for the adolescent, providing patient education regarding alternative therapies that may alleviate some symptoms is important.
• Behavioral counseling and stress management may help the patients regain control during times of high emotionalism.
• Relaxation techniques may also help. Areas of stress should be identified. Relaxation techniques such as yoga, biofeedback, and self-hypnosis may be beneficial.
• Regular exercise often decreases the symptoms of PMS.
• Patients should be counseled to avoid salt, caffeine, alcohol, and simple carbohydrates.
• For excellent patient education resources, visit eMedicine's Women's Health Center. Also, see eMedicine's patient education article Premenstrual Syndrome (PMS).

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• It is important to rule out other conditions that cause erratic or dysphoric behavior before diagnosing PMS. Rare conditions, such as temporal lobe epilepsy, may cause behavioral changes consistent with PMS. However, these behaviors should not cluster during the luteal phase.
• Some parents view their daughter's dysphoria as PMS instead of recognizing a more serious depression and suicidal ideation. In this situation, the parent often is looking for a way to avoid recognizing the possibility that their child is experiencing mental health symptoms. If the physician accepts this history uncritically, a serious depressive disorder may be misdiagnosed as PMS.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: May 22, 2006