Premenstrual Syndrome

The definitive cause of PMS is unknown. Incorrect older theories about the causes of PMS include estrogen excess, estrogen withdrawal, progesterone deficiency, pyridoxine (vitamin B6) deficiency,[4] 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), which 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 those of 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 acid (GABA) system, and hypoprolactinemia ^{[5, 6, 7]}
• The results of a large longitudinal study carried out by Bertone-Johnson et al suggested that the experience of abuse (emotional, sexual, or physical) in early life places women at higher risk for PMS in the middle-to-late reproductive years ^[8]

United States statistics

Symptoms of PMS have been reported to affect as many as 90% of women of reproductive age sometime during their lives. Nearly 20% of women experience PMS; approximately 10% are affected severely. Studies indicate that 14-88% of adolescent girls have moderate-to-severe symptoms. Another 3-5% of women meet the criteria for PMDD. PMDD is reported to affect 3-8% of women of reproductive age.

Two risk factors for PMS are obesity and smoking. Research reveals that women with a body mass index (BMI) of 30 or above are nearly three times as likely to have PMS than women who are not obese. Women who smoke cigarettes are more than twice as likely to have more severe PMS symptoms.[9, 10, 11, 12, 13]

Age- and sex-related demographics

By definition, only females are affected. PMS affects women with ovulatory cycles. Older adolescents tend to have more severe symptoms than younger adolescents do. Women in their fourth decade of life tend to be affected most severely. PMS resolves completely at menopause.[14]

Inability to maintain normal activities is part of the definition of this condition; hence, morbidity is related to loss of function. Complications of PMS may include school absence and behavioral problems. PMS and PMDD have been associated with a higher risk of bulimia nervosa.[15]  PMS may also be associated with an increased risk of future hypertension.[16]

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

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 patient education resources, see the Women's Health Center, as well as Premenstrual Syndrome (PMS).

Elicit a description of cyclic symptoms that occur before the menstrual period and resolve with menses from patients with suspected premenstrual syndrome (PMS).

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

Advise the patient to use a numeric scoring system to specify severity (1 for mild, 2 for moderate, 3 for severe) when recording symptoms. Ask the patient to bring her lists to the next appointment. The categories of PMS symptoms may be divided into five basic categories—A, C, D, H, and O—as follows.[17, 18, 12, 19]

PMS-A (anxiety) symptoms include the following:

• Difficulty sleeping
• Tense feelings
• Irritability
• Clumsiness
• Mood swings

PMS-C (craving) symptoms include the following:

• Headache
• Cravings for sweet foods
• Cravings for salty foods
• Cravings for other types of food

PMS-D (depression) symptoms include the following[20] :

• 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) symptoms include the following:

• Weight gain
• Abdominal bloating
• Breast tenderness
• Swelling of extremities

PMS-O (other) symptoms include the following:

• Dysmenorrhea
• Change in bowel habits
• Frequent urination
• Hot flashes or cold sweats
• General aches or pains
• Nausea
• Acne
• Allergic reactions
• Upper respiratory tract infections

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.[18]

At present, there are no laboratory studies that reliably assist in the diagnosis of premenstrual syndrome (PMS).

Imaging studies are not needed to make the diagnosis of PMS, but they may be helpful for excluding other possible causes of the symptoms.

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

Medical care of premenstrual syndrome (PMS) is primarily pharmacologic and behavioral, with an emphasis on relief of symptoms.[22, 23] No single pharmacologic 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.[24, 19, 21, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47] At present, selective serotonin reuptake inhibitors (SSRIs) are commonly considered suitable first-line therapy for premenstrual disorders.[48, 49]

Because of the difficulty of treating PMS and the variations in response to treatments experienced by patients, complementary and 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; practicing for 10-20 minutes daily is recommended
• Biofeedback and guided imagery
• Cognitive behavioral therapy and group therapy
• Light therapy - Bright-light therapy uses 10,000 lx cool-white fluorescent light daily for 30 minutes
• Massage
• Chiropractic therapy
• Homeopathy and herbal medicines - Studies have examined the efficacy of various homeopathic and herbal medicines, including Crocus sativus L (saffron) and Chinese herbal medications; one pilot study found that 90% of patients receiving a homeopathic treatment regimen experienced improvement in symptoms, compared with 37.5% of those receiving placebo ^[39] ; several studies have concluded that some alternative methods may be beneficial in symptom alleviation and that further research is warranted ^{[50, 51, 52, 45, 41]}

In women who are severely affected, bilateral oophorectomy has been effective in alleviating symptoms because it renders the patient postmenopausal. A hysterectomy is not needed to gain the symptomatic relief. For obvious reasons, this therapy is not recommended for adolescents and young women.

Despite a lack of evidence to indicate that dietary changes can definitively change PMS symptoms, healthy lifestyle recommendations are worth making in that they benefit the patient overall, as well as give her a sense of control.[53]

Eating four to six smaller meals per day during the premenstrual period may help reduce symptoms or food cravings.

One study found that women with PMS typically consume more dairy products, refined sugar, and high-sodium foods than women without PMS. Accordingly, many clinicians recommend reducing or eliminating these foods from the diet. Avoidance of salt, caffeine, alcohol, chocolate, or simple carbohydrates may alleviate symptoms.

A written sheet with foods to avoid (eg, cola, coffee, hot dogs, potato chips, and canned goods) and foods to encourage (eg, fruits, vegetables, milk, complex carbohydrates, high-fiber foods, and low-fat meats) may assist patients in making helpful food choices.[54, 55, 44]

The benefits of exercise include physical improvements as well as stress reduction. Regular aerobic exercise has been found to decrease symptoms in some adolescents and young women.[56] A systematic review showed that exercise reduced physical symptoms such as pain, constipation, and breast sensitivity, as well as psychological symptoms such as anger and anxiety.[57]  Preliminary studies suggest that yoga may also alleviate symptoms in some women.[58, 59]

Outpatient management primarily involves monitoring, keeping 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 to be hoped that continued research in this area will lead to better treatment.

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.[19, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 58]

Class Summary

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.

Leuprolide (Lupron), nafarelin (Synarel)

GnRH agonists. Suppresses ovarian and testicular steroidogenesis by decreasing LH and FSH levels.

Class Summary

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.

Danazol (Danocrine)

Synthetic steroid analog with strong antigonadotropic activity (inhibits LH and FSH) and weak androgenic action.

Class Summary

These agents are useful for managing the general aches, pains, and dysmenorrhea associated with PMS. The US Food and Drug Administration (FDA) has issued a warning regarding the increased risk of serious cardiovascular thrombotic events, myocardial infarction, and cerebrovascular events associated with cyclooxygenase-2 (COX-2) selective NSAIDs (eg, celecoxib, valdecoxib, and rofecoxib). Valdecoxib (Bextra) and rofecoxib (Vioxx) are no longer marketed. Nonselective NSAIDs (eg, ibuprofen, naproxen) also carry this risk. For more information, see the FDA Drug Information Page on COX-2 Selective and Nonselective NSAIDs.

Tolmetin (Tolectin)

Acetic and salicylic acids NSAID derivatives. Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclooxygenase, which, in turn, decreases formation of prostaglandin precursors.

Ibuprofen (Advil, Motrin, PediaCare Children's Pain Reliever/Fever Reducer IB)

Propionic acid NSAID derivatives. Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclooxygenase, which, in turn, decreases formation of prostaglandin precursors.

Mefenamic acid

Fenamate NSAID derivatives. Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclooxygenase, which, in turn, decreases formation of prostaglandin precursors.

Sulindac (Clinoril, Sulin)

Acetic and salicylic acids NSAID derivatives. Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclooxygenase, which, in turn, decreases formation of prostaglandin precursors.

Diclofenac (Cambia, Cataflam, Dyloject)

Acetic and salicylic acids NSAID derivatives. Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclooxygenase, which, in turn, decreases formation of prostaglandin precursors.

Naproxen (Aleve, Anaprox, Anaprox DS)

Propionic acid NSAID derivatives. Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclooxygenase, which, in turn, decreases formation of prostaglandin precursors.

Ketoprofen (Nexcede)

Propionic acid NSAID derivatives. Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclooxygenase, which, in turn, decreases formation of prostaglandin precursors.

Meclofenamate

Fenamate NSAID derivatives. Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclooxygenase, which, in turn, decreases formation of prostaglandin precursors.

Class Summary

These drugs are alternatives to standard NSAIDS and work by inhibiting prostaglandin synthesis via inhibition of COX-2. The FDA has issued a warning regarding the increased risk of serious cardiovascular thrombotic events, myocardial infarction, and cerebrovascular events associated with COX-2 selective NSAIDs (eg, celecoxib, valdecoxib, and rofecoxib). Valdecoxib (Bextra) and rofecoxib (Vioxx) are no longer marketed. Nonselective NSAIDs (eg, ibuprofen, naproxen) also carry this risk. For more information, see the FDA Drug Information Page on COX-2 Selective and Nonselective NSAIDs.

Celecoxib (Celebrex)

Inhibits primarily COX-2. COX-2 is considered an inducible isoenzyme, induced during pain and inflammatory stimuli. Inhibition of COX-1 may contribute to NSAID GI toxicity. At therapeutic concentrations, COX-1 isoenzyme is not inhibited, thus GI toxicity may be decreased.

Class Summary

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

Spironolactone (Aldactone)

Competes with aldosterone for receptor sites in distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions.

Hydrochlorothiazide (HydroDiuril)

May be beneficial in reducing edema. Inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water, as well as potassium and hydrogen ions.

Class Summary

The selective serotonin reuptake inhibitors (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 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 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 associate obsessive compulsive disorder (OCD) and other anxiety disorders treated with SSRIs with an increased risk of suicide. For more information, see the FDA Web site on Antidepressant Use in Children, Adolescents, and Adults.

In July 2006 the FDA issued a Public Health Advisory highlighting the dangers of taking SSRIs and triptans (eg, sumatriptan) concurrently. As both of these drug classes increase levels of serotonin, simultaneous use of them may lead to serotonin syndrome. The FDA recommends that those who are taking both medications speak with their physician before stopping either medication.

Fluoxetine (Sarafem), sertraline (Zoloft)

SSRIs are used to treat premenstrual dysphoric disorder.

Clomipramine (Anafranil)

A tricyclic antidepressant. Affects serotonin uptake whereas its metabolite desmethylclomipramine affects norepinephrine uptake.

Nefazodone (Serzone)

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.

Class Summary

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

Alprazolam (Xanax)

A benzodiazepine antianxiety agent. Binds receptors at several sites within the central nervous system, including the limbic system and reticular formation. Effects may be mediated through GABA receptor system.

Buspirone (BuSpar)

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.

Class Summary

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

Calcium carbonate (Caltrate, Os-Cal)

Calcium moderates nerve and muscle-performance by regulating action potential excitation threshold.

Magnesium (Almora, Magonate)

Selectively causes a depletion of brain dopamine, which may alter mood. The most common adverse effect is diarrhea. May use other PO supplements, including magnesium oxide or magnesium hydroxide.

Class Summary

Combination oral contraceptive agents have been pursued as treatment for PMS due to their ovulation suppression effects. However, studies have suggested that treatment with combination oral contraceptive agents does not significantly improve symptoms compared to treatment with placebo.

Combination oral contraceptives (estrogen and progesterone)

Reduces secretion of LH and FSH from pituitary by decreasing amount of gonadotropin-releasing hormones.

Dysmenorrhea can be prevented altogether in some patients by use of OCs, although these agents are not approved by the FDA for this indication. OCs may be an appropriate treatment choice in patients who do not wish to conceive. The combination OCs suppress the hypothalamic-pituitary-ovarian axis and thereby inhibit ovulation and prevent PG production in the late luteal phase. This generally significantly reduces the amount of menstrual flow and effectively alleviates primary dysmenorrhea in most patients.

Combination OCs and depot medroxyprogesterone acetate provide effective pain relief and are associated with a reduced menstrual flow. The use of NSAIDs in combination with an OC may be necessary, especially during the first few cycles after initiation of the OC. The dose of ethinyl estradiol generally should be less than 50 mcg. A monophasic OC containing 30 mcg of ethinyl estradiol is a reasonable choice. To date, studies comparing the efficacy of various OC formulations in the management of dysmenorrhea have not been performed.