Somatic Symptoms	Emotional Symptoms	Cognitive Symptoms
• Breast tenderness • Abdominal bloating • Ankle edema • Weight gain • Headache • Backache • Constipation or diarrhea	• Irritability • Depression • Mood swings • Hypersensitivity to trivial events • Loneliness and social withdrawal	• Impaired memory • Confusion • Difficulty concentrating

Etiology

Although PMS is clearly of neuroendocrine origin, the exact cause has not been established. At one time, abnormal hormone levels were suspected. However, we now know that hormone levels in women who experience PMS are identical to those in women who do not. Hence abnormal levels can’t be the cause. Nonetheless, because symptoms are synchronized with the menstrual cycle, it would seem that hormones are in some way involved—even if levels are normal. One reasonable hypothesis is that women who experience PMS are sensitive to hormonal changes in a way that other women are not. Because of this altered sensitivity, normal hormonal changes are able to trigger PMS. Current evidence points to altered responsiveness in the brain. In particular, the ability of selective serotonin reuptake inhibitors (SSRIs) to relieve psychologic symptoms—as well as some physical symptoms—suggests an abnormality in circuits that use serotonin as their transmitter.

Diagnosis

To make a diagnosis of PMS, symptoms must be intense and intermittent. That is, symptoms should be prominent in the luteal phase of the menstrual cycle, and minimal or absent in the follicular phase. Practically all women experience some PMS-like symptoms in the late luteal phase. However, in the majority of women, symptoms are relatively mild, and hence do not constitute PMS. Only 20% to 30% of women have symptoms that are strong enough to be considered PMS. An even smaller number—3% to 5%—have symptoms that constitute premenstrual dysphoric disorder (PMDD), an especially severe form of PMS described in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders.

Timing of symptoms is critical. On days 4 through 12 of the menstrual cycle, symptoms should be absent—or at least no greater than would be expected in the population at large. Symptoms should begin following ovulation (around day 14 of the cycle), become most intense in the fourth week of the cycle (late luteal phase), and then stop before or shortly after onset of menstruation. To make a diagnosis, total symptom severity in the fourth week must be at least twice the intensity of any symptoms present in the second week. Daily charting of symptoms for at least three menstrual cycles is needed to establish whether symptoms occur in the appropriate pattern and are of sufficient intensity to permit a diagnosis of PMS or PMDD.

When diagnosing PMS, it is essential to rule out conditions whose symptoms can intensify in the late luteal phase or menstrual phase, a phenomenon known as “menstrual magnification.” Common conditions subject to menstrual magnification include depression, migraine headaches, chronic fatigue syndrome, and irritable bowel syndrome. The differential diagnosis is relatively easy to make, in that, unlike PMS, these disorders are symptomatic throughout the cycle—they simply can become more intense as menstruation approaches.

Treatment guidelines

In 2000, the American College of Obstetricians and Gynecologists (ACOG) issued guidelines for the diagnosis and treatment of PMS (“Clinical Management Guidelines for Premenstrual Syndrome,” ACOG Practice Bulletin No. 15). For women with a positive diagnosis of PMS, the guidelines recommend stepwise intervention, beginning with lifestyle changes and then progressing to drug therapy if needed.

For women with mild symptoms, lifestyle changes may provide relief. Regular aerobic exercise can reduce depressive symptoms and has numerous other health benefits. Eating foods rich in complex carbohydrates can enhance mood and reduce food cravings. Getting enough sleep can also help. In addition, small clinical trials have shown that dietary supplements (200 to 400 mg of magnesium/day and 1200 mg of calcium/day) can improve symptom scores.

If lifestyle changes fail to suppress symptoms, drug therapy may be needed. Two types of drugs are recommended: SSRIs and ovulation suppressants. SSRIs are the initial drugs of choice, especially for women with severe PMS. According to the guidelines, ovulation suppressants should be used only if SSRIs are inadequate.

Agents that are ineffective should be avoided. Among these are progesterone and various supplements, including black cohosh, red clover, dong quai, and evening primrose oil. Progesterone has been used for years on the theory that it may produce a favorable hormonal balance. However, we now know that progesterone is no more effective than placebo, and in fact may exacerbate some symptoms (bloating, breast tenderness, and emotional lability).

Selective serotonin reuptake inhibitors

SSRIs such as fluoxetine [Prozac, Sarafem] and sertraline [Zoloft] are the most effective treatment for the psychologic symptoms of PMS or PMDD, and hence are considered first-line therapy. These drugs, which were developed as antidepressants (see Chapter 32), can significantly reduce depression, anger, irritability, tension, dysphoria, fatigue, and confusion. Success rates range from 50% to 75%. Moreover, benefits develop quickly—within 2 to 3 days, compared with 2 to 4 weeks when SSRIs are used for depression. Why were SSRIs ever tried for PMS? Because the psychologic symptoms of PMS are much like those of depression. Interestingly, although SSRIs are most effective at reducing affective symptoms of PMS, they can also reduce physical symptoms, such as breast tenderness, bloating, and headaches.

In clinical trials, about 15% of women discontinued treatment because of side effects. The most prominent are sexual dysfunction (anorgasmia and decreased libido), sleep disturbances (insomnia or hypersomnia), and GI distress (nausea and diarrhea). If side effects are intolerable, dosage can be reduced.

Most research on using SSRIs for PMS has been conducted with either fluoxetine or sertraline. However, other SSRIs—paroxetine [Paxil], fluvoxamine [Luvox], citalopram [Celexa], and escitalopram [Lexapro]—are probably effective too. Hence, if a patient fails to respond to fluoxetine or sertraline, a trial with a different SSRI may be merited. It should be noted that, although the SSRIs are highly effective in PMS, none of these drugs is approved for PMS. However, three SSRIs—fluoxetine, sertraline, and paroxetine—are approved for PMDD.

With fluoxetine, sertraline, and paroxetine, dosing may be done either (1) every day throughout the menstrual cycle or (2) just during the luteal phase, the time when symptoms are present. With the second option, dosing is begun on day 14 of the cycle and stopped on day 2 of the following cycle (ie, the day after menstruation begins). The intermittent schedule has two obvious advantages: it’s cheaper than continuous dosing and side effects are minimized. Hence, unless a woman has depression in addition to PMS, intermittent dosing may be preferred. Specific dosages for three SSRIs are as follows:

• Fluoxetine—The usual dosage is 20 mg/day, given continuously or just during the luteal phase.

• Sertraline—The usual dosage is 50 to 150 mg/day, given continuously or just during the luteal phase.

• Paroxetine—The usual dosage is 12.5 to 25 mg/day, given continuously or just during the luteal phase.

Ovulation suppressants

Two classes of drugs—gonadotropin-releasing hormone (GnRH) agonists and oral contraceptives (OCs)—can suppress ovulation, and may thereby suppress both menstrual cycling and associated symptoms of PMS. Of note, these drugs reduce physical symptoms better than psychologic symptoms. Ovulation suppressants are considered second-line drugs for PMS, and hence should be used only if first-line agents are ineffective or intolerable.

GnRH agonists (eg, leuprolide) can reduce physical and psychologic symptoms of PMS. Treatment can relieve breast tenderness, bloating, depression, nervous tension, anxiety, and loss of control. These agents act by suppressing release of LH and FSH from the pituitary, and thereby cause levels of estrogen and progesterone to fall to postmenopausal concentrations. Unfortunately, although GnRH agonists are effective, these drugs are expensive. In addition, with prolonged treatment (more than 6 months), there is a risk of osteoporosis (owing to loss of estrogen). The risk of osteoporosis can be overcome by giving supplemental estrogen and progestin. Nonetheless, because of the expense and need for supplemental estrogen and progestin, use of GnRH agonists is limited.

Oral contraceptives can reduce physical symptoms of PMS (eg, bloating, breast tenderness), but are generally less effective at reducing emotional symptoms. However, in 2005, investigators reported that Yasmin—an OC composed of 30 mcg ethinyl estradiol plus 3 mg drospirenone—could reduce emotional symptoms as effectively as SSRIs. Two years later, a similar combination OC (20 mcg ethinyl estradiol plus 3 mg drospirenone), sold as YAZ, became the only OC actually approved for PMDD.

Other remedies

Calcium supplements (1000 to 1200 mg/day) have been shown to reduce symptoms of mild to moderate PMS. In one study, 2 to 3 months of daily calcium therapy decreased depression and mood swings by 45% (vs. 28% with placebo), generalized aches and pains by 54% (vs. a 15% increase with placebo), food cravings by 54% (vs. 35% with placebo), and water retention by 36% (vs. 24% with placebo). Calcium did not reduce fatigue or insomnia. These data are the first clear indication that a dietary supplement can significantly reduce symptoms of PMS. Moreover, the required dosage is low—about equal to the recommended dietary intake for preventing osteoporosis (1300 mg/day for teenagers and 1000 mg/day for women ages 19 to 40). Hence, women now have two good reasons for ensuring adequate calcium intake: alleviation of PMS and protection against osteoporosis.

Spironolactone, a diuretic and aldosterone antagonist, can counteract water retention and can thereby relieve bloating and water weight gain. In addition, several well-controlled trials have shown the drug can relieve affective symptoms as well. For women with PMS, the usual dose is 100 mg/day during the luteal phase of the menstrual cycle. Of note, spironolactone is similar to drospirenone, the progestin in YAZ, an OC discussed above.

Analgesics, such as ibuprofen and naproxen, have no effect on mood, but can reduce headache, dysmenorrhea, cramps, and muscle and joint pain.

Estrogens and progestins are hormones with multiple actions. They promote female maturation, and help regulate the ongoing activity of female reproductive organs. In addition, they affect bone mineralization and lipid metabolism. The principal endogenous estrogen is estradiol. The principal endogenous progestational hormone is progesterone. Both hormones are produced by the ovaries. During pregnancy, large amounts are produced by the placenta. In addition, small amounts of estrogens and progestins are produced in peripheral tissues.

Clinical applications of the female sex hormones fall into two major categories: contraceptive and noncontraceptive applications. In this chapter, we focus on noncontraceptive uses. Contraception is discussed in Chapter 62. The principal noncontraceptive application of estrogens and progestins is menopausal hormone therapy (HT): estrogens are given to manage hot flushes and other menopausal symptoms; progestins are given to oppose estrogen-mediated stimulation of the endometrium.

The menstrual cycle

Because much of the clinical pharmacology of the estrogens and progestins is related to their actions during the menstrual cycle, understanding the menstrual cycle is central to understanding these hormones. Accordingly, we begin by reviewing the menstrual cycle. The anatomic and hormonal changes that take place during the cycle are summarized in Figure 61–1. As indicated, the first half of the cycle (days 1 through 14) is called the follicular phase, and the second half is called the luteal phase. One full cycle typically takes 28 days.

Ovarian and uterine events.

The menstrual cycle consists of a coordinated series of ovarian and uterine events. In the ovary, the following sequence occurs: (1) several ovarian follicles ripen; (2) one of the ripe follicles ruptures, causing ovulation; (3) the ruptured follicle evolves into a corpus luteum; and (4) if fertilization does not occur, the corpus luteum atrophies. As these ovarian events are taking place, parallel events take place in the uterus: (1) while ovarian follicles ripen, the endometrium prepares for nidation (implantation of a fertilized ovum) by increasing in thickness and vascularity; (2) following ovulation, the uterus continues its preparation by increasing secretory activity; and (3) if nidation fails to occur, the thickened endometrium breaks down, causing menstruation, and the cycle begins anew.

The roles of estrogens and progesterone.

The uterine changes that occur during the cycle are brought about under the influence of estrogens and progesterone produced by the ovaries. During the first half of the cycle, estrogens are secreted by the maturing ovarian follicles. As suggested by Figure 61–1, these estrogens act on the uterus to cause proliferation of the endometrium. At midcycle, one of the ovarian follicles ruptures and then evolves into a corpus luteum. For most of the second half of the cycle, estrogens and progesterone are produced by the newly formed corpus luteum. These hormones maintain the endometrium in its hypertrophied state. At the end of the cycle, the corpus luteum atrophies, causing production of estrogens and progesterone to decline. In response to the diminished supply of ovarian hormones, the endometrium breaks down.