The exact cause of
PMDD is unknown. The most current theory suggests that cyclic changes
in ovarian steroids interact with central neurotransmitters to create
symptoms of PMDD.2 In other words, normal ovarian function rather than hormone imbalance is the inciting factor
for PMDD-related biochemical events in the central nervous system.2,3 Serotonin is the neurotransmitter most studied in PMDD, although
there is likely a role for gamma-aminobutyric acid (GABA) and beta-endorphin.
Deficiencies of trace elements also may be implicated.
Ovarian
Steroids
In 1984, Muse et al4 studied the effects
of medical ovariectomy using the gonadotropin-releasing hormone (GnRH)
agonist leuprolide, which led to resolution of symptoms by eliminating
fluctuation of ovarian hormones. However, cyclic changes in ovarian steroids
may not be the sole explanation for symptoms in PMDD. Estrogen and progesterone
levels of control subjects and women with premenstrual symptoms have been
shown to be the same, suggesting that affected women may have an abnormal
response to normal hormone levels.
Neurotransmitters
The three main neurotransmitters implicated in PMDD are serotonin, GABA,
and beta-endorphin. Evidence currently suggests a leading role for altered
serotonin levels in the etiology of PMDD. Central serotonin levels are
typically low in women with PMDD, and symptoms tend to be aggravated by
depletion of the serotonin precursor tryptophan. Notably, many women report
benefitting from selective serotonin reuptake inhibitors (SSRIs). The
role of GABA has not been clearly defined, but some women improve with
the GABA agonist alprazolam. Differences in beta-endorphin levels between
the periovulatory and premenstrual phases remain unconfirmed.
Vitamins and Minerals
Several attempts to link vitamin and mineral deficiencies with PMDD have
been inconclusive. No observable differences have been found in levels
of vitamin A, vitamin E, or vitamin B6 in affected versus unaffected
women. Treatment with vitamin B6 supplements has shown inconsistent
results. Additionally, initial studies suggested that women with PMDD
may have lower levels of magnesium,5,6 although subsequent studies have not confirmed this finding.7,8 |
Accurate diagnosis
of PMDD is based on a thorough history and physical examination and on
exclusion of other potential causes for the patient's symptoms. The history
must review psychiatric disorders in the patient and her family. The clinician
should be aware that PMDD differs from major depression with premenstrual
exacerbation. Symptoms should be limited to the luteal phase (second half)
of the menstrual cycle, and the patient must be symptom free in the follicular
phase (first half). Symptoms also must be of such magnitude that they
markedly impair the woman's day-to-day functioning. Women must also not
be on hormones, including oral contraceptives.
DSM-IV Criteria
The DSM-IV criteria published in 1994 by the American Psychiatric
Association are most commonly used for diagnosis of PMDD. The presence
of five or more of the following symptoms, which must be documented by
the patient in most menstrual cycles during the past 12 months, is required
to make the diagnosis of PMDD. These symptoms occur 1 week before menses
and resolve in the first few days after menses begins. Also, one of the
five symptoms must be one of the first four listed:9
- Marked depression
with feelings of hopelessness
- Marked anxiety
or tension (patient feels "wound up" or "on edge")
- Marked affective
lability
- Irritability, anger,
and increased interpersonal conflicts
- Decreased interest
in activities of daily living, which may include social withdrawal
- Fatigue and decreased
energy level
- Appetite changes
(overeating or cravings)
- Hypersomnia or
insomnia
- Feeling out of
control or overwhelmed
- Difficulty with
concentration
- Somatic symptoms
such as abdominal bloating, breast tenderness, headaches, or joint pain
Additionally, symptoms
must be severe enough to interfere with usual activities and relationships
and should be confirmed by prospective daily charting for at least two
menstrual cycles. The clinician also should be aware that symptoms
may be superimposed on an underlying psychiatric disorder, although they
may not be an exacerbation of another disorder.9 See Table 2.
Symptom
Inventory
Several questionnaires can be used to record symptoms of PMDD, such as
the Calendar of Premenstrual Experiences (COPE), the Moos Menstrual Distress
Questionnaire (MDQ), the Premenstrual Assessment Form (PAF), and the Prospective
Record of the Impact and Severity of Menstruation (PRISM). These forms
are similar and are all cited in the literature. The patient should be
advised to record her symptoms for at least 2 months using one of the
symptom inventory forms to observe fluctuation of symptoms during the
menstrual cycle. Recently, it has been suggested that there must be at
least a 30% worsening of symptoms between the follicular and luteal phases
within each cycle to diagnose PMDD, regardless of which assessment tool
is used. The percentage of worsening is calculated by the formula:2
Referring a patient
to a women's health psychiatrist may be indicated to evaluate for a mood
or anxiety disorder if there is no symptom-free period.
Differential
Diagnosis
Because PMDD is a diagnosis of exclusion, the clinician should rule out
other conditions that may manifest similar signs or symptoms. Important
differential diagnoses include:
- thyroid disorders
- migraine
- chronic fatigue
syndrome
- irritable bowel
syndrome
- seizures
- anemia
- endometriosis
- psychiatric disorders
- drug or alcohol
abuse
Laboratory
Testing
Initial laboratory testing should include a complete blood count, chemistry
profile, and thyroid-stimulating hormone to evaluate for anemia, electrolyte
abnormalities, and thyroid problems. |
Multiple treatment
options are available for PMDD; however, no single intervention is effective
for all women. Initial treatment should begin with lifestyle changes and
proceed to medications such as SSRIs; anxiolytics such as alprazolam and
buspirone; ovulation suppressants such as GnRH agonists, danazol, and
oral contraceptives (OCPs); and diuretics. Radical treatment, such as
ovariectomy, may be indicated in PMDD cases refractory to medical treatment.
Two studies have demonstrated complete resolution of symptoms in PMDD-affected
patients after ovariectomy.10,11 When considering ovariectomy in women of childbearing age, the clinician
needs to remember that this drastic measure can increase the risk of cardiovascular
disease and osteoporosis in the absence of adequate estrogen replacement
therapy.
Lifestyle Modifications
Treatment should begin with a 2-month to 3-month trial of lifestyle changes
while the patient charts her symptoms. Dietary changes, such as reducing
salt, sugar, caffeine, dairy products, and alcohol, often aid in decreasing
fluid retention, irritability, and bloating. Eating frequent and small
portions of foods high in carbohydrates may improve symptoms; this is
believed to occur by increasing relative tryptophan levels (a precursor
in the serotonin pathway). Exercise, relaxation, and stress management
also are recommended for a general state of well-being. Some women may
benefit from yoga, which improves muscle flexibility and alleviates stress.
If possible, women also can try to schedule their more challenging and
stressful events during the follicular phase (as opposed to the luteal
phase).
Selective
Serotonin Reuptake Inhibitors
SSRIs are considered first-line pharmacologic treatment for PMDD. Studies
have shown that intermittent luteal-phase dosing has fewer adverse effects
and is just as effective as full-cycle dosing.12-14 SSRIs have proved to be effective in more than 60% of treated
patients.15
FDA-approved options
for daily luteal-phase dosing include fluoxetine 10 mg/day to 20 mg/day
and sertraline 50 mg/day to 150 mg/day. A recent study showed that fluoxetine
may be efficacious when given at a dose of 90 mg once weekly for 2 weeks
in the luteal phase.16 Paroxetine 10 mg/day
to 30 mg/day and citalopram 5 mg/day to 20 mg/day also are used to treat
PMDD.
Side effects of SSRIs
include sexual dysfunction, insomnia, fatigue, nervousness, headache,
and nausea. These agents have a fast onset of action-1 to 2 days-in the
treatment of PMDD compared with their treatment of depression.
Alprazolam
Alprazolam, a GABA agonist, is a benzodiazepine anxiolytic that is effective
for symptoms such as tension, anxiety, irritability, and hostility. Treatment
can be initiated at 0.25 mg three to four times daily in the luteal phase
and tapered one to two times daily at the onset of menses, finally stopping
1 to 2 days after menses begins. Due to the addictive potential of alprazolam,
it is considered a second-line treatment.
Buspirone
Buspirone, a partial 5-HT1 receptor agonist, has also been
shown to be effective due to its anxiolytic properties. Unlike alprazolam,
it is nonaddictive. Dosing may be given as 5 mg to 10 mg three times daily
during the luteal phase.
GnRH Agonists
GnRH agonists also are effective in reducing PMDD symptoms. They downregulate
GnRH receptors, causing a decrease in luteinizing hormone and follicle-stimulating
hormone. This subsequently inhibits ovulation, which decreases estrogen
and progesterone levels, thereby creating pharmacologic menopause. Treatment-limiting
side effects include hot flashes, headaches, muscle aches, vaginal dryness,
and irritability; therefore, this class of medication is reserved for
patients with severe symptoms unresponsive to other medical treatment
measures. GnRH agonists are expensive; they also have hypoestrogenic side
effects, which causes concern for the development of osteoporosis. For
this reason, they are not recommended for use longer than 6 months. If
a GnRH agonist needs to be used for longer than 6 months, continued symptom
relief can be provided by using add-back therapy with estrogen and progesterone.17
Danazol
Danazol is a weak synthetic androgen that suppresses ovarian steroid production
by inhibiting luteinizing hormone and follicle-stimulating hormone secretion.
It is given as 600 mg/day to 800 mg/day in divided doses. Danazol's use
is limited due to multiple androgenic and antiestrogenic side effects,
including amenorrhea, weight gain, acne, fluid retention, hirsutism, hot
flushes, vaginal dryness, and emotional lability.
Oral
Contraceptives
The efficacy of OCPs for the treatment of PMDD has not been established
due to conflicting data, and more studies are indicated. Freeman et al18 showed that a unique OCP consisting of 30 µg ethinyl estradiol and
3 mg drospirenone (Yasmin) was beneficial for a number of symptoms, including
bloating, breast tenderness, and swelling. The combination agent also
has antiandrogenic
properties that may relieve acne and hirsutism.
Bromocriptine
Bromocriptine, a dopamine agonist, is useful in decreasing mastalgia by
lowering prolactin levels. It is dosed as 2.5 mg once daily just before
ovulation until the onset of menses. Side effects may include dizziness
and nausea.
Diuretics
Spironolactone is the diuretic most studied due to its antimineralocorticoid
and antiandrogenic properties. Symptoms most likely to improve with spironolactone
treatment include bloating, swelling, breast tenderness, and acne. It
may be tried in dosages of 50 mg/day to 100 mg/day for 7 to 10 days during
the luteal phase. Side effects, including lethargy, headache, and irregular
menses, are more common during continuous dosing. Serum potassium levels
should be monitored because spironolactone can cause hyperkalemia.
Other
Medications
Nonsteroidal anti-inflammatory drugs (NSAIDs) are available over the counter
and are effective for dysmenorrhea. Generic names include ibuprofen and
naproxen. Meclofenamate (Meclomen), an NSAID available by prescription,
can reduce menstrual cramps and flow. The typical dose is 100 mg twice
daily. Acetaminophen may also be beneficial for pain.
Alternative Therapies
In today's modern era, women are likely to seek out other integrative
therapies for PMDD. One large trial has shown that 1,200 mg of elemental
calcium daily is effective in alleviating tension, anxiety, fluid retention,
and food cravings.19 Physicians are often
asked about vitamin supplementation; controlled studies with vitamin A,
vitamin E, and vitamin B6 have failed to consistently show
a benefit. Although popular, herbal products are not FDA approved, and
some have caused significant toxicities as well as drug-herb interactions.
Other innovative therapies include acupuncture, biofeedback, homeopathy,
massage, and light therapy.20
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