Premenstrual dysphoric disorder: A review for the treating practitioner

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 4 APRIL 2004

303

HILE MOST WOMEN of reproductive age

suffer from some degree of premenstrual

syndrome (PMS), usually involving mood

changes and somatic symptoms, only a small

percentage have the more severe form, known

as premenstrual dysphoric disorder (PMDD),

which causes marked impairment.

This review will help the clinician recog-

nize, understand, and treat this disorder. We

also provide an overview of alternative thera-

pies that patients may be using on their own to

treat the condition.

■ CONSTELLATION OF SYMPTOMS

DURING LUTEAL PHASE

PMDD was first defined in 1987 in the

Diagnostic and Statistical Manual of Mental

Disorders (DSM-III-R) and revised in the fol-

lowing edition in 1994.

Its constellation of

somatic and behavioral symptoms occur only

in the 10 to 14 days before menstrual bleeding,

corresponding to the luteal phase of the cycle.

Symptoms are similar to those of PMS, a

condition that affects as many as 75% of

women of menstruating age. Only 3% to 8% of

women

have symptoms severe enough to be

diagnosed with PMDD (

TABLE 1).

■ RISK FACTORS

Some women are more prone to PMDD. Risk

factors include:

• Age—PMDD is most likely to occur in a

woman’s late 20s to mid 30s

• Psychiatric disorders—As many as 70% of

women with PMDD have a history of mood dis-

orders (including major depression), anxiety dis-

orders, personality disorders, or substance abuse

4–6

GURJIT KAUR, DO

Department of General Internal Medicine,

Women’s Health Center at The Gault Women’s

Health and Breast Pavilion, The Cleveland

Clinic Foundation

LILIAN GONSALVES, MD

Department of Psychiatry and Psychology,

Women’s Health Center at The Gault Women’s

Health and Breast Pavilion, The Cleveland

Clinic Foundation

HOLLY L. THACKER, MD

Department of General Internal Medicine,

Department of Obstetrics and Gynecology,

Women’s Health Center at The Gault Women’s

Health and Breast Pavilion, The Cleveland

Clinic Foundation

Premenstrual dysphoric disorder:

A review for the treating practitioner

REVIEW

■ ABSTRACT

Premenstrual dysphoric disorder (PMDD), a severe form of

premenstrual syndrome (PMS), is characterized by physical

and behavioral symptoms that cause marked social impair-

ment during the last half of the menstrual cycle. Symptoms

are believed to result from the interaction of central neuro-

transmitters and normal menstrual hormonal changes.

Treatment usually begins with lifestyle changes, over-the-

counter medications, and if needed, selective serotonin reup-

take inhibitors. Physicians should be aware of the risks of

many of the alternative therapies commonly touted in the

popular press.

■ KEY POINTS

PMDD is diagnosed by prospective recording of symptoms for

two menstrual cycles and by laboratory testing to rule out

thyroid disorders, anemia, and electrolyte disturbances.

The symptoms of PMDD are likely caused by low levels of

serotonin, gamma-aminobutyric acid, and beta-endorphins.

Selective serotonin reuptake inhibitors are the first-line

medications. Anxiolytics, ovulation suppressants, and diuretics

are recommended for specific symptoms.

Patients should be warned of potential risks of herbal prod-

ucts and of large doses of vitamins and food supplements.

PATIENT INFORMATION

What is premenstrual dysphoric disorder (PMDD)?

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*This paper discusses therapies that are experimental or are not approved by the US Food and

Drug Adminstration for the use under discussion.

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CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 4 APRIL 2004

• Genetics—Twin studies suggest a genetic

component is present

4,7,8

• Low parity—Women with fewer preg-

nancies have a higher incidence of PMDD.

Additional exposure to changing levels of

estrogen and progesterone from more men-

strual cycles may predispose women to the dis-

order

9,10

• Psychosocial factors—Studies suggest

that the incidence of PMDD increases after

major life events and stressors

4,9,11

• Menstrual cycle length—Data conflict

on the association of menstrual cycle length

and symptom severity.

4,12,13

■ WHAT CAUSES PMDD?

A number of theories have been proposed to

explain PMDD, but the exact cause is

unknown.

An abnormal response

to normal hormone cycles

The current theory is that premenstrual symp-

toms are caused by normal cyclic changes in

ovarian steroids.

In 1984, Muse et al

studied

the effects of eliminating the hormonal

changes of menstrual cycles in eight patients

over a 6-month period using the

gonadotropin-releasing hormone (GnRH)

agonist leuprolide (Lupron). Symptoms

resolved with GnRH treatment, then recurred

when the medication was withdrawn.

Cyclic changes of ovarian steroids may

not be the only explanation for symptoms.

Estrogen and progesterone levels of women

with premenstrual symptoms are about the

same as those of control subjects, suggesting

that behavioral disturbances in affected

women may be due to an abnormal response of

central neurotransmitters to normal ovarian

function.

4,15

Low levels of neurotransmitters

Serotonin is the most widely studied neuro-

transmitter in women with PMDD: central

serotonin levels tend to be low,

16,17

and symp-

toms are aggravated by depletion of the sero-

tonin precursor tryptophan.

In addition,

many patients with PMDD improve with

treatment using selective serotonin reuptake

inhibitors (SSRIs).

19–21

Gamma-aminobutyric acid (GABA) and

beta-endorphin probably also play a role.

Premenstrual women have reduced GABA

receptor sensitivity and abnormal levels of

allopregnanolone, a progesterone metabo-

lite.

Differences in beta-endorphin levels

between the periovulatory and premenstrual

phases have been suggested but remain uncon-

firmed.

23–25

Vitamin and mineral deficiencies unproven

Attempts to link vitamin and mineral defi-

ciencies with PMDD have been inconclusive.

No differences in levels of vitamin A,

vita-

min E,

or vitamin B

28,29

have been

observed. Initial studies suggested that women

with PMDD may have lower levels of magne-

sium,

30,31

but subsequent studies have not con-

firmed this finding.

32,33

Calcium levels may

also be low in the premenstrual phase.

34,35

■ A DIAGNOSIS OF EXCLUSION

PMDD is diagnosed with a thorough history

and physical examination and by excluding

other causes. No objective diagnostic tests exist.

Record symptoms daily

Symptoms should be recorded as they occur

daily for at least two consecutive sympto-

matic menstrual cycles. Common tools

include the Calendar of Premenstrual

Experiences (COPE),

the Moos Menstrual

Central

serotonin

levels tend

to be low in

women with

PMDD

PREMENSTRUAL DYSPHORIC DISORDER KAUR AND COLLEAGUES

Differences between premenstrual

syndrome (PMS) and premenstrual

dysphoric disorder (PMDD)

PMS PMDD

Prevalence 75% 3%–8%

Symptoms required 1 5 of 11

(see TABLE 2)

Diagnosis ICD-10

DSM-IV

†

Social impairment Not required Required

Prospective charting Not required Required

International Statistical Classification of Diseases and Related Health

Problems

, 10th revision.

†

Diagnostic and Statistical Manual of Mental Disorders

, 4th edition.

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Distress Questionnaire (MDQ),

the

Premenstrual Assessment Form (PAF),

and the Prospective Record of the Impact

and Severity of Menstruation (PRISM).

These questionnaires are similar, and all

have proven useful in gathering objective

and quantified data about PMDD symp-

toms.

Symptoms of PMDD typically include

mood disturbances and somatic symptoms,

and are severe enough to markedly impair

day-to-day functioning (

TABLE 2). Symptoms

occur during the last half of the menstrual

cycle (the luteal phase) and are absent in the

follicular phase, which begins from the first

day of menstruation and lasts about 14 days

until ovulation.

Steiner et al

40,41

proposed that there must

be at least a 30% worsening of symptoms

between the follicular and luteal phases with-

in each cycle, regardless of the assessment tool

used.

Exclude other problems

Other diagnoses need to be excluded (

TABLE 3).

Blood should be tested if clinically indicated:

• A chemistry profile to assess electrolyte

disturbances

• A complete blood cell count to rule out

anemia

• A thyroid-stimulating hormone (TSH)

level to rule out thyroid disorders.

Clinicians should be careful to differenti-

ate PMDD from premenstrual exacerbations

of chronic psychiatric disorders. A referral to

a psychiatrist may be indicated to evaluate for

a mood or anxiety disorder if the patient has

no symptom-free period.

■ TREATMENT OPTIONS

No single intervention has proven effective

for all patients with PMDD, but many options

are available.

Start with lifestyle changes

Treatment should begin with a 2- to 3-month

trial of lifestyle changes while the patient

records her symptoms.

Reducing intake of salt, sugar, caffeine,

dairy products, and alcohol

often helps

decrease fluid retention, irritability, and bloat-

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 4 APRIL 2004

305

Reducing

intake of salt,

sugar, caffeine,

dairy products,

and alcohol

often helps

Criteria for diagnosis of premenstrual dysphoric disorder

Symptoms occur 1 week before menses and resolve in the first few days after menses begins

(over most menstrual cycles during the past year)

Five or more of the following (one must be among the first four):

Markedly depressed mood with feelings of hopelessness

Marked anxiety or tension

Marked affective lability

Irritability and anger

Decreased interest in usual activities and social withdrawal

Lack of energy

Appetite change (overeating or undereating)

Change in sleep pattern (hypersomnia or insomnia)

Feeling out of control or overwhelmed

Difficulty with concentration

Somatic symptoms such as abdominal bloating, breast tenderness, headaches, or joint pain

Symptoms are severe enough to interfere with work, school, usual activities, or interpersonal relationships

Symptoms may be superimposed upon an underlying psychiatric disorder but may not be an

exacerbation of another condition

These criteria must be confirmed by prospective daily charting for a minimum of two consecutive

symptomatic menstrual cycles

MODIFIED WITH PERMISSION FROM THE DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL DISORDERS. 4TH ED. TEXT REVISION.

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CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 4 APRIL 2004

ing. Lactose intolerance commonly causes

bloating in women and may be alleviated by

lactase enzymes such as Lactaid. Eating fre-

quent and smaller portions of foods high in

complex carbohydrates may also improve

mood symptoms, possibly by raising levels of

tryptophan, a precursor in serotonin biosyn-

thesis.

9,42,43

Contemporary women fulfill multiple

social roles, including wife, mother, caregiver

to the elderly, and wage-earner, and often

experience considerable emotional strain.

Exercise, yoga, relaxation, and stress manage-

ment may enhance general well-being. If pos-

sible, scheduling more challenging and stress-

ful tasks during the first half of menstrual

cycles may also help.

Medications

Nonsteroidal anti-inflammatory drugs are

effective treatments for dysmenorrhea

;

ibuprofen and naproxen are available over the

counter. Acetaminophen (Tylenol) may also

alleviate pain. Prescription medications

should be used if lifestyle changes and over-

the-counter medications do not adequately

alleviate symptoms (

TABLE 4).

Selective serotonin reuptake inhibitors

(SSRIs)

45–58

are the first-line drugs for PMDD

and have been shown to be effective in more

than 60% of treated patients.

45,46

Treatment

only during the luteal phase (10–14 days

before menses begins) works as well as full-

cycle dosing, with fewer adverse effects.

47–51

SSRIs have a faster onset of action (1–2

days) when used for PMDD than for depres-

sion and other psychiatric disorders, possibly

due to their ability to alter allopregnanolone

levels.

56–58

Examples include fluoxetine

(Sarafem), sertraline (Zoloft), paroxetine

(Paxil), and citalopram (Celexa).

Common SSRI side effects include sexual

dysfunction, insomnia, fatigue, nervousness,

headache, and nausea.

Other serotonergic agents used to treat

PMDD inhibit the serotonin transporter as

well as the uptake of norepinephrine.

Examples include venlafaxine (Effexor)

and

clomipramine (Anafranil).

60–62

Alprazolam (Xanax) is a GABA agonist

with anxiolytic properties. It has proven effec-

tive in double-blind, placebo-controlled

crossover studies against premenstrual symp-

toms, especially tension, anxiety, irritability, and

hostility.

63,64

The addictive potential of this

medication makes it a second-line treatment.

Buspirone (BuSpar), a partial agonist of

serotonin receptors, is also effective because of

its anxiolytic properties. It is not addic-

tive.

65,66

Gonadotropin-releasing hormone (GnRH)

agonists down-regulate GnRH receptors, which

reduce luteinizing hormone (LH) and follicle-

stimulating hormone (FSH) levels.

This subse-

quently inhibits ovulation, thereby decreasing

estrogen and progesterone levels, creating a

pharmacologic menopause.

GnRH agonists are reserved mainly for

patients with severe symptoms that do not

respond to other treatments. They are expen-

sive and have menopause-like side effects: hot

flashes, headaches, muscle aches, vaginal dry-

ness, and irritability. The low-estrogen state

also raises concern about development of

osteoporosis,

so treatment should be limited

to 6 months. If extended treatment is

required, patients should be given supplemen-

tal estrogen and progesterone.

Danazol (Danocrine) is a weak synthetic

androgen that inhibits FSH and LH secretion,

thus suppressing ovarian steroid production.

Its use is limited due to multiple androgenic

and antiestrogenic side effects such as amen-

orrhea, weight gain, acne, fluid retention, hir-

sutism, hot flashes, vaginal dryness, and emo-

tional lability.

Routinely

ask your

patients about

use of vitamins,

herbs, and

supplements

Differential diagnosis

of premenstrual dysphoric

disorder

Thyroid disorders

Migraine

Chronic fatigue syndrome

Irritable bowel syndrome

Seizures

Anemia

Endometriosis

Psychiatric disorders

(especially bipolar disorder, depression,

or anxiety)

Drug or alcohol abuse

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Bromocriptine (Parlodel), a dopamine

agonist, lowers prolactin levels and is useful in

decreasing breast tenderness.

71,72

Side effects

may include dizziness and nausea.

Spironolactone (Aldactone) is the diuret-

ic most studied due to its antimineralocorti-

coid and antiandrogenic properties. Benefits

have not consistently been found.

73–75

Symptoms most likely to improve include

bloating, swelling, breast tenderness, and acne.

Side effects of lethargy, headache, and irregu-

lar menses are more common during continu-

ous dosing, so administration only during the

luteal phase is recommended. Serum potassi-

um levels should be monitored because

spironolactone can cause hyperkalemia.

Oral contraceptives. Studies of oral con-

traceptives have been conflicting.

76,77

2001, Freeman et al

showed that ethinyl

estradiol 30 mg plus drospirenone 3 mg

(Yasmin) alleviated bloating, breast tender-

ness, and swelling. The drospirenone compo-

nent has antiandrogenic properties and may

also reduce acne and hirsutism.

Meclofenamate (Meclomen) reduces

menstrual flow and cramps.

Progesterone. Some believe that women

with premenstrual symptoms have a deficien-

cy of progesterone in the luteal phase of the

menstrual cycle.

Dennerstein et al,

in a

double-blind, randomized, crossover trial,

treated women with micronized progesterone

in the luteal phase and found progesterone

was more effective than placebo for helping

mood and some physical symptoms. However,

Wyatt et al

conducted a systematic review

on the use of progesterone in premenstrual

women and found no benefit.

■ SURGERY

In severe, refractory cases of PMDD, ovariec-

tomy may be considered if medical treatment

fails. Two studies showed complete relief of

symptoms.

82,83

In women of childbearing age,

the risk of cardiovascular disease and osteo-

porosis may increase with the lack of estrogen.

■ INTEGRATIVE THERAPIES

Physicians should routinely ask patients about

their use of vitamins, herbs, and supplements.

Although none of these alternative therapies

is FDA-approved, they are widely publicized

in the popular press, and many patients report

relief of symptoms with their use.

Some clinicians may choose to recom-

mend a few of these therapies to certain

patients. Most importantly, physicians should

be aware of the adverse effects that may occur

with self-prescribed supplements and should

counsel their patients accordingly.

Vitamins, minerals, and other nutrients

Calcium. Okey et al

reported that plas-

ma calcium levels are lower before menstrua-

tion, and Thys-Jacobs et al

demonstrated in

a large trial that 1,200 mg of elemental calci-

um daily alleviates tension, anxiety, fluid

retention, pain, and food cravings in women

with PMS. Calcium is inexpensive, is safe dur-

ing pregnancy, and helps maintain bone

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 4 APRIL 2004

313

Medications for premenstrual

dysphoric disorder

Selective serotonin reuptake inhibitors

Fluoxetine (Prozac, Sarafem) 10–20 mg/day

90 mg once a week for 2 weeks in the luteal phase

53*

Sertraline (Zoloft) 10–150 mg/day

54*

Paroxetine (Paxil) 10–30 mg/day

55*

Citalopram (Cipramil, Celexa) 5–20 mg/day

Other serotonergic antidepressants

Venlafaxine (Effexor) 50–150 mg/day

Clomipramine (Anafranil) 25–75 mg/day

60–62

Other agents

Alprazolam (Xanax) 0.25 mg 3–4 times daily in the luteal

phase, taper at the onset of menses

Buspirone (BuSpar) 5–10 mg 3 times daily during luteal phase

Gonadotropin-releasing hormone agonists

(nasal spray, daily or depot injection, and subcutaneous

forms available)

Leuprolide (Lupron) depot 3.75 mg IM/month

Danazol (Danocrine) 600–800 mg/day in divided doses.

Bromocriptine (Parlodel) 2.5 mg once daily just before

ovulation until the onset of menses

Spironolactone (Aldactone) 50–100 mg/day for 7–10 days

during the luteal phase

Drospirenone (Yasmin)

Meclofenamate (Meclomen) 100 mg twice a day

Approved by the US Food and Drug Administration for this indication

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317

health. The typical American diet provides

less than half of the recommended 1,200 mg of

calcium daily. Intake should not exceed 2,000

mg daily.

Magnesium. Women with PMS have

lower levels of magnesium in erythrocytes and

leukocytes despite normal plasma magnesium

levels.

30–33

Intracellular magnesium is likely a

better indicator of true levels, since magne-

sium is mostly found within cells. Magnesium

is a cofactor in many enzymatic reactions, and

some believe that supplementation may alle-

viate some PMS symptoms by correcting any

existing deficiency.

Replacing magnesium in doses of 200 mg to

400 mg once daily reduces fluid retention.

85,86

Magnesium occasionally causes a mild osmotic

diarrhea but is usually well tolerated.

Vitamin B

is a cofactor in neurotrans-

mitter synthesis, so it may, in theory, play a

role in relieving premenstrual mood symp-

toms. However, studies using vitamin B

sup-

plementation have shown inconsistent

results.

28,29

The Institute of Medicine of the

National Academy of Sciences recommends

that women should limit vitamin B

intake to

no more than 100 mg daily because of the risk

of peripheral neuropathy.

Vitamin E may relieve some mood and

physical symptoms, including anxiety and

breast tenderness.

It may exert its effect

through prostaglandin synthesis or regulation

of central neurotransmitters.

Dosage: 400 IU

daily.

Manganese levels vary throughout the

menstrual cycle. One small study reported that

women with low intake of dietary manganese

have more premenstrual symptoms of bad

mood and pain.

Further studies are warrant-

ed. Women should be advised that the recom-

mended dose of 6 mg per day to prevent symp-

toms is higher than the recommended daily

allowance of 1.8 mg.

L-tryptophan is an essential amino acid

precursor in the serotonin pathway. It has

been shown to reduce hostility and cravings in

premenstrual women,

but more studies are

needed to demonstrate its efficacy. Foods rich

in tryptophan include milk and turkey.

Treatment in supplement form is not recom-

mended because it has been associated with

eosinophilia myalgia syndrome (EMS). It is

believed that EMS was caused by a contami-

nant, but it was difficult to implicate one spe-

cific substance.

Herbals

Evening primrose oil, derived from the

American wildflower Oenothera biennis, is a rich

source of gamma linolenic acid. This essential

omega-6 fatty acid is a prostaglandin precursor.

Some believe that women in the premenstrual

phase of their cycle are deficient in gamma

linolenic acid, leading to symptoms attributable

to abnormal prostaglandin synthesis.

Evening primrose oil 3 to 6 g daily has been

used to treat breast tenderness; other putative

uses are for irritability and ankle swelling.

Studies, however, have shown no advantage of

evening primrose oil over placebo.

93,94

Black currant oil and borage seed oil

contain a higher content of gamma linolenic

acid; however, borage seed oil may contain

toxic alkaloids and is not recommended.

Chaste tree extract is obtained from a

shrub (Vitex agnus-castus) native to southern

Europe and the Mediterranean. Prolactin lev-

els are believed to be high premenstrually;

chaste tree extract binds to dopamine recep-

tors, inhibiting prolactin release,

95,96

and

thereby perhaps relieving irritability and

breast tenderness.

Chaste tree extract is not safe during preg-

nancy

on the basis of case reports of uterine

stimulation and should not be taken by sexu-

ally active women who are not using reliable

contraception. The dose is 20 mg to 40 mg per

day (aqueous extract). Side effects include gas-

trointestinal upset, rash, and headache.

Black cohosh stimulates estrogen recep-

tors and is used to treat premenstrual anxiety

and breast pain.

Currently, no controlled tri-

als exist to support its efficacy. No toxicity has

been reported with its use, but experts do not

recommend using it longer than 6 months

since the long-term safety is unknown.

Wild yam root contains diosgenin, a com-

pound used in steroid hormone synthesis.

Diosgenin converts to progesterone in vitro,

and some believe that it should therefore alle-

viate premenstrual symptoms. However, not

much is known about its effects in premen-

strual women.

Dong quai is a Chinese herb used for PMS

The typical

diet provides

< half of the

recommended

1,200 mg of

calcium daily

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CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 4 APRIL 2004

and other gynecological conditions, but no

controlled studies support its efficacy.

Dong

quai is not safe in pregnancy and should not

be used by sexually active women who are not

using contraception.

Since dong quai con-

tains a coumarin derivative, it may increase

the prothrombin time and the international

normalized ratio, and should not be used by

women on warfarin (Coumadin).

Kava kava is used by some women to treat

premenstrual anxiety. However, it should not

be recommended, as there have been reports

of hepatotoxicity.

It also may interact with

alprazolam.

100

St. John’s wort (Hypericum perforatum) is

used to treat mild to moderate depression. A

pilot study

101

over two cycles showed

improvement in premenstrual mood symp-

toms, but long-term effects are unknown. St.

John’s wort interacts with SSRIs, transplant

medications, and anti-HIV drugs.

Other alternative therapies

Acupressure and acupuncture are tradi-

tional Chinese forms of medicine thought to

restore the body’s normal flow of energy.

102

Vaginal biofeedback. Patients can learn

to increase their vaginal temperature, warm-

ing the pelvic and vaginal tissue. This emu-

lates the thermogenic effects of progesterone

and may relieve symptoms.

103

Homeopathic remedies may have a role

in the treatment of premenstrual symptoms as

demonstrated by one study,

104

showing the

powerful effects of placebo. More studies are

needed. Homeopathy has been used success-

fully at a London clinic.

105

Chiropractic and massage therapy.

Women may benefit from high-velocity, low-

amplitude spinal manipulation and soft-tissue

kneading two or three times a week premen-

strually.

106

Massage therapy has also been

shown to decrease anxiety, depressed mood,

and pain immediately after massage ses-

sions.

107

Effects over a 5-week period include

reduced pain, menstrual distress, and fluid

retention.

107

Reflexology involves applying manual

pressure to reflex points (ears, hands, and feet)

that correspond to specific areas of the body.

Oleson and Flocco

108

found a reduction in

premenstrual symptoms in patients treated

with reflexology compared with a placebo

form of the practice.

Light therapy. Three studies

109–111

found that bright white light used during the

luteal phase of the menstrual cycle helps

women with PMDD. Women with depres-

sive and physical symptoms are most likely

to benefit.

Acknowledgement: The authors would like to thank Diane

Crouse for her assistance in preparing this manuscript.

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ADDRESS: Gurjit Kaur, DO, Department of General Internal

Medicine, A91, The Cleveland Clinic Foundation, 9500 Euclid

Avenue, Cleveland, OH 44195; e-mail kaur[email protected].

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