Premenstrual syndrome

Revised: January 7, 2014

Copyright Elsevier BV. All rights reserved.

Key points
Premenstrual syndrome (PMS) describes the occurrence of a variety of symptoms during
the luteal phase of the menstrual cycle. Symptoms are relieved by day 4 of menstruation

There should be a symptom-free interval between the end of menses and ovulation

Symptoms may be any combination of psychological, somatic, and behavioral features

present to a degree that significantly impairs mood, behavior, and/or performance

Most common symptoms are irritability, anxiety, depression, mood swings, bloating,
abdominal discomfort, breast pain, headaches, and fatigue

No tests are available to specifically confirm PMS, which is a diagnosis based on history,
daily rating of symptoms, and exclusion

The mainstays of treatment are lifestyle changes and over-the-counter remedies, with oral
contraceptives and antidepressants reserved for patients with more extreme or recalcitrant
symptoms

Background
Description
PMS describes the occurrence of a variety of symptoms during the luteal phase of the
menstrual cycle that are relieved by day 4 of menstruation. The cyclical nature of the
symptoms is the cardinal feature

Symptoms (psychological, somatic, and/or behavioral) should be of sufficient intensity to

negatively impact mood, behavior, and/or performance. For example, PMS symptoms may
contribute to decrease in work productivity

Severity of symptoms is affected by underlying stressful emotional states

Hormonal cycling is necessary for PMS, but ovulation is not. PMS, however, is more
common in, but not confined to, ovulatory cycles
o PMS-like symptoms also are seen in those women receiving hormone
replacement therapy (HRT) or taking a combined oral contraceptive pill

o Women with amenorrhea who continue to have hormonal cycling, such as those
who have undergone hysterectomy with ovarian preservation or endometrial ablation, will
continue to experience PMS

o PMS-like symptoms also can occur following menopause if combined estrogen

and progestogen HRT is given

Women with PMS who seek and receive medical care are most commonly those in their
30s and 40s, but the syndrome can occur in women any time between menarche and
menopause

Distress may be extreme, but sufferers are within a continuous spectrum that ranges from
women who are moderately distressed by cyclical changes to those with significant disability
or impairment

The high percentage of ovulatory women who notice some symptoms but do not regard
them as problematic do not, by definition, have PMS, but instead have premenstrual or
moliminal symptoms

Some women have exactly the same symptoms every month, whereas others find that
their symptoms vary considerably

The syndrome has been noted in many different cultures and ethnic groups

PMS is one of the categories of premenstrual disorders

o Premenstrual disorders include premenstrual dysphoric disorder (PMDD), a

subset of severe PMS with prominent affective symptoms

o Premenstrual exacerbation of an underlying mood or somatic disorder also can be

classified as a premenstrual disorder

Epidemiology
Incidence and prevalence

PMS affects 20% to 40% of women, with up to 20%

experiencing moderate symptoms and up to 40% having
mild to moderate but bothersome symptoms. Of these, 2%
 to 10% are severely affected, giving an incidence of severe
PMS of between 6/1,000 and 40/1,000

Some authorities state that 3 out of 4 women notice

physical or emotional changes associated with the luteal
phase, suggesting there is a wide spectrum of perception of
the symptoms. Those women with non-bothersome mild
symptoms, however, should not be diagnosed with PMS

Frequency

Between 6/1,000 and 40/1,000 women will suffer from

severe PMS at some time in their fertile lives

PMS may come and go during the reproductive life of

an individual woman; however, symptoms tend to persist
until the climacteric, at which time they decline in
prevalence, and PMS symptoms are relieved by menopause

Symptoms are relieved during pregnancy, and are

affected by external factors such as contraceptive use and
social changes. It is difficult to elucidate the natural history

Demographics

Age:
 Any age from menarche to menopause, but most
women seeking help will be in their 30s or 40s

Genetics:

No clear genetic basis but probably familial

Geography:

Not confined to specific regions

Socioeconomic status:

Social disadvantage is associated with increased

likelihood of PMS

Some studies state that divorced or separated women

have greater prevalence

Smoking and poor dietary calcium intake are associated

with increased PMS

Causes and risk factors

Common causes:

Unknown. A single etiology is unlikely because of the

multiple systems affected

Complex hormonal interaction with neurotransmitters

and neuropeptides seems a likely explanation
 Evidence for the hormonal nature of the symptoms is
based on studies that show symptoms are not present in
the premenarchal or postmenopausal years, during
pregnancy, after bilateral oophorectomy, or administration
of gonadotropin-releasing hormone (GnRH) agonists to
create a 'chemical menopause'

The pathogenesis is likely related to changes in gonadal

steroids during the luteal phase and their effect on
neurotransmitters such as -aminobutyric acid (GABA)
and serotonin in the central nervous system

There is some evidence suggesting the role of the

estrogen receptor- gene in PMDD

Brain imaging studies such as positron emission

tomography (PET) and functional magnetic resonance
imagine (fMRI) scans have shown altered brain activity in
various brain regions subserving mood and regulation of
emotion during the luteal phase in women with PMDD

Contributory or predisposing factors:

There is the suggestion that genetic factors may

contribute to PMS. This has been shown mainly in twin
studies. Other biological and environmental factors,
however, play a strong role
 Women with preexisting emotional difficulty or distress
are more likely to complain of mood or physical
disturbances

Anxiety and anxiety disorders such as generalized anxiety

disorder orpanic disorder are often exacerbated by PMS

Depression (in adults or adolescents ) and depressive

disorders such as unipolar or bipolar disorder are often
exacerbated by PMS

Worries about weight and body image in some women

can increase PMS symptoms, as these women are more
likely to be very aware of slight changes in weight and girth

Women who have painful or heavy menstrual periods

are very likely to experience distress in the days leading up
to their period

Social problems, such as lack of social support,

financial or occupational concerns may be risk factors

Domestic violence and substance abuse should be ruled

out

High caffeine or alcohol intake may exacerbate anxiety

and depression
 Smoking increases the likelihood of dysmenorrhea and
premenstrual discomfort

Lower education level may be a risk factor

History of a traumatic event

Stress may precipitate or exacerbate any mood,

behavioral, or somatic disturbance

Associated disorders
Depression or anxiety : Symptoms may overlap, but
women with preexisting psychological or emotional
disturbance are more likely to be distressed by cyclical
symptoms. Also, the hormonal milieu of the premenstrual
phase is associated with exacerbation of affective and
somatic disorders, including a wide range of mood and
pain diagnoses

Sexual or emotional problems: Sexual dysfunction may be

ascribed to PMS, and in the presence of other cyclical
symptoms it can be difficult to distinguish whether the
sexual dysfunction is itself cyclical

Endometriosis : Pain and bloating often begin prior to

menses and may be severe, increasing the likelihood of
depression on entering the luteal phase
 Menstrual disorders: abnormal uterine bleeding ,
menorrhagia, anddysmenorrhea

Obesity or altered body image: Women who are trying

to diet are more likely to be concerned by fluctuations in
appetite and by abdominal bloating

Menopausal symptoms: tiredness, loss of libido, weight

gain, metrorrhagia. If a woman's symptoms begin when
she is in her 40s, perimenopause should be ruled out

Hypothyroidism , anemia, chronic fatigue syndrome , and

chronic pain disorders (eg, fibromyalgia , migraines , chronic
pelvic pain, irritable bowel syndrome ) can be associated with
premenstrual exacerbation and PMS-like symptoms

Screening
Summary approach
There is no public health initiative or evidence supporting
mass screening, but questions regarding PMS should be part
of every woman's routine gynecologic care.

Population at risk
Ovulatory women and women with adverse symptoms on
hormonal contraceptives.
 Screening modalities
PMS is clinically diagnosed by eliciting a history of
symptoms beginning in conjunction with the rise of
progesterone during the luteal phase and resolution of
symptoms 3 to 4 days following onset of menstruation

Prospective daily rating of the symptoms for two cycles

to confirm cyclicity is the main diagnostic tool

Primary prevention
Summary approach
Healthy lifestyle changes, particularly maintaining good
nutrition, adequate calcium intake, physical fitness,
avoiding tobacco and other psychoactive substances, and
importantly lowering stress by making situational changes
or learning a technique to modulate the somatic and
emotional responses to stress may be helpful in preventing
PMS.

Population at risk
Menstruating women

Ovulating women who no longer menstruate due to

surgical interventions
 Women on combined estrogen and progestogen
medications

Preventive measures
Smoking cessation may help prevent PMS. Smoking is
also associated with heavier, more painful periods. May be
causative, or it may be that women who use tobacco and
are unable to quit are also more likely to seek external help
for cyclical symptoms

Alcohol or illegal drugs are likely to worsen mood

swings and depression associated with PMS. Heavy use of
alcohol is also associated with menorrhagia. Alcohol intake
should be limited, especially during menstruation when it
can worsen menorrhagia

Avoidance of caffeine may be beneficial

Hypocalcemia is associated with many affective

disturbances that are similar to the symptoms of PMS.
Calcium supplementation may reduce fatigability, changes
in appetite, and depression in women with PMS, but there
are no current data supporting calcium supplementation in
preventing PMS
 There is no clear evidence that the use of vitamin B6 or
magnesium can prevent PMS

Physical unfitness can contribute to PMS. Physical

exercise improves symptoms by improving physical fitness
and general well-being

Stress reduction

Daily charting of symptoms, at least initially, can

increase the ability to plan for and cope with symptoms

Premenstrual and menstrual pain should be controlled

by effective and well-tolerated measures

Diagnosis
Summary approach
PMS is characterized by the presence of physical and/or
emotional and behavioral symptoms that occur
premenstrually each month with relief by the end of
menses. These symptoms interfere with the woman's life

There are no published diagnostic guidelines for PMS,

but the following criteria are widely accepted among
physicians as defining the disorder appropriately and
screening out patients who do not have PMS:
o Symptoms occur only during the luteal phase, the 2
weeks before menstruation or the premenstrual phase in
those women who are on hormonal contraceptives

o Symptoms are relieved by day 4 of menses

o Symptoms include those typical of PMS; however,

irritability is a cardinal symptom

o If symptoms occur in the follicular phase, after the

cessation of menstrual flow, either it is not PMS or
symptoms represent premenstrual exacerbation of another
underlying condition

Evaluate medications (eg, hormonal therapy)

Evaluate patient for endocrine disorders such

as hypothyroidism orhyperthyroidism

Have patients record prospective daily ratings of the

worst symptoms (eg, on a scale of 0-3 [none, mild,
moderate, severe]) for two cycles, including notation of the
days of menstrual flow

Many conditions may be worse in the luteal phase and

improve, although not necessarily disappear, by day 4 of
menses. Examples of such conditions include the
following:
o Migraine

o Depression and anxiety disorders

o Chronic fatigue syndrome

o Asthma , eczema, and hay fever

o Epilepsy

o Chronic pain disorders, including irritable bowel

syndrome , chronic pelvic pain, vulvodynia, interstitial
cystitis , fibromyalgia

o Connective tissue diseases, such as systemic lupus

erythematosusand rheumatoid arthritis

If there are doubts about the diagnosis of PMS (eg,

symptoms are not clearly cyclical or are rapidly
worsening), reevaluate the patient's history and complete
physical examination and consider other diagnoses such as
multiple sclerosis or Cushing syndrome. Also, depending
on the nature and severity of the symptoms, consider
diagnostic blood tests or scans or referral to an appropriate
specialist

Clinical presentation
Symptoms
 Psychological symptoms are the most common reason
for seeking medical help; they may be restricted to the
premenstrual phase or they may preexist and may worsen
cyclically

Abdominal discomfort is the most common symptom

reported in cross-cultural studies, but it is not necessarily
associated with seeking care

Common psychological symptoms:

Irritability

Depression

Mood swings and emotional lability

Anxiety

Fatigue

Loss of libido

Reduced confidence and concentration

Sleep disturbance (hypersomnia, insomnia)

Anhedonia

Common physical symptoms:

 Abdominal bloating or discomfort

Breast tenderness with or without swelling

Weight gain

Tiredness

Headache

Joint or muscle pain

Acne

Common behavioral symptoms:

Increased appetite with food cravings, particularly for

sugary foods, chocolate, simple carbohydrates. Women
may feel that their tiredness and dizziness represent
hypoglycemia, but hypoglycemia has not been
demonstrated

Alterations in concentration, memory, and learning,

causing problems at school or work

Decreased motivation

Decreased efficiency

Altered sleep cycle

 Difficulty controlling anger

Less common behavioral symptoms:

Increased alcohol intake

Relapse of psychiatric conditions

Decreased tolerance

Possibly an increase in criminal behavior

Other historical information

The symptoms of PMS are by definition cyclical and

occur before menstruation and are relieved by the end of
menstrual flow

Recommend daily rating of symptom for two cycles as

history often minimizes the presence of postmenstrual
symptoms and can lead to failure to diagnose an
underlying mood or somatic disorder. Charting of
symptoms is also therapeutic, as it enhances opportunities
for predictability and self control

Establish what, if anything, has helped or exacerbated

the patient's symptoms as this may provide clues to the
etiology as well as to the patient's understanding of her
symptoms
 Many patients will present saying that they have PMS
or PMDD, but others may not have considered the
possibility

Establish how well informed the patient is about PMS

and other premenstrual disorders

Establish gynecologic and obstetric history, including

menstrual history

Take a thorough medical history

If the patient is unkempt and does not display a normal

affect, such as eye contact and smiling, these may be signs
of depression

Regardless of the patient's appearance, screen for

depression

o Sleep problems and poor appetite are common in

depression. Variability may point to cyclothymia or an
episodic disorder; variability in tandem with the menstrual
cycle may point to PMS

o Changes in weight, especially if not sought, may be

a feature of depression
o Impaired concentration is a common feature of
depression; it may be demonstrated by poor work
performance or by the inability to read a book, concentrate
on a television program, or watch an entire film

o Reduced sex drive is common in depression

o Mood disorders may run in families

o The patient's perception of her mood is important

o It is important to explore suicidal tendency in a

patient with significant depression

Other physical examination factors

Perform a general physical examination with emphasis

on the following:

o Measure height and weight, and determine

whether the body mass index (BMI) is less than 19 or
greater than 25

o Perform a thyroid examination

o Examine the breasts if the patient complains of

breast symptoms
o Include a bimanual pelvic examination if there are
symptoms suggestive of underlying malignancy or chronic
pelvic pain, particularly weight loss, abdominal pain, or
increasing abdominal swelling, presence of gastrointestinal
or genitourinary symptoms, or if fertility is a patient
concern

Perform a mental state examination

Diagnostic testing
No tests are available to specifically confirm PMS,
which is a diagnosis based on history and exclusion

Daily rating of symptoms for at least one or preferably

two menstrual cycles is crucial to ensure the patient is
symptom free after menses

Blood tests are necessary only if other conditions are

suspected or remain in the differential diagnosis after
history and examination

Differential diagnosis
Perimenopausal symptoms
Many of the features of PMS are also found in women
enteringmenopause , when the cycle may be irregular with
 menorrhagia, breast tenderness, moodiness, and bloating
for several weeks prior to bleeding

Features include irregular cycles, menorrhagia,

dysmenorrhea, hot flashes, weight gain, mood swings,
anxiety, depression, headaches, tiredness, sleep
disturbance, skin and hair changes, vaginal dryness, loss of
libido, poor concentration, altered performance

Anovulatory cycling early after menarche

Many girls ovulate irregularly for the first 12 months or
so after menarche. They are likely to be focused on menses
and when these are due, and they may have read about
PMS and be expecting it to occur. They are also often
dieting and may have altered body image and concerns
about weight

During anovulatory cycling menses are often perceived

as very heavy, are usually not painful, and are highly
irregular and variable. Mood disturbance is common.
Cyclical mastalgia is not common

PMS does occur in adolescents but would be unusual in

the first year after menarche. At this time it is very
important to discuss symptoms with a view to promoting
 understanding and healthy behavior and learning how to
recognize and control stress

Depression/anxiety
Depression and anxiety are both common and both may
be exacerbated in the premenstrual phase or may coexist
with or be worsened by PMS

Depression is the main differential diagnosis of PMS,

and presentation in adolescents can differ from that
in adults

There is considerable overlap in symptomatology

between depression and anxiety

The main features include low mood, anxiousness,

appetite changes, sleep disturbance, reduced
concentration, reduced performance, reduced libido,
anhedonia, suicidal ideas

Manic depression
Bipolar disorder is an episodic, recurrent condition
involving periods of mania and possibly periods of
depression

Features include depression with dysthymia

 Cycle is not usually related to the menstrual cycle

There is often long history of mental illness, possibly at

a subclinical level, and cyclothymic personality disorder
may precede

Depressive episodes are often prolonged (months to

years)

Patients also may experience episodes of prolonged

inability to sleep and may display impulsive or reckless
behavior

Cyclothymic personality
Cyclical variation in mood, which may be severe, in
which case it may be referred to as a cyclothymic
personality disorder. Mood fluctuates from week to week;
however, it is not clearly related to the luteal phase of the
menstrual cycle

Where there is an underlying cyclothymic personality

trait, depression may be cyclical but not clearly linked to
the ovarian cycle

Features include low mood, anxiety, appetite changes,

sleep disturbance, reduced concentration, reduced
performance, reduced libido, anhedonia, suicidal ideas
 Premenstrual magnification/somatization
Patients with underlying emotional distress or
depression present with a variety of physical symptoms
and may try to make sense of them based on their own
perceptions of physical disease. Thus they may attempt to
'tailor' a variety of physical symptoms to fit a diagnosis of
PMS in the hope that this will provide a cure

Features include recurrent presentation, nonspecific

aches and pains, multiple different symptoms, low mood,
anxiety

Be aware that patients with somatization can evoke

feelings of dismay or helplessness in the physician

Abnormal uterine bleeding

Abnormal uterine bleeding consists of abnormally heavy or
irregular uterine bleeding. Dysfunctional or anovulatory
bleeding is a diagnosis of exclusion. Most cases of
abnormal uterine bleeding are caused by anovulatory
cycling; ovulatory disorders, such as corpus luteum
dysfunction; or structural lesions, such as polyps, myomas,
uterine hyperplasia, or carcinoma

Features include metrorrhagia, intramenstrual

bleeding, menorrhagia, oligomenorrhea, altered
 intermenstrual interval (<21 days or >35 days is usually
considered abnormal), bloating, abdominal pain (often
colicky)

Pregnancy
Early pregnancy may present with PMS-like symptoms.
It should be ruled out in all patients with new onset of
apparent PMS

In early pregnancy, menses are not always delayed or

absent

Other features of pregnancy include breast pain,

swelling, bloating, constipation, tiredness, nausea, mood
swings, headaches

Polycystic ovary syndrome

Polycystic ovary syndrome consists of oligomenorrhea,
often with androgenization (hirsutism, acne, weight gain)
and with abdominal discomfort and bloating. Diagnosis
may be made based on raised serum androgen levels and
luteinizing hormone/follicle-stimulating hormone ratio or
on ultrasound study of the ovaries

Other features include altered cycle, oligomenorrhea,

and infertility
 Endometriosis
Endometriosis is defined as the presence of functioning
endometrial glands and stroma outside the uterine cavity.
The most common age at diagnosis is the late 20s

Classic triad is dysmenorrhea, dyspareunia, and

subfertility

Pelvic pain does not correlate well with area of

infiltration or amount of ectopic uterine tissue present but
does correlate well with depth of penetration of ectopic
tissue

Pelvic examination is often abnormal and painful

Other features include premenstrual exacerbation of

pain, menorrhagia, bloating, abdominal tenderness, and
deep dyspareunia

Uterine myomas
Uterine myomas , also known as fibroids, are discrete
nodular tumors of variable size that are found in at least
20% of all women of reproductive age. They are most often
asymptomatic and are often diagnosed incidentally. Those
that impinge on the endometrial cavity are often associated
with menorrhagia
 Pelvic pain may be acute, caused by so-called red
degeneration (central infarction of myoma) or torsion of
pedunculated myoma

Other features include dysmenorrhea and abdominal

swelling

Irritable bowel syndrome

Irritable bowel syndrome is common and may worsen
premenstrually or coexist with PMS. Patients are more
likely than average to have anxiety or depression or other
pain disorders. Diagnosis requires exclusion of other bowel
disorders

Pain is associated with altered bowel habit (eg, changes

in form or frequency of stool). Pain is relieved with bowel
movement

Other features include diarrhea, constipation,

abdominal discomfort, bloating, and flatulence. Weight
loss not a feature

Constipation
Constipation is common at all ages, often triggered by
poor fiber content in diet or inadequate drinking; responds
 to regular use of laxatives over several months. Can be
worse premenstrually

Features include abdominal pain, bloating, and hard or

infrequent stools

Hypothyroidism
Hypothyroidism is underactivity of the thyroid gland with
underproduction of thyroid hormone. It may be acquired,
congenital, pituitary, surgical, caused by radiotherapy, or
sporadic related to goiter; it is also common after Graves
disease (autoimmune thyroiditis)

Its prevalence increases with increasing age. It is not

cyclical, but symptoms can be worse premenstrually

Features include the following:

o Tiredness

o Weight gain and edema

o Increased sensitivity to cold

o Slow pulse

o Dry, coarse skin with sallow, yellowish color

o Brittle hair; outer third of eyebrows may be lost

o Coarse facies may develop later

o Thickening of lips and tongue

o Goiter may be present

o Musculoskeletal problems: carpal tunnel

syndrome, meralgia paresthetica (nerve compression
syndrome of lateral cutaneous nerve of thigh), weakness,
muscle stiffness

o Slow deep tendon reflexes with delayed relaxation

phase

o Memory and hearing loss

o Peripheral neuropathies with paresthesias

o Muffled heart sounds; possible pericardial effusion

Hyperthyroidism
Hyperthyroidism is overactivity of the thyroid gland with
excessive production of thyroid hormone, which results in
a hypermetabolic state. It may be due to Graves disease,
toxic multinodular goiter (Plummer disease), toxic
adenoma, transient hyperthyroidism caused by other
thyroiditis (eg, Hashimoto thyroiditis), pituitary tumors
causing hypersecretion of thyroid-stimulating hormone
 (TSH), a teratoma secreting thyroid hormone or TSH, or
amiodarone therapy

Features include the following:

o Anxiety, irritability, emotional lability, panic

attacks

o Palpitations, atrial fibrillation

o Weight loss

o Intestinal rush, diarrhea

o Menstrual dysfunction (oligomenorrhea,

amenorrhea)

o Sweating

o Sensitivity to heat

o Goiter and thyroid bruit may be present

o Clubbing (rare; also called Graves acropathy)

o In Graves disease: blurring of vision, photophobia,

proptosis, diplopia, watering eyes

Treatment
Summary approach
 Treatment choice is directed at predominant symptoms
but is largely by trial and error, starting with the safest and
simplest therapies. Education and understanding may be
sufficient for many patients who may be concerned that
their symptoms could have a sinister cause (eg, breast
cancer)

Daily rating of symptoms can be salutary

Nonpharmacologic therapies:

Stress management and other lifestyle measures may

help: weight loss, exercise, dietary changes, sleep hygiene,
reduction or cessation of smoking, restriction of caffeine,
and alcohol counseling to discuss past and predisposing
difficulties with a view to encouraging self-help. Measures
for tackling alcohol abuse and dependence should follow
recommended guidelines

Massage therapy, relaxation therapy, or cognitive

behavioral therapy also may be of benefit

Pharmacologic therapies:

If nonpharmacologic measures are not successful,

pharmacologic treatments may be started in appropriate
patients with PMDD or severe PMS
 First-line therapy in patients is often considered to be
a selective serotonin-reuptake inhibitor (SSRI), which may be
given either during the luteal phase of the menstrual cycle
(from day 14 until menses) or continuously on a daily
basis. Fluoxetine has been used most frequently; however,
other SSRIs, such as sertraline , paroxetine , orcitalopram ,
may be used with equal efficacy. If there is no response to
one SSRI, another may be tried. Other serotonergic
antidepressants, including serotonin-norepinephrine
reuptake inhibitors (SNRIs) such as venlafaxine,
duloxetine, or nefazadone, also have been used, but
experience is limited

If the patient does not respond to an SSRI, some

experts recommend the premenstrual use of the low-dose
benzodiazepinealprazolam , or the 5-HT1agonist buspirone .
Because of the addictive properties of benzodiazepines,
many physicians recommend luteal-phase dosing rather
than continuous daily dosing

Pain relief may be achieved with analgesics, including

nonsteroidal anti-inflammatory drugs

If the patient requires contraception, an oral

contraceptive may be added to any of the therapies
mentioned previously
o The oral contraceptives containing a low-dose of
estrogen (20 g of ethinyl estradiol) and a progestogen
such as drospirenone administered in a 24/4 (24 active
pills and 4 placebo pills) or in a continuous fashion
without a placebo are likely to be the most effective

o The combined oral contraceptive containing ethinyl

estradiol (20 g) and drospirenone (3 mg) given in a 24/4
regimen has been approved by the U.S. Food and Drug
Administration for use in women with PMDD who also
desire contraception

o Multiple studies of oral contraceptive pills

with ethinyl estradiol (20 g) and levonorgestrel (90 g) given
continuously have shown mixed results

o Tricyclic regimens are not recommended

Patients with severe premenstrual syndrome or patients

who do not respond to the above therapies may be given a
gonadotropin-releasing hormone (GnRH) agonist or
danazol, both of which inhibit ovulation. These agents are
thought to have less effect on depressive symptoms than
other therapies

o GnRH agonists are best used temporarily to confirm

that a complex of symptoms is PMDD or in the planning
 for therapeutic oophorectomy. GnRH agonists have risks
associated with long-term use, such as bone loss and
possibly cardiovascular disease

o Danazol can impair hepatic functioning and is

teratogenic if ovulation does occur. Due to its risk of
adverse effects, danazol should only be used if the patient
is unresponsive to a GnRH agonist

Other medications such

as spironolactone and bromocriptine may be useful for control
of symptom (eg, cyclical bloating, myalgia); however,
further studies are required

Progestogens, once a common therapy for the

treatment of premenstrual syndrome, are no longer
recommended or used due to lack of efficacy

Estradiol implants or patches in doses sufficient to

block ovulation (100-200 g patches) and have been
shown in small studies to be effective. The endometrium
can be protected with a cyclic progestogen if tolerated or
with an intrauterine device that contains a progestogen

Surgical procedures:
 Bilateral oophorectomy is sometimes used in extreme
cases of severe-to-intractable PMS; however, a trial of a
GnRH agonist with estrogen 'add-back' therapy is
recommended first for 3 to 6 months

Hysterectomy is also recommended at the time of

oophorectomy, as estrogen replacement will be needed and
most women with severe PMS/PMDD do not tolerate the
progestogen supplementation needed to protect the
endometrium

Endometrial ablation may help patients with PMS

associated with abnormal uterine bleeding

Other therapies:

Dietary supplementation with minerals and vitamins

may help with symptoms

o Calcium may be of benefit in conjunction with diet

and lifestyle advice

o Magnesium may reduce water retention and

constipation

o Pyridoxine (vitamin B6) may be useful for fatigue,

irritability, and depression. A meta-analysis of rather
 inadequate data suggested that less than 100 mg/d of
vitamin B6 may be helpful

There is limited quality evidence supporting the use

of herbal treatments and other complementary/alternative
therapies

o Vitex agnus-castus(chasteberry) has been shown

to benefit emotional and somatic symptoms compared to
placebo in treatment of women with PMDD

o Hypericum perforatum(St John's wort) may also

have beneficial effect in treatment of PMDD when
compared to placebo. However, caution should be taken
given the known interaction of St John's wort with SSRIs,
as well as the affect St John's wort has on the metabolism
of oral contraceptive pills

o There is evidence that patients with PMDD have

altered circadian rhythms. Bright-light therapy either in
the early morning or in the evening could alleviate
symptoms of PMDD

Medications
Selective serotonin-reuptake inhibitors (SSRIs)
Indications
 SSRIs are used as first-line therapy for the treatment of
PMS in patients who fail lifestyle changes, and who have
moderate-to-severe symptoms that impact daily
functioning

These medications are particularly helpful in women

with depressive symptomatology and/or those who do not
seek contraception

Dose information

Fluoxetine :

20 mg/d orally

Sertraline :

50 to 150 mg/d orally

Paroxetine :

20 to 30 mg/d orally

Citalopram :

20 to 30 mg/d orally

Major contraindications

Citalopram hypersensitivity (citalopram)

 Monoamine oxidase inhibitor (MAOI) therapy
(sertraline, paroxetine, citalopram)

Pregnancy (paroxetine)

Comments

Doses may be given daily on a continuous basis or

during the luteal phase of the cycle

Sixty to seventy percent of symptomatic women will

respond to an SSRI

Adverse effects may occur in up to 15% of women and

contribute to discontinuation of treatment

Evidence
A systematic review evaluated the effectiveness and
safety of SSRIs for treating PMS. The article reviewed 31
randomized, controlled trials (RCTs) comparing SSRIs
with placebo in a total of 4,372 patients with PMS. The
results indicated that SSRIs are effective for reducing
overall symptoms of PMS including mood, behavioral, and
physical symptoms. [1] Level of evidence: 1

A systematic review of 29 double-blind RCTs

comparing SSRIs to placebo indicated that SSRIs were
 effective in the treatment of 2,964 women with PMS and
PMDD. Intermittent dosing regimen (OR 0.55, 95% CI
0.45-0.68) may be less effective than continuous dosing
(OR 0.28, 95% CI 0.18-0.42), but adverse effects and cost
may be lower. [2] Level of evidence: 1

References
Combined oral contraceptives
Indications

Combined oral contraceptives are used as an alternative

first-line treatment of PMDD or PMS

This is an off-label indication (PMS)

Dose information

Ethinyl estradiol/drospirenone:

20 g ethinyl estradiol/3 mg drospirenone (24/4)

Major contraindications

Adrenal insufficiency

Angioedema

Atrial fibrillation
 Breast cancer

Cerebrovascular disease

Cervical cancer

Coronary artery disease

Coronary thrombosis

Endocarditis

Endometrial cancer

Endometrial hyperplasia

Hepatic disease

Hepatocellular cancer

Jaundice

Myocardial infarction

Ovarian cancer

Pregnancy

Renal disease

Renal failure

Renal impairment
 Stroke

Thromboembolic disease

Thrombophlebitis

Tobacco smoking

Uterine cancer

Vaginal bleeding

Vaginal cancer

Valvular heart disease

Comments

In traditional 21/7-day oral contraceptive regimens, the

7-day placebo interval may contribute to hormonal
fluctuation and mimic symptoms of PMS

When comparing 20 g with 30 or 35 g of ethinyl

estradiol, the lower dosage showed greater improvement of
mood symptoms

Lifestyle measures
Lifestyle changes that may be beneficial include the
following:
 Weight loss

Improved general fitness

Exercise, for example, aerobics, yoga, Pilates

Diet modification: low salt, low fat; possibly avoidance

of refined sugars and simple carbohydrates, though one
study suggested that women had improved mood after
consuming simple carbohydrates

Reduction in alcohol (depressant) and caffeine

(stimulant), which may worsen mood disturbance

Reduction or cessation of smoking

Relaxation therapy, for example, through yoga,

meditation

Special circumstances
Comorbidities
In endometriosis or infertility, treatment of the
underlying condition may help PMS

In patients with psychiatric disorders, the premenstrual

exacerbation may be ameliorated if coexistent PMS is
treated
 Symptoms of PMS resolve during pregnancy

Consultation
Referral to an endocrinologist or a psychiatrist for
severe and worsening PMS

Referral to a gynecologist for breast pain that does not

resolve with simple measures

Referral to a gynecologist for patients being considered

for GnRH, high-dose estradiol, danazol, or surgery

Follow-up
Over time, symptoms improve in 90% of women

Unless symptoms are severe or patient is prescribed

medication, follow-up may be at the patient's instigation

Regularly review the patient during treatment, at a

frequency appropriate to symptom severity and type of
treatment offered

Prognosis:

Prognosis is good for true PMS, although perhaps this

is because many women learn to live with it and adapt to
their symptoms so that their symptoms no longer severely
affect their lives
 PMDD improves with treatment in 60% to 85% of
women

Underlying psychiatric disorders, particularly

depression, have a poor long-term prognosis and tend to
recur

Patient education
Patients frequently believe that all cyclical emotional
disorders are PMS, even when symptoms are not clearly
relieved by menstruation

Daily rating of the patient's five worst symptoms will

clarify the diagnosis for the patient and the physician, and
can be an effective educational tool

Many patients also want to believe that all depression is

PMS, even if no cycling occurs

Patients often feel that exogenous hormones, such as

hormonal contraceptives or combined HRT (in menopausal
women) cause PMS. Although some physicians would argue
that this is not true, PMS-like symptoms are sometimes seen

Patients often ask about alternative therapies. A great

deal of complementary and alternative therapy is not
evidence-based but is prescribed by practitioners on the
basis of anecdotal evidence or personal experience of a small
number of patients. There are obvious reasons for bias in
this kind of evidence, particularly positive reporting
(because those in whom the treatment fails tend not to
return to the practitioner to report it but rather go
elsewhere). Although health-seeking behavior should never
be discouraged, patients should be cautious about ingesting
medication that has not been properly tested and evaluated
through hard evidence