Expert Reviews ajog.

org

Premenstrual disorders
Kimberly Ann Yonkers, MD; Michael K. Simoni, MD

criteria are based on the literature and

Premenstrual disorders include premenstrual syndrome, premenstrual dysphoric dis- opinion of experts who worked together
order, and premenstrual worsening of another medical condition. While the underlying over the past 10 years to harmonize
causes of these conditions continue to be explored, an aberrant response to hormonal definitions and subcategorize premen-
fluctuations that occurs with the natural menstrual cycle and serotonin deficits have both strual disorders. The criteria for PMS do
been implicated. A careful medical history and daily symptom monitoring across 2 not stipulate a minimum number of
menstrual cycles is important in establishing a diagnosis. Many treatments have been symptoms nor any particular symptom.
evaluated for the management of premenstrual disorders. The most efficacious treat- The criteria for PMDD are more strin-
ments for premenstrual syndrome and premenstrual dysphoric disorder include sero- gent than those for PMS and reflect the
tonin reuptake inhibitors and contraceptives with shortened to no hormone-free interval. most severe end of the spectrum for
Women who do not respond to these and other interventions may benefit from premenstrual disorders. This also means
gonadotropin-releasing hormone agonist treatment. a greater number of women are likely to
meet criteria for PMS than PMDD (see
Key words: menstrual cycle, premenstrual disorder, premenstrual dysphoric disorder, below). However, PMS and PMDD
premenstrual symptoms, premenstrual syndrome, premenstrual tension criteria share features such as symptom
expression during the luteal phase of the
Introduction from mild to severe. As one fast- cycle with a symptom-free period, as
Dr Robert Frank1 is commonly thought forwards to current times, a lack of well as functional impairment in asso-
to have brought medical attention to clarity continues with regards to the ciation with the condition.3 Problems
premenstrual tension through his case definition of premenstrual disorders with recall bias5 led to recommendations
series published in 1931. He described although expert societies have coalesced that a menstrual calendar should pro-
women who experienced tension in in support of a framework that describes spectively document the timing, dura-
conjunction with a variety of emotional various premenstrual conditions.3 This tion, and severity of symptom
symptoms and worsening of their con- expert review provides an update on expression. The ISPMD group also arti-
current medical conditions during the premenstrual conditions and their culated “variant premenstrual disorders”
few days prior to menstruation. He management. such as premenstrual exacerbation of
posited a connection between “ovarian another medical condition and
function.and other organic symp- Definitions progestin-induced disorders, which
toms.” In their classic article, Greene and Premenstrual symptom severity varies likely have biological bases that differ
Dalton2 argued for the term “premen- from normative, mild premenstrual from core premenstrual disorders.3 The
strual syndrome” (PMS) because they molimina, to severe and disabling framework devised by the ISPMD is
believed candidate symptoms prior to symptoms. The American Psychiatric useful in guiding treatment decisions.6
the onset of menses were far more Association published criteria for a se- In this review, we use the term “PMS”
extensive than tension and could vary vere clinical syndrome, premenstrual to refer to both PMS and PMDD, unless
dysphoric disorder (PMDD), in its the finding is specific to PMDD.
Diagnostic and Statistical Manual of Many different emotional and phys-
From the Departments of Psychiatry (Dr Mental Disorders, Fifth Edition ical symptoms are reported by women in
Yonkers); Obstetrics, Gynecology, and (Table 1).4 This category describes the premenstrual period although the
Reproductive Sciences (Drs Yonkers and women who have at least 5 predomi- frequency of a handful of symptoms
Simoni); and Epidemiology and Public Health (Dr nantly affective symptoms, in associa- stands out. In a study that included a
Yonkers); Yale University School of Medicine,
New Haven, CT.
tion with functional impairment. large community and a clinical cohort of
However, there are also women who women who prospectively recorded
Received April 18, 2017; revised May 15, 2017;
accepted May 22, 2017. experience distress and impairment but symptoms, the most problematic
Dr Yonkers has received royalties from Up-To-
are either subthreshold for PMDD or symptoms were: bloating, mood swings,
Date and consulting fees from Marinus and have predominantly physical symptoms lethargy, irritability, breast tenderness,
Juniper Pharmaceuticals. who are best considered to have PMS. In anxiety/tension, and fear of being rejec-
Corresponding author: Kimberly Ann Yonkers, this instance, criteria put forth by the ted.7 Symptoms were the most severe the
MD. Kimberly.Yonkers@yale.edu International Society for Premenstrual day before and first day of menses.
0002-9378/$36.00 Disorders (ISPMD) and the Royal Col- Diagnostic and Statistical Manual of
ª 2017 Elsevier Inc. All rights reserved. lege of Obstetricians and Gynecologists Mental Disorders, Fifth Edition4 criteria
http://dx.doi.org/10.1016/j.ajog.2017.05.045
(RCOG) are helpful (Table 2). These for PMDD reflects these findings, with

68 American Journal of Obstetrics & Gynecology JANUARY 2018

ajog.org Expert Reviews

TABLE 1
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition4 premenstrual dysphoric disorder
A. In most menstrual cycles, following symptoms must be present in final week before onset of menses, start to improve within few days after
onset of menses, and become minimal or absent in week postmenseseat least 1 symptom must be either (1), (2), (3), or (4) and individual must
experience at least 5 total symptoms:
1. Marked affective lability (eg, mood swings; feeling suddenly sad or tearful or increased sensitivity to rejection)
2. Marked irritability or anger or increased interpersonal conflicts
3. Marked depressed mood, feelings of hopelessness, or self-deprecating thoughts
4. Marked anxiety, tension, feelings of being “keyed up,” or “on edge”
5. Decreased interest in usual activities (eg, work, school, friends, hobbies)
6. Subjective difficulty in concentration
7. Lethargy, easy fatigability, or marked lack of energy
8. Marked change in appetite, overeating, or specific food cravings
9. Hypersomnia or insomnia
10. A sense of being overwhelmed or out of control
11. Physical symptoms such as breast tenderness or swelling, joint or muscle pain, sensation of “bloating,” weight gain
B. Symptoms are associated with clinically significant distress or interference with work, school, usual social activities, or relationships
C. Disturbance is not merely exacerbation of symptoms of another disorder
D. Criterion A should be confirmed by prospective daily ratings during at least 2 symptomatic cycles (diagnosis may be made provisionally prior to
this confirmation)
E. Symptoms are not due to direct physiological effects of substance (eg, drug of abuse, medication or other treatment) or another medical
condition (eg, hyperthyroidism)
Yonkers. Premenstrual disorders. Am J Obstet Gynecol 2018.

the exception that physical symptoms
are clustered into 1 item. A diagnosis of
PMS can be made in the absence of se-
vere emotional symptoms if the physical
manifestations are sufficiently problem-
atic to cause functional impairment.
Epidemiology
Community-based studies that could
provide estimates of PMDD and PMS
are difficult to conduct because retro-
spective reports of symptom timing, the
most efficient manner of querying large
groups of women, frequently differ from
prospectively gathered data.5 Of the few
available surveys that relied on concur-
rent collection of symptom reports in
community populations, the point
prevalence of PMS in menstruating
women was between 20-30%8,9 while
rates of PMDD ranged from 1.2%-
6.4%.9-11 Retrospective data show that
both PMS and PMDD are present in
women across the globe.12
Risk factors
Retrospective surveys from the United
States show that PMS is more prevalent
in white than African American women,
similar to other psychiatric diseases that
may be influenced by cultural differ-
ences.13,14 Risk does not differ among
various premenopausal age groups.15
Dietary factors are shown to moderate
the risk of PMS, although this may
reflect the confounding influence of
positive health habits in general. High
intake of thiamine, riboflavin, non-
heme iron, and possibly zinc protect
against, while high potassium intake may
increase the risk of PMS.16 There is also
evidence that adiposity and metabolic
syndrome increase risk of PMS, partic-
ularly if women are >27.5 kg/m2.17,18
Other factors associated with the devel-
opment of PMS include use of nicotine
cigarettes17 and early sexual abuse and
trauma.19,20 It is also clear that comor-
bidity between depressive and/or anxiety
disorders and PMS is high, although it is
not clear whether these conditions pre-
dispose toward PMS, or whether PMS
increases the likelihood of other condi-
tions.21 PMS appears to be familial with
concordance rates that are higher among
monozygotic than dizygotic twins.22,23
However, familial risk differs for PMS
and common mood and anxiety
disorders.22
Etiopathology
Since PMS does not occur prior to
menarche, in pregnancy, or postmeno-
pause, exposure to changing levels of
gonadal steroids is obligatory. While
research has not supported a simple
excess or deficit of a hormone, it appears
that a woman’s response to hormonal
changes can lead to symptom expres-
sion.24 A leading theory suggests that
some women may have a pathological
response to either withdrawal from25 or
exposure to26 the progesterone metabo-
lite, and gamma aminobutyric acid
agonist, allopregnanolone. It is notable
that blockage of allopregnanolone pro-
duction reduces premenstrual symp-
toms27,28 and some serotonin reuptake
inhibitors (SRIs), which are effective
treatments for premenstrual disorders
(see Evidence Based Treatments), also
effect allopregnanolone levels.29 Treat-
ments that eliminate cyclic changes in
ovarian hormones would be beneficial
per this theory.
The classic and alternative but
compelling view on the pathophysiology
of premenstrual disorders suggests that
the deficit is in functioning of the sero-
tonin system and especially, the serotonin
transporter.30 The neurotransmitter se-
rotonin is implicated in the pathophysi-
ology of mood and anxiety disorders as
well as PMS. Sex steroids and their re-
ceptors are abundant in many brain re-
gions that regulate emotions and
behavior, such as the amygdala, and they
modulate serotonin transmission.31-33 In
human beings, premenstrual symptoms

JANUARY 2018 American Journal of Obstetrics & Gynecology 69

Expert Reviews
TABLE 2
Premenstrual syndrome3
1) Physical and or emotional symptoms
2) Symptoms are present during luteal
phase and abate as menstruation
begins
3) A symptom-free week
4) Symptoms are associated with
significant impairment
during luteal phase
Yonkers. Premenstrual disorders. Am J Obstet
Gynecol 2018.
can be elicited by the depletion of sero-
tonin’s precursor, tryptophan,34 and by a
serotonin receptor antagonist.35 An
abundance of work also shows that
indices of serotonergic transmission are
dysregulated in women with PMS (see
Yonkers et al36 for a review).
Direct exploration of brain functioning
in women with and without premenstrual
disorders have produced promising find-
ings (Hantsoo and Epperson37 and
Comasco and Sundstrom-Poromaa38).
Sections of the frontal cortex exert top-
down control on areas of the brain that
receive and integrate emotional and
physical input, such as the amygdala. Un-
der appropriate hormonal conditions,
differences in circuitry may lead women
with PMS to have greater difficulty exert-
ing sufficient top-down control than
women without premenstrual disor-
ders39,40; this can lead to the expression of
emotional symptoms, impulsivity, and
impaired executive function.41 Thus,
treatments that stabilize emotional symp-
toms and impulsivity can be beneficial.
Evidence-based treatments
Treatments for PMS and PMDD fall into
6 main categories: (1) non-
pharmacological approaches such as
diet, exercise, and psychotherapy; (2)
psychotropic treatment; (3) hormonal
agonists and antagonists; (4) vitamins
and botanicals; (5) surgery; and (6)
complementary medicines.
Nonpharmacological approaches
Many of these recommendations reflect
positive health habits. Exercise, which
stabilizes mood, may be helpful for
mood and physical symptoms that occur
70 American Journal of Obstetrics & Gynecology JANUARY 2018
premenstrually42 but the evidence in
support of this is minimal.6 There is
stronger evidence, including a random-
ized clinical trial, that a complex carbo-
hydrate diet during the luteal phase may
help women with PMS presumably
because this increases the amount of
serotonin that is available centrally.43
Cognitive behavioral therapy (CBT)
may be of benefit to women with PMS in
that it can help women manage
emotional symptoms. The most
rigorous trial compared CBT to fluoxe-
tine and found no difference between
groups or additive effects of both CBT
and fluoxetine. At follow-up, response to
CBT was better maintained than fluox-
etine but attrition was high (nearly
50%).44
Serotonin reuptake inhibitors
The evidence supporting the efficacy of
SRIs, administered either throughout
the menstrual cycle or only during the
second half of the menstrual cycle,45 is
strong.46 Most studies followed criteria
for PMDD although this class of agents is
also helpful for women who are sub-
threshold for PMDD.47 SRIs have a rapid
onset of action for PMDD.48 An inter-
esting implication from this is that
different mechanisms may underlie the
efficacy of SRIs for PMDD compared
with depression.
Hormone agonists and antagonists
Even though combined oral contracep-
tives are commonly used as treatments for
PMS, evidence in support of their efficacy
is remarkably sparse. Rigorous clinical
trials49,50 established that a combination
oral contraceptive comprised of 3 mg of
the progestin drospirenone and 20 mg of
ethinyl estradiol (Yaz; Berlex Pharma-
ceuticals, Wayne, NJ) taken for 24 days of
a 28-day cycle is efficacious for PMDD.
This oral contraceptive is approved to
treat PMDD in women who desire
contraception, however Food and Drug
Administration warnings of risk for blood
clots in drospirenone-containing birth
control pills should be considered. The
shortened hormone-free interval may be
pivotal to the efficacy since a standard 21-
day active treatment phase with these
steroids was not effective51 while a second
ajog.org
oral contraceptive, continuous daily le-
vonorgestrel 90 mg/ethinyl estradiol 20 mg
was helpful in a pivotal trial.52 However,
subsequent trials of daily levonorgestrel
were less supportive53 and it may be the
combination of the type of hormones and
platform for administration that are
responsible for efficacy. At this point, it is
difficult to say that other oral contracep-
tives are effective for PMDD or PMS.
The data in support of estrogen, either
administered orally as ethynyl estradiol
or via patch or implant, are of poor
quality; estrogen can also provoke
symptoms in some women and can
cause side effects.54 Similarly, proges-
terone has been advocated as a treatment
for PMS but research in support of this
treatment is of low quality.55
Gonadotropin-releasing hormones
(GnRH) agonists, used in a continuous
manner, suppress ovarian release of es-
trogen and ovulation leading to an
improvement of PMS symptoms.56-58
Typical treatment in studies and prac-
tice is a monthly injection of leuprolide
acetate 3.75 mg. The resulting hypo-
estrogenic state produces common
adverse effects such as vaginitis, vaso-
motor symptoms, and decrease in bone
density. For this reason, and its high
costs, GnRH agonist are usually reserved
for severe cases of PMS, or as third-line
agents behind selective SRIs and oral
contraceptives.
Surgery
Refractory symptoms may require sur-
gical intervention of total hysterectomy
with bilateral salpingo-oophorectomy to
eliminate menstrual cyclicity. To ensure
a patient would benefit from such a
definitive treatment, GnRH agonists
should be used to produce a similar ef-
fect to assess the benefit and tolerance of
a hypoestrogenic state.
Complementary medicines
The most frequently studied comple-
mentary medicines for PMS include
vitamin B6 (pyridoxine), Vitex agnus-
castus (chasteberry), St John wort,
Gingko biloba, and evening primrose oil.
Vitamin B6 has received the greatest
amount of attention and been the focus
of 13 trials. A Cochrane quantitative
ajog.org
review showed benefit of vitamin B6 in
doses up to 100 mg/d but cautions that
the quality of most studies was low.59
Peripheral neuropathy can occur with
doses of 200 mg/d or higher raising
safety concerns.
Vitex agnus-castus extract was used to
treat PMS in doses of 20-40 mg/d,
although preparations and amounts vary
among studies. The compound binds to
the dopamine-2 receptor, opioid recep-
tor, and b-estrogen receptor. The Euro-
pean Medicines Agency registered it as
“well-established” use for PMS and a
recent meta-analysis showed it was more
effective than placebo in 17 trials.60
However, studies supporting its efficacy
were generally of low quality and avail-
able preparations vary in quality and
quantity of the extract.6
The Chinese plant Ginkgo biloba is
primarily known for its antioxidant
properties, but some data suggest it can
treat several mental health disorders and
improve memory. Its effect on stress and
depressive symptoms and anti-
inflammatory properties may be the
basis for its effect. One placebo-
controlled randomized controlled trial
administered Ginkgo biloba 3 times per
day to 85 women with PMS from the
luteal phase through the beginning of
menses.61 Physical and psychological
effects were significantly reduced by the
end of the first cycle of treatment.61
Hypericum perforatum (St John
wort) may alleviate PMS symptoms via
its effects on neuromodulator synthesis.
Common symptoms such as bloating,
food cravings, headache, and fatigue
were significantly decreased with daily
900-mg tablets in a double-blinded pla-
cebo-controlled randomized clinical
trial consisting of 36 women.62 Mood
and physical symptoms involving pain
remained unaffected.62
Calcium also influences neuro-
modulation and has thus become a
therapeutic target for PMS. Studies
show low calcium in women with
PMS and the possibility that women
with PMS may have secondary hy-
perparathyroidism.63 Trials with sup-
plemental calcium in dosages as low as
500 mg daily in women who experi-
ence moderate-severe PMS have
shown significant decrease in symp-
toms.64,65 However, calcium treatment
showed a smaller effect size than
fluoxetine in 1 small study.66
Management recommendations
The first step in management of PMS
is to accurately establish a diagnosis.
This requires a careful medical, gy-
necological, and psychiatric history
that would include information on
diet and exercise. Laboratory tests,
such as gonadal steroid levels, are not
useful. Thyroid indices can be ob-
tained if the clinician suspects thyroid
dysfunction but this would not lead to
expression of cyclical symptoms.
Mood and anxiety disorders may un-
derlie premenstrual symptoms in
many women and clinicians may be
able to identify them with careful
questioning. However, retrospective
report of symptom offset with the
beginning of menses may be inaccu-
rate and diagnostic certainty is
enhanced with a menstrual calendar.
The prospective calendar of symptoms
a patient keeps should include at least
1, but ideally 2, menstrual cycles
because some women have cycle-to-
cycle variability. This recommenda-
tion should be balanced by the distress
a woman is experiencing, which may
preclude a delay in treatment initia-
tion. Clinicians may devise a tailored
calendar for their patient based on
what she endorses as problematic
symptoms. Symptoms should be
assigned a severity score (eg, 1-5) each
day. Alternatively, there are estab-
lished calendars such as the Daily
Record of Severity of Problems67 or
the Calendar of Premenstrual Experi-
ences68 that patients may use.
After completion of menstrual cal-
endars, women may show: (1) symp-
toms that began in the premenstrual
phase and offset at the beginning of
menses or shortly thereafter (PMS or
PMDD); (2) ongoing symptoms that
worsen during the premenstrual phase
(premenstrual worsening of another
condition); and (3) continuous or
sporadic symptoms not related to a
phase of the menstrual cycle (neither
PMS nor PMDD). Recommendations
JANUARY 2018 American Journal of Obstetrics & Gynecology
Expert Reviews
outlined below depend on the results of
such an evaluation.
Premenstrual symptoms limited to
the premenstrual phase (PMS or
PMDD)
RCOG has published guidelines that
are endorsed by the National Institute
for Health and Care Excellence in the
United Kingdom. First-line treat-
ments, per that guideline, include ex-
ercise, vitamin B6 (100 mg), CBT, oral
contraceptives, and intermittent or
continuous selective SRIs.6 If a woman
has mild symptoms, has a very short
duration of symptoms, or does not
want to undergo treatment with an
oral contraceptive or SRI, it is
reasonable to commence treatment
with diet (complex carbohydrates
during the late luteal phase), exercise,
vitamin B6 (100 mg daily), and cal-
cium (1000 mg daily). Women who do
not want medication could also try a
course of CBT that is typically deliv-
ered in about 12 sessions. Women
who have moderate to severe symp-
toms that lead to functional impair-
ment or women who do not respond
to these interventions are candidates
for oral contraceptives or SRI treat-
ment. The contraceptive with the
strongest efficacy data for PMS and
PMDD is a drospirenone/estrogen
preparation with a shortened
hormone-free interval (24 days on
and 4 days off).69 Women who desire
contraception are appropriate for this
option. Women who are on another
oral contraceptive and have premen-
strual mood and anxiety symptoms
may benefit from switch to a dro-
spirenone/estradiol preparation with a
shortened hormone-free interval or
the addition of SRI.70
Women in the moderate to severe
group who do not need contraception
are candidates for treatment with SRI.
Patients with regular cycles who can
predict the onset of symptoms can try
initiating medication at symptom
onset48 or after ovulation.71 Women
who have difficulty predicting the
onset of symptoms or ovulation, or
who have not fully responded to
intermittent SRI treatment, should
71
Expert Reviews
consider daily treatment. Some evi-
dence suggests that women who have
severe physical symptoms may have a
superior response to daily treatment
rather than intermittent SRI treat-
ment.46 Women who have not
responded to drospirenone/estradiol
should also consider SRI.6 SRI should
be continued at least 1 and ideally 2
months. If a woman does not respond
to SRI at a recommended dose or if
she is unable to tolerate it, another
SRI may be tried before deciding that
this class of medications is ineffective.
Women who do not respond to these
first-line interventions may be candi-
dates for treatment with a GnRH
agonist, which will end monthly cycles.
Women sometimes experience clinical
worsening at the initiation of this
treatment and subsequently improve. If
this is continued for at least 6 months,
supplemental estrogen and progestin
can be given as add-back therapy to
avoid side effects without any dimin-
ished effect of the treatment. Practi-
tioners should aim to use the lowest
dose possible of both hormones to
provide symptom relief and to produce
a withdrawal bleed, otherwise risk a
recurrence of symptoms.72 If a woman
is unable to tolerate systemic progestin,
a levonorgestrel intrauterine device can
also be used with rare side effects,
although there has not been a trial on
this method. For those who experience
PMS symptoms from any addition of
progestin, some SRIs are effective
treatment for vasomotor symptoms.
Tibolone, an androgen and progester-
one agonist, was tested with 2.5 mg
daily as add-back in a randomized
clinical trial with 30 patients on leu-
prolide with significant improvement of
symptoms vs placebo.73 It is important
to use continuous rather than cyclic
hormone suppression to not mimic the
hormone changes of the menstrual cy-
cle. If this is successful, and the only
method that improved the woman’s
symptoms, and if she has completed
childbearing, surgical treatment may be
indicated. It is critical that a trial
of GnRH agonist treatment be
conducted prior to consideration of
surgical options.
72 American Journal of Obstetrics & Gynecology JANUARY 2018
Ongoing symptoms that worsen in
the premenstruum
It is not uncommon for women to
retrospectively report isolated premen-
strual symptoms and then to show
symptoms during the follicular phase
that are not as severe. In this case, the
underlying disorder requires treatment.
If the underlying disorder is a chronic
depressive or anxiety disorder, daily
treatment with SRI may be of benefit. If
premenstrual worsening of symptoms
continues despite this treatment, health
habits should be optimized with diet,
exercise, and the addition of vitamin B6
and calcium. If that is not sufficient, the
dose of SRI may be increased during the
luteal phase or it may be combined with
a drospirenone/estradiol product. Cli-
nicians should monitor for worsening of
mood if the contraceptive is added.
GnRH agonists will not substantially
benefit women with depressive symp-
toms during the follicular phase.74
Continuous or sporadic symptoms
Women who do not have a premenstrual
symptom pattern should be managed for
their underlying condition or referred to
another clinician who can manage
symptoms.
Conclusion
Premenstrual disorders vary in terms of
the severity and timing of symptom
onset. Treatments are well studied and
include lifestyle changes for women with
mild symptoms and use of a SRI or
contraceptive with drospirenone/estra-
diol and shortened hormone-free inter-
val for women with moderate to severe
premenstrual symptoms, including
PMDD. Only a fraction of women will
require use of a GnRH agonist or sur-
gery. Surgical removal of uterus, tubes,
and ovaries should not be contemplated
in the absence of a GnRH trial that shows
benefit. -
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