Adverse effects should be discussed in detail with M.F. because they differ
significantly from the other therapies she has tried. Adverse effects are related to the
induction of the pseudomenopausal state. Nearly all patients experience hot flashes;
vaginal dryness and insomnia also are common. GnRH agonists do not affect SHBG
or testosterone levels, so the androgenic side effects of danazol, including changes in
lipid profiles, are not experienced with these agents.
occur, necessitating adequate calcium and vitamin D intake, and estrogen add-back
A reduction in bone density is a significant concern with GnRH agonists, even at 3
months after the onset of therapy, and is particularly concerning because these agents
are being used in young women, many of whom have not reached their peak bone
mass. Studies have demonstrated a loss of 3.2% in lumbar spine bone mineral density
after 6 months and up to a 6.3% decrease after 12 months of GnRH agonist
It has also been reported that endometriosis itself is also a risk factor for
decreased bone density, although a long-term study did not find any association
between endometriosis and fracture risk during a 20-year follow-up period.
Interestingly, this same study did not find any association between fracture risk and
GnRH agonist therapy, although a significant number of women in the study did take
Monitoring for decreases in bone density should be accomplished via dual-energy
X-ray absorptiometry scan every 24 months if GnRH therapy is continued. M.F.
should also be counseled regarding adequate calcium and vitamin D intake, smoking
cessation, and a regimen of weight-bearing exercise.
medroxyprogesterone. A 6-month trial followed by an evaluation of symptom control
MANAGEMENT OF ENDOMETRIOSIS-RELATED INFERTILITY
Of women presenting to the healthcare system with infertility, 25% to 50% have
endometriosis and 30% to 50% of women with endometriosis are infertile.
Proposed mechanisms contributing to infertility include adhesions that impair oocyte
transport, changes in the peritoneum not compatible with fertility, changes in
hormonal function, endocrine or ovulation dysfunction, and disorders of implantation
(see Chapter XX, Infertility). No evidence suggests that hormonal therapy, including
therapy with GnRH agonists, improves conception rates for women with stage I/II
endometriosis, similar to K.L. On the other hand, surgical ablation or resection of
visible endometriosis implants is beneficial in improving pregnancy rates in women
with stage I/II endometriosis.
For K.L., removal of her IUS, followed by laparoscopic ablation or resection of
visible implants, may improve her ability to conceive, barring other factors
influencing fertility (e.g., PCOS, male factor infertility, tubal patency).
with more advanced disease, or in those patients older than 35 years of age, a more
aggressive treatment regimen is appropriate. Options include the use of agents to
induce superovulation (clomiphene) and the use of in vitro fertilization techniques
with embryo transfer (IVF-ET). In women with endometriosis, the success of IVF-ET
is decreased by as much as 20% when compared with women without
99 For women contemplating IVF-ET, three prospective clinical trials
have demonstrated a potential benefit in women with stage II–IV endometriosis who
were treated for 3 to 6 months or more with GnRH agonists before IVF-ET.
treated subjects had significantly higher pregnancy rates compared with women who
did not use GnRH agonists before IVF-ET.
For women who have not yet demonstrated an inability to conceive, a “wait and
see” approach, with use of an NSAID for pain, emotional support, and reassurance,
for 6 to 12 months is appropriate in women younger than 35 years of age.
PREMENSTRUAL DYSPHORIC DISORDER
Premenstrual symptoms occur in up to 95% of reproductive-age women.
Approximately 30% to 40% of these women have more bothersome symptoms of
premenstrual syndrome (PMS), and it is estimated that 3% to 8% meet the criteria for
premenstrual dysphoric disorder (PMDD), a more severe variant of PMS.
than 200 premenstrual symptoms have been described as occurring during the days
before menstruation, including positive symptoms, such as increased energy, libido,
and ability to relax, as well as negative symptoms including abdominal distension,
fatigue, headaches, and crying spells.
It is not until the symptoms have a decidedly
negative influence on the physical, psychological, or social function of a woman that
No specific physical findings or laboratory tests can be used to make a diagnosis of
PMS. Several different organizations have attempted to provide diagnostic criteria
for PMS and PMDD; their criteria are inconsistent and disparate. The International
Society for Premenstrual Disorders (ISPMD) published a consensus statement in
2011 that defined core premenstrual disorders as typical, pure, or reference
disorders associated with spontaneous ovulatory menstrual cycles and variant
premenstrual disorders that are separate from core premenstrual disorders and exist
where more complex features are present (e.g., symptoms result from underlying
disorder or exogenous progestogen administration).
144 Core premenstrual features
(somatic and psychological symptoms) must occur during all or part of the 2-week
This cyclic pattern must also occur in most (typically two out of three) menstrual
cycles. Lastly, the severity of symptoms must (1) affect normal daily functioning; (2)
interfere with work, school performance, or interpersonal relationships; or (3) cause
significant distress. Core premenstrual disorder is an umbrella term for PMS and
ACOG Diagnostic Criteria for Premenstrual Syndrome
Affective Symptoms Somatic Symptoms
Angry outbursts Abdominal bloating
Anxiety Swelling of extremities
ACOG, American College of Obstetricians and Gynecologists.
2000;95(4); Mishell DR. Premenstrual disorders: epidemiology and disease burden. Am J Manag Care.
The American College of Obstetricians and Gynecologists (ACOG) published a
Practice Bulletin in 2000 that defined PMS diagnostic criteria using cyclic patterns
145 PMS can be diagnosed if at least one of the affective or
one of the somatic symptoms listed in Table 50-5 is reported 5 days before the onset
of menses in the three previous cycles. The symptoms must be prospectively
recorded in at least two cycles, must cease within 4 days of onset of menses, and
must not recur until after day 12 of the menstrual cycle. A key factor that separates
PMS from “normal” premenstrual symptoms is that work or social activities are
adversely affected in PMS. Other diagnoses that may explain premenstrual symptoms
should be excluded, including psychological, thyroid, and gynecologic disorders.
The American Psychiatric Association has developed criteria for PMDD.
criteria for PMDD focus on the mood and mental health symptoms, leading to a
higher level of dysfunction compared with PMS. These criteria require prospective
documentation of physical and behavioral symptoms (using diaries) being present for
most of the preceding year; five or more symptoms present during the week prior to
menses, resolving within a few days after menses starts; and PMDD may be
superimposed on other psychiatric disorders, provided it is not merely an
exacerbation of those disorders. One or more of the following symptoms must be
present: mood swings, sudden sadness, or increased sensitivity to rejection; anger,
irritability; sense of hopelessness, depressed mood, or self-critical thoughts; and
tension, anxiety, or feeling on edge. Additionally, one or more of the following
symptoms must be present to reach a total of five symptoms overall: difficulty in
concentrating; change in appetite, food cravings, or overeating; diminished interest in
usual activities; easy fatigability or decreased energy; feeling overwhelmed or out of
control; breast tenderness, bloating, weight gain, or joint/muscles aches; and sleeping
too much or not sleeping enough. Symptoms must have been present in most menstrual
cycles that occurred the previous year, and the symptoms must be associated with
significant distress or interference with usual activities (e.g., work, school, social
Although criteria for PMS and PMDD are different, they share three essential
characteristics: (a) symptoms must occur in the luteal phase and resolve within a few
days of menstruation, (b) symptoms are documented for at least two menstrual cycles
and are not better explained by other physical or psychological conditions, and (c)
symptoms are sufficiently severe to disrupt normal activities.
The symptoms of PMS and PMDD experienced by women can vary widely. Risk
factors for PMS include advancing age (older than 30 years) and genetic factors.
Symptoms, however, can begin in adolescents around age 14, or 2 years
postmenarche, and persist until menopause.
148 Some studies suggest that women with
mothers reporting PMS are more likely to develop PMS than those with unaffected
mothers (70% vs. 37%, respectively).
149,150 One article found that traumatic events,
such as physical threat, childhood sexual abuse, and severe accidents, increased the
The wide range of symptoms exhibited in patients with PMS or PMDD can be
explained by multiple possible mechanisms, probably a result of interactions
between sex steroids and central neurotransmitters.
neurotransmitters, primarily reductions in serotonin, triggered by normal hormonal
fluctuations of the menstrual cycle appear to be the most probable factors for the
153,154 The levels of estrogen,
progesterone, and testosterone are normal in women with PMS, but they may be more
vulnerable to normal fluctuations.
154 These potential mechanisms provide a rational
basis for the symptoms that appear in PMS and PMDD, but also support the
therapeutic benefits of treatments that increase serotonin or GABA levels. Many
treatments have limited and variable efficacy, which reinforces the argumentation that
PMS or PMDD is a result of multiple factors. Furthermore, placebo responses in
trials can be as high as 50% to 80%, which points to an important psychosomatic
component and the consideration that PMS or PMDD has relevant biological,
psychological, and social factors.
occurring every 28 to 30 days with a light flow lasting 3 to 4 days.
normal limits. Her serum pregnancy test was negative. She is sexually active and uses condoms for
symptoms does C.P. have that are consistent with a diagnosis of PMS?
C.P. has symptoms that meet the ACOG criteria for PMS. Her affective symptoms
include irritability and anxiety, and somatic symptoms include breast tenderness and
abdominal bloating. These symptoms occur during the luteal phase of the menstrual
cycle, resolve within 4 days of menses, and do not recur until after day 12 of her
cycle. C.P.’s symptoms appear to be affecting her social activities. She states that
these symptoms have been present for years and that they occur every month, although
she has not prospectively recorded this information. C.P. does not meet the criteria
for PMDD because her symptoms are not severe or markedly impairing her ability to
participate in daily activities.
Treatment: Premenstrual Syndrome
The management of premenstrual disorders has been outlined by the ISPMD.
Treatment may be aimed at symptoms, especially if one particular symptom is
dominant. Nonprescription options that have been studied and have demonstrated at
least minimal benefit include calcium, magnesium, pyridoxine, chaste tree or
chasteberry, and some mind–body approaches. Acetaminophen and NSAIDs may be
beneficial for the physical symptoms of PMS, but diuretics found in various OTC
products (e.g., ammonium chloride, caffeine, pamabrom) have limited data and
unproven efficacy. Given the high placebo response rate in PMS, only agents with
clinically proven efficacy should be used.
Increased estrogen during the middle of a normal menstrual cycle decreases calcium.
In women with PMS, intact parathyroid hormone (PTH) increases in response to this
change compared with no PTH change in women without PMS.
with PMS have mid-cycle elevations of intact PTH with transient, secondary
hyperparathyroidism that increases calcium demands. Calcium supplementation may
help to normalize these processes and explains why calcium has demonstrated some
Three calcium trials have shown efficacy of PMS symptoms. A randomized,
double-blind crossover trial of 33 women receiving 1,000 mg elemental calcium
daily or placebo for 3 months reported a significant overall 50% reduction in PMS
symptoms for women taking calcium compared with placebo.
study of 10 women assigned to dietary calcium intake, 1,336 mg daily was found to
benefit mood, behavior, pain, and water retention symptoms significantly during the
158 Perhaps the most convincing evidence comes from a prospective,
multicenter, randomized, double-blind, placebo-controlled, parallel-group trial
conducted in 466 women with PMS.
159 Elemental calcium 1,200 mg daily (given as
600 mg BID) for three menstrual cycles significantly decreased negative affect, water
reduction in the placebo group. Because calcium is well tolerated and may provide
other benefits (e.g., osteoporosis prevention), calcium supplementation should be
recommended to women with symptoms of PMS if inadequate through diet or other
Low levels of red cell magnesium have been correlated with women experiencing
PMS; therefore, magnesium supplementation has been evaluated for PMS
160 A Cochrane review of three small trials comparing magnesium and
placebo in women with dysmenorrhea concluded that magnesium was more effective
for pain associated with PMS and the need for additional medication was less for
89 Magnesium doses that have been studied for PMS vary
from 200 to 360 mg orally daily. Trials have reported improvements in fluid
retention and negative affect, but findings have not been consistent.
common side effects affect the gastrointestinal system (e.g., nausea, diarrhea). The
conflicting results may be caused by differences in the dosing regimens of the
magnesium and differing levels of magnesium stores in the study subjects. Available
data support the use of magnesium in PMS, but more research is needed.
Vitamin B6 has been noted to have positive effects on neurotransmitters, such as
162 The most comprehensive information for this nutrient comes from a
systematic review of nine trials representing 940 patients with PMS.
assessment of the review was that women with PMS are likely to benefit from
vitamin B6 supplementation at a dose of 50 to 100 mg daily. An analysis of four of
the trials, which specifically examined depressive symptoms, showed that pyridoxine
was more effective than placebo in reducing depressive symptoms (OR, 1.69; 95%
CI, 1.39–2.06). Although the conclusions of this review were positive, the authors
felt there was insufficient evidence of high quality to recommend vitamin B6
PMS. Because neuropathy has been reported with pyridoxine dosages as low as 200
mg/day, patients should be advised to monitor for symptoms, discontinue therapy, and
seek medical attention if they occur.
from the dried ripe chasteberry are used to make chasteberry capsules and tablets.
The mechanism of action of chasteberry relative to PMS is unclear, but several trials
have reported its beneficial effects. In a study of 1,542 women with PMS taking
chasteberry extract, 33% of subjects reported total relief of symptoms and an
additional 57% reported partial relief after 4 months.
164 Of patients, 2% complained
of adverse events including nausea, allergy, diarrhea, weight gain, heartburn,
menstrual cycles showed a treatment response rate of 52% compared with 24% for
Individual symptoms of irritability, mood alteration, anger,
headache, and breast fullness were reduced. Bloating was not significantly altered
compared with placebo. The incidence of side effects was low, but long-term safety
is unknown. A prospective, randomized, placebo-controlled study in 67 Chinese
women showed that one VAC tablet daily containing 40 mg of herbal drug produced
an 85% efficacy rate compared with a 56% efficacy rate for placebo on symptom
scores after three treatment cycles.
In general, data indicate that chasteberry may
be effective for PMS, but should probably not be used as routine treatment for
Evidence regarding mind–body approaches for PMS is somewhat limited. Because
these modalities are risk-free and they are generally accepted as components of a
healthy lifestyle, they are favored in the treatment of PMS. Mind–body approaches
evaluated acupuncture have demonstrated benefit to patients with PMS, but there are
significant flaws in study designs that prevent it from being recommended as a
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND DIURETICS
NSAIDs have been used to relieve the physical symptoms (e.g., headache, joint pain)
of PMS, but do not improve the mood symptoms.
146 Regimens have included taking
naproxen or mefenamic acid during the luteal phase and stopping therapy after
menses begin. Diuretics commonly found in OTC products, such as ammonium
chloride, caffeine, and pamabrom, are not effective.
Several OTC options are available to C.P. Trials including calcium, magnesium,
pyridoxine, and chasteberry have shown some positive findings, but the evidence is
not compelling due to methodological limitations. These treatments should not be
recommended for the treatment of PMS, but may already be included in a healthy diet
or vitamin regimen. Mind–body approaches, such as yoga and relaxation, are part of
a healthy lifestyle and could be recommended to C.P. Because C.P. is having mood
symptoms (i.e., anxiety), NSAIDs would not be an effective recommendation.
calcium, magnesium, and vitamin B6
for PMS relief. She also has been taking naproxen sodium 220 mg orally
consecutive cycles to document her symptoms. What information should be included in this tool?
C.P. should keep a daily diary for two consecutive menstrual cycles to
demonstrate a temporal relationship between her symptoms during the luteal phase
and to document the severity of these symptoms (Table 50-6). In addition, she should
indicate the presence of menstrual flow, weight, and daily basal body temperature
readings to help determine when ovulation occurs. The diary establishes a baseline
for each patient and documents the most troublesome symptoms. Once therapy is
selected for these symptoms, the diary can aid in assessing patient response.
Treatment: Premenstrual Dysphoric Disorder
CASE 50-6, QUESTION 4: C.P. returns to clinic with the diary presented in Table 50-6. The physician
determines that C.P. actually has PMDD. What evidence supports this diagnosis and what should be
recommended to C.P. for treatment?
C.P. meets the criteria for PMDD as evidenced by her symptoms during the 1 week
before her menstrual cycle (luteal phase). Specifically, she has at least five
symptoms required for the diagnosis of PMDD: sadness or depression (core
symptom), fatigue, irritability, inability to concentrate, breast tenderness, and
bloating. She rated several of those symptoms as severe, which indicates the
symptoms are disabling and she is unable to meet her daily obligations. There is no
reason to suspect any other disorder based on her history. PMDD seems to be the
most likely diagnosis for C.P.
Therapy options at this time include lifestyle modifications, psychosocial
interventions, and pharmacologic therapy. Psychotropic drugs targeted to her most
severe symptoms may include selective serotonin reuptake inhibitors (SSRIs),
serotonergic tricyclic antidepressants, and anxiolytics. Oral contraceptives have also
been approved for PMDD and could be considered.
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
Serotonin is critical in the pathogenesis of PMDD, and for that reason, SSRIs have
become the treatment of choice for PMDD and severe PMS (Table 50-7).
have demonstrated efficacy in reducing irritability, depressed mood, dysphoria,
psychosocial function, and the physical symptoms of PMDD, including bloating,
breast tenderness, and appetite changes. Fluoxetine, sertraline, and paroxetine
controlled release each have an approved indication for PMDD.
The onset of SSRI effect in women with PMDD or severe PMS is much more
rapid than when these agents are used for treatment of major depression or anxiety
169 Women may experience symptom relief or resolution within the first
days of treatment versus 4 to 8 weeks for other psychological disorders.
different dosing strategies have been studied, including continuous dosing (once
daily), intermittent dosing (last 2 weeks of menstrual cycle or luteal phase), and
semi-intermittent dosing (continuous administration throughout the cycle with
increased doses during luteal phase).
169 Continuous dosing would be reasonable for
women with concurrent mood or anxiety disorders or those who may have difficulty
in remembering the timing of the intermittent dosing. Intermittent dosing should be
considered for patients with regular menstrual cycles who are able to adhere to the
169 Studies evaluating these dosing strategies have reported equal
efficacy for continuous or intermittent strategies; treatment should be individualized
based on patient history, willingness to adhere to therapy, and drug response.
In a systematic review of 31 randomized controlled trials including fluoxetine,
dose SSRIs: SMD −0.65, 95% CI −0.46 to −0.84, nine studies, 1,276 women).
Withdrawals due to adverse effects were significantly more likely in the SSRI group
(moderate dose: OR 2.55, 95% I 1.84–3.53, 15 studies, 2,447 women) with side
effects being dose-dependent and most commonly reported as nausea (NNH = 7),
asthenia or decreased energy (NNH = 9), somnolence (NNH = 13), fatigue (NNH =
14), decreased libido (NNH = 14), and sweating (NNH = 14). Overall quality of the
evidence was considered to be low to moderate, with poor reporting of methods as
Non-SSRI antidepressants that affect serotonin are also beneficial in treating PMS
and PMDD (Table 50-7). Venlafaxine, dosed daily, is significantly better than
placebo at relieving psychological and physical symptoms of PMDD.
is a short-acting benzodiazepine that has been assessed for the treatment of PMS in
several studies with differing results.
172 With conflicting data and concerns about
dependence, alprazolam should be reserved for women who are unresponsive to
other PMS treatments. Luteal-phase dosing may limit the risk of drug dependence of
this benzodiazepine, but the dose should be tapered during several days to minimize
mild withdrawal symptoms. Buspirone, a partial 5-hydroxytryptamine receptor
agonist, demonstrated significant reduction in irritability when given daily, but does
not seem to affect the physical symptoms of PMS.
COMBINATION ORAL CONTRACEPTIVES
Two low-dose combination oral contraceptive (COC) formulations containing 20
mcg ethinyl estradiol and 3 mg drospirenone (an antimineralocorticoid
spironolactone analog) with a 4-day hormone-free interval have been approved for
the treatment of emotional and physical symptoms of PMDD.
agent have shown efficacy for reduced mood, physical, and behavioral symptoms of
PMDD, including a 48% improved response with this agent compared with a 36%
response using placebo (p = 0.015).
176 Side effects occurring in at least 10% of
women treated with this medication included intermenstrual bleeding, headache,
nausea, breast pain, and upper respiratory infection. Another COC approved for
PMDD contains 20 mcg of ethinyl estradiol, 3 mg of drospirenone, and 0.451 mg of
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