Women receiving letrozole had more live births compared with those that received
clomiphene (27.5% vs. 19.1%; p = 0.007) without significant differences in
congenital anomalies. The ovulation rate was also higher with letrozole than
clomiphene (61.7% vs. 48.3%; p < 0.001). Letrozole had a higher incidence of
fatigue and dizziness, and clomiphene had a higher incidence of hot flushes. Based on
this information and its potential advantages over clomiphene, letrozole may become
a first-line agent for ovulation induction in women with PCOS.
If the clomiphene or letrozole is not successful, dexamethasone 0.25 mg at bedtime
can be used in combination with clomiphene.
74 Ovarian drilling is the next
alternative, followed by administration of gonadotropins or in vitro fertilization.
Ovarian drilling is a laproscopic procedure by which a small portion of the ovary is
removed via electric current to reduce hyperandrogenemia and improve ovulation. Its
effects may only last a few months, and it will not help with clinical signs of
hyperandrogenism (e.g., hirsutism, acne). Gonadotropins are effective, but are
generally reserved as one of the last options because of ovarian hyperstimulation
syndrome. Egg retrieval and in vitro fertilization may be used in conjunction with
gonadotropins to increase pregnancy rate and minimize the likelihood of multiple
pregnancies by limiting the number of transferred embryos.
Women with PCOS exhibit unique clinical features and have individual concerns
that should be addressed when making treatment recommendations. Assessment
should include gathering relevant medical information, such as menstrual history,
signs and symptoms of hyperandrogenism, time course of symptoms, weight history,
previous agents tried, and family history. If PCOS is suspected, laboratory
assessments should be performed to rule out any other related disorders. Once a
diagnosis has been made, a recommendation about treatment must consider the
patient’s priorities and motivation. For E.F., letrozole would likely be the
pharmacologic agent of choice. Ovulation induction and live birth occur in
approximately 48% and 27% of women with PCOS, respectively, using letrozole.
The initial dose would be 2.5 mg orally once daily for 5 days, started on day 3 after a
spontaneous or progestin-induced menses. If nonresponse occurs, the dose may be
increased by 2.5 mg and up to 7.5 mg daily for 5 days on following cycles. Although
side effects (e.g., fatigue, dizziness) can occur, the benefit of this therapy outweighs
the risk for E.F. Appropriate follow-up for E.F. should include quality-of-life
measures, laboratory monitoring when necessary, and medication adherence
monitoring. Providers should be educators, facilitators, and empathetic listeners to
help women with PCOS become informed and actively engaged in their therapy plan.
Dysmenorrhea, or painful cramping that occurs with the onset and first days of
menstruation, can be categorized as either primary (without underlying uterine
pathology) or secondary (owing to underlying uterine pathology). Secondary
dysmenorrhea can result from uterine conditions, including endometriosis, uterine
polyps, or fibroids; complications of intrauterine device (IUD) use; or pelvic
Up to 93% of adolescents report some pain with menstruation, and up to 15%
experience pain that is sufficiently severe and disabling to interfere with activities of
75 Dysmenorrhea is the single largest cause of lost productivity and school
absence among adolescent girls. It most commonly begins within 1 to 2 years after
the onset of menses, and up to 91% of adult women report some pain with menses, of
which up to 28% experience severe pain and/or limitation of activity.
clinical manifestations in A.B. are consistent with primary dysmenorrhea?
No specific diagnostic criteria exist for primary dysmenorrhea. Typically, the
diagnosis is one of exclusion and is based on response to known effective therapy.
Thus, if patients do not respond to therapy, an investigation of pelvic pathology and
secondary dysmenorrhea should occur.
77,78 A.B.’s symptoms that are typical of
primary dysmenorrhea include cramping pain in the suprapubic area, which may
radiate into the back and thighs, nausea, and diarrhea. Some women also experience
vomiting, fatigue, headache, lightheadedness, flushing, loss of appetite, irritability,
77 Symptom severity seems to correlate with women who
have early menarche (onset of menses before age 8) and those with increased
duration and quantity of menstrual flow.
79 Risk factors for dysmenorrhea include age
younger than 20 years, depression or anxiety, perceived high life or work stress,
nulliparity, menorrhagia, and smoking.
Primary dysmenorrhea occurs only with ovulatory cycles, which typically begin
after the first year following menarche. Dysmenorrhea occurring several years after
menarche is most likely secondary dysmenorrhea and should be investigated as such.
Because A.B.’s pain began within 1 year of menarche and her physical examination
is normal, a trial of therapy can be initiated without further investigation into
secondary causes of dysmenorrhea. The typical pattern of dysmenorrhea is to have
pain beginning up to 12 hours before menses, increasing in severity for up to 24
hours, and continuing with reduced intensity for 24 to 72 hours.
of pain, as a cramping–relaxing cycle, is typical for dysmenorrhea. Likely, her
symptoms will decrease with age, after the onset of sexual activity, as well as after
CASE 50-2, QUESTION 2: What underlying pathophysiology explains A.B.’s symptoms?
In the normal menstrual cycle, prostaglandins are released by the endometrium in
the late luteal phase inducing contraction of the uterine smooth muscle and subsequent
sloughing of the endometrium, leading to menstrual flow and the beginning of the
follicular phase of the next cycle. Women with primary dysmenorrhea appear to have
increased prostaglandin secretion, inducing more intense uterine contractions,
leading to decreased uterine blood flow and uterine hypoxia, which results in the
cramping and pain that are the hallmarks of dysmenorrhea.
progesterone in the late luteal phase trigger the release of arachidonic acid from cell
membranes, ultimately resulting in the production of prostaglandins and
The importance of prostaglandin secretion in the pathology of primary
dysmenorrhea is confirmed by studies of the exogenous administration of
, each of which produce pain and uterine
contractions similar to those observed in women with primary dysmenorrhea.
prostaglandins, with potent platelet disaggregation and vasodilatory properties, also
induce nausea, vomiting, and diarrhea. Thus, A.B.’s pain, nausea, and diarrhea may
be caused by elevated prostaglandin levels. This also explains the rationale for the
effectiveness of the two main treatments for primary dysmenorrhea: nonsteroidal
anti-inflammatory drugs (NSAIDs), which inhibit prostaglandin synthesis, and
hormonal contraceptives, which minimize the progesterone increase typically seen in
Nearly 85% to 90% of women initially thought to have primary dysmenorrhea
respond to NSAIDs with or without oral contraceptive therapy. The remaining
women deserve further investigation into potential causes of secondary
CASE 50-2, QUESTION 3: What nonpharmacologic therapies may be effective for the treatment of A.B.’s
symptoms of primary dysmenorrhea?
A.B. should be educated about the causes of primary dysmenorrhea, its associated
symptoms, and the rationale behind nonpharmacologic and pharmacologic treatment
options. Nonpharmacologic therapies that may have benefit in the relief of A.B.’s
symptoms include aerobic exercise, heat therapy, tobacco cessation, omega-3
polyunsaturated fatty acids, and high frequency transcutaneous electrical nerve
Exercise, particularly aerobic exercise, has been correlated with decreased
menstrual symptoms in observational studies and is, in all patients, associated with
positive general health benefits.
In addition, specifically yoga exercise, in
particular the cobra, cat, and fish poses performed for 20 minutes/day during the
luteal phase, was found to reduce pain in adolescent women.
due to improved pelvic blood flow and decreased ischemia, or increased release of
β-endorphins. Application of local heat to the lower abdomen has been studied in
three well-designed clinical trials.
85–87 Heat plus ibuprofen (400 mg orally TID)
demonstrated a reduction in the time to pain relief compared with an unheated patch
plus ibuprofen in two controlled studies.
85,87 Heat provided better relief than
acetaminophen (1,000 mg orally as a single dose).
85 With few adverse effects, heat,
in the form of a heating pad or heated patch or wrap device; and exercise (aerobic or
yoga) represent reasonable and safe suggestions for women with dysmenorrhea.
Women should be advised and assisted in efforts to stop tobacco use. Although no
direct evidence links smoking cessation with improvement in dysmenorrhea, an
association exists with increased risk and severity of dysmenorrhea in women who
Increased intake of omega-3 polyunsaturated fatty acids, a low-fat
vegetarian diet, or both may decrease the intensity and duration of symptoms.
A.B.’s therapy should be based on her specific symptoms, response to previous
therapy, and any adverse effects of therapy. The regimen of acetaminophen that A.B.
is currently using is not providing relief owing to its relative lack of effect on
prostaglandin activity. For A.B., discussion of the nonpharmacologic therapies,
particularly continuous low-level heat applied at onset of symptoms, exercise/yoga,
and smoking cessation, provides low-risk, potentially beneficial, and low-cost
suggestions for pain relief, in addition to drug therapy. A.B should be informed that
continuous heat therapy via heat “wraps” or hot water bottle or heating pad should be
used cautiously in patients with diabetes and should not be used while sleeping.
expensive and asks about Pamprin. What are some over-the-counter pharmacologic options for A.B.?
Although nonpharmacologic therapy with heat, exercise, and smoking cessation
may have benefit, often the use of pharmacologic therapies is required to significantly
OVER-THE-COUNTER PHARMACOLOGIC THERAPY
Over-the-counter (OTC) pharmacologic therapy for primary dysmenorrhea is focused
on reducing prostaglandin activity. Anti-inflammatory drugs act by directly inhibiting
prostaglandin synthesis. NSAIDs provide relief from the symptoms of primary
dysmenorrhea for most women (See Case 50-2, Question 5, for further information).
Naproxen (as the sodium salt) and ibuprofen are approved without a prescription for
the treatment of primary dysmenorrhea. Acetaminophen is of limited efficacy in the
treatment of dysmenorrhea when compared with NSAIDs or hormonal
Other therapies, including OTC products marketed for dysmenorrhea and other
menstrual disorders (e.g., Pamprin, Midol) (particularly combination products
including diuretics), weak muscle relaxants (such as pyrilamine, pamabrom),
diuretics (caffeine), and acetaminophen, have limited efficacy for the specific
treatment of dysmenorrhea. Because they do not address the underlying
pathophysiology of primary dysmenorrhea, combination products, narcotic
analgesics, and acetaminophen do not have a role in the treatment of primary
dysmenorrhea and may have excessive adverse effects with minimal benefit.
Adolescents with dysmenorrhea frequently use OTC medications to treat primary
dysmenorrhea, usually without consultation from a healthcare professional. This lack
of professional advice results in the use of lower doses that may not be as effective
to treat symptoms. Many women choose ineffective combination medications and/or
acetaminophen, indicating patients will benefit from professional advice regarding
OTC treatments of dysmenorrhea. Other products include vitamin B1
, and omega-3 fatty acids, which have all shown some benefit
in pain relief compared with placebo, with vitamin D, vitamin B1, and magnesium
89,91 Other dietary supplements, including fennel, vitamin
E, Neptune Krill Oil, and Toki-shakuyaju-san, have been evaluated in small trials
82 At this point, given the limited efficacy of non-NSAID,
nonhormonal methods of treatment, they are not an appropriate alternative for A.B.
Ibuprofen 200 to 400 mg orally up to TID could be a solid initial plan for A.B.’s
Prescription Pharmacologic Agents: Nonsteroidal Anti-inflammatory Drugs
CASE 50-2, QUESTION 5: A.B has tried OTC ibuprofen 400 mg TID starting at onset of her cramping
prescription medications could be recommended for A.B’s dysmenorrhea?
The NSAIDs are effective for treatment of dysmenorrhea, but in some cases, OTC
doses are not enough and prescription-strength NSAIDs or hormonal contraceptives
may be required for adequate relief. Hormonal contraceptives reduce the amount of
endometrial proliferation and, as a result, decrease the amount of prostaglandins
secreted. By inhibiting ovulation, hormonal contraceptives eliminate the cyclic
changes in progesterone that induce prostaglandin release. Choice of therapy depends
on the need for contraception, concomitant medical conditions, and patient
preference. Treatment efficacy can be monitored by evaluating pain relief, improved
functionality, reduced absenteeism, and relief of other symptoms (e.g., diarrhea,
nausea) associated with dysmenorrhea. Because A.B. is not sexually active,
prescription-strength NSAIDs should be tried for two to three cycles before
Initial selection of NSAID therapy should be based on effectiveness, incidence of
adverse effects, cost, patient history of previous benefit, and availability. In a
Cochrane review, 73 trials of NSAIDs for treatment of primary dysmenorrhea were
reviewed to assess for any differences in efficacy or safety among the different
92 When compared with placebo, NSAIDs were significantly more effective
(odds ratio [OR], 4.50; 95% confidence interval [CI], 3.85–5.27). When compared
with acetaminophen, NSAIDs were, as expected, significantly better at reducing
symptoms (OR, 1.90; 95% CI, 1.05–3.44). In limited head-to-head trials comparing
NSAIDs, no significant differences in efficacy were seen, with the exception of
aspirin being slightly less effective than other NSAIDs when directly compared.
Adverse effects seen in these trials were generally mild GI (nausea, upset stomach)
and neurologic (sleepiness, dizziness, headache) complaints. When directly
compared with each other, no NSAID was found to be better tolerated than another.
Naproxen offers the advantage of less frequent dosing compared with ibuprofen.
Some data suggest that an oral loading dose of naproxen sodium (550 mg) might
improve pain control in dysmenorrhea. A randomized trial demonstrated increased
relief from dysmenorrhea symptoms in adolescents treated with an NSAID regimen
that started with a loading dose, versus those who used a flat dosing regimen.
Loading doses generally are twice the regular dose. If A.B. experienced adverse
effects with the higher loading dose, an alternative strategy is to initiate dosing 24
hours before menses is expected to start, based on the calendar if the patient has
predictable cycles, or based on the start of premenstrual syndrome-type symptoms.
This prophylactic dosing may be helpful especially for patients who have severe
dysmenorrhea with absenteeism and decreased work or school productivity.
Although no specific evidence supports the use of scheduled NSAID dosing
regimens, avoiding as-needed dosing may provide consistent serum levels to
maintain reduced prostaglandin levels. As the duration of therapy is typically limited
to 2 or 3 days, risk of adverse effects tends to be outweighed by the potential benefit
of loading doses, prophylactic dosing, and scheduled versus PRN therapy.
A good recommendation for A.B. could include initiating naproxen sodium 550 mg
orally at the beginning of menses, followed by 275 mg every 8 hours thereafter for
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