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.

Other Agents

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.

67

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

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

inflammatory disease.

p. 1013

p. 1014

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

daily life.

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.

76

Clinical Characteristics

CASE 50-2

QUESTION 1: A.B., a 17-year-old girl, presents at the pharmacy with complaints of severe cramping pain

associated with her menstrual cycles. The pain predictably begins with the onset of menses and has been

occurring for the past 5 years, but is now limiting A.B.’s ability to play sports in high school. A.B. states that

she experienced her first menstrual period at age 11. The pain usually is “like a fist, clenching and relaxing,”

starts in the pelvic area, and radiates to her lower back. She reports no headache, but usually has diarrhea and

some nausea, without vomiting. Her symptoms are most severe during the first 12 to 24 hours of her menses,

then subside during the next few days. She usually takes two acetaminophen 325-mg tablets when her pain

begins and then one tablet every 4 to 6 hours, as needed, with little relief. She has taken no other medications

for her symptoms, has no known allergies to medications, and is not taking any other medications. She has no

other medical problems. Her social history is significant for occasional social use of less than 10 cigarettes and

two to three alcoholic beverages/weekend. A recent physical examination was within normal limits. What

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,

nervousness, and insomnia.

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.

76,80

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.

77 A.B.’s description

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

childbirth.

79

Pathophysiology

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.

78 The decreasing levels of

progesterone in the late luteal phase trigger the release of arachidonic acid from cell

membranes, ultimately resulting in the production of prostaglandins and

leukotrienes.

78

The importance of prostaglandin secretion in the pathology of primary

dysmenorrhea is confirmed by studies of the exogenous administration of

prostaglandin F2α

(PGF2α

), and PGE2

, each of which produce pain and uterine

contractions similar to those observed in women with primary dysmenorrhea.

81 These

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

the luteal phase.

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

dysmenorrhea.

82

Treatment

NONPHARMACOLOGIC TREATMENT

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

stimulation.

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.

83

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.

84 The benefit may be

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

p. 1014

p. 1015

smoke.

79

Increased intake of omega-3 polyunsaturated fatty acids, a low-fat

vegetarian diet, or both may decrease the intensity and duration of symptoms.

88,89

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.

CASE 50-2, QUESTION 4: A.B states that her pain is decreased about 50% with the use of a heating pad,

but she would rather not be sedentary for hours at a time. She finds the heat wraps uncomfortable and

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

improve functionality.

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

contraception.

90

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

, vitamin D,

magnesium, vitamin B6

, and omega-3 fatty acids, which have all shown some benefit

in pain relief compared with placebo, with vitamin D, vitamin B1, and magnesium

showing the most promise.

89,91 Other dietary supplements, including fennel, vitamin

E, Neptune Krill Oil, and Toki-shakuyaju-san, have been evaluated in small trials

and need further study.

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

menstrual cramps.

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

symptoms, but has not had optimal relief. A.B. presents to her family physician for an evaluation. What

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

switching to other agents.

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

NSAIDs.

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.

93

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.

78,92

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

the 2 to 3 days she experiences dysmenorrhea.

p. 1015

p. 1016