CASE 50-2, QUESTION 6: What adverse effects might A.B. experience from her NSAID?
All NSAIDs have a similar adverse effect profile. Nausea, vomiting, indigestion,
anorexia, diarrhea, constipation, abdominal pain, melena, and bloating are common
Careful attention should be given to previous trials of NSAIDs for dysmenorrhea
and other conditions, because women may respond favorably to one NSAID over
another. If a 2-month or 3-month trial at appropriate doses of one NSAID is
unsuccessful for A.B., another agent from a different chemical class may be tried.
Because dysmenorrhea is most prevalent in younger women who tend to be healthy,
the risk of adverse events may be lower than would be expected in an older
A.B should be questioned about medication allergies and any prior history of
ulceration or GI bleeding; a history of cardiovascular and renal disease, although
uncommon in young women, should be elicited before prescribing therapy. A
thorough medication history, including OTC agents and dietary supplements, should
be conducted. Particular attention should be paid to any potential therapeutic
duplications (e.g., prescription and OTC NSAIDs), drug–drug interaction (e.g.,
warfarin), and drug–disease (hypertension) interaction.
Women who are allergic to aspirin or have a history of allergic reaction to any
NSAID should not use NSAIDs or celecoxib. A.B. has not had a previous allergic
reaction to NSAID or aspirin; she is not taking any medications that may interact and
does not have any history of medical problems that would prevent her from a trial of
CASE 50-2, QUESTION 8: After 6 months of treatment, A.B. has some relief of her pain, nausea, and
As mentioned previously, hormonal contraceptives may be an option in A.B. if
prescription NSAIDs are not adequate for her symptoms. Oral contraceptives (OCs)
suppress ovulation, decrease menstrual fluid volume, and subsequently decrease
prostaglandin production and uterine cramping.
75,77 OCs alone, or in combination
with an NSAID, are appropriate as first-line treatment in women with or without a
94 OCs relieve dysmenorrhea symptoms in 50% to 80% of
women within 3 to 6 months after beginning hormone therapy.
adolescent women with primary dysmenorrhea evaluated the effects of a 20 mcg
ethinyl estradiol/100 mcg levonorgestrel oral contraceptive pill as compared with
placebo during a 3-month period.
96 With OC use, women reported decreased severity
of pain and used less pain medication. A Cochrane review of oral contraceptives and
primary dysmenorrhea found oral contraceptives containing less than 35 mcg of
ethinyl estradiol to be effective at reducing pain, but failed to demonstrate a
significant difference between various 35-mcg ethinyl estradiol OC formulations.
Selection of an OC should be based on factors presented in Chapter 47,
Contraception. A randomized controlled trial has evaluated the use of continuous
dosing of oral contraceptives compared to the traditional 21 active days, 7 placebo
days regimen, with an initial benefit in favor of decreased pain in the continuous
dosing group at 1 and 3 months that was lost after 6 months of use.
Adverse effects and contraindications associated with OC use must be considered
(See Chapter 47, Contraception). Although serious complications from OC use are
uncommon in young, healthy women, breakthrough bleeding and spotting, nausea, and
breast tenderness may occur, especially early in treatment. A.B. may choose to add
an OC to her naproxen sodium, with potentially improved pain relief compared with
either agent alone. If pain does not respond to either course of therapy, investigation
via laparoscopy for causes of secondary dysmenorrhea may be necessary.
Other Hormonal Contraceptive Agents
Other hormonal contraceptive agents that suppress ovulation have also been used in
the treatment of primary dysmenorrhea, although none have undergone rigorous trials
82 The levonorgestrel intrauterine system (IUS) is associated with
amenorrhea and a reduction in dysmenorrhea over time, unlike the copper IUD,
which may result in increased pain, cramping, and blood loss. Three years after
insertion, fewer women with a levonorgestrel IUS reported menstrual pain (60%
baseline, 29% after 3 years), with 47% of women with amenorrhea.
primary dysmenorrhea at low risk of sexually transmitted infections, and desiring
long-term contraception, the levonorgestrel IUS would be a reasonable option.
Medroxyprogesterone depot injection is another hormonal contraceptive agent that
has been used to treat primary dysmenorrhea. Nearly two-thirds of adolescents
reported fewer symptoms of dysmenorrhea with injections every 3 months.
Negative effects of medroxyprogesterone injections on bone density should be
weighed with potential benefit when considering this option (See Chapter 47,
Contraception). Given that A.B.’s past history does not include any absolute
contraindications to combined oral contraceptives and her dysmenorrhea symptoms
have not been well controlled with prescription NSAIDs, she is a candidate for
combined hormonal contraception. A trial of combined oral contraceptives would be
an appropriate plan for better control of her dysmenorrhea. In addition to smoking
cessation, she should be counseled that hormonal contraceptives may require 3 or
more months to provide maximal relief of symptoms. The goals of therapy, namely
reduction in pain and associated symptoms, as well as improvement in functionality,
should be explained to A.B. and reviewed at each contact.
Endometriosis is defined as the presence of functional endometrial tissue occurring
outside the uterine cavity. It is the most common cause of secondary dysmenorrhea in
young women and can result in chronic pelvic pain, infertility, and dyspareunia.
ovaries are commonly the site of endometriosis, which can also be found in the
pelvic peritoneum, cervix, vagina, vulva, rectosigmoid colon, and appendix.
Less common sites of implantation of endometrial tissue include the umbilicus,
scar tissue resulting from surgery, kidneys, lungs, and even arms and legs.
Endometriosis is present in up to 45% of women with infertility. Overall, it is
difficult to determine the prevalence of endometriosis, because many women do not
experience symptoms or seek treatment, and formal diagnostic criteria currently
require visual identification of endometrial tissue during surgery. In women who
have laparotomies for any reason, endometriosis is identified in 5% to 15%. This
increases to 33% in women with chronic pelvic pain.
dysmenorrhea, endometriosis usually occurs in women who have been menstruating
for some time; it can provoke pain that is not limited to the time of the menses, but
can occur anytime throughout the cycle. Endometriosis is rarely seen in women near
the menarche, after menopause, or in amenorrheic women. The average age at
diagnosis is 36.4 years, and even before diagnosis, women with endometriosis have
higher healthcare costs and utilization, particularly emergency room utilization, than
Diagnosis of endometriosis is difficult, with a delay in diagnosis in the range of 8 to
12 years from initial symptom presentation.
101 Endometriosis, interstitial cystitis,
irritable bowel syndrome, and pelvic adhesions represent the four most common
causes of chronic pelvic pain (defined as pain not associated with the menses, severe
in nature, resulting in functional disability, and lasting at least 6 months).
in diagnosis is the unfortunate consequence of the lack of diagnostic laboratory
markers and its similarities to these other conditions. The physical examination is
often normal, although the most common physical finding is a fixed retroverted
uterus, with scarring and tenderness. A definitive diagnosis is only possible with
visualization of endometriosis on laparoscopy, although this is not considered as
absolutely necessary today as it has been in the past.
criteria currently exist, endometriosis can be staged at the time of laparoscopy
according to the Revised American Fertility Society Classification of
104 The stages are classified as minimal (stage I), mild (stage II),
moderate (stage III), and severe (stage IV), as determined by an accumulated point
total, with points based on the location of the endometrial lesions, the size of the
lesions, the presence and extent of the adhesions, and the degree of obliteration of the
posterior cul-de-sac. The classification system is designed to document the location
and extent of endometriosis, does not predict infertility, aid in treatment selection or
outcomes, or predict recurrence of disease. Making diagnosis and prognosis more
difficult is that the reported severity of pelvic pain and level of functional disability
do not seem to be correlated with the stage of endometriosis.
Although the first description of endometriosis was made in the 1860s, the precise
etiology of endometriosis remains a mystery. Several theories exist regarding the
origins of endometriosis, and the exact etiology is probably a complex interplay
between physical and individual patient-specific immunologic factors.
The most commonly cited theory is that of retrograde menstruation or the flow of
menstrual fluid, endometrial cells, and other debris backward through the fallopian
tubes resulting in implantation in the peritoneal cavity. Once endometrial cells reach
the peritoneum, stimulated angiogenesis (potentially by estrogen, among other
factors) appears to be a determinant of the development and growth of lesions.
Also at this point, the lesion stimulates an immune response, triggering the activation
of macrophages, as well as cytokine and growth factor release. Peritoneal lesions
may contribute to more distant disease by spread via hematogenous or lymphatic
routes, or even by movement owing to iatrogenic causes, such as cesarean sections
and other forms of gynecologic surgery. Although the retrograde menstruation theory
makes scientific sense, it has been discovered that retrograde menstruation occurs in
nearly all menstruating women (90%) and not all women have endometriosis. This
suggests that an additional factor, such as genetic susceptibility or altered immunity,
or altered hormone receptor functioning such as progesterone resistance, must be
present for the pathogenesis of endometriosis in certain patients.
Another theory for the etiology of endometriosis is the coelomic metaplasia theory.
This theory rests on the belief that the coelomic epithelium, the fetal originator tissue
for the reproductive tract, retains its ability to differentiate into multiple cell
99,107,108 The trigger for differentiation is thought to be, in part, estrogen or
environmental factors. This theory would explain the presence of endometriosis in
prepubertal girls, in women born without a uterus, and in the rare cases of
endometriosis seen in men. Genetics also play a role in the development of
endometriosis. For first-degree relatives of women with severe endometriosis, there
is a 6 times higher rate of developing endometriosis when compared with women
who do not have affected relatives. These woman also have more severe disease and
disease that appears earlier in life.
101,109 More than 15 different gene and gene
product abnormalities have been documented in women with endometriosis.
Environmental factors, as discussed, are intriguing in their role as potential causative
factors, but are not definitive.
Once endometrial tissue becomes implanted, hormones are necessary for their
continued growth. As with intrauterine endometrium, the implants of endometriosis
possess estrogen, progesterone, and androgen receptors. The endometrial implants
may, however, respond differently to hormonal stimulation than normal endometrium.
In general, estrogens stimulate the implants, whereas androgens or lack of estrogen
results in implant atrophy. Because of their complex hormonal effects, progestins
have variable effects on the implants.
In addition, lesions also show high
levels of estrogen biosynthesis, owing to abnormally increased aromatase activity,
with a concomitant decrease in the inactivation of estrogen, resulting in high
intralesional estrogen concentrations.
107,111 The responsiveness of endometrial
implants to ovarian hormones plays a role in the pathology of endometriosis.
Withdrawal of estrogen and progesterone causes the endometrial implants to bleed,
leading to an inflammatory response in the adjacent tissues. Repetitive cycles of
bleeding and inflammation lead to the development of scar tissue and adhesions
between adjacent peritoneal tissues. On laparoscopy, these areas of involvement
appear as multiple hemorrhagic foci composed of endometrial epithelium, stroma,
and glands. Ovarian endometriosis usually involves the formation of endometriomas,
blood-filled cysts (chocolate cysts) ranging in size from microscopic to 10 cm.
Nodules may form on uterosacral ligaments. Fibrosis usually is present with the
endometrial implants, and extensive adhesions may form between pelvic
QUESTION 1: N.H. is a 32-year-old woman who has been married for 6 years and is currently using the
who described similar symptoms during her childbearing years.
A woman presenting with endometriosis may have signs and symptoms that are
difficult, initially, to distinguish from primary dysmenorrhea
symptoms of lower abdominal cramps accompanying her menses are often mistaken
for primary dysmenorrhea when other history details are not evaluated in total.
N.H.’s age and her nulliparity are consistent with the characteristics of women with
endometriosis. Although endometriosis has been diagnosed in women of all ages, it
most commonly occurs in women in their late 20s and early 30s who have delayed
pregnancy or who have infrequent pregnancies.
N.H.’s menstrual pattern of short cycle length with prolonged flow is
characteristic of women with endometriosis. Risk factors for endometriosis are
related to exposure to estrogen (i.e., early menarche and late menopause), and shorter
menstrual cycle length (<28 days) with longer duration of menstrual flow (≥6 days),
as well as having a mother or sister with endometriosis, as may be true with N.H.’s
114 Women who have four or more pregnancies lasting greater than 6 months
have a 50% lower risk of being diagnosed with endometriosis, and there is a
decrease in risk of endometriosis that is parallel to duration of time spent in
114 Higher BMI and shorter stature are associated with a lower risk of
endometriosis, with a 12% to 14% decreased likelihood of diagnosis for every unit
114 Potential, but not yet confirmed, risk factors that have
been identified include higher social class, exposure to dioxins, and intake of
114 Cigarette smoking appears to reduce the risk for
endometriosis, although studies are not conclusive.
immune-mediated conditions, including rheumatoid arthritis, systemic lupus
erythematosus, hypothyroidism and hyperthyroidism, and multiple sclerosis, also
have a higher rate of endometriosis than women without these immune-medicated
Primary versus Secondary Dysmenorrhea
Characteristic Primary Dysmenorrhea Secondary Dysmenorrhea
Onset Around menarche Any age (while menstruating)
Timing in menstrual cycle Worse on day 1, lasts 24–48 hours Increases in severity, may last days
Change over time Stable, predictable Increasing pain with increasing age
Symptoms Low back pain, premenstrual
Low back pain, dyspareunia, diarrhea or
constipation, dysuria, infertility
Signs Normal pelvic examination Fixed retroverted uterus, tenderness, but
Source: Reddish S. Dysmenorrhea. Aust Fam Physician. 2006;35:82.
Location of Endometriosis and Associated Symptoms
Cervix Abnormal uterine bleeding
Rectovaginalseptum Infertility
Uterosacral ligaments Pelvic pain
Abdominalscars Intestinal obstruction
Sigmoid colon Mid-abdominal pain
endometriosis. Obstet Gynecol. 2010;116:223.
N.H.’s chief complaints center on her progressive pelvic pain occurring throughout
the cycle, with worsening during menses, constipation, and pain with intercourse
(dyspareunia). Women who report pain during intercourse may have a fixed,
retroverted uterus (as N.H. does) or endometriosis located in the posterior fornix of
the vagina or along the uterosacral ligaments.
99 This pain may persist for several
hours after intercourse. Other symptoms such as the constipation and painful
defecation N.H. is experiencing are associated with endometriosis and may (but not
always) depend on the organs affected by the location of the endometrial tissue
(Table 50-3). Depression also is a common symptom in patients with endometriosis,
particularly those with chronic
pelvic pain, and may express as sadness, somatic complaints, and inability to work
or carry on activities of normal living.
Although it is unclear yet whether infertility will be a problem in N.H.,
endometriosis occurs in up to 45% of women with infertility.
endometriosis-associated infertility is not clear, but is probably caused by a
combination of factors, which may include physical distortion of the pelvic
architecture, inflammatory factors (including prostanoids, cytokines, and growth
factors that may interfere with normal reproductive processes), impaired
folliculogenesis (follicle development), or defects in fertilization or
118,119 Treatment for endometriosis, in inducing a “pseudomenopause,”
results in impaired fertility while the disease is actively being treated.
N.H.’s limited physical findings are not uncommon in women with endometriosis;
physical findings, other than visualization of endometrial tissue during exploratory
surgery, may not be present, and outward physical findings may have no correlation
with the stage of endometriosis determined with surgery. Many symptoms and
physical findings of endometriosis can be associated with other gynecologic
conditions or diseases (particularly irritable bowel syndrome), and, if the patient is
not responsive to empiric therapy, laparoscopy is indicated to confirm the diagnosis.
N.H.’s negative pregnancy, chlamydia, and gonorrhea tests, as well as her normal
Pap smear, are reassuring. The CA-125 laboratory test is not sufficiently sensitive or
specific enough as a single test to diagnose endometriosis, and while many
biomarkers are being studied, none have demonstrated sufficient sensitivity and
specificity to be clinically useful.
for the treatment of endometriosis in N.H.?
Therapy for endometriosis should be individualized and should consider N.H.’s
desire for future fertility, severity of symptoms, extent of disease, and potential for
infertility. This should be done with the knowledge that a high likelihood exists of
recurrence and a lack of good prognostic indicators for future severity. The goals of
treatment are to relieve symptoms and, if desired, to preserve or improve fertility.
Options currently available to treat endometriosis include definitive and
conservative surgery, hormonal therapy with estrogen–progestin combinations or
progestins alone, danazol, aromatase inhibitors, or the GnRH agonists, and expectant
management. Pharmacologic treatment of endometriosis is based on manipulation of
this hormonal response: Danazol, GnRH agonists, progestins, aromatase inhibitors,
and estrogen–progestin combination all result in endometrial tissue atrophy. No
treatment has been shown to provide 100% protection against recurrence when
discontinued; even surgical removal of the uterus and ovaries is associated with
recurrence rates of up to 10%.
106 Limited evidence-based guidelines for treatment are
available and are generally limited by the poor quality of evidence and limited depth
of evidence for most treatments, especially those that are emerging.
PAIN MANAGEMENT: PHARMACOLOGIC THERAPY
Nonsteroidal Anti-inflammatory Drugs
NSAIDs, particularly those available as OTC products, are often the first
medications that women try for relief of pain from endometriosis, often before they
are officially diagnosed. NSAIDs may provide some relief of mild symptoms,
particularly in women with endometriosis who have pain associated with the menses
(see Dysmenorrhea section), and are an appropriate first choice for women with mild
symptoms who do not desire contraception. They should not be the only therapy
offered to patients with confirmed endometriosis.
122 Clinicians should be aware of
and consider the potential for endometriosis in patients with noncyclic pain,
including pain that does not respond to an appropriate trial of an NSAID. N.H. has
tried three different NSAIDS with limited relief; a higher dose or trial of another
NSAID is not an appropriate strategy at this time. Additional treatment should be
Combined Hormonal Contraceptives
For women who do not receive pain relief from a trial of an NSAID, a reasonable
next step for those women desiring contraception is the use of oral contraceptives
because they are considerably better tolerated over the long-term versus other
hormonal options. They may be used alone or in combination with NSAIDs. OCs
improve symptoms of endometriosis by inhibiting ovulation, decreasing hormone
levels, and reducing menstrual flow, potentially to the point of amenorrhea. These
mechanisms contribute to atrophy of endometrial implants. When used, the most
appropriate regimen is continuous OC dosing, so that there is not a “placebo week”
that allows for growth of endometrial implants. In a trial of patients who did not
respond to cyclic OCs, use of continuous dosing resulted in significant pain
123,124 A Cochrane review found that the pain reduction seen with OCs (≤35
mcg of ethinyl estradiol) is similar to a GnRH analog (goserelin).
continuous regimens appear to provide better pain symptom control than cyclic
Similar to oral contraceptives, injectable progestins reduce symptoms of
endometriosis by inhibiting ovulation, reducing hormone levels, and inducing
endometrial atrophy. They may be particularly useful if estrogen use is
contraindicated. Regimens used include oral medroxyprogesterone, depot
medroxyprogesterone (see Case 50-3, Question 5), or the levonorgestrel IUS. More
recent studies have evaluated the use of the levonorgestrel IUS as a means of
providing consistent progestin dosing. The IUS has the advantage of providing
longer-term contraception. When compared with leuprolide depot (a GnRH agonist),
the levonorgestrel IUS provided similar benefits in reducing pelvic pain, with a
decreased potential for hypoestrogenic effects, and an increased potential for early
breakthrough bleeding, followed by eventual amenorrhea.
A 3-year direct comparison of the levonorgestrel IUS versus depot
medroxyprogesterone was conducted in patients with moderate-to-severe
endometriosis for medical control of symptoms after conservative surgery.
Although symptoms were improved with both regimens, more IUS patients remained
adherent to the regimen, and at 3 years, bone density was increased in the IUS group
and decreased in the depot group.
Progestins, despite being as effective as GnRH agonists in the treatment of pain,
have increased side effects when compared with OCs, primarily weight gain
(particularly with the depot formulation), initial breakthrough bleeding followed by
amenorrhea, and, with depot formulations, decreased bone density with prolonged
use, placing them after combined hormonal contraception in choice of therapy.
Gonadotropin-Releasing Hormone Agonists
GnRH agonists induce a pseudomenopausal state, resulting in relief of endometriosis
symptoms. Because the GnRH agonists have a longer half-life than endogenous
GnRH, their binding to GnRH receptors in the pituitary results in downregulation of
the hypothalamic–pituitary–ovarian axis, decreasing release of FSH and LH, leading
to low estrogen levels and amenorrhea.
129 GnRH agonists are available in a variety
of dosage forms, outlined in Table 50-4. When compared in clinical trials, GnRH
agonists have efficacy that is similar to oral contraceptives, progestins, and danazol,
but their increased cost and adverse effect profile (including menopausal-type
symptoms and decreased bone density) make them second-line agents, after OCs and
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