KEY CONCEPTS Endometriosis is a chronic condition in reproductive age women that can cause

chronic pelvic pain and infertility. Endometriosis is characterized by endometrial tissue outside the
uterus, but the exact pathophysiology and biological mechanisms are multifactorial and still remain
unclear. Endometriosis should be suspected in any woman of reproductive age presenting with
recurring pelvic pain or otherwise unexplained infertility. Failure of first-line treatment options like
nonsteroidal anti-inflammatory drugs (NSAIDs) or combined hormonal contraceptives (CHCs) to
relieve dysmenorrhea is highly suspect of endometriosis. Definitive diagnosis of endometriosis
requires direct surgical visualization; however, it is acceptable to empirically treat these symptoms
without a definitive diagnosis. Treatment strategies are based on patient symptoms and preferences
with regards to desire for pregnancy. Pharmacologic and surgical options are indicated to treat
endometriosisassociated pain. Surgery/reproductive technology is the only treatment option for
endometriosis-related infertility. Treatment options are not curative of endometriosis and only
provide symptom management. First-line pharmacologic options include NSAIDs, CHCs, and
progestins. Other options include gonadotropin-releasing hormone (GnRH) agonists, GnRH
antagonists, danazol, and aromatase inhibitors. Add-back therapy can be utilized with certain agents
to minimize hypoestrogenic adverse events such as bone mineral density (BMD) loss and vasomotor
symptoms. Preclass Engaged Learning Activity Review the American College of Obstetricians and
Gynecologists (ACOG) bulletin, European Society of Human Reproduction and Embryology (ESHRE)
Guidelines and National Institute for Health and Care Excellence (NICE) guidelines to determine
similarities and differences. INTRODUCTION Endometriosis is a common gynecologic condition that
affects women during their reproductive years, defined as the growth of endometrial tissue outside
the uterus. Clinically, endometriosis can cause several symptoms with the most common being
dysmenorrhea, dyspareunia, and infertility. It is usually diagnosed in women in their thirties and
forties; however, it is also common in adolescent age. Chronic pelvic pain is the most common
complaint, especially in adolescents. Patients are often asymptomatic; therefore, it is difficult to
confirm the true incidence of endometriosis. While the pathophysiology of endometriosis isn’t
completely understood, it is believed that retrograde menstrual flow causes several endometriosis
symptoms. This backflow of fluid often leads to endometrial deposits in various areas of the
genitourinary tract including the bladder, ureter, and ovaries in addition to the gastrointestinal tract.
Other theories include hematogenous or lymphatic transport, stem cells from bone marrow, and
coelomic metaplasia (ACOG). Interventions are focused on the desire of the patient to become
pregnant, relieve symptoms, or both. Pregnancies are often beneficial for improving symptoms.
EPIDEMIOLOGY The incidence of endometriosis in the general population is approximately 10%. 1,2
It is a common cause of infertility and chronic pelvic pain and has an incidence of approximately 38%
in women with infertility (with some estimates of around 50%); and more than 60% of patients with
chronic pelvic pain have a diagnosis of endometriosis (with some reports of 71%-87%). 2 It is
estimated that roughly one in ten women of reproductive age are diagnosed with endometriosis.
However, it is probable that approximately 11% of women are undiagnosed. There is a strong
genetic predisposition, and it has been noted that women with a first degree relative with
endometriosis have a 7- to 10-fold increased risk for developing endometriosis. 2 ETIOLOGY
Endometriosis is characterized by the growth of endometrial tissue outside of the uterus, 1,2 and
while it can be diagnosed in any age; it is most commonly found during the reproductive years. In
addition to genetic predisposition, several risk factors have been identified. The risk of
endometriosis is higher in those with early menarche (defined as the start of menses at 11 years old
or younger), short menstrual cycles (less than 27 days) and heavy, prolonged menses. It is thought
that environmental factors play a role in the pathogenesis of endometriosis. For example, dioxins,
chemicals that have been found in the environment, have been thought to increase a woman’s risk
for developing endometriosis or worsening symptoms. 3,4 Multiple parity has been associated with
a lower risk of endometriosis and/or improvement in endometriosis symptoms. Additionally, regular
exercise of more than 4 hours per week has been associated with a lower risk of the development of
endometriosis. 2,5 In addition to infertility and chronic pain, endometriosis is a major cause of
hysterectomy and hospitalization in the United States and can lead to decreased quality of life.
PATHOPHYSIOLOGY While not well understood, the pathophysiology of endometriosis is related to
the finding of endometrial implants (the tissue forming the lining of the uterus) outside of the
uterus. It is thought that these implants occur outside of the uterus due to retrograde menstrual
flow. Endometrial implants are often found in the peritoneum, ovaries, fallopian tubes, uterus,
bladder, ureters, intestines and rectum. 6,7 The growth of implants is dependent on estrogen, and
throughout a woman’s menstrual cycle they grow and bleed just as the endometrium thickens and
sheds during menstruation. When the implants proliferate, adhesions (collections of scar tissue) can
form that can lead to further bleeding, inflammation, and scarring especially prior to and during
menses. While retrograde menstruation can explain the endometrial deposits in the peritoneal
cavity, there are also other theories regarding the development of endometriotic implants.
Additionally, several women have retrograde menstruation, yet do not develop endometriosis. It is
estimated that there is a 90% prevalence of retrograde menstruation, yet 10% prevalence of
endometriosis. 8 Four well-supported hallmarks of the pathophysiology of endometriosis include
genetic predisposition, estrogen dependence, progesterone resistance, and inflammation. 6,7,9,8,10
In patients with endometriosis, there are alterations in estrogen- and progesterone-dependent
processes including inflammatory and immune responses, angiogenesis, and apoptosis. These
alterations lead to survival and replenishment of endometriotic tissue. Genetic alterations that have
been noted include the upregulation of B-cell lymphoma 2 (BCL-2), which is an antiapoptotic gene
and has been shown in both eutopic and ectopic endometrium from women with endometriosis. 8
An observation that has been found in endometriotic tissue is the increased expression of the
aromatase enzyme and decreased expression of 17β-hydroxysteroid dehydrogenase (17β-HSD) type
2, which leads to an increase in the concentration of estradiol. Estradiol stimulates prostaglandin E2
that further can stimulate aromatase activity. It is also thought that estrogen can stimulate the
release of other inflammatory cytokines such as cyclooxygenase 2 (COX-2). Additionally,
endometriotic lesions have decreased progesterone receptor expression and an absence of
progesterone receptor-B. This can lead to an incomplete transition of endometrium from the luteal
phase to the secretory phase of the menstrual cycle. While estradiol tends to have proinflammatory
and antiapoptotic effects on endometrial cells, progestins inhibit inflammatory pathways and induce
apoptosis in endometriotic cells. Endometriosis has been considered a pelvic inflammatory condition
because the peritoneal fluid tends to contain several inflammatory markers that are believed to
contribute to pain, formation of adhesions, tissue fibrosis, and scarring. In patients without
endometriosis, the immune system clears refluxed endometrial tissue deposits from the
peritoneum. Endometrial lesions can lead to inflammation with the activation of macrophages and
proinflammatory cytokines. The peritoneal fluid of patients with endometriosis often contains
proinflammatory cytokines such as tumor necrosis factor alpha and interleukins 1, 6, and 8 that lead
to prostaglandin induction. There is also thought to be an increased density of nerve fibers and a
high expression of nerve growth factor in endometriotic lesions which further increases pain.
Compression of nerve fibers by endometrial implants along with bleeding from endometrial tissues
can increase a patient’s pain. Lastly, endometriotic nerve fibers influence dorsal root neurons
thereby increasing pain perception. Infertility and the reason for its development has been less well
described, especially in mild cases of endometriosis. In more severe cases, inflammation and
anatomic abnormalities such as ovarian cysts and adhesions can lead to blockage of the fallopian
tubes and hindrance of oocyte and embryo development. The inflammatory cytokines can lead to
damage of sperm DNA and cell membranes and the general inflammation seen may result in
adhesions and scarring. 1 Hormonal dysregulation can also lead to irregularities in the menstrual
cycle, alterations in endometrial receptivity and implantation, and altered oocyte and embryo
quality, or issues with uterotubal transport. 8 CLINICAL PRESENTATION Symptoms Endometriosis
presents in a variable and unpredictable manner with regards to clinical presentation and clinical
course. Dysmenorrhea and infertility are the most commonly reported symptoms in patients;
however, several other symptoms are often present, or a patient can remain asymptomatic. Typical
symptoms include abdominopelvic pain, dysmenorrhea, and dyspareunia; and women experiencing
these classic symptoms are more likely to be diagnosed than those presenting without these
symptoms. Deep pain during or after sexual intercourse, period-related or cyclical gastrointestinal
symptoms, such as painful bowel movements, menorrhagia, ovulation pain, and chronic fatigue are
other possible symptoms. Chronic pelvic pain can vary in severity and may be cyclic or acyclic. Pain
can lead to a decreased quality of life depending on the severity; however, some patients may be
asymptomatic. 2,6,7 Signs Physical examination of a patient with endometriosis often reveals pelvic
tenderness, enlarged ovaries, pelvic masses or nodules, uterosacral ligaments, or a fixed, retroverted
uterus. These signs are usually most significant during menses, so it is recommended to perform the
examination at that time. Imaging studies such as transvaginal ultrasound or magnetic resonance
imaging are also used to visualize endometrial lesions. If a patient with suspected endometriosis has
normal imaging studies, laparoscopic surgery can be considered to further evaluate the pelvis and
endometrial lesions. Lesions can vary in size from small lesions in the ovaries or peritoneum to
endometriomas, which are large cysts. The lesions are often described as “powder burn” or
“gunshot” lesions; dark brown, black or blue lesions, nodules, and cysts; and blood containing
endometriomas are called “chocolate cysts.” 11 Diagnosis The diagnosis of endometriosis can be
challenging and may take several years due to variability of symptoms. Additionally, a definitive
diagnosis can only be made by histological examination of lesions removed during surgery.
Treatment guidelines do discuss ruling out all causes of pain and providing a nondefinitive diagnosis
in patients with chronic pelvic pain. Ultrasonography, magnetic resonance imaging, computed
tomography are often used to assess pelvic or adnexal masses, but have a lower sensitive for
investigating endometrial lesions. However, in some cases pelvic and abdominal examinations can
be used, especially during menstruations and positive findings include pelvic tenderness, enlarged
ovaries, or a fixed, retroverted uterus. Imaging studies can be utilized to determine whether there is
endometrial tissue in the bowel, bladder, or ureter. Transvaginal ultrasounds are used to determine
if endometrial tissue is infiltrating the rectum. Cancer antigen 125 (CA 125) is a marker for ovarian
and endometrial cancer, which has been noted to be elevated in some women with endometriosis
but is not a diagnostic marker. 11 However, for diagnosis of endometriosis, the CA-125
measurement is limited due to the fact that an elevated level is not diagnostic. 2,11 CLINICAL
PRESENTATION Endometriosis Physical Symptoms • Dysmenorrhea • Infertility • Pelvic pain •
Dyspareunia (Deep pain during or after sexual intercourse) • Period-related or cyclical
gastrointestinal symptoms (eg, painful bowel movements) • Menorrhagia • Ovulation pain • Chronic
fatigue are other possible symptoms Other considerations • Chronic pelvic pain can vary in severity
and may be cyclic or acyclic • Pain can lead to a decreased quality of life depending on the severity •
Some patients may be asymptomatic Signs: From physical examination of a patient with
endometriosis • Pelvic tenderness • Enlarged ovaries • Pelvic masses or nodules • Uterosacral
ligaments • Fixed, retroverted uterus • Note: These signs are usually most significant during menses
Data from references 2, 6, and 7. Disease Staging In general, endometriosis disease severity can be
classified according to the American Society of Reproductive Medicine staging system which ranges
from stage I [mild] to stage IV [severe]. This system stages endometriosis according to not only
anatomic location, but also the severity of disease. 2 Although staging of disease can be helpful, it is
limited in its clinical utility because it does not predict pregnancy after treatment and does not
correlate well with symptoms of pain or dyspareunia. 2 Regardless, staging may be useful in guiding
decisions regarding prognosis and treatment for infertility. 2,12 TREATMENT Multiple guidelines and
expert opinions exist for the management of endometriosis, with key guidelines coming from
organizations such as the American College of Obstetricians and Gynecologists (ACOG), the American
Society for Reproductive Medicine (ASRM), Society of Obstetricians and Gynecologists of Canada
(SOGC), National Institute for Health and Care Excellence, 11 and the European Society of Human
Reproduction and Embryology (ESHRE). 12,13 Table 97-1 is a summary of the ESHRE-graded
recommendations. TABLE 97-1 Evidence-based Recommendations for Treatment of Endometriosis-
Related Pain Desired Outcomes Endometriosis is not curable with currently available treatment
modalities; therefore, presently available options allow for the management of disease primarily
through pain relief and correction of infertility treatment. Patient-specific goals and desired
outcomes will vary and should be considered when making a treatment plan, as the individual
patient’s desires will greatly impact the treatment options available. Reducing pain and improving
quality of life can be achieved through pharmacologic options and/or surgery. 2,10,14
Endometriosis-related infertility does not respond to available pharmacologic therapies and requires
surgical intervention. 2,10 General Approach to Treatment Endometriosis-related pain can be
managed with medical treatment, surgical treatment, or both. The best option for an individual
patient will depend on their specific goals for treatment. Current medical therapies relieve
endometriosisrelated pain through induction of a pseudopregnancy or pseudo menopausal state,
which reduces painful lesions, but does not improve fertility. Therefore, individuals looking to
become pregnant will typically require surgical intervention and may also require the use of assisted
reproductive technologies. Pregnancy success rates do increase after surgical procedures, but the
exact magnitude is unclear due to the lack of well-designed clinical studies. 2,10,14 Patient Care
Process for Endometriosis Collect • Patient characteristics (age and pregnancy) • Patient medical
history (personal and family) • Patient’s desire and timeline for fertility • Symptoms (type of pain,
location, frequency, cyclic vs acyclic) • Objective data: Imaging procedure results confirming
diagnosis of endometriosis (if available) Assess • Whether patient is a candidate for drug therapy or
surgical procedures • Patient goals and treatment options (Tables 97-1 and 97-2) • Presence of
contraindications to treatment options • Ability/willingness to use various formulations such as
injections, vaginal ring, transdermal patch, intrauterine device • Ability/willingness to pay for
treatment options • Likely adherence to options Plan* • Drug therapy regimen including specific
medication(s), dose, route, frequency, and duration (Table 97-3) • Monitoring parameters including
efficacy and safety (pain relief, side effects) (Table 97-3) • Prepare patient education • Referrals to
other providers Implement* • Provide patient education regarding all elements of treatment plan •
Use motivational interviewing and coaching strategies to maximize adherence • Schedule follow-up
appointment (typically 2-3 months to determine treatment efficacy) Follow-Up/Monitor • Resolution
of symptoms • Presence of adverse drug events (Table 97-3) • If using GnRH agonists: bone mineral
density and serum lipids • Patient adherence to treatment plan • Duration of therapy depending on
desire to become pregnant or patient entering menopause *Collaborate with patient, caregivers,
and other healthcare professionals. Medical management options include nonsteroidal anti-
inflammatory drugs (NSAIDs), combined hormonal contraceptive (CHCs), progestins,
gonadotropinreleasing hormone (GnRH) agonists, danazol, and aromatase inhibitors. In general, the
NSAIDs, CHCs, and progestins are recommended first line due to their proven success in
dysmenorrhea management, tolerability, and cost. The GnRH agonists and danazol are both highly
effective but are considered second- line options because of their side effect profiles. Aromatase
inhibitors are considered last line after failure of other medical or surgical therapies. The patient’s
chief complaint, possible side effects seen with various pharmacotherapeutic agents, extent of
prescription drug coverage, contraindications to treatment, and adherence should all be considered
when developing a treatment plan. 2,10,12,15 Information regarding drug therapy options can be
seen in Table 97-2. Overall, the NSAIDs are appropriate to use in conjunction with each listed
treatment option, barring the existence of contraindications to use, as endometriosis treatments are
not typically guaranteed to provide full relief of symptoms and may require adjunctive analgesic use.
TABLE 97-2 Evidence- Based Considerations in Endometriosis Treatment Asymptomatic patients with
an incidental diagnosis of endometriosis do not need treatment, but rather can be monitored for the
development of pain or infertility and then managed at that point. 12 Nonpharmacologic Therapy
Laparoscopic surgery is used as a diagnostic and therapeutic tool for endometriosis. 2,10,12 As part
of this procedure, it is generally recommended that surgeons remove any visible lesions when
performing a diagnostic surgery. Otherwise individuals may seek surgery if they are infertile or are
not responding to available medical treatment options. A hysterectomy– oophorectomy is an option
for individuals who do not desire future pregnancy, but, as with other treatment modalities, this
surgery does not guarantee full relief of symptoms. 12 For those undergoing surgery, pre- and
posttreatment with hormone therapy does not improve outcomes related to surgery. The ESHRE
guidelines separate postsurgical treatment into adjunctive (use for 6 months) categories. These
guidelines state that short-term adjunctive hormonal treatment will not improve the surgical
outcomes after surgery, but long-term medical treatment may be started postsurgery for purposes
of contraception or secondary prevention. Secondary prevention recommendations include using
CHCs or the levonorgestrel-releasing intrauterine system (LNG-IUS) for at least 18-24 months to
prevent recurrence of endometriomas. 12,16,17 Pharmacologic Therapy Pharmacologic therapy is
typically the first choice for treatment of endometriosis-related pain to minimize risks from multiple
surgeries such as scarring and tissue adhesions. First-line treatment options are such because they
are equally effective but have an improved tolerability and cost compared to alternative therapy
options (Table 97-3). 2,10,12,15 TABLE 97-3 Drug Dosing/Adverse Drug Reactions
(ADRs)/Monitoring/Comments Drug Treatments of First Choice First-line therapy for endometriosis-
associated pain includes oral CHCs, oral progestins (norethindrone acetate or medroxyprogesterone
acetate), or depot progestin medroxyprogesterone acetate (DMPA). These medications tend to be
well-tolerated and are safe for long-term use, which is important because endometriosis symptoms
typically return shortly after treatment is discontinued. 2,10,12,15 Studies demonstrating direct
comparisons between these products are lacking, so the decision of which product to use should
depend on patient preference, including formulation type, dosing schedule, and potential adverse
events. 2 Although laparoscopic imaging provides the only definitive diagnosis of endometriosis,
these options may be initiated empirically for suspected endometriosis in patients of any age prior to
laparoscopy. 2,10,12,15 Response to hormonal treatment does not predict the presence or absence
of endometriosis, but use of these options before laparoscopy can avoid an invasive procedure. 12
Nonsteroidal Anti-inflammatory Drugs Dysmenorrhea is a primary symptomatic feature of
endometriosis and NSAIDs are indicated as the first-line treatment of menstrual pain with or without
an endometriosis diagnosis. Individuals may initially self-treat with over-the-counter options, such as
ibuprofen and naproxen; however, prescription strength versions of these are available as well, and
individuals may find they need to use the upper end of the recommended dosing range in order to
find relief from pain. 2,10,11 Combined Hormonal Contraception Combined hormonal
contraceptives (CHCs) are a first-line treatment option for suppression of endometriosis and are
widely used due to their efficacy, tolerability, safety profile, and cost. 18 Their exact mechanism of
action for endometrial pain relief is unclear because the pathogenesis of endometriosis is unclear.
However, there are several widely accepted theories. 18 Overall, the CHCs alleviate dysmenorrhea, a
common symptom of endometriosis, reduce the growth of endometrial tissue, decrease menstrual
flow, and reduce prostaglandin generation. 18 They have also been shown to down-regulate cell
proliferation and increase apoptosis in the eutopic endometrium. 18 Secondary benefits of CHCs
include menstrual cycle regulation and contraception. Oral CHCs have demonstrated efficacy in a
small number of observational, placebo-controlled and active-comparator trials. The majority of
studies on CHC efficacy have been for oral products; however, one study demonstrated effectiveness
of the CHC patch and vaginal ring, which may have appealing dosing schedules compared to their
oral counterparts. 19 The decision between CHCs should be based upon patient preference,
including adherence and cost. 2 The CHCs have traditionally been dosed cyclically, with 3 weeks of
active hormone followed by 1 week of placebo, allowing for a withdrawal bleed. However, some
individuals prefer the option to dose continuously, either through commercially available “extended
cycle” options or by skipping the placebo week of their CHC. A prospective trial demonstrated that
continuous dosing may be more efficacious than cyclic dosing after individuals with recurrent
postoperative dysmenorrhea were switched from cyclic to continuous CHC dosing and reported a
significant reduction in pain. 20 Other studies have mimicked these results, and the ESHRE guidelines
now specifically recommend continuous dosing as an option for patients. 12 Due to the proposed
estrogen dependency of endometriotic lesions, it has been proposed that the estrogen dose in CHCs
should be limited to avoid feeding the endometriosis tissue. Even the lowest doses of commercially
available CHCs are four to six times the physiologic dose of estrogen; therefore, clinicians should
consider initiating patients on CHCs with the lowest effective estrogen dose to limit this possibility.
Progestins Progestins are another first-line option for suppression of endometriosis due to their
efficacy in treating dysmenorrhea, the overall tolerability of progestins, and their reasonable price.
Progestins suppress growth of endometriotic implants, eventually causing endometriotic atrophy.
They have also demonstrated inhibition of blood vessel growth and anti-inflammatory action, in
addition to their anovulatory effects, all which relieve the dysmenorrhea associated with
endometriosis. 21–23 Progestins may be administered orally (norethindrone acetate or
medroxyprogesterone acetate), intramuscularly or subcutaneously (depot medroxyprogesterone
acetate–DMPA) or as a levonorgestrel intrauterine system (LNG-IUS). As with other endometriosis
treatment options, studies comparing progestin options directly are limited; therefore, selection
should account for the individual’s opinion about dosage form, as well as cost and potential side
effects and risks. 24 Oral Progestins Oral progestins are widely available as contraceptive and
menopausal hormonal replacement products. Importantly, contraceptive progestin products have
the added benefit of preventing pregnancy and managing other menstrual-related side effects, such
as acne. Injectable Depot Medroxyprogesterone Acetate The downsides to injectable DMPA use
include a slow return to fertility and potential bone mineral density loss, as DMPA carries a black box
warning to avoid use for greater than 2 years due to the risk of potentially irreversible BMD loss.
Controversy exists on the potential irreversibility of BMD loss and despite this labeling, the ACOG
has stated that clinicians may continue its use beyond 2 years in patients who are responding well.
25 For those who wish to become pregnant shortly after discontinuing treatment, this option may
not be preferred because of its associated slow return of normal ovulation. Overall, DMPA has a
mean conception time of 10 months after discontinuation, compared to other hormonal products
that have shorter return to fertility. 26 Levonorgestrel Intrauterine System Insertion of an LNG-IUS is
an option for those seeking long-acting reversible contraceptive benefits in addition to
endometriosis pain relief. There are various forms of LNG-IUSs available in the market.
Approximately 20% to 30% of women experience amenorrhea within the first year of using an LNG-
IUS, reducing the major symptom of endometriosis, dysmenorrhea. 27 Despite their efficacy at
reducing endometriosis-related pain, no LNG-IUSs are currently Food and Drug Administration (FDA)
approved for the treatment of endometriosis. The LNG-IUDs do not inhibit ovulation, yielding a
potential for the growth of ovarian endometriomas. Other disadvantages of the LNG-IUS include
potential difficulty of inserting the device into nulliparous women, a 5% expulsion rate, and cost of
the procedure. 15 Alternative Drug Treatments Other options for treatment of endometriosis pain
include gonadotropinreleasing hormone (GnRH) agonists, GnRH antagonists, danazol, and aromatase
inhibitors. 2,12,15,28 Treatments fall into this category for several reasons: lack of data supporting
their efficacy in treating endometriosis, proven efficacy but intolerable adverse events, or unknown
long-term safety. None of these methods is proven superior over others, so treatment decisions
should be made based on patient preference of dosage form and dosing schedule, patient-specific
response, potential side effects, and medication costs/insurance coverage. 2,10,12,15 Several of the
options in this category can be combined with other medications to limit their adverse events. For
example, GnRH agonists are used with estrogen-progestin products to limit anti-estrogenic side
effects and aromatase inhibitors are prescribed with CHCs, progestins, or GnRH agonists.
Gonadotropin-Releasing Hormone Agonists The GnRH agonists are highly effective at treating
endometriosis-associated pain, but their use is limited by side effects and cost. The ACOG guidelines
recommend their empiric use in the event of NSAID or contraceptive failure. 2 Pharmacologically the
GnRH agonists inhibit follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion,
which effectively mimics an oophorectomy. The GnRH agonists create a gonadotropic flare prior to
their long-term receptor downregulation, which may increase pain during this period. This can be
minimized by initiating therapy during the mid-luteal phase or overlapping therapy with a CHC or
progestin for three weeks. Pain will recur quickly upon discontinuation, making GnRH agonists a
chronic treatment option. 29,30 Although GnRH agonist are approved by the FDA currently for only
12-month courses of treatment, if a patient responds well to therapy it is often continued for longer
with add-back therapy (subsequently discussed). 2 Side effects seen with GnRH agonists are the
result of the hypoestrogenic environment and include BMD loss and vasomotor symptoms, such as
hot flushes, vaginal dryness, and insomnia. With long-term use (>6 months) BMD loss becomes a
major concern. Utilization of add-back therapy minimizes this loss and other adverse events and has
demonstrated safety for up to 10 years. 31,32 It is recommended to start add-back therapy on
immediate initiation of GnRH agonist treatment. 2,12,15 Monitoring for this class of medications
includes physical findings, bone density, and serum lipids. 2 Add-Back Therapy Add-back regimens
may consist of progestins alone, estrogens, and progestins and bisphosphonates and are utilized in
combination with GnRH agonists to reduce or eliminate BMD loss and provide symptomatic relief
against the anti-estrogenic effects of GnRH agonists. Several studies have recently shown that
estrogen-progestin combinations are more effective than progestin monotherapy at protecting for
BMD loss. 30,33,34 Adding estrogen to a GnRH agonist has a potential to negate its antiestrogenic
effects that relieve endometriosis pain. Therefore, the dose of estrogen must be low enough to
maintain a serum estrogen level