Obstetrics and Gynecology Clinics
Volume 27 • Number 3 • September 2000
Copyright © 2000 W. B. Saunders Company
Debra A. Minjarez 1
MD
William D. Schlaff 2
MD
1 University of Texas Southwestern Medical
Center, Dallas, Texas (DAM)
2 Division of
Reproductive Endocrinology and Infertility, Department of Obstetrics and
Gynecology, University of Colorado Health Sciences Center, Denver, Colorado
(WDS)
Address reprint requests
to
William D. Schlaff, MD
Division of Reproductive Endocrinology and Infertility
Department of Obstetrics and Gynecology
University of Colorado Health Sciences Center
Box 198
4200 East 9th Avenue
Denver, CO
e-mail: [email protected]
Endometriosis is a common gynecologic disorder estimated
to affect 71% of women with pelvic pain and 84% of women with infertility and
pelvic pain. [1]
[9]
In asymptomatic women, histologically confirmed endometriosis
has been reported to occur in 45% to 50% of patients at the time of laparoscopy. [42]
The true prevalence of endometriosis is unknown
owing to a lack of well-defined epidemiologic studies. To select the optimal
medical therapy for a patient with endometriosis,
one must be familiar with the varied clinical presentations and its
pathophysiology.
The
classic diagnosis of endometriosis is
made by identifying endometrial glands and stroma in extrauterine locations or
within the musculature of the uterus, defined as adenomyosis. The pelvic
structures most often affected by endometriosis
in decreasing order of frequency are the ovaries, the anterior and posterior
cul-de-sac, the posterior surface of the broad ligament, the uterosacral
ligaments, the fallopian tubes, the sigmoid colon, the appendix, and the round
ligaments. [24]
The cervix, vagina, and bladder are less frequently affected.
Multiple
theories have been proposed in an attempt to explain the pathophysiology of endometriosis. Unfortunately, no single theory
adequately explains the pathogenesis of this disease. The most frequently cited
mechanisms in the development of endometriosis
are transplantation of exfoliated endometrial cells and coelomic metaplasia. [44]
Other working hypotheses are genetic, immune, and toxin induced.
The
transplant theory hypothesizes that, during menstruation, endometrium is
deposited to ectopic locations via retrograde menstruation or dissemination
through the lymphatic or vascular systems. [18]
Multiple studies have demonstrated that endometrial cells within the fallopian
tube and peritoneal cavity are viable and capable of implantation. [15]
[25]
[36]
In addition, animal and human studies have confirmed that placement of
endometrial tissue into ectopic sites results in histologic transformation into
endometriotic lesions [45]
[50]
; however, transplantation alone does not explain why endometriosis develops in only 5% to 10% of women
when efflux of menstrual fluid has been documented to occur in 76% to 90%. [18]
[27]
The
coelomic metaplasia theory cites transformation of the coelomic epithelial
lining of the peritoneal cavity, which is composed of differentiated cells
capable of dedifferentiating into endometrial-type tissue. Research has not
supported that peritoneal cells can undergo transformation, and most
metaplastic processes in humans increase with advancing age, whereas endometriosis is usually found in women of
reproductive age. The mechanism of coelomic metaplasia may explain the
occurrence of endometriosis in women with
mullerian agenesis, postmenopausal women, and women who have undergone
hysterectomy. [41]
The
association between genetic predisposition and endometriosis
has been based on retrospective analysis of family histories indicating a
polygenic and multifactorial inheritance pattern. [31]
[46]
In probands from affected families, the onset of endometriosis
occurs earlier in life, with more severe disease at the time of diagnosis.
First-degree female relatives have a 6.9% occurrence rate versus a 1% rate for
nonrelated controls. [47]
Investigators
have also found alterations in cell-mediated and humoral immunity in women with
endometriosis. Affected patients have
been shown to exhibit increased humoral immune responsiveness and macrophage
activation, decreased T-cell and natural killer cell function, and increased
levels of autoantibodies. [19]
[20]
The significance of autoantibodies and dysfunction of the immune system are
controversial and unclear.
An
increasing area of interest is the role of environmental toxins, such as
dioxin, in inducing endometriosis. Rhesus
monkeys chronically exposed to dioxin develop endometriosis.
[43]
Human studies have also confirmed elevated dioxin levels in patients with endometriosis versus control patients. [16]
Molecular
aberrations in steroidogenic enzyme function have been implicated in the
development of endometriosis. Endometrial
tissue from women with endometriosis
expresses aromatase P450, whereas endometrium from women without identifiable endometriosis does not. [38]
The presence of aromatase within endometriosis
results in higher local production of estrogen necessary to maintain lesions.
Rather
than one theory explaining the etiology of endometriosis,
it is likely that a multitude of factors contribute to its formation.
Retrograde menstruation and transplantation of endometrium into ectopic sites
may be necessary in activating metaplastic transformation of the coelomic
epithelium. In patients with immune dysfunction, genetic predisposition, or
prior environmental toxin exposure, clearance of endometrial tissue may be
impaired, allowing implantation and growth of lesions. On transformation into
endometriotic lesions, aromatase expression may allow continued growth and
spread of endometriosis.
Endometriosis is associated with a wide variety of
clinical symptoms and signs, although most patients are asymptomatic. The
history and physical findings may strongly suggest the presence of endometriosis, but no finding is pathognomonic.
Furthermore, the size of lesions does not correlate with the severity of the
disease, and the pathophysiology of pain in milder stages in not well
understood. [53]
The classic triad of dysmenorrhea, dyspareunia, and infertility has been
described as a characteristic of the disease.
Pelvic
pain generally presents as secondary or worsening primary dysmenorrhea and
dyspareunia. The latter is usually associated with endometriosis
of the uterosacral ligaments, deep pelvic implants, lesions of the rectovaginal
septum, or a fixed retroverted uterus.
Infertility
is also a common symptom of endometriosis.
The detection of endometriosis is higher
among women with infertility than in normal fertile women undergoing laparoscopy. [17]
Despite many proposed etiologies for this association, there is no conclusive
evidence that endometriosis is a direct
cause of infertility, except in women with anatomic distortion and fibrosis of
the pelvis.
The
gross appearance of endometriosis is extremely
variable. Location, size, and age of the lesions determine the gross
appearance. [33]
Clear fluid-containing vesicles seen on the surface of the peritoneum are found
early in the disease process. These vesicles then take on the more
characteristic powder burn appearance surrounded by a stellate scar after
bleeding into the vesicle. Other lesions may appear raised with a red, blue, or
brown discoloration. [8]
[37]
Red lesions are considered to be the most active form of endometriosis.
Frequently,
surgeons will find multiple filmy and dense adhesions from the ovary to the
pelvic sidewall, posterior cul-de-sac, or posterior surface of the uterus.
Ovarian endometriosis is usually
characterized by the presence of dark red fluid cysts, endometriomas, or
reddish blue, fibrin areas on the surface of the ovary. Cyst cavities of
endometriomas are composed of a large concentration of endothelial leukocytes
heavily laden with hemosiderin. [12]
Endometriosis can be managed effectively with medical
therapy, surgery, or a combination of both. Therapy is directed toward the
severity of symptoms, the extent of disease, the location of disease, and
desires for fertility. The role of medical therapy in the treatment of women with
endometriosis has changed dramatically.
Initial treatments consisted of oral contraceptives, androgens such as danazol,
and medroxyprogesterone acetate. In the 1980s, the development of
gonadotropin-releasing hormone (GnRH) agonist created a breakthrough in the
management of endometriosis.
Treatment
is directed toward the estrogen responsiveness of endometriosis,
thus the goal of therapy is to induce either a pseudopregnancy (oral
contraceptives, progestin) or a menopausal state (GnRH analogue) to inhibit or
delay progression. These approaches are supported by the rare incidence of endometriosis in the prepubertal age before
activation of the hypothalamic-pituitary-ovarian axis. Furthermore, during
menopause, spontaneous regression of endometriosis
and associated symptoms occurs in most patients secondary to a decrease in
estrogen production.
The
initial management of the patient suspected of having endometriosis on the basis of history and physical
examination who does not currently desire fertility is empiric therapy with
oral contraceptives and nonsteroidal anti-inflammatory drugs (NSAIDs). Oral
contraceptives create a hormonal milieu in which the progestational agent
impedes the effect of estrogen on the endometrial lining and induces
decidualization and subsequent atrophy of existing endometriotic lesions.
Unfortunately, endometriosis can remain
active despite oral contraceptives, and some patients will continue to complain
of symptoms. If the patient fails to experience relief of symptoms within 3
months of initiating oral contraceptive therapy and concomitant use of NSAIDs,
a more aggressive medical modality is warranted. No evidence supports switching
from one NSAID or oral contraceptive formulation to another in an attempt to improve
response.
Progestins
are frequently used in the management of endometriosis.
Progestational agents inhibit endometriotic tissue growth by causing an initial
decidualization and eventual pseudonecrosis or atrophy. Progestins oppose the
growth-promoting effects of estrogen by altering clearance of the nuclear
estrogen receptor and inducing 17beta-hydroxysteroid dehydrogenase, which
converts estradiol to estrone. At high doses, progestins will also inhibit
gonadotropin secretion and ovarian hormone production, inducing an amenorrheic
state. Associated side effects include weight gain, fluid retention, headaches,
and depression. All of these effects resolve after discontinuation of therapy.
Furthermore, the depot formulation is unpredictable in length of action, and
resumption of menses may take up to 18 months.
Oral
administration of medroxyprogesterone acetate, 50 mg daily, improved symptoms
in 80% of patients with moderate to severe endometriosis.
[29]
Thirty percent of participants experienced some form of bleeding. Other minor
side effects, such as weight gain and edema, were well tolerated. Moghissi and
Boyce [34]
observed subjective improvement in symptoms with 30 mg of medroxyprogesterone
acetate. Unfortunately, recurrence rates have been reported to reach 42% after
2 years of therapy. As an alternative to medroxyprogesterone acetate, one may
choose to administer norethindrone acetate, 5 mg daily for 6 months. A similar
response can also be achieved with 40 mg of megestrol acetate daily. Parenteral
medroxyprogesterone acetate depot may also be given at a dose of 100 mg every 2
weeks for 3 months followed by 200 mg monthly for 3 to 6 months.
Danazol,
a synthetic derivative of 17alpha-ethinyltestosterone, was introduced into
clinical practice in 1971. Danazol directly inhibits steroidogenic enzymes,
endometriotic implant growth, and pituitary gonadotropin secretion, and
interacts with androgen and progesterone receptors. Sex hormone-binding
globulin (SHBG) levels are also reduced, resulting in elevated free
testosterone levels, which promote androgenic side effects such as acne and
hirsutism. Danazol produces a hypoestrogenic hyperandrogenic environment that
is unfavorable for the growth of endometriotic lesions. Other side effects of
danazol include weight gain, hot flushes, mood changes, depression, muscle
cramps, decreased breast size, decreased high-density lipoprotein levels (HDL),
and increased liver enzymes. On average, patients gain 10 lb during the course
of treatment, have a 50% decrease in HDL, and experience a concomitant increase
in low-density lipoprotein. Eighty-five percent of patients experience
bothersome side effects, and at least 10% discontinue therapy. [4]
More
than 80% of patients experience relief or improvement of pain symptoms within 2
months of starting treatment with danazol. [5]
[11]
[35]
Danazol has been shown to reduce pain better than placebo for up to 6 months
after discontinuation of therapy. Unfortunately, the recurrence of symptoms
within 4 to 12 months of discontinuation of therapy approaches 50% in most
studies. Danazol is given orally in divided doses ranging from 400 to 800 mg
daily for 6 months. A 6-year prospective study evaluating the effectiveness of
danazol at 400 and 800 mg found no difference in side effects between the two
doses, and gross resolution of the disease was similar. [5]
A
recent study investigated the use of a vaginal danazol ring for the treatment
of endometriosis. [23]
Eighty-eight percent of participants with deep endometriosis
had a decrease in dysmenorrhea, and 92% had a decrease in tenderness of the
cul-de-sac within 3 months. Preliminary data suggest that danazol rings are
effective in treating severe endometriosis
while avoiding androgenic side effects.
Trials
evaluating the effect of danazol on fertility in comparison with expectant
management have shown no increase in pregnancy rates. Concerns have been
expressed regarding the androgenic action of danazol and potential harm to a
developing female fetus. Despite anovulation owing to decreased gonadotropin
secretion, patients are encouraged to use barrier contraception.
The
most predictable form of medical therapy that inhibits estrogen production by
the ovaries is GnRH agonist. GnRH agonists bind to receptors in the pituitary
gland, initially resulting in a release of follicle-stimulating hormone (FSH)
and leutinizing hormone (LH), followed by modulation, a decrease in
gonadotropin secretion, and, eventually, cessation of estrogen production by
the ovaries. In a hypoestrogenic environment, endometriosis
will undergo quiescence and atrophy with improvement in symptoms.
Several
studies have compared the effects of danazol and GnRH agonist. [10]
[40]
[52]
The absence of a placebo arm and the inclusion of a large number of patients
with mild endometriosis limit the
interpretation of these studies. Overall, treatment with GnRH agonists was
comparable or better than treatment with danazol. A study by Cirkel and
co-workers [7]
in 1995 found a more profound decrease in FSH after 4 weeks of treatment with a
GnRH agonist when compared with danazol. In that study, the decrease in mean serum
estradiol concentration was also more significant with GnRH analogue than with
danazol. [7]
Several investigators have shown that suppression of estradiol levels below 40
pg/mL is associated with better symptom relief. [2]
[21]
GnRH analogue treatment results in improvement or resolution of pain symptoms
in all stages of disease. [28]
As
is true for other medical modalities, GnRH therapy is associated with a
recurrence of symptoms, particularly dysmenorrhea, in 57% of patients within 6
months of discontinuation of therapy. Histologically proven relapse has been
observed in 13.3% to 15.6% of women after GnRH analogue therapy. [14]
Patients with severe forms of endometriosis
are more likely to have recurrence of pain, with an overall recurrence rate of
43.8%. [51]
GnRH agonist formulations are available as nasal sprays or injection. The usual
dose is 400 to 800 mug daily for nasal nafarelin, 3.6 mg for monthly
subcutaneous goserelin, and 3.75 mg for monthly intramuscular leuprolide.
Gonadotropin-releasing
hormone agonists do not have androgenic or progestogenic side effects or
negative impact on lipid profile; however, the side effects associated with a
hypoestrogenic state may be severe. These effects include vaginal dryness, hot
flushes, insomnia, depression, libido changes, headache, and fatigue. A
decrease in trabecular bone density of up to 6% in 6 months has been reported.
This effect is largely reversible after discontinuation of therapy but limits
the time this agent can be used. The long-term effect of multiple courses of
GnRH analogue therapy in young women is unknown, and there is potential for
delayed adverse effects on bone.
The
addition of add-back therapy to GnRH analogue treatment has gained wide acceptance
and minimizes the hypoestrogenic side effects of the analogue while preserving
therapeutic efficacy. The ultimate goal is to decrease vasomotor symptoms and
detrimental effects on bone density to enhance compliance with prolonged
duration of therapy.
The
addition of progestin alone was first employed as add-back therapy. [6]
Vasomotor symptoms and bone density loss could be reduced with a 100-mg daily
add-back of medroxyprogesterone acetate but apparently not with lower doses. [30]
Administration of norethindrone at a dose of 1.7 mg suppressed vasomotor
symptoms; however, a slight degree of bone mineral density loss occurred. [49]
Higher doses of norethindrone have been reported to have a bone-sparing effect
in a prospective randomized trial. [48]
Several studies have shown that transdermal 17beta-estradiol or conjugated
equine estrogens administered with medroxyprogesterone acetate result in
decreased vasomotor symptoms and decreased bone loss without increasing pain.
The addition of bisphosphonates to norethindrone also eliminates bone mineral
density loss; however, in light of the cost of bisphosphonates and concerns
over long-term effects in young women who desire future fertility, further
studies are indicated before this adjunct can be used as a standard approach.
Unfortunately, after discontinuation of GnRH agonist and add-back therapy,
recurrence rates are similar to the rates reported for other medical therapies.
In
the treatment of infertility, data are inconclusive. If patients desire
fertility, treatment should proceed to ovarian stimulation, except in patients
undergoing in vitro fertilization. One study showed suppression of ovarian
function before ovarian stimulation to be associated with increased pregnancy rates
as high as 41.6% versus 16.6% in unsuppressed patients; however, this approach
is not clearly supported by the data and has not gained wide acceptance. [39]
Surgical
treatment is no longer first-line therapy. Surgery is indicated in patients who
have failed medical therapy and who have physical findings of extensive endometriosis such as endometriomas. Several
investigators have advocated empiric therapy with oral contraceptives plus
NSAIDs, followed by GnRH agonist if no improvement. [3]
The rationale for this approach is that endometriotic lesions may not be
recognized by the surgeon. The specificity of laparoscopic diagnosis ranges
from 40% to 80% depending on the knowledge and skill of the surgeon, and
complete excision or ablation is often technically difficult. [13]
[22]
Given the limitations in effectively diagnosing and treating endometriosis, medical treatment based on a
clinical working diagnosis of endometriosis
may be justified. More data are needed before this approach can be fully
endorsed.
In
the treatment of infertility, only one prospective randomized study comparing
surgical ablation of minimal and mild endometriosis
with expectant management has demonstrated a higher pregnancy rate in the
surgically treated group. [32]
This improvement, although statistically significant, does not warrant a
diagnostic laparoscopy in all infertile
patients with normal hysterosalpingograms and bilateral tubal patency for the
purpose of removing endometriosis. In
patients with significant physical findings or symptoms, the threshold for laparoscopy should be lower. [26]
The
treatment of women with endometriosis can
be a challenge. Therapeutic strategies must be tailored to the individual
symptoms, age, and desire for fertility. Medical therapy continues to be based
on endocrine treatment, such as oral contraceptives, progestins, danazol, and
GnRH agonists. Unfortunately, recurrence rates are high after discontinuation
of therapy. Recent clinical research on GnRH analogues plus add-back therapy
has produced favorable results. Long-term treatment of patients using this
approach has successfully reduced pain while minimizing symptoms of
hypoestrogenism and adverse metabolic effects, such as loss of bone mineral
density. Currently, GnRH analogues given with add-back therapy seems to be the
most effective long-term approach to the treatment of symptomatic endometriosis. In the future, other modalities,
such as medicated vaginal rings, inhibitors of steroidogenic enzymes, and GnRH
antagonists, will most likely be options.
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