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Infertility Aspects of Endometriosis

Robert S. Schenken, MD
Chairman, Department of Obstetrics and Gynecology, University of Texas Health Science Center, 7703
Floyd Curl Drive, Mail Code 7836, San Antonio, Texas 78229 3900, USA

INTRODUCTION

FECUNDITY IN INFERTILE WOMEN WITH ENDOMETRIOSIS

ENDOMETRIOSIS AND INFERTILITY: CAUSE AND EFFECT

BIOLOGIC MECHANISMS THAT MAY LINK ENDOMETRIOSIS AND INFERTILITY

DIAGNOSIS AND STAGING

PHARMACEUTICAL THERAPY FOR ENDOMETRIOSIS

SURGERY FOR ENDOMETRIOSIS

COMBINATION MEDICAL-SURGICAL THERAPY

ASSISTED REPRODUCTIVE TECHNOLOGY AND ENDOMETRIOSIS

CLINICAL APPROACH TO INFERTILE WOMEN WITH ENDOMETRIOSIS

REFERENCES

INTRODUCTION

Endometriosis is the presence of tissue that structurally and functionally resembles endometrial glands
or stroma outside the uterine cavity. The structures most commonly affected by endometriosis include
the ovaries, uterosacral ligaments, pelvic peritoneum, rectovaginal septum, and lower genital tract.
Several theories have been proposed to explain the histogenesis of endometriosis.1 The implantation
theory proposes that endometrial tissue from the uterus is shed during menstruation and transported
through the fallopian tubes, where it gains access to and implants upon pelvic structures. The direct
transplantation theory is the probable explanation for endometriosis that develops in episiotomy,
cesarean section, and other scars following surgery. Endometriosis in locations outside the pelvis is
explained by dissemination of endometrial cells or tissue through lymphatics and blood vessels. The
coelomic metaplasia theory proposes that the coelomic (peritoneal) cavity contains undifferentiated
cells or cells capable of dedifferentiating into endometrial tissue. This theory is based on embryologic
studies demonstrating that all pelvic organs, including the endometrium, are derived from the cells
lining the coelomic cavity.

Retrograde menstruation, altered immunity, and genetics may play causative roles in the development
of endometriosis. Anatomic alternations of the pelvis that increase tubal reflux of menstrual
endometrium may increase a woman's chance of developing endometriosis. An increased incidence of
endometriosis is found in girls with genital tract obstructions that prevent expulsion of menses into the
vagina and increase the likelihood of tubal reflux.2 The incidence of retrograde menstruation is similar in
women with and without endometriosis. Consequently, the development of endometriosis could
depend on the quantity of endometrial tissue reaching the peritoneal cavity, the capacity of a woman's
immune system to eliminate the refluxed menstrual debris, and/or the inherent ability of the
endometrium cell to adhere to the peritoneum or ovary.

Women with endometriosis typically present with one of three problems: an adnexal mass, pelvic pain,
or infertility. Surgery for adnexal masses is generally indicated to remove the endometrioma and/or
other pathologic pelvic conditions. Pelvic pain from endometriosis often can be treated successfully with
surgery or medical therapy, but treatment of endometriosis in the female partner of an infertile couple
raises a large number of complex clinical questions that do not have simple answers. There are few
infertility problems requiring greater clinical skills than those required to plan therapy for an infertile
woman with endometriosis.

FECUNDITY IN INFERTILE WOMEN WITH ENDOMETRIOSIS

In normal couples, the monthly fecundity (f) is in the range of 0.150.20.3 In most studies of women with
endometriosis and infertility who have not received treatment, the monthly fecundity is in the range of
0.020.1 (Table 1).4, 5, 6, 7, 8 Some women with endometriosis and infertility have a markedly reduced
monthly fecundity. Early studies suggested that 2550% of infertile women have endometriosis and that
3050% of women with endometriosis are infertile.9, 10 These initial estimates were based on the
incidence of histologically documented endometriosis in women undergoing laparotomy for gynecologic
procedures in referral medical centers. Recent studies in women undergoing laparoscopy have
strengthened the epidemiologic association with infertility. A prospective study of infertile women and
women undergoing tubal ligation demonstrated a higher incidence of endometriosis in infertile women
(48%) compared with fertile women (5%).11 Other studies have confirmed that infertile women are 10
20 times more likely to have endometriosis than fertile women.12, 13 The limitations of the above
retrospective studies should be noted. These observations raise many questions. For example, in
women with endometriosis and infertility, the low fecundity might be from factors other than
endometriosis.

Table 1. Fecundity in women with infertility and stage I or II endometriosis managed without treatment
(expectant management)

Investigator No. of Subjects Fecundity

Toma et al8 17 0.063

Fedele et al9 40 0.045


Investigator No. of Subjects Fecundity

Kemmann et al10 0.028

Serta et al11 25 0.14

Seibel et al12 36 0.05

ENDOMETRIOSIS AND INFERTILITY: CAUSE AND EFFECT

The hypothesis that endometriosis causes infertility or a decrease in fecundity in humans remains
controversial. To address a question of proof of causation, Jansen14 reviewed the pregnancy rate in
patients undergoing artificial insemination by donor. Seven patients had untreated minimal
endometriosis, and the remaining women had normal pelvic findings at laparoscopy. A fecundity rate of
12.0% was reported in patients with a normal pelvis compared with 3.6% in patients with endometriosis.
The results of this prospective study were inconsistent, with two retrospective studies demonstrating
expected fecundity rates in women with minimal endometriosis undergoing donor insemination.15, 16 If
endometriosis does cause infertility, then eradication of the disease process should improve pregnancy
rates. One retrospective study and one quasi-randomized study suggest that surgery improves
fecundity.17, 18 Two randomized studies have assessed pregnancy rates following surgical treatment or
expectant management. The Canadian Collaborative Group of Endometriosis reported a randomized
trial of laparoscopy with and without treatment in 341 women with minimal or mild disease. The
fecundity rate in treated patients was 4.7 versus 2.4 per 100 person-months in controls (95% CI 1.2
3.1).19 However, the Gruppo Italiano per lo Studio dell' Endometriosi conducted a similar study in 111
patients with stage I or II endometriosis. One year after surgery, the pregnancy rate was 29% in the no
treatment group and 24% in the ablation/resection group. These conflicting studies may be attributed to
different patient population or responses of individual patients to therapy. They do indicate that the
pathophysiology of infertility in patients with endometriosis remains enigmatic.20

Experiments on rabbits, rats, and monkeys, however, strongly suggest that surgically induced
endometriosis causes a decrease in fecundity in all three of these species.21, 22, 23, 24 In most of these
animal studies, endometriosis is surgically induced by suturing small squares of endometrium on pelvic
peritoneal surfaces or bowel mesentery. For example, Schenken and Asch removed the right uterine
horn from New Zealand white rabbits, minced the uterine horn into squares measuring 2 5 5 mm,
and sutured the squares onto pelvic peritoneal surfaces.21 Control animals had the right uterine horn
removed but had 2 5 5-mm square of adipose tissue sutured onto their peritoneal surfaces. A second
laparotomy was performed 25 days after the initial surgery. All the uterine horn grafts survived
transplantation and developed into vascularized hemorrhagic solid masses or multioculated cystic
masses. Five of eight animals in the experimental group developed adhesions from bowel to the
implants. The adipose tissue transplants were well vascularized and viable. There was no cyst formation
in these implants. One of eight animals in the control group developed adhesions. Fourteen days later,
the animals received human chorionic gonadotropin and were inseminated with rabbit semen from
bucks with proven fertility. Six of eight control animals became pregnant. Only two of eight animals with
endometriosis became pregnant. Hahn and co-workers observed similar results.22They also noted an
inverse relationship between the severity of the endometriosis and the fecundity: the number of
implanted embryos decreased as the total weight of the endometriotic implants increased.

Vernon and Wilson transplanted uterine squares or adipose tissue to the bowel mesentery of Sprague-
Dawley rats.23 The transplanted uterine squares developed into vascular cysts that measured 5 mm in
diameter and contained clear fluid. Moderate to severe adhesions were present in all animals with
surgically induced endometriosis. Approximately 20% of the sham-operated animals (controls)
developed adhesions. Twenty-five rats with autotransplanted uterine square and 15 controls were
mated. In the controls, the average number of day 14 embryos was 11.3; in the animals with
endometriosis, the average number of day 14 embryos was 8. In another group of experimental animals,
the average number of live-born pups was 9 for the controls versus 4.5 for the rats with endometriosis.
Interestingly, pregnancy appeared to induce regression of the endometriotic lesions.

Schenken and colleagues examined the effects of surgically induced endometriosis on fertility in
monkeys.24 Animals with surgically induced endometriosis and control animals with adipose tissue
autografts were mated. Pregnancy rates were similar between control animals (42%) and animals with
mild endometriosis (35%). Animals with moderate and severe endometriosis, however, had reduced
pregnancy rates (12%). Pelvic adhesions appeared to account, in part, for the reduction in fertility.
Animals that had endometriosis and ovulated from an ovary with adhesions had a 0% per cycle
pregnancy rate. Animals that had endometriosis and ovulated from an adnexa without adhesions had a
33% per cycle pregnancy rate. In addition, some of the animals with endometriosis appeared to have
luteinized unruptured follicles, which accounted for a part of the reduction in fertility. These studies
strongly suggest that the experimental induction of endometriosis reduces fecundity. The experimental
observations in monkeys may be especially relevant to improving our understanding of endometriosis in
humans.

D'Hooghe and colleagues assessed cycle pregnancy rates in baboons with spontaneous (n = 16) or
induced (n = 21) endometriosis.25 There were 9 with minimal, 14 with mild, and 7 each with moderate
and severe disease. All had histologically proven disease, whereas all control animals (n = 34) had a
normal pelvis at laparoscopy. The cycle pregnancy rates were 24%, 10%, 8%, and 13% in women with
minimal, mild, moderate, and severe disease, respectively. The cycle pregnancy rates were significantly
lower in baboons with stage IIIIV endometriosis (9%, 6/64) and with stage II disease (10%, 7/73) than in
animals with stage I endometriosis (24%, 11/45) or in controls (19%). The normal pregnancy rate in
baboons with stage I disease and decreased rate in advanced disease suggests that fertility declines with
increasing stages of endometriosis.

Although the animal data support the hypothesis that endometriosis can cause infertility, the situation
in humans is more complex and controversial. A major problem is that infertility is a clinical problem
of couples, and many couples have multiple factors that decrease fecundity. The complexity of infertility
in the clinical situation often makes it difficult to identify a single causative factor. In addition, our
understanding of the causes of infertility is incomplete. It is possible that in infertile couples who appear
to have a decrease in fecundity from endometriosis, a defect in endometrial or oocyte function may
actually be present.

BIOLOGIC MECHANISMS THAT MAY LINK ENDOMETRIOSIS AND INFERTILITY

Several mechanisms have been proposed to clarify the association between endometriosis and
infertility:

Distorted pelvic anatomy


Altered peritoneal environment
Altered systemic immune function
Endocrine and ovulatory abnormalities
Abnormal tubal function
Abnormal fertilization and implantation
Abnormal endometrial function

None of these mechanisms has been proved to cause decreased fecundity in women. These mechanisms
are briefly discussed below.

Distorted Pelvic Anatomy

Major pelvic adhesions resulting from any disease can impair egg release from the ovary, block sperm
entry into the distal fallopian tube, and inhibit ovum pickup. In animal models of endometriosis, pelvic
adhesions appear to contribute to the observed decreased fecundity noted in animals with advanced
endometriosis.24

Altered Peritoneal Function

Many studies demonstrate that women with endometriosis have an increased volume of peritoneal
fluid, increased macrophage concentration and function, and increased peritoneal fluid concentrations
of prostaglandin, interleukin-l, tumor necrosis factor, and proteases. These alterations may impair
oocyte, sperm, embryo, and fallopian tube function.26,27,28,29

Altered Systemic Immune Function

IgG and IgA antibodies and lymphocytes may be increased in the endometrium of women with
endometriosis. These abnormalities may alter endometrial receptivity to embryo implantation.30,31

Endocrine and Ovulatory Abnormalities

Numerous endocrine and ovulatory disorders may be present in women with endometriosis, including
the luteinized unruptured follicle syndrome, luteal phase dysfunction, abnormal follicular growth, and
premature and multiple luteinizing hormone (LH) surges.32,33,34 In a monkey model, advanced
endometriosis appeared to cause a decrease in fecundity, which was attributed partly to luteinized
unruptured follicle syndrome and partly to luteal phase defects.24
Abnormal Tubal Function

Peritoneal fluid from women with endometriosis reportedly contains an ovum capture inhibitor that
prevents normal cumulus-fimbria interaction.35Ovum capture inhibitor, a protein with a molecular mass
of greater than 100,000 daltons, remains to be purified.

Abnormal Fertilization and Implantation

In women with endometriosis, it is not clear whether abnormal fertilization and implantation contribute
to decreased fecundity. In a rabbit model of endometriosis, Hahn and colleagues reported that
blastocysts failed to implant normally in rabbits with endometriosis.36 Lessey reported that some
women with endometriosis lack endometrial v3 integrin expression.37 They hypothesized that
decreased endometrial integrin production in the mid-luteal phase causes infertility by impairing
implantation. These observations support the concept that endometriosis may represent one
component of a disease that is characterized by dysfunction in multiple components of the mllerian
tract, including the cervix, endometrium, fallopian tubes, and peritoneum.

DIAGNOSIS AND STAGING

The current clinical opinion is that a surgical procedure such as laparoscopy or laparotomy is required
for definitive diagnosis of endometriosis. Given this state of clinical practice, an important question is
when to laparoscope a patient to determine whether endometriosis is present. A history and physical
examination can yield a number of significant historical findings:

Pertinent Historical Finding

Secondary dysmenorrhea
Dyspareunia, especially with deep penetration
Delayed first pregnancy in association with regular, ovulatory menses
Dysmenorrhea unresponsive to medical therapy

Pertinent Physical Findings

Nodular uterosacral ligaments


Cul-de-sac tenderness
A fixed adnexal mass

Endometriosis is a heterogenous disease spanning a spectrum from a single 1-mm peritoneal implant to
10-cm endometriomas with cul-de-sac obliteration. Consequently, a clinical staging system is absolutely
necessary to allow clinicians to communicate effectively with regard to prognosis and treatment. The
revised American Fertility Society (rAFS) system currently is the most widely accepted staging system
(Fig. 1).38 In this system, points are assigned for severity of endometriosis based on the size and depth of
the implant and the severity of the adhesions.

Fig. 1. Revised American Fertility Society classification for


endometriosis. A. Scoring system and patient
information. B. Examples of application of scoring system.
(American Society for Reproductive Medicine: Revised
American Society for Reproductive Medicine classification
of endometriosis: 1996. Fertil Steril 67, 817, 1997).

Unfortunately, the staging system does not correlate well with a woman's chance for conception
following therapy. It is unlikely that any accurate staging system will be introduced until we have a
better understanding of the pathophysiology of endometriosis-associated infertility.

PHARMACEUTICAL THERAPY FOR ENDOMETRIOSIS

Pharmaceutical therapeutic options for endometriosis continue to expand rapidly. Six major options are
currently available: danazol, nafarelin, leuprolide, goserelin, progestins, and combined estrogen-
progestin therapy. The efficacy of these agents in the treatment of endometriosis is attributed to the
steroid responsiveness of endometriosis implants. The majority of human endometriosis implants
contain estrogen receptors, androgen receptors, and progesterone receptors.39, 40 Clinical and laboratory
observations demonstrate that estrogen is critical to the growth and function of endometriotic
implants.41 Clinical observations suggesting that estrogen is critical to the growth of endometriosis
include the findings that endometriosis rarely occurs before menarche; menopause, either surgical or
natural, usually produces an improvement in preexisting endometriosis; and new cases of endometriosis
occur very rarely after menopause unless exogenous estrogen is administered.

As discussed below, there is no evidence that medical treatment of endometriosis in infertile women
improves fecundity. A meta-analysis by Hughes and colleagues included 7 studies comparing medical
therapy to no treatment or placebo.42 The common odds ratio for pregnancy following medical therapy
was 0.85 (95% CI, 0.951.22). However, hormonal treatment is extremely effective in reducing pelvic
pain associated with endometriosis. For infertile women with endometriosis accompanied by
dyspareunia, dyschezia, dysmenorrhea, or nonspecific pelvic pain, hormonal treatment may improve
sexual function as well as the frequency of sexual relations, thereby increasing fecundity. In addition,
hormone therapy may be of value in the postoperative treatment of infertile women with endometriosis
considering in vitro fertilization/embryo transfer(IVF/ET).43, 44

Danazol
Danazol is an isoxazole derivative of ethinyl testosterone (Fig. 2). The pharmacology of danazol is best
understood by examining its interaction with intracellular steroid receptors, circulating steroid-binding
globulins, and enzymes of ovarian steroidogenesis.

Fig. 2. Structure of danazol

Danazol binds to three classes of intracellular steroid receptors: the androgen receptor, the progestin
receptor, and the estrogen receptor.45 Danazol has high affinity for the androgen receptor, moderate
affinity for the progestin receptor, and poor affinity for the estrogen receptor.46 Danazol is both an
androgen and estrogen agonist. Although danazol is an estrogen agonist, the affinity of danazol for the
estrogen receptor is so poor that for clinical purposes danazol has no major effect on the estrogen
receptor system. In contrast, because danazol is an androgen agonist with a very high affinity for the
androgen receptor, danazol has potent androgenic effects in vivo. Many of danazol's side effects can be
attributed to its androgenic properties. These side effects include the following: (1) a decrease in high-
density lipoprotein cholesterol; (2) an increase in low-density lipoprotein cholesterol; (3) a decrease in
hepatic production of sex hormone-binding globulin (SHBG) and thyroxine-binding globulin; and (4) an
increase in bone density. The effects of danazol on the intracellular progestin receptor are complex. In
some model systems, danazol can produce atypical secretory changes in estrogen-primed endometrium,
suggesting that danazol is a progestin agonist.47 In other model systems, danazol blocks the effects of
progesterone, suggesting that danazol is a progestin antagonist. Danazol is best regarded as a mixed
progestin agonist-antagonist.

Danazol has high affinity for SHBG and can displace testosterone and dihydrotestosterone from
SHBG.48 The observation that danazol increases free and bioavailable testosterone suggests that part of
its androgenic effects may be from the displacement of testosterone and dihydrotestosterone from
SHBG.

Danazol inhibits multiple enzymes of ovarian steroidogenesis, including cholesterol side-chain cleavage
enzyme, 3-hydroxysteroid dehydrogenase-isomerase, 17-ketosteroid reductase, 17-hydroxylase,
17,20-1yase, and aromatase.49 Experiments using monkey models and human subjects suggest that
danazol inhibits ovarian estrogen production by a direct effect on ovarian steroidogenesis.50, 51

The pharmacologic properties of danazol create an acyclic, high-androgen, low-estrogen environment


that is hostile to the growth of endometriotic tissue. Danazol produces a high-androgen environment
because it is inherently androgenic and because it decreases the hepatic production of SHBG and
displaces testosterone from SHBG, resulting in an increase in free testosterone. By direct actions on the
ovaries and the hypothalamic-pituitary axis, danazol produces a low-estrogen environment by inhibiting
follicular growth. Acting through hypothalamic and pituitary androgen and progestin receptors, danazol
decreases LH and FSH secretion. By inhibiting multiple enzymes of ovarian steroidogenesis, danazol
decreases ovarian estrogen production. The low-estrogen, high-androgen environment created by
danazol is hostile to the growth of endometriotic tissue. In addition, the acyclic endocrine environment
produced by danazol results in amenorrhea and prevents the reseeding of the peritoneum with new
implants of endometrium.
The major side effects of danazol are weight gain, bloating, decreased breast size, ache, oily skin,
hirsutism, headache, deepening of the voice, hot flashes, and muscle cramps.52 In women receiving 800
mg/day of danazol, the weight gain averages 4 kg. Approximately 80% of women receiving danazol will
report one or more of the above side effects. Danazol can produce a large number of biochemical
abnormalities including mild increases in serum levels of creatine phosphokinase, lactate
dehydrogenase, glutamic-oxaloacetic transaminase, and glutamic-pyruvic transaminase. These typically
are minor, clinically insignificant alterations. Danazol therapy produces marked alterations, however, in
the circulating lipid profile. At doses of 600 mg/day, danazol produces a 50% decrease in high-density
lipoprotein cholesterol and a 40% increase in low-density lipoprotein cholesterol. These lipid alterations
resolve within 3 months of discontinuation of danazol therapy. The clinical impact of this atherogenic
lipid profile in women of reproductive age is unclear.

Seibel and co-workers and Bayer and colleagues conducted prospective, controlled, randomized studies
of the effectiveness of danazol in the treatment of infertility associated with minimal
endometriosis.8, 53 Couples who had 1 year of infertility were eligible for entry into the study after they
completed a basic infertility evaluation, which included semen analysis, basal body temperature chart,
postcoital test, hysterosalpingogram, and endometrial biopsy. Patients (n = 73) then underwent a
diagnostic laparoscopy and tubal lavage. If Kistner stage I endometriosis was observed, the female
patients were randomized to receive danazol (n = 37) or no treatment (n = 36).54 Women who were
randomized to the danazol treatment group received an initial danazol dosage that tapered off
incrementally after the first 2 months, as follows: danazol 800 mg/day for 2 months, 600 mg/day for 2
months, and 400 mg/day for 2 months. Patients were then observed for 12 months, beginning either
immediately after laparoscopy in the untreated group or after completion of danazol therapy in the
treated group. During the 12 months of follow-up, 35% of the danazol-treated women and 47% of the
untreated group became pregnant; this difference was not statistically significant (Fig. 3). In conclusion,
treatment of women with mild endometriosis with danazol did not improve fecundity. In a randomized
study comparing gestrinone with placebo, Thomas and Cooke observed similar results.55

Fig. 3. Cumulative pregnancy rates in danazol-treated and untreated patients with


minimal endometriosis. The cumulative pregnancy rate in an ideal fertile population
is also shown for comparison. (Bayer SR, Seibel MM, Saffan DS et al: The efficacy of
danazol treatment for minimal endometriosis in infertile women: A prospective
randomized study. J Reprod Med 33:179, 1988)

Gonadotropin-Releasing Hormone Analogs: Nafarelin, Leuprolide, Goserelin

Gonadotropin-releasing hormone (GnRH) is a hypothalamic decapeptide (Fig. 4) that controls the


pituitary secretion of LH and FSH. In the follicular phase of the menstrual cycle, the hypothalamus
releases one pulse of GnRH per hour into the portal circulation. The ability of GnRH to stimulate LH and
FSH secretion is critically dependent on the frequency and amplitude of the GnRH pulse. If the GnRH
pulse frequency is chronically slow or too fast, the pituitary will not secrete LH and FSH in response to
the GnRH pulse. A continuous infusion of GnRH, through molecular mechanisms that are poorly
understood, markedly decreases pituitary production of LH and FSH.
Fig. 4. Chemical structure of the hypothalamic decapeptide gonadotropin-releasing
hormone (GnRH). Amino acids 2 and 3 are important for receptor activation.
Degradation of GnRH occurs by cleavage of the decapeptide between amino acids 56
and 67. (Friedman AJ: Leuprolide acetate: Applications in gynecology. Curr Probl Obstet Gynecol Fertil
11:209, 1988)

Because much of the information in the GnRH signal is contained in the pulse frequency, GnRH has a
very short half-life (4 minutes). GnRH is metabolized by endopeptidases present in the pituitary
circulation and pituitary gonadotropes, which cleave the 56 and 67 peptide bonds. By chemically
altering the sixth amino acid, GnRH analogs that are resistant to cleavage by endopeptidases can be
produced. These GnRH analogs have a long half-life (24 hours) and are perceived by the pituitary as a
continuous infusion of GnRH. Consequently, chronic administration of these GnRH analogs decreases LH
and FSH secretion and causes a cessation of ovarian estrogen production.

GnRH analogs currently available include: leuprolide, nafarelin, and goserelin. Leuprolide is administered
as a monthly depot injection. Nafarelin is administered in the form of a nasal spray and goserelin as a
monthly injection. The doses of nafarelin, leuprolide, and goserelin necessary to reduce circulating
estradiol to 15 pg/mL or 30 pg/mL are listed in Table 2.

Table 2. Dose effects of leuprolide, nafarelin, and goserelin

Agent Dosing

Leuprolide Depot 7.5-mg depot IM monthly

22.5-mg IM every 3 months

30-mg IM every 4 months

7.5-mg subQ monthly

22.5 mg subQ every 3 months

30-mg subQ every 4 months

Goserelin 3.6-mg implant-q 4 weeks

Nafarelin 400 g intranasally bid

200 g intranasally bid

In a large randomized clinical trial comparing the efficacy of danazol and nafarelin in the treatment of
endometriosis, Henzl and co-workers observed that both drugs produced symptomatic improvement in
80% of subjects and noted a 43% improvement in the rAFS endometriosis score (Fig. 5).56 Most of the
side effects associated with nafarelin therapy (e.g. hot flashes, headaches, mood changes, decreased
libido, vaginal dryness) are attributed to hypoestrogenism. GnRH analogs decrease vertebral bone
density. Dawood and colleagues reported that 6 months of GnRH analog therapy with buserelin (1200
g/day intranasally) resulted in a 7% decrease in trabecular bone density.57 Six months after completing
GnRH agonist therapy, the trabecular bone density remained 4% below pretreatment values. Similar
losses in trabecular bone density during GnRH agonist therapy have been reported with the use of
nafarelin and buserelin.58, 59 Matta and associates reported that the bone loss was completely reversible
once the GnRH analog was discontinued,59 but remains controversial. One report of six patients reated
with intramuscular leuprolide for 24 weeks found that bone loss in the vertebral spine (as measured by
CT scan) was 14%, recovering to a deficit of 4.2% and 3.3% at six and twelve months after stopping
therapy, respectively.60 Thus, recovery of bone loss occurred after cessation of treatment, but was
incomplete. After treatment with GnRH analogs, the rate of recurrent pelvic pain over five years ranges
from 37% in patients with mild disease to 74% in those with severe disease.61 Repeat courses of
nafarelin have been administered with some success in patients who have had recurrent symptoms
following initial therapy.62

Fig. 5. Pretreatment and post-treatment American Fertility Society


endometriosis scores in women receiving 6 months of intranasal nafarelin
or oral danazol therapy. (Henzl MR, Corson SL, Moghissi K et al:
Administration of nasal nafarelin as compared with oral danazol for
endometriosis: A multicenter double-blind comparative trial. N Engl J Med
318:485, 1988)

In a recently reported controlled trial, Fedele and associates randomized 71 women with rAFS stage I or
II endometriosis either to receive hormonal treatment with the GnRH agonist analog buserelin (400 g 3
times a day for 6 months) or to receive no treatment.63 Median follow-up was 17 months in the
buserelin group and 18 months in the control group, The 1-year actuarial pregnancy rate was similar in
both groups: buserelin, 30%; control, 37%. The 2-year actuarial pregnancy rate was also similar in both
groups: buserelin, 61%; control, 61%. This study suggests that hormonal treatment of rAFS stage I or II
endometriosis with buserelin does not improve fecundity.

Add-back Therapy

Many of the side effects of GnRH therapy can be minimized by modification of the treatment regimen.
As an example, the loss in bone mineral density can be minimized by lowering the dose of GnRH or
incorporating add-back therapy (e.g. estrogen, progestins, bisphosphonates, parathroid hormone,
calcitonin).64, 65, 66, 67, 68, 69, 70

Oral Contraceptive Pills

Oral contraceptive pills (OCPS) can be administered cyclically or continuously to induce decidualization
and subsequent atrophy of endometrial tissue. For most patients with only mild pain, use of OCPs
results in less painful periods and may also retard progression of disease. One observational study with
continuous use of OCPs was effective in relieving dysmenorrhea in women who did not respond well to
cyclic therapy.71 OCPs are a good choice for women with minimal or mild symptoms, since they provide
contraception and have a low rate of side effects. One randomized trial that directly compared goserelin
to low-dose cyclic OCPs showed that both drugs provided significant relief of pain, but goserelin was
superior for treatment of dyspareunia.72

ENDOMETRIOSIS ADD-BACK THERAPY

Norethindrone acetate 510 mg/d

Norethindrone acetate 2.5 mg/d

Sodium etidronate 400 mg/d

Calcium carbonate 500 mg/d

Medroxyprogesterone acetate 2030 mg/d or 100 mg/d

Conjugated estrogen 0.3000.625 mg/d

Medroxyprogesterone acetate 5 mg/d

Micronized estradiol 2 mg/d

Medroxyprogesterone acetate 5 mg/d

Progestin-Only Regimens

Numerous progestins (e.g. medroxyprogesterone acetate, norethindrone acetate, norgestrel acetate,


lynestranol) have been used as single agents for the treatment of endometriosis. These agents produce
a hypoestrogenic hormonal environment by suppressing ovarian estrogen production by inhibition of LH
and FSH secretion. In addition, these agents have a direct antiestrogenic effect on endometriotic tissue
by binding to intracellular progesterone and androgen receptors.

Oral administration of medroxyprogesterone acetate (3050 mg/day) is effective in the treatment of


endometriotic lesions.73 Side effects associated with this therapy include bloating, weight gain,
depression, and irregular uterine bleeding. Parenteral medroxyprogesterone acetate should not be used
for the treatment of endometriosis in infertile women because it can produce prolonged amenorrhea
after termination of therapy.

Despite the longstanding use of progestational agents in the treatment of endometriosis, only three
studies have reported the effects of these medications on subsequent fertility. In one study, 9 months of
treatment with dydrogesterone resulted in a 53% cumulative pregnancy rate in 19 women.74 Another
study utilizing 3 months of oral medroxyprogesterone acetate reported 12 pregnancies in 26 patients
(46%).75 In women with mild and moderate disease, the cumulative pregnancy rate was 55%; however,
neither of the above studies was controlled.
Hull and associates reported a controlled comparative trial with oral medroxyprogesterone, danazol,
and expectant management in women with stage I and II endometriosis.76 On the basis of life table
analysis, pregnancy rates in the three groups, respectively, were 71%, 46%, and 55%, and there were no
significant differences among the treatment groups. This study suggests that progestational therapy is
no more effective than expectant management in the infertile patient with endometriosis.

Combined Estrogen-Progestin Regimens

In 1959, Kistner reported that combined estrogen-progestogen contraceptives were effective in the
treatment of endometriosis when used in a continuous pseudopregnancy regimen.77 Long-term
administration of a combination of estrogen and a progestin results in suppression of LH and FSH,
resulting in the absence of ovarian follicular development and decidualization of the endometrium.
Pseudopregnancy regimens produce an acyclic hormone environment but do expose the endometriotic
lesions to a significant amount of estrogen. Although most synthetic progestins have sufficient
androgenic and progestational activity to block the effects of co-administered estrogen, in some
patients the administered estrogen actually stimulates metabolic activity in endometriotic lesions.
Therefore, the use of pseudopregnancy for women with severe endometriosis is not recommended.

One group of patients may be especially suitable candidates for pseudopregnancy treatment. Young
women with severe, incapacitating dysmenorrhea and minimal or mild endometriosis usually report
marked improvement in their pain during mini-pseudopregnancy therapy. A typical mini-
pseudopregnancy regimen consists of 15 weeks of continuous estrogen-progestin therapy (5 packages
of birth control pills), followed by a 1-week withdrawal of hormone therapy, again followed by 15 weeks
of continuous estrogen-progestin therapy, and so on. This is continued as long as pain relief is
maintained.78

In a recent randomized, controlled trial, an estrogen-progestin regimen was compared with a GnRH
analog regimen for the treatment of pelvic pain caused by endometriosis.72 The GnRH analog was more
efficacious than the estrogen-progestin regimen in reducing dyspareunia. The estrogen-progestin and
GnRH analog regimens were equally efficacious in reducing dysmenorrhea. Because the estrogen-
progestin regimen is much less expensive than any GnRH analog regimen, it may offer an attractive cost-
benefit ratio for the treatment of dysmenorrhea caused by endometriosis. Unfortunately, there were no
randomized-controlled trials assessing the efficacy of oral contraceptive therapy in women with
endometriosis-associated infertility.

Aromatase Inhibitors

Traditional medical therapies for endometriosis have targeted ovarian estrogen production or
antagonized estrogen action. Use of aromatase inhibitors is a novel approach as these agents appear to
regulate local estrogen formation within the endometriotic lesions themselves. In multiple case reports
and small series, aromatase inhibitors have been used off-label successfully to interrupt this pathway in
the treatment of severe endometriosis.79, 80, 81,82, 83, 84 One randomized trial (n = 80 patients) compared
treatment with a GnRH analog plus an aromatase inhibitor versus the GnRH analog alone and
reported fewer patients developed recurrent pain with combination therapy (7.5 versus 35% during 24
months of follow-up).85 Aromatase inhibitors remain investigational.86

The two most widely used agents are anastrozole (1 mg) or letrozole (2.5 mg) daily. Aromatase
inhibitors cause significant bone loss with prolonged use and cannot be used as single agents in
premenopausal women because they cause multifollicular development. They should only be prescribed
in combination with progesterone (200 mg daily), norethindrone acetate (2.5 mg) or in combination
with a GnRH analog or an oral contraceptive to suppress follicular development.83 There is no evidence
that fertility is improved following treatment of endometriosis with aromatase inhibitors.

SURGERY FOR ENDOMETRIOSIS

In general, principles of surgical management of endometriosis are based on clinical opinion, not on
data from controlled trials. Commonly recommended guidelines include:

1. Before recommending surgery for infertility associated with endometriosis, a thorough infertility
evaluation should be completed.

2. Before surgery, suspected involvement of the gastrointestinal and urinary tract with
endometriotic lesions should be evaluated. If gastrointestinal involvement is suspected,
preoperative bowel preparation should be performed.

3. Schedule surgery in the follicular phase to prevent the corpus luteum from bleeding or
interfering with complete removal of endometriosis.

4. Surgical techniques, including atraumatic tissue handling, prevention of tissue drying, and
minimization of hypoxic tissue, should be employed. Fine sutures and microsurgical instruments
should be used.

5. To the fullest extent possible, all endometriotic lesions should be either surgically excised or
vaporized/fulgurated. Deeply invasive endometriotic lesions should be surgically
excised;superficial peritoneal implants may be either fulgurated or surgically excised.

6. Endometriomas should be excised in their entirety, with preservation of as much normal ovarian
tissue as possible.

7. Pelvic anatomy should be restored to normal and all adhesions excised.

8. If extensive areas of the pelvis become deperitonealized, the surgeon should consider placing an
absorbable oxidized regenerated cellulose barriers (Interceed; Johnson & Johnson, Arlington,
TX) or a GoreTeX (W.L. Gore, Flagstaff, AZ) membrane.87, 88

9. Laparoscopy can be successfully used to treat almost all patients with endometriosis. Because a
surgical procedure such as laparoscopy is required to diagnose endometriosis, it is logical to
attempt surgical treatment using operative laparoscopy at the time of initial diagnosis.
Several studies have reported acceptable pregnancy rates after laparoscopic surgery for
endometriosis.89 Unfortunately, the two randomized, controlled studies on the effectiveness of
laparoscopic conservative surgery in enhancing fertility in women with endometriosis report conflicting
results.19, 20Overall, cumulative pregnancy rates have ranged from 3475% when electrical energy or the
argon laser was used for coagulation of endometriotic implants. In one study, a monthly fecundity rate
of 2.5% after this treatment compared favorably with results after other forms of therapy.90 Pregnancy
rates after CO2 laser vaporization of endometriotic implants have ranged from 25100% for mild, 19
66% for moderate, and 2550% for severe disease.91 Pregnancy rates after laser vaporization do not
appear to be related to the stage of disease, an observation also found with conservative laparotomy.

There are two large studies using the CO2 laser in the treatment of endometriosis-associated
infertility.92, 93 One study used life table analysis and stratified outcome by stage of disease and other
infertility factors.92 The life tables failed to reveal any significant difference in pregnancy rates when
patients were stratified by stage of endometriosis. Monthly fecundity rates in patients treated
exclusively with CO2 laser were 3.5%, 2.5%, and 5.6% with stage I, II, and III endometriosis, respectively.

COMBINATION MEDICAL-SURGICAL THERAPY

Combination medical-surgical therapy for endometriosis consists of either preoperative or postoperative


medical therapy. Preoperative therapy is reported to reduce pelvic vascularity and the size of
endometriotic implants, thus reducing intraoperative blood loss and decreasing the amount of surgical
resection needed. Postoperative medical therapy is advocated to eradicate residual endometriotic
implants. This is applicable to patients with extensive disease in whom resection of all implants is
impossible or inadvisable. Postoperative hormonal therapy has also been recommended to treat
microscopic disease. Although theoretically advantageous, combination medical-surgical treatment
has not consistently been shown to enhance fertility.

The efficacy of preoperative danazol, lynestrenol, gestrinone, and buserelin in the treatment of
endometriosis-associate infertility has been reported.94None of the studies involved randomized control
groups. The overall pregnancy rates are consistent with those after medical or surgical therapy alone.
One nonrandomized study did conclude that preoperative danazol resulted in a higher pregnancy rate
than postoperative danazol.95 The difference, however, was not statistically significant.

One study compared different preoperative medical regimens after staging laparoscopy. Patients with
moderate and severe endometriosis received 6 months of medical therapy with danazol, lynestrenol,
gestrinone, or buserelin.96 Laparotomy with microsurgical resection of the implants was performed, and
patients were followed for 18 months. Twenty patients treated with preoperative buserelin had a
significant reduction in disease severity. The investigators concluded that buserelin afforded significantly
higher pregnancy rates than danazol or progestins, but no significant differences among treatment
groups were demonstrated when correcting for stage of disease.

Studies of the efficacy of postoperative medical therapy have involved conservative surgery using
operative laparoscopy followed by testosterone, estrogen and progestin combinations, danazol,
gestrinone, or lynestrenol.94 Pregnancy rates do not appear to be enhanced with postoperative
pseudopregnancy or testosterone therapy. In contrast, one study reported significantly higher
pregnancy rates in patients treated with conservative surgery and postoperative danazol compared with
surgery alone. Rnnberg and Jrvinen suggested that medical therapy alone was superior for patients
with mild or moderate endometriosis.97 Buttram and associates also were unable to demonstrate
improved pregnancy rates with postoperative danazol compared with surgery alone.95

Telimaa and colleagues evaluated postoperative danazol, medroxyprogesterone, and placebo.98 No


significant differences in pregnancy rates were observed among treatment groups. Chong and
colleagues compared danazol alone, CO2 laser laparoscopy alone, and CO2 laser laparoscopy with
postoperative danazol in infertile patients with minimal endometriosis.99 Pregnancy rates were not
statistically different among the three groups (49%, 45%, and 51%, respectively). In conclusion, there is
only one nonrandomized study in the literature demonstrating that postoperative danazol improves
fertility.100 The preponderance of data suggests no efficacy of preoperative or medical therapy.94, 101

ASSISTED REPRODUCTIVE TECHNOLOGY AND ENDOMETRIOSIS

Dodson and Haney reported success with controlled ovarian hyperstimulation/intrauterine insemination
(COH/IUI) in the treatment of endometriosis-associated infertility.102 They observed monthly fecundity
rates of 0.10% for stage I (n = 263), 0.09% for stage II (n = 146), 0.18% for stage III (n = 51), and 0% for
stage IV (n = 14) endometriosis. Deaton and colleagues, in a randomized controlled trial, compared
clomiphene citrate and IUI with preovulatory intercourse in patients with unexplained infertility and
surgically corrected endometriosis.103 A statistically significant increase in cycle fecundity was seen with
four cycles of clomiphene citrate/IUI compared with controls (0.095 vs. 0.033, respectively). No
difference as seen between patents with explained infertility and those with treated endometriosis.

Chaffkin and colleagues randomized patients to receive either human menopausal gonadotropin (HMG)
with intercourse or HMG with IUI.104 All patients had endometriosis previously treated with laser
laparoscopy. The monthly fecundity rate (0.13%) was greater in the insemination group (n = 109) than in
the intercourse group (mean, 0.07%; n = 76). Fedele and colleagues randomized 40 women with stage I
or II endometriosis and infertility to receive either three cycles of HMG-IUI or no treatment (expectant
management).5 The cycle fecundity was 0.15 in the HMG-IUI group and 0.045 in the untreated group
(p < 0.05). Kemmann and associates reported on the effects of expectant management, clomiphene
citrate, HMG, or IVF/ET on cycle fecundity in women with infertility and minimal or mild
endometriosis.6 The cycle fecundity rates were 0.028, 0.066, 0.114, and 0.22, respectively. The improved
fecundity with HMG and IVF/ET was statically significant. Both of these studies suggest that treatment
for women with infertility and minimal or mild endometriosis should involve a gradual increase in the
intensity of empiric therapy (Table 3).5, 6

Table 3. Effects of treatment of infertility on cycle fecundity in women with stage I and II endometriosis

Study
Treatment Fedele et al Kemmann et al

No treatment 0.045 0.028

Clomiphene 0.066

hMG 0.15 0.114

IVF 0.22

HMG, human menopausal gonadotropins; IVF, in vitro fertilization

There are no large randomized, prospective studies that definitively demonstrate that in IVF/ET or
gamete intrafallopian transfer (GIFT) is more effective than expectant management in the treatment of
infertility associated with endometriosis. In one small randomized trial, 21 women with endometriosis
and infertility were randomized to receive either IVF (n = 15) or expectant (n = 6) management. None of
the women in the expectant management group became pregnant. Five of the 15 women who received
IVF/ET became pregnant (33%, p = NS).105

In women with endometriosis, the stage of the disease and a history of previous bilateral ovarian
surgery may influence the response to IVF/ET. Matson and Yovich analyzed the relationship between the
rate of oocyte recovery, fertilization, and pregnancy during IVF/ET and stage of endometriosis in 154
women with endometriosis.106 Forty women with tubal factor infertility served as a control group. In this
study, the number of oocytes recovered was similar in all the groups: tubal factor, 4.3 oocytes; stage I
endometriosis, 4.2 oocytes; stage II endometriosis, 3.8 oocytes; stage III endometriosis, 3.2 oocytes; and
stage IV endometriosis, 3.1 oocytes. The fertilization rate was similar in all groups. The clinical pregnancy
rate was much lower in the women with advanced endometriosis. The per cycle clinical pregnancy rates
were as follows: tubal factor, 18%; stage I endometriosis, 13%; stage II endometriosis, 8%; stage III
endometriosis, 6%; and stage IV endometriosis, 2%. Similar findings have been observed by other
investigators who have made the additional observations that advanced endometriosis is associated
with a high cycle cancellation rate, a poor estradiol response to gonadotropin stimulation, a decreased
number of oocytes per retrieval, and an implantation inhibitory factor.107, 108, 109

Women with advanced endometriosis and a history of a previous oophorectomy and a contralateral
ovarian cystectomy appear to do very poorly in IVF/ET programs.107 It is possible that the previous
ovarian surgery has depleted the available oocyte pool, making the women perimenopausal. In addition,
women with large endometriomas at the start of an IVF/ET cycle may also be at risk for a poor cycle
outcome.110 It is our recommendation that women with an endometrioma have the ovarian mass
resected before initiation of an IVF/ET cycle.
Several studies suggest that in women with advanced endometriosis, long-term treatment with a GnRH
analog prior to initiation of a cycle may improve fecundity.43, 111, 112 Among patients with severe
endometriosis, 6 months of hormonal suppression with GnRH-a resulted in an increased number of
oocytes retrieved, embryos transferred, and pregnancies. The investigators concluded that long-term
GnRH-a therapy may reduce preclinical abortions in patients with severe endometriosis who are
undergoing IVF/ET.43 Remorgida and colleagues studied the effect of 6 months of GnRH agonist therapy
prior to GIFT in patients with minimal and mild endometriosis.44 No difference in oocyte recovery rates
or quality was noted compared with patients receiving a flare-up stimulation protocol or HMG with
GnRH-a. Pregnancy rates were 55% among 18 women treated with 6 months of GnRH-a before
beginning HMG therapy, 31% among 19 patients receiving the flare-up stimulation protocol, and 33%
among 18 women receiving HMG alone. The difference among groups was not statistically significant.

Two recent studies demonstrated the benefits of prolonged down-regulation with GnRH-a before
initiation of IVF/ET in patients with endometriosis.113, 114 In their prospective, randomized study, Kim and
associates achieved significantly better results in patients with advanced-stage endometriosis (stage III
and IV but not stage I and II) with longer GnRH-a treatment regimen (4 weeks).114 In accumulated
experience with 1047 patients undergoing IVF/ET, pregnancy rates improved significantly with increased
time receiving GnRH-a treatment before IVF/ET.114 These and other studies have suggested that longer
periods of pretreatment with GnRH-a will improve implantation rates in patients with endometriosis
who undertake IVF, although not all studies agree.115, 116, 117

CLINICAL APPROACH TO INFERTILE WOMEN WITH ENDOMETRIOSIS

Planning therapy for an infertile woman with endometriosis requires considerable clinical skill.
Contributing to the difficulty of clinical decision-making is the fact that few randomized prospective
clinical trials of treatment for infertility associated with endometriosis have been reported. A few clinical
rules help guide clinicians in planning therapy for these women.

The most important is that the entire infertility evaluation should be complete, including a semen
analysis, postcoital test, tests of ovulatory function, and documentation of tubal patency. The value of a
careful and complete infertility evaluation cannot be overemphasized.

For infertile women with suspected stage I or stage II endometriosis, a decision must be made whether
to perform laparoscopy before empirical treatment with clomiphene, HMG, or IVF/ET. Expectant
management after laparoscopy is an option for younger women. As discussed previously, the largest
randomized trial suggests that laparoscopic treatment of mild endometriosis improves fecundity,
whereas a similar study with fewer patients shows no benefit of surgery. This should be openly
discussed with the patient when planning a treatment paradigm. Of course, if pain is also a concern,
laparoscopy and surgical treatment would seem prudent. The age of the female partner of the infertile
couple is an important factor in designing therapy. After age 35, there is a significant decrease in
fecundity, and the spontaneous abortion rate significantly increases as women age. The decrease in
fecundity due to the two variables of endometriosis and age may be additive. Consequently, the older
the female partner of an infertile couple, a more aggressive therapeutic plan with COH-IUI or IVF/ET in
lieu of expectant management seems reasonable (Table 4).

Table 4. Treatment of women with infertility and stage I and II endometriosis

Step 1 Identify and treat all reversible causes of infertility in the couple

Step 2 Timed cycles or expectant management

Step 3 Empiric clomiphene treatment with or without IUI

Step 4 Empiric gonadotropin treatment with or without IUI

Step 5 Assisted reproductive technology: IVF, GIFT

IUI, intrauterine insemination; IVF, in vitro fertilization; GIFT, gamete intrafallopian tube transfer.

For infertile women with rAFS stage III or stage IV endometriosis and no other identifiable infertility
factor, conservative surgery, laparoscopy and possible laparotomy should be recommended. Three
studies suggest that surgical therapy may increase fertility in women with advanced endometriosis.
Olive and Lee retrospectively analyzed 130 infertile women treated with expectant management or
surgery, or both.118 In women with mild (Acosta classification) or moderate endometriosis, expectant
management and surgical treatment resulted in similar fecundity.119 In contrast, in women with severe
endometriosis, surgical treatment resulted in statistically significant enhanced fecundity as compared
with expectant management. Of 32 women with severe endometriosis treated with expectant
management, none became pregnant within the 231 cumulative months of follow-up. Of 34 women
with severe endometriosis, 10 became pregnant after surgical management within 702 cumulative
months of follow-up. Garcia and David reported similar findings.120 In another important finding,
Telimaa reported that the surgical removal of an endometrioma may improve fecundity in women with
infertility and endometriosis.121 These studies suggest that surgery plays a role in the treatment of
infertility associated with advanced endometriosis. These studies also suggest that no treatment
(expectant management) has no role to play in the treatment of infertility associated with advanced
endometriosis. Table 4 outlines a treatment plan for women with infertility and advanced
endometriosis. Expectant management is not a good option for women with infertility and advanced
endometriosis.

For infertile women who have stage III or stage IV endometriosis and have previously had one or more
infertility operations, IVF/ET is often a better therapeutic options that another infertility operation.
There is no prospective randomized trial comparing the effect of surgical treatment followed by ART and
ART alone on pregnancy outcome. Pagidas and colleagues evaluated the efficacy of repeat operation of
stage III/IV endometriosis versus IVF/ET.122 In a retrospective study, 23 women with severe
endometriosis underwent IVF/ET and 18 women underwent repeat surgery. They reported a pregnancy
rate after two cycles of IVF/ET of 70%, whereas the cumulative pregnancy rate after repeat operation
during a 9-month period was 24%. They concluded that if initial surgery failed to restore fertility in
patients with moderate to severe endometriosis, IVF/ET is an effective alternative. In summary, there
are limited data available to enable us to estimate the effect of surgical treatment in addition to ART on
the outcome of pregnancy in endometriosis-associated infertility.

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