Endometriosis is a condition defined by the presence of endometrial glandular and stromal tissue in areas outside the uterus.

1. The choice of treatment in endometriosis is
dictated by symptom severity and whether
the patient wishes to conceive. Our Drug
Review describes the surgical diagnosis
and medical and surgical treatment options,
followed by sources of further information
and the Datafile.
Endometriosis is a condition defined by the pres-
ence of endometrial glandular and stromal tissue
in areas outside the uterus. It occurs most frequently
in the pelvic organs and peritoneum and is prevalent
in 2.5-3.3 per cent of women of reproductive age.1
Endometriosis can be a debilitating condition
that has a profound effect on the quality of a
woman’s life, causing untold misery and pain over
many years. However, some women can have the dis-
ease and experience no pain at all. The presence
and amount of ectopic endometrium does not nec-
essarily correlate with the patient’s symptoms: she
may have significant endometriosis and be asymp-
tomatic.
Clearly, endometriosis afflicts women in different
ways in terms of how badly the pelvis is affected, the
type and severity of symptoms, and the effect on health
and quality of life. Treatment must therefore be tai-
lored for each woman individually, taking other fac-
tors such as age, response to previous treatment, and
the desire for pregnancy into account.
www.escriber.com Prescriber 19 December 2006 21
Drug review Endometriosis
Diagnosis and medical
management of endometriosis
SkylineImagingLtd
Alex Swanton MRCOG and Enda McVeigh MPhil, MRCOG

2. Diagnosis
Establishing the diagnosis can be difficult because pre-
sentation is so variable and there is considerable overlap
with other conditions, such as irritable bowel syndrome
and pelvic inflammatory disease. As a result there is often
delay between symptom onset and surgical diagnosis,
and the symptom overlap may lead to referral to non-
gynaecological specialists in the first instance. This may
result in frustration and disillusionment for the patient.
The principal symptoms associated with
endometriosis are dysmenorrhoea, dyspareunia and
pelvic pain. Endometriosis may present with any com-
bination of a number of symptoms; the predictive
value, however, of any one symptom or set of symp-
toms remains uncertain.
Laparoscopy is still the gold-standard diagnostic
test when looking for evidence of all types and stages
of endometriosis. However, diagnostic laparoscopy is
associated with a 0.06 per cent risk of major compli-
cations, eg bowel perforation; this risk is increased to
1.3 per cent in operative laparoscopy. During
laparoscopy disease severity is scored according to the
American Fertility Scoring (AFS) system or, more com-
monly now, the revised AFS (rAFS). A score of I-IV is
allocated based upon the severity of the disease, with
I being mild (see Figure 1) and IV the most severe.
The use of transvaginal ultrasound may be helpful
in the diagnosis of cystic ovarian endometriosis
(endometriomas). These so-called ‘chocolate cysts’
have a ground-glass appearance, which supports the
diagnosis (see Figure 2).
Magnetic resonance imaging (MRI) may also be
useful as a noninvasive tool in diagnosis, particularly
deep endometriosis. While MRI has limitations in the
visualisation of the smallest endometriotic implants
and adhesions, it allows characterisation of the lesions
and the study of extraperitoneal locations and the con-
tents of pelvic masses.
Managing symptoms
Symptomatic endometriosis can be managed either
medically (see Figure 3) or surgically. The choice of
treatment will depend upon factors such as the
woman’s age, fertility plans, previous treatment, the
nature and severity of the symptoms, and the location
and severity of disease (see Table 1). Women with
endometriosis-associated infertility and pain may have
to decide which is the priority, as there is no evidence
that hormonal therapy alone improves fertility.
The rationale behind both surgical and medical
treatment is the removal of the ectopic endometrial
gland. This may, however, be flawed in the case of med-
ical treatment as it is based on the erroneous belief that
ectopic implants may regress, degenerate and ulti-
mately disappear due to an unfavourable hormone
milieu, apparently supported by findings at follow-up
laparoscopies that showed reduction in the rAFS scores.
It is now evident that the difference in the appearance
of the lesions before and at the end of treatment is not
definitive. In fact, implants undergo just partial and
temporary regression but not reabsorption or healing.
Alteration in the hormonal milieu may, however, ren-
der the endometriosis quiescent (and make the patient
amenorrhoeic), and therefore control the symptoms.
The choice of which medical treatment – the
combined oral contraceptive (COC), progestogens,
danazol, gestrinone (Dimetriose) or a gonadotrophin-
releasing hormone (GnRH) agonist – depends prin-
cipally upon their side-effect profile (see Table 2) as
they all relieve pain associated with endometriosis
equally well.2
GnRH agonist therapy given for three months may
be as effective as six months’ treatment in relieving
Figure 1. Laparoscopic examination showing grade I disease
Figure 2. Laparoscopic view showing ‘chocolate cysts’ on an ovary
VM/BVLewis
22 Prescriber 19 December 2006 www.escriber.com
Endometriosis

3. www.escriber.com Prescriber 19 December 2006 23
Endometriosis
endometriosis-associated pain. If longer treatment is
required, GnRH agonist use can be extended safely
with ‘add-back’ HRT, usually a low-dose continuous
combined preparation, or tibolone (unlicensed use).
As outlined above, the diagnosis of endometriosis is
a surgical one. It is therefore probably acceptable to treat
a patient initially on a ‘working diagnosis’ based upon
symptoms. Empirical treatment for pain symptoms pre-
sumed to be due to endometriosis without a definitive
diagnosis includes counselling, adequate analgesia,
nutritional therapy, progestogens or the COC. It is
unclear whether the COC should be taken convention-
ally, continuously or in a tricycle regimen. Combination
of an NSAID with a COC is often very effective.
In patients who have already had a diagnosis of
endometriosis made and who return with a recurrence
of symptoms, then recommencing the COC, perhaps on
a three-monthly continuous regimen, or using a GnRH
agonist is appropriate. The levonorgestrel intrauterine
system may be effective at reducing endometriosis-
associated pain, but there is insufficient evidence to make
recommendations. If these options fail to control the
symptoms, then referral to a gynaecologist is required
and surgical management may be necessary.
Endometriosis and infertility
Although pathologically endometriosis is a benign dis-
order, the endometriotic implants are often associated
with an inflammatory process that may lead to the for-
mation of adhesions and consequent alteration in the
normal anatomic relationship of the affected organs.
It is, therefore, easy to understand how dense adhe-
sions, as seen in rAFS stages III and IV, can cause infer-
tility by anatomical distortion that interferes with
normal tube and ovary function. However, the mech-
anism of infertility in stages I and II is less obvious,
resulting in several possible explanations.
Increased concentrations of prostaglandins in the
pelvis may interfere with ovulation, tubal peristalsis,
corpus luteum function, sperm motility and uterine
contractility, and more recent evidence suggests that
pelvic endometriosis may interfere with implantation
of the blastocyst. Endometriosis is also associated with
a higher concentration of peritoneal macrophages,
which probably increase the likelihood of phagocyto-
sis of the sperm. Altered autoimmunity and deficient
cellular immunity may also be involved.
Medical management
There is no role for hormonal drugs in the treatment
of infertility associated with endometriosis. The ben-
efit, as measured by subsequent pregnancy, of ovarian
suppression with danazol, medroxyprogesterone or
gestrinone vs placebo/no treatment has been assessed
in a Cochrane review of 13 randomised controlled tri-
als (RCTs).3 The common odds ratio for pregnancy
vs placebo was 0.83 (95 per cent CI 0.5-1.39). The ben-
efit of treatment with gestrinone, GnRH agonists or
the COC vs danazol has similarly been assessed: the
common odds ratio vs danazol was 1.20 (95 per cent
CI 0.85-1.68).
continue
if ineffective:
further medical treatment or
definitive surgery
pelvic pain and suspected
endometriosis
normal clinical examination
ineffective
abnormal clinical examination
diagnostic laparoscopy +/-
pelvic ultrasound
for proven endometriosis:
GnRH agonist and add-back
therapy, progestogens, COC,
danazol, gestrinone,
conservative surgery
NSAID or COC
Figure 3. Recommended management of endometriosis presenting with pelvic pain
effective
• age
• fertility status
• previous treatments
• pain symptoms
• priorities (possibility of conceiving vs pain
management with hormones)
• attitudes
• best available evidence
• resources and cost
• other infertility factors
Table 1. Factors determining choice of treatment

4. 24 Prescriber 19 December 2006 www.escriber.com
Endometriosis
It can therefore be argued that more harm than
good can be caused by treatment because of side-
effects and the lost opportunity to conceive in women
whose priority is to solve the infertility. A meta-
analysis of published nonRCTs suggests, however, that
surgical treatment of endometriosis-associated infer-
tility results in higher pregnancy rates than medical
treatment or no treatment at all.
Assisted reproduction
When endometriosis-associated infertility is unex-
plained or a consequence of pelvic distortion, it is
appropriate to utilise assisted reproduction tech-
niques when other treatments or no treatment at all
have been unsuccessful. In women with rAFS stages I
or II with patent, mobile fallopian tubes and ovaries,
intrauterine insemination with or without ovarian
hyperstimulation may be considered.
A systematic review comparing intrauterine insemi-
nation and ovarian hyperstimulation to no treatment did
not reveal any improvement in outcome. However, two
large RCTs on the use of ovarian stimulation with intra-
uterine insemination in subfertile women with minimal
or mild endometriosis showed significantly better preg-
nancy rates. The evidence from these studies suggests
that ovarian hyperstimulation using gonadotrophins with
intrauterine insemination is better than no treatment or
intrauterine insemination alone for these women.
A meta-analysis of all published studies analysing
the outcome following in-vitro fertilisation in women
with endometriosis (1070 cycles) compared to those
with tubal infertility (2619 cycles) showed that preg-
nancy rates per cycle were significantly lower in the
endometriosis group (26 vs 36 per cent, p<0.005).
However, analysis of large databases indicates that
there is no difference in outcome.
Severe cases of endometriosis should be referred
to centres of excellence where relevant clinical exper-
tise is available. The role of patient support groups in
management should also be borne in mind.
Endometriosis after hysterectomy
There is very little, if any, evidence to suggest that
endometriosis may be ‘reactivated’ in women following
a hysterectomy and bilateral salpingo-oophorectomy
who commence HRT. However, in keeping with a pre-
cautionary principle, an opposed HRT, either sequen-
tial or continuous combined, should be used.
Conclusions
Endometriosis is a common condition affecting
women of reproductive age. Diagnosis may be sus-
pected by the presence of a number of symptoms but
can only be confirmed by surgery.
The management of endometriosis-associated pain
usually needs to be multifaceted with surgery being
an important, but not the only, component. Symptoms
may be controlled with medical therapy; however, this
is not curative and should not be used in women who
are trying to conceive. A comprehensive long-term
management plan incorporating various treatment
modalities should be developed to optimise each
patient’s management with respect to pain, pelvic
masses and reproductive goals.
Surgical management is designed to remove the
ectopic endometrial tissue and achieve normal pelvic
anatomy. The simple removal of superficial peritoneal
endometriosis appears to improve both pain and fecun-
dity. The surgical management of advanced endometrio-
NSAIDs, eg mefenamic acid gastric irritation
combined oral nausea, migraines,
contraceptives increased risk of
thromboembolism
progestogens, eg fluid retention, bloating
norethisterone and breast tenderness
synthetic androgens, eg androgenic, eg acne,
danazol weight gain
gonadotrophin-releasing menopausal symptoms,
hormone agonists osteoporosis (these can
be countered by ‘add-
back’ therapy with HRT)
Table 2. Potential side-effects of drugs used in endometriosis
Drug treatment Side-effects
• the choice between the COC, progestogens, danazol
and GnRH agonists depends principally upon their
side-effect profiles because they relieve pain
associated with endometriosis equally well
• there is no role for medical therapy with hormonal
drugs in the treatment of endometriosis-associated
infertility
• if a woman is not trying to conceive and there is no evi-
dence of a pelvic mass on vaginal examination, there
may be a role for a therapeutic trial of a COC (monthly
or tricycling) or a progestogen to treat pain and symp-
toms suggestive of disease without performing a
diagnostic laparoscopy first
Key points

5. sis and rectovaginal endometriosis should be carried out
in centres that have a particular expertise in this area.
References
1. Houston DE, et al. Incidence of pelvic endometriosis in
Rochester, Minnesota, 1970-1979. Am J Epidemiol 1987;12:
959-69.
2. Prentice A, et al. Gonadotrophin-releasing hormone ana-
logues for pain associated with endometriosis (Cochrane
Review). In: Cochrane Library, Chichester: John Wiley &
Sons Ltd, Issue 2, 2004.
3. Hughes E, et al. Ovulation suppression vs placebo in the
treatment of endometriosis (Cochrane Review). In:
Cochrane Library, Oxford: Update Software, Issue 3, 1999.
Dr Swanton is a research fellow in reproductive medicine
at the University of Oxford, and Mr McVeigh is consultant
obstetrician and gynaecologist and a subspecialist in
reproductive medicine and surgery at the John Radcliffe
Hospital, University of Oxford
www.escriber.com Prescriber 19 December 2006 25
Endometriosis
Resources
Further reading
The investigation and management of endometriosis. Royal
College of Obstetricians and Gynaecologists Green-
top Guideline No. 24, October 2006.
Groups and organisations
Royal College of Obstetricians and Gynaecologists, 27 Sussex
Place, Regent’s Park, London NW1 4RG. Tel: 020 7772
6200; fax: 020 7723 0575; website: www.rcog.org.uk.
Endometriosis UK (formerly National Endometriosis
Society), 50 Westminster Palace Gardens, Artillery Row,
London SW1P 1RR. Tel: 020 7222 2781; fax: 020 7222
2786; website: www.endo.org.uk; e-mail: enquiries@
endometriosis-uk.org. Runs a national patient
helpline (tel: 0808 808 2227 between 7 and 10pm).
Women’s Health Concern, Whitehall House, 41
Whitehall, London SW1A 2BY. Tel: 020 7451 1377; fax:
020 7925 1505; website: www.womens-health-
concern.org. The helpline (tel: 0845 123 2319)is run
by nurse counsellors to provide up-to-date informa-
tion on women’s health issues.
Patient information
Patient UK: www.patient.co.uk.
GnRH analogues
buserelin Suprecur 150µg per dose nasal spray 150µg in each nostril 3 times daily £76.60
goserelin Zoladex 3.6mg single-dose syringe 3.6mg sc implant every 28 days £84.14
for max. 6 months
leuprorelin Prostap SR 3.75mg powder in vial plus 3.75mg sc or im every month £125.40
diluent for max. 6 months
Prostap 3 11.25mg powder in vial 11.25mg im at 3-month intervals £125.40
plus diluent
nafarelin Synarel 200µg per dose nasal spray 200µg twice daily in alternate nostrils £51.95
triptorelin Decapeptyl SR 3mg microsphere in vial 3mg im every 28 days £69.00
plus diluent
11.25mg microsphere in 11.25mg im every 3 months £69.00
vial plus diluent
Gonapeptyl 3.75mg powder plus diluent 3.75mg sc every 28 days £85.00
in pre-filled syringe
Gonadotrophin release inhibitors
danazol Danol 100mg, 200mg caps 200-800mg daily for 3-6 months £15.75-£63.00
danazol 100mg, 200mg caps £19.61-£78.43
gestrinone Dimetriose 2.5mg caps 2.5mg twice weekly £103.91
Datafile: Drugs used in endometriosis
Drug Available as Strength/form Adult maintenance dosage Cost1
1NHS cost of 28 days’ treatment at usual adult maintenance dosage. Prices MIMS/Drug Tariff November 2006

6. 26 Prescriber 19 December 2006 www.escriber.com
Endometriosis
Progestogens
dydrogesterone Duphaston 10mg tabs 10mg 2-3 times daily on days 5-25 £2.83-£5.66
of cycle or continuously
medroxy- Climanor 5mg tabs 10mg 3 times daily for 90 consecutive £19.62
progesterone Provera 10mg tabs days £20.77
norethisterone Primolut N 5mg tabs 5mg twice daily £3.75
Utovlan 5mg tabs 5mg 3 times daily for min. 6 months £3.92
norethisterone 5mg tabs £9.13
Drugs used in endometriosis (cont.)
Drug Available as Strength/form Adult maintenance dosage Cost1
1NHS cost of 28 days’ treatment at usual adult maintenance dosage. Prices MIMS/Drug Tariff November 2006