Letrozole in Endometriosis

Letrozole in Endometriosis
Dr Sujoy Dasgupta
MBBS (Gold Medalist, Hons)
MS (OBGY- Gold Medalist)
DNB (New Delhi)
MRCOG (London)
Advanced ART Course for Clinicians (NUHS, Singapore)
Consultant: Reproductive Medicine, Genome Fertility Centre, Kolkata
• Managing Committee Member, Bengal Obstetric & Gynaecological Society
(BOGS)- 2019-20
• Secretary, Subfertility and Reproductive Endocrinology Committee, BOGS-
2019-20
• Winner, Prof Geoffrey Chamberlain Award, RCOG World Congress,
London, 2019

ENDOMETRIOSIS is a
chronic, estrogen-dependent,
inflammatory,
painful disorder in which
endometrial tissue grows
outside the uterus.
• Most commonly involves
ovaries, fallopian tubes and
tissue lining the pelvis as
well as bladder, bowel,
vagina or rectum.
• This endometrial tissue
thickens and bleeds, just as
normal endometrium does
during menstrual cycle.

•Occurs in 6–10% of women of reproductive age,
with a prevalence of 38% in infertile women, and
in 71–87% of women with chronic pelvic pain
•Improved recognition of endometriotic lesions may
have led to an increase in detection rate
CONFIDENTIAL;for internal useonly

Prevalence of endometriosis
in India
The Endometriosis Society of India estimates that 25 million
i.e about 35% Indian women suffer from this condition.
 India : Most affected country
 Urban India : stress and lifestyle choices
 The Endometriosis Society : five schools
in Kolkata : 5% of the girls below 18 who
complained of dysmenorrhea

COMMON
ENDOMETRIOSIS
SYMPTOMS
With many women,
progression is slow,
developing over many
years

1. Endometriosis may be a diagnosis of exclusion
2. A significantnumber of womenwithendometriosis remainasymptomatic
Therefore, DIAGNOSIS of endometriosis in awomanwithpelvicpain is often
delayed& stretches over several years!

Differential Diagnosis
Dysmenorrhea
• Primary
• Secondary(e.g., adenomyosis,myomas,infection,cervical
stenosis)
Dyspareunia
• Diminished lubricationorvaginal expansionbecauseof
insufficientarousal
• Infection(PID)
• Vaginigmus
Generalized pelvic pain
• Endometritis
• Neoplasms,benign or malignant
• Non-gynecologiccauses
• Ovariantorsion
• Pelvic adhesions
• Pelvic inflammatorydisease
• Sexualorphysicalabuse
• Gastrointestinalcauses(e.g., constipation,irritablebowel
syndrome)
• Infection
• Musculoskeletalcauses(e.g., pelvic relaxation,levator spasm)
• Pelvic vascularcongestion
• Urinarycauses(e.g., urethralsyndrome,interstitialcystitis)

DIAGNOSIS OF ENDOMETRIOSIS
Clinicians should consider the diagnosis of
endometriosis
in the presence of gynecological symptoms-
 Dysmenorrhea
 non-cyclical pelvic pain
 deep dyspareunia
 Infertility
 fatigue
in women of reproductive age with non-
gynecological cyclical symptoms
 Dyschezia
 rectal bleeding
 Dysuria
 Hematuria
 shoulder pain

Impact of endometriosis in different
patients
Unmarried women
• Chronic pelvic pain
• Presents with signs of
physiological suffering thus
affecting the
• Quality of life.
• 25-30% presenting with
chronic pelvic pain will have
endometriosis
Married women
• Infertility
• Infertility
couples(asymptomatic) upto
50% would be silent
sufferers of endometriosis.
• Endometriosis makes
conception difficult.
Post menopausal women
• Endometriosis affecting post
menopausal women is rare
and can affect between 2%-
6% of postmenopausal
women.
• Although rare, it confers a risk
of recurrence and malignant
transformation

Quality of Life
• Work
• Education
• Relationships
• Social functioning
• Reduced work effectiveness
• Depressive symptoms
• Anxiety
As symptoms become more severe, quality of life isreduced further.
Endometriosis places a considerable economic
burden on families and on society. Delays in
diagnosis, high rates of hospital admission,
surgical procedures, and incidences of comorbid
conditions contribute to make endometriosis a
more costly public health problem than other
chronic conditions such as migraine and
Crohn’s disease.

There is NO permanent cure for endometriosis
• As stated by ASRM, “Endometriosis shouldbe viewed asa chronicdisease that requiresa life-long
management plan with the goal ofmaximizing the use ofmedical treatment and avoiding repeated surgical
procedures”
• No single treatment is ideal for allpatients, management chosenshould bedirected to individual needs of
each patient
• Combination therapy may be ideal; as it is a chronicdisease, we should consider not only efficacy but also
long-term safety and tolerability oftreatment options.
• Long-term treatment / repeated coursesowing to frequentrecurrenceofpain within 6-12 monthsof
completing treatment course(within 5 yearsin about half ofwomen)

ETIOLOGY
Risks factors:
Family history of endometriosis
Early age of menarche
Short menstrual cycles (< 27 d)
Long duration of menstrual flow (>7 d)
Heavy bleeding during menses
Delayed childbearing
Defects in the uterus or fallopian tubes

Visceral Hypersensitivity
• Thresholdsfor pain in
endometriosis groups were
found to be similar to those in
the IBS group

Types of endometriosis
• Peritoneal endometriosis
They are endometriotic implants on the surface of the surface of pelvic peritoneum and ovaries.
• Endometriomas
They are ovarian cysts lined by endometrioid mucosa.
• Rectovaginal endometriotic nodules
It is a complex solid mass comprised of endometriotic tissue blended with adipose and
fibromuscular tissue, residing between the rectum and the vagina.
•Adenomyosis (Endometriosis Interna)
Endometriosis in the myometrium (Musculature of the uterus)
•Extragenital endometriosis
Scar tissue, pleura, omentum, lungs, limbs

The NEW ENGLAND JOURNAL of MEDICINE
REVIEW ARTICLE
Endometriosis
MECHANISMS OF DISEASE
Sedar E. Bulun, M.D.
Endometriosis is an estrogen-dependent
inflammatory disease

Follicular physiology – Ovary - Estrogen
Theca cells
LH
FSH
Granulosa cells
Aromatase
Estrogen
Aromatase Inhibitors
Aromatase
1. Ovary
2. Adipose tissue
3. Brain
androsterone

Normal endometrium & endometriosis
Estrogen is not produced locally, owing to the
absence of aromatase.
Normal endometrium
COX-2 - Cyclooxygenase-2
PGE2
Detectable aromatase activity
Endometriosis
COX-2
PGE2
• High aromatase activity endometrial and
endometriotic tissues
• Severe menstrual cramps and chronic pelvic
pain.
Ectopic endometriosis
full-blown molecular abnormalities
COX-2
PGE2

Complex interaction between aberrant endometrial GENESexpression & altered
HORMONALresponse
Overproduction of
PROSTAGLANDINS by anincreased
COX-2 activity
Overproduction of ESTROGEN by
increased aromatase activity
ENDOMETRIAL LESIONS proliferate  release macrophages and proinflammatory cytokines in
peritoneal fluid inflammation, adhesions, fibrosis, scarring, anatomicaldistortions Pain &
Infertility
1 2

Estradiol also specifically fuels these types of pain through its effects on the
endometriotic tissue
• Estradiol induces COX-2, which increases production of prostaglandin
E2 (PGE2)
• PGE2 directly causes pain and inflammation
• PGE2 in turn leads to increased aromatase, resulting in increased local
estradiol production
Positive feedback loop
is created.

Diagnosis ofEndometriosis
• Clinicalexamination
• CA-125
• TVS
• MRI
• Laparoscopy

NICE, 2017
• Do not exclude the possibility of endometriosis if the abdominal
or pelvic examination, ultrasound or MRI are normal. If
clinical suspicion remains or symptoms persist, consider referral
for further assessment and investigation.

Gold Standard
•The combination of laparoscopy and the histological verification of endometrial
glands and/or stroma
•In many cases the typical appearances of endometriotic implants in the abdominal
cavity are regarded as proof that endometriosis is present.
•Consider laparoscopy to diagnose endometriosis in women with suspected
endometriosis, even if the ultrasound was normal. (NICE, 2017)
•A negative diagnostic laparoscopy (i.e. a laparoscopy during which no endometriosis
is identified) seems to be highly accurate for excluding endometriosis and is
therefore of use to the clinician in aiding decision-making. (ESHRE, 2013)

Standard procedure
A good quality laparoscopy should include systematic checking of
•1) the uterus and adnexa,
•2) the peritoneum of ovarian fossae, vesico-uterine fold, Douglas and pararectal
spaces,
•3) the rectum and sigmoid (isolated sigmoid nodules),
•4) the appendix and caecum and
•5) the diaphragm.
•6) speculum examination and palpation of the vagina and cervix under laparoscopic
control, to check for 'buried' nodules.
•A good quality laparoscopy can only be performed by using at least one secondary port
for a suitable grasper to clear the pelvis of obstruction from bowel loops, or fluid suction to
ensure the whole pouch of Douglas is inspected.
•By a gynaecologist with training and skills in laparoscopic surgery for endometriosis

Biopsy
to confirm the diagnosis of endometriosis (be aware that a
negative histological result does not exclude endometriosis)
to exclude malignancy
1. if an endometrioma is treated but not excised
2. deep infiltrating disease

Stage 1: Lesions are minimal &
isolated
Stage 2: Lesions are mild - may be
several; adhesions are possible.
Stage 3: Lesions are moderate, deep
or superficial with clear adhesions
Stage 4: Lesions are multiple &
severe, both superficial & deep, with
prominent adhesions.
ASRM classification
of endometriosis

Stage is based on location, amount, depth
& size of endometrial tissue
Criteria - Extent of spread of tissue; Involvement of pelvic structures in
disease; Extent of pelvic adhesions; Blockage of fallopian tubes
Limitations - not a good predictor of pregnancy, does not correlate well with
the symptoms of pain and dyspareunia or infertility.
E.g. Woman in stage 1  tremendous pain, while
Woman in stage 4  asymptomatic.

NICE, 2017
• Offer endometriosis treatment according to the woman's
symptoms, preferences and priorities, rather than the stage
of the endometriosis.

Is Laparoscopy is a MUST?
•Empirical treatment can be started without a definitive diagnosis-
1. if signs of deep endometriosis or ovarian endometriosis are not present in
physical examination and imaging.
2. young adolescents or in women that decide not to have a laparoscopy solely
to know if the disease is there.
•Even if peritoneal disease is found it might not be the cause of pain
•Treatment of peritoneal disease does NOT influence the natural course of
the disease.
• If medical pain treatment relieves pain, many women will not be interested
whether or not their pain symptoms were due to peritoneal endometriosis.

Management of endometriosis
• Surgical management
1. Conservative surgery (preferably laproscopy)
2. Hysterectomy (laparoscopy/ laparotomy)
• Medical management
1. NSAIDS
2. GnRh analogs
3. Continuous combined oral contraceptives (COC)
4. Progestins- oral, injectable, Mirena (IUD)
5. Antiprogestins- Danazol

Patient's age
Pain symptoms
Extent of disease
Patient's
reproductive
plans
Treatment risks
Side effects
Cost
considerations
CHOICE OF
TREATMENT

Presented with Pain only, fertility is
not an immediate concern
NSAIDs
Pain NOT resolved
Hormonal treatment
Pain Not resolved
Ovarin endometrioma ≥3 cm
Laparoscopy
Pain resolved
Follow up
Pain resolved
Follow up

Presented with Pain only, fertility is
not an immediate concern
NSAIDs
Pain NOT resolved
Hormonal treatment
Pain Not resolved
Ovarian endometrioma ≥3 cm
Laparoscopy
Pain resolved
Follow up
Pain resolved
Follow up

Empirical treatment of pain
•Counsel women with symptoms presumed to be due to endometriosis
thoroughly, and to empirically treat them with adequate analgesia,
COC or progestagens.
•Before starting empirical treatment, other causes of pelvic pain
symptoms should be ruled out, as far as possible.
•Response to hormonal therapy does NOT always predict the presence
or absence of endometriosis.

Analgesics
• Consider a short trial (for example, 3 months) of paracetamol
or a NSAID alone or in combination for first-line management
of endometriosis-related pain
• If a trial of paracetamol or an NSAID (alone or in combination) does
not provide adequate pain relief, consider other forms of pain
management and referral for further assessment.

Hormonal therapies
•Clinicians are recommended to prescribe hormonal treatment [hormonal
contraceptives, progestagens, antiprogestagens, or GnRH agonists] as one of the
options, as it reduces endometriosis-associated pain
• Explain to women that hormonal treatment for endometriosis can reduce pain and
has no permanent negative effect on subsequent fertility.
•No overwhelming evidence to support particular treatments over other.
Medical treatments listed above, do not eliminate the extra-uterine tissue
growth, they just reduce the symptoms.

Combined hormonal contraceptives
 COC, vaginal contraceptive ring or a transdermal (estrogen/progestin) patch-
-Reduce endometriosis-associated
1. Dyspareunia
2. dysmenorrhea (continuous use of a CHC)
3. non-menstrual pain
• The vaginal ring reduced dysmenorrhea significantly more in patients with
RV endometriosis compared to women in the patch group.

Progesterone, Antiprogesterone
 progestagens [medroxyprogesterone acetate (oral or depot),
norethisterone acetate, dienogest, cyproterone acetate]
 anti-progestagens (gestrinone, danazol)
• Danazol should not be used if any other medical therapy is available.
Recent studies indicate that vaginal danazol may be better tolerated.
• LNG-IUS is particularly suited for deep RV endometriosis

GnRH Agnosists
 Evidence is limited regarding dosage or duration of treatment
 Acts by downregulating the pituitary
 Clinicians are recommended to prescribe hormonal add-back therapy to
coincide with the start of GnRH agonist therapy, to prevent bone loss and
hypoestrogenic symptoms during treatment. This is NOT known to reduce
the effect of treatment on pain relief
 careful consideration to the use of GnRH agonists in young women and
adolescents, since these women may not have reached maximum bone density.
•GnRHa is more effective than placebo but inferior to the LNG-IUS or oral
danazol.
• No difference in effectiveness exists when GnRHa is administered IM/ SC/
intranasally.

Drawbacks Of Conventional Medical
Management
• Medical treatments usually are directed at :
Inhibiting estrogen
production from the ovaries
Do not address local estrogen
biosynthesis by the aromatase
enzyme in endometriotic lesions.
Half of the patients : Refractory.
hypoestrogenic state
Potential side effects.

Surgery as a mode of treatment
 When endometriosis is identified at laparoscopy, clinicians are
recommended to surgically treat endometriosis, as this is effective for
reducing endometriosis-associated pain i.e. ‘see and treat’
• Operative laparoscopy (excision/ablation) is more effective for the
treatment of pelvic pain associated with all stages of endometriosis,
compared to diagnostic laparoscopy only

Surgery for Peritoneal Endometriosis
• Ablation and excision of peritoneal disease are thought to be
equally effective for treatment of endometriosis-associated pain.
•Excision of lesions could be preferred with regard to the
possibility of retrieving samples for histology.
• ablative techniques are unlikely to be suitable for advanced
forms of endometriosis with deep endometriosis component.

Surgery for ovarian endometrioma
• When performing surgery in women with ovarian endometrioma (≥3 cm)
• perform cystectomy instead of drainage and coagulation/ CO2 laser
vaporization- as cystectomy
1. reduces endometriosis-associated pain
2. increases spontaneous pregnancy rates
3. a lower recurrence rate of the endometrioma

Surgery for deep endometriosis
 surgical removal of deep endometriosis, reduces endometriosis-associated pain and improves quality of life-
 in a MDT context
 associated with significant complication rates, particularly when rectal surgery is required.
Colorectal involvement –
•Laparoscopy was as effective as laparotomy
•superficial shaving, discoid resection and segmental resection of the bowel to remove the deep endometriosis nodules.
•It was impossible to make comparisons between different surgical techniques.
Bladder endometriosis
• excision of the lesion and primary closure of the bladder wall
Ureteral lesions
• may be excised after stenting the ureter
• segmental excision with end-to-end anastomosis
• reimplantation

Surgical interruption of pelvic nerve pathways
 Clinicians should not perform LUNA as an additional procedure to
conservative surgery to reduce endometriosis-associated pain
 Clinicians should be aware that presacral neurectomy (PSN) is effective
as an additional procedure to conservative surgery to reduce
endometriosis-associated midline pain, but it requires a high degree of
skill and is a potentially hazardous procedure -
bleeding, constipation, urinary urgency and painless first stage of
labour.

Hysterectomy
 consider hysterectomy with removal of the ovaries and all visible
endometriosis lesions, in women who have completed their family and failed
to respond to more conservative treatments.
 Women should be informed that hysterectomy will not necessarily cure the
symptoms or the disease.
• five studies on the effect of hysterectomy on chronic pelvic pain : 3%–17% of
women reported recurrence of pain 1 year after surgery.
• Hysterectomy with ovarian conservation was reported to have a risk for
development of recurrent pain and a greater risk of reoperation.

Preoperative hormonal therapies
 Clinicians should not prescribe preoperative hormonal treatment to improve the outcome of
surgery for pain in women with endometriosis
•In clinical practice, surgeons prescribe preoperative medical treatment with GnRH analogues as
this can facilitate surgery due to reduced inflammation, vascularisation of endometriosis lesions
and adhesions. However, there are no controlled studies supporting this (ESHRE, 2013)
•Consider GnRH agonist x 3 cycles before surgery for deep infiltrating endometriosis
(NICE, 2017)
• From a patient perspective, medical treatment should be offered before surgery to women with
painful symptoms in the waiting period before the surgery can be performed, with the
purpose of reducing pain before, not after, surgery.

Postoperative hormonal therapies
Short Term (<6 months)
 Do not prescribe
adjunctive hormonal
treatment after
surgery, as it does
not improve the
outcome of surgery
for pain
Long term (>6 months)- Sec Prevention
 role for prevention of recurrence of disease and painful
symptoms in women surgically treated for endometriosis.
 there are limited data
 After cystectomy for ovarian endometrioma in women not
immediately seeking conception, prescribe hormonal
contraceptives
 Deep endometriosis- prescribe postoperative use of a LNG-IUS
or a COC (continuous/ cyclic) for at least 18–24 months, as
one of the options for the secondary prevention of endometriosis-
associated dysmenorrhea, but not for non-menstrual pelvic pain
or dyspareunia
 postoperative pain recurrence is not different in women
receiving GnRH agonists, danazol or MPA or pentoxifylline,
when compared to placebo

Risks associated with surgical treatment
1. Complete excision of endometriotic tissue not possible
2. Invasive procedure and chances of damaging the surrounding
organs increases.
3. Chances of damage to the reproductive organs thus leading to
infertility.
4. Needs skill

Pain due to extragenital endometriosis
 surgical removal is the treatment of choice for symptomatic extragenital
endometriosis
 Diagnosis is usually made by histological confirmation, which is
important to exclude other pathology, particularly malignancy.
 When surgical treatment is difficult or impossible, clinicians may
consider medical treatment of extragenital endometriosis to relieve
symptoms

Causes of Infertility
Unexplained
10%
Endometriosis
25%
Tubal Factor
15%
Ovulation
20%
Male Factor
30%
Diagnosis

Subfertility
• About 1/3rd of women with endometriosis also suffer from subfertility.
• Endometriosis does not equal infertility. It just implies that some women may
have a harder time becoming pregnant.
• Endometriosis causes adhesions and scar tissue which cause the internal organs
to get stuck to each other.
• Once the endometriosis is treated then women can usually conceive naturally
without any assisted reproductive techniques.

Endometriosis and Infertility
• Distorted Pelvic Anatomy.
• Altered Peritoneal Function.
• Hormonal and Ovulatory Abnormalities.
• Impaired Implantation (challenged based on b-3 integrin research)
• Oocyte and Embryo Quality.
• Abnormal Uterotubal Transport.

Unexplained Infertility
• 10-20% of infertile couples
• Reflects an incomplete fertility evaluation
• Many cases represent undiagnosed endometriosis
• Can lead to empiric and costly therapies that may costly therapies that
may be effective

French Study
63% Endometriosis
Eur J Obstet Gynecol Reprod Biol. 2012
Time to Treat
Undiagnosed Endometriosis
In
Unexplained Infertility
Leads to
Recurrent Implantation Failures
Belgium Study
47% endometriosis
Fertility & Sterility Vol. 92, 1, July 2009

Endometriosis and IVF Failure
• Repeated, unexplained IVF failure patients exist in most practices
• IVF centers may not the inclination or skills to diagnose endometriosis
• Studies have suggested endometrial receptivity defects
• Meta-analyses suggest IVF is affected by endometriosis (Barnhart
et al., F&S 2002)
• Brosens suggested aromatase expression is a marker of poor IVF performance
(Brosens et al., HR, 2004)

Molecular expression - Implantation
• Aromatase present in Endometrium of women with endometriosis.
(Noble et al 1995)
• B-3 integrin expression is aberrant in endometrium of women with
endometriosis (Lessey et al 1996)
Implantation Requires Synchrony
• Delayed implantation - leads to miscarriage
• Miscarriage goes up with each day of delay
• Clinical evidence for the window of implantation

Implantation window
• The reception-ready phase of the endometrium of the uterus is usually termed the
"implantation window" and lasts about 4 days.
• The implantation window occurs around 6 days after the peak in luteinizing
hormone levels.
• days 6-10 postovulation
• 20th to the 23rd day after the last menstrual period

Presented with Infertility
Fertility factors Evaluation (Ovarian reserve, tube, semen)
Natural conception is possible
Severe Pain
Laparoscopy
Grade 4
Endometriosis
IVF
Grade 1-3 Enometriosis
OI/ IUI 4-6 cycles
No pregnancy within 6-12 months after Lap
IVF
Prev Surgery
High Age
Large cyst
Offer egg/ embryo
freezing (IVF)) before Lap
No Pain
Ovulation Induction (OI) 4-6 cycles
IUI 3-6 cycles
IVF
Needs IVF
(Male Factor, tubal factor, poor ovarian reserve)
IVF
Egg collection
Freeze all
GnRH Agonists- 3-6
Frozen embryo transfer
Laparoscopy for pain/
large cysts
Laparoscopy ONLY for pain/
inaccessible ovaries

Presented with Infertility
Fertility factors Evaluation (Ovarian reserve, tube, semen)
Natural conception is possible
Severe Pain
Laparoscopy
Advanced
Endometriosis
IVF
Early Enometriosis
OI/ IUI 4-6 cycles
No pregnancy within 6-12 months after Lap
IVF
Prev Surgery
High Age
Large cyst
Offer egg/ embryo
freezing (IVF)) before Lap
No Pain
Ovulation Induction (OI) 4-6 cycles
IUI 3-6 cycles
IVF
Needs IVF
(Male Factor, tubal factor, poor ovarian reserve)
IVF
Egg collection
Freeze all
GnRH Agonists- 3-6
Frozen embryo transfer
Laparoscopy for pain/
large cysts
Laparoscopy ONLY for pain/
inaccessible ovaries
Laparoscopy

Analgesics
• NSAIDs must be avoided around the time of ovulation

NICE, 2017
• Do not offer hormonal treatment to women
with endometriosis who are trying to
conceive, because it does not improve
spontaneous pregnancy rates.
85

Hormonal therapies
•Pregnancy is not possible/contraindicated during hormonal
therapy
•hormonal treatment for suppression of ovarian function does not
improve the chance of natural conception
•Only indicated- if wants to delay Laparoscopy/ IVF and the
pain is severe

Surgery for Peritoneal Endometriosis
• Both ablation and excision improve the chance of spontaneous
conception in ASRM stage I/II endometriosis (CO2 laser vaporization >
monopolar electrocoagulation)
• Complete surgical removal before ART- ?

Surgery for ovarian endometrioma
• Cystectomy improves the chance of spontaneous conception, but
NOT the success of ART
• clinicians counsel regarding the risks of reduced ovarian
function after surgery and the possible loss of the ovary. The
decision to proceed with surgery should be considered carefully
if the woman has had previous ovarian surgery.

Surgery for deep endometriosis
In women with infertility and severe pelvic pain who are resistant to
medical treatment or severe bowel stenosis,
radical excision of endometriosis combined with bowel segmental
resection and anastomosis was associated with
a higher postoperative spontaneous pregnancy rate
•Role before ART- ?

Postoperative hormonal therapies
 Do not prescribe adjunctive hormonal treatment after surgery, in
women trying for pregnancy

Surgical therapies as an adjunct to ART
In infertile women with endometrioma > 3 cm
• there is no evidence that cystectomy prior to treatment with ART
improves pregnancy rates.
• only to consider cystectomy prior to ART to improve
1. endometriosis-associated pain
2. the accessibility of follicles.

Aromatase Inhibitor
Letrozole
A Game Changer
• Failure of current medical and surgical treatments to relieve
pain leads to target the aromatase molecule in endometriosis by
using Aromatase Inhibitor.
• The rationale is that continued local estrogen production in
endometriotic implants during other medical treatments (e.g.,
GnRH analogues) was, in part, responsible for resistance to these
treatments.

Aromatase Inhibitors (ESHRE 2015)
In women with pain from RV endometriosis refractory to other medical or
surgical treatment
consider prescribing aromatase inhibitors in combination with COC,
progestagens, or GnRH analogues, as they reduce endometriosis-
associated pain
•The side effects are mostly hypoestrogenic in nature
•The evidence on the long-term effects is lacking.

1. Pain Management & lesion size:
• Letrozole have successfully treated pelvic pain and significantly
reduced the lesion size.
2. In premenopausal women:
• In premenopausal women, an Aromatase Inhibitor alone may induce
ovarian folliculogenesis, and thus Aromatase Inhibitor are combined with
a progestin, a combination oral contraceptive, or a GnRH analogue.
3. Side-effect profile: The side-effect profile of Aromatase Inhibitor
administered in combination with an oral contraceptive or a progestin is
remarkably benign. : mild headache, nausea, and diarrhea. Compared
with the case of GnRH analogues, hot flashes are milder and infrequent.
Aromatase Inhibitor
Letrozole
AGame Changer

Aromatase inhibitors with Progestins
resistant to existing medical and surgical treatments of
endometriosis
• Premenopausal patients (10) resistant to existing medical and surgical
treatments of endometriosis
• Dosage : AI (letrozole; 2.5 mg) + Progestin (norethindrone acetate; 2.5
mg) daily for 6 months.
• Outcome : Pelvic pain scores & American Society for Reproductive
Medicine laparoscopic scores decreased significantly .
• 9 of 10 patients responded to this regimen with decreased pelvic pain.
• No significant bone loss was detected, and no evidence of ovarian
enlargement was found.
• These results were suggestive that the addition of a progestin (norethindrone
acetate) in moderate doses to an AI suppresses gonadotropins sufficiently in
the majority of premenopausal patients with endometriosis.

Aromatase inhibitors with Progestins

Before treatment with
inhibitors of aromatase
Maria Yarmolinskaya
After treatment with
inhibitors of aromatase

Endometrial receptivity defects during IVF cycles with and
without letrozole
Paul B. Miller Brent A. Parnell Greta Bushnell Nicholas Tallman David A. ForsteinH. Lee Higdon, III Jo
Kitawaki Bruce A. Lessey
• Aim was to study ways to improve IVF success rates in women
with suspected endometrial receptivity defects.
• Effect of letrozole - 5 mg on Days 5–9 of stimulation (aromatase
inhibitor) on integrin expression as a marker of endometrial
receptivity.
• IVF outcomes in 97 infertile women who had undergone ανβ3
integrin assessment
• Unexplained IVF failure in a subset of women with endometriosis
may be avoidable using a simple 5-day treatment of the
aromatase inhibitor, letrozole.

Ongoing pregnancy rate
• Ongoing pregnancy rate in women undergoing IVF
with positive (black) or negative integrins (white). In
standard IVF protocols women with a negative
integrin test had a significantly worse outcome than
those who tested positive (P , 0.02). In integrin-
negative women who underwent IVF with letrozole
(2.5–5 mg/day on Days 2–6), outcomes were similar
to integrin-positive women in non-letrozole cycles.

Are we delivering the embryo
at the wrong time?
Dr Samir Hamamah
Endometrial Receptivity
Is it possible to prolong the
Endometrial Receptive Window to improve
Implantation rate?

Ovarian hyperstimulation by gonadotropins
causes very high estrogen levels
E2 during the pre-implantation period (days 0–6)
Dr. Carlos Simone
ESHRE 1997
Fertility & Sterility
Vol. 70, No. 2, Aug. 1998
Window of uterine receptivity remains open for an extended
period at lower estrogen levels but rapidly closes at higher
levels
High estrogen levels provoke uterine non receptivity

Human Reproduction, Volume 27,
Issue 3, 1 March 2012
Systems Biology in Reproductive
Medicine, Volume 60, 2014
Letrozole improves the
marker of Endometrial Receptivity
Letrozole improves
Integrin expression in IVF
Letrozole improves
Integrin, LIF & L- Selectin
expression in natural cycle
Window of uterine receptivity remains open for an extended period
at lower estrogen levels but rapidly closes at higher levels
PNAS March 4, 2003 100 (5) 2963-296

Letrozole use with gonadotropins in IVF cycles
may increase endometrial receptivity by
increasing integrin expression in the
endometrium and by lowering estrogen
concentrations to more
physiologic levels
Dr. Robert F Casper
MD, FRCS(C)
Editorial Editor of
fertility & Sterility
Restoring the physiological Symphony between
the blastocyst and the endometrium
Fertility-Promoting Endometriosis Therapy

Reduction in
Endometrioma Size
Breaking away from the
treatment
paradigm
(The lancet 2010)
Fertility-Promoting
Endometriosis Therapy

“Excision of endometriomas negatively impact
ovarian reserve & number of oocytes retrieved for IVF”
3 months of Letrozole therapy
75% reduction in
Endometrioma volume
BioMed Research International Volume 2015
50% decrease in
Endometrioma diameter
Fertility-Promoting Endometriosis Therapy

Medical shrinkage of endometriomas with
Letrozole appears to be a viable option for:
• Women interested in avoiding
surgery for endometriomas.
• Women wishing to preserve
fertility for future conception
Wednesday, October 16, 2013 IFFS/ASRM -2013
• Refractory endometriosis
• Chronic pain associated with endometriosis
Indication

Aromatase inhibitor with GnRh-a
(clinical study 2)
• McGill university
• Comparison of 2 months pretreatment with GnRH agonists with or
without an aromatase inhibitor in women with ultrasound-diagnosed
ovarian endometriomas undergoing IVF.
• 126 women aged 21–39 years who failed a previous IVF cycle and all
subsequent embryo transfers and had sonographic evidence of
endometriomas.
• Women were non-randomly assigned to either 3.75 mg intramuscular depo-
leuprolide treatment alone or in combination with 5 mg of oral letrozole
daily for 60 days prior to undergoing a fresh IVF cycle.
• Main outcome measures included clinical pregnancy rate and ongoing
pregnancy rate after 24 weeks’ gestation.
• The combination of depo-leuprolide acetate monthly for 60 days
combined with daily letrozole has better clinical outcomes at IVF in
women with endometriomas than depo-leuprolide acetate treatment
alone.

A comparison of pre-treatment with and without GNRH-agonist or Letrozole in
women with 2 failed embryo transfers undergoing a frozen cycle & no evidence
of endometriosis.
• A prospective cohort study was performed on subjects who failed
two embryo transfers of blastocysts.
• 204 subjects were selected, 143 received 2-months of luprolide-
acetate only and the rest received luprolide acetate 3.75 mg
monthly IM and letrozole 5 mg daily orally for 60 days.
• The study found that clinical pregnancy rates and third-trimester
pregnancies were highest among the GnRH-ag-Letrozole group as
compared to GnRH-ag only group.

New Treatment Protocol
A comparison of pre treatment
with & without GnRH-agonist or Letrozole
in women with 2 failed embryo transfers
undergoing a frozen cycle &
no evidence of endometriosis
New Treatment Protocol
Patient with 2 failed embryo transfers perform
better if pretreated with GnRH-ag - Letrozole,
due to treatment of undiagnosed Endometriosis

Addition of an aromatase inhibitor
improves IVF outcomes
when pre-treating women with
2 months of GnRH Agonist with
Endometriomas.
60 days of
treatment along with GnRH agonist in
Recurrent Implantation Failure

Letrozole Vs Dienogest
According to a study conducted by the Ott‘s
Scientific Research Institute of Obstetrics, Russia
:
Endometriosis induced rats were treated with
different medications like Letrozole, Dienogest,
Cabergoline, Melatonin and Metformin.
It was found that the efficacy of treatment was
same in both the Letrozole and dienogest
treatment group.
This proves that dienogest as well as Letrozole
provides the same efficacy of treatment

It was also worth noticing that….
• After the end of treatment with aromatase inhibitors, 31% of patients with
infertility, genital endometriosis and repeated courses of ineffective
hormone therapy became pregnant
• Among them in 18.2% of women pregnancy occurred spontaneously
• In 31.8% - after ovulation induction with gonadotropins
• in 50% - in IVF protocol with the use of own (16,7%) or donor (33.3%)
oocytes.
• The study showed that aromatase inhibitors can be used for treatment of
patients of reproductive age with endometriosis.
• Application of aromatase inhibitors is an effective, safe and well tolerated
method of endometriosis treatment, especially for patients with recurrence
of endometriosis after GnRH agonist treatment and /or with reduced ovarian
reserve.
Maria Yarmolinskaya

Indications
• Refractory endometriosis
• Endometriosis confirmed during surgery in combination with history
of ineffective treatment with GnRH and / or reduced ovarian reserve.
• Empirical treatment in unexplained infertility/ Recurrent
Implantation failure

Take home message
• Aromatase inhibitors appear to be the first breakthrough in the
medical treatment of endometriosis since the introduction of GnRH-
agonists.
• Patients with endometriosis who do not respond to existing treatments
appear to obtain significant pain relief from AIs.
• The side-effect profiles of the AI regimens (including a progestin or
OC add-back) are more favorable compared with treatments using
GnRH-a or danazol.
• Thus these regimens can potentially be administered over prolonged
periods of time.

Letrozole in Endometriosis

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Editor's Notes