Medical Management of Endometriosis: Comprehensive Guide for Effective Treatment

 Immediate Past Chairperson –Indian College of
OB/GY-ICOG
 National Corresponding Editor-Journal of OB/GY of
India JOGI
 National Corresponding Secretary- Association of
Medical Women, India
 Joint Secretary-Indian Menopause Society
 President –ISOPARB Vidarbha Chapter 2019-21
 Chairperson-IMS Education Committee 2021-23
 Chairperson-fertility enhancement Committee-
ISOPARB
 Member-SAFOG Education Committee
 President-Association of Medical Women, Nagpur
AMWN 2021-24
 Senior Vice President FOGSI 2012
 President Menopause Society, Nagpur 2016-18
 President Nagpur OB/GY Society 2005-06
Dr. Laxmi Shrikhande
MBBS; MD(OB/GY);
FICOG; FICMU; FICMCH
Medical Director-
Shrikhande Fertility Clinic
Nagpur, Maharashtra
 Nagpur Ratan Award @hands of
Union Minister Shri Nitinji
Gadkari
 Received Bharat excellence Award
for women’s health
 Received Mehroo Dara Hansotia
Best Committee Award for her
work as Chairperson HIV/AIDS
Committee, FOGSI 2007-2009
 Received appreciation letter from
Maharashtra Government for her
work in the field of SAVE THE
GIRL CHILD
 Delivered 22 orations and
450 guest lectures
 Publications- 42 National &
21 International
 Sensitized 2 lakh boys and
girls on adolescent health
issues
Awards
Positions

Medical Management of Endometriosis
Dr Laxmi Shrikhande
Consultant-Shrikhande Hospital & Research Centre Pvt Ltd
NAGPUR

Key facts
 Endometriosis affects roughly 10% (190 million) of reproductive age women and girls
globally.
 It is a chronic disease associated with severe, life-impacting pain during periods, sexual
intercourse, bowel movements and/or urination, chronic pelvic pain, abdominal bloating,
nausea, fatigue, and sometimes depression, anxiety, and infertility.
 Endometriosis related pain is attributed to the increase in inflammatory mediators,
neurological dysfunction and estrogen mediated neuromodulation of the peripheral
sensory neurons.
 There is currently no known cure for endometriosis and treatment is usually aimed at
controlling symptoms.

Key facts
The definitive diagnosis of endometriosis can only be made by
histopathology showing endometrial glands and stroma with varying
degree of inflammation and fibrosis.
No serum markers are currently available that can diagnoses
endometriosis.
CA −125 levels can be elevated, however, it has limited clinical utility as
the levels can be elevated in other conditions as well.
Imaging studies like ultrasonography, CT and MRI are helpful in cases of
ovarian cysts or adnexal masses.
Moore J, Copley S, Morris J, et al. A systematic review of the accuracy of ultrasound in the diagnosis of endometriosis. Ultrasound Obstet
Gynecol. 2002; 20(6):630–634. [PubMed: 12493057]

Key facts
Constant supply of estrogen is crucial for the growth and persistence of the
endometriotic implants, which comes from multiple sources.

Key facts
As the endometriotic lesions are hormonally active, modifying the
hormonal milieu of the body helps in suppression of the lesions and
suppress the inflammatory mediators leading to pain.
The medical management of endometriosis is targeted towards controlling
pain and suppression of the hormonally active endometriotic tissue.
Endometriosis related pain leading to dysmenorrhea, pelvic pain,
dyspareunia, dyschezia is often the most common presenting complaint
and can seriously effect the quality of life of women and their mental and
emotional health.
Vitale SG, La Rosa VL, Rapisarda AM, et al. Comment on: Impact of endometriosis on quality of life and mental health: pelvic pain makes the difference. J
Psychosom Obstet Gynaecol. 2016:1–2.

Hormonal
• Combined oral contraceptives
• Progesterone containing contraceptives
➢ Oral or injectable
➢ Implant
➢ Levonorgestrel containing intrauterine system (LNG- IUS)
• Selective progesterone receptor modulators
➢ Mifepristone
➢ Ulipristal acetate
➢ Onapristone
• Gonadotrophin releasing hormone agonists
➢Leuprolide acetate
➢ Nafarelin
➢ Goserelin
• Gonadotrophin releasing hormone antagonists
➢ Oral or Injectable
Non-Hormonal
• NSAIDS
• Aromatase inhibitors
•Danazol
MEDICATIONS USED IN ENDOMETRIOSIS

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)
NSAIDs are the most commonly used first line agents in the management of endometriosis
related pain and dysmenorrhea.
NSAIDs work by blocking the enzyme COX that is crucial for the production of the
inflammatory mediators.
Although, both COX1 and COX2 receptors are present, studies have shown that the
ectopic endometrial tissues have a higher concentration of COX 2 receptors.
Both selective and non-selective COX inhibitors are widely used for symptomatic relief.
Along with pain control, new studies have shown that selective COX 2 inhibitors like
rofecoxib can also inhibit the growth of the endometrial tissue.
Despite inconclusive evidence regarding effectiveness of NSAIDs in controlling
endometriosis related pain and negative gastrointestinal side effect profile, a trial of NSAIDs
is the most common first intervention in patients with pelvic pain.
Marjoribanks J, Ayeleke RO, Farquhar C, et al. Nonsteroidal anti-inflammatory drugs for dysmenorrhoea. Cochrane Database Syst Rev. 2015; 7:CD001751.

COMBINED HORMONAL CONTRACEPTIVES
The suppression of ovaries and disease activity forms the basis of the use of hormonal
contraceptives in endometriosis and they are the most commonly used first line hormonal
therapy.
 Estrogen and progesterone combinations or progesterone alone lead to decidualization
of the endometriotic tissue and is proposed to slow the progression of the disease.
They have been used with varying degree of success in women with endometriosis.
Cost, ease of administration and tolerability are some of the key features that have made
their use popular.
As compared to cyclic administration, continuous therapy with COC has been shown to
have better pain control.
However the limiting factors include long-term administration, risk of thromboembolism,
high rates of recurrence after discontinuation and impaired fertility due to contraceptive
action.
Combinations containing lower dose of ethinyl estradiol (20 micrograms) as compared to
high dose (30 micrograms) have a lower risk of venous thromboembolism and are
currently recommended.

Continuous Combined Hormonal Therapy
Birth Control Pills - Take one active pill every day at the same time
Vaginal Ring - Insert a new vaginal ring every 3-4 weeks
Patch - Change your patch weekly

PROGESTERONE CONTAINING CONTRACEPTIVES
Progesterone has multiple mechanisms of action that form the
pathophysiologic basis of its use in endometriosis.
 It induces decidualization of the endometrium, inhibits estrogen induced
mitosis, alters estrogen receptors, inhibits angiogenesis and expression of
matrix metalloproteinase needed for the growth of the endometriotic
implants.
 Available in different forms oral, injectable or intra-uterine device, they
have gained popularity and are a great option for women with
contraindications to estrogens.
 Some of the progestins that have been studies and used in the treatment
of endometriosis include cyproterone acetate, dienogest, dydrogesterone,
gestrinone, lynesterole, medroxyprogesterone acetate, megesterol
acetate, and norethindrone acetate.
Whitehead MI, Townsend PT, Pryse-Davies J, et al. Effects of various types and dosages of progestogens on the postmenopausal endometrium. J Reprod
Med. 1982; 27(8 Suppl):539–548. [PubMed: 7131447]

Medroxyprogesterone is available as oral and injectable
preparation and can be administered 150 mg intramuscularly
every three months.
 Although there is no standardized oral dose, studies using
different doses of oral medroxyprogesterone from 10 to 100 mg
per day for 3–6 months have reported varying degree of
improvement in endometriosis related pain.
Injectable progesterone offers the added advantage of better
compliance by avoiding daily administration and erratic
gastrointestinal absorption.
Luciano AA, Turksoy RN, Carleo J. Evaluation of oral medroxyprogesterone acetate in the treatment of endometriosis. Obstet Gynecol. 1988;
72(3 Pt 1):323–327. [PubMed: 2970029]

Northethisterone acetate is a 19-nortesterone derivative and
has been proven effective in control of dyspareunia,
dysmenorrhea, pelvic pain and dyschezia with better tolerability
and less side effects in lower doses.
Vercellini et al in their study used Norethindrone acetate at a
dose of 2.5 mg per day for 12 months and achieved similar pain
control when compared to combined oral contraceptive and
cyproterone acetate and suggested that it could be a good
alternative to COC.
Vercellini P, Pietropaolo G, De Giorgi O, et al. Treatment of symptomatic rectovaginal endometriosis with an estrogen-progestogen combination versus low-dose
norethindrone acetate. Fertil Steril. 2005; 84(5):1375–1387. [PubMed: 16275232]

Dienogest, a 19- nortestosterone derivative is another progestin that has been
studied in the treatment of endometriosis.
It has high specificity for progesterone receptors and less anti-androgenic side
effects.
Continuous administration leads to decidualization and atrophy of the endometrial
lesions.
 It also has anti- inflammatory, anti-angiogenic and anti-proliferative effects.
In a dose of 2mg or 4mg per day, dienogest has been shown to have a favorable
profile for safety and efficacy, patients reported improvement in the endometriosis
related symptoms and an overall improvement in quality of life.
It is in general well tolerated and side effects included irregular bleeding, which
improves with time.
Schindler AE. Dienogest in long-term treatment of endometriosis. Int J Womens Health. 2011; 3:175–184. [PubMed: 21792339]
Kohler G, Faustmann TA, Gerlinger C, et al. A dose-ranging study to determine the efficacy and safety of 1, 2, and 4mg of dienogest daily for
endometriosis. Int J Gynaecol Obstet. 2010; 108(1):21–25. [PubMed: 19819448]

LEVONORGESTREL CONTAINING INTRA-UTERINE SYSTEMS (LNG-IUS)
While oral progesterones have a better side effect profile than combined hormonal
contraceptives, daily administration and variable serum concentrations are some of the
limitations associated with them.
LNG- IUS is a T shaped device that contains 52 mg of Levonorgestrel, which releases 20
micrograms of hormone per day over a five-year period.
Multiple studies have shown the efficacy of LNG-IUS, which delivers progesterone locally
and avoids the systemic side effects.
A longer duration of activity further improves compliance.
The theory behind their success in women with endometriosis is progesterone induced
atrophy of the endometrium, hypomenorrhea with possible decreased retrograde
menstruation and higher concentration of progesterone in the peritoneal cavity
suppressing the activity of ectopic endometrium by anti-inflammatory and
immunomodulatory functions.
In their study, Vercellini et al showed LNG IUS to successfully control endometriosis
related pelvic pain and improve patient satisfactions.
Vercellini P, Vigano P, Somigliana E. The role of the levonorgestrel-releasing intrauterine device in the management of symptomatic endometriosis. Curr
Opin Obstet Gynecol. 2005; 17(4):359–365. [PubMed: 15976541]

LEVONORGESTREL CONTAINING INTRA-UTERINE SYSTEMS (LNG-IUS)
There are also reports of successful use in patients with adenomyosis and deep
rectovaginal endometriosis.
 In another study comparing LNG–IUS to depot administration of GnRH analogues, similar
efficacy was reported with lower incidence of hypo estrogenic side effects in women using
the intrauterine device.
 It has also been shown to decrease the rates of recurrence of dysmenorrhea in women
after laparoscopic surgery for symptomatic dysmenorrhea.
With its long term use and better side effect profile LNG-IUS offers a great option in
women who are do not desire to conceive.
 More research is underway to understand the long-term efficacy in women with
endometriosis.
Fedele L, Bianchi S, Zanconato G, et al. Use of a levonorgestrel-releasing intrauterine device in the treatment of rectovaginal endometriosis. Fertil Steril.
2001; 75(3):485–488. [PubMed: 11239528]
Petta CA, Ferriani RA, Abrao MS, et al. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the
treatment of chronic pelvic pain in women with endometriosis. Hum Reprod. 2005; 20(7):1993–1998. [PubMed: 15790607]
Vercellini P, Frontino G, De Giorgi O, et al. Comparison of a levonorgestrel-releasing intrauterine device versus expectant management after conservative
surgery for symptomatic endometriosis: a pilot study. Fertil Steril. 2003; 80(2):305–309. [PubMed: 12909492]

ETONOGESTREL IMPLANT
Another route of progesterone delivery that has been studied is the subdermal implant
also commonly marketed as Implanon and Nexplanon.
Inserted intradermally in the arm, it contains progestin etonogestril and offers
contraceptive benefits for three years.
Reported rates of improvement in dysmenorrhea in women using it for birth control
prompted research for its use in endometriosis.
Walch et al in their study compared the therapeutic efficacy of depot
medroxyprogesterone acetate and implanon in 41 women with endometriosis and
reported that both groups had similar incidence of pain relief and both groups had similar
side effect profile and degree of satisfaction.
Commonly reported side effects include irregular menstrual bleeding, weight gain,
nausea, headache, breast tenderness, acne that are similar to depot
medroxyprogesterone acetate.
In carefully selected women who do not desire fertility etonogestrel implant could be
another option for symptomatic endometriosis, however, larger studies are needed in this
direction.
Walch K, Unfried G, Huber J, et al. Implanon versus medroxyprogesterone acetate: effects on pain scores in patients with symptomatic
endometriosis–a pilot study. Contraception. 2009; 79(1):29–34. [PubMed: 19041438]

GnRH AGONISTS
The successful use of GnRH agonists is based on the fact that it leads to profound
hypoestrogenism by blocking ovarian estrogen production and hence regression of
endometriotic implants.
During the first few days of administration, GnRH agonists stimulate the pituitary releasing
FSH and LH, however, chronic administration leads to downregulation of pituitary GnRH
receptors that results in suppression of the hypothalamic pituitary ovarian axis leading to
anovulation.
This eventually leads to hypoestrogenism, amenorrhea and regression of the
endometriotic implants by depriving the implants of estrogen that is crucial for their
survival.
They are a great option for women who have failed initial therapy with OCPs or are not
candidates for OCPs due to their medical history.
GnRH agonists are available in both nasal and injectable forms and offer high rates of
pain relief and longer symptom free period for up to 12 months.
Winkel CA, Scialli AR. Medical and surgical therapies for pain associated with endometriosis. J Womens Health Gend Based Med. 2001; 10(2):137–
162. [PubMed: 11268298]

GnRH AGONISTS
Leuprolide acetate 3.75 mg monthly injection or 11.25 mg used three monthly, Goserelin
and Nafarelin are the most commonly used preparation.
Studies have shown that GnRH agonists cause significant reduction in pelvic pain in
women with endometriosis, however they are approved for continuous use for only up to
six months due to concerns of side effects secondary to hypoestrogenism like bone loss,
vaginal atrophy and dryness, hot flashes and abnormalities in lipid profile.
The addition of add- back therapy provides symptomatic relief and decreases the rate of
bone loss.
 Norethindrone acetate, a progestrin is the only FDA approved add-back therapy, but low
dose estrogen and a combination of estrogen and progesterone have also been used.
The combination of GnRH agonists and norethindrone acetate are only approved for use
for duration of 12 months, as the data beyond that duration is not available.
Another limitation of the use of GnRH agonists is that they suppress ovulation and cannot
be used in women desiring fertility.
Hornstein MD, Surrey ES, Weisberg GW, et al. Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Lupron Add-Back
Study Group. Obstet Gynecol. 1998; 91(1):16–24. [PubMed: 9464714]

GnRH ANTAGONISTS
These are another group of drugs that have shown promising results in the
treatment of endometriosis.
Compared to GnRH agonists they do not cause the initial flare and have
lower degree of hypoestrogenism and a better side effect profile with
equivalent symptomatic improvement.
In their study, Kupker et al showed that administration of GnRH antagonist
Cetrorelix provided symptomatic relief and regression of the endometriotic
implants as visualized on laparoscopy.
With a lower degree of hypoestrogenemia and better tolerance than the
GnRH agonists they offer a great potential in the treatment of
endometriosis.
Kupker W, Felberbaum RE, Krapp M, et al. Use of GnRH antagonists in the treatment of endometriosis. Reprod Biomed Online. 2002;
5(1):12–16. [PubMed: 12470539]

Elagolix
Elagolix is an oral GnRH receptor antagonist that inhibits endogenous GnRH signaling by
binding competitively to GnRH receptors in the pituitary gland.
It was approved by the FDA in July 2018 for management of moderate to severe pain
associated with endometriosis.
Administration results in dose-dependent suppression of LH and FSH, leading to
decreased blood concentrations of the ovarian sex hormones, estradiol and progesterone.
Approval of elagolix was based on 2 replicate phase 3 clinical trials (n=872). Improvement
of dysmenorrhea was reported in 43.4-46.4% of women in the lower-dose elagolix groups
and 72.4-75.8% in the higher-dose elagolix groups, compared with 19.6-22.7% in the
placebo groups (P< 0.001 for all comparisons). Nonmenstrual pelvic pain improvement
was reported by 49.8-50.4% of women in the lower-dose elagolix groups and 54.5-57.8%
in the higher dose groups, compared with 36.5% in the placebo groups (P = 0.003 and P<
0.001, respectively).
Both elagolix doses are associated with hypoestrogenic adverse effects, including hot
flushes, elevated serum lipids, and greater decreases from baseline in bone mineral
density, compared with women who received placebo. Because of this, treatment duration
recommendations are specified for each dosage regimen.

Relugolix/estradiol/norethindrone
In August 2022, FDA approved relugolix/estradiol/norethindrone combination tablets
(Myfembree) for the treatment of moderate to severe endometriosis-associated pain.
Approval was based on data from two phase 3 studies (SPIRIT 1 and SPIRIT 2) that
studied the efficacy of the combination tablet for treatment of dysmenorrhea.
In both studies, 75% of women who used the once-daily relugolix combination therapy
experienced a significant reduction in dysmenorrhea, compared with 27% and 30% of
women in the placebo groups at Week 2. The combination therapy also significantly
reduced non-menstrual pelvic pain in 59% and 66% of women, compared with 40% and
43% in the placebo groups (P< 0.0001).
In SPIRIT 1 and 2, the relugolix combination therapy group also showed decreases in
dyspareunia and opioid use compared with the placebo groups. Additionally, more women
treated with relugolix combination therapy were opioid free at Week 24 compared with
those in the placebo groups (86% and 82% vs 76% and 66%, respectively).

Add-back therapy and empiric therapy
Much interest has been shown in whether estrogen/progestin "add-back" therapy should
be instituted to prevent osteoporosis and hypoestrogenic symptoms.
Hormone replacement therapy preparations, progestins, tibolone maleate, and
bisphosphonates have all been shown to be effective.
Add-back therapy has been shown to prevent loss in bone density and to relieve
vasomotor symptoms without reducing the efficacy of GnRH regimens. GnRH agonists
have been used for 12 months with norethindrone add-back therapy with good results.
A clinical trial has shown that a 3-month empiric course of GnRH, based on a diagnostic
algorithm without definitive laparoscopic diagnosis, is efficacious. However, long-term
effects of GnRH analogues on bone density in this population remain unproven.
Therefore, add-back therapy remains the standard of care while the patient is on GnRH
treatment. Also, empiric treatment without a firm diagnosis could result in unnecessary
treatment in patients with chronic pelvic pain, whose condition could be due to other
causes. In Ling's study, 13% of subjects were shown to not have endometriosis.

SELECTIVE PROGESTERONE RECEPTOR
MODULATORS (SPRMs)
 SPRMs are a relatively new class of agents that have tissue effect ranging from pure agonists to
agonist/antagonist to antagonist.
 Mifepristone and ulipristal acetate are the two SPRMs that are commonly used.
 Mifepristone, which has a predominant progesterone antagonist effect, has been used for medical
abortions and ulipristal acetate for emergency contraception.
 Selective inhibition of endometrial growth without the side effects of hypoestrogenism, decreased
menstrual bleeding via effect on the endometrial blood supply and suppression of endometrial blood
supply are some of the mechanisms that have provoked interest in their use in endometriosis.
 In animal models, treatment with antiprogestin onapristone and ulipristal acetate has shown to result in
atrophy of the endometrium and suppression of estrogen dependent endometrial growth.
 Decreased expression of COX-2 has also been shown in rat models treated with mifepristone and
ulipristil acetate.
 Studies in humans are however limited.
 In one study, Kettel et al studied nine women with endometriosis. Women were treated with mifepristone
50 mg/day for six months and all nine women reported an improvement in pelvic pain without significant
side effects of hypoestrogenism.
Brenner RM, Slayden OD, Nath A, et al. Intrauterine administration of CDB-2914 (Ulipristal) suppresses the endometrium of rhesus macaques.
Contraception. 2010; 81(4):336–342. [PubMed: 20227552]
Huniadi CA, Pop OL, Antal TA, et al. The effects of ulipristal on Bax/Bcl-2, cytochrome c, Ki-67 and cyclooxygenase-2 expression in a rat model
with surgically induced endometriosis. Eur J Obstet Gynecol Reprod Biol. 2013; 169(2):360–365. [PubMed: 23619346]

AROMATASE INHIBITORS
 Aromatase enzyme helps in the conversion of the steroid precursors into estrogen.
 Although the ovaries and the fat are the predominant source of the enzyme, other sources include skin, placenta and the brain.
 Studies have shown that aromatase activity is absent in normal endometrium, but is over expressed in endometriosis.
 Aromatase induced estrogen synthesis leads to the growth of the endometrial implants, COX expression, prostaglandin
secretion, which further induces aromatase activity.
 Unlike GnRH agonists, aromatase inhibitors block estrogen synthesis both in the periphery and the ovaries.
 This mechanism is particularly helpful in postmenopausal women with endometriosis where peripheral fat is the predominant
source of estrogen.
 Anastrazole, letrozole and exemestane are third generation aromatase inhibitors that can be administered orally.
 They are reversible, more potent and have faster onset of action.
 Used in combination with combined oral contraceptives, GnRH agonists or progesterone, they significantly decrease the
endometriosis-associated pain, improve quality of life and have shown to decrease the size of the lesion.
 However their side effects include ovarian follicular cyst and bone loss with long-term use.
 Combination with GnRH agonists and birth control pills can help prevent follicular development and add back oral contraceptives
and progestins can decrease the bone loss.
Bulun SE, Zeitoun KM, Takayama K, et al. Molecular basis for treating endometriosis with aromatase inhibitors. Hum Reprod Update. 2000;
6(5):413–418. [PubMed: 11045871]
Nawathe A, Patwardhan S, Yates D, et al. Systematic review of the effects of aromatase inhibitors on pain associated with endometriosis. BJOG.
2008; 115(7):818–822. [PubMed: 18485158]

DANAZOL
Danazol, a derivative of 17 alpha-ethinyl–testosterone, is an androgenic agent that inhibits
LH surge and decreases ovarian steroidogenesis by direct inhibition of the ovarian
enzymes.
 Although it has been effective in controlling endometriosis-associated pain, its use has
fallen over the years due to its side effects.
Usually given in divided doses of 400–800 mg per day for six months.
Side effects include acne, hirsutism, deepening of voice, weight gain, muscle cramps,
liver dysfunction and an abnormal lipid profile.
A meta- analysis by Selak et al, showed that when treated with danazol, patients had
improved laparoscopic scores and decreased pain symptoms as compared to placebo or
no treatment.
 However, adverse effects related to hyperandrogenism limit their use.
 As the side effects are mostly associated with oral administration, alternative routes of
like danazol vaginal ring and intrauterine devices are currently in research and studies
have shown improvement in pain symptoms with better tolerability.
Igarashi M, Iizuka M, Abe Y, et al. Novel vaginal danazol ring therapy for pelvic endometriosis, in particular deeply infiltrating endometriosis. Hum
Reprod. 1998; 13(7):1952–1956. [PubMed: 9740456]
Igarashi M, Abe Y, Fukuda M, et al. Novel conservative medical therapy for uterine adenomyosis with a danazol-loaded intrauterine device. Fertil Steril.
2000; 74(2):412–413. [PubMed: 10927074]

NEWER THERAPIES
Endometriosis is a chronic medical condition and requires long duration of
therapy.
 Currently available treatment options have varying degrees of success in
symptom control but are limited by long-term use, side effects of prolonged
hypoestrogenism and high rates of recurrence after therapy is
discontinued.
Also, endometriosis predominantly is a disease of young reproductive age
women and most of the commonly available therapeutic agents interfere
with fertility.
With these drawbacks there is a constant search for newer therapies that
could offer cure and be safely used with fewer side effects.
FUTURE THERAPIES
• Anti- angiogenesis factors
• Statins
• TNF-α blockers
• Peroxisome proliferator activated- receptor gamma ligand (PPAR-γ)
• Pentoxifylline

ANTI-ANGIOGENESIS FACTORS
A network of capillaries surrounds endometriotic lesions and angiogenesis is a crucial
event in the growth and survival of the lesions.
Studies have also shown that these lesions secrete angiogenic factors like vascular
endothelial growth factor (VEGF) and the peritoneal fluid is rich in angiogenic factors.
In theory, halting the growth of new blood vessels could stop the growth of new lesions
and regress older ones.
With this thought a lot of research is being done in understanding the role of anti–
angiogenic factors in the treatment of endometriosis.
 These agents are still in early development with most of the research on animal models.
Agents like TNP-470 (an analog of antibiotic fumagilin), endostatin (a proteolytic fragment
of collagen with endogenous anti-angiogenic activity), anginex (a synthetic peptide that
stops the growth of blood vessels and induces apoptosis) and anti-VEGF antibody
(Avastin) have been successful in decreasing the size of endometriotic lesions in animal
models, however, no data is available in humans.

ANTI-ANGIOGENESIS FACTORS
Dopamine receptor 2 agonists, cabergoline and quinagolide have been shown to reduce
angiogenesis by dephosphorylation of VEGF2.
They have been used safely in humans for the treatment of hyper-prolactinemia and
lactation suppression.
In a human study, Gomez et al studied 9 women with endometriosis-associated
hyperprolactinemia, women first had a surgical procedure where half of the endometriotic
lesions were excised and the other half were marked.
This was followed by treatment with quinagolide for 18–20 weeks followed by a second
laparoscopy.
 They showed a significant reduction in the size of the lesion and down regulation of
VEGF/VEGF2, pro-angiogenic cytokines and plasminogen activator inhibitor (PAI-1).
Delgado-Rosas F, Gomez R, Ferrero H, et al. The effects of ergot and non-ergot-derived dopamine agonists in an experimental mouse model of
endometriosis. Reproduction. 2011; 142(5):745–755. [PubMed: 21862695]
Gomez R, Abad A, Delgado F, et al. Effects of hyperprolactinemia treatment with the dopamine agonist quinagolide on endometriotic lesions in
patients with endometriosis-associated hyperprolactinemia. Fertil Steril. 2011; 95(3):882–888 e881. [PubMed: 21055747]

STATINS
Typically used in the treatment of hypercholesterolemia,
Their anti-inflammatory, antiangiogenic and antioxidant properties have provoked interest
in their use in endometriosis.
Atorvastatin, simvastatin, mevastatin and lovastatin have been tested in in-vitro tissue
cultures and animal models of endometriosis.
In their study Sharma et al reported an increased inhibition of inflammatory and
angiogenic genes (COX-2, VEGF, RAGE and EN-RAGE) in atorvastatin treated
endometrial- endometriotic cells.
 They also reported increased expression of anti-inflammatory genes (PPAR-γ and LXRα
and IGFBP-1).
In another study, simvastatin induced a dose dependent decrease in MMP-3 (matrix
metalloproteinase) and the number and size of the endometriotic lesions in a mouse
model.
Statins offer another potential therapeutic agent, which could be used in the treatment of
endometriosis.
Yilmaz B, Ozat M, Kilic S, et al. Atorvastatin causes regression of endometriotic implants in a rat model. Reprod Biomed Online. 2010; 20(2):291–
299. [PubMed: 20113969]
Sharma I, Dhawan V, Mahajan N, et al. In vitro effects of atorvastatin on lipopolysaccharide-induced gene expression in endometriotic stromal cells.
Fertil Steril. 2010; 94(5):1639–1646 e1631. [PubMed: 19944411]

TNFα BLOCKERS
TNFα is a pro-inflammatory cytokine and its levels have been found to be elevated in the
peritoneal fluid of women with endometriosis with a direct correlation with the stage of the
disease.
Agents targeting TNFα have been successfully used in the treatment of inflammatory
conditions like rheumatoid arthritis and Crohn’s disease.
Infliximab, a monoclonal antibody against TNFα and Etanercept, a fusion protein with the
ability to neutralize TNFα are being actively studied in the treatment of endometriosis.
In animal models, treatment with these agents has shown to reduce the size and number
of the endometriotic implants along with a decrease in the levels of inflammatory
cytokines.
However, there is paucity of evidence in humans regarding the efficacy of these agents.
One study studied the effect of treatment of infliximab versus placebo in women with
endometriosis, however no improvement was reported in the severity of pain.
More studies are needed to fully understand the scope of these agents in the
management of endometriosis.
Koninckx PR, Craessaerts M, Timmerman D, et al. Anti-TNF-alpha treatment for deep endometriosis-associated pain: a randomized placebo-
controlled trial. Hum Reprod. 2008; 23(9):2017–2023. [PubMed: 18556683]

PEROXISOME PROLIFERATOR- ACTIVATED
RECEPTOR GAMMA LIGANDS (PPAR-γ)
PPAR- γ ligands have anti-inflammatory properties and reduce estrogen
biosynthesis by inhibiting aromatase enzyme.
 In experimental models they have been shown to inhibit cell proliferation,
increase apoptosis and inhibit the growth of the endometriotic lesions by
an affect on the angiogenic factor VEGF.
In animal models rosiglitazone and pioglitazone reduce the volume, weight
and size of the endometriotic lesions.
Human studies are underway, however there are concerns about the
possible risk of myocardial infarction and cardiovascular side effects of
rosiglitazone.

PENTOXIFYLLINE
Another agent that has been lately studied in the treatment of endometriosis is
pentoxifylline.
Currently used in the treatment of intermittent claudication, it helps in improving
the vascular supply in stenotic arteries by inhibiting the phosphodiesterase
enzyme.
It also has TNFα blocking properties, suppressing the release of inflammatory
mediators.
In mouse models of endometriosis pentoxifylline has been successful in
improving fertility and reducing the size of the lesions.
Human studies are limited and a recent meta-analysis showed that there was no
significant improvement in pelvic pain or clinical pregnancy rates in women
treated with pentoxifylline.
Therefore, current evidence does not support the routine use of pentoxifylline in
endometriosis related pain or infertility and more research is needed.
Perello M, Gonzalez-Foruria I, Castillo P, et al. Oral Administration of Pentoxifylline Reduces Endometriosis-Like Lesions in a Nude Mouse
Model. Reprod Sci. 2016
Song, Lu D., Li, HY., et al. Pentoxifylline for endometriosis. Cochrane Database Syst Rev. 2012; 1:CD007677. [PubMed: 22258970]

Medical versus surgical treatment for
endometriosis

Prevention
No current methods of prevention are known.
Some evidence suggests that rapid and aggressive medical or
surgical therapy can arrest progression, especially when the
disease is caught in the early (minimal to mild) stages.
Early and prolonged use of oral contraceptive pills, pregnancy,
and breastfeeding seem to afford some degree of protection
against this disease.

Patient Education
Stress to patients the importance of continuing medical therapy for
the full 6-month course.
 Medical therapy often relieves pain but induces uncomfortable
adverse effects, and the patient needs encouragement to complete
the course of treatment.
Recurrence of symptoms after therapy should prompt the patient to
return for further evaluation.
 Educate patients regarding severe disease and the symptoms of
bowel and ureteral obstruction.

Key Take Aways
 Endometriosis is a chronic medical condition that not only negatively
affects a woman’s quality of life but has a huge economic impact often due
to delay in diagnosis, need for ongoing treatment and high recurrence
rates.
Currently, several therapeutic options both hormonal and non-hormonal
are available to provide symptomatic relief and control the progression of
the disease.
 All the options discussed above have been fairy successful in controlling
pelvic pain in women with endometriosis.
In carefully selected women these medications can be used either alone or
in combination with surgery.
However, they are limited by their side effects and negative impact on
fertility.

Key Take Aways
Currently there is no evidence that the medical therapy alone or a combination of
medical therapy with surgery improves fertility.
 Management of infertility in women with endometriosis is a complex issue and
needs to take into account the age, duration of infertility, severity of symptoms
and stage of the disease.
Studies have also shown that women with endometriosis have higher rates of
pregnancy complications like pre-term delivery, pre–ecclampsia, antepartum
bleeding, placental complications and cesarean section rates.
Women desiring fertility often require assisted reproductive techniques.
With more understanding of the pathophysiology of endometriosis, newer
therapies are being developed with the hope of avoiding unwanted side effects
and specifically targeting the lesions without affecting the ovarian function.
Practice Committee of the American Society for Reproductive M. Endometriosis and infertility: a committee opinion. Fertil Steril. 2012; 98(3):591–598.
[PubMed: 22704630]

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Shrikhande Fertility Clinic
Ph- 91 8805577600 / 8805677600
shrikhandedrlaxmi@gmail.com

Medical Management of Endometriosis: Comprehensive Guide for Effective Treatment

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Medical Management of Endometriosis: Comprehensive Guide for Effective Treatment

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