2. Definition:
Presence of endometrial-type mucosa outside uterine cavity
Predominantly, but not exclusively, in pelvic compartment
Estrogen-dependent chronic inflammatory condition that
affects women in their reproductive period
Associated with pelvic pain & infertility
Vercellini P, et al. Nat. Rev. Endocrinol. 10, 261–275 (2014)
3. Determination of prevalence & incidence figures has been
hampered by exclusive reliance upon surgical visualization of
lesions for definite diagnosis
Real incidence of endometriosis is unknown
Estimated: Present in more than 15% of reproductive age
women & in up to 50% of women with pelvic pain
Vercellini P, et al. Nat. Rev. Endocrinol. 10, 261–275 (2014)/ Maestre EN, et al. Fertil Steril. 2012; 98: 1209-17.
6. Angiogenesis, arteriogenesis or vessel maturation &
lymphangiogenesis comprise continuum of vascular
development with overlap and interaction between
mechanisms by which they are controlled
Rogers PAW, et al. Reproductive Sciences Vol. 16 No. 2 February 2009 147-151.
These processes are of clinical interest because they play roles in
endometrial repair, placental development and in gynecological
disorders including endometrial cancer, endometriosis &
abnormal uterine bleeding
8. • Peritoneal fluid of patients with endometriosis is complex suspension
carrying inflammatory cytokines, growth factors, steroid hormones,
proangiogenic factors, macrophages, and endometrial and red blood cells
• These cells & their signaling products concur to promote spreading of new
blood vessels at endometriotic lesions and surroundings which contributes
to endometriotic implant survival
• Experimental studies of several antiangiogenic agents demonstrated
regression of endometriotic lesions by reducing their blood supply
9. Standard medical therapies for patients with endometriosis:
Analgesics (NSAIDs or acetaminophen
OCPs
Androgenic agents (e.g., danazol, progestogens (e.g.,
medroxyprogesterone acetate)
Gonadotropin-releasing hormone analogues (GnRHas; e.g.,
leuprolide, goserelin, triptorelin, nafarelin) &
Antiprogestogens (e.g., gestrinone)
Mounsey AL, et al. Am Fam Physician. 2006; 74: 594-600.
10. NSAIDs Nausea, vomiting, gastrointestinal irritation,
drowsiness, headache
Combined oral contraceptives Nausea, weight gain, fluid retention, depression,
breakthrough bleeding, breast tenderness,
headache, decreased menstrual flow
Progestins Nausea, weight gain, fluid retention, breakthrough
bleeding, depression, amenorrhea, delayed return of
ovulation
GnRH agonists Hypoestrogenism (vasomotor symptoms, vaginal
dryness, decreased libido, irritability, loss of bone
mineral density)
Aromatase inhibitors Hypoestrogenism, induction of ovulation
Danazol Hyperandrogenic side effects (acne, edema,
decreased breast size)
Giudice LC. N Engl J Med 2010;362:2389-98.
11. Fulguration, ablation, &
excision
Risk associated with anesthesia and risk of infection,
damage to internal organs, new adhesions,
hemorrhage
Excision or drainage &
ablation
Risk associated with anesthesia and risk of infection,
damage to internal organs, new adhesions,
hemorrhage
LPSN, nerve-pathway
interruption (with
conservative surgery)
Bleeding in the adjacent venous plexus, urinary
urgency, constipation, painless first-stage labor
Hysterectomy, bilateral
oophorectomy (abdominal,
laparoscopic, total, or
supracervical)
Persistent or recurrent pain in 10% of patients,
residual ovarian tissue
Giudice LC. N Engl J Med 2010;362:2389-98.
12.
13. Emerging evidence that estrogens can both promote & inhibit
endometrial vessel growth under different circumstances,
demonstrates the complex regulation of endometrial
angiogenesis
During angiogenic process endothelial cells proliferate,
migrate & attach to external cellular matrix, inducing matrix
remodeling and formation of new lumen in endometrium of
women with endometriosis
Luisi S, et al. Archives of Perinatal Medicine 20(2), 69-72, 2014.
14. Different antiangiogenetic treatments such as anti-VEGF
agents & other angiostatic drugs have been tested in
experimental models of endometriosis with successful results
inhibiting new vessels formation
These drugs, mainly with cytotoxic properties, target
specifically endothelial cells without penetrate in tissues
Luisi S, et al. Archives of Perinatal Medicine 20(2), 69-72, 2014.
15. Dopamine & dopamine agonists (bromocriptine, cabergoline) are
able to promote VEGFR-2 endocitosis in endothelial cells, blocking
critical step in neoangiogenesis process & reducing expression of
VEGF in ectopic endometrium
Thiazolidinediones: Class of medications used in treatment of Type
2 DM & have been shown to inhibit both monocyte migration and
peritoneal inflammatory cells in mouse model and modulate
angiogenesis
Small trial (limited series of patients) endometriosis treated with
rosiglitazone for 6 months: Possibility of using TZDs for
endometriosis pain relief in conjunction with attempts to conceive
Luisi S, et al. Archives of Perinatal Medicine 20(2), 69-72, 2014.
16. Rocha ALL, et al. Obstetrics and Gynecology International. Volume 2013, Article ID 859619, 8 pages.
17. Rocha ALL, et al. Obstetrics and Gynecology International. Volume 2013, Article ID 859619, 8 pages.
18. Idea to use dopamine agonists as anti-angiogenic
agents began with study by Basu S. et al
1st reported that neurotransmitter dopamine strongly &
selectively inhibits vascular permeabilizing and angiogenic
activities of vascular permeability factor (VPF)/VEGA at non-
toxic levels
Ercan MC, et al. Arch Gynecol Obstet (2015) 291:1103–1111.
19. Hamid AM et al. Arch Gynecol Obstet. 2014 Oct; 290(4): 677-82..
20. RCT on 140 patients
Group 1: Cabergoline 0.5
mg twice a week for 12
weeks (n=71)
Group 2: LHRH, 3
injections, once per
month (n=69)
Hamid AM et al. Arch Gynecol Obstet. 2014 Oct; 290(4): 677-82..
21. Cabergoline is more effective than LHRH agonist in decreasing
endometrioma size >25% of its original size
Hamid AM et al. Arch Gynecol Obstet. 2014 Oct; 290(4): 677-82..
Side effects in both groups:
Not severe & did not require stoppage of study in any patient
Dosage: 0.5 mg
twice a week
for 12 weeks
22. Hamid AM et al. Arch Gynecol Obstet. 2014 Oct; 290(4): 677-82..
Basis of success of Cabergoline in controlling
endometrioma:
Apparently due to diminishing VEGF, thus dealing with
main pathophysiology of endometriosis spread
24. Usmani F et al. International Journa;l of Multidisciplinary Research and Development. 2015; 2(5): 406-408.
1. In endometriosis patients who desired fertility, Cabergoline
therapy offers clear cut advantage over others forms of
therapy available, which delays conception by their
mechanism of actions
2. Cabergoline can be used preoperatively, postoperatively,
alone or in combination with COCs
25. 3. No adjuvant therapy is needed as it does not bring
hypoestrogenic & bone density changes
4. Effective in endometriotic patients with elevated prolactin
levels
5. Reduces pain by its action on nerve fibre
Usmani F et al. International Journa;l of Multidisciplinary Research and Development. 2015; 2(5): 406-408.
26. Usmani F et al. International Journa;l of Multidisciplinary Research and Development. 2015; 2(5): 406-408.
Clear advantage:
Other forms of therapies delay conception by their
mechanism of actions & usually don`t give pain relief
While cabergoline through its action on nerve
fibers decreases pain as well
27. Aim – Evaluate anti-angiogenic properties of Cabergoline on the
growth of established endometriosis lesions and to investigate the
molecular mechanisms by which Cabergoline exerts its anti-
angiogenic effect.
Methods: Human endometrium fragments were implanted in female
nude mice peritoneum, and mice were treated with vehicle, 0.05 or
0.1 mg/kg/day oral Cb2 for 14 days.
Parameters: After treatment, the implants were processed to assess
proliferative activity, neoangiogenesis, VEGFR-2 phosphorylation and
angiogenic gene expression.
28. a) Cabergoline ensures significant regression of active
lesions and cell proliferation
Recovered active lesions was
significantly (P , 0.05) decreased
when low- (58.6+9.7%) or high-
(60.4+8.4%) dose Cabergoline
was employed as compared with
the controls. Proliferation index measures
proliferative activity of
endometriotic cells
29. Ang-1 and Wnt-1 expression (antiangiogenic factors) were
significantly increased by Cabergoline low and high dose
as compared to controls.
31. “These findings support the testing of
dopamine agonists as a novel therapeutic
approach to peritoneal endometriosis in
humans”
32.
33. Conclusion of the review article:
Biomedicine & Pharmacotherapy (March 2017)
Ref: Biomedicine & Pharmacotherapy 90 (2017) 575–585
34. Salient points discussed in the article:
Current therapy has limitations like
• Risk of recurrence
• Side effects
Cabergoline as an effective option for endometriosis treatment
• Cabergoline reduces endometriosis size by its anti angiogenic action
• Reduces expression the VEGF and VEFG receptor proteins.
• Undesired Contraceptive action
• Cost of therapy
Fertility Sterility March 2017
Ref: Fertil Steril2017;107:555–65
35. Clinical trial for publication and reprint:
1. Cabergoline v/s medroxiprogeserone in endometriosis
Study conducted by Dr Amit Koel, Kolkata medical college,
Kolkata
Cabergoline is compared with Medroxy progesterone for
treatment of pain associated with endometriosis
35
39. Study highlights the role of Cabergoline to target
neoangiogenesis in Endometriosis
40. Limitations of currently available hormonal therapies & surgeries
• The currently prescribed hormonal therapies are associated with significant
side-effects & evidence supporting their efficacy is still limited.
• High rate of recurrence is seen after surgery, and appropriate second
preventive therapy is currently recommended.
• Many women gain only partial or intermittent improvement in the
symptoms.
41. Cabergoline effect on Endometrial implants
• Cabergoline a safe & effective dopamine agonist causes endocytosis of VEGFR-
2, thus halting the VEGF & VEGFR-2 binding leading to reduction in
Neoangeogenesis.
• Exposure to Cabergoline was associated with Decreased number of active
lesions, lowered cellularity, and a significantly less developed vascularization.
• Stimulation by cabergoline was associated to reduce phosphorylation of
VEGFR2, to reduced gene and protein expression of vascular endothelial
growth factor, and increased level of antiangiogenic markers.
42. Cabergoline: Yields better results in decreasing size of
endometrioma compared to LHRH by exerting
antiangiogenic effects through VEGFR-2 inactivation
No major side effects
Easy to administer
Cheaper than LHRH-agonist
Reduces pelvic pain associated with endometriosis
significantly
Can be tried as 1st line medical therapy in
endometriomas before resorting to laparoscopic
excision
Hamid AM et al. Arch Gynecol Obstet. 2014 Oct; 290(4): 677-82..
Conclusion
