Pathophysiology

Script
Endometriosis
Menstrual Cycle For the Pathophysiology, we begin with the menstrual cycle since patient C.S. experiences hypogastric pain
during her menstrual period.
- Progesterone
- Vasoconstriction of the spiral
arteries In the absence of absence of a pregnancy, there is progesterone withdrawal due to the declining corpus luteum
- Hypoxia and necrosis of the function.This happens during the late secretory phase or during the premenstrual period. Progesterone
functional layer withdrawal results in increased coiling and constriction of the spiral arterioles leading to hypoxia, necrosis of
- Acute inflammatory response the functional layer of the endometrium. This then leads to an acute inflammatory response where in
(PGs, IL-8, neutrophils)
chemokines and prostaglandins are released and attracted neutrophils help in the destruction of the functional
- Shedding of the endometrial
layer. This leads to the shedding of the endometrial lining manifested as menstruation.
lining

Retrograde Menstruation Theory There are several theories regarding the causes of endometriosis but theres no identified main cause yet.
Endometriosis is said to be multifactorial.
-Genetic predisposition, Altered The retrograde menstruation is the most studied and thus, the most commonly used theory. It states that
Immune Response ~10% of menstrual blood is refluxed through the fallopian tubes into the peritoneal cavity and thus, leading
to ectopic implantation of endometrial tissue.

The other theories include: coelomic metaplasia, lymphatic and vessel metastasis, and immunologic changes.

All menstruating women undergo retrograde menstruation but not all of them develops endometriosis and
thus, retrograde menstruation may be enough to displace the endometrial fragments into the peritoneum but
the genetic predisposition and aletered immune response may be responsible for the attachment, invasion, and
proliferation of the endometriotic tissue.

Implantation of Endometrial Cells In order for the tissue to implant and thrive in an ectopic location, it must attach itself into a new
environment and establish a new blood supply.
-Attachment to the mesothelium The displaced tissue then expresses adhesion molecules such as ICAM-1 and Fibronectin in order to attach to

-Matrix degradation and Invasion the mesothelium.

It also expresses MMPs or matrix metalloproteinases which are enzymes the degrade the cell matrix in order
for them to continue their invasion.
Macrophage activation and Because the body senses this as a foreign body invasion, macrophages are then activated and recruited to the
Recruitment endometriotic tissue site. According to Williams, women who develop endometriosis have more peritoneal
macrophages that are larger and more hyperactive. These abnormal macrophages release inflammatory
-Cytokines (IL-1,IL-6, IL-8, TNF-a) cytokines and growth factors that induce further inflammation, proliferation, and angiogenesis.

-Growth Factors Furthermore, the capability of the Natural Killer Cells (NK Cells) to clear the endometriotic tissue is decreased
leading to decreased clearance of endometriotic tissue.
- NK Toxicity

Neovascularization In order to survive, the endometrial implants must have an additional blood supply and must proliferate.
Thus, the cells express growth factors responsible for cell division and for creation of new blood vessels or
-PDGF, IGF, HGF, VEGF production angiogenesis.

Survival and Inflammation of the Further survival and inflammation of the endometriotic tissue depends on the presence of estrogen and a
endometrial tissue state of progesterone resistance.

-Estrogen dependence

-Progesterone-resistance

IMAGE- Positive Feedback Loop Endometriosis is defined as an estrogen-dependent disease, thus, estrogen plays a key role in its survival and
1st slideEncircle Estradiol subsequent inflammation. There are several sources of estrogen in a woman: the ovaries and the adipose tissue
but in women with endometriosis, the endometriotic tissue locally produces estrogen or in here, Estradiol
which ultimately causes, again, its survival and inflammation.

The next question is how does the endometriotic tissue locally produce estrogen?

2nd slideEncircle STAR, SCC, It produces estrogen locally because endometriotic tissue expresses a complete set of steroidogenic genes,
HSD3B2, 17-hydrolyase-17-20-lyase including aromatase as encircled here. The genes produces enzymes that convert cholesterol to
and Aromatase androstenedione which is then converted to estrone by aromatase. The enzymes include STAR or
steroidogenic acute regulatory protein, SCC or side-chain cleavage enzyme, HSD3B2 or 3Beta-hydroxysteroid
dehydrogenase 2 and 17-hydrolyase-17-20-lyase and aromatase.

3rd slide--- Encircle SF1 (steroidogenic In addition, ER- or Estrogen Receptor Beta and SF-1 or Steroidogenic Factor 1 is overexpressed in endometriotic
ER- tissue and not in normal endometrium. These are essential enzymes in the postive feedback cycle as well see
later.

WITH EXTRA BOXES

4th slideEncricle A LOT-ERB, COX- As estogen binds to ER-B or Estrogen Receptor Beta this induces the production of Cyclooxygenase-2 which
2, PGE2, enter inflammation, converts the arachidonic acid to PGE2 or Prostaglandin E2 which causes inflammation, and also
vasoconstriction, uterine vasoconstriction, uterine contractions, and pain which contributes to the secondary dysmenorrhea & pelvic
contractions, pain which leads to pain as experienced by the patient.
secondary dysmenorrhea & Pelvic
pain

5th slide-Encircle SF1 and (+); Steroidogenic Factor 1 or SF1 is a nuclear receptor which is present in endometriotic tissue and absent in
endometrium and this is Prostaglandin E2 dependent. Upon production of Prostaglandin E2, SF1 amplifies the
expression of the steroidogenic enzymes and aromatase levels which again converts androstenedione to
estrone leading to estradiol, the biologically active form of estrogen and this completes the positive feedback

mechanism.


6th slide- Encircle COX-2, IL-1b, VEGF, It is also important to point out that there are several hormones in addition to estradiol that induce the
and PGE2 expression of COX-2 or cyclooxygenase 2 which are the following: interleukin-1B, VEGF or Vascular
Endothelial Growth Factor, and Prostaglandin E2 itself induces COX-2 expression. All in all there are 4
hormones that induce its expression.



7th slide- Vasoconstriction, uterine
Thus, cytokines, angiogenic factos, prostaglandin E2 itself, and estradiol all induce COX-2 expression in patients
contractions, pain leading to
with endometriosis and thereby ensure production of large quantities of prostaglandin E2, which again causes
dysmenorrhea & pelvic pain
vasoconstrction, uterine contractions, and pain which contributes to the secondary dysmenorrhea and pelvic
pain experienced by the patient.

Formation of adhesions,
Endometrioma
Rectovaginal Endometriotic Nodule

-Immobility of the pelvic organs,
retroverted and retroflexed uterus,
secondary dysmenorrhea, dyspareunia,
chronic pelvic pain & infertility