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Pathophys Semester II > Exam III FGT & Breast > Flashcards

Exam III FGT & Breast Flashcards

1
Q

The Female Genital Tract (FGT) Definitions

A

Fundamental reproductive unit = Single ovarian follicle:

  • Composed of one germ cell (oocyte)
  • Surrounded by endocrine cells

Menarche: Beginning of menstrual cycles

-Avg 11-13 yrs

Female Monthly Sexual Cycle:

-Menstrual cycle controlled by gonadotropins

–Only single ovum is released from ovaries/month

–the uterine endometrium is prepared in for implantation of the fertilized ovum

Ovarian cycle:

  • Follicular phase: avg 15 days
  • Ovulatory phase: ends with ovulation
  • Luteal phase: 13 days
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2
Q

Female Hormonal system

A

Three Hierarchies of hormones:

-A hypothalamus hormone:

–gonadotropin-releasing hormone (GnRH)

-The anterior pituitary sex hormones:

–follicle-stimulating hormone (FSH)

–Luteinizing hormone

-The ovarian hormones:

–Estrogen and progesterone

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3
Q

Normal Female Sexual Cycle

A

Plasma concentrations of the hormones:

FSH:

-early follicular maturation

FSH + LH + estrogen:

-late follicular maturation

LF:

-ovulation causes granulosa and theca cells to produce mainly progesterone-> luteal phase

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4
Q

Menarche

A

add pic

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5
Q

Ovarian & Uterine cycle review

A
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6
Q

Estrogen-associated clinical Disorders

A
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7
Q

Endometriosis

A

A chronic, estrogen-dependent, inflammatory disease

Characterized by: the presence and growth of endometrial tissue outside the uterine cavity

Frequently associated with:

  • Moderate to severe back pain
  • dysmenorrhea, low back pain, and infertility

The most common anatomic sites: in decreased order of frequency, are the ovaries, anterior and posterior cul-de-sac, broad ligaments

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8
Q

Pathogenesis of Endometriosis

A

The Pathogenesis is multifactorial:

  • Ectopic endometrial tissue
  • Inflammation
  • Imbalanced cell proliferation and apoptosis
  • Angiogenesis
  • Genetic factors

Sampson’s theory of retrograde menstruation: endometrial cells flow backward through the fallopian tubes and into the peritoneal cavity during menses

Pre-menarcheal endometriosis: undifferentiated cells of mullerian origin in the peritoneal cavity can differentiate to endometrial tissue

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9
Q

Pathogenesis of Inflammatory Pain in Endometriosis

A

The Three main players involved in the pathogenesis of endometriotic pain:

  • (A) endometriotic lesions
  • (B) the innate immune system
  • (C) the peripheral nervous system

Mediators released from endometrial lesions directly stimulate sensory nerve endings to generate the nociceptive signal

Activation of the innate immune system releases pro-inflammatory and pro-nociceptive mediators, such as nerve growth factor (NGF) to stimulate sensory nerve endings

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10
Q

Uterine Leiomyomas (Fibroids)

A

Benign tumors arising from the smooth muscle cells of the myometrium , the most common pelvic tumor in women

Clinical significance: effect the function and structure of the endometrium causing the pathogenesis of excessive bleeding in uterus

Leiomyoma formation:

  • transformation of normal myocytes into abnormal myocytes
  • growth of abnormal myocytes into clinically apparent tumors
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11
Q

Uterine Leiomyomas Pathogenesis

A

Genetics:

-multiple different genetic pathways

Steroid hormones: estradiol and progesterone induce mature leiomyoma cells to release mitogenic stimuli

Stem Cells: play a key role in fibroid pathogenesis

Vascular abnormalities: increased numbers of arterioles and venules, as well as venular dilation

Fibrotic factors:

  • an increase in ECM components and collagen
  • fibrotic growth factors are also abnormal in leiomyomas
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12
Q

Polycystic Ovarian Syndrome (PCOS)

A

Fundamentally a disorder of intraovarian androgen excess, closely associated with an insulin resistance

Heterogeneous presentation:

  • hirsutism due to the function of hypersecretion of ovarian androgens
  • menstrual irregularity and infertility caused by infrequent or absent ovulation
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13
Q

PCOS Etiology

A

Arises as a congenitally programmed predisposition, first hit that becomes manifest in the presence of a provocative factor, second hit

The congenital factors:

  • Hereditary
  • Acquired (eg, maternal drugs or nutritional disorders affecting the fetus)

The postnatal provocative factor: usually insulin-resistant hyperinsulinism

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14
Q

Unified Minimal Model of PCOS Pathophysiology

A

Funtional Ovarian hyperandrogenism (FOH)

Account for the essential clinical features of PCOS

  • Hirsutism
  • Oligo-anovulation
  • Polycystic ovaries

Hyperinsulinism and obesity:

in the ovary, hyperinsulinism upregulates androgen production in theca cells by sensitizing them to LH, and also prematurely lutenizes granulosa cells

LH excess:

The hyperandrogenemia causes secondary LH elevation by interfering with female hormone negative feedback

In the presence of insulin excess, this LH excess aggravates the ovarian dysfunction

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15
Q

Premenstrual Syndrome (PMS) & Premenstrual Dysphoric Disorder (PMDD)

A

Physical and/or behavioral symptoms in the second half of the menstrual cycle

Physical manifestations:

  • abdominal bloating
  • breast tenderness
  • HA

Risk factors:

  • genetic factors
  • environmental influences

Pathogenesis:

-Ovarian steroids

–an abnormal neurotransmitter response to normal hormonal changes

-Neurotransmitters:

–the evidence is most supportive for a major role of serotonin in the etiology of PMS

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16
Q

Pathophysiology of Menopause

A

Processes contribute to the development of menopause:

  • hypothalamic and ovarian aging
  • environmental, genetic and lifestyle factors
  • systemic diseases

Hypothalamic aging leads to desynchronized GnRH production and an abnormal surge of LH.

17
Q

Anatomy of the Breast

A

Two major structures:

  • ducts
  • lobules

Two types of epithelial cells:

  • luminal
  • Myoepithelial

Two types of stroma:

  • interlobular
  • intralobular
18
Q

Breast Lifestyle Changes

A

Pre-puberty: Lactiferous ducts are formed at birth but lobules remain underdeveloped until puberty.

Puberty: Ovarian estrogen and progesterone induces branching of ductal system and development of lobules

Pregnancy:

  • Progesterone and prolactin induce complete maturation of breast at the time of first full-term pregnancy
  • Permanent increase in number and size of lobules
  • Oxytocin induces myoepithelial proliferation and differentiation
  • Following lactation total breast size decreases due to apoptosis of epithelium and lobule atrophy

Aging and menopause:

  • Lobular and ductal atrophy occurs
  • Interlobular stroma decreases in fibrous connective tissue and increases adipose tissue content
19
Q

Anatomic Locations of Common Breast Lesions

A
20
Q

Classification of Benign Breast Lesions

A

Non-proliferative:

-Not associated with an increased risk of breast cancer

-Simple breast cyst:

–Fluid-filled masses derived from the terminal duct lobular unit

Proliferative without atypia:

-fibroadenomas

-In certain circumstances: small increased risk of developing breast cancer

Atypical hyperplasia

-substantial increased risk of developing breast cancer (especially multifocal lesions)

–Atypical ductal hyperplasia

–Atypical lobular hyperplasia

21
Q

Fibroadenoma

A

SImple fibroadenoma:

Benign solid tumors containing glandular as well as fibrous tissue

Etiology of fibroadenomas is not known

Hormonal relationship likely

For majority, there is no increased risk of developing breast cancer

Complex fibroadenomas:

Associated with a slightly increased risk of cancer with multicentric proliferative changes

22
Q

Pathophys of Fibroadenoma

A

Hormonal:

Estrogen, progesterone, and lactation during pregnancy can stimulate fibroadenomas

Some have receptors on their surface and respond to human growth factor (EGH) and growth hormone

Genetics:

Mediator complex subunit 12 (MED12) gene

23
Q

Estrogen

A

A Steroid Hormone, derived from the androgenic precursors and androstenedione and testosterone by aromatization

Naturally occurring estrogens are:

17 B-estradiol (E2): primarily produced by theca and granulosa cells of the ovary; it is the predominant form of estrogen found in premenopausal women

Estrone (E1): Is the predominant form of circulating estrogen after menopause

Estriol (E3): is the estrogen the placenta secretes during pregnancy

24
Q

Estrogen Receptors (ERs)

A

ER-a is the predominant ER in the uterus, mammary gland

-Sustained estrogenic exposure and activation of ER-a may increase the risk and/or the progression of various cancers, such as breast and endometrium

ER-B is predominantly expressed in ovary and prostate

-In contrast to ER-a, and ER-B activates anti-proliferative and pro-apoptotic pathways in many cancer cells

GPER (G-protein coupled estrogen receptor): mediates rapid estrogen signaling, is expressed in normal ovary and it regulates follicle maturation.

25
Q

Molecular Mechanisms of Breast Carcinogenesis

A

The Human Epidermal Growth factor receptor 2 (HER2) oncogene:

Encodes for the HER2 receptor

The HER2 receptors function:

-Control epithelial <strong>cell growth</strong> and <strong>differentiation</strong> and possibly angiogenesis

Amplification/Overexpression of HER2 in 18 to 20 percent of Human Breast Cancer

Breast Cancer can be broken down into three biologic subgroups:

  1. ER-Positive
  2. HER2-Positive (with or without ER expression)
  3. ER-Negative, PR-Negative, HER2-Negative tumors (triple negative)

-all people with triple negative breast cancer younger than 60 need to be tested for BRCA gene mutations

26
Q

HER2-ER Cross-Talk and Clin Implication

A

The estrogen receptor (ER) and/or HER2 signaling pathways:

the dominant drivers of cell proliferation and survival in the majority of human breast cancers

Clinical implication:

Resistance to both hormone and anti-HER2 therapies occurs frequently and represents a major clinical challenge due to:

-presence of a complex bi-directional molecular crosstalk between the ER and HER2 pathways -> resistance to therapy

27
Q

Types of Breast Carcinoma

A

>95% are adenocarcinomas

Breast Carcinomas are a diverse group of lesions that are different in microscopic appearance and biologic behavior

The in situ carcinomas:

  • Ductal
  • Lobular

The invasive breast carcinomas:

  • Infiltrating ductal: 76%
  • Invasive lobular: 8%
28
Q

Ductal Carcinoma in Situ (DICS)

A

Characteristic: a proliferation of abnormal cells confined within the mammary ductal system

Common features:

-Nuclear grade and/or the presence or absence of necrosis:

–High-grade lesions lack estrogen and progesterone receptors, high proliferative rate, overexpression of the HER2 oncogene, p53 mutations, and angiogenesis

–Low-grade lesions are estrogen- and progesterone receptor-_positive_, low proliferative rate

–Lesions categorized histologically as intermediate grade

29
Q

Invasive (infiltrating) Ductal Based Carcinoma

A

Three grades based on architectural and cytological features

  • Well-differentiated (Grade 1): uniform cells with little or no mitotic activity
  • Moderately differentiated (Grade 2): some glandular differentiation with moderate mitotic activity
  • Poorly differentiated (Grade 3): Without gland differentiation with significant mitotic activity
30
Q

Familial Breast Cancer

A

Mutations in BRCA1 and BRCA2:

-80-90% of familial breast cancers

Normal BRCA1 and BRCA2 are genes that produce proteins to help repair damaged DNA

31
Q

Sporadic Breast Cancer

A

The major risk factors for sporadic breast cancer are related to hormone exposure

  • Gender, age at menarche and menopause, reproductive history, breastfeeding and exogenous estrogens
  • Radiation exposure and exposure to chemicals with estrogen-like effects

Hormonal exposure stimulates breast growth during puberty, menstrual cycles and pregnancy -> increasing the number of cells that can potentially give rise to a cancer

32
Q

Computational Investigation of DNA Repair Deficiency in Sporadic Breast Cancer (explained)

A

BRCAness profile:

Based on gene expression profiles between sporadic & familial breast tumors considering clinical factors

Important influences in management and treatment of PTs with sporadic breast and ovarian cancers

Sample-specific BRCA score:

Indicates homologous recombination (HR) DNA repair pathway

Clinical Significances:

Sporadic Breast & ovarian cancers with defects in HR DNA repair pathway are hypersensitive to alkylating, platinum-based Chemo

For ovarian cancers -> PTs with high BRCA score are more sensitive to chemotherapy and have better prognosis

Pathophys Semester II (14 decks)

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