Lecture 39-41 Flashcards
What are pre-embryonic conceptuses usually resistance to?
Teratogens
What are the odds of birthing a completely normal healthy ifant?
Less than half
When is the spontaneous abotion most likely to occur?
Weeks 1 and 2
What is an EDC?
Endocrine disruption chemicals?
What are the functions of EDCs?
- Mimic endogenous hormones
- Block endogenous hormones
What EDCs mimic?
- Estrogenic chemicals (DES)
- Androgenic chemicals (Trenbolone)
What EDCs block?
Anti androgenic chemicals (Metabolites of DDT and vinclozlin)
Does a hormonal mimic trigger a hormonal response?
Yes, which can be hindering to the organism
What kind of hormonal block doesn’t bind to the binding site directly?
Steric Hindrance
What are the four levels that xenobiotics disrupt endocrine homeostasis at?
- Hormone synthesis (steroidogenesis) via enzymes
- Transport (prohibits binding to SHBG) by keeping endocrine hormones in local circulation and contributing to bioaccumulation
- Activation/Metabolism (Aromatase use/metabolic in activation/5A-reductase) via activation at target tissues and inactivation/degradation
- Receptor Binding (androgen receptor and oestrogen receptor) via internalization
What xenobiotic often affects steroidogenesis?
Phthalates (decreased 3B-HSD)
What xenobiotics often affects the use of aromatase to convert T to Oestradiol?
- Increased atrazine
- Decreased Tributyl Tin
What xenobiotic often affects the binding to SHBG?
Pesticides
What xenobiotics often affects metabolic inactivation/sulphation?
Sulphotransferases (PAHs and PCBs)
What xenobiotic often affects the use of 5a reductase?
Finasteride (proscar/propecia)
What xenobiotic often affects binding to androgen receptors?
p,p’-DDE
What xenobiotic often affects binding to oestrogen receptors?
o,p’-DDE
What the four main categories of EDCs?
- Androgenic
- Anti-androgenic
- Estrogenic
- Anti-estrogenic
What are examples of pharmaceutical androgenic EDCs?
Androgen Receptor Agonists (Trenbolone, Trenbolone acetate)
What are examples of pharmaceutical anti-androgenic EDCs?
- Androgen synthesis inhibitors (Ketoconazole)
- Androgen receptor antagonists (flutamide)
- 5a-reductase inhibitors (finasteride (Proscar, Propecia))
What are examples of environmental anti-androgenic EDCS?
- Androgen receptor antagonists (p,p’-DDT and its metabolites, vinclozolin and its metabolites)
- Androgen synthesis inhibitors (Phthalate esters)
What are examples of pharmaceutical estrogenic EDCs?
Estrogen receptor agonists (ethinyl estradiol, eiethylstilbestrol)
What are examples of environmental estrogenic EDCs?
- Estrogen receptor agonists (o,p’-DDT and its metabolites, Bisphenol A)
- Aromatase stimulant (Atrazine)
What are examples of pharmaceutical anti-estrogenic EDCs?
Aromatase inhibitors (Letrozole (Femara))
What are examples of environmental anti-estrogenic EDCs?
Aromatase inhibitors (Tributyl tin)
What are current hypotheses as to the signs of testicular dysgenesis syndrome?
- Cryptorchidism
- Hypospadias
- Short ano-genital distance (AGD)
- Poor spermatogenesis
- Testicular cancer
What occurs in testicular dysgenesis?
- Decreased Leydig cell function -> Decreased testosterone and INSL3 production -> cryptorchidism, short AGD and hypospadias
- Decreased Sertoli cell function -> Impaired germ cell differentiation -> Impaired spermatogenesis and GCNIS Testicular cancer
- Leydig cell function and Sertoli cell function act as a positive feedback loop on each other when decreased function occurs
What is GCNIS?
Germ Cell Neoplasia in situ
What are the odds of the different locations on cryptorchidism?
- High scrotal (60%)
- Inguinal canal (25%)
- Abdominal (15%)
What is another term for Human papilloma virus?
HPV or wart virus
What areas are known to get cancer due to HPV?
- Cervix
- Vulva
- vagina
- penis
- oropharangea (mouth, tongue and throat >4 times higher in men then women)
- anus
- rectum
What is the most effective method of HPV prevention?
Early vaccination
How many types of HPV are there and which can affect the genital area?
There are over 100 types of which 40 can affect the genital area
Which forms of HPV cause the majority of HPV-related cancer and diseases?
- 6
- 11
- 16
- 18
- 31
- 33
- 45
- 52
- 58
What is special about HPV 6 and HPV 11?
Causes most benign lesions
What is special about HPV 16 and HPV 18?
Causes most malignant lesions of cervical and penile cancer
How does early exposure to Bisphenol A affect the prostate?
- Reprograms human prostate stem-progenitor cells
- Promotes self-renewal
- Increases in vivo carcinogenesis with aging
What is the most common form of ovarian cysts?
Solitary follicular, luteal or theca-lutein cysts
What is polycystic ovary syndrome?
When both ovaries are involved and studded with multiple cysts, and results in obesisty in 50% of cases (hyperinsulinemia)
What is the endocrinopathy of Polycystic Ovary Syndrome?
- Excessive androgen production
- LH:FSH ratio above 2
- Increased testosterone and androstenedione
- Increased estrogen
How does insulin regulate ovarian androgen production?
Increased androstenedione, Testoterone, DHEAS -> act on pituitary to shut off FSH and LH -> shut off estradiol and progesterone
What is DHEAS?
Dehydroepiandrosterone sulphate
What does hyperinsulinemia cause via the regulation of ovarian androgen production?
- Excess hair
- Excess pigment
- Excess acne
- obesity
What is primary amenorrhea?
Absence of menses in a phenotypic female by 16
What is secondary amenorrhea?
Absence of menses for 3 or more years in a previously menstruating woman
What are causes of primary amenorrhea and not secondary?
- Isolated GnRH deficiency
- Congenital defects
- Hypopituitarism
- Polycystic ovary disease
- 17-hydroxylase deficiency
- Vaginal agenesis
- Transverse vaginal septum
- Imperforate hymen
- Testicular feminization
What are causes of secondary amenorrhea but not primary?
- Weight loss
- Pseudocyesis
- Systemic disease
- Post-pill amenorrhea
- Hyperthyroidism
- Cushing’s
- Ectopic ACTH
- Resistant ovary syndrome
- Ovarian Tumors
- Ectopic pregnancy
- Intrauterine pregnancy
- Trophoblastic disease
- Uterine synechiae
What are causes of both primary and secondary amenorrhea?
- Anorexia nervosa
- Strenuous exercise
- Hypothalamic tumor
- Prolactinoma
- Hyperprolactinemia
- Hypothyroidism
- Congenital adrenal hyperplasia (CAH)
- Adenomas/carcinoma
- Ovarian failure
What are the three major causes of amenorrhea?
- Lack of hypothalamic releasing hormones (GHRH, GnRH, TRH)
- Hypopituitarism from structural abnormalities
- Primary hypothyroidism during adolescence may result in sexual infantilism (decreased thyroid -> increased TRH -> increased prolactin release -> decreased GnRH release and function)
What is hypogonadotropic hypogonadism caused by?
Hyperprolactinemia
What is the most common cause of hyperprolactinemia?
It is drug-induced by drugs that act as dopamine receptor antagonists (ex. gut motility stimulator metoclopramide and antipsychotics such as risperidone).
What is the most common cause of pathological hyperprolactinemia?
Prolactin-secreting adenomas
How does hyperprolactinemia affect sex drive?
It decreases it and reproductive function by suppressing gonadotropin secretion.
What is a common treatment for prolactinomas?
Cabergoline, a dopamine receptor agonist)
What effects, outside of aldosterone affects, does 17a-hydroxylase deficiency?
- Shunts precursors into aldosterone pathway -> hypertension
- Amenorrhea
- Lack of secondary sexual characteristics
What effect can reproductive toxicants have on a woman in the womb?
Infertility
What effects can reproductive toxicants have on a woman pre-puberty?
- Sterility
- Accelerated/delayed puberty
- Shortened reproducted life span
What effects can reproductive toxicants have on an adult woman?
- Acyclicity
- Temporary infertility
- Premature menopause
What effects can reproductive toxicants have on a pregnant woman?
- Failed pregnancy
- Lactational effects
What effect can reproductive toxicants have on a woman in menopause?
Neoplasms
What is the potential effect of plasticizers and synthetic estrogens on germ cell nests (mitosis)?
Multi-oocyte follicles -> reduced fertility or infertility
What is the effect of PAHs, solvents and water disinfection byproducts?
Depletion of follicles -> infertility and early reproductive senescense
How does exposure to chemicals that target pre-antral to ovulatory follicles affect the target tissues?
Impair steroid production -> blocks ovulation and hormonal homeostasis -> infertility that may be reverted upon removal of exposure
What leads to impaired steroidogenesis, impaired ovulation, and abnormal cyclicity?
EDCs: PAHs, pesticides, plasticizers, metals, solvents and a variety of endocrine disrupting chemicals
What is produced in Theca Cells, and what triggers the reaction?
Steroidogenesis for T production, triggered by LH.
What occurs in Granulosa cells, and what triggers the reaction?
The conversion of T to E2, triggered by FSH binding and T diffusing from theca cells
What is metrorrhagia?
Bleeding between menstrual periods
What is hypomenorrhea?
Deficient amount of menstrual flow
What is oligomenorrhea?
Infrequent menstruation
What is polymenorrhea?
Increased frequency of menstruation
What is Menorrhagia?
Debilitating increase in the amount and duration of menstruation
What are causes of menorrhagia?
- Endometrial polyps
- Adenomyosis
- Leiomyomas
What is dysmenorrhea?
Higher levels of cramping pain during menstruation
What is primary dysmenorrhea?
- Not related to identifiable pathologic condition, but is due to excessive production of prostaglandins.
- Promote uterine contractions and ischemia of endometrial capillaries resulting in cramping pain
How does one treat primary dysmenorrhea?
- Targeting the pathways for the synthesis of eicosanoids
- Anti-inflammatory steroids (cortisol) inhibit phospholipase A2
- Aspirin and other NSAIDs inhibit cyclooxygenase
What is secondary dysmenorrhea?
Dysmenorrhea associated with disorders such as leiomyomans, pelvic adhesions or endometriosis
When are prostaglandins produced under physiologic conditions?
When there is a decrease in progesterone and estrogen
How does prostaglandins effect menses?
Causes vasoconstriction -> uterine contractions
What do NSAIDs/TCDD (cox-2 inhibitors) cause in the menstrual cycle?
Failure of PG synthesis
What does atrazine cause in the menstrual cycle?
Failure of LH surge
What do Industrial Chemicals cause in the menstrual cycle?
Abnormal cyclicity
What do dioxins cause in the menstrual cycle?
Hemorrhagic follicles and endometriosis
What are the clinical manifestations of endometriosis?
- Dysmenorrhea
- Increased risk for ectopic pregnancy
- Hormonal treatment regimens mimic state of pregnancy or menopause
- Endometrial glands and stroma w/ scattered histiocytes containing hemosiderin
Current treatment options if infertile w/ endometriosis?
Laparoscopic excision of lesions
Current treatment options if fertility not desired w/ endometriosis?
- Oral contraceptive pills or progestogens (w/ or w/o simple analgesics)
- Gonadotropin-releasing hormone analogues (with or without add-back therapy)
- Laparoscopic treatment
- Hysterectomy and oophorectomy
What is dilatation?
Dilators used to be inserted to widen the cervix leading to lacerations in 5% of cases
What is curettage?
The safest use is laminaria, which is dried, sterilized cylinders of seaweed that absorb water and swell to 3-5 times their size, which are inserted in the cervical canal for 3-5 hours before curretage.
How do endometrial adenomas get recognized?
Clinically may not be recognized (may be discarded in menstrual blood) whcih may become indistinguishable from endometrial hyperplasia
How can hyperplastic glands with atypia progress?
Atypia may progress to adenocarcinoma
How are perimenopausal women affected by endometrial hyperplasias and adenomas?
Diminished hormonal signaling often results in incomplete endometrial sloughing, and the endometrium may buildup from cycle to cycle resulting in formation of polyps
How does hyperplasia affect the endometrial lining?
Continues growing after proliferation stage, no regression or menstruation occurs
What is the epidemiology and pathogenesis of endometrial cancer?
- Most common malignant tumor of female genital tract (about 50% of all gynecological malignancies)
- Considered an estrogen-induced malignancy
- 25%-30# of women w/ complex hyperplasia -> atypia -> adenocarcinoma
- E-induced hyperplasia and neoplasia might be related to the inactivation of a tumor suppressor gene (PTEN - phosphatase and tensisn homologue, which is a target of DMRT1)
Staging of endometrial cancer:
I- carcinoma confined to endometrium
II- carcinoma extending into cervix and invading myometrium
III- tumor extending through wall of the uterus but not outside plvis
IV- Carcinoma infilitrating the bladder or rectum or extending outside of pelvis
What is the most common form of cervical cancer?
Squamous cell carcinoma, often due to HPV
What is the vaccine that protects against the 9 oncogenic strains of HPV?
Gardasil vaccine
What is the diagnostic methods of discovering cervical cancer?
- Papanicolaous (PAP) smear (Pre-invasive lesions may be graded as mild, moderate, severe dysplasia or cervical intraepithelial neoplasia (CIN I-III) or as carcinoma in situ)
- Colposcopy
- Punch-, Cone bioposy (Viral studies show that >50% of all CIN lesions contain HPV)
What is the transformation zone in regards to cervical cancer?
The outer surface of the cervix (exocervix) is covered with squamous epithelium vs. the endocervical canal is lined by columnar epithelium. The zone is where they meet, which may widen after trauma
Why is the transformation zone where most cervical carcinomas originate?
Because of the intense proliferation, which leaves the cells susceptible to HPV and can induce neoplastic transformation (increased risk with multiple pregnancies or partnerships)
How does cervical cancer look in stage 0?
Lack of epithelial maturation in CIN in contrast to normal epithelium shows distinct basal, suprabasal and superficial layers + basement membrane intact
What is the survival rate when cervical cancer is detected early?
92%
How is cervical cancer staged?
0- No gross lesions; CIN III limited to mucosa
I- invasive carcinoma confined to cervix or body of uterus
II- carcinoma extending beyond cervix and uterus but not extending below upper vagina
III- tumor reaching the pelvic wall
IV- tumor spread beyond the pelvis/infiltrated adjacent organs (metastases)
How does vulvar cancer form?
Venereal disease -> leukoplakic changes (whitish plaque-like or ulcerated lesions) may precede development of carcinoma
How does vaginal cancer form?
A clear-cell transgenerational adenocarcinoma formed via in utero exposure to diethylstilboestrol (DES).
Why is vaginal cancer so easy to metastasize?
- Thin-walled
- Rich lymphatic drainage
What are ovarian tumors?
- Surface epithelial origin
- Germ cell-origin
- Sex cord stromal cell origin
- Non-specific or metastases from other organs
Ovarian tumors are always malignant
FALSE- They typically are groupings of benign and malignant lesions
What is the epidemiology of ovarian cancer?
- Leading cause of death from gynecologic cancer
- Prophylactic oophorectomy and salpingo-oophorectomy in high-risk women
- Mutations and/or overexpression of HER-2/neu, c-myc, and K-ras (oncogenes) and of p53 (tummor suppressor gene) observed in sporadic ovarian cancer
- High-risk families have BRCA1 and BRCA2 as most frequently involved genes
