Term
| Describe the basic process of LH and FSH regulation |
|
Definition
- GnRH is released into the portal bloodstream at the median eminence(from small diffusely located neurons in the hypothalamus) in a pulsatile pattern
- Frequency of GnRH pulses conveys important information to the anterior pituitary to control LH and FSH secretion (should be matched 1:1).
- FSH/LH release is mediated by DAG/PCK-mediated calcium influx. |
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Term
| What is the pathophysiological basis of "Kallman's Syndrome" and how do you treat? |
|
Definition
1) Failure of GnRH neurons (originiating outside of CNS) to migrate from the epithelial tissue of the nasal placode to the hypothalamus.
2) Give exogenous GnRH to treat hypothalamic hypogonadism. |
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Term
| Why mighty you give a child with precocious puberty a long-acting GnRH agonist? |
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Definition
**Also used in estrogen-dependent breast cancer**
Continuous exposure to GnRH leads to "down regulation" or GnRH receptors and an accompanying decrease in FSH/LH secretion from the pituitary. |
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Term
| How does the Kisspeptin peptide regulate the reproductive hormone axis? |
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Definition
Peptide ligand for GPR54 (GPCR), which is expressed on GnRH-secreting hypothalamic neurons.
Abnormalities in Kisspeptin:GPR54 axis have been associated with abnormal pulsatile GnRH release in Idiopathic Hypogonadotropic hypogonadism. |
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Term
| How is FSH/LH release regulated by GnRH pulsative frequency and hormone levels? |
|
Definition
Independent regulation
1) Inhibin feeds back and inhibits FSH release, but NOT LH
2) High frequency pulsations lead to higher circulating levels of LH compared to FSH, and this is reversed at lower frequencies (FSH> LH) |
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Term
| Why is glycosylation of FSH and LH an important processing step prior to secretion? |
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Definition
Sialic acid is most important sugar.
More sugar= increased half-life (decreasing degradation by the liver)
Less sugar= more potency at receptor |
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Term
| How are the gonadal steroid hormones produced? |
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Definition
All come from cholesterol
Males
1) Leydig cells in testes produce testosterone in response to LH
2) Female
- Ovary produces 17b-estradiol (FSH and later FSH + LH) and progesterone (LH)
- Ovary also produces low levels of androgen intermediate |
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Term
| When does "positive feedback" occur in the sex hormone axis? |
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Definition
Once per menstrual cycle at the FSH/LH surge!
Surge occurs near the end of the follicular phase, prior to the luteal phase of the menstrual cycle.
- acts on pituitary and hypothalamus |
|
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Term
| Describe the basic timing of the reproductive cycle. |
|
Definition
- Number of days of ovulation (luteal phase) to day 1 is relatively fixed (12-16 days)
- Day 1 is the first day of flowing menses (not just spotting)
- Number of days from day 1 to ovulation (follicular phase) varies from woman to woman, cycle to cycle |
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Term
| Describe the functional anatomy of the ovarian follicle. |
|
Definition
Key reproductive structure in the ovary, consisting of Primary oocyte (arrested in first meiotic division) and Granulosa cells
1) Primordial follicle: primary oocyte + single layer of flat granulosa
2) Primary follicle: Primordial follicle, but with single layer of cuboidal granulosa cells
3) Secondary follicle: Several layers of granulosa cells
4) Antral follicle: Oocyte with zona pellucida (many layers of granulosa cells, follicular fluid accumulated, theca cell layer visible outside the granulosa layer)
**Group of follicles eligible for cyclic recruitment to compete to ovulate (2-9mm fluid-filled cyst on ultrasound)
5) Pre-ovulatory follicle (dominant follicle close to time of ovulation): Oocyte with zona pellucida and several layers of cumulus cells (granulosa cell "crown" around oocyte)- 18-25 mm fluid-filled cyst on US
6) Corpus luteum: follicle after ovoluation. Granulosa cells are luteinized and transition to produce progesterone (can make estrogen also)- looks like blood and clot on US |
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Term
Describe the appearance and structure of each of the following follicular stages.
1) Primordial
2) Primary
3) Secondary
4) Antral
5) Pre-ovulatory
6) Corpus luteum |
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Definition
1) Primordial follicle: primary oocyte + single layer of flat granulosa
2) Primary follicle: Primordial follicle, but with single layer of cuboidal granulosa cells
3) Secondary follicle: Several layers of granulosa cells
4) Antral follicle: Oocyte with zona pellucida (many layers of granulosa cells, follicular fluid accumulated, theca cell layer visible outside the granulosa layer)
**Group of follicles eligible for cyclic recruitment to compete to ovulate (2-9mm fluid-filled cyst on ultrasound)
5) Pre-ovulatory follicle (dominant follicle close to time of ovulation): Oocyte with zona pellucida and several layers of cumulus cells (granulosa cell "crown" around oocyte)- 18-25 mm fluid-filled cyst on US
6) Corpus luteum: follicle after ovoluation. Granulosa cells are luteinized and transition to produce progesterone (can make estrogen also)- looks like blood and clot on US |
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Term
| What are the major phases of the Menstrual cycle? |
|
Definition
1) Follicular
- LH/theca cell- FSH/glomerulosa cell model leads to recruitment of antral follicles and selection of dominant follicle by 5-7d
- Estradiol and progesterone exert positive feedback on pituitary to stimulate LH surge
2) Ovulation
- Follicular rupture occurs 36 hours later
3) Luteal (w/o pregnancy, 12-16 days)
- Luteinized granulosa cells produce progesteone, supporting the corpus luteum until pregnancy, or regression |
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Term
| Describe the process of "cyclic recruitment" in the follicular phase of the menstrual cycle. |
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Definition
Antral follicles eligible for recruitment (10 per cycle) respond to rising FSH levels in late luteal and menstrual part of cycle
1) LH binds to theca cells, which make testosterone
2) FSH binds granulosa cells, inducing aromatase to convert testosterone to estradiol and leading to cell proliferation
3) As estradiol rises, FSH lowers by negative feedback and by 5-7 days, dominant pre-ovulatory follicle is chosen |
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Term
| What is the mechanism and role of the Luteal surge during Ovulation? |
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Definition
1) At end of follicular phase, Estradiol is high and granulosa cells make a bit of Progesterone, together leading to the LH surge.
2) LH surge puts the primary oocyte into meiosis
- First division is complete and secondary follicle and first polar body each have 23 chromosomes
- If fertilized, the second division will take place
- After 36h, LH stimulates production of PGE, progesterone and proteolytic enzymes that cause follicular rupture (ovulation). |
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Term
| What is the role of LH in maintainence of the corpus luteum? |
|
Definition
36 hours after onset of LH surge, LH stimulates production of PGE, progesterone and proteolytic enzymes that cause follicular rupture.
Leutinization of granulosa cells is critical to turn the deflated follicle into the progesterone/estradiol factory, the Corpus Luteum!
**If pregnancy occurs in the luteal phase, hCG will take over for LH in maintaining corpus luteum. |
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Term
| Describe the basic steps of the Luteal phase of the menstrual cycle |
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Definition
Luteal phase following follicular rupture in ovulation, which occurs 36h after LH surge.
1) Luteinized granulosa cells produce progesterone and estradiol
2) If pregnancy does not occur in 12-16 days, the leutinized granulosa cells will regress and produce less hormone.
3) IF pregnancy occurs, hCG replaces LH as the stimulus for corpus luteum function (binds and signals via LH receptor).
** You need corpus luteum to support pregnancy until placenta can take over at 7 weeks gestation) ** |
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Term
| What is happening to the Endometrium during the menstrual cycle? |
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Definition
1) Proliferative phase (follicular)
- Estradiol induces glandular cell proliferation
2) Secretory phase (luteal phase)
- Progesterone transforms endometrium into secretory appearance and function
- Late in secretory phase, decline in estradiol and progesterone result in disruption of endometrial tissue (shedding= menstruation). |
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Term
| What percentage of ovarian follicles are function at the time of menopause? |
|
Definition
None!
They do not respond to HPA reproductive signal and do not make estrogen or progesterone. |
|
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Term
| What are the basic sex steroids? |
|
Definition
1) Progesterone (21C)
2) Androgens (19C)
3) Estrogens (18C) |
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Term
| What is the "transformation zone" in reference to cervical anatomy? |
|
Definition
Site of squamous cell carcinoma and dysplasia.
The uterine cervical epithelium is composed of endocervix (columnar/mucin secreting) and the ectocervix (stratified squamous).
These epithelium meet at the SC junction, and the area between the SCJ and the border of metaplastic squamous epithelium is the Transition Zone (the site of squamous cell carcinomas and dysplasia) |
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Term
| What are the major benign lesions in the uterine cervix? |
|
Definition
Acute and Chronic cervisitis
- HPV, Trichomonas, Gonococci, Chlamydiae, HSV-2
pregnancy complications and sexual transmission |
|
|
Term
| What are the most common types of cervical cancer and in whom do they occur? |
|
Definition
30% higher occurrence in african americans, with 2x mortality (average age 47 overall)
1) Squamous (70%)
2) Adeno (25%)
3) Adenosquamous (3-5%) |
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|
Term
Which of the following is NOT a risk factor for developing cervical cancer?
1) Early age at first intercourse
2) Multiple sexual partners
3) Nicotine exposure
4) HPV 18
5) HPV 6 |
|
Definition
5- This is just genital warts
Young age of first sex with multiple partners or partners with multiple partners, as well as nicotine exposure. |
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|
Term
| Describe the viral pathogenesis that is associated with increased risk of cervical cancer. |
|
Definition
HPV 16 and 18- Papillomavirus- dsDNA virus (vs. 6 and 11, which are condyloma warts)
- Over-expression of E6 and E7 proteins immortalize and transform cells by overcoming p53 and RB, respectively, leading to intraepithelial neoplasia.
**Look for Koilocytosis on pap smear and histology** |
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Term
| What are the basic stages of Cervical intraepithelial neoplasia (CIN)? |
|
Definition
HPV 16/18 associated (p53/RB)
1) Low grade dysplasia, correlating to LSIL on pap smear cytology
- Look for epithelial disorganization of lower 1/3, with surface Koilocytotic changes
II) Moderate dysplasia, correlating to HSIL on cytology
- Epithelial disorganization of lower 2/3, with loss of polarity and increased mitoses
III) Severe dysplasia (20% go to carcinoma)
- Epithelial disorganization of full thickness
- Increased N/C ratio |
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Term
| Why is the relative number of cases of cervical adenocarcinoma increasing in the US? |
|
Definition
| Difficulty of detecting glandular lesions on Pap smear compared to squamous cell |
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|
Term
| What are the major anatomical divisions of the uterus? |
|
Definition
1) Uterine corpus (upper 2/3)
- Triangular cavity (endometrium, myometrium, serosa)
- Isthmus (corpus to cervix)
2) Cervix (lower 1/3)
- Endocervix (columnar)
- Ectocervix (stratified squamous)
**Separated by SCJ** |
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Term
Which type of benign lesion of the uterine corpus is described by each of the following?
1) Arias-stella reaction: endometrial glands with abundant clear or eosinophilic cytoplasm and marked nuclear changes (large, hyperchromatic, pleomorfic)
2) Microabscesses (PMN aggregates) with destruction of glandular epithelium and mixed infiltrate
3) Spindly stroma with edema; weakly proliferative glands, with plasma cells, histiocytes and lymphoid follicles
4) Endometrial tissues found outside of the uterus (ovary) causing pain
5) Perimenopausal bleeding
6) Excessive and prolonged unopposed estrogenic stimulation due to lack of ovulation
7) Sessile masses of variable size that project into endometrial cavity
8) Fibroids composed of smooth muscle commonly found in myometrium, which rarely undergo malignant transformation |
|
Definition
1) Pregnancy changes
2) Acute endometritis (post-delivery or miscarriage due to retained products of contraception/instrumentation)
3) Chronic endometritis (PID, IUD, TB, bacteria vaginosis)
4) Endometriosis
- May cause regurgitation, angiolymphatic dissemination and metaplastic changes
5) DUB usually due to Anovulatory cycle or irregular coagulation/shedding
6) Anovulatory cycle (most common cause of DUB)
- Endocrine, Ovarian or general metabolic disorders.
7) Endometrial polyp (associated with tamoxifen)
8) Leiomyoma
- In pregnant women, they can cause spontaneous abortion, birth defects and post-partum hemorrhage. |
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Term
What types of hyperplasia is described by each of the following?
1) Individual glands have "cloverleaf" shape and nuclei are enlarged, irregular and stratified, with abundant mitoses"
2) Apparent proliferation of normal endometrium with uniform nuclei resembling those of proliferation enndometrium |
|
Definition
Increase in gland:stroma ratio caused by prolonged estrogen stimulation by anovulation (menopause) or increased production (endocrine or ovarian)
**Usually produces bleeding**
**Related to inactivation of PTEN tumor suppressor gene**
Based on architecture (simple vs. complex) and typia (atypical vs. non-atypical)
1) COmplex hyperplasia with atypia (29 risk of carcinoma)
2) Simple hyperplasia without atypia (1 % risk)
**Atypia is bigger risk factor than architecture** |
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Term
| What is the treatment of choice for a patient with complex atypical hyperplasia of the uterine corpus? |
|
Definition
29% risk of progression to carcinoma, so Hysterectomy is indicated.
Surgery is first line treatment of choice in most all cases of endometrial carcinoma
Remember, all hyperplasia is due to excess estrogen (anovulation or excess production) with common bleeding |
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Term
| How does the gender-associated risk of Endometrial cancer differ from cervical cancer? |
|
Definition
**Cervical is younger**
Blacks get cervical 30% more and die 2x
Whites get endometrial cancer mroe |
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Term
| What is the classification scheme and grading system of endometrial cancer? |
|
Definition
1)Type 1 (estrogen related- 80%): 3 stages based upon differentation
- 55-65 year old women with back-to-back malignant glands without intervening stroma
- Obesity, DM, HTN and infertility are risk factors
- K-ras, PTEN, beta catenin mutations
2) Type 2 (non-related 20%)
- Older patients without hormonal risk factors
- p53 mutations with poor differentiation and prognosis (no grading system) |
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Term
| What is the most common gynocological malignancy in the US? |
|
Definition
Endometrial cancer
- Type 1 is estrogen-dependent, occurs in younger women, is preceded by atypical hyperplasia and has good prognosis
2) Type 2 (Papillary serous carcinoma and clear cell carcinoma) are not related to hormonal risk factors, occur in older patients, have p53 associations and poor prognosis. |
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Term
Which of the following is NOT characteristic of type 1 endometrial cancer?
1) Estrogen dependent
2) Preceeded by nuclear atypia
3) Good prognosis
4) p53 mutations
5) PNET mutations |
|
Definition
4- This is type 2
- Papillary serous carcinoma and Clear cell carcinoma are associated with p53 mutations in older individuals with poorer prognosis than type 1 |
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|
Term
Which benign ovarian/upper GU tract lesion is described by each of the following?
1) Clear serous filled structures with thin smooth muscle walls comprised of granulosa and thecal cells
2) Clear serous fluid-filled structure with beningn ciliated or nonciliated cuboidal/flattened lining
3) "Chocolate cysts" containing endometrial stroma, endometrial glands and hemosiderin-ladened macrophages
4) Cysts with bright yellow lining and bloody contents |
|
Definition
1) Ovarian cyst
2) Surface epithelial inclusion cyst
3) Endometriosis hemorrhagic cysts
4) Corpus luteal cysts |
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Term
Patient presents with anovulation and oligomenorrhea.
She is obese, diabetic, and shows signs of virilism.
What do you expect to see on histology? |
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Definition
Sounds like PCOD (benign ovarian lesion)
Enlarged ovaries with thick cortex and multiple small follicle cysts |
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Term
Patient who recently had an induced abortion presents with pelvic pain, adnexal tenderness, fever and vaginal discharge.
What might you do next and what might you see microscopically? |
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Definition
Sounds like PID: Complications include peritonitis, intestinal obstruction, bacteremia and infertility
- Culture for Gonococci, chlamydiae and enteric bacteria
- You would see inflammatory changes in affected organs with acute, suppurative infiltrate. |
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Term
| What types of ovarian tumors dominate in older and younger women and what are the important risk factors? |
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Definition
Risks include nulliparity, family history, BRCA mutations (BRCA1> BRCA2)
**80% of tumors are begnign**
1) Older women get surface epithelial tumors (most common overall and most common malignancy)
2) Younger women get germ cell tumors |
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Term
| What is the most common ovarian tumor and what is the most common malignant ovarian tumor? |
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Definition
Both are Surface epithelial tumors (more common in older women- younger women get germ cell tumors like Teratomas)
1) Serous surface epithelial tumor is most common
2) Surface epithelium tumors compromise 90% of malignancies |
|
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Term
| What is the most common ovarian tumor and what is the most common malignant ovarian tumor? |
|
Definition
Both are Surface epithelial tumors (more common in older women- younger women get germ cell tumors like Teratomas)
1) Serous surface epithelial tumor is most common
2) Surface epithelium tumors compromise 90% of malignancies |
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Term
Which type of Surface epithelial tumor of the ovaries is described by each of the following?
1) Unilocular, bilateral cyst with microscopic evidence of epithelial thickening and papillary projections
2) Multilocular, unilateral mass thick with mucus and tall columnar epithelium associated with "jelly belly" ascites
3) Malignant tumor associated with endometrial cancer
4) Maligant tumor associated with endometrial tissue outside of uterus
5) Benign unilateral tumor with nests of cells that resemble urothelial lining of the bladder |
|
Definition
Serous and Mucinous most common
1) Complex Serous Tumor
- Borderline ST or Cystadenocarcinoma based upon complex architecture
- Bilateral, so probably carcinoma
2) Mucinous tumor- Pseudomyxoma Peritonei
3) Endometrioid tumor
4) Clear cell tumor associated with endometriosis
5) Brenner tumor |
|
|
Term
| What are the typical types of germ cell tumors of the ovaries? |
|
Definition
Generally found in younger women (vs. Surface epithelial tumors in older women)
1) Teratoma (95%)
- Mature/benign (dermoid cysts with mature tissue from > 1 germ cell layer)
- Immature/malignant
- Monoderm/specialized (Struma ovarii- thyroid or Carcinoid)
2) Dysgerminoma
- counterpart to male testicular seminoma
- 50% of malignant germ cell tumors with high radiosensitivity
3) Yolk sac (endodermal sinus)
- Rare, associated with AFP and less favorable prognosis
4) Choriocarcinoma
- Usually a mixed tumor with high hCG |
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Term
| What are the typical types of Sex cord-stromal tumors of the ovaries? |
|
Definition
Derived from ovarian stroma, which arises from sex cords of embryonic gonad (mostly benign, except for some granulosa cell and sertoli-leydig cell tumors)
**present as adnexal masses that may produce sex steroid hormones and can be aggressive**
1) Granulosa
- Adult (Call-Exner bodies- rosette with pink lumen)
- Juvenile (dilated, irregular cysts without Call-Excner bodies)
2) Fibroma-Thecoma
- Mixture of fibroblasts (fibroma) and spindle cells with lipid (thecoma)
- Meig's syndrome association
3) Sertoli-Leydig cell tumors (Androblastomas) |
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|
Term
| What are the major products of the male testis? |
|
Definition
1) Inhibin (Down-regulate FSH synthesis and secretion)
- 1 beta (same as activin) and 1 alpha
2) Activin (Up-regulate FSH synthesis and secretion)
- 2 identical beta subunits
3) Sperm
- Spermatogonia, Spermatocytes, Spermatids, Spermatazoa
4) Testosterone |
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|
Term
| What are the major cell types of sperm synthesis in the testes? |
|
Definition
Sperm are formed in seminiferous tubules in testes
Spermatogenesis- Nuclear manipulation to produce round haploid spermatid
Spermiogenesis- Cytoplasmic rmodeling into condensed nucleus, acrosomal cap and flagellar tail (Spermatozoa)
Spermiation: release of spermatozoa into lumen of seminiferous tubule
1) Spermatogonia- most basal cells within tubule, adjacent to BM
- A: Dark (nonmitotic) and then Pale (mitotic)- Both 2N DNA
2) Spermatocytes (middle of tubule wall)
- Primary (4N) in meiosis 1
- Secondary (2N) meiosis 2
3) Spermatid (1N)- final product of meiosis
- small round cells with condensed nuclei
4) Spermatozoa (1N)- Matured with sperm shape |
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Term
| Where are Sertoli and Leydiig cells found and what are their primary functions? |
|
Definition
1) Sertoli cells (Nourish and barrier)
- Large, pale cells with prominent nucleoli that lines the outside of the seminiferous tubules
- Respond to FSH to produce Testosterone-binding protein (testosterone from Leydig cells) and retinol binding protein
- Tight junctions between cells forms Blood-Testis baririer
2) Leydig cells (Sex hormone production)
- Outside of seminiferous tubules, within interstitial stromal comparment
- Large, eosinophillic cells that respond to LH to produce testosterone. |
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Term
| What are the Rete Testes? |
|
Definition
Anastamosing network of tubules that collect mature spermatozoa in the seminiferous tubules and deliver them to the efferent ducts.
**located and hilum of testis** |
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|
Term
| What is the composition and function of prostatic secretions? |
|
Definition
Prostate is located at base of urinary bladder, surrounding ejaculatory duct and urethra.
Alkaline secretions dilute and serve as the vehicle for sperm transport
1) PSA- serine protease that lyses clotted semen in female reproductive tract
2) Citric acid- Ca2+ chelator to limit precipitation of secretions
3) Prostatic acid phosphatase- phospholipid metabolism |
|
|
Term
| Describe the 3 secretory zones of the Prostate. Which is the site of the majority of prostate cancers? |
|
Definition
Peripheral prostate gests cancer 80%
Prostate composed of 30-50 branched tubuloaveolar glands in fibromusclular stroma, secreting alkaline solution (PSA, Citric acid and PAP)
1) Central: directly surrounds ejaculatory ducts that lead from seminal vesicles to fuse with urethra (5% of cancer)
2) Transition: Surrounds proximal urethra, anterior most glands (Site of BPH and 10% of cancer)
3) Peripheral: Posterior wall, surrounds distal urethra (80% of cancer) |
|
|
Term
| Describe the appearance of normal prostatic epithelium histologically. |
|
Definition
1) Basal layer of small cells, which should be anchored to the basement membrane by cytokeritin (sign of normal)
2) Columnar apical layer
*As males age, lamellar deposit of prostatic secretions begin to accumulate within the lumens (corpora amylacea) |
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|
Term
| Which early reproductive tissues are "bipotent"? |
|
Definition
Bipotency remains until 5-7 weeks gestation
1) Genital Ridges: intermediate mesoderm
- Thickenings along medial border of mesonephros that become gonads
- Coelomic epithelial cells lining ridges become sex chords
2) Genital ducts: intermediate mesoderm
- Wolffian (Mesonephric): Epididymis, vas deferens, seminal vesicles
- Mullerian (Paramesonephric): Uterus, cervix, part of vagina (upper 1/3)
3) Mesodermal swellings: UGS surrounding cranial cloaca, becoming external genitalia
4) Primordial germ cells (outside gonadal tissue)
- Arise from cells passing through primitive streak, becoming recognized int he endoderm of the yolk sac
- At 5-6 weeks, PGCs migrate dorsally into hindgut, through dorsal mesentery and into genital ridges, coalesceing with somatic cells to form chords. |
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Term
At 5-6 weeks, Primary germ cells migrate dorsally into hindgut, through dorsal mesentery and into genital ridges, coalesceing with somatic cells to form sex chords.
What happens if this migration fails and they develop in ectopic locations? |
|
Definition
Teratoma!
Most common germ cell tumor of young women's ovaries. |
|
|
Term
| During testicular development, what are the first testes-unique cells to arise and what is their functional importance? |
|
Definition
1) Sertoli cells (vs granulosa cells of ovaries)
2) Function
- Secrete anti-Mullerian hormone (AMH), required for Mullerian duct regression
- Secrete desert hedghod for Leydig cell and Peritubular myoid cell devlopment
- Secrete factors that support PGC growth and maturation
**In adult, Sertoli cells nourish developing sperm in seminiferous tubules and expressing testosterone-binding protein** |
|
|
Term
| What are the primary developmental cells of the Testis and what are their functions? |
|
Definition
At 6 week, emerging cords (Coelomic cells and PGCs) insert into developing gonads (genital ridge)
1) Sertoli (first)
- Secrete AMH, Desert hedghog (Leydig and Myoid cell developing) and support PGC growth
2) Fetal Leydig cells: originate from mesenchymal cells of seminiferous cords
- Secrete androgens (8-14 weeks)
- Secrete Insulin-like factor 3 (INSL3), for transabdominal testi descent.
3) Peritubular myoid cells
- Long flat cells that assemble around testes cords and interact with Sertoli cells to produce ECM proteins of basal lamina
4) Endothelial cells migrate to testes from mesonephros (VEGF) to help formation
5) PGCs divide mitotically as they migrate towards gonads and continue to do so after entering testis (enter Meiosis at puberty)
- Sexually bipotent, but become sperm under somatic environment. |
|
|
Term
| During ovarian development, what are the first ovarian-unique cells to arise and what is their functional importance? |
|
Definition
Granulosa cells (a bit later than male Sertoli cells)
Suppor cells of ovary, producing CYP aromatase in response to FSH (convert androstenedione from Theca cells to estrogen).
**estrogens NOT required for initial ovary formation, but are needed to maintenance of normal structure in adult** |
|
|
Term
| What are the functional equivalents of Sertoli cells and Leydig cells in Females? |
|
Definition
1) Sertoli cells respond to FSH and make AMH and desert Hedgehog (Leydig and Peritubular myoid development), supporting testicular development
- Female equivalent is Granulosa cells, which produce aromatase in response to FSH, converted androstenedione from LH-stimulated Theca cells.
2) Leydig cells respond to LH and produce androgens and INSL3 (descent)
- Female equivalent is Theca cells, which respond to LH and produce androstenedione, which is converted to estrogen in granulosa cella |
|
|
Term
| What is the role of PGCs in the developing female? |
|
Definition
Initiate meiosis in ovary by producing Retinoic acid, and by 14 weeks, allow primordial follicle formation (granulosa cells and oocytes)
They are not required for initial differentiation of gonads, but they are REQUIRED for terminal differentiation (XO females with Turner syndrome have streak gonads because PGCs do not reach genital ridge) |
|
|
Term
| Why might a young girl present with "streak gonads"? |
|
Definition
| XO Turner's, where PGCs cannot migrate to genital ridge and initiate terminal differentiation of the gonads. |
|
|
Term
| Describe the process of testes descent in males. What happens when it is disrupted? |
|
Definition
Requires INSL3 and Androgen hormones from Leydig cells, in response to LH (depend on Sertoli cells for development).
1) Cranial ligament connecting testis to posterior wall degenerated, and Caudal Gubernaculum forms
- Gubernaculum pulls testes through the posterior abdominal wall, over the pelvic rim and into the inguinal canal and scrotum
2) Cryptorchism (3/100) from insulin/androgen deficiency |
|
|
Term
| What are the remnants of the cranial and caudal ligaments involved in ovarian descent? |
|
Definition
1) Cranial= Suspensory
2) Caudal= Round (ovary and uterus) |
|
|
Term
| Describe how Mullerian/Wolffian duct selection occurs during embryonic development. |
|
Definition
Both ducts empty into cloaca, the Mullerian lateral to the Wolffian
**Cranial cloaca (UGS) gives rise to bladder, urethra and prostate**
1) Male
- If Y chromosome is present, testes form and produce AMH (Sertoli), which binds mesenchymal cells of Mullerian ducts, and Testosterone (Leydig), which stimulates masculaniziation of Wolffian ducts (epididymis, vas deferens and seminal vesicles)
2) Female
- Wolffians duct spontaneously regress (no testosterone)
- Mullerian ducts remain (no AMH) and become oviducts, uterus, cervix and upper vagina)
**If mullerian ducts do not meet and fuse at midline, "bicornuate uterus" can results (two separate horn** |
|
|
Term
| Describe the basic development of the external genitalia. |
|
Definition
Bi-potential structures: Genital tubercle, Urethral folds (surrounding UGS) and lateral Genital swellings
1) Males (Requires DHT, produced from testosterone via 5-alpha-hydroxylase)
- Genital tubercle expands to form glans penis, urethral folds form shaft and Genital swellings fuse to form scrotum
** Hypospadias (failed ventral fusion of folds) **
2) Females
- Urethral folds and genital swelling remain separate and become labia major and minor
- Genita tubercle becomes clitoris |
|
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Term
Which external genitalia features arise from each of the following in males and females?
1) Urethral folds
2) Genital tubercle
3) Genital swellings |
|
Definition
**Male needs 5 alpha hydroxylase to make DHT from testosterone!**
1) Shaft of penis (M) and Labia majora (F)
2) Glans penis (M) and Clitoris (F)
3) Scrotum (M) and Labia minora (F) |
|
|
Term
| Which genes are known to play a role in early bi-potential development of gonads? |
|
Definition
1) SF1 encodes transcription factor (NR5A1) as is expressed in early gonad, adrenal, pituitary and hypothalamus
2) WT1 encodes a protein that activates/represses transcription |
|
|
Term
What is the primary determinant of sex in development?
What is the molecular pathway of determination? |
|
Definition
Short:
(M): Y chromosome..SRY..SOX9...FGF9/PGD2
(F): X chromosome..FoxI2...Wnt4/Rspo1
The presence of Y chromosome (NOT number of X), where SRY gene encodes testis-determining factor.
1) Males
- SRY is a transcription factor expressed by Sertoli cells, which alters the balance of factors found in XX and XY individuals
- SRY boosts SOX-9 (cartilage development and testis)
- SOX-9 boosts FGF9 and PGD2, which control sertoli cell proliferation and differentiation (positive feedback)
- FGF9 suppresses Wnt4 in developing testes
2) Female
- Without Y chromosome, SRY does not induce SOX9, FGF9 or PGD2
- FoxI2 is critical for granulose cell differentiation and follicular maturation (represses Sox9)
- Wnt4 and R-spondin 1 (Rspo1) stabilize beta-catenin and repress testi pathway. |
|
|
Term
How might a deactivating mutation in each of the following genes influence sex determination?
1) SRY
2) Wnt4
3) Sox9
4) Rspo1
5) FGF9 |
|
Definition
SRY makes SOX9, which makes FGF9/PGD2, which suppress Wnt4 and mullerian development
1) male to female
2) female to male
3) male to female
4) female to male
5) male to female |
|
|
Term
What might the gonads and external genitalia look like in each of the following scenarios?
1) Congenital adrenal hyperplasia due to excess androgen exposure in an XX genotype
2) Androgen insensitivity in an XY genotype
3) 5-alpha reductase deficiency in XY genotype
4) Loss of AMH receptor function in XY genotype |
|
Definition
1) Ovaries with female ducts and masculanized external genitalia (androgen influence on tubercle, folds and swellings)
2) Testes, degenerated mullerian ducts but no masculinization of wolffian ducts, with female external genitalia
3) testes, normal ducts and female external genitalia
4) Got both ducts. testes, uterus and oviducts as well as masculinized wolffian duct and male external genitalia (not issue with androgens) |
|
|
Term
| What are the major factors required for sperm production? |
|
Definition
1) Vitamin A (required to enter meiosis)
- Sertoli cells produce retinol-binding protein required for spermatogonia to use vitamin A
2) Hormones: Testosterone and FSH
3) Adjacent sertoli cells |
|
|
Term
Which of the following is NOT characteristic of a normal sperm count
1) >75% alive
2) >30% normal shape and form
3) >10% swimming forward rapidly
4) 20 million/ml
5) At least 2ml |
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Definition
3- >25% should be swimming this way, and 50% should be motile
10% would be Asthenospermia (vs. Teratospermia is shape was abnormal) |
|
|
Term
| What is the most common cause of male infertility? |
|
Definition
Varicocele (35%): dilated blood vessels to testis results in improper cooling of blood
Also, infection, toxicity, endocrine (Kallman's), ect. |
|
|
Term
| What are the common types of Assisted reproductive techniques (ART)? |
|
Definition
1) Intrauterine insemination (IUI)
2) IVF
3) Intracytoplasmic sperm injection (ICSI)
4) Testicular sperm extraction (TESE) |
|
|
Term
| What is Cryptorchidism and how do you treat? |
|
Definition
1) Failed testicular descent (premature or genetic)
2) early (9-10 month) hCG or hCG + GnRH treatments to increase testosterone action to correct localization and improve germ cell function. |
|
|
Term
| Describe the basic functional anatomy of the testis. |
|
Definition
1) Seminiferous tubules enclosed in tunica albiginea support spertamazoa development from spermatogonia
- Interstial tissue is separated by BM and contains Leydig cells for testosterone production
2) Sperm exits tubules via Rete testes into the Epididymis, where further maturation occurs
3) Androgens taken up by Epididymis are converted to DHT, promoting development of thick mass of sperm, which is slowly delivered to Vas deferens.
4) Sperm is stored in vas deferens (removed in urine until ejaculation)
5) Ejaculation of seminal fluid is mediated by accessory glands: seminal vesicles, prostate, ampulla and bulbourethral Cowper's glands (depends on testosterone) |
|
|
Term
| How much of testosterone is "bioavailable" and how is this influenced by elevated estrogen levels? |
|
Definition
1) Bioavailable testosterone is free (2%) or bound to albumin (44%), while the rest is tightly bound to SHBG
2) Estrogen increases SHBG, which should be compensated for by the testis, UNLESS there is HPT axis dysfunciton |
|
|
Term
| What are the 3 ways by which testosterone can exert its action as an androgen? |
|
Definition
1) Muscle and Testis (40%)
- Diffuse into cells and combine with androgen receptor.
- Complex then moves to nuclear where they bind promotor region
2) 6-8%
- Diffuses into cells and is converted to DHT by 5-alpha reductase (intrinsic membrane protein).
- DHT has HIGH affinity for androgen receptor and amplifies effects
**KEY for external genitalia, reproductive tract and skin.
3) 0.3%
- Testosterone converted to Estradiol (Aromatase)
- Required for regulation of linear growth and bone formation/maintenance (VEGF-mediated ossification).
**Non-classical Src kinase/MAPK-ERK pathway is non-classicial, 4th mechanism** |
|
|
Term
| What is the major function of peritubular myoid cells? |
|
Definition
| Give shape to seminiferous tubules and allow for contractile activity requires to force spermatozoa through tubules towards Rete Testis |
|
|
Term
| Describe the basic process of sperm production in the Seminiferous tubules. |
|
Definition
Take 70-75 days to complete spermatogensis and spermiation, but germ cells renew every 16 days
1) Spertamagonia are anchored to BM
- Dark A cells enter myosis and become pale
- B cells divide and detach from BM, forming spermatocytes
2) Spermatocytes pas through meiosis to reduce chromosome number for diploid to haploid (very sensitive to damage)
3) Haploid spermatids undergo differentiation (Spermiogenesis) and are released into the tubular lumen as Spermatozoa |
|
|
Term
| How does Testosterone production regulate spermatogenesis and fertility? |
|
Definition
LH binds Leydig cells, causing them to produce testosterone, which binds to Sertoli cells (which have AR), enabling
FSH and Testosterone synnergize
1) Completion of meiosis and production of spermatids
2) Maintenance of attachment of spermatids to sertoli cells
3) Release of mature sperm |
|
|
Term
| Which paracrine factors are produced by Sertoli cells to regulate spermatogenesis? |
|
Definition
1) GDNF- spermatagonial stem cell maintenance
2) Stem cell factor (kit ligand)
- Promotes spermatoagonia cell division and differentiation (TK-mediated, called c-Kit)
3) Retinoic acid
- Initiation of meiosis
4) Activin
- stimulates DNA synthesis in spermatogonia and spermatocytes |
|
|
Term
| What factors are produced by germ cells to support sertoli cell function? |
|
Definition
1) IGF-1: Lactate production
2) TNF-a and NGF |
|
|
Term
| What are the major androgens produced by the testis, ovaries and adrenal glands in males and females? |
|
Definition
Androgens in Females are from Adrenal cortex
Androgens in Males are from Testis
1) Leydig cells in testes make Testosterone, some of which is converted to DHT by 5-alpha reductase (also some androsterone and androstenedione)
2) Adrenal cortex makes mostly DHEA and DHEAS, as well as a little testosterone
**can be significant in males when there is CAH** |
|
|
Term
| Describe the structure of the Androgen Receptor |
|
Definition
Only one AR in human genome, and it is localized to X-chromosome.
Androgen binding triggers nuclear accumulation of AR where it binds AREs in the promotor regions of target genes.
1) Central: DNA binding
2) COOH- ligand binding (less well conserved)
3) NH3: Transcriptional regulation |
|
|
Term
| What is Congenital hypogonadotropic hypogonadism (CHH)? Is androgen replacement therapy appropriate? Can fertility in these individuals be restored? |
|
Definition
1) CHH is deficiency in GnRH resulting in pituitary deficiencies (LH/FSH) that present in neonates or later in childhood as Micropenis and Cryptochordism
2) Androgen treatment is favored over GnRH in adolescents and adults and mixed treatment is suggested in neonates
3) Fertility CANNOT be corrected with androgen therapy. |
|
|
Term
| What is Constitutive (Idiopathic) Delay of Growth and Puberty (CDGP) and why is therapy controversial? |
|
Definition
1) CDGP presents with short stature , delayed bone age and pubertal development (testitcular volume) in the absence of other endocrine conditions.
2) Will correct on its own (late teens or early 20's)
- Can speed it up with androgens, but you risk premature epiphyseal growth plate closure |
|
|
Term
| What are the common causes of post-pubertal hypogonadism? |
|
Definition
Androgens wil replace secondary sex characteristics, libido and fertility (vs. CHH)
1) Testicular destruction (hypergonadotropic hypogonadism)
2) Hypopituitarism (hypogonadotropic secondary hypogonadism) |
|
|
Term
| True or False: Androgen replacement in late-onset hypogonadism is controversial given evidence of adverse CV events in patients treated with testosterone. |
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Definition
|
|
Term
| What non-reproductive uses are there for Androgens? |
|
Definition
1) Anemia (aplastic/fanconi, leading to bone marrow failure)
- Stimulate EPO in kidney
- In chronic renal failure, use Nandrolone (anabolic)
2) Muscle wasting (cancer, HIV-AIDS) |
|
|
Term
| Which androgens are used clinical in women and for what purposes? |
|
Definition
1) Women with hypopituitarism
- Methyl-testosterone is used in combination with estrogen to facilitate long bone growth and development of axillary and pubic hair
2) Sexual dysfunction in post-menopausal women is DEBATED |
|
|
Term
| What androgen compounds are used to bring about masculinaization? |
|
Definition
1) Long-lasting Enanthate, Cypionate or Propionate esters of testosterone given IM every 2 weeks (less often is worse)
- More lipidophillic compared to testosterone and are hydrolyzed in vivo
2) Oral preps like Alkylated testosterones (Methyltestosterone or Fluoxymesterone)
- short-acting options for postpubertal hypogonadism
**Methyltestosterone is difficult to monitor so it is less popular**
3) Transdermal androderm patches of androgel
- MOST effective at achieving stable circulating hormone levels
4) Anabolics: 19-nortestosterone, oxandrolone, oxymetholone and stanozolol
- Enhanced anabolic:virilizing effects to promote linear growth in children. |
|
|
Term
| What is the advantage of using androgel compared to priopionate ester or methyltestosterone androgen forms? |
|
Definition
Androgel is a transdermal gel preparation that is most effective at achieving stable circulating levels.
- Priopionate esters are long-acting and the most oeffective masculinizing agents; lipidophillic options that are given IM injection every 2 weeks
- Methyltestosterone is a short-acting option used to treat post-pubertal hypogonadism; an oral preparation that has lost popularity due to difficult monitoring |
|
|
Term
| Why have anabolic steroids gained therapeutic popularity for treating growth defects in children? |
|
Definition
| High anabolic:virilization ratio- used for linear growth in kids. |
|
|
Term
| What are SARMs and why are they promising? |
|
Definition
| Andriogenic agents that induce distinct conformation changes in AR in select tissues. |
|
|
Term
| What are the major side effects of androgen therapy in sexually mature males? |
|
Definition
1) Infertility; feedback inhibition of FSH/LH
2) Erythrocytosis or Polycythemia
3) Gynecomastia
- Aromatase effect on androgens
4) Acne
5) BPH, prostate cancer
6) Atherosclerosis (Increase LDL and decrease HDL) |
|
|
Term
| What are the major side effects of androgen therapy in women and children? |
|
Definition
1) Virilization (facial hair and body hirsutism)
2) Premature closure of epiphesial plates and stunted growth in kids. |
|
|
Term
Which of the following is NOT a known side effect of androgen therapy?
1) Acne
2) Infertility
3) Stunted growth in kids
4) Anemia
5) Atherosclerosis
6) Gynecomastia |
|
Definition
4- Steroids cause Polycythemia, not Anemia (they are used to treat aplastic/fanconi anemia)
1- Androgen excess
2- Feedback inhibition on FSH/LH
3- Premature fusion of epiphyseal plates
5- LDL:HDL balance
6- Aromatization |
|
|
Term
| What are the major types of anti-androgen treatment and how are they used? |
|
Definition
Used for female hirsutism, alopecia, precocious puberty and prostate cancer.
1) GnRH agonists (Lupron)
- down-regulation of receptor
- Long-term triptorelin considered for paraphilia (sexual deviance)
2) GnRH receptor antagonists (Abarelix and Centrorelix))
- Initial stages of IVF to prevent LH surge until eggs are ready
3) 5-alpha reductase inhibitors (Finasteride or Dutasteride)
- BPH and patterned baldness
- Impotence is rare side-effect
4) AR antagonists
- Bicalutamide > Flutamide |
|
|
Term
| What anti-androgen agents are used to treat prostate cancer? |
|
Definition
1) Combined Androgen Blockage (CAB)
- AR antagonis (Bicalutamide) with GnRH agonist (Lupron)
2) Non-steroidal AR antagonists
- Flutamide (hepatotoxicity and gynecomastia)'
- Bicalutamide is BETTER |
|
|
Term
| True or False: Androgen deprivation therapy has had limited effectiveness in treating prostate cancer because of hormone-refractory tumors |
|
Definition
True!
Possible mechanisms include
- Increased expression of AR protein
- mutations that increase sensitivity to low levels of androgens
- ligand-independent activation |
|
|
Term
| What are the features of the 3 major forms of male sexual dysfunction? |
|
Definition
Only libido is androgen-dependent (testosterone may influence NO for erection, however)
**age is most important risk factor**
1) Libidinal: Desire/interest in sex
- Psychological, toxic and physical factors
2) Ejaculatory: Premature ejaculation, retrograde, retarded
- Past trauma, nervousness, nerve damage, medications
3) Erectile: Attain or maintain erection sufficient for sufficient intercourse
- 18% over age 50
- HTN, diabetes, CVD, ESRD, Nerve, psychiatric |
|
|
Term
| True or False: Benefits of testosterone therapy for patients with ED is limited to small population of men with abnormally low testosterone levels. |
|
Definition
|
|
Term
| Describe the molecular mechanism underlying penile erection. What 3 factors are absolutely essential? |
|
Definition
Need intact CNS/PNS, corpora cavernosa/spongiosa and blood supply/drainage
Calcium:K+ balance is key
- Erection requires smooth muscle relaxation in Corpora cavernosa. Contraction is caused by increased intracellular Ca2+ and MLCK activation and relaxation by K+ efflux.
Mechanisms
1) K+ (relaxation-erection)
- efflux and connexin 43-gap junction spread of hyperpolarization (relaxation)
2) NE (Contraction-flaccid)
- DAD/IPS mechanism leads to PKC activation, K+ channel closure and increased intracellular calcium
3) PGE1 (relaxation: erection)
- promotes cAMP/PKA activation, which promotes K+ efflux and inhibits calcium channels
4) NO (relaxation: erection)
- Derived from nerve terminals innervating corpora cavernosa (NE, ACh), endothelial lining and cavernosal sinuses
- NO stimulates GC/cGMP activation, which stimulates K+ efflux |
|
|
Term
| Which chemicals promote K+ efflux and erection in corporal cavernosa tissue and which inhibit it? |
|
Definition
1) PGE1 and NO stimulate it
2) NE inhibits it |
|
|
Term
| What is the basic treatment strategy for ED? |
|
Definition
1) Psych counseling
2) 1st line
- Sildenafil (PDE5 inhibitor)
- Vacuum constriction
3) 2nd line
- Intracavernosal injection of alprostadil
- IC injection of other vasoactive amines
3) 3rd line
- Penile prosthesis
- Vascular surgery |
|
|
Term
True or False:
Viagra commonly causes erections during the day in inappropriate contexts |
|
Definition
False!
Normal NO pathway is maintained, and anti-hydrolysis effects of PDE-5 inhibitor require sexual stimulation |
|
|
Term
| What are the common side effects and contraindications associated with Sildenafil use? |
|
Definition
1) SE
- Headache, flushing, dyspepsia, respiratory tract disorders, visual disturbances
2) Contraindications
- Patients taking nitrates for CAD (hypotensive crisis)
- BP monitored in patients on BP meds
3) Drug-drug interactions (CYP 2C9 and 3A4)
- Cimetidine and erythromycin increase plasma concentrations (3A4)
- Affects Warfarin and Tolbutamide metabolism (2C9) |
|
|
Term
| Why might a patient prefer to take Tadalafil instead of Sildenafil for ED? |
|
Definition
| Cialis has a slower onset and longer effect (36 h), so some people prefer spontaneity |
|
|
Term
| What are the major categories of female sexual dysfunction and the important characteristics of each? |
|
Definition
Associated with low estrogen and/or psychological factors
1) Hypoactive sexual desire
- no fantasies or thoughts
2) Sexual aversion
- phobia that causes personal distress (abuse)
3) Sexual arousal disorder
- Caa't attain maximum excitement
4) Sexual pain (dyspareunia, vaginismus)
- Pain or involuntary contractions
5) Organismic disorder: no organsms |
|
|
Term
| Who qualifies for estrogen therapy and what are the benefits/risks? |
|
Definition
Post-menopausal women and women after oophorectomy complaining of sexual dysfunction
Most cases are NOT physical, and will noo benefit, but for those that are, LOCAL estrogen is indicated.
1) Benefits
- Vaginal tone and lubrication
- Relief of hot flashes, night sweats
- Less bone loss
- Improved sleep
2) Risk of Venous thrombosis, stroke and breat cancer |
|
|
Term
| True or False: Supraphysiological doses of testosterone can improve sexual function in surgical post-menopausal women. |
|
Definition
True:
17-alpha-methyltestosterone for those after oophorectomy, but NOT clear in regular post-menopausal women and long term effects have not been adequately measured. |
|
|
Term
| What drugs are available to treat female sexual dysfunction that is related to low estrogen levels? |
|
Definition
1) Estrogen
2) Testosterone for post-oophorectomy
3) Sildenafil
4) Tibolone (synthetic steroid with weak estrogenic/androgenic properties)
5) Other options under development
- L-arginine (NO precursor)
- PGE1
- Phentolamine (alpha blocker)
- Apomorphine (DA agonist) |
|
|
Term
| What types of drugs are associated with sexual dysfunction? |
|
Definition
1) Antidepressents
- Buproprion is better than others (not better for desire)
- Improved with PDE5 inhibitor addition and possibly psychostimulant (Ritalin)
2) Anti-hypertensives
3) Antipsychotics
4) Anticonvulsants
5) Antiulcer
6) Anti-cancer |
|
|
Term
True or False:
Prostate cancer is a relatively rare occurrence and is almost always untreatable |
|
Definition
False on both accounts.
1) Most common cancer in american men after skin cancer, and the second leading cause of cancer related deaths in men.
2) Treated surgically and/or pharmacologically with 5-alpha-reductase inhibitors like Finasteride and Dutasteride for chemoprevention (androgen-dependent tumors- NOT FDA approved) |
|
|
Term
| How can prostate screening be performed and who should get it? |
|
Definition
The issue is that screening identifies prostate cancer at an early, treatable stage, but also leads to treatment of many clinically silent tumors.
1) DRE and PSA levels
- Transrectal US won't help, but can assess prostate size
2) Men over 50 and those with family h/x |
|
|
Term
| How is prostate cancer screened and staged? What is the utility of each? |
|
Definition
Most important prognostic factors are PSA at diagnosis, TMN stage and Gleason grade
Treatments include radical prostatectomy (younger patients) and radiation or brachytherapy (low risk)
Chemo added for metastasis
1) TMN staging is clinical
- Help determine risk and treatment
2) Gleason is Histological grading
- Score based on 2 most representative biopsies, with 1-5 depending upon architectural effacement. |
|
|
Term
| What are the important benign lesions of the prostate that should be considered when working up a patient? |
|
Definition
1) Prostatitis
- Acute bacterial (reflux, surgery, STD)
- Bacterial (low back pain, dysuria, perineal discomfort)
**hard to treat b/c of penetration of antibiotics
2) Nodular hyperplasia (BPH)- NO cancer risk
- Common in older men at the transition (periurethral) zone
- See squamous metaplasia and small infarcts
- Can treat surgically or with antagonists |
|
|
Term
| What is the most common cancer of the prostate? How is it diagnosed and treated? Where do you find metastasis? |
|
Definition
1) Prostatic Adenocarcinoma of posterior peripheral zone
2) Diagnosed by DRE and serum analysis (PSA used to monitor treatment)
3) Surgery, irradiation and/or hormonal therapy (advanced metastasis) with LHRH analogs and anti-androgens
4) If it metastasized, look to bone for Osteoblastic carcinoma |
|
|
Term
| What are the important benign lesions of the testis that should be considered when working up a patient? |
|
Definition
1) Cryptochordism
- Risk of seminoma later in life (higher in abdominal)
- Infertility risk
- Treat before age 2-3 with orchiopexy
2) Hydrocele
- Accumulation of fluid between visceral and parietal layers of tunica vaginalis (trauma and epididymitis)
- Diagnose with transillumination
3) Torsion
- Twisting of spermatic cord with venous obstruction (not arterial)
4) Atrophy
- Atherosclerosis, mumps, estrogen excess or inflammatory orchitis (many causes) |
|
|
Term
Patient presents with painless testicular mass
What are the common tumors of the testis in young, adults and elderly folks? |
|
Definition
20-30 (NSGCT), 30-60 (SGCT), >60 metastatic lymphoma
95% are germ cell (Isochrome 12p!), and the most common pure tumor is a seminoma, while mixed germ cell tumors are most common overall.
LDH level- tumor size/burden
AFP (liver or yolk sac) and hCG (choriocarcinoma)
1) Seminoma (30-50% of germ cell tumors)
- Mean age 40 with 70% at stage 1
- Placental alkaline phosphatase (PLAP) association
- Treat with radiation (95% cure rate)
2) Spermocytic seminoma
- age >55 in patients with descended testis
- No association with ITGCN or NSGCT
- Nodules of cells with edema (3 types: medium cells with round nuclei, small cells with eosinophilic cytoplasm and Giant cells)
3) NSGCT
- More aggressive with 60% presentation at stage 2-3 in younger individuals
- Radioresistant (still cure 90% with surgery + chemo)
3a) Chorio (hcG) from cytotrophoblast (worst)
3b) Embrynal
3c) Teratoma
3d) Yolk sac- age 3 or less with serum AFP
4) Sex cord stromal
5) >60 is lymphoma metastasis |
|
|
Term
| What stage of development are oocytes in at birth? What about those recruited during ovulation? What does the Zona pellucidum have to do with this? |
|
Definition
Arrested= P1
Recruited= M2 (fertilizable)
1) Primary oocytes (germinal vesicles) are halted at diplotene stage of Prophase 1
2) Those that are recruited for ovulation resume meiosis and are released at Metaphase II (fertilizable stage).
3) Primary oocyte synthesizes glycoprotein coat called the "zona pellucidum" (proteins ZP 1-3), which protect it and serve for sperm-specific recognition (ZP3), |
|
|
Term
What is the basic structure of a haploid sperm?
What normal cell components are they missing? |
|
Definition
Stored in epididymis and released into female reproductive tract, where it undergoes "Capacitation" and is "hyperactivated"" to penetrate an egg.
1) Structure
- Acrosomal vesicle (proteases and hyalouronidase)
- Nucleus
- Mid-piece (mitochondria)
- Tail (axoneme and dynein motor proteins)
2) Sperms have no Ribosomes, ER or Golgi, in order to maximize transportation. |
|
|
Term
| What is "sperm capacitation," where does it occur and why is it important? |
|
Definition
After stored sperms are released from epididymus and undergo ejaculation, they enter the female reproductive tract, where they must be primed to penetrate ovulated eggs (Capacitation).
- Stripping of glycoproteins from cell membrane unmasks calmodulin-binding proteins, which leads to increased intracellular Ca2+ levels and cAMP (Hyperactivation).
- Sperms are now primed for acrosome reaction, increasing its velocity and preventing attachment to the fallopian tube |
|
|
Term
| What events occur in the "Acrosome reaction" |
|
Definition
Formation of human zygote.
1) Binding
- Sperm binds ZP3 on egg and sperm protease, "acrosin" is exposed and begins degrading Zona pellucidum
2) Fusion
- Sperm next binds ZP2 and is able to recognize and fuse with plasma membrane
3) Prevention of Polyspermy
- Membrane fusion causes calcium flux/hyper-polarization, leading to cortical granule release and "zona hardening," which in term prevents polyspermy
4) Zygote formation and DNA exchange
- Within oocyte cytoplasm, Sperm nucleus decondenses and sperm protamines are exchanged with histones, forming Zygote
- Male/Female DNA find each other in cytoplasm via Sperm aster microtubule system (do not mix until first mitotic division |
|
|
Term
| What is the blastomere and when does it undergo compaction? |
|
Definition
1) Blastomere is collection of small, totipotent cells arising from early mitotic divisions (every 24h)
- At this stage, embryo can be split to form identical twins
2) At 32-cell stage (5 divisions), cells undergo compaction, where outer cells become structures of developing embryo (Trophoblast) and inner cells remain pluripotent.
- This process forms Blastocyst (fluid-filled cavirty surrounded by trophoectodermal cells, with inner cell mass.. |
|
|
Term
| Describe the process of embryonic implantation. |
|
Definition
7-10 days after fertilization
1) In preparation for blastocyte arrival, endometrial Deciduation takes place (if no implantation occurs, it is shed)
2) Zona pellucidum aids in transport to Uterus, where Blastocyst hatches using proteases
3) 3 steps
- Attachment (up-regulate LNF-1 and heparin sulfate)
- Invasion/degradation (Collagenase, stomelysin, pA)
- Proliferation (trophoectoderm invades stroma) |
|
|
Term
| During what stage of the female reproductive cycle can sperm fertilize egg? What are the normal barriers to sperm access? |
|
Definition
Late follicular phase, when the cervical mucous is thin enough to allow passage.
Sperm move with flagella, but are also aided by vaginal active transport mechanisms
- Expulsion from introitus
- Digestion by vaginal enzymes
- Host defnses |
|
|
Term
| When spre-implantation genetic diagnosis performed? What are the major limitation(s) |
|
Definition
Totipotent cells from lastomere at 6-10 cell stage (day 3) are removed.
- Embryos can then be implanted on day 5
Cannot detect mosaicism (the reason why ICSI has 0.8% risk of chromosomal abnormalities compared to 0.2% in IVF) |
|
|
Term
What is the clinical definition of "infertility" and how common is it?
What methods are available to counter it? |
|
Definition
1) Failed pregnancy of 1 year with unprotect sex (15% of population)
- IVF (mix gametes in dish and form embryo)
- ICIS (inject sperm into oocyte directly)
- PGD (pre-natal diagnosis of genetic issues)
- Oocyte cryopreservation |
|
|
Term
| How is Ovulation induction (OI) and Super-ovulation (SO) used and how does it work? |
|
Definition
Increase FSH signal to ensure LH surge (direct FSH or inhibition of estrogen negative feedback)
- OI establishes ovulation in patient with ovulatory disorder (PCOS) and to maximize yield when male sperms are deficient
-SO tries to achieve multiple ovulations |
|
|
Term
How does Clomiphene citrate (CC) work to induce ovulation?
What are the risks? How do they compare to using an Aromatase inhibitor? |
|
Definition
Non-steroidal, Anti-estrogen SERM taken by mouth for 5d from days 3-7 or 5-9
1) Competitive inhibitor of estrogen receptor at level of hypothalamus, preventing negative feedback and leading to GnRH production (and thus, FSH production)
2) Risks
- Multiple gestation (10%)- Less so with aromatase inhibitors
- Possible long-term ovarian cancer risk |
|
|
Term
What drugs that talk directly to the ovary can be given for ovulation induction in the treatment of infertility?
What are their risks? |
|
Definition
FSH (more common) or FSH + LH that has either been purified from menopausal urine or by recombinant produced in chinese hamster ovary cell lines.
**followed by hCG injection**
1) Injections in early follicular stage cause recruitment of multiple follicles and increased estrogen levels (no LH surge), so they have to take hCG as well.
2) Risks
- Multiple gestation (20%- highest risk)
- Ovarian Hyper-Stimulation Syndrome (20-25%) (iatrogenic, where excessive vasoactive substances lead to increased capillary permeability in peritoneal cavity, with ascites, hypovlemia and hemoconcentration) |
|
|
Term
| Which method of ovulation induction places patients at higher risk for DVT/PE and why? |
|
Definition
FSH + hCG injections have risk (20-25%) of Ovarian Hyper-stimulation Syndrome (OHSS), where high estrogen levels lead to increased vasoactive substances (VEGF), which increase capillary permeability in the peritoneal cavity and produce
- Ascites
- Hypovolemia
- Hemoconcentration
**ALSO highest risk of multiple gestation (20%)** |
|
|
Term
How does each of the following IVF drugs work?
1) Leuprolide acetate (Lupron)
2) Cetrorelix/Ganirelix |
|
Definition
1) GnRH agonist given during luteal stage (prevent flare) that delivers tonic signal to pituitary, which down-regulates GnRH receptors and LH/FSH production
**used for Infertility and for Hyperestrogenism in endometriosis, precocious puberty and estrogen-responsive malignancies**
2) Short-acting GnRH competitive receptor antagonists
Patient takes HIGH dose Gonadotropins on day 3 and GnRH analogue several days later to prevent LH surge (Scheduled ovulation has better yield than endogenous).
- When follicles are large enough of transvaginal ultrasound, she takes hCG for LH surge and eggs are collected 34h later. |
|
|
Term
| Describe the basic steps involved in egg extraction for IVF |
|
Definition
Ex) injection FSH, then Lupron, then hCG. Give progesterone to maintain normal Luteal pahse
1) Patient takes HIGH dose Gonadotropins on day 3 and GnRH analogue several days later to prevent LH surge (Scheduled ovulation has better yield than endogenous).
2) When follicles are large enough on transvaginal ultrasound, she takes hCG for LH surge and eggs are collected 34h later. |
|
|
Term
During IVF, both the use of GnRH analogues and Ovarian stimulation lead to abnormal, shortened Luteal phases, which can lower pregnancy rates.
How can practitioners address this? |
|
Definition
2 ways
1) Amplify signal to corpus luteum by using hCG (also increases risk of OHSS form hyper-stimulation)
2) Give progesterone (treatment of choice**)
- Vaginal and IM preps have best pregnancy outcomes |
|
|
Term
Which of the following drugs is NOT useful in IVF
1) Lueprolide
2) Cetrorelix
3) Progesterone
4) Estradiol
5) hCG |
|
Definition
4- not typically used: SERMS like Clomiphene Citrate are used for ovulatory induction
Give FSH first, then GnRH agonist/antagonist, then hCG for LH surge, and finally progesterone to maintain luteal phase normality |
|
|
Term
| What are the 3 components of Natural Family Planning? |
|
Definition
Monitoring one's own menstrual cycle to prevent pregnancy- Difficult and no STD protection
1) Calendar calculation (6 cycles)
- Onset (shortest cycle length -20)
- Last day (Longest cycle -11)
2) Cervical mucus changes
- Thick to Thin (Ovulation) to Thick
3) Basal body temperature (BBT)
- BBT rises during ovulation and then drops 3 days later |
|
|
Term
| Describe the basics of the Lactational amenorrhea method of contraception. |
|
Definition
LAM is highly effective for first 6 weeks after delivery ad can be 98% effective in first 6 months if woman is breast-feeding
Prolactin release inhibits GnRH, which lowers FSH/LH (no periods) |
|
|
Term
| What are the major barrier methods of contraception in males in females? |
|
Definition
1) Male condom- gold standard for STD
2) Female condom- avoid debating with partner, but difficult to place
3) Diaphragm- combined with spermacide
4) Cervical cap
5) Spermicides- chemical detergents (Nonoxynol-9)
6) Sponge |
|
|
Term
There are numerous hormonal methods of contraception.
How do progestin-only pills (POP) work and how do they compare to combined hormonal contraceptives (CHC)? |
|
Definition
1) POP (min pills)
- Thickens cervical mucus
- No estrogen side effects, but risk of ectopic pregnancy
- Spotting is common
**much less progestin then CHCs**
2) CHC
- Inhibit ovulation by suppression of FSH and LH
- Protective against ovarian and endometrial cancer
- Headaches, mood changes and DVT/PE (smokers) |
|
|
Term
| What types of contraceptive implants are available? |
|
Definition
1) Implanon- single rod that contains progestin
- lasts 3 years
- Central ovulation suppression with maintained estrogen levels
2) Norplant- Six rods with slow, steady-state release
- Thickens cervical mucus (no estrogen side effects)
- 7 years (5 years approved)- compliance is good
- Bleeding,w eight gain and mood changes are possible
- Interactions with Valproic acid
3) Norplant II
- Silicone rods containing solid core of levonorgesterl
- Not marketed in US (FDA approved) |
|
|
Term
| Why might a women choose to use an IUD instead of an oral contraceptive? |
|
Definition
Copper-containing or hormone delivery systems that are safe, cheap and effective, especially in those women who have contraindications for hormonal contraceptives.
Hormonal options have benefits with decreased menstrual bleeding
If they do get pregnant, REMOVE THAT IUD |
|
|
Term
| What are the available options for male and female sterilization? |
|
Definition
1) Vasectomy (M)
2) Tubal occlusion (F)
- Failures rates in younger women and costly reversal
3) Hysteroscopic
- More effective and less invasive than 2 |
|
|
Term
| What methods of emergency contraception (EC) are available? |
|
Definition
Levnoergosterol-only is best, non-prescription option (plan B), and Cu-IUD is best overall with prescription.
1) Yuzpe
- 2 doses of levonorgestrel + 100 ug of ethinyl estradiol take 12h apart.
- Use with 72 h of unprotected sex and expect bleeding 3 weeks later
2) Levonorgestrel-only (Better than Yuzpe)
- 2 doses of levonorgestrel taken 12 hours apart within 5 days
- Requires prescription for 16 or younger.
3) Antiprogestins
- Ulipristal acetate and mfifepristone
- ONLY by prescription
4) Copper-containing IUD
- Most effective form of EC available for those that qualify within 5 days |
|
|
Term
What % of all pregnancies end in spontaneous abortion?
What % are miscarriages and when do they occur? |
|
Definition
50-75% of all pregnancies end in spontaneous abortion (the majority of which occur PRIOR to implantation) and 15-20% result in actual miscarriages
Miscarriages occur bi-modally (87% < 10 weeks and 13% 14-20 weeks) |
|
|
Term
True or False:
The majority of cytogenitic abnormalities leading to spontaneous abortion are structural defects. |
|
Definition
False- Only 3%!
The majority are autosomal trisomy (60%), polyploidy (20%) or monosomy (20%) |
|
|
Term
Which of the following is NOT known to be associated with spontaneous abortion?
1) Chromosomal polyploidy
2) Infection
3) Smoking
4) Radiation expsoure
5) Poorly controlled T1DM |
|
Definition
2) Mycoplasma hominis and Ureaplasma urealyticum were believed to, but data has not held up.
Smoking (>15 a day), Radiation, Chromosomal abnormalities and Diabetes are classic causes. |
|
|
Term
True or False:
Recurrent pregnancy loss is defined as >= 3 spontaneous losses and is largely unexplained. |
|
Definition
True, 57% is mysterious.
After 3, the chance of repeat is 40-60% (vs. only 11% after 1) |
|
|
Term
Which of the following is NOT known to contribute to recurrent pregnancy loss? For those that are, explain why.
1) Luteal phase deficiency
2) Robertsonian translocations
3) Anti-phospholipid/cardiolipin syndrome (APS)
4) CREST syndrome
5) Asherman's syndrome |
|
Definition
4- Not known to be associated with >= 3 pregnancy losses.
1) Inadequate progesterone during "window of implantation" prevents blastocyte invasion.
2) Balanced and Robertsonian translocations are the 2 most common genetic abnormalities in RPL, and are found in 5-6% of cases.
3) Thromboembolism and thrombocytopenia
- **Factor V leiden is also involved**
5) Iatrogenic scarring of uterus from procedures |
|
|
Term
| Which women tend to get elective abortions? |
|
Definition
19 % of all pregnancies
Young impoverished women (20-24) in the 1st trimester (76% suction aspiration and 15% medical) |
|
|
Term
| Describe the strategy if medically-induced abortion. |
|
Definition
Anti-progestin (Mefepristone) with synthetic prostaglandin (Misoprostol) 24-48 hours later as an abortifactant.
- Mifepristone disrupts early pregnancy by blocking progesterone action and resulting in decidual necrosis and uterine cnotractions. Misoprostol results in pregnancy passage. |
|
|
Term
| Why might a patient not qualify for medically-induced abortion? |
|
Definition
Mifepristone (anti-progestin) and Misoprostol (PGE-1) is strategy
1) Allergy
2) Coagulopathy
3) Long-term corticosteroid use (SLE) |
|
|
Term
| describe the procedure of surgical abortion (Curettage). |
|
Definition
Dilation and Evacuation
Antibiotic prophylaxis (Doxi) and re-start birth control immediately after
1) Pelvic exam
2) Local anesthetic
3) Dilation of cervix (Osmotic dilator to absorb mucous and Misoprostol for cervical ripening)
4) Evacuation with suction |
|
|
Term
Women presents complaining of a burning, itchy sensation in her vagina.
On PE, you note discharge and collect some.
What tests do you run on the test and how may they be interpreted? |
|
Definition
Vaginitis symptoms: Usually Trichinosis, Candidiasis or Bacteria (Gardnerella and Mycoplasma hominis)
1) pH
2) Whiff test (fishy odor after adding 10% KOH)
3) Saline preparation looking for clue cells, trichomonads, parabasal cells, white cells, ect.
4) KOH prep for hyphae
- Culture if non-diagnositc
5) Gonorrhea and Chlamydia tests if there is concern of cervicitis |
|
|
Term
Women presents complaining of a burning, itchy sensation in her vagina.
On PE, you note discharge and collect some.
Results:
pH= 5.1
Whiff= No odor
Discharge: frothy, yellow-green
Saline prep= motile organisms
How do you treat? |
|
Definition
Vaginitis with malodorous, frothy, yellow-green discharge at a pH >4.5 is Trichomonas vaginalis (confirmed by trichomonads on saline prep)
**REMEMBER, more are asymptomatic**
Single-dose metronidazole or tinidazole and get partner in there.
**May also presents with punctate mucosal hemorrhages on cervix (strawberry cervix)** |
|
|
Term
Women presents complaining of a strange-smelling vaginal discharge
On PE, you note discharge and collect some.
Results:
pH= 5.1
Whiff= "Fishy"
Discharge: Whitish, creamy and homogenous
Saline prep= Clue cells present
How do you treat? |
|
Definition
Bacterial vaginitis: Oral/vaginal Metronidazole or vaginal Clindamycin
Options include Anaerobes, Gardnerella and Mycoplasmsa hominins
Bacterial vaginitis requires 3 of 4
1) Creamy, white discharge
2) Fishy odor w or w/o KOH
3) Clue cells (epithelial cells heavily stippled with bacteria)
4) pH >4.5 |
|
|
Term
Diabetic women presents complaining of vaginal redness and itching.
On PE, you note discharge and collect some.
Results:
pH= 4.2
Whiff= None
Discharge: Thick, white/yellowish
Saline prep= Nothing
KOH prep= Hyphae present
How do you treat? What are the risk factors for this condition? |
|
Definition
Vaginal Yeast infection (Candida 90%)
1) treat with intravaginal or oral Azoles
2) Pregnancy, obesity, antibiotics, diabetics, steroids
- Diagnosis confirmed by normal pH with thick white discharge and hyphae on KOH prep. |
|
|
Term
| Which causes of vaginitis are sexually transmitted? |
|
Definition
Trichomonas ONLY.
Bacterial (Gardnerella/Mycoplasma) and Candida are NOT. |
|
|
Term
Patient presents complaining of recurrent vaginal bleeding and profuse discharge.
A saline wet prep shows 26 leukocytes per high powered field.
You collect some discharge and it grows as dipplococci on Thayer Martin plates.
What is your diagnosis? |
|
Definition
**Annual screening for sexually active women <25 and women with high-risk behavior**
Cervicitis (friability, discharge and leukocytes >20) due to N. gonorrhea
Treat with Ceftriaxone |
|
|
Term
| What are the major causes of Cervicitis and how does it present? |
|
Definition
1) Inflammatory discharge form endocervical canal, easy bleeding (Friability) and/or ectocervical erythema or ulceration.
**Typically with >20 leukocytes per high-P field***
2) Chlamydia trachomatis and N. gonorrhea, diagnosed with culture and nucleic acid amplification testing(NAAT) |
|
|
Term
| How do you treat the different causes of Cervicitis? |
|
Definition
Annual screening for sexually active women <25 and women with high-risk behavior
**Get it early to reduce PID risk**
1) Gonorrhea
- Ceftriaxone
- Azithromycin macrolide (for SEVERE PCN allergy)
2) C. trachomatis
- One-dose Azithromycin or 7-d Doxicycline |
|
|
Term
| What are the primary bugs and complications of PID? |
|
Definition
1) Bugs
- 50% ascending infection from Gonorrhea or Chlamydia (from cervicitis)
- can be complication of primary bowel disease
2) Complications
- Tubal factor infertility
- Ectopic pregnancy
- Chronic pelvic pain |
|
|
Term
Woman presents complaining of fever and abdominal tenderness.
On PE, you notice oral temperature of 39 C and mucopurulent cervical discharge.
On saline prep, there are abundant WBCs and her ESR and CRP are elevated.
You also note cervical motion tenderness.
How do you approach treatment? |
|
Definition
PID- Give Ceftriaxone + Doxicycline +/- Metronidazole (infection tends to be multibacterial, so go broad spectrum)
Discharge suggests vaginitis, cercicitis or PID, but the fever, ESR/CRP and saline prep suggests PID.
Culture for N. gonorrhea (Ceftriaxone) and C. trachomatis (Azithromycin) and treat appropriately (give treatment above pending gram stain results)
You are worried about infertility, chronic pelvic pain and future risk of ectopic pregnancy. |
|
|
Term
| What are the 2 primary modes of HSV growth? |
|
Definition
dsDNA virus that replicates in nucleus
1) Lytic (vegetative)
- Full reproductive cycle proceeds with cell lysis and release of virions
2) Latent
- Enter nucleus and replicate with host cell genome
- Certain stimuli can induce lytic cycle activity |
|
|
Term
| What is the difference between HSV-1 and HSV-2 infections and what are the potential serious complications of each? |
|
Definition
Both are dsDNA viruses that replicate in nucleus
Diagnose with clinical picture, skin scrapping (look for multi-nucleated giant cells with intra-nuclear inclusion) and/or isolation in cell culture
1) HSV-1: Facial ulcers (VERY common)
- Encepthalitis (Acyclovir)
- Generalized systemic infection in immunocompromised
2) HSV 2: Genital warts and oral (genital- oral contact) (less common)
- neonatal transmission |
|
|
Term
| What anti-viral drugs are available to treat HSV infection? |
|
Definition
**IV-acyclovir for HSV-1 encephalitis**
1) Acyclovir- nucleoside analoge that enters virally-infected cells and inhibits viral thymidine kinase (analogous to 5-FU)
2) Valacyclovir: pro-drug of 1
3) Famcyclovir |
|
|
Term
| How is the myometrium maintained in a resting, non-contracted state? |
|
Definition
Keep intracellular calcium low
1) cAMP-mediated ATPase that transports Calcium out of cell
2) cAMP-mediated ATPase that sequesters calcium in the SR |
|
|
Term
| Describe the molecular basis for myometrial contraction? |
|
Definition
Intracellular calcium release leads to MLCK activation and actin-myosin binding
1) Oxytocin recpetor (OT-R), PGE2 receptor (EP) and PGF2alpha receptor (FP) activate PLC, which hydrolyizes membrane-bound phosphatidyl inositol to IP3 and DAG
2a) DAG activates PKC and cellular lipases, resulting in AA release (PGE synthesis)
2b) IP3 releases SR calcium release
3) Calcium binds calmodulin and Ca-Calmod activates MLCK, phosphorylating MLC protein, which then binds actin
4) Actin-myosin interactions cause contraction. |
|
|
Term
1) How do Terbutamine and Ritodrine relax myometrium to prevent pre-term labor?
2) What about NO? |
|
Definition
1)Terbutamine/ritodrine= cAMP
- Beta adrenergic agonists that bind BAR, increase AC/cAMP signalling and cause calcium efflux and sequestration.
- Low calcium innactivates MLCK and prevent contraction
2) NO= cGMP
- converts GTP to cGMP, which decreases intracellular calcium and MLCK activation. |
|
|
Term
Which of the following are associated with labor vs. pregnancy?
1) PF2a
2) Beta-sympthathomimetics
3) cAMP
4) NO
5) Connexin-43 |
|
Definition
1) Labor
- Binds PF2a receptor and leads to PLC... IP3/DAG signalling,
- IP3 leads to SR calcium release
- DAG leads to AA production and PGE synthesis
2) Pregnancy
- Bind BAR and lead to cAMP/PKA signalling, which activates phosphodiesterase, which inactivates MLCK
3) Pregnancy- relaxation
4) Pregnancy- relaxation (cGMP-mediated)
5) Labor
- Increased gap junction expression for coordinated contractions during labor |
|
|
Term
| Describe the 4 phases of uterine phenotypes in terms of contractility and coordination during pregnancy |
|
Definition
Uterus must transition from being large and relaxed to highly contractile
1) Phase O (conception to week 35-36)
- Myometrial hyperplasia, hypertrophy and unresponsiveness
- Limited availabilty of uterotonins
- Limited propagation of contractile signals
- Cervical rigidity (high collagen, low hyalouronic acid)
2) Phase 1 ("activation"- 36-42 week)
- Increased spontaneous contractility and responsiveness to agonists.
- FUNCTIONAL reduction in progesterone (maturation of HPA axis)
3) Phase 2 (Stimulation)
- Labor and delivery (24h or less)
- Increased production of uterotonins and increased gap junction (conexin-34) expression
4) Phase 3 ("involution")
- Uterus involutes and lactation commences (oxytocin) |
|
|
Term
| What are "Braxton-Hicks" contractions? |
|
Definition
| Benign, long lasting, low frequency "contractures" of myometrium during pregnancy, when uterus is large and accommodative (unresponsive to stimuli) |
|
|
Term
| What factors determine cervical rigidity and how does it change during partuition? |
|
Definition
Collagen: Ground substance ratio
- In phase O, ratio is high and cervix is rigid
- In phase 1, cytokine-induced hyaluronic acid retains water and expands cervix, with PGE increasing distensibility at term.
** Cervical "ripening" occurs as collagen is broken down** |
|
|
Term
| What are the 2 characteristics that mark phase 1 of partuition. What is their basis? |
|
Definition
Transition from phase 0 via HPA maturation, with ACTH release, cortisol and DHEAS production and estrogen synthesis.
There is a "functional" decrease in progesterone activity, with receptor isotype switching.
1) Increased spontaneous myometrial contractions
- # of gap junctions increase
2) Increased responsiveness to uterotonins
- Expression of oxytocin and PGE receptors |
|
|
Term
which of the following does NOT contribute to the transition between phases 0 and 1 of partuition?
1) Increased Cortisol
2) Increased CRH
3) Increased Estrogen levels
4) Decreased Progesterone levels
5) Prostaglandin synthesis |
|
Definition
4- There is a "functional" reduction in progesterone signalling, with receptor isotype switching, but not an absolute decrease.
Maturation of the HPA axis contributes to positive feedback loops that promote cortisol and estrogen production, and prostaglandin synthesis |
|
|
Term
| What characteristics mark phase 2 of partuition and why do they matter? |
|
Definition
1) Increased production of uterotonins
- Get the baby out and keep the uterus contracted afterwards
- PR isotype switching and glucocorticoid signalling promote COX2 signalling and PGE2 synthesis.
- Increased OT-Rs
2) Increased gap junction formation
- Contraction coordination |
|
|
Term
| If a women chooses not to breast feed, how long will they remain infertile following birth? |
|
Definition
4-8 weeks
If they breast feed, lactational amenhorea may last longer. |
|
|
Term
| What is "Cervical ripening"? |
|
Definition
| During phase 1 (36-42 weeks) of partuition, hyaluronic acid levels increase and cause collagen breakdown, leading to water retention and cervical dilation. |
|
|
Term
| What are the primary physiological adaptations that occur int eh uterus during pregnancy? |
|
Definition
1) Increase size (70 kg to 1100 kg)
2) Increased Blood flow (50-100 to 500-1000 ml/min)
- late change compared to CO and renal blood flow
- "physiological anemia of pregnancy", which depends, in part, on iron supplementation |
|
|
Term
| What changes to blood volume occur during pregnancy? |
|
Definition
1) Maternal luteal hormones (progesterone and relaxin) and placental hormones
- Decreased PVR, with increased systemic vasodilation, and decreased MAP (MAP= PVR * CO)
2) Decreased renal perfusion leading to increased aldosterone signalling and intravascular expansion. |
|
|
Term
| What normal changes occur to the heart during pregnancy? |
|
Definition
1) Displaced up and to the left
- Apex moved laterally, causing apparent cardiomegaly on X-ray
2) Systolic flow murmur at left lower sternal border |
|
|
Term
True or False:
BP of 120/80 is not normal during the 2nd trimester of pregnancy |
|
Definition
True.
During pregnancy, hormone signalling reduces TPR, thereby decreasing MAP (MAP= TPR * CO).
BP at the level of 140/90 is concerning for pregnant women, while it might be just a bit high in the regular population. |
|
|
Term
Which of the following hemodynamic changes DOES NOT take place during pregnancy?
1) Decreased TPR
2) Increased HR
3) Increased SV
4) Decreased CO
5) Decreased MAP |
|
Definition
4- CO increased by approximately 50%, to compensate for decreased TPR (thereby maintaining reasonable MAP)
MAP= CO * TPR and CO= SV * HR
CO increases mostly because of SV (40% increase), but also because of HR (20% increase)
Thus, preload increases (SV) to maintain CO |
|
|
Term
Which tissues receive the increased CO during pregnancy?
What periods are considered "highest risk" for hypoxia? |
|
Definition
1) Uteroplacental, Kidneys, Heart, Skin and Breasts get increased perfusion (No change in Brain, GI, MSK)
2) Early pregnancy, 28-32 week (peak of volume increase) and Immediately post-partum |
|
|
Term
| Why should pregnant women worry about lying in the supine position too much? Which positions are best? |
|
Definition
1) Compression of IVC by gravid uterus decreases preload (SV), and CO and can result in Supine hypotensive syndrome?
2) Lateral and knee-chest positions get highest CO |
|
|
Term
| What considerations should be made for a pregnant women with cardiac complications that is giving birth? |
|
Definition
1) Control CO with epidural
2) Avoid pushing
3) Vaginal delivery is best (less hemodynamic shift)
**Look out for "unmasked conditions"* |
|
|
Term
| Why are pregnant women at particularly high risk for thrombotic clots? |
|
Definition
Pro-coagulation state (Virchow's triad)
- Venous stasis
- Vessel wall injury
- Increased coagulation factors (except XI and XIII)
Protective against hemoorhage, but risk of DVT/PE! |
|
|
Term
| What are the primary respiratory changes of pregnancy? |
|
Definition
1) Anatomic
- Elevation of diaphragm
- Chest diameter wider
- Enlarged, left-shifted cardiac silhouette
2) Hormonal/mechanical
- Progesterone-induced relaxation
- Large gravid uterus
3) Functional
- FRC and RV decrease 20%
- VC and RR are unchanged
- Vt increased 40%
** Since minute ventilation increases (from Vt), there is an increased CO2 gradient between fetus and mom, facilitating removal by fetus** |
|
|
Term
True or False:
Fetal sequestration of maternal CO2 during pregnancy occurs because of an increased maternal RR. |
|
Definition
| False- It does occur because of an increased minute ventilation, which creates a greater maternal:fetal CO2 gradient, but the change in minute ventilation is due to an increase in Vt (with decreased FRC and RV), NOT RR |
|
|
Term
| What are the primary renal changes of pregnancy? |
|
Definition
1) Anatomic
- Bigger with dilated collecting systems (right>left), which is secondary to progesterone-mediated relaxation and compression by gravid uterus.
2) Physiological
- Gradual Na/Water retention and volume expansion, with slightly decreased plasma osmolality
- Increased RBF and GRF
- compensation for respiratory alkylosis makes acidotic states troublesome |
|
|
Term
| Why is metabolic acidosis particularly concerning for pregnant women? |
|
Definition
They decreased HCO3- in order to compensate for respiratory alkylosis, which is induced by increased minute ventilation (Vt).
Since HCO3- is low, they cannot ramp it up in order to compensate for acidosis. |
|
|
Term
Which of the following metabolic adaptations does NOT occur during pregnancy?
1) Switch from carbohydrate to fat utilization
2) High insulin levels
3) Low glucose
4) Post-prandial hyperglycemia
5) Decreased lipolysis |
|
Definition
5- There is INCREASED lipolysis
As pregnancy progresses, there is increased insulin resistance, which contributes to post-prandial hyperglycemia and a switch of carbohydrate to fat utilization (AKA lipolysis). Glucose is otherwise low, because of the "fetal sink" |
|
|
Term
There are numerous challenges of pharmacotherapy during pregnancy.
What are the major gestational effects on drug kinetics? |
|
Definition
1) Absorption
- Reduced gastric emptying (progesterone) and decreased gastric acidity increases increase intestinal metabolism
2) Distribution
- Plasma volume increases (40-50%), in combination with fetal availability, lead to major increase in VOD.
3) Metabolism
- Affect oxidizing phase 1 (CYP) and conjugating phase 2 (UGTs, SULTs and NATs) enzymes
- Ex1) Decrease caffeine metabolism (1A2)
- Ex2) Increase beta blocker metabolism (2D6)
4) Elimmination
- 50% increase in renal blood flow and GRF (those drugs are excreted unchanged) |
|
|
Term
True or False:
Most medications given to pregnant women reach the fetus. |
|
Definition
True
The kid is protected by efflux transporters and metabolic abilities
Also, vast majority of drugs are neither teratogenic or toxic |
|
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Term
| What is the major concern when using Ritodrine during pregnancy? |
|
Definition
IV dose too high for some and oral dose too low
Ritodrine, like Terbutaline, is a beta agonist that treats pre-term labor by increasing cAMP/PKA and decreasing MLCK activity in myometrium.
Lack of research on pharmacokinetics led to incorrect, catastrophic mistakes with IV dosing.
Hepatic phase 2 metabolism is different between subjects, meaning that certain "slow metabolizers" get WAY too much after 10 minute increases. |
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Term
| What are the major events that take in the 1st week of embryonic development? |
|
Definition
Cell division without increase in Size
1) Fertilization (24h)
- Sperm penetrates oocyte and within 11h, oocyte extrudes polar body and excess chromosomes, leaving zygote
2) Cleavage (day 1-3)
- First 5 cell division create pluripotent blastomeres
- At 16 cell stage, zygote becomes Morula, which leaves the fallobian tube and enters the uterine cavity at day 3-4
3a) Early blastocyst (day 4)
- As division continues, Blastocele cavity forms in center of Morula, forming Blastocyst
- Cells flatten and compact on inside of cavity, but outer zona pellucida maintains size of morula
**Marks presense of Embryoblasts (inner cell mass) and Trophoblasts (surrounding blastocele cavity**
3b) Late blastocyst (day 5-6)
- Blastocyst "hatches" from zona pellucida, which later degenerates
4) Initial implantation (d 6-7)
- Exposed trophoblasts begin to divide and fuse to create outer Syncytiotrophoblast, which is underlain by cytotrophoblasts.
- Syncytiotrophoblast secretes enzymes to erode uterine lining epithelium (implantation site) and hCG to maintain corpus luteal secretion of estrogen/progesterone. |
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Term
| Where is the ideal site for blastocyst implantation at day 6-7 post -fertilization? |
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Definition
Back wall of the body of the uterus towards the mother's spine.
**Syncytiotrophoblasts create cavity with enzymatic secretions** |
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Term
| What are the major events that take in the 2nd week of embryonic development? |
|
Definition
**Initial blastocyst implantation in uterine wall happens at day 6-7**
"Week of 2's"
1) Implantation completion (8-12)
- Syncytiotrophoblast cells erode uterine lining to create pools (Lacunae) of maternal blood (later become placenta).
2) Bilaminar embryonic disc (8-12)
- Inner cell mass divides into outer Epiblast facing trophoblasts (becomes Embryo and lines amniotic cavity) and inner Hypoblast (becomes yolk sac)
- Trophoblast proliferates as 2 layers (cyto and syncytio)
- Blastocyst cavity is remodeled twice (primary and then definitive yolk sac)
- Amniotic and chorionic cavities appear
- Extraembryonic mesoderm splits into 2 layers that line chorionic cavity |
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Term
Which of the following DOES NOT occur during the 2nd week of embryological development?
1) Blastocyst cavity is remodeled twice (primary and then definitive yolk sac)
2) Amniotic and chorionic cavities appear
3) Formation of Embryoblast and Trophoblast layers in blastocyst
4) Extraembryonic mesoderm splits into 2 layers that line chorionic cavity
5) The inner cell mass splits to form the epiblast and the hypoblast |
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Definition
3- Formation of the trophoblast and embryoblast occurs in week 1, prior to implantation (day 4), as syncytiotrophoblast enzymatic secretions are necessary for implantation and Lacunae formation.
Week 2 is the week of 2's
- Inner cell mass splits to form epiblast (amniotic cavity and embryo) and hypoblast (yolk sac)
- Trophoblast splits and proliferates
- Blastocyst cavity is remodeled twice
- Extraembryonic mesoderm splits into 2 layers that line chorionic cavity |
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Term
| What are the major events that take in the 3rd week of embryonic development? |
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Definition
1) Gastrulation (day 14-16) with establishment of craniocaudal axis and formation of 3 primary germ layers
2) Neurulation (18-19)
- Somites and neural plates form
3) Somite formation (20-30)
- Condensation of paraxial mesoderm to form paired somites flanking the neural tube, extending craniocaudally
- Give rise to vertebral column, ribs, muscles and dermis of skin) |
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Term
| Gastrulation establishes the 3 major germ cell layers. What are the major sets of structures that arise from each germ layer? |
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Definition
1) Definitive Endoderm (lining of gut and internal organs)
- Lungs, Liver, tongue, thyroid, pancreas, tonsils, bladder, GI tract
2) Intraembryonic mesoderm (MSK and circulatory system)
- Heart, Kidneys, Spleen, vessels, muscles, bones, reproductive organs
3) Definitive Ectoderm (skin, brain, nervous system and external tissue) |
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Term
| Describe the process of Gastrulation during the 3rd embyronic week? |
|
Definition
Establishment of 3 germ layers (ectoderm, mesoderm and endoderm)
1) Primitive streak forms as line of cells on surface of Epiblast (primitive pit in center is surrounded by primitive node)
2) Epiblast cells migrate through primitve groove towards hypoblast and displace hypoblast cells laterally, forming the Definitive Endoderm.
3) Second wave of epiblast cells migrate laterally and cranially between endoderm and epiblast and form intraembryonic mesoderm
4) After gastrulation, epiblast layer is referred to as definitive Ectoderm.
** Cranial and Caudal depressions of ectoderm form, which become Buccopharyngeal and Cloacal membranes, respectively** |
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Term
| What structures are derived from Neural crest cells? |
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Definition
4th germ cell layer that extends from lateral sides of Neural tube as it is closing during 4th week
1) PNS
2) Melanocytes
3) Calcitonin cells of thyroid
4) Adrenal medulla cells (Catecholamines)
5) Facial cartilage
6) Dentin of teeth |
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Term
| What are Spina Bifida and Anencephaly and when due they occur in embryonic development? |
|
Definition
Both are failure of closure of neural plate during 4th week of embryonic development to form the neural tube
1) Spina Bifida
- Failure of closure of posterior neuropore (d 23/24)
2) Anencepathaly
- Failed closure of cranial neuropore (d 25/26) |
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Term
| What structures arise from the embryonic somites? |
|
Definition
Somites form days 20-30 post-fertilization, as condensations of paraxial Mesoderm flanking the neural tubes, growing in a craniocaudal manner
1) Ribs
2) Vertebral column
3) Muscles
4) Dermis of skin |
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Term
| What are the major events that occur in the 4th embryonic week? |
|
Definition
1) Embryonic folding with differential growth of disc (fast) and yolk sac (stagnates)
2) Midline fusion of germ layers occurs and the connecting neck of the yolk sac is reduced to Vitelline duct
3) Amnion is carried ventrally to enclose entire embryo and beings producing fluid (continues until it obliterates chorionic cavity)
4) Amniontic cavity wraps around Vitelline duct and connecting stalk to form umbilical cord, which circulates blood between embryo and placenta. |
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Term
| When is the developing embryo particularly sensitive to injury? |
|
Definition
- 1st trimester between weeks 3-8 (during first 2 weeks, embryo has repairative potential)
- Brain between weeks 8-15 |
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Term
| What are the major risk factors for developing breast cancer? What factors reduce a woman's risk? |
|
Definition
1:8 women get it by 92 with one half risk 65 and 1/3 risk after 75
1) Age, Nulliparous (or 1st at later age), Early menarche/later menopause (estrogen), 1st degree family h/x, BRCA 1/2 mutations, endometrial/colon/ovary cancer.
2) Risk-reducing
- Premenpausal bilateral salpingoophorectomy (BSO)
- Prophylactic bilateral mastectomy
- Premenopausal hysterectomy |
|
|
Term
BRCA1/2 mutations are associated with inherited cancer susceptibility syndrome.
What is the normal function of BRCA1/2 and what are the hallmarks of such a syndrome? |
|
Definition
1) Inherited syndrome
- Multiple family members with breast and/or ovarian cancer
- Single member with breast and ovarian cancer
- Early age of onset (<50)
2) BRCA1/2 are tumor suppressor genes that encode DNA repair enzymes in 10% of ovarian cancers and 3-5% of breast cancers (25% of inherited breast cancers)
- Lifetime risk with BRCA1 (17q21) is 39-46% (ovarian) and 65-74% (breast)
- Lifetime risk for BRCA2 (13q12) is 12-20% (ovarian) and 65-74% (breast)- ALSO men
**risk depends upon degree of relatives cancer (postmenopausal, bilateral is worst at 25% risk)** |
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Term
What is the most common type of breast cancer and which tumors are typically found in the following locaitons?
1) Small terminal lobules
2) Large ducts |
|
Definition
Infiltrating ductal (60-70%) followed by Infiltrating Lobular (15-20%)
1) Lobular- bilateral and leads to ductal cancer
2) Ductual- ipsilateral and leads to ductal cancer |
|
|
Term
What are the key characteristics of the following surgical techniques for treating breast cancer?
1) Modified radical mastectomy
2) Simple/total mastectomy
3) Partial/Segmental mastectomy or Quadrantectomy |
|
Definition
Perform sentinal node biopsy to avoid needless axillary node dissection, with 20-40% complication rate.
1) Removal of breast with preservation of pectoralis muscle
- Dissection of axillary nodes levels 1 (lateral) and 2 (beneath) pectoralis minor.
2) Removal of entire breast without underlying muscle of nodes
3) Removal of 8th or 4th of breast with margins. |
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Term
True or False:
Segmental mastectomy, axillary node dissection and post-operative radiation therapy are as effective as modified radical mastectomy. |
|
Definition
True: NSABP trial for patients with stage 1 and II disease
NOT true without radiation |
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Term
| Who should receive adjuvant cytotoxic/hormonal therapy for post-surgical breast cancer? What therapies are available? |
|
Definition
Both node positive and negative patients.
Staging + Prognostic factors (estrogen/progesterone status, primary size and node status) guide therapy
1) Hormonal: Patients with ER + PR positive tumors response 80% to hormonal therapy (ER only is 60-80%) vs. 10% for ER/PR negative
- Pre-menopausal- Tamoxifen
- Post-menopausal- Aromatase inhibitors (Anastrazole, Letrozole, Exemestane)
2) Chemo (many others as well)
- Adriamycin/cyclophosphamide
- Docetaxel/Adriamycin/Cyclophosphamide
3) Biologics
- Herceptin (transtuzimab) in HER2 positive cancers |
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|
Term
| What are the common benign breast lesions and the defining characteristics of each? |
|
Definition
1) Inflammatory lesions
- Acute mastitis- early feeding/staph enters nipple
- Traumatic fat necrosis- histiocytes/scar that can be confused for cancer
2) Fibrocystic changes (FCC)
- Sex hormone-responsive changes in 40-50% of patients
- Blue-domed cysts with frequent apocrine metaplasia, fibrosis and inflammation (rupture)
**only cancer risk if proliferative (1.5-2X)**
3) Fibroadenoma (FA)
- Most common benign tumor of female breast
- Young women (20-30)
- Well circumscribed, mobile nodules ("shellout out") with gray bulging cut surface
- Fibroepithelial tumor that can be multiple/bilateral
4) Gynecomastia
- Small subareolar swelling (bilateral)
- Physiological in puberty and very old, with no clear-cut cancer risk. |
|
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Term
| What is the most common benign tumor lesion of the breast? Which benign lesions can increase risk for breast cancer? |
|
Definition
FCC is most common overall lesion that is diagnosed
1) Fibroadenoma
- Younger women with well-circumscribed, mobile nodules with gray bulging cut surface and homogenous fibroblastic intralobular stroma
2) Proliferative fibrocystic change (pFCC)
- Sex hormone responsive, blue domed cysts with frequent apocrine metaplasia.
Relative risk of invasive cancer increases from proliferative disease without atypia (1.5-2x), with atypia (4-5X) and carcinoma in situ (8-10X) |
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Term
True or false:
Lobule carcinoma in situe harbers an 8-10X breast cancer risk for the ipsilateral breast. |
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Definition
False: LCIS (lobules) is risk for both breasts
DCIS (large ducts) is ipsilerateral |
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Term
Patient presents with breast pain, nipple inversion and a solid mass in her left breast.
What is the most common malignant breast lesion? How are breast cancers diagnosed and what are the most important prognostic factors? |
|
Definition
1) 90% are ductal epithelial carcinomas (usually in 4th or 5th decade with invasion)
- 10% are lobular epithelial carcinoma
2) Triple test (clinical, radiology and pathology)
3) Prognostic factors
- In absence of distant metastasis, Axillary LN status is MOST important |
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|
Term
A variety of tumors can occur in the breast, including benign and malignant, and in-situ and invasive.
What type of tumor is described by each of the following?
1) Neoplastic transformation of ductal epithelium within ducts or lubules, confined by the basement membrane, that is often detected by microcalcifications
2) Neoplastic transformation of epithelial lining of terminal ducts and acini that is restricted by the basement membrane and is usually discovered incidentally.
3) Infiltrates as single cells in classic "indian file" pattern and targetoid "bull's eye" pattern
4) Fibroepithelial neoplasm that may degenerate into frank sarcoma with metastasis to lung
5) Tumor of young individuals that follows radiation therapy and may present with lymphedema after mastectomy
6) In situ carcinoma of lactiferous ducts with extension to epidermis, involving the nipple and areola (discharge) |
|
Definition
1) DCIS- most common, calcifications and ipsilateral risk
2) LCIS- no calcifications and bilateral risk
3) Invasive lobular carcinoma
4) Phyllodes tumor
- Hematogenous spread so sential node is not indicated
5) Angiosarcoma
- Stewart-Treves syndrome is post-mastectomy presentation with lymphedema
6) Paget's disease of breast |
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|
Term
| How can you distinguish between a ductal and lobular carcinoma pathologically? |
|
Definition
1) Ductal has more pleomorphism and solid, cohesive groups of glands (more common)
- ECAD +
2) Lobular has bland cytology with linear chains of cells and plasmacytoid cells
- ECAD- |
|
|
Term
| What types of breast cancer are associated with "good prognosis"? |
|
Definition
1) Mucinous: tumor floating in mucin
2) Tubular: angulated glands with single cell layer
3) Medullary: sheets of tumor cells with lymphocytes
Epithelial types are most common (ductal and lobular), but not best prognosis. |
|
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Term
| How are breast cancers graded? |
|
Definition
Each gets score of 1-3
1) Tubule formation
2) Mitotic count
3) Pleomorphism |
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Term
There are a number of different mechanisms of pathogenesis underlying teratogenesis. What type of defect is each of the following?
1) Open neural tube defect like Spina Bifida
2) Clubbed feet
3) Gastroschisis due to vascular disruption in fetal anterior abdominal wall
4) Achondroplasia |
|
Definition
1) Malformation: defect resulting from an intrinsic abnormal developmental process.
2) Deformation: Abnormal shape or position caused by mechanical forces (in this case, an abnormally shaped uterus from DES exposure or oligohydramnios)
3) Disruption: Normal developmental process is interupted
4) Dysplasia: Abnormal organization or differentiation of cells and tissues (as opposed to organs) |
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Term
| What agents are included in category A, B, C, D and X in terms of teratogenicity according to the FDA? |
|
Definition
1) Category A: No fetal risks by controlled studies
- Vitamins, folic acid, thyroid (T3/4)
2) Category B: No fetal risks by animal studies
- Tylenol, Zofran, PCN, Azithromycin
3) Category C: No adequate studies, or adverse effects in animals without human data.
- Albuterol, Dextromethorphan
4) Category D- evidence of fetal risk, but benefit may outweight
- Diazepman, Alprazolam
5) Category X: Risks are too great
- Isotretinoin |
|
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Term
| Why might an infant be born with digital and nail hypoplasia, depressed nasal bridges, mental retardation and congenital heart disease? |
|
Definition
Fetal Hydrantoin Syndrome due to Dilantin (Phenytoin) use (anti-convulsion)
Full syndrome in 10% and digital abnormalities in 30% |
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Term
| Which anti-convulsion drug is safe to use during pregnancy? Which are dangerous? |
|
Definition
Phenobarbital has no risk
Phenytoin/dilantin is at risk for fetal hydrantoin syndrome (digital, nose, mental retardation and congenital heart defects)
- Valproic acid (Depakote) has 1-2% risk of open neural tube defects and minor craniofacial |
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Term
| Isotretinoin is commonly used to treat cystic acne. Why should pregnant women not take this drug? |
|
Definition
25% risk of fetal malformations (Brain, Face and Heart)
1) CNS (hydrocephalus, deafness, blindness and mental retardation)
2) Facial- Micropthalmia, cleft palate, malformed ears
3) Congenital heart defects |
|
|
Term
Describe what each of the following mean.
1) Omphalocele
2) Holoprosencephatly
3) POsterior urethral valves |
|
Definition
1) Defect in anterior abdominal wall musulature with extrusion of abdominal contents into base of umbilical cord (associated with cardiac and karyotypic abnormalities).
- different from gastroschisis, where contents are not in sac.
2) Formation of midline structures of embryonic brain require ventral induction, and when this happens, the face does not divide at the midline either.
3) Posterior Urethral valves
- Males only,
- Exagegerated development of urethrovaginal folds with abnormal insertion of distal end of wolffian ducts creates blockage obstruction
- Diagnosed on US as "keyhole" bladder, dilated collecting systems and oligohydramnios |
|
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Term
| Describe the formation of the placenta during pregnancy. |
|
Definition
1) Implantation (day 6 or 7)
- Aposition, adhesion, invasion
2) Maternal-Fetal contact
- Decidua basalis makes contact with chorion frondosum, which arises from proliferated villi from trophoblast tissue
3) Formation of placental villi
- primary secondary and tertiary villi (3-4 weeks)
4) Villous tree structure develops
- Placental villi organize into Cotyledons, which are separations of decidua basalis of the placenta (each is a major stem of the chorionic villus)
5) Placental separation
- After birth, placenta and membranes are expessed from uterus |
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Term
| Fetal implantation occurs in 3 stages. Describe these stages. |
|
Definition
day 6-7 post-fertilization (Interstitial process)
1) Apposition
- unstable adhesion of blastocyst to uterine wall, where pinopodes from uterine epithelium interdigitate with microvilli of syncitiotrophoblast.
2) Stable adhesion
- Increased contact
3) Invasion (interstitial)
- Penetration of syncytiotrophoblasts through uterine epithelium, followed by infiltration of mononuclear cytotrophoblasts through entire endometrium, myometrium and vasculature. |
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Term
| Why do trophoblastic cells in the invading embryo not spread throughout the entire uterus? |
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Definition
| Implantation and placentation is a balance between regulatory gradients created by BOTH trophoblast (Integrins and MUC-1) and endometrium (Growth factors, hormones and cytokines) |
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Term
| Describe the major parts of the Decidualized uterine stoma. |
|
Definition
Decidual reaction occurs in maternal endometrium at site of implantation.
1) Decidua basalis: site of implantation, making contact with Chorion frondosum (from trophoblast villi) to form placenta
2) Decidua capsularis: Likes like capsule around chorion
3) Decidua perietalis
- lies on opposite uterine wall to capsularis, ultimately fusing with the later to close the uterine cavity (space taken up by amniotic cavity) |
|
|
Term
| Describe the basic structure of the embryonic chorion |
|
Definition
2 layers, which fuse with Decidua basalis to form Placenta
1) Outer Ectoderm/Trophoblast: undergoes rapid proliferation to form chorion villi
- Inner cytotrophoblast
- Outer syncytiotrophoblast
2) Inner Somatic Mesoderm which contacts the amnion
- Grows into trophoblast, bringing umbilical arteries which take fetal blood to the maternal circulation |
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Term
| What is the chorion frondosum? How does it relate to the chorion laeve? |
|
Definition
1) Chorion frondosum forms from the chorionic villi that make contact with the decidua basalis, with which it ultimately fuses to form the placenta.
2) Chorion laeve is smooth remnant of the greater part of the chorion, which makes contact with the decidua capsularis until it atrophies and fuses with the decidua parietalis. |
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Term
3 distinct trophoblast types arise from the chorion during placental formation.
What are these types? |
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Definition
Make hormone, anchor or invade.
1) Villous syncytiotrophoblast (hCG)
- cytotrophoblasts in the villi fuse to form overlying syncytoptrophoblast, which makes hormones like hCG
2) Anchoring trophoblast
- Cytotrophoblast layer proliferates at point of contact with uterus to form anchoring cell columns
3) Extravillous trophoblast
- Attach and interdigitate through extracellular spaces of endo and myometrium, ultimately to penetrate the maternal spiral arteries within the uterus and make blood-blood contact. |
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Term
Placental villi are formed in 3 stages
Describe these steps. |
|
Definition
1) Primary
- Form from initial trophoblast shell and it invades maternal tissues
- Gaps, called Lacunae form, allowing maternal blood to bathe syncytiotrophoblast.
2) Secondary
- Invasion of extraembryonic mesoderm into primary villi forms the chorion
3) Tertiary villi
- Form when embryonic blood vessels invade connective tissue core of secondary villi (3-4 weeks)
- These villi are organized into lobular units called Cotyledons, which exhange blood with maternal circulation. |
|
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Term
| What hormones are produced by the placenta and what are their functions? |
|
Definition
Many hormones, but hCG is most imporatnt
1) hCG- Maintains corpus luteum that secretes progesterone and estrogens and LH stops handling it.
- Peak levels reached at 8-10 weeks
2) Estrogen/Progesterone
- Trophoblast makes estrogen
- Syncytiotrophoblast makes progesterone (maintains non-contracted uterus
3) Activin/inhibin
- Produced by trophoblast to regulate hCG production
4) TNF-alpha, TGF-beta, EGF
- Proliferation of trophoblast and production of fibronectin
5) hACTH
- small amounts that act like ACTH |
|
|
Term
| How does immune adapation to pregnancy balance immunosuppression and tolerance? |
|
Definition
Maternal immune system shifts from cell-mediated immunity to humoral immunity
1) Altered HLA expression
2) Soluble immunomodulators
3) Shift in lymphocyte population (Tregs increase)
4) Modulation of T cell activity by limiting tryptophan by IDO |
|
|
Term
Describe the following placental complications of pregnancy?
1) Placenta Abruption
2) Placenta Previa
3) Placenta Accreta
4) Pre-eclampsia |
|
Definition
1) Placental Abruption (1:100)
- peels from uterine wall and presents with vaginal bleeding and often discomfort
- Risk of pre-term delivery and still-birth
2) Placenta Previa
- Implantation over cervical os (1:200), potentially blocking fetal exit and causing dangerous, PAINLESS vaginal bleeding
3) Placenta Accreta (increta and percreta)(1:2500)
- Implantation is too deep and firm into uterine wall
- C section and hysterectomy to prevent hemoorhage
4) Preeclampsia
- Shallow invasion of placenta and incomplete invasion of uterine spiral arterioles
- Oxidative stress and hypoxia |
|
|
Term
Describe the following placental complications of pregnancy?
1) Chorioamnionitis
2) Twin-twin transfusion syndrome
3) Ectopic pregancny
4) Gestational trophoblast disease |
|
Definition
1) Fever and uterine tenderness from group B strep ascending infection
- PMN inflammation of membranes and placenta
- Associated with risk of cerebral palsy
2) Twin-twin transfusion
- Twins that share placenta, where blood comes from one and returns to the other.
- One has oligohydramnios and the other polyhydramnios
3) Ectopic pregnancy
- Blastocyst implants outside uterus (chronic salpingitis is a risk)
4) Gestational trophoblast disease
- Hydatidiform moles and choriocarcinoma
- early placenta develops into mass of cysts (mole) that semebles a bunch of grapes
- Complete (46) and Partial (69) forms, both treated with D & C (complete is more persistent and risk of cancer) |
|
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Term
| Describe the 3 basic stages of Labor |
|
Definition
Defined by regular, painful contractions accompanied by dilation and effacement of the cervix.
1) Stage 1 (few-24 with latent and active)
- Begins with regular uterine contractions and ends with complete dilatation at 10cm
2) Stage 2 (<3h)
- Begins with complete cervical dilatation and ends with delivery (PUSH HERE)
3) Stage 3
- Begins with delivery of fetus and ends with delivery of placental and fetal membranes |
|
|
Term
| Describe the progressive fetal movements during delivery. |
|
Definition
| Number of cardinal movements that are determined by anatomy of maternal pelvis and allow for navigation of fetal head through pelvis with least resistance. |
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Term
A pregnant woman has a high BP (>140 or 90) on 2 occasions greater than 6h apart and significant proteinuria of 340 mg/24h
What is going on? What do you do? |
|
Definition
- Pre-eclampsia: Disease of endothelial function (see glomerular endotheliosis) with shallow cytotrophoblast invasion of uterine spiral arterioles
- Give IV MgSO4 to prevent progression to Eclampsia (generalized tonic clonic seizure) and decrease risk of cerebral palsy
- ONLY CURE is delivery of baby and placenta |
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Term
|
Definition
Variant of severe pre-eclampsia with Hemolysis, Elevated liver enzymes and Platelets.
Give IV MgSO4 to prevent Ecclampsia and seizures (risk of cerebral palsy), but need to deliver fetus and placenta to cure. |
|
|
Term
| What is the Pederson hypothesis of Gestational diabetes? |
|
Definition
Explains fat babies
Persistent maternal hyperglycemia (due to development of insulin resistance over pregnancy) leads to fetal hyperglycemia and episodic fetal hyperinsulinemia (Macrosomia)
Remember, women with GD get T2DM later in life. |
|
|
Term
| What are the major risk factors for gestational diabetes and how is it treated? |
|
Definition
1) Risk
- Previous GD diagnosis
- PCOS
- family h/x of T2DM
- Advanced maternal age
- Previous poor gyn history
2) Treat
- Insulin (does not cross placenta) is gold standard
- Glyburide (sulfonylurea) crosses placenta in small ammounts |
|
|
Term
| What is the only FDA-approved drug that prevents pre-term labor and how does it do it? |
|
Definition
Ritodrine- Beta 2 activator that relaxes smooth muscle by increasing cAMP and decreasing calcium entry.
Used to buy enough time to give mom antenatal glucocorticoids to prevent neonatal mortaility and morbidity. |
|
|
Term
| What is the nutrient composition of breast milk? |
|
Definition
1) Fats (half of energy content)
- polyunsaturated FA, DHA and AA that is not in cow's milk.
2) Carbs
3) Proteins (lower than animals)
- Casein- less in humans, easier to digest
- Whey- More alphalactalbumin in humans |
|
|
Term
The human mammary gland is the only organ not fully developed at birth.
Describe the 2 stages of lactogenesis |
|
Definition
At 3 months, secretory material begins to appear in acini (stimulated by prolactin) and by 16 weeks, mother can produce Colostrum.
1) Secretory Differentiation
- Begins in early third trimester with increase in lactose, proteins and IG and a decrease in Na and Cl
2) Secretory Activation
- Defined clinically by mom sensing "milk coming in" (usually day 2-4)
- Increase in citrate, glucose, Ca and fall in pH and peak plasma alpha lactalbumin
**At birth, progesterone drops dramatically, taking away inhibition of lactation** |
|
|
Term
| What are the primary immunologically active components of human breast milk and what are their functions? |
|
Definition
1) Lactoferrin
- Binds iron to assist absorption
- Partially digested to lactoferricin B (antibacterial)
2) Triglycerides
- Digested by lingual and gastric lipase into FFA and monoglycerides in stomach
3) Glycans
- 10% of maternal caloric input for milk
- Engulf pathogens to prevent attachment to intestinal mucosa |
|
|
Term
| Which hormones/chemicals rise just before birth in preparation for the "neonatal transition"? |
|
Definition
1) Cortisol
- Surfactant production and excretion
- Glucose/thermoregulation
2) Catecholamines
- Re-absorption of fetal lung fluid
- Mobilize glycogen |
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Term
| How is fetal blood flow from the placenta and body distributed? |
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Definition
1) Placental blood
- Comes in from umbilical vein and bypasses liver to enter IVC via ductus venosus
- IVC placental blood enters RA atrium and passes across foramen ovale to enter left atrium and supply the upper body
2) IVC/SVC blood from lower body (lower O2 content)
- Enters RV and bypasses pulmonary circulation via PDA, and supplies lower body |
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Term
| Explain how fetal R-L shunting is switched at birth. |
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Definition
When newborn breathes O2, PVR drops and PDA constricts and closes.
With clamping of umbilical cord, low resistance umbilical circulation ceases abruptly, raising SVR and BP to a level that exceeds PVR.
Since SVR>PVR, the shunt switches to L-R |
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Term
Which of the following transitions between fetal and adult circulation DO NOT occur?
1) Absence of exptrapulmonary shunts with a fixed parallel circuit
2) Pulmonary vascular resistance decrease during 1st weeks of infancy
3) Systemic vascular resistance and blood pressure increase during childhood
4) Loss of dilating prostaglandins cause constriction of the muscular ductus arteriosus. |
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Definition
| 1- Circuit becomes fixed "in-series" cirdcuit |
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Term
Which of the following congenital heart defects is acyanotic in infancy?
1) Peristent Truncus arteriosus
2) Total anomylous pulmonary venous return
3) Coarctation of the aorta
4) Tetralogy of fallot
5) Tricuspid atresia |
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Definition
3- Coarctation causes blood to flow through heart and pulmonary circulation in a normal series pattern, fully oxygenating it.
Systemic flow blockage causes HF and shock if not treated.
Pre-ductal- Turner's
Post-ductual- adult |
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Term
| What is "peristent pulmonary hypertension" of the newborn? |
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Definition
PPHN occurs when elevated PVR after birth leads to persistence of fetal circulation post-natally.
Blood continues to be shunted R-L, bypassing the lungs, but absence of placental blood means that it is not oxygenated.
Give O2, NO, assisted ventilation and ECMO if needed until lungs return to normal |
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Term
| What are the 5 major stages of embryonic lung development? |
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Definition
Begins at conception and continues after birth for many years!
1) Embryonic (3-7)
- Lung bud arises from foregut and T/E separation occurs
2) Pseudoglandular (5-17 weeks)
- Formation of tracheo-bronchial tree
- Lymphatics, cilia and globlet cells differentiate
3) Canalicular (17-28 w)
- Alveolar type I and II cells differentiate
- Lamellar bodies form (early surfactant)
4) Saccular stage (29-35)
- Distal air spaces branch and grow
- Surfactant formation escalates
- Fetal lung fluid and fetal breathing
5) Alveolar (36 w- years)
- Alveolar septal walls thin and alveolar surface area increases. |
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Term
| What is the importance of fetal lung fluid and how is reabsorbed at birth? |
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Definition
1) Cl-driven secretion of fluid into lung lumen by epithelial cells
- Support for differentiation and proliferation of tissue
2) At birth, Epi, beta-adrenergic agonists and surfactant cause absorption by stimulating Na/K ATPase-driven sodium uptake by the pulmonary epithelium into the interstitium
- Stimulated by corticosteroids and thyroid hormone. |
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Term
Premature baby is born in respiratory distress, with tachypnea, hypercarbia, retractions and nasal flaring.
What occurs during transient tachypnea of the newborn? |
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Definition
Respiratory transition abnormality
C-section, prematurity and hypoxemia can all cause prolonged clearance of fluid (retention causes respiratory distress)
Treatment is supportive and it should resolve wtihin a few hours to days. |
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Term
| What is the pathophysiological basis of RDS in the newborn? How do you treat? |
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Definition
1) Insufficient surfactant production, secretion or recycling producing low lung compliance and obstructive disease.
2) Combination of prenatal corticosteroids and post-natal respiratory support with O2, PPV and exogenous surfactant.
1) Premature birth
2) Gestational diabetes
3) Hypothyroidism. |
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Term
| When is surfactant synthesized in embyronic development? |
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Definition
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Term
| Which infants are at risk for neonatal hypoglycemia? |
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Definition
1) Premature
2) Small for gestational age
3) Infants of diabetic mothers (large for gestational age usually) |
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Term
| What are the digestive and immune functions of human breast milk for the newborn? |
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Definition
1) Digestion
- Digestive enzymes that aid short gastric emptying time
- EGF for maturation of mucosal tissues, as well as IGF-1, TGF-a and thyroid hormones
2) Immune
- Secretory IgA in Colostrum survive in intestine and provide anti-viral and anti-bacterial support. |
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Term
How can physiological jaundice of the newborn be distinguished from pathalogical conditions?
What are the pathalogical causes? |
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Definition
Pathological forms most often have neurological sequele, such as sensorineural hearing loss.
1) Increased production
- Hemolysis
- Extravasation of blood
- Polycythemia
- Swallowed maternal blood
2) Decreased clearance
- Transport
- Uptake (GIlbert)
3) Conjugation
- Crigler najar 1 or 2
4) Excretion
- Ileus or increased enterohepatic circulation |
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Term
What is a definition of significant growth restriction of the newborn.
What is the difference between asymetrical and symetrical restriction |
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Definition
1) <3rd percentile (3% of births)
2) Asymetric is later gestation while Symmetric is early gestation |
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Term
| Should you be worried if a child is below birth weight in the 3rd post-natal week? |
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Definition
Yes!
They may lose water weight in the first weight, but should regain and exceed birth weight by 2 weeks and then grow 30 grams/day for the first month. |
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Term
What major growth changes occur at the following developmental time points?
1) first year
2) second year
3) preschool (2-5)
4) middle childhood (6-9)
5) adolescence (10-13)
6) middle adolescence (14-16) |
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Definition
1) After 1st week, grow 30 g/d for first month and then 20g/d for rest of year.
2) Appetite declines and changes to be autonomous ("picky " eater)
3) Average weight gain about 2kg and 7cm in height per year.
- Longer, leaner look with peaking energy
4) Growth spurts in discontinuous periods
- Complete myelination by 7 years
5) Growth acceleration begins for both
6) Height peaks for boys (2-3 years later) and girls
- Sexual interest peaks
- Spurts begin distally, with enlarged hands and feet
- Secondary sex characteristics |
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Term
| What are the major "domains of function" in normal childhood development? |
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Definition
Innate basic capabilities combined with differentiation and hierarchnal organiziation and qualitative changes
1) Fine/Gross motor skills
2) Cognition
3) Social/emotional functioning |
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Term
| What are the major components of normal gross motor development in the child? |
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Definition
1) Early reflex patterns
- Moro- abduction/extension of upper + lower followed by adduction of upper
2) Anti-gravity muscle control
- Cephalocaudal progression, paralleling myelination
- Sit independently at 5-8 months with parachute response at 10 months
3) Locomotion
- First steps 9-17 months
4) Complex gross motor patterns
- Balance and coordination of walking |
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Term
| What are the major components of normal fine motor development in the child? |
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Definition
Gained proximal (midline) to distal (extremeties)
1) Grasp (birth)
- reflexive palmar grasp dissapears at 1 month
2) Voluntary grasp (4-5 months)
3) Transfer object independently (5-7 months)
4) Fine pincer grasp (9-12 months) |
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Term
| How is the directional trajectory of fine and gross motor development different? |
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Definition
1) Fine occurs midline to periphery
2) Gross is head to toe |
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Term
| Describe the normal progression of sensori-motor development in a child. |
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Definition
1) Object permanence (first 2 years)
2) Symbolic thinking (second year)
3) Logical thinking (preschool) |
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Term
| What are the clinical signs/symptoms of Cerebral Palsy? |
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Definition
Disorder of (GROSS) movement and posture resulting from injury to motor area of brain
- Abnormalities of tone
- Static (not progressive) motor problems
- Persistent reflexes (e.g. asymmetric tonic neck reflex or ATNR) |
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Term
| What are "specific language disorders"? |
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Definition
| Language difficulties that occur in a child with normal hearing, intellectual functioning and capacity to relate and learn. |
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Term
| What condition of childhood is defined by deviant social development, absent or abnormal speech and language development, and very unusual, concrete cognitive abilities? |
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Definition
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Term
| What is the pre-puberty state of the male and female gonads? |
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Definition
Hypofunction is due to insufficient secretion of LH and FSH
1) Male
- Gonads are structurally complete, but immature
- Leydig cells are present, but making little testosterone.
- Sertoli cells and seminiferous tubules are present, but tubules are short, with small lumens and not mature sperm.
2) Female
- Ovary contains all ova which will ever be available in form of primordial follicles
- No large, mature antral follicles and no corpora lutea |
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Term
| What is the primary reason for quiescent gonads during sexual immaturity. |
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Definition
Very low levels of secretion of GnRH from hypothalamus.
Puberty activation is dependent upon higher-cortical centers, perhaps through kisspeptin:GPR54 interactions.
"Ovaries and Pituitary are competent and just waiting for that kick" |
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Term
| What is Tanner staging and what hormonal changes does it follow? |
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Definition
1) Systematic description of development of secondary sex characteristics of boys and girls
2) Follows GnRH axis, exclusively depending on activation of the gonads and initiation of increased steroid secretion. |
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Term
| What is the physiological basis for the "sexual growth spurt" that occurs at puberty? What does this have to do with why men grow later and taller? |
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Definition
Estradiol in both genders
1) Increase in sex steroids, especially estradiol, which increases liver synthesis of Somatomedin (IGF-1) and GH increases nocturnally with GnRH release
2) Estradiol increases in men occur more slowly, preventing early fusion of epiphyseal growth plates and starts later. |
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Term
What are the classic laboratory/clinical findings of a child with true "central" precocious puberty?
How do you treat? |
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Definition
1) Should follow pace and order of events in normal puberty, just at age 8 (F) or 9 (M)
- Nocturnal increase in LH secretion
- Pituitary response to exogenous GnRH will be appropriate to bone age rather than chronological age
2) Treat
- long-acting GnRH agonist to selctively inhibit FSH/LH secretion by pituitary until child reaches appropriate age |
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Term
| What are the classic findings of a peri-menopausal women who is gradually losing her last follicles? |
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Definition
Primary driver of symptoms is dropping estradiol-17-beta levels due to declining numbers of follicles in ovary.
1) Low estrogen, high FSH and normal LH
- high FSH from loss of inhibin release from follicles
2) Thecal and interstitial cells continue to produce androgens, but they cannot be converted to estrogen (granulosa cell decline with follicles) |
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Term
| Why to women get hot flushes in Menopause? |
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Definition
30 min: Annoying and distrupt REM sleep cycles
Low estrogen levels fail to inhibit ER on temperature-regulation neurons in the anterior hypothalamus (near to GnRH releasing neurons, which are also activated)
- Onset (vasodilation with sweating decreases B.T)
- End (vasoconstriction/shiver increases B.T.) |
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Term
| What are the potential benefits of HRT for treating menopausal women? |
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Definition
Bone and CV system- but results from studies are conflicting.
1) Osetoporosis issue
- Most severe in first months after cessation of cycles, due to increased osteoclast activity and decreased osteoblast function.
2) Cardiovascular
- Estradiol stimulates NO and directly causes vasodilation via ER receptors
- Reduces vascular response to injury and potential for vasoconstrictor injury |
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Term
| What are the 2 major phases of a 30 min hot flush in a menopausal woman? |
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Definition
1) Onset: vasodilation with sweating decreases B.T
2) End: vasoconstriction/shiver increases B.T. |
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Term
| Describe the process of estrogen synthesis |
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Definition
1) Pre-menopausal
- Androstenedione in theca cells is converted to Estradiol within Granulosa cells by Aromatase
2) Post-menopausal (Extragonadal)
- Adipose stromal cells use DHEA produced by adrenal gland
3) Men
- Extra-gonadal synthesis via aromatiziation |
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Term
| Describe the structure of estrogen receptors and what happens to them upon steroid binding. |
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Definition
1) ERs nuclear hormone receptors
- central DNA_binding domain
- carboxy ligand-binding domain
- amino transcriptional regulation
2) Estrogen binds ER, which translocates to nuclear and binds ERE's in cooperation with other recruited proteins to regulation trascription
- ER-alpha is uterine growth and bone metabolism
- ER-beta is high in ovarian granulosa cells and is required for folliculogenesis
3) Plasma-membrane-bound ERs may also have nongenomic effects on the CV system |
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Term
| What is the difference between the actions of the ER-alpha and ER-beta nuclear receptors? |
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Definition
Much overlap, but some specificity as well.
1) ER-alpha
- uterine growth
- bone metabolism
2) ER-beta
- high in ovarian granulosa cells and required for folliculogenesis
- Protective against colorectal cancer |
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Term
| How is estrogen metabolized? |
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Definition
1) Lipophillic with high VOD
2) Rapidly metabolized by liver to 16-alpha-hydroxylated and 17-keto forms in addition to variety of sulfate and glucuronide conjugated forms that are ecreted in urine.
**Conjugated forms undergo enterohepatic circulation** |
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Term
| Why are C17 derivatives of estrogen such as ethyinyl estrogen, Mestranol and Premarin useful? |
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Definition
Substitution dramatically limits first-pass metabolism in liver, making them good oral options.
Unlike natural estrogens (90% of which are bound to SHBG), C17 derivatives circulate in blood bound in lose association with albumin. |
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Term
| What are the important non-steroidal compounds with estrogenic activity and how are they used? |
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Definition
Both plant and industrial derivatives can exert estrogenic actions via direct activation of ER receptor.
- Typically plant derivatives (phytoestrogens) with flavinoids
1) Diethylstilbesterol (DES)
- Not bound to SHBG or rapidly metabolized
- NO LONGER USED
2) Endocrine disruptors (synthetic)
3) Enviornmental
- PCBs
- BPA |
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Term
| What kind of drug is Fulvestrant and how is it used? |
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Definition
once a month by IM
Pure ER antagonist approved for treatment of breast cancer
**ER-positive breast cancers that are Tamoxifan resistant** |
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Term
| What are the available SERM compounds and how are they used? |
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Definition
Bind directly to ER's and induce conformational changes in LBD (Carboxy) of receptors
1) Tamoxifen
- Antagonize estrogen action in breast and agonize it in bone
- Risk of uterine cancer
- Active hepatic metabolite is 4-hydroxytamoxifen
2) Raloxifene
- Treats osteoporosis due to ER agonist effect on bone
- Protective in women with high breast cancer risk.
3) Clomiphene
- Management of infertility
- Estrogen antagonist in hypothalamus leading to enhanced release of GnRH
- Contraindicated in liver dysfunction.
4) Lasofoxifene
- Good for osteoporosis and to reduce risk of cancer, fractures and CAD/stroke.
- Risk of DVT/PE |
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Term
| What agents are used to prevent osteoporosis in post-menopausal women? |
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Definition
Estrogen and Raloxifene (NOT restorative)
**Raloxifene and Tamoxifene induce hot flashes** |
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Term
| What is the treatment(s) of choice for prevention/treatment of ER/PR + breast cancers. |
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Definition
1) Tamoixfen is preventive in high risk women and used to treat.
SERM-resistance (express HER2/neu and A1B1) can be overcome by addition of electrophile, Disulfide Benzamide (DIBA)
2) Aromatase inhibitor like Amastrozole, Letrozole or Exemestane |
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Term
| What are the major Aromatase inhibitors and what is their utility? |
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Definition
Exemestane, Anastrozole and Letrozole are used for early-stage and advanced breast cancer in post-menopausal women (as first line, or in combination with Tamoxifene).
- Reduce estrogen levels in peripheral tissues
1) Type 1 Steroidals are suicide substrates that irreversibly inactivate aromatase
- Formestane and Exemestane
2) Type 2 Non-steroidals reversibly interact with heme group of aromatase
- Anastrozole, Letrozole, Vorozole |
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Term
What is the mechanism of action of each of the following drugs used in breast cancer?
1) Tamoxifene
2) Triptorelin
3) Letrozole
4) Exemestane |
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Definition
1) SERM used for ER/PR + breast cancers
2) GnRH analog given in combination with AI's to suppress estrogen synthesis in pre-menopausal women
3) Type 2 (non-steroidal) aromatase inhibitor
3) Type 1 (steroidal) aromatase inhibitor |
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Term
| Which Aromatase inhibitors have proven to be most useful in treating post-menopausal women with breast cancer? |
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Definition
1) Anastrozole (Non-steroid)
2) Letrozole (Non-steroid)
3) Exemestane (Steroid) |
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Term
| At what points should a sex history be taken? |
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Definition
1) Briefly at initial assessment
2) Annual exams
3) Visits for chronic illness or diasbility magagement
4) Gynecologic visits
5) Post-partum visits
6) Prior to gyn/prostate surgery
7) Infertility assessments |
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Term
| What defines a psychiatric diagnosis of a sexual dysfunction? |
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Definition
Persistent and recurring disturbance causing marked distress or interpersonal difficulty
NOT CAUSED BY
1) Primarilly Axis I (physical)
2) II (personality) diagnosis
3) Direct physiological effects of drugs, alcohol, ect. |
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