GU Flashcards
What is the vulva?
the skin and mucosa of the female genitalia external to the hymen, including the labia major, labia minor, mons pubis, and vestibule
The vulva is lined by what sort of epithelium?
squamous
Bartholin Cyst
- a dilation of the Bartholin gland
- arises as a unilateral, painful cystic lesion at the lower vestibule adjacent to the vaginal canal
- forms due to obstruction and inflammation
- most often in women of reproductive age
What are the Bartholin glands?
two glands, one present on each side of the vaginal canal, which produce a mucus-like fluid for lubrication
Condyloma
- a warty, often large, neoplasm of the vulvar skin
- most commonly due to HPV 6/11 or secondary syphilis
- histology is characterized by koilocytes
- rarely progress to carcinoma
What are the low risk types of HPV? What are the high risk types?
- low risk: those with low malignant potential, including 6 and 11
- high risk: those likely to progress to carcinoma, including 16, 18, 31, and 33
What is koilocytic change?
- a change in the cell morphology of HPV infected cells
- the nucleus takes on a wavy, raisin like shape
Lichen Sclerosis
- a thinning of the epidermis and fibrosis of the dermis of the vulvar skin
- presents as a leukoplakia (white patch), with “parchment-like” skin
- most common in post-menopausal women
- carries some degree of risk for squamous cell carcinoma (more than Lichen simplex chronicus)
Lichen Simplex Chronicus
- a hyperplasia of the vulvar squamous epithelium
- presents as a leukoplakia with thick, leathery skin
- associated with chronic irritation and scratchy
- benign and with no risk for squamous cell carcinoma
How does Lichen Sclerosis compare to Lichen Simplex Chronicus?
- Lichen Sclerosis is a thinning of the epidermis and fibrosis of the dermis that results in thinning of the skin and carries a risk for squamous cell carcinoma
- Lichen Simplex Chronicus is a hyperplastic thickening of the skin that poses no risk for carcinoma
Vulvar Carcinoma
- a carcinoma arising from the squamous epithelium lining the vulva
- presents as a leukoplakia and requires biopsy for diagnosis
- may be HPV or non-HPV related:
- HPV related is seen more often in young women with risk factors for HPV exposure and the carcinoma arises from pre-existing vulvar intraepithelial neoplasia, a dysplastic precursor lesion with koilocytic change
- non-HPV related is more often found in older women (>70) and arises from long-standing lichen sclerosis
What are two pathways for the development of vulvar carcinoma?
- HPV related: seen in younger women following vulvar intraepithelial neoplasia
- non-HPV related: seen in older women following long-standing lichen sclerosis
Extramammary Paget Disease
- the presence of malignant epithelial cells in the epidermis of the vulva
- it represents carcinoma in situ without underlying carcinoma (in contrast to Paget’s disease of the nipple , which is almost always associated with an underlying carcinoma)
- it presents as erythematous, pruritic, ulcerated vulvar skin
- must be distinguished from melanoma: Paget disease will be PAS+, keratin+ and S-100- while melanoma is keratin- and S-100+
How does Extramammary Paget disease differ from Paget disease of the nipple?
- extramammary Paget disease represents carcinoma in situ, usually without underlying carcinoma
- however, Paget disease of the nipple is almost always associated with an underlying carcinoma
What must extramammary Paget disease be differentiated from? How is this done?
- must be differentiated from melanoma
- Paget disease is keratin+ and S-100-
- melanoma is keratin- and S-100+
The vaginal mucosa is lined by what sort of epithelium?
non-keratinizing, stratified squamous epithelium
Adenosis
- a focal persistence of columnar epithelium in the upper vagina (the epithelium that was present during embryonic development from the Mullerian tubes but should have been resorbed)
- seen in females exposed to DES (diethylstilbestrol) in utero
- poses a risk for clear cell adenocarcinoma
What is diethylstilbestrol?
an estrogenic compound no longer used because it increased the risk of breast cancer in pregnant mothers and the risk for adenosis and clear cell adenocarcinoma in females exposed in utero
Clear Cell Adenocarcinoma
- a malignant proliferation of glands with clear cytoplasm
- a complication of DES-associated vaginal adenosis
Embryonal Rhabdomyosarcoma
- a malignant proliferation of immature skeletal muscle also known as sarcoma botryoides
- presents as bleeding and a grape-like mass protruding from the vagina or penis of a child (<5)
- rhabdomyoblasts are the characteristic cell and they exhibit cytoplasmic cross-striations as well as positive immunohistochemistry for desmin and myogenin
Which tumor presents as a grape-like mass protruding from the vagina or penis of a child?
embryonal rhabdomyosarcoma, consisting of rhabdomyoblasts
Vaginal Carcinoma
- a carcinoma arising from the squamous epithelium of the vaginal mucosa
- related to high-risk HPV (16,18, 31, 33)
- develops from a precursor, dysplastic lesion known as vaginal intraepithelial neoplasia
- in the lower ⅓ of the vagina, it spreads to the inguinal nodes, and in the upper ⅔, it spreads to the iliac nodes
To which lymph nodes does the vagina drain?
- lower ⅓ drains to the inguinal nodes
- upper ⅓ drains to the iliac nodes
What sort of epithelium lines the cervix?
- the exocervix is lined by non-keratinizing squamous epithelium
- the endocervix is lined by a single layer of columnar cells
Where along the female reproductive tract does HPV especially like to infect cells?
the transformation zone of the cervix
What happens in most cases of HPV infection?
the infection is resolved by acute inflammation
How is HPV type determined?
DNA sequencing
What makes high risk HPV types more likely to cause CIN and carcinoma?
- they express the E6 and E7 proteins
- E6 increases destruction of the p53 protein, which regulates the G1/S progression based on the presence of DNA damage, calling in repair mechanisms or inducing BAX to inhibit Bcl2 and induce apoptosis
- E7 destroys or inactives the Rb protein, which frees E2F and allows for unrestricted progression from G1/S
What are the functions of the E6 and E7 proteins expressed by high risk HPV?
E6 and E7 destroy or inhibit p53 and Rb proteins, respectively
How are CIN I, II, III and carcinoma in situ defined?
- CIN I involves less than ⅓ of the thickness of the cervical epithelium
- CIN II involves less than ⅔ the thickness
- CIN III involves slightly less than the entire thickness
- CIS involves the entire thickness
- in the progression to each, the chances of reversal diminish
What is the difference between CIN III and carcinoma in situ?
- CIN III involves slightly less than the entire thickness of the cervical epithelium while CIS involves the full thickness
- more importantly, however, is that CIN III may, although rarely, be reversed while CIS is irreversible in all cases
Cervical Carcinoma
- an invasive carcinoma arising from the cervical epithelium
- presents as vaginal bleeding, especially postcoital, or a with a cervical discharge, most often in middle-aged women (40-50)
- key risk factor is high-risk HPV infection, but secondary risk factors include smoking and immunodeficiency
- most common subtypes are squamous cell carcinoma (80%) and adenocarcinoma (15%), which are both related to HPV
- may invade through the anterior uterine wall into the bladder, blocking the ureters and causing hydronephrosis with post renal failure; a common cause of death in these patients
What is the most common type of cervical carcinoma?
squamous cell carcinoma, followed far behind by adenocarcinoma
What is a common cause of death in patients with cervical carcinoma?
invasion of the tumor through the anterior wall of the uterus, blocking the ureters and causing hydronephrosis with post-renal failure
What is the goal of Pap smears?
to catch dysplasia before it develops into carcinoma
The progression from CIN to carcinoma in situ usually takes how long? Why is this important?
10-20 years, making Pap smears an effective screening tool
When does screening begin for cervical carcinoma? How often is it performed?
- Pap smears begin at age 21
- repeated every three years
How do high grade dysplasias present on a pap smear?
the cells have hyperchromatic nuclei and high nuclear to cytoplasmic ratios
What is true about women who develop invasive cervical carcinoma today?
they have not undergone screening
An abnormal Pap smear is followed by what sort of test?
a colposcopy, in which the dysplasia is visualized by a magnifying glass and biopsied
What are the key limitations of the Pap smear?
- can result in false negatives if the transformation zone of the cervix isn’t sampled
- doesn’t appear to be efficacious in screening for adenocarcinoma even though it too is caused by HPV
Which sort of cervical carcinoma are Pap smears largely ineffectual at screening for?
adenocarcinoma
What HPV types does the vaccine cover?
types 6, 11, 16, and 18
Why should those who have received the HPV vaccine still receive Pap smears and monitoring?
because the vaccine only covers four HPV types
Growth of the endometrium is driven by what hormone?
estrogen
What hormonal change leads to shedding of the endometrium during menstruation?
loss of progesterone
Asherman Syndrome
- secondary amenorrhea due to loss of the basalis and scaring
- usually the result of overaggressive dilation and curettage of the uterus
What is the regenerative layer of the endometrium called?
the basalis
Anovulatory Cycle
- a lack of ovulation
- results in an estrogen-drive proliferative phase without a subsequent progesterone-driven secretory phase
- represents a common cause of dysfunctional uterine bleeding, especially during menarche and menopause
Acute Endometritis
- a bacterial infection of the endometrium
- most often associated with retained products of conception after delivery or miscarriage
- presents with fever, uterine bleeding, and pelvic pain
- treat with gentamicin + clindamycin +/- ampicillin
Chronic Endometritis
- chronic inflammation of the endometrium
- defined by the presence of plasma cells in the endometrium (never found there otherwise)
- usually related to retained products of conception, PID, IUD, or TB
- presents as abnormal uterine bleeding, pain, and infertility
Plasma cells in the endometrium are required for the diagnosis of what?
chronic endometritis
Endometrial Polyp
- a hyperplastic protrusion of endometrium
- most often caused by tamoxifen, which has weak pro-estrogenic effects on the endometrium
- presents with abnormal uterine bleeding
Tamoxifen has weak estrogenic effects in what tissue? What side effect does this often give rise to?
- the endometrium
- endometrial polyp
Endometriosis
- the presence of endometrial glands and stroma outside the uterine endometrial lining
- current theory is that it is due to retrograde menstruation
- presents as dysmenorrhea and pelvic pain because it cycles just like normal endometrium
- most commonly involves the ovary and forms a “chocolate cyst”
- may also involve the uterine ligaments (pelvic pain), pouch of Douglas (pain with defecation), bladder wall (pain with urination), bowel serosa (abdominal pain and adhesion), or fallopian tube mucosa (scarring with increases risk for ectopic tubal pregnancy)
- adenomyosis is endometriosis within the myometrium
- risk for carcinoma at the site of endometriosis
- treat with NSAIDs, OCPs, progestins, GnRH agonists, danazol, or laparoscopic removal
What is a “chocolate cyst”?
- a cyst that forms in the ovary as a result of endometriosis
- fills with products of menstruation and has a chocolatey appearance
What site is most commonly affected by endometriosis?
the ovary
What is adenomyosis?
- endometriosis within the myometrium of the uterus
- treat with a GnRH agonist or hysterectomy
Why does endometriosis contribute to infertility?
because it can involve the Fallopian tubes and induce scarring
Endometrial Hyperplasia
- hyperplasia of the endometrial glands relative to stroma
- most often due to unopposed estrogen
- presents as postmenopausal bleeding
- classified according to its architectural (simple or complex) and whether or not there is cellular atypia
- the presence of atypia is the most important predictor of progression to carcinoma
What is the most significant predictor of whether endometrial hyperplasia will progress to carcinoma?
the presence or absence of cellular atypia
What causes endometrial hyperplasia?
unopposed estrogen
Endometrial Carcinoma
- a malignant proliferation of endometrial glands
- the most common invasive carcinoma of the female reproductive tract
- presents with postmenopausal bleeding
- may arise via either the hyperplastic or sporadic pathways:
- hyperplastic is more common and involves carcinoma arising from pre-existing endometrial hyperplasia; risk is related to estrogen exposure and the histology is endometroid
- sporadic arises in an atrophic endometrium without evidence of a precursor lesion; histology is usually serous and characterized by papillary structures as well as psammoma bodies; p53 mutation is common and these are aggressive tumors
What is the most common invasive carcinoma of the female reproductive tract?
endometrial carcinoma
Name and describe the two different pathways leading to endometrial carcinoma.
- hyperplastic: arising from pre-exisitng endometrial hyperplasia; most often due to unopposed estrogen; endometroid histology
- sporadic: arising from an atrophic endometrium; most often associated with a p53 mutation; histology is serous with papillary structures and psammoma bodies
Leiomyoma
- a benign proliferation of smooth muscle arising from the myometrium
- risk is related to estrogen exposure
- enlarge during pregnancy and shrink after menopause because they are estrogen sensitive
- usually asymptomatic but may lead to uterine bleeding, infertility, and a pelvic mass
- gross exam shows multiple, well-defined, white, whorled masses
What is the most common tumor in females?
leiomyoma
How can a leiomyosarcoma be distinguished form a leiomyoma on gross exam?
- leiomyoma is likely to be in multiple without necrosis or hemorrhage and found in premenopausal women
- leiomyosarcoma is likely to be singular with necrosis and hemorrhage and found in post-menopausal women
Leiomyosarcoma
- a malignant proliferation of smooth muscle arising from the myometrium
- arises de novo, not from leiomyomas
- usually seen in post-menopausal women
- gross exam reveals a single lesion with areas of necrosis and hemorrhage
Describe the basic structure of an ovarian follicle.
an oocyte surrounded by granuloma and theca cells
What is a corpus luteum?
the residual follicle that remains after ovulation, which secretes progesterone to drive the secretory phase
Polycystic Ovarian Disease
- multiple ovarian follicular cysts due to a hormone imbalance as hyperinsulinemia contributes to a rise in LH/FSH, which increases androgens
- androgens contribute to hirsutism, effect negative feedback on the HPO, which decreases the rate of follicular maturation resulting in enraptured follicles and anovulation, and gets converted to estrone (not estradiol) which increases risk for endometrial carcinoma
- presents as an obese young woman with infertility, oligomenorrhea, and hirsutism, often developing type 2 diabetes 10-15 years later; ovaries are bilaterally cystic
- treat with weight reduction, OCPs, clomiphene citrate, ketoconazole, spironolactone
- relatively common, affecting 5% of reproductive age women
Polycystic Ovarian Disease is driven by what?
an increase in LH which leads to excess androgens and estrone but reduces FSH
- androgens produce hirsutism and type 2 diabetes
- estrogen produces oligomenorrhea and risk for endometrial carcinoma
- low FSH produces cystic degeneration of ovarian follicles and infertility
Ovarian tumors arise from what three types of cells?
- surface epithelium
- germ cells
- sex cord stroma (granulosa, theca, fibroblast)
What is the most common type of ovarian tumor?
a tumor arising from surface epithelium
What sort of epithelium covers the ovary?
coelomic epithelium
Coelomic epithelium embryologically produces the epithelial lining of what structures?
- fallopian tube (serous cells)
- endometrium
- endocervix (mucinous cells)
Ovarian Surface Epithelial Tumor
- a tumor arising from the coelomic epithelium overlying the ovary, which normally give rise to the epithelial lining of the fallopian tube, endometrium, and endocervix
- classified as mucinous or serous based on the fluid it contains and as benign (cystadenoma), borderline, or malignant (cystadenocarcinoma)
- cystadenomas are usually a simple cyst with a smooth lining whereas cystadenocarcinomas are complex cysts with shaggy linings
- preset late with vague abdominal symptoms or signs of compression such as urinary frequency and the prognosis is generally poor
- tend to spread locally and produce “omental caking”
- CA-125 is a useful serum marker but not used for screening
How do ovarian cystadenomas compare to cystadenocarcinomas?
- cystadenomas are benign, composed of a single cyst with a simple, flat lining, and are most common in premenopausal women
- cystadenocarcinomas are malignant, composed of complex cysts with a thick, shaggy lining, and most common in postmenopausal women
- both are derived from the surface epithelium of ovaries and can be of the mucinous or serous type
Endometroid Tumor of the Ovary
- a malignant tumor derive from the coelomic epithelium of the ovary
- composed of endometrial-like glands, which sometimes arises form endometriosis
- 15% are associated with a second, independent endometrial carcinoma (of the hyperplastic/endometroid variety)
- preset late with vague abdominal symptoms or signs of compression such as urinary frequency and the prognosis is generally poor
- tend to spread locally and produce “omental caking”
- CA-125 is a useful serum marker but not used for screening
Those with an endometroid tumor of the ovary should be screened for what other condition?
an endometroid carcinoma of the endometrium
Brenner Tumor
- a benign tumor derived from the coelomic epithelium of the ovary composed of bladder-like epithelium
- preset late with vague abdominal symptoms or signs of compression such as urinary frequency
- tend to spread locally and produce “omental caking”
- CA-125 is a useful serum marker but not used for screening
How does the prevalence of the varying types of ovarian cancers change with age? Which age groups are most likely to experience each kind?
- germ cell tumors affect younger women (15-40)
- benign surface epithelial tumors tend to affect middle-aged premenopausal women
- malignant surface epithelial tumors tend to affect older, post-menopausal women
Germ cell tumors generally arise during what age range?
15-40 years of age
Cystic Teratoma
- a cystic tumor composed of fetal tissue derived from two or three embryologic layers
- the most common germ cell tumor in females
- bilateral in 10% of cases
- typically benign; however, the presence of immature tissue or somatic malignancy within the teratoma indicates malignant potential
- may present in females with pain secondary to torsion or enlargement of the ovary
- struma ovarii is a special teratoma that is composed mostly of thyroid tissue and may induce hyperthyroidism
What is the most common type of immature tissue found in a teratoma?
neural ectoderm
What is the most common type of somatic malignancy found in a teratoma?
squamous cell carcinoma of the skin
What is struma ovarii?
a teratoma composed primarily of thyroid tissue, leading to hyperthyroidism
What endocrine dysfunction is most likely to arise in females with a teratoma?
hyperthyroidism if the teratoma represents a struma ovarii
Dysgerminoma of the Ovary
- a germ cell tumor composed of large, clear cells with central nuclei (resembling oocytes)
- the most common malignant germ cell tumor
- has a good prognosis as it responds well to radiotherapy
- serum LDH (lactic acid dehydrogenase) may be elevated
Endodermal Sinus Tumor
- a malignant germ cell tumor seen in men (as a nonseminoma) and women that mimics the yolk sac
- the most common germ cell tumor in children
- serum AFP is often elevated
- histology is likely to reveal Schiller-Duval bodies (glomeruloid-like structures)
What are Schiller-Duval bodies?
glomeruloid-like structures seen on histology of an endodermal sinus tumor
Which germ cell tumor is most common in female children?
endodermal sinus tumor
Choriocarcinoma
- a malignant germ cell tumor composed of cyto- and syncytiotrophoblasts
- mimics placental tissue but villi are absent
- it spreads via the hematogenous route early (makes sense because the usual function of trophoblasts is to establish fetal blood flow) and goes to the lungs
- high B-hCG is characteristic and may lead to theca cysts in the ovary or hyperthyroidism (since the a subunit of B-hCG resembles that of FSH, LH, and TSH)
- in women it can arise as a complication of gestation (following hydatidiform mole, spontaneous abortion, etc.) or as a spontaneous germ cell tumor
- when it arises from the gestational pathway it tends to respond well to chemotherapy; but those that arise spontaneously do not
- in men, it is classified as a nonseminoma
Granulosa-Theca Cell Tumor
- a neoplastic proliferation of granuloma and/or theca cells
- often produces estrogen leading to precocious puberty, menorrhagia/metrorrhagia, or endometrial hyperplasia with postmenopausal bleeding depending on the women’s stage of life
- histology shows Call-Exner bodies (granulosa cells arranged around collections f eosinophilic fluid, resembling primordial follicles)
- malignant but with minimal risk for metastasis
Sertoli-Leydig Cell Tumor of the Ovary
- a sex cord-stromal tumor composed of Sertoli cells that form tubules and Leydig cells
- Leydig cells have characteristic Reinke crystals on histology
- may produce androgens, leading to hirsutism and virilization
Meigs syndrome
- a syndrome of ovarian fibroma, pleural effusions, and ascites
- entire syndrome resolves with removal of the tumor
Krukenberg Tumor
- a bilateral metastatic mucinous tumor of the ovaries
- most often due to metastasis of a diffuse type gastric carcinoma; as such, signet cells are common
- bilateral nature helps distinguish it from a mucinous cystadenocarcinoma
A Krukenberg Tumor must be distinguished form what other ovarian carcinoma? How is this done?
- it is a mucinous tumor from gastric carcinoma
- as such it must be distinguished from a mucinous cystadenocarcinoma of the ovary
- this is accomplished because the Krukenberg tumor is most often bilateral while the primary ovarian carcinoma is unilateral
Pseudomyxoma Peritonei
massive amounts of mucus in the peritoneum due to a mucinous tumor of the appendix, often with metastasis to the ovary
What is the most likely place for an ectopic pregnancy?
the lumen of the fallopian tube
What is the major risk factor for ectopic pregnancy?
scarring secondary to PID or endometriosis
Ectopic pregnancy
- a pregnancy outside the uterine lining
- most often found in the lumen of the fallopian tube
- risk factors include prior ectopic pregnancy, history of infertility, PID (salpingitis), endometriosis, ruptured appendix, or prior tubal surgery
- presents as lower quadrant abdominal pain a few weeks after a missed period and lower-than-expected hCG
- is a surgical emergency as it may rupture or bleed into the Fallopian tube
How do we define a spontaneous abortion?
miscarriage of a fetus occurring before 20 weeks gestation
What percentage of recognized pregnancies end in spontaneous abortion?
about 1/4
Teratogens can have a wide array of effects. How do their affects vary based on the point at gestation at which the exposure occurred?
- if exposure occurs in the first 2 weeks, it usually leads to spontaneous abortion
- between weeks 3-8 it is likely to lead to organ malformation
- after 8 weeks, the most likely outcome is organ hypoplasia
What are the most common causes of spontaneous abortion?
- chromosomal anomalies, especially trisomy 16
- hypercoagulable states as in antiphospholipid syndrome
- congenital infection
- exposure to teratogens in the first two weeks of gestation
Placenta Previa
- implantation of the placenta in the lower uterine segment with the placenta overlying the cervical os
- risk factors include multiparty or prior C-section
- presents as third trimester bleeding
- requires delivery by C-section to avoid compressing the arteries in the placenta during vaginal delivery
Placental Abruption
- separation of the placenta from the decider prior to delivery
- risk factors include trauma, smoking, hypertension, and cocaine abuse
- presents with abrupt pain and third-trimester bleeding (bleeding may be concealed if the separation doesn’t extend to the cervical os)
- may cause DIC, maternal shock, or fetal distress; life threatening to both the mother and fetus
- examination of the placenta after delivery/removal will reveal a very blood maternal surface with lots of clots
Placenta Accreta
- improper implantation of the placenta onto the myometrium with little or no intervening decidua
- risk factors are prior C-section, inflammation, or placenta previa
- presents with difficult delivery of the placenta and postpartum bleeding
- often requires a hysterectomy to control the bleeding
- placenta increta and percreta are varying degrees of penetration
Pre-Eclampsia
- pregnancy-induced hypertension with either proteinuria or end-organ dysfunction after the 20th week gestation
- due to an abnormality of the maternal-fetal vascular interface in the placenta
- usually presents in the third trimester and affects 5% of pregnancies
- more common in those with pre-existing hypertension, diabetes, chronic renal disease, or autoimmune disorders
- may border on malignant hypertension with severe headaches and visual abnormalities
- treatment is with anti-hypertensives and IV magnesium to prevent seizures but definitive treatment is delivery
How does eclampsia compare to pre-eclampsia?
- eclampsia is pre-eclampsia (HTN, proteinuria, edema) plus seizures
- may cause maternal death due to stroke, intracranial hemorrhage, or ARDS
What is HELLP?
- pre-eclampsia with thrombotic microangiopathy of the liver
- characterized by Hemolysis, Elevated Liver enzymes, and Low Platelets
- can lead to hepatic sub capsular hematomas, which may rupture and lead to severe hypotension
Sudden Infant Death Syndrome
- death of a health infant (1 month to 1 year old) without obvious cause, typically during sleep
- associated with sleeping on the stomach, exposure to cigarette smoke, and prematurity
What are the teratogenic effects of cocaine?
intrauterine growth retardation and placental abruption
What are the teratogenic effects of thalidomide?
limb defects
What are the teratogenic effects of cigarette smoke?
intrauterine growth retardation
What are the teratogenic effects of isotretinoin?
spontaneous abortion or hearing and visual impairment
What are the teratogenic effects of tetracycline?
discolored teeth
What are the teratogenic effects of warfarin?
fetal bleeding
What are the teratogenic effects of phenytoin?
digit hypoplasia and cleft lip/palate
Hydatidiform Mole
- an abnormal conception that yields growth of abnormal placental tissue instead of a child
- characterized by swollen, edematous villi with proliferation of trophoblasts
- the uterus expands as if a normal pregnancy but the uterus is much larger and B-hCG much higher than expected
- without prenatal care, it presents in the second trimester as passage of grape-like masses
- with prenatal care, it is diagnosed via routine US since fetal heart sounds are absent and there is a “snowstorm” appearance
- can be classified as complete or partial depending on whether the two sperm fertilized an empty or normal egg
- treatment is suction curettage and subsequent monitoring of B-hCG to ensure adequate removal
- poses a risk for choriocarcinoma and requires monitoring
What sets a partial hydatidiform mole apart from a complete mole?
- partial arises from fertilization of a normal egg by two sperm (69 chromosome)
- some fetal tissue is present (hence the term partial)
- some villi are hydropic and some are normal
- focal proliferation is present around the hydropic villi
- the risk for choriocarcinoma is minimal
What sets a complete hydatidiform mole apart form a partial mole?
- complete arises from fertilization of an empty egg by two sperm (46 chromosome)
- no fetal tissue is present (hence the term complete)
- most villi are hydropic and there is diffuse, circumferential proliferation around hydropic villi
- the risk for choriocarcinoma is 2-3%, which is higher than that of partial
Hypospadias
- an opening of the urethra on the inferior surface of the penis due to failure of the urethral folds to close properly
- associated with inguinal hernia and cryptorchidism
Epispadias
- an opening of the urethra on the superior surface of the penis due to abnormal position of the genital tubercle
- associated with bladder exstrophy
Lymphogranuloma Venereum
- a necrotizing granulomatous inflammation of the inguinal lymphatics and lymph nodes in a male
- results from sexual transmission of Chlamydia trachomatis, serotypes L1-L3
- eventually heals with fibrosis, which may cause rectal stricture if there was perianal involvement
Squamous Cell Carcinoma of the Penis
- a malignant proliferation of squamous cells of the penile skin
- risk factors include those that increase the risk for a high risk HPV as well as lack of circumcision which serves as a nidus for chronic inflammation and irritation
- arises from precursor in situ lesions like Bowen disease or Erythroplasia of Queyrat
Bowen Disease
an in situ carcinoma of the penile shaft or scrotum that presents as leukoplakia and serves as a precursor lesion for squamous cell carcinoma
Erythroplasia of Queyrat
an in situ carcinoma of the penile glands that presents as erythroplaki and serves as a precursor lesion for squamous cell carcinoma
Bowenoid Papulosis
- an in situ carcinoma of the penile skin that presents as multiple reddish papule
- seen in younger patients than Bowen disease or Erythroplasia of Queyrat
- does not progress to invasive carcinoma
What is the difference between Bowen disease, Erythroplasia of Queyrat, and Bowenoid Papulosis.
- all are forms of in situ carcinoma involving the skin of the penis, but only Bowen disease and erythroplasia progress to squamous cell carcinoma
- Bowen disease is a leukoplakia of the shaft
- Erythroplasia of Queyrat is a erythroplakia of the glands
- Bowenoid papulosis is presents as multiple reddish papules
Cryptochidism
- failure of the testicle to descend into the scrotal sac after developing in the abdomen
- it is the most common congenital male reproductive anomaly and is more common in premature infants
- most cases resolve spontaneously, but if it hasn’t by age 2 it requires surgical correction
- after age 2, germ cells begin to be damaged by the lack of proper thermoregulation resulting in testicular atrophy with infertility and risk for seminoma
What happens if cryptochidism doesn’t resolve and isn’t corrected by age 2?
- germ cells are damaged by the lack of proper thermoregulation
- results in testicular atrophy with infertility
- also increases the risk for seminoma
What are the four most common causes of orchitis?
- Chlamydia or Neisseria in younger males (via sexual activity)
- E. coli and Pseudomonas in older adults (spread of UTI)
- mumps virus
- autoimmune orchitis
Chlamydia trachomatis Orchitis
- an inflammation of the testicle due to infection with serotypes D-K
- seen primarily in young adults with highest STD risk
- may cause sterility but libido is unaffected because Leydig cells are spared
Which cell type is affected by Chlamydia trachomatis and Neisseria gonorrhoea orchitis?
- Sertoli cells are affected, potentially causing sterility
- Leydig cells are spared, leaving testosterone and libido in tact
Mumps Virus Orchitis
- a potential complication of mumps virus usually only seen in those that contract mumps after the age of ten
- risk for infertility
Autoimmune Orchitis
granulomatous inflammation of the testicles involving the seminiferous tubules
Testicular Torsion
- a twisting of the spermatic cord
- causes the thin-walled veins to collapse while the arteries remain open, resulting in congestion and hemorrhage infarction
- usually due to congenital failure of the testes to attach to the inner lining of the scrotum via the processes vaginalis
- presents in adolescents with sudden testicular pain and an absent cremasteric reflex
Describe the cremasteric reflex.
when you scrap upward on the inner thigh of a male, the scrotum should ascend
Varicocele
- a dilation of the spermatic vein due to impaired drainage
- usually left sided because the left vein drains into the left renal vein while the right vein drains directly into the IVC
- presents as a “bag of worms” appearance upon standing examination and will not be transilluminated
- seen in a large percentage of infertile males because it leaves lots of warm blood in the sac for longer periods
Varicoceles are associated with what neoplasia?
left renal cell carcinoma, which tends to invade and obstruct the left renal vein, impairing drainage of the left spermatic vein
Hydrocele
- a collection of fluid within the tunica vaginalis (a serous membrane covering the testicle and internal surface of the scrotum)
- when it presents in infants, it is often associated with incomplete closure of the processus vaginalis, leaving communication between the scrotum and peritoneal cavity
- in adults, it is more often associated with blocked lymphatic drainage
- presents as a scrotal swelling that can be transilluminated
What does a testicular mass that can be transilluminated suggest about that mass?
that it is not solid and is, instead, likely a hydrocele
What causes hydroceles in infants?
failure of the processes vaginalis to close completely, leaving a duct between the peritoneal cavity and tunica vaginalis
What structure fills with fluid in a hydrocele?
the tunica vaginalis, a remnant of the processus vaginalis
Testicular tumors arise from what two sources?
germ cells and sex cord-stroma (there are no surface epithelial tumors as in ovaries)
How are testicular masses biopsied?
they aren’t because this risks seeding of the scrotum
Why aren’t testicular masses biopsied?
because this risks seeding the scrotum with tumor cells and most testicular tumors are malignant germ cell tumors
What is the most common testicular tumor?
a malignant germ cell tumor
What should be done when you suspect a testicular tumor.? Explain the logic behind this decision.
- do not biopsy because most testicular tumors are malignant germ cell tumors and biopsy risks seeding the scrotum with malignant cells
- instead, proceed with a radical orchiectomy
What are the risk factors for testicular germ cell tumors?
- cryptorchidism
- Klinefelter syndrome
How do we divide testicular germ cell tumors?
as seminomas or nonseminomas
How do seminomas and nonseminoma testicular germ cell tumors compare?
- seminomas are more common, highly responsive to radiotherapy, metastasize late, and have a good prognosis
- nonseminomas are slightly less common, show a variable response to treatment, and often metastasize early
Seminoma
- a malignant testicular germ cell tumor and the most common testicular tumor
- comprised of large cells with clear cytoplasm and central nuclei, resembling an ovarian dysgerminoma
- grossly, it form s homogenous was without hemorrhage or necrosis
- it has the potential but rarely produces B-hCG
- responds well to radiotherapy
Embryonal Carcinoma of the Testicle
- a malignant nonseminoma (testicular germ cell tumor)
- comprised of immature, primitive cells that may produce glands
- in contrast to a seminoma, it forms a hemorrhagic mass with necrosis
- it is aggressive with early hematogenous spread
- may see increases in AFP or B-hCG
- chemotherapy may result in differentiation into another type of germ cell tumor
What reproductive tumor may respond to chemotherapy by differentiating into another type of tumor?
embryonal carcinoma
Embryonal Carcinoma of the Ovary
- a malignant germ cell tumor composed of immature, primitive cells
- aggressive with early hematogenous spread and a poor response to treatment
Why do choriocarcinomas often induce hyperthyroidism?
because they produce B-hCG, which has an alpha subunit mimicking that of LH, FSH, and TSH, which can stimulate the receptors for those substances
How do teratomas seen in men differ from those seen in women?
they are malignant in males, not in females (unless there are signs of immature tissue or somatic malignancy in the teratoma)
How do we determine the prognosis of a mixed germ cell tumor?
the prognosis is based on that of the worst component
Leydig Cell Tumor
- a benign sex cord-stromal tumor seen in men, which produces androgen
- because of this it causes precocious puberty in children or gynecomastia in adults
- characteristic Reinke crystals are seen on histology and gross exam reveals a golden brown mass
Sertoli Cell Tumor
- a benign sex cord-stromal tumor seen in men
- the tumor is comprised of tubules and is clinically silent
What is the most common cause of a testicular mass in males over the age of 60?
lymphoma
Testicular Lymphoma
- the most common cause of a testicular mass in males over the age of 60
- often bilateral and usually of the DLBC type
Prostatic glands are composed of what cells?
an inner layer of luminal cells and an outer layer of basal cells
What sort of fluid does the prostate secrete?
an alkaline fluid
Acute Prostatitis
- usually bacterial; Chlamydia trachomatis and Neisseria gonorrhoeae are common in younger males while E. coli and Pseudomonase are common in older adults (from spread of UTI)
- presents with dysuria, fever, and chills, urgency, and low back pain
- the prostate will feel warm, tender, boggy, and enlarged on digital rectal exam
- prostatic secretions will show WBCs and culture will reveal bacteria
Chronic Prostatitis
- chronic inflammation of the prostate
- presents with dysuria and pelvic or low back pain
- prostatic secretions show WBCs but cultures are usually negative
How does the presentation of acute prostatitis differ from that of chronic prostatitis?
- acute is usually bacterial so prostatic secretions contain WBCs and are culture positive; however, secretions from those with chronic prostatitis are likely culture negative
- additionally, acute presents with dysuria, fever, and chills whereas chronic presents with dysuria and pelvic or low back pain
Benign Prostatic Hyperplasia
- hyperplasia of prostatic stroma and glands
- an age related change, and seen in most men over 60
- poses no increased risk for cancer
- driven by the androgen DHT
- occurs the central periurethral zone of the prostate
- presents with problems starting and stopping urination as well as overflow incontinence, which poses a risk for hydronephrosis
- the obstruction causes hypertrophy of the bladder wall smooth muscle and increase risk for bladder diverticula
- microscopic hematuria may be present
- PSA is often slightly elevated (4 < PSA < 10)
- treatment involves an a1- antagonist, which has the added benefit of lowering BP, or an a1A-antagonist for normotensive patients
- another treatment option is a 5a-reductase inhibitor, to reduce conversion of testosterone to DHT
What portion of the prostate is affected by BPH? What about by prostatic adenocarcinoma?
- BPH: the central, periurethal zone
- adenocarcinoma: the posterior peripheral area
What complications arise from BPH?
- there is no risk for cancer
- but the obstruction may cause overflow incontinence, hypertrophy of the bladder wall smooth muscle, or bladder diverticula
What hormone drives BPH?
dihydrotestosterone (DHT)
How is DHT synthesized in vivo?
testosterone is converted to DHT by 5a-reductase expressed by stromal cells in the prostate
What is the function of PSA?
it is made by prostatic glands to liquefy semen
What is a normal PSA? What level would be consistent with BPH or adenocarcinoma?
- normal is < 4
- BPH is between 4-10
- adenocarcinoma is often above 10
Describe two treatment options of BPH.
- usually start with an a1-antagonist like terazoin, which relaxes smooth muscle to improve bladder function and blood pressure
- if the patient is normotensive, however, consider an a1A-antagonist like tamsulosin, which will act only at the bladder
- can also consider a 5a-reductase inhibitor, which blocks conversion of testosterone to DHT, the hormone that drives the hyperplasia; but this takes months to produce results and may cause gynecomastia or sexual dysfunction
Prostate Adenocarcinoma
- a malignant proliferation of prostatic glands
- risk factors include age, race (AA most and Asians least), and a diet high in saturated fats
- most often, it is clinically silent as it arises in the peripheral, posterior region and does not affect the ureter until late
- screening begins at age 50 with PSA and digital rectal exams
- histology reveals small, invasive glands with prominent nucleoli
- graded on Gleason system which is based solely on architecture (not nuclear atypia) as determined in two areas on a score of 1-5, which is then combined to determine prognosis
- spreads to the lumbar spine or pelvis, forming osteoblastic metastases; at this point, PSA, prostatic acid phosphatase, and serum alkaline phosphatase are all likely elevated
- prostatectomy is performed for localized disease and advanced disease is treated with hormone suppression to reduce testosterone and DHT
At what age and via what methods do we begin screening for prostate cancer?
begin at age 50 with PSA levels and digital rectal exams
What kind of PSA does adenocarcinoma make?
bound PSA, so low percentage free-PSA is suggestive of cancer
What is the Gleason grading system?
- a system for grading prostatic adenocarcinoma
- it takes into account only architecture and not nuclear atypia
- two areas are assessed and scored from 1-5 with the combined score determining the prognosis
When prostatic adenocarcinoma spreads, where is it most likely to go?
the lumbar spine or pelvis
Metastatic prostate adenocarcinoma is likely to have what signs of labs?
- elevated PSA (mostly bound)
- low % of free PSA
- elevated prostatic acid phosphatase
- elevated alkaline phosphatase
How is prostate adenocarcinoma treated?
- prostatectomy is used in cases of localized disease
- advanced disease is treated with hormone suppression aimed at reducing testosterone and DHT levels; this includes continuous GnRH analogs like leuprolide and androgen antagonists like flutamide
The breast is a modified ___ gland.
sweat
Where can breast tissue develop?
anywhere along the milk line between the axilla and the vulva
What is the functional unit of the breast called and what does it consist of?
it is called the terminal duct lobular unit and it is composed of a lobule filled with glands, which drain into a common terminal duct
Describe the ductal epithelium within the breast.
- there is the luminal cell layer, the inner layer which is responsible for milk production
- and there is the myoepithelial layer, which has contractile ability and propels milk towards the nipple
Describe breast tissue before puberty.
male and female breast tissue at this point consists of large ducts under the nipple
Describe development after menarche.
- driven by estrogen and progesterone
- lobules and small ducts form
Where in the breast is the highest density of terminal duct lobular units?
in the upper outer quadrant
What happens to the breast tissue during pregnancy?
there is hyperplasia of the lobules, driven by estrogen and progesterone produced by the corpus lute, fetus, and placenta
What is galactorrhea?
milk production outside of lactation
What are three causes of galactorrhea?
- excessive nipple stimulation
- drugs
- prolactinoma of the anterior pituitary
Acute Mastitis
- a bacterial infection of the breast, usually by S. aureus
- associated with breast-feeding, which causes fissures to develop in the nipple, providing a route for microbe entry
- presents as an erythematous breast with purulent nipple discharge
- an abscess may form and would be palpable
- treatment involves continued drainage (i.e. feeding) and antibiotics (namely, dicloxacillin)
- could be confused with inflammatory type invasive ductal carcinoma
Periductal Mastitis
- inflammation of the subareolar ducts
- seen in smokers because the subareolar ducts are lined by a specialized epithelium requiring vitamin A and smoking reduces the availability of vitamin A
- the lack of vitamin A results in squamous metaplasia of the lactiferous ducts and the keratin that is formed by this epithelium blocks the ducts and results in inflammation
- presents as a subareolar mass with nipple retraction caused by secondary healing and myofibroblast activity
What benign condition of the breast often presents with nipple retraction? Why?
- periductal mastitis
- healing of this process is by secondary intent and myofibroblast activity has the potential to cause nipple retraction
Mammary Duct Ectasia
- chronic inflammation with dilation of the subareolar ducts
- classically arises in multiparous postmenopausal women
- presents as a periareolar mass with a green-brown nipple discharge composed of inflammatory debris
Mammary duct ectasia must be distinguished form what other disorder of the breast? How is this done?
- because it presents as a mass in a postmenopausal women, it needs to be distinguished from malignancy
- the green-brown nipple discharge that is seen in those with mammary duct ectasia allows for this
Fat Necrosis of the Breast
- usually related to trauma although a history of trauma may not be obvious or apparent
- presents as a mass or abnormal calcification on mammography
- biopsy shows necrotic fat with associated calcifications and giant cells
- this biopsy, especially the giant cells, helps distinguish it from malignancy
How is fat necrosis of the breast usually distinguished form malignancy?
- history of trauma
- presence of giant cells and calcifications on biopsy
Fibrocystic Change of the Breast
- development of fibrosis and cysts in the breast; thought to be hormone driven
- the most common change in the premenopausal breast
- presents as vague irregularity of the breast tissue bilaterally, usually in the upper outer quadrant, and cysts have a blue-dome appearance on gross exam
- benign but associated with an increased risk for invasive carcinoma IN BOTH BREASTS
How does fibrocystic change affect your risk for invasive carcinoma?
- fibrosis, cysts, and apocrine metaplasia carry no increased risk
- when also found with ductal hyperplasia (more than two epithelial layers in duct) and sclerosing adenosis (too many glands in lobule), the risk doubles in both breasts
- when also found with atypical hyperplasia, the risk is 5x baseline in both breast
What risk of invasive carcinoma of the breast does apocrine metaplasia carry?
none, it is one of few instances in which metaplasia doesn’t increase cancer risk
What is ductal hyperplasia of the breast?
the finding of more than one layer of each epithelial cell in the ducts of the breast
What is sclerosing adenosis of the breast?
fibrosis change plus too many glands in the lobule, which are often calcified
Intraductal Papilloma
- a papillary growth into a large duct
- characterized by fibrovascular projections lined by luminal and myoepithelial cells
- classically presents as a bloody nipple discharge in premenopausal women
- must be distinguished from papillary carcinoma, which also presents with a bloody nipple discharge; this is done on the basis that papillary carcinoma has fibrovascular projections lined with luminal but not myoepithelial cells
How can we differentiate between intraductal papilloma of the breast and papillary carcinoma?
- both are fibrovascular projections into the duct; however, a papilloma is lined by both luminal and myoepithelial cells whereas a papillary carcinoma is lined by only luminal cells
- furthermore age is a defining risk factor for papillary carcinoma so it is more often seen in postmenopausal women whereas papillomas are more often in premenopausal women
Fibroadenoma of the Breast
- a tumor of fibrous tissue and glands
- the most common benign neoplasm of the breast
- presents in premenopausal women as a well-circumscribed, mobile, marble-like mass
- estrogen sensitive so it grows during pregnancy and may be painful during the menstrual cycle
- carries no risk for carcinoma
Phyllodes Tumor
- a fibroadenoma-like tumor of the breast with overgrowth of the fibrous component, which pushes it out into the lumen, appearing with “leaf like” projections
- most common in postmenopausal women
- very rarely it can be malignant
Which benign tumors and changes of the breast are more common in premenopausal women and which are more common in postmenopausal women?
- premenopausal: acute mastitis, fibrocystic change, intraductal papilloma, fibroadenoma
- postmenopausal: mammary duct ectasia, phyllodes tumor
List six important risk factors for breast cancer.
- female gender
- age
- early menarche/late menopause
- obesity
- atypical hyperplasia seen on prior biopsy
- first-degree relative with breast cancer
Ductal Carcinoma In Situ
- a malignant proliferation of cells in ducts without invasion of the BM
- often detected as calcification on mammography, but does not usually produce a mass
- histologic subtypes are based on architecture, and the most important one is comedo type
- comedo type is characterized by high-grade cells with necrosis and dystrophic calcification in the center of ducts
- Paget disease of the breast is another form of DCIS
Comedo Type DCIS
- an architectural type of ductal carcinoma in situ
- characterized by high-grade cells with necrosis and dystrophic calcification in the center of ducts
Paget Disease of the Nipple
- a form of DCIS i which malignant cells extend up the ducts to involve the skin of the nipple
- presents as nipple ulceration and erythema
- nearly always associated with an underlying carcinoma
Invasive Ductal Carcinoma of the Breast
- presents as a mass on exam or by mammography
- biopsy usually reveals duct-like structures in a desmoplastic stroma
- can be of either the tubular, mucinous, medullary, or inflammatory type:
- tubular forms well-differentiated tubules that lack myoepithelial cells and has a relatively good prognosis
- mucinous are characterized by abundant extracellular mucin, tend to occur in older women, and have a relatively good prognosis
- medullary are characterized by large, high-grade cells growing in sheets with associated lymphocytes and plasma cells; they grow as well-circumscribed and can mimic a fibroadenoma; relatively good prognosis; risk increases with BRCA1 mutation
- inflammatory is carcinoma in dermal lymphatics, which impairs drainage and results in an inflamed, swollen breast with no discrete mass, which can be mistaken for acute mastitis; carries a poor prognosis because it’s already in lymphatic space
What size masses are mammography and physical examination able to detect in the breast?
- mammography typically detects those 1 cm or greater
- physical exam usually detects those 2 cm or larger
Inflammatory Type Invasive Ductal Carcinoma of the Breast
- a form of carcinoma which is found in the dermal lymphatics
- blockage of the lymphatics results in the breast becoming inflamed and swollen without a discreet mass
- may be mistaken for acute mastitis
- carries a poor prognosis because it’s already in the lymphatic space
Medullary Type Invasive Ductal Carcinoma of the Breast
- a form of carcinoma characterized by large, high-grade cells growing in sheets with associated lymphocyte and plasma cells
- typically well-circumscribed
- may mimic fibroadenoma
- carries a relatively good prognosis
- those with a BRCA1 mutation are at increased risk
Lobular Carcinoma In Situ
- a malignant proliferation of cells in lobules with no invasion of the basement membrane
- does not produce a mass or calcifications and is usually discovered incidentally on biopsy
- characterized by dyscohesive cells lacking the E-cadherin adhesion protein
- often multifocal and bilateral
- it has a low risk of progressing to invasive carcinoma but treat with tamoxifen and close follow up
Invasive Lobular Carcinoma
- an invasive carcinoma that characteristically grows in a single-file pattern on biopsy
- may exhibit signet-ring morphology
- don’t form ducts because they lack E-cadherin
What feature is shared by LCIS and invasive lobular carcinoma?
both have cells lacking E-cadherin
What is the most important prognostic factor for patients with breast cancer?
whether there has been metastasis
What is the most useful prognostic factor for patients with breast cancer? Why?
- spread to axillary lymph nodes
- because most patients present before metastasis occurs, so even though metastasis is the most important factor, it doesn’t apply for most of the presenting population
What three factors predict the response of breast cancer to treatment?
expression of estrogen receptors, expression of progesterone receptors, or amplification of the HER2/neu gene
What does the HER2/neu gene code for?
a growth factor receptor
Which population of women is most likely to have “triple negative” breast carcinoma?
African American women
The presence of ER or PR within a breast carcinoma indicates what?
that it will respond to anti-estrogenic agents such as tamoxifen, giving it a better prognosis
Tumors expressing HER2/neu are treated with what agent?
trastuzumab (aka Herceptin), which is an antibody directed against the HER2 receptor
What percentage of breast cancers are hereditary?
10%
What clinical features could suggest that a breast cancer is hereditary?
- the patient has first degree relatives with breast cancer
- the tumor arises at an early age (premenopausal)
- the patient has multiple tumors
BRCA1 is associated with what?
- medullary carcinoma of the breast
- serous cyst adenoma of the ovary and fallopian tubes
BRCA2 is associated with what?
breast carcinoma in males
After someone with a BRCA mutation has a prophylactic mastectomy, what is the next step?
continued monitoring because a small risk for cancer remains
Why must someone with a BRCA mutation who has undergone prophylactic bilateral mastectomy still be monitored for breast cancer?
because some breast tissue may extend into the axilla or elsewhere are remain after the surgery, so there is still a small risk of cancer
How does breast cancer usually present in males?
as a subareolar mass in older males with a nipple discharge
What histologic subtype of breast cancer is most common in males?
- invasive ductal carcinoma
- invasive lobular carcinoma is very rare because men develop very few lobules
Male breast cancer is associated with what two risk factors?
BRCA2 and Klinefelter syndrome
What is the function of the sonic hedgehog gene during fetal development?
produced at the bast of limbs, it is involved in patterning along the AP axis and in CNS development
What is the function of the Wnt-7 gene during fetal development?
produced at the apical ectodermal ridge (the thickened ectoderm at the distal end of each developing limb), it is necessary for proper organization along the dorsal-ventral axis
What is the function of the FGF gene during fetal development?
produced at the apical ectodermal ridge, it stimulates mitosis of underlying mesoderm to promote lengthening of limbs
What is the function of Homeobox genes during fetal development?
they code for transcription factors involved in segmental organization along the craniocaudal axis
Homebox (HOX) gene mutations result in what?
appendages in the wrong locations
What is the apical ectodermal ridge?
a thickened ectoderm at the distal end of each developing limb
What stages follow fertilization of an oocyte prior to implantation?
- a morula forms around day 4
- a blastocyst forms around day 5
- implantation occurs at day 6
On what day does a fertilized oocyte typically implant into the endometrium? What is it called at that point?
day 6 as a blastocyte
What happens during week one following fertilization of an oocyte?
- formation of a morula around day 4
- formation of a blastocyte around day 5
- implantation around day 6
What is a blastocyte?
- a structure formed early in embryogenesis (around day 5 in humans)
- consists of an inner cell mass that will give rise to the embryo and an outer cell layer that will give rise to the trophoblasts
Describe the embryonic disc.
- a bilaminar disc that forms from a blastocyte
- consists of an epiblast and hypoblast, which arise form the inner cell mass
- the epiblast is primitive ectoderm while the hypoblast is primitive endoderm
What happens to an embryo after formation of the embryonic disc?
- gastrulation forms a trilaminar embryonic disc, consisting of ectoderm, mesoderm, and endoderm, as epiblast cells invaginate through the primitive streak
What germ layer gives rise to the notochord?
the mesoderm
When does the neural tube close during fetal development?
by the end of week four
What happens during week four of fetal development?
the heart begins to pump (“4 chambers”) and the limb buds begin to form (“4 limbs”)
At what point does fetal cardiac activity become visible by transvaginal ultrasound?
during week 6
At what point do fetal movements start?
during week 8
When during fetal development do the genitalia have male and female characteristics?
during week 10
Surface ectoderm gives rise to what adult structures?
- epidermis
- adenohypophysis (anterior pituitary from Rathke pouch)
- lens and retina of the eye
- epithelial lining of the oral cavity
- sensory organs of the ear
- olfactory epithelium
- parotid, sweat, and mammary glands
- CNS
- neural crest cells
What is Rathke’s pouch?
an evagination of the ectoderm in what will be the roof of the mouth, which ultimately gives rise to the anterior pituitary (adenohypophysis)
Neural crest cells are a subset of which germ layer?
ectoderm
Neural crest cells give rise to what adult structures?
- the PNS, including dorsal root ganglia, cranial nerves, autonomic ganglia, and Schwann cells
- melanocytes
- chromatin cells of the adrenal medulla
- parafollicular cells of the thyroid
- pia and arachnoid mater
- bones of the skull
- odontoblasts
- aorticopulmonary septum and endocardial cushions
Mesoderm gives rise to what adult structures?
- muscle, bone, and connective tissue
- serous linings of body cavities
- spleen, kidneys, adrenal cortex, and wall of gut tube
- cardiovascular structures and blood
- lymphatics
- upper vagina
- dermis
- testes and ovaries
What is the only adult structure derived from notochord?
the nucleus pulpous of the intervertebral disc
What pneumonic is used to remember the mesodermal defects?
VACTERL
- Vertebral defects
- Anal atresia
- Cardiac defects
- TE fistula
- Renal defects
- Limb defects
What adult structures are derived from endoderm?
- gut tube epithelium
- most of the urethra and lower vagina
- luminal epithelial derivatives like lungs, liver, gallbladder, pancreas, eustachian tube, thymus, parathyroid, and thyroid follicular cells
What is the difference between agenesis and aplasia?
- agenesis is the absence of an organ due to the absence of primordial tissue
- aplasia is absence of an organ despite the presence of that primordial tissue
What is the difference between a malformation and a deformation?
- deformations result from an extrinsic disruption and occur after the embryonic period
- malformations result from an intrinsic disruption and occur during the embryonic period
When is the developing fetus most susceptible to teratogens?
- between weeks 3 and 8
- before that it leads to spontaneous abortion and after it affects growth and function
What are the teratogenic effects of ACE inhibitors?
renal damage
What are the teratogenic effects of alkylating agents?
absence of digits
What are the teratogenic effects of aminoglycosides?
ototoxicity
What are the teratogenic effects of antiepileptics?
neural tube defects, cardiac defects, cleft palate, skeletal abnormalities
What are the teratogenic effects of DES?
increases risk for vaginal clear cell adenocarcinoma
What are the teratogenic effects of folate antagonists?
neural tube defects
What are the teratogenic effects of isotretinoin?
multiple severe birth defects; contraception is required while patients are treated with isotretinoin
What are the teratogenic effects of lithium?
abstain anomaly (apical displacement of the tricuspid valve)
What are the teratogenic effects of methimazole?
aplasia cutis congenita (absence of skin)
What are the teratogenic effects of tetracyclines?
discolored teeth and inhibited bone growth
What are the teratogenic effects of thalidomide?
limb defects
What are the teratogenic effects of warfarin?
bone deformities, fetal hemorrhage, abortion, ophthalmologic abnormalities
What are the teratogenic effects of cocaine?
problem is vasoconstriction: low birth weight, preterm birth, intrauterine growth restriction, placenta abruption
What are the teratogenic effects of smoking?
- problem is nicotine induced vasoconstriction and CO impairing oxygen delivery
- low birth weight, preterm labor, placental problems intrauterine growth restriction, SIDS
What are the teratogenic effects of iodine deficiency or excess?
congenital goiter or hypothyroidism
What are the teratogenic effects of maternal diabetes?
caudal regression syndrome (anal atresia to sirenomelia (“Mermaid syndrome”)), congenital heart defects, neural tube defects, macrosomia
What are the teratogenic effects of methylmercury?
neurotoxicity
What are the teratogenic effects of vitamin A excess?
extremely high risk for spontaneous abortions and bird defects
What are the teratogenic effects of x-rays?
microcephaly, intellectual disability
Fetal Alcohol Syndrome
- the leading cause of intellectual disability in the US
- alcohol results in failure of cell migration
- presents with pre- and post-natal developmental retardation, microcephaly, facial abnormalities (these include a smooth philtrum, thin upper lip, and small palpebral fissures), limb dislocation, and heart defects
- heart-lung fistulas and holoprosencephaly are the most severe form
What are chorionicity and amnionicity?
- the number of chorions and amnions that develop during an instance of monozygotic twinning
- a function of the time at which the fertilized egg splits
At what time period must a fertilized oocyte divide to form dichorionic, diamniotic monozygotic twins? Monochorionic, diamniotic? Monochorionic, monoamniotic?
- di-, di- arises from an early split between 0-4 days after fertilization
- monochorionic, diamniotic arises from a split between 4-8 days post-conception
- mono-, mono- arises from a split between 8-12 days post-conception
What causes conjoined twins?
a division that arises more than 13 days after fertilization
WhatWhat are cytotrophoblasts and syncytiotrophoblasts?
- the fetal component of the placenta
- cytotrophoblasts are the inner layer (nearest fetus)
- syncytiotrophoblasts are the outer layer
What is the function of cytotrophoblasts?
they are the trophoblast stem cell
What is the function of syncytiotrophoblasts?
- they synthesize and secrete hormones, particularly hCG
- additionally they lack MHC-I, reducing the chance the maternal immune system will attack it
What prevents the maternal immune system from attacking the syncytiotrophoblast layer of the placenta?
the syncytiotrophoblast cells lack MHC-I
Which delivers oxygenated blood to the fetus, umbilical arteries or the umbilical vein?
the umbilical vein
The umbilical arteries and vein are derived from what earlier structure?
the allantois
What is the allantois?
a fetal structure that arises during the third week from the yolk sac and gives rise to the urachus as well as the umbilical arteries and vein
What is the function of the urachus in utero?
it is a duct between the fetal bladder and umbilicus, which drains into the allantoic duct
Urachal Cyst
- a partial failure of the urachus to obliterate, leaving a fluid-filled cavity one by urothelium between the umbilicus and bladder
- can lead to infection or adenocarcinoma
What is a vesicourachal diverticulum?
a slight failure of the urachus to obliteration, which leads to an asymptomatic out pouching of the bladder in adults
What would cause urine to discharge from the umbilicus after birth?
a patent urachus
What is the vitelline duct?
a structure which connects the yolk sac to the midgut lumen
What do the 1st, 2nd, 3rd, 4th, and 6th aortic arches give rise to?
- 1st: part of the maxillary artery
- 2nd: the stapedial artery which normally involutes
- 3rd: the common carotid and proximal internal carotid
- 4th: the aortic arch and proximal right subclavian
- 6th: the proximal part of the pulmonary arteries and ductus arteroisus
Where does the left recurrent laryngeal nerve branch off the vagus?
it branches off and loops around the aortic arch, distal to the ductus arteriosus
Describe the structure of the branchial apparatus and the germ layers that contribute to each.
- the cleft is ectoderm and exterior
- the arch is mesoderm and neural crest
- the pouch is endoderm and is interior
What important structures do the branchial clefts give rise to?
- the first develops into the external auditory meatus
- the 2nd-4th form temporary cervical sinuses, which are obliterated by proliferation of the 2nd arch
What is a persistent cervical sinus?
a branchial cleft cyst within the lateral neck, found anterior to the sternocleidomastoid and typically immobile during swallowing
The first branchial arch gives rise to what?
- cartilage: the maxillary process (maxilla and zygomatic), mandibular process (Meckel cartilage and mandible), malleus and incus, and the sphenomandibular ligament
- muscle: muscles of mastication (temporalis, master, pterygoids), mylohyoid, anterior belly of digastric, tensor tympani, and tensor vela palatini
- nerves: CN V2 and V3
The second branchial arch gives rise to what?
- cartilage: stapes, styloid, lesser horn of hyoid, stylohoid ligament
- muscles: muscles of facial expression, stapedius, stylohoid, platysma, posterior belly of digastric
- nerve: CN VII
The third branchial arch gives rise to what?
- cartilage: greater horn of hyoid
- muscle: stylopharyngeus
- nerve: CN IX
The 4th-6th branchial arches give rise to what?
- cartilage: arytenoids, cricoid, corniculate, cuneiform, thyroid
- muscle: 4th to most pharyngeal constrictors, cricothyroid, elevator veil palatini; 6th to all intrinsic muscles of the larynx except the cricothyroid
- nerve: 4th - superior laryngeal branch of CN X; 6th - recurrent laryngeal branch of CN X
Pierre Robin Sequence
- micrognathia
- glossoptosis
- cleft palate
- airway obstruction
Treacher Collins Syndrome
neural crest dysfunction leads to mandibular hypoplasia and facial abnormalities
The first branchial pouch gives rise to what?
middle ear cavity, eustachian tube, and mastoid air cells
The second branchial pouch gives rise to what?
epithelial lining of palatine tonsil
The third branchial pouch gives rise to what?
dorsal wings to the inferior parathyroids and ventral wings to the thymus
The fourth branchial pouch gives rise to what?
dorsal wings to the superior parathyroids and ventral wings to the ultimobranchial body and parafollicular C cells of the thyroid
Describe how an embryo becomes male.
- the SRY gene on the Y chromosome results in the production of testis-determinng factor
- testes develop from the gonadal tissue, giving rise to Sertoli and Leydig cells
- Sertoli cells secrete Mullerian inhibitory factor
- Leydig cells secrete androgens that stimulate development of the mesonephric ducts
The Mullerian duct gives rise to what female structures?
- fallopian tubes
- uterus
- upper portion of vagina
The vagina is derived form what embryologic structures?
- the upper portion is derived from the Mullerian duct
- the lower portion is derived from the urogenital sinus
Mullerian Agenesis
- a potential developmental defect in women
- presents as primary amenorrhea, because the uterus doesn’t develop, in females with fully developed secondary sexual characteristics (ovaries still present)
The Mesonephric duct gives rise to what male structures?
- Seminal vesicles
- Epididymis
- Ejaculatory duct
- Ductus deferens
What role do Sertoli cells play in determining the sex of a fetus?
they secrete Mullerian inhibitory factor to promote degeneration of the Mullerian duct
What role do testosterone and DHT play in fetal development of the reproductive system?
- testosterone drives development of the male internal genitalia from the mesonephric duct except for the prostate
- DHT drives development of the external male genialia sn prostate
Describe the phenotype of an XY individual who fails to properly develop Sertoli cells.
they will lack Mullerian inhibitory factor and develop both male and female internal genitalia but will develop only male genitalia
How would a 5a-reductase deficiency affect sexual development of an XY fetus?
- it would lead to the inability to convert testosterone to DHT
- as such, the individual would have normal internal genitalia (except prostate), and ambiguous external genitalia until puberty when testosterone levels cause masculinization
Describe the roles of testis-determining factor, Mullerian inhibitory factor, testosterone, and DHT in male development and puberty.
- testis-determing factor drives development of the testes, which forms Sertoli and Leydig cells
- Mullerian inhibitory factor promotes degeneration of the Mullerian duct
- testosterone drives development of the internal genitalia except the prostate and later drives masculinization and acquisition of secondary sex characteristics during puberty
- DHT is responsible for driving development of male external genitalia and the prostate in utero
Uterine anomalies arise due to what failure?
failure of the Mullerian ducts to properly fuse or of the septum to complete resorb
What is a septate uterus?
failure of the septum to be resorbed after the Mullerian ducts fuse at the midline
What is a bicornuate uterus?
a uterus that arises due to incomplete fusion of the Mullerian ducts
What is uterus didelphys? How difficult will pregnancy be?
- a double uterus, vagina, and cervix that arises from complete failure of the Mullerian ducts to fuse
- pregnancy is still very much possible
The genital tubercle, urogenital sinus, urogenital folds, and labioscrotal swelling give rise to what male structures?
- tubercle: glans, corpus cavernosum, and corpus spongiosum
- sinus: bulbourethral glands and prostate gland
- folds: ventral shaft and penile urethra
- swelling: scrotum
The genital tubercle, urogenital sinus, urogenital folds, and labioscrotal swelling give rise to what female structures?
- tubercle: glans clitoris and vestibular bulbs
- sinus: Bartholin glands, uruethral/paraurethral glands, and lower vagina
- folds: labia minora
- swellings: labia majora
What is the gabernaculum? What adult structures does it give rise to?
- a band of fibrous tissue
- anchors the testes within the scrotum or forms the ovarian and young ligaments
What is the processes vaginalis? What adult structures does it give rise to?
- it is an evagination of the peritoneum
- gives rise to the tunica vaginalis in men and is obliterated in women
Where does venous blood drain from the gonads?
- left gonad to the left gonadal vein and left renal vein before leading to the IVC
- right gonad to the right gonadal vein, which drains directly into the IVC
Where is the infudibulopelvic ligament? What does it contain and what is clinically relevant about it?
- it is also known as the suspensory ligament of the ovary
- it connects the ovaries to the lateral pelvic wall
- it contains the ovarian vessels and is therefore ligated during oophorectomy
Where is the cardinal ligament? What does it contain and what is clinically relevant about it?
- it connects the cervix to the side wall of the pelvis
- it contains uterine vessels and is ligated during a hysterectomy
The ureter is at risk when ligating which ligaments of the female reproductive system?
- the infundibulopelvic ligament (suspensory of ovary)
- the cardinal ligament
Where is the round ligament of the uterus? What does it contain and what is clinically relevant about it?
derived from the gubernaculum, it connects the fundus of the uterus to the labia major, passing through the inguinal canal as it does
Where is the broad ligament? What does it contain and what is clinically relevant about it?
- it connects the uterus, fallopian tubes, and ovaries to the pelvic side wall
- it actually contains the ovaries, fallopian tubes, and round ligaments of the uterus
- it can be divided into the mesosalpinx, mesometrium, and mesovarium
Where is the ovarian ligament? What does it contain and what is clinically relevant about it?
- it connects the medial pole of the ovary to the lateral uterus
- it too is a derivative of the gubernaculum
The gubernaculum contributes to which ligaments within the female reproductive tract?
the ovarian ligament and the round ligament of the uterus
The vagina is lined by what sort of epithelium?
nonkeratinized, stratified squamous
The endocervix is lined by what sort of epithelium?
simple columnar epithelium
The uterus is lined by what sort of epithelium?
simple columnar with long tubular glands in the proliferative phase and could glands in the secretory phase
The fallopian tubes are lined by what sort of epithelium?
ciliated, simple columnar epithelium
The surface of the ovary is lined by what sort of epithelium?
simple cuboidal
Where are the corpus cavernosum and corpus spongiosum? Which contains the urethra?
- the corpus cavernosum is more superior than the spongiosum
- the spongiosum contains the urethra
Describe the pathway of sperm during ejaculation.
SEVEn UP
- seminiferous tubules
- epididymis
- vas deferens
- ejaculatory duct
- urethra
- penis
What would indicate a urethral injury?
blood at the urethral meatus
What is the difference between an anterior and posterior urethral injury in males?
- the posterior segment is the membranous urethra, most likely damaged by pelvic fracture; urine leaks into the retropubic space and with present as blood at the meatus and a high-riding prostate
- the anterior segment is the bulbar urethra, most likely damaged by perineal straddle injury; blood accumulates in the scrotum and if Buck’s fascia is torn, urine escapes into the perineal space; presents with blood at the meatus and scrotal hematoma
What is the deep fascia of Buck? What is it’s clinical relevance?
- it surrounds both corpus cavernosi and the corpus spongiosum
- in the case of a straddle injury damaging the anterior urethra, it will contain the urine
- if it is ruptured by the injury, urine will instead leak into the superficial perineal space
What is the difference between emission and ejaculation?
emission is movement of semen into the urethra while ejaculation is release of that fluid
What innervation/nerves control male emission and ejaculation?
- emission is controlled by the sympathetic nervous system via the hypogastric nerve
- ejaculation is controlled by visceral and somatic innervation via the pudendal nerve
What are spermatogonia?
male germ cells lining the seminiferous tubules and serve to maintain the germ pool by producing primary spermatocytes
What are Sertoli cells? What functions do they perform?
- they are non-germ cells found lining the seminiferous tubules, which support spermatogenesis
- they secrete inhibin B, androgen-binding protein, and Mullerian inhibiting factor
- they form tight junctions and form the blood-testis barrier, isolating gametes from autoimmune attack
- they support and nourish developing spermatozoa while regulating spermatogenesis
- they are also temperature sensitive, and will down regulate sperm production and inhibin B secretion when temperatures rise
What are three secretory products of Sertoli cells?
- Mullerian inhibiting factor
- inhibin B (inhibits FSH release)
- androgen-binding protein
What is inhibin B?
a hormone secreted by the gonads, which serves to inhibit FSH release
What are Leydig cells?
those found in the interstitium of the testes, which secrete testosterone in response to LH
Why do Sertoli cells produce androgen-binding protein?
to regulate local levels of testosterone
What is the most potent form of endogenous estrogen?
estradiol > estrone > estriol (i.e. E2 > E1 > E3
Where is estrogen produced in males and females? What form of estrogen arises from each source?
- the ovaries produce estradiol
- the placenta produces estriol
- adipose tissue forms estrone
- Sertoli cells produce various estrogens
What sort of GnRH stimulates release of LH and FSH?
pulsatile
Estrogen has what roles in females?
- development of genitalia and breasts
- female fate distribution
- growth of follicles
- endometrial proliferation
- feedback inhibition
- triggering the LH surge
- impairs prolactin secretion
- increases levels of SHBG, transport proteins, and HDL
- lowers LDL
What degree of estrogen increase is expected during pregnancy?
- 50 fold increase in estradiol and estrone
- 1000 fold increase in estriol
What kind of estrogen is produced by the placenta?
estriol
What changes do LH and FSH elicit in theca and granulosa cells?
- LH induces expression of desmolase by theca cells, which produces androgens
- FSH induces expression of aromatase by granulosa cells, which convert those androgens to estrogens, driving endometrial growth, follicle development, and eventually the LH surge that triggers ovulation
How do estrogen and progesterone affect prolactin levels?
they inhibit prolactin secretion until delivery has occurred
What are the functions of progesterone?
- stimulate endometrial glandular secretions and spiral artery development for implantation
- maintenance of pregnancy
- reduced myometrial excitability
- production of a thick cervical mucus
- increase body temperature
- reduce estrogen receptor expression
What is the effect of estrogen or progesterone on myometrial excitability?
- estrogen increases excitability
- progesterone decreases it
When do oocytes complete the various stages of meiosis?
- meiosis I begins in utero and is arrested in prophase I
- meiosis I is completed just prior to ovulation
- meiosis II is arrested in metaphase II until fertilization
What triggers ovulation?
an estrogen surge stimulates LH release, which induces rupture of the follicle
What hormone is responsible for the increase in temperature that coincides with ovulation?
progesterone
What is Mittelschmerz?
a transient mid-cycle ovulatory pain classically that is associated with peritoneal irritation and mimics appendicitis
The menstrual cycle is divided into what two phases?
follicular and luteal
Describe the follicular and luteal phases of the menstrual cycle as well as the hormones controlling progression.
- pulsatile GnRH stimulates the release of a little FSH and LH
- these gonadotropins stimulate theca and granulosa cells, resulting in follicle development and production of estrogen
- estrogen stimulates endometrial growth
- eventually follicular development progresses far enough that estrogen levels rise significantly and induce release of LH, which triggers ovulation
- after ovulation, the follicle becomes a corpus lutem, which shifts more toward the production of progesterone
- progesterone maintains the endometrium to support implantation
- if fertilization does not occur, there is no hCG to maintain the corpus luteum, progesterone levels fall, and the endometrium is sloughed off
- if fertilization does occur, syncytiotrophoblasts produce hCG, which maintains the corpus luteum until the placenta and fetus can take over progesterone production
How long are the follicular and luteal phases of the menstrual cycle?
- the follicular phase varies in length but is usually fourteen days
- the luteal phase is invariably 14 days
Ovulation occurs when during the menstrual cycle?
fourteen days before menstruation begins
What is responsible for the estrogen surge that induces ovulation?
an accelerated growth of the follicle during the second week of the follicular phase
What is dysmenorrhea? What is it most often associated with?
- pain with menses
- often associated with endometriosis
What is oligomenorrhea and polymenorrhea?
- oligo: a cycle lasting more than 35 days
- poly: a cycle lasting less than 21 days
What are metrorrhagia and menorrhagia?
- metrorrhagia: frequent or irregular menstruation
- menorrhagia: heavy menstrual bleeding (> 80 mL or > 7 days)
Where and where are ovulated oocytes usually fertilized?
in the ampulla of the fallopian tube on day 1 of ovulation
What do we used to detect pregnancy? At what point can we detect pregnancy using blood and at home tests?
- we detect the hCG secreted by syncytiotrophoblasts
- this can be detected by 1 week post-conception in the blood and 2 weeks post-conception by a home test
What is the difference between gestational and embryonic age of a developing fetus?
- gestational: calculated from date of last menstrual period
- embryonic: calculated from date of conception (= gestational age - 2 weeks)
What cardiovascular changes occur during pregnancy?
- increase in preload, decrease in afterload, and increase in HR drive an increase in CO
- anemia (because plasma volume increases more than number of RBCs)
- hypercoagulability
- hyperventilation
Why do pregnant women experience an anemia?
because their plasma volume increases more than their hemoglobin does, so there is a dilution anemia
When do hCG levels peak during pregnancy?
8-10 weeks (which is when the corpus luteum is allowed to degenerate because the placenta synthesizes it’s own hormones)
At what point during a pregnancy does the corpus luteum degenerate?
around 8-10 weeks, the time when the placenta is capable of producing it’s own hormones and stops producing hCG
hCG is a structural analog to which other hormones?
it shares an alpha subunit with LH, FSH, TSH but has a unique beta subunit
What part of hCG does a pregnancy test detect?
the beta subunit, because the alpha subunit is shared by LH, FSH, and TSH
What would cause hCG to be higher than usual during a normal pregnancy? What would cause it to be lower than expected?
- higher: multiple gestations, hydatidiform moles, choriocarcinomas, Down syndrome
- lower: ectopic or failing pregnancy, Edward syndrome, Patau syndrome (trisomy 13)
What is Edward syndrome? Patau syndrome?
trisomy 18 and trisomy 13, respectively
How is APGAR score calculated? When is it taken? What score suggests a need for further evaluation?
- score of 0, 1, or 2 is awarded for appearance (how pink), pulse, grimace (pain response), activity, and respiration
- taken at 1 and 5 minutes post-birth
- score of less than 7 requires further evaluation
What would qualify for a 2 on each of the APGAR measures? For a 1 on each? For a 0 on each?
- 2: pink, >100 bpm, cries and pulls away, active movements, strong cry (respirations)
- 1: extremities are blue, <100 bpm, grimaces or weak cry, arms and legs flexed, slow/irregular breathing
- 0: pale or blue, no pulse, no response to stimuli, no movement, no breathing
What does a low apgar score predict?
risk for long-term neurologic damage
How do we define low birth weight?
less than 2500 grams
Low Birth Weight
- defined as weighing less than 2500 grams
- caused by prematurity or intrauterine growth restriction
- increased risk for SIDS and overall mortality
- may contribute to impaired thermoregulation and immune function, hypoglycemia, polycythemia, impaired development, infections, RDS, necrotizing enterocolitis, etc.
What is required to maintain milk production after birth?
suckling is required to maintain prolactin and oxytocin release, which drive lactation
What roles do prolactin and oxytocin play in lactation?
prolactin induces lactation while oxytocin assists with milk letdown
What are the two functions of oxytocin?
promote uterine contractions and milk letdown
What immune components are transferred in breast milk?
- immunoglobulins (mostly IgA)
- lymphocytes
- macrophages
Breast feeding reduces the risk for what diseases in the newborn?
- development of asthma
- allergies
- diabetes mellitus
- obesity
Infants who are breast fed require what additional supplement not found in breast milk?
vitamin D
Why does breast feeding benefit the mother?
- facilitates bonding
- reduces estrogen exposure reducing the risk for breast and ovarian cancer
Menopause
- defined by amenorrhea for 12 months
- caused by an age-related decline in number of ovarian follicles with an average age of onset at 51
- this decline leaves peripheral conversion of androgens as the sole source for estrogen (so androgens rise and contribute to hirsutism)
- FSH levels rise dramatically, estrogen levels drop, LH increases, and GnRH increases
- causes HAVOCS: hot flashes, atrophy of the vagina, osteoporosis, coronary artery disease, and sleep disturbance
- usually proceeded by 4-5 years of abnormal cycles
Menopause before what age suggests primary ovarian insufficiency?
before age 40
How do DHT, testosterone, a nd androstenedione compare?
- they are all androgens
- testosterone and DHT from the testes while androstenedione comes from the adrenal cortex
- DHT > testosterone > androstenedione in terms of potency
What is responsible for closing the epiphyseal plates after puberty?
testosterone converted to estrogen
DHT is responsible for what male changes?
- early: differentiation of external male genitalia
- late: prostate growth, balding, sebaceous gland activity
How is testosterone converted to DHT?
5a-reductase
In the male, where is estrogen produced?
by aromatase in adipose tissue and in the testes (found in Sertoli cells)
Spermatogenesis takes how long?
two months (74 days)
What is the difference between spermatogenesis and spermiogenesis?
- spermatogenesis is the progression from spermatogonium to spermatid
- spermiogenesis is maturation of the spermatid to a spermatozoon via loss of cytoplasmic contents and acquisition of an acrosomal cap
What defines a primary spermatocyte, secondary spermatocyte, spermatid, and spermatozoon?
- a primary spermatocyte is diploid (2N, 4C), poised at the end of G2
- a secondary spermatocyte is haploid (1N, 2C), which has completed meiosis I
- a spermatid is haploid (1N, 1C), which has completed meiosis II
- a spermatozoon is a spermatid that has lost it’s cytoplasmic contents, taken the shape of a sperm, and acquired an acrosomal cap
Tanner staging involves assessment of what features?
genitalia, pubic hair, and breast tissue
What are Tanner stages I-V?
- I is pre-pubertal, II is 8-11.5 years old, III is 11.5-13, IV is 13-15, and V is over 15
- hair: none, sparse, coarsening, coarse but sparing medial thigh, coarse across medial thigh
- breast: flat with raised nipple, breast bud, mound forms, mound on mound with raised areola, adult contour with flattened areola
- penis: pre-pubertal, testicular enlargement, increase in length, increase in width and glands, adult
Klinefelter Syndrome
- XXY males
- causes dysgenesis of the seminiferous tubules, which leads to less inhibin B and more FSH, as well as abnormal Leydig cell function, which causes low testosterone, high LH, and high estrogen
- presents with testicular atrophy, eunuchoid body shape, tall with long extremities, gynecomastia, and a female hair distribution
- it may also present with developmental delay
- often not diagnosed until after puberty and is a common cause of hypogonadism found when working up a patient for infertility
- will find the presence of Barr bodies
Turner Syndrome
- XO females
- most often resulting from meiotic error (in the father), but can be due to a mitotic error after fertilization, which results in mosaicism
- gonadal dysgenesis results in low estrogen and high LH/FSH
- presents with short stature, shield chest with wide nipples, streak ovaries, bicuspid aortic valve, coarctation, lymphatic defects (e.g. webbed neck, lymphedema in feet or hands, cystic hygroma), and a horseshoe kidney
- it is the most common cause of primary amenorrhea
- no Barr body is found
XYY Male
- usually goes undiagnosed and individual is phenotypically normal but very tall
- may be associated with severe acne, learning disability, and autism spectrum disorders
Ovotesticular Disorder of Sex Development
- also known as “true hermaphroditism”
- more common as a 46,XX than 46,XY
- results in the presence of both ovarian and testicular tissue being present with ambiguous genitalia
How will levels of testosterone and LH be altered in those with a defective androgen receptor?
both testosterone and LH are high
How will levels of testosterone and LH be altered in those with primary hypogonadism?
testosterone is low and LH will be high
How will levels of testosterone and LH be altered in those with hypogonadotropic hypogonadism?
both testosterone and LH will be low
46,XX Disorder of Sex Development
- presence of ovaries but virulized or ambiguous external genitalia
- due to excessive or inappropriate exposure to androgenic steroids during early gestation; most often from congenial adrenal hyperplasia or exogenous administration of androgens during pregnancy
46,XY Disorders of Sex Development
- those characterized by the presence of testes but female or ambiguous external genitalia
- most often due to androgen insensitivity syndrome
Placental Aromatase Deficiency
- an inability of the placenta to synthesize estrogens from androgens
- results in 46,XX infants with ambiguous genitalia
- serum testosterone and androstenedione will be high and may cause maternal virilization during pregnancy
Androgen Insensitivity Syndrome
- a defect in the androgen receptor
- patients develop normal functioning testes, which are often localized to the labia majora, but develop as a female otherwise (external genitalia and secondary sex characteristics along with a rudimentary vagina)
- uterus and fallopian tubes are absent because Mullerian inhibiting factor still functions
5a-Reductase Deficiency
- an autosomal recessive condition seen in 46,XY individuals
- lack DHT so they have ambiguous genitalia until puberty when testosterone causes masculinization and growth of external genitalia
- testosterone and estrogen levels are normal; LH is normal or elevated
- internal genitalia are unaffected
Kallmann Syndrome
- failure to complete puberty due to hypogonadotropic hypogonadism
- results from defective migration of GnRH cells and formation of the olfactory bulb
- presents with low GnRH, FSH, LH, and testosterone as well as anosmia
- patient is infertile and will have amenorrhea if female
What is the difference between placenta accreta, increta, and percreta?
- accreta: placenta attaches to the myometrium without penetrating it
- increta: placenta penetrates into the myometrium
- percreta: placenta penetrates through the myometrium and into the uterine serosa
Vasa Previa
- a complication of pregnancy in which the fetal vessels run over or in close proximity to the cervical os
- vessels may rupture when the supporting membranes rupture, presenting with membrane rupture, painless vaginal bleeding, and fetal bradycardia
- frequently associated with velamentous insertion (of the umbilical cord into the chorioamniotic membrane rather than the placenta)
- requires an emergency C-section
What are the causes of postpartum hemorrhage to know?
the 4 T’s
- Tone (uterine atony; most common)
- Trauma
- Thrombin (coagulopathy)
- Tissue (retained products of conception)
What is uterine atony? Why is it clinically relevant?
- a loss of tone in the uterine musculature
- problematic because contraction of uterine muscles during labor normally compresses blood vessels and reduces flow to increase the likelihood of coagulation
- atony is the most common cause of postpartum hemorrhage
Polyhydramnios
- the condition of too much amniotic fluid
- associated with fetal malformations, maternal diabetes, fetal anemia, and multiple gestations
Oligohydramnios
- the condition of too little amniotic fluid
- associated with placental insufficiency, bilateral renal genesis, and posterior urethral valves in males
- may result in Potter sequence
What is gestational hypertension?
- aka pregnancy-induced hypertension
- defined by a BP > 140/90 after the 20th week of gestation without pre-existing hypertension
- lack of proteinuria and end-organ damage differentiates it from pre-eclampsia
- treat with hydrazine, methyldopa, labetalol, or nifedipine
What are the treatment options for gestational hypertension?
Hypertensive Moms Love Nifedipine
- hydralazine
- methyldopa
- labetolol
- nifedipine
Are ovarian, cervical, or endometrial cancers most common in the US? Worldwide?
- cervical is most common worldwide due to lack of screening
- endometrial > ovarian > cervical in the US
What are the most common causes of an ovulation?
pregnancy, PCOD, obesity, HPO abnormalities, premature ovarian failure, hyperprolactinemia, thyroid disorder, eating disorder, competitive athletics, Cushing syndrome, adrenal insufficency
Follicular Cyst
- a distended, enraptured graafian follicle
- may be associated with hyper-estrogenism or endometrial hyperplasia
- the most common ovarian mass in young women
Theca-Lutein Cyst
- a functional cyst filled with serous fluid
- usually bilateral and multiple
- driven by hCG and therefore associated with choriocarcinoma and hydatidiform moles
Gynecomastia
- breast enlargement in males due to increased estrogens relative to testosterone
- physiologic in newborns, during puberty, and in elderly males
- pathologic in cases of cirrhosis, hypogonadism, testicular tumors, and meds
- meds include spironolactone, hormones, cimetidine, ketoconazole (Some Hormones Create Knockers)
Peyronie Disease
- an abnormal curvature of the penis due to a fibrous plaque within the tunica albuginea
- associated with erectile dysfunction and may cause pain or anxiety
- repair surgically once the curvature stabilizes
What is a “penile fracture”?
reupture of the corpora cavernosa due to forced bending
Priapism
- a painful, sustained erection lasting more than four hours
- associated with sickle cell disease and medications such as sildenafil and trazodone
- must be teated promptly with corporal aspiration, intracavernosal phenylephrine, or surgical decompression to prevent ischemia
Spermatocele
- a cyst due to dilated epididymal duct or retention testis
- presents as a fluctuant, paratesticular nodule
What is Leuprolide and how is it used clinically?
- a GnRH analog with agonist properties when used in pulsatile fashion or antagonist properties when used continuously
- indicated for uterine fibroids, endometriosis, precocious puberty, prostate cancer, or infertility
What is the most significant adverse effect associated with estrogens?
risk for thrombotic event
Estrogens are contraindicated in which patients?
those with ER+ breast cancer or a history of DVTs
What is Clomiphene, how does it work, and what are the accompanying side effects?
- it is a SERM with antagonist activities in the hypothalamus to prevent normal feedback inhibition, thereby increasing the release of LH and FSH
- it is used to treat infertility due to an ovulation
- may cause hot flashes, ovarian enlargement, multiple simultaneous pregnancies, or visual disturbances
What is Tamoxifen, how does it work, and what are the accompanying side effects?
- it is a SERM with antagonist activities at breast and agonist activities at bone and in the uterus
- used to treat and prevent the recurrence of ER/PR+ breast cancer
- increases the risk for thromboembolic events and endometrial cancer
What is Raloxifene, how does it work, and what are the accompanying side effects?
- a SERM with antagonist activities at breast and uterus but agonist activities at bone
- used to treat osteoporosis
- increases risk of thromboembolic events but not the risk of endometrial cancer
How does Raloxifene differ from Tamoxifen?
Raloxifene is an estrogen antagonist in the uterus whereas Tamoxifen is a weak agonist, which means that Raloxifene does not increase the risk for endometrial cancers like Tamoxifen does
Anastrozole
an aromatase inhibitor used to treat ER+ breast cancer in postmenopausal women
Letrozole
an aromatase inhibitor used to treat ER+ breast cancer in postmenopausal women
Exemestane
an aromatase inhibitor used to treat ER+ breast cancer in postmenopausal women
Unopposed estrogen replacement therapy in post-menopausal women is a problem for what reason? What is used to oppose it?
- increases the risk for endometrial cancer
- progesterone is added to oppose it
What are the clinical uses of progestins?
contraception, treatment of endometrial cancer, and control of abnormal uterine bleeding
Levonorgestrel
a progestin used for contraception, treatment of endometrial cancer, and control of abnormal uterine bleeding
Progestin Challenge
- a test used to narrow down the source of amenorrhea
- progestin is given and if the patient has sufficient serum estradiol, bleeding should occur in 2-7 days, indicating the patient’s amenorrhea is due to anovulation
Etonogestrel
a progestin used for contraception, treatment of endometrial cancer, and control of abnormal uterine bleeding
Norethindrone
a progestin used for contraception, treatment of endometrial cancer, and control of abnormal uterine bleeding
Megestrol
a progestin used for contraception, treatment of endometrial cancer, and control of abnormal uterine bleeding
What is Mifepristone and how is it used clinically?
a competitive progesterone inhibitor used with misoprostol to terminate a pregnancy
What is Ulipristal and how is it used clinically?
a competitive progesterone inhibitor used as emergency contraception
How does oral estrogen/progestin contraception work?
- they inhibit LH/FSH to prevent ovulation
- progestin causes a thickening of the cervical mucus, which poses a barrier to sperm, and inhibits endometrial proliferation
For whom is combined oral contraception contraindicated?
- smokers over 35 (due to risk of DVT)
- those with increased risk of CVD
- those with migraines (especially with aura)
- those with breast cancer
Explain the mechanism, use, and adverse effects of a copper IUD.
- hormone free; instead, it produces a local inflammatory reaction toxic to sperm and ova
- can be used as long-acting reversible contraception and is the most effective emergency contraception
- disadvantages are heavier/longer menses, dysmenorrhea, and risk of PID with insertion
What is the most effective emergency contraceptive?
placement of a copper IUD
Terbutaline
a B2 agonist used to relax the uterus
Ritodrine
a B2 agonist used to relax the uterus
What is danazol, how is it used, and what are it’s adverse effects?
- it is a synthetic androgen that acts as a partial agonist
- used to treat endometriosis and hereditary angioedema
- may cause weight gain, edema, acne, hirsutism, masculinization, low HDL, or hepatotoxicity
What are the clinical uses and adverse effects of androgen therapy?
- treat hypogonadism and promote the development of secondary sex characteristics in addition to stimulating anabolism in patients after a burn or other injury
- may cause gonadal atrophy, premature closure of the epiphyseal plates, or an increase in LDL and decrease in HDL
What is finasteride and how is it used clinically?
a 5a-reductase inhibitor, which reduces DHT levels, for use in those with BPH or male-pattern baldness
What is flutamide and how is it used clinically?
a non steroidal competitive inhibitor of androgens used to treat prostate carcinoma
What is ketoconazole and how is it used clinically? What are it’s adverse effects?
- a drug used to inhibit steroid synthesis via 17,20-desmolase in those with POCD
- may cause gynecomastia or amenorrhea
What is spironolactone and how is it used clinically in the treatment of GU conditions? What are it’s adverse effects?
- inhibits steroid binding, 17a-hydroxylase, and 17,20-desmolase for use in those with POCD
- may cause gynecomastia or amenorrhea
What is tamsulosin and how is it used clinically?
- it is an a1-antagonist selective for the a1A,D subset of receptors found in the prostate
- used to treat BPH
What naming convention is used for PDE5 Inhibitors? How are they used clinically? What are their adverse effects?
- they end in “-denafil”
- they increase cGMP to prolong smooth muscle relaxation
- used to treat ED, pulmonary HTN, and BPH
- cause headache, flushing, cyanosis, and a life-threatening hypotension in patients taking nitrates
What is minoxidil and what is it used for clinically?
- it is a direct arteriolar vasodilator
- used to treat androgenetic alopecia and severe refractory hypertension
