USMLE (Subject) / Reproductive (Lesson)

USMLE First Aid

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• Ectoderm Surface ectoderm:- Epidermis- Adenohypophysis (from Rathke pouch)- Lens of eye- Epithelial linings of oral cavity, sensory organs of ear, olfactory epithelium- Anal canal below the pectinate line- Parotid, sweat, mammary glandsCraniopharyngioma – Benign Rathke pouch tumor with cholesterol crystals, calcifications. Neural tube:- Brain (neurohypophysis, CNS neurons, oligodendrocytes, astrocytes, ependymal cells, pineal gland)- Retina- Spinal cord Neural crest:- Melanocytes- Myenteric (Auerbach) plexus- Odontoblasts- Endocardial cushions- Laryngeal cartilage- Parafollicular (C) cells of the thyroid- PNS (dorsal root ganglia, cranial nerves, autonomic ganglia, Schwann cells)- Adrenal medulla and all ganglia- Spinal membrane (aorticopulmonary septum)- Pia and arachnoid- Bones of skull
• Mesoderm - Muscle- Bone- Connective tissue, skin- Serous linings of body cavities (eg, peritoneum, pericardium, pleura)- Spleen (derived from foregut mesentery)- Cardiovascular structures- Lymphatics- Blood- Wall of gut tube- Upper vagina- Kidneys- Adrenal cortex- Testes, ovaries Notochord induces endoderm to form neurectoderm (neural plate); its only postnatal derivative is the nucleus pulposus of the intervertebral disc. Mesodermal defects = VACTERLVertebral defectsAnal atresiaCardiac defectsTracheo-Esophageal fistulaRenal defectsLimb defects (bone and muscle)
• Endoderm - Gut tube epithelium (including anal canal above the pectinate line)- Most of urethra and lower vagina (derived from urogenital sinus)- Luminal epithelial derivatives (eg, lungs, liver, gallbladder, pancreas, eustachian tube, thymus, parathyroid, thyroid follicular cells)
• Potter sequence = atypical physical appearance of a fetus or neonate due to oligohydramnios experienced in the uterus - clubbed feet- pulmonary hypoplasia- cranial abnormalities
• Teratogens - Medications - ACE inhibitors → Renal damage- Alkylating agents → Absence of digits, multiple anomalies- Aminoglycosides → Ototoxicity- Antiepileptic drugs (valproate, phenytoin, carbamazepine, phenobarbital) → Neural tube defects, cardiac defects, cleft palate, skeletal abnormalities (eg, phalanx/nail hypoplasia, facial dysmorphism). High-dose folate supplementation recommended.- Diethylstilbestrol → Vaginal clear cell adenocarcinoma, congenital Müllerian anomalies- Folate antagonists (trimethoprim, methotrexate) → Neural tube defects- Isotretinoin → Multiple severe birth defects- Lithium → Ebstein anomaly (apical displacement of tricuspid valve)- Methimazole → Aplasia cutis congenita- Tetracycline → Discolored teeth, inhibited bone growth- Thalidomide → Limb defects (phocomelia, micromelia – "flipper" limbs)- Warfarin → Bone deformities, fetal hemorrhage, abortion, ophthalmologic abnormalities (use heparin; does not cross placenta)
• Teratogens - Substance abuse Alcohol → Intellectual disability; fetal alcohol syndrome Cocaine → Low birth rate, preterm birth, IUGR, placental abruption Smoking (nicotine, CO) → Low birth weight (leading cause in developed countries), preterm labor, placental problems, IUGR, SIDS, ADHD
• Teratogens - Other Iodine (lack or excess) → Congenital goiter or hypothyroidism (cretinism) Maternal diabetes → Caudal regression syndrome (anal atresia to sirenomelia), congenital heart defects (eg, VSD, transposition of the great vessels), neural tube defects, macrosomia, neonatal hypoglycemia, polycythemia Methylmercury → Neurotoxicity (highest in swordfish, shark, king mackerel) Vitamin A excess → High risk for spontanous abortions and birth defects (cleft palate, cardiac) X-rays → Microcephaly, intellectual disability
• Fetal alcohol syndrome Leading cause of intellectual disability in the US. - Pre- and postnatal developmental retardation- Microcephaly- Facial abnormalities (eg, smooth philtrum, thin vermillion border [upper lip], small palpebral fissures)- Limb dislocation- Heart defects (heart-lung fistula and holoprosencephaly in most severe forms) Mechanism is failure of cell migration.
• Placenta Fetal component- Cytotrophoblast: Inner layer of chorionic villi, make cells.- Syncytiotrophoblast: Outer layer of chorionic villi; synthesizes and secretes hormones, eg, hCG (structurally similar to LH; stimulates corpus luteum to secrete progesterone during first trimester). Lacks MHC-I expression → ↓ chance of attack by maternal immune system. Maternal component- Decidua basalis: Derived from endometrium. Maternal blood in lacunae.
• Urachus In the 3rd week the yolk sac forms the allantois, which extends into urogenital sinus.Allantois becomes the urachus, a duct between fetal bladder and umbilicus.Failure of urachus to involute can lead to anomalies that may increase risk of infection and/or malignancy (eg, adenocarcinoma) if not treated.Obliterated urachus is represented by the median umbilical ligament after birth, which is covered by median umbilical fold of the peritoneum. Patent urachus: Total failure of urachus to obliterate → urine discharge from umbilicus. Urachal cyst: Partial failure of urachus to obliterate; fluid-filled cavity lined with uroepithelium, between umbilicus and bladder. Cyst can become infected and present as painful mass below umbilicus. Vesicourachal diverticulum: Slight failure of urachus to obliterate → outpouching of bladder.
• Vitelline duct 7th week – obliteration of vitelline duct (omphalomesenteric duct), which connects yolk sac to midgut lumen. Vitelline fistula: Vitelline duct fails to close → meconium discharge from umbilicus. Meckel diverticulum: Partial closure of vitelline duct, with patent portion attached to ileum (true diverticulum). May have heterotopic gastric and/or pancreatic tissue → melena, hematochezia, abdominal pain.
• DiGeorge syndrome Chromosome 21q11 deletion. - aberrant develoment of 3rd and 4th pouches --> T-cell deficiency (thymic aplasia) and hypocalcemia (failure of parathyroid development) - associated with cardiac defects (conotruncal anomalies)
• Paramesonephric (Müllerian) duct Develops into female internal structures – fallopian tubes, uterus, upper portion of vagina (lower portion from urogenital sinus). - Male remnant is appendix testis. Müllerian agenesis (Mayer-Rokitansky-Küster-Hauser syndrome) – may present as 1° amenorrhea (due to lack of uterine development) in females with fully developed 2° sexual characteristics (functional ovaries).
• Müllerian agenesis (Mayer-Rokitansky-Küster-Hauser syndrome) Congenital malformation characterized by the failure of the Müllerian duct (paramesonephric duct) to develop- 46, XX - 1° amenorrhoe  - Absent or rudimentary uterus and upper vagina - Fully developed 2° sexual characteristics (functional ovaries)
• Mesonephric (Wollfian) duct Develops into male internal structures (except prostate) – Seminal vesicles, epididymis, ejactulatory duct, ductus deferens. - Female remnant is Gartner duct.
• SRY gene --> Testis-determining factor --> Testes 1. Sertoli cells --> Müllerian inhibitory factor --> degeneration of paramesonephric (Müllerian) duct (female internal genitalia) 2. Leydig cells --> Testosterone (Wollfian duct --> male internal genitalia except prostate) --> DHT (male external genitalia, prostate)
• Congenital penile abnormalities Hypospadias: Abnormal opening of penile urethra on ventral surface of penis due to failure of urethral folds to fuse.- Hypospadias is more common than epispadias.- Associated with inguinal hernia and cryptorchidism. Epispadias: Abnormal opening of penile urethra on dorsal surface of penis due to faulty positioning of genital tubercle.- Associated with exstrophy of the bladder.
• Female reproductive anatomy Infundibulopelvic ligament (suspensory ligament of the ovary):- Connects ovaries to lateral pelvic wall- Contains ovarian vessles- Ligate vessels during oophorectomy to avoid bleeding.- Ureters course retroperitoneally, close to gonadal vessels → at risk of injury during ligation of ovarian vessels. Cardinal ligament:- Connects cervix to side wall of pelvis- Contains uterine vessels- Ureter at risk of injury during ligation of uterine vessels in hysterectomy. Round ligament of the uterus:- Connects uterine horn to labia majora- Derivative of gubernaculum. Trabels through inguinal canal; above the artery of Sampson. Broad ligament:- Connects uterus, fallopian tubes, and ovaries to pelvic side wall- Contains ovaries, fallopian tubes, round ligaments of uterus- Fold of peritoneum that comprises the mesosalpinx, mesometrium, and mesovarium. Ovarian ligament:- Connects medial pole of ovary to lateral uterine horn- Derivative of gubernaculum
• Progesterone Source: Corpus luteum, placenta, adrenal cortex, testes Function:- Stimulation of endometrial glandular secretions and spiral artery development- Maintenance of pregnancy- ↓ myometrial excitability- Production of thick cervix mucus, which inhibits sperm entry- ↑ body temperature by 0.5-1.0°F- Uterine smooth muscle relaxation (preventing contractions)- ↓ estrogen receptor expression- Prevents endometrial hyperplasia - ↑ progesterone is indicative of ovulation.- Fall of progesterone after delivery disinhibits prolactin → lactation.
• Human chorionic gonadotropin (hCG) Source: Syncytiotrophoblast of placenta Maintains corpus luteum (and thus progesterone) for first 8-10 weeks of pregnancy by acting like LH (otherwise no luteal cell stimulation → abortion). After 10 weeks, placenta synthesizes its own estriol and progesterone and corpus luteum degenerates.- Used to detect pregnancy because it appears early in urine.- Has idential α subunit as LH, FSH, TSH (states of ↑ hCG can cause hyperthyroidism). β subunit is unique (pregnancy test detects β subunit). ↑ hCG in multiple gestations, hydatidiform moles, choriocarcinoma, Down syndrome. ↓ hCG in ectopic/failing pregnancy, Edwards syndrome, and Patau syndrome.
• Apgar score Assessment of newborn vital signs following delivery via a 10-point scale evaluated at 1 minute and 5 minutes. Appearance (pink, extremities blue, pale or blue)Pulse (>100, <100, no pulse)Grimace (cries and pulls away, grimaces or weak cry, no response)Activity (active, arms and legs flexed, no movement)Respiration (strong cry, slow/irregular, no breathing) - Scores <7 require further evaluation.- If Apgar score remains low at later time points, there is a ↑ risk the child will develop long-term neurologic damage.
• Menopause Diagnosed by amenorrhea for 12 months.↓ estrogen production due to age-linked decline in number of ovarian follicles. Average age at onset is 51 years (earlier in smokers).- Menopause before age 40 suggests 1° ovarian insufficiency (premature ovarian failure) Usually preceded by 4-5 years of abnormal menstrual cycles. Source of estrogen (estrone) after menopause becomes peripheral conversion of androgens, ↑ androgens → hirsutism. - ↑↑ FSH is specific for menopause (loss of negative feedback on FSH due to ↓ estrogen).- Hormonal changes: ↓ estrogen, ↑↑ FSH, ↑ LH (no surge), ↑ GnRH. - Hot flashes- Atrophy of the vagina- Osteoporosis- Coronary artery disease- Sleep disturbances
• Androgens Testosterone, dihydrotestosterone (DHT), androstenedione- Source: Testosterone and DHT – testis, androstenedione – adrenal- Potency: DHT > testosterone > androstenedione Testosterone:- Differentiation of epididymis, vas deferens, seminal vesicles (internal genitalia, except prostate)- Growth spurt: penis, seminal vesicles, sperm, muscle, RBCs- Deepening of voice- Closing of epiphyseal plates (via estrogen converted from testosterone)- Libido DHT:- Early – differentiation of penis, scrotum, prostate- Late – prostate growth, balding, sebaceous gland activity Exogenous testosterone → inhibition of hypothalamic-pituitary-gonadal axis → ↓ intratesticular testosterone → ↓ testicular size → azoospermia.
• Klinefelter syndrome Male, 47 XXY.Dysgenesis of seminiferous tubules → ↓ inhibin B → ↑ FSH.Abnormal Leydig cell function → ↓ testosterone → ↑ LH → ↑ estrogen. - Testicular atrophy- Eunuchoid body shape- Tall, long extremities- Gynecomastia- Female hair distribution- May present with developmental delay Presence of inactivated X chromosome (Barr body)Common cause of hypogonadism seen in infertility work-up.
• Turner syndrome Female, 45 XO.↓ estrogen leads to ↑ LH, FSH.Menopause before menarche.Sometimes due to mitotic error → mosaicism (eg, 45,XO/46,XX). - Short stature (if untreated; preventable with GH therapy)- Ovarian dysgenesis (streak ovary)- Shield chest- Bicuspid aortic valve- Coarctation (femoral < brachial pulse)- Lymphatic defects (result in webbed neck or cystic hygroma, lymphedema in feet, hands)- Horseshoe kidney - Most common cause of 1° amenorrhea. - No Barr body.- Pregnancy is possible in some cases (IVF, exogenous estradiol-17β and progesterone).
• Androgen insensitivity syndrome (46,XY) X-linked defect in androgen receptor resulting in normal-appearing female (46,XY DSD). - Female external genitalia with scant axillary and pubic hair- Rudimentary vagina- Uterus and fallopian tubes absent- Normal functioning testes (often found in labia majora; surgically removed to prevent malignancy). - ↑ testosterone, estrogen, LH
• 5α-reductase deficiency Autosomal recessive. Inability to convert testosterone to DHT. - Sex limited to genetic males (46,XY DSD) - Ambiguous genitalia until puberty, when ↑ testosterone causes masculinization/↑ growth of external genitalia.- Internal genitalia are normal - Testosterone/estrogen levels are normal- LH is normal or ↑
• Kallmann syndrome Failure to complete puberty, a form of hypogonadotropic hypogonadism. - Defective migration of GnRH-releasing neurons and subsequent failure of GnRH-releasing olfactory bulbs to develop → ↓ synthesis of GnRH in the hypothalamus; hyposmia/anosomia. - ↓ GnRH, FSH, LH, testosterone - Infertility (low sperm count in males; amenorrhea in females).
• Hydatidiform mole Cystic swelling of chorionic villi and proliferation of chorionic epithelium (only trophoblast). Presents with vaginal bleeding, uterine enlargement more than expected, pelvic pressure/pain. Associated with hCG-mediated sequelae: early preeclampsia (before 20 weeks), theca-lutein cysts, hyperemesis gravidarum, hyperthyroidism. Treatment: Dilation and curettage and methotrexate. Monitor β-hCG. Complete mole: 46,XX; 46,XY - Mostly enucleated egg + single sperm which duplicates paternal DNA- No fetal parts- ↑↑↑ hCG- ↑ uterine size  - "Honeycombed" uterus or "clusters of grapes", "snowstorm" on ultrasound- 15-20% risk of malignancy (gestational trophoblastic neoplasia)- Risk of choriocarcinoma 2% Partial mole: 69,XXX; 69,XXY; 69,XYY - 2 sperm + 1 egg- Fetal parts- Normal uterine size- ↑ hCG- Risk of malignancy <5%- Risk of choriocarcinoma: Rare
• Placental abruption Premature separation (partial or complete) of placenta from the uterine wall before delivery of infant. Risk factors:- Trauma (eg, motor vehicle accident)- Smoking- Cocaine abuse- Hypertension, preeclampsia Presentation:- Abrupt, painful bleeding (concealed or apparent) in third trimester- Possible DIC, maternal shock, fetal distress - Life threatening for mother and fetus
• Morbidly adherent placenta Defective decidual layer → abnormal attachment and separation after delivery. Risk factors:- Prior C-section or uterine surgery involving myometrium- Inflammation- Placenta previa- Advanced maternal age- Multiparity Placenta accreta – placenta attaches to myometrium without penetrating it; most common typePlacenta increta – placenta penetrates into myometriumPlacenta percreta – placenta penetrates ("perforates") through myometrium and into uterine serosa (invades entire uterine wall); can result in placental attachment to rectum or bladder (can result in hematuria) Presentation: often detected on ultrasound prior to delivery. No separation after delivery → postpartum bleeding (can cause Sheehan syndrome).
• Placenta previa Attachment of placenta to lower uterine segment over (or <2 cm from) internal cervical os. Risk factors:- Multiparity- Prior C-section - Associated with painless third-trimester bleeding
• Ectopic pregnancy Implantation of fertilized ovum in a site other than the uterus, most often in ampulla of fallopian tube. Suspect with history of amenorrhea, lower-than-expected rise in hCG, sudden lower abdominal pain (often mistaken for appendicitis).- Pain +/- bleeding.Confirm with ultrasound. Risk factors:- Prior ectopic pregnancy- History of infertility- Salpingitis (PID)- Ruptured appendix- Prior tubal surgery- Smoking- Advanced maternal age
• Vasa previa Fetal vessels run over, or in close proximity to, cervical os. - May result in vessel rupture, exsanguination, fetal death. Triad:1. Membrane rupture2. Painless vaginal bleeding3. Fetal bradycardia (<110 beats/min) - Emergency C-section usually indicated. - Frequently associated with velamentous umbilical cord insertion (cord inserts in chorioamniotic membrane rather than placenta → fetal vessels travel to placenta unprotected by Wharton jelly).
• Postpartum hemorrhage Loss of >500 ml of blood within the first 24 hours after childbirth. Due to 4 T's:Tone (uterine atony, most common)Trauma (lacerations, incisions, uterine rupture)Thrombin (coagulopathy)Tissue (retained products of conception)
• Amniotic fluid abnormalities Polyhydramnios: Too much amniotic fluid- Often idiopathic, but associated with fetal malformations (eg, esophageal/duodenal atresia, anencephaly; both result in instability to swallow amniotic fluid), maternal diabetes, fetal anemia, multiple gestations. Oligohydramnios: Too little amniotic fluid- Associated with placental insufficiency, bilateral renal agenesis, posterior urethral valves (in males) and resultant inability to excrete urine.- Any profound oligohydramnios can cause Potter sequence.
• Dysplasia and carcinoma in situ - begins at basal layer of squamocolumnar junction (transformation zone) - CIN 1-3 - associated with HPV 16 and 18, which produce the E6 (inhibits p53 suppressor gene) and E7 gene product (inhibits RB suppressor gene) Risk factors:- multiple sexual partners- smoking- starting sexual intercourse at young age- HIV
• Common causes of anovulation - Pregnancy- Polycystic ovarian syndrome- Obesity- HPO axis abnormalities- Premature ovarian failure- Hyperprolactinemia- Thyroid disorders- Eating disorders- Competitive athletics- Cushing syndrome- Adrenal insufficiency- Chromosomal abnormalities (eg, Turner syndrome)
• Polycystic ovarian syndrome Also known asn Stein-Leventhal syndrome.Hyperinsulinemia and/or insulin resistance hypothesized to alter hypothalamic hormonal feedback response → ↑ LH:FSH, ↑ androgens (eg, testosterone) from theca internal cells, ↓ rate of follicular maturation → unruptured follicles (cysts) + anovulation. Presents with:- Enlarged, bilateral cystic ovaries- Amenorrhea/oligomenorrhea- Hirsutism, acne- ↓ fertility- Associated with obesity- ↑ risk of endometrial cancer 2° to unopposed estrogen from repeated anovulatory cycles Treatment: Cycle regulation via weight reduction (↓ peripheral estrone formation), OCPs (prevent endometrial hyperplasia due to unopposed estrogen); clomiphene, metformin to induce ovulation; spironolactone, ketoconazole (antiandrogens) to treat hirsutism.
• Endometrial carcinoma Most common gynecologic malignancy, typically preceded by endometrial hyperplasia.- Peak occurrence at 55-65 years old. - Presents with vaginal bleeding. Risk factors:- Prolonged use of estrogen without progestins- Obesity- Diabetes- Hypertension- Nulliparity- Late menopause- Early menarche- Lynch syndrome
• Endometriosis Non-neoplastic endometrial-like glands/stroma outside of the endometrial cavity. - Most common sites are ovary (frequently bilateral), pelvis, peritoneum. In ovary, appears as endometrioma (blood-filled "chocolate cysts"). - May be due to retrograde flow, metaplastic transformation of multipotent cells, transportation of endometrial tissue via lymphatic system. Characteriyed by:- Cyclic pelvic pain- Bleeding- Dysmenorrhea- Dyspareunia- Dyschezia (pain with defecation)- Infertility- Normal-sized uterus Treatment: NSAIDs, continuous OCPs, progestins, GnRH agonists, danazol, laparoscopic removal
• Gonadal drainage Venous drainage:- Left ovary/testis → left gonadal vein → left renal vein → IVC- Right ovary/testis → right gonadal vein → IVC Because the left spermatic vein enters the left renal vein at a 90° angle, flow is less laminar on the left than on the right → left venous pressure > right venous pressure → varicocele more common on the left. Lymphatic drainage:- Ovaries/testes → para-aortic lymph nodes- Body of uterus/superior bladder → external iliac nodes- Prostate/cervix/corpus cavernosum/proximal vagina → internal iliac nodes- Distal vagina/vulva/scortum/distal anus → superficial inguinal nodes- Glans penis → deep inguinal nodes
• Oogenesis 1° oocytes begin meiosis I during fetal life and complete meiosis I just prior to ovulation. Meiosis I is arrested in prophase I until ovulation (1° oocytes, 2N4C). Meiosis II is arrested in metaphase II until fertilization (2° oocytes, 1N2C). If fertilization does not occur within 1 day, the 2° oocyte degenerates.
• Preeclampsia New-onset hypertension with either proteinuria or end-organ dysfunction after 20th week of gestation (<20th week suggests molar pregnancy). - Caused by abnormal placental spiral arteries → endothelial dysfunction → vasoconstriciton, ischemia. - Incidence ↑ in patients with pre-existing hypertension, diabetes, chronic renal disease, autoimmune disorders (eg, antiphospholipid antibody syndrome). Complications:- Placental abruption- Coagulopathy- Renal failure- Pulmonary edema- Uteroplacental insufficiency- May lead to eclampsia (+ seizures) and/or HELLP syndrome  Treatment:- Antihypertensives- IV magnesium sulfate (to prevent seizure)- Definitive is delivery of fetus
• Eclampsia Preeclampsia + maternal seizures - Maternal death due to stroke, intracrancial hemorrhage, or ARDS. Treatment:- IV magnesium sulfate- Antihypertensives- Immediate delivery
• HELLP syndrome Hemolysis, Elevated Liver enzymes, Low Platelets A manifestation of severe preeclampsia. - Blood smear shows schistocytes.- Can lead to DIC and hepatic subcapsular hematomas → rupture → severe hypotension. Treatment: Immediate delivery
• Gynecologic tumor epidemiology Incidence (US) – endometrial > ovarian > cervical- Cervical cancer is more common worldwide due to lack of screening or HPV vaccination. Prognosis: cervical (diagnosed <45 years old) > endometrial (middle-aged, about 55 years old) > ovarian (>65 years)
• Cervical pathology Dysplasia and carcinoma in situ- Begins at basal layer of squamocolumnar junction (transformation zone)- Classified as CIN 1-3- Associated with HPV-16 and -18, which produce E6 (inhibits p53) and E7 (inhibits Rb)- Koilocytes are pathognomonic of HPV infection- May present as postcoital vaginal bleeding- Risk factors: multiple sexual partners (#1), smoking, early coitarche, DES exposure, immunocompromise (eg, HIV, transplant). Invasive carcinoma:- Often squamous cell carcinoma- Pap smear can detect cervical dysplasia (koliocytes) before it progresses to invasive carcinoma.- Diagnose via colposcopy and biopsy.- Lateral invasion can block ureters → renal failure
• Primary ovarian insufficiency Also known as premature ovarian failure.Premature atresia of ovarian follicles in women of reproductive age. - Most often idiopathic; associated with chromosomal abnormalities (especially in females <30 years).- Need karyotype screening. - Patients present with signs of menopause after puberty but before age 40.- ↓ estrogen, ↑ LH, ↑ FSH
• Breast cancer therapy Positive for human epidermal growth factor 2/neu --> Trastuzumab Positive for estrogen receptor --> Tamoxifen

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