Reproduction Flashcards
Sonic Hedgehog Gene
Produced at base of limbs in zone of polarizing activity
Involved in patterning along anterior-posterior axis.
Involved in CNS development; mutation can cause holoprosencephaly
Wnt-7 gene
Produced at apical ectodermal ridge (thickened ectoderm at distal end of each developing limb)
Necessary for proper organization along dorsal-ventral axis
FGF gene
Produced at apical ectodermal ridge (like Wnt-7).
Stimulates mitosis of underlying mesoderm, providing for lengthening of limbs
Homeobox (Hox) genes
Involved in segmental organization of embryo in a craniocaudal direction.
Code for transcription factors.
Hox mutations lead to appendages in wrong locations
Early Fetal development (through week 10)
Day 0 - Fertilization by sperm, forming zygote, initiating embryogenesis.
Within week 1 - hCG secretion begins around the time of implantation of blastocyst (it “sticks” at day 6)
Within week 2 - Bilaminar disc (epiblast, hypoblast). 2 weeks = 2 layers
Within week 3 - Trilaminiar disc. Gastrulation. Primitive streak, notochord, mesoderm and its organization, and neural plate begin to form.
Weeks 3-8 (Embryonic period) - Neural tube formed by neuroectoderm and closes by week 4. Organogenesis. Extremely susceptible to teratogens
Week 4 - Heart begins to beat. Upper and lower limb buds begin to form. 4 weeks = 4 limbs.
Week 6 - Fetal cardiac activity visible by transvaginal US
Week 10 - Genitalia have male/female characteristics
Gastrulation
Within week 3
Process that forms the trilaminar embryonic disc. Establishes the ectoderm, mesoderm, and endoderm germ layers.
Starts with epiblast invaginating to form the primitive streak.
Ectoderm
External/outer layer
1) Surface Ectoderm - Epidermis; adenohypophysis (from Rathke pouch); lens of eye; epithelial linings of oral cavity, sensory organs of ear, and olfactor epithelium; epidermis; anal canal below the pectinate line; parotid, sweat, and mammary glands
Craniopharyngioma - benign Rathke pouch tumor with cholesterol crystals, calcifications
2) Neuroectoderm - Brain (neurohypophysis, CNS, neurons, oligodendrocytes, astrocytes, ependymal cells, pineal gland), retina and optic nerve, spinal cord
3) Neural crest - PNS (dorsal root ganglia, cranial nerves, celiac ganglion, Schwann cells, ANS), melanocytes, chromaffin cells of adrenal medulla, parafollicular (C) cells of thyroid, pia, and arachnoid, bones of the skull, odontoblasts, aorticopulmonary septum
Mesoderm
Middle/”Meat” layer
Muscle, bone, connective tissue, serous linings of body cavities (peritoneum), spleen (derived from foregut mesentery), cardiovascular structures, lymphatics, blood, wall of gut tube, vagina, kidneys, adrenal cortex, dermis, testes, ovaries
Notochord induces ectoderm to form neuroectoderm (neural plate). Its only postnatal derivative is the nucleus pulposus of the intervertebral disc
Mesodermal defects = VACTERL
V = vertebral defects A = Anal atresia C = Cardiac defects T/E = Tracheo-Esophageal fistula R = Renal defects L = Limb defects (bone and muscle)
Endoderm
Gut tube epithelium (including anal canal above the pectinate line), most of urethra (derived from urogenital sinus), luminal epithelial derivatives (lungs, liver, gallbladder, pancreas, eustachian tube, thymus, parathyroid, thyroid follicular cells)
Organ morphogenesis errors
1) Agenesis - absent organ bc of absent primordial tissue
2) Aplasia - absent organ despite presence of primordial tissue
3) Hypoplasia - Incomplete organ development; primordial tissue present
4) Deformation - Extrinsic disruption; occurs after embryonic period
5) Disruption - Secondary breakdown of previously normal tissue or structure (e.g. amniotic band syndrome)
6) Malformation - Intrinsic disruption; occurs during embryonic period (wks 3-8)
7) Sequence - Abnormalities result from single primary embryologic event (e.g. oligohydramnios leading to Potter Sequence)
Teratogens
Most susceptible in wks 3-8 of pregnancy. Before week 3, “all or none” effects. After week 8, growth and function affected.
Medications that are teratogens
1) ACE Inhibitors - Renal damage
2) Alkylating agents - Absence of digits, multiple anomalies
3) Aminoglycosides - CN8 toxicity
4) Carbamazepine - Facial dysmorphism, developmental delay, neural tube defects, phalanx/fingernail hypoplasia
5) Diethylstilbestrol (DES) - Vaginal clear cell adenocarcinoma, congenital Mullerian anomalies
6) Folate antagonists - Neural tube defects
7) Isotretinoin - Multiple severe birth defects (contraception mandatory)
8) Lithium - Ebstein anomaly (atrialized RV)
9) Methimazole - Aplasia cutis congenita
10) Phenytoin - Fetal hydantoin syndrome - cleft palate, cardiac defects, phalanx/fingernail hypoplasia
11) Tetracyclines - Discolored teeth
12) Thalidomide - Limb defects (phocomelia, micromelia - flipper limbs)
13) Valproate - Inhibition of maternal folate absorption leads to neural tube defects
14) Warfarin - Bone deformities, fetal hemorrhage, abortion, ophthalmologic abnormalities (Use heparin - doesn’t cross placenta)
Substance abuse/teratogens
1) Alcohol - Common cause of birth defects and intellectual disability; fetal alcohol syndrome
2) Cocaine - Abnormal fetal growth and fetal addiction; placental abruption
3) Smoking (Nicotine, CO) - Low birth weight (leading cause in developed countries), preterm labor, placental problems, IUGR, ADHD - Nicotine leads to vasoconstriction. CO leads to impaired O2 delivery
Other teratogens
1) Iodine (lack or excess) - Congenital goiter or hypothyroidism (cretinism)
2) Maternal diabetes - Caudal regression syndrome (anal atresia to sirenomelia), congenital heart defects, neural tube defects
3) Vitamin A (excess) - Extremely high risk for spontaneous abortions and birth defects (cleft palate, cardiac)
4) X-Rays - Microcephaly, intellectual disability - minimized by lead shielding
Fetal Alcohol Syndrome
Leading cause of intellectual disability in the US.
Newborns of alcohol-consuming mothers have higher incidence of congenital abnormalities, including pre and postnatal developmental retardation, microcephaly, facial abnormalities (smooth philtrum, hypertelorism), limb dislocation, heart defects.
Heat-lung fistulas and holoprosencephaly in most severe form. Mechanism is failure of cell migration.
Placenta
Primary site of nutrient and gas exchange between mother and fetus
Fetal component
1) Cytotrophoblast - inner layer of chorionic villi. Cytotrophoblast makes Cells.
2) Syncytiotrophoblast - Outer layer of chorionic villi; secretes hCG (structurally similar to LH; stimulates corpus luteum to secrete progesterone during first trimester)
Lacks MHC-1 expression leading to lower chance of attack by maternal immune system
Maternal component
1) Decidua basalis - Derived from endometrium. Maternal blood in lacunae
Umbilical cord
Umbilical arteries (2) - return deoxygenated blood from fetal internal iliac arteries to placenta
Umbilical vein (1) - supplies oxygenated blood from placenta to fetus; drains into IVC via liver or via ductus venosus
Single umbilical artery (2 vessel cord) is associated with congenital and chromosomal abnormalities
Umbilical arteries and vein are derived from allantois
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 yolk sac.
Patent Urachus - total failure to obliterate leads to urine discharge from umbilicus
Urachal cyst - Partial failure of urachus to obliterate; fluid-filled cavity lined with uroepithelium, between umbilicus and bladder. Can lead to infection, adenocarcinoma
Vesicourachal diverticulum - Slight failure to obliterate leads to outpouching of bladder
Vitelline duct
7th week - obliteration of vitelline duct (omphalo-mesenteric duct), which connects yolk sac to midgut lumen
Vitelline fistula - vitelline duct fails to close leading to meconium discharge from umbilicus
Mechel diverticulum - partial closure of vitelline duct, with patent portion attached to ileum (true diverticulum). May have heterotopic gastric and/or pancreatic tissue causing melena, hematochezia, abdominal pain.
Aortic arch derivatives
Develop into arterial system
1) Part of maxillary artery (branch of external carotid)
2) Stapedial artery and hyoid artery (Second = Stapedial)
3) Common Carotid artery and proximal part of internal Carotid artery (C is 3rd letter)
4) On left, aortic arch; On right, proximal part of R Subclavian artery
6) Proximal part of pulmonary arteries and (on left only) ductus arteriosis)
Branchial apparatus
Also called pharyngeal apparatus. Composed of branchial clefts, arches, pouches
Brancial clefts = derived from ectoderm. Also called grooves
Arches = derived from mesoderm (muscles, arteries) and neural crest (bones, cartilage)
Pouches = derived from endoderm
Branchial cleft derivatives
1st cleft = external auditory meatus
2-4 = temporary cervical sinuses, which are obliterated by proliferation of 2nd arch mesenchyme
Persistent cervical sinus leads to branchial cleft cyst within lateral neck
1st Branchial Arch
Mechel cartilage: Mandible, Malleus, incus, spheno-Mandibular ligament
Muscles of Mastication (temporalis, Masseter, lateral, and Medial pterygoids), Mylohyoid, anterior belly of digastric, tensor tympani, tensor veli palatini
CN V2 and V3 (chew)
Treacher Collins Syndrome - 1st arch neural crest fails to migrate leading to mandibular hypoplasia, facial abnormalities
2nd Branchial Arch
Reichert cartilage: Stapes, Styloid process, lesser horn of hyoid, Stylohyoid ligament
Muscles of facial expression, Stapedius, Stylohyoid, platySma, posterior belly of digastric
CN VII (facial expression - smile)
Congenital Pharyngocutaneous fistula - persistence of cleft and pouch leads to fistula between tonsilar area and lateral neck
3rd Branchial Arch
Cartilage: greater horn of hyoid
Stylopharyngeous (think of styloPHARYNGEOUS innervated by glossoPHARNYGEAL nerve)
CN IX (stylopharyngeous swallows stylishly)
4th-6th Branchial Arches
Cartilage: thyroid, cricoid, arytenoids, corniculate, cuneiform
4th: most pharyngeal constrictors; cricothyroid, levator veli palatini
6th: All intrinsic muscles of larynx except cricothyroid
4th: CN X (superior laryngeal branch) - swallow
6th: CN X (recurrent laryngeal branch) - speak
Arches 3 and 4 form posterior 1/3 of tongue; arch 5 makes no major developmental contributions
1st Branchial pouch
Develops into middle ear cavity, eustachian tube, mastoid air cells
1st pouch contributes endoderm-lined structures to ear
2nd Branchial pouch
Develops into epithelial lining of palatine tonsil
3rd Branchial pouch
Dorsal wings - develop into inferior parathyroids
Ventral wings - develop into thymus
3rd pouch contributes to 3 structures (thymus, L and R inferior parathyroids)
3rd pouch structures end up below 4th pouch structures
4th Branchial pouch
Dorsal wings - develop into superior parathyroids
DiGeorge Syndrome
Aberrant development of 3rd and 4th pouches leads to T cell deficiency (thymic aplasia) and hypocalcemia (failure of parathyroid development)
Associated with cardiac defects (conotruncal anomalies)
MEN 2A
Mutation of germline RET (neural crest cells):
Adrenal medulla (pheochromocytoma)
Parathyroid (tumor): 3rd/4th pharyngeal pouch
Parafollicular cells (medullary thyroid cancer): derived from neural crest cells; associated with 4th/5th pharyngeal pouches
Cleft Lip and palate
Lip - failure of fusion of the maxillary and medial nasal processes (formation of primary palate)
Palate - failure of fusion of the 2 lateral palatine processes with the nasal septum and/or median palate process (formation of secondary palate)
Cleft lip and cleft palate have 2 distinct etiologies, but often occur together.
Genital embryology
1) Female - default development. Mesonephric duct degenerates and paramesonephric duct develops
2) Male - SRY gene on Y chromosome - produces testis-determining factor leading to testes development
- Sertoli cells secrete Mullerian inhibitory factor (MIF) that suppresses development of paramesonephric ducts.
- Leydig cells secrete androgens that stimulate development of mesonephric ducts
3) Paramesonephric (Mullerian) duct - Develops into female internal structures - fallopian tubes, uterus, upper portion of vagina (lower portion from urogenital sinus)
Mullerian agenesis - may present as primary amenorrhea (due to a lack of uterine development) in females with fully developed secondary sexual characteristics (functional ovaries)
4) Mesonephric (Wolffian) Duct - Develops into male internal structures (except prostate) - SEED - Seminal vesicles, Epididymis, Ejac duct, Ductus deferens.
In females, remnant of mesonephric duct becomes the Gartner duct
SRY Gene
1) No sertoli cells or lack of MIF leads to development of both male and female internal genitalia and male external genitalia
2) 5a-reductase deficiency - inability to convert testosterone into DHT leading to male internal genitalia, ambiguous external genitalia until puberty (when higher testosterone levels cause masculinization)
Uterine (Mullerian Duct) abnormalities
1) Septate uterus - common anomaly vs normal uterus. Incomplete resorption of septum. Lower fertility. Treat with septoplasty.
2) Bicornuate uterus - Incomplete fusion of Mullerian ducts. higher risk of complicated pregnancy
3) Uterus didelphys - Complete failure of fusion leads to double uterus, vagina, and cervix. Pregnancy possible
Male/female genital homologs
Estrogen takes things to their female form. Dihydrotestosterone takes things to their male form.
1) Glans Penis/Glans Clitoris = Genital tubercle
2) Corpus Cavernosum and spongiosum/Vestibular Bulbs = Gential tubercle
3) Bulbourethral glands (Cowper)/ Greater vestibular glands (Bartholin) = Urogenital sinus
4) Prostate gland/Urethral and paraurethral glands (Skene) = Urogenital sinus
5) Ventral shaft of penis (penile urethra)/Labia minora = Urogenital folds
6) Scrotum/Labia majora = Labioscrotal swelling
Congenital penile abnormalities
1) 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
Hypo is below
2) Epispadias - Abnormal opening of penile urethra on dorsal surface of penis due to faulty positioning of genital tubercle
Exstrophy of the bladder is associated with Epispadias.
Descent of testes and ovaries
1) Gubernaculum (band of fibrous tissue)
Male remnant = Anchors testes within scrotum
Female remnant = Ovarian ligament + Round lig of uterus
2) Processus vaginalis (evagination of peritoneum)
Male remnant = Forms tunica vaginalis
Female remnant = Obliterated
Venous drainage of gonads
Left ovary/testes - left gonadal vein - left renal vein - IVC
Right ovary/testes - right gonadal vein - IVC
Left takes Longest way. Bc the left spermatic vein enters the left renal vein at a 90 degree angle, flow is less laminar on left than on the right. This leads to left venous pressure being higher than right venous pressure. Also, varicocele is more common on the LEFT.
Lymphatic drainage of gonads
Ovaries/testes - para-aortic lymph nodes.
Distal vagina/vulva/scrotum - superficial inguinal nodes
Proximal vagina/uterus - obturator, external iliac, and hypogastric nodes
Infundibulopelvic ligament
Contains ovarian vessels
Connects ovaries to lateral pelvic wall
Ligate these vessels during oophorectomy to avoid bleeding.
The URETER runs retroperitoneally, close to gonadal vessels. So the URETER is at risk of injury during ligation of uterine vessels
Cardinal ligament
Connects cervix to side wall of pelvis
Contains uterine vessels
URETER is at risk of injury during ligation of uterine vessels during hysterectomy
Round ligament of uterus
Connects uterine fundus to labia majora
Derivative of gubernaculum. Travels through round injuinal 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
Mesosalpinx, mesometrium, and mesovarium comprise this ligament
Ovarian ligament
Connects medial pole of ovary to lateral uterus
Derivative of gubernaculum
Female repro epithelial histology
1) Vagina = Stratified squamous epithelium, nonkeratinized
2) Ectocervix = Stratified squamous epithelium, nonkeratinized
3) Transformation zone = Squamocolumnar junction (most common area for cervical cancer)
4) Endocervix = Simple columnar epithelium
5) Uterus = Simple columnar epithelium with long tubular glands in follicular phase; coiled glands in luteal phase
6) Fallopian tube = Simple columnar epithelium
7) Ovary, outer surface = Simple cuboidal epithelium (germinal epithelium covering surface of ovary)
Autonomic innervation of male sexual response
1) Erection - Parasympathetic (pelvic nerve)
NO leads to increased cGMP leading to smooth muscle relaxation leading to vasodilation - proerectile.
NE leads to increased intracellular Ca causing smooth muscle contraction leading to vasoconstriction - antierectile
2) Emission - Sympathetic (hypogastric nerve)
3) Ejaculation - visceral and somatic nerves (pudendal nerve)
PDE5 inhibitors (sildenafil) lower cGMP breakdown.
Urethral injury
Suspect if blood is seen at urethral meatus
Posterior urethra - membranous urethra prone to injury from pelvic fracture; bulbar urethra susceptible to blunt force. Injury can cause urine to leak into retropubic space
Anterior urethra - penile urethra at risk of damage due to perineal straddle injury. Can cause urine to leak beneath deep fascia of Buck. If fascia is torn, urine escapes into superficial perineal space.
What cells are within the seminiferous tubules?
Spermatogonia (germ cells)
Sertoli Cells (non-germ cells)
Leydig Cells (endocrine cells)
Spermatogonia (germ cells)
Maintain germ pool and produce primary spermatocytes
Line the seminiferous tubules
Sertoli cells
Non-germ cells
1) Secrete inhibin which inhibits FSH
2) Secrete androgen-binding protein. This maintains local levels of testosterone.
3) Tight junctions between adjacent Sertoli cells form blood-testis barrier. This isolates gametes from autoimmune attack.
4) Support and nourish developing spermatazoa
5) Regulates spermatogenesis
6) Produces MIF
7) Temperature sensitive - lower sperm production and lower inhibin when temperature is higher.
8) Lines seminiferous tubules
9) Converts testosterone and androtestosterone to estrogen via aromatase
Sertoli cells Support Sperm Synthesis
Homolog of female granulosa cells.
Estrogen
1) Source: Ovary (17B-estradiol), placenta (estriol), adipose tissue (estrone via aromatization)
2) Potency - estradiol > estrone > estriol
3) Function - Development of genitalia and breast, female fat distribution
Growth of follicle, endometrial proliferation, increased myometrial excitability
Upregulation of estrogen, LH, and progesterone receptors; feedback inhibition of FSH and LH, then LH surge; stimulation of prolactin secretion
Higher transport proteins, SHBG; Raises HDL; Lowers LDL
In pregnancy, there is a 50-fold increase in estradiol and estrone. 1000 fold increase in estriol (indicator of fetal well-being)
Estrogen receptors expressed in cytoplasm; translocate to nucleus when bound by estrogen.
Progesterone
1) Source: Corpus luteum, placenta, adrenal cortex, testes
2) Function: Stimulation of endometrial glandular secretions and spiral artery development.
Maintenance of pregnancy
Lowers myocardial excitability
Production of thick cervical mucus, which inhibits sperm entry into uterus
Increased body temp
Inhibition of gonadotropins (LH, FSH)
Uterine smooth muscle relaxation (preventing contractions)
Lowers estrogen receptor expression
Prevents endometrial hyperplasia
Fall in progesterone after delivery disinhibits prolactin leading to lactation. Increased progesterone is indicative of ovulation.
Tanner stages of development
Tanner stage is assigned independently to genitalia, pubic hair, and breast (You can have tanner stage 2 genitalia and stage 3 pubic hair)
I - Childhood (prepubertal)
II - Pubic hair appears (pubarche); breast buds (thelarche)
III - Pubic hair darkens and becomes curly; penis size/length increases; breasts enlarge
IV - Penis width increases, darker scrotal skin, development of glans; raised areolae
V - Adult; areolae are no longer raised
Menstrual cycle irregularities
Dysmenorrhea: Pain with menses; often associated with endometriosis
Oligomenorrhea: > 35 day cycle
Polymenorrhea: 80 mL blood loss or > 7 days of menses
Menometrorrhagia: Heavy, irregular menstruation
Oogenesis
Primary oocytes begin meiosis I during fetal life and complete meiosis I just prior to ovulation.
Meiosis I is arrested in prophase I for years until ovulation (primary oocytes)
Meiosis II is arrested in metaphase II until fertilization (secondary oocytes)
If fertilization does not occur within 1 day, the secondary oocyte degenerates
Ovulation
Increased estrogen, Increased GnRH receptors on anterior pituitary
Estrogen surge then stimulates LH release leading to ovulation (rupture of follicle)
Increased temperature (progesterone induced)
Mittelschmerz - transient mid-cycle ovulatory pain; classically associated with peritoneal irritation (follicular swelling/rupture, fallopian tube contraction). Can mimic appendicitis
Pregnancy
Fertilization most commonly occurs in upper end of fallopian tube (the ampulla). Occurs within 1 day of ovulation.
Implantation within the wall of the uterus occurs 6 days after fertilization. Syncytiotrophoblasts secrete hCG, which is detectable in blood 1 week after conception and on home test in urine 2 weeks after conception.
Lactation
After labor, the decrease in progesterone and estrogen disinhibits lactation. Suckling is required to maintain milk production, since increased nerve stimulation leads to higher oxytocin and prolactin.
Prolactin - induces and maintains lactation and lowers reproductive function
Oxytocin - assists in milk letdown; also promotes uterine contractions
Breast milk is the ideal nutrition for infants less than 6 months of age. Contains maternal immunoglobulins (conferring passive immunity; mostly IgA), macrophages, lymphocytes. Breast milk reduces infant infections and is associated with lower risk for child to develop asthma, allergies, diabetic mellitus, and obesity. Exclusively breastfed infants require Vitamin D supplementation
Breastfeeding lowers maternal risk of breast and ovarian cancer and facilitates mother-child bonding.
hCG
Source: Syncytiotrophoblast of placenta
Function: Maintains corpus luteum (and thus progesterone) for first 8-10 weeks of pregnancy by acting like LH (otherwise no luteal cell stimulation would lead to abortion)
After 8-10 weeks, placenta synthesizes its own estriol and progesterone and corpus luteum degenerates
used to detect pregnancy bc it appears early in urine
has identical alpha subunit as LH, FSH, TSH. Beta subunit is unique (pregnancy tests detect B subunit).
hCG is elevated in multiple gestations, hydatiform moles, choriocarcinomas, and Down Syndrome
hCG is lowered in ectopic/failing pregnancy, Edward Syndrome, and Patau Syndrome.
Menopause
Lower estrogen production due to age-linked decline in number of ovarian follicles. Average age at onset is 51 years (earlier in smokers)
Usually preceded by 4-5 years of abnormal menstrual cycles. Sources of estrogen (estrone) after menopause becomes peripheral conversion of androgens, increased androgens leads to hirsutism
Much higher FSH is specific for menopause (loss of negative feedback on FSH due to lower estrogen levels)
Hormonal changes: Lower estrogen, Much higher FSH, High LH (no surge), High GnRH
Menopause causes HAVOCS: Hot flashes, Atrophy of the Vagina, Osteoporosis, Coronary artery disease, Sleep disturbances
Menopause before 40 can indicate premature ovarian failure.
Spermatogenesis
Spermatogenesis begins at puberty with spermatogonia. Full development takes 2 months. Occurs in seminiferous tubules.
Produces spermatids that undergo spermiogenesis (loss of cytoplasmic contents, gain of acrosomal cap) to form mature spermatozoon.
Gonium is going to be a sperm. Zoon is Zooming to egg.
Androgens
Testosterone, Dihydrotestosterone (DHT), Androstenedione
1) Source: DHT and testosterone (testis), androstenedione (adrenal)
Potency: DHT > testosterone > androstenedione
2) Function:
Testosterone
- Differentiation of epididymis, vas deferens, seminal vesicles (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
Testosterone is converted to DHT by 5a-reductase, which is inhibited by Finasteride
In the male, androgens are converted to estrogen by cytochrome P450 aromatase (primarily in adipose tissue and testis)
Aromatase is the key enzyme in conversion of androgens to estrogen.
Exogenous testosterone leads to inhibition of hypothalamic-pit-gonadal axis. This leads to lower intratesticular testosterone leading to lower testicular size causing azoospermia
Klinefelter Syndrome
(male 47, XXY)
Tesicular atrophy, eunucleoid body shape, tall long extremities, female hair distribituion, may present with developmental delay. Inactivated X chromosome (barr body) is present. Common cause of hypogonadism in infertility work up.
Dysgenesis of seminiferous tubules leads to lower inhibin and increased FSH.
Abnormal Leydig cell function can cause lower testosterone and higher LH leading to higher estrogen.
Turner Syndrome
(Female, 45 XO)
short stature (if untreated), ovarian dysgenesis (streak ovary), shield chest, bicuspid aortic valve, lymphatic defects (webbed neck or lymphedema in hands and feet), horseshoe kidney, most common cause of primary amenorrhea. No Barr body.
Menopause before menarche.
Lower estrogen leads to higher LH and FSH.
Can result from mitotic or meiotic error
Can be complete monosmy (45 XO) or mosaicism (45 XO/46 XX)
Pregnancy possible in some cases (oocyte donation, exogenous estradiol 17B and progesterone)
Double Y males
Male XYY
Phenotypically normal (usually undiagnosed), very tall. Random nondisjunction event (paternal meiosis II); noninherited; normal fertility
May be associated with severe acne, learning disability, autism spectrum disorders
True hermaphroditism
46 XX or 47 XXY
Also called ovotesticular disorder of sex development. Both ovarian and testicular tissue present (ovotestis); ambiguous genitalia
Diagnosing disorders of sex hormones
High test and LH = defective androgen receptor
Low test and LH = hypogonadotropic hypogonadism
High Test, low LH = Testosterone-secreting tumor or exogenous steroids
Low Test, high LH = primary hypogonadism
Other disorders of sex development
Disagreement between the phenotypic (external genitalia) and gonadal (testes vs ovaries) sex. Includes terms pseudohermaphrodite, hermaphrodite, and intersex
1) Female pseudo-hermaphrodite (XX) - Ovaries present, but external genitalia are virilized or ambiguous. Due to excessive and inappropriate exposure to androgenic steroids during early gestation (e.g. congenital adrenal hyperplasia or exogenous administration of androgens during pregnancy)
2) Male pseudo-hermaphrodite (XY) - Testes present, but external genitalia are female or ambiguous. Most common form is androgen insensitivity syndrome (testicular feminization)
Aromatase deficiency
Inability to synthesize estrogens from androgens. Masculinization of female (46 XX) infants (ambiguous genitalia), higher serum testosterone and androstenedione.
Can present with maternal virilization during pregnancy (fetal androgens cross the placenta)
Androgen insensitivity syndrome (46 XY)
Defect in androgen receptor resulting in normal-appearing female; female external genitalia with scant sex sexual hair, rudimentary vagina; uterus and fallopian absent.
Patients develop testes (often found in labia majora; surgically removed to prevent malignancy)
Higher testosterone, estrogen, LH (vs sex chromosome disorders)
5a-reductase deficiency
Autosomal recessive
Sex limited to genetic males (46 XY). Inability to convert testosterone to DHT.
Ambiguous genitalia until puberty, when increased testosterone causes masculinization/increased growth of external genitalia
Testosterone/estrogen levels are normal
LH is normal or elevated
Internal genitalia are normal
Kallmann Syndrome
Failure to complete puberty; a form of hypogonadotropic hypogonadism.
Defective migration of GnRH cells and formation of olfactory bulb
Lower synthesis of GnRH in the hypothalamus; anosmia
Low GnRH, FSH, LH, Testosterone
Infertility (low sperm count in males; amenorrhea in females)
Gestational HTN (pregnancy-induced HTN)
BP > 140/90 after 20th week. No pre-existing HTN.
No proteinuria or end organ damage.
Tx is antihypertensives (labetolol, hydralazine, nifedipine) deliver 37-39 wks
Preeclampsia
New onset HTN with proteinuria or end-organ dysfunction after wk 20. May lead to eclampsia (+ seizures).
Caused by abnormal placental spiral arteries leading to endothelial dysfunction, vasoconstriction and ischemia.
Higher in pre-existing conditions like HTN, diabetes, chronic renal disease, autoimmune disorders
Complications: Placental abruption, coagulopathy, renal failure, uteroplacental insufficiency, eclampsia
Tx with the antihyperensives plus IV mg sulfate (prevents seisures). Definitive tx is delivery of fetus
Eclampsia
Preeclampsia + maternal seizures
Maternal death due to stroke, intracranial hemorrhage, or ARDS
Tx = IV MgSO4, antihypertensives, immediate delivery
HELLP Syndrome
Hemolysis
Elevated Liver Enzymes
Low Platelets
A manifestation of severe preeclampsia. Blood smear shows schistocytes. Can lead to hepatic subcapsular hematomas leading to rupture leading to severe hypotension
Tx = immediate delivery
Hydatidiform mole
Cystic swelling of chorionic villi and proliferation of chorionic epithelium (only trophoblast)
Associated with theca-lutein cysts, hyperemesis gravidarum, hyperthyroidism
Tx = dilation and curettage and methotrexate. Monitor B-hCG
Complete vs Partial mole
Complete Mole
1) karyotype - 46XX; 46XY
2) B-hCG - wayyyy elevated
3) Uterine size - larger
4) Conversion to choriocarcinoma = 2%
5) Fetal parts? No
6) Components - Most commonly enucleated egg + single sperm (subsequently duplicates paternal DNA)
7) Risk of complications - 15-20% malignant trophoblastic disease
8) Symptoms = First trimester bleeding, enlarged uterus, hyperemesis, pre-eclampsia, hyperthyroidism
9) Imaging = “Honeycombed” uterus or “clusters of grapes,” “snowstorm” on US
Partial Mole
1) karyotype - 69XXX, 69XXY, 69XYY
2) B-hCG - elevated
3) Uterine size - normal
4) Conversion to choriocarcinoma = rare
5) Fetal parts? Yes (partial = parts)
6) Components - 2 sperm + 1 egg
7) Risk of complications - Low risk of malignancy
8) Symptoms = Vaginal bleeding, abdominal pain
9) Imaging = Fetal parts
Placental abruption (abruption placentae)
Premature separation (partial or complete) of placenta from uterine wall before delivery of infant
Risk factors: trauma (motor vehicle accident), smoking, HTN, preeclampsia, cocaine abuse
Presentation: abrupt, painful bleeding (concealed or apparent) in third trimester; possible DIC, maternal shock, fetal distress. Life threatening for mother and fetus
Placenta accreta/increta/percreta
Defective decidual layer leads to abnormal attachment and separation after delivery. Risk factors = prior C Section, inflammation, placenta previa. 3 types distinguishable by the depth of presentation
1) Accreta - placenta attaches to myometrium without penetrating it; most common type
2) Increta - placenta penetrates into myometrium
3) Percreta - placenta penetrates (perforates) through myometrium and into uterine serosa (invades entire uterine wall); can result in placental attachment to rectum or bladder.
Presentation - often detected on US prior to delivery. No separation of placenta after delivery leads to postpartum bleeding (can cause Sheehan Syndrome)
Placenta previa
Attachment of placenta to lower uterine segment over (or
Vasa previa
Fetal vessels run over, or in close proximity to, cervical os. May result in vessel rupture, exsanguination, fetal death
Presents with triad of membrane rupture, painless vaginal bleeding, fetal bradycardia (
Retained placental tissue
May cause postpartum hemorrhage
Increased risk of infection
Ectopic pregnancy
Most often in ampulla of fallopian tube (shows 10mm embryo in oviduct at 7 weeks gestation)
Suspect with history of amenorrhea, lower than expected rise in hCG based on dates, and sudden lower abdominal pain; confirm with US
Often clinically mistaken for appendicitis
Pain with or without bleeding.
Risk factors: History of infertility Salpingitis (PID) Ruptured appendix Prior tubal surgery
Polyhydramnios
Too much amniotic fluid ( > 1.5-2L); associated with fetal malformations (esophageal/duodenal atresia; anencephaly; both result in inability to swallow amniotic fluid), maternal diabetes, fetal anemia, multiple gestations
Oligohydramnios
Too little amniotic fluid (
Gynecologic tumor epidemiology
Incidence (US) - endometrial > ovarian > cervical
Cervical cancer is more common worldwide due to lack of screening or HPV vaccination
Worst prognosis - ovarian > cervical > endometrial
Vaginal tumors
1) SCC - usually secondary to cervical SCC; primary vaginal carcinoma rare
2) Clear cell adenocarcinoma - affects women who had exposure to DES in utero
3) Sarcoma botryoides (rhabdomyosarcoma variant) - affects girls
Cervical pathology - dysplasia and carcinoma in situ
Disordered epithelial growth; begins at basal layer of squamocolumnar junction (transition zone) and extends outward
Classified as CIN 1, CIN 2, or CIN 3 (severe dysplasia or carcinoma in situ), depending on extent of dysplasia.
Associated with HPV 16 and HPV 18, which produce both the E6 gene product (inhibits p53 suppressor gene) and E7 gene product (inhibits RB suppressor gene)
May progress slowly to invasive carcinoma if left untreated. Typically asymptomatic (detected on Pap smear) or presents as abnormal vaginal bleeding (often postcoital)
Risk factors: Multiple sexual partners (#1), smoking, starting sexual intercourse at young age, HIV infection
Cervical pathology - Invasive carcinoma
Often squamous cell carcinoma. Pap smear can catch cervical dysplasia (koilocytes) before it progresses to invasive carcinoma. Diagnose via colposcopy and biopsy
Lateral invasion can block ureters leading to renal failure
Premature ovarian failure
Premature atresia of ovarian follicles in women of reproductive age. Patients present with signs of menopause after puberty but before age 40
Low estrogen
High LH
High FSH
Most 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
PCOS (Stein-Leventhal Syndrome)
Hyperinsulinemia and/or insulin resistance hypothesized to alter hypothalamic hormonal feedback response. This leads to higher LH:FSH, higher androgens from theca interna cells, lower rate of follicular maturation.
This causes unruptured follicles (cysts) + anovulation.
Common cause of subfertility in women.
Enlarged, bilateral cystic ovaries; presents with amenorrhea/oligomenorrhea, hirsutism, acne, subfertility.
Associated with obesity. Increased risk of endometrial cancer secondary to unopposed estrogen from repeated anovulatory cycles.
Tx = weight reduction, OCPs (oral contraceptive pills), clomiphene citrate, ketoconazole, spironolactone
Ovarian cysts
1) Follicular cyst - Distention of unruptured graafian follicle. May be associated with hyperestrogenism, endometrial hyperplasia. Most common ovarian mass in young women
2) Theca-lutein cyst - often bilateral/multiple. Due to gonadotropin stimulation. Associated with choriocarcinoma and hydatidiform moles.
Ovarian neoplasms
Most common adnexal mass in women > 55. Can be benign or malignant. Arise from surface epithelium, germ cells, or sex cord stromal tissue
Majority of malignant tumors are epithelial (serous cystadenocarcinoma most common).
Risk increases with advanced maternal age, infertility, endometriosis, PCOS, genetic predisposition (BRCA-1 or BRCA-2 mutation, hereditary nonpolyposis colorectal cancer, strong family history)
Risk decreases with previous pregnancy, history of breastfeeding, OCPs, tubal ligation.
Presents with adnexal mass, abdominal distension, bowel obstruction, pleural effusion.
Diagnose surgically. Monitor progression by measuring CA 125 levels (not good for screening)
Serous cystadenoma
Most common ovarian neoplasm. Lined with fallopian tube-like epithelium. Often bilateral
Benign
Mucinous cystadenoma
Benign ovarian neoplasm
Multiloculated, large. Lined by mucus-secreting epithelium
Endometrioma
Benign ovarian neoplasm
Endometriosis (ectopic endometrial tissue) within ovary with cyst formation
Presents with pelvic pain, dysmenorrhea, dyspareunia; symptoms may vary with menstrual cycle.
“Chocolate cyst” - endometrioma filled with dark, reddish-brown blood. Complex mass on US
Mature cystic teratoma (Dermoid cyst)
Benign ovarian neoplasm
Germ cell tumor, most common ovarian tumor in women 20-30 years old. Cystic mass containing elements from all 3 germ layers (teeth, hair, sebum)
Can present with pain secondary to ovarian enlargement or torsion. Can also contain functional thyroid tissue and present as hyperthyroidism (struma ovarii)
Brenner Tumor
Benign ovarian neoplasm
Looks like bladder. Solid tumor that is pale yellow-tan and appears encapsulated. “Coffee bean” nuclei on H&E stain
Fibromas
Benign ovarian neoplasm
Bundles of spindle-shaped fibroblasts.
Meigs syndrome - triad of ovarian fibroma, ascites, hydrothorax. “Pulling” sensation in groin
Thecoma
Benign ovarian neoplasm
Like granulosa cell tumors, may produce estrogen
usually presents as abnormal uterine bleeding in a postmenopausal woman
Immature teratoma
Malignant ovarian neoplasm
Aggressive, contains fetal tissue, neuroectoderm. Immature teratoma is most typically represented by immature/embryonic-like neural tissue. Mature teratoma are more likely to contain thyroid tissue
Granulosa cell tumor
Malignant ovarian neoplasm
Most common malignant stromal tumor. Predominantly women in their 50s
Often produces estrogen and/or progesterone and presents with abnormal uterine bleeding, sexual precocity (in pre-adolescents), breast tenderness
Histology shows Call-Exner Bodies (granulosa cells arranged haphazardly around collections of eosinophilic fluid, resembling primordial follicles).
Serous cystadenocarcinoma
Malignant ovarian neoplasm
Most common ovarian neoplasm, frequently bilateral.
Psammoma bodies
Mucinous cystadenocarcinoma
Malignant ovarian neoplasm
Pseudomyoma peritonei-intraperitoneal accumulation of mucinous material from ovarian or appendiceal tumor
Dysgerminoma
Malignant ovarian neoplasm
Most common in adolescents. Equivalent to male seminoma but rarer
1% of all ovarian tumors
30% of germ cell tumors
Sheets of uniform “fried egg” cells.
hCG, LDH = tumor markers
Choriocarcinoma
Malignant ovarian neoplasm
Rare; can develop during or after pregnancy in mother or baby
Malignancy of trophoblastic tissue (cytotrophoblasts, syncytiotrophoblasts); NO chorionic villi present.
Increased frequency of bilateral/multiple theca-leutin cysts.
Presents with abnormal high B-hCG, SOB, hemoptysis
Hematogenous spread to lungs. Very responsive to chemotherapy
Yolk sac (endodermal sinus) tumor
Malignant ovarian neoplasm
Aggressive, in ovaries or testes (boys) and sacrococcygeal area in young children.
Most common tumor in male infants. Yellow, friable (hemorrhagic), solid mass.
50% have schiller-Duval bodies (resemble glomeruli)
AFP = tumor marker
Krukenberg tumor
Malignant ovarian neoplasm
GI malignancy that metastasizes to ovaries - causes mucin-secreting signet cell adenocarcinoma
Polyp
Endometrial condition
Well-circumscribed collection of endometrial tissue within uterine wall. May contain smooth muscle cells. Can extend into endometrial cavity in the form of a polyp
Leiomyoma (Fibroid)
Endometrial condition
Most common tumor in females. Often presents with multiple discreet tumors. Increased incidence in blacks
Benign smooth muscle tumor; malignant transformation is rare.
Estrogen sensitive - tumor size increases with pregnancy and decreases with menopause.
Peak occurrence at 20-40 yrs old. May be asymptomatic, cause abnormal uterine bleeding, or result in miscarriage.
Severe bleeding may lead to iron deficiency anemia. Usually does not progress to leiomyosarcoma
Whorled pattern of smooth muscle bundles with well-demarcated borders
Adenomyosis
Endometrial condition
Extension of endometrial tissue (glandular) into uterine myometrium. Caused by hyperplasia of basal layer of endometrium. Presents with dysmenorrhea, menorrhagia, uniformly enlarged, soft, globular uterus
Tx = GnRH agonists, hysterectomy
Endometriosis
Endometrial condition
Non-neoplastic endometrial glands/stroma outside endometrial cavity. Can be found anywhere; most common sites are ovary (frequently bilateral), pelvis, peritoneum.
In ovary, appears as endometrioma (blood-filled “chocolate cyst”). May be due to retrograde flow, metaplastic transformation of multipotent cells, transportation of endometrial tissue via lymphatic system.
characterized by cyclic pelvic pain, bleeding, dysmenorrhea, dyspareunia, dyschezia (pain with defecation), infertility; normal size uterus
Tx = NSAIDs, OCPs, progestins, GnRH agonists, danazol, laparascopic removal
Endometrial hyperplasia
Endometrial condition
Abnormal endometrial gland proliferation usually caused by excess estrogen stimulation.
Increased risk for endometrial carcinoma.
Presents as postmenopausal vaginal bleeding. Risk factors include anovulatory cysts, hormone replacement therapy, polycystic ovarian syndrome, granulosa cell tumor
Endometrial carcinoma
Endometrial condition
Most common gynecologic malignancy
Peak at 55-65 yrs old.
Presents with vaginal bleeding. typically preceded by endometrial hyperplasia. Risk factors include prolonged use of estrogen without progestins, obesity, diabetes, HTN, nulliparity, late menopause, Lynch Syndrome
Fibroadenoma
Benign breast tumor
Small, mobile, firm mass with sharp edges
Most common tumor in those less than 35 years old
Increased size and tenderness with increased estrogen (pregnancy, prior to menstruation). Not a precursor to breast cancer
Intraductal papilloma
Benign breast tumor
Small tumor that grows in lactiferous ducts. Typically beneath areola
Serous or bloody nipple discharge. Slight (1.5-2x) increase in risk for carcinoma
Phyllodes tumor
Benign breast tumor
Large, bulky mass of connective tissue and cysts. “Leaf-like” projections
Most common in 5th decade
Some may become malignant
Proliferative Breast Disease
Most common cause of “breast lumps” from age 25 to menopause. Presents with premenstrual breast pain and multiple lesions, often bilateral. Fluctuation in size of mass. Usually does not indicate increased risk of carcinoma. Histologic types:
1) Fibrosis - hyperplasia of breast stroma
2) Cystic - fluid filled, blue dome. Ductal dilation
3) Sclerosing adenosis - increased acini and intralobular fibrosis. Associated with calcifications. Often confused with cancer. Higher risk (1.5-2x) of developing cancer
4) Epithelial hyperplasia - increase in number of epithelial cell layers in terminal duct lobule. Increased risk of carcinoma with atypical cells. Occurs in women over 30.
Lactational mass
During breastfeeding, increased risk of bacterial infection through cracks in the nipple
Staph aureus is most common pathogen.
Tx = dicloxacillin and continued breastfeeding
Fat necrosis
Benign, usually painless lump; forms as a result of injury to breast tissue. Abnormal calcifications on mammography; biopsy shows necrotic fat, giant cells
Up to 50% of patients may not report trauma
Gynecomastia
Breast enlargement in males. Results from hyperestrogenism (cirrhosis, testicular tumor, puberty, old age), Klinefelter, drugs (Spironolactone, Digoxin, Cimetidine, Alcohol, Ketoconazole)
“Some Drugs Create Awesome Knockers”
Physiologic (not pathologic) at birth, puberty, old age
Malignant breast tumors
Commonly postmenopausal. Usually arise from terminal duct lobular unit. Overexpression of estrogen/progesterone receptors or c-erbB2 (HER-2, an EGF receptor) is common; triple negative (ER-, PR-, HER2/Neu-) more aggressive
Type affects therapy and prognosis
Axillary lymph node involvement indicating metastasis is the single most important prognostic factor. Most often located in upper-outer quadrant of breast.
Risk Factors: Increased estrogen exposure, higher total number of menstrual cycles, older age at 1st live birth, obesity (high estrogen exposure in adipose tissue), BRCA1 and BRCA2 gene mutations, Blacks (higher risk for triple negative)
Ductal carcinoma in situ (DCIS)
Noninvasive
Fills ductal lumen. Arises from ductal atypia. Often seen early as microcalcifications on mammography
Early malignancy without basement membrane penetration
Comedocarcinoma
Noninvasive
Ductal, central necrosis. Subtype of DCIS
Paget Disease
Noninvasive
Results from underlying DCIS or invasive breast cancer. Eczematous patches on nipple.
Paget cells = large cells in epidermis with clear halo
Extramammary Paget Disease seen on vulva does not suggest underlying malignancy
Invasive ductal carcinoma
Firm, fibrous “rock hard” mass with sharp margins and small, glandular, duct-like cells
Grossly, see classic “stellate” infiltration
Worst and most invasive. Most common (75%) of all breast cancers
Invasive lobular carcinoma
Orderly row of cells (“Indian file”) due to lower E-cadherin expression
Often bilateral with multiple lesions in the same location
Medullary carcinoma
Invasive
Fleshy, cellular, lymphocytic infiltrate
Good prognosis
Inflammatory carcinoma
Invasive
Dermal lymphatic invasion by breast carcinoma. Peau-d-orange (breast skin resembles orange peel); neoplastic cells block lymphatic drainage
50% survival at 5 years
Often mistaken for mastitis or Paget Disease
Peyronie Disease
Abnormal curvature of penis due to fibrous plaque within tunica albuginea. Associated with ED.
Can cause pain, anxiety. Consider surgical repair once curvature stabilizes
Distinct from penile fracture (rupture of corpora cavernosa due to forced bending)
Priapism
Painful sustained erection lasting > 4 hours. Associated with trauma, sickle cell disease (sickled RBCs get trapped in vascular channels), medications (sildenafil, trazodone)
Treat immediately with corporal aspiration, intracavernosal phenylephrine or surgical decompression to prevent ischemia
Squamous cell carcinoma of Penis
More common in Asia, Africa, South America
Precursor in situ lesions: Bowen Disease (in penile shaft, presents as leukoplakia), erythroplasia of Queyrat (cancer of glans, presents as erythroplakia), Bowenoid papulosis (carcinoma in situ of unclear malignant potential, presenting as reddish papules).
Associated with HPV, lack of circumcision
Cryptorchidism
Undescended testis (1 or both); impaired spermatogenesis (since sperm develop best at temperatures below 37C); can have normal testosterone levels (Leydig cells are unaffected by temperature); associated with higher risk of germ cell tumors.
Prematurity increases risk of cryptorchidism.
Lower inhibin, high FSH, High LH
Testosterone is normal in unilateral, but reduced in bilateral.
Varicocele
Dilated veins in pampiniform plexus due to increased venous pressure; most common cause of scrotal enlargement in adult males; most often on left side because of increased resistance to flow from left gonadal vein drainage into left renal vein
Can cause infertility bc of increased temperature
“Bag of worms” on palpation; diagnose by US with Doppler; does not transilluminate
Tx = varicocelectomy, embolization by interventional radiologist
Extragonadal germ cell tumors
Arise in midline locations. In adults, most commonly in retroperitoneum, mediastinum, pineal, and suprasellar regions In infants and young children, sacrococcygeal teratomas are most common
Scrotal masses
Benign scrotal lesions present as testicular masses that can be transilluminated (vs solid testicular tumors)
1) Congenital hydrocele - common cause of scrotal swelling in infants due to incomplete obliteration of processus vaginalis
Transilluminating swelling
2) Acquired hydrocele - benign scrotal fluid collection usually secondary to infection, trauma, tumor. If bloody it leads to hematocele
3) Spermatocele - cyst due to dilated epididymal duct or rete testis
Paratesticular fluctuant nodule
Testicular germ cell tumors
95% of all testicular tumors. Most often occur in young men
Risk factors: cryptorchidism, Klinefelter.
Can present as a mixed germ cell tumor. DDx for testicular mass that does not transilluminate = cancer
Seminoma
Malignant; painless, homogeneous testicular enlargement; most common testicular tumor, most common in 3rd decade, never in infancy
Large cells in lobules with watery cytoplasm and “fried egg” appearance
Increased placental ALP. Radiosensitive. Late metastasis, excellent prognosis.
Yolk sac (endodermal sinus) tumor - testes
Yellow, mucinous. Aggressive malignancy of testes, analogus to ovarian yolk sac tumor
Schiller-Duval bodies resemble primitive glomeruli.
Increased AFP is highly characteristic
Most common testicular tumor in boys younger than 3
Choriocarcinoma - testes
Malignant, high hCG
Disordered syncytiotrophoblastic and cytotrophoblastic elements. Hematogenous metastasis to lungs and brain (may present with hemorrhagic stroke due to bleeding into metastasis)
May produce gynecomastia, symptoms of hyperthryoidism (hCG is structurally similar to LH, FSH, TSH)
Teratoma - males
Unlike in females, mature teratoma in adult males may be malignant. Benign in children.
High hCG and/or AFP in 50% of cases
Embryonal carcinoma - males
Malignant, hemorrhagic mass with necrosis; painful; worse prognosis than seminoma. Often glandular/papillary morphology.
“Pure” embryonal carcinoma is rare; most commonly mixed with other tumor types. May be associated with increased hCG and normal AFP levels when pure (AFP is elevated when mixed)
Testicular non-germ cell tumors
5% of all testicular tumors. Mostly benign
1) Leydig cell - Contains Reinke crystals (eosinophilic cytoplasmic inclusions); usually produce androgens leading to gynecomastia in men, precocious puberty in boys. Golden brown color
2) Sertoli cell - Androblastoma from sex cord stroma
3) Testicular lymphoma - Most common testicular cancer in older men. Not a primary cancer; arises from metastatic lymphoma to testes. Aggressive
Benign prostatic hyperplasia
Common in men older than 50. Characterized by smooth, elastic, firm nodular enlargement (hyperplasia not hypertrophy) of periurethral (lateral and middle) lobes, which compress the urethra into a vertical slit. Not premalignant
Often presents with increased frequency of urination, nocturia, difficulty starting and stopping urine stream, dysuria
May lead to distention and hypertrophy of bladder, hydronephrosis, UTIs.
Increased PSA
Tx = alpha1-antagonists (terazosin, tamsulosin), which cause relaxation of smooth muscle; 5a-reductase inhibitors (finasteride); PDE5 inhibitors
Prostatitis
Dysuria, frequency, urgency, low back pain. Acute: bacterial (E Coli); chronic: bacterial or abacterial (more common)
Prostatic adenocarcinoma
Common in men older than 50.
Arises most often from posterior lobe (peripheral zone) of prostate gland and is most frequently diagnosed by elevated PSA and subsequent needle core biopsies.
Prostatic acid phosphatase (PAP) and PSA are useful tumor markers (increased total PSA, with lower fraction of free PSA)
Osteoblastic metastases in bone may develop in late stages, as indicated by lower back pain and increased serum ALP and PSA
Leuprolide
GnRH analog with agonist properties when used in pulsatile fashion.
Antag when used in continuous fashion (down regulates GnRH receptors in pituitary leading to lower FSH/LH
Used in infertility (pulsatile), prostate cancer (continuous use following androgen receptor blockade), uterine fibroids or early puberty (continuous)
It can cause vomiting and nausea and is anti-androgen
Estrogens
Ethinyl estradiol, DES, mestranol
Bind estrogen receptors
For hypogonadism or ovarian failure, menstrual issues, hormone replacement therapy in postmenopausal women,
Use in men with androgen-dependent prostate cancer.
Higher risk of endometrial cancer, bleeding in postmenopausal women, higher risk of thrombi.
Don’t use in ER positive breast cancer or peeps with DVT history
Selective estrogen receptor modulators
1) Clomiphene: Anatagonist at estrogen receptors in hypothal. Prevents normal feedback inhibition and raises release of LH and FSH from pit, which stimulates ovulation. Treats infertility due to anovulation (PCOS). Can cause hot flashes, ovarian enlargement, multiple simultaneous pregnancies, visual problems
2) Tamoxifen: Antagonist at breast, agonist at bone, uterus. Increases risk of thromboembolic events and endometrial cancers. Treats and prevents recurrence of ER/PR positive breast cancer.
3) Raloxifene: Antag at breast, uterus, agonist at bone. No increased risk of endometrial cancers, used for osteoporosis.
Hormone replacement therapy
Used for relief or prevention of menopausal symptoms (hot flashes, vaginal atrophy), osteoporosis (higher estrogen, lower osteoclast activity)
Unopposed estrogen replacement therapy increases risk of endometrial cancer, so progesterone is added
Possible increased cardiovascular risk
Anastrozole/Exemestane
Aromatase inhibitors used in postmenopausal women with ER+ breast cancer
Progestins
Bind progesterone receptors, lower growth and increased vascularization of endometrium
Used in oral contraceptives and to treat endometrial cancer, abnormal uterine bleeding
Mifepristone (RU-486)
Competitively inhibits progestins at progesterone receptors to terminate a pregnancy.
Administered with misoprostol (PGE1).
Heavy bleding, GI effects (nausea, vomiting, anorexia), ab pain
Oral Contraceptives
Synthetic progestins, estrogen
Estrogen and progestin inhibit LH/FSH and prevent estrogen surge. No estrogen surge leads to no LH surge and no ovulation.
Progestins cause thickening of cervical mucous which limits access of sperm to uterus. They also inhibit endometrial proliferation so implantation becomes harder.
Don’t use if you are a smoker over age 35 (higher risk of CV events), if you have hx of thromboembolism and stroke or hx of estrogen-dependent tumor.
Terbutaline, ritodine
B2 agonists that relax the uterus; used to lower contraction frequency in women during labor
Danazol
Synthetic androgen that acts as partial agonist at androgen receptors
Use in endometriosis, hereditary angioedema
Toxicity
Weight gain, edema, acne, hirsutism, masculinization, lower HDL levels, hepatotoxicity
Testosterone, methyltestosterone
Agonists at androgen receptors
Treats hypogonadism and promotes development of secondary sex characteristics; stimulation of anabolism to promote recovery after burn or injury
Toxicity
Causes masculinization in females; lower intracellular testosterone in males by inhibiting release of LH (via negative feedback) leading to gonadal atrophy.
Premature closure of epiphyseal plates. Higher LDL, lower HDL
Antiandrogens
Testosterone uses 5a-reductase to become the more potent DHT
1) Finasteride - A 5a-reductase inhibitor (lowers conversion of testosterone to DHT). Useful in BPH and male-pattern baldness
2) Flutamide - A nonsteroidal competitive inhibitor at androgen receptors. Used for prostate carcinoma
3) Ketoconazole - Inhibits steroid synthesis (inhibits 17,20-desmolase)
4) Spironolactone - inhibits steroid binding, 17a-hydroxylase, and 17,20-desmolase
Ketoconazole and sprionolactone are used to treat polycystic ovarian syndrome to reduce androgenic symptoms. Both have side effects of gynecomastia and amenorrhea
Tamsulosin
Alpha1-antagonist used to treat BPH by inhibiting smooth muscle contraction. Selective for alpha1A,D receptors (found on prostate) vs vascular alpha1B receptors
Sildenafil
Vardenafil
Tadalafil
Inhibit PDE5 leading to higher cGMP, smooth muscle relaxation in corpus cavernosum, increased blood flow, penile erection
Use for ED
Toxicity
HA, flushing, dyspepsia, cyanopsia (blue-tinted vision). Risk of life-threatening hypotension in patients taking nitrates
Minoxidil
Direct arteriolar vasodilator
Use: Androgenetic alopecia; severe refractory HTN
