[Link]

me/USMLEEndopoint REPRODUCTIVE SYSTEM

EMBRYOLOGY
LIMB DEVELOPMENT = LIMB “PATTERNING”
 Limbs develop along three planes:
1) Proximal to distal: (humerus  radius  wrist.)
2) Dorsal-ventral axis: (dorsal: Extensors, Ventral: Flexors.)
3) Anterior-posterior axis:
 Anterior: towards head, radius and thumb.
 Posterior: ulna fingers.

PROXIMAL TO DISTAL DEVELOPMENT

 Depends on ―apical ectodermal ridge‖.
 Ectoderm overlying mesoderm.
 Area of limb bud formation.
 Removal: Limb stops growing.
 Influences underlying mesodermal growth.
 Key transcription factor: Fibroblast Growth Factor.

DORSAL-VENTRAL DEVELOPMENT
 Wnt-7 gene is a key for dorsal development.

ANTERIOR-POSTERIOR DEVELOPMENT
 Depends on ―zone of polarizing activity”
 Major signaling molecule: Sonic Hedgehog protein ―SHH‖.

Limb development plane Dependent area Important gene

Proximal to distal Apical ectodermal ridge Fibroblast growth factor gene.
Dorsal-ventral Apical ectodermal ridge Wnt-7 gene.
Anterior-posterior Zone of polarizing activity Sonic hedgehog gene.
Homeobox genes (also craniocaudal).

P a g e 1 | 158
[Link] REPRODUCTIVE SYSTEM

IMPORTANT GENES OF EMBRYOGENESIS

SONIC HEDGEHOG GENE

1. Embryonic signaling protein
2. Involved in patterning along anteroposterior
axis.
3. Limb development:
 Produced at base of limbs in zone of
polarizing activity.
4. CNS development:
 Formation forebrain (prosencephalon).
 Signaling separates right and left brain 
Establishes midline.
 Mutation can cause holoprosencephaly (Single-lobed brain.)

WNT-7 GENE:
1. Produced at apical ectodermal ridge (thickened ectoderm at distal end of each
developing limb).
2. Necessary for proper organization along dorsal-ventral axis.

FIBROBLAST GROWTH FACTOR (FGF) GENE

1. Produced at apical ectodermal ridge.
2. Stimulates mitosis of underlying mesoderm, providing for lengthening of limbs.
3. ―Look at that Fetus, Growing Fingers.‖

HOMEOBOX (HOX) GENES

1. Involved in segmental organization of embryo in a craniocaudal direction.
a. Homeosis = transformation of one structure into another.
b. Homeotic genes = lead to formation of body segments.
c. Mutation  appendages in wrong locations (eg, Fruit flies: legs grow from head
instead of antenna!, Polydactyly: extra fingers/toes, Syndactyly: fused fingers/toes).
2. Code for transcription factors.

P a g e 2 | 158
[Link] REPRODUCTIVE SYSTEM

EMBRYOGENESIS

CHROMOSOME (N) VS. CHROMATID (N):

 A chromosome is made up of two chromatids which are joined by the centromere.
The chromatids separate from each other during mitosis to form two new
chromosomes. The DNA making up a chromosome is dispersed as chromatin.

FERTILIZATION
 Haploid mature spermatozoon (1N, 1C) fuses with haploid ovum (1N, 1C)
forming zygote (2N, 2C).

P a g e 3 | 158
[Link] REPRODUCTIVE SYSTEM

DNA SYNTHESIS
 Zygote (2N, 2C)  DNA synthesis  duplication of chromatids  2N, 4C.
 Zygote divides into two cells (2N, 2C).

FETAL DEVELOPMENT
 Two cell stage: first 1-2 days after fertilization.

MORULA
 Morula = ball of cells without cavity.
 Forms after multiple divisions.
 Forms at the 4th day after fertilization.

BLASTULATION
 Formation of a fluid-filled cavity within the
morula.
 This cavity is called blastocoel.
 Forms in the 5th day after fertilization.
 Outer cells: trophoblast:
 Polarized: one side different from other.
 Watery fluid of blastocoel secreted by
trophoblast cells.
 Differentiates into the cytotrophoblast
and syncytiotrophoblast.
 The syncytiotrophoblast invades the
endometrial connective tissue 6-7 days after fertilization and starts secreting β-
hCG which signals to the corpus luteum in the ovary to continue producing
progesterone.
 Inner cell mass: embryoblast (apolar):
 Give rise to all tissues of body.
 Compromised of embryonic stem cells.

IMPLANTATION
 Blastocyst implants in uterus about day 6-10.
 β-hCG secretion begins.

GASTRULATION
 Blastula  3 layered structure called gastrula.
 Three germ layers: Ectoderm, Mesoderm, Endoderm.
 Steps of gastrulation:
 Inner cell mass  bilaminar disc:
 Two cell layers separated by basement membrane.
 Epiblast and hypoblast.
 At the 2nd week.

P a g e 4 | 158
[Link] REPRODUCTIVE SYSTEM

 Formation primitive streak:

 Formed by invagination of epiblast cells.
 Creates a visible line (―streak‖) in blastocyst.
 Presence indicates start of gastrulation.
 Epiblast  three germ layers (Ectoderm, endoderm, mesoderm).

P a g e 5 | 158
[Link] REPRODUCTIVE SYSTEM

SUMMARY OF EARLY FETAL DEVELOPMENT (FA 2018)

Within hCG secretion begins around the time of Blastocyst ―sticks‖ at day 6.
week 1 implantation of blastocyst.
Within Bilaminar disc (epiblast, hypoblast). 2 weeks = 2 layers.
week 2
Within Gastrulation forms trilaminar embryonic disc. 3 weeks = 3 layers.
week 3 Cells from epiblast invaginate  primitive
streak  endoderm, mesoderm, ectoderm.
Notochord arises from midline mesoderm;
overlying ectoderm becomes neural plate.
Weeks 3–8 Neural tube formed by neuroectoderm and Extremely susceptible to
(embryonic closes by week 4. teratogens.
period) Organogenesis.
Week 4 Heart begins to beat. 4 weeks = 4 limbs and 4 heart
Upper and lower limb buds begin to form. chambers.
Week 6 Fetal cardiac activity visible by transvaginal
ultrasound.
Week 8 Fetal movements start. Gait at week 8.
Week 10 Genitalia have male/female characteristics. Tenitalia
 Prior to week 10, genitalia look similar for
males/females.
 SRY gene (Y chromosome)  penis
development.
 Lack of SRY gene  clitoris development.
Ultrasound identification of gender:
 Usually week 15 to 20

P a g e 6 | 158
[Link] REPRODUCTIVE SYSTEM

EMBRYOLOGIC DERIVATIVES

ECTODERM (External/outer layer)

Surface Epidermis; adenohypophysis (from Rathke Craniopharyngioma—

ectoderm pouch); lens of eye; epithelial linings of oral benign Rathke pouch tumor
cavity, sensory organs of ear, and olfactory with cholesterol crystals,
epithelium; anal canal below the pectinate line; calcifications.
parotid, sweat, mammary glands.
Neural tube Brain (neurohypophysis, CNS neurons, Neuroectoderm—think
oligodendrocytes, astrocytes, ependymal cells, CNS.
pineal gland), retina, spinal cord.
Neural crest Melanocytes, Myenteric (Auerbach) plexus, MMOtEL PPASS
Odontoblasts, Endocardial cushions, Laryngeal Neural crest—think PNS
cartilage, Parafollicular (C) cells of the thyroid, and non-neural structures
PNS (dorsal root ganglia, cranial nerves, nearby.
autonomic ganglia), Adrenal medulla and all
ganglia, Spiral membrane (aorticopulmonary
septum), Schwann cells, pia and arachnoid,
bones of skull.

MESODERM

 Muscle, bone, connective tissue, dermis.

 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 ectoderm to form neuroectoderm (neural plate); its only postnatal
derivative is the nucleus pulposus of the intervertebral disc.

ENDODERM ―Enternal‖ layer.

 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).

P a g e 7 | 158
[Link] REPRODUCTIVE SYSTEM

ORGANS WITH SPECIAL EMBRYOLOGIC ORIGIN

PITUITARY GLAND
 Anterior pituitary (adenohypophysis):
 From Rathke’s pouch of ectoderm ―surface ectoderm‖.
 Outpouching of upper mouth.
 Posterior pituitary (neurohypophysis):
 From neural tube ―neuroectoderm‖.

ADRENAL GLAND
 Cortex: Mesoderm.
 Medulla: Neural crest.

TYPES OF ERRORS IN MORPHOGENESIS

INTRINSIC

 Failure of embryo to develop.

 Abnormal genes or other internal processes.
 Examples: Agenesis, Aplasia, Hypoplasia, Malformation.

AGENESIS
 Absent organ due to absent primordial tissue.
 Example  renal agenesis.

APLASIA
 Absent organ despite presence of primordial tissue.
 Example  thymic aplasia.

HYPOPLASIA
 Incomplete organ development; primordial tissue present. Example: microcephaly.

MALFORMATION
 Abnormal development of structure.
 Primary defect in the cells or tissues that form an organ.
 Intrinsic disruption.
 Occurs during embryonic period (weeks 3–8).
 Examples:
 Neural tube defects: Holoprosencephaly which occurs early in 5th week of fetal life.
 Congenital heart disease, polydactyly and syndactyly.
 Cleft lip or palate.
P a g e 8 | 158
[Link] REPRODUCTIVE SYSTEM

EXTRINSIC

 External force impacts normal development.

 The pressure applied by the uterus is one of the most common external forces.
 Examples: Disruption, Deformation

DISRUPTION
 Normal tissue growth arrested due to external force.
 2° breakdown of previously normal tissue or structure.
 Classic example: amniotic band syndrome:
 Fetal structures entrapped by fibrous bands in utero.
 Often involves limbs or digits.

DEFORMATION
 External force leads to abnormal growth (not arrest).
 Occurs after embryonic period.
 Examples:
 Potter’s syndrome.
 Uterine constraint on a fetus in breech position can cause congenital
dislocation of the hip.
 Clubbed feet.

SEQUENCE
 Abnormalities result from a single 1° embryologic event (eg, oligohydramnios 
Potter sequence).

P a g e 9 | 158
[Link] REPRODUCTIVE SYSTEM

TERATOGENS

TERATOGEN TIMING

 First two weeks: ―All or none‖ period  spontaneous abortion or no effect.

 Weeks 2-8: Organogenesis  Structural defects.
 After week 8: Decreased growth, Central nervous system dysfunction. Usually no birth
defects.

DRUG CATEGORIES

 Category A: no risk to fetus in human studies.

 Category B: no risk to fetus in other studies.
 Category C: risk cannot be ruled out.
 Category D: positive evidence of risk.
 Category X: contraindicated in pregnancy.
 Drugs known to be teratogenic in animals and humans.
 Risks clearly outweigh benefits.

TERATOGENIC MEDICATIONS

NB: ACEIs  oligohydramnios  potter sequence.

P a g e 10 | 158
[Link] REPRODUCTIVE SYSTEM

FETAL HYDANTOIN SYNDROME

 Associated with phenytoin use in pregnancy.
 Growth deficiency + abnormal facial features ―Broad, short nose, Wide-
spaced eyes, malformed ears, microcephaly, classically cleft lip and cleft
palate‖.

WARFARIN EMBRYOPATHY
 Fetal hemorrhage, spontaneous abortion.
 Optic atrophy (vision loss).
 Bone and cartilage abnormalities.
 Stippled epiphyses: small, round densities on X-ray.
 Nasal & limb hypoplasia.

P a g e 11 | 158
[Link] REPRODUCTIVE SYSTEM

SUBSTANCE ABUSE IN PREGNANCY

FETAL ALCOHOL SYNDROME

 Leading cause of intellectual disability in the US.
 Alcohol is neurotoxic by many mechanisms mostly; failure of cell migration.
 First trimester:
 Facial abnormalities:
 Smooth philtrum ―groove from base of nose to upper lip‖, short
palpebral fissures ―small opening of eyes‖, thin vermillion border
―upper lip‖.
 Brain abnormalities:
 Microcephaly.
 Small corpus callosum, cerebellum,
basal ganglia.
 Hypotonia.
 Holoprosencephalon.
 Congenital heart disease:
 ASD, VSD, TOF, heart-lung
fistulas.
 Third trimester:
 Mostly affects size of baby, brain
growth.
 Below average height, weight.
 Limb defects: Finger contractions,
congenital hip dislocations.
 Intellectual impairment:
 May occur without facial or brain anomalies
 Heart-lung fistulas and holoprosencephaly in most severe form.

P a g e 12 | 158
[Link] REPRODUCTIVE SYSTEM

OTHER TERATOGENIC AGENTS

CAUDAL REGRESSION SYNDROME

 Classically associated with maternal diabetes.
 May include anal atresia, sacral agenesis or incomplete development of sacrum.
 May include sirenomelia: ―Mermaid syndrome‖  Fusion of legs.
 Often includes a neural tube defect.

MATERNAL PHENYLKETONURIA
 Occurs in women with PKU who consume phenylalanine.
 High levels of phenylalanine acts as a teratogen.
 Serum phenylalanine should be monitored in pregnancy.
 Dietary restriction of phenylalanine essential.
 Phenylalanine, as a teratogen, causes similar effects as alcohol:
 IUGR, microcephaly.
 Intellectual disability (mental retardation).
 Congenital heart defects: coarctation of the aorta, hypoplastic left heart
syndrome.

P a g e 13 | 158
[Link] REPRODUCTIVE SYSTEM

NEONATAL ABSTINENCE SYNDROME

 Complex disorder involving CNS, ANS, and

GI systems.
 Secondary to maternal opiate use/abuse.
 Risk factors for maternal substance abuse
during pregnancy include poor mental
health, poor prenatal care, low SES, lack of
family support, HCV.
 Universal screening for substance abuse is
recommended in all pregnant patients.
 Newborns may present with uncoordinated
sucking reflexes, irritability, high-pitched crying, tremors, tachypnea, sneezing,
diarrhea, and possibly seizures.

PLACENTA
 1º site of nutrient and gas exchange
between mother and fetus.
 Decidual reaction:
 Endometrium reaction at
implantation.
 Decidua = altered uterine lining
during pregnancy.
 Decidua basalis:
 Uterus at site of implantation.
 Interacts with trophoblast.
 Decidua capsularis  surrounds fetus.
 Decidua parietalis  opposite wall of uterus.

P a g e 14 | 158
[Link] REPRODUCTIVE SYSTEM

MEMBRANES

AMNION
 Inner membrane that covers fetus.
 Holds amniotic fluid.
 Protects embryo.

CHORION
 Membrane that surrounds amnion/embryo.
 Derived from trophoblast.
 Supports fetus and amnion.

COMPONENTS OF THE PLACENTA

FETAL COMPONENT = chorionic plate = chorionic villi:

 Cytotrophoblast:
 Inner layer of chorionic villi.
 Proliferates  cells migrate into syncytiotrophoblast.
 Cytotrophoblast makes 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).
 Syncytiotrophoblast synthesizes hormones.

MATERNAL COMPONENT = basal plate:

 Decidua basalis: Derived from endometrium. Maternal blood in lacunae.
P a g e 15 | 158
[Link] REPRODUCTIVE SYSTEM

IMMUNOLOGY OF PREGNANCY:

 The fetus has foreign antigens: (Half of genes from father  HLA proteins differ from
mother)
 Protected from maternal immunity by placenta.
 Several mechanisms:
 Trophoblast cells do not express many MHC class I antigens.
 Placenta secretions block immune response.

P a g e 16 | 158
[Link] REPRODUCTIVE SYSTEM

UMBILICAL CORD
 Two umbilical arteries:
 Return deoxygenated blood from fetal
internal iliac arteries to placenta A.
 One umbilical vein:
 Supplies oxygenated blood from placenta to
fetus.
 Drains into IVC via liver or via ductus venosus.
 Wharton jelly:
 Contains mucopolysaccharides similar to vitreous
humor.
 Allantoic duct:
 Connects fetal bladder to umbilical cord.
 Obliterates in development  becomes urachus.
 NB: Umbilical arteries and vein are derived from
allantois.

SINGLE UMBILICAL ARTERY (2-VESSEL CORD)

 Abnormal variant. Often identified on prenatal ultrasound.
 Associated with fetal anomalies (Aneuploidy, Congenital malformations).

P a g e 17 | 158
[Link] REPRODUCTIVE SYSTEM

ALLANTOIS
 Outpouching from wall of gut.
 Extends into urogenital sinus.
 Walls form umbilical blood vessels.
 Lumen becomes urachus (a duct between fetal bladder and umbilicus):
 Obliterated urachus is represented by the median umbilical ligament after birth,
which is covered by median umbilical fold of the peritoneum.

URACHUS

 Failure of urachus to involute can lead to anomalies that may increase risk of
infection and/or malignancy (eg, adenocarcinoma) if not treated.

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.

P a g e 18 | 158
[Link] REPRODUCTIVE SYSTEM

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.

TWINNING

 Dizygotic (―fraternal‖) twins arise from 2 eggs that are separately fertilized by 2
different sperm (always 2 zygotes) and will have 2 separate amniotic sacs and 2
separate placentas (chorions).
 Monozygotic (―identical‖) twins arise from 1 fertilized egg (1 egg + 1 sperm) that
splits in early pregnancy.

P a g e 19 | 158
[Link] REPRODUCTIVE SYSTEM

 The timing of cleavage determines chorionicity (number of chorions) and

amnionicity (number of amnions) (SCAB):
 Cleavage 0–4 days: Separate chorion and amnion.
 Cleavage 4–8 days: shared Chorion.
 Cleavage 8–12 days: shared Amnion.
 Cleavage 13+ days: shared Body (conjoined).

P a g e 20 | 158
[Link] REPRODUCTIVE SYSTEM

AORTIC ARCH DERIVATIVES

 Develop into arterial system.

P a g e 21 | 158
[Link] REPRODUCTIVE SYSTEM

BRANCHIAL (PHARYNGEAL) APPARATUS

 Embryonic structure which is a key for development of head and neck.
 Three components: branchial clefts, arches, pouches.
 Branchial clefts:
 Derived from ectoderm.
 Also called branchial grooves.
 Branchial arches:
 Derived from mesoderm (muscles,
arteries) and neural crest (bones, cartilage).
 Core of mesenchyme ―mesoderm‖ (connective tissue)  gives rise to
cartilage/bone and muscles.
 Neural crest cells migrate to center  gives rise to cranial nerves.
 Artery  from aortic arches.
 Branchial pouches:
 Derived from endoderm.

BRANCHIAL CLEFT DERIVATIVES

 1st cleft develops into external auditory meatus.

 2nd through 4th clefts form temporary cervical sinuses, which are obliterated by
proliferation of 2nd arch mesenchyme.
 Persistent cervical sinus  branchial cleft cyst.
 Branchial cleft cyst:
o Present as a lateral neck mass:
 Below angle of the mandible, anterior to sternocleidomastoid muscle.
 Often noticed when become infected.
 Fistula to skin may develop.
 Does not move with swallowing.
o Contrast with thyroglossal duct cyst:
 Midline neck mass.
 Moves with swallowing.

P a g e 22 | 158
[Link] REPRODUCTIVE SYSTEM

BRANCHIAL ARCH DERIVATIVES

P a g e 23 | 158
[Link] REPRODUCTIVE SYSTEM

P a g e 24 | 158
[Link] REPRODUCTIVE SYSTEM

TREACHER COLLINS SYNDROME

 First arch syndrome.
 Caused by failure of neural crest cells to migrate into arch 1.
 Resulting in underdeveloped zygomatic bones, mandibular
hypoplasia, lower eyelid colobomas, and malformed ears.
 May lead to difficulty breathing:
 Underdeveloped lower jaw.
 Obstruction of airway by tongue.

PIERRE-ROBIN SEQUENCE

P a g e 25 | 158
[Link] REPRODUCTIVE SYSTEM

BRANCHIAL POUCH DERIVATIVES

DIGEORGE SYNDROME
 Pathogenesis:
 Chromosome 22q11 deletion.
 Failure of 3rd and 4th pouches to develop.
 Classic triad:
 Thymic aplasia  T-cell deficiency, recurrent infections.
 Failure of parathyroid development  hypocalcemia.
 Associated with cardiac defects (conotruncal anomalies = outflow
tract anomalies  eg, TOF, TGA).
 Facial abnormalities:
 Small jaw, small upper lip/mouth.
 Slanted eyes, low set ear.
 Can be associated with cleft palate.

P a g e 26 | 158
[Link] REPRODUCTIVE SYSTEM

CLEFT LIP AND CLEFT PALATE

 Cleft lip and cleft palate have distinct, multifactorial etiologies, but often occur
together.

CLEFT LIP:
 Failure of fusion of the following:
 Maxillary process.
 Merged medial nasal processes (which forms 1° palate and the philtrum).

P a g e 27 | 158
[Link] REPRODUCTIVE SYSTEM

CLEFT PALATE:
 Neural crest has a major contribution to the palate development and there are a
number of molecular, mechanical and morphological steps in involving the fusion of
contributing structures ―multifactorial‖.
 Palate development:
 Primary palate:
 Formed by fusion of the medial nasal processes  forming intermaxillary
segment.
 It is also called median palatine shelf.
 Secondary palate:
 Formed from two lateral palatine shelves as a projection from the maxillary
prominences.
 They both fuse with each other.
 They also fuse with the primary palate and the nasal septum.
 Causes of cleft palate:
 Failure of fusion of the two lateral palatine shelves.
 Or failure of fusion of lateral palatine shelves with the nasal septum and/or
primary palate.

P a g e 28 | 158
[Link] REPRODUCTIVE SYSTEM

GENITAL EMBRYOLOGY

FEMALE
 Default development.
 Mesonephric duct degenerates and paramesonephric duct develops.

MALE
 SRY gene on Y chromosome—produces testis determining factor  testes
development.
 Sertoli cells secrete Müllerian inhibitory factor (MIF) that suppresses development of
paramesonephric ducts.
 Leydig cells secrete androgens that stimulate development of mesonephric ducts.

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-ROKITANSKYKÜSTER-HAUSER SYNDROME)

 May present as 1° amenorrhea (due to a lack of uterine development) in females with
fully developed 2° sexual characteristics (functional ovaries).

MESONEPHRIC (WOLFAN) DUCT

 Develops into male internal structures (except prostate)—Seminal vesicles,
Epididymis, Ejaculatory duct, Ductus deferens (SEED).
 Female remnant is Gartner duct.

P a g e 29 | 158
[Link] REPRODUCTIVE SYSTEM

P a g e 30 | 158
[Link] REPRODUCTIVE SYSTEM

SEXUAL DIFFERENTIATION

P a g e 31 | 158
[Link] REPRODUCTIVE SYSTEM

1) No Sertoli cells or lack of Müllerian inhibitory factor  develop both male and
female internal genitalia and male external genitalia.
2) 5α-reductase deficiency—inability to convert testosterone into DHT  male internal
genitalia, ambiguous external genitalia until puberty (when ↑ testosterone levels cause
masculinization).
3) In the testes:
a. Leydig Leads to male (internal and external) sexual differentiation.
b. Sertoli Shuts down female (internal) sexual differentiation.

UTERINE (MÜLLERIAN DUCT) ANOMALIES

SEPTATE UTERUS
 Common anomaly vs normal uterus A.
 Incomplete resorption of septum B.
 ↓ Fertility and early miscarriage/pregnancy loss.
 Treat with septoplasty.

BICORNUATE UTERUS
 Incomplete fusion of Müllerian ducts C.
 ↑ Risk of complicated pregnancy, early pregnancy loss, malpresentation, prematurity.

UTERUS DIDELPHYS
 Complete failure of fusion  double uterus, cervix, vagina D.
 Pregnancy possible.

P a g e 32 | 158
[Link] REPRODUCTIVE SYSTEM

MALE/FEMALE GENITAL HOMOLOGS

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.
 Hypo is below.

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.
 When you have Epispadias, you hit your Eye when you
pEE.
P a g e 33 | 158
[Link] REPRODUCTIVE SYSTEM

DESCENT OF TESTES AND OVARIES

ANATOMY
GONADAL ANATOMY

ARTERIAL SUPPLY
 The gonadal arteries arise from the abdominal aorta slightly below the renal
arteries at the level of L2.
 The right gonadal artery travels in front of IVC and behind the ileum.
 Whereas the left gonadal artery courses behind the left colic and sigmoid arteries
and iliac colon.

P a g e 34 | 158
[Link] REPRODUCTIVE SYSTEM

VENOUS DRAINAGE
 Left ovary/testis  left gonadal vein  left renal vein  IVC.
 Right ovary/testis  right gonadal vein  IVC.

P a g e 35 | 158
[Link] REPRODUCTIVE SYSTEM

LYMPHATIC DRAINAGE OF GENITAL ORGANS

 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/scrotum/distal anus  superficial inguinal nodes.
 Glans penis  deep inguinal nodes.

UW: Cancers of the pelvis, including the prostate, spread to the lumbosacral spine via
the vertebral venous plexus (VVP).

The VVP communicates with a number of venous networks, including the prostatic
venous plexus which receives the venous supply from the prostate, penis, and bladder.

It runs up the entire spinal column and connects with the venous supply of the brain via
a valveless system, which allows for bidirectional flow and regulation of intracranial
pressure. This venous connection to the cerebral circulation may help explain the
propensity of tumors to metastasize to the brain.

P a g e 36 | 158
[Link] REPRODUCTIVE SYSTEM

ARTERIAL SUPPLY OF THE PELVIS

INTERNAL ILIAC ARTERY

Anterior division Posterior division

1. Visceral: 1. Iliolumbar.
[Link]. 2. Lateral sacral.
[Link] vesical. 3. Superior gluteal.
[Link] vesical (vaginal).
[Link] rectal (hemorroidal).
2. Muscular branch (obturator)
3. Terminal branches
a. Inferior gluteal.
b. Internal pudendal.
NB: - superior rectal artery  continuation of inferior mesenteric artery.
- Inferior rectal artery  branch of internal pudendal artery.

BLOOD SUPPLY OF UTERUS

 Uterine artery  branch from internal iliac artery (ant division).
 Ovarian artery  branch from aorta (at L2).

P a g e 37 | 158
[Link] REPRODUCTIVE SYSTEM

UW: Rectus abdominis muscle:

 The arcuate line is a horizontal line located below the umbilicus that demarcates the lower
limit of the posterior rectus sheath. Above the arcuate line, the rectus abdominis is
surrounded by anterior and posterior sheaths; below, the muscle is covered only by the
anterior sheath.
 The superior and inferior epigastric arteries (branches of the iliac artery) supply the superior
and inferior portions of the rectus abdominis muscle,
respectively.
 The inferior epigastric artery ascends the posterior surface of the rectus abdominis muscle
and enters the lateral aspect of this muscle at the arcuate line. Because there is no
supporting posterior sheath, trauma to the inferior epigastric artery below the arcuate line
can result in significant hemorrhage.
 Regardless of the direction of skin incision, a cesarean delivery typically involves midline
vertical separation of the rectus abdominis muscle.
 Horizontal transection of the rectus abdominis muscle may be considered when additional
space is necessary (eg, due to fetal weight or position). If the rectus abdominis is transected
horizontally, the Inferior epigastric arteries must be identified and ligated bilaterally to
prevent bleeding complications (eg , hematoma).

P a g e 38 | 158
[Link] REPRODUCTIVE SYSTEM

FEMALE REPRODUCTIVE ANATOMY

P a g e 39 | 158
 [Link] REPRODUCTIVE SYSTEM

Ligament Connects Structures Notes

contained
Infundibulopelvic Ovaries to Ovarian  Ligate vessels during
ligament = lateral pelvic vessels oophorectomy to avoid bleeding.
suspensory wall  Ureter courses retroperitoneally,
ligament close to gonadal vessels  at risk of
injury during ligation of ovarian
vessels.
Cardinal Cervix to side Uterine vessels  Ureter at risk of injury during
ligament = wall of pelvis ligation of uterine vessels in
transverse hysterectomy.
cervical ligament  Not shown in diagram.
Round ligament Uterine horn to  Derivative of gubernaculum.
of the uterus labia majora  Travels through round inguinal
canal; above the artery of Sampson.
Broad ligament Uterus, Ovaries,  Fold of peritoneum that comprises
fallopian tubes, fallopian tubes, the mesosalpinx, mesometrium, and
and ovaries to round ligaments mesovarium.
pelvic side wall of uterus
Ovarian ligament Medial pole of  Derivative of gubernaculum.
ovary to uterine Ovarian Ligament Latches to
horn Lateral uterus.
Uterosacral From back of  Formed of 2 pairs (surrounds the
ligament cervix to rectum).
middle sacral  The only true ligament (others are
piece. condensed CT, smooth ms, elastic
fibers).
 UW: The round ligament contains the artery of Sampson (represents
the anastomosis of the uterine artery and ovarian artery), which rarely is a source of
major bleeding. The round ligaments are clamped and divided to enter the peritoneum
of the broad ligament during a hysterectomy.

 UW: The ureter passes inferior to the uterine artery 1 to 2 centimeters from the
cervix (―water under the bridge‖) and must be avoided during surgical procedures.

P a g e 40 | 158
[Link] REPRODUCTIVE SYSTEM

PELVIC FLOOR

PELVIC PERITONEUM:
 It extends from over the bladder to the
uterovesical pouch then over the uterus
then to the posterior surface o of cervix &
vagina (Douglas pouch) then to the
anterior surface of the rectum (lower 1/3 of
rectum not covered)
 Laterally  the two peritoneal folds form
the broad ligament.

PELVIC FLOOR MUSCLES

 The pelvic floor is composed of the levator ani muscles and forms a U-
shaped sling around the pelvic viscera.
 The levator ani muscles hold the bladder and the urethra in the appropriate
anatomic position.
 Injury to these muscles results in urethral hypermobility and/or pelvic organ
prolapse (eg, cystocele).

P a g e 41 | 158
[Link] REPRODUCTIVE SYSTEM

 Urethral hypermobility
 Results in incomplete closure of the urethra and bladder neck against the
anterior vaginal wall, which leads to stress urinary incontinence (SUI).
 Patients with SUI have involuntary urine loss with increased intraabdominal
pressure (eg. coughing, laughing, straining from constipation) and no bladder
contraction.
 First-line management of SUI is through lifestyle modifications, such as
increased dietary fiber to prevent straining. Urethral support can be
strengthened through pelvic floor exercises (eg, Kegel exercises) involving
squeezing and releasing the levator ani muscles a few times each day.

P a g e 42 | 158
[Link] REPRODUCTIVE SYSTEM

LEVATOR ANI MUSCLE

PUBOCOCCYGEUS MUSCLE:
 Origin: From back of S. pubis.
 Insertion:
 Side walls of urethra  Pubourethralis.
 Side walls of vagina  Pubovaginalis.
 Side walls of rectum  Puborectalis.
 Tip of coccyx & anococcygeal raphe 
pubococcygeus proper.
 Nerve supply:
 Pudendal nerve (S2,3,4).
 Function:
 Support of viscera.
 Maintain intrabdominal pressure.
 Sphincter to urethra, vagina & rectum.
 Important role in labor (rotation).

PERINEAL BODY

 Fibromuscular pyramidal condensation.

 Lies between vagina & anal canal.
 Essential to the integrity of the pelvic floor.
 Separates the urogenital and anal triangles:
 Urogenital triangle:
o Makes up the ant portion of the perineum.
o Contains the roots of external genitalia and the openings of urogenital
system.
 Formed by decussation of 8 muscles:
 Bulbospongiosus muscle.
 External anal sphincter muscle.
 Superficial and deep transverse perineal muscles.
 Fibers from the external urethral sphincter, levator ani, and muscular coat of
the rectum.

P a g e 43 | 158
[Link] REPRODUCTIVE SYSTEM

TYPES OF OBSTETRIC LACERATION

P a g e 44 | 158
[Link] REPRODUCTIVE SYSTEM

EPISIOTOMIES

 Used to enlarge the vaginal outlet to facilitate

delivery and reduce the risk of severe (third- or
fourth-degree) perineal laceration.
 Types: medio-lateral & midline.
 Midline episiotomy:
 Vertical incision from the posterior
vaginal opening to the perineal body.
 It transects the vaginal lining and the
submucosal tissue (similar to a second-
degree laceration) but not the external anal sphincter or the rectal mucosa.
 Improper repair of a midline episiotomy or a second-degree laceration may
result in pelvic organ prolapse or dyspareunia.

PELVIC INNERVATION

P a g e 45 | 158
[Link] REPRODUCTIVE SYSTEM

PUDENDAL NERVE

 Pudendal nerve block:

 Landmarks  ischial spines and sacrospinous ligament.
 Complications:
 Internal pudendal artery and inferior gluteal artery, which run
medial to the PN. Inadvertent injection into these vessels can lead to
hematoma or arrhythmia from intravascular infiltration of local
anesthetics (eg, lidocaine).

P a g e 46 | 158
[Link] REPRODUCTIVE SYSTEM

GENITOFEMORAL NERVE (L1-2)

 Courses along the anterior surface of the

psoas muscle.
 Sensory to scrotum/labia majora and the
medial thigh.
 Injury from abdominal retractors during
laparotomy.
 Injury:
 Labial/scrotal anesthesia.
 ↓ anterior thigh sensation below
the inguinal ligament.
 Absent cremasteric reflex.

ILIOHYPOGASTRIC NERVE (T12-L1)

 UW: Injury during closure of Pfannenstiel skin incisions (eg, cesarean section).

P a g e 47 | 158
[Link] REPRODUCTIVE SYSTEM

OBTURATOR NERVE (L2-4)

 UW: Injury during retroperitoneal pelvic lymph node dissection can result in
loss of medial thigh sensation and ability to adduct the thigh.

FEMALE REPRODUCTIVE EPITHELIAL HISTOLOGY

P a g e 48 | 158
[Link] REPRODUCTIVE SYSTEM

MALE REPRODUCTIVE ANATOMY

ANATOMY OF THE PENIS

 Composed of three cavernous bodies:

 Corpus cavernosa: two large spongy tissue beds.
 Corpus spongiosum: smaller spongy tissue bed that surrounds the urethra.
 Tunica albuginea:
 Tunica = covering & albuginea = white.
 White connective tissue covering surrounding the corpus cavernosa.
 Localized fibrosis in tunica albuginea leads to Peyronyie disease.
 Rupture of tunica albuginea occurs in fracture penis.
 Buck’s fascia:
 Covers all three erectile structures.

P a g e 49 | 158
[Link] REPRODUCTIVE SYSTEM

PEYRONYIE DISEASE (PENILE CURVATURE)

 Abnormal tunica albuginea (localized fibrosis).

 It is acquired disorder caused by trauma in
a susceptible individual.
 May cause pain, nodule, abnormal
curvature when erect, and erectile
dysfunction.
 Treatment:
 Pentoxifylline: phosphodiesterase
inhibitor, reduces inflammation,
prevents collagen deposition.

URETHRAL INJURY
 Occurs almost exclusively in men.
 Suspect if blood seen at urethral meatus.
 Urethral catheterization is relatively contraindicated.

Anterior urethral injury Posterior urethral injury

Part of urethra Bulbar (spongy) urethra. Membranous urethra.
Mechanism Perineal straddle injury. Pelvic fracture.
Location OF Blood accumulates in scrotum. Urine leaks into retropubic space.
URINE If Buck fascia is torn, urine escapes
leak/blood into perineal space.
accumulation
Presentation Blood at urethral meatus and scrotal Blood at urethral meatus and high-
hematoma. riding prostate.

P a g e 50 | 158
[Link] REPRODUCTIVE SYSTEM

AUTONOMIC INNERVATION OF MALE SEXUAL RESPONSE

ERECTION
 Parasympathetic nervous system (pelvic splanchnic nerves, S2-S4):
 NO  ↑ cGMP  smooth muscle relaxation  vasodilation  proerectile.
 PDE-5 inhibitors (eg, sildenafil)  ↓ cGMP breakdown.
 Norepinephrine  ↑ [Ca2+]in  SM contraction  VC  antierectile.

EMISSION

 Sympathetic nervous system (hypogastric nerve, T11-L2).

EJACULATION

 Visceral and Somatic nerves (pudendal nerve).

UW: The prostatic plexus lies within the fascia of the prostate and innervates the corpus
cavernosa of the penis, which facilitates penile erection. As a result, prostatectomy or injury to the
prostatic plexus can cause erectile dysfunction.

SEMINIFEROUS TUBULES

Cell Function Location / notes

Spermatogonia  Maintain germ cell pool and produce  Line seminiferous tubules A
1° spermatocytes.  Germ cells
Sertoli cells  Secrete inhibin B  inhibit FSH.  Line seminiferous tubules.
 Secrete androgen-binding protein   Non-germ cells.
maintain local levels of testosterone.  Convert testosterone and
 Produce MIF. androstenedione to estrogens via
 Tight junctions between adjacent aromatase.
Sertoli cells form blood-testis barrier  Sertoli cells Support Sperm
 isolate gametes from autoimmune Synthesis and inhibit FSH.
attack.  Homolog of female granulosa
 Support and nourish developing cells.
spermatozoa.  ↑ Temperature seen in
 Regulate spermatogenesis. varicocele, cryptorchidism.
 Temperature sensitive; ↓ sperm
production and ↓ inhibin B with ↑
temperature.
Leydig cells  Secrete testosterone in the presence of  Interstitium.
LH; testosterone production unaffected  Endocrine cells.
by temperature.  Homolog of female theca interna
cells.
 LH stimulates Leydig cells.

P a g e 51 | 158
[Link] REPRODUCTIVE SYSTEM

Sertoli cells = female granulosa cells.

Leydig cells = female theca cells.

UW: Sertoli cell failure:

 May be caused by mutation in Steroidogenic factor-1 (SF-1) ―nuclear receptor that

regulates the transcription of several genes involved in steroidogenesis sexual development,
and reproduction‖
 Selective impairment in Sertoli cell function would cause:
 ↓ Inhibin  ↑ FSH levels.
 Infertility due to impaired sperm production.
 However, the Leydig cells are unaffected, so no changes in testosterone or LH levels
would be expected.

P a g e 52 | 158
[Link] REPRODUCTIVE SYSTEM

VASECTOMY

 Transection of the vas deferens blocks transport of new sperm from the epididymis,
but has no effect on sperm distal to the ligation (viable sperm may persist for 3
months and at least 20 ejaculations following vasectomy), sexual intercourse may be
resumed within a week following the procedure, sexual desire remains the same or
increases (decreased anxiety about pregnancy), no effect on attaining or maintaining
an erection, on ejaculate volume (sperm is only 2-5% of ejaculate), no effect on
Leydig cells or testosterone production.

ANATOMY OF THE URETER

 Course:
 Enters the pelvis by crossing the bifurcation of the common iliac artery.
 It then passes downwards in front the internal iliac vessels to become
medial to them & behind the infundibulopelvic ligament & ovary.
 It is crossed by the uterine artery at the base of the broad ligament.
 Here the ureter is 2 cm lateral to cervix & 2 cm above vaginal vault.

P a g e 53 | 158
[Link] REPRODUCTIVE SYSTEM

PELVIC IMAGING

P a g e 54 | 158
[Link] REPRODUCTIVE SYSTEM

PHYSIOLOGY
ESTROGEN

SOURCE
 Ovary (17β-estradiol), placenta (estriol), adipose tissue (estrone via aromatization).
 Potency: estradiol > estrone > estriol.

FUNCTION
 Development of genitalia and breast, female fat distribution.
 Growth of follicle, endometrial proliferation, ↑ myometrial excitability.
 Upregulation of estrogen, LH, and progesterone receptors; feedback inhibition of FSH
and LH, then LH surge; stimulation of prolactin secretion.
 ↑ Transport proteins, SHBG; ↑ HDL; ↓ LDL.
 Pregnancy:
 50-fold ↑ in estradiol and estrone.
 1000-fold ↑ in estriol (indicator of fetal wellbeing).
 Estrogen receptors expressed in cytoplasm; translocate to nucleus when bound by
estrogen.

P a g e 55 | 158
[Link] REPRODUCTIVE SYSTEM

PROGESTERONE

SOURCE
Fall in progesterone after delivery
 Corpus luteum, placenta, adrenal cortex, testes. disinhibits prolactin  lactation.

↑ Progesterone is indicative of ovulation.

FUNCTION
Progesterone is pro-gestation.
 Stimulation of endometrial glandular Prolactin is pro-lactation.
secretions and spiral artery development.
 Maintenance of pregnancy.
 ↓ Myometrium excitability.
 Uterine smooth muscle relaxation (preventing contractions).
 ↓ Estrogen receptor expression  prevents endometrial hyperplasia..
 Production of thick cervical mucus, which inhibits sperm entry into uterus.
 ↑ Body temperature.
 Inhibition of gonadotropins (LH, FSH).

P a g e 56 | 158
[Link] REPRODUCTIVE SYSTEM

OOGENESIS
 In the female, gametogenesis begins early in embryonic development (at
approximately four weeks gestation).
 1° 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 (1° oocytes).
 Meiosis II is arrested in metaphase II until fertilization (2° oocytes). ―An egg met a
sperm.‖
 If fertilization does not occur within 1 day, the 2° oocyte degenerates.

P a g e 57 | 158
[Link] REPRODUCTIVE SYSTEM

OVULATION
 ↑ Estrogen, ↑ GnRH receptors on anterior pituitary.
 Estrogen surge then stimulates LH release  ovulation (rupture of follicle).
 ↑ Temperature (progesterone induced).
 Mittelschmerz
 Transient mid-cycle ovulatory pain (―Middle hurts‖).
 Common in women who are not taking OCPS ―who are ovulating‖.
 Due to enlargement of developing follicle which irritates peritoneum (eg,
follicular swelling/rupture, fallopian tube contraction).
 Can mimic appendicitis.
 UW: Ovulation predictor kit: measures urinary LH and becomes positive 24 hours
before ovulation.

MENSTRUAL CYCLE
 Follicular phase can vary in length.
 Luteal phase is 14 days.
 Ovulation day + 14 days = menstruation.
 Follicular growth is fastest during 2nd week of the follicular phase.
 Estrogen stimulates endometrial proliferation ―growth‖.
 Progesterone maintains endometrium to support implantation by stimulating the
secretory activity.
 Progesterone withdrawal  menstruation.
 ↓ Progesterone  ↓ fertility.
 UW: Progesterone released by the corpus luteum causes the uterine glands to coil
and secrete glycogen-rich mucus in preparation for embryo implantation. The
endometrial stroma becomes edematous and completely traversed by tortuous spiral
arteries that extend from the deeper layers to the uterine lumen.

P a g e 58 | 158
[Link] REPRODUCTIVE SYSTEM

 Proliferative phase:
 Estrogen driven.
 ↑ Glands and stroma.
 Secretory phase:
 Progesterone driven.
 ↓ Proliferation.
 Secretory vacuoles appear.
 Prominent spiral arterioles.

P a g e 59 | 158
[Link] REPRODUCTIVE SYSTEM

 Effect of FSH on menstrual cycle:

 Following the onset of menstruation, FSH stimulates one or more dominant
follicles to form in one of the ovaries (follicular phase).
 FSH also stimulates estrogen production from the ovaries.
 As the follicular phase advances, a progressive rise in serum estradiol is
seen.
 High estrogen levels in the late follicular phase have a positive feedback
effect on LH production, resulting in an LH surge.
 Effect of LH on menstrual cycle:
 Ultimately, the LH surge causes the rupture of the dominant follicle, leading
to extrusion of an ovum (ovulation).
 Failure of ovulation (eg, anovulation in polycystic ovary syndrome) is a
common cause of infertility.
 Treatment options include the administration of drugs that act like FSH and
LH.
 Menotropin (human menopausal gonadotrophin ) therapy mimics FSH and
triggers the formation of a dominant ovarian follicle.
 When the follicle appears mature exogenous human chorionic
gonadotropin (hCG) is administered. The alpha subunit of hCG is
structurally similar to LH and therefore simulates the LH surge by inducing
ovulation.

P a g e 60 | 158
[Link] REPRODUCTIVE SYSTEM

ANOVULATORY CYCLE:

 Menstrual cycle without ovulation.

 No ovulation  no corpus luteum formation:
 Absence of the luteal phase of the ovary  no progesterone.
 Excessive endometrial growth from estrogen.
 “Unopposed growth” from lack of progesterone  irregular bleeding
―dysfunctional uterine bleeding‖.
 Common at:
 Menarche due to underdeveloped HPO axis.
 Menopause due to loss of ovulation.
 Thyroid disease, obesity.
 UW: Anovulation is common in the first several years after menarche and the last
few years before menopause. It manifests with marked menstrual cycle variability.

P a g e 61 | 158
[Link] REPRODUCTIVE SYSTEM

IMPERFORATE HYMEN
 Obstructive lesion caused by incomplete degeneration of central portion of fibrous
tissue band connecting walls of vagina.
 Presentation:
 At birth:
 Vaginal secretions stimulated by mother’s estrogen may cause
accumulation of mucus in vaginal canal (mucocolpos), which may
manifest as bulging introitus.
 If undiagnosed, mucus reabsorbed and child asymptomatic until
menarche.
 At puperty (menarche):
 Patient then presents with primary amenorrhea.
 Normal secondary sexual characteristics.
 Cyclic abdominal or pelvic pain due to accumulation of menstrual
blood in vagina and uterus (hematocolpos), resulting pressure may
cause back pain or difficulty defecating.
 Examination may show vaginal bulge with possible mass palpated
anterior to rectum.

UW: primary amenorrhea in the context of normal ovarian and anterior pituitary gland
function is termed eugonadotropic amenorrhea; suggests the presence of an anatomic
defect in the genital tract. The two most frequent causes are imperforate hymen or
mullerian duct anomalies.

P a g e 62 | 158
[Link] REPRODUCTIVE SYSTEM

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.
 Home test in urine 2 weeks after conception.
 Gestational age—calculated from date of last menstrual period.
 Embryonic age—calculated from date of fertilization (gestational age minus 2
weeks).
 Placental hormone secretion generally increases over the course of pregnancy, but
hCG peaks at 8–10 weeks.

P a g e 63 | 158
[Link] REPRODUCTIVE SYSTEM

NORMAL PHYSIOLOGICAL CHANGES DURING PREGNANCY

 Total body volume expands  blood fills placenta  diverted from maternal
circulation  ↑ renin  salt/water retention.
 ↑ Cardiac output:
 ↑ Preload due to rise in blood volume.
 ↓ Afterload due to fall in SVR (placenta is a low resistance system).
 ↑ HR  ↑ placental and uterus perfusion).
 Anemia (↑↑ plasma, ↑ RBCs).
 Hypercoagulability (to ↓ blood loss at delivery).
 Hyperventilation (eliminate fetal CO2).

P a g e 64 | 158
[Link] REPRODUCTIVE SYSTEM

HUMAN CHORIONIC GONADOTROPIN (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  abortion).
 After 8–10 weeks, placenta synthesizes its own estriol and progesterone and corpus
luteum degenerates.
 Used to detect pregnancy because it appears early in urine (see above).
 Two glycoprotein subunits (“heterodimeric glycoprotein”):
 Has α and β subunits.
 LH, FSH, TSH have the same α subunit  states of ↑ hCG can cause
hyperthyroidism.
 Binds LH receptors in corpus luteum to maintain it.
 β subunit is unique (pregnancy tests detect β subunit).
 hCG is ↑ in multiple gestations, hydatidiform moles, choriocarcinomas, and Down
syndrome.
 hCG is ↓ in ectopic/failing pregnancy, Edwards syndrome, and Patau syndrome.

HUMAN PLACENTAL LACTOGEN

 Also known as chorionic somatomammotropin.

Source:
 Syncytiotrophoblast of placenta.

Function:
 Stimulates insulin production; overall ↑ insulin resistance.
 Raises blood glucose level (good for baby).
 Promotes breakdown of fatty acids by mother for fuel.
 Promotes breakdown of proteins for fetal protein synthesis.
 Gestational diabetes can occur:
 If maternal pancreatic function cannot overcome the insulin resistance.
 Screening by serum glucose testing not by urine testing as glycosuria is a normal
finding during pregnancy.

P a g e 65 | 158
[Link] REPRODUCTIVE SYSTEM

APGAR SCORE
 Assessment of newborn vital signs following delivery via a 10-point scale evaluated
at 1 minute and 5 minutes.
 Apgar score is based on Appearance, Pulse, Grimace, Activity, and Respiration.
 Apgar scores < 7 require further evaluation.
 If Apgar score remains low at later time points, there is ↑ risk the child will develop
long-term neurologic damage.

P a g e 66 | 158
[Link] REPRODUCTIVE SYSTEM

INFANT/CHILD DEVELOPMENT
 Milestone dates are ranges that have been approximated and vary by source.
 Children not meeting milestones may need assessment for potential developmental
delay.

LOW BIRTH WEIGHT

 Defined as < 2500 g.
 Caused by prematurity or intrauterine growth restriction (IUGR).
 Associated with ↑ risk of sudden infant death syndrome (SIDS) and with ↑ overall
mortality.
 Other problems include impaired thermoregulation and immune function,
hypoglycemia, polycythemia, and impaired neurocognitive/emotional development.
 Complications include infections, respiratory distress syndrome, necrotizing
enterocolitis, intraventricular hemorrhage, and persistent fetal circulation.

P a g e 67 | 158
[Link] REPRODUCTIVE SYSTEM

LACTATION
 After parturition and delivery of placenta, rapid ↓ in progesterone disinhibits and
initiates lactation.
 Suckling is required to maintain milk production and ejection, since ↑ nerve
stimulation  ↑ oxytocin and prolactin.
 Prolactin:
 Induces and maintains lactation
 ↓ Reproductive function.
 Manufactured due to stimulation by thyrotropin-releasing hormone and is inhibited
by progesterone.
 Oxytocin:
 Assists in milk letdown; also promotes uterine contractions.
 Breast milk is the ideal nutrition for infants < 6 months old.
 Contains maternal immunoglobulins (conferring passive immunity; mostly IgA),
macrophages, lymphocytes.
 Breast milk reduces infant infections and is associated with ↓ risk for child to develop
asthma, allergies, diabetes mellitus, and obesity.
 Guidelines recommend exclusively breastfed infants get vitamin D and possibly iron
supplementation.
 Breastfeeding ↓ maternal risk of breast and ovarian cancer and facilitates mother-child
bonding.

P a g e 68 | 158
[Link] REPRODUCTIVE SYSTEM

MENOPAUSE
 Permanent cessation of menses 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).
 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.
 Causes HAVOCS: Hot flashes, Atrophy of the Vagina, Osteoporosis, Coronary
artery disease, Sleep disturbances.
 Menopause before age 40 suggests 1° ovarian insufficiency (premature ovarian
failure).

ANDROGENS
 Testosterone, dihydrotestosterone (DHT), androstenedione.

SOURCE
 DHT and testosterone (testis), AnDrostenedione (ADrenal).
 Potency: DHT > testosterone > androstenedione.

FUNCTION
 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.

P a g e 69 | 158
[Link] REPRODUCTIVE SYSTEM

 Testosterone is converted to DHT by 5α-reductase, which is inhibited by

finasteride.
 In the male, androgens are converted to estrogen by cytochrome P-450 aromatase
(primarily in adipose tissue and testis).
 Aromatase is the key enzyme in conversion of androgens to estrogen.
 Exogenous testosterone  inhibition of hypothalamic–pituitary–gonadal axis  ↓
intratesticular testosterone Ž ↓ testicular size  azoospermia.

P a g e 70 | 158
[Link] REPRODUCTIVE SYSTEM

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.

NB: blood-testis barrier  isolates sperms to protect them from autoimmune attack.

P a g e 71 | 158
[Link] REPRODUCTIVE SYSTEM

TANNER STAGES OF SEXUAL DEVELOPMENT

 Tanner stage is assigned independently to genitalia, pubic hair, and breast (eg, a
person can have Tanner stage 2 genitalia, Tanner stage 3 pubic hair).

P a g e 72 | 158
[Link] REPRODUCTIVE SYSTEM

PATHOLOGY
REPRODUCTIVE SYSTEM

GYNECOLOGIC TUMOR EPIDEMIOLOGY

 Incidence (US): endometrial > ovarian > cervical; cervical cancer is more common
worldwide due to lack of screening or HPV vaccination.
 Prognosis: Cervical (best prognosis, diagnosed < 45 years old) > Endometrial
(middleaged, about 55 years old) > Ovarian (worst prognosis, > 65 years). CEOs
often go from best to worst as they get older.

P a g e 73 | 158
[Link] REPRODUCTIVE SYSTEM

VULVAR PATHOLOGY

NON-NEOPLASTIC

BARTHOLIN CYST AND ABSCESS

 Cystic dilation of the Bartholin gland.
 One Bartholin gland is present on each side of the vaginal canal and produces
mucus-like fluid that drains via ducts into the lower vestibule.
 Arises due to inflammation and obstruction of gland:
 Usually occurs in women of reproductive age.
 Presents as a unilateral, painful cystic lesion at the lower vestibule adjacent
to the vaginal canal.
 May lead to abscess 2° to obstruction and inflammation.
 Usually in reproductive-age females. Associated with N gonorrhoeae infections.

LICHEN SCLEROSUS
 Characterized by thinning of the epidermis and fibrosis (sclerosis) of the dermis.
 Presents with:
 Porcelain-white plaques (Leukoplakia) with a red or violet border.
 Skin fragility with erosions can be observed B.
 Most commonly seen in postmenopausal women; possible autoimmune etiology.
 Benign, but slightly increased risk for SCC.

P a g e 74 | 158
[Link] REPRODUCTIVE SYSTEM

LICHEN SIMPLEX CHRONICUS

 Hyperplasia of vulvar squamous epithelium.
 Presents as leukoplakia with thick, leathery vulvar skin.
 Associated with chronic irritation and scratching  enhanced skin markings.
 Benign, no risk of SCC.

CONDYLOMA
 Warty neoplasm of vulvar skin, often large.
 Most commonly due to:
1. HPV types 6 or 11 (condyloma
acuminatum).
2. Secondary syphilis (condyloma
latum) is a less common cause.
3. Both are sexually transmitted.
 Histologically, HPV-associated condylomas are characterized by Koilocytes
(hallmark of HPV-infected cells).
 Condylomas rarely progress to carcinoma (6 and 11 are low-risk HPV types).

NEOPLASTIC

VULVAR CARCINOMA
 Carcinoma from squamous epithelial lining of vulva. Rare.
 Presents with leukoplakia, biopsy often required to distinguish carcinoma from
other causes of leukoplakia.
 Etiology may be HPV related or non-HPV related.
 HPV-related vulvar carcinoma:
 Associated with high-risk HPV types 16, 18.
 Risk factors: multiple partners, early coitarche.
 Usually in reproductive-age females.
 Arises from vulvar intraepithelial neoplasia (VIN), a dysplastic
precursor lesion characterized by koilocytic change, disordered cellular
maturation, nuclear atypia, and increased mitotic activity.
 Non-HPV vulvar carcinoma:
 Usually from long-standing lichen sclerosis.
 Females > 70 years old.

P a g e 75 | 158
[Link] REPRODUCTIVE SYSTEM

EXTRAMAMMARY PAGET DISEASE

 Characterized by malignant epithelial cells in the epidermis of the vulva 
intraepithelial adenocarcinoma.
 Presents as erythematous, pruritic, ulcerated vulvar skin.
 Represents carcinoma in situ, usually with no underlying carcinoma.
 Paget disease of the nipple is also characterized by malignant epithelial cells in
the epidermis of the nipple, but it is almost always associated with an
underlying carcinoma.
 Must be distinguished from melanoma, which rarely can occur on the vulva:
1. Paget cells are PAS+, keratin+, and S100-.
2. Melanoma is PAS-, keratin-, and S100+.

VAGINA

BASIC PRINCIPLES
 Upper vagina  from Mullerian duct  columnar epithelium.
 Lower vagina  from urogenital sinus  squamous epithelium.
 During development, squamous epithelium from the lower vagina grows upward to replace
the columnar epithelium lining of the upper vagina  all vaginal mucosa are squamous
epithelium.

VAGINAL ADENOSIS

 Focal persistence of columnar epithelium in the upper 1/3 of the vagina.

 Increased incidence in females who were exposed to diethylstilbestrol (DES) in
utero.

P a g e 76 | 158
[Link] REPRODUCTIVE SYSTEM

VAGINAL TUMORS

VAGINAL SQUAMOUS CELL CARCINOMA

 Usually 2° to cervical SCC; 1° vaginal carcinoma rare.

CLEAR CELL ADENOCARCINOMA

 Affects women who had exposure to DES in utero.

EMBRYONAL RHABDOMYOSARCOMA
 Malignant mesenchymal proliferation of immature skeletal muscle; rare.
 Presents as bleeding and a grape-like mass protruding from the vagina or penis of
a child (usually < 5 yrs of age); also known as sarcoma botryoides.
 Rhabdomyoblast, the characteristic cell:
 Exhibits cytoplasmic cross-striations.
 Positive immunohistochemical staining for desmin and myogenin.

VAGINAL LYMPHATIC DRAINAGE

 Upper vagina  from mullerian duct  iliac lymph nodes.

 Lower vagina  from urogenital sinus  inguinal lymph nodes.

P a g e 77 | 158
[Link] REPRODUCTIVE SYSTEM

CERVICAL PATHOLOGY

BASIC PRINCIPLES
 Anatomically, comprises the "neck" of the uterus.
 Divided into the exocervix (visible on vaginal exam) and endocervix.
1. Exocervix is lined by nonkeratinizing squamous epithelium.
2. Endocervix is lined by a single layer of columnar cells.
3. Junction between the exocervix and endocervix is called the transformation
zone.

P a g e 78 | 158
[Link] REPRODUCTIVE SYSTEM

HPV INFECTION
 Sexually transmitted DNA virus that infects the lower genital tract, especially the
cervix in the transformation zone.
 Infection is usually eradicated by acute inflammation; persistent infection leads to
an increased risk for cervical dysplasia (cervical intraepithelial neoplasia, CIN).
 Risk of CIN depends on HPV type, which is determined by DNA sequencing.
A. High-risk-HPV types: 16, 18, 31, and 33.
B. Low-risk-HPV types 6 and 11.
 High-risk HPV produce:
A. E6 gene product (inhibits p53 which controls the cell cycle G1 to S phase
progression)  uncontrolled growth.
B. E7 gene product (inhibits pRb).

CERVICAL INTRAEPITHELIAL NEOPLASIA = DYSPLASIA

 Disordered epithelial growth.
 Begins at squamocolumnar junction (transformation zone) and extends outward.
 Characterized by:
1. Koilocytic change:
 Immature squamous cell with dense, irregularly staining cytoplasm.
 Perinuclear clearing resulting in a halo.
 Enlarged pyknotic nucleus where the chromatin has condensed as
part of the apoptosis process giving it a "raisinoid" appearance.
2. Disordered cellular maturation, nuclear atypia.
3. ↑ Mitotic activity within the cervical epithelium.
 Divided into grades based on the extent of epithelial involvement by immature
dysplastic cells:
1. CIN I involves < 1/3 of the thickness of the epithelium.
2. CIN II involves < 2/3 of the thickness of the epithelium.
3. CIN III involves slightly less than the entire thickness of the epithelium.
4. Carcinoma in situ (CIS) involves the entire thickness of the epithelium.
 CIN classically progresses in a stepwise fashion through CIN I, CIN II, CIN Ill, and
CIS to become invasive squamous cell carcinoma.
1. Progression is not inevitable (e.g., CIN I often regresses).
2. The higher the grade of dysplasia, the more likely it is to progress to
carcinoma and the less likely it is to regress to normal.
 May progress slowly to invasive carcinoma if left untreated.
1. Smoking increases the likelihood of an HPV infection developing into
intraepithelial neoplasia and cancer.
 Typically asymptomatic (detected with Pap smear) or presents as abnormal vaginal
bleeding (often postcoital).
 Risk factors: multiple sexual partners (#1), smoking, early coitarche, DES exposure,
immunocompromise (eg, HIV, transplant).

P a g e 79 | 158
[Link] REPRODUCTIVE SYSTEM

UW: Human papillomavirus (HPV) infection, especially with strain 16 or 18, is the strongest risk
factor for development of cervical dysplasia and invasive cervical carcinoma. HIV coinfection
allows HPV infection to persist and enhances expression of HPV oncogenes increasing the risk for
cervical dysplasia/cancer. Therefore, patients with HIV require frequent Papanicolaou screening
for cervical dysplasia/cancer.

P a g e 80 | 158
[Link] REPRODUCTIVE SYSTEM

INVASIVE CERVICAL CARCINOMA

 Presentation:
 Vaginal bleeding, especially postcoital bleeding, or cervical discharge.
 Advanced tumors often invade through the anterior uterine wall into the
bladder, blocking the ureters. Hydronephrosis with postrenal failure is a
common cause of death in advanced cervical carcinoma.
 Key risk factors:
 High-risk HPV infection.
 Secondary risk factors include smoking and immunodeficiency (e.g., cervical
carcinoma is an AIDS-defining illness).
 Subtypes:
 Squamous cell carcinoma (80% of cases) and adenocarcinoma (15% of cases).
 Both types are related to HPV infection.
 Pap smear can detect cervical dysplasia before it progresses to invasive carcinoma.
 It detects the presence of Koilocytes.

SCREENING AND PREVENTION OF CERVICAL CARCINOMA

 The goal of screening is to catch dysplasia (CIN) before it develops into carcinoma.
a) Progression from CI to carcinoma, on average, takes 10- 20 years.
b) Screening begins at age 21 and is initially performed yearly.
 Pap smear is the gold standard for screening.
a) Cells are scraped from the transformation zone using a brush and analyzed
under a microscope.
b) Dysplastic cells are classified as low grade (CIN I) or high grade (CIN II and
III).
c) High-grade dysplasia is characterized by cells with hyperchromatic (dark)
nuclei and high nuclear to cytoplasmic ratios.
 Pap smear is the most successful screening test developed to date.
a) It is responsible for a significant reduction in the morbidity and mortality of
cervical carcinoma (cervical carcinoma went from being the most common to
one of the least common types of gynecologic carcinoma in the US).
b) Women who develop invasive cervical carcinoma usually have not undergone
screening.
 An abnormal Pap smear is followed by confirmatory colposcopy (visualization of
cervix with a magnifying glass) and biopsy.
 Limitations of the Pap smear include
a) Inadequate sampling of the transformation zone (false negative screening)
b) Limited efficacy in screening for adenocarcinoma.

P a g e 81 | 158
[Link] REPRODUCTIVE SYSTEM

 Immunization is effective in preventing HPV infections:

a) The quadrivalent vaccine covers HPV types 6, 11, 16, and 18.
b) Antibodies generated against types 6 and 11 protect against condylomas.
c) Antibodies generated against types 16 and 18 protect against CIN and
carcinoma.
d) Protection lasts for 5 years.
e) Pap smears are still necessary due to the limited number of HPV types covered
by the vaccine.

POLYCYSTIC OVARIAN SYNDROME

LH: FSH ratio > 2

Clinical features  Androgen excess: hirsutism, acne, androgenic alopecia.

 Ovarian dysfunction: menstrual irregularity, polycystic ovaries, ↓ fertility.
 Insulin resistance: acanthosis nicgricans, glucose intolerance/ diabetes,
metabolic syndrome  dyslipidemia and an increased risk of cardiovascular
disease.
 Obesity.
Complications  ↑ Risk of endometrial cancer 2° to unopposed estrogen from repeated
anovulatory cycles.
Pathophysiology  Hyperinsulinemia and/or insulin resistance is thought to alter hypothalamic
hormonal feedback response  ↑ LH:FSH, ↑ androgens (eg, testosterone) from
theca interna cells, ↓ rate of follicular maturation  unruptured follicles (cysts)
+ anovulation.
 LH levels are typically elevated, and patients may also have increased LH
activity at the ovary (increased LH receptor expression).
 Increased ovarian and/or adrenal androgen production, likely due to the effects
of LH, insulin, and possibly additional genetic factors.

P a g e 82 | 158
[Link] REPRODUCTIVE SYSTEM

Treatment  Weight loss:

 ↓ Peripheral estrone formation.
 Reverse insulin resistance and restore normal ovulatory function.
 OCPs (prevent endometrial hyperplasia due to unopposed estrogen).
 Induce ovulation:
 Metformin (if hyperglycemia diabetes).
 Clomiphene: SERM that prevents negative feedback inhibition on the
hypothalamus and pituitary by circulating estrogen, resulting in
increased gonadotropin production (FSH and LH) and ovulation.
 Spironolactone, ketoconazole (antiandrogens) to treat hirsutism.
Ultrasound  Enlarged, bilateral cystic ovaries.

OVARIAN CYSTS

FOLLICULAR CYST

 Most common ovarian mass in young women.

 Distention of unruptured graffian follicle.
 Lined by granulosa cells  ↑↑ estrogen  may be associated with endometrial
hyperplasia.
 Classic presentation: young female with pelvic pain + irregular bleeding.
 This is the type of cysts which is associated with PCO “multiple follicular cysts”.

CORPUS LUTEAL CYST

 Failure of the corpus luteum to involute.

 May continue to produce progesterone  delay
menstruation.
 Classic presentation: pelvic pain, missed period, adenexal
mass.
 Normal in pregnancy.
 Yellow cyst as it uses cholesterol to synthesize progesterone.

THECA-LUTEIN CYST

 Often bilateral/multiple. Benign.

 Lutenized theca cells with edema  hyperplasia of the ceca cells.
 Due to gonadotropin stimulation.
o Associated with high levels of hCG  choriocarcinoma and hydatidiform
moles.

P a g e 83 | 158
[Link] REPRODUCTIVE SYSTEM

OVARIAN NEOPLASMS
 Most common adnexal mass in women > 55 years old.
 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).
 Presents with adnexal mass, abdominal distension, bowel obstruction, pleural
effusion.
 Monitor response to therapy/relapse by measuring CA-125 levels (not good for
screening).

SURFACE EPITHELIUM TUMORS

 Most common type of ovarian tumor.

 Surface tumors clinically present late with vague abdominal symptoms (pain and
fullness) or signs of compression (urinary frequency).
 Prognosis is generally poor for surface epithelial carcinoma (worst prognosis
of female genital tract cancers).
 Epithelial carcinomas tend to spread locally, especially to the peritoneum.
 Risk factors of epithelial cancer ovary:

 Risk ↑ also with advanced age, PCOS, strong family history.

 Derived from coelomic epithelium that lines the
ovary:
 Coelomic epithelium embryologically
produces the epithelial lining of the fallopian
tube (serous cells), endometrium, and
endocervix (mucinous cells).
 The two most common subtypes of surface epithelial
tumors are serous and mucinous; both are usually
cystic.
 Serous tumors are full of watery fluid.
 Mucinous tumors are full of mucus-like fluid.

P a g e 84 | 158
[Link] REPRODUCTIVE SYSTEM

 Mucinous and serous tumors can be benign, borderline, or malignant:

1. Benign tumors (cystadenomas)
a. Composed of a single cyst with a simple, flat lining.
b. Most commonly arise in premenopausal women (30- 40 years old).
2. Malignant tumors (cystadenocarcinomas)
a. Composed of complex cysts with a thick, shaggy lining.
b. Most commonly arise in postmenopausal women (60-70 years old).
3. Borderline tumors
a. Have features in between benign and malignant tumors.
b. Better prognosis than clearly malignant tumors, but still carry metastatic
potential.
 BRCA1 mutation carriers:
 Have an increased risk for serous carcinoma of the ovary and fallopian tube.
 BRCA1 carriers often elect to have a prophylactic salpingo-oophorectomy
(along with prophylactic mastectomy due to the increased risk for breast
cancer).
 Less common subtypes of surface epithelial tumors include:
 Endometrioid tumors:
 Composed of endometrial-like glands and are usually malignant.
 May arise from endometriosis.
 15% of endometrioid carcinomas of the ovary are associated with an
independent endometrial carcinoma (endometrioid type).
 Brenner tumors:
 Resembles bladder epithelium (transitional
cell tumor).
 Solid tumor that is pale yellow-tan and
appears encapsulated.
 ―Coffee bean‖ nuclei on H&E stain.
 Usually benign.

SEROUS CYSTADENOMA
 Most common ovarian neoplasm.
 Lined with fallopian tube–like epithelium.
 Often bilateral.

MUCINOUS CYSTADENOMA
 Multiloculated, large.
 Lined by mucus-secreting epithelium A.

P a g e 85 | 158
[Link] REPRODUCTIVE SYSTEM

SEROUS CYSTADENOCARCINOMA
 Most common malignant ovarian neoplasm, frequently bilateral.
 Psammoma bodies.

MUCINOUS CYSTADENOCARCINOMA
 Rare malignant mucinous ovarian epithelial tumor.
 May be metastatic from appendiceal or other GI tumors.
 Can result in pseudomyxoma peritonei—intraperitoneal accumulation of
mucinous material.

GERM CELL TUMORS

 2nd most common type of ovarian tumor (15% of cases).

 Usually occur in women of reproductive age.
 Tumor subtypes mimic tissues normally produced by germ cells.
1. Fetal tissue  cystic teratoma and embryonal carcinoma.
2. Oocytes  dysgerminoma.
3. Yolk sac  endodermal sinus tumor.
4. Placental tissue  choriocarcinoma.

MATURE CYSTIC TERATOMA (DERMOID CYST)

1) Cystic mass composed of fetal tissue derived from two or three embryologic
layers (e.g., skin, hair, bone, cartilage, gut, and thyroid) B.
2) Most common ovarian tumor in females 10–30 years old.
3) Can present with pain 2° to ovarian enlargement or torsion.
4) Benign, but presence of immature tissue (usually neuroectoderm) or somatic
malignancy (usually squamous cell carcinoma of skin) indicates malignant
potential.
5) Immature teratoma:
 Aggressive, malignant, contains fetal tissue, neuroectoderm.
 Commonly diagnosed before age 20.
6) Struma ovarii:
 A teratoma composed primarily of thyroid tissue C ―monodermal form‖.

P a g e 86 | 158
[Link] REPRODUCTIVE SYSTEM

DYSGERMINOMA
1) Tumor composed of large cells with clear cytoplasm and central nuclei (resemble
oocytes)  sheets of uniform “fried egg” cells.
2) Most common malignant germ cell tumor  most common in adolescents.
3) Testicular counterpart is called seminoma, which is a relatively common germ cell
tumor in males.
4) Good prognosis; responds to radiotherapy.
5) hCG, LDH = tumor markers.

ENDODERMAL SINUS TUMOR = YOLK SAC TUMOR

1) Malignant tumor that mimics the yolk sac.
2) Most common germ cell tumor in children. Most common tumor in male infants.
3) Serum AFP is often elevated.
4) Aggressive, in ovaries or testes and sacrococcygeal area in young children.
5) Histology:
a) Yellow, friable (hemorrhagic), solid mass.
b) Schiller-Duval bodies (glomerulus-like structures).

P a g e 87 | 158
[Link] REPRODUCTIVE SYSTEM

CHORIOCARCINOMA
1) Malignant tumor composed of trophoblasts and syncytiotrophoblasts; mimics
placental tissue, but villi are absent.
2) Small, hemorrhagic tumor with early hematogenous spread.
3) High B-hCG is characteristic (produced by syncytiotrophoblasts).
4) May lead to thecal cysts in the ovary.
5) Poor response to chemotherapy.

EMBRYONAL CARCINOMA
1) Malignant tumor composed of large primitive cells.
2) Aggressive with early metastasis.

SEX CORD STROMAL TUMOR

FIBROMA (BENIGN)
 Benign tumor of fibroblasts  bundles of spindle-shaped fibroblasts.
 Meigs syndrome—triad of ovarian fibroma, ascites, hydrothorax.
 ―Pulling‖ sensation in groin.

THECOMA (BENIGN)
 Like granulosa cell tumors, may produce estrogen.
 Usually presents as abnormal uterine bleeding in a postmenopausal woman.

P a g e 88 | 158
[Link] REPRODUCTIVE SYSTEM

GRANULOSA CELL TUMOR (MALIGNANT)

 ―Give Granny a Call!‖

SERTOLI-LEYDIG CELL TUMOR

 Composed of Sertoli cells that form tubules and Leydig cells (between tubules)
with characteristic Reinke crystals (pink).
 May produce androgen; associated with hirsutism and virilization.

P a g e 89 | 158
[Link] REPRODUCTIVE SYSTEM

METASTATIC TUMOR TO THE OVARY

KRUKENBERG TUMOR
 Metastatic mucinous tumor that involves both ovaries.
 Bilaterality helps distinguish metastases from primary mucinous
carcinoma of the ovary, which is usually unilateral.
 Mucin-secreting signet cell adenocarcinoma.
 Most commonly due to metastatic gastric carcinoma (diffuse type):

PSEUDOMYXOMA PERITONEI
 Massive amounts of mucus in the peritoneum.
 Due to a mucinous tumor of the appendix, usually with metastasis to the ovary.

P a g e 90 | 158
[Link] REPRODUCTIVE SYSTEM

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.

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, chromosomal abnormalities (eg,
Turner syndrome).

P a g e 91 | 158
[Link] REPRODUCTIVE SYSTEM

ENDOMETRIAL & MYOMETRIUM CONDITIONS

 Endometrium is hormonally sensitive:
1. Growth of the endometrium is estrogen driven (proliferative phase).
2. Preparation of the endometrium for implantation is progesterone driven
(secretory phase).
3. Shedding occurs with loss of progesterone support (menstrual phase).

POLYP

 Hyperplastic protrusion of endometrium. May contain smooth muscle cells.

 May be asymptomatic or present with painless abnormal uterine bleeding.
 Can arise as a side effect of tamoxifen, which has anti-estrogenic effects on the breast
but weak pro-estrogenic effects on the endometrium.

ADENOMYOSIS

 Extension of endometrial tissue (glandular) into uterine myometrium.

 Caused by hyperplasia of basal layer of endometrium.
 Presentation:
 Heavy menstrual bleeding, which is due to an increased endometrial surface.
 Dysmenorrhea, which results from endometrial tissue growth in the confined
myometrial space.
 Uniformly enlarged, soft, globular uterus. This is due to hormonal
stimulation of endometrial glandular tissue in the myometrium.
 Biopsy  normal-appearing endometrial tissue (vs. endometrial
hyperplasia).
 Treatment:
 GnRH agonists, hysterectomy or excision of an organized adenomyoma.

P a g e 92 | 158
[Link] REPRODUCTIVE SYSTEM

ENDOMETRIOSIS

 Non-neoplastic endometrium-like glands/stroma outside endometrial cavity.

 Can be found anywhere; most common sites are ovary (frequently bilateral), pelvis,
peritoneum.
 Sites of involvement:
1. Ovary  'chocolate' cyst.
2. Uterine ligaments  pelvic pain.
3. Douglas pouch  pain with defecation ―dyschazia‖.
4. Bladder wall (pain with urination).
5. Bowel serosa  abdominal pain and adhesions.
6. Fallopian tube mucosa  scarring increases risk for ectopic tubal pregnancy &
infertility.
7. implants classically appear as yellow-brown 'gun-powder' nodules

 Histopathology:
 Hemosiderin deposits and endometrial glands or stroma outside of the
uterus.
 In ovary  endometrioma:
 As the endometrial implants shed through the menstrual cycle, they can
accumulate old blood which appears as ―chocolate-colored‖ fluid inside an
ovarian cyst ―chocolate cysts‖.
 In pelvis & peritoneum  flesh-colored nodules, powder bum patterns, or
adhesive disease.

P a g e 93 | 158
[Link] REPRODUCTIVE SYSTEM

 Pathogenesis:
 May be due to retrograde flow, metaplastic transformation of multipotent
cells, and transportation of endometrial tissue via lymphatic system.
 Ectopic endometrium responds to hormonal influences of the menstrual cycle
in the same way as uterine endometrium.
 Bleeding and shedding of extrauterine endometrium leads to formation of
blood collections in the ectopic locations.
 Over time, the blood undergoes hemolysis and induces inflammation.
 Local inflammation is followed by adhesion formation, which in turn distorts
organ structure and function.
 Adhesions may interfere with ovulation and fallopian tube function, resulting
in infertility.
 Implants and adhesions involving the uterosacral ligament can result in a
fixed, retroverted uterus.
 Infiltration of the posterior cul-de-sac can result in painful intercourse and
tenderness with palpation of the posterior vaginal fornix.
 Shedding of the ectopic tissue causes dysmenorrhea (painful menses).
 Risk factors:
 Nulliparity, early menarche, and prolonged menses.
 In contrast, multiparity extended lactation, and late menarche decrease the
risk due to less frequent menstrual cycles and opportunity for endometrial
cells to be disseminated outside the uterus.
 Causes of infertility in endometriosis:
 The ovary is covered by simple cuboidal cells that divide and proliferate rapidly to
repair ovarian surface defects from ovulation.
 Ectopic endometrial tissue in the ovary may impair fertility by disrupting
folliculogenesis oocyte release, and oocyte fertilization.
 Endometriosis involving the fallopian tubes is also common and can impair fertility
by obstructing tubal transport.
 Adhesions.

P a g e 94 | 158
[Link] REPRODUCTIVE SYSTEM

 Treatment:
 NSAIDs
 Suppress endometrial cycle: continuous OCPs, progestins, GnRH agonists,
danazol, laparoscopic removal.

ASHERMAN SYNDROME

 Adhesions and/or fibrosis of the endometrium.

 Due to loss of the basalis (regenerative layer of the endometrium) and scarring.
 Often associated with overaggressive dilation and curettage of intrauterine cavity.
 Presents with ↓ fertility, recurrent pregnancy loss, abnormal uterine bleeding, pelvic
pain.

LEIOMYOMA (FIBROID)

 Most common tumor in females.

 Often presents with multiple discrete tumors A .
 ↑ Incidence in African Americans.
 Benign smooth muscle tumor; malignant transformation to leiomyosarcoma is rare.
 Estrogen sensitive—tumor size ↑ with pregnancy and ↓ with menopause.
 Peak occurrence at 20–40 years old.
 May be asymptomatic, cause abnormal uterine bleeding, or result in miscarriage.
 Severe bleeding may lead to iron deficiency anemia.
 Whorled pattern of smooth muscle bundles with well-demarcated borders B.
 Leiomyosarcoma:
 Malignant smooth muscles of the uterus.
 Arises de novo (not from fibroids).
 Occur in postmenopausal women.
 Usually a single large mass with necrosis and hemorrhage.
 Histological features include necrosis, mitotic activity, and cellular atypia.

P a g e 95 | 158
[Link] REPRODUCTIVE SYSTEM

ENDOMETRIAL HYPERPLASIA

 Abnormal endometrial gland proliferation.

 Usually caused by excess estrogen stimulation “unopposed estrogen”:
 Usually occurs in peri/postmenopausal women:
 Menstruation has slowed or stopped.
 Anovulation  no progesterone from the ovary.
 Any estrogen source  hyperplasia.
 Risk factors include anovulatory cycles, hormone replacement therapy,
polycystic ovarian syndrome, granulosa cell tumor.
 Obesity (increased conversion of androgens to estrogens)
 ↑ Risk for endometrial carcinoma:
 Nuclear atypia is greater risk factor than complex (vs simple) architecture.
 Presents as postmenopausal vaginal bleeding.
 Same presentation as endometrial carcinoma  biopsy  abundant crowded
glands.

ENDOMETRIAL CARCINOMA

 Most common gynecologic malignancy.

 Peak occurrence at 55–65 years old.
 Presents with postmenopausal bleeding.
 Typically preceded by endometrial hyperplasia.
 Risk factors include prolonged use of estrogen without progestins, obesity, diabetes,
hypertension, nulliparity, late menopause, early menarche, Lynch syndrome.

P a g e 96 | 158
[Link] REPRODUCTIVE SYSTEM

 Arises via two distinct pathways: hyperplasia and sporadic

 In the hyperplasia pathway (75% of cases):
 Carcinoma arises from endometrial hyperplasia.
 Risk factors are related to estrogen exposure and include early menarche/late
menopause, nulliparity, infertility with anovulatory cycles, and obesity.
 Histology is endometrioid (i.e., normal endometrium-like).
 In the sporadic pathway (25% of cases):
 Carcinoma arises in an atrophic endometrium with no evident precursor
lesion.
 Histology is usually serous and is characterized by papillary structures with
psammoma body formation.
 p53 mutation is common, and the tumor exhibits aggressive behavior.

ENDOMETRITIS

 Inflammation of endometrium.
 Types:
 Acute: pregnancy-related:
 Associated with retained products of conception following delivery,
miscarriage, abortion, or with foreign body (eg, IUD).
 Retained material in uterus promotes infection by bacterial flora from vagina
or intestinal tract  “Polymicrobial”.
 Caesarian section is a major risk factor  prophylactic AB is usually given
before CS.
 Chronic: non-pregnancy-related:
 Causes: IUD, PID, TB.
 Characterized by presence of plasma cells on histology.
 Presentation:
 Fever, abdominal pain, discharge, uterine tenderness.
 Treatment:
 Gentamicin + clindamycin +/- ampicillin.

P a g e 97 | 158
[Link] REPRODUCTIVE SYSTEM

ABNORMAL UTERINE BLEEDING

 Characterized as either heavy menstrual bleeding (AUB/HMB) or intermenstrual

bleeding (AUB/IMB).
 These are further subcategorized by PALMCOEIN:
 Structural causes (PALM):
 Polyp, Adenomyosis, Leiomyoma, or Malignancy/ hyperplasia.
 Non-structural causes (COEIN):
 Coagulopathy, Ovulatory, Endometrial, Iatrogenic, Not yet classified.
 Terms such as dysfunctional uterine bleeding, menorrhagia, oligomenorrhea are no
longer recommended.

P a g e 98 | 158
[Link] REPRODUCTIVE SYSTEM

SEX CHROMOSOME DISORDERS

 Aneuploidy most commonly due to meiotic nondisjunction.

KLINEFELTER SYNDROME

Genetics  Caused by a meiotic nondisjunction event during parental gametogenesis that results
in a 47,XXY karyotype (male).
 Variants include [Link]/[Link] mosaicism and [Link].
 In general, patients with higher numbers of X chromosomes are more likely to have
more severe manifestations.
 Presence of inactivated X chromosome (Barr body)

Findings  The disorder is usually not diagnosed until puberty when the characteristic physical
signs begin to develop.
 The major features are as follows:
1. Primary testicular failure:
a. Due to hyalinization and fibrosis of the seminiferous tubules.
b. This results in small, firm testes (testicular atrophy) and azoospermia
(infertility).
c. Dysgenesis of seminiferous tubules  ↓ inhibin B  ↑ FSH.
d. Abnormal Leydig cell function  ↓ testosterone  ↑ LH  ↑
estrogen.
2. ↓ Testosterone & ↑ estrogen result in:
a. Eunuchoid body habitus.
b. Tall stature.
c. Gynecomastia.
d. Female hair distribution.
e. Muscle mass is decreased.
3. Mild intellectual disability is seen in some patients, although the majority
have normal intelligence.
4. Psychosocial abnormalities (eg. lack of insight, poor judgment) are also
common.

P a g e 99 | 158
[Link] REPRODUCTIVE SYSTEM

TURNER SYNDROME

Genetics  Most commonly caused by paternal meiotic nondisjunction during

gametogenesis.
 The loss of the parental X chromosome in the sperm results in a missing X-
chromosome in most or all cells.
 Turner has 3 forms:
1. Complete loss of an X chromosome ([Link]): most of patients.
2. Mosaicism:
a. Missing the X chromosome in some of cells.
b. This is known as mosaic Turner syndrome (45, X / 46, XX).
c. Due to non-disjunction in mitosis after fertilization.
3. Abnormal X-chromosome:
a. Some patients have both X chromosomes, but one is
abnormally shaped, missing some genetic material, or has
structural abnormalities (eg, X fragments, isochromosomes).
b. No Barr body.
 The loss of the X chromosome results in a missing SHOX gene, which is
responsible for long bone growth. Therefore, patients with Turner syndrome
typically have short stature.

Findings  Short stature (if untreated; preventable with growth hormone therapy).
 Shield chest (broad, with widely spaced nipples), and webbed neck (broad
neck with low hairline).
 Streak ovaries (degeneration of the ovarian follicles with replacement by
fibrotic tissue)  ↓Estrogen will lead to:
1. Most common cause of primary amenorrhea.
2. ↓ Breast development.
3. ↓ Estrogen leads to  ↑ LH, FSH.
4. Pregnancy is possible in some cases (IVF, exogenous estradiol-17β
and progesterone).
 Lymphatic defects (result in webbed neck or cystic hygroma; lymphedema
in feet, hands). The swelling decreases with age.
 Coarctation of the aorta, bicuspid aortic valve.
 Horseshoe kidney.

P a g e 100 | 158
[Link] REPRODUCTIVE SYSTEM

DOUBLE Y MALES

 47, XYY.
 Phenotypically normal (usually undiagnosed), very tall.
 Normal fertility.
 May be associated with severe acne, learning disability, autism spectrum
disorders.

OVOTESTICULAR DISORDER OF SEX DEVELOPMENT

 46,XX > 46,XY.

 Both ovarian and testicular tissue present (ovotestis); ambiguous genitalia.
 Previously called true hermaphroditism.

DIAGNOSING DISORDERS OF SEX HORMONES

P a g e 101 | 158
[Link] REPRODUCTIVE SYSTEM

OTHER DISORDERS OF SEX DEVELOPMENT

 Disagreement between the phenotypic sex (external genitalia, influenced by

hormonal levels) and the gonadal sex (testes vs ovaries, corresponds with Y
chromosome).
 Includes the terms pseudohermaphrodite, hermaphrodite, and intersex.

46,XX DSD
 Ovaries present, but external genitalia are virilized or ambiguous.
 Due to excessive and inappropriate exposure to androgenic steroids during early
gestation (eg, congenital adrenal hyperplasia or exogenous administration of
androgens during pregnancy).

46,XY DSD
 Testes present, but external genitalia are female or ambiguous.
 Most common form is androgen insensitivity syndrome (testicular feminization).

PLACENTAL AROMATASE DEFICIENCY

 Inability to synthesize estrogens from androgens.
 Masculinization of female (46,XX DSD) infants (ambiguous genitalia), ↑ serum
testosterone and androstenedione.
 Can present with maternal virilization during pregnancy (fetal androgens cross the
placenta).

5Α-REDUCTASE DEFICIENCY
 Autosomal recessive; sex limited to genetic males (46,XY DSD).
 Inability to convert testosterone to DHT.
 Ambiguous genitalia until puberty, when ↑ testosterone causes masculinization/ ↑
growth of external genitalia.
 Testosterone/estrogen levels are normal; LH is normal or ↑.
 Internal genitalia are normal.

P a g e 102 | 158
[Link] REPRODUCTIVE SYSTEM

ANDROGEN INSENSITIVITY SYNDROME

 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.
 Patients develop normal functioning testes (often found in labia majora; surgically
removed to prevent malignancy).
 ↑ Testosterone, estrogen, LH (vs sex chromosome disorders).

P a g e 103 | 158
[Link] REPRODUCTIVE SYSTEM

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/anosmia.
 ↓ GnRH, FSH, LH, testosterone.
 Infertility (low sperm count in males; amenorrhea in females).

P a g e 104 | 158
[Link] REPRODUCTIVE SYSTEM

EVALUATION OF PRIMARY AMENORRHEA

P a g e 105 | 158
[Link] REPRODUCTIVE SYSTEM

HYDATIDIFORM MOLE
 Hydatid = fluid filled cyst. Mola = Greek for ―false pregnancy‖.
 Cystic swelling of chorionic villi:
 Villi form clusters - ―clusters of grapes‖.
 Ultrasound: ―snow storm appearance‖.
 Proliferation of chorionic epithelium (only trophoblast).
 Associated with hCG-mediated sequelae: early preeclampsia (before 20
weeks), theca-lutein cysts, hyperemesis gravidarum, hyperthyroidism.
 Presents with:
 Vaginal bleeding due to Separation of molar villi from decidua.
 Uterine enlargement more than expected.
 Pelvic pressure/pain.
 Treatment:
 Dilation and curettage and methotrexate.
 Monitor β-hCG.

COMPLETE MOLE
 Fertilization of “empty” egg.
 All chromosomes of paternal origin, no maternal chromosomes.
 Cells usually 46,XX karyotype: due to duplication of the haploid sperm.
 23 X  46 XX
 46,YY does not occur  lethal
 Rarely 46,XY moles occur  ―Empty egg fertilized by two sperm‖.
 p57-negative on immunostaining:
 Cyclin dependent kinase.
 Only expressed by maternal chromosomes (imprinted).
 No fetal tissue:
 Because maternal chromosomes needed for fetal tissue.
 No fetus to drain villi = massively swollen villi.
 Most common form of molar pregnancy.

PARTIAL MOLE
 Less common form.
 Fertilization of normal egg by two sperm.
 Some fetal tissue (maternal chromosomes).
 Some villi drainage = less swollen villi.
 Cells usually triploid (69,XXX - 69,XXY - Rarely 69,XYY).
 P57-positive (maternal genetic material).

P a g e 106 | 158
[Link] REPRODUCTIVE SYSTEM

P a g e 107 | 158
[Link] REPRODUCTIVE SYSTEM

P a g e 108 | 158
[Link] REPRODUCTIVE SYSTEM

CHORIOCARCINOMA
 Malignancy of trophoblastic tissue A (cytotrophoblasts, syncytiotrophoblasts).
 No chorionic villi present.
 Choriocarcinoma may arise as a complication of gestation (spontaneous abortion,
normal pregnancy, or hydatidiform mole) or as a spontaneous germ cell tumor.
 Choriocarcinomas that arise from the gestational pathway respond well to
chemotherapy; those that arise from the germ cell pathway do not.
 Presents with:
 Develop during or after pregnancy in mother or baby.
 Abnormal vaginal bleeding, uterine enlargement.
 Significantly ↑ β-hCG  ↑ frequency of bilateral/ multiple theca-lutein cysts.
 Shortness of breath, hemoptysis.
o Early hematogenous spread to lungs  “cannonball” metastases B.
 Pathology:
 Gross picture:
o Bulky intrauterine mass that is usually soft and yellow-white.
o Extensive areas of necrosis and hemorrhage.
 Microscopic:
o Abnormal proliferation of mononuclear cytotrophoblasts (red arrows)
and multinuclear syncytiotrophoblasts (green arrows).
o No chorionic villi are present (vs. molar pregnancy).

P a g e 109 | 158
[Link] REPRODUCTIVE SYSTEM

P a g e 110 | 158
[Link] REPRODUCTIVE SYSTEM

PREGNANCY COMPLICATIONS

ABRUPTIO PLACENTAE

 Premature separation (partial or complete) of placenta from uterine wall before

delivery.
 Presents in 3rd trimester.
 Abrupt onset of painful vaginal bleeding.
 Pathophysiology:
 Blood loss from maternal vessels.
o Rupture of maternal vessels in decidua basalis.
 Blood separates decidua from uterus.

 Complications:
1. Maternal shock.
2. Fetal distress/demise.
3. Disseminated intravascular coagulation (DIC).
4. Ischemic cortical necrosis:
 Rare cause of acute renal failure.
 Related to ischemia and DIC.
 Can lead to permanent renal failure.
 Clinical presentation: acute renal failure, anuria, hematuria (may be
gross), flank pain.

P a g e 111 | 158
[Link] REPRODUCTIVE SYSTEM

MORBIDLY ADHERENT PLACENTA

 Normal placenta attaches to decidua.

 Abnormal decidua  abnormal attachment  placenta attaches directly to
myometrium.
 Risk factors:
 Prior C-section ―most important risk factor‖ or uterine surgery involving
myometrium. This will leave a scar tissue which will inhibit the normal
decidualization later on.
 Inflammation, placenta previa, advanced maternal age, multiparity.
 Three types distinguishable by the depth of penetration:

PLACENTA ACCRETE
 Placenta attaches to myometrium without penetrating it.
 Most common type.

PLACENTA INCRETA
 Placenta penetrates into myometrium.

PLACENTA 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).

P a g e 112 | 158
[Link] REPRODUCTIVE SYSTEM

 Presentation of morbidly adherent placenta:

 Often detected on ultrasound prior to delivery.
 No separation of placenta after delivery  postpartum bleeding (can cause
Sheehan syndrome).

PLACENTA PREVIA

 Previa = ―going before‖  placenta before baby.

 Attachment of placenta to lower uterine segment over (or < 2 cm from) internal
cervical os. A ―preview‖ of the placenta is visible through cervix.

P a g e 113 | 158
[Link] REPRODUCTIVE SYSTEM

VASA PREVIA

 Previa = before. The blood vessel comes before the baby.

 Fetal vessels run over, or in close proximity to, cervical os.
 May result in vessel rupture, exsanguination, fetal death.
 Presents with triad of
1) Membrane rupture.
2) Painless vaginal bleeding.
3) Fetal bradycardia (< 110 beats/min).
 Emergency C-section usually indicated.
 Frequently associated with velamentous umbilical cord insertion:
1) Normal umbilical cord: inserts into central placenta.
2) Velamentous cord: cord inserts in chorioamniotic membrane rather than
placenta  fetal vessels travel to placenta unprotected by Wharton jelly 
risk of rupture/bleeding.

P a g e 114 | 158
[Link] REPRODUCTIVE SYSTEM

POSTPARTUM HEMORRHAGE

 Due to 4 T’s: Tone (uterine atony; most common), Trauma (lacerations, incisions,
uterine rupture), Thrombin (coagulopathy), Tissue (retained products of conception).

ECTOPIC PREGNANCY

 Implantation of fertilized ovum in a site other than the uterus, most often in ampulla
of fallopian tube ―midportion of the fallopian tube‖.
 Presentation:
 Suspect with history of amenorrhea and sudden lower abdominal pain.
 Pain +/- bleeding.
 Lower-than-expected rise in hCG based on dates.
 Confirm with ultrasound.
 Often clinically mistaken for appendicitis.
 Risk factors:
 Prior ectopic pregnancy, History of infertility, Salpingitis (PID), Ruptured
appendix, Prior tubal surgery, Smoking, Advanced maternal age.
 Treatment: surgery or methotrexate.

SPONTANEOUS ABORTION = MISCARRIAGE

 Pregnancy loss before 20 weeks.

 After 20 weeks: stillbirth or fetal demise.
 Presents as vaginal bleeding, often requires D&C to remove all tissue.
 50% cases due to fetal chromosomal abnormalities.
 Risk Factors:
 Maternal smoking, alcohol, cocaine.
 Maternal infection (TORCH).
 Hypercoagulable states.
 Lupus/antiphospholipid syndrome.

P a g e 115 | 158
[Link] REPRODUCTIVE SYSTEM

SEPTIC ABORTION

AMNIOTIC FLUID ABNORMALITIES

POLYHYDRAMNIOS

 Too much amniotic fluid.

 Causes & risk factors: (often idiopathic):
 Fetal swallowing malformations.
o Esophageal/duodenal atresia, anencephaly.
 Maternal diabetes:
o Fetal hyperglycemia  polyuria.
 Fetal anemia:
o Leads to high fetal cardiac output  ↑ urine production.
o Can occur in parvovirus infection.
 Multiple gestations  more fetal urine.

P a g e 116 | 158
[Link] REPRODUCTIVE SYSTEM

OLIGOHYDRAMNIOS

 Too little amniotic fluid.

 Causes:
 Fetal renal abnormalities:
 Bilateral renal agenesis, posterior urethral valves (males).
 Placental insufficiency:
 Preeclampsia, maternal vascular diseases.
 Premature rupture of membranes
 Any profound oligohydramnios can cause Potter sequence.

HYPERTENSION IN PREGNANCY

GESTATIONAL HYPERTENSION

 BP > 140/90 mm Hg after 20th week of gestation.

1. No pre-existing hypertension.
2. No proteinuria or end-organ damage.
 Treatment:
1. Antihypertensive (Hydralazine, α-Methyldopa, Labetalol, Nifedipine), deliver
at 37–39 weeks. Hypertensive Moms Love Nifedipine.

P a g e 117 | 158
[Link] REPRODUCTIVE SYSTEM

PREECLAMPSIA

 If these symptoms appear before 20th week suggest molar pregnancy.

 Pathophysiology:
1. Caused by abnormal placental spiral arteries  endothelial dysfunction,
vasoconstriction, ischemia.
2. Abnormal placental vasculature leads to placental hypoxia and ischemia,
which in turn result in the release of antiangiogenic factors into maternal
circulation.
3. The release of these inflammatory factors from the hypoxic placenta causes
endothelial injury. Damage to the endothelium increases its permeability,
resulting in proteinuria.
4. In addition, dysregulation of vascular tone results in elevated blood pressure,
which can cause end-organ damage, such as to the brain (eg, headaches,
visual changes) and liver (eg, abdominal pain).
 Incidence ↑ in patients with pre-existing hypertension, diabetes, chronic renal disease,
autoimmune disorders (eg, antiphospholipid antibody syndrome).
 Complications:
1. Placental abruption, coagulopathy, renal failure, uteroplacental insufficiency.
2. May lead to eclampsia (+ seizures) and/or HELLP syndrome.
3. Pulmonary edema.

P a g e 118 | 158
[Link] REPRODUCTIVE SYSTEM

ECLAMPSIA

 Preeclampsia + maternal seizures.

 Maternal death due to stroke, intracranial 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. The definitive treatment is
 Treatment: immediate delivery. delivery of the baby.

P a g e 119 | 158
[Link] REPRODUCTIVE SYSTEM

MATERNAL DIABETES

 Macrosomia may lead to shoulder dystocia.

 Hypoglycemia in the neonate of a diabetic mother typically resolves within 3-7 days
of birth as the hyperinsulinemia remits. Persistent hypoglycemia should prompt
investigation for inborn metabolic abnormalities or genetic defects affecting insulin
secretion (eg, persistent hyperinsulinemic hypoglycemia of infancy).

P a g e 120 | 158
[Link] REPRODUCTIVE SYSTEM

POSTPARTUM ENDOMETRITIS
 Pathophysiology:
 Cervix serves as protective barrier to normally sterile upper genital tract.
 With labor and delivery (esp. prolonged labor with rupture of membranes),
uterine cavity becomes increasingly contaminated with cervicovaginal flora.
 After C-section the presence of foreign bodies (e.g. suture material, surgical
instruments) and post-surgical collections of blood (e.g. hematomas) serve as
nidus for microbiological inoculation.
 Suture repair of uterine incision can produce necrosis of myometrial tissue,
which further contributes to uterine inflammation and infection.

 Polymicrobial:
 Typical organisms include Gardnerella vaginalis, Peptococcus, Bacteroides,
Staph epidermidis, and Strep agalactiae (GBS).
 Presents with:
 Fever, lower abdominal pain, and malodorous lochia (e.g. vaginal discharge)
following delivery.
 Uterine (fundal) tenderness and leukocytosis.
 Complications:
 Peritonitis and sepsis via hematogenous spread of pathogens.

P a g e 121 | 158
[Link] REPRODUCTIVE SYSTEM

POSTPARTUM OVARIAN VEIN THROMBOSIS

 Septic pelvic vein thrombosis that can occur as a complication of vaginal delivery or
C-section.
 Caused by Virchow’s Triad:
1. Stasis: pregnancy-related venous dilation and compression of the IVC and
iliac veins by the gravid uterus.
2. Hypercoagulable state: physiologic increases in factors 7, 8, 10, vWF, and
fibrinogen to protect from hemorrhage during miscarriage or birth.
3. Endothelial damage: due to uterine infection or intrapartum vascular trauma.
 Presents with: (diagnosis of exclusion)
1. Fever unresponsive to antibiotics.
2. Localized abdominal pain one week after delivery.
3. Diagnose with CT or MRI.
4. Most commonly right-sided, clot may extend to IVC (note: right uterine vein
drains into IVC, left into left renal vein), but pulmonary emboli are rare,
morbidity and mortality are low.

SUPINE HYPOTENSION SYNDROME (AORTOCAVAL COMPRESSION SYNDROME)

 Pathophysiology:
 Caused by gravid uterus compressing and obstructing IVC  ↓ venous
return (decreased preload)  ↓ cardiac output  hypotension  reflex
tachycardia ―palpitations‖.
 In severe cases may result in loss of consciousness or fetal demise.
 Presentation:
 Combination of hypotension, pallor, sweating, nausea, and dizziness that
occur when a pregnant woman lies supine (on her back).
o Symptoms resolve with sitting, standing, or when assuming a left lateral
decubitus position.
o Arises predominantly in women >20 weeks gestation.

P a g e 122 | 158
[Link] REPRODUCTIVE SYSTEM

DIFFERENTIAL DIAGNOSIS OF DYSMENORRHEA

P a g e 123 | 158
[Link] REPRODUCTIVE SYSTEM

ACUTE ABDOMINAL/PELVIC PAIN IN WOMEN

P a g e 124 | 158
[Link] REPRODUCTIVE SYSTEM

BREAST PATHOLOGY

INTRODUCTION

 The terminal duct lobular unit is the functional unit of the breast.
 Lobules make milk that drains via ducts to the nipple.
 Lobules and ducts are lined by two layers of epithelium:
1. Luminal cell layer: inner cell layer lining the ducts and lobules; responsible
for milk production in the lobules.
2. Myoepithelial cell layer: outer cell layer lining ducts and lobules; contractile
function propels milk towards the nipple.
 Breast tissue is hormone sensitive:
1. Before puberty, male and female breast tissue primarily consists of large ducts
under the nipple.
2. Development after menarche is primarily driven by estrogen and progesterone;
lobules and small ducts form and are present in highest density in the upper
outer quadrant.
3. Breast tenderness during the menstrual cycle is a common complaint,
especially prior to menstruation.
4. During pregnancy, breast lobules undergo hyperplasia.

P a g e 125 | 158
[Link] REPRODUCTIVE SYSTEM

 Hyperplasia is driven by estrogen and progesterone produced by the

corpus luteum (early first trimester), fetus, and placenta (later in
pregnancy).
5. After menopause, breast tissue undergoes atrophy.
 Galactorrhea refers to milk production outside of lactation.
1. It is not a symptom of breast cancer.
2. Causes include nipple stimulation (common physiologic cause), prolactinoma
of the anterior pituitary (common pathologic cause), and drugs.

BENIGN BREAST DISEASE

FIBROCYSTIC CHANGES

 Development of fibrosis and cysts in the breast.

1. Most common change in the premenopausal
breast.
2. Thought to be hormone mediated.
 Presents as vague irregularity of the breast tissue
('lumpy bumpy breast'):
1. Usually in the upper outer quadrant.
2. Often bilateral and multifocal.
 Pathophysiology: (all are benign).
1. Simple cysts:
 Fluid-filled duct dilation with dark fluid  blue-dome appearance on
gross exam.
 Leads to lumpy bumpy breast.
2. Fibrosis:
 Cyst ruptures  inflammation  stromal fibrosis.
3. Apocrine metaplasia:
 Also called benign epithelial alteration.
 Alteration to lobular epithelial cells ―papillary metaplasia‖.
 Take on the appearance of apocrine (gland) cells.
 Subtypes include:
1. Sclerosing adenosis:
 Increased number of compressed acini.
 Acini and stromal fibrosis, associated with calcifications.
 Slight (1.5–2 ×) ↑ risk for cancer.
2. Epithelial hyperplasia:
 ↑ Luminal & Myoepithelial cells  distended ducts or lobules filled with
cluster of cells.
 ↑ Risk of carcinoma with atypical cells.

P a g e 126 | 158
[Link] REPRODUCTIVE SYSTEM

INFLAMMATORY PROCESSES

FAT NECROSIS
 Benign, usually painless, lump due to injury to breast tissue.
1. Up to 50% of patients may not report trauma.
 Calcified oil cyst on mammography; necrotic fat and giant cells on biopsy.

LACTATIONAL MASTITIS
 Occurs during breastfeeding, ↑ risk of bacterial infection through cracks in nipple.
 S aureus is most common pathogen.
 Treat with antibiotics and continue breastfeeding (continued drainage to avoid breast
abscess formation).

P a g e 127 | 158
[Link] REPRODUCTIVE SYSTEM

PERIDUCTAL MASTITIS
 Inflammation of the subareolar ducts.
 Usually seen in smokers:
 Relative vitamin A deficiency results in squamous metaplasia of lactiferous
ducts, producing duct blockage and inflammation.
 Clinically presents as a subareolar mass with nipple retraction.

MAMMARY DUCT ECTASIA

 Inflammation with dilation (ectasia) of the subareolar ducts.
 Rare; classically arises in multiparous postmenopausal women.
 Presents as a periareolar mass with green-brown nipple discharge (inflammatory
debris).
 Chronic inflammation with plasma cells is seen on biopsy.

BENIGN TUMORS

FIBROADENOMA
 The most common benign tumor of the breast.
 Most common in women < 35 years old.
 Small, well-defined, mobile mass.
1. ↑ Size and tenderness with ↑ estrogen (eg, pregnancy, prior to menstruation).
2. Usually regress after menopause.
 Risk of cancer is usually not increased.
 Histopathology: cellular or myxoid stroma that encircles and sometimes compresses
epithelium-lined glandular and cystic spaces.
 On ultrasound: hypoechoic mass (vs black cyst in fibrocystic disease).

P a g e 128 | 158
[Link] REPRODUCTIVE SYSTEM

INTRADUCTAL PAPILLOMA
 Proliferation of normal epithelium within lactiferous ducts, typically beneath areola.
1. Cells grow in a finger-like projections ―papilla‖.
 Most common cause of nipple discharge (serous or bloody) in premenopausal.
1. No associated mass or lymphadenopathy.
 Slight (1.5–2 ×) ↑ risk for cancer.
 Must be distinguished from papillary carcinoma, which also presents as bloody
nipple discharge:
1. Papillary carcinoma is characterized by fibrovascular projections lined by
epithelial cells without underlying myoepithelial cells.
2. Risk of papillary carcinoma increases with age; thus, it is more commonly
seen in postmenopausal women.

P a g e 129 | 158
[Link] REPRODUCTIVE SYSTEM

PHYLLODES TUMOR
 Fibroadenoma-like tumor with overgrowth of the fibrous component; characteristic
'leaf-like' projections are seen on biopsy.
 Large mass of connective tissue and cysts with ―leaf-like‖ lobulations.
 Most common in 5th decade.
 Some may become malignant.

P a g e 130 | 158
[Link] REPRODUCTIVE SYSTEM

GYNECOMASTIA

 Breast enlargement in males due to ↑ estrogen compared with androgen activity.

 Physiologic causes:
1. Newborn male baby: due to placental transfer of maternal estrogen; transient.
2. At puberty in males: due to some androgen to estrogen conversion; transient.
3. Elderly males: less testosterone & more fatty tissue.
 Pathologic causes:
1. Cirrhosis (↓ liver metabolism of estrogen).
2. Hypogonadism (eg, Klinefelter syndrome) (↓ testosterone).
3. Testicular tumors.
4. Drugs (Spironolactone, Hormones, Cimetidine, Finasteride, Ketoconazole:
―Some Hormones Create Funny Knockers‖).

P a g e 131 | 158
[Link] REPRODUCTIVE SYSTEM

MALIGNANT BREAST TUMORS

BASIC PRINCIPLES:
 Commonly postmenopausal. Usually arise from terminal duct lobular unit.
 Most often located in upper-outer quadrant of breast.
 Risk factors: ↑ estrogen exposure, ↑ total number of menstrual cycles, older age at 1st
live birth, obesity (↑ estrogen exposure as adipose tissue converts androstenedione to
estrone), BRCA1 or BRCA2 gene mutations, African American ethnicity (↑ risk for
triple ⊝ breast cancer).

P a g e 132 | 158
[Link] REPRODUCTIVE SYSTEM

NONINVASIVE

DUCTAL CARCINOMA IN SITU

 Malignant proliferation of cells in ducts with no invasion of the basement
membrane.
 Arises from ductal atypia.
 Often detected as calcification on mammography; DCIS does not usually produce a
mass.
1. Mammographic calcifications can also be associated with benign conditions
such as fibrocystic changes (especially sclerosing adenosis) and fat necrosis.
2. Biopsy of calcifications is often necessary to distinguish between benign and
malignant conditions.

COMEDO CARCINOMA
 Ductal, dystrophic calcification in the center of ducts.
 Subtype of DCIS.

P a g e 133 | 158
[Link] REPRODUCTIVE SYSTEM

PAGET DISEASE
 DCIS that extends up the ducts to involve the skin of the nipple.
 Eczematous patches on nipple:
1. Crusty, scaly redness on the nipple and areola with oozing and bleeding.
 Paget cells = intraepithelial adenocarcinoma cells.

LOBULAR CARCINOMA IN SITU (LCIS)

 Malignant proliferation of cells in lobules with no invasion of the BM.
 Usually discovered incidentally on biopsy:
1. LCIS does not produce a mass or calcifications.
 Characterized by dyscohesive cells lacking E-cadherin adhesion protein.
 Often multifocal and bilateral.
 Treatment is tamoxifen (to reduce the risk of subsequent carcinoma) and close
follow-up; low risk of progression to invasive carcinoma.

INVASIVE

INVASIVE DUCTAL CARCINOMA

 Invasive carcinoma that classically forms duct-like structures.
 Most common type of invasive carcinoma in the breast, accounting for > 80% of
cases.
 Presents as a “rock-hard” mass with sharp margins detected by physical exam or by
mammography.
1. Clinically detected masses are usually 2 cm or greater.
2. Mammographically detected masses are usually 1 cm or greater.
3. Advanced tumors can deform suspensory ligaments result in dimpling of the
skin or retraction of the nipple.
 Biopsy usually shows duct-like structures in a desmoplastic stroma.
 Special subtypes of invasive ductal carcinoma include:
1. Tubular carcinoma: characterized by well-differentiated tubules that lack
myoepithelial cells; relatively good prognosis.
P a g e 134 | 158
[Link] REPRODUCTIVE SYSTEM

2. Mucinous carcinoma: characterized by carcinoma with abundant

extracellular mucin ('tumor cells floating in a mucus pool').
 Tends to occur in older women (average age is 70 years).
 Relatively good prognosis.
3. Medullary carcinoma: characterized by large, high-grade cells growing in
sheets with associated lymphocytes and plasma cells.
 Grows as a well-circumscribed mass that can mimic fibroadenoma on
mammography.
 Relatively good prognosis.
 Increased incidence in BRCA1 carriers.

P a g e 135 | 158
[Link] REPRODUCTIVE SYSTEM

INVASIVE LOBULAR CARCINOMA

 Invasive carcinoma that characteristically grows in a row of cells ―single-file
pattern.” Lines of cells = Lobular
 Cells may exhibit signet-ring morphology.
 No duct formation & raw pattern are due to lack of E-cadherin.
 Often bilateral with multiple lesions in the same location.

INFLAMMATORY BREAST CANCER

 Dermal lymphatic invasion by breast carcinoma.
 Peau d’orange (skin texture resembles orange peel E due to edema leading to
tightening of Cooper’s suspensory ligament); neoplastic cells block lymphatic
drainage.

P a g e 136 | 158
[Link] REPRODUCTIVE SYSTEM

PROGNOSTIC AND PREDICTIVE FACTORS OF BREAST CANCER

 Prognosis in breast cancer is based on TNM staging:
1. Metastasis is the most important factor, but most patients present before
metastasis occurs.
2. Spread to axillary lymph nodes is the most useful prognostic factor (given that
metastasis is not common at presentation); sentinel lymph node biopsy is used
to assess axillary lymph nodes.
 Predictive factors predict response to treatment:
1. Most important factors are estrogen receptor (ER), progesterone receptor
(PR), and HER2/neu gene amplification (overexpression) status.
2. Presence of ER and PR is associated with response to antiestrogenic agents
(e.g., tamoxifen); both receptors are located in the nucleus.
3. HER2/neu amplification is associated with response to trastuzumab
(Herceptin), a designer antibody directed against the HER2 receptor;
HER2/neu is a growth factor receptor present on the cell surface.
4. 'Triple-negative' tumors are negative for ER, PR, and HER2/neu and have a
poor prognosis; African American women have an increased propensity to
develop triple-negative carcinoma.

P a g e 137 | 158
[Link] REPRODUCTIVE SYSTEM

HEREDITARY BREAST CANCER

 Represents 10% of breast cancer cases.
 Clinical features that suggest hereditary breast cancer include multiple, first-degree
relatives with breast cancer, tumor at an early age (premenopausal), and multiple
tumors in a single patient.
 BRCA1 and BRCA2 mutations are the most important single gene mutations
associated with hereditary breast cancer.
1. BRCAl mutation is associated with breast and ovarian carcinoma.
2. BRCA2 mutation is associated with breast carcinoma in males.
 Women with a genetic propensity to develop breast cancer may choose to undergo
removal of both breasts (bilateral mastectomy) to decrease the risk of developing
carcinoma. A small risk for cancer remains because breast tissue sometimes extends into the
axilla or subcutaneous tissue of the chest wall.

MALE BREAST CANCER

 Breast cancer is rare in males (represents 1% of all breast cancers).
 Usually presents as a subareolar mass in older males.
1. Highest density of breast tissue in males is underneath the nipple.
2. May produce nipple discharge.
 Most common histological subtype is invasive ductal carcinoma.
1. Lobular carcinoma is rare (the male breast develops very few lobules).
 Associated with BRCA2 mutations and Klinefelter syndrome.

P a g e 138 | 158
[Link] REPRODUCTIVE SYSTEM

PENILE PATHOLOGY
PRIAPISM
 Painful sustained erection lasting > 4 hours.
 Two types: ischemic and non-ischemic.

ISCHEMIC PRIAPISM:
 Most common type (95%).
 Lack of outflow  tissue ischemia.
 Associated with sickle cell disease (sickled RBCs block venous drainage of corpus
cavernosum vascular channels), medications (eg, sildenafil, trazodone).
 Treat immediately with corporal aspiration, intracavernosal phenylephrine, or surgical
decompression to prevent ischemia.

NON-ISCHEMIC PRIAPISM:
 High flow priapism.
 Fistula between arteries & corpus cavernosum.
 Often follows trauma.

SQUAMOUS CELL CARCINOMA

 More common in Asia, Africa, South America.
 Precursor in situ lesions:
1. Bowen disease (in penile shaft, presents as leukoplakia).
2. Erythroplasia of Queyrat (carcinoma in situ of the glans, presents as
erythroplakia).
3. Bowenoid papulosis (carcinoma in situ of unclear malignant potential,
presenting as reddish papules).
 Associated with uncircumcised males and HPV.

P a g e 139 | 158
[Link] REPRODUCTIVE SYSTEM

CRYPTORCHIDISM
 Undescended testis (one or both).
 Prematurity ↑ risk of cryptorchidism.
 Impaired spermatogenesis (since sperm develop best at temperatures < 37°C); can
have normal testosterone levels (Leydig cells are mostly unaffected by temperature).
 Associated with ↑ risk of germ cell tumors.
 ↓ Inhibin B, ↑ FSH, ↑ LH; testosterone ↓ in bilateral cryptorchidism, normal in
unilateral.

ORCHITIS
 Inflammation of the testicle.
 Causes:
1. Chlamydia trachomatis (serotypes D-K) or Neisseria gonorrhoeae:
 Seen in young adults.
 Increased risk of sterility, but libido is not affected because Leydig
cells are spared.
2. Escherichia coli and Pseudomonas:
 Seen in older adults; urinary tract infection pathogens spread into the
reproductive tract.
3. Mumps virus (teenage males):
 Increased risk for infertility.
 Testicular inflammation is usually not seen in children< 10 years old.
4. Autoimmune orchitis:
 Characterized by granulomas involving the seminiferous tubules.

P a g e 140 | 158
[Link] REPRODUCTIVE SYSTEM

TESTICULAR TORSION
 Rotation of testicle around spermatic cord and vascular pedicle.
 Commonly presents in males 12–18 years old.
 Characterized by acute, severe pain, high-riding testis, and absent cremasteric reflex.
 Treatment:
1. Surgical correction (orchiopexy) within 6 hours, manual detorsion if surgical
option unavailable in timeframe. Orchiopexy, when performed, should be
bilateral because the contralateral testis is at risk for subsequent torsion.
2. If testis is not viable, orchiectomy.

P a g e 141 | 158
[Link] REPRODUCTIVE SYSTEM

VARICOCELE
 Dilated veins in pampiniform plexus due to ↑ venous pressure.
 Most common cause of scrotal enlargement in adult males.
 Most often on left side because of ↑ resistance to flow from left gonadal vein drainage
into left renal vein.

 Scrotal swelling without transilluminattion.

P a g e 142 | 158
[Link] REPRODUCTIVE SYSTEM

SCROTAL MASSES
Benign scrotal lesions present as testicular masses that can be transilluminated (vs solid
testicular tumors).

CONGENITAL HYDROCELE

 Hydrocele: fluid collection within the tunica vaginalis

 Common cause of scrotal swelling A in infants.
 Due to incomplete obliteration of processus vaginalis leading to communication
with the peritoneal cavity.
 Most spontaneously resolve by 1 year old.
 Transilluminating swelling.

ACQUIRED HYDROCELE

 Scrotal fluid collection in tunica vaginalis usually 2° to blockage of lymphatic

drainage by infection, trauma, tumor ―non-communicating‖
 If bloody  hematocele.

SPERMATOCELE

 Cyst due to dilated epididymal duct or rete

testis.
 Paratesticular fluctuant nodule.

P a g e 143 | 158
[Link] REPRODUCTIVE SYSTEM

TESTICULAR TUMORS

 Arise from germ cells or sex cord-stroma.

 Present as a firm, painless testicular mass that cannot be transilluminated.
 Usually not biopsied due to risk of seeding the scrotum; removed via radical
orchiectomy.

GERM CELL TUMORS

 ∼ 95% of all testicular tumors.

 Most often occur in young men.
 Risk factors: cryptorchidism, Klinefelter syndrome.
 Divided into seminoma and nonseminoma:
1. Seminomas (55% of cases) are highly responsive to radiotherapy, metastasize
late, and have an excellent prognosis.
2. Nonseminomas (45% of cases) show variable response to treatment and often
metastasize early.

SEMINOMA
 Malignant tumor comprised of large cells with clear cytoplasm and central nuclei
(resemble spermatogonia)  similar to dysgerminoma of the ovary ―fried egg‖
appearance‖.
 Forms a homogeneous mass with no hemorrhage or necrosis.
 Painless, testicular enlargement; most common testicular tumor.
 Does not occur in infancy.
 ↑ Placental ALP.
 Good prognosis:
1. Highly radiosensitive.
2. Late metastasis.

P a g e 144 | 158
[Link] REPRODUCTIVE SYSTEM

YOLK SAC TUMOR

 Also known as testicular endodermal sinus tumor.
 Most common testicular tumor in boys < 3 years old.
 Yellow, mucinous.
 Aggressive malignancy of testes, analogous to ovarian yolk sac tumor.
 Schiller-Duval bodies resemble primitive glomeruli.
 ↑ AFP is highly characteristic.

EMBRYONAL CARCINOMA
 Malignant tumor comprised of immature, primitive cells that may produce glands.
 Forms a hemorrhagic mass with necrosis.
 Aggressive with early hematogenous spread.
 Chemotherapy may result in differentiation into another type of germ cell tumor
(e.g., teratoma).
 Painful; worse prognosis than seminoma.
 ―Pure‖ embryonal carcinoma is rare; most commonly mixed with other tumor types.
 May be associated with ↑ hCG and normal AFP levels when pure (↑ AFP when
mixed).

CHORIOCARCINOMA
 Malignant, ↑ hCG.
 Disordered syncytiotrophoblastic and
cytotrophoblastic elements.
 Hematogenous metastases to lungs and
brain.
 May produce gynecomastia, symptoms of
hyperthyroidism (α-subunit of hCG is
structurally similar to LH, FSH, TSH).

P a g e 145 | 158
[Link] REPRODUCTIVE SYSTEM

TERATOMA
 Unlike in females, mature teratoma in adult males may be malignant.
 Benign in children.

TESTICULAR NON–GERM CELL TUMORS

 5% of all testicular tumors. Mostly benign.

LEYDIG CELL TUMOR

 Golden brown color; contains Reinke crystals (eosinophilic cytoplasmic inclusions).
 Produces androgens or estrogens  gynecomastia in men, precocious puberty in
boys.

SERTOLI CELL TUMOR

 Androblastoma from sex cord stroma.

TESTICULAR LYMPHOMA
 Most common testicular cancer in older men > 60 years old.
 Usually of diffuse large B-cell type.
 Not a 1° cancer; arises from metastatic lymphoma to testes. Aggressive.

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.

P a g e 146 | 158
[Link] REPRODUCTIVE SYSTEM

PROSTATE

BASIC PRINCIPLES
 Small, round organ that lies at the base of the bladder encircling the urethra.
 Sits anterior to the rectum; posterior aspect of prostate is palpable by digital rectal
exam (DRE).
 Consists of glands and stroma:
1) Glands are composed of an inner layer of luminal cells and an outer layer
of basal cells; secrete alkaline, milky fluid that is added to sperm and
seminal vesicle fluid to make semen.
2) Glands and stroma are maintained by androgens.

PROSTATITIS
 Presentation:
1. Dysuria, frequency, urgency, low back pain.
2. On DRE  warm, tender, enlarged prostate.
 Acute bacterial prostatitis:
1. In older men  most common bacterium is E coli.
2. In young males  consider C trachomatis, N gonorrhoeae.
3. Prostatic secretions show WBCs; culture reveals bacteria.
 Chronic prostatitis:
1. Either bacterial or nonbacterial (eg, 2° to previous infection, nerve problems,
chemical irritation).
2. Prostatic secretions show WBCs, but cultures are negative.

P a g e 147 | 158
[Link] REPRODUCTIVE SYSTEM

BENIGN PROSTATIC HYPERPLASIA

 Hyperplasia of prostatic stroma and glands.
 Age-related change (present in most men by the age of 60 years); no increased risk
for cancer.
 Occurs in the central periurethral zone of the prostate.
 Pathophysiology: prostate enlargment causes urinary obstruction by 2 mechanisms:
 Static urinary obstruction (androgen-mediated enlargement of the prostate).
 5-a reductase inhibitors (eg, finasteride) inhibit the action of androgens on the
prostate gland preventing the conversion of testosterone to DHT and thereby
limiting further prostate enlargement.
 Or dynamic urinary obstruction (prostate smooth muscle contraction via α-
adrenoceptors).
 α-adrenergic blockers (eg. tamsulosin) relax the smooth muscle in the bladder
neck and prostate.
 Pathology:
 Characterized by smooth, elastic, firm nodular enlargement (hyperplasia not
hypertrophy) of periurethral (lateral and middle) lobes, which compress the
urethra into a vertical slit.
 Presentation:
 Often presents with ↑ frequency of urination, nocturia, difficulty starting and
stopping urine stream, dysuria.
 May lead to distention and hypertrophy of bladder, hydronephrosis, UTIs.
 Prostate-specific antigen (PSA) is often slightly elevated (usually less than
10 ng/ mL) due to the increased number of glands; PSA is made by prostatic
glands and liquefies semen.
 Treatment:

 PDE-5 inhibitors (eg, tadalafil).

 Surgical resection (eg, TURP, ablation).

P a g e 148 | 158
[Link] REPRODUCTIVE SYSTEM

PROSTATIC ADENOCARCINOMA
 Common in men > 50 years old.
 Prostatic carcinoma is most often clinically silent:
1. Usually arises in the peripheral, posterior region of the prostate and, hence,
does not produce urinary symptoms early.
2. Screening begins at the age of 50 years with DRE and PSA.
 Normal serum PSA increases with age due to BPH (2.5 ng/mL for ages 40-49
years vs. 7.5 ng/mL for ages 70- 79 years).
 PSA > 10 ng/dL is highly worrisome at any age.
 Decreased% free-PSA is suggestive of cancer (cancer makes bound PSA).
 Arises most often from posterior lobe (peripheral zone) of prostate gland and is most
frequently diagnosed by ↑ PSA and subsequent needle core biopsies.
 Prostatic acid phosphatase (PAP) and PSA are useful tumor markers (↑ total PSA,
with ↓ fraction of free PSA).
 Osteoblastic metastases in bone may develop in late stages, as indicated by lower
back pain and ↑ serum ALP and PSA.

P a g e 149 | 158
[Link] REPRODUCTIVE SYSTEM

PHARMACOLOGY
CONTROL OF REPRODUCTIVE HORMONES

P a g e 150 | 158
[Link] REPRODUCTIVE SYSTEM

LEUPROLIDE

 Mechanism:
 GnRH analog with agonist properties when used in pulsatile fashion;
antagonist properties when used in continuous fashion (downregulates GnRH
receptor in pituitary  ↓ FSH and ↓ LH).
 Leuprolide can be used in lieu of GnRH.
 Clinical use:
 Uterine fibroids, endometriosis, precocious puberty, prostate cancer,
infertility.
 Adverse effects:
 Hypogonadism, ↓ libido, erectile dysfunction, nausea, vomiting.

ESTROGENS

 Ethinyl estradiol, DES, mestranol.

 Mechanism:
 Bind estrogen receptors.
 Clinical use:
 Hypogonadism or ovarian failure, menstrual abnormalities (combined OCPs),
hormone replacement therapy in postmenopausal women.
 Adverse effects:
 ↑ Risk of endometrial cancer (when given without progesterone), bleeding in
postmenopausal women, clear cell adenocarcinoma of vagina in females
exposed to DES in utero, ↑ risk of thrombi.
 Contraindications—ER ⊕ breast cancer, history of DVTs, tobacco use in
women > 35 years old.

P a g e 151 | 158
[Link] REPRODUCTIVE SYSTEM

SELECTIVE ESTROGEN RECEPTOR MODULATORS

CLOMIPHENE
 Antagonist at estrogen receptors in hypothalamus.
 Prevents normal feedback inhibition and ↑ release of LH and FSH from pituitary,
which stimulates ovulation.
 Used to treat infertility due to anovulation (eg, PCOS).
 SERMs may cause hot flashes, ovarian enlargement, multiple simultaneous
pregnancies, visual disturbances.

TAMOXIFEN
 Mechanism: (mixed agonist/antagonist)
 Antagonist at breast.
 Agonist at bone, uterus.
 Uses:
 Treat and prevent recurrence of ER/PR ⊕ breast cancer.
 Estrogen-dependent benign breast lesions (eg, fibroadenoma, cystic changes).
 Adverse effects:
 Hot flashes.
 Endometrial hyperplasia & carcinoma.
 Endometrial polyps (36%).
 Venous thromboembolism.

RALOXIFENE
 Mechanism:
 Antagonist at breast, uterus.
 Agonist at bone.
 ↑ Risk of thromboembolic events but no increased risk of endometrial cancer (vs
tamoxifen).
 Used primarily to treat osteoporosis.

P a g e 152 | 158
[Link] REPRODUCTIVE SYSTEM

AROMATASE INHIBITORS

 Anastrozole, letrozole, exemestane.

 Mechanism  Inhibit peripheral conversion of androgens to estrogen.
 Clinical use  ER ⊕ breast cancer in postmenopausal women.

HORMONE REPLACEMENT THERAPY

 Used for relief or prevention of menopausal symptoms (eg, hot flashes, vaginal
atrophy), osteoporosis (↑estrogen, ↓ osteoclast activity).
 Unopposed estrogen replacement therapy ↑ risk of endometrial cancer,
progesterone/progestin is added. Possible increased cardiovascular risk.

PROGESTINS

 Synthetic progestins include:

 Levonorgestrel (found in combination pills and some intrauterine devices).
 Etonogestrel (found in the vaginal ring and implant).
 Norethindrone (found in the progestin-only pill).
 Medroxyprogesterone, megestrol .
 Many others when combined with estrogen.
 Mechanism:
 Bind progesterone receptors, ↓ growth and ↑ vascularization of endometrium.
 Thicken cervical mucus.
 Clinical use:
 Contraception (forms include pill, intrauterine device, implant, depot
injection), endometrial cancer, abnormal uterine bleeding.
 Progestin challenge: presence of withdrawal bleeding excludes anatomic
defects (eg, Asherman syndrome) and chronic anovulation without estrogen.

P a g e 153 | 158
[Link] REPRODUCTIVE SYSTEM

ANTIPROGESTINS

 Mifepristone, ulipristal.
 Mechanism:
 Competitive inhibitors of progestins at progesterone receptors.
 Clinical use:
 Termination of pregnancy (mifepristone with misoprostol); emergency
contraception (ulipristal).

CONTRACEPTIVES

COMBINED CONTRACEPTION

 Progestins and ethinyl estradiol; forms include pill, patch, vaginal ring.
 Estrogen and progestins inhibit LH/FSH and thus prevent estrogen surge.
 No estrogen surge  no LH surge  no ovulation.
 Progestins cause thickening of cervical mucus, thereby limiting access of sperm to
uterus.
 Progestins also inhibit endometrial proliferation  endometrium is less suitable to the
implantation of an embryo.
 Contraindications: smokers > 35 years old (↑ risk of cardiovascular events), patients
with ↑ risk of cardiovascular disease (including history of venous thromboembolism,
coronary artery disease, stroke), migraine (especially with aura), breast cancer, liver
disease.

P a g e 154 | 158
[Link] REPRODUCTIVE SYSTEM

COPPER INTRAUTERINE DEVICE

 Mechanism:
 Produces local inflammatory reaction toxic to sperm and ova, preventing
fertilization and implantation; hormone free.
 Clinical use:
 Long-acting reversible contraception.
 Most effective emergency contraception.
 Adverse effects:
 Heavier or longer menses, dysmenorrhea.
 Risk of PID with insertion (contraindicated in active pelvic infection).

P a g e 155 | 158
[Link] REPRODUCTIVE SYSTEM

MEDICATIONS USED TO TERMINATE PREGNANCY

P a g e 156 | 158
[Link] REPRODUCTIVE SYSTEM

TOCOLYTICS

 Medications that relax the uterus; include terbutaline (β2-agonist action), nifedipine
(Ca2+ channel blocker), indomethacin (NSAID).
 Used to ↓ contraction frequency in preterm labor and allow time for administration of
steroids (to promote fetal lung maturity) or transfer to appropriate medical center with
obstetrical care.

DANAZOL

 Mechanism:
 Synthetic androgen that acts as partial agonist at androgen receptors.
 Weak progesterone activity  ↓ LH surge  anovulation.
 Clinical use:
 Endometriosis, hereditary angioedema.
 Adverse effects:
 Androgen effects:
 Weight gain, edema, acne, hirsutism, masculinization.
 ↓ HDL levels, hepatotoxicity.
 Pseudotumor cerebri ―headache, papilledema‖.

TESTOSTERONE, METHYLTESTOSTERONE

 Mechanism:
 Agonists at androgen receptors.
 Clinical use:
 Treat hypogonadism and promote development of 2° sex characteristics;
stimulate anabolism to promote recovery after burn or injury.
 Adverse effects:
 Masculinization in females; ↓ intratesticular testosterone in males by
inhibiting release of LH (via negative feedback)  gonadal atrophy.
Premature closure of epiphyseal plates. ↑ LDL, ↓ HDL.

ANTIANDROGENS

FINASTERIDE
 5α-reductase inhibitor (↓ conversion of testosterone to DHT).
 Used for BPH and male-pattern baldness.
 Adverse effects: gynecomastia and sexual dysfunction.

FLUTAMIDE
 Nonsteroidal competitive inhibitor at androgen receptors.
 Used for prostate carcinoma.

P a g e 157 | 158
[Link] REPRODUCTIVE SYSTEM

KETOCONAZOLE
 Inhibits steroid synthesis (inhibits 17,20 desmolase/17α-hydroxylase).
 Used in PCOS to reduce androgenic symptoms.

SPIRONOLACTONE
 Inhibits steroid binding, 17,20
desmolase/17α- Both can cause gynecomastia and amenorrhea.
hydroxylase.

TAMSULOSIN

 α1-antagonist.
 Used to treat BPH by inhibiting smooth muscle contraction.
 Selective for α1A/D receptors (found on prostate) vs vascular α1B receptors.

PHOSPHODIESTERASE TYPE 5 INHIBITORS

 Sildenafil, vardenafil, tadalafil.

 Mechanism
 Inhibit PDE-5  ↑ cGMP  prolonged smooth muscle relaxation in
response to NO  ↑ blood flow in corpus cavernosum of penis.
 ↓ Pulmonary vascular resistance.
 Clinical use
 Erectile dysfunction, pulmonary hypertension, BPH (tadalafil only).
 Adverse effects
 Headache, flushing, dyspepsia.
 Cyanopia (blue-tinted vision) as the drug may cross react with PDE-6 in retina.
 Risk of life-threatening hypotension in patients taking nitrates.
 ―Hot and sweaty,‖ but then Headache, Heartburn, Hypotension.

MINOXIDIL

 Mechanism
 Direct arteriolar vasodilator.
 Clinical use
 Androgenetic alopecia (pattern baldness), severe refractory hypertension.

P a g e 158 | 158