Week 1 Flashcards
1
Q
Sacrotuberous ligament
connects _______ to _______
creates the _______ foramen through which ________, ________, and _________ pass ______ (superficial/deep) to sacrotuberous ligament to enter the perineum
A
ischial tuberosity → sacrum/coccyx
Creates greater sciatic foramen (pudendal nerve and internal pudendal a/v pass deep to ST lig to enter perineum)
2
Q
Sacrospinous ligament
connects _______ to _______
creates the _______ foramen through which ________, ________, and _________ pass ______ (superficial/deep) to sacrospinous ligament to enter the perineum
A
ischial spine → sacrum/coccyx
Creates greater and lesser sciatic foramen (pudendal n and internal pudendal a/v pass superficial to SP lig to enter perineum)
3
Q
Obturator membrane
A
covers obturator foramen
Attachment for obturator internus/obturator externus muscle
Superior gap provides exit of obturator n, a, and v (supplies medial thigh)
4
Q
True pelvis
A
between pelvic inlet and pelvic outlet
Contents supported inferiorly by pelvic diaphragm
5
Q
Greater pelvis/False pelvis
A
superior to pelvic inlet (contain abdominal viscera)
6
Q
Perineum
A
inferior to pelvic diaphragm, contains external genitalia
7
Q
Gubernaculum
A
fibrous tract guiding descent of gonads
Connected to abdominal wall at deep inguinal ring → testes enter and descend through deep ring
Degenerates
8
Q
Male embryonic development:
28th week: testes pass through _________ and enter _______ following ______ (anterior/posterior) to processus vaginalis (NOT through it)
→ Testes ensheathed in layers from abdominal wall
A
28th week: testes pass through inguinal canal and enter scrotum following POSTERIOR to processus vaginalis (NOT through it)
→ Testes ensheathed in layers from abdominal wall
9
Q
Processus Vaginalis
A
peritoneal diverticulum, transverses developing inguinal canal to developing scrotum carrying with it layers of muscle and fascia from abdominal wall
10
Q
Tunica Vaginalis
A
remnant of processus vaginalis
Closed peritoneal sac surrounding testes with 2 pleural layers separated by potential space (like lungs)
11
Q
Cryptorchidism
A
undescended testes, often unilateral, often self-resolves
12
Q
Spermatic cord:
Contents: (5)
A
1) Ductus deferens
2) Testicular artery (direct branch from abdominal aorta)
3) Pampiniform venous plexus (converges into R/L testicular vein → R side goes to IVC, L side goes to L Renal Vein)
4) Vestige of processus vaginalis
5) Artery of ductus deferens
13
Q
Layers of spermatic cord (3) and from which layer of the abdominal wall they originate
A
Internal spermatic fascia (from transversalis fascia)
Cremasteric fascia and muscle (from internal oblique)
External spermatic fascia (from external oblique)
14
Q
Sperm travels (8)
A
Seminiferous tubules of testes → rete testis → epididymis → ductus deferens → ejaculatory duct → prostate (prostatic urethra) → Penile urethra → external urethral orifice
15
Q
Tunica albuginea
A
tough outer surface of testes
16
Q
Seminiferous tubules
A
long, highly coiled tubes in which sperm are produced - joined to rete testis by straight tubules
17
Q
Rete Testis
A
collects sperm from tubules, passes them to efferent ductules → epididymis
18
Q
Epididymis
A
posterior side of testes, concentrates sperm before it passes to ductus deferens for expulsion
Head → Body → Tail (continuous with ductus deferens)
19
Q
Ductus deferens
A
continuation of epididymis
Thick muscular wall, narrow lumen
Ascends via spermatic cord → enter abdominal cavity via inguinal canal → join duct of seminal gland (posterior/inferior to bladder) → forms ejaculatory duct
Key relationships: anterior and superior to ureter and anterior to external iliac artery
20
Q
Ejaculatory duct
A
where ductus deferens terminates
Burrow into back of prostate gland
21
Q
Seminal glands (vesicle)
A
secretes thick alkaline fluid with fructose and coagulant that mixes with sperm as they pass into the ejaculatory ducts
22
Q
Bulbourethral glands
A
paired glands that produce mucus-like secretion during sexual arousal
Secrete into spongy urethra
23
Q
Testicular torsion
A
wisting of spermatic cord → obstruct venous drainage → edema → block arterial supply to testis
Associated with congenital malformation of processus vaginalis
24
Q
Varicocele
A
enlargement/dilation of pampiniform plexus of veins in spermatic cord
Cause: incompetent/absent valves in testicular veins → pooling/backflow
More common on left side
25
Fallopian Tubes:
| Four parts:
1) Infundibulum: catches egg, distal end has fimbriae projections
2) Ampulla: where fertilization typically occurs
3) Isthmus: narrows and thickens to enter uterine horn
4) Uterine part: within walls of uterus
26
Ovarian ligament
remnant of upper gubernaculum, connects ovary to uterus
27
Suspensory Ligament of ovary
peritoneal fold continuous with mesovarium
Contains ovarian blood vessels, lymph vessels, nerves
28
Round Ligament of the Uterus
Ligamentum teres
Remnant of female lower gubernaculum
Attaches uterus near junction of uterine tube and labia majora via inguinal canal
29
Broad ligament: 3 parts
1) Mesovarium: broad ligament that suspends ovaries
2) Mesosalpinx: broad ligament around uterine tubes
3) Mesometrium: largest part of broad ligament, mesentery for uterus
30
Blood supply to ovaries
ovarian artery from abdominal aorta (via suspensory ligament of ovary)
31
Blood supply to uterus
Uterine artery from internal iliac artery
| Anastomoses with ovarian artery
32
Blood supply to vagina
Vaginal branch from uterine artery (superior and middle)
Inferior pudendal artery (inferior)
33
Indirect inguinal hernia
make up 2/3s of inguinal hernias
Herniated loop of intestine (usually small intestine) traverses entire Inguinal Canal, from DEEP INGUINAL RING to superficial inguinal ring
**Originates LATERAL to inferior epigastric vessels
Hernia located within persistent processus vaginalis, thus inside spermatic cord → MAY EXTEND INTO SCROTUM**
34
Direct inguinal hernia
Originates within INGUINAL TRIANGLE, MEDIAL to inferior epigastric vessels
Herniated intestine pushes directly through abdominal wall, follows medial part of Inguinal Canal to Superficial Inguinal Ring
Herniated loop lies parallel to spermatic cord, NOT within it → RARELY ENTERS SCROTUM
35
Normal Differentiation of Testis/Ovary
Chromosomal sex → gonad development → hormone production → differential development of internal duct systems and external genitalia
36
Bipotential process of testes/ovary differentiation
undifferentiated structures either male or female direction, but current biological environment determines path (may change) at each stage
37
Sex Determining Region of Y
KEY to sexual dimorphism is Y chromosome (SRY → short arm of Y chr)
protein transcription factor which activates other transcription factors and initiates testicular differentiation from indifferent gonad
- Activates SOX-9
- Inhibits WNT-4 and RSPO1
38
Process of Gonad Development:
1) Undifferentiated gonads appear at ___-____ wks as paired _________
Formed from proliferation of _______ and condensation of underlying ________
Just medial to developing _________ (1st kidney)
1) Undifferentiated gonads appear at 4-5wks as paired genital ridges
Formed from proliferation of epithelium and condensation of underlying mesenchyme
Just medial to developing mesonephros (1st kidney)
39
Key transcription factors expressed early in gonadal development (2)
WNT-1
| SF1
40
WT-1
what is it?
what happens if there is a deletion/mutation?
TF expressed in developing genital ridge, kidney, gonads → activates SRY
WT1 deletion/mutation → gonadal dysgenesis, Wilms tumor, nephropathy
41
NR5A (Steroidogenic Factor, SF1)
what is it?
what happens if there is a deletion/mutation?
expressed in developing genital ridge - regulates transcription of genes involved in gonadal and adrenal development, steroidogenesis and reproduction
SF1 deletions → gonadal dysgenesis, adrenal failure, persistent Mullerian structures (low AMH)
42
Process of Gonad Development:
2) Germ cells migrate from _______ and invade ________ at wk 6
If germ cells don’t migrate..._________
Before/during germ cell invasion, epithelium of genital ridge proliferates and penetrates mesenchyme → ___________.
-These become__________ in males
2) Germ cells migrate from yolk sac and invade genital ridge at wk 6
If germ cells don’t migrate, gonads do not develop
Before/during germ cell invasion, epithelium of genital ridge proliferates and penetrates mesenchyme → primitive (medullary) sex cords.
-These become seminiferous tubules in males
43
3) Different for males/females
Males: ______ expressed at 6 weeks →
1) Primitive sex cords continue to proliferate and penetrate into _______ to form _______ (medullary cords)
2) Migration of _________ cells into developing testis
3) Differentiation of _______ cells (from surface epithelium, supporting cells) and differentiation of ________ cells (testosterone producers)
Males: SRY expressed at 6 weeks →
1) Primitive sex cords continue to proliferate and penetrate into medulla to form testis (medullary cords)
2) Migration of mesonephric cells into developing testis
3) Differentiation of sertoli cells (from surface epithelium, supporting cells) and differentiation of leydig cells (testosterone producers)
44
Leydig cells begin production of testosterone by ______ wk
Located where?
8th week
between testis cords in seminiferous tubules
45
Important transcription factors in male/female differentiation (5)
1) SOX-9
2) SRY
3) DAX
4) WNT-4
5) RSPO1
46
SOX-9
upregulated by SRY
essential for normal testis formation
elevates AMH concentrations
47
Deletion/mutation in SOX-9 causes what?
Campomelic dysplasia-->
- Severe skeletal dysplasia
- Gonadal dysgenesis
48
WNT-4 and RSPO1
expressed in females, activate B-catenin pathway, inhibit testis development, promote ovary development
49
DAX
| -single vs. double DAX gene
single DAX → testicular development
double DAX → activate ovarian development, inhibit testes
50
What is required for female differentiation
2 things + 4 TFs
1) requires 2 X chromosomes and absent Y
2) Requires migration of primitive germ cells
3) Important genes: DAX1 (2 copies), WNT-4, RSPO1, FOXL2
51
The gonads of both males and females develop from the __________
In males the ________ form the testes
In females the cortex develops into the ________, while the medulla _________
germ cells in the urogenital ridge
In males the medullary cords form the testes
In females the cortex develops into the ovaries, while the medulla degenerates
52
Internal ducts differentiation determines ______________
Initially, both ________ (Wolffian) and __________ (Mullerian) ducts develop in both sexes
phenotypic sex
Initially, both mesonephric (Wolffian) and paramesonephric (Mullerian) ducts develop in both sexes
53
Male internal duct differentiation:
wolffian ducts --> what 3 structures
Wolffian ducts → 1) epididymis, 2) vas deferens, 3) seminal vesicle
54
Male internal duct differentiation:
Duct differentiation requires testicular secretions:
1) High _________ produced by _______ cells = _________ effect
2) ________ hormone produced by ________ cells
→ Mullerian duct regression
Must be expressed before end of wk ______
Duct differentiation requires testicular secretions:
1) High LOCAL [testosterone] produced by Leydig cells = PARACRINE effect
2) Antimullerian hormone (AMH) produced by Sertoli cells
→ Mullerian duct regression
Must be expressed before end of wk 8
55
Internal duct differentiation of females:
requires ABSENCE of _______ and _______
_________ ducts regress
Requires absence of local testosterone and AMH
Wolffian ducts regress
56
Internal duct differentiation of females:
Paramesonephric (Mullerian ducts) →what 3 structures?
Paramesonephric (Mullerian ducts) → 1) Fallopian tubes, 2) midline uterus, 3) upper portion of vagina
57
External Genitalia differentiation:
Develop from three initially indifferent structures:
1) Genital tubercle → __________
2) Urethral folds → ___________
3) Labial-scrotal swellings → __________
1) Genital tubercle → glans penis/clitoris
2) Urethral folds → penile urethra/labia minora
3) Labial-scrotal swellings → scrotum/labia majora
58
Male external genital differentiation relies on _________, especially for the formation of the _________
Male external genital differentiation is complete by _____ weeks
Gonadal descent (testes reach scrotum) occurs by ______ weeks
Dependent on DHT (T → DHT via 5a-Reductase) especially formation of penile urethra
Complete by 13 weeks
Gonadal descent: testes reach scrotum by 33 weeks
59
Male external genital differentiation:
During first trimester, _________ stimulates Leydig cells to make ________
After → requires ___________ for continued testosterone production
During first trimester, placental HCG stimulates Leydig cells to make testosterone
After → requires Hypothalamic-Pituitary-Testicular axis for continued testosterone production
60
In females, excessive androgen exposure...
before 13 weeks can cause what?
after 13 weeks can cause what?
Excessive androgen exposure after 13 weeks can cause cliteromegaly, but cannot result in posterior labial fusion or penile urethra
PRIOR to 13 wks → affects urogenital sinus and causes insertion of urethra into vagina (more androgen exposure = more severe defect)
61
Rokitansky Syndrome
Mullerian duct abnormality
absent or underdeveloped mullerian (paramesonephric) structures in 46 XX female → presents as primary amenorrhea
62
Persistent mullerian ducts in 46 XY
caused by what 2 things?
presentation?
normal virilization, with unilateral hernia
Defect in AMH synthesis
Defect in AMH receptor
63
Disorder (difference) of Sex Development (DSD)
congenital conditions in which development of chromosomal, gonadal, or phenotypic sex is atypical
Genital ambiguity
Discordance between genital appearance and prenatal karyotype
64
Classification of DSDs (2)
1) 46XX DSD: virilized XX fetus
| 2) 46XY DSD: undervirilized XY
65
46XX DSD
4 possible causes?
virilized XX fetus
1) Congenital adrenal hyperplasia (95% of cases)
2) 46 XX sex reversal (SRY translocation) - baby looks male
3) Ovotesticular DSD
4) Gestational hyperandrogenism
66
46XY DSD
3 possible categories of causes
1) Abnormal testicular development
2) Defects in adrenal and testicular steroidogenesis
3) Defects in testosterone/androgen metabolism
67
5a-Reductase deficiency
AR cause of 46XY DSD
- T not converted to DHT
- -> Wolffian ducts differentiated (normal) and testes normal, BUT external genitalia undervirilized (ambiguous at birth)
- Testes in inguinal canal or labial-scrotal folds
- Spontaneous virilization at puberty possible
- Typically male gender identity
68
Androgen insensitivity syndrome
Mutation in androgen receptor on X chromosome
can be complete or incomplete
69
Complete androgen insensitivity
- Gonads intraabdominal or in inguinal canal
- ->Bilateral inguinal hernias common
- blind vaginal pouch (Testicular Feminization)
- Spontaneous breast development at puberty
- Little/no pubic/axillary hair
- Female gender identity
70
Types of Congenital Adrenal Hyperplasia (CAH)
| 5
1) 21 hydroxylase deficiency: 95% of CAH cases
2) 11B hydroxylase deficiency
3) StAR protein deficiency
4) 3B-Hydroxysteroid dehydrogenase deficiency
5) 17a hydroxylase deficiency
71
21 hydroxylase deficiency
what is blocked, what is overactivated?
normal function of enzyme?
21 hydroxylase normally converts progesterone → 11-deoxycorticosterone and 17-OH progesterone to 11-deoxycortisol
Aldo and cortisol pathways blocked, androgen pathway overstimulated
72
21 hydroxylase deficiency
features (4)
1) Virilization → female (virilization of external genitalia), male (no genital abnormalities)
- Degree of androgen exposure determines degree of virilization
2) Hyperpigmentation (too much ACTH and POMC)
3 and 4) Hyponatremia/Hyperkalemia due to aldo deficiency
Mild forms may present later
73
21 hydroxylase deficiency
diagnosis and treatment
Diagnosis:
- Virilized XX infant or XY infant with hyperkalemia/hyponatremia
- 17-OH progesterone tested on newborn screen
Treatment:
- Surgery in females
- Replace hormones and suppress ACTH overproduction
74
11B hydroxylase deficiency
normal function of enzyme
what is overproduced, what is blocked?
11B hydroxylase normally converts 11-deoxycorticosterone → corticosterone and 11-deoxycortisol → cortisol
increased 11-deoxycorticosterone
increased androgens
decreased cortisol
75
11B hydroxylase deficiency
features (3)
1) Virilization similar to 21-OH
2) NO salt wasting because 11-deoxycorticosterone has mineralocorticoid activity
3) HTN
76
StAR protein deficiency
normal protein function?
Steroidogenic Acute Regulatory Protein
Normally transfers cholesterol from outer to inner mitochondrial membrane allowing for conversion of cholesterol → pregnenolone
deficiency causes build up of cholesterol esters in adrenocortical tissues (Congenital Lipoid Hyperplasia)
77
StAR protein deficiency
features (3)
1) UNDERVIRILIZATION - Females have normal genitalia, Males have female external genitalia
2) Salt wasting
3) Fatal if not detected early in infancy
78
3B-Hydroxysteroid dehydrogenase deficiency
normal enzyme function?
Normally involved in conversion of:
pregnenolone → progesterone
17-OH pregnenolone → 17-OH progesterone
DHEA → androstenedione
79
3B-Hydroxysteroid dehydrogenase deficiency
features (3)
1) Virilization in girls
2) Undervirilization in boys
3) Salt wasting
80
17a hydroxylase deficiency
Normally converts pregnenolone → 17-OH pregnenolone and progesterone → 17-OH progesterone
81
17a hydroxylase deficiency
features (4)
1) HTN (increased 11-deoxycorticosterone)
2) Hypokalemia
3) Females born with normal genitalia and present at puberty with failure to develop secondary sex characteristics
- Males born undervirilized
82
Four Cardinal Steps in Mullerian Development:
1) Elongation
2) Fusion
3) Canalization
4) Septal resorption
83
Four Cardinal Steps in Mullerian Development:
1) Elongation
1) Elongation:
Formation: 37 days after fertilization, Mullerian ducts (paramesonephric ducts) first appear lateral to Wolffian ducts (mesonephros)
→ Elongation of Mullerian duct: occurs medially and caudally
84
Four Cardinal Steps in Mullerian Development:
2) Fusion
2) Fusion: Mullerian ducts fuse in midline and subsequently fuse with urogenital sinus at Muller tubercle
Wolffian ducts regress
85
Four Cardinal Steps in Mullerian Development:
3) Canalization
3) Canalization: Mullerian duct initially solid structures, but will canalize and become tubes
Metanephric ducts (kidneys) fully develop and establish connection with cloaca/bladder
86
Four Cardinal Steps in Mullerian Development:
4) Septal Resorption
septum separating uterus into two is resorbed → uterus joins with urogenital sinus to form lower vagina
Sinovaginal bulb elongates and develops into full vagina
87
After septal reapsorption step of Mullerian development what happens?
Mullerian system (cephalad) fuses with urogenital sinus (caudad)
88
Imperforate hymen
failure of caudal end of sino-vaginal bulbs to canalize → cyclical pain and build up of menstrual blood upon starting menstruation
thin membrane covering vaginal opening
89
Transverse vaginal septum
failed canalization of the vaginal plate (where mullerian ducts meet urogenital sinus)
Vagina ends in pink tissue
Presents with cyclical pain
more involved surgery to repair than imperofrate hymen --> remove septum, sew vagina closed with possible graft to prevent pain with intercourse
90
Vaginal atresia
failure of urogenital sinus to canalize below vaginal plate
Presents with cyclical pain
Treatment: vaginal dilators or surgical vaginoplasty
91
Mullerian Agenesis or Hypoplasia
Class I Mullerian defect
Most severe form
*Failure of elongation - Mullerian structure never came down
92
Mullerian Agenesis or Hypoplasia presentation
amenorrhea
Blind ending vagina - NO UTERUS or FALLOPIAN TUBES but do have ovaries so develop secondary sex characteristics
93
Unicornuate uterus
Class II Mullerian defect
Failure of one mullerian duct to elongate or reach urogenital sinus with contralateral duct
typically have normal menstruation
94
Uterine didelphys
Class III Mullerian defect
- Occurs if Mullerian ducts completely fail to fuse in midline
- Completely separate cavities with 2 distinct endometrial cavities and cervixes, each with one fallopian tube
Can occur with obstructed hemivagina if septum comes down and obstructs one uterus
95
Bicornuate Uterus
Class IV Mullerian defect
Incomplete fusion of midline Mullerian ducts during embryogenesis partially or completely divides the endometrial cavity into two longitudinal halves
Complete or partial
Occurs at 9th week
96
Septate Uterus
Class V Mullerian defect
Failure of septum resorption
Fibrous or fibromuscular septum may extend partially into the uterine cavity or may extend the entire length
Usually asymptomatic
MOST COMMON type of mullerian anomaly (55% of cases)
97
Arcuate Uterus
Class VI Mullerian defect
- Variant of normal
- Near complete resorption of utero-vaginal septum with some remnant
- Asymptomatic
- Normal external contour
- No adverse reproductive outcomes
- No surgical intervention
98
DES Drug Related Mullerian Defect
Class VII Mullerian defect
Diethylstilbestrol-induced uterine anomalies
69% of women with DES exposure had uterine anomalies
→ T shaped uterus (most common), fundal constriction rings, hypoplastic uterus, intrauterine adhesions
Also associated with cervical hypoplasia, vaginal adenosis, and clear-cell vaginal adenocarcinoma, SAB, EP, and cervical incompetence
99
Reproductive implications of DES drug related Mullerian defect (5)
```
Endometriosis
Recurrent miscarriage
Preterm delivery
Malpresentation
Associated renal anomalies
```
100
Sertoli Cells function (6)
1) Form blood-testis barrier (tight junctions)
2) Nurture developing sperm
3) Secrete androgen binding protein (APB) → maintain high local level of testosterone
4) Convert androgens to estrogen (via aromatase)
5) Secrete inhibin and other growth factors
6) Respond to FSH through GPCR
101
Role of Leydig Cells:
1) Required for spermatogenesis
2) Synthesis of testosterone (via 5a-reductase)
3) Synthesis of steroidogenic acute regulatory protein (StAR) and sterol carrier protein (SCP)
- -> Transport cholesterol to mitochondrial side chain cleavage enzyme
4) Stimulate steroidogenesis
5) Respond to LH through GPCR
102
BOTH leydig and sertoli cells are necessary for _____________
testicular function
103
hCG looks like what?
TSH and LH
104
Androgens inhibit ______, _______, and ________
Inhibin suppreses _________
Activin activates _________
Follistatin binds and controls activity of _________
Androgens (testosterone) inhibit GnRH release
Androgens (and estrogen) inhibit LH and FSH release
Inhibin suppresses FSH production
Activin → activates FSH
Follistatin → binds and controls activity of activin
105
DHT
most potent, highest affinity for AR
Receptors for DHT in external genitalia, sebaceous glands, hair follicles
Generated from testosterone via 5a-reductase
106
Male Puberty:
Increased growth hormone
Increased testosterone
Pubertal growth spurt (11 inches) - later in puberty than female growth spurt
Prepuberty males/females have equal body mass, skeletal mass, and body fat →
POST puberty males have:
150% female muscle mass, 150% female skeletal and lean body mass, 200% female muscle cell number, 50% female body fat
107
Consequence of steroid abuse:
```
Infertility, decreased sperm production
Gynecomastia - breast development
Testicular atrophy
Baldness and excessive body hair
Short stature
Tendon rupture
Increase LDL, decreased HDL → atherosclerosis
High BP
Heart attack and stroke
Enlargement of LV
Liver cancer, blood filled cysts
Severe acne, cysts, oily scalp
Fluid retention, kidney failure
Psychiatric disturbances Mania, delusions, irritability, insomnia
```
108
Growth hormone vs. sex steroids in bone growth:
Growth hormone: causes BALANCED growth and ossification
-Bones continue to lengthen through childhood and pubertal ages under its influence in absence of sex steroids
Testosterone and estrogen: stimulates bone growth, accelerates bone maturation, promotes epiphyseal closure
- NARROWs growth window limiting long-bone growth
- Growth “levels off” after puberty
109
Effects of androgens in puberty:
1) androgenic effects (3)
2) Anabolic effects (4)
3) Interactions with GH and IGF1 (3)
1) Androgenic effects:
- Growth and development of male reproductive tract
- Secondary sexual characteristics
- Behavioral responses
Anabolic effects:
- Growth of somatic tissues
- Linear body growth (long bones)
- Nitrogen retention, protein synthesis
- Muscle development
Interacts with insulin like growth factor (IGF-1) and growth hormone axis
- GH/IGF1 → stimulate gonadal function
- IGF1 → stimulate GnRH secretion
- Testosterone and estrogen → stimulate GH secretion and growth
110
First signs of puberty
testicular enlargement (FSH/LH mediated) or breast bud development
111
7 Estrogen stimulated changes in puberty
1. Breast development
2. Genital growth (labia minora)
3. Maturation of vaginal mucosa
4. Uterine/endometrial growth
5. Body composition changes (female fat distribution)
6. Menarche (estrogen and progesterone) - occurs mid-late puberty
7. Growth acceleration (mediated by ESTROGEN) - not as fast as boys
112
Testosterone mediated changes in puberty (7)
occur up to a year after growth of testes
1. Scrotal changes
2. Sexual hair (upper lip, chin, sideburns, axilla, pubic area)
3. Penile growth
4. Prostatic/seminal vesicle growth
5. Deepening of voice
6. Increase in muscle mass
7. Linear growth acceleration mediated by increased GH (mediated by ESTROGEN)
113
Normal age of pubertal onset for boys
9-14
114
Normal age of pubertal onset for girls
8-13
115
What occurs durin pubertal onset
:re-emergence of hypothalamic GnRH secretion → stimulates gonadotrope secretion of FSH and LH → bind receptors in ovaries/testes → gonadal maturation and production of sex steroids (gonadarche** = breast development, testicular enlargement)
116
Puberty: Night time increases in GnRH pulses →
predominantly LH response
Prepuberty: FSH > LH
Puberty: LH > FSH
117
What eventually happens to GnRH pulses in puberty?
GnRH pulses eventually continue throughout the da
118
Test of pubertal axis maturation
Can test if pubertal axis has matured with leuprolide stimulation test (GnRH analog) to measure LH response
LH > 5 → puberty has begun
Primary response is FSH → prepubertal
119
Adrenarche
maturation of adrenal gland (zona reticularis) and production of adrenal androgens (DHEA-S and androstenedione)
Cause the physical signs of pubic hair, axillary hair, body odor, and acne in both boys and girls
120
Juvenile pause
HPG axis is active in fetal development and infancy, but enters quiescent state after infancy
121
Delayed puberty
lack of onset or lack of normal progression of puberty
Signs:
Boys: no testicular enlargement by age 14
Girls: no breast development by age 13 or no menses after pubertal onset or by age 16 years
122
Causes of delayed puberty
lack of pubertal maturation of HPG axis or gonadal dysfunction
123
Hypergonadotropic hypogonadism
GnRH level?
FSH/LH level?
(high GnRH)
high FSH and/or LH + impotence
primary gonadal failure
124
Congenital causes of hypergonadotropic hypogonadism (5)
1. Klinefelter's
2. Turner
3. 46 XX or 46 XY gonadal dysgenesis
4. Testicular regression syndrome
5. Noonan syndrom
125
Klinefelters:
what is the defect?
what cells are absent, what cells are intact?
Levels of FSH, LH, and testosterone?
genetic defect of XXY
Failing testes with no spermatogenic elements
-Dysgenesis of seminiferous tubules --> decreased inhibin B --> increased FSH
Abnormal Leydig cell function --> low testosterone, increased LH, increased estrogen.
HIGH FSH (no inhibin) + NORMAL LH + LOW/NORMAL TESTOSTERONE
126
Testicular regression syndrome is usually due to ___________
vascular event
127
Acquired causes of hypergonadotropic hypogonadism (7)
Levels of FSH, LH, and testosterone?
1. Chemo (especially alkylating agents)
2. Irradiation to pelvic region
3. Galactosemia
4. Autoimmune oophoritis
5. Testicular torsion, trauma
6. Mumps orchitis
7. Cryptorchidism
HIGH FSH (early, loss of inhibin), HIGH LH (later), LOW TESTOSTERONE (later)
128
Hypogonadotropic hypogonadism
Level of LH, FSH, and testosterone?
LOW GnRH→ congenital or acquired deficits of GnRH and/or LH/FSH (hypothalamic or pituitary problem, central)
low LH, FSH, and Testosterone + impotence
129
Hypogonadotropic hypogonadism is usually due to
Usually constitutional delay of growth and puberty (timing/progression of puberty goes with bone age)
Low FSH and LH
TX: testosterone
130
Reversible disorders of hypogonadotropic hypogonadism
chronic illness, malnutrition, stress, excessive exercise, anorexia nervosa, hyperprolactinemia, hypothyroidism
-OSA, narcotics, repeated glucocorticoid injections
Hypothyroidism → Low FSH and LH, elevated TSH
131
5 congenital causes of hypogonadotropic hypogonadism
1. Isolated gonadotropin deficiency
2. Kallman syndrome
3. Congenital hypopituitarism
4. Midline CNS defects
5. prader-willi (why my balls are small. Sorry Maddie)
132
Acquired CNS lesions causing hypogonadotropic hypogonadism
1) Pituitary or hypothalamic tumor (prolactinoma)
2) Infiltrative disease (e.g. hemochromatosis)
3) Trauma, irradiation, infection, autoimmune hypophysitis
133
Isolated gonadotropin deficiency
Low GnRH in absence of any structural abnormalities of hypothalamus/pit.
Low FSH and LH
134
Kallman syndrome
(GnRH deficiency + anosmia)
Agenesis or hypoplasia of olfactory sulci/lobes
Low FSH and LH
135
Evaluation of hyper vs hypogonadism
Hypergonadotropic hypogonadism → primary gonadal failure, no negative feedback of sex steroids to brain
Hypogonadotropic hypogonadism → low GnRH levels
136
Other tests for hypogonadotropin
Bone age, Pubertal staging, Sense of smell, Thyroid panel, ESR, CBC, BMP, prolactin, testosterone, estradiol, karyotype (if hypergonadotropic)
137
Tx of hypogonadism
testosterone replacement therapy (boys), low dose estrogen replacement + cyclic therapy with estrogen and progestin (girls)
138
Precocious puberty
pubertal development begins before age 8 (girls) or age 9 (boys)
139
Complete precocious puberty
early onset AND progression of pubertal development with evidence of linear growth acceleration and bone age advancement
→ early closure of growth plates, compromised final height
140
incomplete precocious puberty:
signs of puberty not progressive= benign premature thelarche, benign premature adrenarche
No treatment required
141
Benign premature adrenarche:
pubic hair, acne, etc. development but NO breast or height changes
Prepubertal with FSH > LH
No advanced bone age
142
Premature benign thelarche:
no height changes, no pubic hair development, do get breast development
143
Central precocious puberty
(gonadotropin-dependent):
premature activation of HPG axis
More common in girls
BOTH breast and pubic hair development or enlargement of testes + growth acceleration
Pubertal response with LH > FSH
Advanced bone age
TX = continuous GnRH agonist
144
Peripheral precocious puberty
(gonadotropin-independent): independent of GnRH and gonadotropin stimulation
145
Peripheral precocious puberty in boys (6)
1. Familial toxicosis
2. hCG secreting tumor
3. Leydig cell tumor
4. Congenital adrenal hyperplasia
5. Adrenal tumor
6. Exogenous androgens
146
Familial testotoxicosis
Mutation of LH receptor causing it to be constitutively activated → Leydig hyperplasia
- Testes enlarged
- Penile enlargement, pubic hair development
Suppressed GnRH, elevated testosterone
147
Tx of familial testotoxicosis
aromatase inhibitor + androgen blocker/ketoconazole
148
hCG secreting tumor
hCG acts like LH and TSH → increased testicular size, with no/decreased adrenarche → disproportionately low degree of virilization
149
Leydig cell tumor
Assymetric testes
150
Congenital adrenal hyperplasia
secondary sex characteristics (virilization, penile enlargement) without testes enlargement (LH not elevated)
151
Tx of CAH
glucocorticoids (suppresses androgens)
152
Peripheral precocious puberty in girls (3)
excess estrogens caused by ovarian cyst, ovarian granulosa cell tumor, exogenous estrogens
153
Ovarian cyst
signs of estrogenization (breast development, dark areola), no pubic hair, no height acceleration
SHORT time frame of estrogenization
No advanced bone age
Suppressed/prepubertal GnRH in stim test
TX = watchful waiting
154
Peripheral precocious puberty in both boys and girls
1. Hypothyroidism
| 2. McCune Albright Syndrom
155
Hypothyroidism and precocious puberty
TSH > 500
| TSH can act like FSH and stimulate FSH receptor → estrogen production (females), enlarged testes/normal T (males)
156
McCune Albright Syndrome
cafe-au-lait spots, polyostotic fibrous dysplasia, precocious puberty (breast development, menarche, but NO adrenarche),
due to activating mutation in a-subunit of G protein
Can also get high GH and TH (G-protein mechanism)
Advanced bone age
Suppressed/prepubertal GnRH stim test
157
Tx of McCune Albright
Aromatase inhibitor
158
Bilateral testicular enlargement →
central precocious puberty, activation of LH receptor by HCG tumor, testotoxicosis, McCune-Albright Syndrome
159
Unilateral testicular enlargement
Testicular tumor
160
Evaluation of precocious puberty
1. Bone age, height, growth rate
2. LH, FSH,
3. estradiol/testosterone
4. GnRH stimulation test
5. Cranial MRI (with central)
6. Testicular/ovarian ultrasound
161
GnRH Stimulation test:
- pubertal LH response to GnRh
Central precocious puberty
162
GnRH Stimulation test:
- prepubertal LH response to GnRH
Peripheral precocious puberty
163
Goal of tx of precocious puberty
arrest/cause regression of signs of puberty, alleviate psychosocial stress of early puberty, slow bone age advancement, preserve final adult height
164
GnRh analogues
(IM leuprolide acetate, histrelin implant) used for CENTRAL precocious puberty → down regulate pituitary GnRH receptors → decrease GnRH secretion
165
Aromatase inhibitors
(McCune Albright Syndrome) → block conversion of androgens to estrogens
166
Ketoconazole + androgen blocker + aromatase inhibitor
→ familial testotoxicosis
167
Conditions of androgen excess
Prostate cancer, BPH, androgenetic alopecia, precocious puberty, hirsutism
168
Finasteride
inhibits type II 5a-reductase (prevents conversion of T → DHT)
Used to treat prostate cancer
169
Propecia
inhibits 5a-reductase
| Used to treat hair loss
170
Dutasteride
Type I and II 5a reductase inhibitor
| Used to treat prostate cancer
171
Conditions of androgen deficiency
- Androgen replacement therapy in hypogonadal boys and men
- Osteoporosis
- Muscle wasting with AIDS
- Hormone replacement therapy in aging men (controversial)
172
MOA testosterone
diffuses across membrane → interact with cytosolic receptor → dimerization and binding to DNA response elements → alteration of target gene transcription → growth, differentiation, synthesis of enzymes/functional proteins
Only free, unbound, hormone active
173
Actions of testosterone
synthesized in testes (95%) and adrenal (5%) (in women most synthesized in adrenal)
Converted to DHT by 5a-reductase
Converted to Estradiol by aromatase
174
Principles of testosterone tx
ONLY in men distinctly subnormal T (<200-300 ng/dL) with multiple occasions with symptoms
Symptoms = low libido, decreased morning erections, low bone mineral density, gynecomastia, small testes, fatigue, depression, anemia, reduced muscle strength, increased fat****
**** Mnemonic: Charlie
175
"Hey doc, my spermatogenesis is impaired. Will you prescribe me some of that testosterone stuff?"
HELL NO
NOT indicated for impaired spermatogenesis as T suppression of GnRH secretion would further impair spermatogenesis
176
Intramuscular testosterone
given every 1-3 weeks
Testosterone ethane, Testosterone cypionate
Less frequent injections → greater fluctuations in serum T levels
177
Transdermal testosterone gel
given every 24 hours
Advantage: maintain most stable T levels throughout dosing period
Most expensive
178
Transdermal testosterone patch
androderm, applied once daily
Advantage: maintain stable T levels throughout dosing period
Can cause severe rash in ⅓ of patients
179
Subcutaneous testosterone
Testopel (pellets) given every 3-4 months as implanted pellets in subdermal fat of buttocks
180
Buccal testosterone
tablet 2x a day
181
Nasal testosterone
gel administered to nostrils via metered pump 3x daily
182
Oral testosterone
methyltestosterone
| Hepatic side effects
183
Adverse effects of testosterone
1. Avoid androgens in infants and young
2. Decreased spermatogenesis:
- Decreases LH/FSH release (testicular shrinkage)
- Conversion of androgens to estrogens (gynecomastia)
- Return to normal function after discontinuation
3. Reversible cholestatic jaundice (higher with oral agents)
4. Edema → weight gain
5. Increased susceptibility to arterial thrombosis (dec. HDL, inc. LDL)
6. Prostate enlargement
184
MOA Finasteride-dutasteride
5a-reductase inhibitors (decreased DHT)
185
Use of Finasteride Dutasteride
BPH, androgenetic alopecia
186
Pharmacokinetics of finasteride-dutasteride
Orally 1x daily
187
ADR of finasteride dutasteride
decreased libido, ejaculatory or erectile dysfunction, weakness
188
MOA Bicalutamide/flutamide
androgen receptor antagonist
189
Use bicalutamide/flutamide
prostate cancer, hirsutism of PCOS
190
Phamacokinetics of biclutamide/flutamide
orally 1x daily
191
ADRs of biclutamide/flutamide
androgen deprivation effects (loss of libido, gynecomastia), nausea, transient abnormal LFTs
192
MOA leuprolide
GnRH analog
193
Phamacokinetics leuprolide
SC or IM
| Duration of 1-3-4-6 months
194
Use of leuprolide
continuous administration for prostate cancer, precocious puberty in boys
195
ADRs leuprolide
headache, nausea, injection site reaction, hypogonadism with prolonged treatment
196
Spirinolactone MOA
androgen receptor antagonist
197
Use of spirinolactone
prostate cancer, hirsutism in PCOS
198
Pharmacokinetic of spirinolactone
orally 1x daily
199
ADRs spirinolactone
hyperkalemia, gynecomastia
200
MOA ketoconazole (in reference to antiandrogen effects)
inhibits 17a-hydroxylase, inhibits testosterone synthesis
201
Type A spermatogonia: ___N?
4N
202
Type A spermatogonia
undergo initial mitotic division
Outer region of tubules
True stem cells that can divide mitotically to totipotent progenitors
203
Type B spermatogonia: ___N ?
2N
204
Type B spermatogonia
commited to meiosis
205
Primary spermatocytes
4C (4 chromatids)
Large nuclei
Develop as primary spermatocytes for about 3 weeks → complete meiosis I (crossing over occurs)
206
Secondary spermatocytes
primary spermatocytes that have completed meiosis II, only around for about 2 hrs before they become spermatids
207
Spermatids
- haploid, different stages of nuclear condensation toward central part of tubules
- Have residual body connected (taken up by sertoli cells)
- Cells derived from a given spermatogonium, remain linked as a syncytium with connected cytoplasmic bridges → RNA exchange between developing haploid spermatids
- Surrounded by supportive Sertoli cells
208
Sertoli cells (8)
1. have tight junctions, form blood-testes barrier that seal off spermatocytes from immune system
2. Surround developing spermatid
3. Spermatogonia at base of seminiferous epithelium are not contained in this barrier
4. Secrete androgen binding protein into these compartments → sequester high levels of T required for spermatogenic process
5. Have FSH receptors
6. Produce inhibin
7. Provide nutrient to developing spermatocytes and spermatids
8. Phagocytose residual bodies and degenerating cells
209
Location of Leydig cells
outside seminiferous tubules
210
Rete Testes:
contain non-motile spermatozoa
- Lined by cuboidal epithelium with cells have a single cilium
- Contain connective tissue with myoid cells → contract and aid in moving sperm through channels
211
Ductuli efferentes
- tubule leading from Rete to epididymis
- Lined by cells that are a mixture of columnar ciliated cells (move immotile sperm along) and cuboidal absorptive cells
- Coni vasculosi
212
Coni vasculosi
part of ductuli efferentes that are outside the testes,
- highly coiled, fuse to form a single epididymal duct
- Contain band of circularly arranged smooth muscle around each ductule to propel spermatozoa into epididymis
213
Spermatozoa _____ when leaving testes, gain motility en route along _____
Spermatozoa non motile when leaving testes, gain motility en route along epididymis
214
Spermatozoa NOT fully capacitated (able to fertilize) until they enter ______
Spermatozoa NOT fully capacitated (able to fertilize) until they enter female reproductive tract
215
Epididymis is Lined by _________ epithelium with layer of ________ outside basal lamina → propel spermatozoa along tube
Lined by pseudostratified columnar epithelium with layer of smooth muscle outside basal lamina → propel spermatozoa along tube
216
Vas deferens Conducts spermatozoa to ejaculatory duct by ________
peristaltic contraction
217
3 layers of muscle in vas deferes
inner longitudinal, medial circular, outer longitudina
218
Innervation of vas deferens
sympathetic nerves to expel contents into urethra during ejaculation
219
Vas deferens is lined by _____ with _______
columnar epithelium
| microvillar surface
220
Seminal vesicles
- Paired glands leading to a single vas deferens
- Glandular structure, highly irregular extension of tissue lined with pseudostratified columnar epithelium with a microvillar surface
- Outer muscular layer that contracts during ejaculation
221
Prostate glands
- Where ejaculatory duct meets the urethra
| - Peripheral glandular tissue which empties via small ducts into urethra and contributes fluid to semen
222
Primordial germ cells in fetus divide to produce ____ → ______ (arrested in ______)
Ceases at around ___ months gestation
oogonia → oocytes (arrested in meiosis I)
6 months gestation
223
Primordial follicles
4C oocytes surrounded by single layer of flattened follicular cells → over several years acquire outer arrangement of flattened thecal cells
224
After menarche, primary follicles → ____ follicles → ____ proliferate, ____ cells increase and enlarge → ______ follicles
After menarche, primary follicles → antral follicles → granulosa cells proliferate, thecal cells increase and enlarge → Graafian follicles
225
Thecal cells contain____
vasculature
226
Monthly, one large ______ becomes dominant, increasing in volume to ovulatory stage
Graafian follicle
227
Hours prior to ovulation, meiosis___ completed → ___ oocyte → first polar body released
Hours prior to ovulation, meiosis I completed → 2C oocyte → first polar body released
228
Second polar body released after
oocyte penetrated by sperm → Oocyte then haploid
229
oocyte penetrated by sperm → Oocyte then haploid
follicular cells become cuboidal
230
Secondary (preantral) follicles:
contain more than one layer of granulosa cells
231
Antral (Graafian) follicles:
after puberty, some primary follicles develop to antral follicles → advanced antral (Graafian) follicles due to FSH
232
Atretic follicles:
fate of the majority of primary follicles
233
Corpus luteum:
after ovulatory follicle releases oocyte, remaining granulosa/thecal cells remodeled into endocrine group of cells
- Occurs monthly
- Driven by LH production at Day 12 into cycle = Luteinization
- Cells become distended by lipid, secrete progesterone and estrogen ⇒ prepare uterine endothelium for implantation
234
No implantation of corpus luteum->
corpus albicans
235
Implantation of corpus luteum->
enlarges, influenced by HCG to maintain pregnancy
236
Corpus albicans:
degenerated corpus luteum if implantation does not occur
237
Germinal epithelium:
```
mesothelial layer (thin) that lines ovary
Thin so that oocyte can exit ovary
```
238
Zona pellucida:
structured region around oocyte with nutrients
239
Corona radiata
ayer of granulosa cells, stay with oocyte even after ovulation
240
Oviduct
aka Fallopian tube
| Contain fimbriae that embrace ovary, conduct egg to uterus
241
Infundibulum → ______ → ______
Infundibulum → ampulla → isthmus
242
Fertilization occurs where?
Ampulla
243
Lining of oviduct
Mucosal lining highly folded (most in ampulla, least in isthmus)
Ciliated in infundibulum
244
Musculature of oviduct
inner circular + outer longitudinal layer of smooth muscle
Contract/agitate inner compartment
Peristalsis + cilia → move egg toward uterus
245
Oviduct, estrogen sensitive or resistant>
Sensitive
246
Secretory cells of fallopian tube
release protein, sugar, etc. important for egg and sperm viability and fertilization
247
2 zones of endometrium
Functionalis and basalis
248
Zona functionalis of endometrium
hormonally responsive, cycles monthly from puberty to menopause
- Contains coiled, tubular glands, lined by epithelium
- Proliferates as follicle develops in ovary
- No implantation → menstrual phase
249
Zona basalis of endometrium
not shed, contains basal region of endometrial glands
250
Proliferative stage and endometrium
zona functionalis proliferates and stroma expands
251
Secretory stage and endometrium
driven by progesterone, gland becomes highly coiled, secretes glycoprotein, becomes thicker
- Spiral arteries develop within uterine stroma
- No adequate estrogen/progesterone → arteries contract, become kinked → ischemia, necrosis → bleeding
252
Myometrium
Bundles of smooth muscle
| Hypertrophy and hyperplasia during pregnancy
253
Cervical portion:
lined by single layer of tall epithelial cells that extend into deep slit-like invaginations along wall (endocervical mucus glands)
Ends at endo cervix (stratified squamous)
254
Mammary glandular structure:
Before lactation:
Glandular tissue arranged as acini with ducts leading to larger ducts → nupple
Acini lined with secretory epithelial cells with outer layer of myoepithelial cells, connective tissue, and adipose tissue
255
Mammary glandular structure:
During lactation:
prolactin stimulates milk production → extensive elaboration of glandular tissue filled with milk
Myoepithelial cells under influence of oxytocin contract and propel milk into lactiferous sinuses
256
Spermatogenesis:
spermatogonium (__ploid, _N, _C) stem cell → [Interphase] → primary spermatocyte (__ploid, _N, _C) → [Meiosis I] → secondary spermatocyte (__ploid, _N, _C) → [Meiosis II] → spermatid (__ploid, _N, _C)
Spermatogenesis: spermatogonium (diploid, 2N, 2C) stem cell → [Interphase] → primary spermatocyte (diploid, 2N, 4C) → [Meiosis I] → secondary spermatocyte (haploid, 1N, 2C) → [Meiosis II] → spermatid (haploid, 1N, 1C)
257
Proliferative phase of spermatogenesis
spermatogonia → spermatocytes
258
3 Types of spermatogonial cells
- Type Ad (dark) → can differentiate into Type Ap
- Type Ap (pale) → divide by mitosis and give rise to type B
- Type B → divide to produce preleptotene spermatocytes that enter meiosis
259
Meiotic phase of spermatogenesis
spermatocytes undergo meiosis (2C→ 1C)
| Spermatid contains prominent round nucleus, golgi apparatus, centrioles, and mitochondria
260
Spermiogenic phase of spermatogenesis
spermatids undergo significant morphological changes and mature into spermatozoa
261
Spermatogenesis from spermatogonia → spermatozoa takes __ days
64
262
Spermiogenesis
spermatid (haploid, 1N, 1C) → mature spermatozoon (haploid, 1N, 1C)
Spermatid matures, elongates, develops flagellum
Once spermatid matures, sperm released into seminiferous tubule out rete testis
263
4 stages of spermiogenesis
1) Golgi Phase: formation of acrosomal vesicles by Golgi apparatus → cause centrioles to move to opposite end of nucleus
2) Cap Phase: Acrosomal vesicles become acrosomal cap → will allow the sperm to penetrate egg corona
3) Acrosomal Phase: centriole continues to extend away from nucleus to form flagellum
4) Maturational phase
264
Post-testicular sperm maturation
occurs in epididymis
Develop motility, become capable of fertilizing
265
Hormonal Control of Spermatogenesis:
Sertoli cells express FSH receptors → FSH stimulation from pituitary
→ androgen binding protein (binds T) → maintain high [androgen] within seminiferous tubules
→ secrete inhibin → negative feedback on FSH from pituitary
Leydig cells → secrete androgens (primarily T) → negative feedback on pituitary to control release of LH
266
Hemochromatosis can cause hypogonadotropic hypogonadism how?
Production/release of pituitary LH/FSH blocked
Iron deposits selectively in gonadotropes
+ liver disease, diabetes, CHF
267
Klinefelter’s syndrome
Presentation
Presentation: small testes, delayed/incomplete puberty, gynecomastia, eunuchoid body habitus, infertility
- Tubular fibrosis and destruction of Leydig cells over time
- Increased risk of breast cancer
HIGH FSH (no inhibin) + NORMAL LH + LOW/NORMAL TESTOSTERONE
268
Congenital anorchia and Vanishing testes syndrome
Levels of LH, FSH, and testosterone
insult to fetus before 10-12 weeks gestation interrupts testicular development
HIGH LH AND FSH + LOW TESTOSTERONE
269
Levels of LH, FSH, testosterone, and estradiol in complete androgen insensitivity
HIGH LH, FSH, TESTOSTERONE AND ESTRADIOL
No clinical effects of testosterone due to receptor insensitivity/mutation
