Male Repro/Infertility Flashcards
Surgical sperm extraction source preference
Epidydimal > testicular (when possible)
Best predictor of success for vasectomy reversal
Time since vasectomy
Time since vasectomy and pregnancy rates after reversal (<3, 3-8, 9-14, and 15+ years)
< 3 years -> 76% pregnancy rate
3-8 years -> 53% pregnancy rate
9-14 years > 44% pregnancy rate
15+ years -> 30% pregnancy rate
Most likely abnormality found in fertile population
Abnormal SA
Semen paramenter most likely associated with chromosomal abnormality
Low sperm count/concentration
Rate of karyotypic abnormality in fetuses conceived via ICSI in men with severe oligospermia
6-7%
Sildenifil drug class/MOA
Phosphodiesterase 5 enzyme inhibitor (vasodilation)
Sildenifil target population
Effective in the setting of spinal cord injury and peripheral neuropathy (NOT peripheral vasculopathy)
Sildenifil side effects
Priapism, color vision, dyspepsia (NOT ptosis/proptosis)
What initiates spermatogenesis
Testosterone
Initiation of spermatogenesis in hypo/hypo patient
HCG (if testicular volume >4 mL) +/- HMG/FSH (if not responsive)
When do sperm get their final methylation marks?
Primary spermatocytes
When do primary spermatocytes begin differentiation?
Puberty
Cystic Fibrosis & CBAVD genetics
Either compound heterozygotes (carrying different mutations in their two CFTR genes) or carry a mutation in one of their CFTR genes and an intron 8 5T splice variant, associated with low levels of functional CFTR protein, in their second gene.
Number of known mutations in CF
Over 1600 known mutations in CFTR gene
Classic mutation for CF
Delta 508 mutation
Other common mutations to know in CF
5T splice variants
How many patients with CF have CBAVD?
Nearly all (>75%)
Males with 5T variant and delta 508 mutation phenotype
Have CBAVD but not CF
Location of Y chromosome microdeletions
Y microdeletions occur on the long arm of the Y chromosome (q11)
SA results by location of Y chromosome microdeletions
o Deletions in the AZF (azospermia factor) A (“awful”) or B (“bad”) typically result in azosopermia
o Deletions in AZF C region cause infertility of varying severity, ranging from oligospermia to azoospermia
Percentage of men with Y chromosome microdeletion with small testicular volume
25%
Klinefelter syndrome prevalence
1/1000 men
Klinefelter syndrome genetics
47 XXY
o Related to androgen receptor on X chromosome (increase CAG repeats, decrease receptor activity)
o Phenotype varies with number of X chromosomes
Klinefelter syndrome clinical presentation
Primary testicular failure (azoospermia, low T), decreased intelligence, long arms/legs, increased risk of breast cancer (unopposed estrogen), cryptorchidism [NOT delayed puberty]
Klinefelter syndrome male offspring genetics
Offspring (following TESE/ICSI) most likely to have normal, 46XY karyotype
Mutations of long arm (q) of X chromosome (1)
Androgen receptor gene (AIS)
Mutations of short arm (p) of X chromosome (5)
KAL gene (Kallman’s), FMNR1 gene (Fragile-X), DAX-1 (gonadal dysgenesis), Steroid sulfatase gene (Icthyosis), SHOX (Turner’s; pseudoautosomal region)
Mutations of long arm (q) of Y chromosome (1)
AZF (Y-chromosome microdeletion/azoospermia)
Mutations of short arm (p) of Y chromosome (1)
SRY (Swyer)
Where does the sperm become capable of fertilization?
Cauda epididymis
Path of of sperm maturation
- Seminiferous tubules
- Start of spermatogenesis – contain spermatogonium
- Spermatogenesis begins at wall and completes at lumen
- Rete testis
- Caput epididymis
- Corpus epididymis
- Cauda epididymis
What is the acrosome reaction? What ZP is needed?
Enables sperm to penetrate the zona pellucida
Initiated by contact between the sperm and the zona
ZP3
What acrosomal enzymes does ZP3 binding release?
Hyaluronidase
Acrosin
Steps for sperm process to increase fertility success?
- Washing
- Swim-up
- Density gradient centrifuge
- Test egg yolk buffer w/ preincubation (?)
Prevalence of azoospermia (in gen pop & infertiles)
- 1% of general population
- 10-15% of infertile men
Types of azoospermia, %, causes
Obstructive (40%) - infx, trauma, CBAVD
Non-obstructive (60%) - hypo/hypo, hyperPRL, testicular failure
When to do testicular biopsy?
azoospermia & normal hormone levels (non-obstructive)
What does a fructose test for obstruction look at?
to rule out possible ejaculatory duct obstruction or agenesis of seminal vesicles or CBAVD
fructose comes from seminal vesicles - if low, then agenisis or CBAVD (usually they also dont have a seminal vesicle)
normal semen - alkaline or acidic?
alkaline
prostatic secretions are…acidic or basic?
acidic (and no fructose)
% of males w/ azoospermia are due to CF or AZF mutation
CF: 10%
AZF: 8%
Which race is at highest/lowest risk for CF?
- White 1:3,000
- Hispanic 1:9,000
- Native American 1:11,000
- Black 1:15,000
- Asian 1:30,000
Immotile cilia syndrome
Inheritence? Symptoms? Screen? Associated condition? How to treat?
AR
Sx: Chronic cough, Chronic rhinitis, Chronic sinusitis, Infertility
Screen: exhaled NO
50% have situs inversus
Male - ICSI (female, 50% will have subfertility)
What sperm cells affected by chemo?
Spermatogonia
What % of men w/ Hodgkin’s Lymphoma have abnormal SA?
60%
Sperm antibodies - prevalence? SA shows? dx?
4-8% of subfertile men
clumping/agglutination +/- isolated asthenozoospermia (reduced motility)
Diagnosed using beads/latex particles with attached antibodies
Components of Leydig Cell Regulation (3)
- LH stimulates T production
- Prolactin induces expression of LH receptor
- Signaling by cytokines & growth factors from the Sertoli cell
Components of Sertoli Cell Regulation (3)
- FSH stimulates inhibin production to feedback to pituitary
- Testosterone - androgen receptors on Sertoli cells
- Local growth factors
When is fetal form of Leydig cell active?
8-18w, then later at puberty
What cell forms the blood-testis barrier?
Sertoli cells
Most common congenital abnormality in males?
Cryptorchidism (1 in 30)
(Hypospadias is 1 in 250)
Evolution of sperm germ cell
Inactivating FSHR mutation in men - what is the problem?
subfertile w/ reduced testis size, but not azoospermic
(tells you spermatogenesis is mainly LH/T-dependent)
FSH & LH & T roles in spermatogenesis
FSH moreso for QUANTITY, not QUALITY
LH/T has no role in spermatogonial proliferation and maturation but it supports spermatocyte and spermatid survival probably by an antiapoptotic mechanism
T is absolutely required for the second meiotic division in meiosis (but has synergy w/ FSH)
Spermatogenesis
vs
Spermiogenesis
Spermatogenesis - A dynamic process that results in the continuous production of sperm (1. Mitotsis/proliferation, 2. Meiosis (where crossing-over occurs), 3. Spermiogenesis)
Spermiogenesis - Differentiation/cellular remodeling of haploid spermatids to mature sperm
How many & what types of Spermatogonia?
- Stem Cell Spermatogonia: Capable of reestablishing spermatogenesis after toxic insult
- Proliferative Spermatogonia: Undifferentiated and undergo self-renewal (forms the pool of sperm)
- Differentiating spermatogonia: Committed to enter the pathway resulting in production of mature sperm
What acts directly on the spermatogonia to stimulate their entry into the meiotic pathway and differentiate into type B spermatogonia?
Retinoic acid
What are Type B Spermatogonia?
Able to differentiate into spermatocytes that enter meiosis
Spermiogenesis:
What does the sperm start out as? and what 3 things need to occur?
Round Spermatid
- Development of the acrosome (sock over the head)
- Development of flagellum
- Nuclear condensation
What does the acrosome store?
Hydrolytic enzymes needed to penetrate ZP
Where do sperm acquire a forward motility & fertilizing potential?
Epididymis (head → body → tail)
Sperm should be immotile (maybe vibrating) in testis
How long does spermatogenesis take?
How long does sperm migration through epididymis take?
spermatogenesis: ~74d
epididymis: ~10-16d
90d total
Where are mature sperm stored?
In cauda epididymis & vas deferens
Components of Spermatic cord (4)
Vas deferens
Cremaster muscle
Spermatic artery
Veins of Pampiniform plexus
Volume & % of ejaculate provided by Seminal Vesicle
2-2.5 mL or 45-80% of ejaculate
Volume & % of ejaculate provided by Prostate
0.5 mL or 15-30% of ejaculate
Where do enzymes for coagulation of ejaculate come from?
Seminal Vesicle
What is in prostatic fluid? (5)
- citric acid
- acid phosphatase
- calcium
- zinc
- enzymes which cause liquefaction of ejaculate coagulum (kallikrein)
Tissue masses in penis (3)
Corpora cavernosa (right and left)
Corpus spongiosum
