83 - Male Reproduction Flashcards
Recall: what hypothalamic nucleus releases GnRH (AKA LHRH)?
PON (pre-optic nucleus)
High pulse frequency of GnRH stimulates the release of _____, low pulse stimulates the release of _____.
- LH - FSH
What does the release of LH stimulate in males? Females? (Where does this occur?)
Stimulates steroidogenesis in ovaries and testes
What does the release of FSH stimulate in males? Females? (Where does this occur?)
Stimulates gametogenesis in ovaries and testes
What is the role of Kisspeptin?
Required to initiate increased GnRH release at the time of puberty - presumed signal for pubertal onset.
What is the role of gonadal steroidal hormones (testosterone, estrogen) in regulating the HPA axis?
Exert negative and positive feedback on GnRH (many factors affect GnRH, such as PRL, opioids, stress, and most of them inhibit it)
Mutations in the KISS1 receptor (binds kisspeptin) causes:
Hypogonadotropic hypogonadism
How does PRL affect GnRH?
Inhibits
What is the role of inhibin B? Where is it expressed?
- Specific inhibitor for FSH - Gonads
What specific cells does inhibin B bind to inhibit FSH synthesis?
Inhibits FSH-beta subunit synthesis in gonadotropes
What is the role of activin? Where is it expressed?
- Activator of FSH and LH - Pituitary and gonads
What specific location does activin bind to activate FSH and LH synthesis?
Stimulates FSH-beta, LH-beta, and GnRH receptor synthesis in pituitary
Why am I referring to FSH-beta and LH-beta, rather than just FSH and LH, when speaking of what activin and inhibin affect?
The alpha subunit of FSH, LH, TSH, and hCG are all the same, but the beta subunits differ
What cells form the blood-testes-barrier?
Sertoli cells (AKA nurse cells, nurse the sperm)
Sertoli cells have high affinity ________ receptors. Leydig cells have high affinity ________ receptors.
FSH LH
Name all of the effects that FSH has on sertoli cells (7).
- Stimulates spermatogenesis 2. Increases sperm motility 3. Stimulates growth of seminiferous tubules 4. Stimulates androgen-binding protein (ABP) 5. Stimulates aromatase 6. Stimulates inhibin 7. Stimulates growth factors
What is the purpose of the ABP released by Sertoli cells?
Maintains high local T levels
What is the function of the aromatase released by Sertoli cells?
Converts testosterone to estradiol
What is the function of the inhibin released by Sertoli cells?
Inhibits FSH release (negative feedback mech)
Name all of the effects that LH has on Leydig cells (4).
- Stimulates steroidogenesis from cholesterol 2. Makes androgens 3. Stimulates StAR protein (rate-limiting) 4. Stimulates Leydig cell growth
How many carbons are contained in androgens?
19 C
What (4) products of Leydig and Sertoli cells can negatively feed back on gonadotrophs?
- Testosterone 2. Inhibin (Leydig) 3. DHT 4. Estradiol (E2)
Describe the pathway of androgen synthesis (don’t name enzymes).
- Cholesterol to pregnenolone 2. Pregnenolone to progesterone 3. Progesterone to 17(OH)-progesterone 4. 17(OH)-progesterone to androstenedione 5. Androstenedione to testosterone (T) 6. Testosterone to Estradiol + dihydrotestosterone (DHT)
In what 4 tissue types are testosterone precursors made?
Extragonadal tissues: brain, adrenal, skin, adipose tissue
What organ is the primary source of circulating T?
Testes
In circulation, T is bound to:
SHBG (very little free T in the blood)
Once inside cells, T can be converted into either ___________ or ____________.
- DHT - Estrogens
Metabolized T forms:
Diols, triols
What cells does androgen synthesis occur in?
Leydig cells
What receptor does T bind?
Androgen receptor (AR) - A nuclear steroid receptor
What receptor does DHT bind?
Androgen receptor (AR) - A nuclear steroid receptor
Which has higher affinity for the androgen receptor, T or DHT?
DHT
What is DHEA? Where is it produced?
- Weak androgen - Produced in zona reticularis
How is DHEAS formed?
Sulfation of DHEA
What other hormone can DHEA be converted to? Via what hormone?
Androstenedione via 3beta-HSD enzyme
What important hormone is androstenedione directly converted into? Via what hormone?
T via 17beta-HSD (can also be converted to estrone)
What is the most abundant hormone in young adults?
DHEA
Recall: what enzyme converts T to estradiol?
Aromatase
Recall: DHT binds w/higher affinity to AR than does T. Which has the higher potency, T or DHT?
DHT
What enzyme is required to convert T to DHT? Where is this found?
5alpha-reductase - Genital skin, prostate
3beta-diol is converted from what hormone? What is significant about 3beta-diol?
- DHT - Binds estrogen receptor (even though it’s an androgen product)
What enzyme is responsible for converting prenenolone to progesterone?
3beta-HSD
What gene/enzyme is responsible for converting progesterone to 17(OH) progesterone?
CYP17 17-hydroxylase
What enzyme is responsible for converting androstenedione to T?
Type III 17beta-HSD
What gene is responsible for converting T to estradiol?
CYP19 - Adipose tissue
What % of daily T is excreted as free T? What happens to the remainder?
- Less than 2% - Remainder converted to 17-ketosteroids and DHT (conjugated to water soluble forms and excreted)
What are some of the effects of T, DHT, and E2? (lots)
Masculinization of the brain requires ________ to ________ conversion
T to E
What hormone is responsible for male pattern baldness?
DHT
What are the phenotypic effects of T alone (not with DHT or E2)?
- Development of epididymus, vas deferens - RBC formation - Muscle mass - Abdominal visceral fat deposition - Skeleton growth - Larynx devo (male voice)
In fetal development, T is important for development of what 3 things?
Epididymis, vas deferens, seminal vesicles
In fetal development, DHT is important for development of what 3 things?
Penis/penile urethra, scrotum, prostate
In pubertal development, T is important for development of what 6 things?
Penis, seminal vesicles, musculature, voice, skeleton, spermatogenesis
In pubertal development, DHT is important for development of what 4 things?
Scrotum, prostate, male pattern hair distribution (beard, balding, diamond-shaped pubic escutcheon), sebaceous glands
Name the accessory glands of the penis (4)
- Seminal vesicles
- Prostate gland
- Bulbourethral gland
- (Cowper’s gland)
What is cryptorchidism?
Why is this condition bad?
“hidden testis, often result of undescended testes that remain in abdominal cavity. (most common congenital abnormality of urogenital tract)
- Need to be 1-2 degrees below core body temp for sperm development
What is occurring during counter-current heat transfer of in the testes?
- Warm blood comes in thru testicular a., wraps around pampiniform plexus
- Returning venous blood absorbs some of the arterial heat to reduce the temp
Besides the testicle, what else does the testicular a. supply?
Caput and part of corpus of epididimys
What 3 structures are w/in the spermatid cord?
- Ductus deferens
- Gonadal artery
- Gonadal vein
Describe the general layout of the testicular tissue (just read)
Each adult testis weighs ~ 40 grams with 80% germinal tissue and 20% supportive CT with Leydig cells.
What is the name of the tube w/in the testes?
What is it called right after it leaves the testicle?
What does it them become? (3)
- Seminiferous tbule (200 meters)
- Rete testes (first called “sperm”)
- Head, body, and tail of epididymis (sperm more mature by the tail)
What is contained w/in the peritubular space of the testes?
- Leydig cells
- Myoid cells
- Blood supply
What is contained w/in the intratubular space of the testicles?
- Sertoli cells
- Developing germ cells
- Lumen
Stem cells that develop into spermatogonia lie along the BM of _______________.
Seminiferous tubules (basal compartment)
(Spermatogonia are outside the blood-testis barrier to protect them from immune system)
Spermatogenesis, starting with differentiation of spermatogonia into spermatozoa (meiosis) occurs in the _____________ of the seminiferous tubules.
inner (adluminal) compartment
Spermatids lienear lumen of seminiferous tubules, attached to adjoining __________ cells by tight junctions.
This interaction creates the __________________.
Sertoli
Blood-testis-barrier
The paracrine actions of activin and inhibin are the opposite of action they are named for in pituitary.
What does inhibin do in the testes?
What does activin do in the testes?
- Inhibin: Increases LH-induced testosterone production in Leydig cells
- Activin: Inhibits testosterone production in Leydig cells
What receptors do Leydig cells have that lead to the production of T?
What receptors do Sertoli cells have?
LH receptors
FSH receptors
Testosterone in Leydig cells supports what process?
Spermatogenesis
How would exogenous T (e.g. steroids) affect testicular T?
Would decrease it due to decreased release of LH (testicular shrinkage)
Upon FSH binding its receptor on Sertoli cells, what processes occur?
- Inhibins produced (feed back to shut off FSH)
- ABP produced, leaves cell
- Aromatase produced (T -> E2)
- Growth factors produced (can act on Leydig cells as well)
What’s the specific purpose of producing ABP in Sertoli cells?
Binds T, and increased T supports sperm development
Define spermatogenesis.
The process by which spermatogonia become 4 haploid spermatids
Define spermiogenesis.
Maturation of spermatids into flagellated spermatozoa.
Define spermiation.
Release of spermatozoa from Sertoli cells into lumen.
Spermatogenesis, spermiogenesis, and spermiation all occur in the:
Seminiferous tubules
What specific events occur during spermiogenesis (spermatids -> spermatozoa)
Nuclear condensation, shrinkage of the cytoplasm, formation of the acrosome, devo of the tail
Generally, describe the pw that maturing spermatogonia take as they develop inside the testicle.
Move from periphery towards lumen as they mature.
Where do spermatozoa go after exiting the seminiferous tubules (s/p spermiation)? How do they get there?
Passive movement to rete testes (not yet mobile)
What is contained w/in the acrosome and why (generally)?
Sperm “cap” containing hydrolyzing enzymes used to penetrate ovum.
(formed during spermiogenesis)
What happens to the sperm while they’re stored in the epididymis? (acts as a reservoir)
Gain motility (and lose most of their cytoplasm as they become more efficient swimmers)
Sperm maturation not fully complete until sperm enter ____________, a process known as ____________.
- Vagina
- Capacitation
About what % of semen is sperm?
What gland contributes the majority of sperm’s fluid?
- 10%
- Seminal vesicle
Paired seminal vesicles form the __________ duct.
ejaculatory
What (3 things) do the seminal vesicles contribute to the semen?
- Nutrients (fructose, citric acid…)
- Buffer (nl pH optimal for survival in acidic vag)
- Prostaglandins (induce contraction of uterus/fallopian tubes to help sperm go)
What is the urethra called at the prostate gland, of which the prostate gland itself surrounds?
Prostatic urethra
(prostate produces 1st fluid to be expelled in ejaculate)
What (2 things) does the prostate gland contribute to the semen?
- Alkaline secretions (neutralizes acidic vagina)
- Proteolytic enzymes (to liquify the semen)
Describe the order that the male accessory glands occur to make semen.
- Seminal vesicles
- Prostate
- Cowpers/bulbourethral glands
After the prostate, the urethra is known as the:
spongy urethra
Describe the secretions produced by the Cowper’s/bulbourethral glands.
Mucous w/some sperm (hence withdrawal method can fail)
What is the major issue w/benign prostatic hyperplasia (BPH)?
What is a biomarker for prostate growth? Is this indicative of Ca?
- Constricts urethra, leading to urinary retention (increases w/age)
- PSA: useful for dx but not indicative of Ca (“free” PSA actually lower in Ca compared to benign)
What is the hypothesized pathology of BPH? (just read)
Pathology unclear. Some evidence for higher estradiol:testosterone ratio as men age. Possible increased sensitivity to testosterone due to increased androgen receptors.
What NS controls erection vs. ejaculation?
“Point and shoot”
- P = parasymp for erection
- S = symp for ejaculation
Name the bv that constricts to lead to the flaccid state. Is this under symp or parasymp control?
- Helicine a.
- Tonic symp control
What is the name of the tissue that surrounds the spongy urethra? What is the other one, which is bilateral and also fills w/blood when the helicine aa. relax?
- Corpus spongiosum
- 2x corpus cavernosum
Describe what is occurring anatomically to cause and maintain an erection.
- Relaxation of vascular smooth muscle (corpora cavernosa and corpus spongiosum) leads to increased blood flow in cavernous tissue
- Engorgement compresses outflow pathway (veins) and creates tumescence (swelling)
*Recall: erection is under parasymp control. What are the 2nd msger pw’s that occur for this? (first think of the 2 primary NT’s involved)
- Parasympathetic postganglionic nerves release ACh and NO
- ACh can bind muscarinic receptors and activate PLC (via Gαq). This increases Ca2+ and activates NO synthase
- NO activates guanylyl cyclase (GTP -> cGMP -> relaxation)
- NOTE: NO can also be released directly from nerve terminals
What is the molecular mech of Viagra (sildenafil)?
What class of drugs is it in?
Does it require anything else to achieve erection?
- Inhibits phosphodiesterases that would normally decrease cGMP
- Maintains chronic state of vasodilation
- Type 5 PDE inhibitors
- Still requires CNS arousal
(Note: not specific to penile circulation, can cause heart problems)
Contraction of mm. around the base of the penis is important for:
Ejaculatory force (not maintaining erection)
Define emission.
Movement of ejaculate into the prostatic/proximal part of urethra.
- Sets the stage for ejaculation
How, specifically, does emission occur (symp control)?
- Peristaltic rhythmic contractions via smooth m. of portions of vas deferens, seminal vesicles, prostate
- Direct innervation of smooth m. cells via alpha adrenergic receptors
What triggers ejaculation?
How does it occur?
What controls the reflex?
(just read the first time)
- The reflex is triggered by entry of semen to bulbous urethra from prostatic urethra, leading to forceful expulsion of semen.
- Rhythmic contractions of ischiocavernosus and bulbospongiosus muscles propel semen through the urethra
- Spinal cord reflex (as well as cerebral control?); afferents reach sacral spinal cord (S2 – S4) triggering efferent somatic motor neurons via pudendal nerve.
- Note lack of direct voluntary control…
ANS, then spinal reflex
What are the 3 classes of male fertility disorders?
- Pre-testicular
- Testicular
- Post-testicular
What occurs w/primary hypergonadotropic hypogonadism? (levels of pituitary hormones/gland hormones)
What are some eg’s?
- High LH/FSH, low T/DHT
- Klinefelter syndrome, enzyme deficiencies
What occurs w/secondary/teritary hypogonadotropic hypogonadism? (levels of hypothalamic/pituitary hormones/gland hormones)
What are some eg’s?
- Low GnRH, low LH/FSH, low T/DHT
- Kallman syndrome, panhypopituitarism, *hyperprolactinemia (most common)
Name 3 eg’s of testicular male fertility disorders.
Which is the most common cause of sub-fertility in men?
- Klinefelter syndrome
- Cryptorchidism
- Varicocele: *most common cause of subfertility in men
What is varicocele? (testicular fertility disorder)
Dilated scrotal veins lead to increased temp, sperm die
Name 3 eg’s of post-testicular fertility disorders.
- Ductal obstructions
- Premature ejaculation
- Impotence
What c’some carries the androgen receptor?
X c’some
What is the physical sign that you’d have complete androgen resistance in male hypogonadism vs. partial?
W/ complete, you’d have no growth of axillary or pubic hair.
