Male reproductive system

How is the male reproductive system divided up?

-Spermatogenesis
-Sexual function
-Regulation by hormones

What organ does sperm formation occur in?

Testis

Where does sperm ejaculate from?

Epididymis

At what point in the male's life does spermatogenesis start to occur?

Puberty

Where does spermatogenesis occur in the testis?

Seminiferous tubules

During puberty, spermatogenesis occurs due to the stimulation of what hormones? And what gland are these hormones released from?

-Follicle stimulating hormone (FSH) and Luteinizing hormone (LH)
-Anterior pituitary (which is when GnRH released from the hypothalamus acts on gonadotropes of the anterior pituitary)

What cells provide structural support to the spermatogonium as they migrate toward the central lumen of the seminiferous tubules?

Sertoli cells (helps with developing the sperm cells)

Why do spermatids have a lot of mitochondria?

To provide energy

What enzyme does the Golgi apparatus form on the sperm to help break down the egg upon fertilization?

Acrosome

What part of the sperm contracts to cause movement?

Axoneme

The movement of sperm is enhanced in what pH environment?

Neutral-slightly basic pH

What cells in the testis does FSH act on?

Sertoli cells

What cells in the testis does LH act on?

Leydig cells

When LH acts on the Leydig cells of the testis, what hormone is released?

Testosterone

What happens in the absence of GnRH and gonadotropins?

-Testis atrophy
-Sperm production stops (b/c no GnRH so no FSH to act on Sertoli cells so no spermatogenesis)
-Testosterone production stops (b/c no GnRH so no LH to act on Leydig cells so no testosterone made)

If spermatogenesis occurs too quickly, what do the Sertoli cells release to slow down the process?

Inhibin

What happens to the life-span and motility of sperm if there is an increase in temperature?

-Decrease in life-span
-Increase in motility

What hormone is essential for Sertoli cells to be stimulated so spermatogenesis can occur?

Testosterone

Role of FSH:

FSH acts on Sertoli cells to aid in sperm production

Role of LH:

LH acts on Leydig cells to release testosterone

What is the primary male androgen?

Testosterone

How is estrogen formed?

By testosterone in the Sertoli cells via FSH release

Negative feedback effect of Testosterone:

-If testosterone levels are low, then there will be an increase in LH and FSH
-If testosterone levels are high, then there will be a decrease in LH and FSH

If inhibin is released from the Sertoli cells, what hormones are inhibited?

GnRH and FSH

During Wolffian development in gestational development, what hormone is essential for the development of male genitalia?

Testosterone

What are the primary androgens?

Testosterone and Dihydrotestosterone

What enzyme is responsible for the conversion of testosterone to dihydrotestosterone?

5a-reductase

What two hormones agonize the androgen receptors (AR)?

Testosterone and Dihydrotestosterone

Where is dihydrotestosterone highly expressed?

Prostate and scalp

What hormone is responsible for the prostate gland to be enlarged causing BPH?

Dihydrotestosterone

When testosterone or dihydrotestosterone act on androgen receptors, what happens?

Dimerization causing the transcription of testosterone-dependent genes which are responsible for genitalia development and etc.

What are some physiological effects that occur when dihydrotestosterone acts on androgen receptors?

-External genitalia formed during gestation
-External genitalia enhanced during puberty
-Adulthood prostatic diseases
-Increased hair follicle growth is increased during puberty

What are some physiological effects that occur when testosterone acts on androgen receptors?

-Internal genitalia formed via Wolffian development during gestation
-The mass and strength of skeletal muscle increases during puberty
-Erythropoiesis (production of red blood cells)
-Bone

What are some physiological effects that occur when estradiol acts on estrogen receptors?

-Epiphyseal closure in bone and increased bone density
-Libido

Where is the deficiency occurring in primary hypogonadism?

Deficiency is within the gonad itself

Where is the deficiency occurring in secondary hypogonadism?

Outside of the testis

What are some examples of primary hypogonadism?

-Cryptorchidism (when testes don't descend during development)
-Lack of testes
-Trauma
-Viral infections like mumps
-Autoimmune
-Androgen receptor defect

What are some examples of secondary hypogonadism?

-Pituitary disorders like adenomas
-Autoimmune
-Kallmann syndrome (deficiency in pubertal GnRH production thus causing low GnRH, low LH, low FSH, low Testosterone, and lack of testicular development)

What are some symptoms of hypogonadism?

-Delayed or incomplete sexual development
-Reduced libido
-Decreased nighttime erections
-Gynecomastia (formation of breast tissue)
-Decrease in growth of facial and body hair
-Testicular atrophy
-Infertility
-Low bone mineralization
-Reduced muscle mass, increased fat
-Decreased energy, motivation, drive
-Depression & anxiety
-Sleep disturbance

While a small quantity of sperm is stored in the epididymis, where is most of the sperm stored?

Vas deferens

When does sperm become motile?

After ejaculation

What do the Sertoli cells and epidydimal cells secrete that are essential for sperm maturation?

Nutrient fluid contains:
-Nutrients
-Enzymes
-Testosterone
-Estrogens

What does the prostate gland secrete?

A thin, milky, alkaline fluid that contains calcium, citrate, phosphate, clotting enzyme, and profibrinolysin

What do the seminal vesicles secrete?

Fructose, citric acid, and prostaglandins (during ejaculation the vesicles will contract into the ejaculatory duct along with the fluid/sperm from the vas deferens)

How do prostaglandins aid in fertilization?

React with female cervix mucous to increase sperm motility thus causing reverse peristaltic contractions of the uterus/tubes to move the sperm toward the ovaries

What are the components of Semen (seminal fluid)?

-Sperm (2-5%)
-Vas deferens fluid (10%)
-Prostatic fluid (30%)
-Seminal vesicle fluid (60%)
- the clotting factors form a coagulum upon ejaculation
- provides a 24-48 hr life to the sperm

What part of the penis is the source of sensory nerve signals?

Glans penis

What part of the penis is filled with blood causing the penis to be erect?

Corpus cavernosa

What part of the penis keeps the urethra opened during an erection?

Corpus spongiosum

What happens when norepinephrine is released into the penis?

Flaccidity (smooth muscle contraction, decrease in cavernous blood)

What happens when acetylcholine is released into the penis?

Erection (smooth muscle relaxation, increase in cavernous blood)

What happens when norepinephrine binds to alpha-2 receptors (Gi coupled receptors) of the smooth muscle cells of the corpus cavernosum?

-Contraction so flaccidity

What are the steps of alpha-2 receptors (Gi) being agonized?

-Norepinephrine binds to alpha-2 receptor
-Causing decrease in cAMP
-Decrease in PKA
-Increase in Calcium due to active PLC and PKA inhibiting Ca ATPase
-Increase in Ca causes myosin to be phosphorylated thus causing contraction

What happens when norepinephrine binds to alpha-1 receptors (Gq coupled receptors) of the smooth muscle cells of the corpus cavernosum?

Contraction so flaccidity

What are the steps of alpha-1 receptors (Gq) being agonized?

-Norepinephrine binds to alpha-1 receptor
-Active PLC will cause an increase in DAG which causes an increase in PKC causes phosphorylation of myosin thus causing contraction
-The increase in Calcium continues due to alpha-2 agonism causing Ca ATPase to be inhibited from previous step thus indirectly causing contraction as well

What blocks norepinephrine from being released to the penis during psychogenic or physical stimulation?

The hypothalamus will release dopamine which inhibits the release of norepinephrine, thus increasing erections

When acetylcholine is released from the hypothalamus and acts on the penis, what is released to cause smooth muscle relaxation (erection)?

Nitric oxide

SNS and PNS

-SNS: Thoracolumbar
-PNS: Sacral

What happens when neuronal NO synthase and endothelial NO synthase release NO into the smooth muscle cell?

-NO will cause GTP to be converted to cGMP
-cGMP will allow PKG to turn MLCP (myosin light chain phosphatase) to be active
-MLCP will remove phosphate group from Myosin-P to myosin thus causing relaxation
-PKG also causes hyperpolarization due to K influx which inhibits Ca influx, also allowing relaxation to occur
-Ca ATPase will also be activated as well to thus contributing to relaxation of cell

What breaks down cGMP to GMP?

Phosphodiesterase (PDE)

If phosphodiesterase is inhibited, what will happen to the smooth muscle cells of the corpus caveronosa?

Relaxation (due to increase in cGMP)

Why does the Bulbourethral gland secrete Cowper's fluid?

-Fluid helps lubricate the urethra for sperm passage
- can flush out sperm from previous ejaculate

PNS and SNS

PNS: erection
SNS: emission and ejaculation

What is the emission and ejaculation process?

-Intense stimulus causes sympathetic impulses
-Impulses will close urinary sphincter and contract muscles of the genital organs (prostate)
-Contraction of vas deferens (where sperm is stored) and ampulla causes expulsion of sperm into internal urethra
-Contraction of prostate and seminal vesicles expel prostatic and seminal fluid into urethra to force the sperm forward
-ALL of these fluids will mix in the internal urethra with the mucous that was secreted by Cowper's gland to form semen
-This is the process of emission
-Then, the filling of internal urethra with semen elicits sensory signals that gives feeling of fullness in the internal genital organs
-This stimulation causes contraction of the ischiocavernosus and bulbocavernosus muscles at the base of the penile erectile tissue
-This causes increase in pressure of erectile tissue and genital ducts, ejaculating the semen

What is the process called when an erection stops after 1-2 minutes after ejaculation?

Resolution

How can 5-HT inhibit ejaculation?

Because an increase in serotonin levels can inhibit the prostate, colon/rectum, bladder, and genitalia

What are some drug classes that can increase serotonin and lead to ejaculation dysfunction?

-SSRIs
-TCAs
-MAOIs
-Antipsychotics
-Lithium

What are some vascular problems that cause erectile dysfunction?

-Atherosclerosis
-HTN
-Vascular injury
-Smoking

What are some neurogenic problems that cause erectile dysfunction?

-Stroke
-Degenerative disorders
-Spinal cord injury
-DM (neuropathy)

What are some hormonal problems that cause erectile dysfunction?

-Hypogonadism
-Pituitary tumors

What are some psychogenic problems that cause erectile dysfunction?

-Anxiety
-Stress
-Depression
-Performance anxiety

What are some drug-induced causes of erectile dysfunction?

-Anticholinergic
-Antihistamines
-Tricyclic antidepressants
-Dopamine receptor antagonists
-Estrogens
-ETOH
-Opioids
-Diuretics
-Beta blockers
-Amphetamine

What is benign prostatic hyperplasia?

Enlargement of the prostate that is DHT dependent

What are some obstructive symptoms of BPH?

-Hesitancy when urinating
-Poor urine stream
-Dribbling
-Large residual volume
-Straining to urinate

What are some irritative symptoms of BPH?

-Urinary urgency
-Increase frequency of urination
-Nocturia (3-4 times per night)

What is a result of the size of the prostate increasing as will as an increase in adrenergic response?

Further tightening of the urethra

What are the two types of cells in the prostate gland?

Stromal cells and epithelial cells

What are the stromal cells of the prostate gland?

-Smooth muscle that are responsible for contraction alpha-1 adrenergic receptors (respond to NE)
- they are located in the peripheral zone of the prostate gland

What are the epithelial cells of the prostate gland?

They produce prostatic fluid via activation of androgen receptors

What are some ways to stop BPH?

-Inhibit 5alpha-reductase
-Block a1-adrenergic receptors (this is quicker because there are more stromal cells)

What are some pharmacotherapies for erectile dysfunction?

-PDE inhibition (specifically PDE5) ( papaverine, sildenafil, vardenafil, tadalafil)
-alpha-2 blockers ( yohimbine)
-alpha-1 blockers ( phentolamine)
-Local delivery of prostaglandins ( alprostadil)

How do phosphodiesterase inhibitors work?

They prevent cGMP from being broken down which then allows for decrease in Ca thus causing relaxation ( erection)

Papaverine

-Opium alkaloid
-Direct injection into penis causing smooth muscle relaxation and filling of corpus cavernosa

How do selective PDE5 inhibitors work?

-These drugs mimic cGMP so PDE grabs ahold of them instead of breaking down cGMP which then causes relaxation
-These drugs highest affinity for PDE5 which is enriched in the corpus cavernosa
-Promotes erection

What are the selective PDE5 inhibitors?

-Vardenafil (Levitra, Staxyn ODT)
-Sildenafil (Viagra)
-Tadalafil (Cialis)
-Avanafil (Stendra)

Which is the most potent PDE5 inhibitor?

Vardenafil (Levitra, Staxyn)

Which is the most selective PDE5 inhibitor?

Tadalafil (Cialis)

At therapeutic doses, what can sildenafil cause?

Color-vision abnormalities due to slight affinity to PDE6

Which PDE5 inhibitor has a higher degree of muscle pain?

Tadalafil, due to PDE11 affinity

Which PDE5 inhibitor has the longest duration?

-Tadalafil (due to long half-life): 17 hours

What is a result of PDE5 inhibitors inhibiting the breakdown of NO metabolism?

-This intensifies vasodilatory properties of nitrovasodilators (like Nitroglycerin)
-Can cause severe hypotension

Phentolamine (Regitine)

-Intracevernosal injection causing vasodilation of penile blood flow by blocking a1 and a2 adrenergic receptors preventing NE from acting on a1 and a2 receptors and preventing contraction ( prevent flaccidity)
-Time to peak is 10 mins
-Used in patients who don't respond to PDE5 inhibitors
-Promotes erection by inhibiting flaccidity

Yohimbine (Yocon)

-Selective alpha 2 adrenergic antagonist

Alprostadil (Caverject, MUSE)

-Synthetic PGE1 (prostaglandin)
-Caverject is a intracavernosal injection
-MUSE is a intraurethral suppository
-Local delivery of PGE1 causes vasodilation and smooth muscle relaxation by acting on PGE1-receptors (Gs coupled receptors) which activates cAMP/PKA, PKA activates NO release
-Adding Papavarine and Phentolamine is highly synergistic

What is priapism?

Prolonged erection where penis does not return to flaccid state in the absence of stimulation for 4+ hours

What are some treatments for priapism?

-Dopamine receptor antagonists like trazadone
-Alpha agonists like pseudoephedrine or phenylephrine

When taken in high doses, androgens suppress gonadotropin secretion, which ultimately causes what?

Atrophy of testis due to suppression of endogenous testicular function

What is the result of a decrease in endogenous testosterone and sperm production?

Infertility and decrease in testicular size

What are alkylated androgens?

- has androgenic effects at first but at high doses have anabolic effect
-selectively increase protein synthesis resulting in increased cellular catabolism which leads to muscle growth
- development of masculine traits ( hair , voice, growth)

What can be an effect of anabolic steroids taking at high doses?

- they can feedback to inhibit the release of gonadotropin secretion when taken in high doses and this can cause atrophy of testes
- decrease testosterone and sperm production resulting in diminished fertility and testicular size