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Male Physiology and Pharmacology
Lecture 13
54
Pharmacology
Professional
10/04/2012

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Term
What are the three divisions of male reproduction?
Definition
- Spermatogenesis
- Sexual function
- Regulation of functions by hormones
Term
What are the components of the male reproductive system?
Definition
- Testis - major male machinery. Composed of coiled seminiferous tubules. Empties into epididymis
- Epididymis very long, stores sperm. Tail empties into vas deferens
- Vas deferens - smooth muscle responsible for ejaculation. Goes to prostate gland and urethra.
Term
What are the 2 layers of the testes?
Definition
- tunica vaginalis - outer capsule
- tunica albuginea - inner fibrous capsule
- septa divide testis into ~250 lobules. Each lobule contains the seminiferous tubules
- Tubules converge --> straight tubule to direct sperm to rete testis.
- Leaves via efferent ductules --> epididymis
Term
How is sperm ejaculated?
Definition
Through the epididymis, not the testes
Term
When and where does spermatogenesis occur?
Definition
In the seminiferous tubules during active sexual life. Stimulation by anterior pituitary - LH/FSH
Term
What is the first stage of spermatogenesis?
Definition
Spermatogonia (germ cells) migrate while being nourished by Sertoli cells, undergo mitosis --> primary spermatocyte. Miosis --> secondary spermatocyte. Starts to undergo Miosis 2 but does not finish -- finishes upon fertilization --> spermatid --> spermatozoa. 23 pairs of chromosomes.
Term
How are sperm formed?
Definition
- Acrosome - proteolytic enzymes used to penetrate the egg
- Tail - microtubules (axoneme) and mitochondria
- moves faster in semen, slower in acid (vagina)
- Body temperature affects sperm production - scrotum controls
Term
How do hormones control spermatogenesis?
Definition
- LH - control the leydig cells, involved in synthesis and release of testosterone. Testosterone --> Sertoli cells to support spermatogenesis
- Sertoli cells also make some testosterone and convert to estrogen. FSH has a positive effect on Sertoli cells
- Inhibin - comes from sertoli cells, has negative feedback on hypothalamus and anterior pituitary
- GnRH - produce LH/FSH. In it's absence, testis atrophy and testosterone/sperm production stops.
Term
What hormones are critical to spermatogenesis?
Definition
- GnRH - induces release of LH/FSH
- Testosterone - Secreted by Leydig cells. Needed for spermatogonia
- LH - Stimulates Leydig cells to secrete testosterone
- FSH - Stimulates sertoli cells to convert spermatids to sperm
- Estrogens - formed by Sertoli cells, necessary for spermatogenesis
- hGH - controls metabolism of testes, w/o = infertility
- Inhibin - released from Sertoli cells, negative feedback on GnRH and FSH
Term
What are anabolic and androgenic effects of testosterone?
Definition
Anabolic - increased muscle and tissue mass, bone density
Androgenic - growth of penis, scrotum, testes. Hair growth, prostate growth, skin thickening.
Term
What are metabolites of testosterone?
Definition
- DHT - converted by 5alpha-reductase, removing 4-5 double bond. Also acts on androgen receptor
- Estradiol - converted by aromatase. Acts on estrogen receptor
Term
What is Wolfian development?
Definition
During gestation, caused by testosterone binding to the androgen receptor. Internal genitalia development
Term
What do high levels of DHT/low testosterone lead to?
Definition
Male pattern baldness, BPH, prostate cancer
Term
What is the only stage in life where testosterone is not maintained?
Definition
Childhood.
gestation and infancy, testosterone is high to differentiate
Gradual decline later in adulthood (senescence) - decreased energy and libido.
Term
Where is sperm stored and for how long?
Definition
In the vas deferens, for up to 1 month. Sperm is continually made, up to 120 million/day. Maturation and motility happens after ejaculation.
- Both sertoli and epididymis necessary for sperm maturation.
Term
What is the function of the prostate gland?
Seminal vesicles?
Definition
- Secretes a milky basic fluid upon contraction of the vas deferens, neutralizing acid in the vas deferens AND the vagina
- Allows sperm to be more motile in a more basic environment
---------
- Seminal vesicles lined w/ secretory cells, high levels of fructose and prostaglandins. 60% along w/ sperm and prostate gland fluid.
- Prostaglandins aid in fertilization by helping move the sperm up into the cervix
Term
What are the characteristics of semen?
Definition
All the fluids:
Semen (2-5%), vas deferens (10%), prostatic fluid (30%), seminal vesicle fluid (60%)
Slightly alkaline, pH 7.5. Has clotting factors - coagulates upon ejaculation. Dissolves over a 15-30 min period and sperm become motile, can live for 24-48 hours in the vagina.
Term
What is the most important source for for sensory nerve signals in the penis?
What are 2 areas inside the penis?
Definition
Tip of the penis/glans penis
Corpus cavernosum - two sponge pieces which hold the deep arteries
Corpus spongiosum - smaller, holds the urethra
- flaccid - both Corpi are constricted and lack blood
- Erect - Both are relaxed and fill with blood. ED: chambers cannot fill with blood.
Term
How is the penis innervated?
Definition
- At rest/flaccid - NE/adrenergic output --> smooth muscle contraction, decr blood filling
- Erect - PNS/sacral tracts dependent on Ach and NO --> smooth muscle relaxes and incr blood filling.
Term
How is penis flaccidity mediated by innervation?
Definition
SNS innervates SM surrounding corpus cavernosum. NE released and acts on alpha2 receptors --> Gi receptor. Decreased cAMP increases calcium and contraction of SM --> flaccidity.
NE --> alpha1 --> IP3/DAG pathway, increased calcium and phosphorylation of myosin
Term
How does CNS stimulation affect the penis?
Definition
Stimulation prompts the release of dopamine --> INHIBITS NE release.
Ach release from sacral portions--> erection. PSNS releases NO and VIP. NO relaxes arteries of the penis
Degree of erection is proportional to degree of stimulation
Term
How is the penile erection facilitated by innervation?
Definition
- Decr in SNS tone affects cavernous neuron --> nNOS releases NO. NO (eNOS) also released by Ach acting on M3.
- NO promotes cGMP --> K efflux and hyperpolarization. Without calcium, the tissue relaxes, allowing blood flow
Term
What drugs can improve an erection?
Definition
- Alpha1 antagonists
- Alpha2 antagonists
- ARBs
- DA agonists
- PDE5 inhibitors
Term
What is the purpose of the corpus spongiousum?
Definition
Surrounds the urethra, 10% of blood. Provides a buffer to keep the swelling of the corpus cavernosum from closing the urethra
**Maintain the integrity of the urethra
Term
What is the purpose of the bulbourethral gland?
Definition
At the base of the urethra, secretes Cowper's fluid, which lubricates the urethra for sperm passage, neutralizes urine, and can flush out old sperm.
Term
What role does the spinal cord have in ejaculation?
Definition
Thoracic and Lumbar areas close off the bladder to the urethra (serotonin
Sacral area leads to expulsion via vas deferens into urethra
- Entry of other fluids mix in internal urethra = emission, a feeling of fullness
- Ejaculation - contraction of ischiocavernosus and bulbospongiosus muscles, wavelike increases in pressure
- Resolution - SNS inhibits erection
Term
What is BPH?
Definition
non-cancerous enlargement of the prostate gland, DHT dependent.
Occludes the urethra
Term
What are the symptoms associated with BPH?
Definition
- Obstructive symptoms - poor stream, dribbling, large residual volume
- Irritation - urination hesitancy, increased frequency, nocturia
- Increased by Alcohol, cold, immobility, OTC sympathomimetics and anticholinergics.
Term
What improves BPH symptoms?
Definition
Blocking 5alpha reductase - inhibits to conversion to DHT
Term
What drugs can be used to tread erectile dysfunction?
Definition
- PDE(5) inhibition: Paparavine, Sildenafil/Viagra, Vardenafil/Levitra, Tadalafil/Cialis
- alpha2 receptor blockade - Yohimbine
- Alpha1 blockade/vasodilation - Phentolamine
- local prostaglandin delivery - Alprostadil
Term
How does blocking PDE help in erectile dysfunction?
Definition
PDE inhibited, cannot break down NO. Increase in cGMP --> hyperpolarization and calcium removal --> relaxation and erection
PDE5 enriched in the corpus cavernosum.
Term
Why do PDE5 inhibitors cause visual disturbances?
Definition
Have some affinity for PDE6, which is found in the retina
Sildenafil/Viagra more likely.
PDE11 - muscle pain - tadalafil/Cialis
Term
What are similarities and differences between the PDE5 inhibitors?
Definition
All cause hearing loss, 3A4 metabolism.
Tadalafil lasts 17 hours due to structure changes
Tissue MUST be able to generate NO to work.
Term
How does Phentolamine/Rogitine work?
Definition
Alpha1 and 2 blocker -- vasodilation due to relaxation at SM, swelling of c. cav.
- Remember NE affecting alpha2/cAMP contracted SM, blockade leads to erection
- Remember NE --> alpha1/IP3-DAG contracted SM, blockage leads to erection
= blockade of anti-erectile fxns
Term
How does Yohimbine/Yocon work?
Definition
Pre- and post- synaptic alpha2 antagonist
- pre-synaptic antagonism leads to greater NE release, but alpha2 is block so still get an erection.
- Used in tandem w/ phentolamine
Term
What is the MoA for alprostadil/Caverject or Muse?
Definition
synthetic PgE1 for intercavernosal injection or intraurethral suppository --> vasodilation and relaxation via cAMP/PKA
- sometimes used w/ paparavine or phentolamine
Term
What is priapism? What is the treatment?
Definition
Penis remains erect w/o stimulation for more than 4 hours - can cause permanent damage
Caused by ALL ED agents.
Tx: Injected phenylephrine
Term
What is the hypothalamic-pituitary-reproduction axis in men?
Definition
Hypothalamus secretes GnRH --> anterior pituitary secretes LH/FSH --> Leydig and Sertoli cells in testes secrete testosterone
Testosterone acts on muscle development, adipose, and ducts.
Testosterone exerts negative feedback on hypothalamus and ant. pituitary. Inhibin inhibits FSH.
Term
How does androgen signalling take place?
Definition
Testosterone circulates bound to SHBG
Unbound, crosses cell membranes and acts as testosterone or DHT on an androgen receptor
Androgen binding knocks heat-shock protein off receptor, allowing it to dimerize.
Dimers move into nucleus and make new proteins.
Term
What are the consequences of androgen deficiency?
Definition
Depends on when it occurs;
- In utero: Complete absence = female phenotype. Mild absence = impaired spermatogenesis
- Failure to complete puberty. Gynecomastia
- after puberty: decr libido, decr energy, decr muscle mass/bone, decr Hct/Hgb
Term
Why are androgens not orally bioavailable?
Definition
1st pass metabolism - rapid hepatic metabolism
Term
How do injectable testosterone esters work?
Definition
Esterified to be lipophilic, lasts 2-4 weeks.
Levels go higher than normal, then slowly return to sub-therapeutic. Must maintain injections
Test. Enanthate/Delatestryl
Test. Cypionate/Depo-testosterone
Test. Propionate/Testex
Term
What characteristics are increased by anabolic steroids/alkylated androgens?
Definition
Incr appetite
Incr bone and muscle growth
Stimulation of bone marrow and RBC
Incr libido, sebaceous gland activity
Androgen:anabolic effect is key.
Term
Which drugs are alkylated androgens and what are their properties?
Definition
- Methyltestosterone/Oretin Methyl. 17-methyl, has 1:1 activity. This addition increases oral activity
- Fluoxymesterone/Halotensin - 17-methyl and 9-Fluoro yields 1:2 and:ana but has MR affinity
- Oxandrolone/Oxandrin - looks like DHT (double bond reduced). Incr anabolic, decr androgenic
- Stanozolol/Winstrol - Incr anabolic, decr androgenic
- Danazol/Danocrine - ring substitute and 17-ethinyl. Decreases LH/FSH in cancer = antigonadotrophic
Term
Why would transdermal androgen be used?
Definition
Avoids 1st pass
Facilitates transport
MUCH more stable concentrations
Term
What is the main side effect of androgen replacement therapy?
Definition
Suppresses endogenous testicular function --> atrophy and infertility
Risks: BPH, liver dmg, gynecomastia, increased fluid retention, oil/acne, body hair.
Term
What are the sites that anti-androgen therapies act?
Definition
- Ketoconazole - all steroidogenesis by inhibiting SCC in the testes and elsewhere
- Spironolactone in the testes and androgen receptors
- Finasteride and dutasteride inhibit 5alpha reductase
- Flutamide and Cyproterone are androgen receptor antagonists.
- GnRH agonism
Term
How do GnRH agonists work?
Definition
Desensitization: downregulation of the GnRH receptor on the anterior pituitary --> decrease in entire pathway
Term
What drugs are GnRH agonists?
Definition
- Leuprolide/Leupron
- Buserelin/Suprefact
- Nafarelin/Synarel
- Histrelin/Supprelin
- Goserelin/Zoladex
- Deslorelin/Suprelorin
Term
What are 5alpha-reductase inhibitors used to treat?
Definition
BPH. DHT causes BPH, enzyme necessary for conversion of testosterone.
Can reverse BPH to some extent
2 isoforms: type II more selective for DHT.
- Finasteride/Proscar - more potent for type II isoform
- Dutasteride/Avodart - inhibits both isoforms.
AE: hair growth, IMPOTENCE
Term
Do alpha blockers affect androgen levels?
Definition
NO! They simply relax prostate tissue.
-alpha1A expressed in prostate/urethra
- Antagonism = relaxation. Can be a1-antagonists or specific for alpha.
Term
What drugs are alpha blockers?
Definition
- Prazosin/Minipress
- Terazosin/Hytrin
- Doxazosin/Cardura
- Alfuzosin/Uroxatral
- Tamsulosin/Flomax - alpha selective
- Silodosin/Rapaflo - alpha selective
Term
What drugs are androgen receptor antagonists, and how do they work?
Definition
Pure anti-androgens: block the kicking off of the HSP from the androgen receptor, receptor can't dimerize. Used in cancers.
- Flutamide/Eulexin
- Biclutamide/Casodex
- Nilutamide/Nilandron
- Cyproterone/Androcur
Term
What is the problem with androgen receptor antagonists, and how is it solved?
Definition
Negative feedback on the hypothalamus and anterior pituitary is loss, leading to a surge in GnRH and LH/FSH
- Fix: given with GnRH agonist
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