2 - Male Reproductive System Flashcards
Where does Spermatogenesis (sperm production) occur?
When does this process begin?
What occurs in Leydig Cells?
Spermatogenesis ocurs within the seminiferous tubules
Begins at puberty
Steroid Hormon Synthesis occurs in the Leydig Cells
What is the major hormone produced in the testes?
Where is estradiol made in males?
Major hormone produced by the testes in testosterone
Majority of estradiol in males in made in adipose tissue from testosterone
What is the source of bioavailable testosterone?
Albumin-bound testosterone readily dissociates from albumin
and is taken up by tissues along with free testosterone
These two sources of testosterone are bioavailable
What receptor regulates androgen synthesis?
What type of receptor is it? What pathways does it activate?
What gene transcription is increased?
LH Receptor
G protein-coupled receptor; Activates Adenylyl Cyclase/cAMP signaling
Genes of steroidgenesis: StAR, Side Chain Cleavage Enzyme (P450scc), 17a-Hydroxylase, proteins/enzymes of cholesterol synthesis
What are the two possibilities of testosterone metabolism?
How is DHT formed?
How is estradiol formed?
Testosterone can be converted to other biologically active steroids or to excretory metabolites
In androgen-sensitive tissues testosterone can be converted to DHT by 5a-reductase
In some tissues, testosteron is metabolized via Aromatase Enzyme to form estradiol
What can be useful in treating benign postatic hyperplasia or prostate cancer?
What tissues does the aromatization of testosterone occur?
Where does inactivation of testosterone occur?
5a-Reductase Inhibitors
In some tissues testosterone is metabolize via aromatase to form estradiol
Tissues: Some CNS nuclei, Leydig/Sertoli Cells, Adipose Tissue
Inactivation of testosterone occurs primarily in liver; conjugated with sulfate/glucuronic for excretion in urine
How does plasma testosterone profile change during lifepsan of normal man?
Neonatal
Puberty
Remainder of life
- Leydig cells differentiate from mesenchymal cells (8-9 wks gestation);
- primary stimulus hCG
- Mid-gestation, fetal pituitary gonadotropins affect secretion
- Testosterone LOW during childhood
- At puberty, LH promotes androgen biosynthesis in Leydig Cells
- General age related decline during 40s-50s
- Age related increase of Steroid Hormone Binding Globulin (SHBG) decreases bioavailable fractio nof testosterone
What type of receptor is the andorgen receptor?
How does affinity compare between testosterone and DHT?
How does DNA binding begin?
The androgen receptor is a ligand-activated transcription factor
Androgen receptor binds testosterone and DHT but has greatest affinity for DHT (androstenedione/DHEA have weak effects due to low affinity)
Androgen receptor does not bind to DNA unless hormone is bound to its appropriate binding site on receptor
Androgen Actions at Stages of Development:
Fetus
Puberty
Adult
Protein effects?
Erythropoietin?
- Fetus:
- Adrogens promote differentiation of male reporductive tract and external genitals
- Puberty:
- Androgens promote growth and maturation of reproductive structures
- Development of male secondary sexual characteristics
- Enlargement of larynx and thickening of vocal cords (deeper voice)
- Adult
- Functional integrity of the reproductive system and regulate spermatogenesis
- Promote growth of hair and sebaceous glands in both genders + male hair pattern
- Behavioral effects (aggression / libido)
- Androgens promote protein anabolism
-
Stimulates erythropoietin; increased hematocrit
*
How do androgens effect bone growth?
Androgens promote bone growth and formation; actions of testosterone may involve its conversion to estradiol
Stimulates GH release
Stimulate pubertal growth spurt
Promotes closure of epiphyseal plate
What are the purpose of Sertoli Cells?
Sertoli cells line the basal lamina of the seminiferous tubules; main fx are to transfer nutriets to developing germ cells and creat environent conducive for germ cell differentiation into mature spermatozoa
Nourish, clean up debris, lubricate/move sperms along
What is formed by the tight junction between adjacent Sertoli Cells?
These tight junctions between adjacent Sertoli Cells divide the seminiferous tubules into two functional compartments–basal (early sperm) and adluminal (later, mature sperm)
They also form a blood-testis barrier that limits exchange of materials between interstitial fluid and the lumen of the seminiferous tubules–may help prevent auto-antibodies against sperm
What substances are secreted by Sertoli Cells?
- Androgen Binding Protein
- TGB-B glycoproteins:
- Anti-Muerian Hormone (AMH)
- Inhibits
- Activins
- Estradiol (E2)
Androgen Binding Protein (ABP)
Secreted?
Action?
Stimulation?
Clinical use?
- Secreted by Sertoli Cells
- Keeps testosterone levels elevated in the seminiferous tubules and epididymis ( [T]Tubule = 100 x [T]Circulation )
- Stimulated by: FSH / Testosterone
- Clinical: [ABP] = Method to assess Sertoli Cell function
Anti-Mullerian Hormone (AMH)
Family?
Action?
Mechanism?
- Family - TGF-B family of growth factors
- Action - Promotes regression of mullerian ducts in male embryo
- Mechanism
- Receptor: Transmembrane Serine-Threonin Kinase (RI / RII)
- AMH binds RII, RII recruits RI and phosphorylates
- RI phosphorylates Smad3
- Smad4 complexes w/Smad3
- Complex translocates nucleus to regulate genes that promote apoptosis
Inhibins and Activins
Synthesis?
Family?
Actions of Inhibin
- Synthesis: Secretory product of Sertoli Cells
- Family: TGF-B glycoproteins
- Actions:
-
Inhibin B = Principle circulating inhibin in males; feedback regulation of FSH secretion
- FSH and Testosterone stimulate Inhibin B
- Inhibin B blocks GnRH-stimulated FSH release
-
Inhibin B = Principle circulating inhibin in males; feedback regulation of FSH secretion
Estradiol (E2)
Formation?
Estradio is formed by aromatization of androgens in response to FSH stimulation
What are the three distinct phases of Spermatogenesis?
- Mitosis to increase number of spermatogonia
- Meiosis to provide haploid spermatids
- Spermiogenesis to transform immature spermatids to mature spermatoza
What two things does normal spermatogenesis in adults require?
What is the role of GnRH and FSH?
- Functional Sertoli Cells
- Intact Hypothalamic-Pituitary-Gonadal Axis
- - -
GnRH is delivered in pulsatile fashion; required for appropriate FSH / LH secretion
*FSH action on sertoli cells is necessery for maintenance of normal levels of sperm production
In males, what are the only cells to express FSH receptors?
What are the actions of FSH on such cells?
- Sertoli Cells are only cells to express FSH receptors (males)
- FSH actions on Sertoli Cells:
- Promotes proliferation / differentiation of Sertoli Cells in immature testes
- FSH maintains Sertoli Cell function (in absence testicular size decreases and spermatogenesis reduced)
-
Spermatogonia appear to be principle target of FSH action
- Growth Factors / Anti-Apoptic Factors
- Synthesis / Release of Androgen-Binding Protein
- Stimulates Inhibin release
What type of receptors regulate the actions of FSH on Sertoli Cells?
Mediated by G protein-coupled receptors that activate cAMP signaling pathway
What is the role of LH in spermatogenesis?
LH is required for spermatogenesis
Sertoli Cells do NOT have LH receptors; however it INDIRECTLY affects spermatogenesis by stimulating release of testosterone from Leydig Cells
How does testosterone affect spermatogenesis?
Testosterone acts as local regulator of spermatogenesis
Low levels of testosteron will result in decreased sperm production
- Activates Sertoli Cells to promote spermatogenesis
- Tends to work synergistically with FSH
Estradiol also plays role in spermatogenesis
Summary of Endocrine Regulation on Spermatogenesis:
Pituitary Gonadotropins: FSH and LH
Testosterone
- FSH - Direct stimulation of Sertoli Cells
- LH - Indirect via increasing testosterone synthesis by Leydig Cells
- Testosterone
- Activates Sertoli Cells
- Basis for Estradiol
- Stimulates synthesis of Androgen-Binding Protein
What forms the blood-epididymis barrier?
What function to spermatozoa gain while at the epididymis?
Why are the sperm covered with special substances?
What role does testosterone play in this section?
The tight epithelium of the epididymis forms the blood-epididymis barrier
Gain unidirectional motility
Spermatazoa coated with substance to block acrosomal reaction (decapacitation)
Testosterone (either blood borne, or entering lumen as T-ABP) plays role in regulation of function
What are the gonadotropins?
What type of cell secretes them?
What stimulates their secretion?
What is special about the delivery of said stimulus?
What will occur if this delivery varies? (clinical)
- Gonadotropins - Ant. Pituitary hormones that regulate gametogenesis/steroidogenesis
- Follicle Stimulating Hormone (FSH)
- Luteinizing Hormone (LH)
- FSH / LH secreted by Gonadotropes @ Ant. Pituitary
- FSH / LH stimulated by GnRH; which is released in secretory bursts–modulated by CNS neurons
- Continuous exposure of gonadotropes to GnRH will suppress secretory activity (can be clinically manipulated w/”functional castration” to treat prostate cancers)
How does the Hypothalamic-Pituitary-Gonadal (HPG) Acid change with age?
Fetal
Neonatal
- Fetal Development
- Established during 1st trimester
- Peaks at mid-gestation, declines toward birth due to placental estrogens
- Low levels of gonadotropin at birth
- Fetal
- Short after birth, HPG becomes active again
- Males - Testosterone secretion begins after rise in LH
- Females - Estradiol levels fluctuate
- Elevated levels of gonadotropin for first few months; gradully decline as CNS inhibits HPG axis
How does the Hypothalamic-Pituitary-Gonadal (HPG) Acid change with age?
Childhood
Late Prepubertal
Puberty
- Childhood
- CNS inhibits GnRH pulse generator
- HPG axis remains quiescent during childhood
- Late prepubertal
- Gradual disinhibition of GnRH pulse generation
- First detectable = Sleep associated surge in LH release
- Puberty
- Levels of gonadotropins stay elevated during day
- Adult pattern of HPG activity is established
What are the major events associated with puberty?
What can affect the timing of puberty?
- Establishment of adult HPG activity pattern
- Maturation of reproductive system and development of secondary sexual characteristics
- Growth spurt
- Development of gametes capable of fertilization
- Timing of Puberty
- Affected by genetics, ethnicity, environmental cues (nutrition, weight gain)
- Leptin connects nutrition to change timing
What are the negative feedback effects of testosterone?
Testosterone inhibits the hypothalamic pulse generator
Causes reduction of GnRH pulse frequency, lowers ratio of LH / FSH in pituitary secretions
What are the feedback regulation mechanisms of Inhibin in males?
- Inhibin secreted by Sertoli Cells
- FSH / Testosterone increase production of Inhibin
- Inhibin INHIBITS FSH release
- Little effect on LH release
Explain the physiology of the penis with regards to the erectile response?
Flaccid State
Tissue organized into a single corpus spongiosum, and two corpora cavernosa
Corpus Cavernosa surrounded by Tunica Albuginea; blood flow is supplied by helicine arteries
In FLACCID STATE blood flow is minimal because these vessels are constricted
Explain the physiology of the penis with regards to the erectile response?
Erection State
- Erectile State mediated by tactile (lower motor neuron reflex) or psychic (mediated over corticospinal pathways) stimuli
- Arterial flow increased into cavernous spaces; parasympathetics relax smooth muscle of helicine arteries
- Venous efflux reduced due to compression of subtunical venous plexus against wall of tunica albuginea
Explain the physiology of the penis with regards to the erectile response?
Where is the response a reflex mechanism of? Nerve?
What is effect of parasympathetics? What do they release?
- Reflex mechanism integrated in sacral portion of spinal cord (S2-S4)
- Afferent tactile stimuli transmitted via pudendal nerve
-
Efferent Parasympathetic Fibers (cavernous nerve) to helicine arteries are vasodilatory
- Release Nitric Oxide (NO) / Vasoactive Intestinal Peptide (VIP)
- Cause relaxation of helicine arteries and smooth muscle fibers in sinusoids
Explain the physiology of the penis with regards to the erectile response?
What does NO bind to? Action?
What can be a treatment for erectile dysfunction?
What can be a cause of erectile dysfunction?
NO binds to and activates soluble form of guanylyl cyclase, rise in cGMP leads to smooth muscle relaxation/dilation
cGMP-phosphodiesterase Inhibitors (Viagra) can be used to treat erectile dysfunction
Alterations in NO formation can result in impaired smooth muscle relaxation and ED
What is the role of urethral and bulbourethral glands during sexual stimulation?
What mediates this?
Increased mucus secretion
Mediated by parasympathetic nerves
Explain emission during sexual intercourse
What mediates emission? Nerve? Neurotransmitter?
What prevents retrograde ejaculation?
Emission is movement of semen into proximal part of urethra
Emission is mediated by Sympathetic Neurons in upper lumbar region (L1-L2); signals reach via hypogastric nerve; Norepinephrine acts on a1-adrenrgic receptors
Sympathetic Signals promote constriction of urethral sphincter to prevent retrograde ejaculation into bladder
Explain the ejaculatory response.
Initiation?
Efferent signals? Nerve? Key muscles?
Male orgasm?
- Filling the urethra with semen elicits sensory signals that are transmitted to the sacral portion of the spinal cord by pudendal nerve
-
Efferent Signals, transmitted by somatic efferent fibers in pudendal nerve, trigger contraction of striated musculature of perineum
- Especially bulbocavernous muscle
- Wavelike Contractions propel semen
- Awareness of these contractions = male orgasm
What are three clinical manifestations of testicular dysfunction?
Infertility
Decreased Libido
Poor development of Secondary Sexual Characteristics
Clinical: Gynecomastia
Estrogens have a stimulatory effect on growth/differentiation of breast tissue; testosterone inhibits this
Males - Exposure to excessive estrogen (or estrogen-like) compounds can decrease testosterone production
Other Causes: Prolactin, anti-androgens, medicinal (spirolactone, ketoconazole, cimetididne) and marijuana
Primary Hypogonadism - Primary Testicular Failure
Clinical - Klinefelter Syndrome
Common Karyotype
Internal Structure Dysfunction
Phenotype
Hormonal Lab Findings
- Most common cause of hypogonadism
- Caused by Excessive X Chromosome
- Most common = XXY
- Testes small/firm
-
Seminiferous Tubules = fibrotic/hylanized
- Usually infertile
- Degress of Leydig Function = Variable
- Phenotype
- Male, but signs of androgen deficiency / Estrogen Excess; Gyneocomastia common
-
Lab Findings
- High FSH / LH
- Low Testosterone
- High Estradiol
Primary Hypogonadism - Primary Testicular Failure
Orchitis
Irradiation
Inflammation of testes; usually secondary to mumps
Seminiferous Tubule destruction
Leydig Cells usually not affected
Seminiferous tubules more sensitive to radiation; Leydig Cells more resistant
Secondary Hypogonadism - Impaired Gonadotropin Secretion
Hypopituitarism
Kallmann Syndrome
May result from destruction of pituitary by tumor, trauma, surgery, irradiation
Deficient production of GnRH by hypothalamus
Second most common reproductive disorder in mlales
Testes = Arrested spermatogenesis, low gonadotropins, androgen deficiency appears at puberty, often associated with defective sense of smell
