Male Reproduction Flashcards
1
Q
Genotypic Sex
A
- Y chromosome = male
- it can have as many Xs as long as it has a Y
2
Q
Gonadal Sex
A
- SRY gene encodes testis determining factor a transcription factor
- when SRY is present, indifferent gonad becomes testes and germ cells develop into spermatogonia (6-8 weeks of gestation)
3
Q
Phenotypic sex
A
- hormones produced by the gonads
- development of the accessory sex organs, external genitalia (penis, scrotum, urethra) that require the presence of dihydrotestosterone (DHT), secondary sex characteristics
4
Q
XX Male
A
- in rare cases the SRY gene translocates to the X chromosome during male meiosis
- the ovum receiving the X chromosome with the SRY gene with develop into a male
- 1 in 100,000
- normal testes are never produced
5
Q
Differentiation of the testes
A
- primordial gonad: contains the germ cells that determine the fate of the gonad, it is indifferent before that
- when indifferent, it is closely associated with the mesonephros and Wolffian duct, as well as Mullerian ducts which form uterovaginal primordium
- in males the mesonephros develops into the epidymis.
- the Wolffian duct develops into vas deferens, seminal vesicles, and ejaculatory duct and Mullerian ducts degnerate in males
6
Q
How does embryonic gonad affect the development of
A
- androgens produced by the Leydig cells promote the development of 1) the wolffian (mesonephric) ducts and derived structures (epididymis, vas deferens, seminal vesicles, ejaculatory duct; requires testerone NOT DHT
- the prostate develops from a series of endodermal buds located proximal to the urethra REQUIRES DHT
7
Q
Differentiation of External Genitalial
A
- in absence of testerone the undifferentiated external genitalial develop into the female structures
- testerone after conversion to DHT stimulates the formation of male external genitalial
8
Q
Hypothalamic Pituitary Gonadal Axis
A
- regulates spermatogensis and androgen production
- GnRH stimulation is pulsatile-it binds G protein coupled gonadotroph receptors and activates phospholipase C that causes Ca2+ release, DAG production and protein kinase C activation
- LH and FSH release is pulsatile
- constant levels of GnRH prevents LH and FSH release (treat prostate cancer to low testerone production)
- products of testes have a negative feedback on the hypothalamus and anterior pituitary
9
Q
Kallmann Syndrome
A
- hypogonadotropic hypogonadism
- lack LH and FSH and have congenital anosmia due to ageneis of olfactory lobes
- more prevalent in males
- Genes Kal-1 (X linked), FGFR1 (autosomal dominant) and PROKR2
- prevent the neurosensory neurons from extending their axons into the brain and this failure prevents the migration of GnRN neurons into the hypothalamus
- danger of osteoporosis
10
Q
Prenatal Stage of Hypothalamic-Pituitary Gonadal Axis
A
- Leydig cells, the source of sex steriod production in testes make up more than half the testes by 60 days of gestation
- increase in Leydig cells is dependent on maternal chorionic gonadotropin (hCG) or embryonic LH
11
Q
Prior to puberty Hypothalmic-Pituitary Gonadal Axis
A
- Few GnRH pulses and low FSH and LH levels
- hypothalamus and pituitary very sensitive to negative feedback inhibition by androgens
- spermatogonia exist in diploid, undifferentiated form in basal compartment of testes
12
Q
Puberty Hypothalmic Pituitary Gonadal Axis
A
- frequency and amplitude of GnRH pulses increase
- sensitivity of H-P axis to negative feedback of testosterone decreases
- gonadotroph sensitivity to GnRH increases
- LH and FSH production increases
- Testosterone increases and spermatogenesis begins
- androgen driven changes characteristic of puberty occur
13
Q
Hypothalamic pituitary testicular axis feedback
A
- small bodied neurons in the arcuate nucleus and preoptic area of the hypothalamus secrete GnRH
- reaches the gonadotrophs in the anterior pituitary through long portal veins
- stimulation by GnRh causes gonadotrophs to synthesize and release FSH and LH
- the LH binds to receptors on Leydig cells, thus stimulating the transcription of several proteins involved in the biosynthesis of testosterone
- FSH binds to receptors on the basolateral membrane of the Sertoli cells, thereby stimulating gene transcription and protein synthesis
- theses proteins include ABP, aromatase, growth factors and inhibin
- negative feedback on the hypothalamic-pituitary testicular axis occurs by two routes
- first testosterone inhibiits the pulstile release of GnRH by the hypothalamic neurons and the release of LH by the gonadotrophs in the anterior pituitary
- second inhibin inhibits the release of FSH by the gonadotrophs in the anterior pituitary
14
Q
Leydig Cells and Sertoli Cells
A
- Leydig has receptors for LH
- Sertoli has receptors for FSH
- LH stimulates G protein coupled receptor to produce cAMP and activate PKA. This increases the transcription of enzymes involved in testosterone synthesis, stimulates the rate limiting step (cholesterol to pregnenolone), sterol carrier protein, sterol activating protein
- FSH-primary action on Sertoli cells, activates a similar signaling pathway to LH and increases transcription of androgen binding protein- keeps local testosterone levels high, P450 aromatase- produces estrogen, growth factors that support production of sperm, inhibins that suppress Leydig cell proliferation, suppress FSH secretion, factors that act on Leydig cells
- secondary effects on Leydig cells and on sperm
15
Q
Crosstalk between Leydig and Sertoli cells
A
- Leydig cells make testosterone which then Sertoli cells
- Leydig cells make B-endorphin which inhibit Sertoli cell proliferation
- Sertoli cells make estrogen (via aromatase) which then goes to Leydig cells
- Sertoli cells make growth factors which increase LH receptor on Leydig
16
Q
Androgen synthesis
A
- cholesterol is the obligate precursor for androgen synthesis
- synthesized de novo from acetyl coenzyme A
- or taken up LDL
- first step occurs in the mitochondria
- P450 side chain cleavage enzyme remove the side chain of cholesterol
- desmolase produces pregnenolone- this is the rate limiting step and it is upregulated by LH
- testes produce approximately 95% of testosterone
- other sites of androgen production include adipose tissue, skin, adrenals
17
Q
Male Pseudohermaphroditism
A
- any deficit in the mechanism by which androgens act in genetic males may cause this syndrome
1) 5 alpha reductase deficiency - DHT levels reduced, testerone levels OK
- failure in DHT-dependent development (urogenital sinus and external genitalia)
2) Androgen insensitivity syndrome
- normal levels of testerone and DHT
- androgen receptors are absent or defective
- urogenital sinus and external genitalial develop according to female pattern, Wolffian ducts to degenerate
- normal levels of AMH suppress Mullerian development
18
Q
Androgens Actions
A
-affect nearly every tissue in the body
androgenic or anabolic
19
Q
Androgenic Effects
A
- maturation of the sex organs particularly the penis
- development of secondary sexual characteristics
- deepening of the voice, growth of the beard and axillary hair
20
Q
Anabolic effects
A
- promote protein synthesis and growth of tissues expressing androgen receptors
- growth of muscle and increase in strength
- increase in bone density and strength, linear growth and maturation
- males have larger hearts, lungs, liver, erythrocytes
- bone maturation occurs indirectly through estradiol metabolites and is more gradual in men than women
- men have a larger brain but women have more dendritic connections
21
Q
Androgens Effects on Organs
A
- FSH levels are approx 8 fold higher in males than female. This male pattern of gonadotropins is regulated by the combined actions of E2, T and DHT
- androgens increase the expression of erythropoietin from the kidneys which leads to a higher hematocrit in men
- estrogens regulate male sexual behavior
- men have 20-40% more muscle mass than females
- the penis, seminal vesicles and prostrate increase in size during puberty. This is dependent upon the indicated hormones
22
Q
Androgen receptors
A
- free form of testerone enters cells by diffusion
- binds homodimeric receptor (AR/AR)
- directs transcriptional activity of target genes
- DHT binds the same receptor (has greater activity)
- testerone is bound by sex hormone-binding globulin and albumin
- only 2% of testosterone is free and this is the biologically active fraction
23
Q
Plasma Testosterone Versus Age in Human Males
A
-with the exception of a short lived increase in testosterone after birth levels remain low until puberty
24
Q
Senescence (Andropause)
A
- unlike menopause no abrupt loss of fertility
- testosterone decreases with age especially >40 years
- quantitity and quality of sperm also decreaes
- FSH and LH levels increase
- reduced testosterone causes some of the problems of aging: decreased bone formation, muscle mass, appetite, libido, blood hematocrit
- testosterone levels fall by 10% per year beginning in the 30s. By mid fifties 30% of men experience andropause
25
Low Testosterone
- small percentage of men have levels of testosterone far below levels considered normal (<300 ng)
- low sex drive, erectile dysfunction, loss of muscle mass, mood problems, fatigue, sleep disturbances, loss of body and facial hair
- a high percentage of men with symptoms of low testosterone will benefit from treatment
- men with prostate or breast cancer should not be treated with testosterone
26
Finasteride (Propeica)
- blocks productions of DHT, uses to treat male pattern baldness
- side effects include: impotence, abnormal ejaculation, depression
27
effects of anabolic steroid abuse
- anabolic steroids abused by individuals attempting to increase muscle mass or gain a competitive advantage
- reduced sperm count, shrinkage of the testicles
- permanent damage to heart, liver, and kidneys, psychiatric problems
- irreversible breast enlargement in men
- women and girls can develop excessive body hair and deepening of the voice
- anabolic steroid use can cause premature heart failure, high blood pressure, liver tumors, stroke and kidney failure
- also causes increase in LDL and decrease in HDL
- since it is often injected, there is the potential to transmit diseases such as HIV and hepatitis
28
Kennedy's Disease
- lower motor neuron disease caused by mutation in the androgen receptor
- expansion of CAG repeat in the gene causes a polyglutamine expansion in the androgen receptor
- the mutation in the receptor causes a toxic gain of function
- patients display progressive weakness due to degeneration of motor neurons in the brain stem and spinal cord
- X linked
- early signs include weakness of the tongue and mouth muscles, fasciculations and progressive weakness of limbs
29
Interaction of the Sertoli Cells and Sperm
- spermatogenesis is inititated at puberty through the action of FSH and LH
- interaction of the Sertoli cells and sperm
- a single Sertoli cell spans from the basal lamina to the lumen of the seminiferous tubule. The adjacent Sertoli cells are connected by tight junctions and surround developing germ cells
- from the basal lamina to the lumen of the tubule, gradual maturation of the germ cell occurs
- spermatogenesis is inititated at puberty by FSH via Sertoli cells and further supported by LH driven increases in testosterone and Sertoli cell growth factors
30
Sperm maturation
- after spermatids move passively into rete testis and epididymis
- testosterone-dependent maturation required for fully mobile/fertile sperm
- total process takes approximately 70 days
- after the sperm are ejaculated they undergo several physiological changes in the female genital tract which activates them for fertilization
- during capacitation the sperm becomes hyperactive
- the acrosome provides protection and carries enzymes necessary for the acrosomal reaction that dissolves jelly coat of the egg
31
Accessory Male Sex Glands Produce the Seminal Plasmid
- semen is only 10% sperm
- seminal fluid contains a plethora of sugars and ions
- derived from seminal vesicles, prostate gland, bulbourethral glands
- seminal vesicles provide 70% of volume and fructose
- normal concentration > 20 million sperm/mL
32
Sympathetic of male
- fibers arise from T11-L2 segments of the spinal cord and reaches the genitals via the inferioir mesenteric, hypogasteric and pelvic plexuses, and the hypogastric and cavernous nerves. It is responsible for emission and ejaculation
- sympathetic tone maintains detumescence
33
Parasympathetic
- fibers arise from S2-S4 segments of spinal cord and travel via pelvic nerve to pelvic plexus
- post-ganglionic fibers reach penile corpora and vasculature via cavernous nerves
- it is responsible for corporeal vasofilation and corporeal smooth muscle relaxation leading to tumescence (erection)
34
Somative innervation
-fibers travel via the pudendal nerve to striated muscles of penis
35
Sensory innervation
- afferent fibers are carried mainly in the dorsal nerve of the penis which reaches the spinal cord via the pudental nerve
- compression of which can lead to temporary sexual dysfunction
36
Erection
- primarily under parasympathetic control
- nerve terminals release ACh (via M3 receptors) and NO
- NO relaxes smooth muscles leading to vasodilation of arteries
- NO increases intracellular cGMP level
- decrease in sympathetic tone allows relaxation of the corpora and increase blood flow
37
Viagra
- treats erectile dysfunction by inhibiting cGMP-specific phosphodiesterase type 5 keeping cGMP levels high
- stimulates erection only during sexual arousal
- side effects include blue visions
- Viagra taken with other vasodilators can leads to sudden death
38
Mechanics of erection
- in the flaccid state, arterial vessels are constricted and venous vessels are noncompressed
- on erection, smooth muscle relaxation in the trabeculae and arterial vasculature results in increased blood flow, which rapidly fills and dilates the cavernosal spaces
- venous outflow drops as the expanding cavernosal spaces compress the venous plexus and the larger veins passing through the tunica albuginea
39
Emission
- movement of ejaculate into urethra
- sympathetic stimulation of hypogastric causes contraction of smooth muscle of distal epididymis, vas deferens and accessory glands
- semen propelled into prostatic urethra
- internal sphincter of the bladder prevents retrograde flow of sperm
- often accompanies by orgasm (CNS involvement)
40
Anejaculation
- the pathological inability to ejaculate due to:
- sexual inhibition
- pharmacological inhibition
- ANS malfunction
- prostatectomy
- ejaculatory duct obstruction
