Male Reproductive Physiology (Lopez) Flashcards
1
Q
How is sex determined biologically?
A
- if Y chromosome present: SRY gene expressed > determines genetic sex (male) > testes develop > determined gonadal sex > Sertoli cells secrete Antimullerian hormone (to prevent development of female characteristics), Leydig cells secrete testosterone > male genital tract and external genitalia (determines phenotypic sex)
- if no Y chromosome present: genetic sex determined by XX chromosomes > ovaries develop > determines gonadal sex > no antimullerian hormone or testosterone produced > female genital tract and external genitalia develop (determines phenotypic sex)
2
Q
How does gonadotropin (LH/FSH) secretion vary over a lifetime?
A
- small amounts secreted as a fetus
- secretion levels off within childhood (FSH > LH)
- levels slowly begin to rise during puberty
- for females, secretion becomes pulsatile during adult reproductive period, which is indicative of the menstrual cycle (LH > FSH)
- for males, secretion remains consistent from puberty to adult reproductive period
- levels slowly begin to rise and remain consistently elevated during senescence (FSH > LH)
3
Q
How is puberty initiated in terms of hormonal signaling?
A
- puberty is initiated by pulsatile secretion of GnRH, which drives pulsatile secretion of FSH and LH
- pulsatile secretion of FSH and LH stimulates secretion of gonadal steroid hormones (testosterone and estradiol)
- increased circulating levels of sex steroid hormones are responsible for appearance of secondary sex characteristics at puberty
- if GnRH analogue is administered in intermittent pulses to replicate nml pulsatile secretion, puberty is initiated and reproductive function is established
- if long-acting GnRH analogue is administered, puberty is not initiated
4
Q
What anatomical structures are involved in male reproduction?
A
- testes
(seminiferous tubules, Sertoli cells, Leydig cells)
- scrotum
- epididymis
- vas deferens
- seminal vesicles
- prostate gland
5
Q
What are the 2 main functions of the testes?
A
- spermatogenesis
- secretion of testosterone
6
Q
What is the main function of the scrotum?
A
keeps testes at a lower temperature than body (1-2° C below) which is essential for spermatogenesis
7
Q
What are the main functions of the epididymis?
A
primary location for maturation and storage of sperm
8
Q
What is the main function of the vas deferens (ductus deferens)?
A
- provides another storage area for sperm (ampulla)
- part of the tract that transports sperm for ejaculation
9
Q
What structures and cell types are within the seminiferous tubules of the testes?
A
- seminiferous tubule: epithelium formed by Sertoli cells, w/ interspersed germ cells
- germ cells: spermatogonia (most immature germ cells, located near periphery of tubule), spermatozoa (mature germ cells, located near lumen of tubule)
- Leydig cells: interstitial cells that lie between tubules
- adult testes: 80% seminiferous tubules and 20% connective tissue interspersed w/ Leydig cells
10
Q
What are the main functions of Sertoli cells?
A
- provide nutrients to differentiating sperm
- form tight junctions w/ each other, creating a barrier between testes and blood stream
- secrete aqeuous fluid into lumen of seminiferous tubule (helps transport sperm through tubules into epididymis)
11
Q
What is the main function of Leydig cells?
A
synthesis/secretion of testosterone
12
Q
What hormones do the testes secrete?
A
- androgens: testosterone, dihydrotestosterone (DHT), androstenedione
- testosterone is most adundant, most of it is eventually converted to DHT
13
Q
What enzymes are necessary for testosterone synthesis in the testes?
A
(major andorgenic hormone, synthesized/secreted by Leydig cells)
- testes lack 21β-hydroxylase and 11β-hydroxylase: no glucocorticoids or mineralocorticoids are synthesized
- testes have 17β-hydroxysteroid dehydrogenase: converts androstenedione to testosterone; end prod of steroid synthesis in testes is T (not DHEA or androstenedione like in adrenal glands)
14
Q
How does testosterone transport and signaling occur?
A
- in lumen of seminiferous tubules, T is concentrated by binding to androgen-binding protein (ABP)
- T diffuses to target cells and binds to androgen receptors (AR)
- T is not active in all androgenic target tissues: in some tissues, DHT is active androgen (e.g. prostate gland in adult and external genitalia in male fetus, skin, liver); 5α-reductase in peripheral tissue converts T to DHT
- most of circulating T is bound to plasma proteins and albumin: sex hormone-binding globulin (SHBG)
15
Q
How is DHT produced and what is the purpose of producing it?
A
- 5α-reductase, in peripheral tissue, converts T to dihydrotestosterone
- DHT also binds to androgen receptors, except w/ greater affinity
- plays important role in causing changes at puberty
- deficiency of 5α-reductase results in ambiguous external genitalia
16
Q
How is estrogen produced in males?
A
- small amnts of estrogen are formed in males
- estrogen conc in seminiferous tubules fluid is quite high: putative source of estrogen is Sertoli cells (product of conversion of T to estradiol mediated by aromatase (CYP19)); potential important role in spermatogenesis (human sperm cells express at least 1 isoform of estrogen receptor)
- larger amnts of estrogens are prod from T and androstenediol in other tissues of body (esp adipose tissue): accounts for as much as 80% of total male estrogen prod
17
Q
What is the rate limiting step of testosterone production (and androgen prod in general)?
A
- conversion of cholesterol to pregnenolone
- mitochondrial pathway for T synthesis: cytochrome P450 side-chain cleavage (P450SCC) enzyme removes side-chain (carbons 22-27) from carbon at position 20 of cholesterol > pregnenolone
18
Q
How is testosterone synthesized/secreted from Leydig cells?
A
- cholesterol > (P450SCC) > pregnenolone > (3β-HSD) > progesterone > (17-hydroxylase) > 17(OH)-progesterone > androstenedione > (type III 17β-HSD) > testosterone
- Leydig cells make limited amnts of DHT and estradiol-17β
- T diffuses into seminiferous tubules and peritubular capillary network to be carried into peripheral circulation: in seminiferous tubules, T is conc by binding to ABP; T is carried to peripheral circulation by SHBG and albumin
19
Q
How do Leydig cells acquire/store cholesterol?
A
- Leydig cells 1) synthesize cholesterol de novo; they can also 2) acquire it from circulation through LDL and HDL receptors
- store cholesterol as cholesterol esters
- free cholesterol is generated within the testis, particularly in Leydig cells, by cholesterol hormone-sensitive lipase (HSL): converts cholesterol esters to free cholesterol for androgen production
- cholesterol is then transferred within mitochondrial membranes via steroidogenic acute regulatory protein (StAR) and then converted to pregnenolone
20
Q
What is the role of LH in testosterone production?
A
- LH stimulates conversion of cholesterol to pregnenolone and regulates overall rate of testosterone synthesis by Leydig cells
- LH promotes pregnenolone synthesis in 2 ways: increases affinity of P450scc enzyme for cholesterol; stimulates synthesis of P450scc enzyme (long-term action)
(*another name for P450scc is cholesterol desmolase)
21
Q
What are the possible fates of testosterone?
A
- as T enters peripheral circ, it quickly reaches equilibrium w/ serum proteins: ~60% of circ T is bound to sex hormone-binding globulin (SHBG), ~38% of circ T is bound to albumin, ~2% remains as free T which is the most biologically important form
- T and its metabolites are excreted primarily in urine: ~50% of excreted androgens are found as urinary 17-ketosteroids; remainder being conjugated androgens or diol/triol derivatives
22
Q
What are the actions of testosterone on fetal development?
A
- T is present at 2nd month of embryonic life, presence/absence of T determines development of genital organs/characteristics: (+) T > penis, scrotum; (-) T > clitoris, vagina
- fetal actions: differentiation of internal male genital tract (epididymis, vas deferens, seminal vesicles); causes descent of testes into scrotum during last 2-3 months of pregnancy (cryptorchidism: lack of decent)
23
Q
What are the actions of testosterone during puberty?
A
- increased muscle mass
- pubertal growth spurt
- closure of epiphyseal plates
- growth of penis/seminal vesicles
- deepening of voice
- spermatogenesis
- libido
24
Q
What are the specific actions of DHT on male reproductive development?
A
- fetal differentiation of external male genitalia (i.e. penis, scrotum, prostate)
- male hair distribution and male pattern baldness
- sebaceous gland activity
- growth of prostate
- b/c growth of prostate gland and male pattern baldness depend on DHT rather than T, 5α-reductase inhibitors can be used as tx for benign prostatic hypertrophy and hair loss in males
25
What are the androgenic actions of androgens on male development?
- regulate differentiation of male internal/external genitalia in fetus
- stimulate growth/development of secondary sex characteristics at puberty
- maintain reproductive tract and production of semen
- initiate maintenance of spermatogenesis
26
What are the anabolic actions of androgens within male development?
- stimulate erythropoietin synthesis (red blood cell prod)
- stimulate sebaceous gland secretion
- control protein anabolic effects (nitrogen retention)
- stimulate linear body growth, bone growth, and closure of epiphyses
- stimulate ABP synthesis
- maintain secretions of sex glands
- regulate behavioral effects (e.g. libido)
27
- condition that affects over 80% of males over 80 y/o
- signs/sx: urinary frequency, urinary urgency, nocturia, difficulty initiating/maintaining urinary stream, feeling of postvoid bladder fullness, dribbling
- conc of DHT is prostatic tissue are **not higher** in men w/ this condition compared to men w/o this condition
- men w/ this condition **might have more DHT receptors on their prostates**
benign prostatic hyperplasia
28
What is the intracellular mechanism of action of testosterone?
- **Leydig cells,** **LH receptor (cAMP-PKA pathway)**: results in steroidogenesis and testosterone prod; testosterone diffuses into seminiferous tubules and peripheral circulation
- **Sertoli cells stim by T and FSH (cAMP-PKA pathway)**: results in protein synthesis and prod of inhibin (inhibits FSH release), ABP, aromatase, and other products
29
What is the role of testosterone in Sertoli cells?
- FSH stimulates Sertoli cells to secrete ABP into lumen of seminiferous tubules
- binding of T in lumen provides a local T supply for developing spermatogonia
- aromatiziation of T to estradiol-17β also occurs within Sertoli cells
30
What are the supportive functions of Sertoli cells?
- maintain blood-testis barrier
- phagocytosis
- transfer of nutrients from blood to sperm (transferrin, Fe, lactate)
- receptors for hormones and paracrines
31
What are the exocrine functions of Sertoli cells?
- prod of fluid
- prod of ABP
- determination of release of sperm from seminiferous tubule
32
What are the endocrine functions of Sertoli cells?
- expression of ABP, T, and FSH receptors
- prod of Antimullerian hormone (AMH)
- aromatization of T to estradiol-17β
- prod of inhibin to regulate FSH levels
33
What are the 3 phases of spermatogenesis?
1) mitotic divisions
2) meiotic divisions
3) spermiogenesis
34
Describe the 1st phase (mitotic divisions) of spermatogenesis:
(spermatocytogenesis)
- proliferative phase
- at puberty, mitotic cycles increase and spermatogonia or stem cells divide to prod daughter spermatogonia
- after last division, resulting cells are called primary spermatocytes
35
Describe the 2nd phase (meiotic divisions) of spermatogenesis:
(production of haploid gamete)
- primary spermatocytes undergo 2 meiotic divisions
- first division produces 2 secondary spermatocytes, each w/ a haploid number of duplicated chromosomes
- secondary spermatocytes enter second meiotic divison, producing 2 spermatids, each w/ a haploid number of unduplicated chromosomes
36
Describe the 3rd phase (spermiogenesis) of spermatogenesis:
(maturation)
- spermatids undergo spermiogenesis and mature into spermatozoa
- nuclear and cytoplasmic changes produce mature spermatozoa
- ends in testis w/ release of spermatozoa from Sertoli cells
37
What structural changes occur within spermatozoon during spermiogenesis?
38
What hormones stimulate spermatogenesis?
- **LH**: secreted by anterior pituitary, stimulates Leydig cells to secrete testosterone
- **FSH**: secreted by anterior pituitary, stimulates Sertoli cells to nurse/form sperm, w/o this stimulation spermiogenesis would not occur
- **growth hormone (GH)**: necessary for controlling background metabolic functions of the testes, promotes early division of sperm themselves, w/o it (pituitary dwarfism) spermatogenesis is severely deficient/absent rendering person infertile
- **testosterone**: secreted by Leydig cells, essential for growth/division of testicular germinal cells (beginning of sperm formation)
- **estrogens**: formed from T by Sertoli cells when they are stimulated by FSH, might also be essential for spermatogenesis
39
What happens when exogenous testosterone is administered?
- increased circulating androgen levels exert negative feedback of anterior pituitary to lower LH secretion below normal
- lowered LH levels leads to lower endogenous T production by Leydig cells, which leads to lowered intratesticular levels of T
- lower intratesticular levels of T leads to insufficient spermatogenesis
40
How do the plasma testosterone and sperm production levels vary throughout the stages of male sex function (fetal, neonatal, pubertal, adult, old age)?
41
What is the function of the epididymis in sperm maturation?
- sperm spend ~1 month in epididymis undergoing further maturation after release from rete testis
- sperm are weakly motile upon entering epididymis, but strongly motile upon exiting
- decapacitation occurs here, which involves adding molecules to membranes of sperm to prevent acrosomal reaction before contact w/ an egg
- can act as storage site for mature sperm for several months
42
What is the function of seminal vesicles?
- secrete mucoid material containing nutrients, prostaglandins, and fibrinogen
- adds **considerable nutrient value** for ejaculated sperm
- **prostaglandins aid in fertilization**: react w/ female cervical mucus to make it more receptive to sperm movement (make cervical mucus less thick); cause backward, reverse peristaltic contractions in the uterus and fallopian tubes to move ejaculated sperm toward ovaries
43
What are the functions of the prostate gland?
- secretes a thin, milky fluid containing Ca2+, citrate ion, phosphate ion, clotting enzyme, and profibrinolysin (secreted during emission)
- **helps w/ pH adjustment**: slightly alkaline prostatic fluid helps neutralize acidity of other seminal fluids during ejaculation and thus enhances motility/fertility of sperm
44
What are the characteristics/composition of semen?
- composed of fluid/sperm from vas deferens, fluid from seminal vesicles, prostate, and mucous glands (bulbourethral gland)
- final pH = 7.5: alkaline fluid neutralizes mild acidity of other semen components
- can live for many week in male genital ducts
- once sperm are ejaculated in semen, their maximal life span is ~24-48 hours at body temperature
- each ejaculation contains ~2-6 ml, 20-200 million sperm (\<20 million = infertile)
45
How are sperm conveyed within the reproductive tract?
- once spermatozoa emerge from efferent ductules, they leave gonad and enter extratesticular portion of reproductive tract (epididymis, vas deferens, ejaculatory duct, prostatic urethra, membranous urethra, penile urethra)
- two main differences from female tract: continuous lumen from seminiferous tubule to end of male tract (i.e. the tip of penile urethra); male tract connects to the distal urinary tract (i.e. male urethra)
46
Describe the process of erection in men:
- neurovascular event
- 3 erectile bodies in penis: 2 corpora cavernosa and 1 corupus spongiosum (composed of anastomosing network of potential cavernous vascular spaces lined w/ continuous endothelia within loose CT support)
- **during flaccid state**: blood flow to erectile tissue is minimal due to vasoconstriction of vasculature
- **during erection**: parasympathetic nerves innervating vascular SM of helicine arteries that supply blood to cavernous spaces release NO
- **NO activiates guanalyl cyclase**: increases cGMP, decreases intracellular Ca2+, causes relaxation of vascular SM
- **vasodilation** allows blood to flow into spaces, causing **engorgement and erection**
- engorged tissue presses veins against noncompliant outer fascia, **reducing venous drainage**
- **somatic stimulation increases contraction** of muscles at base of penis, further **promoting erection**
47
Describe the process of emission in males:
- movement of semen from epididymis, vas deferens, seminal vesicles, and prostate to ejaculatory ducts
- under sympathetic control (adrenergic transmitter)
- causes sequential peristaltic contraction of SM of vas deferens, closing internal sphincter of bladder: prevents retrograde ejaculation of semen into bladder (destruction of sphincter by prostatectomy often results in retrograde ejaculation)
- emission normally precedes ejaculation but also continues during ejaculation
48
Describe the process of ejaculation in males:
- propulsion of semen out of the male urethra
- caused by rhythmic contraction of bulbospongiosus and ischiocavernous muscles (striated muscles), which surround the base of the penis
- striated muscles are innervated by somatic motor nerves, contraction causes semen to exit rapidly and outwardly through urethra
49
What is capacitation of spermatozoa?
- sperm are mature when they leave epididymis, but their activity is held in check by secretions from genital duct epithelia
- changes that occur when they come in contact w/ fluids of female tract allow for **capacitation** of sperm
- **changes include**: uterine and fallopian tubes wash away inhibitory factors; loss of cholesterol that builds up on acrosome which makes the head weaker; membrane of sperm is much more permeable to Ca2+ which increase motility
50
What does the effects of testosterone deficiency depend on?
(**T deficiency effects depend on age of onset**)
- **2nd-3rd month of gestation**: results in varying degrees of ambiguity in male genitalia
- **3rd trimester of pregnancy**: leads to problems in testicular descent (cryptorchidism) along w/ micropenis
- **puberty**: leads to poor secondary sexual development and eunuchoid features (eunuchoidism is persistence of prepubertal characteristics, and often present of characteristics of other sex)
- **post-puberty**: leads to decreased libido, erectile dysfunction, decreased facial/body hair growth, low energy, infertility
51
- genetic disorder that occurs when GnRH neurons fail to migrate into hypothalamus during embryonic development
- sx: delayed/absent puberty and impaired sense of smell
- form of hypogonadotropic hypogonadism
- occurs more often in males
Kallman's syndrome
52
- genetic condition where individuals have 47,XXY genotype
- individuals are phenotypically male b/c of the presence of Y chromosome, thus they appear male at birth
- at puberty, increased levels of gonadotropins fail to induce normal testicular growth/spermatogenesis
- androgen prod is usually low (highly variable among individuals), whereas levels of gonadotropins are elevated (indicating primary hypogonadism)
- seminiferous tubules are largely destroyed, resulting in infertility
Klinefelter's syndrome
| (seminiferous tubular dysgenesis)
53
How does prolactin secretion affect FSH/LH secretion?
prolactin suppresses FSH and LH secretion
54
What conditions are treated w/ 5α-reductase inhibitor?
- male pattern baldness: caused by DHT
- benign prostatic hypertrophy
55
What treatments are used for prostate cancer?
- androgen receptor antagonist
- radiotherapy
- radial prostatectomy
56
A tumor of the testis (interstitial cell tumors) produces:
Whereas, a germinal epithelial tumor produces:
A **tumor of the testis** (interstitial cell tumors) produces: large amnts of testosterone
Whereas, a **germinal epithelial tumor** produces: no hormones
57
What happens to androgen production as men age?
(**"andropause****"**)
- gonadal sensitivity to LH decreases and **androgen prod drops**, thus serum LH and FSH levels rise (FSH \> LH)
- **testosterone prod decreases slowly after age 40**: decreased bone formation, muscle mass, growth of facial hair, appetite, libido
- **sperm prod typically begins to decline after 50 y/o**, many men can maintain reproductive function/spermatogenesis throughout life
- loss of sexual activity typically occurs ~68-70 y/o
