Male Reproductive Endocrinology I Flashcards
The normal male has a chromosome complement of 44 autosomes and the two sex chromosomes
X and Y
The Y chromosome contains a 14-kilobase region termed the
Sex-determining region of the Y chromosome (SRY)
The SRY encodes the
Testis-determining factor (TDF)
A sequence specific transcription factor that regulates the expression of genes that are critical for male gonadal development
TDF
Although TDF and other loci on the Y chromosome are essential for testicular development and masculinization, they are not sufficient for
Complete maleness
Other autosomal- and X-chromosome genes are also important for maleness, such as the gene for the
Androgen Receptor (AR)
Sensitizes the genitsal ducts and external genitalia to the masculinizing effects of androgens
-located on the X chromosome
AR
The genes for SOX-9 and steroidogenic factor-1, both essential for gonad development and steroidogenesis, are which types of chromosomes?
Autosomal
During the first 4-7 weeks of development, the gonadal tissue of male and female embryos are
Indistinguishable
This indistinguishable gonadal tissue is organized into an
Outer cortex and inner medulla
In the normal male embryo, when do we see the formation of
- ) Sertoli cells
- ) Leydig cells
- ) 7 weeks
2. ) 8-9 weeks
At 9 weeks, the primordial germ cells become enclosed within the medulla forming
Spermatogonia
At this point, there is a recognizable testes that initiates the secretion of
Testosterone
In the normal XX female embryo (and thus in the absence of the SRY gene), differentiation of the indifferent gonad into the ovaries starts at
Week 9
During the sexual indifferent stage (4-7 weeks of development), two different genital ducts develop on each side of the embryo termed the
Wolffian and Mullerian ducts
In males, at about 8-9 weeks, testosterone acts to trigger Wolffian duct to differentiate into the internal male genitalia, including the
Epididymis, vas deferens, and seminal vesicles
The leydig cells secrete
Testosterone
The sertoli cells secret
Anti-Mullerian Hormone (AMH)
In males, at about 8-9 weeks, the Mullerian ducts atrophy and regress under the influence of
AMH
Belongs to a family of growth regulating factors (e.g., activin and inhibin)
AMH
In the absence of testosterone or AMH secretion, the Wolffian ducts regress and the Müllerian ducts will differentiate into the
Female genitalia
Starting at around week 10 of development, male external genitalia differentiates into the masculine format via testosterone secretion and conversion into
Dihydrotestosterone (DHT)
With DHT stimulation, the genital tubercle grows into the
Glans penis
With DHT stimulation, the genital swellings form the
Scrotum
With DHT stimulation, the urogenital sinus gives rise to the
Prostate
The male reproductive system comprises not only male-specific genitalia, but also the
Hypothalamus and pituitary gland
Sperm generated in the testis empties into the
Epididymus
This in turn leads into a long, straight tube called the
Vas deferens
The vas deferens from each testis rises up through the scrotum and inguinal canal and descends along the posterior end of the bladder. Here each vas deferens widens into an ampulla, which is attached to a
Seminal vesicle
Generate roughly 60% of the fluid volume of the semen, including the secretion of fructose that serves to nourish sperm
Seminal Vesicles
The contents of the ampullae and seminal vesicle pass into the prostate gland via an
Ejaculatory duct
Generates roughly 30% of the fluid volume of semen
Prostate
Along with simple sugars and proteolytic enzymes, the prostate gland secretes a slightly alkaline, milky white fluid that helps neutralize the acidity of the
Vaginal Tract
The urethra is supplied with lubricating mucus via the bilateral
Bulbourethral glands (Cowper’s glands)
The predominant source of testosterone in males and the exclusive site of male gamete maturation
Testes
Situated in the scrotum where they are maintained at a temperature 1 to 2 degrees C below the core body temperature
Testes
The testes receive blood from the spermatic arteries which originate directly from the
Aorta
About 80% of the testes is made up of
Seminiferous tubules
The remaining 20% of the testes is comprised of connective tissue containing
Leydig Cells
A coiled mass of loops, lead into the epididymis, a maturation and storage site for spermatozoa
Spermatogenic Tubules
Each spermatogenic tubule is bounded by a basement membrane that separates it from the
Leydig cells, Peritubular (myoid) cells, and the adjacent capillaries
Just below this membrane are the
Sertoli Cells and spermatogonia
As the spermatogonia divide and differentiate into spermatocytes and then spermatids, columns of maturing germ cells span from the basement membrane to the lumen of the tubule where it culminates in the formation of
Spermatozoa
Each column lies between the cytoplasm of two adjoining
Sertoli Cells
Nurture the germ cells and directly facilitate their differentiation from spermatogonia to spermatozoa
Sertoli Cells
Two adjoining Sertoli cells fuse at defined areas called
Tight Junctions
This creates two compartments of intercellular space between the basement membrane and the tubule lumen. The spermatogonia reside in the
Basal compartment
Where as the spermatozoa reside in the
Adluminal compartment
This compartmentalization of the intercellular space forms a
Blood-testes barrier
This barrier also prevents developing sperm from reaching the blood stream where they may initiate an
Autoimmune response
Also, this compartmentalization maintains a high local concentration of
Testosterone
It is the expression of 17β hydroxysteroid dehydrogenase that converts androstenedione into
Testosterone
Cholesterol, derived either from low-density lipoproteins circulating in the blood, or synthesized in situ from acetyl coenzyme A, is the
Starting substrate for this conversion
The rate-limiting step in testosterone biosynthesis is the conversion of cholesterol into pregnenolone, which is catalyzed by
CYP11A
Within the testes, a small amount of testosterone undergoes 5-α-reduction to
-Androgen w/ much higher potency
Dihydrotestosterone (DHT)
Importantly, a much larger conversion of testosterone to DHT occurs at target tissues via the enzyme
5α-reductase
For both males and female, androgens are the obligate precursors of
Estrogens
The P-450 enzyme complex CYP19 (also termed aromatase) converts androstenedione and testosterone into
Estrone and estradiol respectively
The majority of circulating estradiol in males comes from testosterone conversion in
Adipose tissue
What are three peptide hormones secreted by Sertoli cells?
Activin, inhibin, and anti-Mullerian hormone (AMH)
The primary source of circulating inhibin in males are
Sertoli Cells
In contrast is produced by many tissues including the hypothalamus, anterior pituitary, liver, and placenta and acts in an autocrine paracrine manner
Activin
Acts in an endocrine manner to inhibit follicle stimulting hormone (FSH) secretion from the pituitary
Inhibin
Whereas activin secretion from pituitary gonadotropic cells acts in an autocrine-paracrine manner to stimulate
FSH secretion
Can stimulate testosterone secretion from Leydig cells, while activin inhibits secretion
Inhibin
Transforming growth factors α and β (TGF α and β) and insulin-like growth factor-1 (IGF-1) are also synthesized by both
Leydig and Sertoli Cells
Serve to regulate cell growth and hormone responses in the testes in a paracrine manner
TGF α and β and IGF-I
Finally, a number of trace metal binding proteins, steroid-binding proteins, proteases, cytokines, extracellular matrix factors, and proteoglycans are also synthesized predominantly in
Sertoli Cells
These factors act locally to promote the development of spermatogonia in the seminiferous tubules and subsequently, to facilitate the release of mature sperm from the
Testes
The two major endocrine activators of the testes, generally termed gonadotropins, are
Leutenizing hormone (LH) and FSH
Heterodimeric glycoproteins that resemble thyroid stimulating hormone (TSH)
LH and FSH
The α subunits of LH and FSH are
-β subunits are uniwue
Identical
Both LH and FSH are synthesized in the anterior pituitary gland in
Gonadotrophic cells
In turn, LH and FSH secretion from pituitary gonadotrophs is stimulted by
Gonadotropin-releasing Hormone (GnRH)
A decapeptide synthesized from a much larger preprohormone, is synthesized in two clusters of neurons in the arcuate and preoptic nuclei of the hypothalamus
GnRH
Under dopaminergic, serotonergic, noradrenergic, and endorphinergic influence
GnRH releasing Hormones
GnRH is released from the hypothalamus into the pituitary portal veins in a pulsatile fashion. Normal men have
8-10 pulses per day
GnRH binds to its receptor on the surface of gonadotroph cells and triggers an influx of extracellular calcium that acts as a secondary messenger to stimulate the simultaneous release of
LH and FSH
Acts on Leydig cells to stimulate the synthesis and secretion of testosterone
LH
A member of the G-protein coupled receptor superfamily that activates signal transduction via the cAMP secondary messenger cascade
LH receptor
LH-induced cAMP production acts mainly to stimulate the conversion of cholesterol into
Pregnenolone
Expressed primarily on Sertoli cells, and is also a member of the G protein coupled receptor superfamily that utilizes a cAMP secondary messenger cascade
FSH receptor
Acts on Sertoli cells to stimulate the upregulation of a number of proteins including the gonadotropin-regulating factor inhibin
FSH
FSH secretion from the pituitary, together with testosterone from Leydig cells, act in concert on Sertoli cells to promote
Sperm production from seminiferous vesicles
Elevated serum levels of testosterone in men can negatively feedback on testosterone biosynthesis by inhibiting the secretion of
GnRH at the hypothalamus and LH at the anterior pituitary
Feeds back negatively to block FSH release from the pituitary and possibly GnRH secretion from the hypothalamus
FSH induced secretion of inhibin from Sertoli cells
This classical endocrine regulatory feedback circuit is termed the
HPT axis
Fetal GnRH is detected in the hypothalamus at
4 weeks of gestation
FSH and LH are detected in the pituitary at
10-12 weeks
There is a surge of gonadotropin secretion in the fetal plasma at midgestation, a drop at birth, and then a transient rise during the first
6-18 months
Then, for the rest of childhood, GnRH, FSH and LH levels remain low, despite the fact that serum levels of androgens, estrogens, and inhibins are
Very low
Thus, during childhood, either the HPT negative feedback axis is inoperable, or the hypothalamus and/or pituitary are hypersensitized to very low levels of
Testosterone, estradiol, and inhibin
When the child reaches the transition from a non reproductive to reproductive individual (i.e. puberty), their hypothalamic neurons mature and begin to gradually release increasing levels of
GnRH in a pulsatile manner
Subsequently, a pulsatile pattern of LH and FSH secretion gradually appears with
LH levels being greater than FSH
Also at puberty, the response of gonads to increasing levels of LH and FSH becomes amplified and hence there is a sharp increase in
Testosterone levels in males and estrogen levels in females
Stimulated by the increase in sex hormone levels, we also see an increase in pituitary secretion of
GH
When the adult pattern of gonadotropin secretion is established, the major distinguishing feature between males and females is that females exhibit a monthly cycle of gonadotropin secretion in which
LH pulsation is greater than FSH pulsation
Around the fifth decade of life, despite normal serum levels of gonadotropins, there is a loss of responsiveness of the gonads to
LH and FSH
The loss of estradiol/testosterone induced negative feedback leads to increased serum levels of gonadotropins with
FSH levels exceeding LH levels
Each spermatagonia can give rise to
64 spermatozoa
