Male Reproductive Endocrinology I Flashcards by Joel Glotfelty

The normal male has a chromosome complement of 44 autosomes and the two sex chromosomes

X and Y

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The Y chromosome contains a 14-kilobase region termed the

Sex-determining region of the Y chromosome (SRY)

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The SRY encodes the

Testis-determining factor (TDF)

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A sequence specific transcription factor that regulates the expression of genes that are critical for male gonadal development

TDF

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Although TDF and other loci on the Y chromosome are essential for testicular development and masculinization, they are not sufficient for

Complete maleness

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Other autosomal- and X-chromosome genes are also important for maleness, such as the gene for the

Androgen Receptor (AR)

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Sensitizes the genitsal ducts and external genitalia to the masculinizing effects of androgens

-located on the X chromosome

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The genes for SOX-9 and steroidogenic factor-1, both essential for gonad development and steroidogenesis, are which types of chromosomes?

Autosomal

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During the first 4-7 weeks of development, the gonadal tissue of male and female embryos are

Indistinguishable

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This indistinguishable gonadal tissue is organized into an

Outer cortex and inner medulla

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In the normal male embryo, when do we see the formation of

) Sertoli cells
) Leydig cells

) 7 weeks

2. ) 8-9 weeks

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At 9 weeks, the primordial germ cells become enclosed within the medulla forming

Spermatogonia

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At this point, there is a recognizable testes that initiates the secretion of

Testosterone

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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

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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

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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

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The leydig cells secrete

Testosterone

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The sertoli cells secret

Anti-Mullerian Hormone (AMH)

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In males, at about 8-9 weeks, the Mullerian ducts atrophy and regress under the influence of

AMH

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Belongs to a family of growth regulating factors (e.g., activin and inhibin)

AMH

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In the absence of testosterone or AMH secretion, the Wolffian ducts regress and the Müllerian ducts will differentiate into the

Female genitalia

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Starting at around week 10 of development, male external genitalia differentiates into the masculine format via testosterone secretion and conversion into

Dihydrotestosterone (DHT)

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With DHT stimulation, the genital tubercle grows into the

Glans penis

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With DHT stimulation, the genital swellings form the

Scrotum

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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

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

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