Transcript Control of Testicular Function Leydig Cells

Hormonal Control of
Reproduction in the Male
Spermatogenesis
• Spermatogenesis goes on continuously from
puberty to senescence along the entire length of
the seminiferous tubules
• Though a continuous process, spermatogenesis
can be divided into three discrete phases:
– Mitotic divisions, which maintain a stem cell
population of spermatogonia and provide the cells
destined to become mature sperm
– Meiotic divisions, which reduce the chromosome
number and produce a cluster of haploid spermatids
– Transformation of spermatids into mature
spermatozoa, a process involving the loss of most of
the cytoplasm and the development of flagella
Dr. M. Alzaharna (2014)
Control of Testicular Function
• Physiological activity of the testis is governed by two
pituitary gonadotropic hormones
– follicle stimulating hormone (FSH)
– and luteinizing hormone (LH)
• The same gonadotropic hormones are produced in
pituitary glands of men and women
• FSH and LH are closely related glycoprotein hormones
that consist of a common α subunit and unique β
subunits that confer FSH or LH specificity
Dr. M. Alzaharna (2014)
Control of Testicular Function
• Both gonadotropins are
synthesized and secreted
by a single class of
pituitary cells, the
gonadotropes
• Their sites of stimulation
of testicular function,
however, are discrete:
– LH acts on the Leydig cells
and
– FSH acts on the Sertoli
cells in the germinal
epithelium
Dr. M. Alzaharna (2014)
Control of Testicular Function
Leydig Cells
• The principal role of Leydig cells is synthesis and
secretion of testosterone in response to
stimulation by LH
• In addition to stimulating steroidogenesis, LH
controls:
– the availability of its own receptors (downregulation)
– and governs growth and differentiation of Leydig cells
• In male embryos androgen secretion by the
Leydig cells is initiated by human chorionic
gonadotropin (hCG)
Dr. M. Alzaharna (2014)
Control of Testicular Function
Leydig Cells
• As with the adrenal cortex, the initial step in the
synthesis of testosterone is the conversion of
cholesterol to pregnenolone
• In maintaining the functional integrity of the Leydig
cells, LH maintains the levels of all steroid transforming
enzymes
• Testosterone released from Leydig cells may diffuse
into:
– nearby capillaries for transport in the general circulation
– or it may diffuse into nearby seminiferous tubules where it
performs its essential role in spermatogenesis
Dr. M. Alzaharna (2014)
Control of Testicular Function
Leydig Cells
• The testes also secrete
small amounts of
estradiol and some
androstenedione, which
serves as a precursor for
extratesticular synthesis
of estrogens
• Leydig cells are the main
source of testicular
estrogens
Control of Testicular Function
Leydig Cells
• Estradiol is present in seminal
fluid and is essential for fluid
reabsorption in the rete testis
• The presence of estrogen
receptors in the epididymis
and several testicular cells,
including Leydig cells,
suggests that estradiol may
have other important actions
in normal sperm formation
and maturation
Dr. M. Alzaharna (2014)
Control of Testicular Function
Germinal Epithelium
• The function of the germinal epithelium is to produce
large numbers of sperm that are capable of fertilization
• The Sertoli cells harbor and nurture sperm as they
mature
• Sertoli cells are the only cells known to express FSH
receptors in human males and therefore are the only
targets of FSH
• FSH increases Sertoli cell proliferation and
differentiation in the immature testis and maintains
the functional state of the stable population of Sertoli
cells in the mature testis
• In its absence testicular size is severely reduced and
sperm production, which is limited by Sertoli cell
availability, is severely restricted
Dr. M. Alzaharna (2014)
Control of Testicular Function
Germinal Epithelium
• Sertoli cells lack receptors for LH but are richly
endowed with androgen receptors, indicating
that the actions of LH on Sertoli cell function
are indirect, and are mediated by testosterone
• FSH and testosterone have overlapping
actions on Sertoli cells and act synergistically
– Testosterone is indispensable for spermatogenesis
– FSH is required for production of normal quantity
and quality of sperm
Dr. M. Alzaharna (2014)
Testosterone: Secretion and Metabolism
• Testosterone is the principal androgen secreted
by the mature testis
• Normal young men produce about 7 mg each day,
of which less than 5% is derived from adrenal
secretions
• Testosterone in blood is largely bound to plasma
protein, with only about 2 to 3% present as free
hormone
– About half is bound to albumin,
– and slightly less to sex hormone-binding globulin
(SHBG), which is also called testosterone-estradiolbinding globulin (TeBG)
Dr. M. Alzaharna (2014)
Testosterone: Mechanism of Action
• Like other steroid hormones,
testosterone penetrates the
target cells whose growth and
function it stimulates
• Androgen target cells generally
convert testosterone to 5 αdihydrotestosterone before it
binds to the androgen receptor
• The androgen receptor is a
ligand-dependent transcription
factor that belongs to the
nuclear receptor superfamily
Dr. M. Alzaharna (2014)
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Testosterone (T)
Androgen receptor (AR)
5 α-dihydrotestosterone (DHT)
The thickness of the arrows reflects
the quantitative importance of each
reaction
Testosterone:
Effects on the Male Genital Tract
• Testosterone promotes growth,
differentiation, and function of accessory
organs of reproduction
• Maintenance of normal reproductive function
in the adult also depends on continued
testosterone secretion
• It also affects organs directly related to
transport and delivery of sperm
Dr. M. Alzaharna (2014)
Testosterone:
Effects on secondary sexual characteristics
• Contributes to the morphological and
psychological components of masculinity
• Stimulate growth of pubic, chest, axillary, and
facial hair
• Adequate amounts of Dihydrotestosterone
allow expression of genes for baldness
• Growth and secretion of sebaceous glands in
the skin are also stimulated, a phenomenon
undoubtedly related to the acne of
adolescence
Dr. M. Alzaharna (2014)
Testosterone:
Effects on secondary sexual characteristics
• Stimulates growth of the larynx and thickening
of the vocal chords
• Adolescent growth spurt results from the
interplay of testosterone and growth hormone
• Promote growth of muscle
• Testosterone also stimulates red blood cell
production
• In both men and women androgens increase
sexual drive ( libido )
Dr. M. Alzaharna (2014)
Sexual Differentiation
• The early embryo has the potential
to form either testes or ovaries and
develop either the male or female
phenotype
• Differentiation of the testes
depends upon the transient
expression of a single gene on the Y
chromosome (SRY, sex-determining
region of the Y chromosome)
• It encodes a transcription factor
that stimulates expression of some
genes and repress expression of
others
Dr. M. Alzaharna (2014)
SOX 9: transcription factors
FGF9: autocrine factor (fibroblast growth factor 9)
DHH: desert hedgehog
PDGF: platelet-derived growth factor
AMH: antimüllerian hormone
Development of internal reproductive
ducts and their derivatives
• Wolffian ducts are progenitors of the
upper male genital tract
• The müllerian ducts are the progenitors
of the upper female genital tract
• Thus, regardless of its genetic sex, the
embryo has the potential to develop
supposedly either as male or female
• The Sertoli cells begin to secrete the
antimüllerian hormone (AMH), which,
causes epithelial cells of the müllerian
ducts to undergo apoptosis
• A similar fate awaits the wolffian ducts unless they are rescued by
testosterone produced by the developing Leydig cells
Dr. M. Alzaharna (2014)
Regulation of Testicular Function
• Testicular function depends on
stimulation by two pituitary hormones,
FSH and LH
• Without them, the testes lose
spermatogenic and steroidogenic
capacities
• Secretion of these hormones by the
pituitary gland is driven by the central
nervous system through its secretion
of the gonadotropin releasing
hormone (GnRH)
• Signals from the testis are inhibitory
– Castration results in a prompt increase
in secretion of both FSH and LH
• FSH stimulates the Sertoli cells to synthesize and secrete a
glycoprotein called inhibin, which acts as a feedback inhibitor of FSH
Dr. M. Alzaharna (2014)