Male reproductive endocrinology Flashcards
What are the functions of the testes?
Secrete testosterone
Produce sperm by process called spermatogenesis
Describe the microscopic anatomy of the testes
Consists largely of convoluted seminiferous tubules
o Separated by interstitial tissues => contains blood vessels, lymph vessels and nerves
o Leydig cells are located here
Sertoli cells create the epithelium within the seminiferous tubule
o Tight junctions between them form the blood-testis barrier between the lumen and interstitial
tissue
What is spermatogenesis?
Process by which immature stem cells (spermatogonia) proliferate and differentiate into mature sperm.
Starts at puberty and lasts until death in most males, although fertility decreases with age
Thespermatogeniccells divide bymitosis, thenmeiosisto formgametes, which mature into sperm by the process of spermiogenesis.
Unusually, the developing spermatogenic cells remain connected by cytoplasmic bridges, until they
have formed a mature spermatozoan
What are the three phases of spermatogenesis?
1) Proliferation: massive amplification of cell numbers
o Human makes 100 million sperm/day.
o Boar produces ~ 1 million sperm/minute
2) Two rounds ofmeiotic division, in which one diploid cell gives rise to 4
haploid cells.
3) Spermiogenesis round developing germ cells differentiate into motile sperm
o cell differentiation must occur to generate a motile “DNA package”
Describe phase I - proliferation
Spermatogonia => very large and active population of dividing, self-sustaininggerm cells found in the
seminiferous tubules
Proliferation phase takes place on the basement membrane of seminiferous tubule
The spermatogonia haven’t yet cross blood-testis barrier at this stage
What are the 3 types of spermatogonia?
Adark => reserve stem cells
o backup if there is severe damage to spermatogenesis (e.g. irradiation, cytotoxic drugs)
o Can repopulate the testis with developing germ cells
Apale => renewing stem cells
o Main type to undertake reproductive development
B => spermatogoniathat are differentiating progenitors, and form spermatocytes
Describe the mitotic process of spermatogonia
one of the daughter cells is used for self-renewal of type A spermatogonia
The other becomes a type B spermatogonium.
o These divide and their daughter cells migrate towards the lumen
o Will give rise to primary spermatocytes
o All descendants of a B spermatogonium remain connected by cytoplasmic bridges, forming a
syncytium - like cell clone which undergoes synchronous development
It takes about 2 months for pale A spermatogonia to form new spermatozoa, the total production time
for mature human spermatozoa is 74 days
Describe phase II - meiosis
in order to create sperm that can combine with a female gamete, each sperm must be haploid and
contain only one copy of each chromosome.
To create haploid gametes, a cell must go through the process of meiosis, which involves replicating its
genome and then TWICE to create four haploid gametes
each of the four gametes produced by meiosis develops into a mature spermatozoan.
1 o spermatocytes are the largest cells in the spermatogenic series and are located approximately midway
within the seminiferous epithelium.
Each 1 o spermatocyte divides to give rise to two short-lived secondary (2 o ) spermatocytes
2 o spermatocytes give rise to twospermatidseach.
Describe the process of meiosis
Type of cell division that reduces the number of
chromosomes in the parent cell by half and
produces four gamete cells.
This process is required to produce egg and sperm
cells for sexual reproduction.
During reproduction, when the sperm and egg
unite to form a single cell, the number of chromosomes is restored in the offspring.
Meiosis begins when a diploid parent cell
undergoes one round of DNA replication followed
by two separate cycles of nuclear division.
The process results in four daughter cells that are
haploid, which means they contain half the
number of chromosomes of the diploid parent
cell.
Describe what happens to primary spematocytes
The freshly createdprimary spermatocytes enter into the first meiosis.
They then go immediately into the S phase (that is, into thepreleptotenemeiosis)
o double their internal DNA
o leave the basal compartment and reach the special milieu of the luminal compartment.
Following the S phase, these cells attain the
complex stage of theprophase
After the long prophase follow metaphase, anaphase and telophase that take much less time.
One primary spermatocyte yields two secondary spermatocytes.
What are the 5 stages of prophase
(lasts 24 days) o Leptotene o Zygotene o Pachytene o Diplotene o Diakinesis
Describe prophase of primary spematocytes
At leptotene, cells move off basement membrane and move through the blood testis barrier in towards
the lumen of the seminiferous tubule
This means spermatocytes and spermatids are “sealed off” inside the lumen of the tubule by the blood-
testis barrier between Sertoli cells
This is important as haploid cells are protected from the immune system in the lumen of the seminiferous
tubule.
Would otherwise be recognised as foreign, and the immune system would attack the haploid cells
What complication can occur from mumps?
the BTB can break down => can result in infertility as the body attacks spermatids
Describe what happens to secondary spermatocytes
Thesecondary spermatocytesgo directly into the second meiosis
Give rise to spermatids that contain only half the original DNA content.
second meiosis can take place quickly, as neither DNA reduplication nor a recombination of the genetic
material occurs.
It lasts only around five hours and for that reason secondary spermatocytes are rather seldom seen in a
histological section.
In a process lasting several weeks (spermiogenesis), spermatids are transformed into sperm cells
What major changes occur within the spermatids?
Condensation of nuclear chromatin in the head to form a dark-staining structure stops all DNA activity
Formation of theacrosome from the golgi apparatus
o covers the cranial part of the head.
o acrosome will contain hydrolytic enzymes to allow fusion of sperm and egg for fertilisation
Tail develops opposite the acrosome from a centriole
Cytoplasm re-distributed loss of excess cytoplasmic material which is shed as a residual body.
o Residual body is phagoctosed by the Sertoli cells.
Mitochondria re-arrange in middle piece of the developing spermatozoa
Describe Phase III: spermiogenesis
Differentiation phase
Spermatids undergo transformation intospermatozoa.
Describe the spermatozoa
Essentially a nucleus with a tail.
Head: nucleus with compacted and inactive DNA (no transcription/DNA replication)
o Surrounded by the acrosome – contains enzymes for penetrating the egg
Midpiece: contains many mitochondria which generate power
Tail: generates movement
How long does spermatogenesis take?
Takes 64 days in humans, but there is continuous production
As a B spermatogonium develops into a spermatocyte and passes blood testis barrier, another B spermatogonium forms behind it in a continuous production line
How is male reproduction controlled?
Testes are controlled primarily by endocrine regulation
The hypothalamus secrets gonadotrophin-releasing hormone (GnRH)
This causes release of luteinising hormone (LH) and follicle- stimulating hormone (FSH)
LH and FSH stimulate testis growth and function
o Stimulates androgen release
o Androgens are a class of steroids, testosterone is an
androgen
System is controlled by negative feedback => homeostatic system,
designed to be relatively stable
Describe the endocrine control of the testis
FSH stimulates Sertoli cell function (and thereby spermatogenesis)
LH stimulates Leydig cells to secrete testosterone
o Testosterone stimulates Sertoli cells (and peritubular myoid
cells)
Testosterone secreted into the blood acts to maintain androgen- dependent structures (eg prostate, SV) and stimulates sex-drive in the male
Describe the hormonal control of spermatogenesis
Control is largely via sertoli cells
Sertoli cells are controlled largely by FSH (and testosterone)
FSH stimulates spermatogonial proliferation
FSH and testosterone stimulate spermatogonial
differentiation to spermatocytes
Critically, testosterone is essential for passage of
spermatocytes through meiosis
Testosterone stimulates spermiogenesis
What is the role of epididymis on spermatogenesis?
Spermatogenesis depends on the function of the epididymis
Functions to induce sperm maturation
Non-motile, non-fertile sperm enter at the head and then become
fertile and motile as they travel down the epididymis
The tail acts as a sperm storage area until ejaculation takes place
What are endocrine disruptors?
Exogenous (natural or man-made) chemicals
which disrupt normal endocrine function
o Do this because they have similar structures to endogenous
hormones
Generally, their effects are not desirable
The developing foetus is particularly sensitive to endocrine disruptor effects
What are the mechanisms of endocrine disruptors
- mimic hormone biological activity by binding to receptor and activating it (agonistic)
- bind to receptor so preventing binding of the natural hormone (antagonistic)
- interfere with metabolic processes in the body
What are the effects of endocrine disruptors on reproduction?
Cause a range of reproductive problems: o Reduced fertility o Developmental abnormalities o Menstrual problems o Early puberty o Brain/behavioural problems o Cancers
NB: may affect other (endocrine) systems as well, e.g. thyroid
What are phthalates?
Man-made chemicals Soften and increase the flexibility of polyvinyl chloride plastics. Commonly found in: o Dialysis tubing o Solvents o Insect repellents o Building materials o Car parts o “Enteric coatings” of some tables o cosmetics Some phthalates may pose a risk to human development, especially for male infants Animal studies: o Exposed to different compounds at different times at different concentrations
What changes occur to the foetus when exposed to DBP (phthalate) in utero?
o Major reduction in testosterone & Insulin-like 3 production by Leydig cells
o Abnormal testis development
o Decreased germ cell numbers and delayed differentiation
What consequences can occur postnattaly when exposed to DBP (phthalate) in utero?
o Cryptorchidism – undescended testes
o Hypospadias – malformation of the penis
o Infertility
o Germ cell cancer
these conditions are increasingly seen in humans
o Commonly labelled testicular dysgenesis syndrome (TDS)
o All of the symptoms are linked with a common origin in foetal life
Cryptorchidism increases the risk of low sperm count and cancer
Intrauterine growth restriction is also a risk factor for TDS
o Reduced androgen action is associated with all TDS disorders
This is not surprising given the importance of androgens in reproductive development
What is testicular dysgenesis syndrome (TDS)
All symptoms are due to altered foetal testis development
o Leydig cells hypospadias and cryptorchidism
Results from insufficient androgen secretion
o Sertoli cells testicular germ cell cancer and decreased semen quality
Some symptoms of TDS are not seen until adult life, e.g. testicular germ cell cancer and reduced sperm
quality
o But the underlying cause is still altered foetal testis development
o Irreversible!
o Can treat symptoms, but not cure TDS
What is Diethystilbestrol
Synthetic oestrogen
prescribed to ~ 5 million pregnant women to block spontaneous abortion and promote foetal growth
banned early in the 1970s
o DES affected reproductive development and caused vaginal cancer in the exposed children
o Not noticed until the exposed children were pubertal
What is the effect of maternal smoking during pregnancy?
Cigarettes contain a complex mixture of chemicals and endocrine disruptors
Associated with adverse reproductive outcomes in offspring
Largest preventable cause of adverse foetal outcomes
20% of women still smoke during pregnancy
