Male reproductive hormones

2. HORMONAL REGULATION IN MALE [ENDOCRINE SYSTEM]



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MALE REPRODUCTIVE HORMONES
The reproductive hormonal axis in male consists of three main components: the hypothalamus, the
pituitary gland and the testis. This axis normally functions in a tightly regulated manner to produce
concentrations of circulating hormones required for normal male sexual development, sexual
function and fertility. Hormones produced by this axis include the hypothalamic gonadotropin
releasing hormone GnRH , pituitary gonadotropins FSH and LH and testicular steroids.
These hormones function in an integrative way to ensure normal development and regulation of
male reproductive system. Dysfunction in this axis can result in widespread effects such as
ambiguous genitalia, delayed puberty and loss of fertility. This easy briefly reviews the properties,
function and regulation of male reproductive hormones as well as common disorders associated
with their abnormalities.

GONADOTROPIN-RELEASING HORMONE
Gonadotropin-releasing hormone (GnRH) is small neuropeptide .It is composed of 10 amino acids, so it is
called decapeptide hormone.

GnRH is synthesized as part of a large prohormone that is cleaved enzymatically and further modified within
the secretory granules. GnRH is degraded by proteolysis within few minutes, so it has a short half-life,
approximately 2-4 min.
The gene, GnRH1, for the GnRH precursor is located on chromosome 8.
Production & Secretion of GnRH
GnRH is considered a neurohormone, a hormone produced
in a specific neural cell that are distributed diffusely
throughout the hypothalamus and released at its neural
terminal. A key area for production of GnRH is the preoptic
area of the hypothalamus, which contains most of the GnRH-
secreting neurons.
GnRH secretion is pulsatile in all vertebrates. in periodic
pulses usually occurring every 1–2 hours. These GnRH-
containing neurons project to the median eminence where
they release GnRH from their axon terminals into the
hypophysial portal system, Figure 1.
In the portal capillaries, GnRH travels to the anterior pituitary
gland.
Pulsatile activity can be disrupted by hypothalamic-
pituitary disease, either dysfunction (i.e.,hypothalamic
suppression) or organic lesions (trauma, tumor).
Function of GnRH
The portal blood carries the GnRH to the pituitary gland, which contains the gonadotrope cells (considered
as receptors of GnRH). GnRH activates its receptor, gonadotropin-releasing hormone receptor (GnRHR), a
seven-transmembrane G-protein-coupled receptor that stimulates the beta isoform of Phosphoinositide
phospholipase C, which goes on to mobilizecalcium and protein kinase C. This results in the activation of
proteins involved in the synthesis and secretion of the gonadotropins LH and FSH.
So, from the previous paragraph, the main function of GnRH is Stimulation of the synthesis and secretion of
luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the anterior pituitary gland.

Figure 1 Hypothalamic hypophysial portal system.

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The pathway of hormones in male from the hypothalamus to the pituitary gland to the target organ is : -
- Hypothalamus → GnRH → Pituitary → FSH → Testes → Spermatogenesis.
- Hypothalamus → GnRH → Pituitary → LH → Testes →Testosterone.
Requirement for pulsatile GnRH secretion:
The Importance of pulsatile secretion of GnRH to stimulate release of
LH and FSH. The secretion of both LH and FSH sharply decline as GnRH
secretion is changed from pulsatile to continuous, but restoring pulsatile
secretion of GnRH rapidly restores secretion of both hormones, Figure2.
Activity Of GnRH
GnRH activity is very low during childhood, and is activated
at puberty adolescence.
GnRH is found in organs outside of the hypothalamus and pituitary , its role in other life processes
is poorly understood.
The body carefully controls the production of testosterone. Chemical signals
from tow location – the pituitary gland and the hypothalamus.The
hypothalamus controls hormone production in the pituitary gland by means of
gonadotropin – releasing hormone "GnRH".
This hormone tells the pituitary gland to make follicle – stimulating hormone "FSH" and luteinizing hormone
"LH".

GONADOTROPINS HORMONES IN MALES
Follicular stimulating hormone (FSH)
Luteinizing hormone (LH)
Secretion of gonadotropins hormones:
Both FSH and LH are secreted from the anterior pituitary gland by same cells called gonadotropes cells
under the stimulation of gonadotropin releasing hormone (GnRH), Figure 3.
GnRH is secreted by the hypothalamus under the feedback inhibiting mechanism of the
testosterone and inhibin hormones.
GnRH is secreted intermittently a few minutes at time once every 1 to 3 hours
The intensity of this hormone’s stimulus is determined in two ways: by the frequency of these
cycles of secretion and by the quantity of GnRH released with each cycle
The secretion of LH by the anterior pituitary gland is also cyclical, with LH following fairly
faithfully in the pulsatile release of GnRH. Conversely FSH secretion increases and
decreases only slightly with each fluctuation of GnRH secretion instead it changes more
slowly over a period of many hours in response to longer-term changes in GnRH.
So duo to the much closer relation between GnRH secretion and LH secretion, GnRH is also widely known as
LH releasing hormone
In the abscens of GnRH the gonadotropes cells almost don’t secrete LH or FSH.
GONADOTROPINS METABOLISM
The gonadotropins are a family of closely related heterodimeric glycoprotein hormones present in mammals,
which are important to the correct functioning of the reproductive system, but much less information is available
concerning their metabolic processing.
In mammals, the glycoprotein hormones consist of a common ALPHA subunit and BETA subunit.
The solved crystal structure of human chorionic gonadotropin (hCG) showed that each of the gonadotropin
subunits is densely disulfide bridged, resembles the other in structure, and also has structural homology to the
disulfide-knot growth factor proteins.
Elevated prolactin levels
decrease GnRH activity.

Figure2


Figure 3

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The disulfide-knot feature leads to protease generation of disulfide-bridged core fragments (the main urinary
metabolites of the gonadotropins), which retain significant immunogenic features that render them measurable
in many assays forintact subunits.
The hypothesis of this study was that urinary excretion of such stable and discrete glycoprotein core
metabolic fragments of similar or identical structures is a common degradative pathway in both humans and
nonhuman species.
Function of Gonadotropins hormones
LH and FSH exert their effect on their target tissues in the testes mainly by activating the cyclic adenosine
monophosphate second messenger system which activates specific enzymes in the respective target cells.
Luteinizing hormone (LH) stimulates the interstitial (Leydig) cells in the testes to secrete the Testosterone
hormone.
The amount of secreted testosterone increase approximately in direct proportion to the amount of LH. SO the
mainly function of LH in the males is determining of secondary sexual characteristics by stimulation the
secretion of Testosterone.
Follicle stimulating hormone (FSH) stimulates the Sertoli cells in the semineferous tubules of the testes to
grow and secrete various spermatogenesis substances, At the same time the testosterone and
dihydrotestosterone diffuse into the semineferous tubules to act on the spermatogenesis. This mean to initiate
the spermatogenesis both FSH and testosterone are required
Regulation of FSH secretion
(Negative Feedback Control of Semineferous Tubule Activity- Role of the Hormone Inhibin)
When the semineferous tubules fail to produce sperm, secretion of FSH by the anterior pituitary gland
increases markedly. Conversely, when spermatogenesis proceeds too rapidly, pituitary secretion of FSH
diminishes. The cause of this negative feedback effect on the anterior pituitary is believed to be secretion by
the Sertoli cells of still another hormone called inhibin This hormone has a strong direct effect on the anterior
pituitary gland to inhibit the secretion of FSH and possibly a slight effect on the hypothalamus to inhibit
secretion of GnRH.
Potent inhibitory feedback effect on the anterior pituitary gland provides an important negative feedback
mechanism for control of spermatogenesis, operating simultaneously with and in parallel to the negative
feedback mechanism for control of testosterone secretion.

TESTOSTERONE
is a steroid hormone from the androgen group. In mammals, testosterone is primarily secreted in the
testes of males and the ovaries of females, although small amounts are also secreted by the adrenal
glands. It is the principal male sex hormone and an anabolic steroid. Testosterone is evolutionarily
conserved through most vertebrates.
On average, an adult human male body produces about ten times more testosterone than an adult human
female body, but females are, from a behavioral perspective (rather than from an anatomical or biological
perspective), more sensitive to the hormone. However, the overall ranges for male and female are very wide,
such that the ranges actually overlap at the low end and high end respectively.
Secretion
It secretes by the interstitial cells of Leydig, Figure 5, which are almost nonexistent in testes during childhood
when the testes secrete almost no testosterone, but they are numerous in the newborn male infant for the first
few months of life and in adult male any time after puberty, at both these times the testes secrete large
quantities of testosterone, Figure 4.

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Figure 4 The secretion by age. Figure 5 The secretion by interstitial cells.

Metabolism:
After secretion of the testosterone it will circulate in the
blood as:
1. Testosterone bound (tightly) to SHBG – 80%
2. Testosterone weakly bound to Albumin
3. Free Testosterone (very small amount).
For 30minutes to several hours by that time the
testosterone either is transferred to the tissues or it will
degraded into inactive products that are subsequently
excreted.
The effect on target tissues
Mechanisms: by activation of the androgen receptor
(directly or as DHT), and by conversion to estradiol and
activation of certain estrogen receptors.
The amplification pathway Free testosterone (T) is
transported into the cytoplasm of target tissue cells,
where it can bind to the androgen receptor, or can be
reduced to 5α-dihydrotestosterone (DHT) by the
cytoplasmic enzyme 5-alpha reductase, Figure 7. This
enzyme expressed by two genes I and II. Type one
found in liver, kidney and skin, while type two found in
the prostate and to less extend in the skin. DHT binds
to the same androgen receptor even more strongly than
T, so that its androgenic potency is about 5 times that of
T. The T-receptor or DHT-receptor complex undergoes a
structural change that allows it to move into the cell
nucleus and bind directly to specific nucleotide
sequences of the chromosomal DNA. The areas of
binding are called hormone response elements (HREs) ,
and influence transcriptional activity of certain genes
producing the androgen effects, Figure6 . It is important
to note that if there is a 5-alpha reductase deficiency, the
body (of a human) will ''continue'' growing into a female
with testicles.


Figure6 An anabolic-androgen steroid binds to an
androgen receptor located in the cytoplasm and is then
carried into the nucleus, where it instructs DNA to
transcribe mRNA and, further, undergo translation to
enhance the process of protein synthesis and ultimately
muscle or bone growth.

Figure 7 Pathways of testosterone action.

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Androgen receptors occur in many different tissues especially prostate gland, external genitalia in the adult.
Both males and females respond similarly to similar levels of testosterone.
The diversification pathway of testosterone action allows testosterone to modulate its biological effects via
estrogenic effects that often differ from androgen receptor mediated effects. The diversification pathway,
characteristic of bone and brain, involves the conversion of testosterone to estradiol by the enzyme aromatase,
Figure 7.
The bones and the brain are two important humans' tissues where the primary effect of testosterone is by
way of aromatization to estradiol. In the bones, estradiol accelerates maturation of cartilage into bone, leading
to closure of the epiphyses and conclusion of growth. In the central nervous system, testosterone is aromatized
to estradiol. Estradiol rather than testosterone serves as the most important feedback signal to the
hypothalamus (especially affecting LH secretion). In many mammals, prenatal or perinatal "masculinization" of
the sexually dimorphic areas of the brain occurs by the estradiol derived from testosterone and this area
programs later male sexual behavior.
Finally the inactivation pathway occurs mainly in the liver
with oxidation and conjugation to biologically inactive
metabolites that are excreted by the liver into the bill and by
the kidney into the urine.
Factors influence the testosterone
The testosterone used in women to treat
or prevent loos of bone density and to
treat certain kinds of depression .



Figure 8 Factors influence the testosterone

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Figure 9 Testosterone functional roles on the
body.

FUNCTION OF TESTOSTERONE:
During fetal development:
1- Causes formation of the prostate gland, seminal vesicles
and male genital ducts. 2- Suppressing the formation of female
genital organs. 3- Just before birth, it causes the descent of the
testes from the abdominal cavity into scrotal sac.
During puberty development:
1 -Causes enlargement of penis, scrotum and testes. 2-
Influence the secondary male sex characteristics as
aggressive behavior and body hair patterns (over pubis, face
and chest). 3- Stimulates maturation of sperm cell. 4-
Stimulates bone growth by increases the total quantity of bone
matrix and causes calcium retention. 5- Stimulates protein
buildup in muscles production muscular development, typical
of males with more bulk and firmness in their muscular
physique. and 6- Causes enlargement of the thyroid cartilage , resulting in the visible Adam's apple in males
and deepening of the voice due to hypertrophy of laryngeal mucosa and enlargement of the larynx .
REGULATING MALE REPRODUCTION
The hypothalamic pituitary gonadal hormones are a critical part
in the development and regulation of body system, Such as
reproductive and immune system.
The hypothalamic produces gonadotropin–releasing hormone
(GnRH), the anterior portion of pituitary gland produces luteinizing
hormone (LH) and follicle –stimulating hormone (FSH) and gonads
produces estrogen and testosterone.
( GnRH) secreted by hypothalamus that located in brain , travels
down the anterior part of pituitary gland via hypophysial portal
system and bind to receptor on the secretary cells of
adenohypothysis . In response to (GnRH) stimulation these cell
produce (LH) and (FSH) which travel into blood stream. These two
hormones play an important role in communicating to the gonads.
In male (LH) stimulate the interstitial cells located in the test is to
produce testosterone and (FSH) play role in spermatogenesis.
The production of (GnRH) (LH) (FSH) are similar but the effect
of these hormones are different, ( FSH) stimulate sustertacular
cells to release androgen binding protein which promote
testosterone binding , ( LH ) binding to interstitial cells causing
them to secrete testosterone .
Testosterones is required for normal spermatogenesis and
inhibits the hypothalamus, inhibin is produced by spermatogenesis
cells.

Figure 10 Feedback regulation of hypo-
thalamic-pituitary-testicular axis in male.

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In general, androgen (testosterone one of them) promote protein synthesis and growth of these tissue with
androgen receptor, testosterone effect can be classical as vitalizing and anabolic effect. Anabolic effects
include growth of muscle mass and strength and stimulation of bone maturation.
Androgenic effect: include maturation of sex organ particular the penis and the formation of scrotum in the
fetus and after birth (usually at puberty) a Deeping of voice, growth of the beard and axiliary hair and pubic
hair.
MALE HORMONAL DISORDERS
The most important male sex hormone is
testosterone, which influences sperm production,
fertility, and sex drive. Male sex hormones also
promote the development of secondary sexual
characteristics at puberty. Over- or underproduction
of male sex hormones may be due to a variety of
factors, including inherited disorders, long-term
illnesses, tumors, or lifestyle factors.
Male sex hormones, or androgens, are produced
mainly by the testes but also by the adrenal glands.
The production of male sex hormones is controlled
by hormones secreted by the pituitary gland. In turn,
the pituitary gland is under the control of the
hypothalamus. The changes that occur at puberty
are controlled by the sex hormones. The early or late
onset of puberty in boys, which may be a symptom of
under- or overproduction of male sex hormones,
Table 1.
Hypogonadism, in which male sex hormones are
underproduced. In boys, this condition can suppress
sexual development; in men, hypogonadism lowers
sperm production and fertility, Table 2. The
Gynaecomastia, breast enlargement in males that
temporarily affects nearly half of all boys during puberty. Male hormonal disorders may lead to sexual
problems and can sometimes be a cause of infertility.
Abnormal puberty in males
Very early or late onset of puberty, usually due to a hormonal imbalance.
The natural process of sexual development and maturation that takes place over several years is known as
puberty. In boys, puberty is normally characterized by enlargement of the genitals; development of hair on the
face, in the armpits, and in the pubic region; a growth spurt, in which the body gets bigger and more muscular;
and deepening of the voice. Puberty in boys usually begins between the ages of 10 and 14. Abnormal puberty
starts either earlier than normal (precocious puberty) or later (delayed puberty). Precocious puberty is rare and

Table 1 Symptom of under- and overproduction of
testosterone.

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is usually an indication of an underlying hormonal disorder. Delayed puberty is more common and less likely to
indicate a serious underlying condition.
Precocious puberty is caused by the overproduction of male sex hormones in a young boy. Boys in whom
puberty is delayed are usually just late developers, a tendency that often runs in families. However, delayed
puberty may also be caused by the underproduction of male sex hormones. Rarely, there is a more
serious underlying cause, such as a brain tumour pressing on the hypothalamus or pituitary gland,
or a chromosome disorder, such as Klinefelter’s syndrome, in which the sex organs do not develop
normally.
Some long-term illnesses, such as Crohn’s disease, kidney failure, cystic fibrosis, and diabetes mellitus, can
also cause delayed puberty and growth.
Certain lifestyle factors, such as excessive
exercise and an inadequate diet, may delay
the onset of puberty. Rarely, a pituitary
tumour may lead to either precocious or
delayed puberty.
Early or late puberty should be investigated
by a doctor, who will carry out a physical
examination to see if puberty has started or
how far it has progressed. A blood test may
also be performed to measure hormone levels and to check for a chromosomal abnormality. X-rays of the wrist
and hand may be used to assess bone maturity, and ultrasound scanning of the testes or adrenal glands may
also be carried out to look for abnormalities. If a pituitary tumour is suspected, MRI or CT scanning may be
performed. If tests identify an underlying cause for abnormal puberty, it will be treated. For example,
precocious puberty may be treated with drugs that block the production of male sex hormones or inhibit their
action. These drugs may be given in the form of injections, implants under the skin, or nasal sprays. If delayed
puberty runs in the family, treatment may not be needed. In many other cases, puberty is induced by giving
injections of testosterone. Some boys benefit from counselling for psychological problems caused by abnormal
puberty. Abnormal puberty is often treatable, but lifelong treatment may be needed
Hypogonadism in males
Under activity (Reduced activity) of the testes, resulting in low levels of the sex hormone testosterone and
impaired production of sperm.
In boys who have not reached puberty, testicular growth and the development of secondary sexual
characteristics (such as growth of facial, armpit, and pubic hair, muscle growth, and deepening of the voice)
may be delayed or arrested.
Abnormal development of the testes due to a chromosome disorder, such as Klinefelter’s syndrome, may
cause hypogonadism (primary hypogonadism), as may failure of the pituitary gland to produce sufficient
hormones, which may be the result of a pituitary tumor.(secondary hypogonadism), Table 2.
If hypogonadism occurs after puberty, the only effect may be infertility (see Abnormal puberty in males).
The doctor will carry out a physical examination to determine whether the genitals and secondary sexual
characteristics have developed normally. A blood test may be done to measure the levels of testosterone and
other hormones and to look for a chromosomal abnormality. Treatment is aimed at the underlying cause. For

Table 2 Type of hypogonadism.

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example, synthetic male hormones may be used to treat disorders of the testes. If underactivity of the pituitary
gland is the cause, pituitary hormones may be given. A pituitary tumour may be removed surgically. In boys,
hormone treatment stimulates puberty, including growth and sexual development; in men, it encourages growth
of facial hair, muscle strength, potency, and sex drive. Side effects of treatment with hormones may include
temporary breast development (see gynaecomastia" If the genitals are normal, treatment may improve sexual
potency and fertility; if hypogonadism is due to a testicular disorder, fertility is rarely achieved.
Gynaecomastia
Noncancerous enlargement of one or both breasts in males.
All males produce small amounts of the female sex hormone estrogen. If too much estrogen is produced,
breast enlargement, called gynaecomastia, occurs. One or both breasts may be affected, Figure 11. The
condition is common in newborn boys and affects 1 in 2 male adolescents. It is usually temporary in both of
these age groups. Older men can also be affected.
Gynaecomastia An excess of the female sex hormone estrogen in the
blood may cause one or both male breasts to enlarge. Gynaecomastia
in the newborn occurs when the fetus has been exposed to the
mother’s estrogen within the uterus. Increased levels of estrogen,
resulting in breast enlargement, are also common during puberty.
Drugs that affect levels of female sex hormones, such as
spironolactone and corticosteroids, may lead to enlargement of the breasts. Some drugs for prostate cancer
may have the same effect.
The symptoms of gynaecomastia may include Tender and swollen breast or breasts. Firm or rubbery button of
tissue that can be felt underneath the nipple and discharge from the nipple
One breast may enlarge more than the other. The symptoms listed above should always be investigated so
that breast cancer can be excluded.
Newborn boys do not need treatment, and gynaecomastia usually disappears within a few weeks. In most
adolescents, the condition disappears in less than 18 months without any treatment. In older men, the doctor
will ask about lifestyle factors and carry out a physical examination. He or she may arrange for tests to
measure hormone levels and to look for evidence of breast cancer. The treatment and outlook depend on the
underlying cause, but, if gynaecomastia persists, the excess tissue may be removed surgically.
Male infertility
A small percentage of male infertility is caused by hormonal problems. The hypothalamus-pituitary endocrine
system regulates the chain of hormonal events that
enables testes to produce and effectively
disseminate sperm. Several things can go wrong
with the hypothalamus-pituitary endocrine system:
1- The brain can fail to release gonadotrophic-
releasing hormone (GnRH) properly. GnRH
stimulates the hormonal pathway that causes
testosterone synthesis and sperm production.
2- A disruptionin GnRH release leads to a lack of testosterone and a cessation in sperm production
Unlike the causes of female infertility, which are
more easily identifiable, the cause of infertility can be
difficult to determine in some men. A cause is
discovered in only 1 in 3 men investigated.


Figure 11 Gynaecomastia.

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3- The pituitary can fail to produce enough luteinizing hormone (LH) and follicle stimulating hormone
(FSH) to stimulate the testes and testosterone/sperm production. LH and FSH are intermediates in the
hormonal pathway responsible for testosterone and sperm production.
4- The testes’ Leydig cells may not produce testosterone in response to LH stimulation.
5- A male may produce other hormones and chemical compounds which interfere with the sex-hormone
balance.


REFERECES
Books:
- Guyton & Hall Textbook of medical physiology "tenth edition"
- Delmar's Fundamentals of Anatomy and Physiology by Donald C.Rizzo,PH.D.
Web sites:
-Wikipedia and free encyclopedia.
- Micro anatomy of endocrine gland (http://www.studyblue.com)
- Cold Spring Harbor Laboratory Press-
- PPP HealthCare
- http://www.stanford.edu/class/siw198q/websites/reprotech/New%20Ways%20of%20Making%20Babies/causemal.htm
- http://www.livestrong.com/article/174398-male-testosterone-facts/
- http://www.foxnews.com/health/2012/12/17/dealing-with-low-testosterone/
- http://men.webmd.com/testosterone-15738
- www.tbeeb.net/
- http://genesdev.cshlp.org/content/14/24/3075.fullhttp://genesdev.cshlp.org/content/14/24/3075.full

24.5.2013