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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2885_Библиотеки_им_академика_М_И_Перельмана.pdf
HORMONAL CONTROL
OF REPRODUCTION
PART I:
MALE REPRODUCTIVE
SYSTEM
Chapter objectives
After studying this chapter, you should be able to:
1. Describe the structure and function of the testes.
2. Explain the control of steroid hormone production by the testes.
3. Describe the hormonal regulation of spermatogenesis.
4. Understand the endocrine abnormalities that may affect men’s
sexual health.
5. Describe the uses of androgens as therapeutic drugs and substances
of abuse.
8
8
Bulbocavernosus muscle
Testis
Corpora cavernosum
Seminiferous tubules
Tunica albuginea
Introduction
The male reproductive system has two functions. First
is the production of the male gamete, called sperm, by
a process called spermatogenesis. The second is the
production of the male sex hormones, a class of steroid
hormones called the androgens, which are necessary for
spermatogenesis to occur and for maintaining sexual
potency and secondary sex characteristics. The testes, or
testicles (Fig. 8.1), are the pair of male gonads (the singular is testis) and the principal androgen they produce
is testosterone. Testicular function is controlled by the
hypothalamo–pituitary–testicular axis which regulates
MALE REPRODUCTIVE SYSTEM
both androgen synthesis and spermatogenesis.
Where are the testes?
It may not come as a big surprise to learn that the testes
are located outside the abdominal wall in a sac called the
scrotum (Fig. 8.1). During foetal life, the testes develop
within the abdomen and descend to the scrotum during
the later stages of foetal development. The location of the
testes is significant; spermatogenesis requires a temperature somewhat lower than the normal body temperature,
and this is achieved by locating the testes in the scrotum.
In an adult male, each testis is usually 20–25 mL in volume. In a small proportion of boys (approximately 3% of
baby boys delivered at term, but 30% of preterm boys),
at least one testis has failed to descend fully into the
scrotum, a condition known as cryptorchidism (meaning ‘hidden testis’), which is treated surgically (Fig. 8.2).
During foetal development, the testes descend from
the abdominal cavity into the scrotum via a gap in the
abdominal wall called the inguinal canal. The route of
descent of the testes is shown in Fig. 8.2. Failure of the
inguinal canal to close fully can allow a loop of intestine
to pass through as well and become trapped. This results
in a very common condition called an inguinal hernia.
Interesting fact
The fact that a relatively low temperature is required for
spermatogenesis has led to the myth that taking a hot
bath before sexual intercourse diminishes a man’s fertility
enough to act as a contraceptive. Given that the process
of sperm maturation takes 70 days, it would need to be a
very long hot bath!
Like many myths, this one has its basis in fact. Over the
longer term, conservative measures like wearing looser
clothing and avoiding hot baths can improve fertility in
subfertile men.
Vas deferens
Corpus spongiosum
Urethra
Glans penis
Bladder
Seminal vesicle
Vas deferens
Prostate gland
Bulbourethral gland
Vasa efferentes
Epididymis
Rete testis
Scrotum
Fig. 8.1 Structure of the male reproductive system.
90 SYSTEMS OF THE BODY
A
Cranial suspensory
C
Gubernaculum
ligament
Foetal testis
Kidney
Epididymis
Gubernaculum
Bladder
8
MALE REPRODUCTIVE SYSTEM
Bladder
Inguinal canal
Testis
Scrotum
B
Fig. 8.2 Descent of the testes from their original site adjacent to the kidney into the scrotum. This is a complex process, and the testis can
become ‘stuck’ at almost any point during its descent (A). The foetal testis is held next to the kidney by the cranial suspensory ligament. It is also
attached to the gubernaculum testis, a jelly- like ligament that connects the testis and epididymis to the scrotum. The action of androgens causes
the cranial suspensory ligament to dissolve, and the action of growth factors causes the gubernaculum to contract. The combined effect is that
the testis is drawn into the lower abdomen adjacent to the inguinal canal at around 12 weeks’ gestation (B). Under the influence of androgens,
the testis passes through the inguinal canal into the scrotum between 27 and 30 weeks’ gestation (C).
Kidney
Cranial suspensory
ligament
Testis
Gubernaculum
Bladder
What are the testes?
The testes are made up of two functional parts: the seminiferous tubules and Leydig cells (Fig. 8.3). The bulk of the
testicular volume (approximately 90%) is made up of seminiferous tubules, which give the testis its lobular appearance. Each seminiferous tubule would be about 60 cm long
if stretched out, but luckily is tightly coiled within the testis.
The seminiferous tubules are the location of spermatogenesis. The second functional part of the testis, comprising
the Leydig cells (or interstitial cells), lies between the seminiferous tubules (Fig. 8.4). The Leydig cells can function
independently of the seminiferous tubules. However, the
seminiferous tubules need functioning Leydig cells.
The seminiferous tubules consist of two cell types:
Sertoli cells and germ cells (Fig. 8.5). At puberty, there are
around 600 million germ cells, called spermatogonia, per
91THE ENDOCRINE SYSTEM
8
Interstitial space
Residual
between Sertoli cells
Leydig cellsBlood vesselFibroblasts
MALE REPRODUCTIVE SYSTEM
Fig. 8.3 Histological appearance of the testis. (Courtesy Dr Dan
Berney.)
Blood vessel
Leydig cell
A seminiferous
tubule
Lumen of the
tubule
Germ cell
Fig. 8.4 Structure of the testes showing the arrangement of
seminiferous tubules and a section through a seminiferous
tubule. The area in the box is shown in more detail in Fig. 8.5.
testis. The Sertoli cells provide both nutrition and hormonal support to allow the germ cells to develop into
sperm, and functional Sertoli cells are required for spermatogenesis to occur. Each Sertoli cell is in contact with a
number of germ cells. However, the relationship between
the germ cells and Sertoli cells is not fully understood.
The seminiferous tubules lead to the epididymis where
sperm maturation occurs. The epididymis is connected
to the urethra by the vas deferens (Fig. 8.1).
There is a blood–testis barrier, formed by the very tight
contact between adjacent Sertoli cells. This barrier has an
important role in maintaining an internal environment
within the testis that is different from the blood or extracellular fluid. The intratesticular fluid contains a testosterone
binding protein which has an important role in maintaining a high intratesticular testosterone concentration. The
Sertoli cell
Basement
membrane
body
Sertoli
cell
Sertoli
cell
Fig. 8.5 Cells of the seminiferous tubule and the process of
spermatogenesis. The germ cells originate next to the basement
membrane, between the Sertoli cells. As these germ cells, known
as spermatogonia, develop, they migrate towards the lumen of the
seminiferous tubule, passing between the Sertoli cells. The immature
spermatids are released from the secondary spermatogonia into the
lumen of the seminiferous tubule, leaving ‘residual bodies’ behind.
The spermatids mature into spermatozoa as they pass along the
tubules and through the epididymis.
Late spermatids
Early spermatids
Spermatocyte
undergoing meiosis
Tight junction
Primary
spermatocyte
Spermatogonium
Basement
membrane
blood–testis barrier also functions to prevent fragments of
immature sperm from entering the bloodstream and triggering an immune response. Disruption of the blood–testis barrier has been proposed as the triggering event in the
production of anti- sperm antibodies, resulting in subfertility. It is also thought that this barrier may protect sperm to
some extent from blood- borne toxins.
Case
8.1
Unexpected fracture: 1
Case history
John Smith, a 25- year- old man, came to the A&E department after a fall. He had tripped while crossing the road
and had fallen awkwardly. The main impact was on the
right side of the chest. After the fall he had severe chest
pain over the site of the impact.
The past medical history was unremarkable. Mr Smith was
taking no medications and did not smoke or drink alcohol.
He lived with his wife and worked as a chef. The couple had
been attempting to have a baby for 2 years, with no success.
The examination showed him to be tall with long arms
and legs. There was swelling of the breast tissue underlying
the nipple on both sides. The doctor found the right lower
ribs to be very tender, and there was bruising over the skin.
There was scanty body, pubic, and axillary hair, and the testes were very small (∼2 mL in volume; normal, ∼0 mL).
Chest radiography revealed several fractures in the right
lower ribs. The doctor was concerned about the severity of the
fractures despite the relatively trivial fall. The doctor was also
concerned about the other findings on clinical examination.
92 SYSTEMS OF THE BODY
8
Cholesterol
bb
reductase
cd
a = cholesterol side-chain cleavage
b =
c = 17
d = 17,20 lyase
e = 17
H
Testicular blood and nerve supply
Blood supply to each testis is independent and originates mainly through the left or right testicular artery,
each of which arises from the aorta. However, the testicular artery forms a network of connections with the
internal iliac artery, which supplies the vas deferens, so
that the blood supply to the testis effectively has two
origins. Venous drainage is into the inferior vena cava
on the right and the renal vein on the left. It is thought
that the dual- origin blood supply may protect the testis
from possible disruption. However, as the testis descends
from the abdomen into the scrotum, it trails its blood
vessels and nerves behind it. During the process of testicular descent, or at a later stage in life, the testis can
twist, causing restriction of the blood supply or impaired
venous drainage; this is treated as a surgical emergency.
The nerve supply to the testis is via the sympathetic
chain from the thoracic spine. The vas deferens receives a
parasympathetic nerve supply from the pelvic chain. The
sympathetic supply controls erection, while the parasympathetic supply controls ejaculation. An intact nerve supply is therefore essential for normal sexual function.
Spermatogenesis
ejaculate as normal due to the intact endocrine functions
of the testis; however, as no sperm are able to get through
the cut vas deferens, he is effectively infertile. He still produces sperm, but these are simply absorbed back into the
body. One interesting effect of vasectomy is the appearance of antibodies against spermatozoa; this occurs in
about half of all vasectomised men. It is not known why
this occurs, but it contributes to the problems associated
with attempted reversal of the vasectomy procedure.
Androgen production
The Leydig cell produces androgens, which like all steroid hormones, are made from cholesterol (Fig. 8.6). A
range of androgens is made in the body, and although
most of these come from the testes, some are made in the
adrenal cortex (see Ch. 6). The most potent and important of these androgens is testosterone, and by far the
highest production of testosterone is in the testes. The
testis is not a highly vascular tissue like the adrenal cortex, and the presence of the blood–testis barrier and a
specific androgen binding protein in the interstitial fluid
of the testis means that high concentrations of testosterone accumulate. These high local levels of testosterone in
the testis are important for spermatogenesis.
MALE REPRODUCTIVE SYSTEM
Spermatogenesis is the process by which the germ cells
in the seminiferous tubules develop into mature sperm
(Fig. 8.5). There are three distinct stages to this process:
proliferation of the spermatogonia, reduction of the
number of chromosomes (meiosis), and development of
the mature sperm structure. The spermatogonia are not
used up during this process: after the second division
of each stem cell, three of the spermatogonia continue
on the pathway of cell division that leads to the production of sperm, while the fourth remains as a stem cell and
begins dividing again to produce more spermatogonia. A
healthy man produces around 200 million sperm every
day, from puberty to old age. This adds up to several
trillion sperm over a lifetime. The whole process, from
the start of spermatogonium differentiation to the formation of a mature sperm, takes 70 days, with a further
12–21 days required for transport of the sperm through
the epididymis to the ejaculatory duct. Each spermatogonium gives rise to a total of 64 sperm. Each ejaculate contains approximately 200 million sperm, with the volume
of the ejaculate (usually around 3 mL) made up of fluids
from the seminal vesicles and prostate gland.
Interesting fact
Vasectomy is an irreversible form of contraception. A
vasectomy is performed by cutting both of the vas deferens (Fig. 8.1) and tying the cut ends. This prevents sperm
from entering the ejaculate. A man who has had a vasectomy is still able to maintain an erection and to produce
a
Pregnenolone
b
Progesterone
3β hydroxysteroid dehydrogenase
α hydroxylase
β hydroxysteroid dehydrogenase
Fig. 8.6 Pathway of testosterone synthesis in Leydig cells and of
5- alpha dihydrotestosterone in the peripheral tissues. Cholesterol
is the starting point for steroid biosynthesis in all steroid secreting
tissues. The key shows all the enzyme activities involved in this
biosynthetic pathway. DHEA, dehydroe piandrosterone.
c
17αOH pregnenolone
17αOH progesterone
O
O
d
DHEA
Androstenedione
e
OH
Testosterone
5α
OH
5α dihydrotestosterone
93THE ENDOCRINE SYSTEM
8
Testosterone
Inhibin
Hormonal
cholesterol
Luteinising
Hormonal control of testicular function
Both spermatogenesis and androgen secretion are controlled by the hypothalamus and pituitary glands (Fig.
8.7). The hypothalamic hormone gonadotropin releas-
ing hormone (GnRH) is secreted in a pulsatile manner
to stimulate luteinising hormone (LH) and follicle stimulating hormone (FSH) secretion. This pulsatile pattern
of secretion is important: if GnRH is given as a constant
infusion, it actually inhibits the secretion of these hormones (see below).
MALE REPRODUCTIVE SYSTEM
Control of testosterone secretion (Leydig cell function)
LH acts on the Leydig cells to stimulate testosterone synthesis. It binds to specific G- protein coupled receptors
linked to adenylyl cyclase and therefore increases cAMP
production. The actions of LH on the Leydig cell are very
similar to the actions of ACTH on the adrenal cell (see Ch.
6), with the involvement of StAR protein transporting
cholesterol to the inner mitochondrial membrane to initiate steroidogenesis (Fig. 8.8).
There is negative feedback inhibition of the hypothalamo–pituitary–testicular axis, with testosterone inhibiting LH secretion. In addition to the effects of testosterone
on LH secretion, the two peptide hormones secreted by
the Sertoli cells also have a role in regulating this axis:
activin, which stimulates GnRH and FSH secretion, and
inhibin, which inhibits FSH secretion.
In common with the hypothalamo–pituitary–adrenal
axis, there is marked diurnal variation in the activity of
the hypothalamo–pituitary–testicular axis. Plasma testosterone levels in healthy men peak at around 0700 and
decline during the day to reach a nadir of around 60% of
peak levels by early evening. The clinical significance of
this variation has only recently been recognised, and it is
now recommended that plasma testosterone is sampled
in the morning, as there can be a 25% decline in plasma
testosterone between 1000 and 1600.
hormone
βγ
AC
GnRH
LH + FSH
Negative
feedback
functions
Fig. 8.7 Hypothalamo–pituitary–testis axis. Gonadotropin releasing
hormone (GnRH), released from the hypothalamus, stimulates the
gonadotroph cells of the anterior pituitary to release luteinising
hormone (LH) and follicle stimulating hormone (FSH). LH acts on the
Leydig cells to stimulate testosterone production, which acts with FSH
on the Sertoli cells to stimulate spermatogenesis. Testosterone and
inhibin, a peptide secreted by Sertoli cells, exert negative feedback
control of this axis.
Seminiferous tubule
Hypothalamus
Pituitary
Sertoli
cell
Leydig
cell
ATP
cAMP
Protein kinase A
Cholesterol
ester
hydrolase
Nuclear effects
↑ CYP gene expression
Fig. 8.8 Effects of luteinising hormone (LH) on the Leydig cells. The
binding of LH to its receptor activates (via a G- protein, Gs) adenylyl
cyclase (AC), which causes an increase in intracellular cyclic adenosine
monophosphate (cAMP), resulting in activation of cAMP- dependent
kinase. This phosphorylates and activates cholesterol ester hydrolase,
liberating free cholesterol from intracellular pools, and also causes an
increase in steroidogenic acute regulatory (StAR) protein. StAR protein
facilitates the transport of cholesterol from the outer to the inner
mitochondrial membrane (shown by an asterisk), allowing cholesterol
access to the first enzyme of steroidogenesis: cholesterol side chain
cleavage (P450
to the inner mitochondrial membrane is what determines the rate of
steroidogenesis—called the ‘rate limiting step’.
). The rate of transfer of cholesterol from the outer
scc
Cholesterol
ester
Free
StAR
protein
P450
*
SCC
94 SYSTEMS OF THE BODY
8
Control of spermatogenesis (Sertoli cell function)
Testosterone secreted by the Leydig cells acts together
with FSH on the Sertoli cells to stimulate spermatogenesis (Fig. 8.7). The process of spermatogenesis is absolutely dependent on the presence of an appropriate level
of testosterone within the testis. However, although FSH
stimulates Sertoli cell spermatogenesis, a low level of this
activity can occur in the absence of FSH. Like LH (Fig.
8.8), FSH binds to a G- protein- coupled receptor and
stimulates adenylyl cyclase activity. However, a number of other pathways are also activated, including several kinase cascades. The action of testosterone on Sertoli
cells appears to involve a membrane receptor coupled
to the opening of ligand- gated ion channels, in addition
to the more usual transcriptional effects expected of a
steroid.
We have already seen that Sertoli cells also have an
endocrine function, with the secretion of the regulatory
peptides activin and inhibin. Inhibin may be used as
a marker of Sertoli cell function, as the serum concentrations of this hormone are directly related to sperm
count.
In addition to stimulating spermatogenesis, FSH also
causes the Sertoli cells to produce an androgen binding protein (ABP). This protein binds testosterone and
helps maintain a high concentration of testosterone
within the testes; this is essential for spermatogenesis to
occur.
Plasma testosterone tends to decrease with age in men.
Testosterone is metabolised in the liver, mostly to form
androsterone and aetiocholanolone, which are excreted
in urine.
Actions of testosterone
Testosterone has four main actions: the initiation and
maintenance of spermatogenesis; the development
and maintenance of secondary sexual characteristics; the development of the male phenotype in foetal development; and testosterone also has effects on
behaviour, both during foetal development and in
adults. The effects of testosterone on foetal development are discussed in Chapter 10. In order to achieve
many of its actions, testosterone must be converted to
5- alpha dihydrotestosterone (DHT) (see Fig. 8.6). This
conversion happens outside the testes, in the peripheral tissues. Consequently, testosterone is sometimes
described as a ‘pre- hormone’ or hormonal precursor,
although this is not entirely correct as testosterone
itself has a number of direct actions, including a range
of metabolic effects, as well as the maintenance of
spermatogenesis. Furthermore, both testosterone and
DHT act on the same receptor, the androgen receptor (AR). In general, when the actions of testosterone
are described, the effects of DHT are included in the
description.
MALE REPRODUCTIVE SYSTEM
Interesting fact
High concentrations of testosterone within the testes are
required to support spermatogenesis, whereas only relatively low concentrations are needed to maintain potency
(the ability to have and maintain an erection) and secondary sexual characteristics of men. This difference has been
the basis for the development of a hormonal form of male
contraceptive (see Ch. 10).
Transport of testosterone in blood
Testosterone is transported in blood bound to a carrier protein, called either testosterone binding globulin (TeBG) or more commonly, sex hormone binding
globulin (SHBG). In healthy men, only about 2% of the
circulating testosterone is unbound, with 44% bound to
SHBG and 54% to serum albumin. The protein- bound
testosterone is protected from metabolism in the liver
and provides an easily accessible pool of hormone, as
the testosterone readily dissociates from its binding
protein. The levels of SHBG in the plasma are regulated
by androgens, oestrogens, and thyroid hormones. In
healthy men, SHBG levels are fairly constant, but may
need to be considered when steroid replacement therapy
is used. Plasma testosterone concentrations are around
9–41 nmol/L in healthy men and 1–3 nmol/L in women.
Cellular actions of androgens
As steroids, testosterone and DHT act on an intracellular receptor, the androgen receptor, to alter the rate
of transcription of certain genes and thus increase the
production of certain proteins (Fig. 8.9). The androgen
receptor is located in the cytoplasm of target cells, and
in the absence of ligand, it is associated with a chaperone protein called the heat shock protein. When an
androgen binds to the receptor, the heat shock protein
dissociates from the receptor, which then moves into
the nucleus and forms a dimer with another androgen
receptor. This dimer binds to an androgen response element on a gene promoter and also binds a number of
co- activator proteins. Together, this complex is able to
activate gene transcription. Given that both testosterone and DHT bind to the same receptor, it is not clear
why the formation of DHT is necessary for some of the
actions of testosterone. A defect in the gene encoding
the androgen receptor can cause androgen insensitivity.
The developmental consequences of this are considered
in Chapter 10.
Interesting fact
The androgen receptor (AR) is encoded by a gene located
on the X chromosome; therefore, each male has just one
95THE ENDOCRINE SYSTEM
8
Adult effectsPuberty
Testosterone
HSP
HSP
AR
HSP
HSP
MALE REPRODUCTIVE SYSTEM
Fig. 8.9 Cellular actions of androgens. Androgen receptors are
intracellular and in the absence of testosterone, they are bound
to heat shock protein (HSP) and located in the cytoplasm. In the
presence of androgen, the HSP dissociates from the receptor allowing
the hormone receptor complex to move into the nucleus where it
dimerises with another androgen receptor–hormone complex and
binds to the androgen response element on a gene promoter. Various
co- activators are attracted to the complex, and gene transcription
occurs.
AR AR
Nuclear pore
AR AR
Androgen
response element
AR
Cell membrane
Co-activators
Initiation of
transcription
Nucleus
mRNA
copy of this gene, while paradoxically every female has
two copies. This means that mutations of the AR gene
are inherited as an X- linked recessive condition, known as
androgen insensitivity syndrome (AIS), with carrier mothers having a 50% chance of passing the defective gene
on to their sons. As with other X- linked recessive conditions, AIS affects almost exclusively men, although some
carrier women may have a partial effect with sparse
pubic and axillary hair. Affected men with complete AIS
are genetically male (46XY) but phenotypically female
(see also Ch. 10).
Physiological actions of androgens
The main physiological actions of testosterone and DHT
are shown in Fig. 8.10 and Table 8.1. In puberty, testos-
terone stimulates the growth of the long bones, causing an initial growth spurt, but then leads to fusing of
the epiphyseal plates, resulting in the cessation of long
bone growth. Testosterone also causes laryngeal growth,
which results in deepening of the voice at puberty; this
is pronounced in boys, but much less so in girls. In boys
at puberty, testosterone causes growth of the penis, scrotum, prostate, seminal vesicles, epididymis, and vas
deferens.
In an adult man, testosterone is essential for the maintenance of secondary sexual characteristics. It enhances
libido; is necessary for achieving and maintaining an
Voice deepening
(laryngeal growth)
Growth and development
of the sex organs
fusion of epiphyseal plates
Stimulation of libido
(sex drive)
Growth of pubic, axillary,
and facial hairt
Increased muscle bulk
Maintains bone healthGrowth of long bones then
Fig. 8.10 Actions of androgens. The actions
specific to puberty are shown on the left and
the effects in adult men on the right. The
actions shown are mainly physiological effects
on men. However, it should be noted that in
women testosterone has an important role in
stimulating libido, even though it circulates in
only very low concentrations.
96 SYSTEMS OF THE BODY
Table 8.1 Actions of androgens in men.
OH
stosterone
HO
Oestradiol
8
MALE REPRODUCTIVE SYSTEM
Intrauterine:
Development of male phenotype
Development of penis, scrotum, prostate, etc.
Testicular descent into scrotum
Programming of male behaviour
At puberty:
Development of male secondary sex characteristics
Hypertrophy of larynx (deepening of voice)
Development of seminal vesicles and prostate and
initiation of sperm production
Increased muscle mass
Increased skin thickness and sebum formation
Development of pubic and axillary hair
Fusion of epiphyseal plates in long bone
In the adult man:
Reproductive effects
Maintenance of spermatogenesis
Maintenance of secondary sex characteristics including
beard growth
Maintenance of libido (sex drive)
Feedback inhibition of hypothalamic GnRH secretion
Metabolic effects
Lipid metabolism, increasing circulating VLDL and LDL,
decreasing HDL
Increased metabolic rate
Increased red blood cell number
Maintenance of muscle mass
Maintenance of bone density
erection (potency); and stimulates the growth of facial,
pubic, and axillary hair. Testosterone is also necessary
for bone health: testosterone deficiency causes osteoporosis. Testosterone is an anabolic androgenic steroid and
has a range of metabolic effects, acting to increase lean
body mass, stimulate red blood cell production, and alter
plasma lipid composition. It also causes growth of skeletal muscle, an effect that is exploited by some athletes
and bodybuilders (see below).
The behavioural effects of testosterone have been
extensively studied, but some aspects remain controversial. Despite much media attention to the notion of ‘roid
rage’, supposedly experienced by abusers of anabolic
androgenic steroids, there is little evidence that physiological levels of androgens cause aggressive behaviours.
However, it is clear that testosterone has a role in maintaining libido in adults and in determining play preferences in children. Children whose brains were exposed
to androgens in utero show a preference of classically
male- type toys such as cars and construction tools, rather
O
Aromatase
Fig. 8.11 Conversion of testosterone to 17- beta oestradiol by the
actions of aromatase, an enzyme found in adipose tissues.
Te
OH
than dolls and homemaking toys. This effect is also
seen in girls with congenital adrenal hyperplasia which
resulted in high androgen levels in utero, mimicking the
physiological foetal brain exposure to androgens which
is usually seen in boys.
Actions of oestrogens in men
It may seem surprising that many of the actions of testosterone are brought about not by testosterone itself,
but by an oestrogen. Androgens can be readily interconverted to oestrogens through the actions of an enzyme
called aromatase (Fig. 8.11). This enzyme is encoded
by a member of the CYP family of steroid hydroxylase
genes, CYP19. This gene is expressed in the adipose tissue, brain, and testis. In oestrogen- dependent tissues
or cells, the aromatase enzyme is co- located with the
oestrogen receptor. Circulating levels of oestrogens are
very low in healthy men, but circulating testosterone,
converted locally by aromatase, may then have local
oestrogenic actions.
Oestrogens are responsible for a wide range of actions
in men. They act on the brain to affect sex drive and
behaviour and to mediate part of the negative feedback
effects of testosterone on the hypothalamo–pituitary–
testicular axis. Oestrogens also have a role in: epiphyseal closure at puberty; maintaining bone density and,
perhaps most surprisingly; the testis itself. The gene
encoding the oestrogen receptor is expressed throughout
the testis, as is the gene encoding the aromatase enzyme
responsible for converting androgens to oestrogen.
Consequently, high levels of oestrogen are present in the
testis. This locally produced oestrogen has a role both in
the foetal development of the male reproductive system
and in the maintenance of normal testicular function in
adult men.
97THE ENDOCRINE SYSTEM
8
Loss of muscle definition
Case
8.1
Unexpected fracture: 2
Case note: Examination
Mr Smith had rib fractures after a small fall, and this suggested that the underlying bones were not healthy. The
most likely reason was osteoporosis due to a reduced
level of sex steroids. The examination showed small testes, reduced body hair, increased breast tissue, and long
arms and legs. These observations are all consistent with
decreased androgen activity.
Testosterone is required for male development and
MALE REPRODUCTIVE SYSTEM
bone function. In Mr Smith’s case, testosterone deficiency
resulted in gynaecomastia, osteoporosis, and reduced body
hair. The long limbs are due to continuing growth due to
delayed fusion of the growth plates, which is controlled by
testosterone.
Interesting fact
Because the enzyme aromatase is found mainly in adipose
tissue, very obese men tend to convert more of their testosterone to oestrogen than do lean men. This can lead to
significant levels of circulating oestrogens which have feminising effects, including breast development, decreased
facial hair, and altered pubic hair distribution. (The male
pattern of pubic hair is more of a diamond shape going up
to the umbilicus, whereas the female pattern is more triangular with the base of the triangle level with the pubic
symphysis.)
Hormone- dependent cancer in men
that the release of hormone is constant. This constant
release very effectively switches off LH and testosterone
secretion.
The other treatment is to stop testosterone from acting on prostate cells by using an anti- androgen which
blocks testosterone binding to the androgen receptor.
An example of this type of drug is cyproterone acetate.
Oestrogens are also used as anti- androgenic drugs. These
are both taken as daily tablets.
All these treatments have the aim of reducing testosterone effects in the body, and therefore, the adverse
effects of treatment are related to the removal of testosterone: erectile dysfunction and some degree of feminisation. They can also cause osteoporosis and mood
changes, and a significant proportion of men experience
‘hot flushes’, similar to those experienced by women as
a result of oestrogen loss in menopause. It hardly needs
saying that prostate cancer is a serious disorder, with the
adverse effects of treatment contributing significantly to
the distress caused by the diagnosis itself.
Disorders of male reproduction
Hypogonadism can arise through the failure of testicular
function (primary hypogonadism), pituitary failure (secondary hypogonadism), or more rarely, hypothalamic
failure (tertiary hypogonadism). The symptoms of hypogonadism are the same, regardless of the cause, including infertility, impotence, and loss of male secondary
sexual characteristics (Fig. 8.12). There is also a syndrome
Depression, fatigue,
loss of libido
Little facial hair growth
Prostate cancer is a common condition in older men.
The prostate gland is dependent on testosterone for
its normal functioning, and most prostate cancers are
testosterone- dependent, making it a classical example of
a hormone- dependent cancer. As with other hormonedependent cancers, treatments can aim to block the target hormone’s effects on the cancer cells’ growth and cell
division. Hormone treatment is not usually a first- line
treatment option but is used in conjunction with other
treatments to shrink the tumour. The aim of treatment is
to prevent testosterone from acting on the cancer cells.
There are two ways of doing this, either by removing the
testosterone itself or by stopping it from acting.
The oldest way of removing the testosterone is to
remove the testes: an orchidectomy. However, there are
also drug treatments which can stop the production of
testosterone by the Leydig cells. The most effective treatment is with an LHRH agonist. LHRH is another name
for GnRH. We have already noted that this hormone has
to be released in a pulsatile fashion in order to be effective at stimulating LH secretion. An LHRH agonist is
either given as a long- acting injection or an implant, so
98 SYSTEMS OF THE BODY
Muscle weakness
Scant body hair
Small size of testes
Muscle weakness
Fig. 8.12 Signs and symptoms of hypogonadism.