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Presented by
Freddy Teilang Nongkhlaw.

Neurohormonal Control Of The Male
Reproductive System
Figure Hormonal control of the male reproductive system. FSH,
follicle-stimulating hormone; GnRH, gonadotrophin-releasing
hormone; ICSH, interstitial cell-stimulating hormone.

 Testosterone is the main natural androgen.
It is synthesised mainly by the interstitial cells of the
testis, and in smaller amounts by the ovaries and adrenal
cortex.
Adrenal production of androgens is under the control of
adrenocorticotrophic hormone (corticotrophin).
As for other steroid hormones, cholesterol is the starting
substance.
Dehydroepiandrosterone and androstenedione are important
intermediates.
They are released from the gonads and the adrenal cortex,
and converted to testosterone in the liver.

– In general, the effects of exogenous androgens are the same as
those of testosterone, and depend on the age and sex of the
recipient.
– If administered to boys at the age of puberty, there is rapid
development of secondary sexual characteristics, maturation of
the reproductive organs and a marked increase in muscular
strength.
– Height increases more gradually.
Actions:-

– The skin thickens and may darken, and sebaceous glands become
more active (which can result in acne).
– There is growth of hair on the face and on pubic and axillary
regions.
– The vocal cords hypertrophy, resulting in a lower pitch to the
voice.
– Androgens cause a feeling of well-being and an increase in
physical vigour, and may increase libido.
– Whether they are responsible for sexual behaviour as such is
controversial, as is their contribution to aggressive behaviour.

• If given to prepubertal males, the individuals concerned do not reach
their full predicted height because of premature closure of the
epiphyses of the long bones.
• Administration of 'male' doses to women results in masculinisation,
but lower doses (e.g. 300μg/day testosterone patches) restore
plasma testosterone to normal female concentrations and improve
sexual dysfunction in women following ovariectomy, without adverse
effects

– In most target cells, testosterone works through an active
metabolite, dihydrotestosterone, to which it is converted
locally by a 5α-reductase enzyme.
– In contrast, testosterone itself causes virilisation of the
genital tract in the male embryo and regulates LH/ICSH
production in anterior pituitary cells.
– Testosterone and dihydrotestosterone modify gene
transcription by interacting with intracellular receptors.

– Testosterone itself can be given by subcutaneous
implantation or by transdermal patches.
– Various esters (e.g. enanthate and proprionate) are
given by intramuscular depot injection. Testosterone
undecanoate and mesterolone can be given orally.
Preparations

– Unwanted effects of androgens include
eventual decrease of gonadotrophin release,
with resultant infertility, and salt and water
retention leading to oedema.
– Adenocarcinoma of the liver has been
reported. Androgens impair growth in children
(via premature fusion of epiphyses), cause
acne, and lead to masculinisation in girls.
Unwanted effects

• Androgens (testosterone preparations) as hormone replacement
in:
– male hypogonadism due to pituitary or testicular disease
(e.g. 2.5 mg/day patches)
– hyposexuality following ovariectomy (e.g. 300μg/day
patches).
• Antiandrogens (e.g. flutamide, cyproterone) are used as part of
the treatment of prostatic cancer.
• 5α-Reductase inhibitors (e.g. finasteride) are used in benign
prostatic hypertrophy.
Clinical use of androgens and antiandrogens

• Anabolic steroids are synthetic, or human-made, variations
of the male sex hormone testosterone. The proper term for
these compounds is anabolic-androgenic steroids. "Anabolic"
refers to muscle building, and "androgenic" refers to
increased male sex characteristics. Some common names for
anabolic steroids are Gear, Juice, Roids, and Stackers.
• They are drugs that mimics the
male hormone testosterone in its ability to increase the
growth of muscle tissue and in its promotion of male
secondary sex characteristics.
What are anabolic steroids?

• Anabolic steroids work by binding with the cytoplasmic (free
within the cell) androgen receptor. Like all steroids, the
steroid-receptor complex has a strong affinity for the
nucleus. The complex is translocated into the nucleus and
binds to DNA. It is also possible that the steroid and
receptor dissociate in the nucleus and act on DNA
separately.

• Unwanted effects are described above, under Androgens
Adverse Side Effect of anabolic
steroids?

Anabolic steroids are used medically in humans to
treat a variety of conditions,
including anemia, breast cancer, hypogonadism, short
stature, malnutrition, osteoporosis, and human
immunodeficiency virus (HIV) wasting syndrome. The
drugs are also used in veterinary medicine (e.g., to
aid recovery from starvation or injury)
Such 'anabolic steroids' (e.g. nandrolone)
increase protein synthesis and muscle
development, but clinical use (e.g. in debilitating
disease) has been disappointing.
They are used in the therapy of aplastic
anaemia, and (notoriously) abused by some
athletes.
.

Figure:- Hormonal control of the female reproductive system. The Graafian
follicle (GF) is shown developing on the left, then involuting to form the corpus
luteum (CL) on the right, after the ovum (•) has been released. FSH, follicle-
stimulating hormone; GnRH, gonadotrophin-releasing hormone; LH, luteinising
hormone.

Androgens, Anabolic steroids, Oestrogen, progesterone.pptx

– Oestrogens are synthesised by the ovary and placenta,
and in small amounts by the testis and adrenal cortex.
– As for other steroids, the starting substance for
oestrogen synthesis is cholesterol.
– The immediate precursors to the oestrogens are
androgenic substances-androstenedione or testosterone
.
– There are three main endogenous oestrogens in
humans: oestradiol, oestrone and oestriol.
– Oestradiol is the most potent and is the principal
oestrogen secreted by the ovary.

– As with other steroids, oestrogen binds to type 4 nuclear
receptors.
– There are at least two types of oestrogen receptor, termed
ERα; and ERβ, the roles of which are currently being
investigated using mice in which the gene coding one or other
of these has been 'knocked out‘ .
– Binding is followed by interaction of the resultant complexes
with nuclear sites and subsequent genomic effects-either
gene transcription (i.e. DNA-directed RNA and protein
synthesis) or gene repression (inhibition of transcription).

• Clinical use of oestrogens and antioestrogens
• Replacement therapy:
– primary ovarian failure (e.g. Turner's syndrome)
– secondary ovarian failure (menopause) for flushing, vaginal
dryness and to preserve bone mass.
• Contraception.
• Prostate and breast cancer (these uses have largely been
superseded by other hormonal manipulations;
• To treat oestrogen-sensitive breast cancer (tamoxifen).
• To induce ovulation (clomiphene) in treating infertility.

• Unwanted effects of oestrogens include tenderness in the
breasts, nausea, vomiting, anorexia, retention of salt and water
with resultant oedema, and increased risk of thromboembolism.
• Used intermittently for postmenopausal replacement therapy,
oestrogens cause menstruation-like bleeding.
• Oestrogen causes endometrial hyperplasia unless given
cyclically with a progestogen.
• When administered to males, oestrogens result in feminisation.
• Oestrogen administration to pregnant women can cause genital
abnormalities in their offspring.
• Carcinoma of the vagina is more common.

– The natural progestational hormone (progestogen) is
progesterone.
– This is secreted by the corpus luteum in the second part of
the menstrual cycle, and by the placenta during pregnancy.
– Small amounts are also secreted by testis and adrenal
cortex.
Mechanism of action:-
Progestogens act, as do other steroid
hormones, on nuclear receptors.
The density of progesterone receptors
is controlled by oestrogens .

• There are two main groups of progestogens.
– The naturally occurring hormone and its
derivatives (e.g. hydroxyprogesterone,
medroxyprogesterone,
dyhydrogesterone).
– Progesterone itself is virtually inactive
orally, because after absorption it is
metabolised in the liver, and hepatic
extraction is nearly complete.
– Testosterone derivatives (e.g.
norethisterone, norgestrel and
ethynodiol) can be given orally.

Side effects:-
Unwanted effects of progestogens
include weak androgenic actions.
Other unwanted effects include acne,
fluid retention, weight change,
depression, change in libido, breast
discomfort, premenstrual symptoms,
irregular menstrual cycles and
breakthrough bleeding.
There is an increased incidence of
thromboembolism.

• Contraception:
– with oestrogen in combined oral contraceptive pill
– as progesterone-only contraceptive pill
– as injectable or implantable progesterone-only
contraception
– as part of an intrauterine contraceptive system.
• Combined with oestrogen for oestrogen replacement
therapy in women with an intact uterus, to prevent
endometrial hyperplasia and carcinoma.
• For endometriosis.
– In endometrial carcinoma; use in breast and renal cancer
has declined.
• (Antiprogestogens) Medical termination of pregnancy:
mifepristone (partial agonist) combined with a
prostaglandin (e.g. gemeprost).
Clinical Uses:-

• Types of oral contraceptives:-
– combinations of an oestrogen with a progestogen (the
combined pill)
– progestogen alone (the progestogen-only pill).
– Postcoital (Emergency) Contraception
• The combined pill
– The combined oral contraceptive pill is extremely
effective, at least in the absence of intercurrent illness
and of treatment with potentially interacting drugs.
– The oestrogen in most combined preparations (second-
generation pills) is ethinylestradiol, although a few
preparations contain mestranol instead

• The progestogen may be norethisterone, levonorgestrel, ethynodiol,
or-in 'third-generation' pills-desogestrel or gestodene, which are more
potent.
• The oestrogen content is generally 20-50μg of ethinylestradiol or its
equivalent, and a preparation is chosen with the lowest oestrogen and
progestogen content that is well tolerated and gives good cycle
control in the individual woman.
– This combined pill is taken for 21 consecutive days followed by 7
pill-free days, which causes a withdrawal bleed.
– Normal cycles of menstruation usually commence fairly soon after
discontinuing treatment

The mode of action is as follows:-
oestrogen inhibits secretion of FSH via negative
feedback on the anterior pituitary, and thus suppresses
development of the ovarian follicle
progestogen inhibits secretion of LH and thus prevents
ovulation; it also makes the cervical mucus less suitable
for the passage of sperm
oestrogen and progestogen act in concert to alter the
endometrium in such a way as to discourage
implantation.
They may also interfere with the coordinated
contractions of cervix, uterus and fallopian tubes that
facilitate fertilisation and implantation.

• Potential unwanted and beneficial
effects of the combined pill
• The common effects are:
– weight gain, owing to fluid
retention or an anabolic effect, or
both
– mild nausea, flushing, dizziness,
depression or irritability
– skin changes (e.g. acne and/or an
increase in pigmentation)
– amenorrhoea of variable duration
on cessation of taking the pill.
Side Effects:-

• The combined pill markedly decreases menstrual
symptoms such as irregular periods and
intermenstrual bleeding.
• Iron deficiency anaemia and premenstrual tension
are reduced, as are benign breast disease, uterine
fibroids and functional cysts of the ovaries.
• Unwanted pregnancy, carrying a maternal
mortality ranging from 1 in 10000 in developed
countries to 1 in 150 in Africa, is avoided.
Clinical Uses:-

• The progestogen-only pill
– The drugs used in progestogen-only pills include
norethisterone, levonorgestrel or ethynodiol.
– The pill is taken daily without interruption.
– The mode of action is primarily on the cervical
mucus, which is made inhospitable to sperm.
– The progestogen probably also hinders
implantation through its effect on the
endometrium and on the motility and secretions
of the fallopian tubes.

• Potential beneficial and unwanted effects of the
progestogen-only pill
– Progestogen-only contraceptives offer a suitable
alternative to the combined pill for some women in
whom oestrogen is contraindicated, and are suitable
for women whose blood pressure increases
unacceptably during treatment with oestrogen.
– However, their contraceptive effect is less reliable
than that of the combination pill, and missing a dose
may result in conception.
– Disturbances of menstruation (especially irregular
bleeding) are common.
– Only a small proportion of women use this form of
contraception, so long-term safety data are less
reliable than for the combined pill.

POSTCOITAL (EMERGENCY) CONTRACEPTION
Oral administration of levonorgestrel, alone or
combined with oestrogen, is effective if taken within 72
hours of unprotected intercourse, repeated 12 hours
later. Nausea and vomiting are common (and the pills
may then be lost: replacement tablets can be taken with
an antiemetic such as domperidone).
 Insertion of an intrauterine device is more effective
than hormonal methods, and works up to 5 days after
intercourse.

Drugs acting on the uterine smooth muscle.

• Drugs that stimulate the pregnant uterus and are important in
obstetrics include oxytocin, ergometrine and prostaglandins
• OXYTOCIN
– the neurohypophyseal hormone oxytocin (an octapeptide) regulates
myometrial activity.
– Oxytocin release is stimulated by cervical dilatation, and by
suckling, but its role in parturition is incompletely understood.
– Oxytocin for clinical use is prepared synthetically.
Actions
– On the uterus.
– Oxytocin contracts the uterus.
– Oestrogen induces oxytocin receptor synthesis and, consequently,
the uterus at term is highly sensitive to this hormone.
– Given by slow intravenous infusion to induce labour, oxytocin
causes regular coordinated contractions that travel from fundus to
cervix.
– Larger doses further increase the frequency of
the contractions

• Unwanted effects of oxytocin
– Unwanted effects of oxytocin include dose-related hypotension
(arising from its vasodilator action), with associated reflex
tachycardia.
– Its antidiuretic hormone-like effect on water excretion by the
kidney causes water retention and, unless water intake is curtailed,
consequent hyponatraemia(low levels of Sodium).

ERGOMETRINE
Ergot (Claviceps purpurea) is a fungus that grows on
rye and contains a surprising variety of
pharmacologically active substances.
Ergot poisoning, which was once common, was often
associated with abortion.
In 1935, ergometrine was isolated and was recognised
as the oxytocic principle in ergot.
Actions :-
Ergometrine contracts the human uterus. This action
depends partly on the contractile state of the organ.
On a contracted uterus (the normal state following
delivery), ergometrine has relatively little effect.
Ergometrine also has a moderate degree of
vasoconstrictor action.
The mechanism of action of ergometrine on smooth
muscle is not understood.
It is possible that it acts partly on α adrenoceptors, like
the related alkaloid ergotamine

• Myometrial stimulants (oxytocics)
• Oxytocin is used to induce or augment labour when the uterine
muscle is not functioning adequately. It can also be used to treat
postpartum haemorrhage. (excessive bleeding after childbirth)
• Ergometrine can be used to treat postpartum haemorrhage.
• A preparation containing both oxytocin and ergometrine is used for
the management of the third stage of labour; the two agents
together can also be used, prior to surgery, to control bleeding due
to incomplete abortion.
• Dinoprostone given by the extra-amniotic route is used for late
(second trimester) therapeutic abortion; given as vaginal gel, it is
used for cervical ripening and induction of labour.
• Gemeprost, given as vaginal pessary following mifepristone, is used
as a medical alternative to surgical termination of pregnancy (up to
63 days of gestation).
• Myometrial relaxants The β-adrenoceptor agonists (e.g. ritodrine)
are used to delay preterm labour.
• Atosiban (oxytocin antagonist) also delays preterm labour.
Clinical Uses of drugs acting on the uterus:-

• Prostaglandin (PG) analogues, for example dinoprostone (PGE2)
and dinoprost (PGF2α), contract the pregnant uterus but relax the
cervix. Cyclo-oxygenase inhibitors inhibit PG synthesis and delay
labour. They also alleviate symptoms of dysmenorrhoea and
menorrhagia.
• The β2-adrenoceptor agonists (e.g. ritodrine) inhibit spontaneous
and oxytocin-induced contractions of the pregnant uterus.
• Drugs
dinoprostone (PGE2) dinoprost (PGF2α)
• Effects
Stimulation of rhythmic uterine contraction
• Clinical use
For inducing abortion
• contraindications
﹡ Similar to oxytocin
﹡ PGF2α is banned for patient with asthma
﹡ PGE2 is banned for patient with glaucoma
Prostaglandin

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