Reproductive

Pharmacology
Androgens
• Testosterone is the main natural androgen
• Synthesized mainly by the interstitial cells of the
testis, and in smaller amounts by the ovaries and
adrenal cortex
Actions
• Depend on the age and sex of the recipient
• To boys at the age of puberty
– Rapid development of secondary sexual characteristics
– Maturation of the reproductive organs
– Increase in muscular strength
– Height
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Androgen: actions
• The anabolic effects can be accompanied by retention of
salt and water
• The vocal cords hypertrophy, resulting in a lower pitch to
the voice
• Cause a feeling of well-being and an increase in physical
vigour, and may increase libido
• To prepubertal males
– do not reach their full predicted height
– because of premature closure of the epiphyses of
the long bones
• To women
 Male dose ….. Masculinisation
 Lower dose ….. improve sexual dysfunction in women
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Androgens :pharmacokinetics
• Preparations
– Subcutaneous implantation or by transdermal
patches…..testestrone
– Intramuscular depot injection….. enanthate and
proprionate (esters)
– Orally….. Testosterone undecanoate and
mesterolone

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Androgen :pharmacokinetics
• If given orally, testosterone is rapidly metabolized in
the liver….usually injected
• Bound to plasma protein-mainly to the sex steroid-
binding globulin
• The elimination half-life of free testosterone is short
(10-20 minutes)
• Inactivated in the liver by conversion to
androstenedione
• Synthetic androgens are less rapidly metabolized, and
some are excreted in the urine unchanged

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Androgen : Adverse effect
• Eventual decrease of gonadotrophin release,
with resultant infertility
• Salt and water retention leading to oedema
• Adenocarcinoma of the liver has been reported
• Impair growth in children (via premature
fusion of epiphyses), cause acne, and lead to
masculinisation in girls

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Antiandrogens
• Oestrogens
• mainly by inhibiting gonadotrophin secretion
• Progestogens
• by competing with androgens in target organs
• Cyproterone
• Derivative of progesterone
• Partial agonist at androgen receptors
• Depresses the synthesis of gonadotrophins
• Used as an adjunct in the treatment of prostatic
cancer during initiation of GnRH treatment
• Used in the therapy of precocious puberty in males,
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and of masculinisation and acne in women 7
Antiandrogens
• Flutamide
– Non-steroidal antiandrogen used with GnRH in the
treatment of prostate cancer
• Finasteride
– Inhibits the enzyme (5α-reductase) that converts
testosterone to 5α dihydrotestosterone, which has
greater affinity than testosterone for androgen
receptors in the prostate gland
– It is used to treat benign prostatic hyperplasia

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Clinical use of Androgens and
Antiandrogens
• 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
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Anabolic steroids
• Androgens can be modified chemically to alter
the balance of anabolic and other effects
• Nandrolone
• Increase protein synthesis and muscle development
• Used in the therapy of aplastic anaemia
• Notoriously abused by some athletes
• Cholestatic jaundice, liver tumors and
increased risk of coronary heart disease are
recognised adverse effects of high-dose
anabolic steroids
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Drugs used for contraception
Oral Contraceptives
• Two main types
– combinations of an oestrogen with a progestogen
(the combined pill)
• monophasic forms (constant dosage of both
components during the cycle)
• Biphasic forms(dosage of one or both components is
changed once during the cycle)
• triphasic forms (dosage of one or both components is
changed twice during the cycle)
– progestogen alone (the progestogen-only pill)

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The phasic system
OCPs: The combined pill
• Extremely effective
• The oestrogen is ethinylestradiol(mostly) and
mestranol
• The progestogen may be norethisterone,
levonorgestrel, ethynodiol, desogestrel or
gestodene
 The oestrogen content is generally 20-50μg of
ethinylestradiol or its equivalent
 This combined pill is taken for 21 consecutive days
followed by 7 pill-free days, which causes a
withdrawal bleed
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21 days of active pills
7 days of placebo pills (may contain iron and vitamins)
No placebos (sugar pills) in progestin-only packs…..come in a
pack of 28 active
OCPs: MoA
• 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
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OCPs: Pharmacokinetics
• Metabolized by hepatic cytochrome P450
enzymes
• Any increase in oestrogen may result in
contraceptive failure
• Enzyme inducing drugs
– Rifampicin and Rifabutin, as well as
Carbamazepine, Phenytoin, Griseofulvin and
others

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OCPs: common adverse effect
• 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

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 OCPs:risks?
• Cardiovascular disease (venous thromboembolism,
myocardial infarction, stroke)
 With second generation pills(oestrogen content less
than 50μg)….. the risk of thromboembolism is small
…. smoking , long-continued use of the pill…the risk
is greatest
 For preparations containing the third-generation
progestogens desogestrel or gestodene, the incidence
of thromboembolic disease is very small
• Cancer
 Breast cancer….0.5/10000 (age 16-19) and
4.7/10000(age 25-29)
 Less advanced and treatable
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OCPs:risks?
• Blood pressure
 increase in arterial Bp occurs in a small percentage of
women shortly after starting the combined OCPs
 Disappears when stopped
 BP should be monitored carefully when OCP is started

• Impairment of glucose tolerance

 Only older progestogens

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Beneficial effects
– decreases
• Menstrual symptoms such as irregular periods and
intermenstrual bleeding
• Iron deficiency anaemia and premenstrual tension
• Benign breast disease
• uterine fibroids and functional cysts of the ovaries
are reduced
• Risk for endometrial and ovarian cancer by as much
as 50 %
• Few studies claim reduction in risk for colorectal
cancer
• Unwanted pregnancy, carrying a maternal mortality
ranging from 1 in 10000 in developed countries to 1 in 150
in Africa, is avoided
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OCP: Contraindications
• Patients with
– Thrombophlebitis
– Thromboembolic phenomena, and
– Cardiovascular and cerebrovascular disorders or a
past history of these conditions
– known or suspected tumors of the breast or other
estrogen-dependent neoplasms
• Avoid /use in caution
– Patients with liver disease, asthma, eczema,
migraine, diabetes, hypertension, optic neuritis,
retrobulbar neuritis, or convulsive disorders
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The progestogen-only pill
• Norethisterone , levonorgestrel or
ethynodiol
• Taken daily without interruption
MoA
• On the cervical mucus, which is made
inhospitable to sperm
• hinders implantation through its effect on the
endometrium and on the motility and
secretions of the fallopian tubes
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The progestogen-only pill
• Suitable alternative to the combined pill for some
women in whom oestrogen is contraindicated
• Suitable for women whose blood pressure increases
unacceptably during treatment with oestrogen
• Their contraceptive effect is less reliable than that of
the combination pill…. missing a dose may result in
conception
• Disturbances of menstruation (especially irregular
bleeding) are common

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 Other drugs used for contraception

Postcoital (emergency) contraception

• Plan B (Levonorgestrel)
– A dose of 1.5 mg, either as two 0.75mg doses 12
hours apart
– First dose should be take within 72 hrs postcoital,
second dose 12 hrs later
– Nausea and vomiting are common
• Preven ECP Kit (Yuzpe regimen)
– 4 tablets (2 tablets/dose), each tablet with 50 mcg
ethinyl estradiol and 0.25 mg levonorgestrel
– To be taken 12 hrs apart within 72 hrs postcoital
– Less tolerable and less effective???
• Insertion of an intrauterine device is more effective than
hormonal methods, and works up to 5 days after intercourse
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Other…
Long -acting progestogen-only contraception
• Medroxyprogesterone
– given intramuscularly …150 mg of depot
medroxyprogesterone acetate (DMPA) every 3 months
– effective and safe
– menstrual irregularities are common, and infertility may
persist for many months after cessation of treatment
• Levonorgestrel
– Implanted subcutaneously in non-biodegradable capsules
– The tubes release their progestogen content slowly over 5
years
– Irregular bleeding and headache are common
– A levonorgestrel-impregnated intrauterine device has
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contraceptive action for 3-5 years 27
 Drugs that stimulate the uterus

• Oxytocin
• Ergometrine
• Prostaglandins

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OXYTOCIN
• Participates in labor and delivery and elicits milk
ejection in lactating women
• During the second half of pregnancy, uterine smooth
muscle
– Shows an increase in the expression of Oxytocin
receptors and
– Becomes increasingly sensitive to the stimulant
action of endogenous Oxytocin
• Pharmacologic concentrations of Oxytocin
powerfully stimulate uterine contraction

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Absorption, Metabolism and Excretion
• Oxytocin is administered intravenously for initiation
and augmentation of labor
• It also can be administered intramuscularly for
control of postpartum bleeding
• Oxytocin is not bound to plasma proteins and is
eliminated by the kidneys and liver, with a circulating
half-life of 5 minutes

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 Pharmacodynamics
• Oxytocin acts through
– Gq GPCR
– Stimulates the release of prostaglandins and
leukotrienes that augment uterine contraction.
• Oxytocin in small doses increases both the frequency and
force of uterine contractions.
• At higher doses, it produces sustained contraction.
• Oxytocin also causes contraction of myoepithelial cells
surrounding mammary alveoli, which leads to milk
ejection.
• At high concentrations, oxytocin has weak antidiuretic and
pressor activity due to activation of vasopressin receptors
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Clinical use
• To induce labour in cases of
– Rh problems, maternal diabetes, preeclampsia, or
ruptured membranes
• To augment abnormal labor that is protracted or
displays an arrest disorder
• Oxytocin has several uses in the immediate
postpartum period, including the control of uterine
hemorrhage after vaginal or cesarean delivery
• It is sometimes used during second-trimester
abortions

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Administration
• Before delivery, oxytocin is usually administered
intravenously via an infusion pump with appropriate fetal
and maternal monitoring
• For induction of labor, an initial infusion rate of 0.5–2
mU/min is increased every 30–60 minutes until a
physiologic contraction pattern is established
• The maximum infusion rate is 20 mU/min
• For postpartum uterine bleeding, 10–40 units are added to
1 L of 5% dextrose, and the infusion rate is titrated to
control uterine atony.
• Alternatively, 10 units of oxytocin can be administered by
intramuscular injection after delivery of the placenta

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Administration con’t
• During the antepartum period, oxytocin induces uterine
contractions that transiently reduce placental blood flow to
the fetus
• The oxytocin challenge test measures the fetal heart rate
response to a standardized oxytocin infusion and
provides information about placental circulatory reserve
• Infused at an initial rate of 0.5 mU/min, then doubled every
20 minutes until uterine contractions decrease the fetal
blood supply.
• An abnormal response, seen as late decelerations in the
fetal heart rate, indicates fetal hypoxia and may warrant
immediate cesarean delivery

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 Toxicity & Contraindications
 When oxytocin is used judiciously, serious toxicity is rare
• The toxicity that does occur is due either to
 Excessive stimulation of uterine contractions
– Cause fetal distress, placental abruption, or uterine
rupture
 Inadvertent activation of vasopressin receptors
– High concentrations of oxytocin with activation of
vasopressin receptors can cause excessive fluid
retention, or water intoxication, leading to
hyponatremia, heart failure, seizures, and death.
• Bolus injections of oxytocin can cause hypotension.
– To avoid hypotension, oxytocin is administered
intravenously as dilute solutions at a controlled rate
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.....
• Contraindications to oxytocin include
– Fetal distress
– Prematurity
– Abnormal fetal presentation
– Cephalopelvic disproportion and
– Other predispositions for uterine rupture

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Ergometrine
• Contracts the human uterus
• Also has a moderate degree of vasoconstrictor action
Ergometrine: Pharmacokinetics
• Ergometrine can be given orally, IM or IV
• It has a very rapid onset of action and its effect lasts for 3-6
hours
Unwanted effect
• Vomiting, probably by an effect on dopamine D2 receptors
in the CTZ
• Vasoconstriction with an increase in blood pressure
associated with nausea, blurred vision and headache can
occur
• Vasospasm of the coronary arteries, resulting in angina 37
09/30/2023
Ergometrine :clinical use
• Used to treat postpartum haemorrhage
• Preparation containing oxytocin and
ergometrine
– for the management of the third stage of labour
– prior to surgery, to control bleeding due to
incomplete abortion

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Prostaglandins
• Endometrium and myometrium have
substantial prostaglandin-synthesising
capacity
• PGF2A…. implicated in the ischaemic
necrosis of the endometrium that precedes
menstruation
• PGE2 and PGI2 (prostacyclin)
– Vasodilator prostaglandins
– generated by the uterus

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Prostaglandins

• Prostaglandins also play a part in two of the main

disorders of menstruation
– Dysmenorrhoea (painful menstruation) and
menorrhagia (excessive blood loss)
Prostaglandin preparations
• Prostaglandins of the E and F series promote
coordinated contractions of the body of the pregnant
uterus, while relaxing the cervix
• E and F prostaglandins reliably cause abortion in
early and middle pregnancy
– unlike oxytocin, which generally does not cause
expulsion of the uterine contents at this stage
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• The prostaglandins used in obstetrics are
• Dinoprostone (PGE2)
– intravaginally as a gel or as tablets, or by the extra-
amniotic route as a solution
• Carboprost (15-methyl PGF2α)
– given by deep intramuscular injection
• Gemeprost or misoprostol (PGE1 analogues)
– are given intravaginally

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Prostaglandins :unwanted effect
• Uterine pain, nausea and vomiting, which
occur in about 50% of patients when the drugs
are used as abortifacients
• Dinoprost may cause cardiovascular collapse
if it escapes into the circulation after intra-
amniotic injection
• Phlebitis can occur at the site of intravenous
infusion

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Prostaglandins :clinical use
• Dinoprostone
– Used for late (second trimester) therapeutic
abortion
– 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).

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Drugs that inhibit uterine contraction
• Selective β2-adrenoceptor agonists, such as ritodrine
or salbutamol, inhibit spontaneous or oxytocin-
induced contractions of the pregnant uterus

• Used in selected patients to prevent premature labour

occurring between 22 and 33 weeks of gestation in
otherwise uncomplicated pregnancies

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Uterine relaxants
• They can delay delivery by 48 hours
– Time that can be used to administer
glucocorticoid therapy to the mother
– To mature the lungs of the baby and reduce neonatal
respiratory distress,
– Optimize logistics such as making sure the baby is
born in a facility with neonatal intensive care
• Risk to mother
– pulmonary oedema
– myometrial response is reduced
so prolonged treatment is avoided
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Uterine relaxants
• Cyclo-oxygenase inhibitors (e.g. indometacin) inhibit
labour
– but their use could cause problems in the baby,
including
• renal dysfunction and delayed closure of the ductus
arteriosus, both of which are influenced by
endogenous prostaglandins
• An oxytocin receptor antagonist, atosiban,
– provides an alternative to a β2-adrenoceptor agonist
– It is given as an iv bolus followed by an iv infusion for
not more than 48 hours
– Adverse effects include symptoms of vasodilation,
nausea, vomiting, and hyperglycaemia
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Drug affecting milk production
• Prolactin is the principal hormone responsible for
lactation
– Milk production is stimulated by prolactin when
appropriate circulating levels of estrogens, progestins,
corticosteroids, and insulin are present
– A deficiency of prolactin—which can occur in rare
states of pituitary deficiency—is manifested by failure
to lactate or by a luteal phase defect
– No treatment is available
Prolactin is elevated in
– Amenorrhea and galactorrhea in women, and loss of
libido and infertility in men
• Treatment :Dopamine agonists 47
DOPAMINE AGONISTS
• Bromocriptine, cabergoline, and pergolide,
Quinagolide
 Suppress prolactin release very effectively
 Hyperprolactinemia
– Shrink pituitary prolactin-secreting tumors
– Lower circulating prolactin levels, and
– Restore ovulation in approximately 70% of
women with microadenomas and 30% of
women with macroadenomas
 Growth Hormone release is reduced in patients
with acromegaly..at high dose
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Pharmacokinetics
• All available dopamine agonists are active as oral
preparations, and all are eliminated by metabolism
• They can also be absorbed systemically after vaginal
insertion of tablets
• Cabergoline, with a half-life of approximately 65
hours, has the longest duration of action
• Pergolide and quinagolide have half-lives of about 20
hours
• The half-life of bromocriptine is about 7 hours.
• Following vaginal administration, serum levels peak
more slowly
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Toxicity & Contraindications
• Cause nausea, headache, light-headedness,
orthostatic hypotension, and fatigue
• Psychiatric manifestations occasionally occur, even at
lower doses, and may take months to resolve.
• Erythromelalgia occurs rarely
• Pulmonary infiltrates have occurred with chronic
high-dosage therapy.
• Cabergoline appears to cause nausea less often than
bromocriptine
• Vaginal administration can reduce nausea, but may
cause local irritation
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Drug for termination of pregnancy
o 4-12 weeks of gestation:
Mifepristone, 200mg P.O., stat followed by after 24 hours
misoprostol 800 microgram, then the same dose 4 hours
o 12-24 weeks gestation:
Misoprostol, 400micrograms P.O., 4 hourly until expulsion
OR
Mifepristone, 200mg P.O., stat, followed by Misoprostol
200microgram P.O., after 24 hours
MOA
• Mifepristone - antiprogesterone
• Misoprostol – prostaglandin E1 analog

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