Transcript 8 drugs used in Gona..

Drugs used in gonads
disorders II
Dr.Hazar
+oxy
Clinical use of oestrogens and
antioestrogens
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Oestrogens
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Replacement therapy:
 primary ovarian failure (e.g. Turner's syndrome)
 secondary ovarian failure (menopause) for flushing,
vaginal dryness and to preserve bone mass( osteoporosis
associated with menopause)
Contraception.
To treat oestrogen-sensitive breast cancer (tamoxifen).
To induce ovulation (clomiphene) in treating infertility.
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Oestrogens
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The endogenous oestrogens are oestradiol (the most potent), oestrone and
oestriol; there are numerous exogenous synthetic forms (e.g. ethinylestradiol).
Mechanism of action involves interaction with nuclear receptors (termed ERα
or ERβ) in target tissues, resulting in modification of gene transcription.
Their pharmacological effects depend on the sexual maturity of the recipient:
 before puberty, they stimulate development of secondary sexual
characteristics
 given cyclically in the female adult, they induce an artificial menstrual
cycle and are used for contraception
 given at or after the menopause, they prevent menopausal symptoms and
protect against osteoporosis, but increase thromboembolism.
Synthetic steroids
Used in oral contraceptives
Inactive prodrug metabolized
in the liver (demethylated)
Adverse Effects
Nausea
 Breast tenderness
 Weight gain
 Endometrial cancer (estrogen alone)
 Breast cancer (vs. protection from CVD,
Alzheimer’s, and bone fractures)
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Estrogens- Drug
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are competitive antagonists or partial agonists.
Tamoxifen is used in oestrogen-dependent breast
cancer. Clomiphene induces ovulation by
inhibiting the negative feedback effects on the
hypothalamus and anterior pituitary.
Selective drugs that are oestrogen agonists in some
tissues but antagonists in others are being
developed. Raloxifene (SERMs (selective estrogen
receptor modulators) is used to treat and prevent
osteoporosis.
Breast cancer
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↑Estrogen →↑breast proliferation→↓ TGF- β
Progression of malignancy is associated with ↓ level
cytokines transforming growth factor β (TGF- β ).
Tamoxifen→ ↓Estrogen →↑↑ TGF- β
side effects1.nausea, vomiting, hot flashes, menstrual irregularities,
cataracts.
2.Increase in endometrial cancer (2-fold).
Ostrogen receptor antagonist
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1-fulvestrant
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Monthly IM injection
“for hormone receptor-positive metastatic
breast cancer in postmenopausal women
whose breast cancer has recurred or
progressed following antiestrogen therapy.”
Used to treat tamoxifen resistant breast cancer
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1-Tormifene
Used in estrogen –sensitive breast cancer.
Aromatase Inhibitors
Aromatase Inhibitors
1-Formastane
As effective as tamoxifen, but don’t increase uterine cancer
treatment for breast cancer
 2 Letrozole
 Mainly used as adjuvant therapy for post-menopausal
women with ER+ early stage breast cancer & for
metastatic breast cancer
 Not for premenopausal women
 3-Anastrozole
Used for the treatment of postmenopausal breast cancer
 4-Exemestane
in treatment for breast cancer
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Clomiphene
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Clomiphene citrate. Taken orally
Acts as a competitive inhibitor to Estrogen Receptors
cis- weak agonist
trans- potent antagonist
Prevents the feedback inhibition by estrogens on the
anterior pituitary, increasing gonadotropin secretion and
stimulating ovulation.
M.O.A is induction of ovulation by inhibits-ve feedback
effects of endogenous estrogen →↓binding in the ant.
Pit.→↑secretion of GnRH & LH,FSH→ ↑estrogen secretion.
•Used to treat infertility.
(oligomenorrhea, PCOD)
•sometimes used in combination
with gonadotropins
• Major side effect is ovarian
enlargement, also multiple births,
nausea, vomiting, vision problems
Progesterone
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1. Progesterone
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In the ovary, progesterone is produced by the
corpus luteum ,circulating levels are highest in
luteal phase of cycle.
Stimulates the development of the uterine
endometrium and vagina
Important in the maintenance of pregnancy.
Suppresses menstration and uterine
contractility & Stimulates lactation.
Complement the action of estrogen on primary and
secondary sex characteristics
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Progestins
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Drugs which mimic the action of progesterone
agonists of the progesterone receptor
Longer acting and enhanced oral effectiveness
compared with progesterone Receptors: one gene,
two isoforms, PR-A and PR-B (longer) & both
bind ligand the same
nuclear transcription factors
PR-B primarily mediates progesterone responses .
A variety of progestational agents have been
synthesized,
ex. orally active, ex. Norgestrel,
Desogestrel
Types of PROGESTERONE
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Many are used as oral contraceptives:
1.Progesterone & analogues.
Dydrogesterone ,Gestronol , Megestrol
Medroxyprogesterone.
2. Testosterone analogues
Norethindrone , Norgestrel , Ethynodiol .
3.Derivative of Norgestrel
levonorgestrel,Desogestrel and Norgestimate
Gestadone.
However,Desogestrel and Gestadone are associated with
higher risk ofvenus thromboembolism.
Adverse effects
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may reduce plasma HDL
*venus thromboembolism
weight gain( fluid retension )
Depression
Acne
menstrual irregularities
Therapeutic uses
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Contraception,IVF
hormone replacement therapyHRT
dysfunctional uterine bleeding
Dysmenorrhea PMT
Anti-progestin
Mifepristone
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Partial agonist at progesterone receptor in the
uterus and sensitize the uterus to the action of
PG
Progesterone is required for the maintenance of
early pregnancy
High amounts induce prostaglandin F2, leading
to abortion and is used with Gemeprost as a
medical alternative to surgical termination of
pregnancy
Drugs acting on the
uterus
Drugs acting on the uterus
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At parturition, oxytocin causes regular
coordinated uterine contractions, each
followed by relaxation;
Ergometrine, an ergot alkaloid, causes
uterine contractions with an increase in basal
tone.
Atosiban, an antagonist of oxytocin , delays
labour.
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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 oxytocininduced contractions of the pregnant uterus
Clinical uses of drugs
acting on the uterus
Myometrial stimulants
(oxytocics)
Oxytocin
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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.
Ergometrine can be used to treat postpartum
haemorrhage. Carboprost can be used if patients do
not respond to ergometrine.
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.
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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
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The β-adrenoceptor agonists (e.g. ritodrine)
are used to delay preterm labour.
Atosiban (oxytocin antagonist) also delays
preterm labour
HRT
Short term effects of the
menopause - physical
 Vasomotor
symptom ex.Hot flushes
Palpitations , Night sweats
 Headaches
 Feeling dizzy
 Feeling tired
 Urinary symptoms
 Crawling sensation under the skin
Short term effects of the
menopause - Mental
Irritability
 Mood swings
 Anxiety
 Insomnia
 Loss of concentration
 Lack of confidence
 Memory disturbance
 Loss of libido
 Panic attacks
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Medium term effects of
menopause
 Vaginal
dryness ( vaginitis )
 Dyspareunia
 Urinary problems
 Bladder and vaginal infections
 Thinning hair
 Aches and pains
 Skin thinning
Long term effects of the
menopause
 Osteoporosis
 Increased
CHD,M.I
Patient Concerns
 Breast
cancer
 Weight Gain
 Mensruations
 Duration
Partial agonists
1-Raloxifene
Used to prevent fractures in postmenopausal at risk of
Osteoporosis
No effect on Vasomotor symptom
2- Tibolone
Combine activities of estrogenic +proges.+weak
androgenic
For Vasomotor symptom & Osteoporosis prophylaxis
Osteoporosis
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Bone mineral homostasis:
Ca & Po4 , are major mineral constituents of
bones.
PTH & vit.D are primary regulators.
2ndry ( Cal., Glucocort., estrogens)
Bones provide structural support &
hematopoiesis.
Osteoporosis
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Natural Estrogens↓ bone resorption by:
1.Antagonizing the effect of PTH &
interlukin-6 on bones but but it does not
↑bone formation .
2.Promoting apoptosis of oesteoclasts.
Antiresorptive
 1.Bisphosphonates
alendronate, risedronate, ibandronate, etidronate
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2.SERMs (Selective estrogen receptor
modulators)ex. Raloxifene
3.Estrogen.
4.Calcitonin
Pro’s and Con’s of Available Osteoporosis
Therapies
Agent
Calcium/Vit D
HRT
Raloxifene
Pro’s
Con’s
Cheap, accessible
Effective
Partial efficacy
breast ca, DVT, MI
 vert Fx,  breast ca?
Bisphosphonates  vert and nonvert Fx
Teriparatide
Effective
GI intolerance
Expensive, daily injections