Drugs used in gonads disorders II

Dr.HazarDr.Hazar

+oxy+oxy

Clinical use of oestrogens and antioestrogens

Oestrogens Replacement therapy: Replacement therapy:

primary ovarian failure (e.g. Turner's syndrome) primary ovarian failure (e.g. Turner's syndrome) secondary ovarian failure (menopause) for secondary ovarian failure (menopause) for

flushing, vaginal dryness and to preserve bone flushing, vaginal dryness and to preserve bone mass(mass( osteoporosis associated with menopause)

Contraception. Contraception. To treat oestrogen-sensitive breast cancer To treat oestrogen-sensitive breast cancer

(tamoxifen). (tamoxifen). To induce ovulation (clomiphene) in treating To induce ovulation (clomiphene) in treating

infertility. infertility.

Oestrogens 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 steroidsSynthetic 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)

Estrogens- Drug

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

↑Estrogen →↑breast proliferation→↓ TGF- β Progression of malignancy is associated with ↓ level

cytokines transforming growth factor β (TGF- β ). Tamoxifen→ ↓Estrogen →↑↑ TGF- β side effects-side effects- 1.nausea, vomiting, hot flashes, menstrual 1.nausea, vomiting, hot flashes, menstrual

irregularities, cataracts. irregularities, cataracts. 2.Increase in endometrial cancer (2-fold).2.Increase in endometrial cancer (2-fold).

Ostrogen receptor antagonist

1-fulvestrant 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

1-Tormifene Used in estrogen –sensitive breast Used in estrogen –sensitive breast

cancercancer..

Aromatase Inhibitors

Aromatase Inhibitors 1-FormastaneAs 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

Clomiphene

Clomiphene citrate. Taken orally Acts as a competitive inhibitor to Estrogen

Receptorscis- 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

1.1. ProgesteroneProgesterone 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 Complement the action of estrogen on primary and secondary sex primary and secondary sex characteristicscharacteristics

Progestins Drugs which mimic the action of Drugs which mimic the action of

progesteroneprogesterone 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 Types of PROGESTERONE

Many are used as oral contraceptives:Many are used as oral contraceptives: 1.Progesterone & analogues1.Progesterone & analogues.. Dydrogesterone ,Gestronol , Megestrol Dydrogesterone ,Gestronol , Megestrol

Medroxyprogesterone.Medroxyprogesterone. 22. Testosterone. Testosterone analogues analogues Norethindrone , Norgestrel , Ethynodiol .Norethindrone , Norgestrel , Ethynodiol . 3.Derivative of3.Derivative of Norgestrel Norgestrel levonorgestrel,Desogestrel and Norgestimatelevonorgestrel,Desogestrel and Norgestimate Gestadone.Gestadone. HoweverHowever,Desogestrel and Gestadone,Desogestrel and Gestadone are

associated with higher risk ofvenus thromboembolism..

Adverse effects

may reduce plasma HDL *venus thromboembolism weight gain( fluid

retension ) Depression Acne menstrual irregularities

Therapeutic uses

Contraception,IVF hormone replacement

therapyHRT dysfunctional uterine

bleeding Dysmenorrhea PMT

Anti-progestin

Mifepristone

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 Drugs acting on the uterusthe uterus

Drugs acting on the Drugs acting on the uterusuterus

At parturition, oxytocin causes At parturition, oxytocin causes regular coordinated uterine regular coordinated uterine contractions, each followed by contractions, each followed by relaxation;relaxation;

ErgometrineErgometrine, an ergot alkaloid, , an ergot alkaloid, causes uterine contractions with causes uterine contractions with an increase in basal tone. an increase in basal tone.

AtosibanAtosiban, an antagonist of , an antagonist of oxytocin , delays labour. oxytocin , delays labour.

Prostaglandin (PG) analogues, for Prostaglandin (PG) analogues, for example example dinoprostonedinoprostone (PGE2) and (PGE2) and dinoprostdinoprost (PGF2α), contract the (PGF2α), contract the pregnant uterus but relax the cervix. pregnant uterus but relax the cervix. Cyclo-oxygenase inhibitors inhibit Cyclo-oxygenase inhibitors inhibit PG synthesis and delay labour. They PG synthesis and delay labour. They also alleviate symptoms of also alleviate symptoms of dysmenorrhoea and menorrhagia. dysmenorrhoea and menorrhagia.

The β2-adrenoceptor agonists (e.g. The β2-adrenoceptor agonists (e.g. ritodrineritodrine) inhibit spontaneous and ) inhibit spontaneous and oxytocin-induced contractions of the oxytocin-induced contractions of the pregnant uteruspregnant uterus

Clinical uses of Clinical uses of drugs acting on drugs acting on

the uterusthe uterus

Myometrial Myometrial stimulants stimulants (oxytocics)(oxytocics)

OxytocinOxytocin

Oxytocin is used to Oxytocin is used to induce or augment induce or augment labourlabour when the uterine muscle is not when the uterine muscle is not functioning adequately. It can also be used functioning adequately. It can also be used to treat to treat postpartum haemorrhagepostpartum haemorrhage. .

Ergometrine can be used to treat Ergometrine can be used to treat postpartum postpartum haemorrhagehaemorrhage. Carboprost can be used if . Carboprost can be used if patients do not respond to ergometrine. patients do not respond to ergometrine.

A preparation containing both oxytocin and A preparation containing both oxytocin and ergometrine is used for the management of ergometrine is used for the management of the third stage of labour; the two agents the third stage of labour; the two agents together can also be used, prior to surgery, together can also be used, prior to surgery, to control bleeding due to incomplete to control bleeding due to incomplete abortion. abortion.

DinoprostoneDinoprostone given by the extra- given by the extra-amniotic route is used for late amniotic route is used for late (second trimester) (second trimester) therapeutic therapeutic abortionabortion; given as vaginal gel, it is ; given as vaginal gel, it is used for cervical ripening and used for cervical ripening and induction of labour. induction of labour.

GemeprostGemeprost, given as vaginal pessary , given as vaginal pessary following following mifepristonemifepristone , is used as a , is used as a medical alternative to surgical medical alternative to surgical termination of pregnancytermination of pregnancy (up to 63 (up to 63 days of gestation). days of gestation).

Myometrial relaxantsMyometrial relaxants

The β-adrenoceptor agonists The β-adrenoceptor agonists (e.g.(e.g. ritodrine ritodrine) are used to ) are used to delay delay preterm labourpreterm labour. .

AtosibanAtosiban (oxytocin antagonist) (oxytocin antagonist) also also delays preterm labourdelays 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

Medium term effects of Medium term effects of menopausemenopause

Vaginal dryness ( vaginitis ) Dyspareunia Urinary problems Bladder and vaginal infections Thinning hair Aches and pains Skin thinning

Long term effects of the Long term effects of the menopausemenopause

OsteoporosisIncreased CHD,M.I

Patient ConcernsPatient Concerns

Breast cancerBreast cancer Weight GainWeight Gain MensruationsMensruations DurationDuration

Partial agonistsPartial agonists

1-1-RaloxifeneRaloxifene

Used to prevent fractures in Used to prevent fractures in postmenopausal at risk of postmenopausal at risk of Osteoporosis

No effect on No effect on Vasomotor symptom

2-2- Tibolone

Combine activities of estrogenic +proges.Combine activities of estrogenic +proges.+weak androgenic +weak androgenic

ForFor Vasomotor symptom & & Osteoporosis prophylaxis

Osteoporosis

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

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.Bisphosphonatesalendronate, risedronate, ibandronate,

etidronate 2.SERMs (Selective estrogen

receptor modulators)ex. Raloxifene

3.Estrogen. 4.Calcitonin

Pro’s and Con’s of Available Osteoporosis Therapies

Agent Pro’s Con’s

Calcium/Vit D Cheap, accessible Partial efficacy

HRT Effective breast ca, DVT, MI

Raloxifene vert Fx, breast ca?

Bisphosphonates vert and nonvert Fx GI intolerance

Teriparatide Effective Expensive, daily injections