Agents used in Female

reproductive system including

pregnancy
Syed Tajamul
 Estrogens and Progestins
• Natural Estrogens: The major estrogens produced by women are estradiol • Pharmacokinetics:
(estradiol-17β, E 2), estrone (E 1), and estriol (E 3). In the first part of the • When rel eased into the ci rculation, estradiol binds strongly to a n α2 globulin (sex hormone-binding globulin [SHBG]),
menstrual cycle estrogens are produced in the ovarian follicle by the theca and Es tra diol is converted by the liver a nd other tissues to estrone and estriol, metabolized in liver by cyp450, excreted i n bile,
mi l k.
granulosa cells. During pregnancy, a large amount of estrogen is synthesized by the
fetoplacental unit. • Pharmacodynamics:
• Synthetic Estrogens: A variety of chemical alterations have been applied to the • MOA:
natural estrogens. • Estradiol is converted by the liver and other tissues to estrone and estriol-binds to two
estrogen steroid receptors α,ß ̶ The receptor-hormone complex bind to a specific
• Agents: sequence of nucleotides called estrogen response elements (EREs ) ̶ The receptor
bind to transcription factors activate genes to produce genomic effect (RNA
• Conjugated estrogens (Premarin) transcription) and non genomic effect like Ca intake and increased uterine blood flow.

• Oral: 0.3, 0.45, 0.625, 0.9, 1.25 mg tablets Parenteral: 25 mg/5 mL for IM, IV • Clinical uses:
injection, Vaginal: 0.625 mg/g cream base • Primary Hypogonadism
• Diethylstilbestrol (Stilphostrol)Oral: 50 mg tablets Parenteral: 0.25 g • Postmenopausal Hormonal Therapy (HRT)
• Esterified estrogens (Cenestin, Enjuvia, Menest) Oral: 0.3, 0.45, 0.625, 0.9, 1.25, • Contraception
2.5 mg tablets • Osteoporosis
• Estradiol cypionate in oil (Depo-Estradiol) Parenteral: 5 mg/mL for IM injection • Senile vaginitis
• Estradiol transdermal (generic, Estraderm, many others) Transdermal patch: 0.014, • Dysmenorrhea
0.025, 0.0375, 0.05, 0.06, 0.075, 0.1 mg/d • Breast cancers
• Estradiol valerate in oil (generic) Parenteral: 10, 20, 40 mg/mL for IM injection • Adverse Effects:
• Estrone (Menest) Oral: 0.3, 0.625, 1.25, 2.5 mg tablets • Uterine bleeding, weight gain, cramps, hyperpigmentation, N/V, breast cancer,
migraine, cholestasis, hypertension.
• Estropipate (generic, Ogen) Oral: 0.625, 1.25, 2.5, 5 mg tablets Vaginal: 1.5 mg/g
cream base • Contraindication> bleeding disorders, estrogen dependent neoplasms, heavy
smoking
 Progestins
• PharmacoKinetics :
• Progesterone is the most important progestin in humans, produced • Progesterone is rapidly absorbed, extensively metabolized by the liver with poor oral
primarily by the corpus luteum. Normal males secrete 1–5 mg of bioavailability, and half-life in the plasma is approximately 5 minutes, It is excreted into
progesterone daily, The level is only slightly higher in the female during the urine.
the follicular phase of the cycle, which are further elevated and reach
their peak levels in the third trimester of pregnancy. • Pharmacodynamics
• Levonorgestrel (Norplant) MOA of progesterone is similar to that of other steroid hormones.

• Kit for subcutaneous implant: 6 capsules of 36 mg each Intrauterine • Progestins enter the cell and bind to progesterone receptors-- The ligandreceptor
system: 52 mg complex binds to a progesterone response element (PRE) to activate gene
transcription– sends negative feedback to anterior pituitary to decrease FSH anh LH
• Medroxyprogesterone acetate (generic, Provera) Oral: 2.5, 5, 10 mg tablets stimulating hormones levels– prevents ovulation and maturation of oocytes.
Parenteral (Depo-Provera): 150, 400 mg/mL for IM injection • Clinical uses
• Megestrol acetate (generic, Megace) Oral: 20, 40 mg tablets; 40, 125 • Hormonal Replacement Therapy,
mg/mL suspension
• Contraception
• Norethindrone acetate (generic, Aygestin) Oral: 5 mg tablets
• Dysmenorrhea
• Progesterone (generic) Oral: 100, 200 mg capsules Topical: 4, 8% vaginal • Endometriosis
gel, 100 mg insert Parenteral: 50 mg/mL in oil for IM injection Intrauterine
contraceptive system: 38 mg in silicone • Bleeding disorders due to estrogen
• Diagnostic uses in bleeding disorders, amenorrhea.
• Adverse effects:
• Increased BP, risk of breast cancer in menopause, , swelling in extremities, diplopia,
mood changes and headach.
HORMONAL CONTRACEPTION
(ORAL, PARENTERAL, & IMPLANTED CONTRACEPTIVES)
• Two types of preparations are used for oral contraception:
• (1) combinations of estrogens and progestins and,
• (2) continuous progestin therapy without concomitant administration of estrogens, divided into:
• Monophasic forms (constant dosage of both components during the cycle),
• Biphasic or triphasic forms (dosage of one or both components is changed once or twice during the cycle)
• Mechanism of Action
The combinations of estrogens and progestins exert their contraceptive effect largely through selective inhibition of pituitary function that results
in inhibition of ovulation.
• Chronic use of combination agents depresses ovarian function. the cervix may show some hypertrophy and polyp formation.
Adverse Effects
Mild : Nausea, mastalgia, breakthrough bleeding, and edema, head ach, withdrawal bleeding,
Moderate: bleeding due to use of progesterone, weight gain, increased pigmentation, acne,uterine dilation, hirsutism, infections, amenorrhea,
Severe: thromboembolism, venous thromboembolic disease, MI, CVAs, depression, Cancer and tumors, alopecia, erythema, and skin disorders.
Contraindications & Cautions: thrombophlebitis, CV diseases, unkwon vaginal bleeding, tumors, fibroids.
• Male contraceptives:
• Testosterone and testosterone enanthate, in a dosage of 400 mg per month, produced azoospermia, intramuscular
administration of 100 mg of testosterone enanthate weekly together with 500 mg of levonorgestrel daily orally can
produce azoospermia in 94% of men.
• Cyproterone acetate, a very potent progestin and antiandrogen, also produces oligospermia;
Postcoital Contraceptives & contraceptive implants

• Pregnancy can be prevented following

coitus by the administration of
estrogens alone, progestin alone, or in
combination ( “morning after”
contraception). When treatment is
begun within 72 hours, it is effective
99% of the time.
• Contraceptive implants :the
contraceptive implant is a small,
flexible rod inserted under the skin of
the upper arm. It releases progestin,
synthetic hormone, preventing
pregnancy by ovulation and thickening
of cervical mucus, common agent-
etonogestrel. It can be placed for 3-
5years.
ESTROGEN & PROGESTERONE
INHIBITORS & ANTAGONISTS
• MIFEPRISTONE: binds strongly to the progesterone receptor and inhibits the activity of progesterone., mechanism of this effect is
unknown.
• Uses:
• Medical termination of pregnancy, cushings syndrome, endometriosis and meningioma, softening of cervix, emergency contraceptive.
• Adverse effects: n/v, bleeding, abortion
• DANAZOL: Danazol inhibits the midcycle surge of LH and FSH, binds to androgen, progesterone, and glucocorticoid receptors and
can translocate the androgen receptor into the nucleus to initiate androgen-specific RNA synthesis.
• Uses:
• endometriosis., fibrocystic disease of the breast and hematologic or allergic disorders, including hemophilia, Christmas disease, idiopathic
thrombocytopenic purpura, and angioneurotic edema.
• Adverse effects:
• weight gain, edema, decreased breast size, acne and oily skin, increased hair growth, deepening of the voice, headache, hot flushes, changes
in libido, and muscle cramps.
• Others:
Finasteride Oral: 1 mg tablets (Propecia); 5 mg tablets (Proscar)
Letrozole (Femara) Oral: 2.5 mg tablets
Tamoxifen (generic, Nolvadex) Oral: 10, 20 mg tablets; 10 mg/5 mL oral solution
Toremifene (Fareston) Oral: 60 mg tablets
 HORMONAL THERAPY (Hormonal Replacement Therapy-HRT)
• Hormonal “replacement” therapy (HRT, correctly called HT). It is the use of
exogenous gonadal hormones, estrogen, progesterone in females and
testosterone in males for the treatment of gonadal hormone deficiencies.
• Indications:
• Females: feminizing HRT
• Menopause symptoms, oophorectomy, or premature ovarian failure, Primary
Hypogonadism, prevention of osteoporosis, total hysterectomy, amenorrhea,
• Estrogen and progesterone agents or estrogens alone and, anti-androgen spironolactone or
Cyproterone acetate are administered to maintain the physiologic levels of hormones in the
blood. duration of treatment 5-7days/w for 3-5 yrs.
• Adverse effects: rise in plasma cholesterol and LDL concentrations, increased cardiovascular
risk, bleeding, risk of breast cancer, thromboembolism.
• Males : masculinizing HRT-- Androgen Replacement Therapy.
• Primary hypogonadism, hypopituitarism, Use as Protein Anabolic Agents, Anemia,
Osteoporosis, Use as Growth Stimulators, Age related weaknesses, Sex therapy.
• Testosterone and anabolic steroids
• Duration of treatment temporary or life long.
 OVULATION-INDUCING AGENTS – Fertility Drugs
• 1. Clomiphene citrate (generic, Clomid, Serophene, • 3. GONADOTROPINS:
Milophene)Oral: 50 mg tablets
• FOLLICLE-STIMULATING HORMONE (FSH) ANALOGS
• Pharmacokinetics:
• Follitropin alfa [rFSH] (Gonal-f) Parenteral: 75, 450, 1050 unit powder in vials to
• well absorbed when taken orally, distributed to adipose reconstitute or 300, 450, 900 units in prefilled pens with needles for SC injection.
tissues. It has a half-life of 5–7 days and is excreted primarily
in the urine. • MOA>
• MOA: • Activates FSH receptors, Mimics effects of endogenous FSH.
• Controlled ovulation hyperstimulation in women,infertility due to
• In humans it leads to an increase in the secretion of hypogonadotropic hypogonadism in men.
gonadotropins and estrogens by inhibiting estradiol’s
negative feedback effect on the gonadotropins in • Adverse effects: Ovarian hyperstimulation syndrome and multiple
hypothalamus– stimulates ovulation. pregnancies in women gynecomastia in men headache, depression, edema in
both sexes.
• Clomiphene is used in the treatment of disorders of
ovulation in patients who wish to become pregnant. • LUTEINIZING HORMONE (LH) ANALOG
• Adverse effects: hot flushes, headache, constipation, • Human chorionic gonadotropin (hCG) IM injection
allergic reactions, reversible hair loss, nausea and vomiting,
increased nervous tension, depression, fatigue, breast • Choriogonadotropin alfa [rhCG] (Ovidrel) Parenteral: 250 mcg in single-dose
soreness, weight gain, urinary frequency, and heavy menses prefilled syringes for SC injection
• Contraindications: enlarged ovaries. • Lutropin alfa [rLH] (Luveris) Parenteral: 75 unit powder to reconstitute for SC
2. Others: injection

Letrozole (Femara) Oral: 2.5 mg tablets • MOA> Agonist at LH receptors Mimics effects of endogenous LH,

• MoA: androgen antagonist, a selective nonsteroidal inhibitor of • Initiation of ovulation during controlled ovulation hyperstimulation • ovarian follicle
development in women with hypogonadotropic hypogonadism • male
aromatase (the enzyme required for estrogen synthesis leading hypogonadotropic hypogonadism.
increased FSH and LH production.
• Adverse effects: like of FSH analogs.
Metformin 500mg daily PO ( insulin senszitizer, see antidiabetic
drugs)
Used in PCOS related ovulation problems.
Agents used in medical termination of pregnancy- MTP
• 1. Progesterone inhibitor
• Mifepristone 200mg pill see early slides
• MOA: blocks the action of progesterone leading to breakdown of uterine lining and detachment of
embryo.
• 2. Prostaglandin analog
• Misoprostol 800mg sublingual, buccal or vaginally.
• Gameprost
• MOA: mimic the action of prostaglandin E1, stimulates the uterus contractions, softens and dialates
the cervix, facilitates the expulsion of uterine content – medical abortion.
• Dosage: for MTPs upto 10 weeks, 200mg of mifepristone PO f/a/ 1-2 days Misoprostol 800mg sublingual,
buccal or vaginally. 97% success.
• Gameprost + mifepristone terminates the pregnancy upto 24 weeks of gestation.
• Complications:
• Incomplete/ failed abortion,
• septic shock
• Heavy bleeding
• Retained conception tissue
• Uterine perforation and infections
• diarrhoea
UTERINE STIMULANTS ( oxytocics/ Abartofacie)
• 1. posterior pituitary hormone • Effects of Oxytocin
• Oxytocin is the drug of choice and is preferred over
• Oxytocin, Desamino oxytocin ergometrine/PGs for induction of labour.
• Pharmacokinetics: • Oxytocin as neurotransmitter in the hypothalamus and
brainstem to regulate autonomic neurones.
• Oxytocin is administered intravenously for initiation • Oxytocin levels are peak in near term and quick fall during
and augmentation of labor. It also can be puerperium
administered intramuscularly for control of • Oxytocin increases the force and frequency of uterine
postpartum bleeding. Oxytocin is not bound to contractions.
plasma proteins and is eliminated by the kidneys • Increased contractility is due to hightened electrical activity of
and liver, with a circulating half-life of 5 minutes. the myometrial cell membran
• MOA: • Oxytocin contracts myoepithelium of mammary alveoli and
forces milk into the bigger milk sinusoids—‘milk ejection reflex’
• Oxytocin binds G protein-coupled receptors and the • Oxytocin in high doses exerts an ADHlike action—urine output
phosphoinositide-calcium second-messenger system— is decreased.
depolarization of muscle fibres and influx of Ca2+ ion-- • Preparations and uses
contraction of uterine smooth muscles.
• 1 IU of oxytocin = 2 μg of pure hormone.
• Oxytocin also stimulates the release of prostaglandins
and leukotrienes that augment uterine contraction. • Desamino-oxytocin 25–50 IU buccal tablets, i.v
• Adverse Effects: • For induction of labour:
• Hypotension (Low Blood Pressure, Nausea and Vomiting, • 5 IU is diluted in 500 ml of glucose or saline solution (10 milli
Uterine Hyperstimulation, Water Retention and IU/ ml), started at a low rate to 0.2–2.0 ml/min
Hyponatremia, Alleric reactions, Arrythmias, PPH. • Usually a total of 2–4 IU is needed.
• For postpartum haemorrhage,: Oxytocin 5 IU may be
injected i.m. or by i.v. infusion for an immediate response,
Cont…
2.Ergot alkaloids
Ergometrine (Ergonovine) 0.25, 0.5 mg tab, 0.5 mg/ml inj. • Clinical uses:
Methylergometrine( Methergine) 0.2mg PO, IM, IV.
PK: rapidly and nearly completely absorbed from the oral route. onset of
• Inevitable, incomplete
uterine action is: Oral—15 min; i.m.—5 min; i.vPlasma t½ is 1–2 hours last
3–4 hours extensively metabolized in the body, eliminated through urine. and missed abortions
MOA: The stimulant effect on the uterus is associated with agonist or
partial agonist effects at 5-HT receptors on vascular smooth muscle. • Induction of labour
It has Vasoconstrictive effect on blood vessels—prevents blood loss.
Clinical uses: PPH, induction of labour in CS/ instrumental delvery, for
• Augmentation of labour
uterine involution, diagnosis of variant angina.
AdverseEffects: N/V, headache, HT, uterine spasms, peripheral • Evacuation of vesicular
vasoconstriction.
3. Prostaglandins :
mole
Caboprost (methyl PG-F2 alfa) , 100-250mcg IM f/b 250-500 mg. • Prophylaxis and
Dinoprost trimethamine PG F2-Alfa,20mg vaginal suppository every 3-5
hrs, treatment of
Gameprost, Mesoperistol (PGE1), postpartum
MOA: changes in myometral memberane permeabilityand alteration of ca
channels. Also sensitizes uterus to oxytocin, promotes cervical ripening. haemorrhage.
4. Others: mifepristone, Quinine, Ethacridine
Uterine Relaxants (Tocolytics)
• These are drugs which decrease uterine motility, used to delay or postpone labour, arrest threatened • 4. Oxytocin Antagonist
abortion and in dysmenorrhoea.
• Atosiban a modified form of oxytocin,
• 1. Beta Adrenergic Agonists or sympathomimitics administered by IV infusion for 2–48 hours
• Ritodrine 10 mg/ml inj (5 ml amp), 10 mg tab. • MOA: Blocks oxytocin receptors, Decreased
• started as 50 μg/min i.v. infusion, rate is increased every 10 min till uterine contractions cease or
uterine contractions Tocolysis for preterm labor
maternal HR rises to 120/min. Delivery can be postponed in about 70% cases.
IV infusion
• Isoxsuprine 10-40mg oral/i.m used to stop threatened abortion, • Toxicity:Concern about increased rates of
infant death; not FDA approved
• Adverse effects:
• 5. Miscellaneous Drugs
• cardiovascular (hypotension, tachycardia, arrhythmia, pulmonary edema) and metabolic
(hyperglycaemia, hyperinsulinaemia, hypokalaemia) complications and anxiety, restlessness, • Ethyl alcohol, nitrates, progesterone, general
headache anaesthetics and PG synthesis inhibitors are
• 2. Calcium Channel Blockers
the other drugs, which can minimize uterine
contractions.
• Nifidipine 10 mg every 20–30 min till uterine contractions subside, reduce the tone of myometrium
and oppose contractions. • INDICATIONS:
• 3. Magnesium sulfate (Epsom Salt) • Preterm labour
• An i.v. bolus (2–4 g over 10–20 min) is followed by 1 g/hr i.v. infusion regulated by the response. • Delaying or Postponing Labor
• MOA: • Uterine irritability
• It causes direct inhibition of action potentials in myometrial muscle cells. Magnesium sulfate • Fetal distress
reduces striated muscle contractions and blocks peripheral neuromuscular transmission by
reducing acetylcholine release at the myoneural junction. • Arresting Threatened Abortion
• Additionally, Magnesium inhibits Ca2+ influx through dihydropyridine-sensitive, voltage-
dependent channels. This accounts for much of its relaxant action on vascular smooth muscle. • Reduce post parum hemorrhages
• Used for immediate control of life-threatening convulsions in the treatment of severe toxemias (pre- • Dysmenohrria
eclampsia and eclampsia) of pregnancy and in the treatment of acute nephritis in children. popularity
as an initial treatment in the management of various dysrhythmias, particularly torsades de pointes,
• Adverse reactions include hypotension, ECG changes, diarrhea, urinary retention, CNS depression and
respiratory depression.
• Physiological Effects of estrogen
• Female maturation: Estrogens are required for the normal
sexual maturation and growth of the female. They stimulate
the development of the vagina, uterus, and uterine tubes as
well as the secondary sex characteristics.
• Endometrial Effects: normal human menstrual cycle, regular
periodic bleeding and shedding of the endometrial lining.
• Metabolic and Cardiovascular Effects: normal structure and
function of the skin and blood vessels in women, decrease the
rate of resorption of bone by promoting the apoptosis of
osteoclasts and by antagonizing the osteoclastogenic and pro-
osteoclastic effects of parathyroid hormone and interleukin-6.
Alterations in the composition of the plasma lipids caused by
estrogens are characterized by an increase in the high-density
lipoproteins (HDL), a slight reduction in the low-density
lipoproteins (LDL), and a reduction in total plasma cholesterol
levels.
• Effects on Blood Coagulation: Estrogens enhance the
coagulability of blood. Increased plasminogen levels and
decreased platelet adhesiveness.
• Other effects: induce the synthesis of progesterone receptors,
stimulates central components of the stress system, promotes
sense of well being, also facilitate the loss of intravascular fluid
into the extracellular space, producing edema. Also increses
libido and modulate sympathetic nervous system.