Steroidal Hormones

Adrenocorticosteroids

Adrenocorticoids Corticosteroids Corticoids

II MID TERM EXAM ON 4 MAY 2011 (1 JUMADA II. 1432 H)
Section-20050

Human Steroidogenesis

Human steroidogenesis is the biological process by which steroids are generated from cholesterol and transformed into steroidal hormones: Cortisol (in adrenal cortex) Aldosterone ( in adrenal cortex) Corticosterone (in adrenal cortex) Androgens Testosterone and dihydrotestosterone (in testes mainly and in adrenal cortex as minor steroids) Estrogens and Progesterone (in ovaries mainly and in adrenal cortex as minor steroids)

STEROIDAL HORMONES

Cholesterol (C-27) (Precursor of Steroidal hormones)

ADRENAL CORTEX

The adrenal glands are located on the superior surface of the kidney. They are two glands in a single capsule. The Adrenal cortex secrets corticosteroids Steroidal Hormones Adrenocorticosteroids Adrenocorticoids Corticosteroids Corticoids Secretion:

Adrenal cortex of the adrenal gland.

Regulation of Corticosteroids
Regulation:
Stimulation: ACTH. Inhibition: Feed back Mechanism. Hypothalamus
Corticotropin Releasing Factor (CRF)

(-) (-)

Anterior Pituitary
ACTH

Adrenal Cortex
Glucocorticoids

Classification of corticosteroids

They are all C-21 hormones.

Corticosteroids

Glucocorticoids
Regulate carbohydrates, lipids and proteins metabolism

Mineralocorticois
Control electrolytes and water balance

e.g. Hydrocortisone

e.g. Aldosterone.

Numbering System of Steroidal ring:

21 20 12 11 1 2 3 4 19 9 10 5 6 7 8 13 14 15 18 17 27 16 22 23 24 26 25

HO

18

18

Hydrocortisone
(Glucocorticoid)

Aldosterone
(Mineralocorticoid)

Biosynthesis of Adrenocorticosteroids
O O

HO

HO

Cholestrol

Pregnenolone

Progesterone

HO O O OH

21-Hydroxyprogesterone

17-Hydroxyprogesterone

HO HO O

HO O OH

Conns syndrom: Inability of adrenal cortex to carry out 17-hydroxylation of pregnenolone. That leads to low level of Cortisol and high level of Aldosterone.

Corticosterone

11-Deoxycortisol

HO HO HO CHO O HO O OH

O O

Aldosterone

Cortisol Hydrocortisone

Control of Cortisol Secretion: Feed Back Loop

Circadian Rythm The amount of cortisol present in the blood undergoes diurnal variation; the level peaks in the early morning (approximately 8 am) and reaches its lowest level at about midnight-4 am, or three to five hours after the onset of sleep CRH

Stress
Long Loop Negative Feedback

Hypothalamus

(-)

ACTH

Pituitary Pituitary

(-)

External stimuli Hypothalamic (CRH) Anterior Pituitary (ACTH) Adrenal cortex Tissues
Immune System

Cortisol

Adrenal Cortex Adrenal Cortex

(-)

Liver

Muscles

Adipose Tissues

Gluconeogenesis Protein Catabolism Funtion Supressed

Lipolysis

Summary Of Glucocorticoid Effects

Hypothalamopituitary adrenal (HPA) axis

Stress Circadian rhythm
Immune system: altered

Hypothalamus

CRH
Anterior Pituitary Gland
Posterior Pituitary Gland

Muscle: Net loss of amino Acids (glucose) Liver: Deamination of proteins into amino acids, gluconeogenesis (glucose) Fat Cells: Free fatty acid mobilization Heart rate: Increased

(-)

ACTH
Glucocorticoids, Adrenals Catecholamines, etc..

Kidney

Effects of Glucocorticoids (eg. Cortisol) : Stress Hormone

The glucocorticoids get their name from their effect in raising the blood sugar (glucose) level through: Stimulating gluconeogenesis in liver conversion of fat and protein into intermediate metabolites that are ultimately converted into glucose. Decrease peripheral utilization of glucose (counteract insulin). Enhance lipolysis of triglycerides. Skeletal muscle breakdown Increase resorption of Ca+2 and matrix of bone. Anti-inflammatory Anti-allergic effects Immunosuppressive Effects (decrease the WBCs). Retardation of cell division and cell growth. Increase hemoglobin and Red blood cells. Regulation of electrolytes level (Na+ & H2O retention Increase urinary excretion of potassium.

Effects of Mineralocorticoids Aldosterone plays an imoprtant role in regulation of extracellular fluid (ECF) and blood volume and maintain K+ balance. On of ECF and blood volume (e.g. hemorrhage, diarrhea) renin release from kidney angiotensin II level stimulation of adrenal cortex aldosterone release acts on kidney, sweat and salivary glands K+ excretion, Na+ and H2O retention + acts on blood vessels vasoconstriction Blood pressure . Also, hyperkalemia stimulate its secretion, while congestive heart failure inhibit aldosterone secretion.

Disease States

Addisons disease: (due to Adrenal insufficiency or Hypocortisolism)

Rare syndrome 1/100,000 due to Hypoadrenalism. Causes: Atrophy of adrenal gland. Tuberculosis cortisol and aldosterone levels (hypoaldosteronism) Low level of ACTH. Symptoms: Weakness, fatigue, apathy, depression and irritability. Anemia and low blood pressure. Loss of sodium and dehydration. Hypersensitivity to Insulin. Hyper pigmentation.

2. Hyperaldosteronism (syndrome caused by elevated aldosterone) generally results from adrenal cancers. Symptoms: Excessive Na+ and H2O retention Hypertension and edema Accelerated excretion of hypokalemia muscle weakness eventually paralysis. K+ and

Cushings disease: due to Hyperadrenalism (Hypercortisolism) : Rare syndrome 2- 5/Million. Causes: Tumor of the Adrenal Cortex. Tumor of the Pituitary gland. Iatrogenic cause (Physician cause) Symptoms: Alteration of fat distribution. Hypertension. Osteoporosis. Growth retardation. Decrease Immunity.

Conns syndrom: Causes: Inability of adrenal cortex to carry out 17hydroxylation of pregnenolone. That leads to low level of Cortisol and high level of Aldosterone. Symptoms: Hypertension. Alkalosis. Polyuria. Edema.

Structure-Activity Relationship
Halogen & halomethylene greatly increase Topical antiinflammatory activity Essential for activity -F increase all activities if no OH at C-17 -F with 16dihydroxy--inactive compounds

HO
Essential for antiinflammatory activity & carbohydrate regulatory activity 18 12

21

O HO
11 19 9 -CH3 increase glucocorticoid activity 1 2 10

Ether & esters increase antiinflammatory & glucocorticoid activities

17 1, 2 Double bond improve carbohydrate metabolism to Na+ retention 13

OH
Essential for antiinflammatory activity 16 CH3 or OH eleminate Na+ retention activity

C
14

A
3 5

B
6 9-Fluoro increase all activities F Br Cl

Essential for activity

-CH3 in Cortisol increase all activities -CH3 in Prednisolone increase antiinflammatory activity &Decrease Na+ retaining activity

Adrenocorticoid Drugs

Systemic Corticosteroids:
They can be administered by IV, IM injections, oral, topical or by inhalation. They can be short, intermediate or long-acting. Unlike natural corticoids they do not undergo first pass metabolism.

Cortisone and Cortisone acetate:

Can be given orally or by IM injection. Acetate has longer duration of action. Drug of choice in replacement therapy.
HO HO O OH O HO O OH

Cortisol Hydrocortisone

Cortisone

Fludrocortison:
9-fluorocortisone. 10 times more active than cortisone as antiinflammatory. 300- 800 times more active as mineralocorticoids.

Prednisone and Prednisolone:

They are 1 corticoids. 3, 4 times more active than cortisone and hydrocortisone. It is particularly effective as immunosuppressant, and affects virtually all of the immune system. It is used to treat certain inflammatory diseases and (at higher doses) cancers. Prepared by microbial dehydrogenation (Corynebacterium simplex) or by chemical oxidation using SeO2. It has more glucocortocoid effects than mineralocorticoid.

HO HO O OH O

HO O OH

Prednisolone

Prednisone

Active form

In Liver

Inactive Form

Triamcinolone:

9-fluoro, 16-hydroxyprednisolone. Activity equal to prednisolone but with less mineralocorticoid activity. 9-fluoro, 16-methylprednisolone. 5- 7 times more active than prednisolone. 9-fluoro, 16b-methylprednisolone. Slightly more active than Dexamethasone.
HO O HO OH CH3 F F O HO HO O OH CH3

Dexamethasone:

Betamethasone:

Dexamethasone

Betamethasone

Topical Corticosteroid:

Beclomethasone:
9-fluoro, 16b-methylprednisolone. 9-chloro analog of Betamethasone. Topical activity 500 times more than Betamethasone.

HO O HO OH CH3 Cl O

Inhaled Corticosteroids:

Beclomethasone 17, 21-dipropionate (BDP):

Prodrug metabolized to more active 17-BMP. 17-BMP is 30 times more active than BDP. Topical activity 500 times more than Betamethasone.

Triamcinolone Acetonide:

Clinical uses of Corticosteroids

Hypoadrenalism. Rheumatic diseases. Renal diseases. Collagen diseases. Ocular diseases. Skin diseases (Psoriasis, Urticaria) GIT inflammation. Liver diseases. Allergic Reactions Status Asthamaticus (Not respond to bronchodilators)

Diagnostic uses:

Cause of Hyperadrenalism:
Non specific due to obesity or stress. Cushings syndrome. 2 mg Dexamethasone every 6 hr for 8 doses to diagnose the cause.

Side effects of Corticosteroids

Due to Prolonged use: Fluid and electrolyte disturbances, edema and hypertension. Hyperglycemia and glucosuria. Peptic ulcer. Osteoporosis Myopathy Growth arrest Increase susceptibility to infections. Withdrawal Symptoms: If corticosteroids are taken for a long time , it should be gradually reduced in 5-7 days to allow the adrenals time to recover and begin normal cortisol production, otherwise symptoms of severe hypoadrenalism may happen e.g. extreme fatigue, weakness, stomach upset, dizziness, etc.

Pharmacokinetics:

Absorption:

Well absorbed from all sites of administration.

Plasma Protein binding:

90% to albumin or globulin.

Half life (t1/2):

1- 1.5 hr.

Metabolism and Excretion:

Excreted in urine after glycosylation with glucuronic acid.

Aldosterone Inhibitors Spironolactone is synthetic C-17 spirolactone. It inhibits the effect of aldosterone by competing for intracellular aldosterone receptors in the cortical collecting duct reabsorption of Na+ and water and K+ secretion . It has also anti-androgen activity by binding to the androgen receptor.

Uses:
Diuretic particularly in treatment of heart failure, ascites in patients with liver disease Anti-androgen. Treatment of Conns syndrome (1ry aldosteronism) Treatment of Hypertension and hypokalaemia (K+ sparing agent)

SEX HORMONES

Pathway for Steroid Hormone Synthesis is Testis and Ovary

Cholesterol

Pregnenolone
Progestogens Androgens
In Ovary In Testis

Oestrogens

Testosterone

Progesterone

Regulation of Female Sex Hormones

(Estrogens and Progestins)

Follicle Stimulating Hormone (FSH) : Stimulate the production of Estrogens.

Luteinizing

Hormone (LH) : Stimulate the production of

Progestins.

Regulation of Female Sex Hormones (Estrogens and Progestins)

Natural Estrogens: Estrogens are 10-demthylated C18 steroids with an aromatic A ring (produced from androgens by enzymatic actions). Estradiol is the predominant form in non-pregnant females, estrone is produced during menopause, and estriol is the primary estrogen of pregnancy.
OH O OH OH

Estrogens

HO 17b-estradiol

HO Estrone

HO Estriol

Biosynthesized in ovary, placenta, adrenal cortex & testes. Estradiol (most potent estrogen) : estrone : estriol = 10 :5 :1 Oral estradiol has short duration of action due to first pass liver metabolism into the less active estrone and estriol. So, estrogen analogs (with a different chemical structure) must be used for effective oral estrogen therapy

Biosynthesis of Female and Male sex Hormones

O OH

HO HO

HO

Cholestrol

Pregnenolone

17-Hydroxypregnenolone

Progesterone

Androstenedione

OH

HO

Testosterone
aromatase

Estrone

OH

HO

17b-estradiol

Functions of Estrogens

Development of the female sexual organs. Development of the female secondary sex characters. Control of the menstrual cycle.

Required for optimal progesterone effects (e.g. in uterus). Accelerate maturation of ovarian follicle. Promote the proliferation of endometrium. Thickens the mucosa of vagina glycogen discharge lactic acid production by Dderleins bacillus (Lactobacillus acidophilus) acidic pH vaginal infection. Make cervical mucus conducive to sperm penetration and survival, especially around the time of ovulation. Regulate speed of ovum travels in fallopian tube.

Extragonadal effect of estrogens.

-Slow longitudinal bone growth. - Accelerate epiphyseal closure (in men and women) and osteoblast activity. Therfore, estrogen deficiencies in menopause loss of bone mass (osteoporosis). - Induce LDL and HDL (arteriosclerosis is less common in premenopausal women than in men). -Influences a number of central nervous functions, e.g. sexual response, social behavior, and mood.
Low Estrogen level promotes the bone growth but higher levels speed up the epiphyseal maturation.

Uses

Birth control pills. Failure of ovarian development. Menstrual disturbances. Suppress lactation after birth. Postmenopausal osteoporosis. Prostate cancer.

Side Effects

Nausea, vomiting and diarrhea. Sodium and water retention. Inhibition of ovulation in large doses. Accelerate epiphyseal closure.

Structure Activity Relationships:

Aromatic ring with C-3-OH is essential for activity. Steroidal structures is not essential for activity. Alkylation of the aromatic ring decrease the activity. The 17b-hydroxyl with constant distance from 3-OH is essential for activity. The group between the two hydroxyl must be hydrophobic. Unsaturation of ring B decreases the activity. 17- and 16 position when modified enhance the activity.

The group between the two hydroxyl must be hydrophobic.

SAR of 17-estradiol

The 17b-hydroxyl with constant distance from 3-OH is essential for activity.

Aromatic ring with C-3-OH is essential for activity. 1 2 A

B

C D

17- and 16 position when modified enhance the activity.

3
4 Alkylation of the aromatic ring decrease the activity Unsaturation of ring B decreases the activity

Steroidal Estrogenic Drugs:

1. Estradiol:
Most active natural estrogen. Very short duration of action due to first pass metabolism. Mainly used for local effect on the uterus. As replacement therapy at the beginning of menopause or after oophorectomy) in combination with a progestin. Treatment of infertility in women due to sperm-unfriendly cervical mucus or unappropriate uterine lining (in combination with Clomid).

OH OH C CH

HO
17b-estradiol

HO
Ethinyl estradiol
(Stertoidal Semisynthetic estrogen)

2. Ethinyl estradiol:
15- 20 more potent than estradiol orally. Most frequently used as an estrogen component of combined oral contraceptives. Also used for the treatment of menopausal and post menopausal symptoms, especially the vasomotor effects.

Nonsteroidal Synthetic Estrogens

Diethylstilbesterol (Stilboestrol. 5mg/day): The trans form is the active one.

Advantages:

As active as Estradiol. Longer duration of action. Orally active Cheap.

OH

HO

Disadvantages: Increase the risk of uterine cancer. Uses:

1. Treatment of advanced prostate cancer, where the cancer has spread beyond the prostate gland for example, to the bones. 2. Treatment of advanced breast cancer in postmenopausal women.

Non Steroidal Natural Estrogens (Phytoestrogens)

Estrogenic compounds with weak activity present in herbs, food and drinks. Isoflavones and comesterols derivatives, present in family Leguminosae (e.g. Soya, Fenugreek), are examples of phytoestrogens.

Phytoestrogens exert their effects primarily through binding to estrogen receptors. The similarities, of estrogens and phytoestrogens allow them to mildly mimic and sometimes act as antagonists of estrogen. Evidences showed that phytoestrogens (dietary estrogens) may protect against diverse health disorders such as prostate, and cancers, cardiovascular. disease, and osteoporosis.

Phenolic ring essential for binding to estrogen receptor Low MW (272) similar to estrogens. Distance between two OH groups is similar to that occurring in estradiol Optimal hydroxylation pattern

SAR of Phytoestrogens

Xenoestrogens
(Nonsteroidal Enviromental Estrogens)

Estrogenic compounds with weak activity present in food and drinks. Isoflavones and comesterol derivatives present in family Leguminosae are examples of xenoestrogens.
O O O

HO

OH

O OH Genisten

O OH Coumesterol

Xenoestrogens (Nonsteroidal Enviromental Estrogens)

Xenoestrogens are industrial or endocrine disrupting chemicals found in food, soil and compete with the natural estrogen hormone, at the estrogen receptors disrupt hormone balance, disturb menstrual cycles, affect prostate induce fibroids, induce uterine cysts, endometriosis, polycystic ovary and can damage ova and sperm. Many Xenoestrogens activate the CYP-lBl enzyme, which convert the natural estrogens to catechol-toxic metabolites DNA damage increase risk of developing cancer, including breast cancer. Xenoestrogens include Dioxins (shampoo additive), polychlorinated biphenyls, DDT (dichlordophenyltrichloroethane), chlorinated products, chemicals present in pesticides, fertilizers, plastics, and cleaning solutions. These products are not biodegradable and remain in environment for long periods of time, over time moving their way up the food chain of larger animals and humans.

Estrogen They act by 1. Competitive antagonism with estrogen at the estrogenic receptors e.g. Triphenylethylene (Stilbene) antagonists (Tamoxifen): Uses: Treatment of both early and advanced estrogen receptor positive (ER+ ) breast cancer in pre- and postmenopausal women. Additionally, it is the most common hormone treatment for

Antagonists estrogen dependent

cancers.

Uses: Treatment of

Structure of Tamoxifen

2. Enzymatic inhibition of biosynthesis of estrogen from androgens e.g. aromatase inhibitors: They are of two types: Steroidal Irreversible inhibitors by forming permanent complex with the aromatase enzyme (ex. Exemestane). Non-steroidal reversible inhibitors which inhibit the enzyme by reversible competition. (ex. Anastrozole) Uses: Treatment of both breast cancer with or without tamoxifen.

Progestogens have C21 skeleton and function in maintaining pregnancy (support gestation), although they are also present at other phases of estrous and menstrual cycles. Exogenous or synthetic hormones are called progestins.
O

Progestins

Progesterone

Progestins
Progesterone is the major natural progestin.
Secretion: By the ovary mainly the corpus luteum during the second half of the menstrual cycle. Progesterone, the most potent pro-gestational (pregnancy-sustaining) hormone, is produced by corpus luteum (during the 2nd of menstrual cycle), placenta, and adrenal cortex of male and female.

Like estradiol, oral doses of progesterone are almost ineffective due to rapid metabolism by liver.

Physiological Functions of progesterone

1. Prepare uterus for implantation and maturation of fertilized ovum and to sustain pregnancy (main function) with associated

changes:
- Stimulates growth of myometrium. - Stimulate formation of secretory endometrium (at day 22 of the cycle). - Reduce myometrial activity (important in pregnancy), narrows cervix, and make cervical mucous plug to be sperm impregnable. 2. Its administration during the follicular phase inhibits ovulation. This with its effects on the cervix, progesterone therefore have contraceptive effect . 3. It exerts thermogenic action (raises basal body temperature). 4. Development of the mammary gland during pregnancy. 5. Milk secretion starts when its level decrease with birth.

Structure Activity Relation-ships:

Steroidal nucleus essential for activity. Have some androgenic activity. Removal of the 19 CH3 increase activity. Unsaturation of ring B or C increase the activity. Removal of the keto function remove androgenic activity. Removal of

O
19 Keto group

C
B

Progesterone

Progestrogenic Drugs

Lynestrenol:

Semisynthetic progestin with pure progestrogenic activity.

After oral administration lynestrenol is quickly resorbed and converted into pharmacologically active Norethisterone

OH C CH

Progesterone (Natural)

Lynesrenol (Synthetic)

Uses of Lynestrenol and Norethisterone

Oral Contraceptive combined with estrogens. Uterine bleeding. Prevention of abortion. Menstrual disorders like Amenorrhea, dysmenorrhea, endometriosis. Suppression of lactation. Endometrial, renal and breast carcinoma. Enhance respiration (for Hypoventilation).

Side Effects:
Nausea, vomiting, irregular bleeding, edema, weight gain, breakthrough bleeding, beast disconfort.

Progestin Antagonists:

Mifepristone:
It compete with the progesterone receptors. Uses:

Emergency contraceptive in smaller doses. Abortifacient in the first two months of pregnancy. Labor induction in fetal death in utero. Termination of pregnancies between 3 and 6 months of gestation in combination with Gemeprost (prostaglandin E1 analog).

Female Oral Contraceptive

Sequential Preparations:

Estrogens for 16 days then Estrogen and Progesterone for 5- 6 days. 98- 99% successful.

Combination Preparation:

Estrogens and Progesterone from the beginning to the end in small doses. 99- 100% successful.

Mechanism: The above two types inhibit both FSH and LH so

prevent ovulation.

Minipills:

Small doses of Progesterone from the beginning to the end. 97- 98% successful.

Mechanism:

Alter the structure of the Endometrium. Increase consistency of the cervical mucus.

Side Effects of Oral Contraceptives (Due to Estrogens):

Increase risk of breast, vaginal and uterine cancers. Increase risk of thromboembolic and vascular problems. Nausea, vomiting, headache, menstrual disturbances and weight gain.

Male Sex Hormones (Androgens)

Control:

Luteinizing Hormone (LH) or Interstitial CellStimulating Hormones (ICSH) stimulate the production of Androgens (testosterone and dihydrotestosteron e) in Leydig cell.

Natural Androgens:
OH OH

O
H

Testosterone (Natural)

Dihydrotestosterone (Natural)

Physiological Functions of Testosterone

Male sexual differentiation during embryonic life. Induction of spermatogenesis and sperm growth. Improvement of genitalia, prostate and seminal vesicle. Development of male sexual organs and secondary sex characters around the time of puberty e.g. body hair distribution physique - laryngeal siz (voice change), acne, etc. Necessary for normal sex drive (libido), procreative capacity (fertility) and coital capacity. Stimulates hematopoiesis Anabolic effect, leading to increased muscle mass. Central nervous effects and influencing behavior e.g., aggressiveness.

Uses of Testosterone Hormone replacement therapy in cases of hypogonadism (little or no natural endogenous testosterone production). Anabolic and muscle builder. Prevention or reduction of type II diabetes (Insulin Independent), cardiovascular disease, obesity, depression and anxiety. Women may also use testosterone therapies to treat or prevent loss of bone density, muscle mass and to treat certain kinds of depression and low libido state. Appetite stimulation and bone marrow stimulation. Not used by oral administration (why?)

Side Effects:

Sodium and water retention leads to edema. Masculinization of women. Hepatic dysfunction. Erythro-cythemia (abnormal increase of erythrocytes in the

Structure Activity Relation-ships:

Steroidal nucleus essential for activity. The C-3 and C-17 oxygenation is not essential but they increase the activity. Oxidation of C-17 to carbonyl eliminates activity. C-17 esters prolonged the activity. Trans A/B ring junction is essential for activity. 17 -substitutions render compounds orally active. Removal of CH3 at C-19 removes the androgenic activity.
OH

17
1 19 2
O 3

Androgenic Drugs (Testosterone Analogs)

OH

17 -methyltestosterone:

CH3

Semisynthetic Orally active. Prolonged action. Androgenic and anabolic effects.

17-Methyltestosterone (Semisythetic)
OH C2H5

Synthetic Anabolic Steroids:

Norethandrolone
(Sythetic-Pure anabolic)

Norethandrolone and Oxandrolone

Orally active. Anabolic effects. In norethandrolone C-10 CH3 group removed to eliminate androgenic effect.
Oxandrolone

Androgen Antagonists

They act either by competition with androgens at the androgenic receptors or by inhibition of androgens biosynthesis.

1. Androgen Receptor Antagonists:

Cyproterone acetate:

Has antiandrogenic and progestrogenic activity. Used for treatment of acne, hirsutism, prostate hypertrophy, prostate cancer and precocious puberty. Non steroidal antiandrogen. Used for treatment of hirsutism and prostate cancer

Flutamide:

2. Androgen Biosynthesis inhibitor 5-Reductase inhibitors:

They prevent conversion of testosterone into dihydrotestosterone.

Used for treatment of Benign Prostatic Hyperplasia (BPH), androgenic alopecia, prostrate cancer. Eg. Finasteride , Dutasteride

Male Contraceptives

Gossypol:
It is a phenolic compound present in cotton seed oil. It decreases number of sperms and impairs their motility. Its effect is reversible.

Side

Effects:
weakness, diarrhea and edema.

Hypokalemia,

It has been abandoned now for the contraceptive use because it was found to cause permanent infertility in 10-20% of users.

Thanks