Nomenclature of Steroids

Number of Nuclear Positions and Steroid Classification

CH3

CH3

C-27 skeleton… Cholestanes

CH3

CH3

C-24 skeleton… Cholanes

CH3

CH3

C-21 skeleton… Pregnanes

CH3

CH3

C-19 skeleton… Androstanes

CH3

C-18 skeleton… Estranes

Nomenclature of Steroids

Usage of ‘Nor’ terminology

CH3

CH3

C-27 skeleton… Cholestanes

CH3

CH3

C-19 skeleton… Androstanes

CH3

18-Nor C-27 skeleton… 18-nor cholestane

CH3

19-Nor C-19 skeleton… 19-nor androstane

Female Sex Hormones(Estrogens and Progestins)

Control: Follicle –Stimulating Hormone (FSH) stimulate the production of Estrogens.

Luteinizing Hormone (LH) stimulate the production of Progestins.

Estrogens• Natural Estrogens:

HO

OH

OH

HO

O

HO

OH

17-estradiol Estrone Estriol

CH3OH

OH

12

3

4 5 67

8

910

1112

13

1415

1617

18

Excreted by human ovaryExcreted by human ovary.It has 1/3 the effect of estradiol.It is the metabolite by oxidationof estradiol.

Physiological EffectsUses• 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.

– 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.– 17a- and 16 position when modified enhance the activity.

SARCH3OH

OH

12

3

4 5 67

8

910

1112

13

1415

1617

18

Steroidal Estrogenic Drugs• Estradiol:

– Most active natural estrogen.– Very short duration of action due to first pass metabolism.– Mainly used for local effect on the uterus.

• Ethinyl estradiol (17-α-ethynylestradiol).– 15- 20 more potent than estradiol orally.

HO

OHC CH

HO

OH

17-estradiol Ethinyl estradiol(Stertoidal Semisynthetic estrogen)Estra-1,3,5(10)triene-3,17-diol

Nonsteroidal Estrogens• 1. Diethylstilbesterol:

– The trans form is the active one.– Advantages:

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

– Disadvantages:• Increase the risk of uterine cancer.

– Uses:• Treatment of prostate cancer.

OH

HO

OH

OH

CH3OH

OH

4.5A

4.5A

Trans -diethylstilbene-4,4'-diol.

Cl

OMe

OMe

MeO

2.Chlortrianisene:Tris(p-anisyl)chloroethene.Active orally

Nonsteroidal Estrogens

Xenoestrogens (Enviromental Estrogens)

• Estrogenic compounds with weak activity present in food and drinks.

• Isoflavones and coumestrol (Coumestan derivatives) present in family Leguminosae are examples of xenoestrogens.

O

OH

OH

HO

O

Genisten

O

OHO

O

Coumesterol

Estrogen Antagonists• Triphenylethylene antagonists:

– They are related to stilbene in structure.– Antagonist bind strongly to the receptors.

• Aromatase inhibitors:– Steroidal or nonsteroidal.– Block conversion of androgens to estrogens.

• Uses: Treatment of estrogen dependent cancers.

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1.Clomiphene (clomid)R = ClIt acts as ovulation stimulant by increasing gonadotrophin hormone (GRH).50 mg dose for 5 days starting from 5th day of menstruationIf ovulation dose not occur, the dose is increased to 100 mg.

2. Tamoxifen (Nolvadex):R = CH3CH2-.Used in treament of early & advanced breast cancer in postmenopausal women.

R

O CH2

CH2

N

CH2CH3

CH2CH3

AntiestrogensTriphenylethylene antagonists

Progestins• Progesterone is the major natural progestin.• Secretion: By the ovary mainly the corpus luteum during the

second half of the menstrual cycle.

• Physiological Effects:– Development of the endometrium.– Development of the mammary gland during pregnancy.– Milk secretion starts when its level decrease with birth.– Thermogenic action.

O

O

Preg-4-ene-3,20-dione.

– 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.

SARO

O

Progestrogenic Drugs• 1. Lynestrenol:

– Semisynthetic progestin with pure progestrogenic activity.

O

O

Progesterone(Natural)

OH

Lynestrenol(Synthetic)

C CH

Uses:• Contraceptive pills.• Uterine bleeding.• Prevention of abortion.• 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, breast discomfort.

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2. Medroxyprogestrone (provera)17-α-acetoxy-6-α-methylpreg-4-ene-3,20-dione.

Uses: Oral contercetptive.

CH3

CH3

CH3

O

O

OCOCH3

CH3

Progestrogenic Drugs

Progestin Antagonists

• 1. Mifepristone:– Compete with the progestin receptors.– Uses:

• Contraceptive.• Abortifacient.

CH3OH

O

N

CH3

CH3CH3

11-β-(p-dimethylaminophenyl)-

17-β-hydroxy-17-α-(1-propynyl)-

estra-4,9-diene-3-one.

Male Sex Hormones(Androgens)

Control:

Luteinizing Hormone (LH) or Interstatial Cell-Stimulating Hormones (ICSH) stimulate the production of Androgens.

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Androgenic Steroids – Physiological Activities

Androgenic Activity• Growth and development of male sex organs• Important for male sex drive and performance• Development of secondary sexual characteristics• Important role in spermatogenesis

Primarily two activities – Androgenic and Anabolic

Anabolic Activity• Development of muscle mass• Reverse catabolic or tissue-depleting processes

Side Effects:Sodium and water retention leads to edema.Masculinization of women.Hepatic dysfunction.

• Natural Androgens:

O

OH

Testosterone(Natural)

O

OH

Dihydrotestosterone(Natural)

H

22

Structure Activity Relationships in Androgens

Generalizations

• Steroid skeleton is necessary• An electronegative (may not be oxygen) at 3 position is

required• A/B ring fusion should be either trans or presence of a

double bond at 4 position

• Alkyl group (CH3) at 17a-position is necessary for anabolic

activity• Alkyl group at 17a- confers oral activity

CH3

OH

O

CH3

23

1.Testosterone: 17-β-hydroxy-androst-4-ene-3-one

In male:FSH stimulates sperm productionLH stimulates secretion of testosterone.

Medical Uses:1. Treatment of hypogonadism {decreased functional

activity of the gonads, thus resulting in lower amounts of testosterone}.

2. Androgens possess anabolic activity.3. Treament of breast cancer in menopausal women.4. Dysmenorrhea but of no advantage over Progestins

& estrogens.

Androgens & anabolic agents

CH3

CH3

OH

O

Adverse effects of testosterone

• Virilization (female)• Feminizing side effects (male)• Precocious puberty (i.e early

puberty) & stunted growth (reduced growth rate).

• Cholestatic jaundice • Enlargement of prostate • Atherosclerosis• Hepatic carcinoma • Oedema

Androgenic Drugs• 2. 17 a-methyltestosterone: (17-β-hydroxy-17-α-methyl-androst-4-ene-3-one)

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

O

OH

17-Methyltestosterone(Semisythetic)

CH3

CH3

CH3

OH

O

CH3

F

OH

* 3. Fluoxymestrone: 10 times more potent than testosterone.

Anabolic Steroids

• Class of steroid hormones related to the male hormone – testosterone

• Increase protein synthesis within cells which results in growth of muscle

• Also have androgenic properties which include the development and maintenance of males characteristics

• Have both medical and sport performance uses

Anabolic SteroidsAnabolic Effects

• Two different, but overlapping effects

• Anabolic – promote cell growth. Increased protein synthesis, appetite, bone remodeling and growth, and production of red blood cells

• Increase the size of muscle fibers (hypertrophy) leading to increase in muscle mass and strength

• Decrease the amount of fat in muscle

Anabolic SteroidsAndrogenic Effects

• Androgenic (virilizing) - development and maintenance of male characteristics:

• Increased growth of pubic, beard, chest and limb hair

• Enlargement of vocal cords • Suppression of natural sex hormones

Anabolic SteroidsAdverse Effects

• Most side effects are dose dependent

• Elevated blood pressure (most common)

• Increase LDL cholesterol and decrease HDL

• Increase risk of CV disease and coronary artery disease, arrhythmias, and heart attacks (chronic use)

Anabolic SteroidsAdverse Effects

• Accelerate the rate of premature baldness (male and female)

• Acne – stimulates the sebaceous glands

• Liver damage (cancer) – increased demand on liver as oral steroids are changed (increase bioavailability and stability)

Anabolic SteroidsAdverse Effects

• Tendon rupture has been linked to AS• Stiffer and less elastic tendon• Probably tendon does not adapt as fast.• Gynecomastia – development of breast tissue in males• Conversion of testosterone to estrogen by an aromatase

enzyme• Temporary infertility (decreased production of sperm)• Testicular atrophy (caused by decrease levels in natural

testosterone)

Anabolic SteroidsBehavioral Effects

• Controversial• Mood swings• Aggression (roid rage)• Mania• Depression• Withdrawal• Dependence

Anabolic SteroidsMedical Uses

• Bone marrow stimulation – aplastic anemia• Growth stimulation – use GH now• Appetite stimulate – AIDS, cancer• Induction of male puberty – extreme delay• Reversible male contraceptive - future• Hormone replacement therapy (men)• Gender dysmorphia - psyciatric

Oral Anabolic Steroids

• 17-alpha methyl testosterone (Android)

• 17-alpha ethyl testosterone (Maxibolin)

• 1-methyl testosterone (Primobolan)• Androstenediol (“Andro” food

supplements)• Androstenedione• Dihydroepiandrosterone (DHEA)

Injectable Anabolic Steroids• 19-nortesterone ester derivitives (Durabolin)• Testosterone ester derivatives (Oreton)• Testosterone cypionate derivatives (Virilon)• Boldenone• Stanozolol (Winstrol) oral form as well

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O

OH

Norethandrolone(Sythetic-Pure anabolic)

C2H5

Synthetic Anabolic Steroids:1. Norethandrolone

Orally active.Anabolic effects.C-10 CH3 group removed eliminate androgenic effect.

CH3

OH

O

CH3

Stanozolol

2. Stanozolol Orally active.Anabolic effects.

CH3

OH

N

CH3CH3

NH

H

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3. Oxymetholone:17-β-hydroxy-17-α-methyl-2-

(hydroxy-methylene)androstan-3-one.

Anabolic agents

4. Oxandrolone:17-β-hydroxy-17-α-

methyloxandrostan-3-one

5. Nandrolone: (nortestosterone)

Used as ester (decanoate or phenylpropionate)

CH3OH

O

O

CH3

CH3

OH

O

CH3

CH3

CH3

OH

O

CH3

CH

OH

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Structure Activity Relationships in Androgens

CH3

OH

O

CH3

Anabolic Androgenic

Testosterone 1 1(injectable)

CH3

OR

O

CH3

Testosterone 1 1esters (injectable)

R = COCH2CH3 propionate

= CO(CH2)5CH3 enanthate

= COCH2CH2(C5H9) cypionate

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Structure Activity Relationships in Androgens

CH3

OH

O

CH3CH3

Anabolic Androgenic

17a-methylTestosterone 1 1(oral)

CH3

OH

O

CH3OH

FFluoxymesterone 1 1(oral)

CH3

OH

O

CH3

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Structure Activity Relationships in Androgens

Anabolic Androgenic

Nandrolone 2.5 1(injectable)

H

OH

O

CH3

CH3

OH

O

CH3CH3

OH

H

Oxymetholone 2.5 1(oral)

CH3

OH

O

CH3

41

Structure Activity Relationships in Androgens

Anabolic Androgenic

Stanozolol 3 1(oral)

Dromostanolone 4 1(oral)

CH3

OH

N

CH3CH3

NH

H

CH3

OH

O

CH3

H

CH3

CH3

CH3

OH

O

CH3

Androgen Antagonists• Androgen Receptor Antagonists:

1. Danazol * Weak androgenic, anabolic, progestational & glucocorticoid action

2. Cyproterone acetate:• Has antiandrogenic and progestrogenic activity.• Used for treatment of acne, hirsutism, prostate hypertrophy, prostate

cancer and precocious puberty.

3. Flutamide:• Non steroidal antiandrogen.• Used for treatment of hirsutism and prostate cancer

4. 5a-Reductase inhibitors:– They prevent conversion of testosterone into dihydrotestosterone.– Used for treatment of Benign Prostatic Hyperplasia (BPH).

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Androgens Antagonists

NH

CF3

O

CH3

NO2

CH3

O

CH3

CH3OH

CH

N

CH3

CH3

NH

O

O

NH

CH3CH3

CH3

HDanazol

(endometriosis)Finesteride (5 reductase inhibitors)

(baldness)

Cyproterone acetate(prostate cancer)

Flutamide(prostate cancer)

Male Contraceptives

• Gossypol: – Is a phenolic compound present in cotton seed oil. – Decrease number of sperms and impairs their motility.– Its effect is reversible.– Side Effects:

• Hypokalemia, weakness, diarrhea and edema.

1,25-Dihydroxy Vitamin D3

1,25-dihydroxy Vitamin D3 is also derived from cholesterol and is lipid soluble

Not really a “vitamin” as it can be synthesized de novo

Acts as a true hormone

HO Vitamin

D3

Diet

HO

OH

25(OH) D3

Liver

25-OHase

OHHO

OH

1,25(OH)2 D3

(active hormone form)

Kidney1-OHase

HO

7

Provitamin D3

(7-dehydrocholesterol: Intermediate in cholesterol synthesis)

UV fromsunlight

Skin

Photobiosynthesis of vitamin D3 and its metabolism

Specific receptors in intestine, bone, kidney

Ca:Intestinal absorptionRenal reabsorption

PO4:Intestinal absorption Renal reabsorption

OHase = hydroxylase

The hormonal interactions controllingbone mineral homeostasis

Actions of Vitamin D on Gut, Bone, and Kidney  Vitamin D Intestine Increased calcium and phosphate absorption by 1,25

(OH)2D 

Kidney Calcium and phosphate excretion may be decreased by 25(OH)D and 1,25(OH)2D1

 

Bone Increased calcium and phosphate resorption by 1,25(OH)2D; bone formation may be increased by 1,25(OH)2D and 24,25(OH)2D 

Net effect on serum levels

Serum calcium and phosphate both increased