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Steroid-based Drugs

• AdrenocorticalHormones

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Adrenocortical Hormones

Adrenal gland:• Medulla:

– produces Epinephrine(stimulated by sympathetic impulse)

• Cortex:– Zona glomerulosa – produces Aldosterone

(stimulated by Angiotensin II and ACTH)– Zona fasciculata – produces Glucocorticoids

(stimulated by ACTH = Corticotropin)– Zona reticularis – produces Androgens

(physiological role unclear)

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Adrenocortical Hormones

Steroid hormone synthesis:• Pregnenolone synthesis is rate-limiting step• C21 hydroxylase:

– Prevents hydroxylation of C17 (-> c)=> Only mineralocorticoids

• C17 hydroxylase:– Hydroxylation of C17 (-> f, g) can be followed

by hydroxylation of C11 and C21 (-> h, j, k)=> Sex hormones and glucocorticoids

• P450C17α hydroxylase:– Produces 17-Keto-steroids (-> l)

=> Sex hormones

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Adrenocortical HormonesSteroid hormone classification:• Progesterone:

– C21– C 3: =O– C17: -OH or =O

• Mineralocorticoids:– C21– C21: -OH– C3: =O

• Glucocorticoids :– C21– C21, C17: -OH– C 3: =O– C11: -OH or =O

• Estrogens :– C18– C17: -OH or =O– C 3: -OH

• Androgens :– C19– C17: -OH– C 3: =O

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Adrenocortical Hormones

Glucocorticoids (GC):• Inhibit all phases of inflammatory reaction• Promote fetal development (lungs)• Inhibit NFκB nuclear translocation => transcription of proinflammatory

mediators is prevented• Upregulate lipocortin => inhibits PLA2 => no PG and LT synthesis

• Undesirable effects of increased GC:– Immune suppression– Increased glucose release (=> “steroid diabetes”)– Glucose coverted to fat => adiposity– Increased protein catabolism => muscle atrophy– Salt and water retention (increased GC lead to reduction in ACTH => decreases

levels of aldosterone) => hypertension– Osteoporosis

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Adrenocortical Hormones

Glucocorticoids (GC):• Adrenal cortex failure (= Addison’s disease)

Lack of GC production:– Chronic fatigue and muscle weakness.– Loss of appetite, inability to digest food, and weight loss.– Low blood pressure (hypotension)– Blotchy, dark tanning and freckling of the skin

(feedback missing => increased corticotropin)– Blood sugar abnormalities– Inability to cope with stress

• Adrenal cortex tumors (= Cushing Syndrome)GC overproduction– Upper body obesity– “Buffalo hump”– Red, round face– Hypertension– Water retention– Thin skin and bruising– Poor wound healing

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Adrenocortical Hormones

Glucocorticoids (GC):Clinical uses:• Allergic Rhinitis• Rheumatoid Arthritis• Asthma• Multiple Sclerosis• Carpal Tunnel Syndrome• Dermatitis• COPD• Osteoarthritis• Gout• Psoriasis• Inflammatory Bowel Disease • Sinusitis• Lupus Erythematosus

• Many conditions flare up if GC therapy is discontinued dueto adreno-corticol atrophy

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Adrenocortical Hormones

Glucocorticoids (GC):• Hydrocortison (= Cortisol)

– Main glucocortocoid in humans– Also binds mineralocorticoid receptor

(Cortison does NOT)– Used for replacement therapy (Addison’s Disease)– Otherwise mostly topical application due to

sodium-retaining effects

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Adrenocortical Hormones

Glucocorticoids (GC):• Prednisone

– Inactive until converted to

• Prednisolone– Drug of choice for systemic application– Lower sodium-retaining effects

CH3

CH3

O

OOH

OHOH

Prednisolone

CH3

CH3

O

OOH

OHO

Prednisone

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Adrenocortical Hormones

Glucocorticoids (GC):• Triamcinoline

– Stronger anti-inflammatory (5x) than cortisol– No sodium-retaining effect

Halogenated GC• Betamethasone• Dexamethasone

– 30x more potent than cortisol– No water and sodium retaining effects

CH3

CH3

O

OOH

OOH

O

CH3

CH3

O

OOH

OHOH

F

CH3

CH3

CH3

O

OOH

OHOH

F

CH3

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Adrenocortical Hormones

Glucocorticoids (GC):• Administration

– Oral– Nasal– Cutaneous– IV– Inhalation

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Steroid-based Drugs

• Sex Steroids

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Sex Steroids

• Female reproductive cycle– Gonadotropin Releasing Hormone

(GnRH) = Gonadoliberinstimulates release of

– Follicle stimulating hormone(FSH) = Follitropin

and– Luteinising Hormone

(LH) = Lutropinwhich trigger production of

– Estrogens (E) and Gestagens (G)which in turn negatively regulate

– Pituitary (E+G) and Hypothalamus (G)hormone production

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Sex Steroids

• Female reproductive cycle– Cycle length varies from 21-35 days

• Menstruation 3-6 days– First (= Proliferative) phase:

• Variable (7-21 days)• FSH and LH promote follicle development• One follicle becomes the Graafian follicle

(the rest degenerate)• Graaffian Follicle:

– Consists of thecal and granulosa cellswhich surround the ovum

• FSH-stimulated granulosa cells produceestrogens from androgen precursorsgenerated by LH-stimulated thecal cells

• Estrogens are responsible for theproliferative phase: increase in thicknessand vascularity of endometrium; secretionof protein+ carbo-rich mucus

• Constant low estrogen inhibits LH/FSH production BUT high estrogen causesurge of LH production => swellign and rupture of Graafian follicle = Ovulation

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Sex Steroids

• Female reproductive cycle– Second (= Secretory) phase:

• Secretory phase constant (~ 14 days)• LH-stimulated ruptured follicle develops

into Corpus luteum which secretsProgesterone

• Progesterone (Pg) is responsible for thesecretory phase: endometrium becomessuitable for implantation; mucus thickens

• Thermogenic effects of Pg =>body temperature increase 0.5º C

• Without implantation: Pg secretion stops=> menstuation is triggered

• With implantation: continued Pg productionwhich (via inhibition of LH and FSH prod.)blocks further ovulation

• Chorion (“precursor” of placenta) secreteshuman chorionic gonadotropin (HCG) whichmaintains endometrium lining throughoutpregnancy (HCG -> see pregnancy test)

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Sex Steroids

• Female reproductive cycle

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Sex Steroids

EstrogensAll produced from androgen precursors

Three main endogenous estrogens:

• Estradiol– Primary estrogen in humans– Breast development– Improving bone density– Growth of the uterus– Accelerating bone maturation and epiphyses closure– Development of the endometrium to support pregnancy– Promoting vaginal mucosal thickness and secretions– Increase HDL

• Estrone

• Estriol– only during pregnancy (made by fetus)

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Sex Steroids

Estrogens– Estrogens induce expression of progesterone receptors– Progesterone inhibits expression of estrogen receptors– Two types of estrogen receptors => potential for selective drugs

• Estradiol– Not suitable for oral administration (rapid hepatic elimination)

=> stable derivatives:• Ethinylestradiol

• Diethyl-Stilbestrol– Stilbene derivative

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Sex Steroids

Estrogens• Mestranol

– Used in oral contraceptives– Inactive => Cleavage of C3-methoxy group

yields ethinylestradiol

• Raloxifene– Selective estrogen receptor modifier (=SERM)– Antiestrogenic effects on breast and endometrium– Estrogenic effects on bone and lipid metabolism

=> use in postmenopausal osteoporosis

Clinical uses of estrogens:– Replacement therapy (Turner syndrome; menopause)– Contraception– Cancer therapy

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Sex Steroids

Anti-Estrogens• Tamoxifen

– Antiestrogenic effects on mammary tissue– Weak estrogenic effects on bone and lipid metabolism

• Clomiphene– Inhibits estrogen binding in the pituitary

=> prevention of negative feedback=> ovulation

Clinical uses of anti-estrogens:– Breast cancer therapy (Tamoxifen)– Infertility (Clomiphen)

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Sex Steroids

Progesterons• Progesterone

– Inhibits rhythmic contractions of the myometrium– Not suitable for oral administration

(rapid hepatic elimination) => stable derivatives:

• Hydroxyprogesterone• Medroxyprogesterone

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Sex Steroids

ProgesteronsTestosterone derivatives with progesterone activity:

• Norethindrone• Norgestrel

• Desogestrel

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Sex Steroids

Anti-Progesterons• Mifepristone (RU486)

– developed during the early 1980s by the French company Roussel Uclaf– while investigating glucocorticoid receptor antagonists, they discovered compounds

that blocked the similarly shaped progesterone receptor. Further refinement led to theproduction of RU 486

– Clinical testing of mifepristone as a means of inducing medical abortion began inFrance in 1982. Results from these trials showed that when used as a single agent,mifepristone induced a complete abortion in up to 80% of women up to 49 days’gestation.

– Addition of small doses of a prostaglandin analogue (=> see misoprostol) a few dayslater to stimulate uterine contractions, a complete medical abortion is achieved innearly 100 percent of women

– approved in the US in 2000 for the termination ofearly pregnancy (defined as 49 days or less)

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Sex Steroids

• Male reproductive system– Gonadotropin Releasing Hormone

(GnRH) = Gonadoliberinstimulates release of

– Follicle stimulating hormone (FSH)(Stimulates Sertoli cells =>promotes gametogenesis) and

– Luteinising Hormone (LH) =Interstitial Cell Stimulating Hormone (ICSH)which triggers production of

– Testosterone (T) (by Leydig cells)which in turn negatively regulates

– Pituitary and Hypothalamus hormone production

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Sex Steroids

Androgens• Testosterone

– Primary androgen in humans– Possesses androgenic and anabolic effects:

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

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

• Dihydro-Testosterone– Active metabolite– Mediates most of testosterone actions

CH3

OH

O

CH3

CH3

OH

O

CH3

H

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Sex Steroids

Androgens• Testosterone

– Hepatic elimination after oral administration– Also short half-life after injection => ester derivatives:

Proprionate, enanthate, cypionate…

• Fluoxymesterone– Hepatic elimination after oral administration

CH3

OH

O

CH3OH

F

CH3

CH3

OH

O

CH3 R

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Sex Steroids

Anabolic AndrogensTestosterone derivatives: anabolic effects dominant• Nandrolone

– Injection

• Stanozolol– oral administration

CH3

OH

O

CH3

H

OH

O

CH3

CH3

OH

N

CH3CH3

NH

H

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Sex Steroids

Anabolic Androgens• Dehydroepiandrosterone (DHEA)

– Popular item in health food stores: DHEA was prescription only untilrecently when changes in federal law labeled it as a nutritionalsupplement (DHEA sales now equal that of melatonin)

– Is actually a testosterone precursor– Supposedly by maintaining youthful DHEA levels one can improve mood,

memory, energy and libido, while preserving lean body mass and counteractingthe effects of stress hormones.

– DHEA may have serious side effects:• If it abnormally increases testosterone, then testosterone side effects may be

expected, including acne, testicular atrophy and increased risk of prostate cancer.• Women taking excessive doses of DHEA have reported acne and facial hair.

– DHEA can also be converted into estrogen, so high levels of DHEA can lead toestrogen side effects as well, including gynaecomasty and increased risk ofbreast cancer.

– DHEA is often marketed as an anabolic steroid: This is misleading since as anandrogen precursor its metabolism will produce testosterone which has anabolicproperties

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Sex Steroids

Anti-Androgens• Flutamide

– Non-steroidal receptor antagonist– Used in prostate cancer treatment

• Finasteride– Inhibits 5α-reductase => prevent conversion of

testosterone into the more potent dihydrotestosterone (DHT)– Used to treat prostate gland enlargement and hair loss

(bald man have higher average levels of DHT)

NH

CF3

O

CH3

NO2

CH3

CH3

CH3

NH

O

O

NH

CH3CH3CH3

H

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Sex Steroids

GnRH analogs/modifiers• Danazol

– Inhibits GnRH release => no FSH/LH production=> no steroid production

– Used to treat endometriosis(growth of endometrial tissue outside of the uterus)

• Synthetic GnRH (Gonadorelin, Buserelin, Leuprorelin…)– Up to 200x more potent than GnRH– If given in pulses (s.c.) stimulate gonadotropin release => induce ovulation– If given continously they desensitize the GnRH receptors => gonadal

suppression (“medical castration”)– Used in sex hormone-dependent conditions (prostate, breast cancer;

endometriosis; uterine fibroids…)– Side effects: menopausal symptoms

O

CH3

CH3OH

CH

N

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Sex Steroids

Oral Contraceptives• History

– 1937: Investigators demonstrated that the femalehormone progesterone could halt ovulation in rabbits

– 1949: Scientists at the University of Pennsylvaniaachieved the production of synthetic progestins

– 1953: Margaret Sanger, Katherine McCormick and Gregory Pincus team up todevelop a reliable contraceptive

– 1950s: Large scale testing of “the pill” was successful– 1960: FDA approves first oral contraceptive

(Early pill formulations contained up to 150 micrograms (mcg) of estrogen!)– 1982/84: Introduction of the bi- and tri-stage formulation– 1988: FDA recognized several severe long-term side effects (high estrogen!)– Currently used by 16 mill. women in the US (40% of women between 18 and 24

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Oral ContraceptivesEither combination estrogen/progesterone of progesterone alone• Combination pills:

– Highly effective– Estrogen component is mostly ethinylestradiol, sometimes mestranol– Progesterone component varies– 21 day cycle with 7 day break (causes withdrawal bleeding)– Can be mono- or biphasic

Mechanism:– Estrogen inhibits FSH secretion (neg. feedback loop!)

=> suppression of follicle development– Progesterone inhibits LH secretion (neg. feedback loop!)

=> inhibition of ovulation; also increases mucus viscosity– Both steroids alter endometrium => prevent implantation

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Sex Steroids

Oral Contraceptives

EstrogenProgesterone

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Contraceptives• “Mini Pill”:

– Contains only a progesterone (Levonorgestrel, Ethynodiol…)– Used when estrogen in contraindicated (e.g. thrombosis)– Taken daily without interruption– Acts mainly by increasing viscosity of mucus

(Mucolytica in cough medicine can cause failure)– Less reliable than combination pill

• Postcoital contraceptives (“Morning after pill”)– High dose of progesterone (Levonorgestrel)– Must be taken within 72 hrs– Nausea and vomiting are common side effects

• Depot and patch formulations– Injection of oily depot formulations every 3 month– Transdermal delivery systems

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Oral ContraceptivesSide effects:

– Thrombosis– Hypertension– Intermittant bleeding– Weight gain– Depression– Nausea– Loss of libido

Drug interactions:– Steroids are metabolized by P450 enzymes– Minimal dose of steroid is used to prevent risk of thrombosis– Any increase in clearance by P450-inducing drugs can result in contraception failure

– Frequent cause of OC failure is diarrhea (diminished time for absorption)