-based Drugs

• Adrenocortical BIMM118 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 (stimulated by ACTH = Corticotropin) – Zona reticularis – produces Androgens (physiological role unclear) BIMM118 Adrenocortical Hormones

Steroid 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- (-> l) => Sex hormones BIMM118 Adrenocortical Hormones Steroid 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 BIMM118 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 ”) – 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 BIMM118 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 BIMM118 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 due to adreno-corticol atrophy BIMM118 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 BIMM118 Adrenocortical Hormones

Glucocorticoids (GC): • Prednisone – Inactive until converted to

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

Prednisolone O Prednisone O CH3 OH CH3 OH HO OH O OH

CH3 CH3

O O BIMM118 Adrenocortical Hormones

Glucocorticoids (GC): O CH OH HO 3 • Triamcinoline O CH3 O – Stronger anti-inflammatory (5x) than cortisol – No sodium-retaining effect O

Halogenated GC O CH3 OH • Betamethasone HO OH CH CH • 3 3 – 30x more potent than cortisol F – No water and sodium retaining effects O O

CH3 OH HO OH

CH3 CH3 F O BIMM118 Adrenocortical Hormones

Glucocorticoids (GC): • Administration – Oral – Nasal – Cutaneous – IV – Inhalation BIMM118 Steroid-based Drugs

• Sex Steroids BIMM118 Sex Steroids

• Female reproductive cycle – Gonadotropin Releasing Hormone (GnRH) = Gonadoliberin stimulates release of – Follicle stimulating hormone (FSH) = Follitropin and – Luteinising Hormone (LH) = Lutropin which trigger production of – Estrogens (E) and Gestagens (G) which in turn negatively regulate – Pituitary (E+G) and Hypothalamus (G) hormone production BIMM118 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 cells which surround the ovum • FSH-stimulated granulosa cells produce estrogens from androgen precursors generated by LH-stimulated thecal cells • Estrogens are responsible for the proliferative phase: increase in thickness and vascularity of endometrium; secretion of protein+ carbo-rich mucus • Constant low estrogen inhibits LH/FSH production BUT high estrogen cause surge of LH production => swellign and rupture of Graafian follicle = Ovulation BIMM118 Sex Steroids

• Female reproductive cycle – Second (= Secretory) phase: • Secretory phase constant (~ 14 days) • LH-stimulated ruptured follicle develops into Corpus luteum which secrets Progesterone • Progesterone (Pg) is responsible for the secretory phase: endometrium becomes suitable 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 production which (via inhibition of LH and FSH prod.) blocks further ovulation • Chorion (“precursor” of placenta) secretes human chorionic gonadotropin (HCG) which maintains endometrium lining throughout pregnancy (HCG -> see pregnancy test) BIMM118 Sex Steroids

• Female reproductive cycle BIMM118 Sex Steroids

Estrogens All 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) BIMM118 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 BIMM118 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 BIMM118 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) BIMM118 Sex Steroids

Progesterons • Progesterone – Inhibits rhythmic contractions of the myometrium – Not suitable for oral administration (rapid hepatic elimination) => stable derivatives:

• Hydroxyprogesterone • Medroxyprogesterone BIMM118 Sex Steroids

Progesterons Testosterone derivatives with progesterone activity:

• Norethindrone • Norgestrel

• Desogestrel BIMM118 Sex Steroids

Anti-Progesterons • Mifepristone (RU486) – developed during the early 1980s by the French company Roussel Uclaf – while investigating receptor antagonists, they discovered compounds that blocked the similarly shaped progesterone receptor. Further refinement led to the production of RU 486 – Clinical testing of mifepristone as a means of inducing medical abortion began in France 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 days later to stimulate uterine contractions, a complete medical abortion is achieved in nearly 100 percent of women – approved in the US in 2000 for the termination of early pregnancy (defined as 49 days or less) BIMM118 Sex Steroids

• Male reproductive system – Gonadotropin Releasing Hormone (GnRH) = Gonadoliberin stimulates 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 BIMM118 Sex Steroids

Androgens • Testosterone CH OH – Primary androgen in humans 3 – Possesses androgenic and anabolic effects: CH3 Androgenic effects: • Growth and development of male sex organs • Important for (male) sex drive and performance O • Development of secondary sexual characteristics • Important role in spermatogenesis

Anabolic effects: • Development of muscle mass • Reverse catabolic or tissue-depleting processes OH CH3 • Dihydro-Testosterone CH3 – Active metabolite – Mediates most of testosterone actions O H BIMM118 Sex Steroids

Androgens

• Testosterone CH OHR – Hepatic elimination after oral administration 3 – Also short half-life after injection => ester derivatives: CH3 Proprionate, enanthate, cypionate…

O

• Fluoxymesterone – Hepatic elimination after oral administration CH OH HO 3 CH3 CH3 F O BIMM118 Sex Steroids OH CH3 CH Anabolic Androgens 3 Testosterone derivatives: anabolic effects dominant O • Nandrolone OH – Injection CH3 H

O • Stanozolol – oral administration OH CH3 CH3 CH3 HN N H BIMM118 Sex Steroids

Anabolic Androgens • Dehydroepiandrosterone (DHEA) – Popular item in health food stores: DHEA was prescription only until recently when changes in federal law labeled it as a nutritional supplement (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 counteracting the 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 to estrogen side effects as well, including gynaecomasty and increased risk of breast cancer. – DHEA is often marketed as an : This is misleading since as an androgen precursor its metabolism will produce testosterone which has anabolic properties BIMM118 Sex Steroids

Anti-Androgens

• Flutamide O CH3 – Non-steroidal receptor antagonist HN CH – Used in prostate cancer treatment 3

CF3

NO2

• 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)

O CH3 CH3 CH3 N H CH3

CH3

O N H H BIMM118 Sex Steroids

GnRH analogs/modifiers

OH • Danazol CH3 – Inhibits GnRH release => no FSH/LH production CH CH => no steroid production 3 – Used to treat endometriosis N (growth of endometrial tissue outside of the uterus) O

• 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 BIMM118 Sex Steroids

Oral Contraceptives • History

– 1937: Investigators demonstrated that the female hormone progesterone could halt ovulation in rabbits – 1949: Scientists at the University of Pennsylvania achieved the production of synthetic progestins – 1953: Margaret Sanger, Katherine McCormick and Gregory Pincus team up to develop 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 BIMM118 Sex Steroids

Oral Contraceptives Either 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 BIMM118 Sex Steroids

Oral Contraceptives

Estrogen Progesterone BIMM118 Sex Steroids

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 BIMM118 Sex Steroids

Oral Contraceptives Side 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) BIMM118