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Steroid-based Drugs Adrenocortical Hormones.

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Presentation on theme: "Steroid-based Drugs Adrenocortical Hormones."— Presentation transcript:

1 Steroid-based Drugs Adrenocortical Hormones

2 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)

3 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 P450C17a hydroxylase: Produces 17-Keto-steroids (-> l) => Sex hormones

4 Adrenocortical Hormones
Steroid hormone classification: Progesterone: C21 C 3: =O C17: -OH or =O Mineralocorticoids: C21: -OH C3: =O Glucocorticoids : C21, C17: -OH C11: -OH or =O Estrogens : C18 C 3: -OH Androgens : C19 C17: -OH

5 Adrenocortical Hormones
Glucocorticoids (GC): Inhibit all phases of inflammatory reaction Promote fetal development (lungs) Inhibit NFkB 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

6 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

7 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

8 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

9 Adrenocortical Hormones
Glucocorticoids (GC): Prednisone Inactive until converted to Prednisolone Drug of choice for systemic application Lower sodium-retaining effects Prednisolone Prednisone

10 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

11 Adrenocortical Hormones
Glucocorticoids (GC): Administration Oral Nasal Cutaneous IV Inhalation

12 Steroid-based Drugs Sex Steroids

13 Female reproductive cycle
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

14 Female reproductive cycle
Sex Steroids Female reproductive cycle Cycle length varies from 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 => swelling and rupture of Graafian follicle = Ovulation

15 Female reproductive cycle
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 => menstruation 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)

16 Sex Steroids Female reproductive cycle

17 Sex Steroids Estrogens Three main endogenous estrogens: Estradiol
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)

18 Sex Steroids Estrogens Estradiol Ethinylestradiol Diethyl-Stilbestrol
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

19 Sex Steroids Estrogens Mestranol Raloxifene
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

20 Sex Steroids Anti-Estrogens Tamoxifen Clomiphene
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)

21 Sex Steroids Progesterons Progesterone Hydroxyprogesterone
Inhibits rhythmic contractions of the myometrium Not suitable for oral administration (rapid hepatic elimination) => stable derivatives: Hydroxyprogesterone Medroxyprogesterone

22 Sex Steroids Progesterons
Testosterone derivatives with progesterone activity: Norethindrone Norgestrel Desogestrel

23 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 the production of RU 486 Clinical testing of mifepristone as a means of inducing medical abortion began in France in 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)

24 Male reproductive system
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

25 Sex Steroids Androgens Testosterone Dihydro-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

26 Sex Steroids Androgens Testosterone Fluoxymesterone R
Hepatic elimination after oral administration Also short half-life after injection => ester derivatives: Proprionate, enanthate, cypionate… Fluoxymesterone R

27 Sex Steroids Anabolic Androgens
Testosterone derivatives: anabolic effects dominant Nandrolone Injection Stanozolol oral administration

28 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 anabolic steroid: This is misleading since as an androgen precursor its metabolism will produce testosterone which has anabolic properties

29 Sex Steroids Anti-Androgens Flutamide Finasteride
Non-steroidal receptor antagonist Used in prostate cancer treatment Finasteride Inhibits 5a-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)

30 GnRH analogs/modifiers
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

31 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

32 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

33 Sex Steroids Oral Contraceptives Estrogen Progesterone

34 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

35 Sex Steroids Oral Contraceptives Side effects: Drug interactions:
Thrombosis Hypertension Intermittent 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)

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