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Thyroid hormones Adrenal steroids Sex hormones

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Thyroid hormones Adrenal steroids Sex hormones Powered By Docstoc
					Lecture outline (April 2, 2008)
10:10-11:00 am 1. Thyroid hormones 2. Adrenal steroids 11:15-11:50 am 3. Sex hormones
Yan Zeng, 2-110 NHH zengx033@umn.edu

1. Thyroid Hormones
As an overview…
     

Classes of thyroid hormones Production of thyroid hormones Function Thyroid disorders Therapeutic applications Implications in dental pharmacology

1

Regulation of thyroid hormone production

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Pharmacokinetics of thyroid hormones


Thyroid hormones are synthesized from iodinated tyrosines and released by the thyroid gland More T4 is released than T3 Production is stimulated by cold, down during stress More than 99.5% of hormones in plasma are bound to plasma proteins; only a tiny fraction is free and functional Thyroid hormones are eliminated primarily by the liver T3 and T4 metabolism takes place slowly. Thus T3 and T4 have prolonged half-lives  T3 t1/2 = 1.5 days; T4 t1/2 = 1 week

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Function of thyroid hormones


T3 and T4 bind to receptor-transcription factors inside the cells to regulate the transcription of target genes Thyroid hormones regulate metabolism in the whole body They are also essential for the development of various organs

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Two disorders associated with thyroid hormones


Hypothyroidism results mainly from iodine deficiency in the diet, or autoimmune destruction of thyroids Hyperthyroidism- -metabolism too fast  Graves’ Disease, accounts for 70-80% of cases  Plummer’s Disease (toxic nodular goiter)  Other causes



Many Signs & Symptoms of Hyper & HypoThyroidism

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Hypothyroidism
   

A common endocrine disorder Affects 1-2% women and 0.1-0.2% men 5-10% women over 50 5-6x more common than hyperthyroidism in the population

Hypothyroidism in Adults


Usually due to malfunction of thyroid itself
  

Principle cause is chronic autoimmune disease Other causes include insufficient iodine in the diet May also result from altered secretion of TSH



Therapeutic Strategy: replacement therapy with oral thyroid hormones (tablets)
 

Levothyroxine (L-thyroxine - synthetic T4) Levothyroxine (T4) plus liothyronine (T3)

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Hypothyroidism in Infants (cretinism)
  

 

Much more serious problem than adult-onset Usually results from a failure in thyroid development Other causes include autoimmune disease, iodine deficiency, TSH deficiency, and exposure to radioactive iodine Therapeutic strategy: replacement therapy with thyroid hormones, the earlier, the better Replacement therapy must continue for life

Thyroid Hormone Preparations for Hypothyroidism
Thyroid hormones are available as pure, synthetic compounds and as extracts of animal thyroid glands  They have very similar effects  The synthetic preparations are more stable and better standardized than the animal extracts, and are thus preferred


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Hyperthyroidism
 

Consequence of excessive thyroid hormone action Has a number of causes
      

Graves’ disease (toxic diffuse goiter) Plummer’s disease (toxic multinodular goiter) Toxic adenoma Iodine induced hyperthyroidism Painful subacute thyroiditis Excessive pituitary TSH or trophoblastic disease Excessive ingestion of thyroid hormone

Graves’ Disease
   

Is the most common case of excessive thyroid hormone secretion in the US Incidence in females is 6x greater than in males Occurs most frequently in women 20 to 40 years old Cause:  Autoimmune disease of unknown origin
Patient produces antibodies against TSH receptor, which activates the receptor, same effect as TSH. The antibodies mimic the stimulatory effect of TSH on the thyroid gland, thereby producing excessive thyroid hormones.

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Graves’ Disease: Treatment


Treatment of hyperthyroidism is directed at decreasing the production of thyroid hormones
Surgical removal of the thyroid tissues  Destruction of thyroid tissues with radioactive I131  Suppression of thyroid hormone synthesis with antithyroid drugs (propylthiouracil, methimazole)
 

 

I131 method is preferred for adults Anti-thyroid drugs are preferred for younger patients who still need hormones for development

Radioactive Iodine 131


I131 is concentrated in only thyroid cells and better, over-active thyroid cells. The destruction by electrons from I131 is specific and local. Half life is short. No effect on fertility, birth defects, or increased risk of cancer in patients or offsprings Most patients develop hypothyroidism eventually and require thyroid replacement therapy Not used during  Pregnancy: may ablate fetal thyroid  Breast-feeding: appears in breast milk

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Dental Implications


Dentists should be able to identify hypothyroidism and hyperthyroidism and refer unsuspected patients for appropriate evaluation Some symptoms of subclinical hypothyroidism are like those of depression, such as decreased mood, decreased interests, etc Hypothyroidism also directly affects dentistry: leads to delayed eruption of teeth, malocclusion, skeletal retardation, tongue enlargement, and exaggerated response to sedatives and opioids

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Dental Implications
Hyperthyroidism in children leads to more rapid development of teeth and jaw, early loss of deciduous teeth, and early eruption of permanent teeth

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2. Adrenal Steroids –Lecture Objectives

1. Define the mechanisms involved in the regulation of adrenal steroid synthesis and secretion 2. Define the mechanism of action of glucocorticoids and mineralocorticoids 3. Define the main uses of glucocorticoids and mineralocorticoids 4. Define the major side effects of glucocorticoids 5. Implications for Dental Pharmacology

Location of Adrenal Gland

• Adrenal glands are small, triangular glands located on top of the kidneys

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Adrenal glands produce three families of steroid hormones
Glucocorticoids Mineralocorticoids

Functionally different

Sex hormones (later)

Production of adrenal steroids
Stress Daily variations

+
Hypothalamus

+ +

-

CRH (peptide)

+
Anterior Pituitary

IL-1, IL2, IL-6 TNF-α

ACTH (peptide)

Immune System

Adrenal Cortex release Adrenal steroids
Peripheral Actions

Exogenous Glucocorticoids

CRH=corticotropin releasing hormone ACTH=adrenocorticotropic hormone

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Pharmacology of Adrenal Steroids
•Naturally occurring steroids are well absorbed from the gut •Glucocorticoids are well absorbed systemically from sites of local administration (e.g., skin and respiratory tract) •In the plasma, ~ 90% steroid is reversibly bound to protein. Only unbound steroid can enter cells to mediate steroid effects •Two plasma proteins account for almost all of the steroid binding capacity 1. Corticosteroid binding globlulin 2. Albumin • Steroids are metablized by cytochrome P450 enzymes in the liver

Mechanism of Action by Adrenal Steroids 1. Steroids are lipid soluble and can diffuse across cell membrane 2. Once inside a cell, steroid binds to receptors (cytoplasmic or nuclear) 3. Binding of steroid to receptor converts the receptor to an active form 4. The active receptor (steroidreceptor complex) binds to specific DNA sequences 5. Binding results in the regulation of gene expression, which can be positive or negative
S

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Principal effects of glucocorticoids
A. Metabolic Effects Mainly an increase in the availability of metabolic fuels (glucose, amino acids, fatty acids) during times of stress or fasted state, but takes hours to see the effects due to mechanism of action. • • • • Increased blood glucose levels Breakdown of protein Breakdown of lipid Effects are useful in maintaining normal glucose levels and opposing insulin action. But too much can cause hyperglycemia and diabetes

Glucocorticoid Effects
B. Anti-inflammatory and Immunosuppressive Effects
• Glucocorticoid reduces the expression of many proteins involved in the inflammation and immune responses • A common use of glucocorticoids as drugs • Very effective drugs at reducing inflammation • Can nonspecifically inhibit inflammation caused by numerous stimuli (mechanical, infection, chemical, or immunological) • But the anti-inflammatory response is primarily soothing -manifestations of the disease are suppressed, but the underlying cause of the disease remains

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Side effects of glucocorticoids
Glucocorticoids are used at high doses for treating inflammation. Too much or too long (~ week) glucocorticoid treatment can inhibit bone formation, suppress calcium absorption (both of which can lead to osteoporosis), delay wound healing, lead to muscle weakness, and increased risk of infection Solution is to use alternative drugs or to use glucocorticoids at a low dose for a short period of time locally whenever possible

Mineralocorticoid Effects
• Very different from glucocorticoid effects • Regulates body fluid content and plasma volume • Decreased plasma volume, low blood pressure and low Na+ content induces the production of aldosterone, a major mineralocorticoid. • Aldosterone acts mainly on the distal tubules of the kidney to: -promote Na+, water and Cl- retention -promote K+ and H+ excretion

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Therapeutic Uses of Adrenal Steroids
• Used for: - Hormone replacement therapy (adrenal insufficiency: acute crisis or the chronic Addison’s disease) - Allergic disorders (asthma, bee stings, hay fever, etc) - Arthritis, bursitis - Immunosuppression (e.g., graft rejection) - Lung maturation in preterm fetuses - Collagen vascular disorders (rheumatoid arthritis, lupus erythematosus) - Eye diseases (allergic conjuctivitis) - Gastrointestinal diseases (inflammatory bowel disease) - Bronchial asthma - Skin diseases - Cerebral edema - Hematological disorders ( multiple myeloma, leukemia) • Steroids are available in a variety of forms: oral, topical, injectable, inhalable • Because of potential side-effects, they should be applied as close to the disease tissue as possible

• Oral, injectable and topical preparations available, except for prednisone (oral only) • Glucocorticoid potency refers primarily to anti-inflammatory actions • Mineralocorticoid potency refers to propensity for Na+ retention, increases in plasma volume, hypertension, and edema (tissue swelling)

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Short Acting Glucocorticoids
•Cortisol (hydrocortisone) -is used mainly for replacement therapy and emergencies, e.g., to treat potentially fatal adrenal crisis -has 8 to 12 hour biological half-life -major glucocorticoid in the body; normal adult produces about 10 mg/day

•Cortisone -basically inactive until converted to cortisol -avoid use in patients with abnormal liver function -injection of cortisone and its derivatives relieves local inflammation.

Intermediate Acting Glucocorticoids
• Prednisone - most common, orally effective steroid used for many inflammatory disorders and to prevent organ rejection -4x as potent as cortisol as anti-inflammatory -avoid use if patient has abnormal liver function

Prednisolone

• Prednisolone - active metabolite of Prednisone

Biological half-lives of 18-36 hours

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Long Acting Glucocorticoids
• Dexamethasone -25-50x more potent than cortisol as anti-inflammatory -growth retardation potential is great, so long term use questionable. -drug abuse?

Biological half-lives of 36-54 hours

Adverse Effects
There are two categories of toxic effects result from the therapeutic use of corticosteroids: 1. Those resulting from withdrawal of steroid therapy 2. Those resulting from continued use of supraphysiological doses These side effects are potentially life threatening and mandate a careful assessment of the risks and benefits in each patient.

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1. Withdrawal of Steroid Therapy
• The prolonged use of glucocorticoids suppresses the HPA so that natural hormone production is inhibited •Adrenal insufficiency results if therapy is stopped abruptly • It will take 2 to 3 months for the pituitary to become responsive again and cortisol levels may not be normal for 6 to 9 months • To stop therapy, therefore, the dosage should be tapered slowly • 25 mg or less of prednisone per day taken at 8 am for up to 10 days will not usually suppress the HPA, therefore, is an option • Another option: alternate day steroid therapy is recommended for children

2. Continued Use of Pharmacological Corticosteroid Doses

• Cushing’s syndrome - condition resulting from corticosteroid excess • Hypertension • Peptic ulcer • Growth retardation • Muscle wasting • Osteoporosis • Diabetes (hyperglycemia) • Cataracts, glaucoma • Psychosis • Increased vulnerability to infection

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Implications for Dentistry
• Patients treated with large doses of glucocorticoid for a long period of time have decreased resistance to stress and infection and poor wound healing response Therefore, infection in the oral cavity such as carious teeth, inflamed tissue should be promptly and properly treated.

Implications for Dentistry
Patients on glucocorticoids show signs and symptoms of adrenal insufficiency -unable to increase cortisol production during stress Inject 100mg of cortisone 8 hours before dental surgery; taper off over a 2-3 day period after surgery

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3. Sex Hormones Female sex hormones-Lecture Objectives
• • • • • • • • Classes of female sex hormones Biosynthesis Regulation of secretion Pharmacokinetics Mechanism of action Functions Therapeutic application Side effects and contraindications

Two Classes of Female Gonadal Hormones
Estrogen Progestin (Progesterone)

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Biosynthesis of Estrogen and Progestin
• Both estrogens and progestins are produced in multiple tissues • Ovaries are the principal source of circulating estrogens in nonpregnant, pre-menopausal women • The fetal-placental unit produces large amounts of both steroids during pregnancy • Estrogens can be produced in other places such as fat cells and adrenal gland • The main progestin, progesterone, can be synthesized in the ovary, testis, adrenal gland and placenta

Regulation of Estrogen/Progesterone Secretion
Hypothalamus GnRH Anterior Pituitary

Estrogen
(midcycle surge)

+? +

-

GnRH=Gonadotropin releasing hormone FSH=follicle stimulating hormone LH=luteinizing hormone

Inhibin

FSH + LH

Ovaries Estrogen + Progesterone
Target Tissue Actions

-

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Physiological Actions of Endogenous Estrogens
• Essential for
-development of female primary and secondary sex characteristics

-growth and support of female reproductive structures

• Regulate the menstrual cycle • Metabolic effects include
-Decrease bone resorption
-Decrease cholesterol and LDL, increase HDL -Enhance blood coagulation

• Libido and Mood

Physiologic Actions of Endogenous Progesterone • Slows the mitotic growth of the estrogen-stimulated uterus • Breast development • Decreases triglycerides and HDL, increases LDL, increase lipoprotein lipase, increases fat deposition • Increases basal and stimulated insulin secretion • Maintenance of pregnancy: suppress menstruation and uterine contractility • Raise body temperature (0.25-0.5oC)

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Hormonal Relationships of the Menstrual Cycle

• Estrogen: decreases FSH and LH release during most of the cycle -triggers a surge of LH only at midcycle •Progesterone: decreases the frequency of GnRH release and also increases the amount of LH released in the luteal phase (increased amplitude)

Mechanisms of Action
• The hormones bind to their intracellular receptors, which are ligand-activated transcription factors • Estrogen -two receptors (α and β) - separate gene products and these show differential expression and have nonredundant functions -mechanistically similar to glucocorticoid receptors • Progesterone -two receptors (A and B) -mechanistically similar to other steroid hormones Regulation of transcription can be positive or negative

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Therapeutic Uses of Estrogens/Progestins 1. Peri- and post-menopausal hormone replacement therapy 2. Oral contraception 3. Treat hypogonadism in females 4. Infertility 5. Hormone-sensitive breast cancer-tamoxifen 6. Endometriosis 7. Androgen-dependent prostatic tumors 8. Dysmenorrhea or uterine bleeding

Metabolism of Estrogen Drugs
• Estrogens are available for oral, parenteral, transdermal, or topical administration - rapidly absorbed • Oral preparations: - synthetic estrogens -modified estrogens to slow first-pass metabolism - conjugated equine estrogens or esterified esters • In plasma, estrogens are extensively bound to – Sex steroid binding globulin (SSBG) – Albumin • Metabolized in the liver

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Metabolism of Progestin Drugs • Several synthetic progestin preparations are available and are rapidly absorbed when taken orally and have long half-lives (5-45 hours) • Progesterone itself is not used orally because of extensive first-pass metabolism - half-life = 5 min • Progestins are also extensively bound to proteins in plasma • Metabolized in the liver

Some Side Effects of Estrogens/Progestins
• Weight gain • Fluid retention • Depression • Withdrawal bleeding • Abdominal Cramps • Anxiety • Irritability • Increased triglycerides, decreased HDL • Decrease in insulin sensitivity and glucose tolerance • Acne

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Hormone Replacement Therapy (HRT)
• Postmenopausal therapy usually consists of a mixture of conjugated horse estrogens with a progestin (medroxyprogesterone acetate) • Most of the desirable effects are due to estrogens • Established benefits of HRT - relief of hot flashes, sweating - prevention of bone loss -estrogen decreases bone resorption, no effect on formation -treatment should begin as early as possible and continue - improved feeling of well being - reduction in atherosclerosis - improve sleep

Controversies surrounding HRT currently exist Cardiovascular disease • Numerous retrospective and prospective studies have shown that estrogen
treatment of healthy women reduced heart disease by 35-50% • Heart Estrogen/Progestin Replacement Study (HERS - 1998) -JAMA 280, 605-613 (1998) -randomized, double-blind, placebo controlled intervention trial -subjects had coronary disease -treatment with conjugated estrogen + medroxyprogesterone acetate (Prempro) -Results: -no decrease in heart attacks in 4 years with HRT (however, more in first year) -increased thrombotic tendencies (blood clot) with HRT -increased risk of gallbladder disease

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HRT: More Problems Women’s Health Initiative (NIH, 1990s-)
JAMA 288, 321-333 (2002)

• large, randomized, double-blind, placebo controlled trial
• subjects did not have heart disease, but relatively old (~63, followed for ~ 5 y) • women with uterus were treated with conjugated estrogen plus progestin • women without uterus were treated with estrogen alone •Results show: -estrogen plus progestin arm discontinued in 2002 due to increased risks of breast cancer, cardiac events and thromboembolic events -benefits for osteoporesis and colon cancer Suggestions: -prescribe for shortest duration and smallest doses possible • Estrogen only arm was stopped in March 2004 (strokes and blood clots) • Problems with the studies: Will younger women near menopause benefit more? Only certain drugs were examined: other preparations may have different properties

Oral Contraceptives
• Hormonal contraceptives are among the most effective drugs available • Many options exist: variety of components, doses and side effect profiles • It is not appropriate to extrapolate side effects between contraceptives and hormone replacement therapy • Oral contraceptives offer substantial health benefits besides contraception - lower estrogen/progestin ratio, which decreases diseases such as
- anemia - benign breast disease - uterine cancer

- Inhibition of ovulation, which decreases
-ovarian cancer -functional ovarian cysts - Other benefits include decreased -bone loss

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How do oral contraceptives work?
• Estrogens - suppress FSH secretion - inhibit follicle development - stabilize the endometrium to prevent irregular shedding and breakthrough bleeding - increase progesterone receptors - potentiates progestin action • Progestins - suppress LH secretion and prevent ovulation - produce endometrium that is not receptive to ovum implantation - exhausted and atrophied glands - thick, viscous cervical mucus inhibits sperm transport - prevents uterine overgrowth stimulated by estrogens

Two Types of Oral Contraceptives
• Combination oral contraceptives (99.9% theoretical effectiveness) - Pill contains both estrogens and progestins - Usually take the pill for 21 days, then inert pills for 7 days - monophasic treatment- single dose of estrogen and progestin for the whole 21 days - biphasic - 1 dose of estrogen with a lower dose of progestin for the first 10 days, then higher dose of progestin for the next 11 days - triphasic – have 3 dose levels of progestin and either 1 or 2 dosage levels of an estrogen

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Oral Contraceptives
• Progestin only (99% effectiveness) - single daily oral administration of a small dose of progestin, the so-called mini-pill - does not routinely inhibit ovulation - main effects are on the uterus and cervical mucus - associated with irregular menses - can be used by nursing mothers - safer for women older than 35, who smoke, have high blood pressure, are overweight or have a history of blood clots

Oral Contraceptives -- Side Effects
• The currently available low dose preparations pose minimal health risks to women without predisposing risk factors (smoking) and may provide health benefits • Combination birth control pills - cardiovascular effects - no increase in incidence of myocardial infarction or stroke - increased risk of venous thrombosis - cancer - 50% decrease in endometrial cancer (persists 15 years) - decrease in ovarian cancer - small increase in risk for breast cancer - hepatic adenoma and hepatocellular carcinomas (rare) - other - nausea, edema, mild headache, or migraines - menstrual irregularities - bleeding during 21 day cycle and no withdrawal bleeding during 7 day off cycle - weight gain, acne, hair growth • Progestin only preparations - menstrual irregularities - acne - headache

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Oral Contraceptives -- Contraindications
• Use of birth control pills should be careful in women with certain risk factors: - presence or history of thromboembolic disease, coronary artery disease, cerebral vascular disease, etc
-the risk of serious cardiovascular side effects is great in women over 35 who smoke heavily - even with low dose preps

-suspected or known breast cancer, cancer of the reproductive tract or other known hormone-dependent/responsive neoplasms - abnormal undiagnosed vaginal bleeding - past or present liver tumors or impaired liver function - considered on an individual basis: migraine headaches, hypertension, diabetes mellitus, gallbladder disease These women can use other types of contraception methods.

Androgens: Objectives
1. Define the sites and mechanism of action of androgens 2. Define the potential therapeutic uses and adverse effects of androgen drugs.

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Male Gonadal Hormones

Testosterone

Dihydrotestosterone, DHT

Regulation of Testosterone Secretion
Hypothalamus

-

GnRH Anterior Pituitary LH + FSH Leydig Cells (Testis)

Inhibin Androgen binding protein

Sertoli Cells
(Seminiferous tubules)

Testosterone
GnRH=Gonadotropin releasing hormone FSH=follicle stimulating hormone LH=luteinizing hormone

Target Tissue Actions

31

Metabolism of Androgens
•Testosterone is transported in circulation to target tissues ~ 44% bound to SSBG ~ 54% bound to albumin ~ 2% free • Oral testosterone is rapidly absorbed and metabolized by the liver -- synthetic androgens are used clinically • DHT is the major active metabolite of testosterone and is the dominant androgen in tissues

Mechanism of Action
• Intracellular receptors for testosterone are ligandactivated transcription factors -- androgen receptors • Similar mechanisms as for adrenal steroids, estrogen, progestins, etc. • DHT has a higher affinity than testosterone for the receptors

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Uses of Androgens
• Use of androgens for normal physiological effects
1. Male hypogonadism 2. Male senescence 3. AIDS-related muscle wasting 4. Angioneurotic edema

• •

Male contraceptive to reduce sperm formation ? Anti-aging and enhancement of athletic performance
1. Promote protein synthesis (muscle mass, etc. - anabolic effects) 2. Significant side effects (low HDL, high LDL, reduced spermatogenesis, and increase incidence of hepatic tumors)

•

Agents which antagonize the effects of androgens are used to treat
1. Benign prostatic hypertrophy 2. Prostate cancer 3. Acne, hirsutism, precocious puberty

Inhibitors of Testosterone Synthesis

•GnRH Analogs
-primarily used to treat prostate cancer -inhibit testosterone synthesis by inhibiting LH secretion -major side effects are decreased libido, impotence, disease flare up

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Regulation of Testosterone Secretion
Hypothalamus

-

GnRH Anterior Pituitary LH + FSH Leydig Cells (Testis)

Inhibin Androgen binding protein

Sertoli Cells
(Seminiferous tubules)

Testosterone
GnRH=Gonadotropin releasing hormone FSH=follicle stimulating hormone LH=luteinizing hormone

Target Tissue Actions

Implications for dentistry
Fluctuation of sex hormone levels affects periodontal tissues: indications that too much hormone may lead to gingival disease Bone loss from lower estrogens Estrogens potentiate corticorcosteroids; careful about mixing the drugs

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