kuliah sex hormone uwk

8/9/2019 Kuliah Sex Hormone UWK

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Gonadal Hormones

Estrogens and Progestins

Androgens

Steroid hormones

Bind to cytoplasmic receptors

Alter DNA transcription


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Mechanism of Action

gonadalgonadal

hormoneshormones

receptor

hormone

receptorcomplex

H/R

DNA

tramscription

Nucleus

Estrogens and Progestins

Estrogens: Potency (females): 17-estradiole> estrone > estriol

estriol: increases greatly during pregnancy(index fetal viability)

Progestins: most important: progesterone

Synthesis: major site in females: ovary and

fetoplacental unit (90%); peripheral (10%)major site in males and postmenopausalfemales: peripheral (100%)


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Estrogens & Progestins

Estrogens used forpost-menopausal

hormone replacement

therapy.

estradiol (Estrace)

conjugated estrogens(Premarin)

estropipate (Ogen)

Progestin

Diminish side effects ofestrogen therapy

Nausea, fluid retention,breast tenderness

medroxyprogesteroneacetate (Provera)

norethindrone acetate(Aygestin)


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Synthetic estrogens: substitutions onsteroid nucleus; affect pharmacologicalproperties; some lack steroid nucleus:ex., DES

Antiestrogens: antagonize actions ofestrogens; ex., clomiphene and tamoxifen

(nonsteroidal)

Clinical Uses

Limited by Side Effects

Oral Contraceptives

estrogen and progesterone (low doses)

progesterone only (mini-pill)

Norplant (levonorgestrel-progesterone)

Mechanism of action: (combination pill)

Inhibits ovulation

Prevents surge of FSH and LH (feedbackinhibition anterior pituitary)


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Oral Contraceptives

Combination of estrogen and progestin

Loestrin, Levora, Nordette, Ovocon,

Norinylplus many others

Minipill: progestin only

Micronor, Nor-Q.D., Orvette

Prime side effect: risk ofthromboembolism


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Clinical Uses

Menopause90% decrease in estrogen

99% decrease in progesterone

Vasomotor, urogenital atrophy, osteoporosis,psychological factors

Other:replacement therapy

infertilityinduces ovulation

cancer

Estrogen/Progestin Therapy

Side EffectsNausea, weight gain, edema, depression,headache; develop tolerance

Drug InteractionAntibiotics decrease efficacy

Contraindications (oral contraceptives)heart disease, vascular, liver failure (jaundice),breast cancer, smoking


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Normal bone Osteoporosis


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Infertility Agents

Promote maturation of ovarian follicles

clomiphene (Clomid)

urofollitropin (Metrodin)

bromocriptine (Parlodel)


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Androgens and Anabolic

SteroidsThree major androgens:

Testosterone: principle androgen; 90%synthesized from pregnenolone by leydigcells in testis

Androstenedione: synthesized in testisand adrenal cortex

Dihydroepiandrosterone (DHEA):produced by adrenal cortex; weak androgen

Gonadal Hormone Binding Proteins

Both androgens and estrogens bindreversibly to plasma proteins; prolongshalf life; only 2% hormones circulateunbound: biologically active

Albumin: nonspecific; low affinity; highcapacity (40% binding)

Gamma globulin: sex hormone bindingglobulin (SHBG); specific; high affinity; (58%binding); levels of binding vary with estrogen


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Testosterone Synthesis

Leydig Cells: synthesize testosterone (LH) Sertoli Cells: important in spermatogenesis

(FSH); synthesize androgen binding protein;

testosterone reservoir and transport protein;secreted into seminiferous tubules

LH: regulates testosterone synthesis

activates adenyl cyclase on Leydig cells

FSH: regulates sertoli cell function

Mechanism of ActionTestosterone

Diffuses into target cell

Metabolized to dihydrotestosterone

Binds to cytoplasmic receptor

Active complex translocates to nucleus,

binds to promoter regions on genes(transcription factor sites) and alters genetranscription


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Pharmacologic Actions

Virilizing Effects

gonadotropin regulation;spermatogenesis; sexual development

Protein Anabolic Effectsincrease in bone density, muscle mass, RBC

mass

Pharmacologic Actions

Morphogenic Actions: irreversible; occurduring embryogenesis

Excitatory Actions: puberty (hair, vocalchords, long bones)

Maintenance Actions: reversible; behavior,

libido, reproductive function Other Actions: decreases lymphoid tissue;

stimulate erythropoiesis.


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Clinical Uses

Replacement Therapy

Hypogonadism

prepuberal: congenital and acquired; treat 2-3 yr until

puberty; low maintenance dose; low-actingtestosterones (ex., enathate, cypionate, propionate)

postpuberal: primary testicular dysfunction; secondary

to destruction of anterior pituitary

Aging and Impotence

Clinical Uses

Breast Cancer; Endometriosis

limited use due to virilizing effects

Protein Anabolic Action:

increase amino acid uptake; increase RNA

polymerase in skeletal muscle; antagonize theactions of glucocorticoids which are catabolic;

used to treat short stature (19-nortestosterone);

Athletes: used for anabolic and virilizing effects


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Adverse Reactions

Masculinization in females; dependentupon dose, duration and drug.

Decreases spermatogenesis (feedback)

Fluid retention, edema: congestive heart

failure, kidney failure

Anti-Androgens

Used to treat prostate cancer, hirsutism,precocious puberty

Gonadotropin Antagonists (DES,estradiol); decrease LH synthesis; decreasesteroidogenesis; prostate cancer

Androgen Biosynthesis Inhibitorshigh dose ketaconazole

Androgen Receptor Antagonistsspironolactone (mineralocorticoid antagonist)


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Male Reproductive Agents

Testosterone Replacement

methyltestosterone (Metandren)

fluoxymesterone (Halotestin)

Benign Prostatic Hypertrophy

Surgery

finasteride (Proscar)

SELECTIVE ESTROGEN RECEPTORMODULATORS (SERM)

TAMOXIFEN, TOREMIFEN

Antagonist in breast agonist in endometrial

Breast Ca treatment

RALOXIFEN

Antagonist in bone

Treatment for Osteoporosis


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Parathyroid Gland Anatomy Four Parathyroid

glands are usually

found posterior tothe thyroid gland

Total weight of

parathyroid tissue is

about 150mg

Parathyroid hormone(PTH) is made by

these glands


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Control of Calcium Balance &

Metabolism Parathyroid H

Vitamin D

Sun/diet

Calcitonin

Thyroid

C-cells

(Phosphate balance)

Parathyroid

Target Action

Parathyroid(PTH)

BoneKidneyGI Tract

Calcium


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Biological Activity of PTH BONE

PTH stimulates bone osteoblasts to increase growth &metabolic activity

PTH stimulated bone resorption releases calcium &phosphate into blood

KIDNEY

PTH increases reabsorption of calcium & reducesreabsorption of phosphate

Net effect of its action is increased calcium & reducedphosphate in plasma

INTESTINE

Increases calcium reabsorption via vitamin D


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Calcitonin

Calcitonin is a peptidehormone secreted by theparafollicular or C cells ofthe thyroid gland

It is synthesized as thepreprohormone & released inresponse to high plasmacalcium

Calcitonin acts on boneosteoclasts to reduce boneresorption.

Net result of its action is adecline in plasma calcium &phosphate


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GUT

SERUM

Ca P

URINE

BONE

D (+)

D (-)

PTH (+)

CT (+)

D (-)

PTH (-)

CT (+)

D (+)

PTH (+)

CT (-)

Synthesis, Release & Activity of Active Vitamin D

Vitamin D3 is may beobtained from the diet ormade in the skin

It is converted to the activeform (1,25-OH-D3 bysequential enzymaticreactions in the liver andkidney (stimulated by PTH)

Vitamin D3 stimulatesintestinal calcium uptake,increased bone calciumresorption & increased

kidney phosphate uptake


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Osteoporosis: Disease of Bone Growth &

Calcium Metabolism

Bone reabsorption

exceeds deposition

Osteoclasts mobilize

Ca++ to plasma

Factors: inadequateCa++ intake, genes,hormones, smoking


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Summary

PTH & calcitonin release are regulated by plasma Ca

levels

Bone Ca & phosphate serve as a ready reserve for

maintenance of plasma levels

Bone, kidney & intestine participate in the regulation

of plasma calcium

PTH, Vitamin D, & calcitonin balance plasma [Ca++]

for bone synthesis, muscle contraction, & cellsignaling

Endocrine diseases result from pathway or glandular

hypo or hyper secretion

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