endo2007 part 1 final€¦ · clinical and/or licensure exams. ... • sex hormones: estrogens,...

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Endocrine Pharmacology

Phar 754/Spring 2007M. Leid

Office: Phar 407Lab: Phar 405Tel: 737-5809

Internet: [email protected] hours: Daily 2:50 - 3:50 p.m. or appointment

Assigned reading: Goodman and Gilman chapters 56-60 (pages 1539-1677)

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Endocrine Pharmacology: Student Evaluation• Exam 1 (I will be responsible for ~120 out of the 130 points

possible on this exam and my questions will be entirely multiple-choice) => This exam will be given on Wednesday, 11 April 2007

• Exam 2 (I will be responsible for approximately 100 out of the160 points possible on this exam) => Wednesday, 25 April 2007

• Optional assignment for eternal, inner peace and enlightenment Write at least 10 multiple-choice questions, complete with 5

answers, four of which are incorrect but reasonable and fair. Try to avoid questions of the form: "which of the following is

true/false of drug X or condition Y…" Instead, try to create questions that require thinking as

opposed to strict memorization. All questions will be complied and distributed electronically

in an unedited form as study material. Selected questions will be used for testing purposes.

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The Handout

• The purpose of this handout is to free your handand mind so that you may participate in class morefully (in real-time).

• You may also find it useful in preparation to takeclinical and/or licensure exams.

• You may prefer to take notes without the aid ofthe handout, this is completely up to you.

• The handout is fairly complete but you will also beresponsible for additions to it made during thecourse of lectures.

• The endocrinology sections of the text are greatsupplements to this handout.

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Endocrine Overview• Major functions of body are regulated by two systems

Endocrine System

Nervous System

• The two are linked at the level of the anterior pituitaryand adrenal medulla

• Endocrine systems control metabolism, growth anddevelopment, and the phenotypic state of cells

• Endocrine: Signaling at a distance, general hormones

• Paracrine: Signaling in the vicinity, regional hormones

• Autocrine: "Self-signaling"

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Some drugs affecting endocrine system• Growth hormone, somatostatin• Bromocriptine• Sex hormones: estrogens, progestins, androgens (agonists,

antagonists, somewhere in between--"selective receptor modulators")• Gonadotropins• Glucocorticoids and antagonists• Mineralocorticoids• Thyroid hormone, anti-thyroid meds• GnRH analogs• Vasopressin, Oxytocin (posterior pituitary hormones)• Insulin "sensitizers" such as the thiazolidinediones• Vitamins A and D• Potentially a huge number of other drugs coming to a pharmacy near

you in the future

The objective of these lectures isto provide a framework for

understanding current and futuretherapeutic agents that affect the

endocrine system.

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Pituitary Gland Anatomy• 1 cm in diameter, 0.5-1g, sits in sella tursica• Anterior, posterior, and intermediate lobes with different wiring

and functions• Ten AP hormones are known• Wiring:

http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/hypopit/anatomy.html

Hypothalamus andHypothalamic neurons

Hypophyseal artery

Hypothalamic-hypophysealPortal veins

Anterior Pituitary

Hypophyseal vein

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Hypothalamic RF

GHRH (+)Somatostatin (-)

Suckling (+)Dopamine (-)

GnRH

CRF (aka CRH)

TRH

AP cell type

Somatotropes

Lactotropes

Gonadotropes

Corticotropes

Thyrotropes

AP hormone

Growth Hormone

Prolactin

FSH

LH

ACTH

TSH

Systemic Effects• Growth Promotion (GH, IGFs)• Gluconeogenesis, TG catab.• Lactogenic activity

• Stimulate lactation• Induction of genes encoding

milk proteins (casein)

• Induce secretion ofspermatogenic factors fromSertoli cells and inhibin

• Follicular maturation (E secretion)

• T secretion from Leydig cells (M)• P secretion from granulosa and

thecal cells (F)

• Cortisol secretion (Ad. Cortex)

• Stimulate thyroid gland to takeup I, synthesize T4 and T3

• Increases size and secretion ofthyroid gland

Hypothalamic/Anterior Pituitary Hormones and Releasing Factors

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Pharmacology of AP hormones/RFs: HistologySomatotropes• Most abundant cell type in AP (50% of all cells)• GHRH induces and somatostatin blocks GH release from

somatotropes• GHRH release is constant, somatostatin release is pulsatile,

therefore, GH secretion is pulsatile• GH secretion is highest in children, lowest in adults• GH is structurally related to PRL, activates PRL-R and can

induce lactation• GH-R signaling involves JAKS kinases, STAT proteins• GH induces release of insulin-like growth factors (IGF1,

IGF2) from liver and these "somatomedins" mediate many ofthe growth promoting effects of GH.

• GH pharmacology = GH + IFG1 + IGF2

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Pharmacology of AP hormones/RFsSomatotropes—Uses of GH• Treatment of short stature in GH-deficient kids• Adult GH deficiency (increased body fat, decreased

muscle and bone mass with reduced strength andendurance, impaired psychological well-being, reducedvitality, and poor quality of life)

• Preparations Somatrem (Protropin) contains an additional N-

terminal Met Somatropin (Humatrope) is native GH (N-terminal

Phe) Both given IM or SC, 25-50 mg/kg q.o.d. throughout

childhood

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Pharmacology of AP hormones/RFs

Somatotropes—Acromegaly• Acromegaly is a condition characterized by excessive

growth hormone levels (endogenous or exogenous) andgrowth of flat bones.

• Acromegaly usually results from a GH-secreting tumor(98% are benign adenomas)

• Can result in compression of and injury to the pituitarygland, optic nerves and optic chiasm.

• Untreated acromegaly results in marked bony and softtissue alterations to face, enlargement of the hands andfeet, sleep apnea, and carpal tunnel syndrome.

• More serious problems may include acceleratedcardiovascular disease, hypertension, diabetes mellitusand possibly an increased risk of colon cancer.

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Pharmacology of AP hormones/RFsSomatotropes—Acromegaly• Gigantism results from acromegaly prior to long bone

closure.• Diagnosis: elevated levels of both GH and IGF-1.• Treatment:

• Surgical: Transsphenoidal removal of tumor• Medical

Octreotide may achieve long-acting suppression ofGH in about 70% of patients.

Bromocriptine (Parlodel) and Cabergoline (Dostinex)are "dopamine agonist" which lower GH secretion inabout 15% of acromegalic patients.

Pegvisomant (Somavert): GH-R antagonist, veryeffective in lowering IGF-1 levels, it does not shrinkthe pituitary tumor (PEGylated GH).

• Radiation

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Pharmacology of AP hormones/RFs

Somatotropes — GH abuse potential• GH abuse is common in body builders (muscle mass, no

effect on long bone growth) and elderly men trying torecapture/maintain their youth.

• GH is a controlled substance in Oregon due to its abusepotential

• GH is listed as a prohibited class E substance by theInternational Olympic Committee

• Detection is difficult, but possible: the similarity between the amino acid sequences of

biosynthetic and naturally produced GH; the pulsatile nature of GH secretion

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Pharmacology of AP hormones/RFsSomatostatin and analogs• Somatostatin is a peptide hormone consisting of 14 amino

acids that is present in the hypothalamus, the cerebralcortex, the brain stem, the GI tract, and the pancreas.

• In the CNS, somatostatin acts as a neurotransmitter• Somatostatin hormonal activities: inhibition of the release

of growth hormone, insulin, glucagon, gastrin, TSH, ACTH,secretin, pancreozymin, cholecystokinin, pepsin, vasoactiveintestinal peptide, and renin => Octreotide is a generalinhibitor of secretory events (not just GH secretion)

• Most common analog is Octreotide (Sandostatin), anoctapeptide

• Multiple somatostatin receptor subtypes exist

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Pharmacology of AP hormones/Octreotide

• Octreotide is used to treat:Primary adenomas secreting GHMetastatic islet cell cancers especially vipomas and

glucagonomasMetastatic carcinoid tumorsAcute esophageal variceal bleedingPancreatic and enteric fistulasSecretory diarrhea (cryptosporidiosis, microsporidiosis,

intestinal amoebiasis)AIDS-related diarrhea

• The initial dose is 50 µg SC once or twice daily.• Number of injections and dosage may be increased

gradually based on tolerance and response

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Pharmacology of AP hormones/RFsLactotropes• 3-5% of AP cells• Secrete prolactin, which promotes lactation• Prolactin and lactation

Secretion begins around week 5 of pregnancy High levels of E and P prevent lactation during pregnancy After parturition, there is a sharp drop in hormone (E +

P) levels, prolactin begins to exert an effect on lactation. Prolactin secretion becomes pulsatile, stimulated by

suckling, returning to baseline between nursing cycles. If nursing is stopped, mammary glands loose ability to

produce milk within approximately one week. Milk production can continue for several years is

stimulation persists.

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Pharmacology of AP hormones/ProlactinLactotropes, cont'd

• Hypothalamic control of Prl secretion is negative (DA)• In general, hyperprolactinemia suppresses the HPG

axis and can result in disruption of menstrual cyclingand infertility

• 50% of women do not resume cycling while lactatingsuggesting that Prl and/or suckling may inhibit GnRHrelease from hypothalamus

• Don’t bet on it, lots of pregnancies have occurred innursing females

• Prl receptor Prl-R is nearly identical to GH-R and uses same signaling

pathway (JAKS-STAT-regulation of TXN) GH has lactogenic activity by activating Prl-R, but converse

is not true. Prl is incapable of stimulating tissue growth through GH-R. Found in mammary gland, hypothalamus (negative feedback),

liver, testes, ovaries, prostate, and T cells.

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Pharmacology of AP hormones/ProlactinLactotropes, cont'd• Relevant drugs

No clinically useful Prl receptor agonists or antagonists DA receptor agonists have an anti-lactogenic effect DA receptor (D2) antagonists, including many

antipsychotics, exert a lactogenic effect• Bromocriptine (DA agonist) is used for hypersecreters

DOC for hyperprolactinemia in either gender Can be used for post-partum inhibition of lactation

although this is becoming less common Approximately 80% of hyperprolactinemic females

resume normal menstrual cycling when givenbromocriptine

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Placental Lactogen (human chorionic somatomammotropin, HCS)• Belongs to somatotropic hormone family (GH, Prl, HCS)• Placental secretion begins at approximately 4 weeks,

increasing to 1-2 g/d at term• Indicative of placental health• After delivery, levels drop to zero (t0.5 = 20 min)• 96% identical to GH, 3% of activity at GH-R => Think

"Mass Action…"• Stimulates lipolysis and gluconeogenesis like GH• Physiological role: glucose delivery to fetus• Stimulates IGF2 secretion by placenta• Positive effect on fetal growth (autocrine)• Excessive secretion of HCS is most likely cause of

gestational diabetes, a major problem• Some gestational diabetics go on to develop T1 or T2DM

and require therapy for the rest of their lives.

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Pharmacology of AP hormones/RFsGonadotropes• Secrete FSH and LH in response to GnRH*

• 3-5% of AP cells

• Control majority of sexual functions in males and females

• Pulsatile nature of GnRH release from hypothalamus is crucial:

Constant release (or therapeutic administration) desensitizesGnRH receptors on gonadotropes

Results in decreased FSH/LH release

Exploited clinically in the treatment of prostate CA, andendometriosis

"Chemical castration"

• Strenous exercise inhibits GnRH release causing infertility in bothsexes

*Note: Other species express multiple GnRHs (3) and receptors (3).Genomic work suggests that the same is true for humans but thephysiological relevance of this is completely unknown.

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GnRHLH FSH

Sertoli CellsLeydig Cells

InhibinTestosterone SpermatogenicFactors

AnabolicEffect

Male 2°Sex

Characteristics

Spermatogenesis

Hypothalamus MALES

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Pharmacology of AP hormones/Sex hormonesHPG Axis in the Male• LH: Stimulates T production by Leydig cells and has a trophic effect on

testicular size/volume T has a strong trophic effect on spermatogenesis and testicular

size/volume T is required for maintenance of sexual libido T is required for development and maintenance of secondary

sexual characteristics in the male T has a potent anabolic effect, particularly on skeletal muscle,

and this leads to abuse by some body builders and athletes

• FSH: Induces secretion of spermatogenic factors by Sertoli cells andhas a trophic effect on testicular size

Not involved in gonadal hormone production Both FSH and T are required for initiation of spermatogenesis

but T alone can maintain it FSH also induces Sertoli cell secretion of Inhibin, which feeds

back and inhibits FSH secretion by the gonadotropes

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Pharmacology of AP hormones/Sex hormonesSummary of HPG axis in the male• Main negative regluatory pathways in the male

T inhibition of GnRH release from hypothalamus Inhibition of FSH release from AP by inhibin T may also inhibit FSH/LH release from AP

• Selective inhibition of FSH action (for example by aninhibin receptor agonist) Would impair spermatogenesis Would not affect gonadal T production Should not affect libido or 2º male sex characteristics May work as a male contraceptive

• Inhibin receptor antagonists: potential use?

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Pharmacology of AP hormones/Sex hormones

HPG Axis in the Female• Females also secrete GnRH in a pulsatile fashion• Results in cyclic release of FSH, LH, E, P, Inhibin• The complexity of the menstrual cycle is superimposed

upon the pulsatile release of GnRH in the female FSH

Stimulates E production and secretion by ovary Induces maturation of a limited number of follicles per cycle

LH LH surge is required in terminal stages of follicular maturation

and for ovulation Regulates secretion of sex hormones (mainly P) by corpus

luteum after ovulation and during initial stages of pregnancy

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Pharmacology of AP hormones/Female sex hormones

Day

FollicularPhase

LutealPhase

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CorpusLuteum

PrimaryUnilaminar

Follicle

PrimordialFollicule

PrimordialGerm Cell

CorpusAlbicans

PrimaryMultilaminar

Follicle

GraafianFollicle

Ovulation

FSH

FSH

FSH

FSHE2

LHLH

FSH

Progestins• Prepare endometrium for implantation• Maintain favorable endometrial environment• Uterine smooth muscle relaxants

E2

Follicular Development

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• Birth to puberty At birth, females have a combined total of approximately 1

million ovarian primordial follicles (ovum surrounded by granulosacells)

In addition to providing nutrients, the granulosa cells secrete afactor, oocyte maturation inhibitory factor, which maintains theovum in an immature state (suspended in prophase of meiosis)

Pharmacology of AP hormones/Female cycling

CorpusLuteum

PrimaryUnilaminar

FolliclePrimordialFollicule

PrimordialGerm Cell

CorpusAlbicans

PrimaryMultilaminar

FollicleGraafianFollicle

Ovulation

FSH

FSH

FSH

FSHE2LHLH

FSH

Progestins• Prepare endometrium for implantation• Maintain favorable endometrial environment• Uterine smooth muscle relaxants E2

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•Puberty 300,000-400,000 follicles remain FSH/LH secretion from AP begins to increase, exerts a

trophic effect on primordial follicle As a result of FSH stimulation, the primordial follicle

increases by 2-3 fold in size by addition of granulosa celllayers and is now known as a primary follicle.


CorpusLuteum

PrimaryUnilaminar


PrimordialGerm Cell

CorpusAlbicans

PrimaryMultilaminar


Ovulation

FSH

FSH

FSH

FSHE2LHLH

FSH


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• Reproductive cycling and ovulation 2-3 days after onset of menstruation, FSH and LH levels rise

slightly FSH induces 6-12 follicles to begin maturation process by

inducing:Proliferation of granulosa cellsFormation of the theca (a layer of cells encasing the follicle)


CorpusLuteum

PrimaryUnilaminar


PrimordialGerm Cell

CorpusAlbicans

PrimaryMultilaminar


Ovulation

FSH

FSH

FSH

FSHE2LHLH

FSH


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• Reproductive cycling and ovulation Under FSH stimulation, granulosa cells secrete follicular fluid into

the antrum of the follicle Follicular fluid contains large amounts of E2, which has two

important effects on follicular maturation:Induction of FSH-RER and FSH-R cooperate to induce LH-R expression and this

renders follicle sensitive to LH


CorpusLuteum

PrimaryUnilaminar


PrimordialGerm Cell

CorpusAlbicans

PrimaryMultilaminar


Ovulation

FSH

FSH

FSH

FSHE2LHLH

FSH


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• Reproductive cycling and ovulation Explosive follicular growth and secretion occur as a result Normally, only one follicle (of the 6-12 that are maturing) complete

the maturation process and ultimately give rise to a mature folliclethat can be fertilized in the Fallopian tubes

Atresia is the process by which non-selected follicles die off (days7-10)


CorpusLuteum

PrimaryUnilaminar


PrimordialGerm Cell

CorpusAlbicans

PrimaryMultilaminar


Ovulation

FSH

FSH

FSH

FSHE2LHLH

FSH


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LH is obligatory for final stages of follicular growth and ovulation LH surge occurs 2d prior to ovulation, possible due to:

Transient positive effect of E2 on GnRH secretionPositive effect of progesterone and/or metabolite on GnRH/LH

secretion LH increases P and decreases E2 secretion by granulosa cells and

theca approximately 1d prior to ovulation

Pharmacology of AP hormones/Female cycling• LH and ovulation

CorpusLuteum

PrimaryUnilaminar


PrimordialGerm Cell

CorpusAlbicans

PrimaryMultilaminar


Ovulation

FSH

FSH

FSH

FSHE2LHLH

FSH


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LH and FSH cooperate to induce rapid swelling of follicular cavity andthecal secretion of a protease that digests follicular casing

Eventually the follicle ruptures and discharges the ovum and a limitednumber of granulosa cells into the distal end of the Fallopian tube(normally day 14 of cycle).


• LH and ovulation

CorpusLuteum

PrimaryUnilaminar


PrimordialGerm Cell

CorpusAlbicans

PrimaryMultilaminar


Ovulation

FSH

FSH

FSH

FSHE2LHLH

FSH


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The ovum is now fertilization-competent for approximately 24 hrs. Ideally, fertilization would occur in the mid- to proximal region of

the tube and the fertilized ovum would reach the 16-cell stagebefore tumbling out of the tube and implanting in the uterineendometrium.

Pharmacology of AP hormones/Female cycling• LH and ovulation

CorpusLuteum

PrimaryUnilaminar


PrimordialGerm Cell

CorpusAlbicans

PrimaryMultilaminar


Ovulation

FSH

FSH

FSH

FSHE2LHLH

FSH


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• Formation of corpus luteum (lutenization) The majority of granulosa cells derived from the

ruptured follicle give rise to cells which form thecorpus luteum in the ovary.


CorpusLuteum

PrimaryUnilaminar


PrimordialGerm Cell

CorpusAlbicans

PrimaryMultilaminar


Ovulation

FSH

FSH

FSH

FSHE2LHLH

FSH


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• Formation of corpus luteum (lutenization) Soon after follicular rupture, granulosa cells which do not

accompany the ovum into Fallopian tube enlarge (due to lipidaccumulation), become highly vascularized and develop anextensive smooth endoplasmic reticulum which is capable of large-scale biosynthesis of sex hormones (predominantly progesteronebut also E2) and inhibin.


CorpusLuteum

PrimaryUnilaminar


PrimordialGerm Cell

CorpusAlbicans

PrimaryMultilaminar


Ovulation

FSH

FSH

FSH

FSHE2LHLH

FSH


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• Formation of corpus luteum (lutenization) These cells are now referred to as lutein cells (and the

process, luteinization). Corpus luteum = thecal + lutein cells. Thecal cells secrete androgens, which are taken up and

converted to female sex hormones by the lutein cellsand ultimately secreted as P and E.


CorpusLuteum

PrimaryUnilaminar


PrimordialGerm Cell

CorpusAlbicans

PrimaryMultilaminar


Ovulation

FSH

FSH

FSH

FSHE2LHLH

FSH


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Function of corpus luteum: Fertilization has occurred• Grows to ~ 1.5 cm in diameter in 7-8d after ovulation• If fertilization and implantation occur, the corpus luteum

continues to secrete high levels of female sex hormones for3-4 months under stimulation by placenta-derived chorionicgonadotropin (HCG), which is a LH-R agonist.


CorpusLuteum

PrimaryUnilaminar


PrimordialGerm Cell

CorpusAlbicans

PrimaryMultilaminar


Ovulation

FSH

FSH

FSH

FSHE2LHLH

FSH


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Function of corpus luteum: Fertilization has occurred• P and E both induce proliferation of breast ductal tissue for lactation.• Endometrium: E induces proliferation, whereas P causes the

proliferated endometrium to become highly secretory. Both enhancethe hospitality of the endometrium for implantation and pregnancy.

• Once sufficiently developed, the placenta begins secreting female sexhormones and the corpus luteum degenerates.


CorpusLuteum

PrimaryUnilaminar


PrimordialGerm Cell

CorpusAlbicans

PrimaryMultilaminar


Ovulation

FSH

FSH

FSH

FSHE2LHLH

FSH


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If fertilization and implantation do not occur, the corpusluteum involutes (decreases secretion and lipid content) 7-8d after ovulation and is replaced by connective tissue.

Involution probably results from feedback inhibition ofGnRH and/or FSH/LH secretion by high levels of E2,progesterone and inhibin.

• Function of corpus luteum: In the absence of fertilizationPharmacology of AP hormones/Female cycling

CorpusLuteum

PrimaryUnilaminar


PrimordialGerm Cell

CorpusAlbicans

PrimaryMultilaminar


Ovulation

FSH

FSH

FSH

FSHE2LHLH

FSH


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Because of its dependence on LH (predominantly) and FSH formaintenance and secretory function, decreased levels of these hormonesresult in atrophy of the corpus luteum and menstruation.

A decrease in E2/P levels also relieves negative feedback repression ofLH/FSH release from anterior pituitary (and GnRH release fromhypothalamus to a lesser extent) and the cycle begins again.

• Function of corpus luteum: In the absence of fertilization


CorpusLuteum

PrimaryUnilaminar


PrimordialGerm Cell

CorpusAlbicans

PrimaryMultilaminar


Ovulation

FSH

FSH

FSH

FSHE2LHLH

FSH


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Physiological effects of sex hormones in humans

Androgens• Development of secondary male sex characteristics

• Initiation and propagation of spermatogenesis

• Anabolic activity

• Masculinization (CNS)

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Estrogens• Development of secondary female sex characteristics• Proliferation of glandular tissue in uterus and tubes• Enlargement of uterus, tubes, vagina, and external genitalia• Enhancement of endometrial gland development• Increase in number and activity of ciliated epithelial cells in

tubes• Prepare for, but do not induce lactation• Increase in breast stromal development• Increase in breast ductilization• Increase deposition of fat• Increase osteoblast activity in both sexes• Induction of epiphyseal plate closure in both sexes• Increase expression of LDL-R, clearance of LDL cholesterol• General vasodilatory effect• Feminization

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Progestins• Development of secondary female sex characteristics• Preparation of uterus for implantation and pregnancy

Induction of a secretory phenotype Maintenance of pregnancy Inhibition of uterine contractions Promotion of secretory alterations that affects

mucosal lining of tubes• Sudden drop in circulating P that triggers menstruation• Preparation of breasts for, but no induction of, lactation

Promote development of breast lobules and alveoli Induction of alveolar cell proliferation, enlargement,

and secretory capacity Increased breast swelling due to fluid accumulation in

subcutaneous tissue

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Agents affecting GnRH action• Gonadorelin

Fractel, Lutrepulse Authentic GnRH Given really only in a pulsatile fashion: To normalize menstrual cycle disorders related

to GnRH deficiency To treat infertility and delayed puberty For induction of ovulation For in vitro fertilization procedures To treat cryptorchidism unrelated to anatomical

blockage

Pharmacological agents that modify endocrine system activity

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•GnRH analogs (agonists; metabolically more stable than GnRH)Gonadotropin-dependent precocious pubertyProstate cancer (combined an antiandrogen initially)Breast cancer (ER positive)Polycystic ovarian syndromeBenign prostatic hypertrophyEndometriosis (see Endometriosis lecture)Uterine leiomyomas (fibroids)HirsutismMale contraceptive?Premenopausal women with metastatic breast cancerAgents, are typically long-acting with or without depot

forms Leuprolide Buserelin Nafarelin

Deslorelin Goserelin Histrelin

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GnRH analogs (agonists)—Mechanism of action• Initial stimulation of FSH/LH release• Eventual desensitization of GnRH receptors and

decreased release of gonadotropins, sex hormones• Long-term usage (constant administration)

essentially results in a reversible pharmacologicaloophorectomy or orchiectomy

• Would also happen with continuous infusion ofauthentic GnRH?

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GnRH antagonists• Bind to receptor, block GnRH access• Prevents premature LH surge in IVF procedures• Timing is everything• May be useful in advance prostate CA• Examples

Cetrorelix Ganirelix Abarelix - fairly severe allergic rxns have been

reported

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FSH/LH-related agents•Directly stimulate gonadal tissue•Used to treat female or male infertility,cryptorchidism and in in vitro fertilizationprocedures.

•ProductsMenotropins (Pergonal; FSH/LH)Urofollitropin (Metrodin, Fertinex; primarilyFSH)

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Pharmacological agents that modify endocrine system activityESTROGENS• Estrogen biosynthesis

Dehydroepiandrosterone(DHEA)

Estriol(E3)

Androstenedione

Testosterone (T) Estradiol (E2)Aromatase

AromataseEstrone (E1)

DHT

5! reductase

16α-

OHase

3β-O

H-SD

H17β-

OH-S

DHAr

omatase

SEE TEXT PAGE 1599

inhibited by Chrysin(5,7-dihydroxyflavone)

inhibited by Chrysin

Chrysin is a naturally occurring isoflavone chemically extracted from the plant Passiflora coerulea.

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Pharmacological agents that modify endocrine system activityESTROGENS cont'd--Most common forms and equivalentpo doses (other routes available) Conjugated estrogens (Premarin, Ortho-Est, Ogen) 0.625mg

(sulfated forms of estrone) Ethinyl estradiol (Estinyl) 5 - 10 µg (reduced metabolism) Estradiols (Estrace, Estraderm) 1 - 2 mg or 0.05 - 0.1mg Quinestrol (Estrovis): long-acting, stored in fat and etabolized to

ethinyl estradiol Mestranol: Metabolized to ethinyl estradiol Esterified estradiol (valerate, cypionate): used for depot IM

injections Topical (vaginal) preparations of estradiol and conjugated estrogens Combination preparations: Estrogen (+) medroxyprogesterone

together in one tablet (Prempro and Premphase) Bioidentical hormones

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ESTROGENS cont'd• Uses

Replacement therapy (emotional, osteoporosis, CAD,vaso)

Women taking supplemental estrogen aftermenopause or oophorectomy have 15% lower levelsof LDL, higher levels of HDL and somewhat elevatedtriglycerides

Contraceptive (low dose estrogens and/orprogestins, feedback inhibit FSH/LH release at thelevel of anterior pituitary)

Palliative treatment of metastatic breast andprostatic CA

Emergency contraception (see below)

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Is HRT a good idea?• In general, there is a higher risk of endometrial CA in

postmenopausal patients taking E only.• This risk is reduced when P is added, hence one aspect

of the logic of E/P combination therapy (either as asingle dosage form or separate therapies).

• However, a relatively recent report suggest that theremay be an increased incidence of breast CA in patientson E/P as compared to E alone (8% vs. 1%, respectively).

• Breast CA in postmenopausal women is a big deal.• In addition, a recent WHI study found that

postmenopausal women taking E+P were at greater riskfor:

MIStrokeVenous thromboembolism

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Pharmacological agents that modify endocrine system activityIs HRT a good idea, cont'd?• Yes, but what about "quality of life" issues?

HRT does not objectively improve post-menopausalquality of life for the majority of patients after threeyears of treatment (NEJM issue of May 8, 2003)

"No significant effects on general health, vitality, mentalhealth, depressive symptoms, or sexual satisfaction."

"…small and not clinically meaningful benefit in sleepdisturbance, physical functioning, and bodily pain afterone year of therapy."

• Limitation of study: patient willingness to be randomizedmay exclude the worst cases of vasomotor symptoms, forexample.

• The original WHI study indicated that HRT does decreasethe risk of hip fractures and colon CA, as well as theincidence of vasomotor symptoms but the overall harmprobably outweighs these beneficial effects of HRT.

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Pharmacological agents that modify endocrine system activityIs HRT a good idea, cont'd?

• Given the availability of other agents totreat osteoporosis, use of HRT for itsprevention is not appropriate for mostwomen.

• Vasomotor symptoms are not deadly butcan be very disabling.

• Other agents (megestrol, SSRIs,clonidine) provide some relief forvasomotor Sx but HRT is the mosteffective.

• Other effects of HRT: perceptions ofyouthfulness and attractiveness, skintone have been attributed to HRT

• "I just feel so much better."

• Note that a sizable placebo effect isassociated with HRT

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Post-menopausal HRT and cognitive disorders

• HRT can enhance cognitive function if given early in menopause, OR• HRT can reduce cognitive function if given late in menopause (65-79

years)

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Emergency contraception (“Morning after” contraception)• High-dose, limited duration estrogen (or E + P) therapy

taken up to 72 hours post-coitum• Initiated in the 1960s with administration of large doses of

estrogens (50 mg diethylstilbestrol or 5 mg ethinylestradiol for 5 days)

• 1980s: 0.1 mg ethinyl estradiol + 1 mg norgestrel (2 doses,12 hours apart) was shown to be as effective, less sideeffects

• Premedication with antiemetics decreases risk of nausea.• See the Planned Parenthood webpage for a bunch of

information:http://www.plannedparenthood.org/library/BIRTHCONTROL/EC.html

• Any BCP will probably work, Plan B® (progestin-only) andPreven® (estrogen and progestin) are marketed specificallyfor emergency contraception

58


• Combined estrogen and progestin ECs reduces the risk ofpregnancy by roughly 75 percent.

• Not every woman at risk of pregnancy becomes pregnant.• On average, only eight out of 100 women will become

pregnant after having unprotected sex during the second orthird week of their menstrual cycles.

• But if they take ECs, only two out of those 100 women willbecome pregnant.

• When used correctly, progestin-only ECs were found toreduce the risk of pregnancy by 89 percent.

• When taken within 24 hours of unprotected intercourse, P-only ESs were found to reduce the risk of pregnancy by 95percent.

• IUDs are also effective• FDA waffling on OTC availability of these agents

ESTROGENS—EMERGENCY CONTRACEPTION

30

59

Mechanism of action of ECs Alteration of ciliary motility (increase) Inhibition of implantation of fertilized ovum

in endometrium Suppression in LH surge (if taken before)

Oral prostaglandins may also be effective as ECs Thought to work by inducing uterine

contraction and adversely affectingimplantation.

•Methotrexate can also be used and is thought tocause resorption and/or tubal abortion of conceptus.

ESTROGENS—EMERGENCY CONTRACEPTION, cont'dPharmacological agents that modify endocrine system activity

60

• FIRST DOSE Within 72 hours after having unprotected sex. If not using progestin-only pills, consider eating

saltines/soda crackers, drinking a glass of milk 30minutes before taking each dose, or use OTC anti-nauseants to avoid vomiting.

• SECOND DOSE 12 hours after first dose (or sooner to prevent N/V) If vomiting occurred after first dose, use an anti-nausea

medication 30 minutes before taking the second. Or insert second dose as a vaginal suppository as high

into the vagina as possible. If vomiting occurs after second dose, do not take any

extra pills.

EMERGENCY CONTRACEPTION—PATIENT INFOPharmacological agents that modify endocrine system activity

31

61

After taking ECs….• Next period may be earlier or later than usual.• Flow may be heavier, lighter, or more spotty than usual.• Inform all health care providers of events• Schedule a follow-up visit with clinician if subsequent period

does not occur within 3 weeks or if symptoms of pregnancyare apparent.

• Stress the use of another method of contraception ifvaginal intercourse occurs before next period.

• Stress the importance of using the birth control method ofchoice for as long as contraception is desired.

• ECs should not be used as a general method ofcontraception

ESTROGENS—EMERGENCY CONTRACEPTION—PATIENT INFO


62

After taking ECs—Side Effects• Side effects associated with the use of ECs usually taper off one or

two days after the second dose has been taken.• Half of the women who take the combined pills feel sick to their

stomachs, but only for about 24 hours.• Up to one out of three women throw up with combined pills.• The risk of nausea and vomiting is lower with progestin-only ECs.• Breast tenderness, irregular bleeding, fluid retention, dizziness, and

headaches may also occur.• Frequent use of ECs may cause periods to become irregular and

unpredictable.• Emergency contraception may not prevent ectopic pregnancy.• An ectopic pregnancy is a medical emergency, seek medical attention

immediately if severe pain on one or both sides of the lower abdomenis observed with or without spotting (along with missed/light peroid).

• ECs will not "harm" a fetus.

ESTROGENS—EMERGENCY CONTRACEPTION—PATIENT INFOPharmacological agents that modify endocrine system activity

32

63

Pharmacological agents that modify endocrine system activityESTROGENS—EMERGENCY CONTRACEPTION

Trade name Manufacturer 1st Dose 2nd Dose (12 hrs later)*Alesse® Wyeth-Ayerst 5 pink 5 pink Levlen® Berlex 4 lt. orange 4 lt. orange Levlite® Berlex 5 pink 5 pink Levora® Watson 4 white 4 white Lo/Ovral® Wyeth-Ayerst 4 white 4 white LowOgestrel® Watson 4 white 4 white Nordette® Wyeth-Ayerst 4 lt. orange 4 lt.orange Ogestrel® Watson 2 white 2 white Ovral® Wyeth-Ayerst 2 white 2 white Ovrette® Wyeth-Ayerst 20 yellow 20 yellow PlanB® WCC 1 white 1 white Preven® Gynétics 2 blue 2 blue Tri-Levlen® Berlex 4 yellow 4 yellow Triphasil® Wyeth-Ayerst 4 yellow 4 yellow Trivora® Watson 4 pink 4 pink http://www.plannedparenthood.org/library/BIRTHCONTROL/EC.html

P only

*May take closer together to avoid nausea

64

SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMS)

• Also known as Designer Estrogens• Structurally-distinct compounds• Interact with ERα and β in a manner that is

different from that of estradiol (a full agonist)• "Partial" agonists: tamoxifen, raloxifene, clomiphene

possess tissue-specific agonist or antagonistactivity

• Pure antagonists: ICI 164,384 or ICI 182,780(known as Fulvestrant, Faslodex®)• The molecular basis for partial agonist and

antagonism of ERs will be covered later


33

65

LIGAND17β-ESTRADIOL17α-ESTRADIOLESTRIOLESTRONEDIETHYLSTILBESTEROL4-HYDROXYESTRADIOL2-HYDROSYESTRADIOLTAMOXIFENRALOXIFENEGENISTENECOUMESTROLDIADZEIN4-OCTYLPHENOLNONYLPHENOL

1005814604681324694200.10.020.05

10011213726570.2316871400.50.070.09

ERβERαDIFFERENTIAL ACTION OF ER LIGANDS

Bigger numbers = higher affinity = lower KD


66


ERα AND ERβ ARE DIFFERENTIALLY EXPRESSED IN HUMANS

ERα ERβCNSBone

BreastUGTCV

GILiver

• Breast ERα expressed in epithelial cells lining ducts and lobules ERβ expressed predominantly in myoepithelium

• CV ERα mediates protective effects of E2 on endothelium ERβ mediates vasodilatory effects of E2, most likely

through iNOS

But…

34

67

SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)• Uses

Ovulatory stimulant (clomiphene) Breast CA Prostatic CA??? Prevention of cardiovascular disease (LDL-R;

unlike E2, RAL and Tam do not increase HDL-cholesterol)

Male infertility HRT Osteoporosis

• Neither TAM nor RAL stimulate breastsignificantly

• TAM, but not RAL stimulates the endometrium


68

Side Effect

Hot Flashes (BRAIN)

Uterine Bleeding (UTERUS)

Risk of Endometrial CA (UTERUS)

Prevention of Bone Loss (BONE)

Risk of Breast CA (BREAST)

Favorable pattern of serum lipids (LIVER)

Venous Thrombosis (LIVER/VASC.)

Estrogen

↓↓↓

↑↑↑

↑↑

↑↑↑

↑↑

↑↑↑

↑↑

TAM TOR

↑*

↑

↑

↑

↓↓

↑

↑↑

↑*

↑

?

↓↓

↑↑

?

RAL

↑*

↑↑

↓↓

↑

↑↑

*Further increased in perimenopausal women

*SIDE EFFECT PROFILE OF SERMS

TOR = TOREMIFENE (FARESTON) NEJM 348:618-629 (2003)

35

69


SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMS)Pure antagonists• ICI 164,384 and ICI 182,780 (Fulvestrant,

Faslodex® is more potent)• Both ER agonists and antagonists increase

degradation of the receptors• This is via shuttling through the 26S

proteosomal pathway• Fluvestrant is being marketed as a compound is

a "negative modulator of estrogen receptors"• Tissue-specific degradation of ERα may be a

good thing in BC cells but would not be a goodthing in bone or liver (among other tissues)

70

GENISTENE

DAIDZEIN

ENTEROLACTONE

Pharmacological agents that modify endocrine system activityPHYTOESTROGENS "MAY" PROTECT AGAINST BREAST,

PROSTATE AND COLON CA, CVD, OSTEOPOROSIS

• Isoflavonoid• Soybeans, clover

• Isoflavonoid• Soybeans, clover

• Lignan• Green tea and legumes

36

71

• Inhibitors of aromatase inhibit E2production

• Aromatase is fairly highly expressed by manymammary tumor cells and adipose tissue

INHIBITORS OF ESTROGEN BIOSYNTHESISPharmacological agents that modify endocrine system activity

72

INHIBITORS OF ESTROGEN BIOSYNTHESIS

• Representative aromatase agents 4-hydroxyandrostenedione aminoglutethimide Anastrozol (Arimidex) Letrozole Exemestane Formestane

• Indicated for post-menopausal women withmetastatic breast CA whose disease progressesdespite TAM therapy

• Why post-menopausal? Relief of NF?


37

73

• Inhibitors of aromatase, cont'dINHIBITORS OF ESTROGEN BIOSYNTHESIS

STEROIDALINHIBITORS

NON-STEROIDALINHIBITORS


74

• PR has most limited distribution of any nuclear receptor(female repro. tract, including breast, and brain).

• In general, P favors cellular differentiation to asecretory phenotype, whereas E favors cell growth(proliferation).

• Note that a membrane-bound receptor (GPCR) forprogesterone has been identified recently

• Uses of progestins Contraception (in combination with an estrogen) Supplemental therapy in combination with an

estrogen Dysfunctional uterine bleeding PMS Threatened/habitual abortion

PROGESTINS


38

75

• Use of antiprogestins contraceptives procedures requiring dilation of the cervix induction of labor treatment of some types of breast cancer endometriosis Leiomyoma chemical abortifacients (contragestionals)

ANTI-PROGESTINS

• Use of antiprogestins as chemical abortifacients Effective up to 50 days after last menses RU-486 was initially developed by Roussel-Uclaf as a glucocorticoid

antagonist for use in the treatment of patients with Cushing'ssyndrome.


76

RU-486 also reduces intraocular pressureassociated with glaucoma (anti-GR effect)

Subsequently, it was discovered that RU-486blocked the supportive role of progesterone duringpregnancy by antagonizing the action of thishormone at the level of its receptor in uterus.

This property was quickly recognized as a means toterminate pregnancy medically rather thansurgically.

60% effective as a single-dose oral abortifacient 97% when the single dose of RU-486 is followed

(48 hours later) by administration of the orally-active prostaglandin E1 derivative, misoprostol.

other orally active antiprogestins include ZK 98734(lilopristone) and ZK 98299 (onapristone)

ANTI-PROGESTINS USES, cont’d


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77

MECHANISMS OF RU-486 ABORTIFACIENT ACTION

1. DECIDUAL BREAKDOWN2. BLASTOCYST DETACHMENT3. DECREASED HCG

SECRETION BY PLACENTA4. DECREASED CL FUNCTION5. DECREASED P SECRETION

A. HASTENS DECIDUALBREAKDOWN

B. INCREASES UTERINECONTRACTILITY

C. CERVICAL SOFTENING6. ORAL PROSTAGLANDIN

ENHANCES UTERINECONTRACTILITY(PHYSIOLOGICALANTAGONIST OF P,EXPLUSION OF EMBRY0)

1

2

3

4

P

55A

5B

5C

6


78


ANDROGENS

• FORMATION AND METABOLISM OF T, DHT

Dehydroepiandrosterone(DHEA)

Androstenedione

Testosterone (T)

DHT

5! reductase Aromatase

Estradiol (E2)

• Action of testosterone is sum of T, DHT, and E2• Men synthesize approximately 50 µg of estradiol

per day (from testosterone) which is critical forepiphyseal closure.

40

79

SEXUAL DETERMINATION: ROLE OF ANDROGENS

• Genital ridge (near adrenal) gives rise to the bilateral, primitive gonad(PG) that is composed of a cortex and medulla

• Until ~ 6 weeks, the PG and duct work are bipotent, i.e., thesestructures are identical in females and males Mullerian ducts give rise to uterus and tubes Wolffian ducts give rise to vas and epididymis

• At 7 weeks the medulla of the PG develops into a testis in geneticmales (driven by sex-determining region Y, SRY) and the cortexregresses Leydig cells begin to secrete T, which promotes development of vas

and epididymis from the wolffian ducts Sertoli cells begin secreting mullerian inhibitory substance, which

causes regression of mullerian ducts• External genitalia are also bipotent until around the 8th week at which

time the urogenital slit disappears and male genitalia form (in XY)• In the absence of T the slit remains open and female external genitalia

form, the wolffian ducts degenerate, and the mullerian ducts develop• In the absence of testis-determining factor, the cortex of the PG

gives rise to an ovary that is mostly non-secretory at this time

80

Pharmacological agents that modify endocrine system activityANDROGENS

• Negative feedback pathway is less sensitive during teensand this may result in an exaggerated interest in firearms,motorcycles, high-speed automobiles (usually combined withEtOH), and sexual activity

• T secretion drops off considerably early in the thirddecade of life through middle age, during which time thetypical male may feel an inadequacy that is relieved bypurchasing sports cars, preferably brightly colored

• Aromatase is expressed in brain and may play a role infeedback inhibition of GnRH and/or FSH/LH secretion.

• Weak androgens androstenedione (T precursor, adrenal androgen) dehydroepiandrosterone (DHEA, an adrenal androgen) 5α-androstane-3α, 17β -diol androsterone

41

81


USES OF ANDROGENS• Primarily used in androgen-deficient males who

exhibit abnormal development of secondary sexualcharacteristics due to hypogonadism and tomaintain secondary sexual characteristics.

• Also positively regulates nitrogen balance and maybe used to reverse muscle wasting syndromes--questionable value.

• Stimulates erythropoiesis--EPO is much moreuseful

• Breast CA--antiestrogenic activity, palliative effect• Osteoporosis• Male contraceptive??• Treating aging males for profit => Male HRT• To stimulate female libido (methyltestosterone + E)

82


ANDROGENS cont’d• Dosage forms

PO, IM Dermal patches Testoderm® (Alza): Non-adhesive patch (Testoderm

or Testoderm with Adhesives, apply to shavedscrotum; Testoderm TTS--apply anywhere EXCEPTscrotum)

Androderm® (SKB): Adhesive patch, apply anywhere• Adverse effects

Virilizing side effects, especially when patient is nothypogonadal.

Feminization--only really a problem with testosteronebecause of its conversion to E2 by aromatase

Edema due to salt and water retention Jaundice, Hepatic carcinoma

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83

ANDROGENS cont’dAnabolic steroid abuse• Anabolic steroids are controlled substances• Anabolic steroids DO promote muscle growth and

this is mediated by AR.• Cannot separate anabolic from androgenic effects

(yet)• Enhancement of athletic performance is difficult to

evaluate because of problems with negativecontrols

• Health Hazards to Men Abusing Anabolic Steroids Testicular atrophy Reduced sperm count Impotence Baldness

Difficulty/pain in urinating Development of breasts Enlarged prostate


84

43

85

Pharmacological agents that modify endocrine system activityANDROGENS cont’d• Health Hazards to Women Abusing Anabolic

Steroids Growth of facial hair Changes in or cessation of menstrual cycle Clitoral enlargement Deepened voice Breast reduction

• Health Hazards to Both Men/Women AbusingAnabolic Steroids Acne Jaundice, liver damage, cancer Muscle tremor Edema in dependent extremities Bad breath Reduction in HDL, Hypertension Increased chance of injury to tendons,

ligaments and muscles

Heidi 1986

Andreas2003

(Oral-Turinabol)

86

Representative Androgens/Anabolic Steroids

20Aet-1 (WHOmale contraceptive)

Testosterone-trans-4-n-butylcyclohexyl-

carboxylate

TestexTestosteronepropionate

DelatestrylTestosterone enanthateDepo-TestosteroneTestosterone cypionate

WinstrolStanozololAnadrol-50Oxymethelone

AnavarOxandrolone

Deca-DurabolinNandrolone decanoateMetandrenMethyltestosteronePrimobolanMethenolone acetateDianabolMethandrostenolone

AndrovironMesteroloneHalotestinFluoxymesteroneTradenameGeneric Name

chlordehydromethyltestosterone Oral-Turinabol

44

87

ANTI-ANDROGENS•Classes of antiandrogens

GnRH agonists (see above and endometriosis lecture) AR antagonists Cyproterone: progesterone-like activity decreases

gonadotropin release (in Canada) Flutamide (Eulexin): pure anti-androgen, induces

massive release of gonadotropins, testosterone.Only really useful in castrated males or when givenwith GnRH analogs.

Bicalutamide (Casodex): qd dosing, lower GI upset? Spironlactone (Aldactone) is a weak AR antagonist

and inhibits androgen biosynthesis Nilutamide (Niladron): newest agent in class


88

CLASSES OF ANTI-ANDROGENS CONT'D 5α steroid reductase 2 inhibitors inhibit conversion of T => DHT Finasteride (Proscar) is prototype Saw palmetto products also inhibits 5α steroid

reductases Imidazole antifungal agents Ketoconazole Liarozole Inhibit P450 enzymes involved in steroid

biosynthesis Has been exploited in the treatment of prostate

CA Lack of specificity: glucocorticoid biosynthesis

is also inhibited


45

89

USES OF ANTI-ANDROGENS• prostatic hyperplasia/CA• acne• MP baldness• virilizing syndrome in females• precocious puberty in males• inhibition of sex drive in male sex offenders


90

CORTICOTROPES• comprise ~ 20% of all cells in anterior pituitary• secrete adrenocorticotropic hormone (ACTH,

adrenocorticotropin) in response to a hypothalamicreleasing factor, corticotropin releasing factor (CRF orCRH)

• The regulation of cortisol is complex and under thecontrol of a circadian rhythm. Positive effectors: Stress (via the limbic system) The clock (secretion of ACTH and cortisol are

highest from 4-10a) Negative effector: cortisol via negative feedback

Pharmacology of AP hormones/Corticotropes

46

91

CORTICOTROPES, cont'd


92

REGULATION OF CORTICOTROPES• Stress can be either physical or mental• Limbic system refers to hippocampus and amygdala in this case• Negative regulation by cortisol is at the level of hypothalamus (CRF) and

anterior pituitary (proopiomelanocortin)--both genes are repressed byglucocorticoids

• ACTH is synthesized as part of a large precursor (proopiomelanocortin orPOMC)

• CRF secretion is regulated by circadian clock—highest secretion occursbetween 4-10a during which ~ 80 % of daily cortisol is secreted


47

93

ACTH ACTIONS• Increase de novo synthesis of glucocorticoids which,

in general, are not stored• ACTH-R is coupled to Gs• Rate-limiting step in GC biosynthesis is conversion of

cholesterol to pregnenolone which is catalyzed byP450scc.

• Rapid effects: delivery of cholesterol tomitochondrial inner matrix (sec. to min.)

• Delayed effects: increased expression of P450scc(transcriptionally).

• Only clinical use of ACTH is diagnostic


94

Adrenal medula(Epinephrine)

Zona glomerulosa(Aldosterone)

Zona fasiculata(Cortisol, Androgens)

Zona reticularis(Cortisol, Androgens)

ADRENAL GLAND ANATOMY


48

95

ADRENAL GLAND ANATOMY• Adrenal medulla

essentially it is a sympathetic ganglion in whichthe post-ganglionic cells (chromaffin cells) havelost their axons in the process of gaining asecretory function

secretes mainly EPI and some NE but this regionof the adrenal gland is not under direct ACTHcontrol

Cortisol-activated GR transcriptionally regulatesPNMT


96

ADRENAL GLAND ANATOMY• Adrenal cortex

Zona glomerulosa most external layer functions independently of cells deeper in

cortex expresses AII receptors and aldosterone

synthase secretes aldosterone aldosterone secretion is regulated by

extracellular [K+] and RAS aldosterone tightly regulates body Na+ stores by

increasing Na+ resorption in late distal tubuleand collecting duct.


49

97

ADRENAL GLAND ANATOMY• Adrenal cortex, cont'd

Zona fasciculata and Zona reticularis synthesize and secrete glucocorticoids

(absolutely essential for life) synthesize and secrete androgens (major

extragonadal source). lack AII receptors but expresses 17α and 11β

hydroxylase enzymes which are necessary forglucocorticoid biosynthesis


98

GLUCOCORTICOIDS (GCs, cortisol, corticosterone, corticosteroids)• increase blood glucose by

stimulation of gluconeogenesis in liver peripheral breakdown of protein and fat inhibition of peripheral uptake of glucose (except

brain and heart) stimulation of glycogen disposition Glucose mechanism evolved to protect brain and

heart from hypoglycemia• maintenance of fluid and electrolyte balance (MR)• preservation of normal function of cardiovascular

system• preservation of normal function of immune system• preservation of normal function of kidney• preservation of normal function of skeletal muscle


50

99

GLUCOCORTICOID ACTIONS, cont'd

• preservation of normal function of nervous system• increase fat redistribution• divergent effects on formed elements of blood

Increase circulating PMNs (and other cells ofmyeloid origin)

Decrease circulating lymphocytes (B, T, and NKcells)


100

GLUCOCORTICOID ACTIONS, cont'd

• Glucocorticoid anti-inflammatory properties Inhibition of NF- κB signaling induction of IκB direct interaction of GR with NF-κB

Repression of phospholipase A2 Induction of lipocortin (an inhibitor of PLA2) Repression of cyclooxygenase Antagonism of pro-inflammatory AP-1


51

101

GLUCOCORTICOID THERAPEUTIC PRINCIPLES• Dose is empirical for any patient with any disease and must

be re-evaluated with time as stage/activity of diseasechanges

• Glucocorticoid therapy is palliative except in the treatmentof adrenal insufficiency

• A single, even large, dose of glucocorticoid is essentiallywithout adverse effects

• A limited duration course of glucocorticoids (in absence ofcontraindications) is also without adverse effects unlessextremely large doses are given

• The incidence of disabling and potentially lethal effects ofglucocorticoid therapy increases with duration of therapy

• Abrupt cessation of prolonged, high dose corticosteroidtherapy is associated with risk of adrenal insufficiency andcan be life-threatening


102

THERAPEUTIC USES OF GLUCOCORTICOID AGONISTS• Substitution therapy (replacement)

Primary adrenal insufficiency (Addison’s disease; autoimmune) Secondary adrenal insufficiency (lack of ACTH, more common)

• Congenital adrenal hyperplasia (mutated 21-hydroxylase; can’tsynthesize cortisol or aldosterone; steroidal precursors are shuttledto androgens; basically replacement Tx that provides Cort + Aldo andsuppresses ACTH)

• Arthritis (systemic vs. intraarticular)• Rheumatic carditis• Inflammatory renal diseases (glomerulonephritis)• Inflammatory collagen diseases (Lupus)• Allergic disorders (chronic, late phase)• Bronchial asthma• Ocular inflammatory diseases• Dermatological diseases (many)• Inflammatory bowel diseases• Cerebral edema• Acute lymphocytic leukemias/lymphomas• Shock• Diagnostic procedures


52

103

"…corticosteroids have been used for almostevery human disease for which there is noeffective treatment."

Postnatal Corticosteroids for PretermInfants: Do What We Say, Not What We Do.

Jobe, A.H. NEJM 25 March 2004


104

CORTICOSTEROIDS IN CLINICAL USE

0.7536-72025Dexamethasone0.7536-72025Betamethasone

412-3605Triamcinolone512-360.84Prednisolone512-360.84Prednisone

N/A8-1212510Fludrocortisone258-120.80.8Cortisone208-1211Cortisol

Equivalentdose (mg)

Duration(hr)

MRactivity

GRactivity

Agent


53

105

TOXICITY OF GLUCOCORTICOIDS•Acute withdrawal => life threatening

acute adrenal insufficiency (fever, myalgia,arthralgia, malaise, cerebral edema).

exacerbation of the disease for which GC was used•Prolonged usage

suppression of hypothalamic-pituitary-adrenalfunction

fluid/lyte disturbances, hypertensionhyperglycemia, glycosuria increases susceptibility to infectionpeptic ulcersosteoporosis (direct inhibition of osteoblasts)myopathy


106

TOXICITY OF GLUCOCORTICOIDS, cont'd


•Prolonged usage (cont'd)behavioral disturbancescataractsgrowth arrest (may be reversed with GH) induced Cushing’s disease (moon face, buffalo hump,

central obesity, ecchymoses, acne, hirsutism) skin thinning, GCs repress 5’-deiodinase possibly

creating a localized hypothyroidism in skin

54

107

ANTI-GLUCOCORTICOIDS, cont'd• Inhibitors of corticosteroid biosynthesis arenon-selective and may be used for Cushing’sdiseaseMetyrapone (Metopirone) inhibits P45011βAminoglutethimide (Cytandren) inhibits

P450sccKetoconazole inhibits P45017αTrilostane (Modrastane) inhibits 3β

hydroxysteroid dehydrogenase• Glucocorticoid receptor antagonists => RU-486 and relatives


108

THYROTROPES• Comprise 3-5% of AP cells• Secrete thyroid TSH (thyrotropin) in response to hypothalamic TRH• Regulation:

Hypothalamus PortalCirculation

AnteriorPituitary

Blood ThyroidGland

Blood Tissue

MultipleHypothalamic

Nuclei

TRH(ThyrotropinReleasingFactor)(E-H-P)

Thyrotropes(TRH-R is

coupled to Gq)

TSH(Thyroid

StimulatingHormone;

Thyrotropin

FollicularCells

T4 Regulationof gene

expression(enzymes ofintermediarymetabolismand others)

T35'-DI

ColdAnxietyStress

+ - -

Pharmacology of AP hormones/Thyrotropes

55

109

THYROTROPES• TRH secretion is pulsatile and circadian (highest at

night)• Glucocorticoids, somatostatin and dopamine have a

negative influence on TSH secretion by anterior pituitary• Thyroid hormone biosynthesis

Thyroglobulin: large protein in follicular cellcytoplasm, loaded with tyr

Iodide is taken up and oxidized rapidly Iodine is attached to the 3 position of tyr forming

mono-iodinated tyr (MIT) MIT is re-iodinated (5 position) to form DIT 2 moles of DIT oxidatively condense to eliminate

alanine and form T4 T3 = MIT (+) DIT Reverse T3 = DIT (+) MIT Secretory process must involve proteolysis


110

THYROTROPES• Functions of TSH

Stimulates iodide pump Increases iodination of tyr (thyroid

peroxidase) Increases size and secretion of thyroid gland Alters thyroid cell phenotype (cuboidal to

columnar with greater surface area) Stimulates proteolysis of thyroglobulin


56

111

FUNCTIONS OF THYROID HORMONE, cont'd• Regulation of growth and development

tadpoles grow limbs and lungs and lose tail inassociation with becoming terrestrial

important roles in mammals Important in brain development/neurogenesis Hypothyroidism during development = Cretinism retardation related to iodine deficiency is the major

cause of preventable mental retardation• Calorigenic effect

increase basal rate of metabolism in most tissues(heart, muscle, liver, kidney)

Implicated in temperature regulation


112

FUNCTIONS OF THYROID HORMONE, cont'd• Cardiovascular effects

increases β1AR and contractile protein expression in heart

Antagonists of β1AR can be useful in treatment of hyperthyroidism

• Metabolic effects

T3 tends to decrease serum cholesterol levels (perhaps viainduction of LDLR)

T3 stimulates fat metabolism

T3 increases triglyceride levels

hypothyroid patients tend to have elevated lipid levels

T3 stimulates essentially all forms of carbohydrate metabolism

• Negative feedback: T3 decreases TSH release by anterior pituitary


57

113

Disorders ofthyroid gland

function

• Hyperthyroidism• Hypothyroidism

114

Cheng, S.-P. et al. N Engl J Med 2005;352:918

N Engl J Med 2005;352:918, Mar 3, 2005

Dermopathy of Graves' Disease

58

115

• A 51-year-old woman presented with weight loss (despite good appetite),palpitations, tremor, and heat intolerance.

• On examination, she had typical features of Graves' disease, including adiffusely enlarged thyroid , periorbital edema, and proptosis, as well as mildthickening of the skin in the pretibial area.

• The diagnosis was confirmed by the results of thyroid-function tests, whichshowed a thyroid -stimulating hormone level of less than 0.1 mU per milliliter(normal range, 0.5 to 5.15); a triiodothyronine level of 557 ng per deciliter (8.5nmol per liter; normal range, 100 to 190 ng [1.5 to 2.9 nmol]); and a thyroxinelevel of 17.9 µg per deciliter (230.6 nmol per liter; normal range, 4.4 to 12.5 µg[56.6 to 160.9 nmol]).

• She responded to anti-thyroid treatment with methimazole and propranolol andthen had recurrent thyrotoxicosis when the medications were discontinued.

• Two years later, she underwent a near-total thyroidectomy. Postoperatively,she had normal thyroid function with levothyroxine supplementation, but herpretibial skin changes worsened. The dermopathy extended bilaterally from justbelow the knees to the feet (Panels A and B). The skin was leathery in texture,with hyperkeratosis, fissuring, formation of verrucous nodules, and a change inpigment. A trial of therapy with topical steroids and compressive dressings wasinitiated without any noticeable improvement after one year.

N Engl J Med 2005;352:918, Mar 3, 2005

Dermopathy of Graves' Disease (legend for figure)

116

Hypothyroidism• T3 influences sexual

development and reproductivefx in both sexes

• delay in onset of puberty• anovulatory cycles

(paradoxically, primaryhypothyroidism may also causeprecocious sexual developmentand galactorrhea)

• Adult women: decreased libido,failure of ovulation, inadequatesecretion of P (probably 2º todecreased LH secretion)

• Men: dimished libido, impotence,and oligospermia

• Both sexes: metabolism of T andE is altered

Hyperthyroidism• Delayed sexual maturity,

although physical developmentis normal and skeletal growthmay be accelerated

• Thyrotoxicosis differentiallyaffects females: menstrualcycle alterations, increasedrisk of miscarriage iffertilization does occur,enhanced GnRH signaling

• Men: increased conversion of Tto E, resulting in gynecomastiaand ED

INFERTILITY IN THYROID DISEASE

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HYPERTHYROIDISM• Thyrotoxicosis/thyroid storm• Sx: see slide 113• Most common form is Graves’ disease which is an auto-

immune disorder characterized by presence of anti-TSHreceptor antibodies (resulting in persistent activation ofTSH-R)

• Drug therapy Inhibit synthesis (peroxidase)

Prophythiouracil (also inhibits peripheral deiodinase)MethimazoleCarbimazole

Block I- transport (thiocyanate; note the environmentalcontaminant perchlorate acts similarly)


118

HYPERTHYROIDISM Iodide: high levels inhibit proteolysis and inhibit T4 secretion. Also

used to protect thyroid against radioiodide damage. Radioactive iodine

[131I], 4 - 15 mCi, t1/2 = 8d, generation of hypothyroid state[123I] has a half-life of 13 hours and is used in imaging

procedures[131I] is also concentrated in salivary glands => where it is

concentrated and secreted into the saliva.Dose related damage to the salivary parenchyma results from

the [131I] irradiation Surgery: in Graves’ disease it is almost impossible to allow even a

small piece of gland to survive because Abx will stimulate it Adjuvant therapy

Ca++ channel blockersUse of βAR antagonists to block myocardial effectsGlucocorticoids can repress 5’-deiodinase


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119

HYPOTHYROIDISM• Due to thyroid (1°), pituitary (2°) or hypothalamic (3°)

disease• Hashimoto’s thyroiditis is an autoimmune disease• Severe form in adults = myxedema• Severe form in infants results in cretinism (dwarfed and

mentally retarted).• Perchlorate may cause hypothyroidism• Hypothyroid patients also develop goiter• Thyroid resistance may be due to TR mutations (TRβ)• Therapy is for replacement• Dosage forms:

Thyroid USP T4 (Synthroid, Levothroid) T3 = Liothyronine (Cytomel, Triostat injectable) T4 (+) T3 = Liotrix (Thyrolar)


120

CALCITONIN• secreted by thyroid gland in response to high

serum Ca++.• Not part of HPT axis• Decreases osteoclast activity and increases the

renal excretion of Ca++

• Antagonizes (physiologically) the actions ofvitamin D3 and parathyroid hormone.


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VASOPRESSIN*• Anti-diuretic hormone• Secreted in response to high serum osmolarity• Used clinically as a pressor (DDAVP), NOCTURAL

ENURESIS• Activates a GPCROXYTOCIN*• Secretion is stimulated by uterine stretch and strongly

induces uterine contractions• Secretion is stimulated by tactile stimulation of breast

and induces breast contractions• Used clinically to induce uterine contractions• Activates a GPCR


endo2007 part 1 final€¦ · clinical and/or licensure exams. ... • sex hormones: estrogens,...

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