Endocrinology Pharmacology

Hormone agonists, antagonists & modulators

General Preview

 ENDOGENOUS HORMONES perform in the

normal state
 Malfunctions that lead to disease states
 Identify drugs that work to correct these
disease states
Includes

 Hypothalamic-Pituitary Hormones
 Thyroid Hormones
 Gonadal Hormones and Inhibitors
 Agents Affecting Bone Homeostasis
 Glucocorticoids and Mineralocorticoids
 Insulin and Anti-diabetic drugs
Hypothalamic-Pituitary Hormones
 General Overview Peptides &
biogenic amines
 Hypothalamus and pituitary
work in concern to regulate
the endocrine system
 Reproduction, body
growth, cellular metabolism Tropic
 Homeostasis
 Body temperature to moods
to food/water intake
 Anterior Pituitary
Hypothalamic- Hypophyseal Portal System

cell bodies of
hypothalamic
neurons hypothalamus

venus and arterial capillary

posterior pituitary
venous capillaries local action via diffusion

Figure 1
Anterior Pituitary
 Posterior Pituitary
Neural control
cell bodies of
hypothalamic
neurons
hypothalamus

axon bundles

blood flow
Vasopressin
Oxytocin
Figure 2
Posterior Pituitary
 Negative Feedback Inhibition

Hormone Homeostasis-
Maintenance of hormone
levels within a particular
physiological range
Figure 3
 Summary chart
Table 1

Target Target Organ

Hypothalamic Hormone Pituitary Hormone
Organ Hormone

Growth hormone-releasing hormone Growth hormone {GH, Insulin-like growth

{GHRH} (+) somatotropin} hormone {IGH,
Liver
Somatotropin release-inhibiting somatomedins}
hormone {SRIH, somatostatin} (-)

Corticotropin-releasing hormone Adrenocorticotropin Glucocorticoids,

Adrenal
{CRH} (+) {ACTH} mineralocorticoids,
cortex
androgens

Thyrotropin-releasing hormone {TRH} Thyroid-stimulating Thyroxine,

(+) hormone {TSH} Thyroid thiiodothyronine

Gonadotropin-releasing hormone Follicle-stimulating Estrogen,

{GnRH} hormone{FSH}, Luteinizing Gonads progesterone,
hormone {LH} testosterone

Dopamine (-) Prolactin {PRL} Breast ---

 Therapeutic Overview
 Hypothalamic releasing hormones are
primarily used for diagnostic purposes
 Pituitary hormones
 Cannot be given orally
 Replacement therapy
 Drugs used to regulate the secretion
Hypothalamic Hormones
 Growth Hormone-Releasing
Hormone (GHRH)
 44 amino acid peptide
 Full biological activity in 1-29
 Structural homologies to GI peptide hormones
 Function
 Stimulates synthesis and release of growth
hormone (GH) from the anterior pituitary
 Research purposes only
 IV, SubQ
 IV half life is 4 minutes
 Growth Hormone-Releasing
peptides (GHRPS)
 Group of synthetic peptide analogs
that can stimulate GH secretion
 Withdrawn from US market in 2002
 Sermorelin {Geref}
 Synthetic 1-29 terminal end of GHRH
 Must have properly functioning pituitary
Somatostatin (Growth Hormone-
Inhibiting Hormone, Somatotropin Release-inhibiting
hormone)

 Structure- 14- or 28-amino acid structure

 Function
 Inhibits growth hormone release in normal
individuals, thus opposes GHRH
 Inhibits the release of glucagon, insulin TSH, LH
and gastrin (GI hormones)
 Lowers the rate of gastric empting and reduces
smooth muscle contractions and decreases blood
flow the intestine
Somatostatin
 Half life 1-3 minutes
 Kidney is key in metabolism and
elimination
Octreotide {Sandostatin LAR}

 Somatostatin analog
 Inhibits release of GH from pituitary
 Pharmacokinetic
 Half life of 80 minutes
 Administered SC or IV
 45x more potent than endogenous
peptide
 Octreotide
 Therapeutic use
 Treatment of a variety of hormone-secreting
tumors
 Acromegaly
 Adverse reactions
 Biliary tract abnormalities
 Gallstones, sludge without stones, biliary duct dilation
 Bradycardia, nausea, vomiting, abdominal cramps,
flatulence
 Acromegaly

 Excess GH in adults
 Usually from a pituitary
carcinoma
Gonadotropin-Releasing Hormone
Luteinizing hormone-releasing hormone

 Pulsatile GnRH secretion stimulates the

gonadotroph cells in the anterior pituitary
to produce and release luteinizing
hormone and follicle stimulating hormone
 Sustained non-pulsatile administration
inhibits the release of FSH and LH by the
pituitary in both males and females
 Gonadorelin {Factrel}
 Synthetic GnRH
 Small peptide
 Diagnostic purpose only
 Portable pump system
 Male and female infertility
 Administered SC and IV
GnRH Analogs (Table 3)
 Synthesized by selective substitution of amino acids
 Buserelin
 Sc, nasal spray

 Leuprolide {Eligrad}
 Highly effective at decreasing estrogen levels

 Nafarelin {Synrel}
 Nasal spray

 Goserelin {Zoladex}
 Implantable cylinders
GnRH Analogs
 Treatment of
 Endometriosis and Uterine fibroids
 Breast cancer
 Prostate cancer
 Central precocious puberty
 Male and female infertility
 Adverse reactions
 Hot flashes, acne, depression, vaginal bleeding
 Tachycardia, lightheadedness
 Usually transient
 Possibility of a LH surge during treatment
GnRH Antagonist
 Binds to pituitary GnRH receptors
without activation
 Blocks secretion and release of LH and
at high doses FSH
 Immediate suppression of LH
 Ganirelix {Antagon}
 Cetrorelix {Cetrotide}
GnRH Antagonist
 Treatment of
 In vitro fertilization
 Endometriosis and uterine fibroids
 Advantage
 Decrease risk of LH surge
 Injectables
 Adverse reactions
 Nausea
 HA
 Vaginal bleeding
Corticotropin-Releasing Hormone
 Secreted in response to stress
 Stimulates corticotropin cells to produce
adrenocorticotropic hormone (ACTH)
 Diagnostic use only
Thyrotropin-Releasing Hormone
 Stimulates secretion of thyroid
stimulating hormone (TSH) from the
anterior pituitary
 Protirelin {Relefact TRH}
 Diagnostic purposes only
Anterior Pituitary Hormones
Growth Hormone (Somatotropin)
 Polypeptide hormone, 191 amino acids
 Released from the anterior pituitary in
response to GHRH
 Inhibited by GHIH
(somatostatin)
 Recombinant human
growth hormone
Growth Hormone (Somatotropin)
 Induces lipolysis in adipose tissue and
growth in skeletal muscle
 Binding to its receptor (direct)
 Adipose tissue stimulated to break down
triglyceride and stops the uptake of circulating
lipids
 Insulin-like growth factor-1 (indirect)
 Stimulates the liver to release IGF-1
target tissues>produces growth at open
epiphyses
GH Available
 Recombinant human GH
 Somatropin {Humatrope, Genotropin,
Norditropin, Nutropin, Saizen, Serostim,
Zorbtive}
 Identical to natural hGH
 Somatrem {Protropin}
 US market in 1985
 IM or SC injections
 Appear to be equipotent
Disease States
 Deficiency
 Children
 Failure to grow conditions
 Kidney disease, Turner’s syndrome

 GH deficiency; genetic or acquired

 Adults
 Generalized obesity, reduced muscle mass,
asthenia and reduces cardiac output
 Widely abused hormone
GH
 Adverse reactions
 Intracranial hypertension
 HA, muscle weakness, visual changes,
nausea, vomiting
 Gynecomastia
 Contraindications
 Children with closed epiphyseal plates
 Diabetes
 Monitor very closely
Growth Hormone Receptor Antagonist
 Binds to GH receptors, blocks GH-
stimulated, hepatic production of IGF-1
 Pegvisomant {Somavert}
 Injection/Rx only
 Treatment of
 Acromegaly
 Increased growth hormone in adults
Pegvisomant {Somavert}
 Adverse reactions
 Liver- yellowing of the skin, abdominal
pain, dark urine, vomiting
 Allergic reactions, discomfort at injection
site
 CI
 Liver disease
Follicle Stimulating Hormone
 Glycoprotein hormone consisting of two
chains
 Produced by gonadotroph cells in the
anterior pituitary
 Stimulates gametogenesis and follicular
development in women and
spermatogenesis in males
 Stimulates androgen conversion into
estrogen
Menotropin {Humegon}
 Commercially available since 1960s
 human Menopausal Gonadotropins (hMG)
 Purified from urine of post-menopausal females
 Combination of FSH and LH
 MENOPAUSE happens when no follicles
remain in the ovaries
 ESTROGEN and PROGESTERONE are no longer
made, thus leading to high levels of circulating
FSH and LH
Urofollitropin {Bravelle}
 Purified FSH
 Derived from post-menopausal females
Follitropin Beta {Follistim}
 1996, recombinant technology
 Batch to batch consistency, and highly
pure
 Cost 3x as much as hMG
 Injectables
 Treatment
 Anovulatory females
 Pituitary and hypothalamic hypogonadism
with infertility
Follitropin Beta {Follistim}
 Adverse reactions
 Abdominal pain, vaginal bleeding, ovarian
cysts
 Injection site pain, rash
 Risk of multiple births
Luteinizing Hormone
 Glycoprotein consisting of two chains
 Regulation of gonadal steroid
production
 No LH clinically available
 human Chorionic Gonadotropin
(hCG)
 IM injection
 Half life of 8 hours
human Chorionic
Gonadotropin (hCG)
 Diagnostic use
 Treatment of infertility
 Induce ovulation
 Adverse reactions
 Headache
 Depression
Adrenocorticotropin Hormone
(ACTH)
 Cosyntropon {Cortrosyn}
 Synthetic subunit of human ACTH
 Exhibits the full activity of natural ACTH
 Diagnostic use only
Thyroid Stimulating Hormone
(TSH)
 Thyrotropin Alpha {Thyrogen}
 Recombinant DNA technology
 Comparable biochemical properties to
human TSH
 Diagnostic use only
Prolactin
 198 amino acid peptide with three
disulfide bonds
 Lactation
 Recombinant agents not available
 Hypothalamic dopamine inhibits the
secretion and release of prolactin
(Figure 4)
Prolactin

Positive regulation on
prolactin release:
Thyroid-releasing
hormone and
gonadotropin-releasing
hormone, stimulation of
the nipple and
mammary gland, and
estrogens
Dopamine Agonists
 Decrease prolactin secretion through a
dopamine-mimic action
 Bromocriptine {Parlodel}
 Pergolide {Permax}
 Cabergoline {Dostinex}
 Quinagolide {Norprolac}
 Oral administration
Dopamine Agonists
 Treatment of
 Prolactin secreting adenomas
 Acromegaly
 Parkinson’s disease
 Restless legs syndrome
 Adverse reactions
 Headache, light headedness, fatigue
 Psychotic reactions
Posterior Pituitary
Oxytocin {Pitocin}
 Induce labor
 IV or nasal spray
Vasopressin
 Anti-Diuretic Hormone (ADH)
 Octapeptide with a six amino acid ring
and three amino acid side chain
 {Pitressin}
 Two functions
 Renal
 Blood vessels
 Vasopressin Function
1 Stimulates the
insertion of water
channels or
aguaporins into the
membranes of the
kidney tubules >
increasing water
permeability>
decreasing urine
output
2 Vascoconstriction
Desmopressin {DDAVP}
 Synthetic vasopressin
 Injection, nasal spray, tablets
 4000X as potent as natural vasopressin
 Treatment for DIABETES INSIPIDUS
 Adverse reactions
 HA
 Nausea
 Abdominal cramps
 Well tolerated
Thyroid and Anti-Thyroid
Agents
General Overview
 Responsible for
 Growth
 Development
 Function and maintenance of all body
tissues
 Hypothyroidism
 Autoimmune destruction, Hashimoto’s Dz
 Hyperthyroidism
 Grave’s disease
 Toxic nodular goiter
Goiter
Grave’s Disease

Thyroid Eye Disease

 Thyroxine (T4) and Triiodothyronine (T3)
 Thyroid releasing
hormone
 Thyroid
stimulating
hormone
 Negative
feedback loops
intact
Thyroxine (T4) and Triiodothyronine (T3)

 Produced by the thyroid gland

 Iodinated tyrosine molecules
 T4 produced within the thyroid
 T3 converted (from T4) at peripheral
tissues
 Thyroid peroxidase
 Iodide organification
 Coupling
Biosynthesis of TH
 Iodide + H2O2= I2

Tyrosine scaffold;
each molecule
contains 134
tyrosines
Coupling
Organification
Hypothyroidism
 T4 or T3 supplementation

Hyperthyroidism
 Anti-thyroid drugs
 Radioactive iodine
 Surgery
Levothyroxine {Synthroid}
 Synthetic human T4
 Table, one time/day dosing
 Half-life 7 days
 Drug of choice for thyroid
replacement therapy
Liothyronine {Cytomel}
 Synthetic human T3
 3-4x more potent than levothyroxine
 Tablet or injectable
 Half life 24 hours, required multiple dosing
 Short term suppression of TSH
 Becoming more commonly used in thyroid
hormone replacement therapy
 Desiccated Thyroid
{Amour Thyroid}
 Animal origin
 Mixture of T3 and T4
 Tablets
 Not used much anymore
Adverse Reactions
 Thyrotoxicosis
 Therapeutic overdose
 Hypersensitivity reactions
 Hair loss
 Fairly well tolerated medication
 Anti-Thyroid Agents
 Perchlorate
 Decreased thyroid
production by
competing with
iodide for the
sodium/iodide
symporter
 Rarely used clinically
 Aplastic anemia
 Thioamides
 Bind to thyroid
peroxidase
 I- not converted to I2
 Inhibits
organification and
coupling
Thioamides
 Propylthiouracil (PTU)
 Inhibits deiodination of T4 to T3 at
peripheral tissues
 Generic only
 Tablet, tid dosage
 Half-life 1.5 hours
Thioamides
 Methimazole {Tapazole}
 10x more potent than PTU
 May be less consistent than PTU
 Tablet, once a day dosing
 Half life 6 hours
Thioamides
 Accumulate in thyroid gland
 Adverse reactions
 Flu-like symptoms
 Fever- serious (aplastic anemia)
 Insulin-autoimmune syndrome
(hypoglycemic coma)
 Skin rash, hair loss, drowsiness
Gonadal Hormones and
Inhibitors
The Female
 Major sex hormones
 Estrogens
 Progestins
 Function
 Development of secondary sex
characteristics
 Control pregnancy
 Control Ovulatory-Menstrual cycle
 Bone Homeostasis
 Estrogens
 17Beta-Estradiol
 Principle ovarian estrogen
 Most potent
 Estriol
 Principle placental estrogen
 Estrone
 Metabolite of 17Beta-estradiol
 Major ovarian and post-menopausal estrogen
Estrogens
 Functions
 Conversion of girls into sexually-mature women
 Participate in the monthly preparation of the
body for a possible pregnancy
 Participate in pregnancy, if occurs
 Non-reproductive Functions
 Antagonize the effects of parathyroid hormone
 Minimize the loss of calcium from bones (help bones
stay strong)
 Promotes blood clotting
Progestin
 Progesterone
 Secreted by the
 Corpus luteum
 Placenta
 Functions
 Preparing the body for pregnancy
 Maintains pregnancy
Negative Feedback Loops
 Estrogen synthesis
and secretion
stimulated by FSH
 Progesterone
production stimulated
by LH
 Inhibin
 Ovarian protein
 Negatively affects
FSH
 Menopause
 No Follicles remain in
the ovaries
 Estrogen and
progesterone no longer
produced, leading to
high levels of
circulating FSH and
LH
 Adrenal androgens
are still produced
Therapeutic Overview
 Fertility control
 Contraception
 Infertility Therapy
 Replacement therapy
 HRT for most-menopausal females
 Osteoporosis
 Cancer chemotherapy
 Breast cancer
 Endometrial cancer
Major drugs
 Estrogens
 Progestins
 Combinations of above (contraception)
 Anti-progestins
 Inhibitors of steroidogenesis
 SERMs
Biosynthesis
 Estrogen
 Ovary
 Other tissues produce significant amounts
 Progesterone
 Placenta
 Corpus luteum in ovary
Steroidogenesis
 Cholesterol is
converted to
pregnenolone
 Converted directly to
progesterone or to
17alpha-
hydroxypregnenolone
 Androgen steroids
 Testosterone
 Androstenedione
Steroidogenesis
 By an AROMATASE
(enzyme), the
androgens can be
converted to
ESTRONE and
ESTRADIAL
Receptors
 Primarily in nucleus
 Estrogen alpha & beta
 Progesterone A & B
Estrogen Agents
 Naturally occurring (human)
 Rapidly inactivated
 Not much value therapeutically
 Conjugated, esterified or mixed
estrogenic substances
Conjugated estrogens {Premarin}
 Estrogens produced by natural source,
stallions
 Widely prescribed form of estrogens in the
US
 Tablets, vaginal cream, injectables
 Treatments
 Menopausal symptoms (HRT)
 Prevent osteoporosis
Estrogen Agents
 Chemical alterations: increase oral effectiveness
 Steroidal, synthetic
 Ethinyl Estradiol

 Mestranol

 Quinestrol {Estrovis}
 HRT
 Contraception in combos with progestins
 Non-steroidal, synthetic
 Diethylstilbestrol (DES)

 Chlorotrianisene {Tace}
 HRT
Adverse Reactions
 Black box warnings
 Unopposed estrogen therapy increases risk of

endometrial cancer
 Increase risk of venous thromboembolism

 Increase risk of uterine bleeding

 Hypertension
 Breast tenderness, migraines
 Weight changes, water retention, swelling of ankles
and legs
Progestin Agents (Table 4)
 Natural (human)
 Diagnostic test
 Women having difficulty conceiving or
maintaining pregnancy
 Injectable only
Progesterone Derivatives
 Hydroxyprogesterone caproate
 Medroxyprogesterone {Depo-Provera,
Provera}
 Megestrol acetate (PO)
 Treatment of anorexia or unexplained weight loss
in AIDS patients
 Most closely related to natural progesterone,
both structurally and pharmacologically
Synthetic Progesterones
 Altered to give better oral
effectiveness
 Possess some degree of androgenic
effects
 19-nortestosterones derivatives
 Levonorgestrel {Plan B}
 Combo with estrogen {Alesse}
 Norethindrone {Micronor}
 Norgestrel {Ovrette}
19-nortestosterones Derivatives

 Produce unproductive changes in

endometrial stroma
 Do not support pregnancy in test
animals
 Effective gonadotropin inhibitors
Progesterone Derivatives
 Treatment
 Contraception
 Produce long-term ovarian suppression
 Methoxyprogesterone acetate {Depo-Provera}
 150 mg IM q90days
 Anovulation and Amenorrhea

 Black box warning

 Bone loss with prolonged use
Adverse Reactions
 Peripheral edema
 Depression
 Acne, hirsutism, weight gain
 Combo HRT
 Increased risk of pulmonary embolism,
stroke and breast cancer
 65 years and older> increased risk of
developing demensia
 Danazol {Danocrine}
 Synthetic hormone derived from ethisterone
 Anti-progestin; non-specific inhibitor of
steroidogenesis (Figure 1)
 Used to suppress ovarian function by
inhibiting the mid-cycle surge of LH
 Inhibits FSH
Danazol {Danocrine}
 Oral; bid dosing
 Treatment of endometriosis
 Adverse reactions
 Acne and oily skin, weight gain,
decreased breast size, hirsutism, and
edema
Selective Estrogen Receptor
Modulators (SERMs)
 Medications that act on estrogen receptors
 Action differs tissue to tissue, thereby
granting the possibility to selectively inhibit
or stimulate estrogen-like action in
various tissues
 Clomifene, toremifene, bazedoxifene,
lasofoxifene, ormeloxifene
 Stereochemically similar to 17beta-estradiol
 Tamoxifen {Nolvadex D®,
Soltamox®, Tamofen®}
 Competitive partial agonist inhibitor of
ESTRADIOL at the estrogen receptor, so
transcription of estrogen-responsive genes is
inhibited
 Non-steroidal agent, given orally
 Used in the treatment of breast cancer
 FDA approved for the reduction of incidence
of breast cancer in high risk women and
contralateral breast cancer
 Prevents gynecomastia in bodybuilders using
steroids
Adverse Reactions
 Hot flashes
 Altered menses
 Bone pain
 Head ache
 Nausea and vomiting
Raloxifene {Evista}
 Partial estrogen agonist-antagonist
at some, but NOT all target tissues
 Effects lipid and bone, but appears not
to stimulate the endometrium or breast
 Reduces resorption of bone and
decreases overall bone turnover
 Once a day oral dose
 Treatment of osteoporosis
Adverse Reactions
 Hot flashes
 Leg cramps
 Well tolerated in clinical trials
Inhibitors of
Steroidogenesis
 Aminoglutethimide {Cytadren}
 Blocks conversion of cholesterol to
pregnenolone, resulting in decreased production
of adrenal glucocorticoids, mineralocorticoids,
estrogens and androgens
 Blocks several other steps in steroid synthesis,
C-11, C-18 and C-21 hydroxylations and
aromatase enzymes
 PO, tablets
Aminoglutethimide {Cytadren}
 Treatment of
 Cushing's syndrome
 Breast carcinoma
 Adverse Reactions
 Adrenocortical insufficiency
 Drowsiness
 Dizziness, lowered vascular resistence
 Skin rash
 Anorexia
Letrozole {Femara}
 Non-steroidal aromatase inhibitor,
thus decreasing estrogens
 Treatment of breast cancer
 PO, once a day
 Adverse reactions
 Generally well tolerated
 Hot flashes
Anastrozole {Arimidex}
 Non-steroidal aromatase inhibitor, thus decreases
estrogens
 Potent and very selective
 PO, once a day
 Treatment of breast cancer
 Preferred medical therapy for postmenopausal women
 Adverse reactions
 Hot flashes and sweats
 Vaginal dryness
 Nausea and vomiting
 Hair thinning
Exemestane
{Aromasin}
 Irreversible, steroidal aromatase
inhibitor, significantly lowers circulating
levels of estrogens (85% suppression)
 Structurally related to natural
androstenedione
 Treatment of hormonally-responsive breast
cancer in post-menopausal females
 Adverse reactions
 Hot flashes and sweating

 Fatigue, difficulty sleeping

 Joint pain, HA
The Male
 Testosterone
 Stimulates virilization and important in
spermatogenesis
 Androgens (in both sexes)
 Stimulate hair growth
 Bone growth
 Muscle development
 erythropoiesis
 Therapeutic Overview
Androgens
Primary testicular insufficiency
Hypogonadotropic hypogonadism
Constitutional delay of growth in adolescence
Osteoporosis, anemia
Male contraception
Anti-androgens and androgen antagonists
Virilization in women
Precocious puberty in boys
Prostate cancer
 Synthesis of Testosterone

Principle pituitary
hormone LH

Important prostate
androgen
Hypothalamic-Pituitary-Testis Axis
Androgen Agents
 Natural
 Not used therapeutically
 Synthetic androgens
 Testosterone Enanthate {Delatestryl}
 Commonly prescribed in the US
 Slow-acting ester with release time between 8-
10 hours
 Injectable; once every week to once every
three weeks
Synthetic Androgens
 Testosterone Cypionate {Depo-
testosterone}
 Slow-acting ester
 Testosterone Propionate {Testovis}
 Fast-acting ester with a release time of 3-4
days
 Injectable, 1-3x/week
Synthetic Androgens
 Treatment
 Replacement therapy
 1:1 androgenic/anabolic ratio
 Fluoxymesterone
 Oxymetholone {Androl-50}
 Schedule III drug
 50 mg tablets, PO
 Very low affinity for the androgenic receptors
 Considered by body builders to have the strongest
anabolic effect of any oral steroid
 20 lbs in 2 weeks
Androgen Agents
 Oxandrolone {Oxandrin}
 Majority of effects are due to reaction with
the androgen receptor
 Class I steroid
 Orphan drug status
 Alcoholic hepatitis
 Turner’s syndrome
 Weight loss caused by AIDS
Treatments
 Androgenic insufficiency
(REPLACEMENT THERAPY IS PRIMARY
THERAPEUTIC USE)
 Severe burns and senile osteoporosis
(anabolic effect)
 Promote growth in children
 Unapproved uses- increase lean body
mass, muscle strength and
aggressiveness/DRUGS OF ABUSE
Adverse Reactions
 Fluid and electrolyte disturbances:
retention of sodium, chloride, water,
potassium and calcium
 Nervous system: increased or
decreased libido, HA, anxiety,
depression
 Male pattern baldness, acne, infertility
(at high doses), enlargement of
prostate gland
Finasteride {Propecia}
 Inhibits 5-reductase, enzyme responsible
for the conversion of testosterone to
dihydrotestosterone (DHT)
 Dihydrotestosterone is the ESSENTIAL
androgen in the PROSTATE, therefore
reducing the enzyme leads to a reduction in
DHT
 PO
 Treatment of benign prostate hyperplasia
(reduces size) and male pattern baldness
Adverse Reactions
 Well tolerated
 Mild and transient
Flutamide {Eulexin}
 Potent non-steroidal, anti-androgen
 Competitive antagonist at the receptor
and inhibits androgen uptake
 PO
 Treatment of prostate cancer
 Black box warning
 Liver failure
 Adverse reactions: hot flashes, loss of libido,
impotence, gynecomastia
Agents Affecting Bone
Mineral Homeostasis
General Overview
 Two important minerals
 Phosphate
 Calcium
 Concentration in plasma maintained within a
narrow range, 8.5-10.4 mg/dL
 Allows the normal conduction of electrical
currents along nerves
 Causes muscles to contract
 Makes bones strong
Calcium Regulation
 Two principle hormones
 1,25 (OH)2D3
 Parathyroid hormone (PTH)
 Minor hormone
 Calcitonin
 Gut
 Bone
 Kidney
Gut
 0.5-1.5 mg/day ingested
 Vitamin D affects absorption
 Present enhances absorption
 Absent impairs absorption
 10-20% dietary calcium absorbed
 Intestinal disease disrupts bone mineral
homeostasis
Kidney
 Steady state renal excretion balances
intestinal absorption
 10-20 gms/day
 Renal tubular reabsorption recovers 99%
 Vitamin D, calcitonin and PTH
 Increase phosphorus excretion
 Decrease Calcium excretion
 Diuretic can alter reabsorption of calcium
 Kidney disease disrupts bone mineral
homeostasis
Bone
 Major storehouse of calcium
 1 gram/70 kg person
 99% in stable pool
 1% in exchangeable pool
 Turnover about 20g/day
 Passive physicochemical process
 85% of phosphorous
 Increase input of calcium and
phosphorus into serum
Specific Disorders (Table 1)
 Hypocalcemia
 Inadequate dietary calcium and/or Vitamin D
 Malabsorption disorders
 Hypoparathyroidism
 Renal failure
 Increased excitability, tetany, and impairment
of mineralization of the skeleton
 Treatment
 Vitamin D compounds and calcium
 Specific Disorders
 Hypercalcemia
 Hyperparathyroidism
 Hypervitaminosis D
 Sarcoidosis
 Neoplasia
 Hyperthyroidism
 Immobilization
 Results in life threatening cardiac dysrhythmias,
kidney stones and CNS abnormalities
Treatment
 Bisphosphonates
 Calcitonin
 Glucocorticoids
 Anti-inflammatory agents
 Loop diuretics
 Low calcium diet
 Sulfate
 Plicamycin
Specific Disorders
 Osteoporosis
 Loss of normal bone structure and increased
fracture susceptibility
 Treatment
 Bisphosphonates
 Calcitonin
 Estrogen, SERMs
 Calcitriol
 Anabolic steroids
 Calcium and Vitamin D
Table 2: Therapeutic Overview

Vitamin D & metabolites, and Vitamin D analogs

Rickets Hypoparathyroidism
Osteomalacia Psoriasis
Hypocalcemia
Parathyroid Hormone
Osteoporosis

Calcitonin
Paget’s disease of bone
Osteoporosis
EDTA, furosemide, ethacrynic acid, glucocorticoids, plicamycin
Hypercalcemia

Calcium, estrogen, SERMs, bisphosphonates, calcitonin

Osteoporosis
Parathyroid Hormone
 84 amino acid peptide; 1-34 full activity
 Produced in the parathyroid gland
 Function
 Regulation of calcium level
 Leaves phosphorous levels unchanged
 Low calcium levels = more PTH
 High calcium levels = less PTH
 Parathyroid Hormone
 Both bone absorption and bone formation are
enhanced by PTH
 Net effect of excess PTH is to increase bone
absorption
 Low or intermittent doses, increases bone
formation without first stimulating bone resorption
 Indirect effect
 PTH binds to osteoblasts >>> expression of RANKL
>>> bind to osteoclast precursors containing RANK
>>> stimulates formation of new osteoclasts>>
enhances bone resorption
Disorders
 Hypoparathyroidism
 Hypocalcemia
 Extremity and periorbital paresthesias
 Muscle cramping and spasms
 Altered mental status
 Psychosis
 Pain
 Surgical misadventure, autoimmune disorders
or inborn errors of metabolism
Disorders
 Hyperparathyroidism
 Hypercalcemia
 Altered mental status (depression)
 Osteoporosis
 Heartburn
 Nausea, vomiting and abdominal pain
 High blood pressure
 “moans, groans, stones, and bones… with
psychotic overtones”
 Benign adenoma, chronic renal failure
Teriparatide
{Forteo}
 Synthetic PTH 1-34 produced by rDNA
technology
 Anabolic (bone building)
 Increases bone density at the spine and (to a
lesser degree) at the hip over a two year period
 Treatment of osteoporosis
 SC injection once/day
 Adverse reactions
 Produced osteosarcoma in animal studies
 Dizziness, muscle cramps, hypercalcemia
Vitamin D
 Secosteroid
 Binds to receptors in the nucleus of target
cells
 Synthesized from cholesterol in the skin
in response to UV light
 Pro-hormone that is converted to active
metabolites in the liver and kidney
 Figure 2: Synthesis of Vitamin D

24,25[OH]2D3 = Secalcifediol

In Liver In Kidney
Calcitriol

Vitamin D3 first goes to the liver and is hydrolyzed to 25-

hydroxycholecalciferol, then travels to the kidney and is
further converted to many metabolites.
Metabolic Regulation
 PTH
 Most important
 Stimulates production of 1,25(OH)2D3 by
the kidney in response to low phosphate
concentration
 Net effect increase both calcium and
phosphate serum levels
Receptors for Calcitriol
 Exist in a wide variety of tissues
 Regulation of parathyroid hormone
 Insulin secretion from the pancreas
 Cytokine production by macrophages and T
cells
 Proliferation and differentiation of a large
number of cells, including cancer cells
 Clinically utility of Vitamin D analogs is likely
to increase
Natural Occurring Vitamin D
 Calcifediol {Calderol}
 Synthetic 25(OH)D3
 PO, rapid absorption: requires bile salts
 Calcitriol {Rocaltrol, Calcijex}
 Synthetic 1,25 (OH)2D3
 Capsule or solution, PO, rapid absorption:
requires bile salts
 Parenteral
 Higher risk of causing hypercalcemia
Treatment of
 Hypocalcemia
 Hypoparathyroidism
 Osteomalacia
 Rickets
 Chronic renal failure
 Osteoporosis
Adverse Reactions
 Nausea/vomiting
 Loss of appetite, unusual weight loss
 Constipation
 Increased thirst and urination
 Bone/muscle pain
 Weakness, tiredness
 Tachycardia
 Vitamin D Analogs (Table 3)
Dihydrotachysterol
 Manipulation Active even in absence of renal enzymes
of natural Oral
metabolites Calcipotriene (calcipotriol)
Currently being used in the treatment of
to extend psoriasis
the 1alpha-hydroxyvitamin D2: Doxercalciferol
therapeutic 19-nor-1,25-Dihydroxyvitamin D2:Paricalcitol
usefulness Less action on calcium metabolism, less
chance of hypercalcemia
Parental
Used to suppress elevated PTH secretion in
chronic renal disease
 Calcitonin
{Miacalin, Nasal spray; Calcimar}
 Single chain peptide hormone with 32 amino
acids
 Secreted by the mammalian thyroid gland
 Principal effect to lower serum calcium and
phosphate by actions on bone and kidney
 Salmon calcitonin: longer half life and
reduced metabolic clearance
 Injectable, nasal spray
Calcitonin
 Act directly on osteoclasts via receptors
on the cell surface, osteoclasts shrink
and stop bone resorption
 Treatment of
 Paget’s disease
 Osteoporosis
 Relieve pain from broken bones
 Hypercalcemia
 Effect diminished with continued use
Adverse Reactions
 Rhinitis
 Nausea and vomiting
 Diarrhea
Glucocorticoids
 Lower serum calcium
 Treatment of
 Hypercalcemia
 Vitamin D intoxication
 Prolonged use leads to osteoporosis
and stunted skeletal growth in children
Estrogens
 Prevent accelerated bone loss during
immediate postmenopausal period
 Transiently increase bone in
postmenopausal women
 Reduces the bone absorbing action of
PTH
Bisphosphonates
 Non-hormonal small molecules
 Actions
 Inhibit osteoclast activity
 Selectively inhibit bone resorption
 Accumulate in bone; retained in bone for years (10
years)
 Eliminated unchanged in urine
 Prevents fractures
 PO, injectable
Bisphosphonates
 Etidronate {Didronel}
 Known to cause hyperphosphatemia and
osteomalacia
 Pamidronate {Aredia}
 Alendronate {Fosamax}
 Risedronate {Actonel}
 Zoledronate {Zometa}
 Ibandronate {Boniva}
Bisphosphonates
 Treatment
 Paget’s disease
 Osteoporosis
 Men and Women
 Adverse Reactions
 Increase PTH
 Oral preparations
 Hypocalcemia
 Upper GI irritation
 Bone pain
 Esophageal
ulceration
 Skin rash