34 - endocrine 2 Flashcards
chemical composition of bone
67% _
33%_
67% inorganic HA
33% organic (28%collagen) 5%noncollagenous proteins
bone generating cells
osteoblasts
mature bone cells, spider shaped and maintain bone tissue
osteocytes
bone destroying cells
osteoclasts
Bone formation is the process by which osteoblast cells
synthesize bone. In the process of bone formation,
osteoblasts function in groups of connected cells.
Individual cells cannot make bone, and the group of
organized osteoblasts together with the bone made by
a unit of cells is usually called the _
osteon
Bone resorption is the process by which
osteoclasts break down bone and release the
minerals, resulting in a transfer of _ from
bone fluid to the blood.
calcium
If the body is low on Ca++, _ will be released and these 3 things happen
1) bone resorption will increase, 2) Ca++ elimination by the kidney will decrease, 3) Ca++ absorption by the gut will increase
Parathyroid hormone (PTH)
3 - indirect effect - due to vitamin D kidney Enhance vitamin D production (calcitriol) - enhances absorption of Ca from gut
Release of Parathyroid Hormone (PTH)
high/low levels of:
Ca
PO4
vitamin D
Ca++ sensor is a G protein
coupled receptor
High Ca++ diminishes PTH release
low Ca stimulates PTH release
High PO4
3- increases PTH
release by binding Ca+
Vitamin D diminishes PTH release through
changes in gene expression (feedback effect)
when PTH is released what happens to blood levels of
Ca
PO4
Ca increases
PO4 decreases (because Ca increases)
PTH
t½ in plasma, _ minutes
Acts on two receptors
PTHR1: _ and _
PTHR2: CNS, pancreas, testis, placenta
only 4 min 1/2life
bone and kidney
PTHR1, sometimes Gαs, sometimes Gαq
PTH
Activation of PTHR1 receptors on osteoblasts, induces
expression of _, This leads to binding and
activation of osteoclasts and bone resorption
what does osteoprotegerin do?
RANK ligand (RANKL)
Important in the context of osteoporosis pharmacology
osteoprotegerin - inhibs this from happening - will bid to rankl and block osteoclast binding
PTH effects on the kidney
Maximize _ resorption, decrease _
3- resorption
Enhance vitamin _ production
Maximize Ca++ resorption, decrease PO4
3- resorption
Enhance vitamin D production (calcitriol) - enhances absorption of Ca from gut
Calcitriol plays a complex role in Ca++ homeostasis
but overall it causes _
increased Ca absorption from the gut
(decrease kidney excretion of Ca, increase bone resorption and mineralization, increase osteoclast development, decreases PTH secretion )
_ is released by parafollicular cells of the
thyroid in response to high serum Ca++. It
counteracts the effects of PTH.
Calcitonin
Increases bone formation
Decreases kidney resorption of Ca++.
Decreases Ca++ absorption by the gut
Dental Abnormalities due to PTH issues can also be an indication of _ malfunction.
kidney
Treatment of hypoparathyroidism
Oral _ tablets
Vitamin _
Parathyroid hormone analogues (see osteoporosis)
Oral calcium carbonate tablets
Vitamin D
Parathyroid hormone analogues (see osteoporosis)
Treatment of hyperparathyroidism
The calcimimetic cinacalcet: an allosteric activator of the calcium sensor. The
drug tricks the parathyroid glands into releasing _
Hormone replacement therapy (i.e. for postmenopausal women)
Osteoporosis drugs (next)
less parathyroid hormone.
_ is a disease where increased bone weakness
increases the risk of a broken bone. It is the most common
reason for a broken bone among the elderly. Osteoporosis may
be due to lower-than-normal maximum bone mass and greaterthan-normal bone loss
Osteoporosis
Menopause or ovariectomy, (due to lower levels of estrogen),
alcoholism, anorexia, hyperthyroidism, kidney disease
Medications: antiseizure medications, chemotherapy, proton
pump inhibitors, selective serotonin reuptake inhibitors, and
corticosteroid
Smoking and sedentary lifestyle
Drugs to treat osteoporosis
_ drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis
Bisphosphonates
Inhibit bone resorption and osteoclast activity
Restore bone density
Mechanism not totally understood
Drugs to treat osteoporosis
Denosumab (trade names Prolia and Xgeva) is a _ that binds and inhibits RANKL.
Denosumab is contraindicated in people with low blood
calcium levels
human
monoclonal antibody
administered by a health care professional (60 mg subcutaneously every
6 months).
Drugs to treat osteoporosis
_ bind estrogen receptors and act as agonists to enhance
estrogen activity in some tissues and act as antagonists to inhibit
estrogen activity in other tissues
Estrogen and SERMS (selective estrogen receptor
modulators
Hormones, such as estrogen, and SERMS can play a
role in osteoporosis prevention and treatment. However, there has
been some concern about potential side effects tied to the use of
hormone therapy. Some recommendations suggest using the lowest
dose of hormones for the shortest period of time
Drugs to treat osteoporosis
Teriparatide is a recombinant protein form of _ hormone consisting of the
first (N-terminus) 34 amino acids, which is the bioactive portion of the hormone
parathyroid hormone
Endogenous PTH is the primary regulator of calcium and phosphate metabolism in
bone and kidney. PTH increases serum calcium, partially accomplishing this by
increasing bone resorption. Thus, chronically elevated PTH will deplete bone
stores.
However, intermittent exposure to PTH will activate osteoblasts more than
osteoclasts.
Thus, once-daily injections of teriparatide have a net effect of
stimulating new bone formation leading to increased bone mineral density.
Teriparatide is the first FDA approved agent for the treatment of osteoporosis that
stimulates new bone formation
_ the
principal plasma
androgen
Testosterone
95% of testosterone comes
from Leydig cells of the testes
(other 5% from adrenal gland).
Some made in the ovary
Testosterone synthesis and
release stimulated by _
LH
The three
major
natural
estrogens
Estradiol (E2) - main secretory product of ovary
Made in liver
from estradiol
Estrone (E1)
Estriol (E3)
Estrogen Receptors and Treatment of Breast Cancer
If the breast cancer cells are estrogen receptor positive, estrogen is likely to be driving cell proliferation. The drug tamoxifen antagonizes the effect of estrogens in breast cancer cells and blocks _
cell
proliferation
Binding of agonist(e.g. estradiol to estrogen receptor) produces a conformational change that exposes the AF-2 region of the receptor
Co-activator proteins such as SRC-1 can only bind to the receptor if AF2 is exposed. Thus, the co-activators only bind to the receptor if agonist is bound.
Antagonists bind perfectly well to the receptor but their binding does not lead to
exposure of AT-2. Therefore, the antagonist receptor binds to the DNA, but does not
bind co-activators and the antagonist does not activate transcription.
It is speculated that things like availability of _
determines whether the SERM acts as an agonist or antagonist.
co-activators
Progestins
synthesized in
precursor to:
biological role in
males have progesterone receptors too. Not
tremendously well understood effects on male sexuality
synthesized in - corpus luteum
placenta
adrenal cortex
precursor to - androgens
estrogens
adrenocortical
hormones
bio role in menstrual cycle and
pregnancy
_ and _ Hormones during the Menstrual Cycle
these fluctuate at specific times
Pituitary and Ovarian hormones
Coordinated pattern of FSH and LH secretion during
menstrual cycle required for follicle development,
ovulation and pregnancy
Oral Contraceptives
estrogen +
progesterone
they block Block _
from the pituitary
progesterone
alone?
LH and FSH release
progesterone
alone - Thickening of cervical mucus (blocks
sperm from contacting egg), Block release of eggs from the ovary
Emergency Oral Contraceptive Pills
Higher doses of progesterone alone, or progesterone plus
estrogen
RU486, (mifepristone) a low efficacy _ partial
agonist
also a glucocorticoid antagonist
Lower dose: emergency oral contraceptive
Higher dose: abortifacient (first several months)
progesterone partial agonist
