Download Pituitary hormones - Department of Molecular & Cell Biology

Ryan Klimczak
Discussion 7
April 16th, 2007
Lectures 27,28,2932
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Hypophysiotopic hormones
(A hormone secreted by the hypothalamus that stimulates or inhibits the
adenohypophysis portion of the pituitary gland)
CRH - corticotropic releasing hormone - released from the hypothalamus. It interacts
with the pituitary to produce adrenocorticotropin hormone. Involved in the stress
response.
GHRH - growth hormone releasing hormone - The hormone released from the
hypothalamus that causes the release of growth hormone from the pituitary gland
GHIH - growth hormone inhibitory hormone - (somatostatin) - inhibits the release of
GH and TSH, suppresses the release of gastrointestinal and pancreatic hormones
and also suppressed the exocrine secretory function of the pancrease
PRH - prolactin releasing hormone - A polypeptide hormone that originates in the
hypothalamus and stimulates the secretion of prolactin in the pituitary gland.
GnRH - gonadotropin releasing hormone - A hormone made by the hypothalamus
(part of the brain). GnRH causes the pituitary gland to make luteinizing hormone (LH)
and follicle-stimulating hormone (FSH). These hormones are involved in reproduction
TRH - thyrotopin-releasing hormone - hormone released by the hypothalamus that
controls the release of thyroid-stimulating hormone from the anterior pituitary
Pituitary hormones
ACTH - adrenocorticotropin hormone - Hormone produced by the pituitary gland,
which stimulates the adrenal glands to produce cortisone
LH - lutenizing hormone - A pituitary hormone that stimulates the gonads. In the
man LH is necessary for spermatogenesis (Sertoli cell function) and for the
production of testosterone (Leydig cell function). In the woman LH is necessary for
the production of estrogen. When oestrogen reaches a critical peak, the pituitary
releases a surge of LH (the LH spike), which releases the egg from the follicle.
[Gonadotropin]
FSH - follicle stimulating hormone - hormone secreted by the pituitary gland in the
brain that stimulates the growth and maturation of eggs in females and sperm in
males, and sex hormone production in both males and females. [Gonadotropin]
Vasopressin: hormone secreted by the posterior pituitary gland and also by nerve
endings in the hypothalamus; affects blood pressure by stimulating capillary
muscles and reduces urine flow by affecting reabsorption of water by kidney
tubules
Oxytocin: involved in reproductive behaviour in both men and women, and
apparently triggers "caring" behavior. It is also the hormone which allows
contractions of the womb during pregnancy and labour
Pituitary hormones (con’t)
PL - prolactin - hormone produced by the pituitary gland that stimulates breast
development and milk production.
TSH - thyroid stimulating hormone - A hormone secreted by the anterior
pituitary gland, that controls the production and release of the thyroid hormones
(T4 and T3)
GH - growth hormone - A peptide hormone, made in the anterior pituitary, that
stimulates tissue and skeletal growth
MSH - melanocyte stimulating hormone - stimulates the production and release
of melanin (melanogenesis) by melanocytes in skin and hair. MSH is also
produced by a subpopulation of neurons in the arcuate nucleus of the
hypothalamus. MSH released into the brain by these neurons has effects on
appetite and sexual arousal.
Adrenal hormones (glucocortocoids)
Cortisol - One of the primary catabolic hormones in the body. It is
typically secreted in response to physical trauma or prolonged stress. Its
functions include controlling inflammation, increasing muscular
catabolism and glycolysis, suppressing immune response, and
maintaining normal vascular circulation and renal function, among others.
Epinephrine (Adrenaline) - A hormone produced by the adrenal glands
that also acts as a neurotransmitter for nerve cells. As part of the fight-orflight response, epinephrine signals the heart to pump harder, increases
blood pressure and has other effects on the cardiovascular system. It
helps the liver release glucose (sugar) and limits the release of insulin.
Norepinephrine (Noradrenaline) - A neurotransmitter and a hormone. It
is released by the sympathetic nervous system onto the heart, blood
vessels, and other organs, and by the adrenal gland into the bloodstream
as part of the fight-or-flight response. Norepinephrine in the brain is used
as a neurotransmitter in normal brain processes.
DHEA - (dehydroepiandrosterone) steroid precursor produced by the
adrenal gland and converted to testosterone or the estrogens by the
body's tissues. Adequate DHEA levels give the body the building blocks
necessary to produce these hormones.
Thyroid:
Thyroxine: The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are
tyrosine-based hormones produced by the thyroid gland. They act on the body to
increase the basal metabolic rate, affect protein synthesis and increase the
body's sensitivity to catecholamines (such as adrenaline). An important
component in the synthesis is iodine.
Sex hormones:
Testosterone - the male sex hormone, secreted by the testes but also
synthesised in small quantities in the adrenal glands. Testosterone is necessary
in the foetus for the development of male genitalia, and increased levels of
testosterone at puberty result in the further growth of genitalia and the
development of male secondary sex characteristics such as facial hair.
DHT - Dihydrotestosterone - The enzyme 5 alpha reductase converts
testosterone into its more potent form DHT. considered to be an aging-biomarker. Among its affects are the appearance of body-hair, the loss of scalp hair
and the onset of prostate gland problems.
Estrogen - The female sex hormone produced by the ovary. Estrogens are
responsible for the development of secondary sexual characteristics and cyclic
changes in the viginal epithelium and endothelium of the uterus.
Sex hormones (con’t)
Progesterone: A female hormone secreted by the corpus luteum after ovulation
during the second half of the menstrual cycle (luteal phase). It prepares the lining
of the uterus (endometrium) for implantation of a fertilized egg and allows for
complete shedding of the endometrium at the time of menstruation. In the event
of pregnancy, the progesterone level remains stable beginning a week or so after
conception.
Inhibin: Peptide that is an inhibitor of FSH synthesis and secretion and
participates in the regulation of the menstrual cycle.
Table 10.1 Factors Influencing Evaluation
of Endocrine Function in Aging
Physiologic Factors
Metabolic rate, body composition, dietary regimen, physical exercise,
exposure to stress (environmental and psychosocial)
Relations with other endocrines and body systems
Secretory cells and their rates of secretion
Transport of the hormones to target cells
Metabolism of the secreted hormones
Metabolites may be more or less biologically active than the
secreted hormones (e.g. more active, conversion of T to DHT)
Number and affinity of hormone receptors
Intracellular postreceptor molecular events
Occurrence of disease and use of medications
•Gene expression & new protein
synthesis
•Activation/repression of preexisting cell proteins
•Relatively long latency of onset
•Rapid onset of action
•Medium & long term cell
program
•Rapid adaptation to changes in
the milieu
•Organization of cell networks
for complex functions
•Dynamic modifications of long
term cell programs
Changes with Aging in the
Hypothalamo-Pituitary-Adrenal
Axis
No significant changes in healthy, non-stressed, elderly
The few changes that occur are rapidly compensated for
(e.g. decreased secretion of GCs from the adrenal cortex)
but also
less rapid metabolism in the liver & less urine excretion
Therefore the circulating levels remain constant
Also, normal ACTH & cortisol responses to CRH administration
Some alterations of the circadian rhythm
Exposure to Stress Generates:
• Specific responses: vary with the stimulus
(specialized responses) and generate
different responses with each different
stimulus.
• Nonspecific responses: (also called nonspecialized) are always the same
– regardless of the stimulus
– mediated through stimulation of neural,
endocrine, and immune axis
Homeostasis
From Walter B. Cannon (1871-1945)
Wisdom of the Body, 1932
From Greek: homeo “the same” stasis “state”
Indicates that for optimal function of the
organism, a steady state (or equilibrium)
must be achieved
This “constancy” of the internal environment
allows survival despite continuing changes in
the external environment (stress)
Homeodynamics
A constant environment obtained through a series of dynamic
adjustments
This continual need for adjustment is implicated in the term
“allostasis”
(From Greek allo “different” stasis “state”)
Emphasizes the dynamism of adaptive responses to stress
This adaptation to stress is often achieved with a price -- a
declining ability to adapt and/or an increased pathology and
disease
*Prof. T. Seeman, Geriatrics, UCLA (UCB alumna)
Table 10.6
Patho physiologic Responses During Stress
During Str ess
Energy st orage ceases b ecause:
 sympat het ic act ivit y
(i.e. incr eased vigilance/ arousal)
 parasympath et ic act ivity
 insulin secret ion
Access t o energy stor age is facilita t ed
and e nergy sto rage st eps are reversed because o f :
 gluc ocorti coid secret ion
 epinephrine/ norepinephr ine secret ion
gluc agon s ecret ion
glucagon secretion
Table 10.6
Patho physiologic Responses Aft er Stress
If physiologic respon ses are insuf f icient and ad apt at ion is inco mplet e,
sym pto ms of poor health are regist ered ( e.g. loss of energy wh en
f reeing energy f ro m st orage and retu rning to st orage)
Examples of consequenc es:
Muscle wast ing
Diabet es (T ype 2 )
Ulcers, colit is, diarrh ea
Inh ibit ion of growth ( in childhood)
Ost eoporo sis ( in old age)
 LHRH,  t est ost erone
Beneficial effects of Hormesis
may be due to:
DNA repair
Immune competence
Neurologic acuity
Neuromuscular activity
Better memory
Resistance/ adaptation to stress
Several lines of investigations have shown that
manipulation of the genome will result in changes of
the phenome. These changes involve alteration of
the endocrine signaling with a shift
From
• High energy
consumption
• Active growth &
development
• Active reproductive
function
To
• Reduce energy
consumption
• Arrest of growth,
development,
reproductive function
• High resistance to
stress
Shift in HPA secretory priorities during stress
STRESS
HYPOTHALAMUS
–
CRH
(corticoreleasing
hormone)
–
GHRH
GnRH
GH
Gn
Releasing Hormone
–
–
–
HYPOPHYSIS
somatotropic
hormone
–
ACTH
(adreno corticotropic hormone)
gonadotropic
hormones
ADRENAL CORTEX
Increased production of
gluccocorticoids &
inhibition of gonadal
hormones
GROWTH INHIBITION
INHIBITION OF MALE SEX
ORGANS
FSH, LH
IRREGULARITIES OF
MENSTRUAL CYCLE
Suppressing signaling from hormones such
as: insulin, growth hormone, insulin-like
growth hormone and others
by
constructing mutants with lack of the hormone
or the hormone receptors
can prolong the lifespan
as much as six times the lifespan in C.
Elegans, delaying the aging process
“I cannot, and should not, be cured of my
stress but merely taught to enjoy it” Hans
Selye, l950
Responses to stress are indispensable to our
survival as they allow us to maintain the
internal equilibrium necessary for optimal
function
Responses to stress are multifactorial (depend
on interactions of several systems)
• If response to stress is severe & prolonged it may
represent a major risk for the “diseases of
adaptation”
(e.g. cardiovascular, cognitive, emotional, metabolic
diseases)
& shorten the lifespan
• If the response to stress is moderate & of short
duration, it may stimulate hormesis:
–
–
–
–
–
–
the functions of alertness, vigilance & motivation
a greater availability & utilization of metabolic energy
favor DNA repair
improve protein folding (chaperone stimulation)
prevent/decrease free radical accumulation
promote survival and may delay aging
ON FLIES, WORMS, RODENTS:
LONGEVITY is associated
With stimulation (up-regulation)
Of genes involved in response to
stress including those of HSP
HSPs act as chaperones and
promote greater tolerance/resistance
to stress (thermic and others)
Hence, increased longevity and hormesis may depend on
Increased HSPs and their actions as chaperones
With Age:
• Incidence of Diabetes Mellitus Type 2 (late
onset diabetes, non-insulin dependent
diabetes) increases considerably
• Diabetes Mellitus Type 2 is the most common
form of diabetes
• Onset occurs years before symptoms are
appreciated
– therefore, it is important to screen high risk
individuals
Morphologic Changes
• A certain degree of atrophy
• An increased incidence of tumors
• Presence of amyloid material & lipofuscin
granules (signs of abnormal cellular
metabolism)
Pancreatic endocrine functions
•
 cells: insulin (stores glucose)
•
 cells: glucagon (mobilizes glucose)
•
 cells: Somatostatin (regulatory, inhibits
endocrine pancreas)
•
PP cells: pancreatic polypeptide
(regulatory, inhibits exocrine pancreas)
•
The pancreas also has exocrine
functions, secreting enzymes needed in
digestion (pancreatic amylase, trypsin,
chymotrypsin, etc.)
Table 14-2
Major actions of insulin
Glucose transport into
muscle & adipose cells
blood
glucose
intracellular
metabolic use
of glucose
glycogen synthesis
in liver and muscle
cells
gluconeogenesis
(in liver)
intracellular transport of
amino acids & lipids &
protein and triglyceride
synthesis
overall body
growth (general
effect)
When blood glucose is high
(hyperglycemia), glucose balance is
maintained by:
Insulin secretion
Glucose cellular
uptake (in muscle)
Endogenous production of glucose
Utilization of glucose
(muscle & adipose cells)
Storage of glucose
(in liver as glycogen), fat & amino
Acids arriving in the blood form
GI tract
How does glucose cause insulin
release?
How does insulin lower blood sugar?
Glucose from blood
vessel
Insulin primarily targets
muscle cells / adipocytes
Table14 -5 Some fa ct ors responsible for
glucose int olerance* wit h aging
Insulin alterations:
 Unchanged or elevate d plasma levels of insulin.
 Alt erat ion in insulin recept ors and t heir inte rna lizat ion in t arget t issues.
 Decreased num ber of glucose t ran spor t er units in t arget cells.
 Alt erat ions in act iviti es of cellular enzymes involved in po st -recept or cellular
respons es.
 Increased secret ory rati o of pro -insulin (less biologically act ive) t o insulin (mor e
biologically act ive).
Carbohydrate metabolism alterations:
 Decrease of bod y’s muscle mass and increase in adipo sit y.
 Diminished physical act ivity .
 Increased fas ti ng plasma fr ee fa tty acids t hat inhibit cellular glucose oxidati on.
 Increased liver gluconeogenesis.
Table 14-7 Characteristics of Diabetes Mellitus
glucose uptake
Hyperglycemia
glycogenesis
hepatogluconeogenesis
Glycosuria
Polyuria
Polydipsia
Polyphagia
protein catabolism
plasma amino acid
gluconeogenesis
Weight loss, growth inhibition
Negative nitrogen balance
lipolysys
free fatty acids
Ketosis
Acidosis
Microangiopathies
Vascular changes
Theories of Complications
1.
High levels of glucose lead to formation of Advanced Glycosylation End
products (AGEs). They cross-link proteins and accelerate atherosclerosis,
kidney damage, artery wall damage
2.
Excess Glucose is metabolized through a different pathway, the sorbitol
pathway which more readily forms reactive oxidative species
3.
Excess glucose activates Protein Kinase C and alters other cellular
pathways, leading to deleterious changes in transcription/translation and thus
causing damage
4.
?
Table 14-8
Diabetes and Accelerated Aging
DIABETES
Microangiopathy
Cataracts
Neuropathy
Accelerated Atherosclerosis
Early decreased fibroblast
proliferation
Autoimmune involvement
Skin changes
AGING
--Cataracts
Neuropathy
Atherosclerosis
Decreased fibroblast
proliferation
Autoimmune involvement
Skin changes
Anatomy of the Male Reproductive Tract
• In humans the principal reproductive organ is the
brain
• In addition to the brain, the male reproductive
system consists of the:
TESTIS
Primary sex organ suspended outside of the body in
the scrotum
Secondary male sex organs include:
EPIDIDYMIS,
VAS DEFERENS,
EJACULATORY DUCTS
which carry sperm to the urethra
SEMINAL VESISCLES, PROSTATE, & BULBOURETHRAL GLANDS
which secrete seminal fluid
PENIS with URETHRA
through which flow both urine and semen
A simplified version of
the male reproductive
endocrinology:
The hypothalamus releases
GnRH into the circulatory
system and, through blood,
directly into the pituitary.
GnRH triggers the release of
the pituitary LH and FSH that
stimulate the testes to
testosterone secretion and
sperm production.
The testis, the male primary reproductive
organ, contains three types of cells, all
necessary for reproduction:
the GERM CELLS or GAMETES,
involved in fertilization.
the INTERSTITIAL CELLS of LEYDIG
that secrete testosterone, the major
androgen
the SERTOLI CELLS
with secretory and reproductive functions
With Age:
• On the average, the male reproductive function remains
normal (or only slightly diminished in some individuals)
until advanced old age (80+ years) when it decreases
• Subtle changes include:
GnRH
Sensitivity of androgen secretion to LH
Sensitivity of negative feedback between
GnRH and LH
Table 19-13
Normal Aging of the Prostate
After age 40:
Outer regions:
Atrophy of smooth muscle and proliferation of
connective tissue
Flattening of secretory epithelium
Inner region:
Increase in the number of cells present (hyperplasia)
After age 60:
Slower, but more uniform atrophy of the prostate
Accumulation of prostate concretions
Table 19-12
The Prostate and Testosterone
The healthy prostate is dependent on androgens for growth
In the prostate: testosterone  dihydrotestosterone (DHT)
The enzyme catalyzing this reaction is 5--reductase
DHT stimulates growth of the prostate
Table 1 9- 15 Possible Risk Factor s for Benign Prostat ic
Hyperplasia ( BPH) and Prostat e Cancer






Possible Risk Factor s f or BPH
Aging
Use of a nabolic st ero ids
Dieta ry f act ors
Genet ic pre disposit ion
Env ironm ent al to xins
No oth er m ajor risk fa cto rs








Possible Risk Factor s f or Prost at e Cancer
Genet ic predisposit ion
To bacco exp osure
Cadmium expos ure
Vit amin A def iciency
Vasecto my
Sexually t ransmit t ed d iseases
Muta genic hor monal f acto rs
Dieta ry f act ors ( part icularly h igh le vel of
animal fa t)
Table 1 9- 14 Synopsis of Benign Prostat ic Hyperplasia
Charact eristics




( BPH)
Caused by g rowt h of th e pro st at e f ro m about age 40 un t il deat h
Af f ect s 50 % of m en > 5 0 ye ars o ld
Af f ect s 95 % of m en > 7 0 ye ars o ld
Clinical sympt oms d ue t o obstru cti on of th e ur eth ra are present up to
2 5 % of me n w it h histo logic e videnc e of BPH
 BPH t issue resembles no rmal prosta t e t issue w it h inc re ased am ount s
of smoot h muscle, g land ular, and / or str omal c ompon ent s
 An enlarg ed prost at e can str angle th e ur eth ra
 BPH is not f ound in men who have been castr at ed or m en who lack 5 -reducta se
Treatment of Prostate Cancer
Depends on
Life expectancy
Overall health status
Personal preferences
Size of the prostate
State of disease
Treatments include:
Watchful waiting
Surgery
Radiation Therapy
Hormonal Therapy
Cryotherapy
**PSA controversary pp. 353, 354**
Ovary Characteristics
• Ovaries
– Contain germinal cells
– Contain endocrine
producing cells
• Thecal
• Granulosa
– Determine secondary
structures and sexual
characteristics
Hypothalamus
GnRH
Pituitary
FSH, LH
Ovaries
E2, P
Normal Female
Hormone Patterns
Hormonal Changes From
Aging
• Gonadotropins:
– LH
• Change to pulsatile
pattern: hDuration,
iFrequency
– FSH
• “Monotropic FSH h
• 1st Noticed prior to any
change in cycle length
• Ovarian Steroidal
Hormones
– Estrone levels h early
in the cycle in older
ovulatory women
• Possible due to LH/FSH
alterations
– Eventually, H-P-G axis
is unable to generate
LH surge needed for
ovulation
Ovarian Structural Changes
• Abnormalities in Older
Oocyte
– Change in microtubule
and chromosome
placement at the second
metaphase of meiosis
– May be linked to
increased aneuploidy
seen in offspring of older
women
• Declining Follicular Reserve
– 2 Million Primordial Follicles
during fetal development
– Declines to 1 million at birth and
250,000 by puberty
– Primordial Follicles develop to
primary and secondary follicles
independent of hormone status
– In the absence of LH/FSH,
follicles undergo atresia
– Once follicles are depleted,
ovarian hormone production
declines
Menopause Symptoms
• Hot Flashes
– Most common reported symptom
– 70-80 % of women report signs of hot
flashes
– This rate increases in women with
oopherectomy and thin women that smoke
– Asian women have much lower rate
• 10-25 % Reported
• Possibly due to genetics, diet, lack of reporting
Physiological Characteristics
of Hot Flashes
•
•
•
•
•
•
Sweating
Increased Skin Conductance
Increased Core Body Temperature
Increased Metabolic Rate
Increased Skin Temperature
Hot flashes appear to be the result of noradrenergic
control independent of estrogen regulation
– ERT alleviates the symptoms of hot flashes
– Adrenergic receptor agonists also show promise for
treatment
Effects on Non-Reproductive
Steroidal Targets
• Skin
– Thinning of epidermis
– Atrophy of sebaceous glands
– Increased sensitivity to temperature, humidity, and trauma
• Bladder
– General Atrophy
• Results in urinary incontinence
• Hair
– Body hair undergoes redistribution
Menopause and
Non-reproductive Targets
• Skeletal System
– Osteoporosis
• Decreased bone mass following menopause that appears to be
the result of declining estrogen level
• Central Nervous System
– Psychological
• Anxiety/Depression
– Cognition/Memory
• Cardiovascular System
– Possibly due to role of estrogen in lipid metabolism