Ryan Klimczak

Discussion 7

April 16th, 2007

Lectures 27,28,29-32

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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-or-flight 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-bio-marker. 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 systemsSecretory cells and their rates of secretionTransport of the hormones to target cells

Metabolism of the secreted hormonesMetabolites 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 receptorsIntracellular postreceptor molecular eventsOccurrence of disease and use of medications

•Gene expression & new protein synthesis

•Relatively long latency of onset

•Medium & long term cell program

•Organization of cell networks for complex functions

•Activation/repression of pre-existing cell proteins

•Rapid onset of action

•Rapid adaptation to changes in the milieu

•Dynamic modifications of long term cell programs

Changes with Aging in the Hypothalamo-Pituitary-Adrenal

AxisNo 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 non- specialized) are always the same – regardless of the stimulus– mediated through stimulation of neural,

endocrine, and immune axis

HomeostasisFrom 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)

HomeodynamicsA 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)

Pathophysiologic Responses During StressDuring Stress

Energy storage ceases because:↑ sympathetic activity

( i.e. increased vigilanc /e arousal)↓ parasympathetic activity↓ insulin secretion

Access to energy storag e is facilitateda nd energy storage steps are reversed becaus e of:

↑ glucocorticoid secretion↑ epinephrine/ norepinephrin e secretion

↑ glucag on secretion glucagon secretion

Table 10.6

Pathophysiologic Responses After StressIf physiologic responses are insufficient and adaptation is incomplete,

symptoms of poor health are registered (e.g. loss of energy whenfreeing energy from storage and returning to storage)

Examples of consequences:Muscle wastingDiabetes (Type 2)Ulcers, colitis, diarrheaInhibition of growth (in childhood)Osteoporosis (in old age)↓ LHRH, ↓ testosterone

Table 10.6

Beneficial effects of Hormesis may be due to:

DNA repair

Immune competence

Neurologic acuity

Neuromuscular activity

Better memory

Resistance/ adaptation to stress

• High energy consumption

• Active growth & development

• Active reproductive function

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

• Reduce energy consumption• Arrest of growth, development, reproductive function• High resistance to stress

FromTo

STRESS

HYPOTHALAMUS

HYPOPHYSIS

ADRENAL CORTEX

Increased production of gluccocorticoids &inhibition of gonadal hormones

GHRH GH

GnRH Gn

somatotropichormone

gonadotropic hormones

GROWTH INHIBITION

INHIBITION OF MALE SEX

ORGANS

IRREGULARITIES OF

MENSTRUAL CYCLE

FSH, LH

Releasing Hormone

CRH(cortico-releasinghormone)

ACTH(adreno cortico-tropic hormone)

– –

–

–

–

–

Shift in HPA secretory priorities during stress

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 onIncreased 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.)

Glucose transport into

muscle & adipose cells

Table 14-2 Major actions of insulin

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 & aminoAcids 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 factors responsible forglucose intolerance* with aging

Insulin alterations:• Unchanged or elevate d plasma levels of insulin .

• Alt erat ion in insulin recept ors and t heir inte rnalizat ion in t arget t issues.

• Decreased number of glucose t ranspor t er units in t arget cells.

• Alt erat ions in act iviti es of cellular enzymes involved in post -recept or cellularrespons es.

• Increased secret ory rati o of pro-insulin ( less biologically act ive) t o insulin (mor ebiologically act ive).

Carbohydrate met abolism alterations:

• Decrease of body’ s muscle mass and increase in adiposit y.

• Dimin ished 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

GlycosuriaPolyuriaPolydipsiaPolyphagia

protein catabolism plasma amino acid gluconeogenesisWeight loss, growth inhibitionNegative nitrogen balance

lipolysys free fatty acidsKetosisAcidosis

Vascular changes Microangiopathies

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 AGINGMicroangiopathy ---Cataracts CataractsNeuropathy NeuropathyAccelerated Atherosclerosis AtherosclerosisEarly decreased fibroblast Decreased fibroblast proliferation proliferationAutoimmune involvement Autoimmune involvementSkin changes 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:

TESTISPrimary 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 GLANDSwhich secrete seminal fluid

PENIS with URETHRAthrough 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 GERM CELLS or GAMETES,involved in fertilization.

the INTERSTITIAL CELLS of LEYDIGthat secrete testosterone, the major

androgen

the SERTOLI CELLSwith secretory and reproductive functions

The testis, the male primary reproductiveorgan, contains three types of cells, all

necessary for reproduction:

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 tissueFlattening of secretory epitheliumInner region:Increase in the number of cells present (hyperplasia)

After age 60:Slower, but more uniform atrophy of the prostateAccumulation 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 19-15 Possible Risk Factors for Benign ProstaticHyperplasia (BPH) and Prostate Cancer

Possible Risk Factors for BPH Possible Risk Factors for Prostate Cancer• Aging • Genet ic predisposit ion• Use of a nabolic st eroids • To bacco exposure• Dieta ry f act ors • Cadmium exposure• Genet ic predisposit ion • Vit amin A def iciency• Environment al to xins • Vasecto my• No oth er major risk fa cto rs • Sexually t ransmit t ed d iseases

• Muta genic hormonal facto rs• Dieta ry f act ors (part icularly h igh level of

animal fa t)

Table 19-14 Synopsis of Benign Prostatic Hyperplasia (BPH)Characteristics

• Caused by g rowt h of th e prost at e f rom about age 40 un t il deat h• Af fect s 50 % of m en > 50 years o ld• Af fect s 95 % of m en > 70 years o ld• Clinical sympt oms due t o obstru cti on of th e ureth ra are present up to

25% of men w it h histo logic evidence of BPH• BPH t issue resembles normal prosta t e t issue wit h increased am ount s

of smoot h muscle, g landular, and/ or str omal component s• An enlarged prost at e can str angle th e ureth ra

• BPH is not found in men who have been castr at ed or men who lack 5-α-reducta se

Treatment of Prostate CancerDepends on

Life expectancyOverall health statusPersonal preferencesSize of the prostate

State of disease

Treatments include:Watchful waiting

SurgeryRadiation TherapyHormonal 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

Ovaries

Pituitary

E2, P

GnRH

FSH, LH

Normal Female Hormone Patterns

Hormonal Changes From Aging

• Gonadotropins:– LH

• Change to pulsatile pattern: Duration, Frequency

– FSH• “Monotropic FSH • 1st Noticed prior to any

change in cycle length

• Ovarian Steroidal Hormones– Estrone levels 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