~4 of these on the thyroid gland.

Arise from the 3rd and 4th pharyngeal pouches.

Secrete PTH.

Principal Cells (aka Chief cells) are the more numerous type but are smaller and have less cytoplasm. Principal cells secrete PTH. Oxyphil cells are larger and have cytoplasm and are arranged in clumps throughout the gland. Function unknown.

Located on the trachea, a bilobed gland (only palpatable endocrine gland)

Arises from the foregut.

Secretes T3, T4 and Calcitonin. TH regulate BMR and are essential for growth/development.

Functional unit is the Thyroid Follicle which is a mass of Colloid (T3/T4) surrounded by follicular cells (which produce the T3/T4 and Tg) and networks of capillaries.

C-Cells (aka Parafollicular cells) release calcitonin and are next to follicular cells and Calcitonin is carried into the blood instead of into the colloid of the follicles.

Follicular cells have a unique GPCR which attaches to/is stim by TSH which stimulates all the functions of the thyroid cells (I uptake via NIS, synthesis/release of TH, ↑ blood flow, and growth of the thyroid.

Beta cells (15-20% of cells) secrete Insulin and make up the core of the islets.

Alpha Cells (70% of cells) secrete Glucagon and are located on the periphery of the islets.

Delta cells (5%) secrete Somatostatin (function unclear) and are located between the alpha and beta cells.

F cells secrete pancreatic polypeptide

Located as the innermost part (middle) of the adrenal glands, one on each kidney.

Consists of large medullary veins and pale staining cells compared with the cells of the cortex. Chromaffin Cells are the main cells of the medulla which are modified neurons innervated by the sympathetic nervous system. These cells are filled with dense core vesicles of Norepi and clearer vessicles of Epi which are released upon sympathetic stimulation. Also contain Ganglion Cells which are actual neurons whose axons extend out into the cortex to modulate secretory activities there.

Do not conduct AP's but just secrete hormones (mainly Epi) into the blood. Plasma Epi is from the adrenal and Norepi is mostly sympathetic overflow).

Releases Epinephrine and Norepineprhine.

Located on top of each of the kidneys, the cortex is the outer portion of the adrenal glands. Secretes Cortisol (GC), Aldosterone (MC), DHEA and Adrostenedione  (adrenal androgens)

3 Zones: Glomerulosa (outermost, Aldosterone), Fasiculata (middle, Cortisol, responds to trophic effects of ACTH), and Reticularis (innermost, adrenal androgens, responds to trophic effects of ACTH). Some animals also have an X zone that secretes adrenal androgens). Fetal adrenal cortex is lare and secretes Sulfated androgens that are converted to estrogens and androgens by the placenta and released into the maternal circulation.

Secrete Estradiol (E2) and Progesterone (PG)

3 Key cell types present in these female gonads:

Ovum/Oocytes

Granulosa Cells (stimulated by FSH, secrete Inhibin [-FB on FSH secretion], and convert androgens from thecal cells to estrogens).

Thecal Cells (stimulated by LH to secrete androgens [T and androstendiol] which diffuse to granulosa cells where they can be converted to estrogens.

These cells make up the Follicle which secretes mainly E in increasing amounts for the first 2 weeks (as estradiol 17-beta) but also some androgen and some prgesterone (see above for cell origins).

Many follicles begin to develop each cycle but one predominates.

Contains ~1 million germ cells at birth, though many regress. Menopause sets in when there are no more eggs left (no ovulation, ↓ E, ↑ FSH/LH)

Male Gonads and Primary Sex Organs

Seminiferous Tubules (with sertoli cells) + Leydig Cells

Located in the Scrotum and need T<37°C (facilitated by the pampliform plexus, cremaster muscle, and scrotal movements)

Have 3 key cell types: Primary Spermatogonia

Sertoli Cells (stimulated by FSH, nourish sperm, secrete Inhibin which - FB on FSH secretion, and MIS)

Leydig Cells (timulated by LH to secrete androgens)

Site of Spermatogenesis: The process whereby spermatogonia mature to spermotozoa and then sperm.

Requires 2 hormones directly (FSH and T) and 2 indirectly (LH for T and GnRH for FSH and LH)

(TRH) A tripeptide

Released from the Hypo, travels to the Ant Pit in the portal venous system and maintains the responsiveness of Thyrotrophs.

Stimulates the secretion of TSH and Prolactin.

Controlled by a negative feedback system. Ample levels of T3/T4 in the blood inhibits TRH secreting neurons which lowers TSH levels and shuts off Thyroid secretion of T3 and T4.

SS aka Somatotropin release-inhibiting hormone (SIRF) Peptide

Released from the Hypo

Inhibits secretion of growth hormone acting by blocking the actions of GHRH on the somatotrophs of the ant pituitary. Decreases thyroid secretion and, when secreted from the pancreas, decreases levels of insulin and glucagon. Part of the negative feedback loop for GH release: high levels of GH and/or somatomedins induce somatostatin release from the hypo which inhibits GH release from the anterior pituitary.

TSH Peptide (N-linked glycoprotein)

Secreted from the Thyrotrophs of the Ant Pit.

Short half life, diurnal rhythm with max near midnight.

Levels also ↓ during PG due to + effect of hCG on TH levels in the maternal circulation.

Binds to GPCRs on the basolateral membrane of thyroid cells→cAMP release in follicular cells.

Stimulates enlargement of the follicular cells and the development of apical microvilli which invade the colloid storage and engulf Tg into cells which allows secretion of thyroid hormones (T3/T4). TSH also ↑ blood flow and size of the thyroid gland (trophic).

TSH release ↑ by ↓ T4/3, ↓ iodine diet or thyroidectomy (trying to compensate for low T4/3 levels). Release ↓ by ↑ T4/3 and TH Rx.

Key actions of TSH: ↑ activity of NIS, ↑ iodination of Tg in the follicle, ↑ conugation of I-Tyr residues to generate T4/3, ↑ endocytosis of I-Tg into follicular cells, ↑ proteolysis of I-Tg in lysoendosomes, ↑ secretion of T3/4, and has growth factor effects on the thyroid ↑ size and # of cells.

Thyrotrophs can also deiodinate intrapituitary T4 to T3 which inhibits production and secretion of TSH (another form of negative feedback.

(FSH) Peptide (N-linked glycoprotein)

Secreted by the Anterior Pituitary

FSH is the first hormone to rise at/trigger the onset of puberty in M and F.

In Females

Acts on the Gruanosa cells of the ovarian follicles to [image]↑ follicular growth and E secretion.

Release of FSH is ↑ by GnRH and ↓ levels of E/removal of the ovaries.

Release  is ↓ by low GnRH, ↑ E, or ↑ Inhibin.

In Males

[image]

FSH acts on the Sertoli cells of the testis to ↑ spermatogenesis/maturation of sperm.

FSH release is  ↑ by ↑ GnRH and ↓ T (castration)

Release is ↓ by ↓ GnRH and ↑ Inhibin

(LH) Peptide (N-linked glycoprotein)

Secreted by the Anterior Pituitary

Secretion is pulsitile* (so T secretion is also pulsitile) however compared to other steroid hormones their levels are relatively constant.

In Females: Acts on the Thecal Cells of the ovarian follicle to trigger ovulation→formation of the CL (↑ E and PG synthesis/secreiton/concentrations)

LH secretion ↑ by ↑ GnRH and by removal of the ovaries. Also (via + feedback) by Increasing/rising levels of Estorgen.

LH secretion is ↓ by ↓ GnRH and by high levels of E and/or P OR by low E + moderate PG (birth control).

In Males: Acts on the Leydig cells of the testis to ↑ syntheiss/secretion/concentration of T (indirectly ↑ spermatogenesis).

LH release is ↑ by ↑ GnRH and ↓ T/castration. LH release is ↓ by ↓ GnRH and ↑ T.

(GH) Peptide Secreted by Somatotrophs of the Ant Pit.  Secretion requires ↑ in GHRH and ↓ in SS.

 Release is pulsatile with highest rates just after reaching deep sleep at night (highest in puberty).

↑ protein and nucleic acid synthesis. ↑ fat metabolism/lipolysis. ↑ N, Na+, K+ and PO4 levels.

↑ Overall growth (↑ in body mass and height in juvenile/pubertal periods) and ↑ long bone growth (via growth plate effects) and ↑ bone thickness. Dibetogenic effects (causes insulin resistance and ↑ blood glucose levels).

MoA:Somatomedin Hypothesis: GH→liver→ ↑ IGF1 secretion→ effects on long bones etc→Growth

*Dual Effector Hypothesis:(GH acting directly on tissues in addition to increasing levels of IGHF1)

GH→bones, muscle, adipose etc.. (direct effects)

GH→ ↑ IGF-1 → local and autocrine effects

GH→liver→hepatic effects (↑ IGF-binding proteins)

(PL) Peptide. Secreted by Lactotrophs of the Ant Pit.

Stimulates milk production and secretion in the breast. Levels ↑ in pregnancy when lactotrophs become more active due to increased estrogen.

Gene transcription is promoted by TRH and inhibited tonically by Dopamine. To get PRL release you must have both an increase in TRH and a decrease in Dopamine*

Present in almost the same amounts in females and males (unknown function in M)

Nonapeptide w/ a SS bridge originally synthesized as a larger molecule (neuropeptide)

[Similar structure to ADH]

Secreted by the Post Pit (1° associated with the SON)

↑ contractility of uterine smooth muscle and of myoepi cells of mammary glands triggering milk ejection/let down.

OT does not initiate partuition but greatly assists it!

Secretion of OT is triggered via neural afferents from the dilation of the cervix (stretch receptors) and suckling (touch receptors).

T3, Amine

Secreted by the Thyroid Gland

Half life of ~1 day.

Is the more active form of TH, present in smaller qtys.

Delayed response since TH exert their effects by binding to DNA/Mitochondria.

T3 enters the cell and binds its nuclear receptor (THR), dimerizes with RXR and binds to the promotor to drive gene transcription (in all tissues except in the pituitary where it is inhibitory).

Protein products stimulate skeletal growth, oxygen consumption, heat production, utilization of protein, fat and carps and perinatal maturation of the CNS.

T4

Released from the Thyroid Gland

Half life ~8 d.

Stimulates skeletal growth, oxygen consumption, heat production, utilization of protein, fat and carbs and perinatal maturation of the CNS.

Sidenote: The relatively long half life of TH's as well as the fact that they mediate their effects via nuclear receptors means that serum TSH and TH concentrations are typically constant (TSH is prefered for assays).

 (CT) Peptide

Secreted by the Parafollicular cells of the Thyroid Gland

↑ Secretion by ↑ ECF [Ca2+]

Decreases serum [Ca2+] (antagonizes PTH)

Has little effect in adult humans but may play an important role in children and pregnant/nursing women.

Medullary THyroid Carcinoma is a a disease of Calcitonin hypersecretion.

Peptide ("intact PTH" is the only form with all biological activity; many inactive fragments present in circ).

Released from the Parathyroid Glands

Secretion is ↑ by ↓ ECF [Ca²⁺] below 9.5 mg/dl (Sees ionized/free Ca only) and has an unusual mechanism of secretion: Continually produces and degrades PTH. In order to release, it ↓ the rate of PTH degredation.

Release of PTH is ↓ by ↑ plasma Ca.

Note that Urinary cAMP is a marker that tells you that PTH is working on the DCT of the kidneys.

On Bone:  ↑ resorption of Ca²⁺ and PO₄ (action on osteoclasts) and ↑ Ca permiability of osteocytes.

Random action on bone:  ↑ bone formation* depends on sporatic dosing/bursts of PTH; clinically useful.

On Kidneys: ↑ Ca reabsorption in DCT (↑ Ca in blood and ↓ in urine) + ↓ PO4 reabsorption in PCT (↓PO4 in blood and inc in urine) + Activates Vitamin D in PCT.

On the Intestines: No direct effects, but by activation of Vit D: ↑ Ca absorption and ↑ PO4 absorption (↑ their amounts in the blood and ↓ in urine).

Overall: Increases serum [Ca2+] (antagonizes Calcitonin)

Glucocorticoid (GC)/Steroid Released from the Z. fasicuata of the Adrenal Cortex.

Corticosterone (main in rats but also sig in humans)

Peaks at the hour of waking (Circadian released due to same pattern of ACTH release).

Transported in plasma: 99.5% bound to CBG:secreted by the liver and ↑ in pregnacy and by estrogens. (↑ in CBG does raise total cortisol but does not raise biologically active/free amts of CBG).

Metabolized by liver: reduced and conjugated with glucuronic acid. Steroid-glucuronides are excreted.

Actions of GCs (permissive: allows metabolites to flow acting mainly on the Liver)

Hepatic Actions (mainly Anabolic): ↑ gluconeogenesis, ↑ amino acid uptake and catabolism, ↑ urea synthesis (from released aa), ↑ glycogen synthesis, ↑ size of liver! ↑ synthesis of key enzymes. *Has synergistic actions on blood Glc acting with Epi and Glucagon*

Peripheral Actions (mainly catabolic to provide more substrates for the liver):↑ proteolysis. Mild inhbiiton of Glu and aa uptake, Inhibits Glu utilization, ↑ lipolysis (acting with GH and T3).

***↑ vascular responsiveness to catecholamines***to maintain bp as an anti-shock mechanism.

 Permits Stress Resistance: ↓ inflammatory/immune responses, inhibits secretion of CRH and ACTH*

↑ GFR (preventing water toxicity), ↑ brain excitability.

Phys levels are vital for proper growth but excess stunts growth!

Excess GCs: Cushing's Syndrome and Deficiency of GCs: Adrenal Insufficency.

Pharmacaologic uses of GCs: Anti-inflammatory treatment of arthritis and other inflammatory disorders. GCs can stabilize lysosomal membranes (less degrading enzymes released), ↓ capillary permeability (less leak) and suppressess the immune system (i.e. T cell actions)

Are Anti-allergic and are useful at reducing severe asthma attacks.

Potent Mineralocorticoid (MC) and Steroid

Released from the Z. Glomerulosa of the Adrenal Cortex

Note that DOC is the other key mineralocorticoid*

Synthesis is from cholesterol: Pregnelone→Progesterone→Deoxycorticosterone→ (11B hydroxylase) Corticosterone→(Ald Synthase/AII) 18-hydroxycorticosterone → (Ald Synthase) Aldosterone

*Acts to conserve body sodium: Preserve ECFV and bp*

Retains Na and excretes K and H+

Release of aldosterone is triggered by ↑ [K], ↑ activity of Renin-AT system (RAS) or by ACTH (small effect)

↓ [Na+] also triggers aldosterone secretion.

Excess (rare) causes Hypokalemia (due to excess excreiton of K) which causes periodic paralysis due to depressed nerve/m function. Hypertension due to ↑ Na and H2O retention.

Deficiency: Very Serious, Hyperkalemia causes cardiac toxicity, ↓ ECFV and circulatory shock.

Addison's Disease: no GC and no MC (aldosterone)

An adrenal androgen.

Steroid. Released from the Adrenal Cortex

See actions of testosterone from testes.

Present in both males and females.
Note that this is a major source of androgens in females and that levels in males and females are similar.

(T) Steroid. Secreted from the Leydig cells of the Testes when stimulated by LH.

Levels peak in the male fetus at the midpoint of gestation (promotes the development of the Epididymis, vas deferens, and seminal vessicles from the Wolffian Ducts, peak is triggered by placental hCG), small peak in early childhod and big at puberty)

Stimulates spermatogenesis and male secondary sex characteristics (see card on Effects of T for full list)

Synthesis of Testosterone: From Cholesterol under the influence of LH in Leydig cells.

Can be converted into estradiol by Aromatase

Metabolism of Testosterone: 2 pathways

1) In some tissues T reaches the tissue in the blood, binds a T-receptor in the cytoplasm, is transolcated to the nucleus and exerts its effects. *Libedo, growth of skeletal muscle, penis and scrotum do not require conversion of T.

2) In other tissues, T must be converted to DHT which binds a DHT-receptor and can be transported to the nucleus where it can perform its functions.

*Fetal formation of the prostate and external genitalia and pubertal enlargement of teh prostate, hair changes and acne require conversion of T to DHT*

T is present in females! Key for libedo

(E2) Steroid. Generated from the ovaries and CL.

ACTIONS (Know All)

*Stimulates growth and hormone secretion of the ovaries/follicles that produced it (esp dominant follicle)

*Low [E] inhibits FSH/LH release from the ant pit.

*rising [E] triggers LH surge (some FSH secretion)

*Very high [E] inhibits FSH/LH release

*Very low [E]+mod PG prevents FSH/LH secretion prevents ovulation (high FSH alone too)=Birth Control.

*Produces female figure

*Ovaducts: ↑growth of m and epi, ↑motility, ↑cilia beats

*Myometrium: ↑growth and contractility

*Endometrium: ↑growth, gland devel and blood supply

*Cervical mucous: ↑supply of watery mucous (ferning)

*Vagina: ↑ lubrication and growth of epi (cornification)

*↑ growth of mammary glands and duct branching

*Induces PG receptors in the endometrium (Levels climb throughout the course of PG)

*Initially ↑ height but then closes the growth plates

*Promotes growth of F ext genitalia

*Anti-athrogenic (↑ HDL/LDL ratio)

*↑ size of the pituitary (lactotrophs)

*↑ Prl secretion (but inhibits Prl stim of milk synthesis)

*anti-osteoperotic (↓ bone loss by ↓ cytokines)

*↑ libedo (acting with androgens)

*Varied effects on appitite (↓ appitite in rats)

*↓ wrinkling (by ↑ water and collagen content and reversing collagen loss)

Present in Males (particularily in fat and pituitary cells, majority is converted from precrsors through some is produced by the testis)

(PG) Steroid

Released from the Ovaries, Corpus Luteum, and Placenta. Stimulates the luteal phase of the menstrual cycle. Maintains pregnancy. (PROmotes GESTation)

Inhibitory actions on the Uterine muscle: ↓ motility and prevents coordinated contractions, antagonizes estrogen's enhancement of motility (↓ # E receptors), ↓ sensitivity of uterine muscle to OT, hyperpolarizes muscle membranes (↓ excitibility)

Stimulatory actions on the Endometrium: After endometrial priming by E, PG ↑ endometrial gland secretion and prepares the uterus for implantation.

Pituitary: Inhibits FSH & LH secretion (esp in presence of low amts of E)

Stimulates growth of Mammary Glands but inhibits Prl stimulation of milk synthesis.

↑ body temperature (↑ BBT post ovulation)

Cervix: produces sticky mucous to keep bacteria out.

A temporary endocrine gland.

Develops from the follicular cells starting shortly BEFORE ovulation and persists ~2 weeks.

Secretes E, lots of PG, Inhibin* and 17-hydroxyprogesterone (unknown effects)

Inhibin(GnSAF) and/or PG(with a little E) inhibits FSH and LH secretion.

Luteolysis is the process of CL regression/degeneration which begins ~8d post-ovulation. Degredation of the CL=↓ levels of E and P (loss of their effects to maintain the endometrium)

Rescued by exogenous LH or by hCG (natural, produced by the placenta upon implantation of the blastocyst)

Maintenance of the CL (in the event of PG)

Once the placenta begins to develop it secretes hCG. Sharp ↑ plasma [hCG] which acts like LH and rescues the CL from degeneration. CL under hCG influence maintains its size and continues ot secrete E and P (ness for endomentrial functions).

CL is maintained for the entire pregnancy but is important only for the first 6-8 wks (until the placenta can produce its own E and P) at this time hCG levels also ↓.

(HCG) A peptide

Released from the Placenta

Stimulates estrogen and progesterone synthesis in the corpus luteum of early pregnancy.

Maintains the CL for the first 6-8 weeks and declines after this (CL persists but is no longer significant for E and P secretion).

Overall, hCG levels spike in the first 2 months of PG and return to basal levels during the rest of PG.

hCG Spike acts to raise levels of TBG, total T4 and TBG early in PG which triggers a ↓ levels of TSH by - FB on the maternal thyroid!

* During PG total TH ↑ but free T4 levels out due to ↓ TSH*

PG tests based on maternal hCG levels are common. Qualitative tests (urine) and quantitive tests (blood).

(hPL) aka Human Chorionic Somatomammotropin

Protein

Secreted from the placenta Has GH-like and prolactin-like effects (on mom not fetus) during PG.

Levels gegin to rise at the end of the first trimester (when hCG levels fall).

Chief functions of hPL are to act as an anti-insulin inhibiting maternal uptake and utilization of glucose. This is to spare glucose for use by the fetus as its primary source of E.

Is a cause of gestational diabetes.

Peptide Released from the beta cells of the pancreas.

Proinsulin→Insulin + C-peptide

*note that C-peptide is diagnostically useful because its levels reflect the levels of endogenous insulin.

Insulin levels ↑ at times of meals and ↓ between meals.

Major Stimuli for Insulin Secretion: ↑ in [P_Glc], [P_aa], GI hormones (GIP ↑ β cell responsiveness), Parasympathetics AND/OR ↓ Sympathetic imput to pancreas/circulating levels of Epi/Norepi/SS (via inhibition of GH release).

GH, Cortisol and GIP are permissive for the actions of In

Sites of Action: affects most tissues but primarily Muscle, Liver and Adipose.

-Stimulates Glc uptake and utilization in these tissues

-Generally ↑ [P_Insulin] → ↓ [P_Glc]

Insulin exerts its actions by binding to receptors on its target tissues and triggering the exocytosis of vessicles containing glucose transporters (allows ↑ Glc uptake)

Non-insulin-dependant tissues: Brain (except hypo), Intestinal mucosa (Ins does not directly stimulate the uptake of dietary Glc), RBC, and Kidney Tubules.

Peptide Released from the alpha cells of the pancreas.

Levels seldom change with a meal, rather the ratio of Insulin:Glucagon is altered producing effects. In fact, Glucagon levels generally remain steady all day.

Stimuli for Glucagon secretion: ↓ [P_Glc], ↑ Sympathetic imput (Ach, Epi, Norepi, VIP, CCK).

↑ [P_aa] (just like In), Counterintuitive but a mechanism to prevent sudden hypoglycemia in the event of a high protein meal w/o carbohydrates.

Inhibition of Glucagon secretion: ↑ [P_Glc], Insulin, SS, Ketones, or FFA.

Actions of Glucagon (See seperate slide)

***Has synergistic actions on blood glucose acting with Epinephrine and Cortisol***

Steroid aka Calcitriol

D3 (Cholecalciferol) is hydroxylated in the liver (25-hydroxylase) then in kidney PCT (1-alpha-hydroxylase) to its most active form Calcitriol [or to an inactive form by renal 24-hydroxylase].

Regulated by feedback from products at each enzyme and by PTH which ↑ activity of 1-hydroxylase.

↓ in Ca levels causes an ↑ in serum D3 which helps ↑ plasma Ca by ↑ Ca (and P) absorption from the gut by binding to a cytosolic receptor and ↑ transcription of Ca-binding protein (CBP) which allows more Ca uptake and ↑ activity of basolateral Ca-pump (slow).

Also by facilitating Ca and P flux both into and out of bone (allows Ca in bone to go where it needs to go).

Norepi Amines (catecholamines, neuroendocrines) Released from dense vesicles in the chromaffin cells of the Adrenal Medulla.

Actions: Effects are often additive with those of the SNS. Different receptor classes exist and actions of Epi and Norepi sometimes oppose one another.

On the heart: acts to ↑ TPR (unlike Epi) and ↑ bp*

↑ alertness and activate RAS by ↑ bp. Decrease neural threshold.

In the liver: ↑ glocogenolysis (potent) and ↑ gluconeogenesis. ↓ glycogen synthesis.

In the pancreas: ↓ insulin secretion which results in in ↓ uptake and utilization of glucose by m. and adipose.

Is most key in activating hormone-sensitive lipase (HSL) which ↑ FFA and spares glu for CNS.

↑ metabolic rate.

On GI: ↑ sphincter tone and ↓ motility and blood flow.

Causes dilation and ↑ air flow in lungs.

Dilation of the pupils

↓ blood flow to the skin giving a pallad appearance and ↑ the activity of sweat glands.

↑ tension generation and NMJ transmision in skeletal muscle, ↓ fatiguability.

***Causes Vasoconstriction which ↓ blood flow via the alpha receptor***

Majority of Norepi in circulation is from sympathetic overload. Levels of Norepi are typically much below the level of threshold fro response and rarely exceed it (unlike epi which is usually over threshold)

Very short half life in the blood (~2min) and metabolic breakdown products are excreted in the urine Norepi→normetanephrine + VMA

Using Catechol-O-methyl transferase (COMT) or Monoamine oxidase (MAO)

Caused by insufficent dietary iodine or by autoimmune causes: ↓ I intake, Hashimoto Thyroditis, Cretinism/Dwarfism.

Causes sluggishness and edema of CT.

A condition of excess TH secretion

Key example is Graves' Disease

An Autoimmune Disease caused by abnormal levels of Abs (Thyroid stimulating Ig) that bind and stimulate TSH receptors on follicular cells of the thyroid→excessive TH production.

Causes protruding eyes (exopthalmos) due to increased CT behind the eyes and increased sympathetic activity.

Also cuases weight loss, sweating, fatigue, tremor, hyperexcitability.

Epi Catecholamine/Neurohormone Released from small, clear vesicles of the chromaffin cells of the adrenal medulla upon sympathetic stimulation.

Actions: Causes Adrenal Rush

On the heart: ↑ hr,  ↑ CO but does not ↑ MAP.

↑ alertness and activate RAS by ↑ bp. Decrease neural threshold.

In the liver: ↑ glocogenolysis (potent) and ↑ gluconeogenesis. ↓ glycogen synthesis. *Has synergistic actions on [P_Glc] acting w/Glucagon and Cortisol*

In the pancreas: ↓ insulin secretion which results in in ↓ uptake and utilization of glucose by m. and adipose.

MINOR role in activating hormone-sensitive lipase (HSL) which ↑ FFA and spares Glu for CNS.

↑ metabolic rate.

On GI: ↑ sphincter tone and ↓ motility and blood flow.

Causes dilation and ↑ air flow in lungs.

Dilation of the pupils

↓ blood flow to the skin giving a pallad appearance and ↑ the activity of sweat glands.

↑ tension generation and NMJ transmision in skeletal muscle, ↓ fatiguability.

***Causes Vasodilation which ↑ blood flow via the beta2 receptor***

Majority of Norepi in circulation is from sympathetic overload. Levels of Norepi are typically much below the level of threshold fro response and rarely exceed it (unlike epi which is usually over threshold)

Very short half life in the blood (~2min) and metabolic breakdown products are excreted in the urine Norepi→normetanephrine + VMA

Using Catechol-O-methyl transferase (COMT) or Monoamine oxidase (MAO)

Most circulating Epi is from the adrenal medulla.

Levels exist often over threshold for action.

Peptide

Released from the hypo

Triggers the release of FSH and LH (the Gonadotropins) from the anterior pituitary.

High Estrogen ↓ the amplitude of the GnRH pulses.

High Testosterone both Estrogens ↓ GnRH and ↑ the intervals between pulses of GnRH.

=IGF1

Mediates some of the actions of GH particularly on bone elongation and on adipocytes.

Peaks in puberty just like GH.

Is used often as a marker of GH. present in elevated levels in acromegalic adults and is not present in hypopituitary individuals (no GH).

MoA: Released from somatomedin-producing cells and acts to carry out many of the actions of GH in addition to acting to promote the differentiation of adipocytes and chondrocytes.

Is a useful exogenous treatment for individuals who are GH-insensitive, ↑ their growth velocity.

What is the result of GH excess/deficiency?

TH excess/deficiency?

Androgen excess/deficiency?

Cortisol Excess?

GH Excess: ↑ linear growth, ↑ adult stature to maximum genetic potential (Giantism)

GH Deficiency: ↓ linear growth, delayed skeletal maturation and ↓ adult stature (if severe=Hyposomatotropic Dwarfism)

TH Excess: minimal effects on growth

TH Deficiency: ↓ linear growth, ↓ skeletal maturation, and ↓ adult stature (can be caused by Rx glucocorticoids(?)

Androgen Excess: ↑ then ↓ in linear growth, advanced skeletal maturation and ult. ↓ adult stature!

Androgen Deficiency: ↑ linear growth, delayed skeletal maturation, Euchnoidal adults (↑ stature, long arms and legs).

Cortisol Excess: ↓ in linear growth, delayed skeletal maturation and ↓ in adult stature.

T3 potentiates the actions of GH and ↑ levels of GH.

T3 ↑ the sensitivity of somatotrophs to GH-RH and ↓ the actions of SS on these cells.

T3 ↑ synthesis of GH by somatotrophs.

T3 ↑ responsiveness of somatotrope target cells

Factors that ↑ GH Secretion: GH-RH, deep sleep, hypoglycemia, acute stress, exercise, TH, Puberty (Testosterone/Estrogen), post-meal Glu decrease.

Estrogens, Insulin, Arg/Leu, Starvation, over secreting Pituitary tumors (acromgaly)

Factors that ↓ GH Secretion: SS/SS Rx, light sleap and waking, elevated endogenous/Rx GH, ↑ IGF1, aging, hyperglycemia.

Glucocorticoids, hypo and hyperthyroidism, progesterone, and a pituitary tumor (can compress and shut down pituitary secretion)

 *Release is pulsatile with highest rates just after reaching deep sleep at night (highest in puberty).

Calcium

Stores, imput, output, and renal handling.

99% of Calcium in the body in bones/teeth as hydroxyapatite crystals rest in ECF and soft tissues.

Oral intake~1,000 mg/day (dairy products)

GI absorption is regulated directly by Vit D and indirectly by PTH (which mediates Vit D activation).

Fecal excretion is 90% of imput meaning that only 10% (100 mg)  is absorbed in the gut (though more in kids).

Normal plasma Ca (bound+free/ionized) = 10 mg/dl*

~45% each in protein-bound and free Ca2+ states with minimal amounts exisiting as the anion-bound form.

Renal handling of Ca: ~60% of circulating (only the free and anion-bound) Ca is filtered in the kidneys~10,000 mg! (note: not protein bound Ca). However, tubular reabsorption is 99% (most is in the PCT but sig amt along nephron)! Efficent retention-only 1% of filtered Ca (100 mg) is excreted in urine.

PTH and Vit D promote the excretion of Ca2 in the DCT*

In bone: there is ~20,000 mg Ca that is readily exchangable as Amorphous Calcium Phosphate, in "bone fluid" and the rest is tightly bound as a stable hydroxyapatite mineral.

Fibroblast Growth Factor 23

A phosphaturic hormone produced by bone.

↓ PTH secretion (prevents Ca release into blood from bone)

↓ activity of renal 1-alpha-hydroxylase (prevents the formation of the most active form of Vit D)

Sources: Soft drinks and food additives/preservatives.

Net absorption is a small percentage of dietary intake.

Normal plasma P: 4 mg/dl (↑ in kids + ↑ in evening).

55% as the free (HPO4/H2PO4) form with the rest complexed to cations (35%) or protein-bound (10%).

The kidney filters 6,000 mg of phosphate (little P is protein-bound so more is filtered) and reabsorbs ~90% of FL in the PCT, excreting the rest.

PTH acts on the PCT to inhibit PO4 reabsorption (Phosphaturic hormone, ↑ Ca at expense of P)

* The amount of Phosphate reabsorbed vs. secreted is highly variable based on diet and time of day (usually calcium, not phosphorus is used for measuring purposes.

Note that increased phosphate absorption (as in high phosphate diets) is bad because exces phosphates bind up calcium and impair Ca absorption.

aka C cells

Arise from neural crest cells.

Scattered around the parynchema of the thyroid gland outside the follicular cells.

Produce Calcitonin and release it directly into the blood stream (instead of into the colloid like T3/4)

Tg

A large glycoprotein that is synthezided and stored by the thyroid follicular cells.

Na+/I- symporter

Located int eh basolateral/basement membrane of thyroid cells (as well as in the gastric mucosa, salavary duct and mammary gland).

Allows concentration of Iodine in the thyroid.

Excess Iodine can overwehlm the NIS and temorarily stop synthesis/release of thyroid hormone.

Thyroperoxidase

The enzyme located at the apex of thyroid follicular cells that carries out the iodination of Tg.

Iodinated Tg is secreted into the storage pool in the colloid where it undergoes rearrangement (a coupling of diiodotyrosines, also influenced by TPO).

Synthesis: Tg is conjugated to I by TPO and secreted into the colloid from follicular cells. In the colloid it undergoes a rearrangement to couple its diiodotyrosine groups.

Storage: Diiodotyrosine in Tg is the inactive, storage form.

Release: Upon signaling by TSH, Iodinated Tg is endo/pinocytosed. In the enolysozomes it is hydrolyzed to T4 and some T3 (active forms) which are exocytosed into circulation.

Propylthiouracil

An antithyroid drug that prevents TPO from iodinating Tg.

Used to treat hyperthyrodism.

Also inhibits peripheral deiodination of T4 to T3.

Same MoA as Methimazole (except meth does not prevent peripheral deiodination).

Anions that compete with I- at the NIS and prevent uptake of Iodine which hinders the synthesis of thyroid hormones.

Used as a hyperthyroidism treatment.

An autoimmune disease whereby the cells of they thyroid gland are gradually destroyed by autoreactive cell and Ab-mediated responses.

It is thought that it may result from thyroid damage that results in the release of TPO and Tg into the circulation & the immune system makes Ab's to them.

Thyrotropin receptor Abs (TRAb) are produced by lymphocytes within the thyroid and are autoimmune Ab which bind and block the TSH receptors (Thyrotrobin binding hinhibitrs, TBIs). Also may play role in Graves.

Transthyretin, aka prealbumin

Nearly all TH released circulates in a protein-bound form: TBG, TTR, Albumin

TBG: Thyroid binding globulin which binds large fractions of TH in serum with high binding constant.

TTR: Produced by the choroid plexus and by hepatocytes.

Aids in the transfer of TH into the CSF.

Binds less TH with less affinity than albumin.

Albumin: a major serum protein that binds TH with small affinity.

The low affainity of Albumin and TTR results in a significant avialibility of free T3/T4 to all the cells of the body and continous delivery of TH to the cells throughout the passage of blood through the tissues.

Removal of the 5' I from T4 by deiodinase enzymes is vital for the production of effective hormone.

Note that deiodination can take two courses:

1) Removal of an inner ring Iodine leaves an outer ring iodine and produces Reverse T3 (RT3) which has little or no biological activity.

2) Removal fo an outer ring Iodine leaving an inner ring iodine produces active T3.

5'DI-1: Found in the Thyroid, kidney and liver.

Produces both T3 and RT3.

Contains and requires Selenium

Is upregulated in in hyperthyroidism and downregulated in hypothyroidism. Activity is impaired by caloric restriction and ↓ T4 and is induced by ↑ T4.

5'DI-2: In Brain, pituitary, and brown fat. Does not contain Sel. Only converts T4 to T3 (does not make RT3).

Is downregulated in hyperthyroidism and upregulated in hypothyrodism. Induced by low T4 and inhibited by high T4 (a normalizing deiodinase).

5'DI-2 is the main source of T3 in the cerebral cortex.

A deiodinase that is ubiquitously present in all tissues, less specific than the 5'DI's.

Carries out: T4→RT3

T3 → T2 →T0 (deiodination of reminants in order to conserve Iodine).

Increased activity in hyperthyrodism and decreased activity in hypothyrodism (like 5'DI-1).

Hypothyrodism caused in regions of endemic thyroid deficiency resulting in lack of TH during early development.

Causes profound ID, short stature, delayed motor development.

Can be corrected with TH Rx within a few days of birth but after this window mental delay persists.

Long-lived cells of bone that are trapped inside bone but connected to outer cells.

Osteocytes were once osteoblasts before becoming trapped in bone matrix.

Are the site of rapid shifts of Ca and PO4 between ECF and bone. Take up Ca and PO4 from amorphous Ca-Phos that is nearby and transport it ot osteoblasts which pump it into the ECF/plasma.

Are stimulated by PTH (retain the PTH receptors of their osteoblast precursors).

Activity is enhanced by active Vitamin D (Calcitriol)

Short-lived cells located on the outer surfaces of bone and are fomed from progenitor cells.

Have PTH receptors. [PTH inhibitory?]

Promote bone formation, synthezise matrix proteins and release ALK PHOS and Osteocalcin which leads to crystallization of Ca-PO4 into the osteoid.

Short-lived, large, multinucleate cells that are located on teh surface of bone and are formed by fusion of monocytes.

Cause net breakdown of mineralized by by degrading osteoid, thereby releasing Ca and P (↑ levels in blood)

Stimulated indirectly by PTH (do not have PTH receptors) but probably receive a singal from Blasts)

This signal is reduced by Estrogen (with reduced levels of estrogen at menapause the action of osteoclasts is greater leading to bone degredation).

Clasts are inhibited by Calcitonin.

Leads to ↑ neuromuscular excitability which may progress to tetany.

Chvostek's sign: tap the angle of the jaw and there is a quick contraction of the ipsilateral face muscles.

Trousseau's sign: spasum of muscles of the upper extremity leading to flexion of the wrist and thumb and extension of the fingers.

Note: Can be caused by a tight bp cuff.

Caused by parathyrodectomy or insufficinet dietary vitamin D/sunlight (usually in kids, rickets).

Treatment with high dose Vit D and a high Ca diet.

High blood Ca, low blood PO4.

Causes bone thinning (demineralization), ↑ incidence of fractures, hypercalciuria (due to ↑ filtered load which overwhelms ability of kidney to reabsorb Ca), and Ca-based kidney stones.

MCC: high [PTH] as from a parathyroid adenoma and treatment is typically surgical removal of the adenoma.

aka P450 c11

Catalyzes:

11-deoxycortisol → Cortisol

and

11-deoxycorticosterione → Corticosterone

in the Z. fasiculata of the adrenal cortex.

Is blocked pharmacologically by Metyrapone

Deficit in this enzyme is associated with a form of congenital adrenal hyperplasia.

Caused by a great excess of Glucocorticoids (Cortisol) from an adrenal or ACTH-secreting tumors or by massive exogenous doses of GCs.

Shows red, moon face, buffalo hump, brusability, thin skin, poor wound healing, huge abdomen and thin, weak legs.

Also causes excess protein loss due to ↓ protein synthesis and ↑ breakdown) leads to Glu intolorance/Insulin resistance (can lead to DM), bone dissolution, mental abberations, acne and hirsutism/masculinization (due to adrenal androgens not GC).

Often due to inborn errors in the syntheiss of cortisol (such as a defect in 11beta-hydroxylase)

Reduced negative feedback inhibition of the pituitary leads to ↑ ACTH secretion which hyperstimulates the adrenals producitng excessive amounts of intermediates which can cause Androgenital Syndrome (masculinization, hair on body, smaller breasts, male escutcheon, bladness, and clitoral growth).

↑↑ACTH can cause MSH-like effects due to similar structure (incl ↑ pigmentation).

Developmental adrenal failure may be fatal but the loss of one is easily survivable where loss of both is difficult (requires excess Na in diet, inability to tolorate fasting, porr tolorance to stress and inability to excrete excess water intake.

Genetic (46, XX; XY) In the absence of Y=F and in the on Y presence of Y=M due to the presence of an SRY gene which encodes Testis-determining factor (TDF)

Anatomic: Ovaries/testis, external genitalia which are determined exclusively by the presence/absence of Androgen. Internal genitalia (no gonads, F internal genitalia develop fro Mulleruian Ducts and M genitalia fail to develop).

Secondary Sex Charactaristics

Endocrine: Ovary (estrogens), Testes (androgens), Adrenals (weak androgens), extraneous (by mother during gestation).

Gender Identity/Self-perception

Phenotypic/Outward sex manifestations

Mullarian Inhbiting Substance

Secreted by the Sertoli cells of the testis and by the granulosa cells of the ovaries.

Dominates in early fetal gestation of normal males.

In Males: Triggers the regression of the Mullerian Duct allowing the Vas deferens and seminal vessicles to develop from the Wolffian Ducts.

[Unilateral castration=Failure of Mullerian ducts to regress and development of oviduct and uterus/vagina on the side lacking the testis]

Still present in later years of life, unknown function.

In Females: MIS is secreted by the granulosa cells and tehre is high [MIS] in the antral fluid. Unknown functions.

MIS levels can be diagnostic for sex of a patient with ambiguous genitalia or for testicular tumors of sertole/granulosa cells.

Wollfian Ducts

Mullerian Ducts

Wolffian Ducts

Develop into the epididymis, vas deferens and semina vesicles in males (requires T) and disappear in females (due to lack of T).

Mullerian Ducts

Disappear in males due to release of MIS.

Develop into fallopian tubes, uterus and upper 1/3 of the vagina in females (spontaneously in teh absence of androgen*)

aka the Interstitial cells of Leydig

Located in the seminiferous tubules of the testis.

Secrete testosterone upon stimulation by LH

Androgen acts on/works through Sertoli cells to promote the development of germ cells.

Female analogs are the Thecal Cells

Are part of the seminiferous tubule of the testis, make up the bulk of the mass of the gonads.

Site of FSH (and Androgens from the Leydig) actions.

Nourish growing sperm/influence sperm development.

Secrete Inhibin which negatively feeds back on the secretion of FSH from the gonadotrophs of the anterior pituitary.

Make up the blood-testis barrier*

Secrete Luminal Fluid which contains Androgen-binding Protein (ABP) which binds and carries T in the fluid.

Carries out phagocytosis of dead/defective sperm and of excess cytoplasm around sperm.

Analogs in Females=Granulosa Cells.

In the ovaries

Influenced by LH, triggers the secretion of androgen (which diffuses to the granulosa cells of the ovaries which convert it to estradiol).

The bulk of the cells in the ovaries (gonads).

Under the influence of Androgens (from the thecal cells) and FSH.

Convert androgens to estradiol (which influences oocyte development) and Inhibin which negatively feeds back on FSH secretion from the anterior pituitary.

Menstrual Cycle

Endocrine, Ovarian, Uterine, and Endometrial changes.

*Look at this graph, know it*

Menstruation (d 0-4)

Endocrine: FSH and LH are low but slightly elevated. P is low, E is low but rising.

Ovarian: Primordial and Primary follicles

Endometrium: Menstrual phase, sloughing off stratum functionalis via coiled arteries/mechanical stress.

Follicular Phase (d 4-14 but length varies causing varied cycle length as the 2nd part is constant)

Endocrine: FSH and LH levels decline and then there is a rapid peak of both (esp LH) at d 13.5. P is low but climbs 2 d before ovulation. E is rising and peaks ust before ovulation.

Ovarian: Vesicular follicle→mature/graffian follicle

Endometrial: Proliferative Phase, building up the endometrium, straight ducts.

Ovulation (d 14)

Triggered by LH surge, rupture of follicular membrane after proteolytic degredation, local bleeding.

Endocrine: LH, FSH, and E all sharply decline and P is gradually rising.

Ovarian: Ovulation

Endometrial: End of the Proliferative Phase and beginning of Secretory phase.

Luteal Phase (d. 14-28, Constant)

Endocrine: FSH and LH are low, rising slightly just prior to mestruation. E and PG both rise steadily, peak and then fall again, just prior to menstruation.

Ovarian: Early CL→Late CL

Endometrium: Secretory Phase (coiling of arteries and prep to slough off the stratum functionalis).

Temperature/BBT: also rises ~1 degree F druing the luteal phase.

↑ mitotic rate of mammary gland cells: due to the actions of E+PG on the glands

↓ concentrations of E, PG, and Inhibin at the end of the life of the CL (~8d post ovulation) reduces the negative feedback on FSH/LH secretion which allows ↑ FSH/LH levels during menstruation.

However, steadily rising levels of Estrogen first cause the midcycle surge of LH (due to ↑ response of the anterior pituitary to GnRH from the hypo*)

The Ovary is vital in regulating the cycle. With at least 1 functional ovary, an intact hypo-hypophyseal axis, primary gonadotropes and pulses of GnRH you can have a normal cycle.

There are significant influences from the CNS, Hypothalamus, excercise, stress, emotions and pathology.

Semen = Sperm + Secretions

Secretions are from the Seminal Vesicles (60%:Pgs, Fructose, citric acid etc...) and from the Prostate (20% of the volume, secretes Spermine)

Contain Sertoli Cells (responsive to FSH, secrete inhibin) and sperm at various stages in development.

Surrounding the seminiferous tubules are clusters of Leydig Cells (LH-responsive, produce androgens/T) and blood vessels.

An abundantly circulating steroid hormone of the adrenal cortex (reticularis) [though 10% is from the testis]

Present in males and females

Transport of T: I the blood it is bound to Gonadal steroid-Binding Protein (GBG) which is also clalled Sex Hormone BG (SHBG), TeBG, and TEBG [70% of circulating T is bound to this]

Remaining 30% circulates bound to Albumin

Actions of T

a. Induce fetal differentiation of male accessory organs

b. Induce changes in tissues at puberty

c. Maintain size and function of most of the male accessory organs (i.e the seminal vessicles/prostate-↑ fructose content and volume of secretion).

d. Stimulates spermatogenesis

e. ↑ protein anabolism + muscle/long bone growth

f. Enhances sex drive/libido (M and F)

g. Negatively feedsback on LH secretion*

h. Stimulates teh production of a thick secretion of the skin as well as the growth of pubic, axillary and facial hair (+hair recession in those predisposed to it).

i. Probably don't ↑ aggression in men and have no link to homosexulaity.

j. ↑ Erythropoesis (M have a higher mean Hct than F)

Control of T Levels

Negative feedback pathways both hypothalmic (↑ GnRH or ↓ time between pulses ↑ T) and Pituitary (mainly via ↑ LH but weakly ↑ FSH.

Inhibin acts at the pituitary (not at the hypo) to ↓ secretion of FSH

Estrogens ↓ the amplitude of the GnRH pulses.

Release from the Sertoli and Granulosa Cells respectively is triggered by FSH actions on the gonads.

Inhibin then acts on the anterior pititary to ↓ FSH release.

In males, androgens stimulate inhibin release and inhibin may have a role in local regulation of spermatogenesis.

Excitement/Arousal

Triggered by psychic/physical stimuli and initaites an ↑ in skeletal muscle tone and ↑ blood flow to the genitals leading to vasocongestion.

In Females: Nipple errection and slight size increase of the breasts. Lubrication appears, clitoris and labia swell.

In Males:Erection and partial elevation of the testis

Plateau

May persist fro some time and consists of rising tension that will be rapidly released in orgasm.

In Females:highly variable. Enlargement of areolae and Sex flush of the breasts. Labial color chage, expansion of the inner vagina and appearence of the orgasmic platform in the outer vagina.

In Males: Increased testicular size and full elevation, Cowper's gland secretion, deepened penile color.

Orgasm

↑ in hr, bp, RR, OT rel, tension/rigidity and coordination.

Sweating, relief from allergies.

↓ bleeding from cuts, sensation of pain and gag reflex.

In Females: Can exerience multiple orgasms. Said to be felt in the pelvic region. Contraction of the rectal sphincter, uterus, and rhythmic of orgasmic platform.

In Males: Associated with Ejaculation (emission+ ejaculation proper) and is followed immedeatly by a refractory period. Rectal sphincter, prostate gland, seminal vessicles, internal urethral sphincter, urethra and penis all contract.

Resolution

Consists of a reversal of the excitement phase where the skeletal muscles relax and vasocongestion is lost. The length of resolution often depends on whether or not orgasm has been reached and is highly variable.

In Females: Prolonged if orgasm is not reached. Size reduction and sex flush disappearence in breasts. Uterus lowers aand vagina returns to normal size, orgasmic platform disappears.

In Males: Includes a refractory period during which excitement cannot be reached. Scrotum thins and descends, erection disappears.

~Note that though there is great variation, both are present in men and women~

Myotonia

*Increased muscle tension

*Can be rhythmic

*At times agonist and antagonist muscles contract causing muscular rigidity.

Vasocongestion

*Increased blood flow primarily caused by increased influx of blood (allowed by arteriolar vasorelaxation)

Male Sexual Response

The first physiologic response of males is erection of the penis (excitatory phase). This is a vascular phenomenon that is mediated by the PNS (Sacral S2-4 (errection center) spinal cord) and does not require the brain [inherent reflex]. Erection is maintained throughout the plateau and undergoes slight enlargement near orgasm.

Pelvic Nerve →vasodilation of arterioles

↑ NOS activity→ ↑NO → ↑ guanylate cyclase→ ↑ cGMP* → ↑smooth m relaxation →vasodilation→ ↑ blood flow

The testes are elevated during excitement and plateau.

Ejaculation: Coordinated by the Lumbar SC (L1, L2). Emission of seminal fluid from the seminal vessicles and prostate into the prostatic ureathra involves smooth m rhythmic contractions of the epididymism vas and these glands + the prostatic urethra.

Ejaculation Proper: is mediated by the Pudendal nerves and involves rhythmic contractions of the bulbocavernosus, perineal, ischiocavernosis, and urethral muscles + urethral sphincters (to prevent retrograde ejaculation)

Female Sexual Response

First response is vaginal lubrication (likely trasudate)

Breasts: (see phases of the response slide)

External Genitalia: Labia minora ↑ in size and become red in color. Clitoral hood covers the clitoral glans (which are engorged).

Vagina: enlarges (inner 1/3) with the outer 1/3 narrowing to create the orgasmic platform which may play a role in retaining semen.

Menopause

Occurs in F when all follicles disappear (and therefore cannot release E, P and Inhibin). Leads to genital atrophy, ↓ vaginal secretions, bone loss, ↑ athrogenicity of lipoproteins and ↑ plasma levels of LH and FSH which leads to excretion of large volumes of gonadotropin by menopausal women (hMG) which is used pharmacologically whic is FSH-like in activity and uesed to promote follicle development in sub-fertile F.

 Climateric

Reproductive aging in M. Decline in T production is accompanied by a rise in gonadotrophin levels, however many men remain virile into their 80s.

Commencement of Puberty

Hyp fails to secrete sig GnRH until pubertal age (possibly due to - FB by circulating adrenal androgens or CNS inhibition) but mondifcation of hypo neurons causes them to start pulsitile secretion of GnRH.

Body fat, sufficient sleep and nutritional/psychosocial depirvation can all effect pubertal onset.

Signs of onset in girs includes growth spurt then breast growth (thelarche) and in boys ↑ testicular size (due to ↑FSH) then, later, pubic hair appears (due to androgens, called Pubarche)

Hallmarks of puberty

Varied time span for pubertal commencement but once it begins the timecourse is fairly regular.

Requires that the sperm gets from teh vagina, through the cervical mucus, up the uterus and most of the way through the fallopian tube (Fertilization usually occurs in the Upper Ovaduct*)

Sperm and egg must meet between 5-24 h post-ovulation

When they meet, the sperm must have been capacitated so it is capible of binding and penetrating the zona pellucida.

Lots of sperm released (100-300 million in a few ml), thinning of the cervical mucous by Estradiol, and ↑ motility of the F tract by estradiol all help!

Noe that timing is important! Sperm can survive at most a few days (men have more constant sexual interest) and teh egg can survive between 6 and 24 hrs (↑ sex drive prior to ovulation/menstruation).

Age is a factor in acheiving and maintaing pregnancy (fertility drops after the age of 35).

Following successful fertilization the zygote divides inot the blastocysts and migrates to the endometrium.

The Endometrium has been prepared by Estrogen in the follicular phase and Estrogen + Progesterone in the early luteal phase and is ready for the arrival of the blastocyst between days 18-19 post fertilization.

The blastocyst burrows into the endometrium and establishes connections with maternal cells begining the formation of the placenta.

LH Surge: Triggers ovulation

Estrogen/E2: levels ↑ throughout the course of PG but has a distinct peak just prior to the LK peak/ovulation and then rises again and begins to climb after implantation and the CL rescue by hCG

*Ovaducts: ↑growth of m and epi, ↑motility, ↑cilia beats

*Myometrium: ↑ growth and contractility

*Endometrium: ↑growth, gland devel and blood supply

*Cervical mucous: ↑supply of watery mucous (ferning)

*Vagina: ↑ lubrication and growth of epi (cornification)

*↑ growth of mammary glands and duct branching

*Induces PG receptors in the endometrium (Levels climb throughout the course of PG)

*↑ size of the pituitary (lactotrophs)

*↑ Prl secretion (but inhibits Prl stim of milk synthesis)

Note: The Placenta makes E2 from maternal and fetal adrenal androgens.

Progesterone levels rise progressively along with E2 throughout the course of PG with several tasks...

Inhibitory actions on the Uterine muscle: ↓ motility and prevents coordinated contractions, antagonizes estrogen's enhancement of motility (↓ # E receptors), ↓ sensitivity of uterine muscle to OT, hyperpolarizes muscle membranes (↓ excitibility)

Stimulatory actions on the Endometrium: After endometrial priming by E, PG ↑ endometrial gland secretion and preps the uterus for implantation.

 ↑ growth of Mammary Glands but inhibits Prl stimulation of milk synthesis.

Cervix: produces sticky mucous to keep bacteria out.

hCG maintains the CL during the early weeks of PG (maintains E and P levels) and also triggers a spike in TH levels in the maternal circulation (which results in ↓ maternal TSH)

Mammary Glands

and

Lactation

Exist in their inactive state as ducts without alveoli or the production of milk.

During PG: the glands enlarge due to the growth of ducts and glandualr strucutres, however, very little milk is produced at this time.

E inhibits PRL and hPL from triggering milk production while stimulating the growth of the 'factory' that will supply the milk after birth.

Lactation requires PRL, E, P, Insulin, Cortisol, T3 and OT (+PTH conserves Ca)

PRL stimulates milk synthesis for the next nursing period and its actions are dependant on T3*

OT stimulates milk let down, getting milk made in the glands down to the nipple.

*Both PRL and OT are stimulated via neural pathways with suckling being the afferent limb.

Milk must be removed to maintain lactation*

Nursing a bably is not sufficient/individually effective birth control (though can suppress follicular growth)

Duct Growth stim by E, GH, and Cortisol

Alveolar Growth (factories) E, P, PRL, Cort, GH (hPL?)

Lactogenesis by PRL (w/ T3), Cortisol, Insulin, IGF-1

Factors that Increase (↑)

Body weight (~25%), salt/water retention (↑ E2, Ald, ADH), blood volume (40%), #RBCs (↑ Epo), PV, CO, HR, Min Volume, metabolic rate, FA turn over, insulin resistance, insulin secretion (hPL, ↑ Cortisol), appetite.

Factors that Decrease (↓)

Hematocrit (due to ↑ V>↑RBC#), TPR (allows MAP to remain stable), Pa_CO2 (good for baby), and Glucose tolrance (due to hPL & ↑ cortisol).

Factors that remain Constant

MAP (due to ↑ HR but ↓ TPR)

We don't know exactly what triggers it but OT is not the initiator (through it does greatly assist it)

Proposed series of events: ACTH release from the fetal pituitary→ rel Cortisol & DHEA-S from the fetal adrenals.

Fetal Cortisol →maturation of the lugs and glycogen storage in the fetal liver (for survival after birth)

Fetal DHEA-S→converted to Estrogen by the placenta→ ↑ P binding → ↓ freel local [P] → ↑ E:P ratio →  ↑ Prostaglandins.

Lower [P], higher rel [E] & Prostaglandins act on the myometrium of the uterus to ↑ contracitility and stretch the crevix.

Cervical stretch feeds back + onf the maternal Pituitary to ↑ OT secretion which ↑ and coordinates contractions.

Rapid-response and short duration of action.

Promotes glucose release from the liver (to maintain normal [P_Glc] and complements the actions of the SNS*

Hepatic Actions: ↑ glycogenolysis, amino acid uptake (backbone for Glc synt), gluconeogenesis and ketogenesis.

↑ hepatic production and secretion of Glc → ↑ [P_Glc]

Glucagon alters the action of many enzymes:

Alt. via↑cAMP/PKA

↑ Phosphorylase activity (Catalyzes the rate lim step in glycogenolysis)+ ↓ Phosphorylase Kinase activity (activates glycogen phosphorylase, allowing glycogenolysis)

↓ glycogen synthetase activity

↓ formation of F-2,6-BP (↓ PFK-1 activity→↓ glycolysis) +↑ F-1,6-BPase activity which ↑ glucoeogenesis)

↓ AcCoA carboxylase activity (↓ AcCoA release→ ↓ malonyl CoA → ↓ LCFA synthesis AND ↑ beta-ox of LCFA via removal of mal-CoA inhibition of CPT-1)

Alt via unknown mechanisms.

↑ PEP carboxykinase synthesis (PEPCK cat a key reaction in gluconeogenesis)

Slight ↑ Pyruvate carboxylase (cat Pyr→OAA)

Speed/Duration of actions varies from fast (Glc uptake, sec-mins) to slower (enzyme synthesis, hours).

Insulin levels increase during/after a meal.

Insulin is the MOST POTENT hormone*

Anabolic Insulin is the major storage hormone (promotes synthesis of Protein, Glycogen, and TAG)

Anti-Catabolic In also slows or inhibits catabolic processes of protein degredation, glycogenolysis, lipolysis and gluconeogenesis (counter-intuitive*)

Actions of Insulin on Muscle: ↑ Glc and aa uptake, and ribosomal protein synthesis (not on forearm m.) ↑ LPL synthesis (extracts FA from VLDL and chylomicrons t be used for energy by muscle instead of glucose*)

↓ protein breakdown and aa release.

Actions on Adipose: ↑ Glc uptake, ↑ synthesis of FA, Glycerol phosphate, LPL, and TGs* from Glc.

↓ lipolysis (via ↓ activity of HSL, sensitive to SNS*)

Actions on Liver: ↓ release of glucose, ↑ lipid/TAG synthesis (but remember that In ↓ VLDL/apoB synthesis so Insulin ↑ hepatic stores of TAGs. ↑ protein synthesis. ↓ ketogenesis (w/o In, ketosis occurs as in DM).

During/just after a Meal

Describe the body's Objectives, Major processes (with regards to carbs, fats, and proteins) and the major hormones involved.

Objectives: Replinish glycogen stores, don't wast Glc, use ingested materials for energy then package excess.

Major Processes

Carbs: ↑ Glc uptake/use, glycolysis, and glycogenesis.

↓ gluconeogenesis and glycogenolysis.

Fats: ↑ lipogenesis and fat stores. ↓ lipolysis (via inhibition of HSL in adipose) and ↓ ketogenesis.

Proteins: ↑ protein synthesis and stores. ↓ degredation

Major Hormones

GH: Constant levels. ↑ protein synthesis

T3: constant level but ↑ protein synthesis (synergizes w/ GH) and ↑ glycolysis.

Glucagon/Epi/Norepi: levels ↓ but have little effect on fed state.

Insulin: levels ↑↑ causing an ↑ in anabolic and anticatabolic processes.

Between Meals

Describe the body's Objectives, Major processes (with regards to carbs, fats, and proteins) and the major hormones involved.

Objectives: Keep [Glc] constant for CNS, ↓ Glc utilization, burn FA and KP for E, use sparable proteins for their aa's. Mantain some glycogen in reserve.

Major Processes

Carbs: ↓ Glc uptake, Glc use, and glycolysis. ↑ Glycogenolysis. Small ↓ glycogenesis and glycogen stores.

Fats: ↓ lipogenesis and fat stores. ↑ lipolysis/FFA ↑ Ketogenesis.

Proteins: ↑Protein degredation and ↓ synthesis (↓stores)

Hormones

Cortisol: levels constant, acts premissively to allow catecholamine actions (↓ in Glc uptake and use, ↑ gluconeogenesis and lipolysis).

GH: levels constant but acts like cortisol with catecholamines (↑ lipolysis, ↓ Glc uptake/use)

T3: levels constant, permissive to ↑ lipolysis

Glucagon: may ↑ in liver. Acts in liver to ↑ glycogenolysis, gluconeogenesis, and ketogenesis. ↓ glycogen syntehsis and glycolysis.

Epi/Norepi: levels ↑. ↑ Glycogenolysis, lipolysis, gluconeogenesis. ↓ Insulin secretion and Glc uptake.

Insulin: levels ↓↓. ↓ in anabolic and anti-catabolic processes allowing domination of catabolic processes.

Which hormoes are short-acting?

Long-acting?

Short-Acting Hormones

Rapid onset of actions (sec-mins) and brief (mins) duration of actions (act to ↑ or ↓ protein activity).

Insulin, Epinephrine, Norepi, Glucagon

Long-Acting Hormones

Delayed onset of actions (min-hours) and prolonged effect of actions (hours-d). Often act to ↑ or ↓ the amount of protein/enzyme.

GH, TH, Glucocortiocoids (Cortisol) and Sex Steroids

The cycle of energy use that runs between Adipocytes of fat and myocytes of muscle.

In Adipocytes FA are liberated from TG and released in the blood as FFA → FFA + KB are taken up by the myocytes which can metabolize them to generate ATP.

Glucose is taken up by both adipocytes (which use it to make FA/TG) and myocytes which → G-6-P → ATP

Hormone-Sensitive Lipase

Has 2 chief functions:

1) Liberates cholesterol from cholesterol esters in steroidogeneic tissues.

2) Liberates FA from TAG in adipose.

Very sensitive to Epinephrine*(meidated by cAMP/PKA)

As blood glucose drops below ~85 mg/dL, there is a ↓ in insulin.

Below ~70 mg/dL there is an ↑ in glucagon, Epinephrine and GH followed by cortisol***

Below ~65 mg/dL symptoms (sweats, pallor, shakes etc...) ensue followed by Hepatic Glucose Autoregulation (a hormone-independant process).

Below ~50 mg/dL there is a reduction in cognition and death below 45.

Type I Diabetes Mellitus

(IDDM)

Hyposecretion of Insulin

↓↓ in plasma insulin

↑ plasma Glc (fasting, with food, or in GTT, takes much longer to decrease after a meal).

*In Type II plasma glucose levels can be elevated but can also be noram (in this case they still take longer to come down after a meal)