Comprehensive Study Notes on Chemical Communication and Endocrinology

General Concepts of Chemical Communication and Mediators

Chemical communication involves various mediators that regulate physiological processes. Nitric Oxide ($NO$) is a significant chemical mediator produced by endothelial cells when blood oxygen ($[O_2]$) levels decrease. This production leads to the diffusion of $NO$ towards the media, causing muscular relaxation and subsequent vasodilation, a process of critical importance for erections. Additionally, $NO$ functions as an inhibitory neurotransmitter. Growth factors, which are protein-based (peptides or proteins), play a crucial role in controlling the cell cycle, specifically the transition from the $G0$ to $G1$ phase, as well as in cellular differentiation processes. Examples include $EGF$, $IGF$, $NGF$, and $VEGF$.

Cytokines are proteinaceous substances produced within the context of the immune response, such as $IL-1$, $IL-2$, $TNF-\alpha$, and $IFN$. Chimiokines are a specific subset of cytokines characterized as chemo-attractants. Prostaglandins ($PG$), specifically the $PG2$ type, are derived from arachidonic acid. Arachidonic acid is a polyunsaturated $\omega-6$ fatty acid containing $20$ Carbon atoms, found in membrane phospholipids. Their synthesis occurs via cyclo-oxygenases: $COX1$ maintains basal levels, while $COX2$ levels increase during inflammatory reactions. Prostaglandins comprise several classes with distinct functions. Classes $I2$, $E2$, and $D2$ stimulate the inflammatory response, cause vasodilation, recruit leukocytes, and are partly responsible for fever and pain, while also inhibiting blood coagulation. Under basal conditions, $COX1$ produces $PGE2$, which stimulates mucus production by stomach cells and decreases the production of hydrochloric acid ($HCl$). Non-steroidal anti-inflammatory drugs ($AINS$) like aspirin and ibuprofen inhibit prostaglandin synthesis, which can have negative long-term effects on the stomach.

Other functions of prostaglandins include those related to reproduction. $E2$ and $F2$ are secreted by seminal vesicles and are present in sperm; they activate the contraction of smooth muscles in the uterine wall to assist sperm transport. During childbirth, the placenta secretes $E2$ and $F2$ (along with $E1$ and $F1$) to induce uterine muscle contractions. Misoprostol, an analogue of $E1$, is utilized for medical abortions ($IVG$) and to induce labor. Finally, Thromboxane ($TxA2$), produced by platelets, stimulates coagulation. Aspirin, used at low doses regularly, thins the blood to prevent the formation of clots.

Nature and Modes of Action of Hormones

An hormone is defined as a substance secreted into body fluids at low concentrations that transmits regulatory commands from a distance to specific target cells. A neurohormone is a hormone produced by secretory neurons. It is noted that some hormones also function as neurotransmitters, and some, known as pheromones, act outside the body. Chemically, hormones are classified into three groups: proteins and peptides, amines (derived from amino acids like tyrosine or tryptophan), and steroids (derived from cholesterol).

Hormonal action follows a three-step process: reception of the stimulus, conversion and amplification of the stimulus (signal transduction), and the final response. The mechanism differs based on solubility. Hydrosoluble hormones are released by endocrine cells via exocytosis and bind to receptors on the surface of the target cell. This triggers a signaling cascade in the cytoplasm, leading to either a direct response (such as the activation of an enzyme or a membrane transporter) or the activation of a transcription factor that modulates gene expression. Liposoluble hormones are transported in the blood associated with proteins, such as $T3$ and $T4$, which are largely carried by $TBG$ (thyroxine-binding globulin), albumin, or transthyretin. They sometimes require a surface transporter. Their receptors are located in the nucleus or cytoplasm and often function as transcription factors that can be activated, deactivated, or transported between the cytoplasm and the nucleus.

The Endocrine System and Simple Pathways

The endocrine system consists of endocrine glands and isolated endocrine cells. In simple endocrine pathways, a stimulus triggers secretion from an endocrine gland, such as a drop in $pH$ in the duodenum or fluctuations in blood sugar (hypo or hyperglycemia). These pathways utilize negative feedback loops (retroinhibition) once the stimulus decreases. In simple neuroendocrine pathways, a stimulus is received by a sensory neuron, which then stimulates a neurosecretory cell to produce neurohormones. An example is the positive feedback loop (retroactivation) in milk secretion, where the act of nursing stimulates further production. However, negative feedback also exists; the presence of milk in the alveoli can decrease production via the protein $FIL$ (Feedback Inhibitor of Lactation), which acts in an autocrine fashion.

The Hypothalamus and Pituitary Glands

The hypothalamus and the pituitary gland (hypophysis) serve as the integration center for the endocrine system, connecting it with the nervous system. The hypothalamus contains secretory neurons. The neurohypophysis, or posterior lobe of the pituitary, consists of the nerve endings of neurons originating in the hypothalamus. Secretion here is triggered by nervous stimuli. It stores and releases two hormones produced in the hypothalamus: Oxytocin and Antidiuretic Hormone ($ADH$).

Oxytocin is released via sensory stimulation, such as nipple suctioning. It stimulates milk ejection from mammary glands and uterine muscle contractions during childbirth, triggered by the pressure of the baby against the uterine walls. It is also known as the "pleasure and anti-stress hormone," decreasing the secretion of $ACTH$ and cortisol, and favoring maternal care, attachment, and sexual activity. Antidiuretic Hormone ($ADH$) is a peptide that regulates water retention by the kidneys. Osmoreceptors in the hypothalamus detect hyperosmolarity and trigger $ADH$ release, increasing the permeability of renal collecting tubules to urea and water. These osmoreceptors also trigger the sensation of thirst through nervous pathways.

The Adenohypophysis and Cascade Pathways

The adenohypophysis, or anterior pituitary, is composed of endocrine epithelial cells and is regulated by hormones from the hypothalamus known as Releasing Hormones (libérines) and Inhibiting Hormones (inhibines), which are transported via a portal system. The hormones produced by the adenohypophysis can act directly on target tissues (like prolactin) or on other endocrine glands (stimulines).

Growth Hormone ($GH$) is controlled by $GHRH$ (releasing) and somatostatin (inhibiting). It is an anabolic protein that promotes growth across a wide range of cells, both directly (bone and cartilage growth) and indirectly by stimulating the synthesis of other growth factors like $IGF$ produced by the liver. It is used to treat growth retardation in children but is also used as a doping agent; in excess, it causes acromegaly or gigantism. Prolactin ($PRL$) is regulated by $PRH$ and $PIF$ (dopamine). In mammals, it stimulates mammary gland growth and milk synthesis ($FIL$ decreases $PRL$ receptor expression) and inhibits $GnRH$ secretion, which explains the absence of ovulation during lactation in some species. In non-mammals, it regulates osmoregulation, growth, metabolism, and immune behavior.

Proopiomelanocortin ($POMC$) is a precursor protein controlled by $CRH$ (corticoliberin). It is processed into several hormones: Corticotrophin ($ACTH$), which acts on the adrenal cortex during stress; Melanocyte-stimulating hormone ($MSH$), which affects skin pigmentation and fat metabolism; and $\beta$-endorphins, which inhibit pain perception. $POMC$ is also expressed in the brain and skin. $\alpha-MSH$ plays a major role in pigmentation; UV exposure increases $MSH$ and $ACTH$ production by keratinocytes. Red hair is associated with mutations in the $MS1R$ receptor, which prevents it from binding $\alpha-MSH$.

Adrenal Glands and Stress Response

The adrenal glands are divided into the medulla and the cortex. The adrenal medulla is composed of secretory neurons and is stimulated by the nervous system for "fast" stress responses. It produces catecholamines, namely Adrenaline and Noradrenaline. These hormones trigger the "fight or flight" response: breakdown of glycogen into glucose in the liver ($\alpha1$ and $\beta2$) and muscles ($\beta2$), inhibition of insulin secretion ($\alpha2$), release of fatty acids from adipocytes ($\beta1$ and $\beta2$), increased heart rate ($\beta1$) and blood flow, bronchiole dilation ($\beta2$), and selective vasoconstriction ($\alpha1$) or vasodilation ($\beta2$) to favor the heart, brain, and skeletal muscles.

The adrenal cortex consists of endocrine epithelial cells and is stimulated by $ACTH$ for "slow" or long-term stress responses. It produces steroids (corticosteroids). Glucocorticoids, such as cortisol, increase blood glucose and circulating fatty acids through protein degradation in muscles and lipolysis. They promote gluconeogenesis in the liver and kidneys using glycerol and amino acids. At high doses, they have anti-inflammatory effects and are used for autoimmune diseases. Mineralocorticoids, like aldosterone, promote the reabsorption of $Na^+$ and water in the kidneys, increasing blood volume and pressure. The $CRH-ACTH-$Corticoïdes axis follows a circadian rhythm, peaking at waking and reaching a minimum at midnight. The adrenal cortex also produces gonadocorticoïdes (androgens and small amounts of estrogen/progesterone), which play roles in sexual stimulation, puberty, and hair growth.

Thyroid and Parathyroid Glands

Thyroid hormone production ($T3$ and $T4$) involves a multi-step process: (1) Synthesis of thyroglobulin in the ER and Golgi. (2) Accumulation of iodine in follicle lumens via a $I^-/Na^+$ symporter and $Na^+/K^+$ pump. (3) Oxidation of $I^-$ by thyroid peroxidase ($TPO$) and $H_2O_2$. (4) Iodination of tyrosine residues on thyroglobulin to form mono-iodotyrosine and di-iodotyrosine. (5) Coupling of these residues to form $T3$ and $T4$. (6-11) Endocytosis and enzymatic degradation release $T3$ and $T4$, which are then transported in the blood bound to proteins like $TBG$. Active hormones are those circulating freely. $T4$ is more concentrated but less active; most $T3$ is produced locally at target organs by deiodination of $T4$. $TSH$ increases iodine import and production of thyroglobulin and $TPO$.

$T3$ and $T4$ control growth and development (e.g., metamorphosis in amphibians, bone formation in mammals), homeostasis (heart rate, blood pressure), and cellular energy metabolism (increasing heat production and oxygen consumption). They also stimulate dopamine and serotonin circuits. Hyperthyroidism (excessive $T3/T4$) leads to high internal temperature, weight loss, and hypertension (e.g., Graves-Basedow disease where auto-antibodies activate the $TSHR$). Hypothyroidism leads to cretinism, obesity, lethargy, and goiter if iodine is lacking.

Calcium regulation involves the Parathyroid Hormone ($PTH$) and Calcitonin. Low blood calcium ($[Ca^{2+}]$) causes muscle convulsions, while high levels lead to calcium phosphate precipitates. $PTH$, from the four parathyroid glands, increases blood calcium by stimulating bone resorption (osteoclasts), renal calcium reabsorption, and Vitamin D activation. Calcitonin, from the thyroid's parafollicular cells, decreases blood calcium by stimulating bone fixation and decreasing renal reabsorption. In humans, its role is primarily during bone growth.

The Pancreas and Diabetes

The pancreas has both exocrine and endocrine functions. The islets of Langerhans contain alpha cells (glucagon), beta cells (insulin), delta cells (somatostatin, which inhibits glucagon, insulin, and gastrointestinal hormones), and PP cells (pancreatic polypeptide, which regulates satiety). Diabetes is characterized by insulin deficiency or insensitivity, leading to high blood glucose, glucose in urine, dehydration, and a drop in blood $pH$ as fats fuel cellular respiration.

Type I diabetes (insulin-dependent) is an autoimmune disease destroying beta cells. Type II (non-insulin-dependent) accounts for $90\%$ of cases and involves insulin insensitivity linked to heredity and obesity. There are $350 \times 10^6$ diabetic people globally. In cats, prevalence is $0.2$ to $2\%$, mostly Type II. In dogs, Type I is more common, sometimes caused by pancreatitis. Type II in dogs can occur after steroid treatment.

Gonads and Reproductive Cycles

Embryonic development is influenced by the $SRY$ gene on the Y chromosome, which leads to Sertoli cell differentiation. These produce anti-müllerian hormone, causing the degeneration of female ducts. Testosterone then directs the formation of male ducts (vas deferens, seminal vesicles, prostate). In XX individuals, the absence of these hormones allows female duct development (uterus, vagina). Approximately $1$ in $2000$ births results in intersex individuals.

The ovarian cycle consists of the follicular phase and the luteal phase. During the follicular phase, $GnRH$ stimulates $FSH$ and $LH$, which matures a follicle. The follicle secretes estrogens, which initially inhibit $FSH/GnRH$ but later trigger a peak in $GnRH$ and $LH$ (positive feedback). The $LH$ peak triggers ovulation. In the luteal phase, the remaining follicle becomes the corpus luteum, secreting progesterone and estrogens to develop the endometrium. If fertilization occurs, the fetus produces human chorionic gonadotropin ($hCG$), maintaining the corpus luteum. If not, the corpus luteum degenerates, leading to menstruation. Endometriosis occurs when endometrial cells move to other areas, causing pain as they still respond to hormones.

Hormonal Control of Amphibian Metamorphosis

In amphibians, prolactin inhibits metamorphosis until environmental conditions are favorable. Before metamorphosis in tadpoles, $CRH$ triggers $TSH$ production. Environmental stimuli then trigger $TRH$ and $CRH$, leading to $TSH$ secretion from the adenohypophysis and subsequent $T3/T4$ production by the thyroid. These thyroid hormones cause programmed cell death (apoptosis) of larval tissues (gills, tail) and the development of adult organs (limbs, lungs). During metamorphosis, $CRH$ also leads to $ACTH$ expression, stimulating interrenal cells (equivalent to adrenal glands) to produce hormones.