Typical anatomy:

The penile urethra passes through the penis and opens at its distal end.
Dorsal surface of penis faces abdomen; ventral surface faces the legs.

Urethral defects

Be aware that urethral displacement can also occur in female embryos, but is more common in males.

Hypospadias are defects on the ventral aspect (the underbelly) of the urethra

• “Hypo” means “below”
• Occurs when urtheral fold fusion is interrupted, leaving openings in the ventral urethra.
  — Current thinking is that hormonal abnormalities lead to this defect.
• Hypospadias is problematic because of the cosmetic abnormality, the voiding abnormalities (which are of varying severity), and the associated chordee (the bent penis) that can accompany it (we’ll explore it further in a moment).
  — Corrective surgery is typically performed for hypospadias.
• Hypospadia variants:
  — Perineal hypospadias lie in the perineum
  — Scrotal hypospadias pass through the scrotal tissue
  — Penile hypospadias occur along the shaft of the penis
  — Glanular hypospadias pass through the ventral surface of the glans, aka, tip, of the penis

Epispadias are mis-placed openings in the dorsal surface of the urethra.

• “Epi” means “above”
• Associated with dorsal chordee
• Variants:
  — Penopubic (occurs when the pubic bones do not fuse and the urethra remains open)
  — Penile epispadia
  — Glanular epispadia

• Epispadias can be associated with bladder exstrophy:
  — The flattened urinary bladder protrudes from the abdomen and the unfused pubic bones are widely apart.
  — Penis is superiorly displaced.

Testicular defects

Normal location:

• Within the scrotum outside of the body, where temperature is held slightly lower than that of the body.

Cryptorchidism

• Undescended testes; can be found anywhere along the typical migratory path:
  — Abdomen
  — Inguinal canal
  — Just superior to the scrotum (aka, suprascrotal)
• Can be uni- or bilateral, and tends to resolve itself within a few months after birth.
  — However, if it does not, surgery is usually required to avoid infertility, increased risk of testicular cancer, and increased risk of testicular torsion (see reference below) (recall that sperm function only when kept slightly cooler than body temperature; it is thought that, when the temperature is chronically high, cancerous cells are more likely to proliferate).

Hydrocele

• Fluid accumulates in the tunica vaginalis, which surrounds testis in scrotum.
• Recall that the tunica vaginalis forms a sac and precedes the testis into the scrotum during testicular migration; typically, the fluid within the sac is reabsorbed and the tunica vaginalis loses its attachment to the abdominal peritoneum.
• In some cases, peritoneal attachment is lost but the fluid is not reabsorbed, creating a non-communicating hydrocele.
• Such hydroceles form visible swellings within the scrotum and are typically benign; they often resolve themselves over time.
• However, in other cases, the connection between the tunica vaginalis and abdominal cavity persists, allowing fluid to accumulate in a “communicating hydrocele.”
  — Because this persistent communication can lead to intestinal herniation, surgery is often necessary.

Typical anatomy & Embryological Origins

• Distal vagina arises from the endodermal urogenital sinus
• Recall that this is a point of contention; other research indicates the distal vagina arises from the paramesonephric ducts.

• Proximal vagina, uterus, and uterine tubes are derived from the paramesonephric ducts.
• Ovaries are located near the distal ends of the uterine tubes.

Atresia

• Results from incomplete canalization of lumen.
• Can be vaginal or cervical.
• Can be complete or incomplete.
  • In some women, dilators can be used to non-surgically correct vaginal atresia; in others, vaginoplastic surgery is needed to create a functional vagina.
• Vaginal atresia may be noticed during neo-natal examination, but cervical atresia often goes undiagnosed until puberty
  • Amenorrhea (absence of menstrual flow) and abdominal pain signify disorder. – – However, because the two often occur together, findings of vaginal atresia warrant inspection of the cervix via ultrasound.

Incomplete fusion of the paramesonephric ducts

aka, Müllerian ducts

• Anomalies of the uterus.

5-class schema based on the type of malformation

• Distinction between the types is important, because some classes are associated with higher risks of infertility and pain.

Class I comprises Müllerian hypoplasia and agenesis.

• For example, cervical agenesis is characterized by the absence of the cervix.
  • Other variants include vaginal and/or uterine tube absence or underdevelopment.

Class II anomalies arise when development one of the paramesonephric ducts is arrested, producing a unicornuate, aka, single-horned, uterus.

• It’s helpful to know that “uni” means “one”, and “cornuate” means “horn”; the uterus typically has two horns, i.e., where the uterine tube meets the body of the uterus
• Unicornuate uteri can present in 4 basic variations, based on how the “rudimentary” horn develops.
  • A communicating hemiuterus connects the primary uterine cavity with that of the rudimentary horn. Be aware that the non-communicating horn with a cavity can present as abdominopelvic pain because of obstructed menstrual flow.
  • Additional variants include uteri with no rudimentary horns, with rudimentary horns with non-communicating cavities, and rudimentary horns with no cavities. # Be aware that some authors refer to unicornuate uteri as “banana shaped.”

Class III comprises the didelphys, aka, double uterus

Though not typical in humans, the double uterus is common in other animals, including cats and dogs.

• Two uteri open to the vagina via separate cervical openings; though it is possible to carry two fetuses to term, one in each uterus, this phenomenon is rare.
• In some cases, a septum divides the vaginal canal to form double vaginas.

Class IV comprises the bicornuate uterus

• The bicornuate uterus has two distinct horns separated by a cleft, thus, they appear “heart-shaped.”
• This condition is the result of incomplete fusion of the paramesonephric ducts; incidentally, the horns may be undeveloped.

Class V comprises the septate defects.

• The most common Müllerian duct anomalies.
• The septum of the uterus arises from the inner wall of the fundus and extends towards the cervix.
• The septum is created by incomplete resorption of the paramesonephric duct septum.
• It may comprise fibrous or muscular tissue; tissue type informs surgical intervention.

Final Notes:

Be careful not to confuse the septate uterus with the bicornuate uterus; notice that the septum divides the inner uterine cavity, but the cleft of the bicornuate uterus is visible on the external surface of the uterine fundus (the superior most region of the uterus).
This distinction is clinically important, as the septate uterus is more often associated with reproductive impairment than is the bicornuate uterus.

Overview

• Adrenal cortex hormones, which are steroid hormones that regulate water and salt balance, blood sugar, and sexual characteristics, among other actions.
• Production of these hormones occurs in the mitochondria and smooth endoplasmic reticulum, and requires several enzymes, most of which belong to the family of cytochrome P-450 oxidases.
• As we’ll see, some key enzymes are only present in specific layers, which is why the layers produce different hormones.
• Adrenal capsule and cortex sublayers:

  – The zona glomerulosa, which produces mineralocorticoids.
  – The zona fasciculata, which produces glucocorticoids.
  – The zona reticularis, which produces androgens.

Pathways

• Begin at the top of the diagram with cholesterol, which is the precursor for all steroid hormones.
  – The adrenal gland can synthesize cholesterol, but the primary source of cholesterol is circulating LDL.
• Show that cortisol entry into adrenocortical cell mitochondria is facilitated by a transport protein called the steroidogenic acute regulatory protein – StAR.
• Show that cholesterol side chain cleavage cleaves cholesterol to form pregnenolone.
  – This step occurs in all layers of the adrenal cortex, and is upregulated by ACTH.

• From here, the pathway depends on the available enzymes.

We’ll first follow the pathway that leads to the production of aldosterone, the primary mineralocortioid, in the zona glomerulosa.

• So, show that pregnenolone is oxidized by 3 beta-hydroxysteroid dehydrogenase (3B-HDS) to form progesterone.

• Be aware that 3 beta-hydroxysteroid dehydrogenase, which plays a role in each layer of the adrenal cortex, is the only non-P-450 enzyme we’ll see in this diagram; we’ll come back to this point, later.

• Next, show that, within the zona glomerulosa, 21 alpha-hydroxylase converts progesterone to 11-deoxycortisterone (DOC), which is a weak mineralocorticoid.

• Then, 11 beta-hydroxylase converts 11-deoxycorticosterone to corticosterone.

• Lastly, show that aldosterone synthase, which is only present in the zona glomerulosa, converts corticosterone to aldosterone, the main mineralocorticoid.

• Show that angiotensin II facilitates aldosterone production in both early and late stages of aldosterone synthesis: like ACTH, it increases cholesterol side chain cleavage enzyme activity, and, it uniquely increases the activity of aldosterone synthase.
• Be aware that elevated potassium also increases aldosterone synthesis.

Now, let’s learn about cortisol production in the zona fasciculata.

• First, return to progesterone, and show that, in the presence of 17 alpha-hydroxylase, which is present in the zona fasciculata, progesterone is converted to 17-hydroxyprogesterone.

• Pause and show another pathway to 17-hydroxyprogesterone formation:
  – Return to pregnenolone, and show that 17 alpha-hydroxylase converts it to 17-hydoxypregnenolone, which, in the presence of 3 beta-hydroxysteroid dehydrogenase, is converted to 17-hydroxyprogesterone!

• Next, show that, in the presence of 21 alpha-hydroxylase, 17-hydroxyprogesterone is converted to 11-deoxycortisol.

• Then, show that 11 beta-hydroxylase adds a hydroxl to 11-deoxycortisol to produce cortisol, the primary glucocorticoid.

Finally, let’s see the pathway for adrenal androgen biosynthesis.

• Return to 17-hydroxypregnenolone, and show that, in the presence of 17 alpha-hydroxylase, it is converted to dehydroepiandrosterone (DHEA).
  – Be aware that some texts show this step occurring via 17,20 desmolase, aka, 17,20-lase; however, because these enzymes are encoded by the same gene as 17 alpha-hydroxylase, we can consider them to be the same enzyme for simplicity.

• Next, show that DHEA is converted to Androstenedione (A4)by 3 beta-hydroxysteroid dehydrogenase.

• Pause to show another pathway to A4:
  – 17-hydroxyprogesterone, which we saw in the pathway to cortisol biosynthesis, can be converted to androstenedione by 17 alpha-hydroxylase.

• Show that androstenedione is a precursor to testosterone, which is only minimally produced by the adrenal glands.

Sex steroids in the Peripheral Tissues

• Relatively weak adrenal androgens are converted to stronger sex hormones in the peripheral tissues:
  – Androstenedione and testosterone are converted to estroneand estradiol, respectively, via aromatase.
  – Testosterone is converted to dihydrotestosterone (DHT) via 5 alpha-reductase.

• Be aware that, although the adrenal glands are not the primary source of androgens in adult males, they are a significant source of androgens in children and women.

Key Enzymes

• 3 beta-hydroxysteroid dehydrogenase, which we indicated is involved in the production of all three hormone groups (mineralocorticoids, glucocorticoids, and androgens).
  – Non-P-450 enzyme.

• The rest of the enzymes we’ll show are P-450 enzymes and the gene names for each of these enzymes (some texts refer to them this way).

• Cholesterol side-chain-cleavage, aka, P-450SCC, gene name CYP11A1.
  – Recall that this enzyme was involved in the very early steps of steroid hormone biosynthesis, so it is a rate-limiting enzyme for all steroid hormones.
  – Be aware that this enzyme is sometimes called cholesterol desmolase.

• 11 beta-hydroxylase, aka, P-450-C11, gene name CYP11B1.
  – Notice that this enzyme is active in the formation of both aldosterone and cortisol, but not the androgens.
  – Another way to think of this is that this enzyme is only present in the zona glomerulosa and zona fasciculata.

• 17 alpha-hydroxylase, aka, P450-C17, gene name CYP17.
  – This enzyme is active in the production of cortisol and androgens, but not in the production of aldosterone
  – 17 alpha-hydroxylase is not significantly present in the zona glomerulosa.

• 21 alpha-hydroxyalse, aka, P-450-C21, gene name CYP21A2.
  – Notice that this enzyme is involved in the production of aldosterone and cortisol.

• Aldosterone synthase, aka, P-450-Aldo, gene name CYP11B2.
  – Recall that this enzyme is only present in the zona glomerulosa, and is responsible for the final steps of aldosterone synthesis.

Enzyme Deficiencies

• Generally speaking, when one enzyme is absent, its downstream hormone products are not synthesized, but upstream precursors and, therefore, other hormones, are produced in excess.
  – We’ll address the causes and consequences of these deficiencies elsewhere (i.e., congenital adrenal hyperplasia).

• Deficiency of 11 beta-hydroxylase:
  – Both aldosterone and cortisol levels are decreased.
  – Upstream hormones, such as 11-deoxycortisol, are increased.
  – 11-deoxycortisol is a weak mineralocorticoid, but show that, in excessive quantities, it can cause hypertension, hypokalemia, and reduced renin activity (remember that blood pressure follows aldosterone).
  – Androgen production is increased due to excessive quantities of “upstream” hormones in the shared pathway.
  In females, increased androgen production leads to virilzation (the development of “masculine” characteristics, like increased muscle mass and body hair); in male children, look for precocious puberty.

• Deficiency of 17 alpha-hydroxylase:
  – Decreased cortisol and androgen production, and, therefore, increased mineralocorticoid production.
  – Increased mineralocorticoid production (i.e., DOC) leads to hypertension and hypokalemia.
  – Congenital 17 alpha-hydroxylase deficiency produces ambiguous genitalia with undescended testes in males, and in females, lack of secondary sex characteristics.

• Deficiency of 21 alpha-hydroxylase:
  – Reduced mineralocorticoid and cortisol production.
  – Thus, potassium levels, renin action, and androgen levels will be elevated, but blood pressure will be low due to decreased mineralocorticoid action.
  – Indicate that reduced aldosterone will cause salt wasting, and, in females, increased androgen secretion will cause virilization.

• Shortcut:
• Notice that androgens are increased when the deficient enzyme ends in 1 (both 11 beta-hydroxylase and 21 alpha-hydroxylase deficiencies lead to virilization).
• When the deficient enzyme starts with 1, hypertension can occur (both 11 beta-hydroxylase and 17 alpha-hydroxylase deficiencies are associated with increased blood pressure).

Key Drugs:

• Ketoconazole, which is an antifungal drug, blocks steroid hormone synthesis by inhibiting cholesterol side chain cleavage.

• Metyrapone blocks cortisol production via inhibition of 11 beta-hydroxylase; thus, it is used to treat hypercortisolemia.

• Anastrozole and letrozole inhibit aromatase, thereby inhibiting estrone and estradiol production; these drugs can be used as part of anti-breast cancer treatments.

• Finasteride blocks 5 alpha-rectuase, and, therefore, conversion of testosterone to dihydrotestosterone; finasteride, aka, propecia, is used to treat enlarged prostate and male hair loss.

Overview:

• The adrenal gland is structurally and functionally divided into the outer cortex and inner medulla.
• Cortex
  – Embryologically derived from mesoderm
  – Produces steroid hormones from cholesterol.
  – The cortex can synthesize cholesterol de novo, but about 80% of the cholesterol used is obtained from circulating LDLs.
  – Each of the three layers of the adrenal cortex is regulated by ACTH (adrenocorticotropin), though the outermost layer, the zona glomerulosa, is primarily regulated by angiotensin II.
  ACTH upregulates adrenocortical cell LDL receptors and increases enzymatic activity of cholesterol side chain cleavage, which releases cholesterol from the LDLs.
  – Steroid hormones are metabolized in the liver, and secreted in the feces and urine.
• Medulla
  – Neural crest cell origins.
  – Secretes catecholamines in response to sympathetic nervous system stimuli (the adrenal medulla is sometimes called a specialized ganglion).

Anatomy – Blood Supply

• The adrenal gland receives substantial blood flow given its relatively small size.
• The right and left adrenal glands are situated at the superior poles of the kidneys (thus, their alternative name, “suprarenal glands”).
• We show the aorta and renal arteries, and the vena cava and the left renal vein.
• The inferior phrenic arteries arise from the aorta and give rise to the superior suprarenal arteries, which supply the superior regions of the adrenal glands.
• The middle suprarenal arteries arise directly from the aorta and travel to the adrenal glands.
• The inferior suprarenal arteries branch off the renal arteries.
• Venous drainage of the adrenal glands is asymmetrical:
  – The right adrenal gland drains directly into the vena cava, but, because of its relative distance from the vena cava, the left adrenal gland first drains into the left renal vein.

Physiology – Hormone secretion

Cortical hormones

• These are the steroid hormones, which are regulated by ACTH.
• Neurosecretory cells originate in the arcuate nucleus of the hypothalamus, and their axons terminate on capillaries of the hypothalamic-pituitary portal system.
• The hypothalamus secretes Corticotropin-Releasing Hormone (CRH) into the neurosecretory cells.
• When it reaches the anterior pituitary, CRH stimulates corticotrophin release of ACTH, which then travels in the blood to the adrenal cortex.
• In response to ACTH, the adrenal cortex releases cortisol and androgens.
• Regulation of Hypothalamic-Pituitary Axis:
  – At the hypothalamus: Hypoglycemia and stress trigger the release of CRH, whereas ACTH and Cortisol provide negative feedback.
  – ACTH negative feedback on the hypothalamus represents a “short feedback” loop, whereas the cortisol negative feedback is a “long feedback” loop.
  – At the anterior pituitary gland: Cortisol provides negative feedback to inhibit the release of ACTH.
  – This is the “short feedback” loop for cortisol.
• Aldosterone: ACTH also stimulates aldosterone secretion – however, aldosterone secretion is primarily regulated by the renin-angiotensin II response to low renal blood pressure, and, by extracellular potassium concentrations.
  – Thus, low renal blood pressure and elevated potassium levels stimulate aldosterone secretion.

Medulla hormones

• The adrenal medulla is regulated by the sympathetic nervous system: preganglionic sympathetic fibers release acetylcholine on the chromaffin cells of the medulla, which triggers catecholamine release.

Histology and Hormones

• From outer to inner, show the capsule, cortex, and medulla.
• The cortex comprises three sub-layers, each with their own products:
• The zona glomerulosa produces mineralocorticoids
  – Aldosterone, which regulates salt and water balance – thus, when you think of the zona glomerulosa layer, think: mineralo = Salt.
• The zona fasciculata produces glucocorticoids
  – Cortisol, regulates blood sugar – thus, when you think of the zona fasciculata, think: gluco = Sugar.
  – This layer also produces a small quantity of androgens.
• The zona reticularis produces androgens
  – Specifically, DHEA (dehydroepiandrosterone) and A4 (androstenedione), which regulate sex characteristics – thus, when you think of the zona reticularis, think: androgens = Sex.
  – For completeness, indicate that this layer also produces a small quantity of glucocorticoids.
• The *medulla, which comprises the center of the adrenal gland, produces norepinephrine and epinephrine – so, think medulla = Sympathetic nervous system.

Notice that we’ve indicated, from superficial to deep: Salt, Sugar, Sex, and Sympathetic regulation (hence, the mnemonic “the deeper the sweeter” doesn’t capture the full range of adrenal functions, it only describes the cortex!).

• Capsule comprises fibrocollagen fibers and capillaries.
• Zona glomerulosa comprises secretory cells with round nuclei arranged in irregular, rounded nests or clusters – aka, glomeruli.
  – Indicate that these nests are separated by fibrous extensions of the capsule – these are the trabeculae.
  – This is the thinnest layer of the cortex.
• Zona fasciculata comprises columns or cords – aka, fascicles– of cells separated by collagen fibers and capillaries.
  – These cells have abundant cytoplasm, which stains pale due to the presence of abundant lipid droplets.
  – This is the widest layer of the cortex.
• Zona reticularis comprises small branching cells that form a network – aka, reticulum – with capillaries.
  – Because these cells have low lipid levels, they stain dark; indicate that you may see brown lipofuscin pigments in this layer.
• Medulla comprises chromaffin, which are arranged in clusters around venous channels that deliver catecholamines to the blood.

Overview

• Growth hormone, aka, somatotropin, (somatotrophin) is secreted by anterior pituitary cells called somatotrophs.
• Somatotrophs make up more than half of the anterior pituitary, and growth hormone is the most abundantly secreted anterior pituitary hormone.
• Growth hormone is responsible for growth of almost all tissues, whether directly or indirectly via insulin-like growth factor 1 (IGF-1).
• Growth hormone secretion is pulsatile, and is highest during sleep.
• Growth hormone levels vary throughout life; they begin to fall after adolescence.
• Negative feedback loops regulate growth hormone secretion.

Growth Hormone Physiology

• First, we draw the hypothalamus and pituitary gland.
• Neurosecretory cells originate in the arcuate nucleus of the hypothalamus, and their axons terminate on capillaries of the hypothalamic-pituitary portal system.
• Within the anterior pituitary, there are various collections of endocrine cells;
  – We label the somatotrophs with an S, and show the nearby capillaries that deliver hormone products to the blood supply.

Growth Hormone Release

• The hypothalamus secretes growth hormone releasing hormone (GHRH) into the neurosecretory cells.
• When it reaches the anterior pituitary, GHRH stimulates somatotropin release of Growth Hormone (GH), which then travels in the blood to tissues throughout the body.

Growth Hormone Effects

• Growth effects: it increases cell growth, proliferation, and differentiation throughout the body.
• Direct effects on growth:
  – Increases bone length and muscle mass (growth hormone promotes protein deposition).
• Indirect effects on growth:
  – Diabetogenic effects: growth hormone increases glycogen breakdown in the liver to increase blood glucose, which can be used as fuel by growing body tissues.
  – Growth hormone also increases insulin-like growth factor 1release from the liver, which in turn promotes growth and differentiation of various tissues.

Be aware that IGF-1 is sometimes referred to as somatomedin-C

– Glucose-sparing effects: it increases lipolysis, and decreases glucose uptake by skeletal muscle and adipose tissue, which frees up energy for growth of tissues.

Growth Hormone Regulation

• Key regulators:
  – At the hypothalamus:
  Sleep, hypoglycemia, and stress trigger the release of growth hormone releasing hormone.
  Age and obesity are associated with reduced GHRH release, and, via negative feedback loops, glucose, IGF-1, and growth hormone also reduce GHRH release.
  – At the level of the anterior pituitary:
  Release of growth hormone is inhibited by growth hormone inhibitory hormone (aka, somatostatin, which is released by the hypothalamus), and via negative feedback signals from IGF-1 and Growth hormone (notice that IGF-1 and growth hormone provide negative feedback at both the hypothalamus and the anterior pituitary).

• Additional factors that promote and inhibit growth hormone secretion:
  – Stimulates Secretion:
  Growth hormone releasing hormone
  Decreased blood glucose
  Decreased blood free fatty acids
  Increased blood arginine (an amino acid)
  Protein deficiency and starvation
  Stress and excitement (including a variety of experiences, including exercise and trauma)
  Testosterone and estrogen
  Deep sleep
  Ghrelin, which is a growth hormone secretagogue (GHS) that is produced mainly in the stomach.

– Inhibits Secretion:
Growth hormone inhibiting hormone (aka, somatostatin)
Increased blood glucose
Increased free fatty acids
Exogenous growth hormone
Insulin-like growth factor 1 (via negative feedback)
Aging
Obesity

Pause to recognize that low blood glucose, low levels of free fatty acids, and increased levels of amino acids in the blood stimulate growth hormone release, which ultimately reverses each of these states to maintain homeostasis.

Growth Hormone Pathologies

Growth Hormone Defects

Growth hormone deficiency

• Characterized by low levels of growth hormone and IGF-1
  – If there is not enough growth hormone to trigger its production, IGF-1 will necessarily be low.
• Isolated growth hormone deficiency is often due to defects in the GH1 gene, which is responsible for growth hormone production.
• In other cases, growth hormone deficiency is an aspect of general hypopituitarism, in which other anterior pituitary hormones are also low.
• Patients can be treated with recombinant human growth hormone.
  Growth hormone insensitivity is characterized by normal or high levels of growth hormone, and low levels of IGF-1.
• This is the result of growth hormone receptor defects
  – May be hereditary, as in Laron Syndrome.
  – May acquired as a result of malnutrition, liver disease, diabetes, growth hormone receptor antibodies, or other pathologies.
• Patients can be treated with recombinant IGF-1.
• In Children:
  – Linear growth is slow (sometimes called pituitary dwarfism).
• Children often have delayed puberty, with small gonads and genitalia (micropenis).
• In Adults:
  – Body composition changes, including reduced muscle and bone mass, and increased fat mass.
  – Increased risk of cardiovascular disease (including left ventricular dysfunction and hypertension), and are more likely to develop insulin resistance.
  – Additionally, reduced exercise capacity, lethargy, and depression contribute to a lower quality of life in these patients.

Growth Hormone Excess

• Excessive section of growth hormone leads to elevated growth hormone and IGF-1
  – Be aware that prolactin is also often elevated.
• In both children and adults, the most common cause of growth hormone hypersecretion is an adenoma in the anterior pituitary.
  – Treatment often requires tumor removal.
• In Children: Gigantism
  – Growth hormone hypersecretion occurs prior to fusion of the epiphyseal plates.
  – This causes accelerated linear growth, and children are taller than their age/sex-matched peers; delayed puberty is also likely.
• In Adults: Acromegaly
  – Growth hormone hypersecretion occurs after epiphyseal plate fusion.
  – Thus, linear growth can’t occur, but bone deformation, soft tissue swelling, and enlargement of facial features, hands, and feet are common.
  – Patients are more likely to experience sleep apnea, diabetes, cardiovascular disease, arthropathy, carpal tunnel, headaches and visual disturbances due to tissue swelling and metabolic changes.

Overview:

• The hypothalamus collects information from throughout the body and uses it to regulate pituitary hormone secretion.
• Hypothalamic neuroendocrine cell axons terminate in the median eminence and posterior pituitary, where they secrete various neurohormones.
  – 5 hypothalamic hormones act on the anterior pituitary lobe.
  – 2 hypothalamic hormones are released by the posterior pituitary lobe.
• The anterior lobe, sometimes referred to as the adenohypophysis because of its gland-like components, comprises “-troph” cells that receive inhibitory and/or releasing signals from the hypothalamus via the hypothalamic-hypophyseal portal system.
  – The anterior lobe synthesizes and releases 6 peptide hormones that regulate growth, reproduction, and metabolism.
• The posterior lobe, sometimes referred to as the neurohypophysis because it comprises nervous tissue, releases 2 peptide hormones that are synthesized in large-bodied neurons with cell bodies in the hypothalamus.
• “Tropic” means that a hormone acts on other endocrine cells, as opposed to having direct actions on target organs; this will be an important function of several hypothalamic and anterior pituitary lobe hormones.

Hypothalamus and Pituitary Gland

• First, we draw the hypothalamus and pituitary gland; indicate anterior and posterior lobes.
• Within the anterior lobe reside the following clusters of endocrine cells:
  – Somatotrophs, Corticotrophs, Thyrotrophs, Lactotrophs, and Gonadotrophs.
  – Be aware that some authors end these cells with the suffix “tropes” instead of “trophs” (for example, corticotropes).
• Hypothalamic hormones that act on the anterior lobe:
  – Growth-hormone Releasing hormone (GHRH)
  – Growth-hormone Inhibiting hormone (GHIH)
  – Corticotropin-releasing hormone (CRH)
  – Thyrotropin-releasing hormone (TRH)
  – Prolactin-Inhibiting hormone (PIH)
  – Gonadotropin-Releasing hormone (GnRH).
  Notice that there are 2 inhibitory hormones and 4 releasing hormones in this group.

Anterior Lobe Hormones

Growth-hormone releasing hormone stimulates somatotroph release of growth hormone (aka, somatotropic hormone, aka, somatotropin).

• Growth hormone has multiple effects throughout the body: it facilitates bone and muscle growth and has diabetogenic effects on metabolism (it increases blood glucose).
• Growth hormone inhibiting hormone, aka, somatostatin, inhibits somatotrophic cell release of growth hormone.

Corticotropin-releasing hormone triggers corticotrophrelease of adrenocorticotropic hormone (ACTH) (aka, corticotropin).

• ACTH, in turn, stimulates the adrenal glands to release cortisol, which has a variety of effects, including reduction of inflammatory and immune responses and increases in gluconeogenesis, lipolysis, and proteolysis.
• ACTH release is inhibited via short and long negative feedback loops (see the links in our notes for more details).

Thyrotropin-Releasing hormone stimulates thyroprophicrelease of thyroid-stimulating hormone (TSH).

• Thyroid-stimulating hormone stimulates thyroid glandproduction and release of thyroid hormone, which promotes growth and maturation, increases metabolism, and stimulates beta-adrenergic receptors.

Prolactin-inhibiting hormone, which is dopamine, tonically inhibits lactotroph release of prolactin.

• Dopamine’s effects ensure that prolactin is secreted in low levels in males and non-pregnant/non-breastfeeding females; be aware that prolactin receptors are located in various tissues, including the prostate and immune cells, but its exact effects are uncertain.
• In pregnant and breastfeeding women, dopamine’s effects are inhibited, and lactotrophs release prolactin, which stimulates breast development and lactogenesis (milk formation).

Gonadotropin-releasing hormone (GnRH) promotes gonadotroph release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which act on the gonads.

• Follicle stimulating hormone works at the testes to support Sertoli cell growth sperm cell proliferation.
• In the ovaries, FSH promotes granulosa cell growth, follicle maturation, and aromatase synthesis; aromatase is the enzyme that converts androgens to estrogens.
• In the testes, Luteinizing hormone promotes Leydig cell secretion of testosterone.
• In the ovaries, LH has multiple effects:
  – It promotes thecal cell secretion of androgens, which are then converted to estrogens by the nearby granulosa cells;
  – The LH surge induces ovulation;
  – Post-ovulation, LH promotes the development and functioning of the Corpus Luteum (notice that “luteinizing” hormone promotes the “luteum”).

Posterior Lobe Hormones

• Neurons in the hypothalamus produce Oxytocin and Anti-diuretic hormone (aka, vasopressin), which are transported to the posterior pituitary, which releases them into the blood.

Oxytocin is responsible for myometrial contractionsduring childbirth to expel the fetus, and, during lactation, it promotes milk ejection.
– Recall that prolactin was necessary for milk production and secretion; oxytocin is required for its ejection.

Anti-diuretic hormone (ADH) regulates body water and blood pressure via the following mechanisms:
– In the kidney, ADH acts on the nephron collecting ducts to promote water reabsorption, thus increasing body water (and, therefore, blood volume, blood pressure, and cardiac output).
– Vasoconstriction is a secondary function of ADH, which binds to vascular smooth muscle receptors (hence its alternative name, vasopressin); in hypovolemic shock, increased endogenous production of ADH is an important compensatory mechanism.

Here we’ll learn which drugs are used to treat common cardiovascular disorders; because there are so many of them, antiarrhythmic drugs are discussed separately.

Hypertension

• First, indicate that the goal of these drugs is to reduce blood volume, systemic vascular resistance, or cardiac output, so as to return the blood pressure to normal.
• Many patients will require combination therapy to achieve these goals.

Vasodilation reduces systemic vascular resistance:

• Angiotensin-converting-enzyme inhibitors (ACE inhibitors):
  – These drugs tend to end in “pril” (ex: Lisinopril, benazapril, captopril), and are considered first line therapy; additionally, they protect against diabetic kidney disease, which makes them particularly useful in patients with hypertension and diabetes mellitus.
  – However, they are not recommended as first line therapy in patients with asthma (because they can cause coughing), and that they are contraindicated in pregnancy and bilateral renal stenosis.
• Angiotensin II receptor blockers (ARBs):
  – Often end in “sartan” (ex: candesartan, azilsartan, eprosartan, etc.).
  – As their name suggests, these drugs block the angiotensin II receptors on blood vessels, thereby prohibiting the vasoconstrictor effects of angiotensin II.
  – Like ACE inhibitors, these drugs should not be used in pregnancy or by patients with bilateral renal stenosis; however, they are suitable for patients with asthma, as they are not associated with respiratory side effects.
• Calcium channel blockers:
  – Predominantly act on the vessels to produce vasodilation are the dihydropyridines; the specific drugs end in “pine” (ex: felodipine, nifedipine, amlodipine, etc.).
  Write that these are another example of first line therapy for hypertensive patients, and evidence suggests that they are particularly effective in elderly and African American individuals.
• Hydralazine (brand name: Apresoline):
  – Sometimes used to treat severe hypertension, and, as we’ll see, hypertension during pregnancy.

Cardiac Output Reduction

• Beta-blockers:
  – End in “lol” (ex: metoprolol, acebutolol, bioprolol, labetalol, etc.).
  – These drugs block norepinephrine and epinephrine receptors on blood vessels.
  – Because of their effects on the heart, beta blockers are contraindicated in patients with bradycardia and AV nodal block.
  – Be aware that, in patients with diabetes, beta blockers can mask signs of low blood sugar;
  – And, non-selective beta blockers should not be prescribed to patients with asthma or COPD, because they can induce bronchoconstriction.

Increase Urine Output

• Thiazide diuretics:
  – Typically end in “ide” (ex: chlorothiazide, indapamide, etc.), and thiazide-like diuretics.
  – Thiazide diuretics are another example of first line therapy, but be aware that they should not be given to patients with sulfa allergies.
• Aldosterone antagonists:
  – End in “one” (spironolactone and eplerenone) are used in resistant hypertension, and are contraindicated in pregnancy.

Hypertensive Emergency

• Defined as systolic BP > 180 mmHg or diastolic BP > 120 mmHg with acute organ damage.
• Nitrates (ex: nitroprusside and nitroglycerine)
• Calcium channel blockers (ex: clevidipine and nicardipine)
• Dopamine-1 – agonists (fenoldopam)
• Adrenergic blockers (labetalol)

Hypertension during Pregnancy

• Methyldopa
• Labetalol
• Nifedipine
• Hydralazine

Hypotension

• Hypotension medications work to increase cardiac output and/or systemic vascular resistance.
• Vasoconstrictors include alpha-agonists; examples include methoxamine and phenylephrine.
• Cardiostimulatory drugs used to increase cardiac output include beta-agonists, which increase heart rate and contractility; examples include norepinephrine and dopamine.

Heart Failure w/ Reduced Ejection Fraction

• Treatment objectives are to improve cardiac functioning and relieve symptoms.
  Increase urine output to lower blood volume:
  – Diuretics
  – Aldosterone antagonists
  Vasodilators:
  – ACE inhibitors
  – ARBs
  Cardioinhibitory drugs
  – Beta-blockers (once the patient is stable)
  – Ivabradine, which is a sinus node inhibitor that is prescribed to patients with persistent heart rate above 70 beats per minute, despite treatment with beta blockers.
  Inotropic drugs
  – Digitalis (ex: digoxin), may be given to some patients to improve cardiac contractility and cardiac output.
  Digitalis should not be given to patients with hypokalemia, sinus or AV block, or reduced renal function.

• Be aware that there are no proven medication strategies for treating heart failure with preserved ejection fraction.

Angina

• The objective of treatment is to reduce the ratio of oxygen demand to supply in order to reduce the symptoms and improve prognosis.
  Vasodilator
  – Nitroglycerine is used to prevent and treat sudden attacks; nitroglycerine be administered sublingually, orally, or transdermally.
  Cardioinhibitory drugs reduce contractility and heart rate, and include:
  – Beta-blockers
  – Non-dihydropyridine calcium channel blockers, verapamil and diltiazem, which are more cardio-selective than are the dihydropyridine calcium channel blockers used to treat hypertension.
  Ranolazine
  – A late sodium current blocker, ranolazine, is also sometimes prescribed; this drug decreases heart wall tension and improves coronary blood flow.
  Anti-thrombotic drugs
  – Anti-platelets and anti-coagulants may be prescribed to reduce clotting and improve blood flow.

Myocardial infarction

• Therapeutic goal is to reduce the ratio of oxygen demand to oxygen supply.
  Restore coronary blood flow
  – Thrombolytic and antiplatelet drugs
  Vasodilators
  – Nitroglycerine
  Reduce oxygen demand
  – Beta blockers
• Other drugs may also be used to alleviate pain and MI complications, including morphine, anti-arrhythmics, and diuretics.

Be aware that the medications we’ve learned here may not be appropriate in all cases, and that other interventions, such as lifestyle changes and surgical procedures, may also be necessary. Furthermore, be aware that underlying disease states, such as dyslipidemia, may need to be addressed.

Overview

• Asthma and COPD are obstructive respiratory diseases characterized by airflow obstruction, chronic inflammation, and airway remodeling.
• Asthma is defined as intermittent, reversible obstruction and hyper-reactivity with excessive mucus production in the bronchi.
• COPD is chronic, progressive, irreversible obstruction.
  – COPD is an umbrella term that includes chronic bronchitis, small airway disease, and emphysema.
• Asthma-COPD overlap syndrome, which involves the airway hyper-reactivity associated with asthma plus elements of COPD.
• Asthma and/or COPD have shared treatment goals:
  – Open their airways and reduce air trapping, which will relieve dyspnea, and, reduce airway remodeling and prevent exacerbations.

BRONCHODILATORS

• Used to treat both asthma and COPD.

We draw a bronchial tube with thick layers of smooth muscle.

Beta-2-adrenoreceptor agonists (often shortened to simply “beta-2 agonists”) bind beta 2 receptors on the bronchial smooth muscle, which increases local cAMP and induces smooth muscle relaxation and bronchodilation.

• Beta-2 agonist bronchodilators may cause adverse effects associated with sympathetic activation (tremors, irregular heartbeat).

• Short-acting beta-2 agonist bronchodilators (SABAs) are used as “rescue” interventions for acute dyspnea due to bronchoconstriction and hyper-reactivity; they are effective within 1-5 minutes of administration and the effects last up to 4 hours.
  – Selective beta-2 agonists include: albuterol, terbutaline, pirbuterol, and metaproterenol (“ols”).
  – Non-selective beta agonists, such epinephrine, are associated with more adverse effects; fortunately, selective beta-2 agonists have replaced them.

• Long-acting beta-2 agonist bronchodilators (LABAs) are administered once or twice daily as “maintenance” treatments to maintain open airways; onset is slower, but the effects last for 12-24 hours.
  – Some important examples of LABAs are salmeterol and formoterol (“ols”).

Muscarinic antagonists are also used to treat asthma and COPD. They block acetylcholine from binding muscarinic receptors in the bronchial smooth muscle, which prevents bronchoconstriction; these drugs also reduce vagal-mediated mucus secretion in the bronchi.

• Muscarinic antagonist bronchodilators are associated with dry mouth, dizziness, gastrointestinal problems, and cough.
• Short-acting muscarinic antagonist bronchodilators (SAMAs) are used as “rescue” treatments; they take effect within minutes of administration and last about 4 hours.
  – Ipratropium is a commonly used short-acting muscarinic antagonist.
• Long-acting muscarinic antagonist bronchodilators (LAMAs) are used for maintenance therapy, as their effects last 12-24 hours.
  – Tiotropium, aclidinium, and umeclidinium are examples of these drugs (“iums”).

• Dual Therapy: Beta-2-adrenoreceptor agonists and muscarinic antagonists work synergistically to open the airways, so they are often used together in dual therapy to maximize their effects.

Methylxanthines

• Theophylline can be used to treat asthma, but that it is not a first-line therapy. Theophylline is a nonselective phosphodiesterase-4 inhibitor that also blocks adenosine receptors to induce smooth muscle relaxation.
  – The high dosages required to effectively open the airways produce systemic side effects, including convulsions and arrhythmias, as well as gastrointestinal problems and headache.
• Rofumilast improves exercise tolerance in COPD patients. Rofumilast is thought to work via histone deacetylation, which produces anti-inflammatory effects.
  – Thus, it can be prescribed to enhance the anti-inflammatory effects of corticosteroid treatments.

ANTI-INFLAMMATORIES

Recall that inflammation is a key part of the pathology of asthma and COPD, and promotes infiltration of various immune cells, remodeling, and constriction of the airways. Thus, reducing inflammation is an important component of treating obstructive pulmonary diseases, especially asthma.

• Corticosteroids, i.e., glucocorticoids, downregulate inflammatory genes to reduce inflammatory cytokines, chemokines, adhesion molecules, and other pro-inflammatory mediators; thus, they reduce the infiltration of inflammatory cells in the airways.
• Inhaled corticosteroids such as beclomethasone, are first-line therapy for moderate to severe asthma.
  – Used alone, they are less effective in patients with COPD, but can be combined with long-acting beta-2-agonist bronchodilators.
  – Be aware that use of inhalers increases risk of infection in COPD patients.
  – Oropharyngeal candidiasis is a common adverse effect in patients using inhaled glucocorticoids.
• Oral glucocorticoids, such as prednisone, produce systemic adverse effects, including increased risk of infection, hypertension, osteoporosis, and ocular disorders.
  – Thus, they are reserved for severe exacerbations and/or patients who are unresponsive to other therapies.

MONOTHERAPIES

Anti-IgE Antibodies such as omalizumab, bind free IgE and prevent it from binding to mast cell receptors. Thus, omalizumab is given to reduce exacerbations in severe allergic asthma.
– Recall that that IgE binding to mast cells triggers release of allergic mediators.

Anti-IL-5 drugs such as mepolizumab, reslizumab, and benralizumab.
– Interleukin 5 activates eosinophils and promotes airway inflammation.
– Anti-Interleukin-5 receptor blockers and antagonists prevent eosinophil activation and are therefore used as add-on therapies in severe eosinophilic asthma.

Cromolyn reduces mast cell release of inflammatory mediators; though it may be helpful to prevent asthma exacerbations in some patients, it is generally less effective than inhaled corticosteroids.

ANTI-LEUKOTRIENES

• These drugs can be used to prevent aspirin- and exercise-induced asthma.
• Leukotrienes aid in inflammatory cell migration, increase capillary permeability, and induce smooth muscle contraction.
• Zileuton is a leukotriene synthesis inhibitor; montelukastand zafirlukast are leukotriene receptor blockers.

ADDITIONAL COPD THERAPIES

• Smoking cessation is key to slowing progression of the disease.
• Mucolytics help break up mucus and facilitate removal for easier breathing.
• Oxygen therapy is recommended if oxygen saturation falls below 88%.
• Infection prevention is important for reducing harmful exacerbations; patients may be prescribed antibiotics, such as azithromycin, to ward off bacterial infections, and influenza and pneumonia vaccines are recommended

Here we’ll learn about medications used to treat rhinitis and cough; although we’ll single out specific drugs and their actions, keep in mind that many over-the-counter medications comprise various combinations of drugs.

RHINITIS

• Rhinitis: the nasal passages are inflamed, causing a “runny” and/or “stuffy” nose, sneezing, and sinus congestion. * Rhinitis may be caused by allergies (IgE-mediated) or viral pathogens or irritants.

Decongestants are alpha-adrenoreceptor agonists that promote vessel constriction in the nasal mucosa, which reduces edema and swelling.

• Epinephrine and oxymetazoline are nasal sprays.
  – Afrin is the name-brand version of oxymetazoline, which is also used in Visine for itchy, red eyes.
• Phenylephrine is available in both sprays and tablet formulas.
• Pseudoephedrine comes in tablet form.
  – Because it can be used to create methamphetamine, it has largely been replaced by phenylephrine in over-the-counter drugs.
• Pseudoephedrine acts on both alpha and beta receptors,and is therefore associated with more systemic effects.
• Adverse effects of alpha-adrenoreceptor decongestants are due to sympathetic activation, which particularly affects the central nervous and cardiovascular systems (again, this is especially true for pseudoephedrine).
  – If patients experience serious adverse effects, including irregular heart beat, shaking, or anxiety, they should stop using these medications.
  – Rhinitis medicamentosa: Although nasal sprays are better tolerated due to their localized effects, patients should not use them for more than 3-5 days at a time, as they can cause rhinitis medicamentosa, which is a form of rebound congestion.
• Avoid or use caution in prescribing alpha-adrenoreceptor agonists to patients with heart disease, hypertension, thyroid disease, diabetes, enlarged prostate, pregnancy, or those who have used monoamine oxidase inhibitors in the last two weeks.

Glucocorticoids are available as nasal sprays; glucocorticoids bind to intracellular glucocorticoid receptors and downregulate the inflammatory response by up-regulate anti-inflammatory genes and suppressing pro-inflammatory genes.

• Very effective against allergic rhinitis with discharge and blockage, and, that antihistamines are added to some formulas.

Cromolyn sodium blocks mast cell release of histamine and other inflammatory mediators that cause rhinitis; it is occasionally used in asthma, as well.
– However, because cromolyn has to be used multiple times a day and is generally less effective than other available drugs, it is not a first-line treatment.

Antihistamines are used to treat allergic rhinitis.

• Histamines cause nasal vessel dilation and edema, which produces the increased watery discharged associated with a “runny” nose.
• Anti-histamines block the action of histamines:
  – H1 antihistamines are inverse agonists that keep H1 receptors in their inactive states, which prevents mast cell degranulation and NF-kB (nuclear factor kappa B) activation.
  – Thus, these drugs reduce nasal discharge; antihistamines are also used to treat allergic inflammation and itching of the eyes and skin.
  – Additionally, some H1 antihistamine drugs also have other, non-histamine receptor effects (for example, some have anti-tussive effects).
• Use caution when prescribing antihistamines to pregnant patients and those with cardiovascular disease, hypertension, urinary retention, and elevated ocular pressure.

• First-generation antihistamines include diphenhydramine (aka, Benadryl), chlorpheniramine, brompheniramine, and hydroxyzine.
  – First-generation antihistamines readily cross the blood-brain barrier, and often cause sedation;
  headaches and weigh gain are also reported.
  – Additionally, these drugs have anticholinergic effects: blind as a bat, hot as a hare, mad as a hatter, dry as a bone, red as a beet.
  – First-generation antihistamines are also used as sleep aids and to prevent or treat motion sickness

• Second-generation antihistamines* include loratadine (Claritin), cetirizine (Zyrtec), azelastine, and olopatadine (the last two are available in eye and nasal sprays).
  – Second generation formulas were designed to cause less sedation and have fewer anticholinergic side effects; they do not cross the blood-brain barrier as readily as the first-generation antihistamines.

• Third generation antihistamines* include fexofadine, desloratadine, and levocetirizine.
  – These drugs are metabolites of the second generation H1 antihistamines, and, like those drugs, cause less sedation and fewer anticholinergic effects than first-generation antihistamines, and do not readily cross the blood-brain barrier.

Saline

Found in over-the-counter sprays and nasal irrigation systems.

• Saline solutions flush away mucus and nasal irritants and sooth nasal membranes.

COUGH MEDICATIONS

Cough suppressants (aka, anti-tussives) target the medullary cough center.

• They are NMDA receptor antagonists and Sigma-1 receptor agonists (NMDA stands for N-Methyl-D-aspartate).
• These medications suppress cough caused by bronchial irritation due to flu and cold viruses, but are not used for chronic cough caused by smoking and lung disorders such as emphysema.
• Dextromethorphan is a common over-the-counter anti-tussive drug.
  – Adverse effects are rare and include GI upset, drowsiness, and dizziness.
  – This should not be used by patients who have taken an MAOI in the last two weeks, nor should it be prescribed to children under four years old.
  – Furthermore, beware of dextromethorphan abuse;when taken at high dosages, it can cause euphoria, but it can also cause brain damage, seizures, and cardiovascular events.
• Opioids (codeine, hydrocodone, etc.) also suppress the cough reflex.
  – Because of the potential for addiction and abuse, they are contraindicated in children and are not first-line therapy in adults.

Mucoactive agents are drugs that modify the production, secretion, or components of mucus, or that act on the respiratory cilia to facilitate easier mucus removal from the bronchi.

• Guaifenesin (the main ingredient in Mucinex) is an expectorant – it increases the volume of watery mucus to facilitate productive coughing.
• N-acetylcysteine is a mucolytic – it breaks down mucus components to reduce overall mucus viscosity.
  – It is sometimes used by patients with COPD.
  – In IV form, can be used to treat acetaminophen overdose.
• Ambroxol is a mucokinetic drug – it increases the transportability of mucus by acting on the respiratory epithelium cilia.
• Anticholinergic agents act as mucoregulators – they reduce mucus hypersecretion.

KEY VALUES

• Vmax
  – Maximal rate of a reaction (every active site bound by substrate)
• Km
  – Inversely proportional to binding affinity of enzyme to substrate

ENZYME INHIBITION

• Occurs when a substance reduces activity of an enzyme

Types of inhibition

• Competitive
  – Substrate & inhibitor compete for active site
  – Greater [S] overcomes inhibition
  – Increases the apparent Km but does NOT affect Vmax
• Noncompetitive
  – Inhibitor reversibly binds to enzyme outside of active site to deactivate it.
  – Enzymes regain function when inhibitor removed from system
  – Does NOT change Km but lowers Vmax

NOT uncompetitive inhibition in which inhibitors bind enzyme-substrate complexes

• Uncompetitive inhibition: requires preassembled enzyme-substrate complexes–>more effective when [S] is high
• Irreversible
  – Inhibitor binds to and permanently deactivates enzyme
  – Only overcome by synthesis of new enzymes

CLINICAL CORRELATION

• Heavy metals (mercury & lead)
  – Irreversible inhibitors: bind tightly to sulfur groups in enzymes
  – Permanently deactivate them
• Ethylene glycol (antifreeze) metabolites
  – Toxic to human body
  – Ethanol (competitive inhibitor): used to inhibit alcohol dehydrogenase active site to prevent metabolism of ethylene glycol
• Angiotension-converting enzyme (ACE) inhibitors
  – Blood pressure lowering agents: noncompetitively inhibit ACE
  – Prevent formation of angiotensin (acts on kidneys to inc. blood pressure)