Physiology, Endocrine Hormones

Issues of Concern

Hypothalamus

Posterior Pituitary (neurohypophysis) Hormones

The posterior pituitary is an extension of axonal projections from the supraoptic and paraventricular nuclei of the hypothalamus nervous tissue, where oxytocin and anti-diuretic hormones are stored in the axonal ends or Herring bodies.[1] Oxytocin secretion results in a positive feedback loop during childbirth, increasing contractions. Oxytocin also affects lactation. Oxytocin is discussed in detail in this article.[2]

Anti-diuretic hormone (ADH) or vasopressin is important in regulating blood volume and electrolyte levels, especially sodium. Its primary function is to regulate serum osmolarity. The ADH levels are lower when the osmolality is below 280 mOsm/kg in a normal individual. This results in water excretion. Conversely, when the plasma osmolality rises above 280 mOsm/kg, the ADH levels increase, resulting in water reabsorption. In addition to osmoreceptor stimulation, volume-sensitive receptors can also trigger ADH release.[3] Volume-sensitive receptors increase ADH if there is a sudden and significant drop in pressure. Small incremental decreases are insufficient to activate ADH – renin and norepinephrine handle these smaller changes instead.[4][5] ADH increases water retention and raises blood pressure via 2 different receptors. In the distal nephron, V2 receptors help increase water reabsorption by increasing the aquaporin channels in the principal cells of the collecting duct. Increased ADH also stimulates V1 receptors, which increase vascular resistance throughout the body.[6][7] This topic is discussed in detail.[8]

Anterior Pituitary Affecting Hormones

The hypothalamic-pituitary-adrenal (HPA) axis is a blood portal system connecting the hypothalamus and anterior pituitary, allowing control of several hormones. The hypothalamus is connected anatomically to the pituitary gland via the infundibulum. Within the infundibulum are capillaries that pour into portal veins, flowing directly to the anterior pituitary. This system ensures that the hormones released from the hypothalamus circulate directly into the anterior pituitary gland, never entering the general circulation. The hormones released from the hypothalamus include corticotropin-releasing hormone, thyrotropin-releasing hormone, gonadotropin-releasing hormone, growth hormone-releasing hormone, somatostatin, prolactin-releasing hormone, and dopamine.[1]

Gonadotropin-releasing hormone (GnRH) is released from the hypothalamus and acts on the pituitary to control reproductive functions. There are 2 important factors for proper GnRH function: proper neuron migration during development and pulsatile secretion.[9] A small number of hypothalamic neurons release GnRH, and the fetal cells migrate to the olfactory bulb and olfactory tract, from where they continue to the mediobasal hypothalamus in the preoptic area as well as the arcuate nucleus. Fetal cells in the olfactory area can detect odorant stimuli and release GnRH. The importance of GnRH neuron migration received confirmation in the case of an aborted fetus diagnosed with Kallmann syndrome.[10] The fetus had an older brother with the same X chromosome deletion; however, further neuropathologic examination revealed GnRH neurons had been arrested at the cribriform plate. The fetus was old enough that these neurons should have already migrated to the hypothalamus.[10] Additionally, the belief is that anosmia presents in GnRH-deficient patients due to the close association of GnRH neurons with the olfactory bulb and tract. The pulsatile property of GnRH neurons was demonstrated when immortalized in vitro tissue continued to release GnRH in a pulsatile fashion – not only implicating a possible intrinsic hypothalamic pulse generator but emphasizing the importance of the pulse itself.[9] The pulse generator secretes GnRH in discrete, random, but regular bursts. It is now well established that GnRH pulsation results in appropriate physiologic gonadotropin levels. However, when GnRH is given continuously, serum gonadotropins increase initially but quickly decrease due to desensitization.[11][12][13] This has important clinical implications for various cancers and gynecological pathology. With the discontinuation of continuous GnRH, spontaneous GnRH pulses return, restoring the gonadotropin response.

GnRH has a very short half-life, only 2 to 4 minutes, and stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) – the 2 hormones are commonly referred to as gonadotropins.[14] Gonadotropins and sex steroids have both negative and positive feedback loops on GnRH pulsation. How these loops work is not fully understood. However, not only sex hormones impact GnRH but multiple other molecules have been found to influence GnRH. These molecules include opiates, gonadal steroids, kisspeptin, neurokinin B, catecholamines, neuropeptide Y, corticotropin-releasing hormone, galanin, dynorphin, and prolactin. GnRH, LH, and FSH regulate various functions important to human sexual development, sex production, and fertility.[15][16] For more information, see the sections on LH and FSH. It is discussed in detail in this article.[17]

Corticotropin-releasing hormone (CRH) is another hormone in the hypothalamic-pituitary-adrenal (HPA) axis. CRH is produced in the paraventricular nucleus of the hypothalamus (PVH), which is released and stimulates the anterior pituitary gland to release adrenocorticotrophic hormone (ACTH).[18] 

Growth hormone-releasing hormone (GHRH) is a hypothalamic hormone that binds to pituitary receptors to stimulate growth hormone (GH) release. Binding to its receptor activates a linked G protein, stimulating cAMP production. This intracellular signaling results in the actual release of GH and somatotroph proliferation. It is suspected that GHRH is released in a pulsatory manner since GH is pulsatory. However, this is not yet fully understood.[19] 

Somatostatin – has 2 biologically active forms – somatostatin-14 (S14) and somatostatin-28 (S28) – 14 and 28 amino acids, respectively. It is synthesized by delta cells of the islets of Langerhans within the pancreas and by paracrine cells scattered throughout the gastrointestinal tract. Somatostatin is found throughout the body but is notably abundant in the nervous tissue of the spinal cord, brainstem, hypothalamus, and cortex.[20] When released, somatostatin has a very short half-life. After IV administration, 50% are removed from circulation in less than 3 minutes. As a result, the somatostatin concentration found within the blood is quite low, usually in sub-picomolar amounts. Somatostatin receptors are G protein-coupled receptors that, when activated, reduce cAMP levels. Five receptor subtypes exist, subtypes 1-5. All 5 are present within the brain; however, each receptor has tissue specificity. Subtype 1 is present in the brain, lung, pancreas, liver, and GI tract. Subtype 2 is found in the brain and kidney. Subtype 3 is in the brain and pancreas. Subtype 4 is present in the brain and lungs. Subtype 5 occurs in the brain, skeletal muscle, GI tract, heart, adrenals, and pituitary.[21]

Once somatostatin binds to its receptor, it inhibits GH release from the pituitary.[22] In addition to inhibiting GH, somatostatin has additional physiologic properties in multiple organs. Within the brain, it has antinociception properties. In the liver/gallbladder, somatostatin decreases blood flow, inhibits gallbladder contraction, and inhibits bile duct secretion. The pancreas has both endocrine and exocrine secretions. It is discussed in detail in this article. Finally, somatostatin inhibits salivary amylase, gastric acid, and gastrointestinal hormone secretions within the gastrointestinal system. It also delays gastric emptying, slows motility, inhibits absorption, and decreases splanchnic blood flow.[23][24] It is discussed in detail in this article.[25]

Dopamine is an important molecule in the human body; it plays roles in many organs. It is most commonly discussed in psychiatric and neurological settings due to its role as a neurotransmitter. However, dopamine is also an endocrine hormone secreted from the hypothalamus to the pituitary. The primary role of endocrine hormone physiology is to inhibit prolactin secretion. It has been well established and studied that pathology or medication side effects of decreased dopamine lead to hyperprolactinemia and the pathophysiology associated with this state.[26] It is discussed in detail in this article.[27]

Thyrotropin-releasing hormone (TRH) is composed of 3 peptides, pyroglutamyl-histidyl-prolineamide. TRH begins as pro-TRH and, through a process of peptization and cyclization of glutamine, forms a pyroglutamyl residue.[10] TRH metabolizes rapidly, with a plasma half-life of approximately 3 minutes. TRH is another hormone involved in the HPA axis, helping determine the regulation of TSH secretion. Specifically, TRH is found in the highest concentrations in the PVH and median eminence of the hypothalamus. However, it is also present in the central nervous system, gastrointestinal tract, pancreatic islets, pituitary gland, and reproductive tracts – TRH function at these sites is unknown. Lastly, either high levels or exogenous administration of TRH stimulates additional hormones besides TSH, especially prolactin.[28][29][30][31]

Anterior Pituitary

Follicle-stimulating hormone (FSH) and Luteinizing hormone (LH) – see endocrine sex hormones section below.

Prolactin is a hormone produced by lactotrophs found in the anterior pituitary gland. Prolactin regulation is by the hypothalamus in an inhibitory manner – dopamine is released from the hypothalamus to decrease prolactin secretion. All other hormones depend on a stimulation signal from the hypothalamus to be synthesized and released. This explains why prolactin levels increase with the severing of the HPA axis, whereas other hormone levels decrease.[32]

When prolactin is secreted, it stimulates milk production in the mammary glands. During pregnancy, elevated estrogen acts on the anterior pituitary to further increase prolactin secretion, preparing the mammary glands for breastfeeding. However, progesterone levels also become elevated, inhibiting prolactin at the breast. This is why milk secretion does not begin until after birth, because postpartum physiology results in drastically decreased progesterone levels, resulting in loss of prolactin inhibition.[33] It is discussed in detail here.[34]

 In primary hypothyroidism, TRH elevates in an attempt to increase TSH levels. TRH can act on the anterior pituitary to increase prolactin levels. Anti-psychotics are dopamine antagonists, meaning the usual inhibitory hormone is lost – resulting in elevated prolactin. In either of the above scenarios, hyperprolactinemia is present in addition to several others (prolactinoma, for example). Elevated prolactin inhibits GnRH, and decreased pulsation leads to decreased levels of FSH and LH. Commonly exhibited symptoms include amenorrhea and infertility in both males and females.[35][36][37][38]

Thyroid-stimulating hormone (thyrotropin) (TSH) – TSH is synthesized and released from cells within the anterior pituitary gland, known as thyrotrophs. This hormone is composed of 2 subunits: 1 alpha and 1 beta. TSH is 1 of the 4 hormones which share the same alpha unit. The beta unit makes TSH unique and determines its specificity within the human body. Due to the physiologic effects of thyroxine (T4) and triiodothyronine (T3), these 2 hormones help tightly control the levels of TSH released into the body.[39] Minute increases in serum T3 and T4 result in TSH inhibition. Conversely, small decreases in serum T3 and T4 result in increased TSH. T3 and T4 levels also work to increase/decrease TRH through a negative feedback look, another mechanism for modulating TSH levels.[40]

TSH levels slowly change depending on several factors, such as the initial TSH level, the hormone (T3 or T4), and the hormone dose. A higher TSH level takes longer to decrease and gradually declines over several days. TSH levels respond faster to T3 than to T4. Additionally, when given a higher dose, TSH responds more rapidly. If high doses of T3 are administered, TSH levels begin to decline over several hours in hypothyroid patients. Other inhibitors of TSH  include somatostatin, dopamine, and glucocorticoids. Dopamine can cause a rapid decrease in TSH levels, and accordingly, dopamine antagonists can acutely raise TSH levels. Patients in the intensive care unit (ICU) often have altered TSH levels when receiving dopamine or dopamine antagonists. TSH is 1 of 4 endocrine hormones (hCG, TSH, LH, FSH) that all share the same alpha unit. There are pathologic states, such as choriocarcinoma, where the severe elevation of hCG leads to hyperthyroidism symptoms because TSH receptors bind hCG due to the shared alpha unit.[41][42] It is discussed in detail here.[43]

TSH is an essential hormone for the thyroid. It stimulates each step in hormone synthesis within the thyroid, affects the expression of multiple genes, and can cause thyroid hyperplasia or hypertrophy. The action begins when TSH binds to a plasma membrane receptor, activating adenylyl cyclase, which increases cyclic adenosine monophosphate (cAMP), activating several protein kinases. Via the same receptor, TSH stimulates phospholipase C, increasing phosphoinositide turnover, protein kinase C activity, and intracellular calcium concentration. How the above steps specifically link to T3 and T4 synthesis, release, and other thyroid metabolic processes is not fully understood.[44][42]

Growth hormone (GH) is a hormone synthesized by pituitary somatotroph cells. It has 5 distinct genes which influence the final spliced mRNA hormone.[45] The predominant form is a 22 kDa GH; the other is a 20 kDa GH (only 10%). Many factors influence the production and release of GH, the 2 primary factors being GHRH and somatostatin–stimulating and inhibiting, respectively. However, gender, age, nutrition, and insulin-like growth factor-1 (IGF-1) modulate GH levels.[46] Its production begins in the fetus. Maternal GH levels decline due to the increasing placental GH, which replaces maternal levels. GH levels peak during puberty, the time of extensive growth, at about 150 mcg/kg. As aging continues, GH levels decline, paralleling the decline in body mass index. Every 7 years, GH levels decrease by about 50%. By the age of 55 years, GH levels are roughly 25 mcg/kg.[47]

GH release is pulsatile, suspected to be caused by somatostatin's reduced tonic inhibition and possibly GHRH bursts. Each day, 10 pulsations last 90 minutes, each 1 separated by 128 minutes. As previously mentioned, gender influences GH levels. In men, GH pulsations are more notable, whereas, in women, the GH secretion appears to be more continuous. Peak GH secretions occur within 1 hour of deep sleep onset. The average nighttime serum GH level is 1.0 ± 0.2 ng/mL. In contrast, average daytime GH levels are only 0.6 +/- 0.1 ng/mL. IGF-1, leptin, age, obesity, and hyperglycemia are all factors that act to inhibit GH release. Conversely, ghrelin, insulin-induced hypoglycemia, estrogen, dopamine, alpha-adrenergic agonists, and beta-adrenergic antagonists all stimulate GH. While many factors modulate GH levels, it is important to remember that GHRH and somatostatin primarily determine GH levels.[48][49][50] It is discussed in more detail here.[51]

Upon GH binding its receptor, primarily found in the liver, a phosphorylation cascade involving the JAK/STAT pathway is activated. The prevailing action is to stimulate the liver to synthesize and secrete IGF-1. IGF-1 is an extremely critical protein induced by GH and is believed to be responsible for most of the growth properties of GH. Some of the specific effects of GH include stimulation of linear growth in children, increased lipolysis, increased protein synthesis, retention of phosphate, sodium, and water, and antagonism of insulin. Again, most of these actions are believed to be from GH in tandem with IGF-1.[45][52][53]

Adrenocorticotrophic hormone (ACTH) is secreted from the anterior pituitary in response to CRH. ACTH travels through the systemic circulation to act upon the adrenal glands, specifically the adrenal cortex's zona fasciculata and zona reticularis. ACTH primarily acts directly in the zona fasciculata to release cortisol. ACTH stimulates the enzyme cholesterol desmolase, the first enzyme to convert cholesterol into several steroid hormones. ACTH also stimulates androgen production in the zona reticularis, a byproduct of cortisol synthesis (see adrenal androgens below for more information).[54][55]

Pineal Gland

Melatonin is a hormone synthesized within the pineal gland from the amino acid tryptophan.[56] Tryptophan is hydroxylated and then decarboxylated to form 5-hydroxytryptamine or serotonin. When there is sunlight, serotonin is stored within pinealocytes, making it unavailable to monoamine oxidase, the enzyme that converts serotonin to melatonin. In the absence of light, sympathetic input increases, causing a release of epinephrine. This causes the serotonin within pinealocytes to be released. Simultaneously, norepinephrine activates monoamine oxidase, serotonin-N-acetyltransferase, and hydroxyindole-O-methyltransferase.[57][56][58] The result is a rapid increase in melatonin from 2 to 10 pg/mL to 100 to 200 pg/mL.[56] Melatonin is highly lipid-soluble, allowing it to diffuse freely across cell membranes and the blood-brain barrier.[59] Its release sends messages throughout the body, primarily the brain, affecting the synthesis of secondary messengers. Melatonin has 3 receptors: M1, M2, and M3. All 3 are expressed within the hypothalamus's suprachiasmatic nucleus (SCN). The 3 receptors are expressed variably, depending on the tissue. However, within the SCN, M1 inhibits SCN neuron firing during nighttime.

Additionally, M2 within the SCN inhibits the SCN’s circadian rhythm. These effects may contribute to the sleep-promoting effects of melatonin. M1 and M2 are easily desensitized, so higher doses may be required to achieve the same effect when exogenous melatonin is given chronically.[60][61] The melatonin cascade primarily influences sleep and circadian rhythms. Melatonin is suspected to be 1 of the primary drivers of sleep induction and maintenance due to its marked increase in the evening. As alluded to earlier, the circadian rhythm is characterized by low daylight melatonin levels and markedly increased levels at night – peaking between 11 PM and 3 AM – and rapidly decreasing again before sunrise.[56] Light from the environment has strong links with circadian rhythm; however, the rhythm persists when people remain in a dark room for several days.[62]

Also, if a person travels across time zones to a new location where the sun rises and sets at different hours, the circadian rhythm is not changed immediately.[63] Melatonin is not produced in significant amounts in other areas of the body – post-pinealectomy, humans have virtually no melatonin and a complete lack of circadian rhythm.[64] These findings indicate the importance of melatonin in circadian rhythms and sleep induction and maintenance.

Thyroid Gland

General T3/4 actions – thyroid hormones are crucial throughout the entire life of an individual. In childhood, thyroid hormones help develop several body systems, particularly the brain. In adulthood, the thyroid hormones help drive metabolic activity and function of nearly all organs. Since it is necessary for so many different systems, a constant thyroid hormone supply is required, yet the total serum levels are always tightly controlled; if not, pathology occurs. Two mechanisms control the production of thyroid hormones. The first is through hormonal pathways and negative feedback loops. TRH, TSH, T4, and T3 levels signal the thyroid whether to increase or decrease thyroid hormone levels. The second is via hormone consumption by extrathyroidal tissues based on nutritional, hormonal, and illness-related factors – the effect varies depending on the tissue.

The first mechanism helps protect the thyroid from hyper/hypo-secreting, and the second mechanism helps respond to rapid changes within the tissue. As mentioned in the TSH section, there are 2 thyroid hormones, T3 and T4. However, before either hormone can begin synthesis, iodide must undergo oxidation to iodine and become incorporated into tyrosine residues within the colloid. Iodide is an essential ion in thyroid physiology, and it is discussed again in pathophysiology. The remaining hormone synthesis steps include combining 2 diiodotyrosine (DIT) molecules to make T4 or combining 1 monoiodotyrosine and 1 DIT to create T3. Thyroglobin is a glycoprotein incorporated into exocytotic vesicles that fuse to the apical cell membrane. Only when these steps have occurred can the iodination and coupling of T4 and T3 happen. To release these hormones into the extracellular fluid and eventually circulation, thyroglobulin must be resorbed into the thyroid follicular cells to create colloid droplets. These colloid droplets fuse with lysosomes to create phagolysosomes, allowing hydrolyzation of the thyroglobulin and hormone secretion.[65][40][42]

T4 (99.95%) and T3 (99.5%) are mostly bound within the bloodstream, preventing it from being metabolically active. The proteins that bind T4 and T3 listed in most common to least common are as follows: thyroxine-binding globulin (TBG), transthyretin (TTR), albumin, and lipoproteins. The remaining 0.02 percent free T4 leaves only 2ng/dL within the body. Similarly, 0.05 percent of T3 leaves only 0.4 ng/dL. Since most T4 and T3 are bound within the serum, changes in serum concentrations of binding proteins result in drastic effects on serum total T4 and T3. However, changes in binding proteins do not affect the free hormone concentrations or the rate at which T4 and T3 get metabolized.[66]

Thyroxine (T4) - T4 is less metabolically active and produced exclusively within the thyroid. The daily production rate is 80 to 100 mcg and degraded at roughly 10% daily. Approximately 80% is deiodinated – of this, 40% converts to T3, and the other 40% converts to reverse T3 (rT3). The final 20% conjugates to tetraiodothyroacetic. The conversion in the periphery of T4  to T3 is mediated via the enzyme 5’-deiodinase. T3 is the primary metabolite of T4, which has physiologic activity; other T4 metabolites are inactive. This conversion process is regulated in extrathyroidal tissue. Thus, T3 production may change independently of the pituitary-thyroid state.[67]

Tri-iodothyronine (T3) – T3 is the primary metabolic hormone from the thyroid and is the driver behind metabolic and organ processes. About 80% of T3 production is in extrathyroid tissue from the deiodination of T4. The remaining 20% gets synthesized within the thyroid. Daily production is 30 to 40 mcg, but the extrathyroidal reserve of T3 is roughly 50 mcg. The fraction of T3 produced throughout the body from T4 varies considerably from tissue to tissue. Certain tissues, like the anterior pituitary and liver, contain high levels of T3 nuclear receptors, making them more responsive to serum T3.[67][68]

T3 acts by modifying gene transcription. Due to the wide-reaching effects of T3, it affects nearly all tissues' ability to synthesize protein and turnover substrate. The nuclear actions of T3 depend on 4 factors: availability of hormone, thyroid hormone nuclear receptors (TRs), receptor cofactors, and DNA regulatory elements. Within most tissue, T3 enters by simple diffusion. However, T3 is actively transported into cells in the brain and thyroid. Depending on the tissue, T3 has different actions, which are determined by the local production of T3 and the quantity and distribution of TR isoforms. The isoforms consist of TR-alpha-1 and 2 and TR-beta-1,2, and 3. There are insufficient studies on the TR isoforms, but due to regional or cell-specific distributions of the TRs, it is suggestive of different functions even within the same tissue. For example, TR-alpha is the dominant isoform in the brain, but TR-beta-2 is present at very high levels within the hypothalamus and pituitary.

The data that does exist for TR isoforms comes primarily from knockout mice with TR gene point mutations. Mice with TR-alpha deletion show poor feeding and growth, slowed heart rate, low basal body temperature, and reduced bone mineralization. Mice with inactivation of the TR-beta gene showed indications of inappropriately normal serum TSH levels, high serum T4 concentrations, and thyroid gland hyperplasia. Finally, knockout mice without TR-alpha and beta genes showed thyroid hyperplasia and markedly high serum concentrations of T4, T3, and TSH – 11 times, 30 times, and 160 times greater than normal, respectively.[69][70][42][39]

As previously mentioned, T3 binds to TR on the nucleus, modulating gene expression. All genes affected have specific DNA sequences that bind TR with high affinity. Ultimately, the human genome project provided data that allowed specific DNA sequences to be identified. T3-dependent gene activation is minimal or absent without these specific DNA sequences.

Different tissues have 1 of 3 deiodinases within the periphery that convert the prohormone T4 to active T3. Three enzymes are expressed depending on a specific development pattern and tissue type.[68][71]

• Type 1 5’-deiodinase (Dio1) is found primarily in the liver, kidneys, and muscle. Dio1 was found to have reduced activity in hypothyroid subjects.
• Type 2 5’-deiodinase (Dio2) was studied in rodents and displayed a higher prevalence in the cerebral cortex, brown fat, and the pituitary. Dio2 is also expressed in skeletal muscle, heart, and thyroid in humans. Within humans, Dio2 produces the majority of circulating T3. Dio2 was found to increase in hypothyroid and iodine-deficient subjects.
• Type 3 5’-deiodinase (Dio3) inactivates T4 and is found primarily in the placenta, skin, skeletal muscle, and the developing brain. It is essential for sensory development, particularly within the inner ear. During human development, Dio3 is expressed first; as Dio1 and Dio2 increase, Dio3 expression decreases.

It is well known that T4 and T3 have wide-reaching effects and can influence nearly every organ system within the body; specifically, 3 major areas include bones, heart, and metabolism regulation.

• Bones – Patients in infancy who were born with congenital hypothyroidism and are not treated with hormone replacement have delayed epiphyseal development and poor growth. This same finding was present in patients with thyroid hormone resistance [18, page 6]. All TR isoforms are expressed in bones. However, TR-alpha and alpha/beta knockout mice showed abnormal bone development.[72][73]
• Heart – Patients with T3 resistance demonstrate elevated T3 levels, resulting in tachycardia. This likely demonstrates that patients resistant to T3 do not have cardiac resistance. Patients with TR-beta mutations phenotypically present this way, a concept supported by T3-beta knockout mice that also do not have cardiac resistance to T3.[74]
• Metabolism regulation – T3 regulates the metabolic rate and can influence modest body weight changes. Humans with TR-beta mutations and T3 resistance demonstrate increased T3-alpha activity—this stimulation results in increased feeding and fatty acid oxidation. T3 also influences glucose metabolism, increasing its uptake. When Dio2 is not functioning properly, an association with glucose intolerance is evident. It is not yet well studied, but patients with impaired mitochondrial oxidative metabolism (seen in metabolic syndrome and type 2 diabetics) may have reduced T3 hormone action. The complications of improper metabolism are discussed in Thyroid hormone pathology.[75][76][42]

Parathyroid

Parathyroid hormone (PTH) – PTH is the primary regulator of calcium and phosphate homeostasis in the human body. PTH gets synthesized as pre-pro-PTH, which is 115 amino acids long. Within parathyroid cells, it is cleaved to pro-PTH, 90 amino acids, and finally to PTH, 84 amino acids. The 84 amino acid version of PTH is the hormone's primary stored, secreted, and active form. The short-term control of serum calcium is mediated exclusively by PTH. On a long-term basis, PTH is responsible for converting calcidiol to calcitriol, which occurs within renal tubular cells.[77][78][79]

PTH is quickly cleared from the bloodstream by the kidney and liver. Intact PTH only has a half-life of 2-4 minutes. It is cleaved into active amino fragments (PTH 1-34) and inactive carboxyl fragments. Since PTH primarily controls calcium levels, calcium regulates the amount of PTH released, synthesized, and degraded. In a hypocalcemic state, PTH degradation decreases, and the opposite is true during hypercalcemia.[80] Changes in serum ionized calcium concentrations as small as 0.1 mg/dL result in increased/decreased PTH depending on the direction in which calcium shifts. These minute changes are sensed by extremely sensitive calcium-sensing receptors (CaSR) on the parathyroid cells' surface.[81] At baseline, CaSRs become activated via guanine nucleotide-binding proteins, which use secondary messengers (intracellular calcium, cAMP, or inositol phosphates) to inhibit PTH.

When CaSRs deactivate during hypocalcemia, parathyroid cells become stimulated to release PTH. CaSR mediates the following actions of PTH: exocytosis of PTH into the bloodstream (seconds to minutes), decreases the intracellular breakdown of PTH (minutes to an hour), increases PTH gene expression (hours to days), proliferation of parathyroid cells (days to weeks).[77] While calcium is the main driver of PTH, other molecules impact PTH release as well; they include extracellular phosphate, calcitriol, and fibroblast growth factor 23 (FGF23).[82][83][84]

PTH's primary receptor, PTH1R, binds and responds to PTH, PTH-related protein (PTHrP), and PTH1-34. The receptor is expressed heavily in bone and kidney but may also be present in the breast, heart, skin, pancreas, and vascular tissue. When PTH1R becomes activated, multiple intracellular signaling pathways (cAMP, phospholipase C pathway, protein kinase C, and intracellular calcium) help mediate the effects of PTH. The biological actions of PTH include increased bone resorption (within minutes), increased GI absorption of calcium, mediated by calcitriol (24 hours or more [PTH stimulates the hydroxylation of calcidiol to calcitriol]), and decreased urine excretion of calcium (within minutes).

Diving a little deeper into the actions of PTH on the bone, 2 primary phases mediate the increase in calcium. First, PTH mobilizes calcium from skeletal stores almost immediately. Second, as previously mentioned, PTH increases bone resorption, releasing calcium and phosphate (these actions are not immediate). Finally, the kidney reabsorbs calcium via different mechanisms depending on the nephron region in which reabsorption occurs. For example, calcium is passively reabsorbed in the proximal tubule via favorable electrical gradients compared to the distal nephron, where calcium is actively reabsorbed. These simultaneous pathways' net effect is the increase of calcium, helping return the body to a homeostatic level.[79][85][86]

Pancreas

Insulin – directly and indirectly- affects several tissues; however, this article focuses on adipose tissue, muscle, and the liver. Insulin is a 51-amino acid peptide that is synthesized and secreted by the beta cells of the pancreas. Its action begins when it binds a cell membrane heterotetrameric receptor. The receptor has 2 alpha subunits, which bind insulin, and the 2 beta subunits, which transduce the signal. Through a cascade of cell signaling, insulin is a powerful regulator of metabolic action. When there is a breakdown in cell signaling, resistance, or decrease in insulin, many different pathologies can occur – see pathology section for more information. Several factors may act to either further stimulate insulin release or inhibit it. Glucose, mannose, leucine, and vagal stimulation all increase insulin secretion. Alpha-adrenergic effects, somatostatin, and several drugs can inhibit insulin secretion.

One of the primary functions of insulin is to control glucose levels. Glucose can be attained from gluconeogenesis, oral intake, and glycogenolysis. Once glucose is inside cells, 1 of 2 things occur – it can be stored as glycogen or undergo glycolysis and convert to pyruvate. Insulin modulates what happens to glucose in a few ways, such as stimulating glycogen synthesis, increasing glucose transport into muscle and adipose, inhibiting glycogenolysis and gluconeogenesis, and increasing glycolysis in muscle and adipose. While most tissues can produce glucose within their cells, only the kidney and liver possess glucose-6-phosphatase, which is needed to release glucose into the blood. The liver produces 80 to 90% of glucose in patients without glucose-related pathology, making the liver the primary target for insulin. Through several different pathways, insulin acts upon the liver, both directly and indirectly. Directly, insulin inhibits hepatic glycogen phosphorylase, the glycogenolytic enzyme, thereby inhibiting glucose output. Indirectly, insulin decreases the flow of glucose precursors, along with decreased glucagon secretion. A study of insulin infusion in dogs demonstrated the primary effects of insulin on hepatic glucose due to the direct insulin pathway. However, the indirect effect became more predominant with the infusion of substantial amounts of insulin.

The utilization of glucose is possible through cellular uptake, made possible by glucose transporters, GLUT-1,2,3,4, and 5. GLUT-4 is the primary transporter in muscle and adipose; it resides within the cytoplasm until an insulin signal causes translocation to the cell membrane. When the body is euglycemic, most glucose uptake, mediated by insulin, occurs in the muscle. Less than 10% of glucose is taken up by adipose tissue, primarily due to insulin-inhibiting lipolysis. Muscle get most of the glucose because when free fatty acids are unavailable, increased glucose uptake is required to supply muscle tissue. Insulin optimizes glycolysis in muscle by catalyzing the glycolytic pathway by increasing hexokinase and 6-phosphofructokinase activity.

As previously mentioned, in euglycemic states, insulin inhibits lipolysis. After a meal, insulin promotes triglyceride storage in adipose cells. This is mediated via 3 primary mechanisms. First, insulin increases the clearance of chylomicrons rich in triglycerides by increasing lipoprotein lipase. However, insulin only stimulates lipoprotein lipase expression in adipose tissue; insulin inhibits lipoprotein lipase, resulting in triglyceride storage in muscle. The second mechanism is via insulin-stimulated re-esterification of fatty acids into triglycerides in adipose cells. Finally, the third mechanism is insulin-inhibiting lipolysis. The overall effect of insulin on fat metabolism is potently reducing hepatic gluconeogenesis and hepatic glucose release by blocking the supply of fatty acids to the liver.

Ketone and insulin dynamics – Under physiologic states that result in deficient insulin levels, such as prolonged fasting or uncontrolled diabetes mellitus, fat is mobilized to meet metabolic demands. The liver cannot handle all the fatty acids being shuttled its way, resulting in ketone body production. This results from incomplete beta-oxidation of the long-chain fatty acids, which are oversupplied to the liver. Ketoacids can be employed as fuel in extrahepatic tissue, such as skeletal muscle and the heart. However, under very prolonged periods of fasting, the brain also uses ketoacids for energy. Insulin keeps ketone bodies' levels low; it potently drops circulating levels via 3 mechanisms. First, insulin inhibits lipolysis, so the fatty acids needed to make ketone bodies are unavailable. Second, insulin acts within the liver to directly inhibit ketogenesis. Thirdly, insulin helps increase the peripheral clearance of ketone bodies.

Protein metabolism and paracrine effects—As previously mentioned, insulin inhibits gluconeogenesis, keeping amino acids readily available for protein synthesis. Insulin expedites the transportation of amino acids into the liver and skeletal muscle. Also, insulin escalates the amount and efficiency of ribosomes. Lastly, insulin inhibits protein breakdown; roughly 40% of proteolysis is influenced by insulin. The net result is increased protein synthesis.

Insulin has many influences on other hormones within the body. The pancreatic islet cells have alpha, beta, and delta cells. Alpha secretes glucagon, beta secret insulin, and delta secretes somatostatin. When these hormones get secreted, they have paracrine effects on the surrounding cells. Insulin specifically reaches alpha cells first and inhibits the release of glucagon, which causes an increased effect of its metabolic actions. In hyperglycemic states, somatostatin can also be secreted, inhibiting alpha cells from releasing glucagon to reduce glucose levels.[87][88][89][90][91]

Insulin has other functions outside of energy metabolism, which are important for the clinical setting, as abnormal responses to insulin can lead to several different pathologies. Insulin impacts steroidogenesis, fibrinolysis, vascular function, and growth.[92][93][94][95][96]

Glucagon – is a 29 amino acid peptide secreted from the alpha cells of the islets of Langerhans. It opposes the action of insulin, functioning to increase glucose levels within the body. Ingestion of protein, hypoglycemia, and exercise produce glucagon secretion to raise glucose levels. Glucagon can raise glucose levels within the body by increasing glycogenolysis, the end product being glucose. It also promotes gluconeogenesis, which produces glucose by using precursor molecules like amino acids and glycerol within the liver.[97][98]

Adrenal Glands

The adrenal gland is located just above the kidney and produces hormones such as aldosterone, cortisol, DHEA, norepinephrine, and epinephrine. Different regions of the adrenal gland produce these hormones. The cortex has 3 layers: zona glomerulosa, zona fasciculata, and zona reticularis – which secrete aldosterone, cortisol, and DHEA, respectively. The medulla of the adrenal gland is composed of chromaffin cells and is responsible for synthesizing and releasing norepinephrine and epinephrine. 

Cortisol is a glucocorticoid hormone synthesized in the zona fasciculata of the adrenal gland, and ACTH stimulates its production. Cortisol primarily increases glucose levels in the body, which occurs via increased gluconeogenesis, lipolysis, and proteolysis. To keep glucose levels high, cortisol also increases insulin resistance, which is why high cortisol levels can lead to diabetes mellitus. Since cortisol is a glucocorticoid, it has additional properties and utility as a medication in hospitalized patients. It can increase appetite, raise blood pressure, decrease bone formation, and, most importantly – decrease inflammatory and immune responses. Cortisol has a negative feedback loop that acts on the hypothalamus, anterior pituitary, and adrenal gland to inhibit CRH release, ACTH, and cortisol.[99][100]

Aldosterone – Aldosterone is a crucial mineralocorticoid hormone in the renin-angiotensin system (RAS) – which is important for regulating cardiac, renal, and vascular physiology. The RAS pathway begins with renin cleaving angiotensinogen into the inactive angiotensin I, which then converts via angiotensin-converting enzyme (ACE) action angiotensin II (primarily in the lungs). Angiotensin II mediates aldosterone release from the zona glomerulosa of the adrenal gland via angiotensin II type 1 receptors (AT1Rs).[101]

The RAS pathway is the primary aldosterone stimulus; however, the adrenal gland produces small levels of angiotensin II, ACTH from the anterior pituitary, and potassium, all of which stimulate aldosterone release.[102] The main action of aldosterone occurs in the kidney, increasing sodium channels' expression on the epithelium within the distal tubule. This, in turn, increases sodium reabsorption and, as a result, water, too, while secreting potassium. The result is increased extracellular fluid volume, decreased serum potassium, and increased blood pressure. Previously, primary aldosteronism was thought to be a rare cause of hypertension. However, studies over the last 15 years have shown the prevalence to be much higher.[103][104] Initial workup for primary aldosteronism involves measuring renin: aldosterone ratios, helping guide what further workup is necessary for patients suspected of the disease.[103]

Adrenal Androgens are primarily dehydroepiandrosterone (DHEA) and DHEA sulfate. The production of these androgens within the adrenal gland is a byproduct of cortisol synthesis. As a result, the primary stimulant of DHEA and DHEA sulfate is ACTH. These 2 hormones have minimal if any, inherent androgenic properties. However, it is well established that the excess secretion of DHEA and DHEA sulfate are hallmarks of congenital adrenal hyperplasia (CAH). A small percentage is converted to androstenedione and then to testosterone (and potentially estrogen) in both the adrenals and peripheral tissue. Once this conversion has occurred, physiologic effects of androgens occur (see endocrine sex hormones for more information). Therefore, DHEA and DHEA sulfate do not cause virilization in young females; rather, the elevated levels are converted to more potent androgens, which cause the classic phenotype seen in CAH.

Normally, in both genders, DHEA and DHEA sulfate rise throughout puberty and for a couple of years post puberty. Levels peak in the third decade before gradually declining; by age 80, adrenal androgens are about 25% compared to 25. The significance of this finding (also known as adrenopause) is unknown. In males, testosterone from the adrenal gland is less than 5%. However, in women, the total amount of serum testosterone derived from DHEA and DHEA sulfate is significantly higher. In the menstrual cycle, specifically the follicular phase, 65% of testosterone production comes directly or indirectly from adrenal androgens.[105][106][107]

Epinephrine (adrenaline) and norepinephrine (noradrenaline) – these 2 hormones are discussed together since they are both produced from the medulla of the adrenal glands and have many similarities. This discussion explains the different effects of stimulation of alpha-1, beta-1, and beta-2 receptors. Understanding what happens when certain receptors are activated makes understanding the effects of epinephrine and norepinephrine easier. In clinical settings, epinephrine and norepinephrine have several uses depending on dose and patient indication.[108][109]

• Alpha–1–stimulation utilizes the IP3-DAG cascade, increasing intracellular calcium. Activation in peripheral arteries results in vasoconstriction, increased resistance, and an elevated mean arterial pressure (MAP). Alpha-1 constricts not only arteries but also veins. Venoconstriction results in an increased venous return to the heart. Some additional random effects of alpha-1 include mydriases (pupil dilation) and urine retention via contraction of the urethral sphincter and prostatic smooth muscle.
• Beta-1 – these receptors are primarily present in the heart and, when stimulated, produce increased inotropy and chronotropy without influencing vessels. Beta-1 can also increase renin release, resulting in increases in blood pressure.
• Beta-2—Stimulation of these receptors in blood vessels results in vasodilation, decreasing systemic vascular resistance (SVR) and diastolic blood pressure. Within the lungs, beta-2 results in bronchodilation, in the liver, it promotes gluconeogenesis, and in the eye, it can increase aqueous humor production.

Epinephrine binds and stimulates all 3 receptors. The predominance of the receptor affected depends on the dose administrated. At lower doses, the beta receptor action predominates, resulting in increased cardiac output (CO) from the inotropic and chronotropic effects of beta-1. The stimulation of alpha-1, which would usually cause vasoconstriction, is offset by the vasodilation of beta-2. The result of all 3 receptors being stimulated is increased CO, decreased SVR, and a variable effect on the MAP. High-dose epinephrine results in predominant alpha-1 stimulation. This results in increased SVR and CO. Epinephrine is released into the bloodstream under times of great stress, like “fight or flight” scenarios, or stress from life (school, sports, etc). Strong emotions, including anger or fear, can also stimulate secretion. It was aptly named adrenaline because epinephrine is released when you need a surge of energy (facilitated by the above physiologic effects).[110][111][112]

Norepinephrine acts on alpha-1 and beta-1 receptors, with the predominant action coming from alpha-1 stimulation. As a result, there is a potent vasoconstriction and a mild increase in cardiac output. A mild chronotropic effect is noted, but the effect is canceled due to the reflex bradycardia from increased MAP. Norepinephrine is often secreted in tandem with epinephrine because the stressors that induce epinephrine also cause a release of norepinephrine. However, there are times when these 2 hormones are secreted independently of each other. Norepinephrine and epinephrine have other functions; however, these are outside the scope of endocrine hormones and are not discussed here.[113]

Endocrine Sex Hormones

Endocrine sex hormones, due to their intricate and overlapping properties in both genders, are explained and discussed from a gender standpoint rather than by organ. Each of the sex hormones is expressed and active in both males and females; it is the levels and concentrations that help develop and define the external and internal function of the human body. Studies and patient cases have shown mutations in classical male hormones or classical female hormones can still lead to pathology when absent in either gender.

Female Sexual Development and Hormone Expression and Activity

Physiologist Alfred Jost formulated a simple model of normal sexual development. Chromosomal sex (XX or XY) dictates gonadal sex, which, in turn, determines phenotypic sex (male or female).[114] Based on this module, 3 interdependent yet sequential steps must occur. First, establishing the chromosomal sex, male and female development is identical within the first 6 weeks of gestation. After 6 weeks, the gonad develops into the appropriate tissue, testes if male, or an ovary if female. The testes begin to secrete hormones around week 6; the ovary is hormonally silent.[115] Finally, in week 12, the male phenotype is complete; the female completion occurs a little later than the males. The anatomic structures include the internal urogenital tract – Müllerian or Wolffian ducts – and external genitalia. The female Müllerian ducts become the upper vagina, fallopian tubes, and uterus.

The external genitalia has 3 common structures: genital folds, genital swellings, and genital tubercles. Depending on the hormones secreted by the gonads determine the structure. In the male, genital folds elongate and fuse to make the shaft of the penis and urethra; the genital tubercle becomes the glans penis, and the genital swellings become the scrotum. Conversely, in females, genital folds become the labia minora, genital swellings become the labia majora, and the genital tubercle becomes the clitoris.[116][117] In abnormal development, when gonads are absent, phenotypic development is female. This suggests the default development of a fetus is female unless influenced by androgens. It is unknown if female development depends on hormones since gestation occurs in the female body. There is no method for isolating hormones within the fetus to determine if their role is crucial for female development.

The menstrual cycle divides into 2 phases, follicular and luteal, which are determined by the endocrine hormones that drive it.

• Follicular Phase – The follicular phase begins with the initiation of menses and ends 1 day before the luteinizing hormone (LH) surge. The ovary has little hormone activity early in the phase, resulting in low estradiol and progesterone levels. However, LH pulsation increases from once every several hours in the late luteal to once every 90 minutes. The mid-follicular phase increases follicle-stimulating hormone (FSH), stimulating folliculogenesis and increased estradiol. FSH increases estradiol levels by stimulating aromatase so the follicles continue developing. The increase in estradiol eventually leads to a negative feedback loop on both LH and FSH. Late in the follicular phase, FSH and LH remain low, but FSH activates LH receptors in the ovary, producing intrauterine growth factors.[118][119]
• Luteal Phase – From the follicular into the luteal phase, estradiol rises, peaking 1 day before ovulation. At this time, a unique endocrine phenomenon switches from negative to positive feedback – resulting in the midcycle surge. There is a 10-fold increase in LH and a smaller surge of FSH. The LH surge cannot be simulated in women by administering high estrogen and progesterone levels, indicating that other factors are involved. Roughly 36 hours after the LH surge, the follicle releases the oocyte, and it makes its way through the fallopian tube to the uterine cavity. Progesterone begins to rise due to secretions from the corpus luteum. Progesterone raises body temperature, relaxes uterine smooth muscle, and prevents endometrial hyperplasia. In simple terms, estrogen stimulates the proliferation of the endometrium in preparation for implantation, and progesterone maintains the endometrium as a suitable environment for fertilization and implantation. Late in the luteal phase, if the oocyte does not undergo fertilization, LH levels decrease, and progesterone and estrogen levels decrease – sloughing off the outer layer of the endometrium, resulting in menses. If the oocyte does get fertilized, it implants in the endometrium. The embryo begins secreting human chorionic gonadotropin (hCG), which sustains the corpus luteum and progesterone levels.[120][121][122]

Females only have a limited number of ovulation cycles before eventually going through menopause, which is caused by the decline in the number of ovarian follicles. The definition of menopause is amenorrhea for 12 months and typically happens around age 50. The lack of ovarian follicles results in decreased estrogen – extremely elevated levels of FSH mark this condition. This results from the loss of the negative feedback loop because estrogen is no longer present to inhibit FSH.[123] Estrogen is important for the development of secondary sex characteristics as well as the reproductive cycle. The action of estrogen is facilitated via estrogen receptors (ER). There are 2 ER molecules, ER-alpha and ER-beta.[124]

When estrogen penetrates a cell and makes it to the nucleus, it binds the ER and ultimately modulates transcriptional rates of genes responsive to estrogen. In females, if estrogen is not present and able to bind ER properly, there is a lack of sexual development, delayed epiphyseal closure, low bone density, and infertility.[125][126] 

Other health concerns that affect low estrogen function are cardiovascular responsiveness, insulin resistance, and obesity; however, more research is needed. In females, secondary sex characteristics develop via stimulation of ERs, which cause the upregulation of genes, leading to changes in body habitus. For example, the binding of ER-alpha in the mammary gland stimulates bud formation. Progesterone and estrogen are required for normal breast duct formation via ERs and Progesterone receptor (PR) stimulation. Cell proliferation rate in the breast's lobular structures is directly proportionate to the level of PRs and ERs in the tissue.

Regarding fertility, females and males rely on estrogen and its effects to reproduce properly. Like males, ER-alpha or ER-alpha and ER-beta deficient mice are infertile, while ER-beta deficient mice are sub-fertile. Additionally, mice who lack aromatase are anovulatory and thus infertile. Testosterone also plays a significant role in women's development, particularly in muscle, overall growth, reproductive tissue, and psychological behavior. It is known that supra or sub-physiologic levels result in deviation from typical female features; however, the degree to which testosterone impacts women is not fully understood.[127][128]

Male Sexual Development and Hormone Expression and Activity

As mentioned in the female section, the default development is female from an embryological standpoint. Males genetically are XY – the region on the Y chromosome critical to testicular development is the SRY (sex-determining region of the Y chromosome) gene. This is the gene causing neutral gonads to develop into testes. Fetal testes secrete 3 hormones: anti-Müllerian hormone (AMH), testosterone, and 5-alpha-dihydrotestosterone (DHT). AMH primarily causes the regression of the Müllerian ducts – testosterone and DHT (androgens) are the hormones we primarily focus on.[129][130]

• The internal urogenital tract driver is initially by human chorionic gonadotropin (hCG) and later in development by luteinizing hormone (LH) secreted by the fetal anterior pituitary gland. Depending on the development stage, either hCG or LH causes the fetal testes to secrete testosterone – this propagates the differentiation of the Wolffian ducts into the epididymis, vas deferens, seminal vesicles, and ejaculatory ducts.[129]
• The external urogenital tract is driven by the conversion of testosterone into DHT by the enzyme 5-alpha-reductase. DHT regulates the fetal development of the prostate and external genitalia, which completely form by the twelfth week of gestation. By studying 5-alpha-reductase-deficient animals and humans, the conclusion is that testosterone is responsible for internal sexual development, while DHT is necessary for external development. Patients with 5-alpha-reductase have normal internal male anatomy but have ambiguous external genitalia and lack secondary male sex characteristics. This is due to the normal function of testosterone but low levels of DHT. Androgens, in addition to sexual development, affect body composition – there has been a direct correlation of birth weight to the degree of androgenization rather than chromosomal sex.[129][131]

As previously discussed, GnRH regulates the luteinizing hormone (LH) and follicle-stimulating hormone (FSH). GnRH’s pulsatile secretions from the hypothalamus cause a similar pulsatile appearance of LH and FSH – the half-life of LH is significantly shorter than FSH. The secretion of GnRH acts upon the gonadotrophic cells of the anterior pituitary, resulting in the release of FSH and LH.[132]

• LH acts primarily on Leydig cells by binding to receptors on the cell membrane. This stimulates and releases cAMP, which activates protein kinase A, resulting in Leydig cells producing its primary hormonal product, testosterone. Production of testosterone averages 5 to 7 mg each day.[133]
• FSH binds to the cell membrane of Sertoli cells, causing stimulation and release of cAMP, activating protein kinase A. The result of intracellular signaling increases gene expression and protein levels to support spermatogenesis.[134]

These are the primary roles of FSH and LH. In a broad overview, it can be summarized that LH acts on Leydig cells to secrete testosterone, and FSH acts on Sertoli cells to promote spermatogenesis. Testosterone, like all steroid hormones, originates from cholesterol. Once testosterone is produced, it can be metabolized further via aromatization to become estradiol or reduced by 5-alpha-reductase to DHT. Cells with androgen receptors (AR) can be bound and activated by testosterone or DHT, with a much higher binding affinity. Regardless of which molecule stimulates the AR, a conformational change is induced, allowing translocation to the nucleus. Within the nucleus, a homodimer forms by combining with a second hormone-AR molecule. This creates an active molecule that can bind to androgen response elements – inducing upregulation/downregulation of transcription genes and, ultimately, protein synthesis.[135] The physiologic action of testosterone is mediated via the hormone itself and its active metabolites – DHT and estradiol, resulting in the following major functions in males[136][137]:

• Development of the male phenotype in embryological development (as discussed above)
• Feedback communication on the gonadotropic hypothalamic-pituitary axis
• Provocation of sexual maturity at puberty and maintenance throughout adulthood
• Sexual function (libido, sexual satisfaction, and erectile function)
• Muscle and bone mass at puberty and throughout adulthood
• Maintenance of lower fat mass, initiation, and maintenance of spermatogenesis
• Maintenance of erythropoiesis and hematocrit levels

The negative feedback loop of LH secretion works via 2 mechanisms. Estradiol inhibits GnRH inhibition at the level of the hypothalamus, while testosterone and DHT inhibit the pituitary gland directly.[138] The negative feedback loop of FSH is mediated via 2 molecules: inhibin B (testicular peptide) and estradiol – inhibin B being the more important regulatory molecule.[139][140][141]

Estradiol is produced normally in men when testosterone undergoes aromatization; approximately 20% of estradiol synthesis is in the testes. The remaining 80% is produced in adipose, skin, brain, and bone tissue – adipose being the most notable site of estradiol production in men. When estradiol is deficient, men may have the following problems: increased body fat, delayed epiphyseal closure, and decreased bone density. Rats and mice with ER-alpha deficiency have been studied and been shown to be infertile. The testes of these rodents lack ER-alpha and have dilated seminiferous tubules containing no sperm. ER-alpha is not necessary for sperm function, but it is necessary for sperm maturation. ER-alpha, ER-alpha, and ER-beta, or aromatase-deficient mice, have been shown to have abnormal mating behavior. ER-beta-only deficient mice exhibit normal mating. While it is not fully understood, ER-alpha and estradiol are suspected to be necessary for normal mating and the aggressive behaviors seen in the male genotype.[136][137][142]

Appetite Regulation

Ghrelin – Classically considered the “hunger hormone” due to its appetite stimulation. It is a 28 amino-acid peptide synthesized predominantly in the stomach, specifically the gastric fundus where oxyntic gland P/D1 cells are found.[143] These cells come in 2 types. The open type is exposed to the lumen of the stomach and is secreted directly into the stomach to intermix with gastric contents. The closed type is found close to the lamina propria and is secreted directly into the vasculature.[144] Ghrelin is also present in the pancreas, placenta, kidney, and pituitary but at much lower levels.[145] Ghrelin receptors (growth hormone secretagogue receptor [GHS-R]) have 2 forms: GHS-R1a and GHS-R1b. GHS-R1a is found in the central nervous system and peripheral tissue and mediates food intake and satiety. GHS-R1b has a wider distribution, but its function is unknown since it has no links to the same G protein complex that GHS-R1a is.[146][147] Ghrelin levels increase during fasting, starvation, and anorexia – surges are also noted before meals. Nutrients suppress ghrelin, carbohydrates having the greatest inhibitory effect, followed by protein and lipids. The decrease in ghrelin occurs via non-vagal signals from the stomach and intestines.[148]

Ghrelin primarily stimulates GH secretion, possibly GHRH itself, further stimulating GH secretion. The resultant effect is increased appetite and a positive energy balance, in addition to the effects of GH (see GH section for more information). Ghrelin acts locally in the stomach to increase gastric contraction and potentiate stomach emptying. GH is known to affect bone formation and mass, but interestingly, osteoblasts express GHS-R1a, suggesting a possible direct effect. Defects in GHS-R have been linked to short stature, further implicating its impact on bone formation.[149][150]

Ghrelin has been demonstrated to increase the frequency of meals, yet not the size. Ghrelin also plays a regulatory role in long-term body mass. In normal BMI ranges, ghrelin levels are within 550 to 650 pg/mL. Whereas obese individuals have a range of 200 to 350 pg/mL – indicating ghrelin has an inverse relationship with BMI.[151][152][153] Ghrelin levels are highest in fasting, anorexic, and cachectic states – where levels, on average, exceed 1000 pg/mL.[154] In obese subjects, decreased ghrelin levels correlate with gastritis (regardless of Helicobacter pylori presence).[155]

Leptin – Conversely, leptin is classically considered the “satiety hormone” due to its appetite suppression. It is a 167 amino acid protein produced from the ob gene and expressed primarily in adipocytes.[156] It mediates its actions by binding leptin receptors (LEPRs), of which 6 isoforms exist, LEPR-a to LEPR-f. The longest form, LEPR-b, is found in many organs, but importantly, it is found in the brain – specifically the hypothalamic and brainstem nuclei. Mutations in this isoform result in severe obesity.[157][158]

Individuals within normal BMI ranges have been shown to decrease food intake when leptin levels increase. In obese patients, leptin response is blunted, even with exogenous leptin administration at supraphysiologic levels.[159][160][161] The percentage of body fat correlates directly with leptin production and circulation.[158] Overeating increases leptin levels by roughly 40% in just 12 hours. In comparison, fasting decreases leptin levels by 60 to 70% in 48 hours and can reach 80% in 72 hours.[162][163] With regular food ingestion, leptin communicates with adipose tissue, and based on body adipose percentage, adipocytes secrete leptin accordingly. Leptin is influenced by gender since hormones influence its secretion rates. In females, estrogen increases leptin levels; interestingly, the placenta and breast milk are sources of leptin. In males, androgens decrease the level of serum leptin.[164][165] A link between nutrition and immune function is also mediated by leptin. In subjects with low leptin levels (as seen in prolonged starvation or cachexia), Th1/Th2 imbalance, low CD4 counts, and decreased T-cell production.[156][166] Lastly, leptin has both direct and indirect effects on bone. However, studies have concluded a positive and negative correlation between leptin concentration and bone density. It is unclear what effect leptin has on bone, and it is an area of ongoing research.[167][168]

Clinical Significance

Understanding how hormones interact to maintain the body tightly within the strict limits of homeostasis is imperative. With a firm grasp of endocrine physiology, pathology often becomes straightforward. When a hormone is either elevated or decreased, it presents a certain way – due to its lack or excess of action; this allows providers to hone in on their differential diagnosis, order the appropriate laboratory tests and imaging, pinpoint the diagnosis, and provide treatment. This diagnosis is not always as easy as it sounds since hormones are often intricately related and may influence other hormones, which are the primary presenting symptoms. For example, when prolactin is elevated, GnRH is inhibited, resulting in amenorrhea and infertility because of low FSH and LH levels.

It may be tempting to focus only on the reproductive organs or their hormones for not functioning correctly when, in actuality, hyperprolactinemia is the culprit. Rarely, one has to consider hormone resistance syndromes when there is a discrepancy between elevated hormone levels and target organ function, ie, receptor defects such as nephrogenic diabetes insipidus pseudohypoparathyroidism, etc.