The hypothalamic releasing hormones stimulate pituitary secretion of tropic hormones; tropic hormones stimulate endocrine secretion of hormone; endocrine hormone acts on target tissue.

Primary, secondary, and tertiary disease states are related to the endocrine axis, and it works from bottom up. So primary issues are related to the target tissue; secondary are related to the pituitary, and tertiary (which are less common) are related to the hypothalamus.

Thyroid:
Thyrotropin releasing hormone (TRH), produced by the hypothalamus, stimulates the pituitary to release thyroid stimulating hormone (TSH). TSH stimulates the thyroid gland to produce thyroxine (T4) and triiodothyronine (T3). T4 is deiodinated in the liver to produce T3 (70-90% of T3 is produced outside of the thyroid). T3 and T4 work on a negative feedback loop with TSH, so if T3 and T4 are high, they will send a signal to decrease TSH. If T3 and T4 are low the signal will be less and more T3 and T4 will be produced.

Thyroid hormones are responsible for numerous metabolic processes. Most of the thyroid hormones T4 and T3 are in the bound form; about 99.98% of T4 is bound to thyroxine binding globulin (TBG), transthyretin, and albumin, and 99.7% of T3 is bound, mostly to TBG. Bound T3 and T4 are inactive, it is the small fraction of free T3 and T4 that is physiologically active. T3 is also the more active form although T4 measurement is useful in the clinical lab. Why measure the free T3 and T4? TBG levels effect total T3 and T4 levels. A person with normal thyroid function could have abnormal total T3 and T4 levels if TBG is out of whack. Free levels are a more reliable measurement and are not effected by TBG.

Nerdy Note:
Iodine is a necessary for the synthesis of T3 and T4. Iodine deficiency will cause the thyroid to produce less T3 and T4 which can result in an enlarged thyroid gland and the condition goiter. Iodine is a necessary micronutrient our bodies can’t synthesize on its own and must obtain through diet. In the 1920’s iodine was added to salt in the form of potassium iodide to prevent conditions like goiter which used to be very prevalent. It’s also been shown iodine is important for brain development during gestation. This is why a lot of the salt you see in the grocery store is iodized.

Thyroid conditions:

Hyperthyroidism:
An increase in thyroid hormones T3 and T4. Most cases of hyperthyroidism (~80%) are caused by Grave’s disease. Grave’s disease is caused by a stimulatory antibody to TSH that makes it produce too much T3 and T4. TSH will also be decreased in Grave’s disease.

Hypothyroidism:
A decrease in thyroid hormones T3 and T4 generally caused by thyroid antibodies. The major condition associated with hypothyroidism is Hashimoto’s thyroiditis which will have decreased T3 and T4, and increased TSH.

Parathyroid:
Physiologically the parathyroid is located near or within the thyroid but they have completely different functions. The parathyroid consists of four glands which regulate calcium through a negative feedback loop with parathyroid hormone (PTH) and calcium. If calcium is low, PTH will increase, and if calcium is high, PTH will decrease. Calcium, PTH, and vitamin D all work together in a complex fashion to regulate bone health. Vitamin D increases gastrointestinal calcium absorption and renal reabsorption.

Primary hyperparathyroidism:
Primary hyperparathyroidism is associated with hyperplasia or a benign tumor on one or more of the parathyroid glands. The effected gland or glands will lead to an elevated serum PTH, hypercalcemia, hypophosphatemia, and decalcification of bone. This condition can be remedied by removing one or more of the glands.

Secondary hyperparathyroidism:
Secondary hyperparathyroidism is associated with increased secretion of PTH due to decreased calcium levels. The decreased calcium levels can be due to decreased vitamin D, kidney failure, defective PTH calcium receptors, or a number of other processes. PTH will be elevated while calcium will be low or normal.

Adrenal cortex:
Corticotropin releasing hormone (CRH), produced by the hypothalamus, stimulates the pituitary to release adrenocorticotropic hormone (ACTH) which stimulates the adrenal cortex to release the steroid molecules cortisol, aldosterone, and a small amount of androgens and estrogens. Cortisol and aldosterone are both derived from cholesterol.

Aldosterone functions mostly in electrolyte and water balance; cortisol in the regulation of carbohydrate, protein, and lipid metabolism.

Cortisol works as a negative feedback loop with ACTH.

Adrenal conditions:

Hyperaldosteronism:
An increase in aldosterone can lead to increased Na+, decreased K+, and hypertension. It’s known as Conn’s disease.

Hypoaldosteronism:
A decrease in aldosterone can lead to decreased Na+, decreased cortisol, and decreased hemoglobin. It’s known as Addison’s disease. If the disease is primary there will be an increase in ACTH, if it’s secondary, a decrease in ACTH. Aldosterone and ACTH work on a negative feedback loop just like TSH and T3 and T4. When aldosterone is low, ACTH will increase, and when aldosterone is high ACTH will decrease.

Cushing’s Disease:
Cushing’s disease results in increased cortisol, glucose, Na+, and urinary steroids.

Bone and cartilage:
Growth hormone releasing hormone (GHRH), produced by the hypothalamus, stimulates the pituitary to produce growth hormone (GH). GH acts on the liver to produce insulin-growth-factor-I (IGF-I) which together with GH modulates bone and muscle growth and differentiation. GH also catabolizes fat tissue. IGF-I has a negative feedback effect on GHRH and GH secretion.

Testis/Ovaries:
Gonadotropin releasing hormone (GnRH), produced by the hypothalamus, stimulates the pituitary to release either follicle stimulating hormone (FSH), or luteinizing hormone (LH), depending on the pulsatile frequency. Higher frequency GnRH stimulates FSH secretion; lower frequency stimulates LH secretion.

In women, FSH stimulates estradiol synthesis; LH stimulates progesterone synthesis.

In men, FSH stimulates sertoli cells which are related to spermatogenesis and inhibin secretion; LH stimulates leydig cells which is related to testosterone production.

*GnRH is also known as luteinizing hormone-releasing hormone (LHRH), they’re used interchangeably.