Cecil’s Chapter 65: Hypothalamic-Pituitary Axis
The pituitary is at the base of the skull in the sella turcica in the sphenoid bone, with the cavernous sinus on each side, and the optic chaiasm over its superior
The anterior pituitary gets lots of blood, mainly from the hypothalamic-pituitary portal system, which is used by the hypothalamus to send hormones to the pituitary
The anterior pituitary makes ACTH, GH, prolactin, TSH, LH, and FSH
ADH and oxytocin are made in the hypothalamus, and sent down the pituitary stalk to the posterior pituitary, where it is stored and ready to be secreted
Prolactinomas are the most common secretory pituitary tumors
Pituitary tumors show symptoms of the hormone they secrete, and if they’re big they can put pressure on things around them, causing headache
If it extends to the suprasellar space, it can compress the optic chiasm, classically causing bitemporal hemianopia
Lateral extension into the cavernous sinus can cause opthalmoplegia, diplopia, or ptosis by getting cranial nerves 3, 4, or 6
The tumor can also compress other parts of the pituitary, causing hormone hyposecretion
Destructive pituitary lesions cause hormone loss o Normally the pattern is GH is lost first, then LH and FSH, then TSH, and ACTH is last
The most common cause of an enlarged sella is primary congenital defect, or herniation of the arachnoid membrane through an incompetent diaphrgma sella after pituitary surgery or radiation
Up to 20% of normal people have a nonfunctional asymptomatic pituitary microadenoma
(incedentaloma)
Page 661 – pituitary hormones, where they come from, and what they affect
Page 662 – tests for pituitary hormone problems
Growth hormone (GH):
GH release from the anterior pituitary is stimulated by growth hormone-releasing hormone
(GHRH) from the hypothalamus, and inhibited by somatostatin from the hypothalamus o GHRH and somatostatin bind to pituitary somatotroph cells to regulate GH release
GH binds to receptors in the liver, and induces secretion of IGF-1, which circulates in the blood bound to binding protein (BP’s), the most important of which is IGF-BP3 o IGF-1 mediates most of the growth-promoting effects of GH
Tests to stimulate somatotrophs are necessary to assess GH deficiency, since basal GH levels are often very low even in normal people

o The gold-standard test is insulin-induced hypoglycemia (insulin tolerance test (ITT))
 Insulin is given IV to decrease blood glucose to half what it was to cause hypoglycemia, which is a potent stimulus for GH release
 A normal response to this would be GH levels peaking over 5 ng/mL at 60 minutes in adults and 10 ng/mL in kids o Combined infusion of GHRH and arginine is just as sensitive and specific of a test as ITT for adults, and recommended for elderly or those with heart issues or seizures o A single GH stimulation test is enough to diagnose
 Those with low IGF-1 and decrease of at least 3 other hormones have a 97% chance of having low GH, so you don’t need a GH stimulation test then o Low GH causes low IGF-1 and low IGF-BP3
 Normal IGF does not rule out low GH
GH deficiency during childhood will cause growth retardation, shortness, and fasting hypoglycemia
Adult GH deficiency shows increased abdominal fat, decreased muscle strength and exercise capacity, decreased lean body mass and increased fat mass, decreased bone density, glucose intolerance and insulin resistance, abnormal blood lipids, and psychosocial problems o Treat with GH subcutaneous injection
Tests for GH hypersecretion: o GH is secreted in a pulsatile way, so dynamic GH testing is more valuable than a single measurement o Symptoms of GH hypersecretion include cirrhosis, starvation, anxiety, type 1 diabetes, and acute illness o IGF-1 is a good indicator, because its levels do not fluctuate during the day
 IGF-1 levels are elevated in almost all cases of GH hypersecretion o Another test is give them oral glucose, which should suppress GH levels after 2 hours
In childhood, GH hypersecretion leads to gigantism
In adults, who had their epiphyses fused, GH excess causes acromegaly with overgrowth of bone in the acral areas (means the extremities)
GH hypersecretion is almost always caused by a GH secreting pituitary adenoma o 2/3 of patients with acromegaly have macroadenomas
Ectopic GHRH secretion can happen with pancreatic islet cell tumors and bronchial or intestinal carcinoids, and is rare
Clinical features of acromegaly are insidious and take several years to develop o The most classic feature of acromegaly is extremity enlargement, seen as widening of the hands and feet, and a coarsening of the facial features (sinuses enlarge, leading to prominent supraorbital ridges, and the mandible grows down and forward, which widens the teeth and causes the jaw to protrude out o Soft tissue & bone enlargement of the hands & feet will cause ring and shoe sizes to ↑ o Page 663 – table of features in acromegaly
The initial therapy of choice for GH tumors is trans-sphenoidal surgery o Microadenomas have a 90% success rate for cure

Can use drugs to decrease GH secretion from the pituitary tumor (somatostatin analogues and
dopamine agonists) or block the action of GH at the liver receptor (GH receptor antagonists) o Octreotide acetate – a long acting somatostatin analogue that decreases GH and IGF-1 and can shrink tumors half the time
 Side effects of octreotide are diarrhea, abdominal cramps, flatulence, and gallstones o Pegvisomant – binds the GH receptor on the liver to block GH action, so non IGF-1
Prolactin is made by pituitary lactotrophs
Dopamine from the hypothalamus inhibits prolactin release
Thyrotropin-releasing hormone (TRH) and vasoactive intestinal polypeptide (VIP) cause release of prolactin
Prolactin release is episodic: o Estrogens increase prolactin release, while glucocorticoids and TSH block TRH-induced prolactin release
Prolactin release increases during pregnancy
After childbirth, prolactin stimulates milk making, but high prolactin isn’t needed to maintain lactation, so prolactin levels fall while the infant suckling causes a reflex to maintain lactation
Microprolactinomas are more common in women, and macroadenomas are more common in men
Prolactin inhibits gonadotrope release, so it blocks the LH surge in women and therefore causes menstrual problems
Hyperprolactinemia in women can cause hypogonadism that causes estrogen deficiency
In men with hyperprolactinemia, test is decreased
Clinical features of prolactinomas: o Noticed earlier in women because of menstrual irregularities and infertility o Men show decreased libido and erectile dysfunction from hypogonadism o Most women with hyperprolactinemia have amenorrhea, galactorrhea, or infertility
 If it happens in teen girls before menarche, they have primary amenorrhea o Prolactinomas cause up to 1/5 of secondary amenorrhea o Prolactinomas can cause anovulation that cause infertility o Estrogen deficiency can cause osteopenia, vaginal dryness, hot flashes, and irritability o Prolactin stimulates adrenal androgen making, and excess androgens can cause weight gain and hirsutism o Hyperprolactinemia can cause anxiety and depression
Basal prolactinomas over 200 ng/mL imply prolactinomas
Treat prolactinomas with a dopamine agonist like bromocriptine or cabergoline to restore gonad function and fertility o They also make the tumor shrink o Side effects are more common in bromocriptine, and include dizziness, nausea, vomiting
(vomiting center is triggered), stuffy nose, and orthostatic hypotension

Thyroid-stimulating hormone (TSH) is made by pituitary thyrotroph cells
TSH release is stimulated by TRH from the hypothalamus
Thyroid hormones and somatostatin inhibit TSH release o Thyroid hormones also inhibit TRH release
TSH attaches to receptors on the thyroid and activates adenylyl cyclase, stimulating iodine uptake and the making and release of thyroid hormones thyroxine (T4) & triiodothyronine (T3)
TSH is measured with ultrasensitive assays
If you see low TSH when there’s low thyroid hormone levels, it’s secondary (central) hypothyroidism from hypothalamic-pituitary dysfunction
Primary hypothyroidism shows low thyroid hormone levels with high TSH
TSH deficiency causes thyroid gland involution, hypofunction, and hypothyroidism
Symptoms of hypothyroidism are lethargy, constipation, cold intolerance, bradycardia, weight gain, poor appetite, dry skin, and delayed relaxation time of peripheral reflexes
You treat TSH deficiency with thyroxine
Thyrotropin secreting pituitary tumors are very rare, and show hyperthyroidism, goiter, and high or normal TSH even though there’s high thyroid hormone o They usually secrete other hormones too, like GH, prolactin, and glycoprotein hormone
α subunit o Octreatide can decrease TSH release and decrease tumor size
Adenocorticotropic hormone (ACTH) is made from the precursor pro-opiomelanocortin (POMC), which then gets cleaved into β-lipotropin, ACTH, and joining peptide
ACTH is then cleaved into β-melanocyte stimulating hormone (β-MSH) and corticotropin-like peptide (ACTH), and β-lipotropin is split into lipotropin and β-endorphin
Corticotropin releasing hormone (CRH) from the hypothalamus, and ADH, stimulate ACTH secretion by pituitary corticotroph cells
ACTH stimulates cortisol making and release form the adrenal glands
Cortisol exerts negative feedback on ACTH and CRH release
CTH is secreted in pulses and under circadian control, reaching max levels just before you wake up, and then declines till evening
Both psychosocial and physical stresses increase ACTH and cortisol secretion
Glucocorticoids inhibit ACTH secretion and CRH and ADH making and release
ACTH maintains adrenal size by increasing protein synthesis
Random basal ACTH measurements are unreliable because of the short plasm half-life and pulsatile secretion of ACTH o Cortisol levels are the better indicator o ACTH can be used to differentiate between primary and secondary adrenal insufficiency
 Plasma ACTH will normal to high in primary adrenal insufficiency, and low in secondary adrenal insufficiency from hypothalamus or pituitary problem
You can test it with the insulin-induced hypoglycemia test, and is the most reliable way

o Contraindicated in older patients and in those with cerebrovascular problems, seizures, or heart disease
Can test by giving them metyrapone, which inhibits 11 β hydroxylase needed to make cortisol o So if you give them metyrapone, you should have high 11-deoxycortisol (due to the block) and low cortisol, triggering CRH and ACTH
If the adrenals are hurt, both tests are hazardous
Prolonged ACTH deficiency causes adrenal atrophy
Cortrosyn (aka cosyntropin) is synthetic ACTH o Impaired response to cortrosyn means either impaired pituitary ACTH secretion, or primary adrenal failure
ACTH hypersecretion can be caused by pituitary corticotroph adenomas of Cushign disease, or ectopic ACTH making tumors
ACTH deficiency causes adrenal failure, which shows lethargy, weakness, nausea, vomiting, dehydration, orthostatic hypotension, coma, and death if untreated o Treat with hydrocortisone, cortisone acetate, or prednisone
ACTH-secreting pituitary tumors cause hypercortisolemia, which shows obesity, moon face, cervicodorsal dysplasia, striae, thinning of the skin, hirsutism, hypertension, menstrual irregularities, glucose intolerance, mood changes, proximal myopathy, and osteopenia (p. 665) o Treat with trans-sphenoidal resection, radiation, or drugs that block steroid making, like ketoconazole, metyrapone, aminoglutethimide, mifepristone, and trilostane
LH and FSH are secreted by gonadotrophs
They’re release is mediated by gonadotropin-releasing hormone (GnRH) from the hypothalamus
GnRH is released in a pulsatile manner, causing LH and FSH to be released in a pulsatile manner
Gonadal steroids (estrogen and testosterone) and peptides (inhibin and activin) regulate negative feedback inhibition of LH and FSH
GnRH determines the onset of puberty
Gonad polypeptide inhibiin is made by ovary granulosa cells and testicular Sertoli cells, and
inhibits FSH release
Activins stimulate FSH secretion
LH and FSH bind to receptors of the ovaries and testes, and stimulates sex steroid secretion
(mainly LH) and gametogenesis (mainly FSH)
LH stimulates gonadal steroid secretion by testicular Leydig cells and ovarian follicles
In women, the ovulatory LH surge causes rupture of the follicle and then luteinization
FSH stimulates Sertoli cell spermatogenesis in men, and follicle development in women
Prepubery gonadotropin levels are low, and postemenopausal women have high levels o In ages in between, levels fluctuate
Male FSH and LH levels are pulsatile, but fluctuate less than women
During the follicular phase of the menstrual cycle, LH levels rise steadily, with a midcycle spike that stimulates ovulation

FSH rises during the early follicular phase, falls in the late follicular phase, and peaks at midcycle at the same time as the LH surge
Both LH and FSH levels fall after ovulation
In men you measure basal test and FSH, and if they’re low, it indicates hypogonadism o Take 3 samples 20 minutes apart since it’s pulsatile relase
In women with amenorrhea, you measure serum LH, FSH, estradiol, prolactin, and human chorionic gonadotropin (hCG) to tell if it’s primary ovarian failure (high FSH and LH with normal prolactin), hyperporlactinemia (high prolactin with normal to low LH, FSH, and estradiol), or pregnancy (positive hCG, normal to high prolactin, normal LH, and high estradiol)
Low or normal FSH and LH when there’s low test in men or low estradiol in women will confirm gonadotropin deficiency
Low levels of gonadal steroids when there’s high gonadotropin levels suggests primary gonadal failure
Central hypogonadism in childhood causes failure to enter puberty o Girls have delayed breast development, little pubic hair, and primary amenorrhea o Guys have testes and phallus that stay small, and little body hair o Sex steroids are needed to close the epiphyses of long bones, so growth will continue when there’s no steroids, resulting in tall teens with eunuchoid look (means they look
“leggy” with longer lower body than upper body)
Central hypogonadism in adult women shows breast atrophy, loss of pubic hair, and secondary amenorrhea o In men, it shows testicular atrophy, decreased libido, erectile dysfunction, decreased muscle mass and bone mineral density, loss of body hair, high LDL
Men with low test should receive test, and women with low estrogen should get estrogen replacement therapy, and progesterone if they have uterus to protect the uterine lining
Gonadotropin-secreting pituitary tumors are rare, and usually only secrete FSH
The most common cause of a hypothalamus problem is craniopharyngioma
Symptoms of hypothalamus tumors include visual loss, symptoms of increased intracranial pressure
(headach and vomiting), hypopituitarism, and diabetes insipidus
Diabetes is common of hypothalamus tumors, but no pituitary tumors
Hypothalamic problems cause problems with thirst (polydipsia, polyuria, dehydration), appetite
(hyperphagia, obesity), temperature regulation, and consciousness
In panhypopituitarism, you wanna fix glucocorticoids before you give them T4, because T4 may make adrenal insufficiency worse and cause acute adrenal failure
The posterior pituitary gland secretes ADH and oxytocin, which were made I the hypothalamic nuclei in neuron cell bodies that extend from the hypothalamus to the posterior pituitary
Oxytocin causes uterine smooth muscle contraction

ADH binds to receptors on the renal tubule to increase water permeability of the lumen membrane and cause reabsorption of water and concentration of the urine
ADH causes small urine volume with high osmolarity
Deficiency of ADH causes large volume of dilute urine
ADH also binds to peripheral arteriole receptors, causing vasoconstriction and increase in BP o But then ADH also causes bradycardia and inhibits symps
Deficiency of ADH or insensitivity of the kidneys to it causes diabetes insipidus, which shows polyuria and polydipsia
Excess ADH causes syndrome of inappropriate antidiuretic hormone (SIADH) production, causing hyponatremia and dehydration
Diabetes insipidus – shows polyuria, polydipsia, and nocturia
Caused by a posterior pituitary problem where not enough ADH is released (neurogenic) or a kidney problem where they don’t listen to ADH (nephrogenic)
A large volume of urine is excreted, leading to dehydration, and thirst
Diabetes insipidus shows a dilute urine with osmolarity less than plasma, which is normal or high
Test with the water deprivation test – they don’t drink anything for 12-18 hours, and you measure body weight, blood pressure, urine volume, urine specific gravity, and plasma and urine osmolarity, every 2 hours o Normal response is decreased urine output and increased urine concentration o Diabetes insipidus maintains a high urine output that’s still dilute
Giving them ADH and seeing if urine gets concentrated or not will tell you if it’s neurogenic or nephrogenic
Treat with desmopressin acetate (DDAVP) – a synthetic analogue of ADH