Neuroendocrine Axis Case File

Neuroendocrine Axis Case File

EUGENE C.TOY, MD, RAHUL JANDIAL, MD, PhD, EVAN YALE SNYDER, MD, PhD, MARTIN T. PAUKERT, MD

CASE 29

A 51-year-old previously healthy man visits his primary care physician with the chief complaint of changes in the appearance of his face. Specifically, he is unhappy with recent increases in the size and shape of both his nose and ears. Later, in his presentation he states that he recently had to have his wedding ring removed because it was compressing his finger to the point of causing a sensory disturbance. Of note, he states that he has not regained full sensation of several of the fingers in his right hand following removal of the ring. On physical examination, the physician finds a man who appears his age with a distinct facial morphology including a large, bulbous nose, enlarged auricles, and a protruding jaw. His hands are disproportionately large with sausage-shaped fingers. On neurological examination, the only abnormal finding is decreased vision in both temporal fields. Based on these findings, the patient is diagnosed with acromegaly secondary to a growth hormone (GH)–releasing neoplasm.

• What is the most likely location of this neoplasm?
• How would the physician confirm his diagnosis?

ANSWERS TO CASE 29: NEUROENDOCRINE AXIS

Summary: A 51-year-old man is noted to have physical findings of GH excess, so called acromegaly.

• Diagnosis: GH releasing neoplasms most frequently occur in the anterior pituitary gland. Here, somatotropes are activated by growth hormone–releasing hormone (GHRH) secreted from the hypothalamus. The final point about a bitemporal homonymous hemianopia should be the convincing point that the lesion localizes to the pituitary gland.
• Confirmation of diagnosis: There are a series of diagnostic tests that should be performed on this patient. IGF-1 levels seem to be the most sensitive and useful laboratory test for the diagnosis of this condition. An MRI of the head should also be performed to evaluate the extent of tumor growth and compression of structures surrounding the sella turcica. Because assessing random levels of GH does not provide accurate information secondary to the inconsistent secretion of GH, GH levels should be measured after administration of a glucose load (normally, GH is suppressed by glucose).

CLINICAL CORRELATION

This patient exhibits the typical features of acromegaly: a large bulbous nose, enlarged auricles, a protruding jaw, and sausage-shaped fingers. Because this patient is an adult with fused epiphyseal plates, he does not exhibit features of gigantism that children with GH-releasing neoplasms exhibit. Most commonly, acromegaly is caused by a GH-producing tumor derived from somatotrophic cells in the anterior pituitary gland. The excess GH stimulates the liver to secrete even more IGF-1, the primary mediator of the growthpromoting effects of GH. Research shows that many of these pituitary tumors contain a mutation involving the alpha subunit of a stimulatory guanosine triphosphate (GTP)–binding protein, which leads to a persistent elevation of cyclic adenosine monophosphate (cAMP) in the somatotrophs, resulting in excessive GH secretion. Diagnosis of this condition is critical as the disease can lead to early death if unchecked. Diagnosis involves measuring IGF-1 levels, an MRI of the brain focusing on the sella turcica, and measuring GH levels after administration of glucose.

APPROACH TO NEUROENDOCRINE AXIS

Objectives

1. Be able to recognize the symptoms which cause acromegaly.
2. Be able to decide on the mode of treatment for the disease.

Definitions

Thyroid-stimulating hormone (TSH): Released from the anterior pituitary gland and stimulates the thyroid to produce thyroid hormone.

Adrenocorticotropic hormone (ACTH): Released from the anterior pituitary and stimulates the adrenal gland to produce glucocorticoids.

GH: Released from the anterior pituitary and stimulates the peripheral tissues to release IGF-1.

Luteinizing hormone (LH) and follicle-stimulating hormone (FSH): Released from the anterior pituitary gland and stimulates estrogen/progesterone production in females and testosterone production in males. Both hormones have roles in gametogenesis.

Prolactin-inhibiting factor (PIF): Most likely dopamine; secreted from the hypothalamus and results in inhibition of PRL release from the anterior pituitary.

Prolactin (PRL): Released from the anterior pituitary gland and stimulates lactation at the breast.

Vasopressin (VP): Also known as ADH. This hormone is created in the hypothalamus and released from the posterior pituitary to cause water reabsorption in the collecting ducts.

DISCUSSION

The hypothalamic nuclei responsible for production and secretion of the releasing hormones include the periventricular, preoptic, arcuate, and paraventricular nuclei. The axons of neurons that produce the releasing hormones targeted for the anterior pituitary terminate at the base of the hypothalamus in a region of tissue called the median eminence. Here, a microvascular network of capillaries and veins formed by penetrating branches of the superior hypophyseal artery forms a portal system for hormone delivery to the anterior pituitary. The portal system carries the releasing hormones from the tuberoinfundibular system and bathes them around the cells of the anterior pituitary. The cell bodies that produce VP and oxytocin project their axons through the median eminence and into the posterior pituitary, where they terminate around capillaries formed by the inferior hypophyseal artery. The anterior and posterior lobes of the pituitary subsequently secrete stimulating hormones that act on various end organs.

Interestingly, the secretion of both releasing and stimulating hormones occurs in a pulsatile fashion. Disruption of this rhythmicity can lead to corruption of the regulatory functions of the neuroendocrine axis. Although there are multiple levels of internal regulation within the neuroendocrine axis, the principle factor governing hormone secretion is negative feedback inhibition by end-organ hormones on the hypothalamic releasing factors.

TRH and TSH

Neurons in the paraventricular nucleus of the hypothalamus are responsible for production of TRH. TRH stimulates TSH secretion which results in thyroid hormone production within the thyroid gland itself. Thyroid hormone affects protein synthesis and metabolic activity in all organ systems. Thyroid hormone is essential for fetal and neonatal development. Hypothyroidism can cause devastating central nervous system developmental abnormalities during the first 3 months of fetal development. Thyroid hormone circulates and will negatively inhibit both TRH and TSH release by acting on both the hypothalamus and thyroid gland.

CRH and ACTH

This subsection of the neuroendocrine axis is intimately involved in the stress response as well as establishing basal levels of cortisol. CRH is synthesized in the paraventricular nucleus and descends into the anterior pituitary through the portal system where it stimulates ACTH release. ACTH will enter the systemic circulation and bind to cells in the cortical layer of the adrenal gland. This binding will activate glucocorticoid production. Although this process can occur in response to stresses such as sepsis, there is a rhythmic release of these hormones resulting in peak cortisol levels just before waking and lowest levels before midnight. Similarly to thyroid hormone, cortisol circulates to negatively inhibit both the hypothalamus and pituitary gland. Interestingly, acute stress phases result in improved memory and learning while chronic levels of elevated cortisol result in poorer hippocampal function.

GHRH and GH

The hypothalamus produces both GHRH and somatostatin to stimulate and inhibit GH release, respectively. There are a couple of major differences in both the action and regulation of GH compared to both TSH and ACTH. First, GH lacks a specific organ target. It acts on a variety of tissues to stimulate anabolic drive. Also, GH only feeds back onto the hypothalamus rather than both the hypothalamus and anterior pituitary to inhibit its own secretion. GH stimulates IGF-1 in its target tissues and both hormones stimulate an anabolic drive. However, where GH only negatively inhibits the hypothalamus, IGF-1 negatively inhibits both the hypothalamus and pituitary.

GnRH and FSH/LH

GnRH is produced diffusely throughout the hypothalamus and travels into the anterior pituitary along the hypophyseal portal system. In males, LH stimulates Leydig cell production of testosterone. FSH and testosterone act in concert to stimulate spermatogenesis. Testosterone also results in secondary sexual characteristics in males. In females FSH stimulates ovarian follicle formation. Both FSH and LH control the timing of ovulation as well as estrogen and progesterone production. Analogous to males, these sex steroids are responsible for the secondary sexual characteristics in females.

PIF and PRL

Prolactin (PRL) is different from the other hormones secreted by the anterior pituitary in that it does not have a secreting factor. Instead, it is tonically inhibited by PIF, which is most likely dopamine. Sucking decreased levels of PIF, which allows PRL to be secreted and stimulates lactation.

Oxytocin

Oxytocin is synthesized in the paraventricular and supraoptic nuclei of the hypothalamus and released directly into the systemic circulation. Its major functions are stimulation of uterine contractions and assisting the flow of milk during lactation.

Vasopressin

Vasopressin is another hormone produced in the hypothalamus and directly released into the circulation at the posterior pituitary. It has multiple effects including vasoconstriction and renal regulation of water homeostasis.

Treatment for these tumors is usually multimodal, utilizing a combination of medical and surgical therapies. Often first-line therapy is surgical resection of the tumor by a neurosurgeon. The medical therapies including use of a dopamine agonist, somatostatin, and GH receptor antagonists are all indicated.

COMPREHENSION QUESTIONS

[29.1] A 33-year-old man with ulcerative colitis who is taking chronic steroid therapy for control of his symptoms comes into your office for a routine checkup. You do some blood work, as usual, and find that his steroid level is therapeutic; his cortisol level is undetectable, as is his ACTH level. The suppression of ACTH by the exogenously administered steroids is an example of what basic neuroendocrine principle?

A. Positive feedback

B. Negative feedback

C. Stimulated release

D. Pulsatile release

[29.2] A 27-year-old woman comes into your office with the complaint that she has not had a period for 3 months. She also has noticed a whitish discharge from both of her nipples. The first test you check is a pregnancy test, which is negative. You follow that with a PRL level, which comes back 150, very elevated. You are concerned that this woman has a prolactinoma, a functional tumor of PRL-producing cells of the anterior pituitary. By what mechanism is the secretion of PRL normally controlled?

A. Release stimulated by dopamine

B. Release inhibited by dopamine

C. Release stimulated by GnRH

D. Release stimulated by CRH

[29.3] A 32-year-old woman is being evaluated for infertility. Her husband’s sperm count and function was normal, and she has no apparent abnormalities with her ovaries or reproductive tract. On testing, however, it is found that she has very low levels of FSH and LH. Consideration is being given to administration of GnRH to induce FSH/LH secretion from the pituitary. Which of the following is critical to remember in the administration of GnRH for this purpose?

A. It must be administered at the same time each day.

B. It must be administered at an increased dose each day.

C. It must be administered in a pulsatile fashion.

D. It must be administered intracerebrally.

Answers

[29.1] B. This is an example of negative feedback. In the normally functioning neuroendocrine system, the hypothalamus releases CRH, which causes the pituitary to release ACTH, which causes the adrenal glands to secrete cortisol. When the level of cortisol in the blood becomes high enough, it exerts inhibitory signals on both the hypothalamus and pituitary through a process known as negative feedback. When a patient is taking exogenous steroids, they are not measurable as cortisol but they act in the same way on the hypothalamus and pituitary gland, suppressing CRH and ACTH secretion. Most of the hypothalamic-pituitary-endocrine organ systems work in a similar manner as well.

[29.2] B. PRL is tonically inhibited from being released by dopamine. For this reason, when patients are placed on antidopaminergic drugs (some antipsychotics) they can develop gynecomastia and nipple discharge. One of the interesting things about PRL is that its regulation is different than that of the other anterior pituitary hormones. The rest are under stimulatory control, released from the adenohypophysis when the releasing factor is present in the hypophyseal portal system.

[29.3] C. All of the hypothalamic releasing hormones with the exception of TRH are released in a pulsatile fashion, GnRH included. If they are not pulsatile, they have decreased efficacy. Constant, high levels of GnRH actually serve to inhibit pituitary release of FSH and LH, producing the opposite effect that we are looking for in this patient. The normal pulse frequency of GnRH is approximately once every hour, so in order to induce ovulation in this patient, the medication must be administered that often via IV. This is a difficult regimen to adhere to, and for this reason women are often treated with FSH supplements rather than GnRH supplements, it is easier and more convenient and achieves similar results.

NEUROSCIENCE PEARLS ❖ The periventricular, preoptic, arcuate, and paraventricular nuclei of the hypothalamus are responsible for secretion of releasing hormones. ❖ Axons carrying antidiuretic hormone (ADH) and oxytocin travel (1) through the median eminence, (2) into the posterior pituitary, and (3) terminate around capillaries from the inferior hypophyseal artery. ❖ The hypothalamus produces somatostatin which inhibits GH release from the anterior pituitary.

REFERENCES

Bear MF, Connors B, Paradiso M, eds. Neuroscience: Exploring the Brain. 3rd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006. 

Kandel E, Schwartz J, Jessell T, eds. Principles of Neural Science. 5th ed. New York, NY: McGraw-Hill; 2000. 

Zigmond MJ, Squire LR, Bloom FE, Landis SC, Roberts JL, eds. Fundamental Neuroscience. 2nd ed. San Diego, CA: Academic Press; 1999.

HomeNeuroscience Case FileNeuroendocrine Axis Case File