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Hypopituitarism: Clinical practice

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Hypopituitarism: Clinical practice

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A 32-year-old man comes to the clinic because of fatigue and baldness. He has had recent endoscopic transsphenoidal surgery. In addition to his fatigue, he admits to other endocrinological symptoms, including a feeling of inadequacy, depression, and decreased sexual function. His blood thyroid-stimulating hormone concentration is 3.6 µg/L and his free T3 and T4 concentrations are 5 µg/L and 12.5 µg/L, respectively. Which of the following is the most appropriate test to confirm the diagnosis?

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Content Reviewers:

Rishi Desai, MD, MPH

Hypopituitarism refers to the decreased secretion of one, some, or all of the anterior pituitary hormones, and it usually happens when there’s a pituitary or hypothalamic disease.

The hypothalamus and the pituitary work together to make 5 different hormones.

First, the hypothalamus secretes corticotropin releasing hormone, which stimulates pituitary production of adrenocorticotropin hormone, or ACTH.

ACTH makes the adrenal glands release cortisol, a hormone in charge of the stress response and keeping blood pressure and blood sugar in the normal range.

Second, the hypothalamus secretes Thyroid Releasing Hormone (TRH), which stimulates pituitary production of thyroid stimulating hormone, or TSH, which then makes the thyroid gland release thyroid hormones, T3 and T4.

Thyroid hormones speed up the basal metabolic rate in all cells, so it keeps cellular processes going at an optimal rate.

Third, there’s hypothalamic growth-hormone releasing hormone, which stimulates pituitary production of growth hormone, or GH.

GH acts directly on target tissues to stimulate growth and development.

Fourth, the hypothalamus has a word to say about reproduction - it makes gonadotropin releasing hormone, or GnRH, which stimulates pituitary production of gonadotropins, Follicle-Stimulating Hormone, or FSH; and Luteinizing Hormone (LH), that stimulate ovarian or testicular production of sex cells and sex hormones.

Fifth, the anterior pituitary makes one hormone without the help of the hypothalamus - that’s prolactin.

Prolactin secretion is important in females, where is plays a role in breast milk production.

Ok, so that being said, the clinical presentation of hypopituitarism varies, depending on which pituitary hormones are deficient.

ACTH deficiency may present with mild symptoms, like orthostatic hypotension and reflex tachycardia, weakness and lethargy.

Sometimes mild symptoms of ACTH deficiency can worsen during periods of stress, like illness or during surgery, and precipitate an adrenal crisis - which is when individuals have vascular collapse and shock, nausea, vomiting, abdominal pain and mental status changes ranging from confusion to coma.

When ACTH deficiency is suspected, an 8 AM serum cortisol level and serum ACTH should be obtained.

A serum cortisol below 3 micrograms per deciliter confirms adrenal insufficiency, and a low serum ACTH confirms secondary adrenal insufficiency - meaning, low serum cortisol because of low pituitary ACTH secretion.

When serum cortisol is between 3 and 18 micrograms per deciliter, an ACTH-stimulation test can be done to confirm the diagnosis.

This is when the individual is given 250 micrograms of Cosyntropin, which is the synthetic analog of ACTH, and serum cortisol is measured one hour later.

If cortisol levels rise following Cosyntropin administration, that confirms a deficiency in pituitary ACTH production.

Next, there can be a TSH deficiency, and the individual will have symptoms of hypothyroidism, like fatigue, cold intolerance, bradycardia, decreased appetite, and constipation, as well as dry skin and a puffy face. The diagnosis is based on having a low serum T4 level.

Growth hormone deficiency is more obvious in children, who present with short stature and failure to thrive - meaning, low height and weight for their age.

In adults, it can cause a decrease in bone mineral density and muscle mass, and an increase in fat content. Because these are so vague, in adults, growth hormone deficiency is usually screened for when other pituitary hormones are deficient.

Now, screening for growth hormone deficiency is done by using insulin growth factor 1, or IGF-1, levels. That’s because daily growth hormone secretion is pulsatile, but the mean concentrations of growth hormone are sufficient to make the liver release a constant amount of IGF-1 throughout the day - so IGF-1 levels are a better estimate of growth hormone secretion.

Low serum IGF-1 levels indicate a growth hormone deficiency, but it needs to be confirmed. One way to do that is using the arginine-L-Dopa combination test.

This involves administering 30 grams of arginine hydrochloride in a 10% solution, which is given as an infusion over 30 minutes. At the start of the infusion, 500 milligrams of levo-dopamine are given orally. Serum growth hormone is sampled right before the infusion starts, and then 30, 60, 90, and 120 minutes later.

Growth hormone levels lower than 1.5 micrograms per deciliter confirm a growth hormone deficiency.

Additionally, blood work in adults with growth hormone deficiency may have dyslipidemia, so high levels of total cholesterol and LDL-cholesterol, as well as increased inflammatory markers like a CRP and fibrinogen, all of which increase the risk of cardiovascular events.

Now for the reproductive hormones. First, FSH and LH deficiency results in decreased sex hormone production in both females and males, with different consequences.

Pre-menopausal females can have menopause-like symptoms like infertility, irregular periods or amenorrhea, hot flashes, and vaginal atrophy.

In females who have already gone through menopause, these symptoms may not be present, because the ovaries are already at rest.

Males can have infertility, as well as a decreased libido, low energy, in severe cases, they can also have hot flashes.

In males, a gonadotropin insufficiency causes a low serum testosterone, low serum LH and low FSH levels.

In females who present with menstrual irregularities, serum FSH, LH, and estradiol levels should be obtained, as well as a 10-day medroxyprogesterone test - this is when the female is given 10 milligrams of medroxyprogesterone daily, for 10 days, to see if that causes menstrual bleeding.

Low FSH, LH, or estradiol levels, as well as not bleeding following medroxyprogesterone, demonstrate gonadotropin insufficiency.

Finally, moving on to prolactin deficiency, it causes an inability to lactate after delivery. In fact, this is a clinical cue for Sheehan’s syndrome, which is pituitary necrosis following delivery, in postpartum women.

Serum prolactin levels are typically not measured, because what’s considered a normal level, can vary from person to person. As a result, the clinical definition of prolactin deficiency is a postpartum female who can’t lactate.

These deficiencies occur because of an issue with the pituitary, or when both the hypothalamus and the pituitary are injured.

Most frequently, hypopituitarism develops over a long period of time, and pituitary hormones tend to become deficient in the opposite order in which they’re needed for survival. Think about it this way - if you were running from a pack of kangaroos across the Australian desert, reproduction and normal growth and development would probably be the last things on your mind.

So in chronic hypopituitarism, the first signs are those of gonadotropin deficiency, like decreased libido, infertility and menstrual irregularities in females, and growth hormone deficiency - like short stature and changes in body composition.

In postpartum females, prolactin deficiency would translate as an inability to produce breast milk.

What you really need to stay ahead of those kangaroos are thyroid hormones - to accelerate cellular processes, and cortisol, to increase your blood pressure and blood sugar, and give you a boost for the run.

So only after a long period of hypopituitarism, will there be signs of TSH and ACTH deficiency.

The most common cause of hypopituitarism is a pituitary macroadenoma, which is a benign tumor of the pituitary larger than 1 centimeter.

Non-endocrinologic symptoms of a macroadenoma include compression symptoms, like headache and visual impairment. These symptoms typically trigger obtaining a head MRI to identify the tumor.

On an unenhanced or non-contrast MRI, normal pituitary tissue has a greater signal intensity than brain tissue - so it looks whiter.

A pituitary adenoma, on the other hand, has a signal that is similar to surrounding brain tissue - so it’s “just as grey” instead.

Following administration of Gadolinium as contrast, normal pituitary tissue lights up like a christmas tree.

An adenoma typically takes in more contrast than the central nervous system, but less than the healthy part of the pituitary - so grey-wise, it’s somewhere in between the two.

Identifying a macroadenoma warrants testing for pituitary hormone deficiencies, even in the absence of symptoms, so serum cortisol, ACTH, and an ACTH stimulation test should be obtained to screen for secondary adrenal insufficiency, as well as serum T4 to check for secondary hypothyroidism.

Additionally, IGF-1 levels and an arginine-L-DOPA stimulation test could spot a growth hormone deficiency, and reproductive hormones FSH, LH, estradiol and testosterone should be checked to look for reproductive function.

Serum prolactin levels should also be determined in this situation. This isn’t done to screen for prolactin deficiency, because in that setting the results can vary from person to person, but rather for prolactin excess.

See, sometimes macroadenomas that derive from lactotrophic cells secrete excess prolactin, even though they compress the rest of the pituitary and cause other pituitary hormone deficiencies.