Hypopituitarism: Pathology review

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Case study0:00–1:14

On your rounds, you admit 28-year-old Regina who presents with an 8-month history of depression, cold intolerance, fatigue, and reduced libido.
History revealed she delivered a healthy baby eight months ago, and that the delivery was complicated by a severe postpartum hemorrhage.
She has also been unable to breastfeed and hasn’t had her menstruation since giving birth. Physical examination is remarkable for bradycardia, weight loss, and delayed relaxation of her reflexes.
Then you see Alexander, a 58-year-old male with difficulty seeing things in his peripheral vision. He also describes a loss of sex drive, erectile dysfunction, and significant weight gain, all starting approximately two years ago.
The examination revealed moderate obesity, bilateral gynecomastia, and bitemporal hemianopsia. Basal serum hormone measurements were performed, showing decreased T4 levels in Regina and decreased FSH, LH, and testosterone levels in Alexander.Both people have hypopituitarism.

Pathology1:14–2:10

So hypopituitarism refers to the decreased secretion of one, some, or all of the anterior pituitary hormones. These hormones are ACTH, or adrenocorticotropic hormone; TSH, or thyroid stimulating hormone; GH, or growth hormone; FSH, or follicle-stimulating hormone; LH, or luteinizing hormone, and prolactin.Posterior pituitary hormone deficiency can also occur, but it’s extremely rare.
This part of the pituitary gland releases oxytocin and antidiuretic hormone, or ADH.Hypopituitarism typically occurs because of an acquired or congenital issue where the hypothalamus or pituitary is injured.
Now, the clinical picture of hypopituitarism depends on which hormone is missing. First, ACTH deficiency can present with symptoms such as orthostatic hypotension and tachycardia, weakness and lethargy, especially during periods of stress, like illness or during surgery.Stress can also precipitate an adrenal crisis where the individuals have vascular collapse and shock, nausea, vomiting, abdominal pain, and mental status changes ranging from confusion to coma.

Symptoms2:10–2:10

Symptoms2:10–4:11

Next, TSH deficiency presents with symptoms of hypothyroidism, like fatigue, cold intolerance, depression, bradycardia, decreased appetite, and constipation, as well as dry skin and a puffy face and slow relaxing reflexes.
Third, 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. Now for the reproductive hormones, gonadotropin deficiency results in decreased sex hormone production in both females and males, with different consequences.
Pre-menopausal females can have menopause-like symptoms such as infertility, irregular periods or absent periods, hot flashes, and vaginal atrophy.
By contrast, females who have already gone through menopause are mostly asymptomatic because the ovaries are already at rest.
Males can have infertility, as well as a decreased sex drive, erectile dysfunction, low energy, weight gain, and in severe cases, hot flashes.
Finally, moving on to prolactin deficiency, it causes an inability to lactate after delivery, which is called agalactorrhea; absent menstruation, or amenorrhea; and cold intolerance.Diagnosis is based on suggestive symptoms and basal serum hormone measurements; however, dynamic testing may also be required in some cases.

Diagnosis4:11–6:30

First, when ACTH deficiency is suspected, an 8 AM serum cortisol level and serum ACTH are required, both of which should be low.
If results are inconclusive, an ACTH-stimulation test with Cosyntropin, a synthetic analog of ACTH, is required. Serum cortisol is measured one hour after Cosyntropin administration, and if it rises, that confirms a deficiency in pituitary ACTH production.
Second, TSH deficiency is based on having a low serum T4 level. Third, a GH deficiency diagnosis is based on insulin growth factor 1, or IGF-1, levels.
That’s because although daily growth hormone secretion is pulsatile, it stimulates the liver to release a constant amount of IGF-1 throughout the day which can be used as an indicator for GH secretion.
Low serum IGF-1 levels indicate a growth hormone deficiency. However, this needs to be confirmed by using the arginine-L-Dopa combination test, where growth hormone levels are measured before and after giving an arginine hydrochloride infusion and oral levo-dopamine.
Fourth, FSH and LH deficiency diagnosis in females with menstrual irregularities is based on low serum FSH, LH, and estradiol levels, as well as on a 10-day medroxyprogesterone test.
This is when a female is given medroxyprogesterone, a type of progesterone, for 10 days, to see if that triggers menstrual bleeding.
Low FSH, LH, or estradiol levels, as well as not bleeding following medroxyprogesterone, signify gonadotropin insufficiency.
In males, gonadotropin insufficiency diagnosis is based on low serum testosterone, FSH, and LH levels. And fifth, serum prolactin levels are typically not measured because what’s considered a normal level, can vary from person to person.
Now, in terms of the medications that are used to treat anterior pituitary hormone deficiencies, ACTH deficiency is usually treated with synthetic glucocorticoids like hydrocortisone.

Treatment6:30–6:30

Treatment6:30–6:30

Treatment6:30–6:30

Treatment6:30–7:09

Treatment for TSH deficiency is done with thyroid hormone substitution therapy with levothyroxine. Growth hormone deficiency is treated by administering growth hormone.
Gonadotropin insufficiency is treated with testosterone in males, and combined estrogen and progestin therapy for females to replace the missing sex hormones.
Finally, at the moment, there are currently no treatments available for prolactin deficiency.Ok, so there are a few causes of hypopituitarism to know.

Sheehan syndrome7:09–8:44

The first high-yield cause is Sheehan syndrome, which is hypopituitarism secondary to ischemic pituitary necrosis due to severe postpartum bleeding, often this causes a decrease in all hormones.
Normally, labor and delivery can cause mild blood loss without any long-term complications. However, severe bleeding can decrease blood supply to the pituitary, causing ischemia and necrosis.
Another factor is pregnancy-induced pituitary growth where the gland outgrows available blood supply during pregnancy. This growth is usually the result of the estrogen surge that occurs during pregnancy, which leads to hyperplasia of lactotrophs, the cells responsible for prolactin production.
Symptom-wise, the syndrome is suspected in those who just gave birth and present with failure to lactate and absent menstruation, both due to prolactin deficiency.
In other cases, individuals can develop additional features of hypopituitarism, like hypothyroidism or cortisol deficiency, depending on the extent of necrosis.
Diagnosis is clinical, based entirely on history of pregnancy and birth and symptoms like galactorrea. Although prolactin levels are usually not measured, the basal levels of the other pituitary hormones are necessary.
Treatment consists of lifelong hormone substitution therapy for each individual hormone that’s missing.Next, empty sella syndrome is when the pituitary gland shrinks due to atrophy or compression and the sella turcica is filled with CSF.

Empty sella syndrome8:44–10:10

The syndrome can occur as a primary disorder, where the cause of the atrophy is unknown but it’s commonly associated with obese women.
Some high-yield secondary causes include pituitary surgery, head trauma, and idiopathic intracranial hypertension, previously known as pseudotumor cerebri, which is increased intracranial pressure without a detectable cause.
Now, most individuals are asymptomatic because pituitary function is typically normal. Others can develop hypopituitarism, headaches, high blood pressure, and, rarely, increased intracranial pressure, cerebrospinal fluid leakage through the nose, or cerebrospinal rhinorrhea, and vision abnormalities.
Diagnosis is made by head CT or MRI, which shows an abnormally-sized or absent pituitary and accumulation of CSF in sella turcica.
Full basal serum hormone measurements might also be required. No specific therapy is needed for an empty sella alone, but hormonal replacement might be needed.Next, pituitary adenomas are a group of mostly benign tumors of the pituitary gland that may or may not secrete hormones, depending on their cell of origin.

Pituitary adenoma10:10–11:41

A high-yield fact is that most adenomas are hormone-secreting, with prolactinomas, a tumor that secretes prolactin, accounting for more than half of the cases.
However, the most common tumors that cause hypopituitarism are macroadenomas larger than 1 centimeter that don’t secrete any hormones.
They are harmful because as they grow, they can compress the normal tissue in the gland, impairing hormone secretion. These tumors can also compress the optic chiasm, which is where the optic nerves partially cross, due to its close proximity to the pituitary.
This causes compression symptoms like headaches and visual abnormalities like bitemporal hemianopsia, or decreased vision in the outer half of both the right and left visual field, which is almost pathognomonic for pituitary tumors.
Diagnosis is based on brain MRI, which identifies the tumor after a contrast substance called gadolinium is administered.
For non-secreting macroadenomas, treatment is transsphenoidal resection, which is when the tumor is removed through the nose.
If the surgery is successful, the pituitary function can recover completely. If not, hormonal replacement therapy might be needed.Another hypopituitarism-causing tumor is craniopharyngioma, the most common childhood supratentorial tumor.

Craniopharyngioma11:41–14:29

Craniopharingyoma is mostly benign and a high-yield fact is that it originates from the remnants of the anterior pituitary embryonic tissue, called Rathke's pouch.
Rathke’s pouch derives from ectoderm, one of the three primary germ layers in the very early embryo. This tumor can also compress the pituitary gland, causing symptoms similar to an adenoma, for which it is frequently mistaken.
That being said, symptoms of craniopharyngioma depend on the tumor’s location. If it involves the area of the pituitary gland itself, it can cause pituitary hormone deficiency and symptoms of hypopituitarism.
Also keep in mind that if it comprises the pituitary stalk, which is the connection between the hypothalamus and the posterior pituitary, that decreases the amount of antidiuretic hormone secreted by the posterior pituitary.
This leads to diabetes insipidus with symptoms like excessive thirst and frequent urination. An additional high-yield fact is that it can also increase prolactin levels, causing galactorrhea.
This is because prolactin, unlike the other hormones, is under constant inhibition by dopamine secretion from the hypothalamus.
Because craniopharyngioma compresses the pituitary stalk dopaminergic inhibition is lost, leading to uncontrolled prolactin secretion.
Just like in adenoma, compression symptoms like headaches and bitemporal hemianopsia, are common as well. Diagnosis is based on contrast MRI showing a suprasellar cystic lesion with calcifications, and screening for pituitary hormone deficiencies, especially for cortisol deficiency due to their strong association.
Sometimes, a biopsy might be necessary, where the diagnosis is suggested by three main components which you need to know for your exam.
The solid component is represented by the actual tumor cells. There’s also a cystic component, which contains a “motor-oil-like”fluid.
The fluid has a brown-yellow color and is rich in proteins, blood, and cholesterol crystals. And the third component is represented by dystrophic calcifications, which are white masses within the tumor.
Treatment consists of surgical removal and in some cases, radiotherapy. If cortisol deficiency is identified, emergency treatment with hydrocortisone should be initiated before the tumor is removed to prevent cardio-vascular collapse.Next, pituitary apoplexy is a sudden hemorrhage of the pituitary gland, usually in the presence of a pituitary adenoma.

Pituitary apoplexy14:29–16:23

It occurs when the blood vessels of the adenoma rupture and cause a hemorrhage. Subsequently, the blood collects in the interstitium, and compresses the blood vessels of the pituitary itself, which leads to pituitary ischemia and loss of pituitary function.
What you need to know is that the symptoms of pituitary apoplexy can include excruciating headache and visual impairment like bitemporal hemianopsia.
Diplopia, or double vision, and ophthalmoplegia, which is the paralysis or weakness of the eye muscles, can also occur due to the blood buildup compressing cranial nerve III, which innervates the eye muscles.
Individuals might also have symptoms like hypopituitarism, especially signs of cortisol deficiency, like vascular collapse, shock, and mental status changes ranging from confusion to coma.
Diagnosis is based on a brain MRI, where the hemorrhage looks bright white compared to the general grey shade of the central nervous system and the pituitary is usually enlarged.
Hormone deficiency screening is also mandatory. Just as in craniopharyngioma, if cortisol deficiency is detected, treatment with hydrocortisone should be initiated immediately, to prevent life-threatening cardio-vascular collapse.
Once the individual is stable, transsphenoidal surgery can be tempted to remove the mass and relieve compression symptoms.
Hypopituitarism following apoplexy is usually permanent and global - meaning all hormones are deficient, so individuals usually require lifelong hormone substitution therapy.Finally, hypopituitarism can occur following head surgery and trauma and radiation, where presentation depends on the cause and on which hormone is deficient.

Other causes16:23–16:56

Diagnosis is based on head and imaging, like CT and MRI, and on hormone deficiency screening. Management depends on the cause and whether or not there are symptoms of hypopituitarism.
In an acute setting, if there are signs of cortisol deficiency, hydrocortisone should be initiated immediately. Alright, as a quick recap… with hypopituitarism there’s a deficiency in at least one anterior pituitary hormone, and more rarely, posterior pituitary hormones.

Review16:56–18:21

Symptoms depend on which hormone is missing and diagnosis is based on basal serum measurements or dynamic testing as well as imaging studies like CT or MRI.
One cause of hypopituitarism is Sheehan syndrome, which occurs in women following delivery with heavy blood loss. In empty sella syndrome, the pituitary is atrophied and the sella turcica is filled with CSF.
It may occur as a primary disorder, or it can be due to pituitary surgery, head trauma, or idiopathic intracranial hypertension.
Macroadenomas and craniopharyngiomas are benign tumors that cause compression symptoms like headaches and bitemporal hemianopia, alongside possible hypopituitarism if the gland is damaged.
Finally, pituitary apoplexy is when a pituitary tumor hemorrhages into itself. Management depends on eliminating the cause, like surgical removal of the tumor.
If there’s permanent damage to the gland, life-long hormone therapy might be needed depending on which hormone is deficient.Now back to our cases.

Summary18:21–19:34

Regina presented with symptoms like depression, cold intolerance, fatigue, bradycardia, and delayed relaxation of reflexes, which are suggestive of hypothyroidism and this diagnosis was confirmed by the low serum T4 levels.
This decrease is likely due to hypopituitarism secondary to Sheehan syndrome, which can be diagnosed clinically, based on her history of an inability to lactate and amenorrhea following a post-partum hemorrhage.
On the other hand, Alexander presented with loss of sex drive, erectile dysfunction, and significant weight gain. These can be caused by decreased FSH, LH, and testosterone levels.
He also presented with bitemporal hemianopsia, and, together with his other symptoms we can suspect a pituitary tumor, most likely an adenoma, which causes gonadotropin insufficiency, and, subsequently, hypopituitarism.
The next step in Alexander’s case would be brain imaging to confirm the tumor’s presence and location. Surgical resection of the tumor might be required.
Hypopituitarism: Pathology Review: Video, Causes | Osmosis