Non-functioning pituitary adenoma

A NFPA can remain unnoticed for a long time. Symptoms primarily arise when the tumor, due to its size, exerts pressure on surrounding structures.

• Pressure on the optic chiasm or the optic nerve can impair the visual field and visual acuity.
• Pressure on the healthy pituitary gland can lead to a deficiency of pituitary hormones.
• Depending on the hormone affected, symptoms may include, among others, a deficiency of cortisol, thyroid hormones, or sex hormones, as well as a deficiency of ADH (diabetes insipidus).

The diagnosis is often made following an incidental finding on a head imaging study. Subsequently, further tests are recommended to assess hormonal function and any potential effects on vision.

To rule out a hormone-producing tumor, an endocrinological evaluation should always be performed. This includes, in particular, measuring IGF-1 and prolactin, as well as testing for cortisol if clinically indicated *. If the tumor is 6 mm or larger, it may also be advisable to rule out a hormone deficiency.

A possible cortisol deficiency is best assessed based on the fasting cortisol level in the blood measured between 8 and 9 a.m. No cortisol or other steroid medication should be taken immediately before the test, as this would render the measurement invalid. Hydrocortisone should not be taken for at least 18 hours prior to the measurement. If results fall into a gray area, a Synacthen test may also be performed.

A thyroid hormone deficiency is diagnosed through a blood test; the fT4 level is particularly crucial in this regard.

A deficiency in sex hormones is assessed based on FSH, LH, and testosterone in men, and estradiol (E2) in premenopausal women. After menopause, measuring FSH and LH is sufficient, provided that the patient is not taking hormone replacement therapy.

An ADH deficiency (diabetes insipidus) is diagnosed based on sodium and osmolality levels in the blood and urine, as well as urine output.

If the tumor is located near the optic chiasm or the optic nerve, an eye exam is recommended. During the exam, visual acuity and the visual field are assessed.

Non-functioning microadenomas that do not cause any symptoms do not require active treatment. They can be monitored with regular follow-up examinations. The intervals between follow-up visits are determined on an individual basis and depend primarily on the tumor size and the distance to the optic chiasm. As a general guideline *:

• Non-functioning microadenoma: Follow-up after 2–3 years.
• Non-functioning macroadenoma at least 5 mm away from the optic chiasm: Follow-up after 1 year.
• Non-functioning macroadenoma less than 5 mm from the optic chiasm: Discuss surgery; alternatively, follow-up after 6 months. 

For small tumors under 5 mm that remain unchanged in size after 2–3 years, further follow-ups are often not necessary *.

Treatment should be initiated or discussed if:

• cranial nerve deficits, visual field defects, or visual disturbances related to the tumor occur;
• the adenoma reaches the optic chiasm – depending on the patient’s age and overall health. In older patients with intact visual function, a «watch-and-wait» approach may be considered under close monitoring;
• tumor growth is detected on follow-up imaging;
• a macroadenoma is present without symptoms – depending on the patient’s age and the distance to the optic chiasm;
• a new hormone deficiency develops due to pressure on the healthy pituitary gland. Surgery may then be considered, although recovery of pituitary function is not guaranteed.

Radiation therapy is used as the first-line treatment only in exceptional cases. Its use is often limited by the tumor’s proximity to the optic nerve and the risk of damage to the healthy pituitary gland. However, in cases of a residual tumor or a recurrent tumor, it is an important component of a multimodal treatment plan.

According to the current WHO classification, pituitary tumors are classified based on their cell lines and specific transcription factors. Pituitary adenomas are also referred to as PitNET; the abbreviation stands for «pituitary neuroendocrine tumor» *.

Approximately 75% of non-functioning pituitary adenomas are gonadotrophic at the molecular level. They express the sex hormones FSH and LH and belong to the SF-1 cell line *, *. These tumors account for about 40% of all surgically removed pituitary adenomas. Active hormone secretion is rare *, *.

In rare cases, a non-functioning pituitary adenoma corresponds at the molecular level to a silent corticotropic adenoma of the T-Pit lineage or a tumor of the Pit-1 lineage. This classification is relevant for follow-up management: A residual portion of a common gonadotrophic adenoma can generally be monitored, whereas follow-up treatment should be considered for the two rarer forms due to their somewhat more aggressive growth *.

A hormone deficiency must be managed by an endocrinologist. Missing hormones—particularly cortisol and thyroid hormones—are replaced with medication.

A cortisol deficiency is diagnosed based on fasting cortisol levels measured in the blood. Blood is drawn in the morning between 8 and 9 a.m. Hydrocortisone must not be taken for at least 18 hours prior to the test; otherwise, the result will be inconclusive. If the results are unclear, a Synacthen test may also be performed. A confirmed cortisol deficiency is treated with hydrocortisone. The dosage is determined on an individual basis and is usually 20–30 mg per day. To avoid metabolic and cardiovascular side effects, the lowest effective dose is selected. Affected patients should always carry an emergency ID card, as cortisol requirements increase during illness, fever, or an accident.

In cases of thyroid hormone deficiency, hormone replacement therapy is recommended; for borderline findings, close monitoring is advisable.

In cases of sex hormone deficiency, treatment with testosterone may be beneficial to improve energy levels, libido, and sexual function, as well as to maintain muscle mass and bone structure *.

ADH deficiency occurring after pituitary surgery is often temporary and requires short-term replacement therapy.

Internationally, the overall rate of complete tumor resection is approximately 50–66% *, *. For very large pituitary adenomas over 4 cm, this rate is significantly lower, at approximately 30–40 % *, *. These tumors present a complex surgical challenge and require an experienced team.

If a tumor residue remains after surgery, it continues to grow in 50–80% of cases within the following 5–10 years *, *, *, *. The larger its volume, the higher the probability of further growth *, *, *. If the residual tumor is small – less than 0.5 ml – this risk is lower *. 

After complete removal, a tumor recurs within 10 years in 10–20% of cases *, *.

Regular MRI follow-ups after surgery are therefore necessary.

In the case of a growing residual tumor or a recurrent tumor, radiation therapy is usually an option. Alternatively, depending on the tumor’s location and volume as well as the patient’s condition, a second surgery may be performed. In individual cases—such as when the tumor has invaded the cavernous sinus in older patients—a planned partial resection may be a sensible approach tailored to the risk.

In cases of larger tumors requiring surgery, hormone deficiency is already present in approximately 56% of cases prior to surgery *.

If this deficiency is already present before the procedure, hormone function recovers after tumor removal in about 20–25% of cases *, *. 

Depending on the tumor size, a hormonal axis failure occurs in 5–20% of cases following surgery *, *, *. This is often temporary but also requires medication.

Treatment of a hormone deficiency

If vision is impaired by the tumor, this usually leads to surgery. The prognosis for improvement is generally good. It depends on the extent and duration of the impairment, the patient’s age, and the thickness of the retinal nerve fiber layer *, *, *. The more severe and prolonged the impairment, the lower the chances of recovery.

With timely surgery, vision improves at least partially in 70–80% of cases *, *, *, *, *. Recovery can take a long time: Further improvements are possible even more than three months and up to one year after surgery *.