Keywords

Secretory Pituitary Adenomas

Pituitary adenomas can cause symptoms by hormonal hypersecretion. Hypersecretion of prolactin (PRL) is responsible for amenorrhea–galactorrhea in women and decreased libido in men, growth hormone (GH) for acromegaly, adrenocorticotropic hormone (ACTH) for Cushing’s disease, and thyroid-stimulating hormone (TSH) for hyperthyroidism. Tumor mass-related effects such as headaches, visual field abnormalities, and depression of hormonal secretion (hypopituitarism) may also be present.

All patients who present with a pituitary tumor should be evaluated for gonadal, thyroid, and adrenal function as well as an assessment of PRL and GH. To detect the cause of hypersecretion and response to treatment, specific pituitary hormone stimulation and suppression tests are performed, in selected cases. To determine the presence, size and extent of the lesion magnetic resonance (MR) imaging (unless contraindicated) is the gold standard.

Pituitary tumor classification is based on cell cytoplasm staining properties as viewed by light microscopy and immunocytochemistry. Silent functioning adenomas (clinically nonfunctioning adenomas) also exhibit positive pituitary cell-type immunostaining. Most commonly, these include silent gonadotroph adenomas, silent corticotroph adenomas, and silent somatotroph adenomas.

In the last few decades, significant improvement in surgical technique (>99 % of cases performed via a transphenoidal route) has resulted in low mortality rates. Medical treatment with therapeutics such as dopamine agonists (DA), somatostatin analogs (SSA), GH-receptor antagonists, and glucocorticoid receptor (GR) antagonists has had a profound impact on the indications for radiotherapy. Generally, drugs are now utilized as a second-line treatment, (after surgery) or even as a first-line treatment (Fig. 1.1). Radiotherapy, in selected cases, using stereotactic techniques such as gamma-knife, has been relegated to a third-line treatment. Recently, temozolomide, an orally active alkylating agent used principally in the management of glioblastomas, was shown to be effective in controlling aggressive/invasive pituitary adenomas/carcinomas.

Fig. 1.1
figure 1

Adapted from Neurosurg Focus 29(4):E15, Fleseriu, M., Delashaw, J.B., and Cook, D.M. Acromegaly: a review of current medical therapy and new drugs on the horizon, page 3, Copyright (2010), with permission from Journal of Neurosurgery Publishing Group and American Association of Neurological Surgeons

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Pituitary tumor patients are best cared for by a multidisciplinary neuroendocrine team at a specialized center; one that includes neurosurgeons, endocrinologists, radiation oncologists, neuro-ophthalmologists, and otolaryngologists. No single treatment algorithm applies to all patients. Treatment should be individualized and include long-term follow-up. Treatment models for individual pituitary adenomas vary and are summarized above (Fig. 1.1).

Prolactinomas

Prolactinomas are the most common type of hormone-secreting pituitary tumor. First-line therapy is with DAs. Surgery is generally reserved for patients who do not respond to medical therapy, with severe pituitary hemorrhage, are pregnant with progressive tumor enlargement or are not responding to DA therapy.

Treatment aims to normalize PRL levels, restore fertility in those of child-bearing age, decrease tumor mass, save or improve the residual pituitary function, and inhibit disease relapse. Dopamine agonists available in the United States (US) are bromocriptine and cabergoline.

Cabergoline is usually better tolerated (less headache, nausea, postural hypotension, and fatigue) and offers the convenience of twice-a-week administration; starting dose is usually 0.25 mg up to a maximum dose of 1 mg. Cabergoline appears to be more effective in lowering PRL levels within the first 2–3 weeks of treatment in about 90 % of patients and in restoring ovulation. The drug usually decreases the size of micro- and macroadenomas (several weeks to months to observe detectable decreases). In cases whereby the adenoma affects vision, improvement may be observed within days of starting treatment. If tumor response to drug is therapeutically good, medical therapy can be withdrawn after 3–5 years. Hyperprolactinemia will not recur in two-thirds of these patients.

The best treatment to restore fertility in women with a microadenoma is a DA. Cabergoline is less used in women attempting conception or in pregnancy. Bromocriptine does not appear to increase the risk of miscarriage or birth defects when discontinued early in pregnancy. Before attempting pregnancy, a detailed discussion with patients should include when to discontinue bromocriptine, the chances that the adenoma will grow during pregnancy and further treatment details as necessary. Microadenomas rarely increase in size during pregnancy. On the other hand, if the adenoma is large or is affecting vision, surgery is usually recommended before attempting to conceive.

Acromegaly

Treatment of GH-secreting adenomas should include a comprehensive treatment strategy to alleviate pituitary tumor effects, normalize GH and insulin-like growth factor-1 (IGF-1) hypersecretion, improve associated comorbidities, and reverse the increase in mortality risk, all while preserving normal pituitary function. Surgery is the first-line treatment choice for acromegaly patients, with two caveats, an experienced surgeon is available and tumor is visible on MR imaging. If the tumor has invaded the cavernous sinus, or has been determined to be not completely resectable, medical therapy can be also offered as first-line treatment in addition to surgery. The treatment of patients with persistently active acromegaly has been facilitated over the past decade by the advent of highly specific and selective pharmacological agents that are sometimes used in combination. Radiation therapy is a potential adjuvant therapy, usually reserved for patients who have some remaining tumor postsurgery. These patients often concomitantly take medications to lower GH levels as there is usually a long waiting period before radiation is effective. Decrease in pituitary function (hypopituitarism) is a significant complication. Radiotherapy remains a third-line treatment option for acromegaly in the US.

Three classes of medical therapy are available to treat acromegaly, each with unique advantages and disadvantages. In patients with uncontrolled hormone levels after surgery, SSAs are the first-line treatment choice. Dopamine agonists and GH receptor antagonists are generally indicated after failure of SSAs or in combination with SSAs (Fig. 1.1).

Somatostatin Analogues

There are three SSAs approved for use in the US: octreotide short release, octreotide long acting release (LAR) or Sandostatin LAR, and lanreotide ATG (Somatuline depot). It is difficult to appreciate the true efficacy of SSAs in achieving biochemical control due to varied clinical trial study entry criteria and “desirable” cut-off goals. Although early on a study data meta-analysis showed that overall GH and IGF-1 were normalized in 49–56 % and 48–66 % of patients, respectively. Other study results suggest symptom control in a large majority, with biochemical control only being achieved in approximately half of patients if “unselected” for responsiveness. Somatostatin analogues are generally safe and well tolerated. The most frequent adverse events of SSA treatment are abdominal symptoms, which usually improve over time glucose intolerance and gallbladder sludge/stones. The distinctions between different types of GH-secreting tumors (sparsely vs. densely granulated tumors), and presence of somatostatin receptor type 2a (SSTR2a) can impact response to therapy as well as prognosis; therefore, accurate classification is important.

It has been suggested that SSA treatment prior to surgery can reduce surgical risks and potentially improve surgical cure rates. Conversely, tumor debulking is often used with SSA therapy when GH is partially but not completely controlled with treatment. In these cases, debulking the tumor may allow SSA therapy to reduce GH and IGF-1 into the normal age-adjusted range.

A number of studies have reported tumor shrinkage in patients with acromegaly treated with SSA therapy, both adjunctive and primary. This shrinkage can be significant (20–80 % in about one-third of patients), however results are unpredictable.

Dopamine Agonists

Dopamine agonists inhibit GH secretion in some acromegaly patients. The beneficial effects could occur even when pretreatment PRL levels are normal and/or there is no evidence of tumor PRL staining. A lower IGF-1 level at the start of treatment seems overall to be the best predictor of efficacy. Cabergoline is administered orally and is thus more convenient, although not as effective as other medical therapies.

Growth Hormone Receptor Antagonists

The GH receptor antagonist, pegvisomant, (Somavert) directly inhibits the peripheral action of GH by interfering with functional dimerization of the two GH receptors subunits and thus blocks the signal for IGF-1 production. In early clinical trials, normalized IGF-1 levels were observed in approximately 90 % of patients, however, data from large observational studies has revealed a much lower IGF-1 normalization rate (70 % of patients), most probably due to inadequate dosage. Pegvisomant adverse events include disturbed liver function tests and injection site reactions. Tumor growth has not been proven to be a concern, but continued long-term surveillance of tumor volume is needed, especially in nonirradiated patients. It is recommended that pegvisomant be reserved for SSA nonresponders or patients intolerant of SSAs, patients whose diabetes is worsened by SSAs or considered in combination therapy.

For acromegaly patients who are poorly or non-responsive to, presently available single drug therapies, the use of combination drug therapy holds promise. However, currently the use of combination therapy is not approved by the Federal Drug Administration (FDA) in the US.

Monitoring Therapy

General consensus is to lower the IGF-1 levels to within the reference range for the patient’s age and gender and to lower the random serum GH levels to <1 ng/mL or <0.4 ng/mL (depending on the assay) after a glucose load (oral glucose tolerance test; OGTT). Pegvisomant is unique in that the drug does not lower GH levels (levels are raised, due to feed-back mechanics), thus making IGF-1 the only available marker for disease activity.

It is recommended that all patients undergo biochemical testing and pituitary MR imaging during long-term follow-up, irrespective of medical treatment.

Drugs in Clinical Trial

The role of SSTRs and dopamine receptors (DR) as molecular targets for the treatment of pituitary adenomas is well established.

Pasireotide (SOM 230; Signifor) is a unique somatotropin release-inhibiting factor with a high binding affinity to SSTR subtypes 1, 2, 3, and 5 and up to a 40-fold greater affinity for SSTR5 than octreotide. Phase III clinical trials results show that subjects treated with pasireotide LAR were significantly more likely to achieve disease control than those treated with octreotide LAR. Also, approximately 20 % of subjects uncontrolled on octreotide achieved full disease control after switching to pasireotide LAR. However, a higher degree and frequency of hyperglycemia has been observed and reported with pasireotide use. The long-term and future role of pasireotide in treating acromegaly remains to be determined.

Alternate drug delivery systems are an exciting and developing area of research. Octreolin, an investigational oral form of octreotide, is currently being studied in a pivotal phase III clinical trial to determine efficacy and safety in acromegaly patients who are currently receiving parenteral SSAs.

Cushing’s Disease

Cushing’s disease (CD) is defined as hypercortisolism caused by an ACTH-secreting pituitary adenoma. While rare, the disease is associated with significant morbidity and mortality.

Treatment goals include the reversal of clinical features, normalization of cortisol levels, minimal morbidity, preservation of pituitary function, and long-term disease control without recurrence. In patients with macroadenomas, removal of the tumor mass is an additional treatment goal.

For most CD patients, primary treatment is transsphenoidal surgery to remove the pituitary adenoma. However, success rates are variable (reportedly, 65–90 % dependent on the surgeon’s expertise) and recurrence rates are observed in more than 25 % of patients during long-term follow-up. Second-line therapy includes more radical surgery, radiation therapy (stereotactic radiosurgery), medical therapy, and lastly bilateral adrenalectomy.

While there are several potential CD therapeutic targets, clinical experience is lacking. Recently, however, prospective studies have demonstrated the potential of pituitary-directed medical interventions that target the underlying adenoma and block GRs. Medical therapies for CD patients are summarized below (Fig. 1.2).

Fig. 1.2
figure 2

Potential targets and medical therapies in Cushing’s disease. Reprinted from Neurosurg Clin N Am volume 23(4);653–668, Fleseriu, M., Medical management of persistent and recurrent cushing disease, page 657, Copyright (2012), with permission from Elsevier

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Pituitary-Targeted Therapy

Corticotroph adenomas frequently express both dopamine (D2) and somatostatin receptors (predominantly SSTR5). Pituitary-targeted therapies may provide both antisecretory and an antiproliferative treatment results. Research into patterns of receptor expression in corticotroph adenomas may lead to increased understanding of tumor pathogenesis, and allow development of therapies specifically tailored to individual patients following surgical pathology analysis.

Somatostatin Analog: Pasireotide (Signifor)

Following promising results in a 15-day phase II clinical trial, a randomized, double-blind phase III trial of pasireotide was undertaken in adult subjects with de novo, persistent, or recurrent CD. Eligible subjects (n = 162) were randomized to receive 600 or 900 mcg of pasireotide twice daily: the majority of subjects had declines in urine free cortisol (UFC) levels at 6 months and 15 % and 26 % of subjects in the 600 mcg and 900 mcg groups, respectively, had normal UFC levels within the normal range without dose increases. Median percentage changes in UFC levels from baseline to 6 months in both groups were −47.9 %. Moreover, subjects who responded to treatment could generally be identified within the first 2 months of treatment. In those subjects with observable tumor on MR images, tumor volume changed by an average of −9.1 % and −43.8 % in the 600 mcg and 900 mcg groups, respectively. There were also significant improvements in the signs and symptoms hypercortisolism, reductions in systolic and diastolic blood pressure, triglycerides, low-density lipoprotein cholesterol, body weight, and health-related quality of life.

The safety and adverse event profiles of pasireotide in the phase III trial were similar to those observed with other SSAs with the exception of the degree and severity of hyperglycemia-related events. Nearly three quarters of the study subjects had hyperglycemia-related adverse events, and nearly half of those subjects who did not have diabetes at baseline developed diabetes. A published proposal for management of hyperglycemia in patients with CD treated with pasireotide recommends metformin as first-line medical treatment for CD patients who develop new or worsening hyperglycemia with pasireotide, with an adjunctive dipeptidyl peptidase 4 (DPP-4) inhibitor, sulfonylurea/glinide, and/or glucagon-like peptide-1 (GLP-1) analog, as required, to achieve glycemic control.

Pasireotide was recently approved in the US and Europe for the treatment of adult CD patients for whom pituitary surgery is not an option or who have failed surgery.

Dopamine Agonists

Like SSTRs, DRs are widely expressed in normal neuroendocrine tissues and pituitary adenomas, including approximately 80 % of corticotroph adenomas. In a single-center study of ten subjects treated with cabergoline (1–3 mg/week for 3 months), a normalization rate of 40 % for UFC was observed. The long-term efficacy of cabergoline (up to 7 mg/week) in selected CD patients is about 30–40 %. The results of these small prospective and retrospective studies have shown promise for the use of cabergoline as medical therapy for CD, but no large-scale trials have been conducted.

Retinoic Acid

Retinoic acid has been shown to be potentially useful in decreasing corticotroph secretion and proliferation in animal models, and more recently, in a small open-label prospective study in humans. Recent animal models indicate that inhibiting epidermal growth factor receptor (EGFR) signaling may be also a valuable strategy for treating CD. Further studies evaluating clinical efficacy and safety in patients with CD are needed.

Adrenal-Targeted Therapeutics

Drugs inhibiting adrenocortical steroidogenesis include ketoconazole, mitotane, etomidate, and metyrapone. There is little prospective information on the long-term use of adrenal-targeted agents; however, small retrospective studies have revealed promising results. In general, use of adrenal targeted drugs requires careful clinical monitoring for adverse effects, including adrenal insufficiency (AI). Ketoconazole has been widely used to treat CD because it inhibits several steps in adrenal steroid synthesis and reduces UFC in the majority of patients. However, ketoconazole also inhibits androgen synthesis and is associated with liver toxicity in some patients. The availability of ketoconazole is also limited in many countries. Mitotane also inhibits several steps in steroidogenesis and at doses >4 g/day can be adrenolytic during long-term therapy. Mitotane is sequestered in adipose tissue and eliminated slowly, as such; pregnancy must be avoided for 5 years after discontinuation. Etomidate is the only adrenal steroidogenesis inhibitor compound available for intravenous administration, and as such is useful in situations where rapid control of hypercortisolism is required, or oral therapy is contraindicated. LCI699, a potent inhibitor of 11-β-hydroxylase and 18-hydroxylase (aldosterone synthase) has shown promising results in a small proof of concept study in CD subjects; LCI 699 is currently under investigation in larger study. No adrenal steroidogenesis inhibitors are approved in the US for treatment of CS.

Glucocorticoid Receptor Blockers

Mifepristone (Korlym)

Mifepristone directly blocks the cortisol glucocorticoid receptor (GR-II) and the progesterone receptor (PR). There are >50 case reports detailing mifepristone use and the multi-center, open-label, 6-month SEISMIC study conducted in the USA, included 50 subjects (43 with CD) treated with daily mifepristone 300–1,200 mg (mean of 900 mg) over 6 months. Overall, 60 % of the 29 subjects with glucose intolerance or diabetes were defined as responders (a ≥25 % reduction in glucose on a standard OGGT as measured from baseline to 24 weeks. Of the 12 subjects taking insulin at baseline, seven cut their daily dose by ≥50 %. There was a statistically significant reduction in mean HbA1c, from 7.43 % to 6.29 %. Over half of the subjects experienced weight loss of ≥5 % when compared to baseline and 87 % of subjects experienced improvement in their individual clinical manifestations (as assessed by eight clinical parameters by a blinded data review board). Elevation in cortisol (up to sevenfold) and ACTH (up to twofold) was observed in all study subjects with CD, which returned to baseline after stopping drug. There were two cases of AI, and symptoms compatible with AI (e.g., weakness, nausea, fatigue, abdominal pain, emesis, and hypotension) were more frequent. Hypokalemia (as expected) was common but generally mild to moderate and associated with alkalosis and edema. All cases responded well to potassium replacement and spironolactone, albeit at high doses. An increase in endometrial thickness (due to antiprogestin effects) was observed in 38 % of the study’s female population including five cases of vaginal bleeding. Overall, for most subjects, mifepristone had an acceptable benefit–risk profile and long-term studies are currently in progress. Monitoring side effects of hypokalemia and hypertension, as well as early recognition of clinical AI, is essential. As there is no biochemical marker to follow (cortisol values are not reliable), treatment efficacy and the potential for AI must be assessed through changes in clinical signs and symptoms and metabolic improvements. Mifepristone was approved in 2012 approved in the USA for treatment of hyperglycemia associated with Cushing’s syndrome.

In conclusion, medical therapy for CD poses unique challenges for the patient and clinician alike. The biochemical control and tumor shrinkage results achieved in patients with prolactinomas and acromegaly have yet to be achieved in CD patients. Generally, patients with moderate to severe hypercortisolism require combination therapy to normalize cortisol production.

Thyroid Stimulation Hormone-Secreting Pituitary Adenomas

Thyroid stimulation hormone-secreting pituitary adenomas (TSH-omas) are a rare cause of thyrotoxicosis. First-line therapy for TSH-omas is surgery, although medical therapy with SSAs is on the increase and has been shown to be effective in reducing TSH secretion in >90 % of patients with resultant normalization of free T4 and free T3 levels and a return to a euthyroid state.

Summary

A substantial number of patients with pituitary adenomas require multimodal therapy; medical therapy, surgery, and rarely, pituitary radiation. The biologic make-up of pituitary adenomas varies considerably and as such any given patient with a pituitary adenoma requires lifelong regular monitoring for; hormone secretion, tumor recurrence, and development of any new pituitary hormone deficiency. If biochemical control is not achieved or the therapy is not well tolerated, a switch to a different medication or a combination therapy should be considered. Cost: benefit ratio for each therapy and the overall burden of uncontrolled disease and complications should also be taken into account. The treating clinician must be prepared to think in terms of today’s therapy for patients, while maintaining an open view to the future. Guidelines for treatment of prolactinomas and acromegaly are available and provide insight.

Two cases of acromegaly and Cushing’s follow. These cases are intended to emphasize and demonstrate that more than choosing the right diagnosis, the importance of selecting the right treatment is paramount. Above is a succinct review of medical therapy for secretory pituitary adenomas; while not comprehensive the suggested readings are intended to supplement the text.