Plurihormonal pituitary adenoma cosecreting ACTH and GH: a rare cause of Cushing’s disease

Abstract

Plurihormonal pituitary adenomas are rare forms of pituitary adenomas that express more than one hormone. The most common association is with growth hormone (GH) and prolactin. Cosecretion of GH and adrenocorticotrophic hormone (ACTH) is rare with only 25 reported cases in literature. Most presented with features of GH excess, and only four presented with Cushing’s disease. We report a case of a woman in her 30s with recurrent plurihormonal pituitary macroadenoma cosecreting GH and ACTH, diagnosed during workup for polycystic ovarian syndrome, and both times presenting uniquely with Cushing’s disease. Biochemical testing showed GH excess and hypercortisolism. She underwent transsphenoidal surgery twice and immunohistochemistry showed positive staining for GH and ACTH on both occasions. We aim to raise more awareness of this rare type of pituitary adenoma, shed light on the importance of recognising rare presentations and highlight the necessity of rigorous follow-up given morbidity and potentially higher mortality risk.

Background

Plurihormonal pituitary adenomas (PHAs) are rare entities, comprising 10% of functional pituitary adenomas (PAs). They may be monomorphous; where different hormones are expressed from a single morphological cell type, or plurimorphous; where hormones are expressed by morphologically different cells. The most common association is with growth hormone (GH) and prolactin (PRL).¹ So far in the literature, only 25 cases reported cosecretion of GH and adrenocorticotrophic hormone (ACTH).^1–5 The predominant presentation was related to GH excess, and only four presented with Cushing’s disease (CD). PHAs are known to be more recurrent especially ones cosecreting ACTH.⁶ We report a case of a woman in her 30s with recurrent plurihormonal pituitary macroadenoma cosecreting GH and ACTH, diagnosed during workup for polycystic ovarian syndrome (PCOS) and presenting both times with CD. We aim to shed light on the importance of recognising rare types of PAs.

Case presentation

We here report a case of a woman in her 30s with a PHA. She was not taking medication, and denied history of smoking, drug use and alcohol consumption. There was no family history of endocrinopathies or malignancies. Our patient initially presented to an outside facility at age 16 with weight gain, hirsutism, acne and irregular menstruation. Her symptoms were initially believed to be solely attributed to PCOS, but over the following 3 years, her family noticed decreased memory, change in school performance, low energy and insomnia. She had moon facies, supraclavicular fat pad, hirsutism and acanthosis. A 24-hour urine cortisol level was elevated (544 nmol/day; normal 50–220). Dexamethasone suppression test (DST) demonstrated inadequate cortisol suppression to low-dose (1 mg) but adequate suppression to high-dose (8 mg) dexamethasone. ACTH showed no suppression (15 pmol/L; normal 0–18). PRL (3 μg/L; normal 2–18) and GH (1.19 μg/L; normal<10.0) levels were normal. No IGF-1 was measured at the time. A 1.4 cm right-sided pituitary macroadenoma with left deviation of pituitary stalk and minimal cavernous sinus invasion was seen on MRI sella. Bone densitometry revealed low bone density for her age. She underwent transsphenoidal surgery (TSS) for selective removal of the macroadenoma and preservation of the remaining gland. Pathology showed a PA staining positive for ACTH, and focal positive staining for GH, PRL and alpha subunit, but negative for thyroid-stimulating hormone (TSH), follicular-stimulating hormone (FSH) and luteinising hormone (LH). Postsurgery, she developed secondary adrenal insufficiency (AI) and required cortisone acetate replacement for 1 year. Her symptoms improved, weight reduced, bone density improved and 24-hour urine cortisol levels normalised.

The patient presented to our facility 9 years after initial surgery with progressive headache, weight gain, widening of the face, worsening acne and hirsutism, oily skin, anxiety, change in mood ongoing for 18 months and irregular menstruation. Examination demonstrated new hypertension requiring antihypertensive agents, moon facies, supraclavicular fat pad, hirsutism, acne, thin but oily skin and weight gain. There were no striae, no enlarged extremities, and visual fields were intact. She was suspected to have recurrence of CD.

Investigations

A 24-hour urine cortisol (346 nmol/day; normal 8–120) and late-night salivary cortisol (13 nmol/L; normal 0–7) were both elevated, and ACTH was inappropriately normal (9.5 pmol/L; normal 1.6–13.9). DST demonstrated no cortisol suppression with low dose (1 mg) dexamethasone but adequate suppression with high-dose dexamethasone (8 mg) (cortisol 31 nmol/L). IGF-1 level was elevated (52 nmol/L; normal 13.3–42.9). Given currently elevated IGF-1 and history of positive GH staining adenoma at the previous surgery, no oral glucose tolerance test was done. The remaining pituitary hormone levels were normal. MRI sella revealed a 0.89×0.77 mm left-sided recurrent pituitary lesion and a 0.43×0.38 mm stable right-sided residual pituitary tumour. Bone densitometry showed low bone density for her age. Transthoracic echocardiography showed no ventricular hypertrophy and normal valves. She was diagnosed with CD and acromegaly secondary to recurrent functional PA and underwent repeat TSS. Pathology of the left-sided lesion showed a PHA staining positive for ACTH and GH on immunohistochemistry. Two subpopulations of cells were identified within the adenoma, one staining positive for ACTH and another for GH. There was negative staining for PRL, TSH, FSH, LH. Stains were positive for T-PIT and PIT-1 (figure 1). CK8/18 was positive in both clusters of cells and the proliferation index was 1%–2%.

Figure 1.

Pituitary adenoma staining positive for the transcription factors PIT-1 (A) which regulates GH, and T-PIT (B) which regulates ACTH.

Treatment

There was no improvement on trial of cabergoline (0.5 mg two times per week then 1 mg two times per week) and ketoconazole (100 mg two times per week) so repeat TSS was done with removal of both pituitary lesions.

Outcome and follow-up

Postsurgery, she developed secondary AI (random cortisol 40 nmol/L, normal 120–535) requiring replacement with hydrocortisone for 5 months. Her headaches resolved, mood slowly improved, weight reduced, hirsutism and acne resolved, and skin became less oily. She continued to have irregular menstruation; likely attributed to known underlying PCOS. IGF-1 and 24-hour urine cortisol levels normalised; 13.8 nmol/L and 87 nmol/day, respectively. Repeat MRI sella showed expected postsurgery changes and stable soft tissue in the right cavernous sinus. She remains stable and continues to have active follow-up 5 years after the second surgery.

Discussion

PAs are tumours arising from the anterior pituitary gland and are usually benign. They can be divided based on size into microadenomas; less than 1 cm in size or macroadenomas; larger than 1 cm. Based on functionality, PA may be functional if producing pituitary hormones or non-functional. PHAs have the ability to express more than one hormone.⁶ They comprise 10% of all pituitary tumours and 31% of PAs. Progenitor cells in the pituitary can differentiate to three cellular lineages that produce FSH and LH; pro-opiomelanocortin a precursor for ACTH; or GH, PRL and TSH. Each group of hormones is regulated by different transcription factors; GATA-2 and STF-1 regulate FSH and LH, T-PIT a T-box transcription factor that regulates ACTH, and PIT-1 regulates GH, PRL, and TSH.¹ Histologically, PHAs can be classified into monomorphous PHAs if hormones arise from a single morphological cell type, or plurimorphous if they arise from morphologically different cells. Most common associated hormones are GH and PRL. This is believed to be related to somatotroph and lactotroph cells originating from the same cell progenitor, and sharing the same regulating transcription factor PIT-1.² Cosecretion of GH and ACTH is considered rare with only 25 cases identified in literature. This uncommon form of PHAs can present quite variably, and features of GH excess is the most common presentation. ACTH expression is often clinically silent or causes subclinical changes. Occasionally, other hormones such as PRL may also be expressed. Of the 25 reported cases, 12 (48%) presented with acromegaly, 5 (20%) with both acromegaly and CD, 3 (12%) with pituitary apoplexy and 1 (4%) presented with mass effect. Only four cases reported presentation with CD (16%) (table 1). Our patient presenting with Cushing’s demonstrated an uncommon presentation of this rare entity. Diagnosis based solely on clinical findings and biochemistry may pose a challenge given the variability of hormone secretion, thus immunohistochemistry plays an important role in diagnosis. On immunohistochemistry staining, 16 of the reported patients (64%) had positive staining for only ACTH and GH, and 8 patients (32%) had additional positive staining for PRL but only 3 had elevated serum PRL levels. Immunohistochemistry of our patient’s initial PHA showed triple positive staining for GH, ACTH and PRL, but staining of the recurrent adenoma was positive for only GH and ACTH. PHAs have been associated with higher risk of recurrence; particularly those cosecreting ACTH as Pawlikowsyky demonstrated in 2020.⁶ Our patient demonstrates the aggressiveness of this rare entity with recurrence occurring less than 10 years from initial surgery despite documented postsurgical clinical and biochemical response. We demonstrated GH and ACTH excess biochemically and on immunohistochemistry during both presentations. Although our patient showed clinical and biochemical improvement after both surgeries, given the nature of this rare disease, one cannot rule out the possibility of future recurrence. Thus, the search for different management options is crucial. Pasireotide is a second-generation somatostatin analogue that is approved for treatment of acromegaly and shown to be effective in patients with persistent or recurrent CD after surgery. Its use in patients with PHA cosecreting GH and ACTH is limited so far, and response has been variable. Rajendran et al presented the first case of pasireotide use in a patient with persistent GH and ACTH secreting PHA. The response was partial and the patient developed poor glycaemic control.⁴ Recently, Fukunaga et al reported the use of pasireotide in a patient with recurrent GH and ACTH secreting PHA and showed good response.⁵ This brings up the possibility of using pasireotide in such cases but future studies are needed to assess its long-term effect in this specific population. Given the high recurrence rate and morbidity related to this rare type of PHAs, we emphasise the importance of maintaining close follow-up.

Table 1.

Summary of reported cases of plurihormonal pituitary adenomas cosecreting GH and ACTH*

Author/year	Age	Sex	Presenting feature	Biochemical tests (high)	Macro/microadenoma	Histology
Arita/1991	29	F	Acromegaly and CD	GH, IGF1, Cortisol	Macroadenoma	Diffuse GH, Focal ACTH
Blevins/1992	40	F	Acromegaly and CD	GH, UFC	Macroadenoma	Distinct groups of ACTH and GH cells
Bugalho/1993	62	M	CD	ACTH	Microadenoma	Distinct groups of ACTH and GH cells
Apel/1994	76	F	Acromegaly	GH, ACTH	Macroadenoma	Distinct groups of ACTH and GH cells
Matsuno/1996	27	M	Acromegaly	GH, ACTH, Cortisol, PRL	Macroadenoma	Positive staining for ACTH, GH, PRL, alpha subunit
Kovacs/1998	62	M	Acromegaly	GH, cortisol	Microadenoma	GH cells, minority of ACTH cells
Duskova/2000	75	F	Acromegaly	ⱡ	Macroadenoma	GH and ACTH cells, dispersed PRL, scattered cells positive for beta subunits of FSH, LH, TSH
Mazarakis/2001	53	M	Acromegaly	IGF-1	Macroadenoma	Diffuse ACTH cells, focal GH cells
Abe/2001	30	M	Pituitary apoplexy	GH, ACTH, cortisol	Macroadenoma	ACTH cells, minority of GH cells
	29	F	Pituitary apoplexy	ACTH	Microadenoma	ACTH cells, minority of GH cells
	59	F	Pituitary apoplexy	ACTH	Macroadenoma	Sparse ACTH and GH cells
Kageyama/2002	45	F	Acromegaly and CD	IGF-1, ACTH, Cortisol	Macroadenoma	Distinct groups of ACTH and GH cells
Tahara/2002	53	F	CD	ACTH, Cortisol	Microadenoma	Colocalisation of ACTH and GH in the same cell
Tsuchiya/2006	5	M	Acromegaly	GH, IGF-1, ACTH	Macroadenoma	Diffuse GH and PRL, focal ACTH
Oki/2009	36	F	Acromegaly	GH, IGF-1	ⱡ	Diffuse GH, Focal ACTH and TSH
Zada/2011	31	F	Acromegaly	ⱡ	ⱡ	ⱡ
Kanman/2012	52	M	Acromegaly	IGF-1, ACTH, Cortisol	Microadenoma	Rare GH positivity, PRL positivity, small ACTH islands
Rajendran/20134	62	M	Acromegaly	GH, IGF-1, PRL	Macroadenoma	Diffuse ACTH, Focal GH and PRL
Rasul/2014	61	F	Acromegaly	GH, IGF-1, Cortisol	ⱡ	Diffuse groups of ACTH and GH cells
	78	F	Acromegaly	GH, IGF-1, Cortisol	ⱡ	Acidophilic cells expressing GH, focal PRL, a single area expressing ACTH and GH
Takiguchi/2017	45	F	Acromegaly and CD	GH, IGF-1, ACTH	Macroadenoma	Acidophilic cells expressing GH, focal PRL, sparse cells expressing ACTH
Roca/20181	60	F	Acromegaly and CD	GH, IGF-1, ACTH, Cortisol	Microadenoma	Heterogenous cells positive for either GH or ACTH
Schwehr/20213	30	F	CD	Cortisol, UFC, IGF-1	Microadenoma	Positive for ACTH and synaptophysin
Allehaibi/20212	65	F	Mass effect	ACTH, UFC, PRL	Macroadenoma	Positive for ACTH, GH, PRL
Fukunaga/20215	21	F	CD	ACTH, UFC, GH, IGF-1	ⱡ	Diffuse ACTH
Present case	35	F	CD	Cortisol, UFC, IGF-1	Macroadenoma	Initial: Positive ACTH, focal GH, PRL, alpha subunit Recurrence: 2 subpopulations of cells, 1 positive for ACTH, 1 positive for GH

*Adapted (with updates) from ‘Plurihormonal ACTH-GH pituitary adenoma: Case report and systematic literature review’, by,¹ World Neurosurgery, 114, e158–e164.

ACTH, adrenocorticotrophic hormone; CD, Cushing’s disease; GH, growth hormone; IGF-1, insulin-like growth factor 1; PRL, Prolactin; UGC, urine free cortisol.

Learning points

• It is important to maintain a high index of suspicion to recognise uncommon presentations or rare entities such as GH and ACTH cosecreting plurihormonal pituitary adenomas (PHA).

• Biochemical testing and immunohistochemistry staining of tissue are highly valuable in detecting plurihormonal adenomas hormone secretion.

• Cosecretion of GH and ACTH is associated with high recurrence rate; thus, we emphasise the necessity of rigorous follow-up given morbidity and potentially higher mortality risk.

• Given high recurrence in GH and ACTH cosecreting PHA, we highlight the importance of the search for further treatment options including research into long-term effect of using pasireotide in this specific patient population.

Ethics statements

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