Hyperprolactinemia as a Rare Cause of Hypertension in Chronic Renal Failure

Abstract

Chronic renal failure (CRF) is associated with a high risk for hypertension. An individualized treatment should be initiated after the diagnosis of hypertension and underlying etiology. Many metabolic and endocrinal abnormalities are encountered in CRF. We present an 11-year-old boy with CRF developing galactorrhea and hyperprolactinemia associated with α-methyldopa, defective dopaminergic control, and resistance to multi-antihypertensive therapy. Cabergoline, a dopamine receptor agonist, was effectively used in the treatment of hypertension. It is important to remember that sometimes treatment of an illness becomes the cause of this illness.

• hyperprolactinemia
• hypertension
• α-methyldopa

INTRODUCTION

Chronic renal failure (CRF) is associated with a high risk for hypertension. The prevalence of systolic and diastolic hypertension is higher when compared with the general population. Fluid retention and left ventricular hypertrophy are the most common causes of hypertension in CRF. An individualized treatment should be initiated after the diagnosis of hypertension and underlying etiology.

Many metabolic and endocrinal abnormalities are encountered in CRF as a result of impairment in excretory functions. It is known that reduced glomerular filtration rate (GFR) and functional renal mass are associated with various degrees of elevation of peptide hormones due to changes in peripheral metabolism.

We present an 11-year-old boy with CRF developing galactorrhea and hyperprolactinemia associated with antihypertensive therapy.

CASE

An 11-year-old boy with CRF since 2.5 years of age, nephrolithiasis, and right nephrectomized due to unknown etiology, ongoing peritoneal dialysis for 5 years, was diagnosed with fungal peritonitis in a local center. He was referred to our hospital for not responding to antifungal therapy. His peritoneal fluid and blood cultures showed Candida parapsilosis. Multidrug antibiotic therapy was started, drainage of peritoneal abscess was performed, and hemodialysis was initiated. He was discharged after stabilization.

A month after discharge, hypertension (170/100 mmHg) and fluid load due to inadequate hemodialysis were detected during follow-up, and he was hospitalized. His biochemical parameters were as follows: blood urea nitrogen: 97 mg/dL, creatinine: 8.36 mg/dL, uric acid: 6.2 mg/dL, sodium: 135 mmol/L, potassium: 4.5 mmol/L, Ca: 10.5 mg/dL, P: 7.1 mg/dL, and albumin: 3.4 g/dL. Antihypertensive therapies including captopril (1.5 mg/kg/day), losartan (1.5 mg/kg/day), and methyldopa (25 mg/kg/day) were taken by the patient for a long time (about 3 years). Amlodipine (1.5 mg/kg/day) was added to the therapy because of his blood pressure being still around 150/90 mmHg after appropriate hemodialysis and adequate ultrafiltration. Methyldopa dose was elevated to 50 mg/kg/day but despite dose arrangement there was no improvement in blood pressure levels. Other etiological factors of hypertension including vascular, tumoral, and endocrine origins were suspected. Abdominal ultrasonography and computerized tomography were performed which showed no pathologies. Cardiac changes compatible with CRF were detected in echocardiography. Normal renin (1.5 ng/mL/h; normal = 0.51–2.64 ng/mL/h) and aldosterone (149 pg/mL; normal = 50–800) levels were found.

He developed galactorrhea on the fifth day of hospitalization. Physical examination revealed bilateral mammary tissue 1 cm in diameter with no gynecomastia. Serum prolactin (PRL) level was higher than the normal range (188.35 ng/mL; normal = 2.6–18.2 ng/mL). Other hormone levels of pituitary and thyroid glands were normal (free thyroxine (fT4): 1.31 ng/dL (normal = 0.7–1.48 ng/dL); thyroid-stimulating hormone (TSH): 1.27 μIU/mL (normal = 0.35–5.6 μIU/mL); luteinizing hormone (LH): 0.1 mIU/mL (normal = 2–12 mIU/mL); follicle-stimulating hormone (FSH): 0.1 mIU/mL (normal = 0.95–11.95 mIU/mL); β-human chorionic gonadotropin (β-HCG): 1.33 mIU/mL (normal = 0–2); alpha-fetoprotein (AFP): 0.59 IU/mL (normal = 0–4.15 IU/mL)). Serum epinephrine (106 pg/mL; normal = 0–60 pg/mL) and norepinephrine (2024 pg/mL; normal = 120–680 pg/mL) levels were elevated. Magnetic resonance imaging of the hypothalamic-pituitary axis performed for exclude hypothalamic pathologies was normal. Drug-induced hyperprolactinemia was suspected. Methyldopa, which is a known agent, that induce hyperprolactinemia was tapered and ceased. Propranolol (1.5 mg/kg/day) was added to the therapy due to levels of blood pressure still being around 150/90 mmHg. In addition, Cabergoline (0.5 mg twice a week), a dopamine receptor antagonist, was started to suppress elevated PRL levels and ongoing galactorrhea. During the second week of Cabergoline therapy, his blood pressure levels were in normal range; PRL level was 16.57 ng/mL (normal = 2.6–18.2 ng/mL), norepinephrine level was 229 pg/mL (normal = 120–680 pg/mL), and epinephrine was 21.2 pg/mL (normal = 0–60 pg/mL). Antihypertensive medication was replaced by amlodipine (0.5 mg/kg/day) and enalapril (0.25 mg/kg/day). During the follow-up, he did not have another hypertensive attack.

DISCUSSION

Hypertension is a common problem in the course of CRF. Hypertension may result from primary renal disease, sodium and water retention, and cardiovascular (left ventricular hypertrophy, etc.), tumoral, and endocrinal origins.

Our patient had high levels of blood pressure during admission and he was irresponsive to multi-antihypertensive therapy (captopril, losartan, amlodipine, propranolol, and α-methyldopa). Circulatory volume overload and cardiovascular and tumoral causes were excluded.

Galactorrhea developed during investigation. The serum PRL level of our patient was high. Human PRL is currently viewed as a hormone of pituitary gland origin, whose production is controlled by dopamine.¹ Pathological hyperprolactinemia occurs in conditions including intake of various drugs, compression of the pituitary stalk by other pathology, hypothyroidism, renal failure, cirrhosis, chest wall lesions, or idiopathic hyperprolactinemia.² Although the mechanism of hyperprolactinemia in uremia is not totally understood, it is may be related to reduced GFR and changes in peripheral metabolism.³ Uremic hyperprolactinemia may be related to vitamin D deficiency and anemia in CRF or it can be attributed to impairment in the hypothalamic pituitary regulator mechanism of PRL secretion.⁴ Hypothalamic pathologies and other hormonal causes were excluded in our patient by magnetic resonance imaging and hormonal investigation. Hyperprolactinemia in our patient cannot be attributed to uremic cause, because he had a long history of CRF but galactorrhea was a new onset sign. Hypertension of the patient became serious with the increase of the α-methyldopa dose.

PRL is mainly inhibited by dopamine. The inhibition of dopamine by various factors including drugs causes PRL levels to increase. α-Methyldopa causes moderate hyperprolactinemia, possibly by inhibiting the enzyme aromatic-l-amino-acid decarboxylase, which is responsible for converting l-dopa to dopamine, and by acting as a false neurotransmitter to decrease dopamine synthesis.⁵ Hyperprolactinemia due to α-methyldopa usage induces increase of serum dopamine level for inhibition of PRL secretion. l-Dopa and dopamine are not effective in suppressing PRL secretion in this condition.⁶ Increased PRL level may reflect elevated dopamine level. Dopamine is converted to epinephrine and norepinephrine. Elevated epinephrine and norepinephrine levels related to defective dopaminergic control result in hypertension. Hyperprolactinemia may be corrected by long-term treatment with dopaminergic agonists, and resolution of hyperprolactinemia contributes to lowering of blood pressure.⁷ Cabergoline, an agonist specific to the D2 dopamine receptor with a long half-life, has been considered superior to bromocriptine for the treatment of hyperprolactinemia and effective in many patients resistant to bromocriptine.⁸ α-Methyldopa was discontinued and Cabergoline was used to suppress our patient’s hyperprolactinemia. Resolution of hyperprolactinemia ended up with normalization of serum epinephrine and norepinephrine levels, and normotensive blood pressure that can be provided with a decrease in the number and dosage of medications.

Hypertension mechanism in children with CRF is not yet completely understood. In our case, hypertension related to CRF was treated with α-methyldopa, which induced hyperprolactinemia. Hyperprolactinemia ended up with defective dopaminergic control and resistance to multi-antihypertensive therapy. Cabergoline was effectively used in the treatment of hypertension. It is important to remember that sometimes treatment of an illness becomes the cause of this illness. We do not know yet that uremic hyperprolactinemia can be one of the causes of hypertension in CRF. Further investigations are needed in this area.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.