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Clinical Vignette
A 62-year-old man is referred for assistance in the management of hyperprolactinemia and diminished libido. Over the past 9 months, he has experienced a steady reduction in his libido, which has resulted in tension with his wife. He sought medical attention from his primary care physician who elicited an additional history of erectile dysfunction. His total testosterone concentration was documented to be 291 ng/dL (10.1 nmol/L) (reference range, 300-900 ng/dL [10.4-31.2 nmol/L]). A subsequent prolactin measurement was 91 ng/mL (4.0 nmol/L) (reference range, 4-23 ng/mL [0.17-1.00 nmol/L]), and he was thus referred for further evaluation.
His medical history is notable for 24 years of moderate to poorly controlled type 2 diabetes mellitus, complicated by chronic renal insufficiency with a creatinine concentration of 2.1 mg/dL (185.6 µmol/L) (reference range, 0.7-1.3 mg/dL [61.9-114.9 mmol/L]). He is currently treated with sitagliptin, 25 mg daily, and glyburide, 2.5 mg daily. His most recent hemoglobin A1c level was 8.3% (67 mmol/mol) (reference range, 4.7%-5.8% [28-40 mmol/mol]). He has hypertension, which is treated with lisinopril, 20 mg daily. In addition, he has a history of depression that has been treated for the past 18 months with bupropion, 100 mg 3 times daily. He has had no headaches or vision changes.
On physical examination, his height is 72 in (182.9 cm) and weight is 188 lb (85.5 kg) (body mass index = 25.5 kg/m2). His blood pressure is 140/86 mm Hg, and pulse rate is 94 beats/min. Findings on genitourinary examination are normal, and he has mild bilateral pedal edema. Visual fields are full to confrontation. There is no evidence of gynecomastia.
You order a repeated prolactin measurement, which returns at 90 ng/mL (3.9 nmol/L).
Which of the following represents the most likely cause of this patient’s hyperprolactinemia?
Hyperprolactinemia associated with hypogonadism and altered libido in men is a relatively uncommon but important pathologic condition. The prevalence of mild hyperprolactinemia in the healthy, asymptomatic population is estimated to be between 0.4% and 5.0%. Hyperprolactinemia may directly inhibit hypothalamic gonadotropin-releasing hormone secretion and result in hypogonadotropic hypogonadism. Similarly, prolactin may have direct action on the central nervous system, which can also reduce libido. Although the mechanism is unclear, prolactin levels may influence metabolism and contribute to insulin resistance. Thus, understanding the cause for hyperprolactinemia and determining an appropriate treatment strategy is essential.
The list of medications that can increase circulating prolactin levels is long. Hypothalamic release of dopamine is the primary tonic inhibitor of pituitary prolactin synthesis and secretion. Thus, medications that block dopamine action, particularly at the D2 receptor, cause hyperprolactinemia. First-generation antipsychotic agents such as chlorpromazine, fluphenazine, and haloperidol are well recognized in this regard. Antiemetics, including domperidone and metoclopramide, work via a similar manner. Some antidepressants can cause hyperprolactinemia (eg, amitriptyline and desipramine), although the mechanism by which they stimulate prolactin release is unknown. Other antidepressants such as bupropion and venlafaxine, as well as most medications in the selective serotonin reuptake inhibitor class, have no effect on prolactin secretion (thus, Answer E is incorrect). Of note, 2 older antihypertensive agents, a-methyldopa and verapamil, can increase prolactin levels. Finally, opioid analgesics have also been reported to cause hyperprolactinemia.
Neither sitagliptin (Answer D), a dipeptidyl-peptidase 4 inhibitor, nor lisinopril (Answer C), an angiotensin-converting enzyme inhibitor, affects prolactin levels.
Renal insufficiency, perhaps as a consequence of reduced prolactin clearance, is associated with mild hyperprolactinemia, with prolactin concentrations usually below 100 ng/mL (<4.3 nmol/L). Symptoms of hypogonadism with altered libido and galactorrhea on examination have been reported. Given that none of the patient’s medications are associated with hyperprolactinemia, chronic renal insufficiency (Answer B) is the most likely underlying cause.
A pituitary tumor as the etiology of the hyperprolactinemia is a possibility, but pituitary macroprolactinomas (tumors larger than 1 cm in diameter) are usually associated with prolactin levels greater than 200 ng/mL (>8.7 nmol/L). Pituitary macroadenomas that do not synthesize and secrete prolactin may still be associated with modest hyperprolactinemia due to mass effect on the pituitary stalk and inhibition of the delivery of hypothalamic dopamine to the lactotrophs. Moreover, this patient has no signs or symptoms of mass effect (thus, Answer A is incorrect). Notably, headaches can occur even in patients with small pituitary prolactinomas for reasons that are not well understood. However, headaches were not part of this patient’s symptoms.
Educational Objective: Perform the differential diagnosis of hyperprolactinemia.
Historical Context Dr. Oscar Riddle, Endocrine Society President 1928-1929
Dr. Oscar Riddle (Endocrine Society President, 1928-1929) was born September 27, 1877, in Indiana. He lived a rural childhood, working on the family farm. His father died when Riddle was 5 years old, forcing him and his 8 siblings to work, sometimes on neighboring farms, to support the family finances. In 1896, he enrolled at Indiana University. Later, under the mentorship of Dr. Charles Whitman at the University of Chicago, Riddle completed his PhD in zoology in 1907 and subsequently remained there on faculty. Thereafter, he took an appointment at Cold Spring Harbor as a member of the Carnegie Institution’s Station for Experimental Evolution.
Dr. Riddle, long known for his keen interest in development and an early believer in the field of endocrinology, is best known for his work in the isolation and characterization of prolactin, which he reported in 1932. He, along with coworkers, identified the protein and discovered that production of crop milk in pigeons was induced by prolactin. He developed a bioassay for prolactin by measuring growth of the pigeon crop.
At the time of Dr. Riddle’s presidency, the United States was entering the Great Depression. The Society was still in its infancy, organized under the name the Association for the Study of Internal Secretions. The annual meeting of 1929 included scientific presentations totaling only 12 papers. Membership dues at the time were $8.00 (equal to $88.43 in 2015 dollars) and the circulation size for Endocrinology was 1520.
Dr. Riddle was recognized by numerous societies and organizations: the American Philosophical Society (1926), the American Academy of Arts and Sciences (1934), and the National Academy of Sciences (1939). Many European and South American societies awarded him foreign membership. He was further honored with his image on the cover of Time (January 9, 1939 edition).
Dr. Riddle married Leona Lewis in 1937 (at the age of 60). They had no children but were well known for being gracious hosts and deeply touched the lives of many coworkers and friends. He remained in excellent health until age 87 when he developed coronary artery disease and subsequently prostate cancer. He died at age 91, followed shortly thereafter by his wife.
References: Corner GW. Oscar Riddle, 1877-1968. A Biographical Memoir. Washington, DC: National Academy of Sciences; 1974.
Huang W, Molitch ME. Evaluation and management of galactorrhea. Am Fam Physician. 2012;85(11):1073-1080.
Bolyakov A, Paduch DA. Prolactin in men’s health and disease. Curr Opin Urol. 2011;21(6):527-534.
Bates RW, Lahr EL, Riddle O. On the protein nature of prolactin and of follicle-stimulating hormones. Proc Soc Exp Biol Med, 1934;31:1223-1224.
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