Hyperprolactinemia differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Overview

Hyperprolactinemia must be differentiated from other diseases that cause virilization and hirsutism in female. The differentials include 21-hydroxylase deficiency, 17-alpha hydroxylase deficiency, 11-β hydroxylase deficiency, 3 beta-hydroxysteroid dehydrogenase deficiency, polycystic ovarian syndrome, adrenal tumors, ovarian virilizing tumors and cushing's syndrome.

Differential Diagnosis

Hyperprolactinemia must be differentiated from diseases that cause virilization and hirsutism in female:

Disease name	Steroid status	Other laboratory	Important clinical findings
Non-classic type of 21-hydroxylase deficiency	Increased: 17-hydroxyprogesterone Exaggerated Androstenedione, DHEA, and 17-hydroxyprogesterone in response to ACTH	Low testosterone levels	No symptoms in infancy and male Virilization in females
11-β hydroxylase deficiency	Increased: DOC 11-Deoxy-Cortisol Decreased: Cortisol Corticosterone Aldosterone	Low testosterone levels	Hypertension and hypokalemia Virilization
3 beta-hydroxysteroid dehydrogenase deficiency	Increased: DHEA 17-hydroxypregnenolone Pregnenolone Decreased: Cortisol Aldosterone	Low testosterone levels	Salt-wasting adrenal crisis in infancy Mild virilization of genetically female infants Undervirilization of genetically male infants, making it the only form of CAH which can cause ambiguous genitalia in both genetic sexes.
Polycystic ovary syndrome	High DHEAS and androstenedione levels	Low testosterone levels	Polycystic ovaries in sonography Obesity PCOS is the most common cause of hirsutism in women No evidence another diagnosis
Adrenal tumors	Variable levels depends on tumor type	Low testosterone level	Older age Rapidly progressive symptoms
Ovarian virilizing tumor	Variable levels depends on tumor type	Testosterone is high	Older age Rapidly progressive symptoms
Cushing's syndrome	Increase cortisol & metabolites Variable other steroids	Variable mineralocorticoid excess	Cushingoid appearance
Hyperprolactinemia	Normal levels of most of steroids	Increased prolactin	Infertility, galactorrhea

Hyperprolactinemia must be differentiated from other causes of irregular menses and hirsutism.

Disease	Differentiating Features
Pregnancy	Pregnancy always should be excluded in a patient with a history of amenorrhea Features include amenorrhea or oligomenorrhea, abnormal uterine bleeding, nausea/vomiting, cravings, weight gain (although not in the early stages and not if vomiting), polyuria, abdominal cramps and constipation, fatigue, dizziness/lightheadedness, and increased pigmentation (moles, nipples) Uterine enlargement is detectable on abdominal examination at approximately 14 weeks of gestation Ectopic pregnancy may cause oligomenorrhea, amenorrhea, or abnormal uterine bleeding with abdominal pain and sometimes subtle or absent physical symptoms and signs of pregnancy
Hypothalamic amenorrhea	Diagnosis of exclusion Seen in athletes, people on crash diets, patients with significant systemic illness, and those experiencing undue stress or anxiety Predisposing features are as follows weight loss, particularly if features of anorexia nervosa are present or the BMI is <19 kg/m2 Recent administration of depot medroxyprogesterone, which may suppress ovarian activity for 6 months to a year Use of dopamine agonists (eg, antidepressants) and major tranquilizers Hyperthyroidism In patients with weight loss related to anorexia nervosa, fine hair growth (lanugo) may occur all over the body, but it differs from hirsutism in its fineness and wide distribution
Primary amenorrhea	Causes include reproductive system abnormalities, chromosomal abnormalities, or delayed puberty If secondary sexual characteristics are present, an anatomic abnormality (eg, imperforate hymen, which is rare) should be considered If secondary sexual characteristics are absent, a chromosomal abnormality (eg, Turner syndrome ) or delayed puberty should be considered
Cushing syndrome	Cushing syndrome is due to excessive glucocorticoid secretion from the adrenal glands, either primarily or secondary to stimulation from pituitary or ectopic hormones; can also be caused by exogenous steroid use Features include hypertension, weight gain (central distribution), acne, and abdominal striae Patients have low plasma sodium levels and elevated plasma cortisol levels on dexamethasone suppression testing
Hyperprolactinemia	Mild hyperprolactinemia may occur as part of PCOS-related hormonal dysfunction Other causes include stress, lactation, and use of dopamine antagonists A prolactinoma of the pituitary gland is an uncommon cause and should be suspected if prolactin levels are very high (>200 ng/mL) Physical examination findings are usually normal As in patients with PCOS, hyperprolactinemia may be associated with mild galactorrhea and oligomenorrhea or amenorrhea; however, galactorrhea also can occur with nipple stimulation and/or stress when prolactin levels are within normal ranges A large prolactinoma may cause headaches and visual field disturbance due to pressure on the optic chiasm, classically a gradually increasing bi-temporal hemianopsia
Ovarian or adrenal tumor	Benign ovarian tumors and ovarian cancer are rare causes of excessive androgen secretion; adrenocortical tumors also can increase the production of sex hormones Abdominal swelling or mass, abdominal pain due to fluid leakage or torsion, dyspareunia, abdominal ascites, and features of metastatic disease may be present Features of androgenization include hirsutism, weight gain, oligomenorrhea or amenorrhea, acne, clitoral hypertrophy, deepening of the voice, and high serum androgen (eg, testosterone, other androgens) levels In patients with an androgen-secreting tumor, serum testosterone is not suppressed by dexamethasone
Congenital adrenal hyperplasia	Congenital adrenal hyperplasia is a rare genetic condition resulting from 21-hydroxylase deficiency The late-onset form presents at or around menarche Patients have features of androgenization and subfertility Affects approximately 1% of hirsute patients More common in Ashkenazi Jews (19%), inhabitants of the former Yugoslavia (12%), and Italians (6%) Associated with high levels of 17-hydroxyprogesterone A short adrenocorticotropic hormone stimulation test with measurement of serum17-hydroxyprogesterone confirms the diagnosis Assays of a variety of androgenic hormones help define other rare adrenal enzyme deficiencies, which present similarly to 21-hydroxylase deficiency
Anabolic steroid abuse	Anabolic steroids are synthetic hormones that imitate the actions of testosterone by increasing muscle bulk and strength Should be considered if the patient is a serious sportswoman or bodybuilder Features include virilization (including acne and hirsutism), often increased muscle bulk in male pattern, oligomenorrhea or amenorrhea, clitoromegaly, gastritis, hepatic enlargement, alopecia, and aggression Altered liver function test results are seen
Hirsutism	Hirsutism is excessive facial and body hair, usually coarse and in a male pattern of distribution Approximately 10% of women report unwanted facial hair There is often a family history and typically some Mediterranean or Middle Eastern ancestry May also result from use of certain medications, both androgens, and others including danazol, glucocorticoids, cyclosporine, and phenytoin Menstrual history is normal When the cause is genetic, the excessive hair, especially on the face (upper lip), is present throughout adulthood, and there is no virilization When secondary to medications, the excessive hair is of new onset, and other features of virilization, such as acne and deepened voice, may be present