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How should you evaluate a toddler for speech delay?
USE A BRIEF SCREENING TOOL to assess children for speech and language delay at every preventive visit. If a delay in speech is identified, evaluate the child for potentially treatable causes, starting with a history and physical examination and a formal audiogram. Additional tests and referral to appropriate specialists may be indicated (strength of recommendation [SOR]: C, expert opinion).
Speech and language therapy improves phonological delays and vocabulary difficulties in young children (SOR: A, systematic review of randomized controlled trials [RCTs]). However, no studies have evaluated long-term outcomes or looked for adverse effects from speech and language screening or interventions.
Evidence summary
Although no studies identify the optimal age or frequency of screening,1 the American Academy of Pediatrics (AAP) recommends surveillance for developmental delays (including speech and language delay [SLD]) at every preventive visit and additional developmental screening at 9, 18, 24, and 30 months.2
No single standardized tool exists to screen for SLDs; no research compares the tools against each other or offers clear evidence of how sensitive they are.1 Commonly used brief screening tools include Ages and Stages Parent Questionnaire (ASQ) (1-66 months of age), Denver Developmental Screen II (1-66 months), Early Language Milestone Scale (1-36 months), Clinical Adaptive Test/ Clinical Linguistic and Auditory Milestone Scale (<24 months), Infant Developmental Inventory and Child Development Review (1-66 months), and the Fluharty Preschool Speech and Language Screening Tests (3-5 years).
When a child screens positive for speech and language delay
When an SLD is recognized, experts recommend a history and physical examination to evaluate for common causes (TABLE). A detailed history should focus on family, social, and environmental aspects affecting speech. A comprehensive physical examination should evaluate the child’s interaction with the examiner and family members, pronunciation of sounds and words, and include a careful examination of the face, external ears and tympanic membranes, nose, palate, teeth, tongue, and neck.3,4
Experts recommend full audiologic assessment and vision testing for all children with SLD and an electroencephalogram or chromosomal studies if appropriate. When no cause for the SLD is found, experts recommend consulting a speech pathologist. Consultation with an audiologist, psychologist, neurologist, occupational therapist, or social worker also may be helpful.1-4
TABLE
Common causes of speech and language delays
| Autism |
| Bilingualism |
| Cerebral palsy |
| Elective mutism |
| Expressive language disorder (developmental expressive aphasia) |
| Hearing loss |
| Maturation delay (developmental language delay) |
| Mental retardation |
| Psychosocial deprivation |
| Receptive aphasia |
| Source: Leung A, et al. Am Fam Physician. 1999.4 |
How effective are speech and language interventions?
A systematic review of 14 RCTs evaluated speech and language therapy interventions ranging from 3 to 6 months’ duration in pre-school children. Investigators reported significant improvements in speech and language outcomes, including articulation, phonation and syntax, and expressive and receptive language with the interventions. Individual studies were limited by small size, heterogeneity, and varied measures of short-term outcomes.1
A Cochrane meta-analysis of 25 RCTs (N=1539 children, of whom 986 were <5 years) found that speech and language therapy produced similar improvements for preschool and elementary school children. Therapy improved phonological delays significantly (standard mean difference [SMD]=0.44; 95% confidence interval [CI], 0.01-0.86), and vocabulary difficulties even more (SMD=0.89; 95% CI, 0.21-1.56). However, in this review, therapy didn’t significantly affect receptive speech difficulties (SMD=?0.04; 95% CI, ?0.64 to 0.56).
The analysis didn’t evaluate whether specific age groups would respond better to therapy.5 No studies evaluated long-term effectiveness or possible harms associated with screening or intervention.4
Recommendations
The AAP Council on Children with Disabilities, Section on Developmental Behavioral Pediatrics recommends general developmental surveillance at every well-child visit for children from birth through 3 years of age and more formal screening tests at the 9-, 18-, and 30-month visits. The AAP doesn’t recommend a specific screening test, however.2
The US Preventive Services Task Force found insufficient evidence that brief formal screening instruments accurately identify pre-school children who would benefit from further evaluation and intervention, but found fair evidence that interventions improve speech in the short term.6
1. Nelson HD, Nygren P, Walker M, et al. Screening for speech and language delay in preschool children: systematic evidence review for the US Preventive Services Task Force. Pediatrics. 2006;117:e298-e319.
2. Council on Children with Disabilities, Section on Developmental Behavioral Pediatrics; Bright Futures Steering Committee; Medical Home Initiatives for Children with Special Needs Project Advisory Committee. Identifying infants and young children with developmental disorders in the medical home: an algorithm for developmental surveillance and screening. Pediatrics. 2006;118:405-420.
3. Feldman HM. Evaluation and management of language and speech disorders in preschool children. Pediatr Rev. 2005;26:131-142.
4. Leung A, Kao CP. Evaluation and management of the child with speech delay. Am Fam Physician. 1999;59:3121-3128, 3135.
5. Law J, Garrett Z, Nye C. Speech and language therapy interventions for children with primary speech and language delay or disorder. Cochrane Database Syst Rev. 2003;(3):CD004110.-
6. US Preventive Services Task Force. Screening for speech and language delay in preschool children: recommendation statement. Pediatrics. 2006;117:497-501.
USE A BRIEF SCREENING TOOL to assess children for speech and language delay at every preventive visit. If a delay in speech is identified, evaluate the child for potentially treatable causes, starting with a history and physical examination and a formal audiogram. Additional tests and referral to appropriate specialists may be indicated (strength of recommendation [SOR]: C, expert opinion).
Speech and language therapy improves phonological delays and vocabulary difficulties in young children (SOR: A, systematic review of randomized controlled trials [RCTs]). However, no studies have evaluated long-term outcomes or looked for adverse effects from speech and language screening or interventions.
Evidence summary
Although no studies identify the optimal age or frequency of screening,1 the American Academy of Pediatrics (AAP) recommends surveillance for developmental delays (including speech and language delay [SLD]) at every preventive visit and additional developmental screening at 9, 18, 24, and 30 months.2
No single standardized tool exists to screen for SLDs; no research compares the tools against each other or offers clear evidence of how sensitive they are.1 Commonly used brief screening tools include Ages and Stages Parent Questionnaire (ASQ) (1-66 months of age), Denver Developmental Screen II (1-66 months), Early Language Milestone Scale (1-36 months), Clinical Adaptive Test/ Clinical Linguistic and Auditory Milestone Scale (<24 months), Infant Developmental Inventory and Child Development Review (1-66 months), and the Fluharty Preschool Speech and Language Screening Tests (3-5 years).
When a child screens positive for speech and language delay
When an SLD is recognized, experts recommend a history and physical examination to evaluate for common causes (TABLE). A detailed history should focus on family, social, and environmental aspects affecting speech. A comprehensive physical examination should evaluate the child’s interaction with the examiner and family members, pronunciation of sounds and words, and include a careful examination of the face, external ears and tympanic membranes, nose, palate, teeth, tongue, and neck.3,4
Experts recommend full audiologic assessment and vision testing for all children with SLD and an electroencephalogram or chromosomal studies if appropriate. When no cause for the SLD is found, experts recommend consulting a speech pathologist. Consultation with an audiologist, psychologist, neurologist, occupational therapist, or social worker also may be helpful.1-4
TABLE
Common causes of speech and language delays
| Autism |
| Bilingualism |
| Cerebral palsy |
| Elective mutism |
| Expressive language disorder (developmental expressive aphasia) |
| Hearing loss |
| Maturation delay (developmental language delay) |
| Mental retardation |
| Psychosocial deprivation |
| Receptive aphasia |
| Source: Leung A, et al. Am Fam Physician. 1999.4 |
How effective are speech and language interventions?
A systematic review of 14 RCTs evaluated speech and language therapy interventions ranging from 3 to 6 months’ duration in pre-school children. Investigators reported significant improvements in speech and language outcomes, including articulation, phonation and syntax, and expressive and receptive language with the interventions. Individual studies were limited by small size, heterogeneity, and varied measures of short-term outcomes.1
A Cochrane meta-analysis of 25 RCTs (N=1539 children, of whom 986 were <5 years) found that speech and language therapy produced similar improvements for preschool and elementary school children. Therapy improved phonological delays significantly (standard mean difference [SMD]=0.44; 95% confidence interval [CI], 0.01-0.86), and vocabulary difficulties even more (SMD=0.89; 95% CI, 0.21-1.56). However, in this review, therapy didn’t significantly affect receptive speech difficulties (SMD=?0.04; 95% CI, ?0.64 to 0.56).
The analysis didn’t evaluate whether specific age groups would respond better to therapy.5 No studies evaluated long-term effectiveness or possible harms associated with screening or intervention.4
Recommendations
The AAP Council on Children with Disabilities, Section on Developmental Behavioral Pediatrics recommends general developmental surveillance at every well-child visit for children from birth through 3 years of age and more formal screening tests at the 9-, 18-, and 30-month visits. The AAP doesn’t recommend a specific screening test, however.2
The US Preventive Services Task Force found insufficient evidence that brief formal screening instruments accurately identify pre-school children who would benefit from further evaluation and intervention, but found fair evidence that interventions improve speech in the short term.6
USE A BRIEF SCREENING TOOL to assess children for speech and language delay at every preventive visit. If a delay in speech is identified, evaluate the child for potentially treatable causes, starting with a history and physical examination and a formal audiogram. Additional tests and referral to appropriate specialists may be indicated (strength of recommendation [SOR]: C, expert opinion).
Speech and language therapy improves phonological delays and vocabulary difficulties in young children (SOR: A, systematic review of randomized controlled trials [RCTs]). However, no studies have evaluated long-term outcomes or looked for adverse effects from speech and language screening or interventions.
Evidence summary
Although no studies identify the optimal age or frequency of screening,1 the American Academy of Pediatrics (AAP) recommends surveillance for developmental delays (including speech and language delay [SLD]) at every preventive visit and additional developmental screening at 9, 18, 24, and 30 months.2
No single standardized tool exists to screen for SLDs; no research compares the tools against each other or offers clear evidence of how sensitive they are.1 Commonly used brief screening tools include Ages and Stages Parent Questionnaire (ASQ) (1-66 months of age), Denver Developmental Screen II (1-66 months), Early Language Milestone Scale (1-36 months), Clinical Adaptive Test/ Clinical Linguistic and Auditory Milestone Scale (<24 months), Infant Developmental Inventory and Child Development Review (1-66 months), and the Fluharty Preschool Speech and Language Screening Tests (3-5 years).
When a child screens positive for speech and language delay
When an SLD is recognized, experts recommend a history and physical examination to evaluate for common causes (TABLE). A detailed history should focus on family, social, and environmental aspects affecting speech. A comprehensive physical examination should evaluate the child’s interaction with the examiner and family members, pronunciation of sounds and words, and include a careful examination of the face, external ears and tympanic membranes, nose, palate, teeth, tongue, and neck.3,4
Experts recommend full audiologic assessment and vision testing for all children with SLD and an electroencephalogram or chromosomal studies if appropriate. When no cause for the SLD is found, experts recommend consulting a speech pathologist. Consultation with an audiologist, psychologist, neurologist, occupational therapist, or social worker also may be helpful.1-4
TABLE
Common causes of speech and language delays
| Autism |
| Bilingualism |
| Cerebral palsy |
| Elective mutism |
| Expressive language disorder (developmental expressive aphasia) |
| Hearing loss |
| Maturation delay (developmental language delay) |
| Mental retardation |
| Psychosocial deprivation |
| Receptive aphasia |
| Source: Leung A, et al. Am Fam Physician. 1999.4 |
How effective are speech and language interventions?
A systematic review of 14 RCTs evaluated speech and language therapy interventions ranging from 3 to 6 months’ duration in pre-school children. Investigators reported significant improvements in speech and language outcomes, including articulation, phonation and syntax, and expressive and receptive language with the interventions. Individual studies were limited by small size, heterogeneity, and varied measures of short-term outcomes.1
A Cochrane meta-analysis of 25 RCTs (N=1539 children, of whom 986 were <5 years) found that speech and language therapy produced similar improvements for preschool and elementary school children. Therapy improved phonological delays significantly (standard mean difference [SMD]=0.44; 95% confidence interval [CI], 0.01-0.86), and vocabulary difficulties even more (SMD=0.89; 95% CI, 0.21-1.56). However, in this review, therapy didn’t significantly affect receptive speech difficulties (SMD=?0.04; 95% CI, ?0.64 to 0.56).
The analysis didn’t evaluate whether specific age groups would respond better to therapy.5 No studies evaluated long-term effectiveness or possible harms associated with screening or intervention.4
Recommendations
The AAP Council on Children with Disabilities, Section on Developmental Behavioral Pediatrics recommends general developmental surveillance at every well-child visit for children from birth through 3 years of age and more formal screening tests at the 9-, 18-, and 30-month visits. The AAP doesn’t recommend a specific screening test, however.2
The US Preventive Services Task Force found insufficient evidence that brief formal screening instruments accurately identify pre-school children who would benefit from further evaluation and intervention, but found fair evidence that interventions improve speech in the short term.6
1. Nelson HD, Nygren P, Walker M, et al. Screening for speech and language delay in preschool children: systematic evidence review for the US Preventive Services Task Force. Pediatrics. 2006;117:e298-e319.
2. Council on Children with Disabilities, Section on Developmental Behavioral Pediatrics; Bright Futures Steering Committee; Medical Home Initiatives for Children with Special Needs Project Advisory Committee. Identifying infants and young children with developmental disorders in the medical home: an algorithm for developmental surveillance and screening. Pediatrics. 2006;118:405-420.
3. Feldman HM. Evaluation and management of language and speech disorders in preschool children. Pediatr Rev. 2005;26:131-142.
4. Leung A, Kao CP. Evaluation and management of the child with speech delay. Am Fam Physician. 1999;59:3121-3128, 3135.
5. Law J, Garrett Z, Nye C. Speech and language therapy interventions for children with primary speech and language delay or disorder. Cochrane Database Syst Rev. 2003;(3):CD004110.-
6. US Preventive Services Task Force. Screening for speech and language delay in preschool children: recommendation statement. Pediatrics. 2006;117:497-501.
1. Nelson HD, Nygren P, Walker M, et al. Screening for speech and language delay in preschool children: systematic evidence review for the US Preventive Services Task Force. Pediatrics. 2006;117:e298-e319.
2. Council on Children with Disabilities, Section on Developmental Behavioral Pediatrics; Bright Futures Steering Committee; Medical Home Initiatives for Children with Special Needs Project Advisory Committee. Identifying infants and young children with developmental disorders in the medical home: an algorithm for developmental surveillance and screening. Pediatrics. 2006;118:405-420.
3. Feldman HM. Evaluation and management of language and speech disorders in preschool children. Pediatr Rev. 2005;26:131-142.
4. Leung A, Kao CP. Evaluation and management of the child with speech delay. Am Fam Physician. 1999;59:3121-3128, 3135.
5. Law J, Garrett Z, Nye C. Speech and language therapy interventions for children with primary speech and language delay or disorder. Cochrane Database Syst Rev. 2003;(3):CD004110.-
6. US Preventive Services Task Force. Screening for speech and language delay in preschool children: recommendation statement. Pediatrics. 2006;117:497-501.
Evidence-based answers from the Family Physicians Inquiries Network
What is the recommended evaluation and treatment for elevated serum prolactin?
History and physical examination can distinguish among most physiologic, pharmacologic, or pathologic causes of an elevated serum prolactin level (SPL) (strength of recommendation [SOR]: C, expert opinion). Patients with unexplained elevations of serum prolactin or with a level above 200 ng/mL should undergo imaging of the sella turcica (SOR: C, expert opinion). Mildly elevated SPL due to physiologic causes may be managed expectantly (SOR: B, cohort studies) and pharmacologic elevations may be treated by discontinuing the causative medication (SOR: C, expert opinion). Elevated SPL due to pathologic causes requires both monitoring for complications and treatment of the underlying condition (SOR: C, expert opinion).
Dopamine agonists are effective for patients requiring drug treatment (SOR: B, systematic review of cohort studies), and cabergoline is more effective and better tolerated than bromocriptine (SOR: B, randomized controlled trial [RCT]). Surgery is reserved for symptomatic patients not controlled medically (SOR: C, expert opinion).
Patients with mildly elevated SPLs can be safely watched with testing and symptom monitoring
Allen Daugird, MD
University of North Carolina at Chapel Hill
Most elevated prolactin levels in my practice have been mild and often secondary to medication, though there are a host of causes, as listed in the TABLE. This Clinical Inquiry reassures us that patients with mildly elevated SPLs can be safely watched with serial testing and monitoring symptoms. Obtaining SPLs only on fasting specimens can help improve test accuracy. The feared risk of vision loss due to a macroadenoma seems to be quite small. Patients with significantly elevated SPLs with amenorrhea or infertility deserve referral to clinicians comfortable with using dopamine agonists because of the high rate of success with this treatment.
Evidence summary
An expert guideline recommends a history and physical examination to determine whether an elevated SPL is due to physiologic, pharmacologic, or pathologic causes (TABLE).1 The fasting morning SPL is least variable and correlates best with a disease state.1 Clinical correlation is necessary to reveal false positives (due to biologically inactive forms of prolactin) or false negatives (due to very high SPLs that exceed the ability of the assay). If an elevated SPL is suspected despite a normal laboratory report, retesting with serum diluted 1:100 can identify a false-negative value.2
A detailed drug history is important since drug-induced elevated SPL is common.1 Laboratory evaluation includes thyroid-stimulating hormone, blood urea nitrogen, and creatinine, as well as pregnancy testing when applicable. If no cause of elevated SPL is identified by initial clinical evaluation or if the SPL is greater than 200 ng/mL, experts recommend imaging of the sella turcica with computed tomography or magnetic resonance imaging.1
Physiologic causes. For patients with a mildly elevated SPL due to a physiologic cause, experts recommend expectant management. Patients should be monitored for symptoms of hypogonadism (amenorrhea, infertility, or sexual dysfunction) and have SPL measured at 6- to 12-month intervals.1 In cohort studies, treatment of the underlying cause of elevated SPL reverses secondary physiologic changes of low estrogen or testosterone, and hypogonadism.3-5
Pharmacologic causes. Eliminating a pharmacologic cause may lead to normalization of SPL, although experts recommend psychiatric consultation before discontinuing neuroleptic medications.1
Pathologic causes. Experts advise treating the underlying cause of a pathologic elevation of SPL. Patients with microadenoma should have SPLs monitored to prevent complications of decreased bone mineral density and sexual dysfunction due to persistently elevated SPL. Patients with a macroadenoma (>1 cm) are at risk for tumor growth and require serial imaging studies in addition to treatment of SPL, according to expert opinion.1-3
Medical therapy. Medical therapy with a dopamine agonist is indicated for patients with either symptoms of hypogonadism due to elevated SPL, or neurologic symptoms due to the size of a macroadenoma.1 In a review of 13 cohort studies, bromocriptine improved symptoms and reduced SPLs to normal for 229 of 280 women (82%).6 A cohort study of 27 patients with macroadenomas treated with bromocriptine found 10% to 50% reductions of tumor size.7 A randomized controlled trial treating 459 women having hyperprolactinemic amenorrhea with either cabergoline or bromocriptine achieved a stable normal SPL in 83% and 59%, respectively (P<.001). Adverse effects were common but were less common with cabergoline (68% vs 78%) and resulted in fewer discontinuations (3% vs 12%).8
Surgical therapy. Surgery is indicated for patients unresponsive to or intolerant of medical therapy, or who have visual field loss, cranial nerve palsy, or headache due to macroadenoma.1 A retrospective review of patients who underwent surgical resection found a 40% recurrence rate.9
Recommendations from others
Williams Textbook of Endocrinology includes the recommendations above and advises seeking consultation for patients with mass effects of macroadenomas such as visual field loss, cranial nerve palsy, or headaches; for patients with progressive elevation of SPL despite medical treatment; and for pregnant women.4 Conventional antipsychotic agents are commonly associated with elevated prolactin due to dopamine agonist activity. Some atypical antipsychotics may lead to lower levels of elevated prolactin, transient elevations or marked elevations.10 Experts recommend following serial SPLs, if antipsychotics are truly needed. Psychiatric consultation may assist in making decisions about medication selection. Patients with symptoms (galactorrhea, amenorrhea, headaches, visual disturbances, sexual dysfunction) or levels of 200 or more, should undergo an MRI or CT. Experts recommend monitoring levels every 1 to 3 months.1
TABLE
Physiologic, pharmacologic, and pathologic causes of an elevated serum prolactin level1
| PHYSIOLOGIC |
| Pregnancy |
| Ectopic pregnancy |
| Lactation |
| Nipple stimulation |
| Stress |
| Sleep disorder |
| PHARMACOLGIC |
| Dopamine receptor antagonists: phenothiazines, butyrophenones, thioxanthene, risperidone, metoclopramide, sulpiride, pimozide |
| Dopamine-depleting agents: α-methyldopa, reserpine |
| Hormones: estrogens, antiandrogens |
| Others: danazol, isoniazid, verapamil, cyproheptadine, opiates, H2-blockers (cimetidine), cocaine and marijuana, tricyclic antidepressants |
| PATHOLOGIC |
| Acromegaly |
| Alcoholic cirrhosis |
| Chest wall trauma or tumor |
| Herpes zoster |
| Hypothalamic and pituitary stalk disease |
| Hypothyroidism |
| Pituitary tumors: prolactinomas, adenomas |
| Polycystic ovarian syndrome |
| Renal failure |
| Sarcoidosis |
1. Biller BM, Luciano A, Crosignani PG, et al. Guidelines for the diagnosis and treatment of hyperprolactinemia. J Reprod Med 1999;44(12 Suppl):1075-1084.
2. Barkan AL, Chandler WF. Giant pituitary prolactinoma with falsely low serum prolactin: the pitfall of the “high hook effect”: Case report. Neurosurgery 1998;42:913-915.
3. Sanfilippo JS. Implications of not treating hyperprolactinemia. J Reprod Med 1999;44(12 Suppl):1111-1115.
4. Melmed S, Kleinberg D. Physiology and disorders of the pituitary hormone axes. In: Williams RH, Larsen PR. Williams Textbook of Endocrinology. 10th ed. Philadelphia, Pa: Saunders; 2003;200-212.
5. Schlechte J, Dolan K, Sherman B, Chapler F, Luciano A. The natural history of untreated hyperprolactinemia: a prospective analysis. J Clin Endocrinol Metab 1989;68:412-418
6. Vance ML, Evans WS, Thorner MO. Drugs five years later. Bromocriptine. Ann Intern Med 1984;100:78-91.
7. Molitch ME, Elton RL, Blackwell RE, Caldwell B, Chang RJ, Jaffe R, et al. Bromocriptine as primary therapy for prolactin-secreting macroadenomas: results of a prospective multicenter study. J Clin Endocrinol Metab 1985;60:698-705.
8. Webster J, Piscitelli G, Polli A, Ferrari C, Ismail I, Scanlon MF. A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. N Engl J Med 1994;331:904-909.
9. Abrahamson M, Snyder P. Treatment of hyperprolactin due to lactotroph adenomas and other causes. UpToDate [database]. Waltham, Mass: UpToDate; 2004.
10. Smith S. Effects of antipsychotics on sexual and endocrine function in women: implications in clinical practice. J Clin Psychopharmacol 2003;23(3 Suppl 1):S27-S32.
History and physical examination can distinguish among most physiologic, pharmacologic, or pathologic causes of an elevated serum prolactin level (SPL) (strength of recommendation [SOR]: C, expert opinion). Patients with unexplained elevations of serum prolactin or with a level above 200 ng/mL should undergo imaging of the sella turcica (SOR: C, expert opinion). Mildly elevated SPL due to physiologic causes may be managed expectantly (SOR: B, cohort studies) and pharmacologic elevations may be treated by discontinuing the causative medication (SOR: C, expert opinion). Elevated SPL due to pathologic causes requires both monitoring for complications and treatment of the underlying condition (SOR: C, expert opinion).
Dopamine agonists are effective for patients requiring drug treatment (SOR: B, systematic review of cohort studies), and cabergoline is more effective and better tolerated than bromocriptine (SOR: B, randomized controlled trial [RCT]). Surgery is reserved for symptomatic patients not controlled medically (SOR: C, expert opinion).
Patients with mildly elevated SPLs can be safely watched with testing and symptom monitoring
Allen Daugird, MD
University of North Carolina at Chapel Hill
Most elevated prolactin levels in my practice have been mild and often secondary to medication, though there are a host of causes, as listed in the TABLE. This Clinical Inquiry reassures us that patients with mildly elevated SPLs can be safely watched with serial testing and monitoring symptoms. Obtaining SPLs only on fasting specimens can help improve test accuracy. The feared risk of vision loss due to a macroadenoma seems to be quite small. Patients with significantly elevated SPLs with amenorrhea or infertility deserve referral to clinicians comfortable with using dopamine agonists because of the high rate of success with this treatment.
Evidence summary
An expert guideline recommends a history and physical examination to determine whether an elevated SPL is due to physiologic, pharmacologic, or pathologic causes (TABLE).1 The fasting morning SPL is least variable and correlates best with a disease state.1 Clinical correlation is necessary to reveal false positives (due to biologically inactive forms of prolactin) or false negatives (due to very high SPLs that exceed the ability of the assay). If an elevated SPL is suspected despite a normal laboratory report, retesting with serum diluted 1:100 can identify a false-negative value.2
A detailed drug history is important since drug-induced elevated SPL is common.1 Laboratory evaluation includes thyroid-stimulating hormone, blood urea nitrogen, and creatinine, as well as pregnancy testing when applicable. If no cause of elevated SPL is identified by initial clinical evaluation or if the SPL is greater than 200 ng/mL, experts recommend imaging of the sella turcica with computed tomography or magnetic resonance imaging.1
Physiologic causes. For patients with a mildly elevated SPL due to a physiologic cause, experts recommend expectant management. Patients should be monitored for symptoms of hypogonadism (amenorrhea, infertility, or sexual dysfunction) and have SPL measured at 6- to 12-month intervals.1 In cohort studies, treatment of the underlying cause of elevated SPL reverses secondary physiologic changes of low estrogen or testosterone, and hypogonadism.3-5
Pharmacologic causes. Eliminating a pharmacologic cause may lead to normalization of SPL, although experts recommend psychiatric consultation before discontinuing neuroleptic medications.1
Pathologic causes. Experts advise treating the underlying cause of a pathologic elevation of SPL. Patients with microadenoma should have SPLs monitored to prevent complications of decreased bone mineral density and sexual dysfunction due to persistently elevated SPL. Patients with a macroadenoma (>1 cm) are at risk for tumor growth and require serial imaging studies in addition to treatment of SPL, according to expert opinion.1-3
Medical therapy. Medical therapy with a dopamine agonist is indicated for patients with either symptoms of hypogonadism due to elevated SPL, or neurologic symptoms due to the size of a macroadenoma.1 In a review of 13 cohort studies, bromocriptine improved symptoms and reduced SPLs to normal for 229 of 280 women (82%).6 A cohort study of 27 patients with macroadenomas treated with bromocriptine found 10% to 50% reductions of tumor size.7 A randomized controlled trial treating 459 women having hyperprolactinemic amenorrhea with either cabergoline or bromocriptine achieved a stable normal SPL in 83% and 59%, respectively (P<.001). Adverse effects were common but were less common with cabergoline (68% vs 78%) and resulted in fewer discontinuations (3% vs 12%).8
Surgical therapy. Surgery is indicated for patients unresponsive to or intolerant of medical therapy, or who have visual field loss, cranial nerve palsy, or headache due to macroadenoma.1 A retrospective review of patients who underwent surgical resection found a 40% recurrence rate.9
Recommendations from others
Williams Textbook of Endocrinology includes the recommendations above and advises seeking consultation for patients with mass effects of macroadenomas such as visual field loss, cranial nerve palsy, or headaches; for patients with progressive elevation of SPL despite medical treatment; and for pregnant women.4 Conventional antipsychotic agents are commonly associated with elevated prolactin due to dopamine agonist activity. Some atypical antipsychotics may lead to lower levels of elevated prolactin, transient elevations or marked elevations.10 Experts recommend following serial SPLs, if antipsychotics are truly needed. Psychiatric consultation may assist in making decisions about medication selection. Patients with symptoms (galactorrhea, amenorrhea, headaches, visual disturbances, sexual dysfunction) or levels of 200 or more, should undergo an MRI or CT. Experts recommend monitoring levels every 1 to 3 months.1
TABLE
Physiologic, pharmacologic, and pathologic causes of an elevated serum prolactin level1
| PHYSIOLOGIC |
| Pregnancy |
| Ectopic pregnancy |
| Lactation |
| Nipple stimulation |
| Stress |
| Sleep disorder |
| PHARMACOLGIC |
| Dopamine receptor antagonists: phenothiazines, butyrophenones, thioxanthene, risperidone, metoclopramide, sulpiride, pimozide |
| Dopamine-depleting agents: α-methyldopa, reserpine |
| Hormones: estrogens, antiandrogens |
| Others: danazol, isoniazid, verapamil, cyproheptadine, opiates, H2-blockers (cimetidine), cocaine and marijuana, tricyclic antidepressants |
| PATHOLOGIC |
| Acromegaly |
| Alcoholic cirrhosis |
| Chest wall trauma or tumor |
| Herpes zoster |
| Hypothalamic and pituitary stalk disease |
| Hypothyroidism |
| Pituitary tumors: prolactinomas, adenomas |
| Polycystic ovarian syndrome |
| Renal failure |
| Sarcoidosis |
History and physical examination can distinguish among most physiologic, pharmacologic, or pathologic causes of an elevated serum prolactin level (SPL) (strength of recommendation [SOR]: C, expert opinion). Patients with unexplained elevations of serum prolactin or with a level above 200 ng/mL should undergo imaging of the sella turcica (SOR: C, expert opinion). Mildly elevated SPL due to physiologic causes may be managed expectantly (SOR: B, cohort studies) and pharmacologic elevations may be treated by discontinuing the causative medication (SOR: C, expert opinion). Elevated SPL due to pathologic causes requires both monitoring for complications and treatment of the underlying condition (SOR: C, expert opinion).
Dopamine agonists are effective for patients requiring drug treatment (SOR: B, systematic review of cohort studies), and cabergoline is more effective and better tolerated than bromocriptine (SOR: B, randomized controlled trial [RCT]). Surgery is reserved for symptomatic patients not controlled medically (SOR: C, expert opinion).
Patients with mildly elevated SPLs can be safely watched with testing and symptom monitoring
Allen Daugird, MD
University of North Carolina at Chapel Hill
Most elevated prolactin levels in my practice have been mild and often secondary to medication, though there are a host of causes, as listed in the TABLE. This Clinical Inquiry reassures us that patients with mildly elevated SPLs can be safely watched with serial testing and monitoring symptoms. Obtaining SPLs only on fasting specimens can help improve test accuracy. The feared risk of vision loss due to a macroadenoma seems to be quite small. Patients with significantly elevated SPLs with amenorrhea or infertility deserve referral to clinicians comfortable with using dopamine agonists because of the high rate of success with this treatment.
Evidence summary
An expert guideline recommends a history and physical examination to determine whether an elevated SPL is due to physiologic, pharmacologic, or pathologic causes (TABLE).1 The fasting morning SPL is least variable and correlates best with a disease state.1 Clinical correlation is necessary to reveal false positives (due to biologically inactive forms of prolactin) or false negatives (due to very high SPLs that exceed the ability of the assay). If an elevated SPL is suspected despite a normal laboratory report, retesting with serum diluted 1:100 can identify a false-negative value.2
A detailed drug history is important since drug-induced elevated SPL is common.1 Laboratory evaluation includes thyroid-stimulating hormone, blood urea nitrogen, and creatinine, as well as pregnancy testing when applicable. If no cause of elevated SPL is identified by initial clinical evaluation or if the SPL is greater than 200 ng/mL, experts recommend imaging of the sella turcica with computed tomography or magnetic resonance imaging.1
Physiologic causes. For patients with a mildly elevated SPL due to a physiologic cause, experts recommend expectant management. Patients should be monitored for symptoms of hypogonadism (amenorrhea, infertility, or sexual dysfunction) and have SPL measured at 6- to 12-month intervals.1 In cohort studies, treatment of the underlying cause of elevated SPL reverses secondary physiologic changes of low estrogen or testosterone, and hypogonadism.3-5
Pharmacologic causes. Eliminating a pharmacologic cause may lead to normalization of SPL, although experts recommend psychiatric consultation before discontinuing neuroleptic medications.1
Pathologic causes. Experts advise treating the underlying cause of a pathologic elevation of SPL. Patients with microadenoma should have SPLs monitored to prevent complications of decreased bone mineral density and sexual dysfunction due to persistently elevated SPL. Patients with a macroadenoma (>1 cm) are at risk for tumor growth and require serial imaging studies in addition to treatment of SPL, according to expert opinion.1-3
Medical therapy. Medical therapy with a dopamine agonist is indicated for patients with either symptoms of hypogonadism due to elevated SPL, or neurologic symptoms due to the size of a macroadenoma.1 In a review of 13 cohort studies, bromocriptine improved symptoms and reduced SPLs to normal for 229 of 280 women (82%).6 A cohort study of 27 patients with macroadenomas treated with bromocriptine found 10% to 50% reductions of tumor size.7 A randomized controlled trial treating 459 women having hyperprolactinemic amenorrhea with either cabergoline or bromocriptine achieved a stable normal SPL in 83% and 59%, respectively (P<.001). Adverse effects were common but were less common with cabergoline (68% vs 78%) and resulted in fewer discontinuations (3% vs 12%).8
Surgical therapy. Surgery is indicated for patients unresponsive to or intolerant of medical therapy, or who have visual field loss, cranial nerve palsy, or headache due to macroadenoma.1 A retrospective review of patients who underwent surgical resection found a 40% recurrence rate.9
Recommendations from others
Williams Textbook of Endocrinology includes the recommendations above and advises seeking consultation for patients with mass effects of macroadenomas such as visual field loss, cranial nerve palsy, or headaches; for patients with progressive elevation of SPL despite medical treatment; and for pregnant women.4 Conventional antipsychotic agents are commonly associated with elevated prolactin due to dopamine agonist activity. Some atypical antipsychotics may lead to lower levels of elevated prolactin, transient elevations or marked elevations.10 Experts recommend following serial SPLs, if antipsychotics are truly needed. Psychiatric consultation may assist in making decisions about medication selection. Patients with symptoms (galactorrhea, amenorrhea, headaches, visual disturbances, sexual dysfunction) or levels of 200 or more, should undergo an MRI or CT. Experts recommend monitoring levels every 1 to 3 months.1
TABLE
Physiologic, pharmacologic, and pathologic causes of an elevated serum prolactin level1
| PHYSIOLOGIC |
| Pregnancy |
| Ectopic pregnancy |
| Lactation |
| Nipple stimulation |
| Stress |
| Sleep disorder |
| PHARMACOLGIC |
| Dopamine receptor antagonists: phenothiazines, butyrophenones, thioxanthene, risperidone, metoclopramide, sulpiride, pimozide |
| Dopamine-depleting agents: α-methyldopa, reserpine |
| Hormones: estrogens, antiandrogens |
| Others: danazol, isoniazid, verapamil, cyproheptadine, opiates, H2-blockers (cimetidine), cocaine and marijuana, tricyclic antidepressants |
| PATHOLOGIC |
| Acromegaly |
| Alcoholic cirrhosis |
| Chest wall trauma or tumor |
| Herpes zoster |
| Hypothalamic and pituitary stalk disease |
| Hypothyroidism |
| Pituitary tumors: prolactinomas, adenomas |
| Polycystic ovarian syndrome |
| Renal failure |
| Sarcoidosis |
1. Biller BM, Luciano A, Crosignani PG, et al. Guidelines for the diagnosis and treatment of hyperprolactinemia. J Reprod Med 1999;44(12 Suppl):1075-1084.
2. Barkan AL, Chandler WF. Giant pituitary prolactinoma with falsely low serum prolactin: the pitfall of the “high hook effect”: Case report. Neurosurgery 1998;42:913-915.
3. Sanfilippo JS. Implications of not treating hyperprolactinemia. J Reprod Med 1999;44(12 Suppl):1111-1115.
4. Melmed S, Kleinberg D. Physiology and disorders of the pituitary hormone axes. In: Williams RH, Larsen PR. Williams Textbook of Endocrinology. 10th ed. Philadelphia, Pa: Saunders; 2003;200-212.
5. Schlechte J, Dolan K, Sherman B, Chapler F, Luciano A. The natural history of untreated hyperprolactinemia: a prospective analysis. J Clin Endocrinol Metab 1989;68:412-418
6. Vance ML, Evans WS, Thorner MO. Drugs five years later. Bromocriptine. Ann Intern Med 1984;100:78-91.
7. Molitch ME, Elton RL, Blackwell RE, Caldwell B, Chang RJ, Jaffe R, et al. Bromocriptine as primary therapy for prolactin-secreting macroadenomas: results of a prospective multicenter study. J Clin Endocrinol Metab 1985;60:698-705.
8. Webster J, Piscitelli G, Polli A, Ferrari C, Ismail I, Scanlon MF. A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. N Engl J Med 1994;331:904-909.
9. Abrahamson M, Snyder P. Treatment of hyperprolactin due to lactotroph adenomas and other causes. UpToDate [database]. Waltham, Mass: UpToDate; 2004.
10. Smith S. Effects of antipsychotics on sexual and endocrine function in women: implications in clinical practice. J Clin Psychopharmacol 2003;23(3 Suppl 1):S27-S32.
1. Biller BM, Luciano A, Crosignani PG, et al. Guidelines for the diagnosis and treatment of hyperprolactinemia. J Reprod Med 1999;44(12 Suppl):1075-1084.
2. Barkan AL, Chandler WF. Giant pituitary prolactinoma with falsely low serum prolactin: the pitfall of the “high hook effect”: Case report. Neurosurgery 1998;42:913-915.
3. Sanfilippo JS. Implications of not treating hyperprolactinemia. J Reprod Med 1999;44(12 Suppl):1111-1115.
4. Melmed S, Kleinberg D. Physiology and disorders of the pituitary hormone axes. In: Williams RH, Larsen PR. Williams Textbook of Endocrinology. 10th ed. Philadelphia, Pa: Saunders; 2003;200-212.
5. Schlechte J, Dolan K, Sherman B, Chapler F, Luciano A. The natural history of untreated hyperprolactinemia: a prospective analysis. J Clin Endocrinol Metab 1989;68:412-418
6. Vance ML, Evans WS, Thorner MO. Drugs five years later. Bromocriptine. Ann Intern Med 1984;100:78-91.
7. Molitch ME, Elton RL, Blackwell RE, Caldwell B, Chang RJ, Jaffe R, et al. Bromocriptine as primary therapy for prolactin-secreting macroadenomas: results of a prospective multicenter study. J Clin Endocrinol Metab 1985;60:698-705.
8. Webster J, Piscitelli G, Polli A, Ferrari C, Ismail I, Scanlon MF. A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. N Engl J Med 1994;331:904-909.
9. Abrahamson M, Snyder P. Treatment of hyperprolactin due to lactotroph adenomas and other causes. UpToDate [database]. Waltham, Mass: UpToDate; 2004.
10. Smith S. Effects of antipsychotics on sexual and endocrine function in women: implications in clinical practice. J Clin Psychopharmacol 2003;23(3 Suppl 1):S27-S32.
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