Hyperprolactinemia

Hyperprolactinemia

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Hyperprolactinemia is a condition of elevated serum prolactin. Prolactin is a 198-amino acid protein (23-kd) produced in the lactotroph cells of the anterior pituitary gland. Its primary function is to enhance breast development during pregnancy and to induce lactation. However, prolactin also binds to specific receptors in the gonads, lymphoid cells, and liver. [1]

Secretion is pulsatile; it increases with sleep, stress, pregnancy, and chest wall stimulation or trauma and therefore must be drawn after fasting. Normal fasting values are generally less than 25-30 ng/mL, depending on the individual laboratory, but can also vary for a number of reasons. Normal levels are also generally higher in women.

Nonpuerperal hyperprolactinemia is a state in which pituitary lactotroph adenomas produce prolactin. These lactotroph adenomas are called prolactinomas and account for approximately 40% of all pituitary tumors. [2] However, hyperprolactinemia can also be from a pharmacologic cause or some other pathologic problem of the hypothalamic-pituitary dopaminergic pathways. Idiopathic hyperprolactinemia is possible though a diagnosis of exclusion.

When symptoms are present, medical therapy for hyperprolactinemia is the treatment of choice. Patients with hyperprolactinemia and no symptoms (idiopathic or microprolactinoma) can be monitored without treatment.

General indications for pituitary surgery include patient drug intolerance, tumors resistant to medical therapy, patients who have persistent visual-field defects in spite of medical treatment, and patients with large cystic or hemorrhagic tumors.

The primary action of prolactin is to stimulate breast epithelial cell proliferation, thereby inducing and maintaining milk production. Estrogen stimulates the proliferation of pituitary lactotroph cells, resulting in an increased quantity of these cells in premenopausal women, especially during pregnancy. However, lactation is inhibited by the high levels of estrogen and progesterone during pregnancy. The rapid decline of estrogen and progesterone in the postpartum period allows lactation to commence. During lactation and breastfeeding, ovulation may be suppressed due to the suppression of gonadotropins by prolactin, but it may return before menstruation resumes. Therefore, this cannot be considered a reliable form of birth control.

Dopamine has the dominant influence over prolactin secretion. Secretion of prolactin is under tonic inhibitory control by dopamine, which acts via D2-type receptors located on lactotrophs. Prolactin production can be stimulated by the hypothalamic peptides, thyrotropin-releasing hormone (TRH), vasoactive intestinal peptide (VIP), epidermal growth factor, and dopamine receptor antagonists. Thus, primary hypothyroidism (a high TRH state) can cause hyperprolactinemia. VIP increases prolactin in response to suckling, probably because of its action on receptors that increase adenosine 3′,5′-cyclic phosphate (cAMP).

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This condition occurs in less than 1% of the general population and in 5-14% of patients presenting with secondary amenorrhea. [3] Approximately 75% of patients presenting with galactorrhea and amenorrhea have hyperprolactinemia. Of these patients, approximately 30% have prolactin-secreting tumors.

Mortality is unlikely, although a study by Soto-Pedre et al (discussed below) did report increased mortality depending on the cause of hyperprolactinemia. [4]  In cases where the condition is due to a large prolactin-secreting tumor, [5] local mass effect can lead to significant morbidity.

The condition causes systemic complaints that often resolve when the prolactin level returns to normal or once the tumor shrinks.

Rare cases of metastatic malignant prolactinoma have been described in the literature, but they number less than 50.

Bone resorption can be seen due to sex steroid attenuation mediated by the hyperprolactinemic state. A 25% decrease in spinal bone density can be seen in women with hyperprolactinemia and may be irreversible, even with normalization of prolactin levels. [6]

A study by Rubio-Abadal et al supported the idea that hyperprolactinemia is associated with sexual dysfunction and found no difference between men and women in the prevalence of sexual dysfunction in such cases. [7]

A study by Ishioka et al indicated that in men receiving antipsychotic agents, a link exists between hyperprolactinemia and an increase in markers of activated coagulation, suggesting that these men are at increased risk for venous thromboembolism. The same association was not found in women. [8]

The aforementioned study by Soto-Pedre et al found that morbidity and mortality in hyperprolactinemia appears to differ according to the condition’s etiology. The investigators reported no link between pituitary tumor–associated hyperprolactinemia and increased morbidity. In contrast, drug-induced hyperprolactinemia was found to be associated with a greater risk of diabetes, cardiovascular disease, infectious disease, and bone fracture. Moreover, the study found no increased mortality risk in hyperprolactinemia patients with pituitary microadenomas, while a greater risk of death was reported in subjects with pituitary macroadenoma– or drug-induced hyperprolactinemia, as well as in patients with idiopathic hyperprolactinemia. However, the investigators stated that the morbidity and mortality increases observed in the study did not appear to be directly caused by the serum prolactin elevations themselves and that hyperprolactinemia could perhaps serve as a biomarker for greater morbidity risk. [4]

Clinical presentation in women is more obvious and occurs earlier than in men. They typically present with oligomenorrhea, amenorrhea, galactorrhea, or infertility. Galactorrhea is less common in postmenopausal women due to lack of estrogen. If a pituitary tumor is present, it is a microadenoma (< 10 mm) approximately 90% of the time.

Prolactinoma is less common in men than in women, typically presenting as an incidental finding on a brain CT scan or MRI, or with symptoms of tumor mass effect. This is most evident as a complaint of visual disturbances or headache. By the time of diagnosis in men, approximately 60% have macroprolactinomas.

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Yatavelli RKR, Bhusal K. Prolactinoma. 2018 Jan. [Medline]. [Full Text].

Lee D-Y, Oh Y-K, Yoon B-K, Choi D. Prevalence of hyperprolactinemia in adolescents and young women with menstruation-related problems. Am J Obstet Gynecol. 2012. 206:213.e1-5.

Soto-Pedre E, Newey PJ, Bevan JS, Leese GP. Morbidity and mortality in patients with hyperprolactinaemia: the PROLEARS study. Endocr Connect. 2017 Nov. 6 (8):580-8. [Medline]. [Full Text].

Melmed S, Casanueva FF, Hoffman AR, et al. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011 Feb. 96(2):273-88. [Medline].

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Rubio-Abadal E, Del Cacho N, Saenz-Navarrete G, et al. How Hyperprolactinemia Affects Sexual Function in Patients Under Antipsychotic Treatment. J Clin Psychopharmacol. 2016 Jul 18. [Medline].

Ishioka M, Yasui-Furukori N, Sugawara N, Furukori H, Kudo S, Nakamura K. Hyperprolactinemia during antipsychotics treatment increases the level of coagulation markers. Neuropsychiatr Dis Treat. 2015. 11:477-84. [Medline]. [Full Text].

Davies PH. Drug-related hyperprolactinaemia. Adverse Drug React Toxicol Rev. 1997 Jun. 16(2):83-94. [Medline].

Erem C, Kocak M, Nuhoglu I, Yilmaz M, Ucuncu O. Blood coagulation, fibrinolysis and lipid profile in patients with prolactinoma. Clin Endocrinol (Oxf). 2010 Oct. 73(4):502-7. [Medline].

Wu ZR, Zhang Y, Cai L, et al. Long-Term Clinical Outcomes of Invasive Giant Prolactinomas after a Mean Ten-Year Followup. Int J Endocrinol. 2016. 2016:8580750. [Medline]. [Full Text].

Krysiak R, Szkrobka W, Okopien B. The effect of bromocriptine treatment on sexual functioning and depressive symptoms in women with mild hyperprolactinemia. Pharmacol Rep. 2018 Feb 20. 70 (2):227-32. [Medline].

Berinder K, Akre O, Granath F, Hulting AL. Cancer risk in hyperprolactinemia patients: a population-based cohort study. Eur J Endocrinol. 2011 Aug. 165(2):209-15. [Medline].

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Andereggen L, Frey J, Andres RH, et al. Long-Term Follow-Up of Primary Medical Versus Surgical Treatment of Prolactinomas in Men: Effects on Hyperprolactinemia, Hypogonadism, and Bone Health. World Neurosurg. 2017 Jan. 97:595-602. [Medline].

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Sathyapalan T, Gonzalez S, Atkin SL. Effect of long-term, high-dose estrogen treatment on prolactin levels: a retrospective analysis. Climacteric. 2009 Oct. 12(5):427-30. [Medline].

Nachtigall LB, Valassi E, Lo J, et al. Gender effects on cardiac valvular function in hyperprolactinaemic patients receiving cabergoline: a retrospective study. Clin Endocrinol (Oxf). 2010 Jan. 72(1):53-8. [Medline].

Kharlip J, Salvatori R, Yenokyan G, Wand GS. Recurrence of hyperprolactinemia after withdrawal of long-term cabergoline therapy. J Clin Endocrinol Metab. 2009 Jul. 94(7):2428-36. [Medline]. [Full Text].

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Lafeber M, Stades AM, Valk GD, Cramer MJ, Teding van Berkhout F, Zelissen PM. Absence of major fibrotic adverse events in hyperprolactinemic patients treated with cabergoline. Eur J Endocrinol. 2010 Apr. 162(4):667-75. [Medline].

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Donald Shenenberger, MD, FAAD, FAAFP Board Certified Dermatologist

Donald Shenenberger, MD, FAAD, FAAFP is a member of the following medical societies: American Academy of Dermatology, American Academy of Family Physicians, Association of Military Dermatologists, Medical Society of Virginia, Uniformed Services Academy of Family Physicians

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Yoram Shenker, MD Chief of Endocrinology Section, Veterans Affairs Medical Center of Madison; Interim Chief, Associate Professor, Department of Internal Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Wisconsin at Madison

Yoram Shenker, MD is a member of the following medical societies: American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.

George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, International Society for Clinical Densitometry, Southern Society for Clinical Investigation, American College of Medical Practice Executives, American Association for Physician Leadership, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.

David M Klachko, MD, MEd Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Missouri-Columbia School of Medicine

David M Klachko, MD, MEd is a member of the following medical societies: Alpha Omega Alpha, Missouri State Medical Association, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Federation for Medical Research, Endocrine Society, Sigma Xi

Disclosure: Nothing to disclose.

The editors would like to thank Treyce Knee, MD, for previous contributions to this article.

Hyperprolactinemia

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