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Hyperprolactinemia Review Article Hyperprolactinemia ABSTRACT Abha Majumdar, Nisha Sharma Mangal Prolactin (PRL) is an anterior pituitary hormone which has its principle physiological Departments of Obstetrics and action in initiation and maintenance of lactation. In human reproduction, pathological Gynecology, Sir Ganga Ram Hospital and Sir Ganga Ram hyperprolactinemia most commonly presents as an ovulatory disorder and is often Kolmet Hospital, New Delhi, associated with secondary amenorrhea or oligomenorrhea. Galactorrhea, a typical India symptom of hyperprolactinemia, occurs in less than half the cases. Out of the causes of hyperprolactinemia, pituitary tumors may be responsible for almost 50% of cases and need Address for correspondence: Dr. Abha Majumdar, Centre of to be investigated especially in the absence of history of drug induced hyperprolactinemia. IVF and Human Reproduction, In women with hyperprolactinemic amenorrhea one important consequence of estrogen Sir Ganga Ram Hospital, deficiency is osteoporosis, which deserves specific therapeutic consideration. Problem in Rajender Nagar - 110060 diagnosing and treating hyperprolactinemia is the occurrence of the ‘big big molecule India. E-mail:abhamajumdar@ hotmail.com of prolactin’ that is biologically inactive (called macroprolactinemia), but detected by the same radioimmunoassay as the biologically active prolactin. This may explain many Submission: 27.07.2013 cases of very high prolactin levels sometimes found in normally ovulating women and Review completed: 19.09.2013 do not require any treatment. Dopamine agonist is the mainstay of treatment. However, Accepted: 09.08.2013 presence of a pituitary macroadenoma may require surgical or radiological management. KEY WORDS: Anovulation, galactorrhea, hyperprolactinemia, prolactin, prolactinomas INTRODUCTION pituitary hormones responsible for gonadal function. Prolactin (PRL) plays a central role in a variety of reproductive functions. Initially, PREVALENCE even though this hormone was recognized in relation to lactation in women, lately immense It is a common endocrine disorder of the interest has been focused on prolactin hypothalamic‑pituitary axis. It occurs more with respect to its effect on reproduction. commonly in women. The prevalence of Hyperprolactinemia is a condition of elevated hyperprolactinemia ranges from 0.4% in an prolactin levels in blood which could be unselected adult population to as high as physiological, pathological, or idiopathic in 9‑17% in women with reproductive diseases. origin. Similarly elevated prolactin levels Its prevalence was found to be 5% in a family could be associated with severe clinical planning clinic, 9% in women with adult manifestations on one side of the spectrum or onset amenorrhea, and 17% among women be completely asymptomatic on the other side. with polycystic ovary syndrome.[1] Access this article online Unlike other tropic hormones secreted by the PROLACTIN MOLECULE Quick Response Code: anterior pituitary gland, prolactin secretion is controlled primarily by inhibition from the Prolactin is a 23 kDa polypeptide hypothalamus and it is not subject to negative hormone (198 amino acid) synthesized in feedback directly or indirectly by peripheral the lactotroph cells of the anterior pituitary hormones. It exercises self‑inhibition by a gland. Its secretion is pulsatile and increases counter‑current flow in the hypophyseal with sleep, stress, food ingestion, pregnancy, pituitary portal system which initiates chest wall stimulation, and trauma. Website: secretion of hypothalamic dopamine, as well www.jhrsonline.org as causes inhibition of pulsatile secretion of Macroprolactin: Even though monomeric 23 kDa DOI: gonadotropin releasing hormone (GnRH). form is the predominant form, prolactin is also 10.4103/0974-1208.121400 This negatively modulates the secretion of present in different molecular forms on which 168 Journal of Human Reproductive Sciences / Volume 6 / Issue 3 / Jul - Sep 2013 Majumdar and Mangal: Hyperprolactinemia the bioactivity of the hormone depends. Macroprolactinemia dopamine receptor antagonists. Serotonin physiologically denotes the situation in which high levels of the circulating mediates nocturnal surges and suckling‑induced prolactin ‘big prolactin’ molecules are present. These big variants of rises and is a potent modulator of prolactin secretion. prolactin molecule are of 50 and 150 kDa (PRL‑IgG complexes) Histamine has a predominantly stimulatory effect due to also known as ‘big prolactin’ and the ‘big‑big prolactin’ which the inhibition of the dopaminergic system. have high immunogenic properties, but poor or no biological effect. The ‘big prolactin’ or macroprolactin represents dimers, Estrogen stimulates the proliferation of pituitary lactotroph trimers, polymers of prolactin, or prolactin‑immunoglobulin cells especially during pregnancy. However, lactation is immune complexes. When these big variants circulate in large inhibited by the high levels of estrogen and progesterone amounts, the condition is referred to as “macroprolactinemia”, during pregnancy. The rapid decline of estrogen and identified as hyperprolactinemia by the commonly used progesterone in the postpartum period allows lactation to immune assays. Such forms are rarely physiologically commence. During lactation and breastfeeding, ovulation active but may register in most prolactin assays.[1] In these may be suppressed due to the suppression of gonadotropins situations even though tests determines high levels of by prolactin, but may resume before menstruation resumes. circulating prolactin hormone the biological prolactin is normal and thus the lack of clinical symptoms.[2,3] Although ETIOLOGY a smaller proportion of patients with macroprolactinemia may have symptoms of hyperprolactinemia,[4,5] it should be Hyperprolactinemia can be physiological or pathological. suspected when typical symptoms of hyperprolactinemia Some of the common causes are listed in Figure 1. are absent.[6,7] As macroprolactinemia is a common cause of hyperprolactinemia, routine screening for macroprolactinemia Physiological hyperprolactinemia is usually mild or could eliminate unnecessary diagnostic testing as well as moderate. During normal pregnancy, serum prolactin rises treatment.[3] Investigation for macroprolactin should always progressively to around 200‑500 ng/mL. Many common be done in cases of asymptomatic hyperprolactinemic subjects. medications cause hyperprolactinemia usually with Many commercial assays do not detect macroprolactin. prolactin levels of less than 100 ng/mL. Polyethylene glycol precipitation is an inexpensive way to detect the presence of macroprolactin in the serum. Pathological hyperprolactinemia can be caused by both hypothalamic‑pituitary disease (prolactinomas) as well as BIOLOGICAL ACTION non‑hypothalamic‑pituitary disease. The main biological action of prolactin is inducing and Prolactinomas account for 25‑30% of functioning pituitary maintaining lactation. However, it also exerts metabolic tumors and are the most frequent cause of chronic effects, takes part in reproductive mammary development[8] hyperprolactinemia.[12] Prolactinomas are divided into and stimulates immune responsiveness.[9] All these effects two groups: (1) microadenomas (smaller than 10 mm) of prolactin are because it binds to specific receptors in the which are more common in premenopausal women, gonads, lymphoid cells, and liver.[10] and (2) macroadenomas (10 mm or larger) which are more common in men and postmenopausal women. Raised Actual serum prolactin level is the result of a complex prolactin levels can also be caused by pituitary adenomas balance between positive and negative stimuli derived cosecreting prolactin hormone. Lesions affecting the from both external and endogenous environments. Plenty hypothalamus and pituitary stalk such as nonfunctioning of mediators of central, pituitary, and peripheral origin adenomas, gliomas, and craniopharyngiomas also results take part in regulating prolactin secretion through a direct in prolactin elevation.[13] or indirect effect on lactotroph cells.[2] Around 40% patients with primary hypothyroidism, 30% Prolactin secretion is under dual regulation by hypothalamic patients with chronic renal failure, and up to 80% patients hormones. The predominant signal is tonic inhibitory on hemodialysis have mild elevation of prolactin levels. control of hypothalamic dopamine which traverses the Many patients with acromegaly have prolactin cosecreted portal venous system to act upon pituitary lactotroph with growth hormone. D2 receptors. Other prolactin inhibiting factors include gamma amino butyric acid (GABA), somatostatin, CLINICAL PRESENTATION acetylcholine, and norepinephrine. The second signal is stimulatory which is provided by the hypothalamic The predominant physiologic consequence of peptides, thyrotropin releasing hormone (TRH), vasoactive hyperprolactinemia is hypogonadotropic hypogonadism intestinal peptide (VIP), epidermal growth factor (EGF), and (HH) which is due to suppression of pulsatile GnRH. The Journal of Human Reproductive Sciences / Volume 6 / Issue 3 / Jul - Sep 2013 169 Majumdar and Mangal: Hyperprolactinemia ,3K\VLRORJLFK\SHUVHFUHWLRQ 3UHJQDQF\ /DFWDWLRQ &KHVWZDOOVWLPXODWLRQ 6OHHS 6WUHVV ,,,GLRSDWKLFK\SHUSURODFWLQHPLD RIFDVHV ,,,+\SRWKDODPLFSLWXLWDU\VWDONGDPDJH 7XPRUV&UDQLRSKDU\QJLRPDPHQLQJLRPDG\VJHUPLQRPDGHUPRLGF\VWSLQHDOJODQGWXPRUV (PSW\VHOOD /\PSKRF\WLFK\SRSK\VLWLV 5DWKNH¶VF\VW ,UUDGLDWLRQ 7UDXPD 3LWXLWDU\VWDONVHFWLRQ 6XSUDVHOODUVXUJHU\ ,93LWXLWDU\K\SHUVHFUHWLRQ
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