Prolactin: Physiologic and Pathologic Associations

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1. Puberty
   
   The major influence on breast growth during puberty is estrogen, which acts by the development of prolactin-dependent estrogen receptors. In most women the first response to rising estrogen levels is an increase in size, pigmentation of the areola, and the formation of abreast mass beneath the areola (thelarche). The primary effect of estrogen is to stimulate growth in the ductal portion of the gland. This growth can begin at any age between 8 to 14 years and normally occurs in a span of four years. Normal development requires prolactin,estrogen, progesterone, growth hormone, insulin, cortisol, thyroid and parathyroid hormone,and growth factors; but this growth is only in anticipation of the development of the fully functional status characterized by full development of the alveoli which occurs only during pregnancy.
   
   Premature thelarche is characterized by the nonprogressive nature and absence of other secondary sexual characteristics. Confirmation is obtained by a normal FSH, LH, prepubertal estrogen concentration, immature vaginal maturation index, and a negative ultrasound exam to rule out ovarian pathology. If other secondary sexual characteristics are noted, a hand film for bone age and a GnRH stimulation test are performed to document precocious puberty.
   
   Cyclic changes in estrogen/progesterone during the normal menstrual cycle result in continued development of breast structures. As estrogen and progesterone levels fall near the end of the cycle, prolactin-induced secretory changes become evident in the alveolar lumen during the first few days of the menses. The breasts are largest in this phase and are smallest on days 4to 7 of the cycle, which is the ideal time for breast self-exam.
   
   

2. Pregnancy
   
   Differentiation of the breast to its mature functional status occurs by the third month of pregnancy. The true glandular acini (true alveoli) develop under the influence of prolactin,human placental lactogen, estradiol, progesterone, insulin, cortisol, growth hormone, IGF-1,and EGF. Thyroid hormones also promote alveolar growth of the glands.
   
   Pregnancy provides a unique opportunity to evaluate the facilitator and inhibitory actions of various hormones; specifically, the interactions of prolactin, estradiol, and progesterone on the development of the lactating breast.
   
   In humans, prolactin acts to (1) increase arginase activity, (2) stimulate ornithine decarboxylase activity, and (3) enhance the rate of transport of polyamines into the mammary gland. All result in increased spermine and spermidine synthesis (polyamines) which are required for milk production. The polyamines stabilize membrane structures, increase transcriptional and translational activities, and regulate enzymes. Prolactin in cultured mammary gland explants also elicits increased messages and synthesis of casein, spermidine,lactose, and phospholipids which are all required for lactation. Estradiol levels, rising throughout pregnancy, act at the hypothalamic level to increase prolactin secretion.
   
   Progesterone interferes with prolactin action at the alveolar cell's prolactin receptor level. While estrogen and progesterone are required to get full activity of the prolactin receptor,progesterone antagonizes the positive action of prolactin on its receptor by (1) inhibiting up regulation of the prolactin receptor, (2) reducing estrogen binding (lactogenic activity), and (3)competing for binding at the glucocorticoid receptor.
   
   Actual lactation occurs after birth by allowing prolonged prolactin elevation without progesterone inhibition because of the more rapid clearance of progesterone in contrast to prolactin. It takes approximately seven days for prolactin to reach non-pregnant levels, while estrogen and progesterone elevations are cleared in three to four days postpartum.
   
   In the first week postpartum, prolactin levels decline 50% (to about 100 ng/ml). Suckling results in increased prolactin, which is important in the initiation of lactation. Until approximately two to three months postpartum, basal levels are 40 to 50 ng/ml in the lactating female, and there are large (10 to 20-fold) increases with suckling. Basal prolactin levels remain normal or slightly elevated with a twofold increase with suckling in the third to sixth months postpartum. Increased prolactin levels are required for lactogenesis; however,nonpregnant levels are adequate to maintain lactation.
   
   Progesterone, while still present postpartum, has less effect once lactation has begun because the number of progesterone receptors has decreased significantly (also related to the precipitous drop in estrogen). Once lactation has begun, progesterone, which has a greater affinity for milk fat than for the progesterone receptor, is cleared rapidly.
   
   Inhibition of lactation postpartum can be accomplished medically by utilizing bromocriptine(an ergot alkaloid which is a dopamine agonist) at 2.5 mg bid for two weeks, although this not necessary and may be dangerous in women with hypertension. Breast-binding, ice, and avoidance of nipple stimulation will result in cessation of lactation in one week.
   
   

1. Evaluation of Prolactin
   
   When evaluating prolactin levels,  physiologic  alterations or conditions may result in transient as well as persistent elevations in prolactin levels. Disorders categorized as physiologic conditions and drug-related do not always require intervention.
   
   Plasma levels of immunoreactive prolactin are 5-27 ng/ml during the menstrual cycle. Samples should not be drawn soon after the patient awakes or after procedures. Prolactin is secreted in a pulsatile fashion with a pulse frequency ranging from about 14 pulses per 24 hours in the late follicular phase to about nine pulses per 24 hours in the late luteal phase. There is also a diurnal variation with the lowest levels occurring the midmorning after the patient awakes. Levels rise 1 hour after the onset of sleep and continue to rise until peak values are reached between 5:00 and 7:00 AM (29,30). The pulse amplitude of prolactin appears to increase from early to late follicular and luteal phases (31-33). Because of the variability of secretion and inherent limitations of radioimmunoassay, an elevated level should always be rechecked. This is preferably drawn midmorning and not after stress, venipuncture,breast stimulation, or physical examination, which increases prolactin levels.
   
   Prolactin and TSH determinations are basic evaluations in infertile women. Infertile men with hypogonadism also should be tested. Likewise, prolactin levels should be measured in the evaluation of amenorrhea, galactorrhea, galactorrhea with amenorrhea, hirsutism with amenorrhea, anovulatory bleeding, and delayed and precocious puberty.
   
   

2. Lactation
   
   Prolactin, the major hormone in lactogenesis, is modulated by a combination of second messenger activities which include cyclic nucleotides, prostaglandin, and calcium ion charges,polyamine production, and growth factors. In pregnancy cAMP and cGMP increase progressively and may be involved in stimulation of mitogenic and morphogenic processes that occur with pregnancy. At delivery cAMP levels fall precipitously, and cGMP levels continue to rise and stay elevated in the lactational period. cAMP stimulators abolish prolactin effects,while cGMP increases (marginally) the activity of prolactin. Prolactin certainly does not work via cAMP nor cGMP, but its activity may be modulated by cGMP.
   
   Prolactin can cause perturbations in phospholipid metabolism via the activation of phospholipase enzymes in the cell membrane. Consequent to this action, protein kinase C maybe activated and modulate prostaglandin production and/or intracellular calcium ions.
   
   As mentioned previously, prolactin increases enzyme activities and results in increased polyamine synthesis with resultant increased message and synthesis of products required for lactation.
   
   Growth factors, such as insulin-like growth factor and epidermal growth factor, have been reported to cause mitogenesis in mammary cells and may play a role in the effects of prolactins.
   
   

3. Galactorrhea

1. Etiologies
   
   Galactorrhea refers to the secretion of milky fluid from the breast at times other than pregnancy (six months after delivery and not nursing) or breast-feeding (six months after cessation). Prolactin is under chronic inhibition by prolactin-inhibiting factor (PIF) which is mediated by dopamine, in contrast to the peptide-releasing hormones for other hypothalamic hormones. PIF is released by specialized neurons in the hypothalamus into the pituitary portal system and is transported to the anterior pituitary where it inhibits the synthesis and release of prolactin by the lactrotrophs. Prolactin in converse inhibits the pulsatile secretion of GnRH. Prolactin has short loop positive effects on dopamine which reduce GnRH by suppressing arcuate nucleus function, perhaps in a method mediated by endogenous opioid activity. PIF appears to be released as a  package  with GnRH from the hypothalamus. Galactorrhea can result from any of the following mechanisms:
   
   
   • Activation of the afferent limb of the neuroendocrine arc. Examples include stimulation of the breast by suckling, excessive manual stimulation, thoracotomy incisions, herpes zoster of thoracic nerves, spinal cord lesions, breast surgery.
     
     
   • Decreased dopamine or PIF release or transport or interference with dopamine binding. Commonly used drugs such as phenothiazines, tranquilizers, opiates (B enkephalin and morphine), reserpine derivatives, amphetamines, estrogens (BCP) can interfere with dopamine metabolism and result in galactorrhea. Numerous drugs interfere with dopamine secretion (Table 1). The same principles utilized in the management of pituitary microadenomas or hyperplasia can be applied in these situations. If discontinuation of the drugs is feasible, resolution of hyperprolactinemia is uniformly prompt. Stress, trauma, surgery, and marathon running can reduce hypothalamic dopamine release. Galactorrhea can also occur after pituitary stalk section or with a hypothalamic or pituitary condition blocking dopamine transport (Tables 1 and 2).
     
     
   • Autonomous pituitary prolactin section. Prolactinomas of the anterior pituitary may cause elevated prolactin. Also, ectopic production of prolactin can be found in tumors such as renal cell, liver, and uterine fibroids.
     
     
   • Elevated TRH, which acts as an enhancer of prolactin release. TSH is the most sensitive method to evaluate for hypothyroidism. Occasionally, patients with hypothyroidism exhibit hyperprolactinemia with remarkable pituitary enlargement due to thyrotroph hyperplasia. These patients respond to thyroid replacement with reduction in pituitary enlargement and normalization of prolactin levels (34).
     
     
   • Chronic renal failure. Hyperprolactinemia occurs in 20-75% of women with chronic renal failure. Prolactin levels are not normalized through hemodialysis but are normalized after transplantation (35-38). Occasionally, women with hyperandrogenemia also have hyperprolactinemia. Elevated prolactin levels may alter adrenal function by enhancing the release of adrenal androgens such as DHEAS (39).
     
     

2. Physical Findings Associated with Galactorrhea
   
   The cessation of normal ovulatory processes attributed to elevated prolactin levels may be related to the following gonadal and hypothalamic-pituitary effects: reduction in granulosa cell number and FSH binding (40); inhibition of granulosa cell 17 estradiol production by interfering with FSH action (40-42); inadequate luteinization and reduced progesterone (43-45); and the suppressive effects of prolactin on GnRH pulsatile release which may mediate most of the anovulatory effects (46-59).
   
   Although isolated galactorrhea is commonly considered indicative of hyperprolactinemia,prolactin levels are within the normal range in nearly 50% of patients (60-62). In such cases,an earlier transient episode of hyperprolactinemia may have existed which triggered persistent galactorrhea despite normal prolactin levels. This situation is very similar to nursing mothers in whom milk secretion, once established, continues despite normal prolactin levels. Repeat testing is occasionally helpful in detecting hyperprolactinemia. Approximately one-third of women with galactorrhea have normal menses. Conversely, hyperprolactinemia commonly(66%) occurs in the absence of galactorrhea, which may result from inadequate estrogenic or progestational priming of the breast.
   
   In patients with both galactorrhea and amenorrhea (including the syndromes described and named by Forbes, Henneman, Griswold, and Albright, 1951; Chiari and Frommel, 1985; and Argonz and del Castilla, 1953), approximately of that two-thirds will have hyperprolactinemia. Of that group, approximately one-third will have a pituitary adenoma (63). Anovulatory women carrying the diagnosis of polycystic ovarian disease are noted to be hyperprolactinemic in 3%to 10% (64,65).
   
   In all cases of delayed puberty, pituitary abnormalities including craniopharyngiomas and adenomas must be considered. Additionally, the multiple endocrine neoplasia type 1syndrome should be considered particularly in patients who present with a family history of multiple adenomas (65). Prolactin and thyroid-stimulating hormone (TSH) levels should be measured in all patients with delayed puberty.
   
   Once an elevated prolactin level is documented, the gynecologist must be familiar with neuroanatomy as well as imaging techniques and their interpretation. Patients can be reassured that hyperprolactinemia usually is associated with a relatively benign condition (pituitary microadenoma or hyperplasia) that requires only periodic monitoring. However, it is critical for the physician to exercise vigilance and to consider the evaluation of other potential etiologies, particularly sellar/suprasellar tumors (Table 1). Levels of TSH should be measured in all cases of hyperprolactinemia.
   
   

3. Imaging Techniques of the Pituitary
   
   Prolactin levels in patients with larger microadenomas and macrdoadenomas are usually higher than 100 ng/ml. However, levels may be lower with smaller microadenomas and other suprasellar tumors that may be missed on a  coned-down  view of the sella turcica. Inpatients with an identifiable drug-induced or physiological etiology for hyperprolactinemia,scanning may not be necessary. Coned-down views of the pituitary are occasionally obtained as a screening technique to rule out a mass effect in the sella. The community standard of care,resources available, and expertise of the operator will influence the imaging technique: coned-down view of sella, CT scan, or MRI. An MRI is considered by neuro radiologists to be the optimal technique to evaluate the sella/suprasellar region (67). The cumulative radiation dose from multiple CT scans may cause cataracts, and the coned-down views or tomograms of the sella are very insensitive and likewise expose the patient to radiation. Even modest elevations of prolactin can be associated with microadenomas or macroadenomas, nonlactotroph pituitary tumors, and other central nervous system abnormalities (Table 2).
   
   For patients with hyperprolactinemia who desire future fertility, MRI is indicated to differentiate a pituitary microadenoma from a macroadenoma as well as to identify other potential sellar-suprasellar masses. Although they are infrequent when pregnancy-related complications occur, sellar-suprasellar masses are associated with macroadenomas twice as often as with microadenomas, and patients should make informed decisions (Table 3).
   
   

1. Microadenoma
   
   Microadenoma.    A pituitary microadenoma or hyperplasia is the cause of hyperprolactinemia in most patients. In over one-third of women with hyperprolactinemia, a radiologic abnormality consistent with an adenoma is found. In the remainder, simple hyperplasia of the pituitary lactotrophs is assumed to be the cause. Most of these abnormalities are microadenomas (< 1 CM), and patients can generally be reassured of a benign course of disease (68,69). Hypotheses for the formation of microadenomas and macroadenomas (> 1 cm) include are duction in dopamine concentrations in the hypophyseal portal system, vascular isolation of the tumor, or both. The tumors, which originate in the lateral aspects of the anterior pituitary,are surrounded by a pseudo capsule. They may be cystic or degenerating and are often discolored (blue, gray or brown) as a result of hemorrhage.
   
   Treatment.    Microadenomas rarely progress to macroadenomas. Therapies include expectant, medical and/or rarely surgical therapy. All women are advised to notify their physician of chronic headaches, visual disturbances (particularly tunnel vision consistent with bitemporal hemianopsia), and extraocular muscle palsies. Formal visual field testing is rarely necessary.
   
   Expectant Management.    In women who do not desire fertility, expectant management can be utilized for both microadenomas and hyperplasia if menstrual function remains intact. Hyperprolactinemia-induced estrogen deficiency, rather than prolactin itself, is the major factor in the development of osteopenia (70). Therefore, estrogen replacement or oral contraceptive pills are indicated for patients with amenorrhea or irregular menses. Patients with drug-induced hyperprolactinemia can also be managed expectantly with attention to the risks of osteoporosis. Repeat imaging for microadenomas is usually performed in 6 to 12 months to insure no further growth of the microadenoma.
   
   Medical Treatment.    Ergot alkaloids are the mainstay of therapy. In the United States, bromocriptine was approved for use in the United States to treat hyperprolactinemia caused by a pituitary adenoma. The ergot alkaloids increase dopamine levels, thus decreasing prolactin levels. The serum half-life is 3.5 hours, and twice-a-day administration is required. Ergot alkaloids are excreted via the biliary tree; therefore, caution is required in the presence of liver disease. The major adverse effects include nausea,headaches, hypotension, dizziness, fatigue and drowsiness, vomiting, headaches, nasal congestion, and constipation. Many patients tolerate the drug on the following regimen: one-half tablet every evening (1.25 mg) at bedtime for one week, an increase of one-half tablet every evening in the second week, and every morning in the third week, and finally 2.5 mg twice a day. The lowest dose that maintains the prolactin level in the normal range is continued.
   
   An alternative to oral administration is the vaginal administration of bromocriptine tablets,which is well tolerated (71). When cannot be used, other medications such as pergolide, cabergoline, metergoline, and CV205-502 may be used. In patients with a microadenoma who are receiving bromocriptine therapy, a repeat MRI scan may be performed at 6 to 12 months after prolactin levels are normal. Normal prolactin levels and resumption of menses should not be considered proof of tumor response to treatment. Further MRI scans should be performed only to evaluate new symptoms. Discontinuation of bromocriptine therapy after two to three years may be attempted because some adenomas undergo hemorrhagic necrosis and cease to function. Further attempted, as some adenomas undergo hemorrhagic necrosis and cease to function.
   
   

2. Macroadenomas
   
   Macroadenomas are pituitary tumors greater than 1 cm in size. Bromocriptine is the best initial and potentially long-term treatment option, but transphenoidal surgery may be required. Evaluation for other trophic hormone deficiencies may be indicated. Macroadenoma symptoms include severe headaches, visual field changes, and rarely, diabetes in sipidus and blindness. After prolactin has reached normal levels, a follow-up MRI is indicated within six months to document shrinkage or stabilization of growth. This may be performed earlier if symptoms develop or exacerbate. Normalized prolactin levels or resumption of menses should not be taken as proof of tumor response to treatment.
   
   Medical Treatment.    Macroadenomas treated with bromocriptine routinely show a decrease in prolactin levels and size; nearly one-half show a 50% reduction in size and another one-fourth show a 33% reduction after six months of therapy. Tumor regrowth occurs in over 60% of cases after discontinuation of bromocriptine therapy; therefore, long-term therapy is the rule.
   
   After stabilization of tumor size is documented, the MRI scan is repeated six months later and,if stable, yearly for several years. Serum prolactin levels are measured every six months. Because tumors may enlarge despite normalized prolactin values, re-evaluation of symptoms at regular intervals (six months) is required.
   
   Surgical Intervention.    Tumors that are unresponsive to bromocriptine or that cause persistent visual field loss require surgical intervention. Unfortunately, despite surgical resection,recurrence of hyperprolactinemia and tumor growth are not uncommon. Complications of surgery include cerebral carotid artery injury, diabetes insipidus, meningitis, nasal septal perforation, partial or pan hypopituitarism, spinal fluid rhinorrhea, third nerve palsy, and recurrence. Pre treatment with bromocriptine may result in fibrosis, making resection more difficult. Periodic MRI scanning after surgery is indicated, particularly in patients with recurrent hyperprolactinemia.
   
   Transphenoidal surgery achieves resolution of hyperprolactinemia with resumption of menses in 40% with macroadenomas, and 80% with microadenomas. Recurrence after surgery is approximately 50% (range 10% to 70%). Unfortunately, 10% to 30% of patients undergoing surgery develop panhypopituitarism. Other problems of surgery include CSF leaks,meningitis, and frequent diabetes insipidus after surgery.
   
   

3. Other Considerations in the Treatment of Pituitary Adenomas
   
   In rodents, rapid pituitary prolactin-secreting adenoma (prolactinoma) occurs with high-dose estrogen administration (72). However, even conditions associated with high estrogen levels,such as pregnancy, do not cause prolactinomas in humans. Indeed, pregnancy may have a favorable influence on pre-existing prolactinomas (73,74). Recent studies (75-77) and autopsy surveys (77) indicate that estrogen administration is not associated with clinical, biochemical,or radiological evidence of growth of pituitary microadenomas or the progression of idiopathic hyperprolactinemia to an adenoma status. For these reasons, estrogen replacement or oral contraceptive use for hypo estrogenic hyperprolactinemic patients secondary to microadenoma or hyperplasia is appropriate.
   
   Pituitary Adenomas in Pregnancy.    Prolactin-secreting microadenomas rarely create complications during pregnancy. However, monitoring of patients with serial gross visual field examinations and fundoscopic examination is recommended. If persistent headaches,visual field deficits, or visual or fundoscopic changes occur, MRI scanning is advisable. Because serum prolactin levels are elevated throughout pregnancy, prolactin measurements are of no value.
   
   Although not recommended, bromocriptine use during pregnancy in women with symptomatic(visual field defects, headaches) microadenoma enlargement has resulted in resolution of deficits and symptoms (79-82).
   
   Women with previous transsphenoidal hypophysectomy and macroadenomas are monitored, as are those with microadenomas, with the addition of monthly Goldman perimetry visual field testing. Periodic MRI scanning may be necessary in women with symptoms or visual changes. Bromocriptine has been used on a temporary basis to resolve symptoms and visual field deficits in symptomatic macroadenoma patients to allow completion of pregnancy before initiation of definitive therapy. Breast feeding is not contraindicated in the presence of microadenomas or macroadenomas (79-82).