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Galactorrhea may be defined as any persistent discharge of milk or milk-like secretions from the breast in the absence of parturition or beyond 6 mo post partum in a non-nursing mother. Formerly regarded as rare, galactorrhea is now often diagnosed, particularly if one includes minimal degrees of secretion that may be evident only by squeezing of the breast. Doubt as to whether the secretion represents milk may be resolved by doing fat stains or, for greater specificity, analysis of specific milk products such as alpha-lactalbumin, casein, or lactose. Clinically, such tests are rarely necessary. Nonmilky nipple discharges (serous, purulent, sanguineous) are rarely reflective of an endocrine disturbance. Most nonbloody secretions are associated not with malignancy but with fibrocystic disease. (130) (131) (132) (133) (134) A careful search for breast nodules should nevertheless
Galactorrhea occurs in a wide variety of endocrine disorders and nonendocrine disorders. The largest series (235 patients) reported is that of Kleinberg and colleagues (135) ; the discussion in this section is based on this series, the findings of which are in general agreement with those of other observers. (136) (137) (138)
The most important diagnostic consideration in galactorrhea is pituitary tumor. Twenty percent of our patients with galactorrhea and 34% of those with both galactorrhea and amenorrhea had pituitary tumors. The true prevalence of tumors is undoubtedly higher than these figures indicate because of failure to detect some small microadenomas before the availability of computed tomographic (CT) scans and magnetic resonance imaging (MRI). The histologic appearance is almost always that of a prolactinoma. A minority of patients have associated acromegaly with elevated levels of both prolactin and growth hormone. As a group, patients with tumors have the highest serum prolactin values (Fig. 17-3) , and the likelihood of finding a tumor is proportional to the level of serum prolactin. In our experience all patients with concentrations higher than 300 mug/L have had tumors, and any value higher than 75 to 100 mug/L should be regarded with great suspicion. Of the few patients with tumors who had normal serum prolactin values, all but two had acromegaly or had received treatment for acromegaly. Amenorrhea occurs in more than 80% of patients with galactorrhea and tumors and was the primary complaint in 10% of these patients. Menses, if present, are apt to be abnormal; only 3 of 48 patients with tumors in our series had regular periods.
The largest category of patients with galactorrhea are those with regular menses and no associated endocrine disease. Galactorrhea is often overlooked because patients may not think it worth reporting. In more than half of patients the galactorrhea represents a residue of postpartum lactation that has never altogether disappeared despite resumption of menses. Most of these patients have prolactin levels within the normal range (see Fig. 17-3) , and fertility is usually normal. In these women the abnormality probably is not primarily hormonal but rather an excessive sensitivity of the breast to normal levels of circulating prolactin. From a clinical standpoint, the combination of regular menses and normal serum prolactin is strong evidence against the presence of pituitary tumor. It is probably unnecessary to do MRI or CT scans in these patients, although the serum prolactin level should be redetermined on one or more occasions.
A minority of women with galactorrhea have associated amenorrhea, no history of drug ingestion, and a normal sella turcica by conventional radiographs. Most such women have hyperprolactinemia (see Fig. 17-3) . Many have small sellar abnormalities on MRI or CT scans. In the absence of definitive radiographic changes, the likelihood of a pituitary tumor increases directly with the level of the serum prolactin. It is probable that the hyperprolactinemia causes the amenorrhea, because any treatment that lowers prolactin to near or within the normal range is likely to restore menses. Possible mechanisms of amenorrhea include interference by prolactin at the hypothalamic level with the release of luteinizing hormone-releasing hormone (LHRH), alteration of pituitary sensitivity to the action of LHRH, and interference with gonadotropin action at the ovarian level. Defective production of LHRH appears to be the predominant factor. (139) (140)
The so-called Chiari-Frommel syndrome is defined as galactorrhea and amenorrhea persisting more than 6 mo post partum in the absence of nursing and without evident pituitary tumor. Some of these patients probably harbor occult microadenomas that later may become radiologically evident, but in about half menses return
Figure 17-3 Plasma prolactin in 235 patients
with galactorrhea of varying causes. Among the patients with tumor, triangles
denote patients with acromegaly. Open circles or triangles denote patients
studied only after radiotherapy or surgical resection. Normal female levels of
prolactin are considered to be less than 25 ng/mL.
(Kleinberg DL, Noel GL, Frantz AG. Galactorrhea: a study of 235 cases
including 48 with pituitary tumors. Reprinted by permission of the New England
Journal of Medicine, 296;589-600, 1977.)
Galactorrhea is less common after discontinuation of oral contraceptives than is amenorrhea, with which it is usually associated. Both sequelae are relatively infrequent. As with the Chiari-Frommel syndrome, some patients eventually develop radiologically evident tumors. As in the postpartum state, milk production in this syndrome is triggered by the withdrawal of estrogen and progesterone after a period of stimulation by these hormones (and also in part by estrogen-enhanced prolactin secretion).
Galactorrhea is a rare accompaniment of primary hypothyroidism both in children in whom it may be associated with precocious puberty (141) (see Chapter 22) and in adults. (142) Among adults with primary hypothyroidism, prolactin levels are usually within the normal range or only slightly elevated (see Fig. 17-3) . (135) (143) (144) Enlargement of the sella turcica may occur in primary hypothyroidism, and if hyperprolactinemia is present the condition may mimic a prolactinoma. (145) Administration of thyroid hormone lowers the prolactin somewhat and usually stops the galactorrhea. In children thyroid hormone may also cause precocious menses to cease until the normal time of menarche. The underlying mechanisms may involve complex alterations of prolactin and gonadotropin production and degradation or changes in breast tissue sensitivity. Administration of thyroid hormone to euthyroid patients with other forms of galactorrhea does not stop milk production. (146)
Galactorrhea was present in a high percentage of women with thyrotoxicosis in one report. (147) The serum prolactin level was normal in all women, and the mechanisms are obscure.
Galactorrhea is associated with a wide variety of drugs that raise serum prolactin levels, (135) (136) (137) including phenothiazines, butyrophenones, reserpine, methyldopa, tricyclic antidepressants, estrogens, opiates, metoclopramide, verapamil, (148) cimetidine, (149) and cocaine. (150) Many of these appear to act as antidopaminergic agents, decreasing dopamine-mediated inhibition of prolactin secretion at the level of the pituitary or hypothalamus, or both.
Galactorrhea occurs occasionally after major surgery such as cholecystectomy, and its likelihood may be greater after oophorectomy. (135) Presumably, the mechanisms involve in part the acute release of prolactin (151) plus the effect of acute estrogen withdrawal when the ovaries are removed. Galactorrhea also occurs in diseases affecting the chest wall, such as herpes zoster, after thoracotomy, (111) (152) and occasionally after augmentation mammoplasty. (153) This has led to speculation that increased prolactin secretion can result from stimulation of nerves originating in the breast and areola; however, sustained hyperprolactinemia does not occur in all patients after chest wall surgery, and it is not clear that galactorrhea is more likely after thoracotomy than after other major surgical procedures. (152)
Conditions occasionally associated with galactorrhea include various hypothalamic and pituitary diseases (sarcoidosis, Schuller-Christian disease, craniopharyngioma, Cushing s disease, and head trauma) in which alteration of normal hypothalamic-pituitary connections may lead to reduced hypothalamic inhibition and consequent hyperprolactinemia. Refeeding after starvation can also cause galactorrhea. (135) Hyperprolactinemia, with or without accompanying galactorrhea, is present in some patients with renal failure (154) and hepatic cirrhosis. (155) Self-manipulation of the breasts in an attempt to reduce gynecomastia has been associated with galactorrhea in adolescent boys. (156)
Serum prolactin concentrations were within the normal range in 46% of our patients. Therefore galactorrhea can be present without hyperprolactinemia. Likewise, hyperprolactinemia can exist without galactorrhea. In the latter case the absence of galactorrhea may result from inadequacy of estrogenic and progestational priming (as in most men) or lack of a suitable triggering event involving estrogen withdrawal (oophorectomy, abortion, cessation of estrogen, or oral contraceptive medication). In many cases of galactorrhea, however, no triggering event is evident from the history. In patients with galactorrhea and normal serum prolactin levels, an earlier transient period of hyperprolactinemia may have existed at the time of onset of the galactorrhea, analogous to the situation in nursing mothers in whom milk secretion, once established, can continue for many months with what appear to be normal prolactin levels. Galactorrhea remains prolactin-dependent, however, because lowering of serum prolactin concentrations with dopamine agonists usually stops the galactorrhea. In summary, although prolactin is essential for milk production, the serum levels of the hormone do not correlate with the magnitude of milk production in patients with galactorrhea.
A careful history is essential, with attention to menses, drug ingestion, and symptoms suggestive of pituitary or hypothalamic disease (e.g., headaches; visual disturbances; abnormalities of temperature, thirst, or appetite regulation), thyroid disease, or adrenal dysfunction. Visual fields should be assessed, and evidence of endocrine disease should be sought, such as abnormal skin texture, pigmentation, or hirsutism and signs of acromegaly, hypothyroidism, Cushing s syndrome, or hyperthyroidism. The breast should be examined for nodules and gently but firmly compressed by the physician or patient to assess the degree of galactorrhea. Serum prolactin and serum gonadotropin levels should be measured in patients with amenorrhea. Thyroid function should be assessed, but other hormonal assays, e.g., for growth hormone and adrenal steroids, are not necessary in the absence of specific indications. MRI or CT scans should be performed if the serum prolactin level is even slightly elevated or if there are other signs suggestive of a pituitary tumor; such scans are not mandatory in cases of minimal galactorrhea if the serum prolactin value is within the normal range and menses are regular. Prolactin stimulation and suppression tests, involving the assessment of response to such agents as levodopa, phenothiazines, thyrotropin-releasing hormone, and metoclopramide, are too variable in their results to be useful. (157) The diagnosis of pituitary tumor rests essentially on the results of the serum prolactin determination and on radiographic evidence. (158)
In most cases the galactorrhea does not require treatment for its own sake. If fertility is not desired and if there is no evidence of pituitary tumor, treatment for elevated prolactin alone is not necessary, because there is no evidence that prolonged hyperprolactinemia in the absence of associated amenorrhea is deleterious. If amenorrhea accompanies hyperprolactinemia, as is often the case, then patients are at increased risk for development of osteoporosis (159) (160) (161) (162) (see Chapters 15 and 25) . Although hypoestrogenism undoubtedly accounts for most of the increased risk of osteoporosis in such patients, hyperprolactinemia itself may contribute independently. (160) Such observations provide a rationale for treating hyperprolactinemia in amenorrheic women, but to date the effects that lowering prolactin levels have on bone mineral content are not wholly clear. (160) (162) (163) The rate of bone loss
If MRI or CT scanning discloses the presence of a pituitary tumor but fertility is not desired, the choice of therapy depends chiefly on the size of the tumor (see Chapter 9) . If the tumor is a microadenoma, i.e., less than 1 cm in diameter, and if the risks of osteoporosis do not appear to necessitate treatment, it may be appropriate to observe such patients without specific therapy. Most of these tumors do not progress to macroadenomas. (167) (168) (169) Furthermore, a gradual reduction of serum prolactin may take place over a period of years, sometimes accompanied by spontaneous resumption of menses and cessation of galactorrhea. (168) The serum prolactin level should be assessed at 6- to 12-mo intervals, with MRI or CT scanning performed less frequently (e.g., at 2- to 5-y intervals). For macroadenomas some form of therapy--surgery, radiotherapy, or prolactin-lowering pharmacotherapy--is usually considered advisable to prevent further growth and to shrink the tumor if local pressure symptoms (e.g., visual field defects) are present.
Transsphenoidal surgery in experienced hands is a safe procedure, with mortality rates averaging 0.9% for macroadenomas and 0.27% for microadenomas. (170) Return of the serum prolactin level to normal after surgery depends both on the initial level of serum prolactin and on the size of the tumor. With initial serum prolactin values of less than 200 to 250 mug/L and with microadenomas, the immediate postoperative cure rates may be as high as 83 to 86%; with higher serum prolactin values and macroadenomas generally, the cure rate is less than 50%. (170) (171) (172) (173) (174) Enthusiasm for surgery as primary therapy for prolactinomas has declined because recurrence rates in patients originally considered cured are higher than originally anticipated. (174) (175) (176) (177) (178) (179) (180) (181) These recurrence rates range from 17% (175) (176) to 91% (179) after several years.
Radiotherapy alone is usually effective in arresting tumor growth and shrinking existing tumors and is followed by a progressive decrease in serum prolactin levels over a period of many years. (182) (183) (184) Because of the slowness of the decline in prolactin levels, the availability of drug therapy, and the possibility of inducing late-developing hypopituitarism (which has ranged from 13% (184) to 100% (183) ), radiotherapy is usually reserved as an adjunct to surgical treatment of larger tumors or for use in patients considered unacceptable risks for surgery. With either surgery or radiotherapy, restoration of menses and cessation of galactorrhea require that the serum prolactin level be lowered to near or within the normal range.
The dopamine agonists such as bromocriptine are more effective than other forms of treatment in lowering serum prolactin, stopping galactorrhea, and restoring ovulatory menses in patients with hyperprolactinemia, whether related to tumor or other causes. (117) (135) (185) The usual dose of bromocriptine is 2.5 mg/d for 1 wk, increased to 2.5 mg twice or three times a day thereafter. Initial nausea is experienced by many patients but usually disappears with time. Postural hypotension and nasal stuffiness may occur. In most cases hyperprolactinemia and the associated abnormalities recur after the agent is withdrawn. Complications related to tumor growth during pregnancy are comparatively few and are easily managed. (186) (187)
In addition to lowering serum prolactin levels, ergot derivatives shrink prolactin-secreting pituitary tumors. Pergolide is as effective as bromocriptine both for tumor shrinkage and lowering of serum prolactin and requires only once-daily therapy. (188) (189) Although tumor shrinkage has approached 100% in some series of patients treated with dopamine agonists, (190) a meta-analysis of several published series indicated that some degree of shrinkage occurs in 89% and that 79% experience reduction in tumor volume of more than 25%. (191) Tumor shrinkage can be rapid, beginning within hours or days after administration of bromocriptine. The degree of tumor shrinkage does not correlate with serum prolactin reduction. Rarely, tumor growth may occur despite continued prolactin suppression. (192) The serum prolactin level remains suppressed as long as ergot drugs are given but usually rises after they are stopped. With continued therapy (2 y or more) dose reduction may be possible, (193) and the serum prolactin level may not rise fully to its original levels on withdrawal of the drug. Some degree of tumor re-expansion must also be anticipated after withdrawal of ergot drugs, but this may not occur for many months if therapy has been prolonged. (190) (194) (195) (196) (197)
Despite the need for indefinite treatment, the success of these agents in lowering serum prolactin values and shrinking tumors has led to their use as first-line therapy instead of surgery for macroadenomas. (190) A long-acting injectable form of bromocriptine may have particular advantages in achieving rapid results with tumors. (198) (199) (200) (201) (202) Cabergoline, an oral derivative with long duration of action, has been effective in preliminary trials, (203) and a nonergot dopamine agonist is effective in some patients who are resistant to bromocriptine. (204) (205) (206) (207) Dopamine agonists may on occasion effect dramatic size reductions in some giant invasive prolactinomas. (188) (208) Short-term therapy with these agents may also be useful before surgery to shrink the tumor and thereby facilitate transsphenoidal resection. (209)
Hypoplasia or aplasia of the breast caused by delayed or absent sexual maturation, as in gonadal dysgenesis, usually responds to cyclic estrogen-progesterone therapy. The same is true of the breast atrophy that follows premature menopause. Occasionally, partial or total failure of breast development, sometimes only one-sided, (210) occurs in women with regular menses and who appear to be endocrinologically normal. Hypomastia is linked in some cases with mitral valve prolapse. (211) The problem in hypomastia may be either a deficiency of breast tissue related to a developmental defect or an insensitivity of breast tissue to normal hormonal stimulation. Estrogen or other hormone therapy should not be used to augment breast size in these patients. Estrogens are unlikely to have any significant effect in doses close to the physiological range, and the pharmacologic doses that could conceivably produce slight improvement carry unacceptable risks. If treatment appears necessary for psychological reasons, mammoplasty is indicated. (210) (212)
Macromastia, usually defined as massive breast enlargement in women, is an uncommon but unsolved problem. (213) As is the case with breast enlargement in men, breast enlargement in women is compounded by problems of definition. To separate macromastia from cases of moderate or minimal breast enlargement, the usual practice is to limit the diagnosis to women in whom the weight bearing itself is uncomfortable or in whom stretching of the overlying skin causes ulceration. If the variant associated with extreme obesity is excluded, the disorder is most commonly classified into three types: pubertal macromastia (approximately 83%), macromastia during pregnancy (about 13%), and macromastia in adult women in whom no initiating cause is identified (about 4%). (214) In addition, the disorder may be associated with penicillamine therapy. In each of these variants the enlargement can be grossly asymmetrical and can be associated with simultaneous development of ancillary breast masses in the axillae.
Macromastia of puberty can commence before or after the onset of menses, may recur after reduction mammoplasty has reduced the size of the breasts by 3 to 8 kg of weight, and may on occasion be associated with hypothyroidism. (215) (216) (217) (218) (219) When associated with pregnancy, macromastia usually has its onset in the first or second trimester; it may begin during the
On biopsy, the histologic characteristics of the breast tissue in all these various disorders are appropriate for the physiological state. Hormonal studies in women with macromastia are usually unremarkable, including normal levels of gonadal steroids, plasma prolactin, and placental lactogen. (233) It is assumed that the disorder results from some type of enhanced end-organ response to physiological amounts of hormone.
Reduction mammoplasty is the most common treatment, (236) (237) but recurrence may make total mastectomy necessary. (218) (228) (238) Various empirical therapies have been tried, including bromocriptine, (227) (229) tamoxifen, (217) (227) (228) dydrogesterone, (213) (219) (228) medroxyprogesterone, (217) and danazol, (233) (234) (235) but the experience is too small to allow assessment of efficacy with any of these agents.
Many women complain at times of pain in the breast. (239) (240) (241) In the large series studied by Preece and colleagues, (239) the pain was commonly diffuse and subject to cyclic premenstrual induction or exacerbation. A smaller group had localized pain ascribed to ductal ectasia and periductal mastitis. Tietze s syndrome, trauma, and cancer were diagnoses in a smaller number of cases. The response to placebo therapy among these patients tends to be so high that careful double-blind studies are necessary to document the effect of hormonal or other therapy. Evening primrose oil, a plant extract with few side effects, and bromocriptine were about equally effective, and both were more effective than placebo in relieving pain in patients with cyclic, as opposed to noncyclic, mastalgia. (242) Danazol, an antigonadotropic agent, is more effective than either of these drugs. (242) (243) (244) In view of the menstrual irregularities, weight gain, and occasional androgenic effects that may occur with danazol, however, this drug should be used, if at all, only in severe cases after other measures have failed and then only for short periods. (245) Tamoxifen, an antiestrogen, may be as effective as danazol with fewer side effects, although its use is still experimental. (246) Because of the chronicity of symptoms and the likely need for long-term therapy, any hormonal treatment should be undertaken with caution. (247)
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