Depo Shot Make Me Lactate Again
Evaluation and Treatment of Galactorrhea
Am Fam Physician. 2001 May 1;63(9):1763-1771.
See patient information handout on galactorrhea, written by the authors of this article.
Article Sections
- Abstract
- Normal Lactation and Prolactin
- Differential Diagnosis
- Evaluation
- Treatment
- References
Galactorrhea, or inappropriate lactation, is a relatively mutual problem that occurs in approximately xx to 25 percent of women. Lactation requires the presence of estrogen, progesterone and, most chiefly, prolactin. Stress, suckling, sleep, sexual intercourse and medications may increment prolactin levels, whereas dopamine inhibits its release. The differential diagnosis of galactorrhea includes pituitary adenomas, neurologic disorders, hypothyroidism, numerous medications, chest stimulation, chest wall irritation and physiologic causes. The evaluation includes a thorough history and physical exam, besides as selected laboratory and imaging studies to rule out secondary causes such as an intracranial mass or a tumor. Diagnostic studies include a pregnancy test, a prolactin level, renal and thyroid function tests and, if indicated, magnetic resonance imaging of the encephalon. Treatment options for prolactinomas include observation, dopamine agonists, surgery and radiation therapy, depending on tumor size and associated symptoms. Fortunately, the prognosis for patients with prolactinomas is good: most prolactinomas remain stable or regress. In meaning women, prolactinomas must be observed closely because the lesions may greatly increase in size.
Patients with breast issues such every bit galactorrhea are often commencement seen by family physicians. The true incidence of galactorrhea is unknown, but information technology is estimated that 20 to 25 percent of women feel this problem at some time in their life.1,2 Although rare, galactorrhea can also occur in males.
Normal Lactation and Prolactin
- Abstract
- Normal Lactation and Prolactin
- Differential Diagnosis
- Evaluation
- Treatment
- References
Before lactation, the female person breast is primed by estrogen, progesterone, growth hormone, insulin, thyroid hormone and glucocorticoids. These hormones assist in the growth of the ductal system and lobules, and in the evolution of secretory characteristics of the alveoli. Ironically, high levels of estrogen and progesterone also inhibit lactation at receptor sites in the breast tissue. The sharp drop in the levels of these hormones after delivery, in the presence of an elevated prolactin level, facilitates lactation.
Prolactin is normally secreted by the anterior pituitary gland at a low basal charge per unit, with secretion continuously suppressed by prolactin inhibiting cistron (Figure 1).two–4 Dopamine, released from the hypothalamus and delivered via the hypothalamic-hypophysial portal arrangement, is the main constituent of prolactin inhibiting gene. Prolactin acts at the breast to promote milk secretion and at the ovaries to regulate the release of luteinizing hormone and follicle-stimulating hormone.
Lactation
FIGURE ane.
Physiology of lactation.
Information from references ii through 4.
Prolactin levels bike and are highest during sleep. Levels in normal nonpregnant women range from 1 to 20 ng per mL (1 to 20 μg per Fifty), depending on the laboratory, and may increase to equally high as 300 ng per mL (300 μg per Fifty) during pregnancy.3 Suckling, stress, aridity, exercise, sexual intercourse and sleep increase the basal secretion rate from the pituitary gland, as do estrogen, thyrotropin-releasing hormone and possibly serotonin.
Differential Diagnosis
- Abstruse
- Normal Lactation and Prolactin
- Differential Diagnosis
- Evaluation
- Treatment
- References
The differential diagnosis of galactorrhea includes weather condition affecting many unlike organ systems, with causes ranging from physiologic to cancerous (Table 1).ii,5–10
TABLE 1
Causes of Galactorrhea
| Physiologic conditions (14 percentage) | ||
| Pregnancy and postpartum country | ||
| Breast stimulation | ||
| "Witch'southward milk" in neonates | ||
| Neoplastic processes (18 pct) | ||
| Pituitary adenoma (prolactinoma) | ||
| Bronchogenic carcinoma | ||
| Renal adenocarcinoma | ||
| Lymphoma | ||
| Craniopharyngioma | ||
| Hydatidiform mole | ||
| Hypernephroma | ||
| Mixed growth hormone-secreting and prolactin-secreting tumors | ||
| Cypher-prison cell adenoma | ||
| Hypothalamic-pituitary disorders (<10 per centum) | ||
| Craniopharyngioma and other tumors | ||
| Infiltrative weather condition | ||
| Sarcoidosis | ||
| Tuberculosis | ||
| Schistosomiasis | ||
| Pituitary-stalk resection | ||
| Multiple sclerosis | ||
| Empty-sella syndrome | ||
| Systemic diseases (<10 percent) | ||
| Hypothyroidism | ||
| Chronic renal failure | ||
| Cushing's affliction | ||
| Acromegaly | ||
| Medications and herbs (twenty percentage)* | ||
| Chest wall irritation (<10 percent) | ||
| Irritating clothes or ill-fitting brassieres | ||
| Canker zoster | ||
| Atopic dermatitis | ||
| Burns | ||
| Chest surgery | ||
| Spinal cord injury or surgery | ||
| Spinal cord tumor | ||
| Esophagitis | ||
| Esophageal reflux | ||
| Idiopathic (35 percent) | ||
| Hyperprolactinemia | ||
| Euprolactinemia | ||
PHYSIOLOGIC Weather condition
Galactorrhea may be considered physiologic. Pregnant women may lactate as early on as the second trimester and may continue to produce milk for up to two years afterwards cessation of breast-feeding. Fluctuating hormone levels, especially during puberty or menopause, may likewise cause lactation. Nipple stimulation, commonly associated with repeated breast self-examinations or sexual activity, causes an increase in prolactin secretion.
Up to five percent of neonates produce "witch'southward milk" for the first calendar month of life.11 This milk production results from the precipitous drib in maternal estrogen and progesterone levels after delivery.
NEOPLASTIC PROCESSES
Although galactorrhea is not associated with breast cancer, it can exist caused by neo-plastic processes in the brain and pituitary gland. Fortunately, nigh of these tumors are benign. Approximately 20 percent of women with galactorrhea have radiologically evident pituitary tumors, and the prevalence increases to 34 percent in women who also have amenorrhea.2
The about common tumor resulting in hyperprolactinemia is the pituitary prolactinoma, a beneficial growth of the prolactin-secreting cells of the anterior pituitary gland. Autopsy reports point that prolactinomas are present in 10 to xxx percentage of the population.4
Pituitary prolactinomas are associated with elevated prolactin levels. Clinical signs and symptoms include headache, galactorrhea, amenorrhea, defects in peripheral vision, hirsutism, acne, and hypogonadism presenting equally decreased libido, decreased fertility or decreased bone density. The prognosis for patients with these tumors is excellent. Most pituitary prolactinomas backslide or remain stable for many years.
Nonpituitary malignancies, such equally bronchogenic carcinoma, renal adenocarcinoma and Hodgkin'southward and T-prison cell lymphomas, may as well release prolactin.
HYPOTHALAMIC-PITUITARY DISORDERS
Whatever disruption of the communication between the pituitary and hypothalamus glands can result in increased prolactin secretion and milk production. Craniopharyngiomas and other tumors, infiltrative diseases, pituitary-stalk resection and empty-sella syndrome may disrupt the commitment of dopamine to the pituitary gland.
SYSTEMIC DISEASES
Systemic diseases must besides be considered in the differential diagnosis of galactorrhea. The well-nigh common is hypothyroidism. Low levels of thyroid hormone result in increased levels of the thyrotropin-releasing hormone, which increases prolactin secretion. Galactorrhea and symptoms of hypothyroidism abate with thyroid hormone replacement therapy.
Chronic renal failure may cause galactorrhea as a result of decreased clearance of prolactin by the kidneys. Hypersecretion of cortisol (Cushing'south affliction) or growth hormone (acromegaly) may as well accept associated hyperprolactinemia.
MEDICATIONS
Galactorrhea can be caused by numerous medications and some herbs (Tabular array 2).12–19 Consequently, the evaluation of this status must include a thorough and accurate review of current and recent medications, including herbal supplements.
Tabular array 2
Medications and Herbs Associated with Galactorrhea
| Antidepressants and anxiolytics | ||
| Alprazolam (Xanax) | ||
| Buspirone (BuSpar) | ||
| Monoamine oxidase inhibitors | ||
| Moclobemide (Manerix; available in Canada) | ||
| Selective serotonin reuptake inhibitors | ||
| Citalopram (Celexa) | ||
| Fluoxetine (Prozac) | ||
| Paroxetine (Paxil) | ||
| Sertraline (Zoloft) | ||
| Tricyclic antidepressants | ||
| Antihypertensives | ||
| Atenolol (Tenormin) | ||
| Methyldopa (Aldomet) | ||
| Reserpine (Serpasil) | ||
| Verapamil (Calan) | ||
| Antipsychotics | ||
| Histamine H2-receptor blockers | ||
| Cimetidine (Tagamet) | ||
| Famotidine (Pepcid) | ||
| Ranitidine (Zantac) | ||
| Hormones | ||
| Conjugated estrogen and medroxyprogesterone (Premphase, Prempro) | ||
| Medroxyprogesterone contraceptive injections (Depo-Provera) | ||
| Oral contraceptive formulations | ||
| Phenothiazines | ||
| Chlorpromazine (Thorazine) | ||
| Prochlorperazine (Compazine) | ||
| Others | ||
| Other drugs | ||
| Amphetamines | ||
| Anesthetics | ||
| Arginine | ||
| Cannabis | ||
| Cisapride (Propulsid) | ||
| Cyclobenzaprine (Flexeril) | ||
| Danazol (Danocrine) | ||
| Dihydroergotamine (DHE 45) | ||
| Domperidone (Motilium; bachelor in Canada and Mexico) | ||
| Isoniazid (INH) | ||
| Metoclopramide (Reglan) | ||
| Octreotide (Sandostatin) | ||
| Opiates | ||
| Rimantadine (Flumadine) | ||
| Sumatriptan (Imitrex) | ||
| Valproic acid (Depakene) | ||
| Herbs | ||
| Anise | ||
| Blessed thistle | ||
| Fennel | ||
| Fenugreek seed | ||
| Marshmallow | ||
| Nettle | ||
| Red clover | ||
| Cherry raspberry | ||
Many antipsychotic medications and metoclopramide (Reglan) accept lactogenic activity because of their antidopaminergic effects. As many every bit xv percent of patients report galactorrhea inside seven to 75 days later starting antipsychotic medication.17
With the increasing utilise of selective serotonin reuptake inhibitors, more women are reporting galactorrhea as a side consequence.12 As a result, researchers at present postulate that serotonin may have a role in regulating prolactin secretion. Tricyclic antidepressants, the monoamine oxidase inhibitor moclobemide (Manerix; bachelor in Canada) and the anxiolytic buspirone (BuSpar) are likewise known to cause galactorrhea.13,fourteen
At to the lowest degree four antihypertensive agents have been reported to crusade inappropriate lactation. Methyldopa (Aldomet) inhibits the formation of dopamine, thereby raising the basal prolactin secretion rate. Galactorrhea has also been reported with the apply of atenolol (Tenormin), reserpine (Serpasil) and verapamil (Calan).14,15
The histamine H2-receptor blockers cimetidine (Tagamet), famotidine (Pepcid) and ranitidine (Zantac) accept all been reported to crusade galactorrhea.16
Estrogen and progesterone, constitute in oral contraceptive formulations and the medroxy-progesterone contraceptive injection (Depo-Provera), may cause lactation. Possible mechanisms include direct actions on the chest tissue or effects on gonadotropins. Galactorrhea occurs more than often after discontinuation of oral contraceptive pills than during prolonged utilise (similar to the hormone withdrawal and lactation that can occur in the postpartum period).
The dosages of estrogen and progesterone used in postmenopausal hormonal replacement therapy are generally not loftier enough to cause galactorrhea. However, some patients with hyperprolactinemia may not have symptoms if they are estrogen deficient. Once hormone replacement therapy is started, the breast tissue is primed, and galactorrhea may then occur.
Nonpuerperal lactation can too be caused by illicit drugs. Close questioning is advised considering patients may be hesitant to written report the utilize of amphetamines, cannabis, benzodiazepines and opiates, all of which tin cause lactation. A number of herbs used in cooking and equally supplements must likewise be considered in the differential diagnosis. In addition, adoptive mothers accept used metoclopramide to facilitate breast-feeding. They accept likewise used fenugreek seed and domperidone (Motilium; available in Canada and Mexico) to accomplish "induced lactation."
CHEST WALL IRRITATION
Galactorrhea tin can occur considering of breast wall irritation from wearable or ill-fitting brassieres. It can also be caused by irritation related to skin conditions such as herpes zoster and atopic dermatitis. Burns have been associated with the evolution of galactorrhea. Breast surgeries, including implant placement and reduction mammoplasty, tin cause postoperative galactorrhea.
Example reports take discussed galactorrhea associated with spinal cord injury or surgery, also as spinal cord tumors.five–vii Severe esophagitis and esophageal reflux may cause galactorrhea by stimulating the thoracic nerves via the cervical and thoracic ganglia.8
IDIOPATHIC GALACTORRHEA
Idiopathic galactorrhea is a diagnosis of exclusion, and patients may have normal or elevated levels of prolactin. In such situations, the machinery of milk production may be an increased prolactin release in response to stimuli, with a normal basal prolactin rate.
The differential diagnosis of galactorrhea is extensive. Even so, patients tin be reassured that this status is not associated with chest cancer. In fact, 1 study found that idiopathic galactorrhea was associated with a reduced risk of breast cancer.20
Evaluation
- Abstract
- Normal Lactation and Prolactin
- Differential Diagnosis
- Evaluation
- Handling
- References
The evaluation of galactorrhea includes a thorough history and physical examination (Figure 2). Selected laboratory tests and imaging studies are besides important.
Evaluation of Galactorrhea
FIGURE 2.
Algorithm for the evaluation of galactorrhea.
HISTORY
The history should include the duration of galactorrhea, previous pregnancies, and other symptoms of hyperprolactinemia, such every bit infertility, decreased libido, acne, hirsutism and menstrual irregularity. The patient's menstrual history is important because hyperprolactinemia, through its result on gonadotropin-releasing hormone, may cause low estrogen levels. As a result, the patient may have amenorrhea or oligomenorrhea, as well equally decreased bone density.
The patient should exist asked about symptoms of an intracranial mass, such as visual-field defects, cranial nerve palsy and headache. It is also of import to inquire about symptoms of systemic diseases, including hypothyroidism and Cushing'due south disease.
An authentic listing of all medications, including over-the-counter and illicit substances, herbs and other supplements, is essential.
PHYSICAL Test
The physical examination includes an evaluation of the patient'south visual fields, thyroid gland, breasts and skin. If the type of nipple discharge is in doubt, the dr. may effort to elicit the belch and examine it under a microscope. In galactorrhea, microscopy reveals numerous fatty globules and footling cellular material. If the doctor is not sure that the discharge is milk, a sample may be sent to a laboratory for special staining and evaluation, including cytology.
LABORATORY TESTS
Laboratory studies may include a serum pregnancy test, a prolactin level, renal function tests and a thyroid-stimulating hormone level.
Considering prolactin levels are influenced by stress and breast stimulation, claret should not exist drawn immediately later on a chest examination. Rather, it should exist fatigued at least one hour afterward the exam and when the patient is relaxed. If the initial prolactin level is borderline, the level should be repeated one or two times because of the great fluctuation in prolactin levels throughout the day. A level greater than 200 ng per mL (200 μg per 50) is almost always associated with a prolactinoma or other prolactin-secreting tumor.
Serum cortisol, growth hormone and insulin-like growth factor levels should be obtained if the patient has signs or symptoms of Cushing'due south disease (cushingoid features) or growth hormone excess (acromegalic features).
IMAGING STUDIES
Imaging studies are also important in the evaluation of abnormal lactation. If the patient has symptoms suggestive of an intracranial mass, galactorrhea with amenorrhea, or an elevated prolactin level (greater than twenty ng per mL), magnetic resonance imaging (MRI) of the encephalon is indicated to detect a pituitary tumor or other intracranial lesion. If the patient has normal menstruation and a normal prolactin level, the risk for pituitary adenoma is depression, and imaging is not necessary. However, if a patient has galactorrhea associated with amenorrhea or oligomenorrhea, even with a normal prolactin level, the take chances of a pituitary adenoma is nevertheless significant, and an imaging study of the gland is warranted.21
Given the lack of association between galactorrhea and chest cancer, mammography is not necessary unless other findings on the physical examination are suggestive of breast pathology. Nipple discharge that is not milky should exist evaluated because it may be caused past intraductal papilloma, papillomatosis, mammary duct ectasia, fibrocystic breasts or carcinoma.
Treatment
- Abstract
- Normal Lactation and Prolactin
- Differential Diagnosis
- Evaluation
- Treatment
- References
The goals of galactorrhea handling include decreasing or eliminating the patient'due south symptoms, curing whatever identified underlying cause, preventing bone loss, relieving the patient'southward anxiety and fears, and, when desired, maintaining the patient'south fertility and ability to lactate.
NORMAL PROLACTIN
Patients with idiopathic or physiologic galactorrhea and normal prolactin levels should be reassured. All patients with galactorrhea should be advised to avoid excessive breast stimulation, including repeated cocky-examinations or excessive nipple manipulation during sexual activity. If galactorrhea is caused past a medication, the agent should be discontinued if possible.
High PROLACTIN LEVEL WITH NORMAL MRI STUDIES
The prevention of osteoporosis is a business concern in any patient with hyperprolactinemia. High prolactin levels, through their effect on gonadotropins and resulting low estrogen levels, decrease bone density and thereby increase the risk of osteoporosis.3 This risk can be reduced with medical therapy using dopamine agonists (e.one thousand., bromocriptine [Parlodel], cabergoline [Dostinex]), even in the absence of a tumor.22
Medical therapy can also be constructive in restoring fertility in the patient with galactorrhea, regardless of the prolactin levels. A prolactin level should be obtained every three to half-dozen months, and further studies should be performed if the level continues to rise.
PROLACTINOMA
The treatment of a prolactinoma depends on its size and the presence or absenteeism of symptoms indicative of increased intracranial pressure or devastation of nearby structures. If the patient has a macroadenoma or symptoms such as headache or changes in vision, medical or surgical handling is indicated. If the patient has no symptoms of an intracranial mass and the tumor is less than one cm in size (microadenoma), handling options include close observation or medical therapy. The prolactin level should be measured every three to six months, and imaging studies should be performed every two to three years (sooner if the prolactin levels ascension).
Medical treatments for prolactinomas include bromocriptine and cabergoline. These agents activate the lactotroph Dtwo-receptor sites and, similar to dopamine, inhibit the synthesis of prolactin. Bromocriptine and cabergoline normalize prolactin levels, rapidly shrink tumors and restore vision, flow and fertility.23,24 Side effects include nausea, airsickness, postural hypotension, headache and nasal congestion, although these are experienced less often with cabergoline. The dosage of either agent is gradually increased and titrated to the patient'south symptoms and prolactin level.
Cabergoline is the agent of choice in patients not wishing to conceive. Its long one-half-life, twice-weekly dosing and tolerability better patient compliance. Cabergoline is also constructive in reducing prolactin levels in some tumors that are resistant to bromocriptine.23
Surgery is indicated in patients who cannot tolerate medications, take tumors that are resistant to medication or experience rapid visual loss that does not answer to medical therapy.25 Unfortunately, long-term surgical cure rates for prolactinomas are poor (50 to lx percent for microadenomas and 25 percent for macroadenomas).24
Radiation therapy is an choice in the patient who cannot tolerate medications and is not a surgical candidate. Irradiation is sometimes used every bit an adjunct to surgical handling.
PITUITARY ADENOMAS AND PREGNANCY
Close observation is required for pregnant women with prolactinomas. From 1 to 5 percent of microadenomas and 23 pct of macroadenomas increase in size during pregnancy.26 The significant patient with a prolactinoma should be referred to a specialist in pituitary disorders, as management is controversial.
Because of its more all-encompassing safe record, bromocriptine is the drug of selection in women with pituitary adenomas who wish to conceive. Although no agin fetal effects have been reported, the drug should be discontinued once pregnancy is suspected, unless in that location is evidence of a very large adenoma or an enlarging adenoma. Prepregnancy surgical debulking of a large macroadenoma, followed by bromocriptine therapy, is another handling option.
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REFERENCES
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3. Katznelson Fifty, Klibanski A. Hyperprolactinemia: physiology and clinical arroyo. In: Krisht AF, Tindall GT, eds. Pituitary disorders: comprehensive management. Baltimore: Lippincott Williams & Wilkins, 1999:189–98.
four. Yazigi RA, Quintero CH, Salameh WA. Prolactin disorders. Fertil Steril. 1997;67:215–25.
five. Yarkony GM, Novick AK, Roth EJ, Kirschner KL, Rayner Due south, Betts HB. Galactorrhea: a complication of spinal cord injury. Curvation Phys Med Rehabil. 1992;73:878–80.
vi. Faubion WA, Nader S. Spinal cord surgery and galactorrhea: a case report. Am J Obstet Gynecol. 1997;177:465–6.
7. Katsuren E, Ishikawa S, Honda K, Saito T. Galactorrhoea and amenorrhoea due to an intradural neurinoma originating from a thoracic intercostal nerve radicle. Clin Endocrinol [Oxf]. 1997;46:631–6.
eight. Turton DB, Shakir KM. Galactorrhea caused past esophagitis. Am J Obstet Gynecol. 1995;173:1629–30.
9. Tolis G, Somma M, Van Campenhout J, Friesen H. Prolactin secretion in sixty-5 patients with galactorrhea. Am J Obstet Gynecol. 1974;118:91–101.
10. Kleinberg DL, Noel GL, Frantz AG. Galactorrhea: a written report of 235 cases, including 48 with pituitary tumors]. North Engl J Med. 1977;296:589–99.
11. Madlon-Kay DJ. 'Witch's milk.' Galactorrhea in the newborn. Am J Dis Kid. 1986;140:252–3.
12. Egberts AC, Meyboom RH, De Koning FH, Bakker A, Leufkens HG. Non-puerperal lactation associated with antidepressant drug employ. Br J Clin Pharmacol. 1997;44277–81.
13. Dunn NR, Freemantle SN, Pearce GL, Isle of mann RD. Galactorrhoea with moclobemide [Letter of the alphabet]. Lancet. 1998;351:802.
14. Physicians' desk reference: companion guide. Montvale, N.J.: Medical Economics, 2000:1293,1315, 1337.
fifteen. Lee ST. Hyperprolactinemia, galactorrhea, and atenolol [Letter]. Ann Intern Med. 1992;116:522.
xvi. Guven One thousand, Kelestimur F. Hyperprolactinemia and galactorrhea with standard-dose famotidine therapy [Letter]. Ann Pharmacother. 1995;29:788.
17. Windgassen Thousand, Wesselmann U, Schulze Mönking H. Galactorrhea and hyperprolactinemia in schizophrenic patients on neuroleptics: frequency and etiology. Neuropsychobiology. 1996;33:142–six.
eighteen. Stuart Thousand, ed. The Encyclopedia of herbs and herbalism. New York: Grosset & Dunlap, 1979:176,191, 239,276–7.
xix. Fetrow CW, Avila JR. Professional's handbook of complementary & alternative medicines. Spring-firm, Pa.: Springhouse, 1999:82–3,248–ix.
20. Rothenberg RE, LaRaja RD, Pryce East, Mueller SC. Breast cancer and idiopathic galactorrhea. J Med Assoc Ga. 1990;79:363–5.
21. Davajan 5, Kletzky O, March CM, Roy Southward, Mishell DR. The significance of galactorrhea in patients with normal menses, oligomenorrhea, and secondary amenorrhea. Am J Obstet Gynecol. 1978;130:894–904.
22. Sanfilippo JS. Implications of not treating hyper-prolactinemia. J Reprod Med. 1999;449(12 suppl):1111–v.
23. Verhelst J, Abs R, Maiter D, Van den Bruel A, Vandeweghe M, Velkeniers B, et al. Cabergoline in the handling of hyperprolactinemia: a study in 455 patients. J Clin Endocrinol Metab. 1999;84:2518–22.
24. Molitch ME. Medical treatment of prolactinomas. Endocrinol Metab Clin Northward Am. 1999;28:143–69, vii.
25. Biller BM. Hyperprolactinemia. Int J Fertil Womens Med. 1999;44:74–7.
26. Molitch ME. Management of prolactinomas during pregnancy. J Reprod Med. 1999;44:1121–6.
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