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Answering questions on galactorrhea, DMPA
Question: What is your clinical experience with galactorrhea, a whitish or greenish discharge in a woman who is not breast-feeding? Is use of the drug depot medroxyprogesterone acetate (DMPA) associated with galactorrhea? How long after breast-feeding has stopped should women be concerned about galactorrhea? — Alice Burin, NP, Arlington (VA) County family planning clinic
Leon Speroff, MD, professor of OB/GYN at Oregon Health Sciences University, in Portland, addresses these questions. For more information about galactorrhea, readers may want to consult A Clinical Guide for Contraception (2nd edition, Baltimore, MD, Williams & Wilkins, 1996), co-written by Speroff and Philip Darney, MD, professor of OB/GYN and reproductive sciences at the University of California at San Francisco.
"Galactorrhea is not associated with the use of DMPA. Prolactin gene transcription is stimulated by estrogen and mediated by estrogen-receptor binding to estrogen-responsive elements. This activation by estrogen requires interaction with Pit-1 in a manner not yet determined. The increase in prolactin during pregnancy parallels the increase in estrogen beginning at seven to eight weeks gestation, and the mechanism for increasing prolactin secretion is believed to be estrogen suppression of the hypothalamic prolactin-inhibiting factor, dopamine, and direct stimulation of prolactin gene transcription in the pituitary.1,2
"Although requiring estrogen for prolactin secretion, prolactin stimulation of breast milk production is prevented by progestational agents and pharmacologic amounts of estrogen. Only colos trum (composed of desquamated epithelial cells and transudate) is produced during gestation. Full lactation is inhibited by progesterone, which interferes with prolactin action at the alveolar cell prolactin receptor level. Both estrogen and progester - one are necessary for the expression of the lactogenic receptor, but progesterone antagonizes the positive action of prolactin on its own receptor, while progesterone and pharmacologic amounts of androgens reduce prolactin binding.3-5
"In the mouse, inhibition of milk protein production is due to progesterone suppression of prolactin receptor expression.6 The effective use of high doses of estrogen to suppress postpartum lactation indicates that pharmacologic amounts of estrogen also block prolactin action.
"Progesterone can directly suppress milk production. A nuclear peptide (a co-repressor) has been identified that binds to specific sites in the promoter region of the casein gene, thus inhibiting transcription.7 Progesterone stimulates the generation of this co-repressor. After delivery, the loss of progesterone leads to a decrease in this inhibitory peptide.
"The principal hormone involved in milk biosynthesis is prolactin. Without prolactin, synthesis of the primary protein, casein, will not occur, and true milk secretion will be impossible. The hormonal trigger for initiation of milk production within the alveolar cell and its secretion into the lumen of the gland is the rapid disappearance of estrogen and progesterone from the circulation after delivery.
"For these reasons, exposure to high levels of progestational agents, such as DMPA, is not associated with the clinical problem of galactorrhea.
"If galactorrhea has been present for six months to one year after breast-feeding, or hyperprolactinemia is noted in the process of working up menstrual disturbances, infertility, or hirsutism, the probability of a pituitary tumor must be recognized and an appropriate evaluation pursued. This recommendation has evolved empirically, with providers knowing that many women have the persistence of galactorrhea for many months after breast-feeding. Therefore, the rule is a soft one. The exact numbers have never been established by appropriate studies. Thus, there is plenty of room for clinical judgment with this problem."
References
1. Tyson JE, Friesen HG. Factors influencing the secretion of human prolactin and growth hormone in menstrual and gestational women. Am J Obstet Gynecol 1973; 116:377.
2. Barberia JM, Abu-Fadil S, Kletzky OA, et al. Serum prolactin patterns in early human gestation. Am J Obstet Gynecol 1975; 121:1,107.
3. Murphy LJ, Murphy LC, Stead B, et al. Modulation of lactogenic receptors by progestins in cultured human breast cancer cells. J Clin Endocrinol Metab 1986; 62:280.
4. Simon WE, Pahnke VG, Holzel F. In vitro modulation of prolactin binding to human mammary carcinoma cells by steroid hormones and prolactin. J Clin Endocrinol Metab 1985; 60:1,243.
5. Kelly PA, Kjiane J, Postel-Vinay M-C, et al. The prolactin/growth hormone receptor family. Endocr Rev 1991; 12:235.
6. Haslam SZ, Shyamala G. Progesterone receptors in normal mammary gland: receptor modulations in relation to differentiation. J Cell Biol 1980; 86:730-37.
7. Lee CS, Oka T. Progesterone regulation of pregnancy-specific transcription repressor to b-casein gene promoter in mouse mammary gland. Endocrinology 1992; 131:2257-62.
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