Editorial Changes in the Anatomy and Function of the Maternal Anterior Pituitary Gland During Pregnancy
s u r e m e n t (or i t s β-subunit) in serum or urine is the basis of "pregnancy" tests. Other polypep tide hormones are also produced by the placenta, including h u m a n placental lactogen, chorionic mammosomatotropin, a n d prolactin (produced by decidual cells). Gonadal steroids are pro duced by the placenta such that estradiol levels In this i s s u e of t h e Proceedings (pages 4 6 1 to are more t h a n 20-fold those found in t h e non 474), Scheithauer a n d colleagues report on a pregnant state. In h u m a n s , there is a family of five growth series of anterior pituitary glands from w o m e n who died during pregnancy. Contemporary hormone (GH) g e n e s that arise from gene dupli techniques of immunocytochemistry a n d cell cation. They are located on a 78-kilobase seg counting were u s e d to identify the changes in the m e n t of chromosome 17 and include the normal pituitary t h a t occurred during pregnancy. T h e GH gene, a h u m a n GH variant gene (hGH-V, study w a s possible only because of the outstand which codes for a protein that differs from GH by ing archives of pathologic a n d clinical material 13 amino acids a n d h a s a n additional 2 amino available at t h e Mayo Clinic. The important acids that are different in t h e leader sequence), conclusions from their study include t h e follow two expressed chorionic somatotropin genes, and ing: (1) a progressive increase i n lactotroph cell an incompletely characterized gene that is m a s s during pregnancy or lactation, which is thought not to be expressed (that is, a pseuonly partially reversible after delivery or wean dogene).^"* Although t h e hGH-V gene is proba ing; (2) a lack of identification of m a m m o s o - bly only minimally expressed in the anterior matotroph cells during pregnancy; a n d (3) no pituitary, the primary site of expression is in the other consistent c h a n g e s i n t h e morphologic placenta. Recently, serum GH variant levels have been substantiated to increase during preg features of the pituitary. Anterior pituitary hormones are tightly regu nancy.* The increase in serum GH variant lated by hypothalamic regulatory hormones and probably feeds back at t h e hypothalamic and by the feedback effects of target organ hormones pituitary levels to decrease pituitary GH secre at both the pituitary and the hypothalamic level. tion during pregnancy. This process may play a Therefore, pituitary secretion is regulated by part in t h e relative decrease in the number of both a central drive from the h y p o t h a l a m u s and GH-immunoreactive cells during pregnancy. The changes that occur in the pituitary gland feedback m e c h a n i s m s by hormones secreted by during pregnancy have been recognized for peripheral target glands. Pregnancy is associated with major endocrine almost a hundred years, but the clear demon changes w h e n the placenta a s s u m e s m a n y pitu stration of lactotroph hyperplasia and t h e time itary functions and secretes a variety of placen course of the changes were first demonstrated in tal and "pituitary" hormones.' The secretion of the current study by Scheithauer and associates. chorionic gonadotropin is responsible for main The earlier studies demonstrated t h e presence tenance of the corpus l u t e u m progesterone pro of "pregnancy" cells, which were presumed to be duction during early pregnancy, a n d i t s m e a - prolactin-secreting cells because of (1) correla tion of the tinctorial changes in pituitary tissue with circulating prolactin levels, (2) increase in Address reprint requests to Dr. M. O. Thorner, Division Of pituitary prolactin content during pregnancy, Endocrinology and Metabolism, Box 511, University of (3) increase in circulating prolactin levels during Virginia Health Sciences Center, Charlottesville, VA 22908. Mayo Clin Proc 65:597-599, 1990
597
598
EDITORIAL
pregnancy, and (4) reduction in prolactin levels and pituitary size by bromocriptine t r e a t m e n t during pregnancy. W h a t is the m e c h a n i s m for lactotroph hyper plasia? Lactotroph hyperplasia occurs in m a n y species but is notably pronounced in the preg nant woman, w h e r e a s in n o n h u m a n primates the prolactin increase during pregnancy is more modest. This difference is t h o u g h t to relate to the lower estrogen levels observed in t h e s e spe cies during pregnancy. Estradiol binds to its intracellular receptor, and this complex t h e n interacts w i t h estrogen response e l e m e n t s on various genes. The prolactin g e n e is k n o w n to be extremely sensitive to estrogen. Estradiol treat m e n t leads to increased mitosis of lactotrophs, prolactin g e n e expression, and prolactin synthe sis and release.^" In the nonpregnant state, autoregulation occurs, such that the hypothala m u s responds to the increased circulating prolactin levels by increasing hypothalamic dopamine secretion to inhibit prolactin release. During pregnancy, this regulation s e e m s to be less effective, i n a s m u c h a s circulating prolactin levels increase.^* Release of prolactin in re sponse to various secretagogues, however, is preserved during pregnancy, a situation that does not prevail in patients with prolactin-se creting pituitary tumors. A s shown by Scheithauer and co-workers, a difference is also present on histologic examina tion of pituitaries from nonpregnant patients w h o harbor prolactinomas, in comparison with pregnant patients with prolactinomas. In the former situation, the nontumorous lactotroph cells are hypoplastic and apparently "switched off." During pregnancy, the nontumorous lac totroph cells are hyperplastic. Normal lacto trophs are responsive to the substantial increases in estrogen. Although dopamine receptor stimu lation can a t t e n u a t e this response, the presence of extremely elevated estradiol levels s e e m s to override hypothalamic dopamine suppression of prolactin. The dose response of dopamine inhi bition of release of prolactin is shifted to the right by estradiol; t h u s , the dopamine effect is attenuated by estradiol. This result, however, is relative because administration of dopamine
Mayo Clin Proc, April 1990, Vol 65
agonists can suppress t h e secretion of prolactin during pregnancy; thus, the dopamine effect m a y predominate if the receptor is maximally stimulated. Therefore, in pregnancy either the hypothalamic set point is changed or the capac ity of the h y p o t h a l a m u s to secrete dopamine is limited. The observations t h a t have been made at the pathologic level correlate well with serum prolactin levels measured during normal preg nancy and the postpartum period and also with noninvasive techniques for monitoring pituitary size during pregnancy (for example, magnetic resonance imaging).^ The known effects of estrogen on prolactin secretion led several investigators to suggest t h a t exposure of w o m e n to orally administered estradiol-containing contraceptives would in crease their risk for development of prolactinsecreting pituitary tumors (see review by Mo litch'"). In a Mayo Clinic case-control study, however, no evidence w a s found to support this h y p o t h e s i s . " In addition, it w a s suggested that pituitary tumors, particularly prolactinomas, would be even more sensitive to effects of estro gen. This relationship m a y occasionally be true, but for most such tumors, it is incorrect because no additional increase in the elevated prolactin levels m a y occur during pregnancy.'^ This unexpected observation is likely to be an impor t a n t clue about w h a t distinguishes the h u m a n prolactinoma cell from the normal lactotroph. In those patients in whom visual field defects and other symptoms develop during pregnancy, the s y m p t o m s m a y be attributable to an increase in size of their tumor or an increase in size of the remaining normal lactotrophs. The increase in pituitary size that produces symptoms may be minimal if the prepregnancy pituitary abuts the optic chiasm and other vital structures (for example, the hypothalamus). In addition, the blood flow a n d vasculature increase substan tially in response to pregnancy (presumably due to estrogen). A potential limitation of the study by Scheit hauer and colleagues is that the description of t h e histologic features of t h e postmortem pitu itary m a y not reflect w h a t happens during nor-
EDITORIAL
Mayo Clin Proc, April 1990, Vol 65
mal pregnancy. S u c h a study, however, could be performed in no other way, and b e c a u s e it corre l a t e s well w i t h indirect clinical observations a n d w i t h s t u d i e s performed in a n i m a l s , w e can be reasonably certain t h a t t h e r e s u l t s and conclu sions are valid. Michael O. Thorner, M.B.,B.S., D.Sc. Division of Endocrinology and Metabolism U n i v e r s i t y of Virginia H e a l t h Sciences Center Charlottesville, Virginia REFERENCES L Pitkin RM, Spellacy WN: Physiologic adjustments in general. In Laboratory Indices of Nutritional Status in Pregnancy. By the National Research Council, Committee on Nutrition ofthe Mother and Preschool Child. Washington, DC, National Academy of Sci ences, 1978, pp 1-8 2. Barsh GS, Seeburg PH, Gelinas RE: The human growth hormone gene family: structure and evolution ofthe chromosomal locus. Nucleic Acids Res 11:39393958, 1983 3. Liebhaber SA, Urbanek M, Ray J, Tuan RS, Cooke NE: Characterization and histologic localization of human growth hormone-variant gene expression in the placenta. J Clin Invest 83:1985-1991, 1989
4.
599
Frankenne F, Rentier-Delrue F, Scippo M-L, Martial J, Hennen G: Expression of the growth hormone variant gene in human placenta. J Clin Endocrinol Metab 64:635-637, 1987 5. Maurer RA, Notides AC: Identification of an estro gen-responsive element from the 5'-flanking region of the rat prolactin gene. Mol Cell Biol 7:4247-4254, 1987 6. Waterman ML, Adler S, Nelson C, Greene GL, Evans RM, Rosenfeld MG: A single domain ofthe estrogen receptor confers deoxyribonucleic acid binding and transcriptional activation of the rat prolactin gene. Mol Endocrinol 2:14-21, 1988 7. Tyson JE, Hwang P, Guyda H, Friesen HG: Studies of prolactin secretion in human pregnancy. Am J Obstet Gynecol 113:14-20,1972 8. Rigg LA, Lein A, Yen SSC: Pattern of increase in circulating prolactin levels during human gestation. Am J Obstet Gynecol 129:454-456, 1977 9. Gonzalez JG, Elizondo G, Saldivar D, Nanez H, Todd LE, Villarreal JZ: Pituitary gland growth during normal pregnancy: an in vivo study using mag netic resonance imaging. Am J Med 85:217-220, 1988 10. Molitch ME: Current concepts: pregnancy and the hyperprolactinemicwoman. NEnglJMed 312:13641370, 1985 11. Coulam CB, Annegers JF, Abboud CF, Laws ER Jr, Kurland LT: Pituitary adenoma and oral contracep tives: a case-control study. Fertil Steril 31:25-28, 1979 12. Divers WA Jr, Yen SSC: Prolactin-producing mi croadenomas in pregnancy. Obstet Gynecol 62:425429, 1983
s u r e m e n t (or i t s β-subunit) in serum or urine is the basis of "pregnancy" tests. Other polypep tide hormones are also produced by the placenta, including h u m a n placental lactogen, chorionic mammosomatotropin, a n d prolactin (produced by decidual cells). Gonadal steroids are pro duced by the placenta such that estradiol levels In this i s s u e of t h e Proceedings (pages 4 6 1 to are more t h a n 20-fold those found in t h e non 474), Scheithauer a n d colleagues report on a pregnant state. In h u m a n s , there is a family of five growth series of anterior pituitary glands from w o m e n who died during pregnancy. Contemporary hormone (GH) g e n e s that arise from gene dupli techniques of immunocytochemistry a n d cell cation. They are located on a 78-kilobase seg counting were u s e d to identify the changes in the m e n t of chromosome 17 and include the normal pituitary t h a t occurred during pregnancy. T h e GH gene, a h u m a n GH variant gene (hGH-V, study w a s possible only because of the outstand which codes for a protein that differs from GH by ing archives of pathologic a n d clinical material 13 amino acids a n d h a s a n additional 2 amino available at t h e Mayo Clinic. The important acids that are different in t h e leader sequence), conclusions from their study include t h e follow two expressed chorionic somatotropin genes, and ing: (1) a progressive increase i n lactotroph cell an incompletely characterized gene that is m a s s during pregnancy or lactation, which is thought not to be expressed (that is, a pseuonly partially reversible after delivery or wean dogene).^"* Although t h e hGH-V gene is proba ing; (2) a lack of identification of m a m m o s o - bly only minimally expressed in the anterior matotroph cells during pregnancy; a n d (3) no pituitary, the primary site of expression is in the other consistent c h a n g e s i n t h e morphologic placenta. Recently, serum GH variant levels have been substantiated to increase during preg features of the pituitary. Anterior pituitary hormones are tightly regu nancy.* The increase in serum GH variant lated by hypothalamic regulatory hormones and probably feeds back at t h e hypothalamic and by the feedback effects of target organ hormones pituitary levels to decrease pituitary GH secre at both the pituitary and the hypothalamic level. tion during pregnancy. This process may play a Therefore, pituitary secretion is regulated by part in t h e relative decrease in the number of both a central drive from the h y p o t h a l a m u s and GH-immunoreactive cells during pregnancy. The changes that occur in the pituitary gland feedback m e c h a n i s m s by hormones secreted by during pregnancy have been recognized for peripheral target glands. Pregnancy is associated with major endocrine almost a hundred years, but the clear demon changes w h e n the placenta a s s u m e s m a n y pitu stration of lactotroph hyperplasia and t h e time itary functions and secretes a variety of placen course of the changes were first demonstrated in tal and "pituitary" hormones.' The secretion of the current study by Scheithauer and associates. chorionic gonadotropin is responsible for main The earlier studies demonstrated t h e presence tenance of the corpus l u t e u m progesterone pro of "pregnancy" cells, which were presumed to be duction during early pregnancy, a n d i t s m e a - prolactin-secreting cells because of (1) correla tion of the tinctorial changes in pituitary tissue with circulating prolactin levels, (2) increase in Address reprint requests to Dr. M. O. Thorner, Division Of pituitary prolactin content during pregnancy, Endocrinology and Metabolism, Box 511, University of (3) increase in circulating prolactin levels during Virginia Health Sciences Center, Charlottesville, VA 22908. Mayo Clin Proc 65:597-599, 1990
597
598
EDITORIAL
pregnancy, and (4) reduction in prolactin levels and pituitary size by bromocriptine t r e a t m e n t during pregnancy. W h a t is the m e c h a n i s m for lactotroph hyper plasia? Lactotroph hyperplasia occurs in m a n y species but is notably pronounced in the preg nant woman, w h e r e a s in n o n h u m a n primates the prolactin increase during pregnancy is more modest. This difference is t h o u g h t to relate to the lower estrogen levels observed in t h e s e spe cies during pregnancy. Estradiol binds to its intracellular receptor, and this complex t h e n interacts w i t h estrogen response e l e m e n t s on various genes. The prolactin g e n e is k n o w n to be extremely sensitive to estrogen. Estradiol treat m e n t leads to increased mitosis of lactotrophs, prolactin g e n e expression, and prolactin synthe sis and release.^" In the nonpregnant state, autoregulation occurs, such that the hypothala m u s responds to the increased circulating prolactin levels by increasing hypothalamic dopamine secretion to inhibit prolactin release. During pregnancy, this regulation s e e m s to be less effective, i n a s m u c h a s circulating prolactin levels increase.^* Release of prolactin in re sponse to various secretagogues, however, is preserved during pregnancy, a situation that does not prevail in patients with prolactin-se creting pituitary tumors. A s shown by Scheithauer and co-workers, a difference is also present on histologic examina tion of pituitaries from nonpregnant patients w h o harbor prolactinomas, in comparison with pregnant patients with prolactinomas. In the former situation, the nontumorous lactotroph cells are hypoplastic and apparently "switched off." During pregnancy, the nontumorous lac totroph cells are hyperplastic. Normal lacto trophs are responsive to the substantial increases in estrogen. Although dopamine receptor stimu lation can a t t e n u a t e this response, the presence of extremely elevated estradiol levels s e e m s to override hypothalamic dopamine suppression of prolactin. The dose response of dopamine inhi bition of release of prolactin is shifted to the right by estradiol; t h u s , the dopamine effect is attenuated by estradiol. This result, however, is relative because administration of dopamine
Mayo Clin Proc, April 1990, Vol 65
agonists can suppress t h e secretion of prolactin during pregnancy; thus, the dopamine effect m a y predominate if the receptor is maximally stimulated. Therefore, in pregnancy either the hypothalamic set point is changed or the capac ity of the h y p o t h a l a m u s to secrete dopamine is limited. The observations t h a t have been made at the pathologic level correlate well with serum prolactin levels measured during normal preg nancy and the postpartum period and also with noninvasive techniques for monitoring pituitary size during pregnancy (for example, magnetic resonance imaging).^ The known effects of estrogen on prolactin secretion led several investigators to suggest t h a t exposure of w o m e n to orally administered estradiol-containing contraceptives would in crease their risk for development of prolactinsecreting pituitary tumors (see review by Mo litch'"). In a Mayo Clinic case-control study, however, no evidence w a s found to support this h y p o t h e s i s . " In addition, it w a s suggested that pituitary tumors, particularly prolactinomas, would be even more sensitive to effects of estro gen. This relationship m a y occasionally be true, but for most such tumors, it is incorrect because no additional increase in the elevated prolactin levels m a y occur during pregnancy.'^ This unexpected observation is likely to be an impor t a n t clue about w h a t distinguishes the h u m a n prolactinoma cell from the normal lactotroph. In those patients in whom visual field defects and other symptoms develop during pregnancy, the s y m p t o m s m a y be attributable to an increase in size of their tumor or an increase in size of the remaining normal lactotrophs. The increase in pituitary size that produces symptoms may be minimal if the prepregnancy pituitary abuts the optic chiasm and other vital structures (for example, the hypothalamus). In addition, the blood flow a n d vasculature increase substan tially in response to pregnancy (presumably due to estrogen). A potential limitation of the study by Scheit hauer and colleagues is that the description of t h e histologic features of t h e postmortem pitu itary m a y not reflect w h a t happens during nor-
EDITORIAL
Mayo Clin Proc, April 1990, Vol 65
mal pregnancy. S u c h a study, however, could be performed in no other way, and b e c a u s e it corre l a t e s well w i t h indirect clinical observations a n d w i t h s t u d i e s performed in a n i m a l s , w e can be reasonably certain t h a t t h e r e s u l t s and conclu sions are valid. Michael O. Thorner, M.B.,B.S., D.Sc. Division of Endocrinology and Metabolism U n i v e r s i t y of Virginia H e a l t h Sciences Center Charlottesville, Virginia REFERENCES L Pitkin RM, Spellacy WN: Physiologic adjustments in general. In Laboratory Indices of Nutritional Status in Pregnancy. By the National Research Council, Committee on Nutrition ofthe Mother and Preschool Child. Washington, DC, National Academy of Sci ences, 1978, pp 1-8 2. Barsh GS, Seeburg PH, Gelinas RE: The human growth hormone gene family: structure and evolution ofthe chromosomal locus. Nucleic Acids Res 11:39393958, 1983 3. Liebhaber SA, Urbanek M, Ray J, Tuan RS, Cooke NE: Characterization and histologic localization of human growth hormone-variant gene expression in the placenta. J Clin Invest 83:1985-1991, 1989
4.
599
Frankenne F, Rentier-Delrue F, Scippo M-L, Martial J, Hennen G: Expression of the growth hormone variant gene in human placenta. J Clin Endocrinol Metab 64:635-637, 1987 5. Maurer RA, Notides AC: Identification of an estro gen-responsive element from the 5'-flanking region of the rat prolactin gene. Mol Cell Biol 7:4247-4254, 1987 6. Waterman ML, Adler S, Nelson C, Greene GL, Evans RM, Rosenfeld MG: A single domain ofthe estrogen receptor confers deoxyribonucleic acid binding and transcriptional activation of the rat prolactin gene. Mol Endocrinol 2:14-21, 1988 7. Tyson JE, Hwang P, Guyda H, Friesen HG: Studies of prolactin secretion in human pregnancy. Am J Obstet Gynecol 113:14-20,1972 8. Rigg LA, Lein A, Yen SSC: Pattern of increase in circulating prolactin levels during human gestation. Am J Obstet Gynecol 129:454-456, 1977 9. Gonzalez JG, Elizondo G, Saldivar D, Nanez H, Todd LE, Villarreal JZ: Pituitary gland growth during normal pregnancy: an in vivo study using mag netic resonance imaging. Am J Med 85:217-220, 1988 10. Molitch ME: Current concepts: pregnancy and the hyperprolactinemicwoman. NEnglJMed 312:13641370, 1985 11. Coulam CB, Annegers JF, Abboud CF, Laws ER Jr, Kurland LT: Pituitary adenoma and oral contracep tives: a case-control study. Fertil Steril 31:25-28, 1979 12. Divers WA Jr, Yen SSC: Prolactin-producing mi croadenomas in pregnancy. Obstet Gynecol 62:425429, 1983
