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Pituitary Disorders During Pregnancy
ENDOCRINE DISORDERS IN PREGNANCY
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PITUITARY DISORDERS DURING PREGNANCY Diane Prager, MD, and Glenn D. Braunstein, MD
ANATOMIC AND PHYSIOLOGIC CHANGES IN THE PITUITARY GLAND DURING PREGNANCY
Pituitary enlargement with the formation of large chromophobe pregnancy cells has long been known to occur. Histologic and immunocytochemical studies of human pituitaries from various stages of pregnancy, obtained at autopsy, demonstrate massive hyperplasia of the lactotrophs with substantial reduction in follicle-stimulatinghormone (FSH) and luteinizing hormone (LH) immunoreactive cells.lo7Lactotroph hyperplasia is secondary to multiplication of preexisting mature lactotrophs, evidenced by numerous mitoses and recruitment of inhibited somatotrophs (reduced growth hormone [GHI mRNA content) to become mammosomatotrophs.121By 11 months postpartum, regression of lactotroph hyperplasia still is not complete.121Thyrotroph and corticotroph populations remain unchanged throughout pregnancy.lo7Overall, the volume of the adenohypophysis increases by about one third during pregnancy, resulting in an upward convexity of the superior surface on radiograph.44,51 By magnetic resonance (MR) imaging the stalk remains midline but the neurohypophysis is not visualized during the third trime~ter.~~ From the Division of Endocrinology, Department of Medicine, Cedars-Sinai Medical CenterUniversity of California at Los Angeles School of Medicine, Los Angeles, California
ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA VOLUME 24. NUMBER 1 MARCH 1995
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Accompanying these morphologic changes in the pituitary, serum prolactin levels begin to rise at 5 to 8 weeks of gestation and are 10 times the nonpregnant level at term.7,'24After delivery, prolactin levels decline rapidly reaching baseline within 2 weeks in nonlactating w ~ m e n . ' ~De,'~~ spite the hyperprolactinemic state of pregnancy the normal dynamics of the prolactin response to thyrotropin-releasing hormone (TRH), antidopaminergic agents, and sleep are p r e s e r ~ e d . ~"7,'33 ~ , ' ~Prolactin ~, prepares lZ4The the breast tissue for the initiation and maintenance of lactation.123, increased prolactin synthesis and secretion, which mainly affects the nonglycosylated fraction of p r ~ l a c t i n70,~71, ~ 89 , is directly or indirectly related to the elevated estrogen levels that accompany p r e g n a n ~ y . ~ Although ~,~~,~~ amniotic fluid prolactin levels may be high, principally from decidual synthesis and secretion, levels of serum prolactin remain low in pregnant woman with pre-existing hypoprolactinemia or who are on bromocryptine therapy.4,", 13,20, 33, 57, 99 Furthermore, although administering bromocryptine during pregnancy decreases maternal and fetal levels of prolactin, it does not affect levels of prolactin in the amniotic fluid.lO'Fetal pituitary secretion of prolactin results in levels between 80 and 500 ng/ mL at birth.4,", 13,20,33,57,99 Maternal serum FSH and LH are decreased to undetectable levels, and the pituitary gonadotropin response to gonadotropin-releasing hormone (GnRH) is blunted or absent.56,78, 98, 104,127 The decreased gonadotropin synthesis and secretion are secondary to the feedback inhibition of elevated levels of estrogen, progesterone, prolactin, and inhibin at the pituitary level.', 72, 75, lo4 The estrogen-induced elevation of thyroxine-binding globulin levels results in an increase in total thyroxine (T4) and triiodothyronine (T3) concentration^.^,^^^ Free T4 and T3 levels may be slightly elevated in early pregnancy.48The high human chorionic gonadotropin (hCG) levels at the end of the first trimester are thought to induce thyroid overactivity with a resultant reduction in maternal thyroid-stimulating hormone (TSH) secretion; however, TSH levels remain within the normal range throughout pregnancy.42,48,83,90,118,135 Both basal and stimulated maternal GH levels are low because of the negative feedback inhibition by placental variant GH on the hypothalamus and pituitary.37,38, 39, 50, 119, 132 Maternal levels of insulinlike growth factor 1 (IGF-I), however, are normal to elevated during pregnancy and are normalized in pregnant women with GH de47, 76 ficien~y.~~, The estrogen-induced rise in cortisol-binding globulin results in an increase in total serum cortisol level^.^^,'^^ Plasma-free cortisol is also consistently elevated in pregnant women with preservation of the diurnal rhythm.85,lo8 Paradoxically, adrenocorticotropic hormone (ACTH) levels are elevated during pregnancy with an exaggerated response of cortisol to ACTH s t i m ~ l a t i o n . ~ The ~ , 'relative ~~ contribution of placental ACTH to maternal serum ACTH is unknown. After dexamethasone ingestion, either overnight or for 2 days, incomplete suppression of total serum cortisol, free serum cortisol, and urine free cortisol is observed.97 927
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ANTERIOR PITUITARY DISORDERS IN PREGNANCY Pituitary Adenomas
Prolactinoma
Hyperprolactinemia is associated with anovulation and infertility; however, treatment of the elevated prolactin restores ovulation in 90% of patients. The major issues to be considered in a pregnant woman with a prolactinoma are (1) the effect of the pregnancy on tumor size, and (2) the effect of dopamine agonists on the fetus. Symptomatic enlargement of pituitary tumors during pregnancy is not surprising in view of the known stimulatory effects of estrogen on the l a ~ t o t r o p h s Data . ~ ~ from two large reviews address the issue of tumor growth during pregnancy. Molitch reported that of 246 patients with microadenomas (less than l cm in diameter) from 16 series, 4 (1.6%) complained of headaches or visual disturbance with tumor enlargement, whereas 11 (4.5%) had asymptomic tumor enlargement (radiologic assessment). No surgery was required. Of 45 patients with macroadenomas (greater than 1 cm in diameter) and no prior surgical or radiation therapy, 7 (15.5%)had symptomatic tumor growth and 4 (8.9%)had asymptomatic tumor enlargement (radiologic assessment), necessitating bromocryptine therapy for 2 patients and surgery for 4.81Of 46 patients with macroadenomas and prior surgery or radiation therapy, only 2 (4.3%)developed symptomatic tumor growth whereas none had evidence of asymptomatic tumor growth. Gemzell and Wango collected data on 187 patients. Of 85 pregnant women with microadenomas (no prior treatment), 1 patient developed severe headaches with visual field disturbances at 12 weeks' gestation. The patient was treated conservatively and underwent transsphenoidal surgery after delivery at 36.5 weeks. Three of the other patients developed headaches and were managed conservatively. In 46 women with previously untreated macroadenomas, 19 developed severe headaches and visual impairment. Twelve patients were treated conservatively, 5 underw e n t t r a n s s p h e n o i d a l surgery d u r i n g pregnancy, 1 received bromocryptine, and 1 received high-dose steroids. The authors40 then compared these findings to 70 women who had received prior irradiation, surgery, or combination therapy. In this treated group, 2 patients reported headaches plus visual field defects, whereas 3 patients reported headache alone. One patient received irradiation, and 4 others were managed conservatively. Summarizing the data from these two reviews, the risk of clinically important enlargement of a microadenoma is 1.6%to 5.5%40,80 but is 15.5% to 35.7%40,80 for macroadenomas, with a considerable reduction if the patient received prior radiation or surgical treatment. Bromocryptine has been used successfully in a number of cases to reduce tumor size. In more than 100 women who took bromocryptine during weeks 20 through 41 of gestation, no neonatal abnormalities except for one infant with a single undescended testicle and second infant with
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a talipes deformity were reported.13,18, 32, 60, 64, 79, lo5,136 Serum estradiol, estriol, progesterone, testosterone, dehydroepiandosterone, dehydroepiandrosterone sulfate, androstenedione, cortisol, and human placental lactogen were unaffected in women given bromocryptine at weeks 6 through 9 or 20 before therapeutic a b ~ r t i o n . ~Maternal ~ , ' ~ ~ and fetal prolactin levels were shown to be s ~ p p r e s s e dFollow-up .~~ studies on 64 infants and children (aged 6 months to 9 years) whose mothers took bromocryptine for tlie first 4 weeks of gestation showed no abn0rmalities.9~Nevertheless, fetal exposure to bromocryptine should be limited. Although the postpartum prolactin levels and tumor sizes vary between series, it is likely that bromocryptine use during pregnancy prevents tumor enlargement.24,54, '06 Precise data are not available but the effect of nursing on tumor growth is probably less than that of pregnancy and therefore need not be discouraged?' Management of Prolactinoma During Pregnancy Treatment choices for anovulatory patients with microadenomas who wish to conceive are (1) bromocryptine, (2) transsphenoidal surgery, or (3) irradiation or surgery followed by bromocryptine. A trial of bromocryptine alone is recommended because of its efficacy in restoring ovulation and the relatively low risk of tumor enlargement.81Eighty percent to 85% of patients with hyperprolactinemia will become pregnant after bromocryptine therapy or surgery.66,'06 In certain rare cases, clomiphene , ~ ~ ,conception, ~~,~~ citrate, hCG, or pulsatile GnRH will be r e q ~ i r e d . ' ~ After the bromocryptine should be stopped and monitored for clinical signs or symptoms suggestive of tumor enlargement. Random prolactin measurements are not helpful since prolactin levels may not rise, as occurs in a normal pregnancy or with tumor enlargement. Similarly, visual field testing and computed tomography (CT) are indicated only in symptomatic patient^.^' Routine CT or MR imaging after delivery is advocated at some centers to detect asymptomatic microadenoma tumor growth:' but probably is unnecessary if the postpartum prolactin level returns to the pregestational range. Molitch8' recommends bromocryptine for patients with intrasellar and inferiorly extending macroadenomas. These patients have a marginally higher risk of tumor enlargement compared with patients with miIn patients with larger macroadenomas, especially if sucroaden~mas.~' prasellar extension is present, debulking surgery (to allow for expansion) before pregnancy followed by bromocryptine therapy to normalize prolactin levels, and thus allow ovulation,.is recommended?' The long-term risk of hypopituitarism after radiation therapy makes this approach less acceptable. Similarly, although continuous use of bromocryptine throughout gestation has been advocated,lo5the data are insufficient to recommend its routine use. Advanced pregnancy diagnosed in a patient on bromocryptine, however, does not justify a therapeutic abortion. Thus, the therapeutic alternatives need to be clearly presented to patients who will have to make highly individualized and informed decisions.
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In patients with macroadenomas treated with surgery with or without bromocryptine, monthly Goldman perimetric visual field testing is recommended during pregnancy. MR imaging is indicated for patients with enlarging visual field defects and those who become symptomatic. Symptomatic tumor growth is best managed with bromocryptine because surgery has a 1.5-fold risk of fetal loss in the first trimester and a fivefold risk in the second trimester.17Those patients with no response to bromocryptine and worsening vision need surgery and urgent delivery if the pregnancy is advanced enough. There are no data on the safety of the other available long-acting dopamine agonist, pergolide, during pregnancy. After delivery, MR imaging should be done to document asymptomatic macroadenoma tumor growth. Acromegaly Menstrual irregularity is a common early finding in acromegaly, but pregnancy may occur. Pregnancy does not not alter the course of acromegaly and therapy can be safely deferred until after delivery. In 34 reported cases of acromegaly and pregnancy, only one patient developed transient blindness that resolved with bromocryptine treatment.' Symptomatic tumor enlargement is treated with surgery or bromocrypl3I In a single acromegalic patient treated with octreotide tine.25,69, 77, during the first trimester, no apparent side effects were observed, and the pregnancy went to term.65Insufficient information exists, however, regarding the safety of octreotide during pregnancy to recommend its routine use. High circulating levels of GH have no apparent deleterious effects on pregnancy.2, 8'9, 15, 25,69,77,82,131 Cushing's Syndrome Suppression of gonadotropin secretion by elevated cortisol and androgen levels results in oligomenorrhea or amenorrhea in 75% of patients ~,"~ rarely occurs, however, and the with Cushing's ~ y n d r o m e . ~Pregnancy symptoms of pregnancy may obscure the diagnosis of Cushing's syndrome. Aron and colleagues5reviewed 58 pregnant patients with Cushing's syndrome. The most common cause was found to be benign adrenal tumors. The increased incidence of hyperfunctioning adrenal adenomas during pregnancy may be because of stimulation of adrenal growth by placental ACTH,97hCG,"O variant GH,37,38, 39, or other growth factors. In contrast, Cushing's disease (pituitary dependent bilateral adrenal hyperplasia) accounts for more than 60% of cases of Cushing's syndrome in nonpregnant adults.43,'02 The diagnosis of Cushing's syndrome during pregnancy is difficult; however, preservation of the normal diurnal rhythm of serum cortisol and assessment of urinary 17-hydroxycorticosteroids may be Although a nonsuppressible level of plasma or urine cortisol by high-dose dexamethasone suggests the presence of ectopic ACTH syndrome or adrenal tumor, lack of suppression with low-dose dexamethasone or overnight testing with dexamethasone may be seen during p r e g n a n ~ y . ~ ~
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Plasma ACTH levels are not helpful in differentiating pituitary-dependent Cushing's disease from normal pregnancy. Patients with mild cases of Cushing's syndrome should be managed expectantly. Major complications include hypertension; gestational diabetes: and pulmonary edema.59Premature onset of labor is common, occurring in 60% of patient^.^ Metyrapone, aminoglutethimide, and ketoconazole should be avoided because of fetal and maternal toxi ~ i t y .22~ , Pituitary Insufficiency During Pregnancy
Lymphocytic Hypophysitis Lymphocytic hypophysitis is a rare autoimmune disorder that presents as a mass lesion of the sella turcica, which may be associated with hypopit~itarism.2~ It is characterized by lymphocytic infiltration and destruction of the anterior pituitary. Thirty-five cases have been reported with most occurring in late pregnancy or up to 1 year postp a r t ~ m . ' 23, ~ ,73, 91 In addition to symptoms of tumor growth, (headaches, visual disturbances), pituitary testing may demonstrate partial or complete hypopituitarism. The commonest partial deficit is in ACTH function with intact gonadal function.23Forty percent of patients have prolactin deficiency and another 40% have hyperprolactinemia secondary to stalk compre~sion.2~ A single patient with diabetes insipidus (in the absence of surgery) has also been reported." Lymphocytic hypophysitis may present with hypoglycemia, in which case steroids should be givens6 Microscopically, the adenohypophysis is infiltrated with lymphocytes and plasma cells, with occasional germinal centers, thus excluding the diagnosis of lymphoma. Fibrosis may be present in the later stagesF3 Approximately 30% of all patients have evidence for other endocrine autoimmune disease including thyroiditis, pernicious anemia, adrenalitis, diabetes mellitus, and parathyroiditis. Antinuclear and antimitochondrial antibodies have been reported as well as a small number of patients with antipituitary a n t i b o d i e ~ . ~ ~ Approximately 25% of patients die, probably from adrenal insufficiency. Surgery is effective for relieving pressure symptoms whereas bromocryptine produced a partial improvement in vision in a few ~ a s e s . 6 , ~ ~ , 91 Pituitary function may spontaneously improve or worsen with time; therefore, hormone replacement should be given as needed.l9rZ3 Sheehan's Syndrome Postpartum pituitary necrosis, or Sheehan's syndrome, is possibly the most common cause of anterior pituitary ins~fficiency.6~ The hypertrophied pituitary gland of pregnancy is more susceptible to a compromised blood supply through the low-pressure pituitary sinusoidal system that accompanies peripartum hem~rrhage."~ Additionally, locally released factors may mediate vascular spasm or constriction of the arterial blood
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supply to the pituitary, since the severity of a postpartum hemorrhage does not always correlate with the presence of Sheehan's syndrome. Pregnant women with insulin-dependent (Type I) diabetes mellitus are prone to develop antepartum pituitary necrosis, presumably because of microvascular disease.I6In these patients, decreasing insulin requirements may accompany the hypopituitarism and serve as a clue to the diagnosis. Sickle cell disease may be associated with occlusion of pituitary small vessels and hypopituitarism. This is not a common occurrence, and the true incidence of pituitary necrosis secondary to a sickle cell crisis during pregnancy is ~ n k n o w n . " ~ Classically, Sheehan's syndrome presents with failure of lactation, rapid breast involution, failure to resume menses, failure to regrow shaved pubic or axillary hair, and skin depigmentation (including the areola). Signs and symptoms of hypothyroidism and hypoadrenalism gradually develop. Diabetes insipidus has been reported but is unusual.21, 45,128 More commonly, defects in vasopressin secretion with loss of maximal urinary concentrating ability occur, correlating with the presence of posterior pituitary infarcts and neuronal destruction in the supraoptic and paraventricular nuclei.H2Steroid therapy in these patients may precipitate overt diabetes insipidus by suppressing vasopression (AVP)secretion and increasing free water clearanceF8Organic psychosis is common in Sheehan's syndrome and responds to hormonal repla~ement.~~ A single case of bone marrow aplasia, which responded to hormone replacement, and a case of hypomagnesemia with cardiac arrhythmia have been reported.34,87 Pituitary necrosis accompanying Sheehan's syndrome is frequently incomplete, with selective loss of hormone secretion.56,120, 129 Thus, subsequent pregnancy may be possible if gonadotropin function is 81
The diagnosis of Sheehan's syndrome is suggested by low or normal levels of TSH, ACTH, FSH, and LH with low levels of T4, cortisol, and estradiol. Subnormal levels of IGF-1 suggest GH deficiency, although stimulation tests may be required to document GH reduction. Impaired prolactin responses to TRH or dopamine antagonists are consistently found in patients with Sheehan's syndrome.28,5 6 ~ Testing for TSH, LH, and FSH reserve may yield normal, subnormal, or delayed responses to TRH or GnRH, suggesting the presence of islands of pituitary cells that have been cut off from the hypothalamic-portal circulati~n."~ CT or MR imaging should be performed to exclude a mass lesion. Remnants of pituitary tissue, or in long-standing cases, an empty sella may be seen on CT.35,116 The differential diagnosis of Sheehan's syndrome includes a number of systemic diseases: chronic infections, HIV, granulomatous diseases, rheumatoid arthritis, amyloidosis, metastatic carcinoma, and hemochromatosis.10Hormone replacement is given as needed and is especially important in women who subsequently become pregnant.45
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POSTERIOR PITUITARY DISORDERS DURING PREGNANCY Pre-Existing Diabetes lnsipidus
These patients usually have normal fertility and pregnancie~.~~ They require increased doses of AVP to control polyuria during pregnancy because of placental synthesis of vasopressinase, an enzyme that rapidly degrades AVP and o x y t o ~ i nVasopressinase .~~ levels increase throughout gestation, peak at term, and disappear within 1 month after delivery, corresponding with a return to normal of AVP requirements after delivery.lo3 Transient Diabetes lnsipidus of Pregnancy
Transient diabetes insipidus of pregnancy may manifest in a number of ways: The vasopressin-responsive form probably occurs only in patients with mild or subclinical central diabetes insipidus who cannot increase their AVP secretion to counteract the effects of placental vasopress i n a ~ e .53~ ~ , Vasopressin-resistant forms manifest as true renal vasopressin resistance or abnormally high vasopressin clearance because of elevated plasma vasopressinase activityF9,30, 63 In patients with transient diabetes insipidus secondary to enhanced vasopressinase activity, there is no response to exogenous AVP, with a normal response to dDAVP, an AVP analogue that is not degraded by vasopre~sinase.~~ In true renal resistance (nephrogenic diabetes insipidus) there is no response to AVP or dDAVP. Krege and colleagues64in a review of 17 cases noticed that in patients with excess vasopressinase activity, symptoms occur during the third trimester. Hypertension, proteinuria, hyperuricemia, and elevated liver enzymes were documented. Multiple gestations with excessive vasopressinase production or the presence of liver abnormalities with the resultant reduction in vasopressinase clearance, or overproduction of a hepatic form of aminopeptidase that may degrade AVP have been implicated in the etiology of this condition. Nephrogenic diabetes insipidus is managed with thiazide diuretics whereas central and transient diabetes insipidus are treated with dDAVPF9 367
Postpartum Diabetes lnsipidus
Central diabetes insipidus in the postpartum period may occur in association with Sheehan's syndromeZ9or lymphocytic hyp~physitis.~~ SUMMARY
A number of morphologic and physiologic changes accompany pregnancy such as an increase in lactotrophs and prolactin production, and a
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decrease in gonadotropins and GH. The hormonal milieu can affect patients with prolactinomas, especially macroadenomas, to cause an increase in size in a minority of patients. Complications are treated with bromocryptine. Enlargement of GH-secreting tumors with acromegaly may respond to bromocryptine and possibly to octreotide. Pituitary tumors causing Cushing's syndrome may need removal if major complications develop. Hypopituitarism during pregnancy may be the result of lymphocytic hypophysitis or antepartum pituitary necrosis, and in the postpartum period may be because of postpartum hemorrhage and pituitary necrosis. These abnormalities need prompt recognition and hormonal replacement therapy with neurosurgical decompression to avoid serious morbidity and mortality. Posterior pituitary problems in pregnancy usually manifest by diabetes insipidus, with a pregnancy-specific variety resulting from excessive degradation of AVP by placental vasopressinase. The condition is treated with an analogue dDAVP, which is resistant to vasopressinase.
References 1. Abe Y, Hasegawa Y, Miyamoto K, et al: High concentrations of plasma immunoreactive inhibin during normal pregnancy in women. J Clin Endocrinol Metab 71:133,1990 2. Abelove WA, Rupp JJ, Paschkis KE: Acromegaly and pregnancy. J Clin Endocrinol Metab 14:32, 1954 3. Ain KB, Mori Y, Refetoff S: Reduced clearance rate of thyroxine-binding globulin (TBG) with increased sialylation: A mechanism for estrogen-induced elevation of serum TBG concentration. J Clin Endocrinol Metab 65:689,1987 4. Anderson AN, Pedersen H, Westergaard JG, et al: Normal and abnormal prolactin levels during human pregnancy. Acta Obstet Gynecol Scand 63:145, 1984 5. Aron DC, Schnall AM, Sheeler LR: Cushing's syndrome and pregnancy. Am J Obstet Gynecol162:244,1990 6. Asa SL, Bilbao JM, Kovacs K, et al: Lymphocytic hypophysitis of pregnancy resulting in hypopituitarism: A distinct clinicopathologic entity. Ann Intern Med 95:166, 1981 7. Barberia JM, Abu-Fadil S, Kletzky OA, et al: Serum prolactin patterns in early human gestation. Am J Obstet Gynecol 121:1107, 1975 8. Barkan AL: Acromegaly. Diagnosis and therapy. Endocrinol Metab Clin North Am 18:277, 1989 9. Beckers A, Stevenaert A, Foidart J-M, et al: Placental and pituitary growth hormone secretion during pregnancy in acromegalic women. J Clin Endocrinol Metab 71:725, 1990 10. Berczi I: Prolactin, pregnancy and autoimmune disease. J Rheumatol20:1095,1993 11. Bergh T, Nillius SJ, Enoksson P, et al: Bromocriptine-induced regression of a suprasellar extending prolactinoma during pregnancy. J Endocrinol Invest 7:133, 1984 12. Bergh T, Skarin G, Nillius SJ, et al: Pulsatile GnRH therapy: An alternative successful therapy for induction of ovulation in infertile normo- and hyperprolactinemic amenorrhoeic women with pituitary tumors. Acta Endocrinol110:440, 1985 13. Bigazzi M, Ronga R, Lancranjan I, et al: A pregnancy m an acromegalic woman during bromocriptine treatment: Effects on growth hormone and prolactin in the maternal, fetal, and amniotic compartments. J Clin Endocrinol Metab 48:9, 1979 14. Biswas S, Rodeck CH: Plasma prolactin levels during pregnancy. Br J Obstet Gynaecol 83:683, 1976 15. Bloch B: Pituitary tumors in pregnancy: A case report. S Afr Med J 55:57,1979 16. Brennan CF, Malone RGS, Weaver JA: Pituitary necrosis in diabetes mellitus. Lancet July 7:12, 1956
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17. Brodsky JB, Cohen EN, Brown BW Jr, et al: Surgery during pregnancy and fetal outcome. Am J Obstet Gynecol138:1165,1980 18. Canales ES, Garcia IC, Ruiz JE, et al: Bromocriptine as prophylactic therapy in prolactinoma during pregnancy. Fertil Steril36:524, 1981 19. Castle D, De Villiers JC, Melvill R: Lymphocytic adenohypophysitis: Report of a case with demonstration of spontaneous tumor regression and a review of the literature. Br J Neurosurg 2:401,1988 20. Chochinov RH, Ketupanya A, Mariz IK, et al: Amniotic fluid reactivity detected by somatomedin C radioreceptor assay: Correlation with growth hormone, prolactin and fetal renal maturation. J Clin Endocrinol Metab 42:983,1976 21. Collins ML, O'Brien P, Cline A: Diabetes insipidus following obstetric shock. Obstet Gynecol53:16S, 1979 22. Connel JMC, Cordiner J, Davies DL, et al: Pregnancy complicated by Cushing's syndrome: Potential hazard of metyrapone therapy. Case report. Br J Obstet Gynaecol 92:1192,1985 23. Cosman F, Post KD, Holub DA, et al: Lymphocytic hypophysitis: Report of three new cases and review of the literature. Medicine 68:240,1989 24. Crosignani PG, Mattei AM, Scraduelli C, et al: Is pregnancy the best treatment for hyperprolactinemia? Hum Reprod 4:910, 1989 25. Cundy T, Grundy EN, Melville H, et al: Bromocriptine treatment of acromegaly following spontaneous conception. Fertil Steril42:134, 1984 26. Daughaday WH, Trivedi B, Winn HN, et al: Hypersomatotropism in pregnant women, as measured by a human liver radioreceptor assay. J Clin Endocrinol Metab 70:215, 1990 27. Demey-Ponsart E, Foidar JM, Sulon J, et al: Serum CBG, free and total cortisol and circadian patterns of adrenal function in normal pregnancy. J Steroid Biochem 16:165, 1982 28. Di Zerega G, Kletzky OA, Mishell DR Jr: Diagnosis of Sheehan's syndrome using a sequential pituitary stimulation test. Am J Obstet Gynecol132:348,1978 29. Durr JA: Diabetes insipidus in pregnancy. Am J Kidney Dis 9:276,1987 30. Durr JA, Hoggard JG, Hunt JM, et al: Diabetes insipidus in pregnancy associated with abnormally high circulating vasopressinase activity. N Engl J Med 361:1070,1987 31. Elias KA, Weiner RI: Direct arterial vascularization of estrogen-induced prolactinsecreting anterior pituitary tumors. Proc Natl Acad Sci USA 81:4549, 1984 32. Espersen T, Ditzel J: Pregnancy and delivery under bromocriptine therapy. Lancet 2:985, 1977 33. Fang VS, Kim MH: Study on maternal, fetal, and amniotic human prolactin at term. J Clin Endocrinol Metab 41:1030,1975 34. Ferrari E, Boss010 PA, Barosi G: Sheehan's syndrome with complete bone marrow aplasia: Long-term results of substitution therapy with hormones. Br J Haematol 33:575, 1976 35. Fleckman AM, Schubart UK, Danziger A, Fleischer N: Empty sella of normal size in Sheehan's syndrome. Am J Med 75:585,1983 36. Ford SM: Transient vasopressin-resistant diabetes insipidus of pregnancy. Obstet Gyneco168:288,1986 37. Frankenne F, Closset J, Gomez F, et al: The physiology of growth hormones (GHs) in pregnant women and partial characterization of the placental GH variant. J Clin Endocrinol Metab 66:1171, 1988 38. Frankenne F, Rentier-Delrue F, Scippo M-L, et al: Expression of growth hormone variant gene in human placenta. J Clin Endocrinol Metab 64635,1987 39. Frankenne F, Scippo M-L, Van Beeumen J, et al: Identification of placental human growth hormone as the growth hormone-V gene - expression product. J Clin Endocrinol Getab 71:15,1990 40. Gemzell C, Wang CF: Outcome of pregnancy in women with pituitary adenoma. Fertil Steril31:363, 1979 41. Gindoff PR, Loucopoulos A, Jewelewicz R: Treatment of hyperprolactinemic amenorrhea with pulsatile gonadotropin-releasing hormone therapy. Fertil Steril46:1156,1986 42. Glinoer D, De Nayer P, Bourdoux P, et al: Regulation of maternal thyroid during pregnancy. J Clin Endocrinol Metab 71:276,1990
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43. Gold EM: The Cushing syndromes: Changing views of diagnosis and treatment. Ann Intern Med 90:892,1979 44. Gonzalez JG, Elizondo G, Saldivar D, et al: Pituitary gland growth during normal pregnancy: An in vivo study using magnetic resonance imaging. Am J Med 85:217, 1988 45. Grimes HG, Brooks MH: Pregnancy in Sheehan's syndrome: Report of a case and review. Obstet Gynecol Surv 35:481,1980 46. Guitelman A, Aparicio NJ, Mancini A, et al: Release of prolactin during pregnancy: Effect of sulpride. Fertil Steril 30:42, 1978 47. Hall K, Enberg G, Hellem E, et al: Somatomedin levels in pregnancy: Longitudinal study in healthy subjects and patients with growth hormone deficiency. J Clin Endocrinol Metab 59:587,1984 48. Harada A, Hershman JM, Reed AW, et al: Comparison of thyroid stimulators and thyroid hormone concentrations in the sera of pregnant women. J Clin Endocrinol Metab 48:793, 1979 49. Hashim IA, Aston R, Butler J, et al: The proportion of glycosylated prolactin in serum is decreased in hyperprolactinemic states. J Clin Endocrinol Metab 71:111,1990 50. Hennen G, Frankenne F, Closset J, et al: A human placental GH: Increasing levels during second half of pregnancy with pituitary GH suppression as revealed by monoclonal antibody radioimmunoassays. Int J Fertil30:27, 1985 51. Hinshaw DB, Hasso AN, Thomson JR, et al: High resolution computed tomography of the postpartum pituitary gland. Neuroradiology 26:299,1986 52. Howlett TA, Rees LH, Besser GM: Cushing's syndrome. Clin Endocrinol Metab 14:911, 1985 53. Hughes JM, Barron WM, Vance ML: Recurrent diabetes insipidus associated with pregnancy: Pathophysiology and therapy. Obstet Gynecol73:462,1989 54. Ikegami H, Aono T, Koizumi K, et al: Relationship between the methods of treatment for prolactinomas and the puerperal lactation. Fertil Steril47:867,1987 55. Jara-Quezada L, Graef A, Lavalle C: Prolactin and gonadal hormones during pregnancy in systemic lupus erythematosus. J Rheumatol 18:349, 1991 56. Jeppsson S, Rannevik G, Kullander S: Studies on the decreased gonadotropin response after administration of LH/FSH-releasing hormone during pregnancy and the puerperium. Am J Obstet Gynecol120:1029,1974 57. Jialal I, Naidoo C, Norman RJ, et al: Pituitary function in Sheehan's syndrome. Obstet Gynecol63:15,1984 58. Kauppila A, Chatelain P, Kirkinen P, et al: Isolated prolactin deficiency in a woman with puerperal alactogenesis. J Clin Endocrinol Metab 64:309,1987 59. Khanna S, Ammini A, Saxena S, et al: Hypopituitarism presenting as delirium. Int J Psychiatry Med 18939, 1988 60. Koerten JM, Morales WJ, Washington SR, et al: Cushing's syndrome in pregnancy: A case report and literature review. Am J Obstet Gynecol 154626,1986 61. Konopka P, Raymond JP, Merceron RE, et al: Continuous administration of bromocriptine in the prevention of neurological complications in pregnant women with prolactinomas. Am J Obstet Gynecol 146:935, 1983 62. Kovacs K: Necrosis of anterior pituitary in humans. Neuroendocrinol4:170, 1969 63. Kreines K, Perin E, Salzer R: Pregnancy in Cushing's syndrome. J Clin Endocrinol Metab 24:75, 1964 64. Krege J, Katz VL, Bowes WA Jr: Transient diabetes insipidus of pregnancy. Obstet Gynecol Surv 44789,1989 65. Krupp P, Monka C, Richter K: The safety aspects of infertility treatments. In Program of the Second World Congress of Gynecology and Obstetrics, Rio de Janeiro, October 1988 66. Landolt AM, Schmid J, Wimpfheimer C, et al: Successful pregnancy in a previously infertile woman treated with SMS-201-995 for acromegaly. N Engl J Med 320:671,1989 67. Laws ER, Fode NC, Randall RV, et al: Pregnancy following transsphenoidal resection of prolactin-secreting pituitary tumors. J Neurosurg 58:685, 1983 68. Lehmann WD, Musch K, Wolf AS: Influence of bromocriptine on plasma levels of prolactin and steroid hormones in the 20th week of pregnancy. J Endocrinol Invest 2:251, 1979 69. Liebhaber SA, Urbanek M, Ray J, et al: Characterization and histologic localization of
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human growth hormone-variant gene expression in the placenta. J Clin Invest 83:1985, 1989 Luboshitzky R, Dickstein G, Barzilai D: Bromocriptine-induced pregnancy in an acromegalic patient. JAMA 244584, 1980 Markoff E, Lee DW: Glycosylated prolactin is a major circulating variant in human serum. J Clin Endocrinol Metab 65:1102,1987 Markoff E, Lee DW, Hollingsworth DR: Glycosylated and non-glycosylated prolactin in serum during pregnancy. J Clin Endocrinol Metab 67:519,1988 Marrs RP, Kletzky OA, Mishell DR Jr: A separate mechanism of gonadotropin recovery after pregnancy termination. J Clin Endocrinol Metab 52:545, 1981 McDermott MW, Griesdale DE, Berry K, et al: Lymphocytic adenohypophysitis. Can J Neurol Sci 15:38, 1988 lMcGarrigle HHG, Sarris S, Little V, et al: Induction of ovulation with clomiphene and human chorionic gonadotropin in women with hyperprolactinaemic amenorrhea. Br J Obstet Gynaeco) 85692, 1978 McLachlan RI, Healy DL, Robertson DM, et al: The human placenta: A novel source of inhibin. Biochem Biophys Res Commun 140:485,1986 Merimee TJ, Zapf J, Froesch EII: Insulin-like growth factor in pregnancy: Studies in a growth hormone deficient dwarf. J Clin Endocrinol Metab 541101, 1982 Miyakawa I, Taniyama K, Koike H, et al: Successful pregnancy in an acromegalic patient during 2-Br-alpha-ergo-cryptine (CB-154) therapy. Acta Endocrinol101:333,1982 Miyake A, Tanizawa 0 , Aono T, et al: Pituitary responses in LH secretion to LHRH during pregnancy. Obstet Gynecol49:549,1977 Modena G, Portioli I: Delivery after bromocriptine therapy. Lancet 2:558,1977 Molitch ME: Pregnancy and the hyperprolactinemic woman. N Engl J Med 312:1365, 1985 Moreira AC, Maciel LMZ, Foss MC, et al: Gonadotropin secretory capacity in a patient with Sheehan's syndrome with successful pregnancies. Fertil Steril42:303, 1984 Nabarro JDN: Acromegaly. Clin Endocrinol26:481, 1987 Nisula BC, Ketelslegers JM: Thyroid-stimulating activity and chorionic gonadotropin. J Clin Invest 54:494,1974 Nolten WE, Lindheimer MD, Reuckert PA, et al: Diurnal pattens and regulation of cortisol secretion in pregnancy. J Clin Endocrinol Metab 51:466,1980 Notterman RB, Jovanovic L, Peterson R, et al: Spontaneous hypoglycemic seizures in pregnancy: A manifestation of panhypopituitarism. Arch Intern Med 144:189, 1984 Nunoda S, Ueda K, Kameda S, et al: Sheehan's syndrome with hypomagnesemia and polymorphous ventricular tachycardia. Jpn Heart J 30:251, 1989 Oelkers W: Hyponatremia and inappropriate secretion of vasopressin (antidiuretic hormone) in patients with hypopituitarism. N Engl Med 321:492, 1989 Pansini F, Bergamini CM, Malfaccini M, et al: Multiple molecular forms of prolactin during pregnancy. J Endocrinol106:81,1985 Pekonen F, Alfthan H, Stenman U-H, et al: Human chorionic gonadotropin (hCG) and thyroid function in early human pregnancy: Circadian variation and evidence for intrinsic thyrotropic activity of hCG. J Clin Endocrinol Metab 66953, 1988 Pestell RG, Best JD, Alford FP: Lymphocytic hypophysitis. The clinical spectrum of the disorder and evidence for an autoimmune pathogenesis. Clin Endocrinol33:457,1990 Petraglia F, Calza L, Garuti GC, et al: Presence and synthesis of inhibin subunits in human decidua. J Clin Endocrinol Metab 71:487, 1990 Prysor-Jones RA, Silverlight JJ,Jenkins JS: Oestradiol, vasoactive intestinal peptide and fibroblast growth factor in the growth of human pituitary tumor cells in vitro. J Endocrinol 120:171, 1989 Prysor-Jones RA, Silverlight JJ, Kennedy SJ, et al: Vasoactive intestinal peptide and the stimulation of lactotroph growth by oestradiol in situ. J Endocrinol 116:259, 1988 Radwanska E, McGarrigle IIHG, Little V, et al: Induction of ovulation in women with hyperprolactinemic amenorrhea using clomiphene and human chorionic gonadotropin of bromocriptine. Fertil Steril 32:187, 1979 Raymond JP, Goldstein E, Konopka P, et al: Follow-up of children born of bromocriptine-treated mothers. Hormone Res 22:239, 1985
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97. Rees LH, Burke CW, Chard T, et al: Possible placental origin of ACTH in normal human pregnancy. Nature 254620,1975 98. Reyes FI, Winter JSD, Faiman C: Pituitary gonadotropin function during human pregnancy: Serum FSH and LH levels before and after LHRH administration. J Clin Endocrinol Metab 42:590, 1976 99. Riddick DH, Luciano AA, Kusmik WF, et al: Evidence for a nonpituitary source of amniotic fluid prolactin. Fertil Steril31:35, 1979 100. Rigg LA, Lein A, Yen SSC: Pattern of increase in circulating prolactin levels during human gestation. Am J Obstet Gynecol 129:454, 1977 101. Rigg LA, Yen SSC: Multiphasic prolactin (PRL) secretion during parturition in humans. Am J Obstet Gynecol 128:215,1977 102. Ross EJ, Linch DC: Cushing's syndrome-killing disease: Discriminatory value of signs and symptoms aiding early diagnosis. Lancet 1:646,1982 103. Rubens R, Thiery M: Diabetes insipidus and pregnancy. Eur J Obstet Gynecol Reprod Bio126:265, 1987 104. Rubinstein LM, Parlow AF, Derzko C, et al: Pituitary gonadotropin response to LHRH in human pregnancy. Obstet Gynecol52:172, 1978 105. Ruiz-Velasco V, Tolis G: Pregnancy in hyperprolactinemic women. Fertil Steril41:793, 1984 106. Samaan NA, Schultz PN, Leavens TA, et al: Pregnancy after treatment in patients with prolactinoma: Operation versus bromocriptine. Am J Obstet Gynecol 155:1300,1986 107. Scheithauer BW, Sano T, Kovacs KT, et al: The pituitary gland in pregnancy: A clinicopathologic and immunohistochemical study of 69 cases. Mayo Clin Proc 65:461, 1990 108. Schulte HM, Weisner D, Allolio B: The corticotropin releasing hormone test in late pregnancy: Lack of adrenocorticotropin and cortisol response. Clin Endocrinol33:99, 1990 109. Scott EM, McGarrigle HHG, Lachelin GCL: The increase in plasma and saliva cortisol levels in pregnancy is not due to the increase in corticosteroid-binding globulin levels. J Clin Endocrinol Metab 71:639, 1990 110. Seron-Ferre M, Larence C, Jaffe R: Role of hCG in regulation of the fetal zone of the human fetal adrenal gland. J Clin Endocrinol Metab 46:834, 1978 111. Shahmanesh M, Ali Z, Pourmand M, et al: Pituitary function tests in Sheehan's syndrome. Clin Endocrinol12:303,1980 112. Sheehan HI, Whitehead R: The neurohypophysis in post-partum hypopituitarism. T Pathol Bacteriol85:145, 1963 113. ~ h e e h a nHL: Simmonds's disease due to post-partum necrosis of the anterior pituitary. Q J Med 8:277,1939 114. Sheehan HL, Davis JC: Pituitary necrosis not primarily related to pregnancy. In Postpartum Hypopituitarism. Springfield, CC Thomas, 1982, p 143 115. Sheehan HL, Stanfield JP: The pathogenesis of post-partum necrosis of the anterior lobe of the pituitary gland. Acta Endocrinol37479, 1961 116. Sherif IH, Vanderley CM, Beshyah S, et al: Sella size and contents in Sheehan's syndrome. Clin Endocrinol30:613,1989 117. Sialy R, Rastogi GK, Gupta AN: Serum prolactin and its response to thyrotropin releasing hormone in normal pregnancy. Ind J Med Res 65:519,1977 118. Silverberg J, O'Donnell J, Sugenoya A, et al: Effect of human chorionic gonadotropin on human thyroid tissue in vitro. J Clin Endocrinol Metab 46:420, 1978 119. Spellacy WN, Buhi WC, Birk SA: Human growth hormone and placental lactogen levels in midpregnancy and late post-partum. Obstet Gynecol36:238, 1970 120. Stacpoole PW, Kandell TW, Fisher WR: Primary empty sella, hyperprolactinemia, and isolated ACTH deficiency after post-partum hemorrhage. Am J Med 74:905, 1983 121. Stephaneau L, Kovacs K, Lloyd RV et al: Pituitary lactotrophs and Aomatotrophs in pregnancy: A correlative in situ hybridization and immunohistochemical study. Virchows Arch B Cell Pathol 62:291,1992 122. Suda T, Iwashita M, Ushiyama T, et al: Responses to corticotropin-releasing hormone and its bound and free forms in pregnant and nonpregnant women. J Clin Endocrinol Metab 69:38, 1989 123. Tyson JE, Friesen H, Anderson M: Human lactational and ovarian response to endogenous prolactin release. Science 177897, 1972
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124. Tyson JE, Hwang P, Guyda H, et al: Studies of prolactin secretion in human pregnancy. Am J Obstet Gynecol 113:14,1972 125. Urbanic RC, George JM: Cushing's disease: 18 years' experience. Medicine 60:14,1981 126. Vance ML, Thorner MO: Prolactinomas. Endocrinol Metab Clin North Am 16:731,1987 127. Vandalem JL, Pirens G, Hennen G, et al: Thyroliberin and gonadoliberin tests during pregnancy and the puerperium. Acta Endocrinol86:695,1977 128. Weiner P, Ben-Israel J, Plavnick L: Sheehan's syndrome with diabetes insipidus. Israel J Med Sci 15:431,1979 129. Westbrock DA, Srivastava LS, Knowles HC Jr: Preservation of normal menstrual cycles in a patient with Sheehan's syndrome. South Med J 76:1065,1983 130. Woeber KA: Tests of thyroid hormone transport. I n Ingbar SH, Braverman LE, (eds): Werner's The Thyroid, ed 5. Philadelphia, JB Lippincott, 1986, p 502 131. Yap AS, Clouston WM, Mortimer RH, Drake RF: Acromegaly first diagnosed in pregnancy: The role of bromocriptine therapy. Am J Obstet Gynecol163:477,1990 132. Yen SSC, Vela P, Tsai CC: Impairment of growth hormone secretion in response to hypoglycemia during early and late pregnancy. J Clin Endocrinol Metab 31:29,1970 133. Ylikorkala 0, Kivenen S, Reinila M: Serial prolactin and thyrotropin responses to thyrotropin-releasing hormone throughout normal human pregnancy. J Clin Endocrinol Metab 48:288,1979 134. Ylikorkala 0, Kivinen S, Ronnberg L: Bromocriptine treatment during early human pregnancy: Effect on the levels of prolactin, sex steroids and placental lactogen. Acta Endocrinol95:412,1980 135. Yoshikawa N, Nishikawa M, Horimoto M, et al: Thyroid-stimulating activity in sera of normal pregnant women. J Clin Endocrinol Metab 69:891,1989 136. Yuen BH: Bromocriptine, pituitary tumors and pregnancy. Lancet 2:1314,1978
Address reprint requests to Glenn D. Braunstein, MD Department of Medicine, Becker B118 Cedars-Sinai Medical Center 8700 Beverly Boulevard Los Angeles, CA 90048
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PITUITARY DISORDERS DURING PREGNANCY Diane Prager, MD, and Glenn D. Braunstein, MD
ANATOMIC AND PHYSIOLOGIC CHANGES IN THE PITUITARY GLAND DURING PREGNANCY
Pituitary enlargement with the formation of large chromophobe pregnancy cells has long been known to occur. Histologic and immunocytochemical studies of human pituitaries from various stages of pregnancy, obtained at autopsy, demonstrate massive hyperplasia of the lactotrophs with substantial reduction in follicle-stimulatinghormone (FSH) and luteinizing hormone (LH) immunoreactive cells.lo7Lactotroph hyperplasia is secondary to multiplication of preexisting mature lactotrophs, evidenced by numerous mitoses and recruitment of inhibited somatotrophs (reduced growth hormone [GHI mRNA content) to become mammosomatotrophs.121By 11 months postpartum, regression of lactotroph hyperplasia still is not complete.121Thyrotroph and corticotroph populations remain unchanged throughout pregnancy.lo7Overall, the volume of the adenohypophysis increases by about one third during pregnancy, resulting in an upward convexity of the superior surface on radiograph.44,51 By magnetic resonance (MR) imaging the stalk remains midline but the neurohypophysis is not visualized during the third trime~ter.~~ From the Division of Endocrinology, Department of Medicine, Cedars-Sinai Medical CenterUniversity of California at Los Angeles School of Medicine, Los Angeles, California
ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA VOLUME 24. NUMBER 1 MARCH 1995
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Accompanying these morphologic changes in the pituitary, serum prolactin levels begin to rise at 5 to 8 weeks of gestation and are 10 times the nonpregnant level at term.7,'24After delivery, prolactin levels decline rapidly reaching baseline within 2 weeks in nonlactating w ~ m e n . ' ~De,'~~ spite the hyperprolactinemic state of pregnancy the normal dynamics of the prolactin response to thyrotropin-releasing hormone (TRH), antidopaminergic agents, and sleep are p r e s e r ~ e d . ~"7,'33 ~ , ' ~Prolactin ~, prepares lZ4The the breast tissue for the initiation and maintenance of lactation.123, increased prolactin synthesis and secretion, which mainly affects the nonglycosylated fraction of p r ~ l a c t i n70,~71, ~ 89 , is directly or indirectly related to the elevated estrogen levels that accompany p r e g n a n ~ y . ~ Although ~,~~,~~ amniotic fluid prolactin levels may be high, principally from decidual synthesis and secretion, levels of serum prolactin remain low in pregnant woman with pre-existing hypoprolactinemia or who are on bromocryptine therapy.4,", 13,20, 33, 57, 99 Furthermore, although administering bromocryptine during pregnancy decreases maternal and fetal levels of prolactin, it does not affect levels of prolactin in the amniotic fluid.lO'Fetal pituitary secretion of prolactin results in levels between 80 and 500 ng/ mL at birth.4,", 13,20,33,57,99 Maternal serum FSH and LH are decreased to undetectable levels, and the pituitary gonadotropin response to gonadotropin-releasing hormone (GnRH) is blunted or absent.56,78, 98, 104,127 The decreased gonadotropin synthesis and secretion are secondary to the feedback inhibition of elevated levels of estrogen, progesterone, prolactin, and inhibin at the pituitary level.', 72, 75, lo4 The estrogen-induced elevation of thyroxine-binding globulin levels results in an increase in total thyroxine (T4) and triiodothyronine (T3) concentration^.^,^^^ Free T4 and T3 levels may be slightly elevated in early pregnancy.48The high human chorionic gonadotropin (hCG) levels at the end of the first trimester are thought to induce thyroid overactivity with a resultant reduction in maternal thyroid-stimulating hormone (TSH) secretion; however, TSH levels remain within the normal range throughout pregnancy.42,48,83,90,118,135 Both basal and stimulated maternal GH levels are low because of the negative feedback inhibition by placental variant GH on the hypothalamus and pituitary.37,38, 39, 50, 119, 132 Maternal levels of insulinlike growth factor 1 (IGF-I), however, are normal to elevated during pregnancy and are normalized in pregnant women with GH de47, 76 ficien~y.~~, The estrogen-induced rise in cortisol-binding globulin results in an increase in total serum cortisol level^.^^,'^^ Plasma-free cortisol is also consistently elevated in pregnant women with preservation of the diurnal rhythm.85,lo8 Paradoxically, adrenocorticotropic hormone (ACTH) levels are elevated during pregnancy with an exaggerated response of cortisol to ACTH s t i m ~ l a t i o n . ~ The ~ , 'relative ~~ contribution of placental ACTH to maternal serum ACTH is unknown. After dexamethasone ingestion, either overnight or for 2 days, incomplete suppression of total serum cortisol, free serum cortisol, and urine free cortisol is observed.97 927
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ANTERIOR PITUITARY DISORDERS IN PREGNANCY Pituitary Adenomas
Prolactinoma
Hyperprolactinemia is associated with anovulation and infertility; however, treatment of the elevated prolactin restores ovulation in 90% of patients. The major issues to be considered in a pregnant woman with a prolactinoma are (1) the effect of the pregnancy on tumor size, and (2) the effect of dopamine agonists on the fetus. Symptomatic enlargement of pituitary tumors during pregnancy is not surprising in view of the known stimulatory effects of estrogen on the l a ~ t o t r o p h s Data . ~ ~ from two large reviews address the issue of tumor growth during pregnancy. Molitch reported that of 246 patients with microadenomas (less than l cm in diameter) from 16 series, 4 (1.6%) complained of headaches or visual disturbance with tumor enlargement, whereas 11 (4.5%) had asymptomic tumor enlargement (radiologic assessment). No surgery was required. Of 45 patients with macroadenomas (greater than 1 cm in diameter) and no prior surgical or radiation therapy, 7 (15.5%)had symptomatic tumor growth and 4 (8.9%)had asymptomatic tumor enlargement (radiologic assessment), necessitating bromocryptine therapy for 2 patients and surgery for 4.81Of 46 patients with macroadenomas and prior surgery or radiation therapy, only 2 (4.3%)developed symptomatic tumor growth whereas none had evidence of asymptomatic tumor growth. Gemzell and Wango collected data on 187 patients. Of 85 pregnant women with microadenomas (no prior treatment), 1 patient developed severe headaches with visual field disturbances at 12 weeks' gestation. The patient was treated conservatively and underwent transsphenoidal surgery after delivery at 36.5 weeks. Three of the other patients developed headaches and were managed conservatively. In 46 women with previously untreated macroadenomas, 19 developed severe headaches and visual impairment. Twelve patients were treated conservatively, 5 underw e n t t r a n s s p h e n o i d a l surgery d u r i n g pregnancy, 1 received bromocryptine, and 1 received high-dose steroids. The authors40 then compared these findings to 70 women who had received prior irradiation, surgery, or combination therapy. In this treated group, 2 patients reported headaches plus visual field defects, whereas 3 patients reported headache alone. One patient received irradiation, and 4 others were managed conservatively. Summarizing the data from these two reviews, the risk of clinically important enlargement of a microadenoma is 1.6%to 5.5%40,80 but is 15.5% to 35.7%40,80 for macroadenomas, with a considerable reduction if the patient received prior radiation or surgical treatment. Bromocryptine has been used successfully in a number of cases to reduce tumor size. In more than 100 women who took bromocryptine during weeks 20 through 41 of gestation, no neonatal abnormalities except for one infant with a single undescended testicle and second infant with
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a talipes deformity were reported.13,18, 32, 60, 64, 79, lo5,136 Serum estradiol, estriol, progesterone, testosterone, dehydroepiandosterone, dehydroepiandrosterone sulfate, androstenedione, cortisol, and human placental lactogen were unaffected in women given bromocryptine at weeks 6 through 9 or 20 before therapeutic a b ~ r t i o n . ~Maternal ~ , ' ~ ~ and fetal prolactin levels were shown to be s ~ p p r e s s e dFollow-up .~~ studies on 64 infants and children (aged 6 months to 9 years) whose mothers took bromocryptine for tlie first 4 weeks of gestation showed no abn0rmalities.9~Nevertheless, fetal exposure to bromocryptine should be limited. Although the postpartum prolactin levels and tumor sizes vary between series, it is likely that bromocryptine use during pregnancy prevents tumor enlargement.24,54, '06 Precise data are not available but the effect of nursing on tumor growth is probably less than that of pregnancy and therefore need not be discouraged?' Management of Prolactinoma During Pregnancy Treatment choices for anovulatory patients with microadenomas who wish to conceive are (1) bromocryptine, (2) transsphenoidal surgery, or (3) irradiation or surgery followed by bromocryptine. A trial of bromocryptine alone is recommended because of its efficacy in restoring ovulation and the relatively low risk of tumor enlargement.81Eighty percent to 85% of patients with hyperprolactinemia will become pregnant after bromocryptine therapy or surgery.66,'06 In certain rare cases, clomiphene , ~ ~ ,conception, ~~,~~ citrate, hCG, or pulsatile GnRH will be r e q ~ i r e d . ' ~ After the bromocryptine should be stopped and monitored for clinical signs or symptoms suggestive of tumor enlargement. Random prolactin measurements are not helpful since prolactin levels may not rise, as occurs in a normal pregnancy or with tumor enlargement. Similarly, visual field testing and computed tomography (CT) are indicated only in symptomatic patient^.^' Routine CT or MR imaging after delivery is advocated at some centers to detect asymptomatic microadenoma tumor growth:' but probably is unnecessary if the postpartum prolactin level returns to the pregestational range. Molitch8' recommends bromocryptine for patients with intrasellar and inferiorly extending macroadenomas. These patients have a marginally higher risk of tumor enlargement compared with patients with miIn patients with larger macroadenomas, especially if sucroaden~mas.~' prasellar extension is present, debulking surgery (to allow for expansion) before pregnancy followed by bromocryptine therapy to normalize prolactin levels, and thus allow ovulation,.is recommended?' The long-term risk of hypopituitarism after radiation therapy makes this approach less acceptable. Similarly, although continuous use of bromocryptine throughout gestation has been advocated,lo5the data are insufficient to recommend its routine use. Advanced pregnancy diagnosed in a patient on bromocryptine, however, does not justify a therapeutic abortion. Thus, the therapeutic alternatives need to be clearly presented to patients who will have to make highly individualized and informed decisions.
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In patients with macroadenomas treated with surgery with or without bromocryptine, monthly Goldman perimetric visual field testing is recommended during pregnancy. MR imaging is indicated for patients with enlarging visual field defects and those who become symptomatic. Symptomatic tumor growth is best managed with bromocryptine because surgery has a 1.5-fold risk of fetal loss in the first trimester and a fivefold risk in the second trimester.17Those patients with no response to bromocryptine and worsening vision need surgery and urgent delivery if the pregnancy is advanced enough. There are no data on the safety of the other available long-acting dopamine agonist, pergolide, during pregnancy. After delivery, MR imaging should be done to document asymptomatic macroadenoma tumor growth. Acromegaly Menstrual irregularity is a common early finding in acromegaly, but pregnancy may occur. Pregnancy does not not alter the course of acromegaly and therapy can be safely deferred until after delivery. In 34 reported cases of acromegaly and pregnancy, only one patient developed transient blindness that resolved with bromocryptine treatment.' Symptomatic tumor enlargement is treated with surgery or bromocrypl3I In a single acromegalic patient treated with octreotide tine.25,69, 77, during the first trimester, no apparent side effects were observed, and the pregnancy went to term.65Insufficient information exists, however, regarding the safety of octreotide during pregnancy to recommend its routine use. High circulating levels of GH have no apparent deleterious effects on pregnancy.2, 8'9, 15, 25,69,77,82,131 Cushing's Syndrome Suppression of gonadotropin secretion by elevated cortisol and androgen levels results in oligomenorrhea or amenorrhea in 75% of patients ~,"~ rarely occurs, however, and the with Cushing's ~ y n d r o m e . ~Pregnancy symptoms of pregnancy may obscure the diagnosis of Cushing's syndrome. Aron and colleagues5reviewed 58 pregnant patients with Cushing's syndrome. The most common cause was found to be benign adrenal tumors. The increased incidence of hyperfunctioning adrenal adenomas during pregnancy may be because of stimulation of adrenal growth by placental ACTH,97hCG,"O variant GH,37,38, 39, or other growth factors. In contrast, Cushing's disease (pituitary dependent bilateral adrenal hyperplasia) accounts for more than 60% of cases of Cushing's syndrome in nonpregnant adults.43,'02 The diagnosis of Cushing's syndrome during pregnancy is difficult; however, preservation of the normal diurnal rhythm of serum cortisol and assessment of urinary 17-hydroxycorticosteroids may be Although a nonsuppressible level of plasma or urine cortisol by high-dose dexamethasone suggests the presence of ectopic ACTH syndrome or adrenal tumor, lack of suppression with low-dose dexamethasone or overnight testing with dexamethasone may be seen during p r e g n a n ~ y . ~ ~
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Plasma ACTH levels are not helpful in differentiating pituitary-dependent Cushing's disease from normal pregnancy. Patients with mild cases of Cushing's syndrome should be managed expectantly. Major complications include hypertension; gestational diabetes: and pulmonary edema.59Premature onset of labor is common, occurring in 60% of patient^.^ Metyrapone, aminoglutethimide, and ketoconazole should be avoided because of fetal and maternal toxi ~ i t y .22~ , Pituitary Insufficiency During Pregnancy
Lymphocytic Hypophysitis Lymphocytic hypophysitis is a rare autoimmune disorder that presents as a mass lesion of the sella turcica, which may be associated with hypopit~itarism.2~ It is characterized by lymphocytic infiltration and destruction of the anterior pituitary. Thirty-five cases have been reported with most occurring in late pregnancy or up to 1 year postp a r t ~ m . ' 23, ~ ,73, 91 In addition to symptoms of tumor growth, (headaches, visual disturbances), pituitary testing may demonstrate partial or complete hypopituitarism. The commonest partial deficit is in ACTH function with intact gonadal function.23Forty percent of patients have prolactin deficiency and another 40% have hyperprolactinemia secondary to stalk compre~sion.2~ A single patient with diabetes insipidus (in the absence of surgery) has also been reported." Lymphocytic hypophysitis may present with hypoglycemia, in which case steroids should be givens6 Microscopically, the adenohypophysis is infiltrated with lymphocytes and plasma cells, with occasional germinal centers, thus excluding the diagnosis of lymphoma. Fibrosis may be present in the later stagesF3 Approximately 30% of all patients have evidence for other endocrine autoimmune disease including thyroiditis, pernicious anemia, adrenalitis, diabetes mellitus, and parathyroiditis. Antinuclear and antimitochondrial antibodies have been reported as well as a small number of patients with antipituitary a n t i b o d i e ~ . ~ ~ Approximately 25% of patients die, probably from adrenal insufficiency. Surgery is effective for relieving pressure symptoms whereas bromocryptine produced a partial improvement in vision in a few ~ a s e s . 6 , ~ ~ , 91 Pituitary function may spontaneously improve or worsen with time; therefore, hormone replacement should be given as needed.l9rZ3 Sheehan's Syndrome Postpartum pituitary necrosis, or Sheehan's syndrome, is possibly the most common cause of anterior pituitary ins~fficiency.6~ The hypertrophied pituitary gland of pregnancy is more susceptible to a compromised blood supply through the low-pressure pituitary sinusoidal system that accompanies peripartum hem~rrhage."~ Additionally, locally released factors may mediate vascular spasm or constriction of the arterial blood
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supply to the pituitary, since the severity of a postpartum hemorrhage does not always correlate with the presence of Sheehan's syndrome. Pregnant women with insulin-dependent (Type I) diabetes mellitus are prone to develop antepartum pituitary necrosis, presumably because of microvascular disease.I6In these patients, decreasing insulin requirements may accompany the hypopituitarism and serve as a clue to the diagnosis. Sickle cell disease may be associated with occlusion of pituitary small vessels and hypopituitarism. This is not a common occurrence, and the true incidence of pituitary necrosis secondary to a sickle cell crisis during pregnancy is ~ n k n o w n . " ~ Classically, Sheehan's syndrome presents with failure of lactation, rapid breast involution, failure to resume menses, failure to regrow shaved pubic or axillary hair, and skin depigmentation (including the areola). Signs and symptoms of hypothyroidism and hypoadrenalism gradually develop. Diabetes insipidus has been reported but is unusual.21, 45,128 More commonly, defects in vasopressin secretion with loss of maximal urinary concentrating ability occur, correlating with the presence of posterior pituitary infarcts and neuronal destruction in the supraoptic and paraventricular nuclei.H2Steroid therapy in these patients may precipitate overt diabetes insipidus by suppressing vasopression (AVP)secretion and increasing free water clearanceF8Organic psychosis is common in Sheehan's syndrome and responds to hormonal repla~ement.~~ A single case of bone marrow aplasia, which responded to hormone replacement, and a case of hypomagnesemia with cardiac arrhythmia have been reported.34,87 Pituitary necrosis accompanying Sheehan's syndrome is frequently incomplete, with selective loss of hormone secretion.56,120, 129 Thus, subsequent pregnancy may be possible if gonadotropin function is 81
The diagnosis of Sheehan's syndrome is suggested by low or normal levels of TSH, ACTH, FSH, and LH with low levels of T4, cortisol, and estradiol. Subnormal levels of IGF-1 suggest GH deficiency, although stimulation tests may be required to document GH reduction. Impaired prolactin responses to TRH or dopamine antagonists are consistently found in patients with Sheehan's syndrome.28,5 6 ~ Testing for TSH, LH, and FSH reserve may yield normal, subnormal, or delayed responses to TRH or GnRH, suggesting the presence of islands of pituitary cells that have been cut off from the hypothalamic-portal circulati~n."~ CT or MR imaging should be performed to exclude a mass lesion. Remnants of pituitary tissue, or in long-standing cases, an empty sella may be seen on CT.35,116 The differential diagnosis of Sheehan's syndrome includes a number of systemic diseases: chronic infections, HIV, granulomatous diseases, rheumatoid arthritis, amyloidosis, metastatic carcinoma, and hemochromatosis.10Hormone replacement is given as needed and is especially important in women who subsequently become pregnant.45
8
PRAGER & BRAUNSTEIN
POSTERIOR PITUITARY DISORDERS DURING PREGNANCY Pre-Existing Diabetes lnsipidus
These patients usually have normal fertility and pregnancie~.~~ They require increased doses of AVP to control polyuria during pregnancy because of placental synthesis of vasopressinase, an enzyme that rapidly degrades AVP and o x y t o ~ i nVasopressinase .~~ levels increase throughout gestation, peak at term, and disappear within 1 month after delivery, corresponding with a return to normal of AVP requirements after delivery.lo3 Transient Diabetes lnsipidus of Pregnancy
Transient diabetes insipidus of pregnancy may manifest in a number of ways: The vasopressin-responsive form probably occurs only in patients with mild or subclinical central diabetes insipidus who cannot increase their AVP secretion to counteract the effects of placental vasopress i n a ~ e .53~ ~ , Vasopressin-resistant forms manifest as true renal vasopressin resistance or abnormally high vasopressin clearance because of elevated plasma vasopressinase activityF9,30, 63 In patients with transient diabetes insipidus secondary to enhanced vasopressinase activity, there is no response to exogenous AVP, with a normal response to dDAVP, an AVP analogue that is not degraded by vasopre~sinase.~~ In true renal resistance (nephrogenic diabetes insipidus) there is no response to AVP or dDAVP. Krege and colleagues64in a review of 17 cases noticed that in patients with excess vasopressinase activity, symptoms occur during the third trimester. Hypertension, proteinuria, hyperuricemia, and elevated liver enzymes were documented. Multiple gestations with excessive vasopressinase production or the presence of liver abnormalities with the resultant reduction in vasopressinase clearance, or overproduction of a hepatic form of aminopeptidase that may degrade AVP have been implicated in the etiology of this condition. Nephrogenic diabetes insipidus is managed with thiazide diuretics whereas central and transient diabetes insipidus are treated with dDAVPF9 367
Postpartum Diabetes lnsipidus
Central diabetes insipidus in the postpartum period may occur in association with Sheehan's syndromeZ9or lymphocytic hyp~physitis.~~ SUMMARY
A number of morphologic and physiologic changes accompany pregnancy such as an increase in lactotrophs and prolactin production, and a
PITUITARY DISORDERS DURING PREGNANCY
9
decrease in gonadotropins and GH. The hormonal milieu can affect patients with prolactinomas, especially macroadenomas, to cause an increase in size in a minority of patients. Complications are treated with bromocryptine. Enlargement of GH-secreting tumors with acromegaly may respond to bromocryptine and possibly to octreotide. Pituitary tumors causing Cushing's syndrome may need removal if major complications develop. Hypopituitarism during pregnancy may be the result of lymphocytic hypophysitis or antepartum pituitary necrosis, and in the postpartum period may be because of postpartum hemorrhage and pituitary necrosis. These abnormalities need prompt recognition and hormonal replacement therapy with neurosurgical decompression to avoid serious morbidity and mortality. Posterior pituitary problems in pregnancy usually manifest by diabetes insipidus, with a pregnancy-specific variety resulting from excessive degradation of AVP by placental vasopressinase. The condition is treated with an analogue dDAVP, which is resistant to vasopressinase.
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