chapter 2. pituitary and adrenal disorders of pregnancy

Chapter 2. Pituitary and Adrenal Disorders of Pregnancy

Pituitary and adrenal disorders provide challenges for diagnosis and treatment dur-ing pregnancy.

PITUITARY DISORDERS IN PREGNANCY

Anterior Pituitary GlandThe pituitary enlarges throughout pregnancy, approximately 136% overall,1and may become hyperintense on scan.2 This enlargement is due primarilyto estrogen-stimulated hypertrophy and hyperplasia of the lactotrophs.3Gonadotrophs decline in number, and corticotrophs and thyrotrophs remainconstant.4 Somatotrophs are generally suppressed, and may function aslactotrophs.5 The peak pituitary size is seen in the first 3 days postpartum, when thegland height may reach 12 mm on MRI.1,6,7 The gland involutes rapidly followingdelivery regardless of breast feeding status, and is of normal size by 6 monthspostpartum.6,7

Prolactin (PRL) is secreted by the pituitary, hypothalamus, lymphocytes, uterus, pla-centa, and lactating mammary gland.8 In combination with other hormones, PRL me-diates mammogenesis, lactogenesis, galactopoiesis (maintenance of milk secretion),and plays a role in the regulation of humoral and cellular immune responses. Pla-cental estrogens stimulate lactotrophic PRL synthesis in the first trimester,9,10 whileprogesterone also stimulates prolactin secretion.11,12 Prolactin levels progressivelyincrease approximately 10-fold throughout gestation,13 then decline postpartum innon-lactating women. Despite increased PRL levels, the normal lactotroph contin-ues to respond to TRH and anti-dopaminergic stimulation. Postpartum, the circadianrhythm of PRL release is enhanced by the effects of suckling.

The placental growth hormone (GH) variant differs from pituitary GH by 13 aminoacids and is synthesized by the syncytiotrophoblastic epithelium of the placenta. Theregulation of placental GH secretion remains unknown, but this variant increasesthroughout gestation to levels of 10-20 ng/ml.14,15 This variant has similar carbo-hydrate, lipid,16 and somatogenic properties as pituitary GH, with less lactogenicactivity.17 With this increase in overall GH activity, insulin-like growth factor 1 (IGF-1) levels increase in the second half of pregnancy,18 contributing to the acromega-loid features of some pregnant women. Through negative feedback, pituitary GHlevels consequently decline in the second half of gestation and the first week post-partum,14,15 with blunted response to hypoglycemic stimulation testing (not recom-mended in pregnancy), but normal response to GHRH.19 Patients with acromegalyhave autonomous pituitary GH secretion, and both forms of GH persist in the bloodthroughout pregnancy.20

There is a transient fall in TSH in the first trimester during the 2nd and 3rd months.This is postulated to be secondary to human chorionic gonadotropin (hCG) stim-ulation of the thyroid due to the structural homology between the TSH and hCGmolecules and their receptors.21 The role of hCG in increasing thyroid stimulatingactivity was first postulated with the thyrotoxicosis noted in molar pregnancies andtrophoblastic disease,22 with cure after surgical excision of the mole or neoplasm.A negative correlation was later demonstrated between hCG and TSH in womenundergoing elective abortion.23 Sequential TSH determinations between 8 and 14weeks gestation revealed that the nadir in TSH coincides with the peak in hCG,24with an inverse correlation found in individual samples such that TSH levels fallin a proportional and mirror response to the rise in <61538>hCG.(Figure 1)25 Thereis also a linear relationship between hCG and free T4 concentrations early in gesta-tion.24 In the majority of patients, this effect is transient and not clinically significant,as the peak of hCG is brief. However, sequential evaluations of TSH in a large co-hort of pregnant women revealed that 18% demonstrated transient subnormal TSH

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in the 1st trimester, with 5% still subnormal in the 2nd trimester, with significantlyhigher levels of hCG found in these women than in those who maintained a nor-mal TSH.26 Furthermore, in hyperplacentosis27 and in twin pregnancies where thehCG peak is generally higher and of longer duration, there is more frequent andgreater lowering of TSH than in singleton pregnancies.28 In the second half of ges-tation, TSH levels return to normal prepregnant levels. In iodine deficient regions,TSH increases near term but remains within the normal range.24 TSH demonstratesan increased response to TRH during gestation. The increase in estrogens producedby the fetal-placental unit stimulates hepatic production of thyroxine-binding glob-ulin and increases the sialylation of the TBG, thereby prolonging its half-life.29,30This increase in TBG results in higher levels of total T4 and T3, starting at 4-6 weeksgestation.30 Free T4 levels may increase transiently in the 1st trimester as a result ofthe hCG peak. However, both free T4 and free T3 generally remain within the nor-mal range throughout gestation,24,29,30 though they may be 10-15% lower at termin iodine-sufficient women. Placental deiodination increases maternal T4 turnover.

Figure 1. Maternal concentrations of serum TSH and hCG as a function of gesta-tional age. The decrease in serum TSH at approximately 10 week’s gestation maybe due to thyrotropic effects of hCG. (From Glinoer D, de Nayer P, Bourdoux P,et al. Regulation of maternal thyroid during pregnancy. J Clin Endocrinol Metab1990; 71:276.)

Synthesis of hCG by syncytiotrophoblasts is itself partially stimulated by placentalcytotrophoblast produced gonadotropin releasing hormone (GnRH). In responseto placental sex steroid production, both hypothalamic GnRH and pituitarygonadotropin (FSH/LH) levels decline in the first trimester of pregnancy, with ablunted gonadotropin response to GnRH.31 FSH levels are initially suppressedpostpartum, and return to normal by 3 weeks postpartum. LH levels tend tonormalize more gradually.

Corticotropin-releasing hormone (CRH) levels, synthesized primarily by theplacental cytotrophoblasts and the decidua, rise several hundred fold by term.32,33It stimulates both syncytotrophoblastic placental and pituitary adrenocorticotropichormone (ACTH) production.34 ACTH levels consequently increase throughout

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gestation, with a further increase in labor.35 The proportion of ACTH of pituitaryvs. placental origin is unknown, however placental ACTH is not suppressible bydexamethasone administration. Cortisol levels progressively increase throughoutgestation with a surge during labor.35 Cortisol binding globulin levels risesecondary to estrogen-stimulated production, leading to an increase in total cortisolof 2-3 fold by term.36 The “free” cortisol also rises 3-fold, with a 2-3 fold elevation inurinary free cortisol.35,36

Pituitary adenomas constitute 6.1% of primary intracranial (malignant andnonmalignant) neoplasms in women, with an age-adjusted incidence rate of 0.93cases/100,000 person-years.37 The stimulatory effect of pregnancy on pituitarylactotrophs will impact a patient with a prolactinoma who becomes pregnant.

ProlactinomasHyperprolactinemia causes one third of all female infertility.38,39 It inhibits pulsatilegonadotropin secretion and the positive feedback of estrogen on gonadotropin secre-tion.39 Hyperprolactinemia has multiple potential etiologies. In patients with pro-lactinomas, treatment choices are defined by the clinical presentation and the thera-peutic goal.

Surgical therapy is initially curative in approximately 70-80% of patients with mi-croadenomas and rarely causes hypopituitarism. The curative rate is much lower(30%) in patients with macroadenomas, and the risk of hypopituitarism and subse-quent infertility increases dramatically.39 For both microadenomas and macroade-nomas there is a recurrence rate of about 20%, therby lowering these long-term curerates.39

Dopamine agonists are the primary therapy for the majority of patients with prolacti-noma. Bromocriptine, pergolide (approved for the treatment of Parkinson’s but notprolactinoma), and quinagolide (not approved in the United States) restore ovulatorymenses in 70-80% of patients. Approximately 50-75% of patients with macroadeno-mas experience a > 50% reduction in size.39,40 Cabergoline is dosed once to twiceweekly and is more effective and better tolerated than bromocriptine therapy withrestoration of ovulatory menses in >90% of women,41 and >90% reduction in tumorsize.39,42-45 To establish the intermenstrual interval prior to a pregnancy, mechan-ical contraception should be used for 2-3 cycles. This allows early recognition of apregnancy so that the drugs are given for only 3-4 weeks of gestation. The long half-life of cabergoline causes fetal exposure for a further 1 or more weeks after cessationof therapy. Bromocryptine and cabergoline are approved for use in pregnancy, butnot pergolide or quinagolide, and caution is certainly advised.

The hormonal milieu of pregnancy may cause significant tumor enlargementin women with prolactin-secreting macroadenomas.(Figure 2) A review ofpublished reports of pregnant patients with microadenomas previously treatedwith bromocriptine showed that only 12 of 457 (2.6%) pregnancies in women withmicroadenomas were complicated by symptoms of tumor enlargement (headachesand/or visual disturbances) (Table 1). Surgical intervention was not required in asingle case but medical therapy with bromocriptine was instituted in 5 individuals.For patients with macroadenomas, 45 of 142 pregnancies (31%) were complicated bysymptoms of tumor enlargement. Surgical intervention was undertaken in twelve ofthese cases and bromocriptine in 17. In addition, 140 women with macroadenomaswere identified who had undergone surgery or radiation prior to pregnancyand their risk of tumor enlargement was 2.5%.46 Reinstitution of bromocriptineor cabergoline therapy generally is successful in reducing tumor size, thoughtranssphenoidal surgery may be required.47,48

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Figure 2. MRI scans with coronal (A,C) and sagittal (B,D) views demonstrating aprolactin-secreting macroadenoma before pregnancy (A,B) that progressively en-larged during pregnancy. The third trimester is shown here (C,D). The patient hadbeen complaining of increasing headaches.

Table 1. Effect of pregnancy on prolactinomas

Total No. Patients SymptomaticEnlargement

% SymptomaticEnlargment

Microadenomas 457 12 2.6

Macroadenomas 142 45 31

Macroadenomas-prior surgery orradiation

140 7 5

Bromocriptine crosses the placenta,49 and continuous administration throughoutgestation is not recommended. Experience with its use during the first few weeksof gestation has not been associated with increased risk for adverse events suchas spontaneous abortion, ectopic pregnancies, multiple gestation, or congenitalanomalies.(Table 2)47,50 Long-term studies of children exposed during the earlyfirst trimester have been limited to 64 children ranging in age from 6 monthsto 9 years, with no ill effects seen.51 In more than 100 pregnancies in whichbromocriptine was used throughout gestation, the only neonatal abnormalitiesnoted were a case of undescended testicle and one case of talipes deformity, whichis in the expected range.47,50

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Table 2. Effect of Bromocriptine on Pregnancies

Bromocriptine NormalPopulation

n % %

Pregnancies 6,239 100.0 100.0

- spontaneousabortion

620 9.9 10 - 15

- terminations 75 1.2

- ectopic 31 0.5 0.5 - 1.0

- hydatidiformmoles

11 0.2 0.05 - 0.7

Deliveries (knownduration)

4,139 100.0 100.0

- at term (> 38weeks)

3,620 87.5 85

- preterm (< 38weeks)

519 12.5 15

Deliveries (knownoutcome)

5,120 100.0 100.0

- single births 5,031 9.3 8.7

- multiple births 89 1.7 1.3

Babies (knowndetails)

5,213 100.0 100.0

- normal 5,030 96.5 95.0

- withmalformations

93 1.8 3 - 4

- with perinataldisorders

90 1.7 > 2

*Data from Krupp P, Monka C, Richter K. Program of the Second World Congressof Gynecology and Obstetrics. Rio de Janeiro, 1988, p. 9.

There are few data on pergolide safety in pregnancy. It is known to cross the placentain mice, with no teratogenicity noted in doses of 60 mg/kg/day.52 In one patienttreated with pergolide in early gestation for Parkinson’s disease, no teratogenic ordevelopmental abnormalities were noted in the offspring.53 However, the authorsmentioned 2 major and 3 minor congenital anomalies in 38 pregnancies exposed topergolide in premarketing studies, with causality not established.53 The manufac-turer, Eli Lilly & Co., has limited data on pregnancies in which the fetus was exposedto pergolide. There was no information on 43.4% of pregnancies, 7.2% of pregnanciesended in spontaneous abortion, 7.2% had minor malformations, 14.3% underwent in-tentional abortions, and 28.6% delivered healthy infants.54 Alternatives to pergolidetherapy should be found for women desiring pregnancy.

Quinagolide should not be used when pregnancy is desired. A review of 176 preg-nancies in which quinagolide was maintained for a median of 37 days, reported13.6% spontaneous abortions, 0.6% ectopic pregnancies, 0.6% stillbirths at 31 weeks,and 5.1% malformations: spina bifida, trisomy 13, Down syndrome, talipes, cleft lip,arrhinencephaly, and Zellweger syndrome.55

Cabergoline has been utilized in the first trimester in more than 350 human pregnan-cies. To date, there is no evidence for increased risk of spontaneous abortion, congen-ital anomalies, multiple gestation, or premature delivery.56-61 Normal physical and

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mental development was seen in 107 infants followed 1-72 months.56

There is little specific data regarding the use of transsphenoidal surgery during preg-nancy. It is presumed that the risks would be similar to other forms of surgery, exceptfor the increased risk of hypopituitarism.

For patients with intrasellar tumors, bromocriptine or cabergoline therapy is pre-ferred as it is safe for the fetus if it is discontinued early in gestation. These tumorsdemonstrate a small risk for tumor enlargement. Patients should be followed on atrimester basis for symptomatic enlargement, such as headaches or visual problems.Visual field testing should be performed if clinically indicated.

Therapeutic options for tumors extending outside the sella include prepregnancysurgical debulking, intensive monitoring without dopamine agonist therapy, or con-tinuous bromocriptine therapy throughout gestation. The latter is not likely to harmthe fetus but the number of cases followed in this way is small. Patients requiremonthly assessments and visual field examinations every trimester. Prolactin lev-els provide little benefit in the clinical assessment, as they may not rise with tumorenlargement.62 With evidence of tumoral enlargement, bromocriptine should be im-mediately reinstituted and the dose rapidly titrated as tolerated. Switching to caber-goline therapy, transsphenoidal surgery, or delivery if gestation length is adequate,should be considered if the response to bromocriptine therapy is inadequate.47

Breastfeeding stimulates prolactin secretion in normal women in the first few weeksor months postpartum.39 However, there is no evidence that suckling stimulates pro-lactinoma growth. Therefore, we do not discourage breastfeeding in women withprolactinomas. However, dopamine agonists must be withheld until the period ofbreastfeeding is over.

Anovulation secondary to hyperprolactinemia in untreated women is associatedwith hypoestrogenemia and a potential for osteoporosis.39 Although the estrogen inoral contraceptives stimulates lactotrophs and mild increases in prolactin levels innormal women, it does not usually cause growth of microadenomas or precipitateneoplastic development in women with idiopathic hyperprolactinemia.63 Prolactinlevels should be evaluated periodically to find the rare estrogen-sensitive tumor. Ifprolactin levels are found to increase substantially, the estrogen should be stoppedto forestall tumor growth. For patients with macroadenomas, dopamine agonists arepreferred because of their efficacy in reducing tumor size.

AcromegalyInfertilily is common in women with acromegaly, as approximately 75% of acrome-galic women of child-bearing years have menstrual irregularity.64 The ovarian dys-function is often the result of the hyperprolactinemia found in 30-40% of cases65 andto possible mass effects of the tumor. An additional factor is the coexisting polycysticovary disease seen in a number of patients.66 Many patients require bromocriptineto ovulate and conceive, and normalization of the hyperprolactinemia frequently re-stores menstruation. GH and IGF-1 also regulate ovarian function, as GH increasesovarian responsiveness to gonadotropins67 either directly or through IGF-1 produc-tion in the ovarian follicle.68

Pituitary growth hormone secretion is autonomous in acromegaly, so both pituitaryand placental GH variants persist throughout pregnancy.69 Diagnosing acromegalyduring gestation may be difficult as conventional assays are unable to distinguishbetween the 2 forms of GH. This distinction requires special assays with antibod-ies which recognize specific epitopes on the pituitary and placental GH variants.14However, pituitary growth hormone secretion in acromegaly demonstrates a pul-satility of 13-19 pulses per 24 hours,70 vs. the tonic secretion seen with the placentalvariant.15 In addition, paradoxical GH release after TRH occurs with pituitary GHexcess,65 and is not seen with the placental variant.69 Postpartum, the placental vari-ant disappears from the circulation within 24 hours.14 IGF-1 levels are not useful in

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the diagnosis of acromegaly in pregnancy, as they elevate in the second half of bothnormal and acromegalic pregnancies.71

Pregnancy was thought to exacerbate the underlying condition in 4 of 24 (17%) preg-nant patients with acromegaly who have been described in the literature.72 Tumorenlargement during pregnancy has been described in 2 patients with acromegaly,leading to a visual field defect in one.73,74 Symptomatic tumor enlargement shouldbe monitored monthly, with visual field testing every trimester. Glucose tolerance,hypertension, and cardiac derangements also require monitoring.65 Glucose intol-erance occurs in 50% of patients with acromegaly, with overt diabetes mellitus in10-20%.65 The risk for gestational diabetes mellitus is consequently increased by theinsulin resistance of acromegaly. Sodium retention leads to hypertension in 25-35%of patients, with potential for exacerbation in pregnancy. Cardiac disease is presentin one third of patients with acromegaly, with underlying cardiomyopathy and in-creased risk for coronary artery disease, which may also be exacerbated during preg-nancy.65,75

GH does not cross the placenta, and maternal acromegaly has little direct impact onthe fetus. Fetal somatic growth is largely GH-independent, and macrosomia in suchpregnancies is likely secondary to maternal glucose intolerance.

Bromocriptine and cabergoline therapy may provide limited benefit in treatingindividuals with acromegaly, with no reduction in tumor size and rarenormalization of GH levels. Their use in pregnancy has been described above.Neither dopamine agonist should be continued throughout pregnancy in mostpatients. Somatostatin analogs can cross the placenta. Ten cases have been describedof women with acromegaly treated with octreotide during pregnancy,75-77 twocases with acromegaly treated with lanreotide,78,79 one with a TSH-secreting tumortreated with octreotide during pregnancy,80 and one with nesidioblastosis treatedwith octreotide during pregnancy.81 In most cases the somatostatin analog wasstopped before the end of the first trimester, but in two cases octreotide was giventhroughout the pregnancy.75,81 No malformations were noted. However, octreotidecrosses the placenta and somatostatin receptors are widespread in many tissuesincluding the brain; therefore, there certainly is the potential for somatostatinanalogs to affect developing fetal tissues.82 Octreotide and lanreotide are notapproved for use in pregnancy. Interruption of medical therapy for 9-12 monthsshould have limited impact on the long-term outcome of patients with acromegaly.For enlarging tumors, reintroduction of somatostatin analogs vs. surgery should beconsidered.

Other Pituitary AdenomasThe ACTH-secreting neoplasms will be described in the adrenal disorders section.

There are few data regarding gonadotropin-secreting or TSH-secreting pituitary ade-nomas in pregnancy. Treatment of three cases of TSH-secreting adenomas has beenreported.80,83-85 Octreotide was used in two cases. In one octretide was continuedto control tumor size, and the second it was reinstituted to control tumor size. Thehyperthyroidism may be controlled with standard antithyroid drug therapy.84

Clinically non-functioning adenomas are primarily gonadotroph adenomas.86Although unlikely to enlarge under the influence of estrogen stimulation inpregnancy, the lactotroph hyperplasia which occurs can cause chiasmal compressionor headaches in a patient with a preexisting clinically non-functioning adenoma.Two cases have been reported of tumor enlargement in pregnancy with resultingvisual field defect.73,87,88 In one case, the patient responded to bromocriptinetherapy which reduced the lactotroph hyperplasia and had little or no direct effecton the neoplasm.88 Two patients with gonadotroph adenomas secreting intactfollicle-stimulating hormone developed ovarian hyperstimulation syndrome.89,90Pregnancy occurred in both, after bromocriptine therapy in one89 and surgery in thesecond.90

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HypopituitarismHypopituitarism, secondary to neoplastic, vascular, traumatic, or infiltrative disor-ders, is commonly associated with gonadotropin deficiency and infertility. Fertility ispossible with the assistance of the reproductive endocrinologist, using human chori-onic gonadotropin and follicle-stimulating hormone, pulsatile GnRH, and in vitrofertilization. During gestation, adrenal and thyroid hormones should be replacedas needed. The average increase in levothyroxine required during gestation is 0.05mg/day. Adrenal hormone replacement in pregnancy is discussed below.

Hypopituitarism may also present during pregnancy or postpartum, secondary toadenoma expansion, lymphocytic hypophysitis, and pituitary infarction. Recognitionmay be difficult because fatigue, nausea, and vomiting are frequent accompanimentsof normal pregnancies. Dynamic testing during pregnancy is also difficult to interpretin light of the physiologic changes during normal pregnancy. Inadequately treatedhypopituitarism may lead to poor pregnancy outcome, including spontaneous abor-tion, intrauterine fetal demise, maternal hypotension, hypoglycemia, and even ma-ternal death.

Sheehan’s SyndromeSheehan’s syndrome consists of pituitary necrosis secondary to ischemia occurringwithin hours of delivery.91,92 It is usually secondary to hypotension and shock froman obstetric hemorrhage. Pituitary enlargement during pregnancy apparently pre-disposes to the risk for ischemia with occlusive spasm of the arteries to the anteriorpituitary and stalk.91,92 The degree of ischemia and necrosis dictates the subsequentpatient course. It rarely occurs with current obstetric practice.93

Acute necrosis is suspected in the setting of an obstetric hemorrhage wherehypotension and tachycardia persist following adequate replacement ofblood products.(Table 1) In addition, the woman fails to lactate and may havehypoglycemia.91,92,94 Investigation should include levels of ACTH, cortisol,prolactin, and free thyroxine. The ACTH stimulation test would be normal, as theadrenal cortex would not be atrophied. Thyroxine levels may prove normalinitially, as the hormone has a half-life of seven days. Prolactin levels are usuallylow, although they are generally 5-10 fold elevated in the puerperium,. Treatmentwith saline and stress doses of corticosteroids should be instituted immediatelyafter drawing the blood tests. Additional pituitary testing with subsequent therapyshould be delayed until recovery. Diabetes insipidus may also occur secondary tovascular occlusion with atrophy and scarring of the neurohypophysis.95

When milder forms of infarction occur, the diagnosis of Sheehan’s syndrome maybe delayed for months or years.95 These women generally have a history of amen-orrhea, decreased libido, failure to lactate, breast atrophy, loss of pubic and axillaryhair, fatigue, and symptoms of secondary adrenal insufficiency with nausea, vomit-ing, diarrhea, and abdominal pain.(Table 3)95 Some women experience only partialhypopituitarism, and may have normal menses and fertility.94 Although the womenmay have episodes of transient polydipsia and polyuria, many demonstrate impairedurinary concentrating ability and deficient vasopressin secretion.96 CT or MRI scansgenerally reveal partial or completely empty sellae.97

Table 3. Symptoms and Signs of Sheehan Syndrome

Acute Form Chronic Form

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Acute Form Chronic Form

Hypotension Light-headedness

Tachycardia Fatigue

Failure to lactate Failure to lactate

Hypoglycemia Persistent amenorrhea

Failure to regrow shaved pubic hair Decreased body hair

Extreme fatigue Dry skin

Nausea and vomiting Loss of libido

Nausea and vomiting

Cold intolerance

(From Molitch ME. Pituitary, thyroid, adrenal and parathyroid disorders. In:Barron WM, Lindheimer MD, eds. Medical disorders during pregnancy. Chicago:Mosby-Year Book, 1991.)

Lymphocytic HypophysitisLymphocytic hypophysitis is thought to be autoimmune in nature, and is manifestedby a massive infiltration and destruction of the parenchyma of the pituitary and in-fundibulum by lymphocytes and plasma cells.98 It generally occurs during preg-nancy or the postpartum period, perhaps related to the <61485>enolase autoantigenshared by both the pituitary and placenta.99 It is associated with symptoms of hy-popituitarism or an enlarging mass lesion with headaches and visual field defects,and is suspected based on its timing and lack of association with an obstetric hemor-rhage or prior history of menstrual difficulties or infertility. It is generally associatedwith mild hyperprolactinemia (<150 ng/ml) and diabetes insipidus. Differentiationfrom a pituitary neoplasm cannot be made based on CT or MRI scans which reveala sellar mass with possible extrasellar extension, but only on biopsy results.100,101Serum antibodies to human pituitary membrane antigens are specific, but not sensi-tive, for diagnosis.102 Treatment is generally conservative and involves identificationand correction of any pituitary deficits, particularly of ACTH secretion, which is par-ticularly common in this condition.103 There are no data to indicate that high dosecorticosteroids are of benefit in treating the destructive process. Surgery to debulk butnot remove the gland is indicated in the presence of uncontrolled headaches, visualfield defects, and progressive enlargement on scan. Spontaneous regression and re-sumption of partial or normal pituitary function may occur, although most patientsprogress to chronic panhypopituitarism.103-105 Other autoimmune disorders mayalso be associated.

Posterior PituitaryHyperventilation in pregnancy leads to hypercapnea, renal bicarbonate wasting,and associated renal sodium loss. The osmostat, the setpoint for plasma osmolalityat which arginine vasopressin (AVP) is secreted, is reduced approximately 5-10mOsm/kg in pregnancy, dropping from 285 to 275 mOsm/kg. As a result, pregnantwomen experience thirst and release AVP at lower levels of plasma osmolalitythan do nonpregnant women.106 This reset osmostat and altered thirst thresholdis possibly due to high levels of human chorionic gonadotropin (hCG).106 The

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placenta produces an amino-terminal peptidase, vasopressinase, an enzyme thatrapidly inactivates AVP and oxytocin. Vasopressinase levels increase 1000-foldbetween the 4th and 38th weeks of gestation.107 AVP consequently has a four- tosixfold increased metabolic clearance rate during gestation.108,109

The lower osmostat and increased clearance of AVP by vasopressinase in pregnancyalter the nomograms of plasma osmolality and AVP used in the nonpregnant pa-tient. Serum sodium levels may also be lower than those normally expected in pa-tients with diabetes insipidus.109 Standard water deprivation tests which require 5%weight loss should be avoided during pregnancy as they may cause uterine irritabil-ity and alter placental perfusion. Instead, dDAVP is used to assess urinary concen-trating ability over 11 hours, with a value greater than 700 mosm/kg considered nor-mal.110 Urinary concentrating ability in the pregnant patient should be determinedin the seated position, as the lateral recumbent position inhibits maximal urinaryconcentration.106,109 Delivery of the placenta generally results in a return to normalAVP metabolism in 2 to 3 weeks.

Plasma oxytocin levels increase progressively during pregnancy, with a dramatic in-crease at term.111,112 Oxytocin levels rise further during labor and peak in the sec-ond stage. Uterine sensitivity to oxytocin increases with a rise in oxytocin receptorsin the myometrium. Hypophysectomy does not alter onset of labor, indicating thatoxytocin provides only a facilitatory role.113 Pulsatile release of oxytocin does notcorrelate with uterine contractions. Oxytocin levels rise rapidly during suckling.114

Diabetes InsipidusThree types of diabetes insipidus may occur in pregnancy; central, nephrogenic, ortransient vasopressin-resistant. Each is manifest with polydipsia, polyuria, and de-hydration.

Central diabetes insipidus may occur spontaneously in pregnancy with an enlargingpituitary adenoma, with lymphocytic hypophysitis, or with the development ofother conditions such as histiocytosis X. Diabetes insipidus usually worsens duringgestation,109 likely due to the increased clearance of AVP by the vasopressinase.Patients with asymptomatic DI may develop symptoms during pregnancy with thelower osmostat for vasopressin release, elevation in vasopressinase levels, andincreased AVP clearance.115-117 Patients with mild disease usually treated withchlorpropamide should discontinue this agent, as it readily crosses the placentaand causes hypoglycemia in the fetus. The AVP analog desmopressin (dDAVP) isresistant to vasopressinase, and provides satisfactory treatment during gestation,although a higher dose may be required.109 During monitoring of the clinicalresponse, clinicians should remember that normal basal plasma osmolality andsodium concentration are 5 mEq/L lower during pregnancy.118 No adverse eventshave been described in the offspring of pregnancies in which dDAVP was usedthroughout gestation.119,120 DDAVP transfers minimally into breast milk109 and ispoorly absorbed from the gastrointestinal tract, so its use will not adversely affect aninfant’s water metabolism.

Transient AVP-resistant forms of DI secondary to placental production of vasopressi-nase may occur spontaneously in one pregnancy, but not in a subsequent one.118Some of these patients may respond to dDAVP therapy. The symptoms resolve withinseveral weeks of delivery.109,118,121

Acute fatty liver of pregnancy and other disturbances of hepatic function suchas hepatitis may be associated with late onset transient DI of pregnancy in somepatients.122,123 It is presumed the hepatic dysfunction is associated with reduceddegradation of vasopressinase, further increasing vasopressinase levels and theclearance of AVP. The polyuria may develop either prior to delivery or postpartum.Complete resolution of the hepatic abnormalities and DI occurs by the 4th weekpostpartum.

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DI that develops postpartum may be a result of Sheehan’s syndrome, particularly inthe setting of an obstetric hemorrhage.(see above) Transient DI of unknown etiologyhas been described postpartum, lasting only days to weeks.124

Congenital nephrogenic DI is a rare X-linked disorder caused by a mutation in the va-sopressin V2 receptor gene, and predominantly affects males. Female carriers of thisdisease may have significant polyuria during pregnancy. Treatment is with thiazidediuretics,109 which should be used with caution in pregnant women.

In patients with idiopathic DI, oxytocin levels are normal and labor may begin spon-taneously and proceed normally.125 Patients with DI secondary to trauma, infiltra-tive disease, or a neoplasm may have adversely affected oxytocinergic pathways,resulting in poor progression of labor and uterine atony.

ADRENAL DISORDERS IN PREGNANCYPregnancy modifies adrenal steroid metabolism substantially. Unlike thehypothalamic-pituitary-adrenal axis, glucocorticoid levels provide a postitivefeedback on the placental corticosteroid axis. Placental CRH rises severalhundred-fold during pregnancy, is extensively protein bound until term, andmodulates both maternal and fetal pituitary-adrenal axes and may regulateparturition.126 Both maternal and placental ACTH levels rise dramatically after16-20 weeks gestation,(Figure 3)127 with a final surge in ACTH and plasma cortisolduring labor. Despite the increase in the placental hormones, the normal maternalcircadian rhythm of ACTH secretion persists throughout pregnancy.

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Figure 3. Plasma concentrations of adrenocorticotropic hormone (ACTH) and corti-sol during normal pregnancy. Blood samples were obtained from five normal preg-nant women weekly at 8:00 to 9:00 AM and from three women during labor and onthe second postpartum day. In addition, umbilical cord plasma was obtained fromthe newborn infants of three of these subjects. The mean plasma concentrations forACTH are denoted by the solid circles, whereas plasma cortisol levels are denotedby open circles. The vertical bars correspond to the magnitude of the standard er-ror of the mean. (From Carr BR, Parker Jr CT, Madden JD, et al. Maternal plasmaadrenocorticotropin and cortisol relationships throughout human pregnancy. AmJ Obstet Gynecol 1981;139:416.)

The fetoplacental unit has a marked capacity for steroidogenesis. At the same time,maternal cortisol levels increase 2- to 3-fold throughout pregnancy,128,129 with an in-crease in the size of the maternal zona fasciculata.130 There is an estrogen-stimulatedincrease in circulating cortisol binding globulin levels, resulting in an increase in to-tal cortisol levels and a decreased rate of cortisol clearance.131 With displacement ofcortisol from CBG by progesterone, free cortisol levels also increase.128 Urine freecortisol levels rise 2-3 fold during gestation.

Numerous changes occur in the renin-angiotensin-aldosterone system as well.Plasma renin activity increases 3- to 7-fold and plateaus at 20 weeks gestationalage, despite the increase in plasma volume with pregnancy.132,133 Angiotensin IIlevels increase approximately 3-fold by term, although there is resistance to itspressor effects. Plasma mineralocorticoid levels increase 5- to 20-fold duringgestation,129,133 but aldosterone secretion continues to respond normally tophysiologic stimuli such as posture and varies inversely to changes in volume or

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dietary salt.134,136 The increase in aldosterone correlates with the pregnancyincrease in GFR and in progesterone,135 which competitively inhibits sodiumretention by aldosterone at the distal renal tubules. Progesterone also demonstratesan anti-kaliuretic effect,136 with a report of amelioration of hypokalemia duringpregnancy in a woman with primary aldosteronism.137

The relative hypercortisolism and hyperaldosteronism of normal pregnancy are notgenerally clinically apparent. Adrenal disorders occurring in pregnancy cause signif-icant maternal and fetal morbidity.

Cushing’s Syndrome During PregnancyCushing’s syndrome is uncommon, with an incidence of 2 in 1,000,000. Just over 100cases have been reported in pregnancy to date.138-156 Fertility is generally reducedby the altered gonadotropin secretion in pituitary disease, and increased adrenalandrogen secretion in adrenal disease. Anovulation may be less prevalent withadrenal Cushing’s syndrome, as the proportion of adrenal and pituitary disease inpregnancy differs from that found in the nonpregnant woman. Approximately40% of cases are secondary to a pituitary adenoma vs. an 80% rate expected inthe nonpregnant woman. Of the remaining, 44% are adrenal adenomas, 11%adrenal carcinomas,138-144 and the remainer a mix of primary pigmentednodular adrenal disease, ACTH-independent hyperplasia, and ectopic ACTHsecretion.140 Several cases of pregnancy-dependent Cushing’s syndrome have beendescribed, with no interpartum adrenal steroid abnormalities noted.145,146,153The placental CRH rise apparently caused a pregnancy-induced exacerbation andrecognition of the hypercortisolism, with occasional improvement in the symptomspostpartum.139,140 Recurrent Cushing’s syndrome may occur in pregnancy withremission postpartum.141,154

It may be difficult to diagnose Cushing’s syndrome during pregnancy because thetypical symptoms of central weight gain, fatigue, emotional lability, glucose intol-erance, hypertension, and edema are also common accompaniments of pregnancy.Pigmentation of striae and development of hirsutism or acne may suggest the hy-perandrogenemia of Cushing’s syndrome, and proximal myopathy may also helpto distinguish Cushing’s syndrome from normal pregnancy symptoms. Pathologicfractures may occur.157 The laboratory evaluation is confounded by the normal preg-nancy rise in ACTH and cortisol levels. The hypercortisolism of pregnancy continuesto exhibit a normal circadian rhythm, though with a higher nighttime nadir; loss ofdiurnal rhythm is characteristic of all forms of Cushing’s syndrome.147 Salivary cor-tisol measurements may assist in determining this lack of diurnal response, but nor-mal midnight levels have not been standardized for pregnancy.153,155,156,158 Uri-nary free cortisol levels greater than 3 times the upper limit of normal may be inter-preted as indicating Cushing’s syndrome in the second and third trimester. There arelimited or no data using antibody-based assays or mass spectrometry. Normal preg-nancy is also associated with “inadequate” suppression of ACTH and cortisoldur-ing the overnight dexamethasone suppression test.141 ACTH levels may not reliablydistinguish between pituitary and adrenal etiologies, as the levels may be normal orhigh in all forms of Cushing’s syndrome, likely from placental ACTH production orfrom the placental CRH-stimulated pituitary ACTH production.138-144,155,156,159When plasma ACTH levels are suppressed, preferably as measured using a two-siteimmunometric assay, no further biochemical testing is needed.

The high-dose dexamethasone suppression test (HDST) will cause > 80% suppressionof serum cortisol in normal pregnancy. Patients with adrenal Cushing’s may be iden-tified with this test as they don’t suppress, but the HDST may misclassify those withCushing’s disease, as three of seven cases failed to suppress in a small series.155,156Petrosal sinus sampling with CRH stimulation (pregnancy category C) has been usedwith no ill effects using the direct jugular vein approach to minimize fetal irradi-ation.148,155 Clear central-to-peripheral ACTH gradients were found. Response toCRH stimulation testing is variable. Ross et al142 described the typical exaggeratedACTH response to CRH in one patient, while Mellor et al152 saw only a doubling of

13


cortisol levels in response to CRH in another patient. Lindsay et al155 found a morethan threefold increase in ACTH but a less than twofold elevation in cortisol levels in2 patients. Pituitary MRI, performed without gadolinium enhancement, is often non-diagnostic in patients with Cushing’ syndrome. Adrenal ultrasound may be used tocharacterize adrenal lesions in patients with borderline or low plasma ACTH or nosuppression on the HDST.

Maternal complications of Cushing’s syndrome include hypertension, preeclampsia,diabetes, myopathy, opportunistic infections, and fracture. Postoperative wound in-fection and dehiscence may occur following cesarean delivery. Premature labor oc-curs in more than 50% of cases.138-144,150-153,155,156 Fetal effects include intrauter-ine growth retardation, effects of prematurity, and 25% mortality from spontaneousabortion, stillbirth, and prematurity.138-144,150-153,155,156 The maternal hypercor-tisolemia may occasionally lead to fetal adrenal suppression,149 and the neonateshould be tested for this and treated prophylactically until the results are known.

Rates of fetal loss and premature labor decrease, though are still significant,in patients who are treated during pregnancy.138,141 In two publishedreviews, fetal loss rates of 30% and 38% were seen in 26 and 43 women forwhom treatment was delayed, vs. 9% and 24% in 11 and 17 women whowere treated during pregnancy.138,141 Similarly, premature labor rates were48% and 72% in the 26 and 43 women for whom treatment was delayed, vs.20% and 47% in the 11 and 17 women who were treated.138,141 Medicaltherapy is generally not effective,140,141,144 though it may be used pendingdefinitive surgical therapy. Metyrapone has proved efficacious in a fewpatients, with side effects including hypertension and preeclampsia.160-162Ketoconazole therapy in three patients was associated with intrauterine growthretardation, but no malformations or neonatal adrenal insufficiency.150,151,155Aminoglutethamide may cause fetal masculinization and mitotane is teratogenic;both should be avoided. Adrenal surgery may be performed using a laparoscopicapproach. The live birth rate is approximately 87% after unilateral or bilateraladrenalectomy.155,156 Because of the high rate of adrenal carcinoma, early surgerymay improve the poor prognosis. Transsphenoidal surgery has also been usedsuccessfully.139,142,148,149,152,153,155,156 The risks of surgery to both motherand fetus are outweighed by the benefits of appropriately treating the Cushing’ssyndrome.

Adrenal InsufficiencyThe prevalence of primary adrenal insufficiency in pregnancy is unknown, with aseries from Norway suggesting an incidence of 1 in 3000 births from 1976 to 1987.163In developed countries, the most common etiology for primary adrenal insufficiencyis autoimmune adrenalitis, which may be associated with autoimmune polyglan-dular syndrome. Primary adrenal insufficiency from infections (tuberculous or fun-gal), bilateral metastatic disease, hemorrhage or infarctions is uncommon. Secondaryadrenal insufficiency, from pituitary neoplasms or glucocorticoid supression of thehypothalamic-pituitary-adrenal axis, is more common.

Recognition of adrenal insufficiency may be difficult in the first trimester as manyof the clinical features are found in normal pregnancies, including weakness, light-headedness, syncope, nausea, vomiting, hyponatremia, and increased pigmentation.Addisonian hyperpigmentation may be distinguished from chloasma of pregnancyby its presence on the mucous membranes, on extensor surfaces, and on non-exposedareas. Weight loss, hypoglycemia, salt craving, hyponatremia more severe than thenormal 5 mmol/L decrease of pregnancy, or seizures, should prompt a clinical eval-uation. If unrecognized, adrenal crisis may ensue at times of stress, such as a urinarytract infection or labor.163 Fetal cortisol production may be protective, shielding themother from severe adrenal insufficiency until postpartum.164

The fetoplacental unit largely controls its own steroid milieu, so maternal adrenalinsufficiency generally causes no problems with fetal development. Maternal anti-

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adrenal autoantibodies may cross the placenta, but usually not in sufficient quanti-ties to cause fetal or neonatal adrenal insufficiency.165 Although earlier studies ob-served intrauterine growth retardation in offspring of women with Addison’s dis-ease,166,167 this observation has not been supported in most subsequent case series.Severe maternal hyponatremia or metabolic acidosis may cause a poor fetal outcome,including death.168 Association with other autoimmune conditions such as anticar-diolipin antibodies may lead to additional risks such as miscarriage.169

Adrenal insufficiency is associated with laboratory findings of hyponatremia, hyper-kalemia, hypoglycemia, eosinophilia, and lymphocytosis. Hyperkalemia may be ab-sent, because of the pregnancy increase in the renin angiotensin system.168,170 Earlymorning plasma cortisol levels of < 3.0 mcg/dl (83 nmol/L) confirms adrenal insuf-ficiency,171 while a cortisol >19 mcg/dl (525 nmol/L) in the first or early secondtrimester excludes the diagnosis in a clinically stable patient.171,172 Plasma corti-sol levels may fall in the normal “nonpregnant” range due to the increase in CBGconcentrations in the second and third trimesters, but will not be appropriately ele-vated for the stage of pregnancy. Appropriate pregnancy-specific cutoffs for diagno-sis with the standard cosyntropin (1-24 corticotropin) test using a 250 mcg dose havenot been established. Plasma cortisol levels were 60% to 80% above nonpregnant re-sponses in normal pregnant women tested in the second and third trimesters in oneseries.173 McKenna et al171 examined the 1 mcg low dose cosyntropin test for di-agnosis of secondary adrenal insufficiency in women at 24-34 weeks gestational age,and found high sensitivity of diagnosis using a cutoff of 30 mcg/dl (828 nmol/L).Accuracy of dosing is more difficult with this than with the standard cosyntropintest. The cosyntropin test is less sensitive to detect early secondary or tertiary formsof adrenal insufficiency. Cortisol and ACTH responses to CRH are blunted in preg-nancy,174 making the CRH stimulation test unreliable for differentiating secondaryand tertiary adrenal insufficiency in pregnancy. With primary adrenal insufficiency,ACTH levels will be elevated, and a level above 100 pg/ml (22 pmol/L) is consis-tent with the diagnosis.172 However, ACTH will not be low with secondary formsbecause of the placental production of this hormone, which is nevertheless insuffi-cient to maintain normal maternal adrenal function. ACTH values fluctuate widely,and a single value is insufficient for diagnosis. Adrenal antibodies may assist in con-firming idiopathic adrenal insufficiency, as approximately 90% of patients will have21-hydroxylase antibodies and 30% will have antibodies to 17-hydroxylase and side-chain cleavage enzymes.175 Aldosterone to renin ratios are low with elevated plasmarenin activity in patients with mineralocorticoid deficiency from adrenal atrophy.176

In the unstable patient, empiric glucocorticoid therapy (hydrocortisone 100 mg IV)should be administered pending the results of diagnostic testing. Thereafter, stressdoses of 50-100 mg every 6-8 hours during the crisis mimics the maximal cortisol pro-duction rates of 200 to 300 mg/day.177 Despite the normal increase in plasma cortisolduring pregnancy, baseline maternal replacement doses of corticosteroids usually arenot different from those required in the non-pregnant state. Higher doses are neededat times of stress, such as during the course of “morning sickness” or during laborand delivery. Patients should be educated in the self-administration of intramuscularhydrocortisone. Hydrocortisone 50 mg IV is generally given in the second stage oflabor.178 Mineralocorticoid replacement requirements usually do not change duringgestation, though some clinicians have reduced doses of fludrocortisone in the thirdtrimester in an attempt to treat Addisonian patients who develop edema, exacerba-tion of hypertension, and preeclampsia.163,179

Patients who have received glucocorticoids as antiinflammatory therapy arepresumed to have adrenal axis suppression for at least one year.180 Thesepatients should be treated with stress doses of glucocorticoids during labor anddelivery. They are at risk for postoperative wound infection and dehiscence as arepatients with endogenous Cushing’s, and their offspring are at risk for transientadrenal insufficiency. Although prednisone readily crosses the placenta,181the maternal:fetal gradient is higher than with other available agents.182,183Corticosteroid therapy during pregnancy is generally safe and suppression ofneonatal adrenal function is uncommon.184 Glucocorticoid therapy during lactation

15


is also safe, as less than 0.5% of the dose is passed into breast milk.167,185

Congenital Adrenal HyperplasiaCongenital adrenal hyperplasia occurs in a family of monogenic inheritedenzymatic defects of adrenal steroid biosynthesis, with manifestations secondary toan accumulation of precursors proximal to the enzymatic deficiency. The mostcommon form of CAH in the population is 21-hydroxylase (CYP21 gene) deficiency,seen in more than 90% of the CAH cases in pregnancy.186-188 Classic, severe21-hydroxylase deficiency is associated with ambiguous genitalia, an inadequatevaginal introitis, and progressive postnatal virilization including precociousadrenarche, advanced somatic development, central precocious puberty, menstrualirregularity, a reduced fertility rate, and possibly salt wasting.187,189,190 Thespontaneous abortion rate is twice that in the normal population,191 and congenitalanomalies are more frequent. Cephalopelvic disproportion from an android pelvismay occur, sometimes complicated by the previous reconstructive surgery.192,193Conception requires adequate glucocorticoid therapy, which then continues atstable rates during gestation, except at labor and delivery. Nonclassic (late-onset)21-hydroxylase deficiency patients present with pubertal and postpubertalhirsutism and menstrual irregularity, and may have improved fertility withglucocorticoid therapy.191

Fetal risk depends on the carrier status of the father. Unfortunately, ACTHstimulation testing to measure 17-OH progesterone demonstrates overlap betweenheterozygotes for CAH and the normal population.194 Ideally, CYP21 genotypingshould be performed.188 Virilization is not seen in the female fetus with nonclassic21-hydroxylase deficiency,195 but occurs in a fetus with classic 21-hydroxylasedeficiency unless fetal adrenal androgen production is adequately suppressed.Dexamethasone most readily crosses the placenta as it is not bound to CBG and isnot metabolized by placental 11 hydroxysteroid dehydrogenase. It is commonlyused at doses of 20 µg/kg maternal body weight per day to a maximum of 1.5 mgdaily in 3 divided doses beginning at recognition of pregnancy before the 9th weekof gestation,187,189 though lower doses are recommended by some.196 Treatmentby the 9th week of gestation is very effective in reducing the risk of virilization inthe affected female fetus.189 Maternal plasma and/or urinary estriol levels reflectfetal adrenal synthesis and are monitored to assess efficacy. Maternal cortisol andDHEA-S levels will represent maternal adrenal suppression. There is little effecton maternal 17-OH progesterone with therapy. As only 25% of female fetuses areaffected in a family with CAH, it is important to discontinue therapy as soon aspossible in the male fetus and unaffected female fetus. Chorionic villus samplingat 9-11 weeks gestation may be used for gender determination and direct DNAanalysis for the 21-hydroxylase gene CYP21.186,189,197 This test is associated witha 1-4% risk of miscarriage and 2% risk of limb defects. An alternative is karyotypingand DNA analysis or measuring androstenedione and 17-OH progesterone levels inamniotic fluid at 16-18 weeks of gestation after dexamethasone has been withheldfor 5 days.197 Side effects of dexamethasone therapy are potentially significant,including excessive weight gain, severe striae with scarring, edema, irritability,gestational diabetes mellitus, hypertension, and gastrointestinal intolerance.189,198In affected pregnancies, dexamethasone may be lowered to 0.75 to 1.0 mg/day inthe second half of pregnancy to decrease maternal side effects while avoiding fetalvirilization.198

Primary Hyperaldosteronism During PregnancyPrimary hyperaldosteronism rarely has been reported in pregnancy,199-203and is most often caused by an adrenal adenoma. There are rare reports ofglucocorticoid-remediable hyperaldosteronism in pregnancy.204 The elevatedaldosterone levels found in patients are similar to those in normal pregnant women,

16


but the plasma renin activity is suppressed.199-202 Moderate to severe hypertensionis seen in 85%, proteinuria in 52%, and hypokalemia in 55%,203 and symptomsmay include headache, malaise, and muscle cramps.205 Placental abruption andpreterm delivery are risks.206 Progesterone has an antimineralocorticoid effect atthe renal tubules, and the hypertension and hypokalemia may ameliorate duringpregnancy.207

The physiologic rise in aldosterone during pregnancy overlaps the levels seen in pri-mary aldosteronism, making diagnosis difficult.133,203 Suppressed renin in the set-ting of hyperaldosteronism is diagnostic. Salt loading tests may be used to diagnosehyperaldosteronism, but there are potential fetal risks and no normative data.200If baseline and suppression testing are equivocal, or radiologic scanning does notsuggest unilateral disease, patients may be treated medically until delivery to allowmore definitive investigations.201 Spironolactone, the usual nonpregnant therapy, iscontraindicated in pregnancy as it crosses the placenta and is a potent antiandro-gen which can cause ambiguous genitalia in a male fetus.202 There is no publishedexperienced with the use during pregnancy of dplerenone, the new aldostgerone re-ceptor antagonist. Surgical therapy may be delayed until postpartum if hypertensioncan be controlled with agents safe in pregnancy, such as amiloride, methyldopa, la-betolol, and calcium channel blockers.201,207,208 Potassium supplementation maybe required, but as noted above, the hypokalemia may ameliorate in pregnancy be-cause of the antikaliuretic effect of progesterone. Both hypertension and hypokalemiamay exacerbate postpartum due to removal of the progesterone effect.209,210

Pheochromocytoma in PregnancyExacerbation of hypertension is a typical presentation of pheochromocytomain nonpregnant patients, but during pregnancy is frequently mistaken forpregnancy-induced hypertension or preeclampsia.211 The prevalence is estimatedat 1 in 54,000 pregnancies.212 As the uterus enlarges and an actively moving fetuscompresses the neoplasm, maternal complications such as severe hypertension,hemorrhage into the neoplasm, hemodynamic collapse, myocardial infarction,cardiac arrhythmias, congestive heart failure, and cerebral hemorrhage may occur.Extra-adrenal tumors which occur in 10%, such as in the organ of Zuckerkandl atthe aortic bifucation, are particularly prone to hypertensive episodes with changesin position, uterine contractions, fetal movement, and Valsalva maneuvers.213Unrecognized pheochromocytoma is associated with a maternal mortality rate of50% at induction of anesthesia or during labor.214,215

There is minimal placental transfer of catecholamines,216,217 likely dueto high placental concentrations of catechol-O-methyltransferase andmonoamine oxidase.216,218 Adverse fetal effects such as hypoxia are a resultof catecholamine-induced uteroplacental vasoconstriction and placentalinsufficiency,219-221 and of maternal hypertension, hypotension, or vascularcollapse.

As always, diagnosis of pheochromocytoma requires a high index of suspicion. Pre-conception screening of families known to have MEN 2 with RET proto-oncogene isessential. Patients with MEN 2A are more likely to have paroxysmal hypertensionand have higher rates of bilateral neoplasms than those with sporadic pheochro-mocytoma.222 Examination for associated evidence for MEN2 may be difficult inpregnancy, with the expected pregnancy alterations in calcium, PTH, and calcitonin.Clinical thyroid examination should be done, with fine needle aspiration of any nod-ules so that overt medullary carcinoma can be treated immediately. Individuals withneurofibromatosis,223 von Hipple-Lindau disease,224 or retinal angiomatosis shouldalso be screened for pheochromocytomas prior to pregnancy.

The diagnosis should be considered in pregnant women with severe or paroxysmalhypertension, particularly in the first half of pregnancy or in association with ortho-static hypotension or episodic symptoms of pallor, anxiety, headaches, palpitations,chest pain, or diaphoresis. Symptoms may occur or worsen during pregnancy be-

17


cause of the increased vascularity of the tumor and mechanical factors such as pres-sure from the expanding uterus or fetal movement.220

Laboratory diagnosis of pheochromocytoma is unchanged from the nonpregnantstate as calecholamine metabolism is not altered by pregnancy per se.225 If possible,methyldopa and labetolol should be discontinued prior to the investigation as theseagents may interfere with the quantification of the catecholamines and VMA.226Provocative testing should be avoided because of the increased risk of maternal andfetal mortality. Tumor localization with MRI, with high intensity signals noted onT2-weighted images, provides the best sensitivity without fetal exposure to ionizingradiation. Metaiodobenzylguanidine and [18F]-dopamine-labeled positron emissiontomography scans are contraindicated in pregnancy, but may be used postpartum toassess extra-adrenal disease.

Differentiation from preeclampsia is generally simple. The edema, proteinuria, andhyperuricemia found in preeclampsia is absent in pheochromocytoma. Plasma andurinary catecholamines may be modestly elevated in preeclampsia and other seriouspregnancy complications requiring hospitalization, though they remain normal inmild preeclampsia or pregnancy-induced hypertension.227 Catecholamine levels are2- to 4-times normal after an eclamptic seizure.228

Initial medical management involves α-<61485>blockade with phenoxybenzamine,phentolamine, prazosin, or labetolol. All of these agents are well-tolerated by thefetus, but phenoxybenzamine is considered the preferred agent as it provides long-acting, stable, non-competitive blockade.220 Phenoxybenzamine is started at a doseof 10 mg twice daily, with titration until the hypertension is controlled. Placentaltransfer of phenoxybenzamine occurs,229 but is generally safe.230,231 If hyperten-sion remains inadequately controlled, metyrosine has also been used successfully toreduce catecholamine synthesis in a pregnancy complicated by malignant pheochro-mocytoma,232 but may potentially adversely affect the fetus. Beta blockade is re-served for treating maternal tachycardia or arrhythmias which persist after full α-blockade and volume repletion. Beta blockers may be associated with fetal bradycar-dia and with intrauterine growth retardation, when used early in pregnancy.225,233All of these potential fetal risks are small compared to the risk of fetal wastage fromunblocked high maternal levels of catecholamines. Hypertensive emergencies shouldbe treated with phentolamine (1-5 mg) or nitroprusside, although the latter shouldbe limited because of fetal cyanide toxicity.

The timing of surgical excision of the neoplasm is controversial and may dependon the success of the medical management and the location of the tumor. As notedabove, pressure from the uterus, motion of the fetus, and labor contractions are allstimuli that may cause an acute crisis, particularly in patients with a tumor at theorgan of Zuckerkandl. In the first half of pregnancy, surgical excision may proceedonce adequate α-blockade is established, although there is a higher risk of miscar-riage with first trimester surgery. In the early 2nd trimester, abortion is less likely andthe size of the uterus will not make excision difficult. If the pheochromocytoma is notrecognized until the second half of gestation, increasing uterine size makes surgicalexploration difficult. Successful laparoscopic excision of a pheochromocytoma in the2nd trimester of pregnancy has been described.234 Other options include combinedcesarean delivery and tumor resection or delivery followed by tumor resection at alater date. Delivery is generally delayed until the fetus reaches sufficient maturity toreduce postpartum morbidity, providing successful medical management exists.

Although successful vaginal delivery has been reported,235 it has been associatedwith higher rates of maternal mortality than cesarean section. Labor mayresult in uncontrolled release of catecholamines secondary to pain and uterinecontractions.236 Severe maternal hypertension may lead to placental ischemiaand fetal hypoxia. However in the well-blocked patient, vaginal delivery maybe possible using intensive pain management with epidural anesthesia andavoidance of mechanical compression, employing techniques of passive descent andinstrumental delivery.

There is no available information regarding the impact of maternal use of phenoxy-

18


benzamine on the nursing neonate.

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chapter 2. pituitary and adrenal disorders of pregnancy

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