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Pituitary Disease and Pregnancy

  • Author: Bernard Corenblum, MD, FRCPC; Chief Editor: George T Griffing, MD  more...
 
Updated: Jul 27, 2015
 

Overview

Magnetic resonance imaging (MRI) scans performed during pregnancy[1, 2] demonstrate a gradual increase in maternal pituitary volume over the course of gestation, with an increased final weight (660-760 mg), as well as a volume increase of 30% above the pregestational volume. This enlargement results in a homogeneous upward convexity of the superior surface of the gland when visualized radiologically, and the gland reaches 12 mm in height a few days postpartum. It usually does not increase more that 2.6 mm. The pituitary gland increases in all dimensions, with an increase of 136%.[3]

Rare reports[4] exist of impingement on the optic chiasm (with resulting visual field changes) in women who have otherwise normal pregnancies. The pituitary stalk remains unchanged and is in the midline. The posterior pituitary, which is normally visualized as an intense, T1-weighted signal on MRI scans (the so-called pituitary bright spot) is not visualized in the third trimester. These changes usually regress after delivery.

Despite the cellular hyperplasia that occurs during pregnancy, pituitary tumor formation and, specifically, prolactinoma formation do not usually increase during pregnancy.[5]

Fertility is often impaired in women with pre-existing pituitary disease. Advances in ovulation induction or medical and surgical therapy has allowed pregnancy to occur in many of these women. MRI in pregnancy should be performed without contrast injection (gadolinium), which appears to be safe but is classified as category C in pregnancy by the US Food and Drug Administration. If possible, MRI may be postponed until after delivery.

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Prolactin: Prolactinomas

Prolactin

Prolactin (PRL)–secreting lactotrophs, which normally constitute up to 20% of pituitary cells in men and in nulliparous women, increase to the extent that, by the end of pregnancy, they make up as many as 50% of pituitary cells. They are large, mitotically active, and display increased immunoreactivity for prolactin. This lactotroph hyperplasia is believed to be secondary to the multiplication of preexisting mature lactotrophs and the recruitment of inhibited somatotrophs (reduced growth hormone [GH] messenger ribonucleic acid [mRNA] content) to become mammosomatotrophs. The hyperplasia is related to the direct effect of increasing estrogen secretion and action.[6]

The number of lactotrophs declines quickly after delivery, especially if lactation is not maintained. However, this regression is not complete, and lactotroph hyperplasia has been demonstrated 11 months postpartum. Complete regression probably never occurs, as evidenced by the fact that lactotrophs constitute up to 25% of pituitary cells in multiparous women.

The very high levels of circulating estrogen that occur during pregnancy result in a parallel increase in the circulating levels of prolactin. The prolactin increase prepares the breasts for lactation. Prolactin levels begin to rise at 5-8 weeks into the gestation period and parallel the increase in the size and number of lactotrophs. At the end of the first trimester, serum prolactin levels are approximately 20-40 ng/mL. They increase further to 50-150 ng/mL and are 100-400 ng/mL at the end of the second and third trimesters, respectively. This is likely mediated by a direct effect on the lactotroph. A combination of factors may be responsible. Prolactin responses to normal stimuli (eg, sleep, meals, suckling) are maintained throughout pregnancy.

Fetal prolactin levels parallel maternal levels because of a similar estrogenic effect; these levels are 80-500 ng/mL at birth. They may be responsible for transient galactorrhea following birth.

Prolactin is produced by maternal decidua during pregnancy. Amniotic fluid prolactin levels are extremely high (4000-6000 ng/mL at the end of the second trimester, falling to 200-800 ng/mL at term); they are the product of the uteroplacental unit, principally the decidua. Decidual prolactin is identical to pituitary prolactin.

There is no inhibition of decidual prolactin production by dopamine or dopaminergic agonist drugs.

While decidual prolactin may be involved in water regulation and ion transport across extraembryonic membranes, no evidence suggests that decidual prolactin contributes to the described elevation of maternal or fetal serum prolactin levels in normal pregnancy.

Maternal prolactin levels decline rapidly following delivery, reaching baseline within 1-3 weeks postpartum in nonlactating women. In nursing women, each suckling triggers prolactin release; the magnitude of release decreases as nursing becomes less frequent. The maintenance of hyperprolactinemia and the consequent suppression of gonadotropins by frequent nursing extend postpartum amenorrhea and infertility for a few months.

In addition to quantitative changes, qualitative differences also occur between circulating prepregnancy and pregnancy prolactin. While most prepregnancy prolactin has a molecular mass of 22 kd, small amounts have weights of 45 kd and 100 kd. Most of the circulating prepregnancy prolactin is glycosylated. During pregnancy, a modest increase in the proportion of the 22-kd fraction of prolactin is observed. More dramatic and probably more significant is the fact that most circulating pregnancy prolactin is nonglycosylated. This affects the biological activity of the prolactin molecule.

A woman with macroprolactinemia (biologically inactive large molecule) produces normal amounts of biologically active prolactin during pregnancy and lactation.

Dopamine agonists and fetal development

Anovulation/amenorrhea and infertility accompany hyperprolactinemia. Prolactin directly inhibits pulsatile gonadotropin releasing hormone (GnRH) secretion; this results in some degree (in relation to the degree to which prolactin levels are elevated) of menstrual dysfunction. Correction of hyperprolactinemia with dopamine agonists restores ovulation in approximately 90% of patients. Two key issues must be addressed when a woman with a prolactinoma becomes pregnant: (1) the effects of a dopamine agonist on early fetal development that occurs before a pregnancy is diagnosed and (2) the effects of pregnancy on the prolactinoma.[7, 8]

In principle, fetal exposure to dopamine agonists should be limited. Ideally, when patients are started on therapy for hyperprolactinemia, mechanical contraception can be advised for the first 2-3 cycles so that an intermenstrual period can be established. By doing this, the woman will know when she has missed a period when unprotected intercourse is resumed. As soon as this occurs, a pregnancy test can be obtained and bromocriptine stopped. This approach limits dopamine agonist exposure to a maximum of 3-4 weeks. In practice, this delay is usually not done.

Bromocriptine appears to be safe in pregnancy.[9, 10] In more than 6000 pregnancies, bromocriptine has been shown not to increase the incidence of spontaneous abortions, trophoblastic disease, multiple pregnancies, or congenital malformations. In 2 studies in which bromocriptine was given before elective therapeutic abortions at 6-9 weeks, no effects were seen on estriol, estradiol, progesterone, testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, cortisol, and human placental lactogen levels.[11] Maternal and fetal prolactin levels were suppressed.

Follow-up of children exposed to bromocriptine during early pregnancy has also not demonstrated any increase in adverse effects up to age 9 years.[12] In approximately 100 women who took bromocriptine during weeks 20-41 of gestation, only 2 abnormalities (1 talipes and 1 undescended testicle) were noted. The incidence was comparable to (or even less than) that of the general population. The author has several female patients who were conceived by mothers who used bromocriptine and who went on to bear normal children of their own.

Cabergoline is a newer dopamine agonist that can be administered in a convenient once-a-week dosing schedule. It is particularly useful in women who are resistant to bromocriptine, as well as in patients who cannot tolerate bromocriptine because of its adverse effects. Outcome data available on 600 pregnancies in which cabergoline was administered to facilitate ovulation do not show increased risk of ectopic or multiple birth deliveries or malformations.[10, 13, 14]

Based on this, one may be reasonably certain that termination of the pregnancy is not necessary if a patient inadvertently becomes pregnant while taking cabergoline. However, until the safety of cabergoline is clearly established, bromocriptine should be considered the therapy of choice if pregnancy is the desired outcome.

Data on the safety of pergolide and quinagolide during pregnancy are too limited to recommend their use. Pergolide was withdrawn from the US market  on March 29, 2007, because of heart valve damage resulting in cardiac valve regurgitation. It is important not to abruptly stop pergolide. Health care professionals should assess a patient’s need for dopamine agonist therapy and consider alternative treatment. If continued treatment with a dopamine agonist is needed, another dopamine agonist should be substituted for pergolide. For more information, see FDA MedWatch Product Safety Alert and Medscape Alerts: Pergolide Withdrawn From US Market.

At present, the heart valve damage seen with high-dose cabergoline has not been demonstrated with the doses of cabergoline used to treat hyperprolactinemia, nor with bromocriptine or quinagolide (a nonergot-based dopamine agonist).[10]

Prolactinoma and pregnancy

Given the stimulatory effects of pregnancy on the normal lactotrophs, enlargement of the normal pituitary can be expected. This does not necessarily mean that the adenomatous pituitary may enlarge. Prolactinomas that symptomatically enlarge during pregnancy are uncommon. Symptoms suggestive of growth are headache, visual field changes, and diabetes insipidus.

Molitch summarized the current data on the effect of pregnancy on prolactinomas.[15] The risk of clinically significant enlargement for women with microprolactinoma is 1.3%. The risk of enlargement for a woman with untreated macroprolactinoma is 23.2%, while a macroprolactinoma that has been previously treated with surgery and/or radiation has a 2.8% risk of clinically significant enlargement. Shrinkage of a prolactinoma with bromocriptine is associated with a less likely chance of symptomatic growth during pregnancy, after the bromocriptine is discontinued.

Re-initiation of bromocriptine is the preferred treatment for pregnant women with prolactinomas who become symptomatic. Most cases quickly show a regression of symptoms (headache) and signs (visual field changes) of tumor enlargement, and the bromocriptine re-administration to date appears to be safe. Given the risks of fetal loss associated with surgery, restarting bromocriptine may be preferable if tumor enlargement occurs. Transsphenoidal surgery or delivery (if pregnancy is advanced enough) is an alternative if the patient does not respond to bromocriptine or if further visual deterioration occurs.

One approach is to use bromocriptine to allow ovulation, discontinue it when pregnancy is documented, and observe the patient carefully for evidence of tumor growth.[16] This is the standard approach today. Another alternative is prepregnancy transsphenoidal surgery. Although this approach reduces the risk of symptomatic adenoma expansion, it does not completely eliminate the risk of tumor enlargement in pregnancy and does not always eliminate the need for added bromocriptine. Furthermore, surgery may introduce another cause of infertility due to hypopituitarism. Thus, medical therapy is the initial treatment of choice.

A third approach includes continuation of bromocriptine throughout pregnancy. Although attractive, this approach must be tempered with caution because safety data on bromocriptine throughout pregnancy is still considered limited. Careful follow-up with frequent visual-field examinations is important in pregnant women with a known macroadenoma. Measurement of serum prolactin is not useful in detecting tumor growth or in indicating any lack of tumor growth. Therefore, periodic measurement of prolactin levels is of no benefit. MRI without gadolinium is performed on patients who develop symptoms of tumor enlargement and/or visual-field defects.

Pregnancy-associated symptomatic prolactinoma growth in a woman who is resistant to dopamine agonists (becoming pregnant by ovulation induction) is a special concern because readministration of a dopamine agonist may fail to reverse these symptoms. The authors have had such a case, with readministration of bromocriptine rapidly reversing the new headache associated with increased sellar mass. This suggests that it was the normal pituitary enlargement (lactotroph hyperplasia) and not the tumor that was causing the headache because the normal pituitary should have retained its responsiveness to bromocriptine. Thus, pregnancy in such women may be attempted after full discussion.[17]

Breastfeeding is safe and has not been associated with the growth of underlying prolactinomas.

Most series on pregnancy-induced tumor growth are old and have selection bias and/or referral bias. The true incidence of symptomatic tumor growth during pregnancy is likely lower than that cited in early reports. The author’s personal experience with a homogeneous population selected, treated, and monitored by 1 person from the onset of the presentation of hyperprolactinemia-amenorrhea to the conclusion of pregnancy is as follows:[18]

  • Of a population of 778 women with pathological hyperprolactinemia, 210 achieved at least 1 pregnancy.
  • In the study, 183 patients were treated with bromocriptine, 8 with cabergoline (because of bromocriptine resistance or intolerance), 16 with pulsatile GnRH (because of bromocriptine or cabergoline failure), and 3 with gonadotropins (because of pulsatile GnRH failure).
  • Underlying diagnoses of microprolactinoma (104 patients) and macroprolactinoma (21 patients) were made, with 85 cases being diagnosed as idiopathic.
  • Two women had symptomatic tumor growth in the first trimester. Both women had macroprolactinomas that had been treated with bromocriptine; administration of the drug had been stopped with the diagnosis of pregnancy. One patient had headaches alone, while the other had headaches and bitemporal hemianopia. Complete resolution occurred within 2 days of re-administration of bromocriptine, and both women delivered healthy male infants.
  • Overall, symptomatic tumor growth occurred in 1% of these women, but in members of the group with macroprolactinomas, 10% experienced symptomatic growth. They readily responded to bromocriptine treatment.

Effect of previous pregnancy on hyperprolactinemia/prolactinoma

A pregnancy induced with a dopamine agonist appears to run a benign course in terms of tumor growth. More interesting is the fact that there is often improvement or resolution of hyperprolactinemia (50-72%) and prolactinoma regression or disappearance following the pregnancy. Crosignani observed a 29% resolution,[19] and Badawy noted a 27% reduction or disappearance of tumor after delivery.[20] Idiopathic hyperprolactinemia cases were even more likely to resolve following pregnancy. The author has had a similar clinical observation. The mechanism of resolution is unknown, but there is speculation regarding vascular ischemia and necrosis in tumor tissue. This does not explain the greater resolution in nontumorous (idiopathic) cases.

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Growth Hormone: Acromegaly

Growth hormone

The number of somatotrophs is reduced in normal pregnancy. Basal and stimulated maternal GH levels are suppressed by the second trimester. Paradoxically, insulinlike growth factor–1 (IGF-1) levels are slightly increased throughout pregnancy, probably as a result of GH secretion by the syncytiotrophoblastic epithelium. In fact, patients with pituitary GH deficiency have normal IGF-1 levels in pregnancy. The placenta produces a variant GH (human growth hormone variant, or GH-V) that is not separated by conventional radioimmunoassay as different from pituitary GH. This placental GH increases through term and rapidly declines after delivery. The placental GH stimulates the production of hepatic IGF-1, which likely suppresses the pituitary secretion of GH through the normal negative feedback mechanism. Pregnancy is a state of physiological GH-IGF-1 excess.

The placenta also produces GH-releasing hormone and IGF-1. While the fetus also produces GH throughout pregnancy, whether this is responsible for fetal IGF-1 production is unclear, because anencephalic fetuses also demonstrate normal IGF-1 and IGF-2 levels.

Acromegaly in pregnancy

Fertility rates are decreased in acromegaly. Menstrual irregularity is a common and early finding in acromegaly, and many patients with acromegaly have amenorrhea. This is attributed either to anatomic compromise of gonadotropin-producing cells (mass effect in the pituitary) or to concurrent hyperprolactinemia. Prolactin hypersecretion may occur from a mass interfering with dopamine action or from cosecretion along with the GH. In addition, prolactinlike effects of GH (specificity spillover) may contribute to the menstrual irregularity observed in acromegaly. Correction of hyperprolactinemia may be necessary for normal ovulation in these patients.

Active acromegaly during pregnancy does increase insulin resistance and thus increase the risk of gestational diabetes and hypertension. Underlying cardiac disease, from metabolic syndrome, hypertension, or acromegaly-associated cardiomyopathy, may become symptomatic during pregnancy. Pregnancy has not been found to alter the course of acromegaly other than in rare, reported cases of asymptomatic tumor enlargement, which may or may not be related to pituitary hyperplasia. If left untreated for the duration of pregnancy, it is thought not to have any adverse effects on the course of acromegaly, which otherwise is a chronic disease that can be addressed after delivery.

Tumor enlargement may theoretically occur if pre-existing therapies such as somatostatin analogues are discontinued with the onset of pregnancy. Acromegalic symptoms may improve during pregnancy, possibly from the increased estrogen production inhibiting hepatic IGF-1 production.

Underlying normal pituitary secretory function needs to be assessed, and any deficiency of thyroxine or cortisol requires that these be replaced.

The diagnosis of acromegaly occurring for the first time in pregnancy is difficult to establish. Standard radioimmunoassays cannot distinguish between normal pituitary GH and the placental variant GH-V. Because basal levels of placental GH are high, results may erroneously indicate acromegaly. Serum IGF-1 is also increased in normal pregnancy. Some otherwise normal pregnancies may be associated with acromegaloid-like phenotypic changes, which generally reverse after delivery.

Suppression of GH to glucose has not been well tested in pregnancy, but placental GH would not be expected to change.

If the patient is pregnant and acromegaly is clinically suspected but has not been diagnosed, definitive diagnosis may not be possible until after delivery. Definitive treatment can usually be delayed until after the delivery.

Clues to the presence of a true increase in pituitary GH include a documentation of pulsatility, which is characteristic of acromegaly,[21] while placental GH secretion is apulsatile. When clinical findings and the limited laboratory examination suggest acromegaly, imaging of the sella with an MRI (without Gd) is warranted to document the presence of tumor. Performing computed tomography (CT) scans and coned-down views of the sella is not recommended in pregnancy, due to radiation exposure.

In most patients, therapy can be delayed until after delivery. In a series of 34 pregnant women with acromegaly, only 1 patient developed transient visual defects due to mass effect and physiologic lactotroph hyperplasia. In this patient, administration of bromocriptine restored visual fields, permitting deferment of definitive therapy until delivery. Octreotide has also been successfully used to treat tumor enlargement symptoms.

In patients with significant tumor enlargement during pregnancy or with severely symptomatic acromegaly, transsphenoidal surgery or bromocriptine therapy is an appropriate treatment option. Several reports have indicated that the use of octreotide or lanreotide has no apparent adverse effects during the course of a pregnancy and none on its outcome. These agents do cross the placenta, however, and the safety of octreotide during pregnancy has not been established.

Birthweight appears to be unaffected in pregnancies exposed to somatostatin-analogues. Initial reports on the use of pegvisomant in pregnancy have been encouraging,[22] but data are insufficient to support using this agent in anything but an exceptional situation.[23] No transfer across the placenta or entering of the breast milk has been noted. Because of the lack of many case reports and no controlled studies, these agents are best avoided during pregnancy other than in clinically indicated situations.

Women with pre-existing acromegaly who have had their drug therapy withdrawn usually have an uneventful pregnancy.[24] Breast feeding does not affect the course of acromegaly. Postpartum pituitary imaging demonstrates no increased tumor growth from the pregnancy.

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Adrenocorticotropic Hormone: Cushing Disease

Adrenocorticotropic hormone (ACTH)

While the corticotroph number is unaltered, significant changes occur in the hypothalamic-pituitary-adrenal (HPA) axis in pregnancy. Maternal serum cortisol gradually increases throughout pregnancy, with preservation of normal diurnal variation. The increase in total serum cortisol is partly due to an increase in cortisol-binding globulin, but the unbound or free cortisol increases as well. The urinary free cortisol reflects the increased unbound or free cortisol and is elevated to 250 mcg/d. The diurnal rhythm of cortisol may be intact or blunted.

Plasma ACTH levels gradually rise throughout pregnancy and appear to be, in part, of placental secretion. Corticotropin-releasing hormone (CRH) levels are increased greatly during pregnancy and are placental in origin. These ACTH and CRH levels may not be subject to feedback control. This CRH is largely protein bound and may or may not be biologically active in the mother, at least until the third trimester. One theory postulates that it has paracrine effects in the placenta.

HPA response to dynamic adrenal testing is altered in pregnancy. Urinary free and total serum cortisol are incompletely suppressed following low-dose and high-dose dexamethasone suppression tests. In addition, ACTH responses to CRH are blunted. The exact mechanism for the altered dynamics is unclear, but it may represent a combination of factors, including an estrogen increase, antagonism of glucocorticoid action by progesterone, autonomous ACTH and CRH secretion by the placenta, and enhanced vasopressin (AVP) secretion (see Vasopressin: Diabetes Insipidus).

Cushing disease in pregnancy

Up to 75% of women with Cushing disease have oligomenorrhea or amenorrhea due to cortisol- and androgen-induced gonadotropin suppression, or a polycystic ovary – like syndrome. Therefore, pregnancy is rare in patients with pre-existing Cushing disease. Fewer than 70 cases of Cushing disease occurring with pregnancy have been reported. Cushing disease may manifest first during pregnancy (or be exacerbated or recur during pregnancy), with improvement following parturition. This pregnancy-induced exacerbation has been attributed to unregulated placental CRH secretion, which is more active in the third trimester, or to a true recurrence of previous disease that was in remission.

More than 50% of patients with Cushing syndrome in pregnancy have an adrenal source, which is a more common cause of Cushing syndrome than it is in the nonpregnant state, likely due to little androgen hypersecretion interfering with ovulatory menses. In pregnancy, benign adrenal adenomas cause over 40% of the cases of Cushing syndrome, and 10% are due to adrenal carcinoma. Cyclical cortisol secretion has been reported.

The diagnosis of Cushing syndrome is difficult to establish.[25] Pregnant women frequently have weight gain, glucose intolerance, hypertension, edema, fatigue, striae, and emotional upset, all of which are common features of Cushing syndrome. In addition, the accuracy of diagnostic testing is confounded by the alterations in cortisol and HPA dynamics observed in pregnancy. Despite this, making a diagnosis of Cushing syndrome during pregnancy is important because of the increased risk of maternal morbidity, prematurity, and high fetal mortality. Striae associated with weight gain and increased abdominal girth are usually white in normal pregnancy and red or purple in a pregnancy complicated by Cushing syndrome. Muscle weakness may be noted, and the presence of thin skin in Cushing syndrome, as opposed to pregnancy (or polycystic ovary syndrome [PCOS]). Hirsutism and acne may indicate excessive androgen production.

When Cushing syndrome is considered, several variations in the diagnostic workup, when compared to that for nonpregnant women, may be necessary. Baseline serum cortisol levels are elevated in normal pregnancy, as is the 24-hour urinary free cortisol. The urinary free cortisol may be normal in the first trimester, but by the third trimester, it may have increased 3-fold. Pregnancy-specific normal ranges may be used, but not generally available. Improved sensitivity in detecting urinary free cortisol elevation from normal levels may be by high-performance liquid chromatography.[26]

An absence of diurnal variation may be a useful clue to the diagnosis because, despite the increase in serum cortisol levels, diurnal variation is usually preserved in normal pregnancy. Loss of diurnal variation is an early feature of Cushing syndrome. Midnight salivary cortisol is as yet untested in pregnancy. The nadir for midnight salivary cortisol is higher in pregnancy. The dexamethasone suppression test is unreliable, because placental ACTH is not glucocorticoid responsive.

Although nonpregnant patients with an adrenal cause (most common in pregnancy) have undetectable ACTH levels, a detectable level of plasma ACTH does not exclude an adrenal etiology due to placental secretion of ACTH in pregnancy. Similarly, while complete nonsuppressibility of cortisol by high-dose dexamethasone suppression testing may indicate an ectopic (or adrenal) source of cortisol excess, borderline suppressibility (which indicates pituitary-dependent Cushing disease in the nonpregnant state) may be normal in pregnancy. No experience has been reported with use of CRH testing in pregnancy. ACTH response to CRH is usually normal in the second trimester and blunted in the third trimester.

Once Cushing syndrome has been biochemically localized, imaging tests become essential. Caution must be used when interpreting sellar imaging because the pituitary volume normally is increased (making a microadenoma less visible) and may often be normal in Cushing disease. MRI without Gd is safe and superior to CT scanning in this regard, and a focal abnormality may be visible on MRI findings in patients with Cushing disease, as opposed to the diffuse enlargement observed in normal pregnancy. Petrosal vein catheterization is best avoided due to radiation exposure.

In most patients who are diagnosed with Cushing syndrome in pregnancy, the management must be expectant, with surgical intervention deferred until after delivery. Only one report has been documented of a successful transsphenoidal resection of a pituitary tumor producing Cushing disease. Premature labor is a risk of surgery. Patients for whom surgery may be indicated during pregnancy include those in whom adrenocortical carcinoma is suggested and those with severe disease. Drug therapy with metyrapone or ketoconazole may be beneficial and has been reported in pregnancy without congenital abnormalities; however, these drugs are best avoided in pregnancy, except under urgent conditions. There are no reports yet regarding the usefulness and safety of pasireotide.

The major maternal complications include hypertension (87%), diabetes (61%), and preeclampsia (10%). Pulmonary edema is observed in a large number of patients (44%) with adrenal adenoma. Poor wound healing and a high incidence of postoperative infections have been reported. The major risks to the fetus are premature labor (which is observed in up to 60% of patients), intrauterine growth retardation (IUGR), and perinatal death. While the fetal HPA axis may be thought to be suppressed by excessive maternal cortisol, neonatal adrenal insufficiency is rare. The placental 11b-hydroxysteroid dehydrogenase inactivates glucocorticoids and protects the fetus from maternal cortisol excess.

Nonsecreting pituitary mass

Decreased fertility may be noted in women with undiagnosed or previously diagnosed pituitary masses that are under observation. The use of ovulation induction therapies may restore fertility.

The presence of a nonsecreting pituitary mass, either microadenoma (< 10 mm) or macroadenoma (>10 mm), may be commonly found on incidental radiologic studies. Patients with these masses often are monitored clinically. Underlying pituitary function should be established at discovery and prior to pregnancy. Any deficiency should be addressed, with adjustment as needed during the pregnancy. Symptomatic tumor growth would not be expected to occur during pregnancy, but the usual pituitary enlargement due to lactotroph hyperplasia may rarely result in mass effects by adding to the tumor mass size. Bromocriptine should reduce the lactotroph hyperplasia and reverse the symptoms. In nonsecreting and secreting pituitary adenomas, increased tumor size may occur from aggressive growth, not related to the pregnancy. Risk factor may be a high Ki-67 index. More careful observation during pregnancy may be needed.

Surgical therapy is not be needed except for symptomatic apoplexy or mass growth otherwise unresponsive to dopamine agonists.

Hypopituitarism

Preexisting hypopituitarism may result from preexisting disease, such as pituitary tumors, or from surgical therapy and/or radiotherapy for these tumors. Pregnancy may have to be induced with ovulation induction. GH and sex steroids do not need to be replaced during pregnancy.

Thyroxine dose is expected to increase about 50 mcg/d. This may be given empirically or based on monitoring during each trimester. The serum TSH cannot be used to indicate if and when a higher dose is needed, so the free thyroxine needs to be measured, with the goal being to keep it in the upper third of the normal range. After delivery, the patient may return to the prepregnancy dose of thyroxine. Optimal thyroxine replacement appears to positively affect fetal outcome.[27]

Glucocorticoid dose does not usually need to be changed during early pregnancy, although symptoms occasionally indicate that a mild increase is required. Symptoms are nonspecific, such as fatigue, weakness, anorexia, and nausea, which are common in otherwise normal pregnancies. The glucocorticoid dose often needs to increase by 50% in the third trimester. Stress levels of cortisol or its equivalent are needed for labor, for 48 hours after delivery, and for any intercurrent major stress during the pregnancy.

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Vasopressin: Diabetes Insipidus

Vasopressin

Plasma sodium concentration falls by approximately 5 mEq/L during pregnancy, representing a downward resetting of the osmostat. The plasma osmolality set point for AVP release during pregnancy is lowered about 10 mOsm/kg from the nonpregnant value of 285 mOsm/kg to approximately 275-280 mOsm/kg. The decrease begins early in pregnancy. However, peripheral plasma AVP levels and AVP response to changes in tonicity are normal throughout pregnancy, at the lower osmostat set point.

AVP secretion during pregnancy is probably increased in response to a 4-fold increase in AVP degradation by placental vasopressinase.[28] Vasopressinase is a cysteine aminopeptidase that is produced by the placenta. Plasma levels increase during pregnancy, peak at term, and decline by 2-4 weeks postpartum. It is cleared by the liver.

Diabetes insipidus in pregnancy

Diabetes insipidus (DI) can occur de novo during pregnancy or in the postpartum period, while preexisting mild or overt DI may be exacerbated during pregnancy. In addition, a transient DI may occur during pregnancy in the absence of a known defect in AVP secretion.

Preexisting central DI

Patients with idiopathic central DI have normal fertility, course of pregnancy, and outcome. Because of increased degradation of circulating AVP by vasopressinase, AVP requirements increase during pregnancy.

An amelioration of central DI may be observed in women who breastfeed, probably due to an antidiuretic effect of oxytocin.

Transient DI of pregnancy

The increased demand for AVP during pregnancy may unmask subclinical or mild central DI. These patients have a decreased AVP secretory reserve and usually are AVP responsive. On the other hand, an abnormally high level of vasopressinase activity may result in an AVP-resistant form of DI. In contradistinction to nephrogenic DI, these patients normally are responsive to the AVP analog deamino-D-arginine vasopressin (DDAVP), which is not degraded by vasopressinase. For this reason, DDAVP is the treatment of choice for transient and preexisting central DI in pregnancy. No adverse maternal or fetal effects have been reported with the use of DDAVP in pregnancy.

Transient DI due to increased vasopressinase has always been reported in the third trimester. In a review of 17 patients, 3 had twins or triplets. The large placentas observed in twin gestation were possibly responsible for an increase in vasopressinase production. Hypertension, proteinuria, hyperuricemia, and elevated liver enzymes were also commonly observed in patients in this series. Acute fatty liver in pregnancy may also cause transient DI in pregnancy. While the mechanism is uncertain, it may be related to decreased degradation of vasopressinase. Overproduction of a hepatic form of aminopeptidase that degrades AVP has also been implicated.[29] Liver function should be checked in women with new DI with onset late in the pregnancy.

Transient DI of pregnancy resolves after delivery.

Transient nephrogenic DI that is unresponsive to DDAVP has been reported in pregnancy. The mechanism is unknown, but it resolves after delivery. It can occur in various disease states, such as preeclampsia, liver disease, and HELLP syndrome (hemolysis, elevated liver function, low platelets). Thiazide diuretics are the mainstays of therapy in nephrogenic DI.

Postpartum diabetes insipidus

Central DI can occur in the postpartum period, rarely in association with Sheehan syndrome, but most commonly with lymphocytic hypophysitis.

If central or nephrogenic DI occurs in pregnancy, the diagnosis is best made by a water deprivation test. Because dehydration is dangerous in pregnancy, caution is needed to ensure that 5% of the patient's body weight is not lost during the test. Caution is needed to judge when to begin the test, after some time of initial water restriction.

Despite the presence of central DI, there is no deficiency of oxytocin in labor and delivery, and there is no effect on lactation.

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Hypopituitarism: Sheehan Syndrome

Advances in ovulation induction may induce a pregnancy in a woman known to have partial or complete hypopituitarism.

Optimal obstetrical care has made postpartum pituitary necrosis, which often results in hypopituitarism, uncommon in developed countries; however, it remains a common cause of hypopituitarism in less developed countries.[30, 31] Important causes of postpartum pituitary necrosis include severe hemorrhage during and before parturition. The blood supply to the already enlarged pituitary gland is seriously compromised in times of acute volume depletion compounded by vasospasm due to circulating vasoconstrictors. The enlarged gland and low pressure in the portal system cause susceptibility to tissue hypoperfusion and infarction. It may be more likely to occur in the presence of a previously known or unknown pituitary mass.

An atrophic, hypofunctioning, scarred gland results. It has been suggested that patients with Sheehan syndrome have a small, rigid sella from the outset. The hyperplastic pituitary in this sella may be more likely to compress its blood supply, predisposing the gland to infarction if hypotension occurs. Pregnant women with type 1 diabetes, especially those with preexisting vascular disease, seem to be particularly at risk.

The most common presentation of the completed form of Sheehan syndrome is breast involution and failure to lactate from prolactin deficiency (although hyperprolactinemia has been reported in some). This is followed by failure of menses to resume and lack of regrowth of shaved axillary and pubic hair. Progressively, symptoms of hypothyroidism and hypoadrenalism supervene. This may result in nonspecific fatigue, anorexia, joint aches, and malaise. Hypotension and acute adrenal crises are uncommon except under stress but are potentially lethal. Skin pigmentation is decreased. Mental disturbances are frequent, and sometimes the patient may have overt psychosis. These changes revert with hormone replacement. Women with type 1 diabetes may present with decreasing insulin requirements.

Autopsy studies show frequent scarring of the neurohypophysis, as well as atrophy of the supraoptic and paraventricular nuclei, the sources of antidiuretic hormone (ADH). Central DI has been reported; however, the full-blown form is rare, and it may manifest more commonly as subtle defects in maximal urinary concentration. In some patients, corticosteroid replacement may unmask latent DI. The pituitary hormone deficiency may be partial in some patients, with the selective loss of 1 or more hormones.

Laboratory evaluation reveals partial hypopituitarism or panhypopituitarism with low free thyroxine, estradiol, and cortisol levels, as well as with low or inappropriately normal thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and ACTH levels. The cortisol response to ACTH is typically blunted. The ACTH stimulation test cannot be used for at least 3 months, because the adrenal cortex needs time to atrophy and lose responsiveness to low-dose ACTH. In the 3-month postpartum period, insulin -induced hypoglycemia or other stimulation tests, such as glucagon, would be needed for definitive diagnosis of ACTH (and GH) deficiency.

Even if a clear temporal association exists with parturition, imaging with MRI (preferably) or CT scanning is indicated to exclude mass lesions. In long-standing Sheehan syndrome, the sella frequently is empty, filled only with cerebrospinal fluid. Occasionally, small remnants of pituitary tissue may be observed. Sellar volume may be small.

Treatment includes hormone replacement with physiologic doses of glucocorticoids (before levothyroxine is given), levothyroxine, and sex steroids, with appropriate increases in glucocorticoid doses for stress. Sex steroids are given through various formulations and routes. Ovulation induction with pulsatile GnRH or exogenous gonadotropins may be needed for subsequent pregnancies. Some women with low libido may require androgen replacement. GH replacement is decided on a case-by-case basis, but the decision is made only after all other deficient hormones have been replaced.

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Hypopituitarism: Lymphocytic Hypophysitis (LHy)

First described in 1962 from an autopsy specimen, LHy is a disorder characterized by autoimmune lymphocytic infiltration and destruction of the anterior pituitary.[32, 33] The vast majority of patients described to date are women. The disease usually has a temporal relationship with pregnancy, with most patients presenting in late pregnancy or up to 1 year postpartum. Many patients who previously were thought to have Sheehan syndrome in the absence of peripartum hemorrhage are being increasingly recognized as probably having unrecognized hypophysitis.

The pituitary gland is firm and gritty after sectioning, is initially enlarged, and is later atrophied. The gland demonstrates infiltration by lymphocytes and plasma cells. Later in the course of the disease, fibrosis is present, with scanty pituitary cells. An autoantibody to a 49-kd cytosolic protein is found in up to 70% of biopsy samples from proven cases of autoimmune hypophysitis. The 49-kd cytosolic protein is expressed in corticotrophs, which probably explains the high incidence of secondary adrenal failure in these patients. Approximately 30-50% of patients have evidence of other endocrine autoimmunity, including Hashimoto thyroiditis, pernicious anemia, and type I diabetes mellitus.

The classic presentation of LHy is peripartum hypopituitarism, often with a pituitary mass and visual failure. The predominant feature appears to be headache out of proportion to the size of the pituitary. Again, adrenal insufficiency seems to be a common feature, which, if not recognized, can be fatal in as many as 25% of patients. Prolactin levels may be elevated or they may be low if pituitary destruction has occurred, causing lactation failure. If discovered during pregnancy, surgical resection is indicated only if mass symptoms and signs warrant urgent therapy. Spontaneous resolution has been reported after delivery. The normal pituitary enlargement in pregnancy may be misdiagnosed as LHy, with expected resolution occurring postpartum.[4]

Isolated DI has been described. The term lymphocytic infundibuloneurohypophysitis was coined for patients with DI and lymphocytic infiltration of the pituitary stalk (ie, "stalkitis"). Necrotizing infundibulohypophysitis has also been reported with DI. Perhaps these are part of the spectrum of LHy.

Hypopituitarism results from autoimmune destruction. Pituitary testing reveals isolated, partial, or complete deficiency. ACTH deficiency is the most common type of pituitary hormone deficiency in LHy and often the first hormone deficiency to occur. Hyperprolactinemia, which probably is secondary to stalk compression, occurs in approximately 40% of patients, although hypoprolactinemia and lactation failure may occur with gland destruction. Thus, it may clinically appear as Sheehan syndrome.

The most important differential diagnosis is pituitary adenoma or another sellar mass. The initial presentation of headaches and possible visual or endocrine disturbance associated with pregnancy helps to distinguish these. A history of infertility is common in patients with adenomas, while nearly all patients with LHy achieve spontaneous pregnancy. In addition, headaches and visual changes are much more common in the LHy group and may seem to be out of proportion to the size of the mass.

Hormone production is compromised in both conditions; the mechanism for this compromise is the compression of the gland in pituitary adenoma and diffuse inflammation in LHy. The sellar mass is usually much larger in pituitary adenomas for a given degree of hormonal derangement. Early changes in LHy are hypoadrenalism and hypothyroidism, while adenomas often show gonadotropin and GH reduction. Thus, quantitative hormonal changes and the relationship to mass size are quite important in making the distinction.

The diagnosis is pathological, but radiologic characteristics can also be used to help distinguish LHy from pituitary adenoma. Plain films may show reactive sellar bony sclerosis from the inflammatory process. CT scans have demonstrated contrast uptake in the sellar bone and sphenoid sinus in LHy, which is absent in pituitary adenoma.

MRI, with its superior ability to help characterize soft tissues, has been invaluable for helping to differentiate these 2 processes. Pituitary adenomas typically have a contrast-enhancing or hypointense area confined to, or compressing, the adjacent normal gland. The picture of LHy is quite different, with the gland appearing diffusely and dramatically enhanced. Also, the presence of a thickened and contrast-enhanced infundibular stalk is nearly pathognomonic of the condition. This enhancement may be homogenous or heterogeneous. Parasellar structures, such as dura mater (dural tail), sphenoid, and cavernous sinuses, may also enhance in LHy. These changes are not specific and have been observed with other conditions, such as sarcoidosis. The loss of the posterior pituitary bright spot may occur and differ from the MRI changes of an adenoma.

The natural history of LHy varies. The disease begins with acute inflammation of the pituitary, marked by edema. This results in headaches and, if extensive, can lead to compression of the optic chiasm. Endocrine changes may occur, ranging from undetectable hypopituitarism to panhypopituitarism. The acute phase of inflammation subsides over time to yield either a scarred, atrophic sellar space or regression of the gland back toward the normal state.

Importantly, a high index of suspicion is necessary to diagnose LHy when only the protean signs of mild headache and malaise are present. This is important, because at least 9 deaths are documented in the literature, most due to a delayed diagnosis of pituitary insufficiency. Patients with LHy need careful endocrinologic follow-up to avoid complications.

The literature is unclear on the correct treatment modality. Patients who present with evidence of intense inflammation, as manifested by visual pathway compression, appear to benefit from surgical decompression. Visual improvement following decompression via the transsphenoidal route has been reported. Many patients have only headache and radiologic evidence of LHy. Multiple reports exist of these patients improving with glucocorticoid administration alone. An exact dosage necessary for treatment has not been determined. However, investigators report successful results with dosing in the range of 60 mg of prednisone per day for a period of 1 month to a year, followed by a gradual tapering, with concurrent monitoring for relapse of symptoms. The natural history is often to regress, so in the absence of a controlled trial, the true response to glucocorticoids remains speculative, and the role of this treatment is unproven.

Surgery probably should be reserved for the following circumstances:

  • The progression of clinical signs of mass effect
  • Failure of the patient to improve, documented on follow-up MRI
  • Recrudescence of symptoms upon cessation of glucocorticoids
  • The need for a definitive diagnosis
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Contributor Information and Disclosures
Author

Bernard Corenblum, MD, FRCPC Professor of Medicine, Director, Endocrine-Metabolic Testing and Treatment Unit, Ovulation Induction Program, Department of Internal Medicine, Division of Endocrinology, University of Calgary Faculty of Medicine, Canada

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, International Society for Clinical Densitometry, Southern Society for Clinical Investigation, American College of Medical Practice Executives, American Association for Physician Leadership, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.

Acknowledgements

Krishna G Seshadri, MD, MBBS, Associate Professor, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, Sri Ramachandra Deemed University, Porur Chennai, India, contributed to this article.

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