Anterior Pituitary Hormone Changes in Pregnancy

During pregnancy, the normal pituitary gland enlarges considerably as a result of estrogen-stimulated lactotroph hyperplasia. Prolactin (PRL) levels rise gradually throughout gestation to prepare the breast for lactation. Beginning in the second half of pregnancy, circulating levels of a growth hormone (GH) variant made by the syncytiotrophoblastic epithelium of the placenta increase, and pituitary GH secretion decreases as a result of the negative feedback effects of insulin-like growth factor I (IGF-1). Pregnant patients with acromegaly have autonomous GH secretion; both forms of GH therefore persist in the blood.

Cortisol levels rise progressively over the course of a normal gestation and result in a twofold to threefold increase by term due both to the estrogen-induced increase in corticosteroid-binding globulin (CBG) levels and an increase in cortisol production, so that the bioactive “free” fraction, urinary free cortisol levels, and salivary cortisol levels are also increased.

Pituitary Tumors

Pituitary adenomas cause problems because of hormone hypersecretion and by causing hypopituitarism, and pregnancy-induced alterations in hormone secretion complicate the evaluation of patients with pituitary neoplasms. The influence of various types of therapy on the developing fetus also affects therapeutic decision making.

Prolactinoma

Hyperprolactinemia commonly causes symptoms of galactorrhea, amenorrhea, and infertility. The differential diagnosis of hyperprolactinemia is extensive, but this discussion will focus on the patient with prolactinoma. The choice of therapy has important consequences for decisions regarding pregnancy. Transsphenoidal surgery for microadenomas is curative in 50% to 60% of prolactinomas after accounting for recurrences, and it rarely causes hypopituitarism when it is performed by experienced neurosurgeons on women with tumors less than 10 mm in diameter. For patients with macroadenomas , tumors 10 mm in diameter or larger, surgical cure rates are lower, and the risk of causing hypopituitarism is considerably greater.

The dopamine agonists bromocriptine and cabergoline are the primary mode of medical therapy, restoring ovulatory menses in about 80% and 90% of cases, respectively, and reducing macroadenoma size. A reduction in size of 50% or more occurs in 50% to 75% of patients with bromocriptine and in more than 90% of patients with cabergoline.

The stimulatory effect of the hormonal milieu of pregnancy and the withdrawal of the dopamine agonist may result in significant prolactinoma enlargement ( Fig. 43-1 ). Tumor enlargement that required intervention during pregnancy has been reported in 18 of 764 (2.4%) women with microadenomas, 50 of 238 (21%) with macroadenomas that had not undergone prior surgery or radiotherapy, and 7/148 (4.7%) with macroadenomas that had undergone prior surgery or radiotherapy. In almost all cases, such enlargement was successfully treated with reinstitution of a dopamine agonist. If the pregnancy is sufficiently advanced, another approach is to deliver the baby electively. Surgical decompression is only resorted to if these other approaches fail.

Coronal and sagittal magnetic resonance imaging scans of an intrasellar prolactin- secreting macroadenoma in a woman before conception ( A and B ) and at 7 months of gestation ( C and D ). Note the marked tumor enlargement at the latter point, at which time the patient was complaining of headaches.

(From Molitch ME. Medical treatment of prolactinomas. Endocrinol Metab Clin North Am. 1999;28:143-170.)

When a dopamine agonist is stopped once a woman has missed her menstrual period and pregnancy is diagnosed, no increase in spontaneous abortions, ectopic pregnancies, trophoblastic disease, multiple pregnancies, or malformations were found in over 6000 pregnancies in which bromocriptine was used and in 822 pregnancies in which cabergoline was used. Although data on safety of continuous dopamine agonist therapy during pregnancy are limited, treatment is probably not harmful.

Patients with large macroadenomas should be assessed monthly for symptoms of tumor enlargement, and visual fields should be tested each trimester. PRL levels may rise without tumor enlargement and may not rise with tumor enlargement; therefore such tests are often misleading and should not be done. In some patients, postpartum PRL levels and tumor sizes are actually reduced compared with values before pregnancy. Therefore many women may be ovulatory postpartum and would not need resumption of a dopamine agonist. Nursing does not cause an increase of PRL levels nor does it increase headaches or visual disturbances suggestive of tumor enlargement.

Hypopituitarism

Hypopituitarism may be partial or complete, and loss of gonadotropin secretion is common. Induction of ovulation may be difficult, and a variety of techniques have been used by reproductive endocrinologists, including administration of hCG and FSH, pulsatile gonadotropin-releasing hormone, and in vitro fertilization. The malformation rate is normal in such pregnancies, but there seems to be an increased frequency of cesarean deliveries, miscarriages, and small-for-gestational-age (SGA) babies.

Because of increased thyroxine turnover and volume of distribution in pregnancy, thyroxine (T ₄ ) levels usually fall and TSH levels rise with a fixed thyroxine dose over the course of gestation. The average increase in thyroxine needed in these patients is about 0.05 mg/day. Because patients with hypothalamic/pituitary dysfunction may not elevate their TSH levels normally in the face of the increased need for thyroxine, it is reasonable to increase the thyroxine supplementation by 0.025 mg after the first 4 to 6 weeks and by an additional 0.025 mg after the second trimester, also following total T ₄ levels.

The dose of chronic glucocorticoid replacement does not usually need to be increased during pregnancy. Hydrocortisone is metabolized by the placental enzyme 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2); thus the fetus is generally protected from any overdose of hydrocortisone. The usual dose is in the range of 12 to 15 mg/m ² given in two or three divided doses; 10 mg in the morning and 5 mg in the afternoon is a common regimen. Additional glucocorticoids are needed for the stress of labor and delivery, such as 75 mg of intravenous (IV) hydrocortisone every 8 hours with rapid tapering postpartum. Prednisolone does not cross the placenta, and prednisone crosses only minimally. Suppression of neonatal adrenal function in offspring of women taking prednisone during pregnancy is very uncommon, and the amounts passed in breast milk are negligible.

Few data are available on the use of GH during pregnancy in hypopituitary individuals, and in most series, GH therapy has been stopped at conception. Because the GH variant, which is biologically active, is produced by the placenta in substantial amounts beginning in the second half of pregnancy, and it can access the maternal circulation (see above), then at most the mother would be GH deficient only in the first half of pregnancy. When Curran and colleagues analyzed 25 pregnancies that occurred in 16 patients with GH deficiency during which GH therapy was not continued, they found no adverse outcome for either the fetus or the mother from omitting GH therapy and concluded that GH replacement therapy during pregnancy is not essential for GH-deficient women.

Sheehan Syndrome

Sheehan syndrome consists of pituitary necrosis secondary to ischemia that occurs within hours of delivery, usually secondary to hypotension and shock from an obstetric hemorrhage. The degree of ischemia and necrosis dictates the subsequent patient course ( Table 43-1 ). This syndrome rarely occurs in current obstetric practice.

Acute necrosis is suspected in the setting of an obstetric hemorrhage in which hypotension and tachycardia persist following adequate replacement of blood products. Failure to lactate and hypoglycemia may also occur. Investigation should include obtaining blood samples for adrenocorticotropic hormone (ACTH), cortisol, prolactin, and free thyroxine. The ACTH stimulation test would be normal because the adrenal cortex would not be atrophied. Free thyroxine levels may prove normal initially because the hormone has a half-life of 7 days, and an additional sample should be sent after 1 week. Prolactin levels are usually low in this setting. Diabetes insipidus (DI) may also occur and would be revealed with dehydration testing.

If acute necrosis is suspected, treatment with saline and stress doses of corticosteroids should be instituted immediately after drawing the blood for testing. If later free thyroxine levels become low, therapy with levothyroxine is indicated. Additional pituitary testing with subsequent therapy should be delayed until recovery.

When milder forms of infarction occur, diagnosis may be delayed for months or years. These women generally have a history of amenorrhea, decreased libido, failure to lactate, breast atrophy, loss of pubic and axillary hair, fatigue, and symptoms of secondary adrenal insufficiency with nausea, vomiting, diarrhea, and abdominal pain. Rarely, some women retain gonadotropin secretion and may have normal menses and fertility.

Lymphocytic Hypophysitis

Lymphocytic hypophysitis is thought to be autoimmune, with infiltration and destruction of the parenchyma of the pituitary and infundibulum by lymphocytes and plasma cells. Generally occurring during pregnancy or in the postpartum period, this condition is associated with symptoms of hypopituitarism or an enlarging mass lesion with headaches and visual field defects, and it is suspected based on its timing and lack of association with an obstetric hemorrhage or prior history of menstrual difficulties or infertility. DI may also occur. On magnetic resonance imaging (MRI) scans, diffuse enhancement is usually seen rather than a focal lesion that might indicate a tumor. The clinical picture often allows a clinical diagnosis to be made without invasive procedures.

Treatment of lymphocytic hypophysitis is generally conservative and involves identification and correction of any pituitary deficits, especially of ACTH secretion, which is particularly common in this condition. Data regarding the beneficial effects of high-dose corticosteroid treatment are inconclusive. Surgery to debulk but not remove the gland is indicated in the presence of uncontrolled headaches, visual field defects, and progressive enlargement on scan. Spontaneous regression and resumption of partial or normal pituitary function may occur, although most patients progress to chronic panhypopituitarism.

Diabetes Insipidus

Central DI may develop in pregnancy because of an enlarging pituitary lesion, lymphocytic hypophysitis, or hypothalamic disease. Because of the increased clearance of AVP by placental vasopressinase, DI usually worsens during gestation, and subclinical DI may become manifest. Desmopressin is resistant to vasopressinase and provides satisfactory, safe treatment during gestation, although a higher dose may be required. During monitoring of the clinical response, clinicians should remember that the normal sodium concentration is 5 mEq/L lower during pregnancy, and dDAVP transfers minimally into breast milk.

Transient AVP-resistant forms of DI secondary to placental production of vasopressinase may occur spontaneously in one pregnancy but not in a subsequent one. Some of these patients may respond to dDAVP therapy. Another rare cause of transient DI of pregnancy is placental abruption, in which the abruption causes a rise in vasopressinase.

Acute fatty liver of pregnancy and other disturbances of hepatic function such as hepatitis may be associated with late-onset transient DI of pregnancy in some patients. In some cases, this has been associated with the hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. It is presumed the hepatic dysfunction is associated with reduced degradation of vasopressinase, which further increases vasopressinase levels and the clearance of AVP. Polyuria may develop either prior to delivery or postpartum.

DI that develops postpartum may be a result of Sheehan syndrome. Transient DI of unknown etiology has been described postpartum, lasting only days to weeks.

Congenital nephrogenic DI is a rare X-linked disorder caused by a mutation in the vasopressin V2 receptor gene, which predominantly affects males. Female carriers of this disease may have significant polyuria during pregnancy. Treatment is with thiazide diuretics, which should be used with caution in pregnant women.

Cushing Syndrome

Fewer than 150 cases of Cushing syndrome in pregnancy have been reported. Less than 50% of the pregnant patients described had pituitary adenomas, a similar number had adrenal adenomas, and more than 10% had adrenal carcinomas. Pregnancies associated with the ectopic ACTH syndrome have been reported only rarely. In many cases, the hypercortisolism first became apparent during pregnancy, with improvement and even remission after parturition. Recently, cases have been reported of pregnancy-induced Cushing syndrome from human chorionic gonadotropin (hCG)-induced stimulation of ectopic luteinizing hormone (LH)/hCG receptors on the adrenal.

Diagnosing Cushing syndrome during pregnancy may be difficult. Both conditions may be associated with weight gain in a central distribution, fatigue, edema, emotional upset, glucose intolerance, and hypertension. The striae associated with normal pregnancy are usually pale, but they are red or purple in Cushing syndrome. Hirsutism and acne may point to excessive androgen production, and proximal myopathy and bone fractures point to Cushing syndrome.

The laboratory evaluation is difficult. Elevated total and free serum cortisol and ACTH levels and urinary free cortisol excretion are compatible with that of normal pregnancy. The overnight dexamethasone test usually demonstrates inadequate suppression during normal pregnancy. ACTH levels are normal to elevated even with adrenal adenomas, perhaps because of the production of ACTH by the placenta or from the nonsuppressible stimulation of pituitary ACTH by placental corticotropin-releasing hormone (CRH).

A persistent circadian variation in the elevated levels of total and free serum cortisol during normal pregnancy may be most helpful in distinguishing Cushing syndrome from the hypercortisolism of pregnancy, because this finding is characteristically absent in all forms of Cushing syndrome. Midnight levels of salivary cortisol during pregnancy have not yet been standardized. In some cases, MRI scanning of the pituitary (without contrast) or ultrasound of the adrenal may be helpful, but the high frequencies of “incidentalomas” in both glands makes interpretation of imaging difficult. Little experience has been reported with CRH stimulation testing or petrosal venous sinus sampling during pregnancy.

Cushing syndrome is associated with a pregnancy loss rate of 25% due to spontaneous abortion, stillbirth, and early neonatal death because of extreme prematurity. The passage of cortisol across the placenta may rarely result in suppression of the fetal adrenals. Hypertension develops in most mothers with Cushing syndrome, and diabetes and myopathy are frequent. Postoperative wound infection and dehiscence are common after cesarean delivery.

In a review of 136 pregnancies collected from the literature, Lindsay and colleagues found that the frequency of live births increased from 76% to 89% when active treatment was instituted by a gestational age of 20 weeks. Therefore treatment during pregnancy has been advocated.

Medical therapy for Cushing syndrome during pregnancy with metyrapone and ketoconazole is not very effective, and IUGR has been reported with ketoconazole. The FDA has issued a black-box warning for ketoconazole with respect to severe liver toxicity; therefore its use cannot be recommended. Mitotane should be avoided because of fetal toxicity. Two new medications have recently been approved for the treatment of Cushing disease. Mifepristone, a cortisol receptor blocker, is highly effective, but because it is also a progesterone receptor blocker and an abortifacient, it cannot be used during pregnancy. Pasireotide is a new somatostatin analogue with modest efficacy in patients with Cushing disease. It has the adverse effect of hyperglycemia, and there is no experience with its use during pregnancy. However, the same cautions discussed above for somatostatin analogues should also hold true for the use of pasireotide in a patient with Cushing disease.

Transsphenoidal resection of a pituitary ACTH-secreting adenoma and laparoscopic resection of adrenal adenomas have been carried out successfully in several patients during the second trimester. The live birth rate is approximately 87% after unilateral or bilateral adrenalectomy. Although any surgery poses risks for the mother and fetus, it appears that with Cushing syndrome, the risks of not operating are considerably higher than those of proceeding with surgery.

Adrenal Insufficiency

In developed countries, the most common etiology for primary adrenal insufficiency is autoimmune adrenalitis. Primary adrenal insufficiency from infections ( tuberculosis or fungal), bilateral metastatic disease, hemorrhage, or infarctions is uncommon. Secondary adrenal insufficiency from pituitary neoplasms or glucocorticoid suppression of the hypothalamic-pituitary-adrenal axis may also occur.

Recognition of adrenal insufficiency may be difficult because many of the clinical features are found in normal pregnancies, including weakness, lightheadedness, syncope, nausea, vomiting, hyponatremia, and increased pigmentation. Addisonian hyperpigmentation may be distinguished from chloasma of pregnancy by its presence on the mucous membranes, on extensor surfaces, and on unexposed areas. Weight loss, hypoglycemia, salt craving, and excessive hyponatremia should prompt a clinical evaluation. If unrecognized, maternal adrenal crisis may ensue at times of stress, such as a urinary tract infection or labor. The fetoplacental unit largely controls its own steroid milieu, so maternal adrenal insufficiency generally causes no problems with fetal development. Women with Addison disease are relatively infertile, and babies born to mothers with Addison disease have increased risks of preterm birth, low birthweight, and an increased rate of cesarean delivery. Severe maternal hyponatremia or metabolic acidosis and poor maternal compliance with therapy may cause a poor fetal outcome. Association with other autoimmune conditions such as anticardiolipin antibodies may lead to additional risks such as miscarriage.

Adrenal insufficiency may be associated with laboratory findings of hyponatremia, hyperkalemia, hypoglycemia, eosinophilia, and lymphocytosis. Early morning plasma cortisol levels of 3.0 µg/dL (83 nmol/L) or less confirm adrenal insufficiency, whereas a cortisol level greater than 19 µg/dL (525 nmol/L) in the first or early second trimester excludes the diagnosis in a clinically stable patient. However, plasma cortisol levels may fall in the normal “nonpregnant” range due to the increase in CBG concentrations in the second and third trimesters, but they will not be appropriately elevated for the stage of pregnancy. Normal basal and cosyntropin (250 µg)-stimulated cortisol values have been established for pregnant women; for the first, second, and third trimesters, basal morning values (mean ± standard deviation [SD]) were 9.3 ± 2.2 µg/dL (257 ± 61 nmol/L), 14.5 ± 4.3 µg/dL (401 ± 119 nmol/L), and 16.6 ± 4.2 µg/dL (459 ± 116 nmol/L). Stimulated values were 29.5 ± 16.1 µg/dL (815 ± 445 nmol/L), 37.9 ± 9.0 µg/dL (1047 ± 249 nmol/L), and 34.7 ± 7.5 µg/dL (959 ± 207 nmol/L). The 1-µg low-dose cosyntropin test has been reported to be accurate at 24 to 34 weeks’ gestation using a cutoff of 30 µg/dL (828 nmol/L). With primary adrenal insufficiency, ACTH levels will be elevated, and a level above 100 pg/mL (22 pmol/L) is consistent with the diagnosis. However, ACTH will not be low with secondary forms because of placental production of this hormone, albeit insufficient to maintain normal maternal adrenal function.

In the unstable patient, empiric glucocorticoid therapy of hydrocortisone 50 to 75 mg IV should be administered pending the results of diagnostic testing. Thereafter, doses of 50 to 75 mg every 6 to 8 hours should be given in the face of severe stress and during labor. Despite the normal increase in plasma cortisol during pregnancy, baseline maternal replacement doses of corticosteroids usually are not different from those required in the nonpregnant state. Mineralocorticoid replacement requirements usually do not change during gestation, although some clinicians have reduced doses of fludrocortisone in the third trimester in an attempt to treat Addisonian patients who develop edema, exacerbation of hypertension, and preeclampsia.

Patients who have received glucocorticoids as antiinflammatory therapy are presumed to have adrenal axis suppression for at least 1 year following cessation of such therapy. These patients should be treated with stress doses of glucocorticoids during labor and delivery. They are at risk for postoperative wound infection and dehiscence, as are patients with endogenous Cushing syndrome, and their offspring are at risk for transient adrenal insufficiency.

Primary Hyperaldosteronism

Primary hyperaldosteronism rarely has been reported in pregnancy and is most often caused by an adrenal ade­noma. Reports of glucocorticoid-remediable hyperaldosteronism in pregnancy are rare. The elevated aldosterone levels found in affected patients during pregnancy are similar to those in normal pregnant women, but the plasma renin activity is sup­pressed. Moderate to severe hypertension develops in 85%, proteinuria in 52%, and hypokalemia in 55% of patients; symptoms may include headache, malaise, and muscle cramps. Placental abruption and preterm delivery are also risks. Interestingly, the very high progesterone levels of pregnancy may have an antimineralocorticoid effect at the renal tubules, and thus the hypertension and hypokalemia may ameliorate during pregnancy in some women.

Spironolactone, the usual nonpregnant therapy for hyperaldosteronism, is contraindicated in pregnancy because it crosses the placenta and is a potent antiandrogen, which can cause ambiguous genitalia in a male fetus. Eplerenone, a more selective aldosterone receptor blocker without antiandrogen activity, has been used successfully in one case during pregnancy without any untoward consequences for the fetus. Surgical therapy may be delayed until after delivery if hypertension can be controlled with agents safe in pregnancy, such as amiloride, methyldopa, labetalol, and calcium channel blockers. On the other hand, laparoscopic removal of an aldosterone-producing adenoma during pregnancy has been reported. Potassium supplementation may be required, but the hypokalemia may ameliorate in pregnancy because of the antikaliuretic effect of progesterone. Both hypertension and hypokalemia may exacerbate postpartum because of removal of the progesterone effect.

Pheochromocytoma

Exacerbation of hypertension is the typical presentation of pheochromocytoma, which can often be mistaken for pregnancy-induced hypertension or preeclampsia. As the uterus enlarges and an actively moving fetus compresses 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. In 10% of patients, tumors may be outside of the adrenal, such as at the aortic bifurcation, and are particularly prone to hypertensive episodes with changes in position, uterine contractions, fetal movement, and Valsalva maneuvers. Unrecognized pheochromocytoma has been associated with a maternal mortality rate of 50%.

Placental transfer of catecholamines is minimal, likely because of high placental concentrations of catechol O-methyltransferase and monoamine oxidase. Adverse fetal effects such as hypoxia are a result of catecholamine-induced uteroplacental vasoconstriction and placental insufficiency and of maternal hypertension, hypotension, or vascular collapse. Placental abruption may also occur.

Diagnosis requires a high index of suspicion. Preconception screening of families known to have multiple endocrine neoplasia (MEN) type 2, von Hippel-Lindau disease, and neurofibromatosis is important. The diagnosis should be considered in pregnant women with severe or paroxysmal hypertension, particularly in the first half of pregnancy or in association with orthostatic hypotension or episodic symptoms of pallor, anxiety, headaches, palpitations, chest pain, or diaphoresis.

Laboratory diagnosis of pheochromocytoma relies on measuring urine metanephrines and catecholamines and plasma metaneprhines. This is unchanged from the nonpregnant state because catecholamine metabolism is not altered by pregnancy per se. If possible, methyldopa and labetalol should be discontinued because these agents may interfere with the quantification of the catecholamines. Tumor localization with MRI, with high-intensity signals noted on T ₂ -weighted images, provides the best sensitivity without fetal exposure to ionizing radiation.

Differentiation from preeclampsia is generally simple. Edema, proteinuria, and hyperuricemia found in women with preeclampsia are absent in those with pheochromocytomas. Plasma and urinary catecholamines may be modestly elevated in severe preeclampsia and other serious pregnancy complications that require hospitalization, although they remain normal in mild preeclampsia or in pregnancy-induced hypertension. Catecholamine levels are two to four times normal after an eclamptic seizure, however.

Initial medical management involves α-blockade with phenoxybenzamine, phentolamine, prazosin, or labetalol. All of these agents are well-tolerated by the fetus, but phenoxybenzamine is considered the preferred agent because it provides long-acting, stable, noncompetitive blockade. Phenoxybenzamine is started at a dose of 10 mg twice daily, with titration until the hypertension is controlled. Placental transfer of phenoxybenzamine occurs but is generally considered safe. However, two neonates of mothers treated with phenoxybenzamine have been reported with respiratory distress and hypotension that required ventilatory and inotropic support. Beta-blockade is reserved for treating maternal tachycardia or arrhythmias that persist after full α-blockade and volume repletion. β-Blockers may be associated with fetal bradycardia and with IUGR but are generally safe, with wide experience concerning their use. All of these potential fetal risks are small compared with the risk of fetal wastage from unblocked high maternal levels of catecholamines. Hypertensive emergencies should be treated with phentolamine (1 to 5 mg) or nitroprusside, although the latter should be limited because of potential fetal cyanide toxicity.

Timing of surgical excision of the neoplasm is controversial and may depend on the success of the medical management and the location of the tumor. Pressure from the uterus, motion of the fetus, and labor contractions are all stimuli that may cause an acute crisis . In the first half of pregnancy, surgical excision may proceed once adequate α-blockade is established, although the risk of fetal loss may be higher with first-trimester surgery. In the early second trimester, fetal loss is less likely with surgery compared with the first trimester, and the size of the uterus will not make excision difficult. If a pheochromocytoma is not recognized until the second half of gestation, increasing uterine size makes surgical exploration challenging. Successful laparoscopic excision of pheochromocytomas has been described in the second trimester. Other options include combined cesarean delivery and tumor resection or delivery followed by tumor resection at a later date.

Although successful vaginal delivery has been reported, rates of maternal mortality have been higher than with cesarean delivery. Labor may result in uncontrolled release of catecholamines secondary to pain and uterine contractions. Severe maternal hypertension may lead to placental ischemia and fetal hypoxia. Cesarean delivery is most common, but in the well-blocked patient, vaginal delivery may be possible with pain management with epidural anesthesia and use of techniques of passive descent and instrumented delivery.