Martin N. Montoro, MD, and Jorge H. Mestman, MD
Changes In The Normal Anterior Pituitary Gland During Pregnancy
Anatomic and functional changes take place in the pituitary gland during pregnancy that have to be taken into consideration to properly evaluate its function, and particularly to diagnose pituitary disorders during pregnancy.
The various anterior pituitary hormonesprolactin (PRL), thyroxine-stimulating hormone (TSH), luteinizing hormone (LH) and follicle-stimulating hormone (FSH), corticotropin (ACTH), and growth hormone (GH) are released into the systemic circulation in response to stimulating or inhibiting messages from hypothalamic peptide hormones. These peptides reach the pituitary gland through the portal circulation. Thus far several have been identified; they include thyrotropin-releasing hormone (TRH), gonadotropin-releasing hormone GnRH), corticotropin-releasing factor (CRF), growth hormone-releasing factor (GHRF), somatostatin (somatotropin release-inhibiting factor [SRIF]) and more recently, a GnRH-associated peptide (GAP) that inhibits prolactin secretion. Dopamine, a biogenic amine, also inhibits PRL secretion. Communications between the hypothalamus and the higher centers of the brain are accomplished by a variety of neurotransmitters, which include the already mentioned dopamine, serotonin, y-aminobutiric acid (GABA), norepinephrine and various opioid peptides, as well as many of the peptides also found in the intestinal tract.
The volume of the anterior pituitary increases progressively during pregnancy and gradually decreases after delivery over a period of several months; the postpartum involution is slower in lactating women. The enlargement is more pronounced in multiparous than in primiparous women. The pituitary volume may increase by one third or more at term, and it is due to both hyperplasia and hypertrophy of the PRL-secreting cells. The pituitary volume, as determined by magnetic resonance imaging (MRI) or at autopsy, has been measured at 300+/- 60 mm in non-pregnant controls and 437 +/- 90 mm, 534 +/- 124 mm, and 702 +/- 123 mm in the first, second, and third trimesters, respectively. The PRL levels increase gradually from early pregnancy up to tenfold above the non-pregnant levels by term (mean, 50 ng/ml at 12 weeks to 270 ng/ml at term; range for the rapid, transient elevations associated with breast-feeding. These gradual changes are thought to be secondary to the stimulating effect of estrogen and perhaps, progesterone. Despite the great PRL elevation, normal diumal rhythm and response to TRH are maintained, as opposed to the hyperprolactinemia of the various disease states (e.g., tumors). The role of PRL elevation during pregnancy remains unclear, but it is believed to be related to the initiation and maintenance of lactation. Some investigators have suggested that PRL plays a role in some of the metabolic changes that occur in pregnancy and perhaps in fetal lung maturation, but the evidence remains inconclusive.
The levels of LH and FSH decrease to the point of becoming undetectable, and the response to GnRH becomes blunted or absent. These changes are thought to be the result of feedback inhibition from the elevated levels of estrogen and progesterone.
Basal GH levels remain with little change, but the response to the usual stimulating tests (hypoglycemia, L-arginine, etc.) becomes blunted and remains so until several weeks after delivery. Various factors have been implicated; until recently the most important was attributed to the elevated levels of human placental lactogen (hPL) to which GH-like activity is attributed. With the advent of more specific assays capable of overcoming interference with hPL, however, the hypersomatotrophism of pregnancy now is attributed to a specific placental GH.
Maternal pituitary TSH may be suppressed during the first several weeks of gestation, and for this reason it may not be used as effectively as a diagnostic test during the early part of gestation (about the first trimester). It is believed that TSH suppression occurs when the levels of human chorionic gonadotropin (hCG) are highest, because hCG has TSH-like activity.
The ACTH levels increase gradually while pregnancy progresses, despite the also gradually increasing levels of both free and bound cortisol seen during pregnancy (because of increased cortisol binding globulin, increased cortisol production rate, and perhaps reduced clearance). Also, an exaggerated cortisol response to ACTH occurs, even in the presence of elevated basal cortisol levels. A CRF has been found in the placenta; the levels of this factor increase gradually with progression of pregnancy, peaking at term and falling abruptly after the delivery of the placenta. It remains unknown whether CRF could be the cause of some of the cortisol changes during pregnancy or whether it may play a role in certain cases of Cushings syndrome. Suppression to exogenous corticosteroid administration is incomplete, but the diumal variations of both ACTH and cortisol are preserved, thus making the measurement of morning and evening cortisol levels a useful test. Free urinary cortisol excretion increases to levels that may overlap with those seen in some cases of Cushings syndrome.
Disorders of the Anterior Pituitary Gland
Anterior Pituitary Insufficiency
The most common causes of partial or complete anterior pituitary insufficiency in women of childbearing age are tumors, hypophysectomy, radiation therapy, and postpartum infarction (Sheehans syndrome). Less common causes include acute intrapituitary hemorrhage, infiltration by granulomatous diseases, some hemoglobinopathies (e.g., thalassemia), and pituitary necrosis in the presence of elevated intracranial pressure. More recently, lymphocytic hypophysitis has come to be recognized as a distinct clinical entity that may present as partial or total anterior pituitary insufficiency during pregnancy or the postpartum period. A few cases of acute pituitary insufficiency during pregnancy in insulin dependent diabetics also have been described.
Pituitary insufficiency occurring for the first time during pregnancy is uncommon, but may occur because of enlargement or infarction of a pituitary tumor, in lymphocytic hypophysitis, and rarely in diabetes mellitus. It may occur as an acute event, which is what usually happens when pituitary apoplexy develops because of pituitary infarction; other times, in tumors or in lymphocytic hypophysitis, compression symptoms due to mass effect or only partial pituitary insufficiency may occur first. In these cases there exists the possibility of making the diagnosis and initiating treatment before acute pituitary insufficiency occurs as a catastrophic event, which may result in maternal or fetal death or both.
Given the recent advances in the treatment of infertility, it is now possible for women with anterior pituitary insufficiency not only to conceive, but also to carry a pregnancy to term with adequate hormonal replacement. Table 1 shows the commonly used tests to assess pituitary reserve and the results in normal pregnancy.
Sheehans syndrome is defined as partial or complete hypopituitarism due to pituitary necrosis after deliveries in which severe blood loss and hypotension have occurred. In about 10% of Sheehans syndrome cases, however, no history of bleeding or hypotension can be documented. Clinically there is failure to lactate, amenorrhea, loss of pubic and axillary hair, or failure of pubic hair to grow back if it was shaved (e.g., after a cesarean section). The skin becomes waxy and the patients develop fine skin wrinkles around the eyes and the corners of the mouth. In more severe cases (when 90% or more of the pituitary is destroyed) anorexia, nausea, vomiting, hypoglycemia, and hypotension may develop (signs of adrenal insufficiency). Other symptoms include postural hypotension, weight loss, fatigue, loss of libido, and breast atrophy. Abnormal laboratory tests may include normochromic, normocytic anemia, and hyponatremia. It is typical, however, for the full-blown picture to take many years (even 10 to 20) to develop with less extensive pituitary destruction. Even in advanced cases of hypopituitarism, enough adrenal reserve still may be present to cope with normal everyday activities, and the diagnosis may be made for the first time when acute adrenal insufficiency develops after a stressful situation such as surgery, infection, or any other serious illness. To exclude a tumor or other pathologic abnormality, the diagnosis is confirmed by provocative hormonal tests of pituitary reserve and computerized axial tomography or preferably, MR imaging.
Some patients with the initial picture clearly showing panhypopituitarism may recover partial pituitary function after cortisol replacement alone, such as thyroid or even gonadotropin function and the return of ovulation. It has been speculated that cortisol may have a permissive effect on other pituitary or hypothalamic hormones. Cases of spontaneous recovery and subsequent normal pregnancies have been reported as well.
A review of the outcome of pregnancies in women with Sheehans syndrome shows that in patients on adequate replacement therapy, the perinatal morbidity and mortality rates are not increased (87% live birth and 13% abortions). Treatment of the acute manifestations requires parenteral corticosteroids and intravenous fluids. Once the patient becomes stable the need for other hormonal replacement can be assessed by pituitary function testing.
This disease entity has been described with increasing frequency in recent years. Most of the cases reported have been women during the last part of pregnancy or the postpartum period. Sheehan and Summers reported lymphocytic infiltration in the pituitary gland of some of their original cases, but the first report of a case of chronic lymphocytic hypophysitis as a distinct entity was not made until much later. It is believed to be an autoimmune disorder, and antibodies against pituitary cells have been described. In several cases there was also evidence of autoimmune involvement of other endocrine glands such as autoimmune thyroiditis and adrenalitis, and therefore these cases may be part of the autoimmune polyendocrine deficiency syndrome.
Almost all of the patients in the literature to date have been women in the last trimester of pregnancy or within 4 to 6 months after delivery; 65% were multiparous and 35% primiparous, and their mean age was 28 years. In more than half of the patients the initial symptoms were related to pressure from the expanding pituitary mimicking a pituitary tumor, including suprasellar extension with visual disturbances and headaches. Even though 78% of these cases had evidence of partial hypoadrenalism and 72% thyroid deficiency, the maternal and fetal survival was much better (7 of 12 survived) in these women than in those whose initial presentation was acute pituitary insufficiency, or if the symptoms went unrecognized until acute pituitary insufficiency occurred, at which point the mortality was very high. Other preceding symptoms noted included weight loss, weakness, hair loss, anemia and, in already postpartum women, oligo-or amenorrhea. Precipitating events were appendicitis, pneumonia, herpes labialis, flu-like illness, and in one case labor was the only obvious stress factor. The development of hypoglycemia along with the other symptoms of adrenal insufficiency was a poor prognostic sign. Unfortunately, the definitive diagnosis cannot be made currently unless pituitary tissue is obtained for histologic examination, and therefore the preoperative diagnosis of this potentially fatal but treatable disease is very difficult. The differential diagnosis during pregnancy includes, mainly, a pituitary tumor, or if the patient has diabetes, a pituitary infarction. After delivery, Sheehans syndrome has to be considered, particularly if there was excessive bleeding during labor.
The treatment of the acute event requires corticosteroid and intravenous fluid administration. Other hormonal deficiencies, if detected, can be replaced at a later date. A course of high-dose steroids has been recommended for those with visual field defects, but if there is no response surgery may be necessary. Spontaneous recovery has been observed as well. Fetal and maternal survival should improve with increased awareness of this disease entity and its symptoms.
Nine cases of antepartum pituitary insufficiency in insulin-dependent diabetes have been reported. The mean maternal age was 28 years (range, 22-40), duration of diabetes was 7 years (range, 1 19) and the mean gestational age was 27 weeks (range, 12 36), with five of the nine cases occurring at 32 to 36 weeks. Three maternal and five fetal deaths occurred. Death has been attributed to pituitary infarction, but in most cases the duration of diabetes did not seem long enough to make vascular complications likely. The pituitary glands that were examined showed necrosis. Clinically the patients developed severe headaches, visual disturbances, decreased insulin requirements, and even hypoglycemia. The acute event was due to adrenal insufficiency. In the survivors, various other pituitary hormonal deficiencies requiring replacement were found.
Isolated Growth Hormone Deficiency
Several pregnancies have been reported in women of short stature caused by isolated GH deficiency. Placental function, fetal growth, pregnancy, and delivery were normal.
Patients with known pituitary insufficiency but already on adequate replacement do not usually require a dosage change in their daily glucocorticoid replacement, which is 20 to 25 mg/m, or 30 to 37.5 mg of hydrocortisone or an equivalent steroid (Table 2). Two thirds (e.g., 20-25 mg) of the daily dosage is given in the morning, and one third (10-12 mg) in the late afternoon. At times of stress, such as with an infection or during labor and delivery, higher doses must be given (up to 300 mg of hydrocortisone or an equivalent steroid per day, given in divided dosages: 100 mg every 8 hours) with gradual tapering to the maintenance dose while the stress subsides. Mineralocorticoid replacement is not necessary if the deficit involves ACTH deficiency alone. Many pregnant women on thyroxine replacement, however, do need higher dosages during pregnancy, and therefore thyroid function tests must be performed at regular intervals (at least each trimester). When the hypothyroidism is because of pituitary or hypothalamic disease, the TSH cannot be used as a gauge for thyroxine replacement. In these patients we recommend keeping the total serum thyroxine in the upper or slightly above normal level, and the free thyroxine index in the middle to upper normal range.
Relative Biologic Effects Of Corticosteroids
|Hydrocortisone or Cortisol
Prolactin secreting pituitary adenomas are the most commonly encountered pituitary tumors in women of childbearing age; they have also become the most frequent pituitary tumors found during pregnancy because of the availability of effective treatments to restore fertility in these women. With the advent of PRL radioimmunoassays and newer radiologic techniques (MR imaging) to detect pituitary abnormalities, the frequency of hyperprolactinemia and infertility caused by pituitary tumors has seen a marked increase. There was speculation that the widespread use of oral contraceptives since the 1960s might have had a role in the development of these tumors, but the Pituitary Adenoma Study Group concluded that no evidence linked estrogen use and prolactinomas in most of the studies reported to date.
Prolactinomas are diagnosed when the PRL becomes high enough to cause galactorrhea or oligoamenorrhea. Sometimes a tumor is not found and these cases are labeled as idiopathic hyperprolactinemia. This diagnosis is made only after an exhaustive work-up has excluded a pituitary tumor or any other cause of hyperprolactinemia, such as drug-induced, renal failure, cirrhosis of the liver, or several endocrine disorders, including primary hypothyroidism, Cushings syndrome, and acromegaly.
Pituitary tumors are divided, according to their size, into micro (less than 10 mm) and macroadenomas; they are further classified according to suprasellar extension or invasion of other adjacent structures. Once the diagnosis is confirmed and the patient desires to become pregnant, several therapeutic modalities are available.
Pituitary radiation had a low curative rate in the earlier reports. Recent studies show more favorable results, but the reduction of PRL level is very slow and hypopituitarism still seems to be a common late sequela. It was formerly used, before pregnancy, with the intention of preventing enlargement of the tumor during gestation, although it did not seem to do so in some cases. Radiation therapy has been more commonly used in patients with residual disease despite surgery. Other forms of radiation, such as implantation of yttrium-90 in the pituitary gland, also have been used in the past.
Surgical treatment, mainly transphenoidal removal of the tumor, has been effective in reducing or normalizing PRL levels and in restoring fertility, particularly in patients with smaller tumors. Long-term (4-5 years) studies have shown, however, recurrence of hyperprolactinemia requiring additional therapy in 25% to 40% of the patients. Despite the expense and potential morbidity, transphenoidal adenomectomy is an accepted form of therapy and may be the more reasonable option for those unable to tolerate bromocriptine or those who do not want to take medication on a long-term basis. The best results are consistently reported in patients with small tumors. Macroprolactinomas are easier to diagnose but surgical cures are obtained much less frequently; in these cases surgical decompression may facilitate postoperative medical therapy and perhaps offer some protection against enlargement during a subsequent pregnancy.
Medical therapy with bromocriptine, a long-acting dopamine receptoragonist, has been very effective in restoring ovulation in 80% to 90% of hyperprotaclinemic women with microadenomas. Most women respond to doses of 2.5 to 7.5 mg/d, although occasionally higher doses are needed. Besides normalizing PRL levels, therapy with bromocriptine has been shown to have a low risk of tumor enlargement and in some cases it may even be able to reduce tumor size. Early reports of successful pregnancies after bromocriptine therapy were encouraging and, since then, more have followed to confirm the initial impression. If conception occurs, bromocriptine is discontinued and the patient is followed closely. It has been recently reported that even in patients with large tumors, including those with suprasellar extension, bromocriptine therapy could be safely withdrawn during pregnancy; others advise to continue therapy without waiting for complications to occur.
Serum PRL levels during pregnancy in women with prolactinomas are not, in general, predictable of tumor growth, and serial measurements are not recommended. In patients with microadenomas the risk of symptomatic tumor growth during pregnancy is very low (1% – 2%) and therefore serial visual field examinations or MR pituitary imaging is not recommended unless symptoms appear. If only computed tomography is available the abdomen should be shielded. If sever headaches occur, even in the absence of visual defects, an MR imaging of the pituitary gland should be considered, and it should be mandatory if visual field defects are present. If tumor enlargement is detected, therapy with bromocriptine is initiated immediately and visual field examinations are performed daily. If no rapid clinical response occurs despite increasing doses of bromocriptine (up to 20 mg/d), glucocorticoid treatment is initiated (e.g., dexamethasone 4 mg every 6 hours). If both treatments fail, surgery should be strongly considered.
In Untreated macroadenomas the risk of tumor growth during pregnancy is higher (15%-25%) but still low (4%) in women treated (bromocriptine, surgery, radiation, single or in combination) before conception. In these women, monthly visual field examinations are recommended, as well as MR imaging if there is suspicion of tumor enlargement. Besides headaches and visual disturbances, diabetes insipidus or pituitary infarction may occur rarely. The first trimester is thought to be when complications are more likely to develop. Surgery during pregnancy has been reported in a few cases, but therapy with bromocriptine generally has been effective, with an occasional failure. The continuation of bromocriptine therapy is recommended until after delivery when tumor growth occurs during pregnancy. Labor and delivery usually are uncomplicated, but in patients who experience tumor growth it may be advisable to shorten the duration of the second stage to avoid the elevation of intracranial pressure that may occur while pushing.
Few complications of bromocriptine therapy during pregnancy have been reported. Early reports of cervical incompetence have not been subsequently confirmed. In 1410 pregnancies where bromocriptine was used, including over 100 treated throughout gestation, the following rates were reported: abortion, 11.1%; multiple gestation, 1.2%; prematurity, 10.1%; and congenital anomaly, 3.5% (2.5% minor, 1% major). These results are similar to those reported for patients in a general infertility population when pregnancy finally occurs. No mental or physical abnormalities have been reported in exposed children aged up to 5 years.
Breast-feeding is not contraindicated in women with prolactinomas. Spontaneous remissions have been observed after delivery, particularly in those with small tumors and PRL levels of 60 ng/mL or less, which has led to the speculation that pregnancy might be even beneficial instead of dangerous in some cases.
The risks versus benefits of the various treatment options should be carefully discussed with the patient before pregnancy. The choice of treatments for patients who desire to conceive is summarized in table 3.
Prepregnancy Management of Hyperprolactinemia
|No special tests
|Bromocriptine* or surgery
|Visual fields/MR imaging
only if symptomatic
Surgery + Bromocriptine
Radiation + Bromocriptine
|Monthly visual field examinations
MR imaging if symptomatic
*Therapy for 1 y before conception?