Pituitary and Adrenal Disorders in Pregnancy

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 (tumors <10 mm) is curative in 50% to 60% of prolactinomas after accounting for recurrences, and it rarely causes hypopituitarism when it is performed by experienced neurosurgeons. For patients with macroadenomas (tumors ≥10 mm), 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 estrogen and the withdrawal of the dopamine agonist may result in significant prolactinoma enlargement during pregnancy ( Fig. 48.1 ). Symptomatic tumor enlargement during pregnancy has been reported in 20 of 800 (2.5%) women with microadenomas, 52 of 288 (18.1%) with macroadenomas without prior surgery or radiotherapy, and 7 of 148 (4.7%) with macroadenomas in women 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 proceed with delivery. Surgical decompression is only resorted to if these other approaches fail.

When a dopamine agonist is stopped once a woman has missed her menstrual period and pregnancy is diagnosed, there is no increase in spontaneous abortions, ectopic pregnancies, trophoblastic disease, multiple pregnancies, or malformations. Although data on safety of continuous dopamine agonist therapy during pregnancy are limited, such treatment is probably not harmful. In contrast to the above reassuring information, Hurault-Delaure et al. reported some adverse outcomes of dopamine agonist use from a French database. Of the 57,408 mother-baby outcome pairs, 183 (0.3%) had received dopamine agonists (bromocriptine, 64.5%; cabergoline, 20.2%; quinagolide, 9.8%) at some time during their pregnancy (75% in the first trimester). Compared with a control group, dopamine agonist exposure was associated with an increased frequency of preterm birth, an increased rate of early pregnancy loss, and an insignificant increase in fetal malformations but no difference in psychomotor development at ages 9 and 24 months.

Patients with microadenomas and intrasellar or inferiorly extending macroadenomas who were treated only with dopamine agonists and had medication withdrawal after conception need only to be followed clinically throughout gestation . 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. Patients with large macroadenomas should be assessed monthly for symptoms of tumor enlargement, and visual fields should be formally tested each trimester . In some women, 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.

Acromegaly

Acromegaly is associated with infertility in about two-thirds of cases because of associated hyperprolactinemia, hypopituitarism due to tumor mass effects, and even increased GH/IGF-1 levels (menses are restored with lowering of GH/IGF-1 levels). Most patients with acromegaly are treated with surgery as primary therapy ; those not cured by surgery are usually treated medically with the somatostatin analogues or, less commonly, with cabergoline.

Conventional assays cannot distinguish between normal pituitary GH and the placental GH variant. If it is critical to make a diagnosis of acromegaly during pregnancy, it may be possible by demonstrating GH pulsatility with frequent sampling, given that GH secretion in acromegaly is highly pulsatile but that of the placental variant is not.

Rarely, GH-secreting tumors can undergo enlargement during pregnancy with a resultant visual field defect. Therefore patients with acromegaly with macroadenomas should be monitored for symptoms of tumor enlargement and visual field testing. However, most studies have documented both biochemical and clinical stability or even improvement in acromegaly during pregnancy.

Because of GH-induced insulin resistance, the risk of gestational diabetes is increased in acromegalic patients along with salt retention and gestational hypertension . In a recent retrospective study, worsening of hypertension (45%) and impaired glucose metabolism (32%) were the most common complications during pregnancies. Cardiac disease has not proved to be an issue in pregnant women with acromegaly.

An expectant approach is appropriate for patients with mild acromegaly, since spontaneous improvement of acromegaly has been reported during pregnancy. The considerations regarding the use of bromocriptine and cabergoline in women with prolactinomas also apply to those with acromegaly. Fewer than 50 pregnant women treated with somatostatin analogues have been reported, and no malformations were found in their offspring. However, a decrease in uterine artery blood flow has been reported with short-acting octreotide, and one fetus appeared to have intrauterine growth restriction (IUGR) that responded positively to a lower dose of long-acting release octreotide. Octreotide binds to somatostatin receptors in the placenta and crosses the placenta, and it can therefore could affect developing fetal tissues in which somatostatin receptors are widespread . We recommend that octreotide and other somatostatin analogues be discontinued if pregnancy is considered and that contraception be used when these drugs are administered, and most but not all others concur. A reasonable option could be to switch to short-acting somatostatin analogues so that these can be continued until pregnancy is diagnosed and then discontinued. We also recommend that medical therapy during pregnancy should be reserved for those with active acromegaly due to severe symptoms from large tumors (e.g., severe headache, vision defects, or tumor enlargement). Pegvisomant, a GH receptor antagonist, is used to control acromegalic symptoms and IGF-1 levels. Use of pegvisomant during pregnancy was recently assessed in the largest reported case series of 35 pregnancies (27 maternal and 8 paternal exposure), including 3 cases in which pegvisomant was continued throughout pregnancy. This small observational study demonstrated no apparent adverse effect of pegvisomant on pregnancy outcome. However, children with GH-insensitivity syndrome (Laron syndrome) due to GH receptor abnormalities have multiple abnormalities so pegvisomant use cannot be recommended during pregnancy.

Thyrotropin-Secreting Tumors

Only six cases of pregnancy occurring in women with thyrotropin (thyroid-stimulating hormone [TSH])–secreting tumors have been reported. Pituitary macroadenomas were found in all but one case. In two cases, the macroadenomas were noted to have significant enlargement during pregnancy, which necessitated treatment. In these reported cases, treatment of TSH-secreting adenomas during pregnancy were targeted to the tumor (surgery, radiation, or octreotide) and/or the hyperthyroidism per se with thionamides.