Other Endocrine Disorders of Pregnancy

Prolactin-Producing Pituitary Adenomas

Approximately 40% of pituitary tumors are prolactinomas. Given that they often present with amenorrhea and infertility, they are most commonly diagnosed prior to pregnancy. The first line of treatment is medical, with a dopamine agonist such as cabergoline or bromocriptine rather than transsphenoidal surgery. ^, If there is insufficient response or adverse effects to medical treatment, surgery is considered. The key issues in pregnancy for a woman with a prolactinoma are the impact of dopamine agonist therapy continuation or discontinuation during the pregnancy, and the risk of tumor growth.

Bromocriptine mesylate is an ergot derivative with potent dopamine receptor agonist activity. Administered orally, it is a potent inhibitor of prolactin secretion. Bromocriptine crosses the placental barrier and can be found in dosage-related concentrations in fetal blood and in the amniotic fluid. ^, The newer synthetic dopamine agonist cabergoline is also approved for treatment of prolactinomas. Its twice-weekly administration and reduced side effect profile make it more palatable for patients. Cabergoline also has been shown to cross the placenta in animal studies. A third dopamine agonist, quinagolide, may not be safe based on a case series of 176 pregnancies with 9 fetal anomalies.

A recent review by Huang summarized data available from over 6000 pregnancies exposed to bromocriptine and 1000 pregnancies exposed to cabergoline ( Table 62.1 ). The results showed that its use was not associated with an increased risk for spontaneous abortion, multiple pregnancy, or congenital malformation in exposed progeny. However, in a cohort study of 183 pregnancies, exposure to a dopamine agonist increased the risk of early pregnancy loss and prematurity. Long-term studies have not identified any concerns. In one study of 546 children followed up to the age of 9 years, no adverse effect on postnatal development was found. In up to 12 years’ follow-up of more than 200 children exposed to cabergoline, none had adverse outcomes. The risks to the mom of long-term dopamine agonist therapy include the reported risk of cardiac valvular defects in patients using cabergoline in large dosages for Parkinson disease. However, the dosages used in patients with prolactinoma are much smaller, and the relevance of these studies to its use in such patients is unknown.

In general, dopamine agonists are discontinued upon diagnosis of pregnancy, which, together with the increase in estrogen levels, puts the woman at risk for tumor enlargement. Most patients with microadenomas have uncomplicated pregnancies, whereas an important number of patients with untreated macroadenomas have symptomatic tumor enlargement. In a summary of published papers from 1979–2018 of 800 pituitary microadenomas, 288 macroadenomas treated medically and 148 macroadenomas treated with radiation or surgery showed a symptomatic enlargement rate of 2.5%, 18.1%, and 4.7% respectively. Based on a small sample of 46 pregnancies with macroprolactinomas, there was a 20% risk of symptomatic tumor expansion requiring reinitiation of medical therapy or surgery. For women with extrasellar extension, it is important to confirm response to dopamine agonist treatment with not only a normalization of prolactin levels but also a reduction in size of the lesion prior to pregnancy. The failure to have tumor size reduction prior to pregnancy of at least 50% may be a predictor of expansion during pregnancy.

Given the tumor-shrinking properties of dopamine agonists, the continuous use of cabergoline or bromocriptine in pregnancy has been advocated and used in some patients with macroadenomas. Experience with its use throughout gestation is limited, but it appears to be safe. Data on the use of bromocriptine throughout pregnancy have been limited to approximately 100 patients; one infant had an undescended testicle, and another a talipes deformity. The continuous use of cabergoline in pregnant women has also been reported in pregnancy with no untoward fetal effect; dopamine agonists are generally considered safer than surgery in pregnancy.

Prolactin levels increase 10-fold in pregnancy; thus following prolactin levels in pregnancy is not helpful for determining if there is disease progression. Visual field testing and MRI, without gadolinium contrast, should be performed in patients with visual changes or symptoms suggestive of tumor expansion in any trimester. For patients with macroadenomas treated with dopamine agonists or surgically, follow-up at 1- to 3-month intervals is recommended, along with visual field testing. Repeat MRI is performed for patients with symptoms or signs of tumor expansion. For women with expansion of the adenoma during pregnancy resulting in space-occupying effects, dopamine agonists, either bromocriptine and cabergoline, can be started and have been shown to reduce the size of the tumor in pregnancy. Bromocriptine should be administered with food and the dosage adjusted according to symptoms (e.g., 2.5 to 5 mg given two or three times daily). Cabergoline is given at a dosage of 0.25 to 0.5 mg twice weekly. Glucocorticoids may also be given to expedite recovery of visual defects. Surgery, preferably in the second trimester, or early delivery, if feasible, is recommended only if there is no response to bromocriptine or cabergoline and there is risk of visual compromise. However, surgery has been associated with a 1.5-fold increase in fetal loss in the first trimester and 5-fold loss in the second trimester. Even in women resistant to dopamine agonists prepregnancy, treatment with bromocriptine during pregnancy may result in improvement of symptoms of tumor expansion, presumed to relate to a decrease in the pituitary hyperplasia of pregnancy.

Recommendations for management of patients with prolactinomas are outlined in Table 62.2 .

There is no reason to avoid breastfeeding and restart dopamine agonists when a patient with prolactinoma wishes to nurse her child unless there is concern over advancing space-occupying effects. In a small study of 14 women with microadenomas who breastfed for 6 to 14 months, the level of serum prolactin was not significantly higher than it was before pregnancy.

Ophthalmologic and radiologic evaluation and determination of serum prolactin concentrations should be performed 2–3 months after delivery or cessation of lactation. In most instances, the sella returns to its original size and prolactin decreases to previous levels. In some women there will be improvement compared to prepregnancy. Decreases in prolactin and tumor size have been reported in patients with bromocriptine-induced pregnancies. Two studies showed 41% and 68% of women with prolactinomas had remission of hyperprolactinemia after pregnancy and lactation at a median of 22 months and 60 months, respectively. ^, If MRI is required during lactation, gadolinium contrast can be used because less than 1% is excreted in breast milk. Alternatively, breastfeeding can be suspended for 24 hours after the scan. Dopamine agonist therapy should be restarted if there is significant extrasellar tumor growth to prevent neurological sequelae.

Acromegaly: Growth Hormone–Secreting Pituitary Adenomas

Acromegaly is the result of excessive GH secretion in adults and is associated with acidophilic or chromophobic pituitary adenomas, with the majority having macroadenomas. Typical clinical features of acromegaly include an insidious onset of coarse facial features, prognathism, and spade-like hands and feet. Hypertension, diabetes, osteoarthritis, compression neuropathies, and sleep apnea may also be present. Menstrual irregularity or amenorrhea is a common finding in acromegalic women. In a study of 55 patients, only 31% were eumenorrheic. Fertility impairment can result from direct ovarian inhibition from the GH excess; hyperprolactinemia from stalk compression by the mass or due to prolactin co-secretion from the pituitary adenoma; or GnRH deficiency from mass effect or intervention such as surgery or radiation. Concerns for women with acromegaly during pregnancy include the optimization and treatment of comorbidities, risk of interruption of medical therapy, safety and efficacy of continuing medical therapy, and the risk of tumor enlargement.

Because the biologic effect of GH is mediated through IGF-I, elevation of serum concentrations of this growth factor is considered a useful screening test outside of pregnancy and is used to monitor progression of the disease. The 75-g glucose tolerance test is still considered the gold standard; lack of suppression of GH below 1 ng/mL during this test is consistent with a diagnosis of acromegaly in nonpregnant patients. In pregnancy, GH secretion is primarily from the pituitary gland during the first trimester. By 15 weeks, the placental variant GH (GH-V) dominates and, in normal women, pituitary production of GH decreases. Pituitary GH secretion is pulsatile, with 13 to 19 pulses daily, as opposed to the placental variant, which is nonpulsatile. The placental variant is undetectable within 24 hours after delivery. IGF-1 levels increase during the second half of pregnancy to 2–3 times the upper limit of normal by 37 weeks. The maternal-fetal transfer of GH is thought to be negligible, and apart from the effects of glucose intolerance, the fetus is not thought to be affected by acromegaly.

To diagnose acromegaly de novo in pregnancy, specific assays are required to distinguish placental from pituitary GH. Because of the production of a placental variant of GH, an interference-free immunofluorometric assay specific for placental GH is required to differentiate placental from pituitary GH. Oral glucose tolerance tests should not be used to diagnose acromegaly in pregnancy due to the placental GH which is not suppressed by glucose. The definitive diagnosis of acromegaly in pregnancy may be difficult and may need to be confirmed postpartum.

Acromegaly may improve in pregnancy; however this is not always the case. ^, In pregnancy GH and IGF-1 levels become difficult to interpret for the woman with acromegaly and generally should not be used to monitor for disease progression as they may be misleading. A reduction in IGF-I during pregnancy in acromegalic patients has been noted, often without the use of medical therapy. This improvement could be attributed to the effect of markedly increased estrogen concentrations, which inhibit GH signaling, resulting in GH resistance. ^, In one recent case series of 17 pregnancies in 12 patients, 75% had normalization of IGF-1 during pregnancy. In patients with GH-secreting macroadenomas, tumor enlargement may rarely occur, and close follow-up and visual field testing each trimester is required. MRI may be done to confirm tumor enlargement, if suspected.

Definitive treatment (tumor size reduction and biochemical control) before conception is the treatment of choice in acromegalic women desiring children. For those that aren’t cured with surgical management, medical therapy or radiation therapy is recommended to normalize IGF-1. Medical therapy for acromegaly may include one or more of somatostatin analogues, dopamine agonists, and GH receptor antagonists. For those with mild, stable disease consideration for stopping these prior to pregnancy should be given; for most others, medical therapy should be discontinued at diagnosis of pregnancy and only restarted if there is evidence of tumor growth or severe symptoms. ^{, ,} For women with poorly controlled acromegaly with severe symptoms and risk of neurological sequela if tumor growth occurs, treatment may be continued. Somatostatin analogues such as octreotide are the most commonly used agents. They do cross the placenta with potential to bind to fetal brain somatostatin receptors and decrease uterine artery blood flow. However, small case series have suggested safety and efficacy in pregnancy. Dopamine agonists, although less efficacious in acromegaly, do have good safety data based on experience in treating prolactin-secreting adenomas (see earlier). In a case reported by Yap and associates, acromegaly was diagnosed in the second trimester. Bromocriptine corrected visual field defects and suppressed prolactin secretion but did not reduce fasting GH levels. It was suggested that suppression of physiologic lactotroph hyperplasia by bromocriptine might permit noninvasive management of the pituitary adenoma in pregnancy and should constitute first-line treatment.

The use of pegvisomant, a GH receptor antagonist, in pregnancy has been limited to a few case reports. However, in a report of 27 women who were taking pegvisomant at the time of conception, three of whom continued the medication during the pregnancy, there appeared to be no link between pegvisomant use up to conception and adverse fetal outcome. Although there are no known adverse pregnancy outcomes, pegvisomant should be avoided if possible in pregnancy. In patients with evidence of tumor growth despite medical treatment or where there is an urgent need for decompression, transsphenoidal surgery should be considered.

Comorbidities associated with acromegaly, including compression neuropathies, sleep apnea, hypertension, and glucose intolerance, may worsen during pregnancy. These should be identified and managed in a “pregnancy-safe way” prior to conception and reassessed during pregnancy. Carbohydrate intolerance occurs in up to 50% and overt diabetes in up to 20% of acromegalic women, and the insulin resistance of pregnancy is additive. Hypertension occurs in 25% to 35% of acromegalic women.

Breastfeeding can be allowed after an uncomplicated pregnancy. Postpartum reassessment of tumor size by MRI and growth hormone production through IGF-1 measurement should be done 2–3 months postpartum. Medical therapy with somatostatin analogues can be reintroduced in the postpartum period. Dopamine agonists need to be delayed until lactation is complete.

Thyrotropin-Secreting Tumors

TSH-secreting tumors result in increased TSH, freeT4, and freeT3 levels. They are extremely rare, with only 6 pregnancies reported to date. Most are large, invasive lesions and may be managed with surgery, somatostatin receptor analogues, and/or radiation.

Cushing Syndrome

Cushing syndrome, a state of hypercortisolemia, may be due to an ACTH-secreting pituitary adenoma (Cushing disease), ectopic ACTH production, or autonomous cortisol production from the adrenal cortex. This is further discussed in the Disorders of the Adrenal Glands section of this chapter.

Hypopituitarism

Diminished or decreased production of anterior pituitary hormones results in inadequate activity of target organs, such as the thyroid gland, adrenal glands, and gonads. The deficiency can be partial—affecting trophic hormones in various degrees—or it can be complete, resulting in panhypopituitarism. It may be preexisting or arise de novo during the pregnancy or postpartum. It is important for the obstetrics provider to be aware of the unique disease processes that can affect the pregnant patient and to recognize and treat hypopituitarism in the pregnant or postpartum patient.