**2. Cushing´s syndrome**

During normal pregnancy, serum cortisol increase gradually from the second quarter, keeping the circadian rhythm. Part of the increase in serum cortisol is due to increased estrógens and secondarily to increased cortisol binding protein (CBG), although serum free cortisol, urine and saliva can be elevated up to 2-3 times. The plasma concentration of ACTH is usually normal, although during pregnancy can be reduced or increased. There is a gradual increase in late pregnancy and during delivery (Lindsay & Nieman, 2005). The placenta during gestation can produce CRH which is released into the maternal circulation, although this may have implications in the regulation of ACTH and cortisol secretion are not well known.

Cushing`s syndrome is uncommon during pregnancy, because hypercortisolism produces anovulation and infertility by altering androgenos and gonadotropin.

The frecuency of ACTH-independent cases is increased in pregnant as compared to non pregnant individuals. Of the approximately 136 reported cases, approximately 60% had ACTH independent Cushing´s Syndrome: 44% adenoma y 11% carcinoma and the remainder a mix of primary pigmented nodular adrenal disease, ACTH independent hyperplasia and ectopic ACTH secretion. Five pregnant women with the ectopic ACTH syndrome have been reported (Guilhaume et al., 1992).

The fetus is partially protected from the hypercortisolemia because placental 11 betahydroxysteroid dehydrogenase converts 85% of maternal cortisol to biologically inactive cortisone. However, untreated Cushing´s syndrome has been associated with spontaneous abortion (25%), premature delivery (50%) and rarely, neonatal adrenal insufficiency (Aron et al., 1990).

Adrenal Disease and Pregnancy 53

approach. There is no clear evidence that early treatment is more beneficial than later treatment, this is likely because treatment is generally begun late. Early second trimester surgical treatment would be optimal. For women who do no want surgery or are diagnosed later, maternal hypercortisolism can be controlled with metyrapone. Metyrapone has side effects including hypertension and preeclampsia. (Blanco et al., 2006). Ketoconazol therapy is associated with intrauterine growth retardation, but no malformation or neonatal adrenal insufficienc (Berwaerts et al., 1999). Aminoglutethamide may cause fetal masculinization

Transsphenoidal surgery and pituitary radiation have both been used without complicating

Treating the Cushing´s syndrome does not reduce the frecuency of intrauterine growth restriction (about 30%) or premature birth (about 65%), but it does appear to prevent

The adrenal insufficiency (AI) is rare, but early diagnosis is very important to improve maternal-fetal treatment. The primary AI or Addison's disease involves adrenal cortex atrophy with response insensitivity to ACTH and angiotensin 2, which causes a deficiency of glucocorticoids and aldosterone. The secondary and tertiary AI due to lack of ACTH or CRH are secondary to hypothalamic-pituitary diseases or chronic administration of exogenous corticosteroids. The secondary and tertiary AI are not associated with mineralocorticoid

The prevalence of primary adrenal insufficiency in pregnancy is unknown, with a series from Norway suggesting an incidence of 1 in 3000 births from 1976 to 1987. The most common etiology for primary adrenal insufficiency is autoinmune adrenalitis, which may be associated with autoinmune polyglandular syndrome. Primary adrenal insufficiency from infections, bilateral metastatic disease, hemorraghe or infarction is uncommon. Secondary adrenal insufficiency, from pituitary neoplasm or glucocorticoid suppression of the

Gestation in patients with AI should be considered high-risk pregnancy (Lindsay & Nieman, 2005). Maternal mortality is rare today, after the introduction of hydrocortisone in 1950, as well as improved diagnosis and early treatment. When AI is not diagnosed during pregnancy, may not have negative effects to mother or fetus, indicating the transplacental passage of maternal fetal glucocorticoids. In these cases, disease appears in the postpartum.When the disease is previously known, it is necessary to adjust the dose of corticosteroids in order to avoid a default adrenal crisis defect or undesirable effects of

The prevalence of fetal mortality is unknown, although cases have been reported about intrauterine death, most undiagnosed in pregnant women. Intrauterine growth retardation and low birth weight are the most frequent effects in untreated mothers.The concomitance between AI and other autoimmune diseases (DM, lupus, anticardiolipin antibodies) increases

and mitotane is teratogenic; both should be avoided.

stillborn deliveries (about 10% with treatment) (Buescher, 1996).

hypothalamic-pituitary-adrenal axis is more common (Stechova, 2004).

excess treatment as hypertension and preeclampsia.

Most cases are diagnosed before pregnancy.

the pregnancy (Casson et al., 1987).

**3. Adrenal insufficiency** 

deficiency (Ambrosi et al., 2003).

maternal-fetal morbidity.

**3.1 Diagnosis** 

Maternal complications also can occur. These include hypertension in nearly 70%, gestational diabetes in 25%, myopathy, opportunistic infections, fractures, preeclampsia and rarely heart failure. Two maternal deaths have been reported (Vilar et al., 2007).

#### **2.1 Diagnosis**

The presence of Cushing´s Syndrome during pregnancy may be masked since some of the symptoms and signs of this disorder (weight gain, hypertension, striae) can also occur in normal pregnant women. Biochemical changes during normal pregnancy can interfere with the diagnosis:

The normal pregnancy rises in ACTH and cortisol levels. The hypercortisolism of pregnancy continues to exhibit a normal circadian rhythm, though with a higher nighttime nadir; loss of diurnal rhythm is characteristic of all forms of Cushing syndrome. Salivary cortisol measurements may assist in determining this lack of diurnal response, but normal midnight levels have no been standardized for pregnancy. Urinary free cortisol levels greater than 3 times the upper limit of normal may be interpreted as indicating Cushing´s syndrome in the second and third trimester. There are limited or no data using antibody based assays or mass spectrometry. Normal pregnancy is also associated with inadequate suppression of ACTH and cortisol during the overnight dexamethasone suppression test (Carr et al., 1981).

ACTH levels may not reliably distinguish between pituitary and adrenal etiologies, as the levels may be normal or high in all form of Cushing syndrome, likely from placental ACTH production. When plasma ACTH levels are suppressed, preferably as measured using a two-site immunometric assay, no further biochemical testing is needed.

The high dose dexamethasone suppression test will cause >80% suppression of serum cortisol in normal pregnancy. Patient with adrenal Cushing may be identified with this test as they don't suppress, but the test may misclassify those with Cushing disease, as three of seven cases failed to suppress in small series (Lindsay et al., 2005).

#### **2.2 Differential diagnosis**

Because of the persistent elevations of ACTH in pregnancy, an ACTH suppressed is not always found in independent causes of Cushing syndrome. Thus, while its measurement may be useful, lack of suppressed value does not exclude and ACTH independent cause.

There are limited data on the response to dexamethasone, 8 mg, of women with adrenal causes of Cushing´s syndrome and pituitary adenomas. In general, those with and adrenal etiology do not suppress, while those with Cushing disease do suppress serum cortisol. (Barasch et al., 1988).

Because adrenal form of Cushing´s syndrome are common in pregnancy, it is reasonable to perform and adrenal ultrasound to look for a mass, as well as an ACTH level and dexamethasone suppression test as an initial evaluation.

CRH stimulation test has been performed rarely in pregnant patients. Magnetic resonance (MRI) cannot be performed in the first trimester because of concerns about potential adverse fetal effects; during the remainder of gestation it is not commonly given with gadolinium contrast.

#### **2.3 Treatment**

Adrenal surgery has been performed at the 16 to 21 weeks of pregnancy without complicating the pregnancy (Buescher, 1996). It can be performed using a laparoscopic

Maternal complications also can occur. These include hypertension in nearly 70%, gestational diabetes in 25%, myopathy, opportunistic infections, fractures, preeclampsia

The presence of Cushing´s Syndrome during pregnancy may be masked since some of the symptoms and signs of this disorder (weight gain, hypertension, striae) can also occur in normal pregnant women. Biochemical changes during normal pregnancy can interfere with

The normal pregnancy rises in ACTH and cortisol levels. The hypercortisolism of pregnancy continues to exhibit a normal circadian rhythm, though with a higher nighttime nadir; loss of diurnal rhythm is characteristic of all forms of Cushing syndrome. Salivary cortisol measurements may assist in determining this lack of diurnal response, but normal midnight levels have no been standardized for pregnancy. Urinary free cortisol levels greater than 3 times the upper limit of normal may be interpreted as indicating Cushing´s syndrome in the second and third trimester. There are limited or no data using antibody based assays or mass spectrometry. Normal pregnancy is also associated with inadequate suppression of ACTH and cortisol during the overnight dexamethasone suppression test (Carr et al., 1981). ACTH levels may not reliably distinguish between pituitary and adrenal etiologies, as the levels may be normal or high in all form of Cushing syndrome, likely from placental ACTH production. When plasma ACTH levels are suppressed, preferably as measured using a

The high dose dexamethasone suppression test will cause >80% suppression of serum cortisol in normal pregnancy. Patient with adrenal Cushing may be identified with this test as they don't suppress, but the test may misclassify those with Cushing disease, as three of

Because of the persistent elevations of ACTH in pregnancy, an ACTH suppressed is not always found in independent causes of Cushing syndrome. Thus, while its measurement may be useful, lack of suppressed value does not exclude and ACTH independent cause. There are limited data on the response to dexamethasone, 8 mg, of women with adrenal causes of Cushing´s syndrome and pituitary adenomas. In general, those with and adrenal etiology do not suppress, while those with Cushing disease do suppress serum cortisol.

Because adrenal form of Cushing´s syndrome are common in pregnancy, it is reasonable to perform and adrenal ultrasound to look for a mass, as well as an ACTH level and

CRH stimulation test has been performed rarely in pregnant patients. Magnetic resonance (MRI) cannot be performed in the first trimester because of concerns about potential adverse fetal effects; during the remainder of gestation it is not commonly given with gadolinium

Adrenal surgery has been performed at the 16 to 21 weeks of pregnancy without complicating the pregnancy (Buescher, 1996). It can be performed using a laparoscopic

and rarely heart failure. Two maternal deaths have been reported (Vilar et al., 2007).

two-site immunometric assay, no further biochemical testing is needed.

seven cases failed to suppress in small series (Lindsay et al., 2005).

dexamethasone suppression test as an initial evaluation.

**2.1 Diagnosis** 

the diagnosis:

**2.2 Differential diagnosis** 

(Barasch et al., 1988).

contrast.

**2.3 Treatment** 

approach. There is no clear evidence that early treatment is more beneficial than later treatment, this is likely because treatment is generally begun late. Early second trimester surgical treatment would be optimal. For women who do no want surgery or are diagnosed later, maternal hypercortisolism can be controlled with metyrapone. Metyrapone has side effects including hypertension and preeclampsia. (Blanco et al., 2006). Ketoconazol therapy is associated with intrauterine growth retardation, but no malformation or neonatal adrenal insufficienc (Berwaerts et al., 1999). Aminoglutethamide may cause fetal masculinization and mitotane is teratogenic; both should be avoided.

Transsphenoidal surgery and pituitary radiation have both been used without complicating the pregnancy (Casson et al., 1987).

Treating the Cushing´s syndrome does not reduce the frecuency of intrauterine growth restriction (about 30%) or premature birth (about 65%), but it does appear to prevent stillborn deliveries (about 10% with treatment) (Buescher, 1996).
