Tumoral Pathology of Pituitary and Pregnancy: Prolactinoma
Prolactinoma is the most common cause of persistent hyperprolactinemia and represents 50% of pituitary tumors [108
]. These are predominantly benign tumors and classified as microprolactinomas (size < 10 mm) or macroprolactinomas (size ≥10 mm).
Effect of prolactinoma on pregnancy. Hyperprolactinemia has no effect on pregnancy or fetal development, but there is a risk of estradiol receptor-related tumor expansion [109
Effect of pregnancy on prolactinoma:
During pregnancy, the pituitary undergoes global hyperplasia due to increased serum levels of estrogenes leading to tumor growth and the possibility of visual loss [108
]. Microadenomas of less than 10 mm rarely cause problems during pregnancy, while macroprolactinomas larger than 10 mm require increased attention regarding pharmacotherapeutic management [110
]. Women with macroprolactinomas require visual field testing every trimester and in case of visual impairment treatment with dopamine agonists (DA) is initiated [111
]. When there is a risk of optic chiasm compression DA are recommended throughout pregnancy.
Management during pregnancy:
The objective of pharmacological treatment depends on the size of the adenoma, the target being maintaining the prolactinoma away from the optic chiasm and levels of prolactin to be within the normal range for pregnancy [110
]. Lack of efficacy of drug therapy requires transsphenoidal surgery for removal of adenomas, only in the second trimester [111
Prolactin secretion is under negative feedback control by dopamine, and consequently DA like Bromocriptine and, more recently, Cabergoline, is the mainstay of treatment in nonpregnant as well as pregnant women.
Bromocriptine, category B according to the FDA [4
], is the DA of choice for pharmacologic treatment of prolactinoma during pregnancy, some studies confirming no adverse effects in treating over 6000 cases [113
]. The effective dosage is 2.5–5 mg/day, seldom being required at 7.5 mg/day or more. Bromocriptine is effective not only for the normalization of prolactin level, but also for reducing tumor size [113
Cabergoline, category B according to FDA [4
], is the alternative DA, because it has a good safety profile without teratogenic effect; although it is not recommended for prolactinoma pharmacotherapy in pregnancy because long-term use (over 1 year) has been associated with fibrosis of the heart valves and constant supervision by echocardiography is necessary [114
Management after pregnancy: After birth, microadenoma presents a negligible risk and breastfeeding is permitted. In case of macroadenoma, breastfeeding is not recommended. It is also recommended to control prolactin and pituitary morphology three months after birth [115
]. Sometimes it was found a total remission of a microprolactinoma (probably by vascular effect) after birth [116
Hyperactivity of Pituitary Gland and Pregnancy: Acromegaly
The occurrence of pregnancy in women with acromegaly is very rare, because the hypersecretion of growth hormone from the pituitary somatotrophs leads to lack of ovulation. The simultaneous appearance of hyperprolactinemia in 40% of cases, with or without macroadenoma, also affects fertility [117
]. The first case of normal pregnancy in a woman with acromegaly was reported in 1954 [93
Risks: Comorbidities in pregnant women are numerous: hypertension, preeclampsia, gestational diabetes due to insulin resistance resulting from the anti-insulin effect of growth hormone (GH), and heart disease [60
]. There is also a potential risk of tumor expansion due to growth stimulation by estrogen, which leads to neurological complications and/or visual complications due to proximity to the optic chiasm, and transsphenoidal surgery is recommended [117
Management: Dopamine agonists can control pregnancy acromegaly in 10% of cases [118
]. Bromocriptine (category B—FDA) is considered safe and is more efficient when there are cosecretant GH and prolactin (PRL) tumors. A higher prevalence of microsomic fetuses in pregnant women treated with bromocriptine was found however compared to untreated women [118
]. Somatostatin analogs, octreotide (category B—FDA), or lanreotide (category C—FDA) cross the placental barrier;their safety in pregnancy has not been precisely established [119
]. All five subtypes of receptors and somatostatin, including somatostatin receptor type 4 (SST4) which has a reduced affinity for Octreotide, are present in the placenta and umbilical cord, suggesting that the maternal–fetal barrier carries a weak functional response to somatostatin analoganalogs [119
]. For the treatment of acromegaly, Octreotide is also administered before pregnancy, as a result, the drug is administered in the first few weeks after conception, but no fetal malformation was reported [119
Studies have demonstrated that administration of somatostatin analoganalogs in pregnant women with acromegaly has been correlated with intrauterine fetal growth retardation and birth of children with low weight (growth-restricted), compared to those who did not receive them [119
]. A partial explanation would be the transient reduction of the uterine artery flow and of systolic velocity after the administration of short-acting Octreotide [120
]. Pegvisomant (category B—FDA) has proven to be a safe and effective drug; fetal concentration is minimal suggesting a low or absent transplacenta passage [120
]. Although medical treatment of pregnant women with acromegaly is not associated with major side effects of the mother or fetus, it should be discontinued during pregnancy. If medical treatment continues, close monitoring of fetal development is recommended.
Hypoactivity of Pituitary Gland and Pregnancy
(A) Hypopituitarism during Pregnancy
Risks: Pregnant women with hypopituitarism (deficiency of hormones secreted by the anterior pituitary), usually secondary to pituitary tumors, have a high risk of cerebrovascular disease and, therefore, pharmacotherapy is very important during pregnancy [122
Management: Glucocorticoid of choice in pregnant women with ACTH deficiency is hydrocortisone 20–30 mg/day (two-thirds of the total dose in the morning and a third in the evening), (category C—FDA). In some clinical situations, the amount of hydrocortisone may be reduced by one third of the total dose, as the effects of cortisone are boosted by estrogen during pregnancy due to increasing in corticosteroid-binding globulin [123
]. The therapeutic alternative to hydrocortisone is represented by synthetic corticosteroids: 5.0–7.5 mg prednisone daily and dexamethasone 0.5–0.75 mg per day, (category C—FDA), mentioning that they are not boosted by estradiol. Because these pregnant women have ACTH deficiency, aldosterone secretion is normal and there is no need of mineralocorticoid replacement therapy.
For Levothyroxine (category A—FDA), the usual dose of 0.1–0.2 mg is adjusted so free-T4 levels are included in the upper normal range for gestational age [55
] because small values of free-T4 especially in the first quarter have a negative impact on psychomotor child development [124
]. TSH is not a useful marker to monitor treatment with Levothyroxine during pregnancy.
Genetic recombinant GH treatment is not approved for administration during pregnancy, although some studies have shown women who became pregnant during treatment with GH and it has no longer been administered in the first trimester had pregnancies with good evolution and development of normal children [125
]. Desmopressin (category B—FDA) administration is considered to be safe during pregnancy, nonteratogenic. Although it has similar chemical structure to vasopressin, it does not seem to increase the frequency or amplitude of uterine contractions although it has oxytocin-like properties [126
(B) Postpartum Hypopituitarism: Sheehan Syndrome
Sheehan’s syndrome (SS) is a very rare condition resulting from infarction and necrosis of the pituitary gland [127
Risks: The pituitary gland, increased physiologically during pregnancy, causes upper pituitary artery compression and hypotension secondary to severe bleeding during childbirth and postpartum causes small blood vessel spasm, apoplexy and subsequent necrosis of the anterior pituitary.
Management: Hormone replacement therapy is fundamental in SS. Glucocorticoid administration is done before treatment with L-thyroxine [127
(C) Panhypopituitarism during Pregnancy
Panhypopituitarism is characterized by a global deficit in anterior and posterior pituitary hormones. A pregnancy in these cases is rare, with an unpredictable evolution as there are only a few reports of cases in the literature. Thus, Shinar et al. recently reported four cases of pregnant women, aged between 26 and 31 years, diagnosed with panhypopituitarism without any detectable pituitary function modification in repeated tests. They delivered to term with spontaneous labors. The pregnancies were obtained using in vitro fertilization and these have been treated all the pregnancy period with hormonal replacement therapy: glucocorticoids, vasopressin, and thyroxin. In none of the four cases the breastfeeding was possible due to the lack of prolactine [128
Tonda et al. presented the case of a young pregnant woman with severe clinical disturbances, such as visual disturbances, intense headache, insipid diabetes, polydipsia, and polyuria, which gave birth prematurely (gestational age 32 weeks). Blood tests revealed panhypopituitarism and imaging explorations showed a pituitary lesion. After six weeks of adequate hormone replacement therapy the imaging explorations showed a normal pituitary gland [129
Diabetes insipidus (DI) is a rare disorder characterized by antidiuretic hormone (ADH) deficiency. Produced in the hypothalamus and stored in the posterior pituitary, ADH acts directly on the distal tubules to allow water reabsorption in response to dehydration [121
]. DI can be a result of ADH hyposecretion in the posterior pituitary gland (central DI, endocrine) or lack of response to its action in the kidney (nephrogenic DI, peripheral) [121
]. As a result, there is an inability to maintain normal plasma osmolarity (275–295 mmol/L) and urine concentrations (>300 mOsmol/kg). Polyuria (>3 lit/24 h) stimulates increased thirst with compensatory polydipsia [121
]. Plasma osmolality decreases by 5 to 10 mOsm/kg shortly after conception and throughout pregnancy remains low [130
]. Accordingly, ADH level remains low throughout pregnancy, especially in the first and second trimester of pregnancy [131
]. The ability to concentrate urine remains in the normal range [132
]. The prevalence of DI during pregnancy is low, ~1:30,000 [133
Transitional DI may occur in the last trimester of pregnancy, due to increased glomerular filtration rate, renal prostaglandins increase with ADH antagonism, and placental production of vasopressinase, an ADH degrading enzyme [134
Risks: Morbidities may occur due to preeclampsia, acute fatty liver of pregnancy, and HELLP syndrome (hemolysis, elevated liver enzyme levels, and low platelet levels). The lack of therapeutic effect of vasopressin is due to the significant increase in plasma clearance of antidiuretic hormone (ADH) [134
]. This explains also the good response to desamino-D arginine vasopressin (1-desamino-8-D-arginine vasopressin) DDAVP (Desmopressin, Minirin) [135
], which is not metabolized by vasopresinase.
Management: DI pharmacotherapy in pregnancy is approached differently depending on etiology.
(A) Central and Transient Diabetes Insipidus
At the beginning of the eighteenth century, drug therapy in pregnancy DI was aggressive hydration and increased fluid intake. At the beginning of the nineteenth century posterior pituitary extract was first used in the treatment of pregnancy DI [136
]. The extract has an irritating and sensitivity effect on the nasal mucosa and it induces formation of antibodies. Since this bovine or porcine extract contains oxytocin in addition to vasopressin, undesirable complications have occurred [136
]. New drugs have been synthesized containing exogenous vasopressin: pitressin—an aqueous solution of vasopressin (vassopresin 20 units/mL); pitressin-tannate—oily solution (vasopressin 5 units/mL); and lypressin (lysin-8-vasopressin)—nasal spray (vasopressin 2 units per spray) but even they are rapidly catabolized by placental vasopressinase due to chemical structures similar to endogenous vasopressin [138
]. Therefore, in women with DI receiving this medication, disease control was not achieved because as the pregnancy advances and placental vasopressinase level increased.
Currently the elective drug treatment for central, preexisting DI and transitional pregnancy DI is 1-deamino-8-D-arginine-vasopressin (DDAVP) (desmopressin, minirin), category B—FDA. DDAVP is a selective activator of V2 receptors in the distal nephron inducing increased water retention with the emergence of hyponatremia [139
]. DDAVP is an analog of vasopressin with a modified N-terminus and a change in the chemical structure of arginine at position 8, and is therefore resistant to the catabolic action of placental vasopressinase [140
If central preexisting DI was controlled by DDAVP before pregnancy, treatment may be continued during pregnancy, sometimes requiring an increase in dose. Diagnosis of DI during pregnancy requires the same drug therapy to that outside of pregnancy [141
]. DDAVP can be administered intranasally, subcutaneously, intravenously, or orally in a starting dose of 10 mcg intranasally before sleep to prevent nycturia. The intranasal or sublingual route is recommended during pregnancy, rarely parenteral [142
]. Higher doses can sometimes be necessary: the effective dose depends on the severity of DI (partially or totally deficient vasopressin) and individual parameters, such as absorption, which affect the pharmacokinetics and pharmacodynamics of the drug. The therapeutic effect is long [141
]. DDAVP standard doses are between 1 and 2 µg once or twice daily by injection; 5 to 20 micrograms twice or three times a day, nasally; and 60 to 120 µg two or three times a day, via the sublingual route [141
For nasal administration, either a graduated tube is used (allowing a variable amount of product to be administered) or a nasal spray, containing about 10 µg per puff of the drug. Sublingual administration is simple, using desmopressin lyophilized and dissolved under the tongue [135
]. Posology is adjusted to the symptoms: the therapeutic target is the elimination of polyurodipsic syndrome and the avoidance of drug overdose [141
]. Usually the pregnant woman shall establish the optimal dose herself, increasing the evening dose gradually until she no longer drinks water at night and nycturia disappears, and then is advised to use the same procedure during the day.
The main side effect of DDAVP is water intoxication due to overdose, the volume of water ingested is disproportionate to the removed volume because desmopressin blocks diuresis and causes hemodilution. This results in hyponatremia, oliguria, edema, headache, lethargy, nausea and vomiting [135
]. Seizures and coma may occur due to hyponatremia. In order to avoid the risk of water intoxication, the patient should be advised to drink only when thirsty. It is also recommended to omit a dose of DDAVP once a week, for example. By producing transient polyuria any gradually accumulated fluid retention is eliminated, thus correcting fluid balance. The pregnant woman may then resume the usual dose of desmopressin [143
]. Monitoring urine output, fluid intake restriction and monitoring of serum sodium osmolality and urine osmolality can minimize the risk of osmotic complications secondary to DDAVP administration in pregnant women with DI [135
In transient pregnancy DI, DDAVP can usually be stopped a few days or weeks before birth because postpartum, vasopressinase produced by the placenta disappears [143
]. Although classified by the FDA as risk category B [4
], there continues to be a lack of controlled studies for DDAVP to provide data on its safety for mother and fetus [126
]. The great advantage of DDAVP is that being a selective V2 receptor activator, it avoids stimulating uterine contractions or blood pressure compared with exogenous vasopressin forms [126
(B) Nephrogenic Diabetes Insipidus
Management: Congenital nephrogenic DI therapy in pregnant women is very rare and requires the corrections of the abnormalities of calcium or potassium. Hydrochlorothiazide is used conventionally to treat nephrogenic DI [144
]. Although included in category B by the FDA, the pregnant women need precautions to avoid hypovolemia and hyponatremia in mother and fetus. Hydrochlorothiazide can create difficult problems during labor due to the difficulty of balancing abundant polyuria by an equivalent fluid intake [144