Management of lactotroph adenoma (prolactinoma) before and during pregnancy

INTRODUCTION — Most women with lactotroph adenomas have anovulatory infertility and even frank hypogonadism but are able to conceive once the lactotroph adenoma has been treated and the serum prolactin concentration has been lowered to normal. Patient counseling before pregnancy should include a discussion about the risks of adenoma growth during pregnancy and the potential effects of exposure to dopamine agonists on the fetus (which is very low).

The management of women with lactotroph adenomas before and during pregnancy will be reviewed here. Other aspects of hyperprolactinemia and lactotroph adenomas are reviewed separately.

●(See "Causes of hyperprolactinemia".)

●(See "Clinical manifestations and evaluation of hyperprolactinemia".)

●(See "Management of hyperprolactinemia".)

PATIENT COUNSELING BEFORE PREGNANCY — Management of a patient with lactotroph adenoma who wants to conceive should begin with a discussion about options for lowering serum prolactin to normal (to restore ovulation) and counseling about the potential risks of treatment during pregnancy to her and the fetus (algorithm 1).

Maternal risk of adenoma growth — The principal risk during pregnancy to a mother with a lactotroph adenoma is an increase in adenoma size sufficient to cause neurologic symptoms, most importantly visual impairment. The risk that an increase in lactotroph adenoma size will be clinically important depends upon the size of the adenoma before pregnancy. Thus, all patients with a lactotroph adenoma should be treated prior to pursuing pregnancy to lower serum prolactin concentrations and decrease adenoma size (macroadenomas) (algorithm 1).

●Pituitary growth during normal pregnancy – The theoretical basis for adenoma growth during pregnancy is lactotroph hyperplasia in response to rising levels of serum estradiol [1]. In a study of 32 pregnant women and 20 nonpregnant women, pituitary volume (as assessed by magnetic resonance imaging [MRI]) was more than double the size in the pregnant women by the third trimester compared with the nonpregnant women (figure 1) [2]. Similarly, in women with lactotroph adenomas who become pregnant, the higher levels of estradiol of pregnancy may increase the size of the lactotroph adenoma.

●Microadenoma – For a microadenoma (<10 mm in diameter), the risk of growth is very low [3-6]. A review of 14 studies reporting a total of 764 patients with lactotroph microadenomas showed that only 2.4 percent exhibited a symptomatic increase in the size of the adenoma during pregnancy [1].

●Macroadenoma – The risk of growth of a lactotroph macroadenoma (≥10 mm) during pregnancy is substantially higher. In the same review as above [1], while only 4.8 percent of 148 women who had macroadenomas that had been treated by prior surgery or radiation developed clinically significant enlargement during pregnancy, 22.9 percent of 214 women without such treatment did. Enlargement not accompanied by symptoms or visual field deficit was not counted.

Fetal risk of dopamine agonist exposure — Although dopamine agonists are typically discontinued when pregnancy is confirmed, pregnancy has usually progressed at least two weeks before confirmation occurs, so the fetus is exposed to the dopamine agonist during that time. Available evidence does not suggest risk to the fetus from this exposure, and a woman considering pregnancy should be so informed (algorithm 1).

Data from over 6000 pregnancies suggest that the administration of bromocriptine during the first month of pregnancy does not harm the fetus [6]. In this series, the incidence of spontaneous abortions (9.9 percent), multiple births (1.7 percent), and malformations (1.8 percent) was no higher than in the general population. In addition, in a study of children followed for up to nine years after exposure to bromocriptine in utero, no harmful effects were noted [7].

Rarely, dopamine agonist treatment is resumed during pregnancy if adenoma size increases so much as to impair vision. Continuous use of bromocriptine during pregnancy has been reported in approximately 100 women. Although the rate of congenital malformations did not appear to be higher than nonexposed pregnancies, there was one case of undescended testis and one of talipes deformity [6,8]. (See 'Treatment of enlarging adenoma' below.)

Although the number of pregnancies in women taking cabergoline at the time of conception is much smaller (968), the evidence suggests that this drug is safe as well. In one review of over 700 cases, the incidence of spontaneous abortions (7.5 percent), multiple births (2.4 percent), and malformations (2.4 percent) was no higher than in the general population [1]. Patients with Parkinson disease treated with high doses of cabergoline (eg, >20 mg per week) have an increased risk of valvular heart disease, but this risk has not been demonstrated using the lower doses used for lactotroph adenomas [9]. (See "Valvular heart disease induced by drugs", section on 'Hyperprolactinemia'.)

TREATMENT BEFORE PREGNANCY

Patients with microadenomas

Restoration of ovulation — Hyperprolactinemia suppresses pituitary gonadotropin secretion, resulting in irregular menstrual cycles and anovulatory infertility. Serum prolactin concentrations between 50 to 100 ng/mL (normal <15 to 20 ng/mL), typically cause either amenorrhea or oligomenorrhea, while levels greater than 100 ng/mL result in deficient estradiol and progesterone secretion and amenorrhea (algorithm 1). (See "Clinical manifestations and evaluation of hyperprolactinemia", section on 'Menstrual cycle dysfunction'.)

For women with lactotroph microadenomas, treatment with a dopamine agonist usually normalizes prolactin and thereby removes the inhibition of gonadotropin secretion and restores normal ovulation and fertility. As noted, available evidence does not suggest risk to the fetus from dopamine agonist use for ovulation induction. (See 'Fetal risk of dopamine agonist exposure' above.)

Dopamine agonist therapy — A dopamine agonist is the treatment of choice for women with a lactotroph adenoma. A marked reduction in the serum prolactin concentration often occurs within two to three weeks (figure 2). Restoration of ovulation occurs in over 90 percent of women with hyperprolactinemia and anovulation (algorithm 1) [10]. (See "Management of hyperprolactinemia", section on 'Overview of dopamine agonists'.)

The occurrence of regular menstrual cycles during treatment indicates that the woman is probably ovulating. Following correction of hyperprolactinemia, successful pregnancy can be achieved in over 85 percent of patients [11]. Neither cabergoline nor bromocriptine has been associated with an increased risk of miscarriage, congenital malformations, or pregnancy complications such as preterm deliveries.

We suggest stopping the dopamine agonist in women with a microadenoma once pregnancy has been confirmed. Because of the limited number of patients who have been treated throughout pregnancy, the safety of continued usage has not been established.

The choice of dopamine agonist and dosing are described below. (See 'Choice of dopamine agonist' below and 'Dosing' below.)

Add clomiphene if needed — For women who do not ovulate or do not conceive with dopamine agonist therapy, clomiphene citrate may be added [12]. If unsuccessful, gonadotropin therapy may be needed, although this therapy is associated with high serum estradiol concentrations during treatment and a significant risk of multiple gestations (algorithm 1). If pregnancy is not achieved using a dopamine agonist and clomiphene, we recommend referral to a specialist in reproductive endocrinology and infertility. (See "Overview of ovulation induction".)

Patients with macroadenomas — For a woman with macroadenoma, adenoma size should be reduced and ovulation restored before pregnancy is attempted. A dopamine agonist may do both, but surgery may also be required. (See 'Transsphenoidal surgery to decrease adenoma size' below.)

Dopamine agonist to decrease size — A woman who has a lactotroph macroadenoma should be advised of the relatively higher risk of clinically important adenoma enlargement during pregnancy, as described above [6]. (See 'Maternal risk of adenoma growth' above.)

We recommend a dopamine agonist as the initial treatment of a lactotroph adenoma, whether or not the adenoma is elevating the optic chiasm. Once the adenoma size has decreased dramatically and is well within the confines of the sella and ovulation has been restored, pregnancy can be attempted. Reduction in size in this way should reduce the chance of clinically important enlargement during pregnancy [3,13].

Transsphenoidal surgery to decrease adenoma size — There are several situations in which we suggest considering transsphenoidal surgery before an attempted pregnancy:

●If the adenoma elevates the optic chiasm and does not shrink substantially in response to a dopamine agonist, we recommend transsphenoidal surgery to reduce adenoma size. Prior surgery reduces the chance that symptomatic expansion will occur during pregnancy [1], but it may still occur. (See "Transsphenoidal surgery for pituitary adenomas and other sellar masses", section on 'Lactotroph adenomas'.)

●If the macroadenoma (≥10 mm) is unresponsive to a dopamine agonist, even if it is not elevating the optic chiasm, because the agonist is unlikely to be effective if the adenoma enlarges during pregnancy.  

●If the macroadenoma is elevating the optic chiasm and causing marked visual impairment.

●If the macroadenoma is responsive to a dopamine agonist but in a prior pregnancy became so large that it caused marked visual impairment.

Choice of dopamine agonist — Most experts now prefer cabergoline over bromocriptine because it is more effective and easier to tolerate. When a dopamine agonist is needed to lower the serum prolactin concentration to permit ovulation, cabergoline has the advantage that it is more likely to be tolerated and more likely to be effective in lowering the prolactin, although bromocriptine has the advantage of the somewhat greater certainty that it does not cause congenital anomalies. (See 'Fetal risk of dopamine agonist exposure' above.)

Dosing

●Cabergoline – The starting dose of cabergoline, 0.25 mg twice a week, should be the same for both micro- and macroadenomas. Bedtime administration reduces the already small chance of nausea and orthostatic hypotension. If the serum prolactin concentration does not normalize after one to two months, the dose can be increased to 0.5 mg twice a week and then, if necessary, titrated up to 1 mg twice a week.

Patients with macroadenomas often require higher doses to reduce the size of the adenoma and the prolactin concentration [11]. However, some macroadenomas, even with serum prolactin concentrations in the tens of thousands, will respond to the lower doses described.

●Bromocriptine – For bromocriptine, start with 1.25 mg at bedtime for one week, then 1.25 mg twice a day for one to two months. If the serum prolactin concentration does not fall to near-normal or normal by then, the dose can be increased to 2.5 mg twice a day and, if necessary, to 5 mg twice a day. If nausea occurs or if serum prolactin does not decrease to normal, consider changing to cabergoline.

DURING PREGNANCY — Women with lactotroph adenomas, in particular those with macroadenomas, should be monitored closely during pregnancy. The approach outlined here is consistent with the 2011 Endocrine Society Clinical Practice Guidelines on the diagnosis and treatment of hyperprolactinemia [14].

Monitoring

●Symptoms – Patients should be seen at routine intervals and asked about headaches and changes in vision (as indicators of potential adenoma growth).

Women with microadenomas should be seen every three months and asked about headaches and change in vision, symptoms that could indicate adenoma enlargement. A change in vision should prompt assessing visual fields.

Women with macroadenomas should also be seen at least every three months (more often the larger the adenoma) and asked about headaches and changes in vision.

●Serum prolactin – During normal pregnancy, serum prolactin concentrations increase to as high as 400 ng/mL. Women with lactotroph adenomas may experience an increase in serum prolactin to pretreatment levels (figure 3). However, not all women with lactotroph adenomas experience a similar increase [6].

The Endocrine Society guidelines recommend against measuring prolactin during pregnancy because it can be difficult to distinguish the normal pregnancy-associated rise in prolactin from that associated with adenoma growth [14]. However, the author of this topic does measure serum prolactin in women with both macro- and microadenomas every three months during pregnancy because it is reassuring if the prolactin does not increase above 400 ng/mL (the upper limit of normal in the third trimester for pregnant women without lactotroph adenomas). If the prolactin does increase to >400 ng/mL, visual field testing should be performed.

Visual field testing — For most pregnant women with lactotroph adenomas, routine visual field testing is not indicated. However, women who develop visual symptoms during pregnancy should have visual field testing. In addition, women whose macroadenomas extend above the sella should undergo visual field testing before pregnancy and every three months during the pregnancy, even if the patient has no visual symptoms. If a visual field defect consistent with a sellar mass is found (diminished vision in the temporal fields [bitemporal hemianopsia]), MRI without contrast should be performed.

Pituitary MRI — Routine pituitary MRI is not indicated in women with lactotroph adenomas during pregnancy, because the risk of adenoma growth is very low. However, if a patient develops severe headaches or visual field abnormalities, pituitary MRI without contrast should be performed to assess adenoma size. (See 'Maternal risk of adenoma growth' above.)

Treatment of enlarging adenoma — If the adenoma has enlarged to a degree that could account for the headaches and/or visual field defect, the patient should be treated with a dopamine agonist throughout the remainder of the pregnancy, and she should be seen at least once a month to reevaluate symptoms and visual fields. This treatment will usually decrease the size of the adenoma and alleviate the symptoms [8,15]. We suggest using the same dopamine agonist the patient took and tolerated previously. (See 'Choice of dopamine agonist' above and 'Dosing' above.)

If cabergoline is not successful in alleviating severely compromised vision after several weeks, we suggest transsphenoidal surgery in the second trimester. In contrast, in the third trimester, surgery for persistent visual symptoms should be deferred until after delivery, if possible.

Pituitary apoplexy — Pituitary apoplexy refers to sudden hemorrhage into the pituitary, a rare event with potential serious neurologic and endocrine consequences. Apoplexy can occur in patients with pituitary micro- or macroadenomas, including women with lactotroph macroadenomas during any trimester of pregnancy [16]. In its most dramatic presentation, apoplexy causes the sudden onset of excruciating headache, diplopia due to pressure on the oculomotor nerves, and hypopituitarism. All pituitary hormonal deficiencies can occur, but the sudden onset of corticotropin (ACTH) and therefore cortisol deficiency is the most serious because it can cause life-threatening hypotension. It should be treated with high-dose hydrocortisone. (See "Causes of hypopituitarism", section on 'Pituitary apoplexy'.)

Most patients who develop apoplexy were not known to have an adenoma previously, and when tissue is excised surgically, it is necrotic, so the cell type cannot be identified.

AFTER PREGNANCY

Breastfeeding and dopamine agonists — Breastfeeding increases serum prolactin concentrations (figure 4) but does not appear to increase the risk of lactotroph adenoma growth [17,18]. Therefore, breastfeeding is an option for women with micro- and macroadenomas that remained stable in size during pregnancy. Dopamine agonist therapy, which lowers serum prolactin and inhibits lactation, should be withheld until breastfeeding is completed.

In contrast, breastfeeding is contraindicated in women who have visual field impairment because they should be treated with a dopamine agonist.

Normalization of prolactin after pregnancy — To evaluate the need for further dopamine agonist therapy after pregnancy, serum prolactin should be measured approximately three months after delivery in women who do not breastfeed and after cessation of breastfeeding in those who do. Serum prolactin normalizes within 6 to 12 weeks postpartum in women who do not breastfeed. (See "Causes of hyperprolactinemia", section on 'Nipple stimulation and breast examinations'.)

●In a study of 143 pregnancies in 91 patients with hyperprolactinemia treated with cabergoline prior to pregnancy, no further treatment was necessary to maintain a normal serum prolactin concentration in 68 percent of the patients for up to 60 months postpartum [19]. Breastfeeding did not affect the results. Recurrence was slightly greater in those who had macroadenomas than in those who had microadenomas.

●In a study of 104 pregnancies in 73 patients with lactotroph adenomas treated with a dopamine agonist prior to pregnancy, 41 percent had a normal serum prolactin concentration a median of 22 months after delivery or cessation of lactation [20]. Those who had normal prolactin levels had pituitary glands of normal size.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyperprolactinemia/prolactinoma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Prolactinoma (The Basics)")

●Beyond the Basics topics (see "Patient education: High prolactin levels and prolactinomas (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Preconception counseling – Management of a patient with lactotroph adenoma who wants to conceive should begin with a discussion about options for lowering serum prolactin to normal (to restore ovulation) and counseling about the potential risks of treatment during pregnancy to her and the fetus. The main concern for the mother is adenoma growth, while the main concern for the fetus has been exposure to a dopamine agonist. Fortunately, available evidence suggests that both bromocriptine and cabergoline are safe. (See 'Patient counseling before pregnancy' above.)

●Dopamine agonists for ovulation induction – When pharmacologic therapy is needed to lower the serum prolactin concentration to permit ovulation, we suggest a dopamine agonist (Grade 2C). (See 'Restoration of ovulation' above.)

We suggest cabergoline rather than bromocriptine as initial therapy (Grade 2C). Cabergoline is more likely to be tolerated and to be effective in lowering the prolactin. However, bromocriptine has the advantage of the greater certainty that it does not cause congenital anomalies. (See 'Dopamine agonist therapy' above.)

●Decrease adenoma size prior to pregnancy

•Dopamine agonists – For women with macroadenomas, we suggest initial therapy with a dopamine agonist rather than transsphenoidal surgery to decrease the size of the adenoma prior to pregnancy, whether the adenoma elevates the optic chiasm or not (Grade 2C). (See 'Dopamine agonist to decrease size' above.)

•Transsphenoidal surgery – We reserve transsphenoidal surgery for patients with:

An inadequate response to dopamine agonists (macroadenomas that do not decrease to a size that is within the sella). Surgery reduces the chance that symptomatic expansion will occur during pregnancy (although it may still occur).

Macroadenomas within the sella that do not respond at all to dopamine agonists. Preconception transsphenoidal surgery is indicated because dopamine agonist therapy is not an option in the event of adenoma growth during pregnancy. (See 'Transsphenoidal surgery to decrease adenoma size' above.)

●During pregnancy

•Stop dopamine agonist – Once pregnancy has been confirmed, we stop dopamine agonist therapy because the safety of continued usage throughout pregnancy has not been established. (See 'Dopamine agonist therapy' above.)

•Monitoring – Women with either a micro- or macroadenoma should be seen every three months to evaluate for possible adenoma growth. (See 'Monitoring' above.)

•Macroadenoma growth – For women with evidence of macroadenoma growth on pituitary MRI (performed for severe headaches or visual field abnormalities), we suggest treatment with cabergoline or bromocriptine throughout the remainder of the pregnancy (Grade 2C). Transsphenoidal surgery is sometimes needed if dopamine agonists are not successful and vision is severely compromised. (See 'Treatment of enlarging adenoma' above.)

●Postpartum use of dopamine agonists – Breastfeeding is not contraindicated in women who have lactotroph adenomas, but dopamine agonists should not be used during breastfeeding, because they impair lactation. An exception is a woman who has visual field impairment, who should not breastfeed and should be treated with a dopamine agonist. (See 'Breastfeeding and dopamine agonists' above.)

●Normalization of prolactin – Forty to 60 percent of women who were treated with dopamine agonists for lactotroph adenomas prior to pregnancy do not require them afterwards. Therefore, women should be reevaluated by measurement of the serum prolactin concentration three months after delivery in women who do not breastfeed or after cessation of breastfeeding. (See 'Normalization of prolactin after pregnancy' above.)