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Because of the increasing popularity and success of in vitro fertilization, the field of reproductive endocrinology and infertility has steadily morphed toward the treatment of infertility. Nevertheless, a physician board certified in reproductive endocrinology and infertility is the referring physician of choice regarding prolactin disorders and gynecologists should be familiar with the symptoms and sequela of prolactin elevations. This month’s column will address when to obtain a serum prolactin and how to appropriately manage hyperprolactinemia.
Of all the anterior pituitary hormones (adrenocorticotropic hormone, follicle-stimulating hormone, growth hormone, luteinizing hormone, prolactin, thyroid-stimulating hormone ), prolactin is the only one under tonic inhibition by dopamine. Disturbances in this dopaminergic pathway result in elevated serum prolactin. The normal range for prolactin is approximately 5-20 ng/mL.
In the nonpregnant state, little is known regarding the purpose of prolactin, which is produced by the anterior pituitary cluster of cells called lactotrophs. To prepare the breast for postpartum lactation, increases in prolactin are necessary and sustained throughout pregnancy. Second to pregnancy, amenorrhea can occur in 10%-20% of cases of hyperprolactinemia. Outside of pregnancy, elevations in prolactin result in hypogonadism, through gonadotropin-releasing hormone suppression, resulting in infertility (48%), headache (39%), oligomenorrhea (29%) and galactorrhea (24%).1 Most hypogonadal symptoms are more likely to occur with prolactin levels greater than 100 ng/mL, whereas infertility and ovulation dysfunction can occur with mild to moderate hyperprolactinemia, respectively. Prolonged amenorrhea can risk bone mineral density loss.
While the focus of our discussion is the effect of prolactin on women, men with hyperprolactinemia can experience hypogonadotropic hypogonadism with resultant decreased libido, impotence, infertility, gynecomastia, or, rarely, galactorrhea.2
The three Ps – physiological, pharmacologic, pathological
Physiological causes of hyperprolactinemia include rising estradiol during the late follicular phase and into the secretory phase of the menstrual cycle or while taking combined oral contraception, nipple stimulation, pregnancy, lactation, meals, sleep, and stress.
Drugs can interrupt the dopaminergic pathway, thereby elevating serum prolactin but usually not above 100 ng/mL, except for the antipsychotic drug risperidone, which can cause marked elevation up to 300 or even 400 ng/mL. Medications that can cause hyperprolactinemia are estrogens, neuroleptic drugs such as risperidone, metoclopramide, antidepressant drugs, cimetidine, methyldopa, and verapamil.
A pituitary MRI can diagnose an adenoma, that is, a collection of cells in the pituitary that are responsible for hyperprolactinemia and is named based on its size. Microadenomas are less than 1 cm and are typically associated with serum prolactin values below 200 ng/mL. Macroadenomas can worsen while a patient is on combined oral contraception and during pregnancy; fortunately, this is not the case with a microadenoma.
Hypothyroidism can elevate serum prolactin since thyrotropin releasing hormone is known to stimulate prolactin secretion.3 Consequently, when a patient presents with both hypothyroidism and hyperprolactinemia, thyroid replacement should be initiated for thyroid regulation and potential restoration of prolactin levels. If hyperprolactinemia persists, then further evaluation is required. Chronic renal impairment can also elevate prolactin levels due to decreased clearance.
Management
The appropriate evaluation of hyperprolactinemia consists of a history to disclose medications, identify galactorrhea, and visual changes. Because of an adenoma compressing the optic chiasm, partial blindness may occur where vision is lost in the outer half of both the right and left visual field, called bitemporal hemianopsia. Mild elevations in prolactin should be tested at a time when physiological influences are at a minimum, that is, during menses, fasting, and in late morning.4 Persistent elevations should be appropriately evaluated rather than by using the empiric “shotgun” approach of prescribing a dopamine agonist. Laboratory testing for repeated elevations in prolactin includes a pituitary MRI looking for a mass in the hypothalamic-pituitary region that interrupts dopamine suppression.
Treatment of hyperprolactinemia begins with a dopamine agonist and is indicated when there is hypogonadism or intolerable galactorrhea. Cabergoline is the first choice because of effectiveness (reduced adenoma size in greater than 90% of patients) and lesser side effects, particularly nausea, than bromocriptine. Dopamine agonists, such as bromocriptine and cabergoline, belong to the category of ergot-derived dopamine agonists and have been used to treat Parkinson’s disease. At high doses used to treat Parkinson’s, cabergoline is associated with an increased risk of valvular heart disease. In the United States, pergolide was voluntarily withdrawn from the market in March 2007 because of this risk. At the lower doses generally used for the treatment of hyperprolactinemia, cabergoline is probably not associated with excess risk.5
Newer dopamine agonists are known as nonergot. These are pramipexole, ropinirole, rotigotine, and apomorphine. They have not been associated with a risk of heart damage and can be prescribed.
The initial prescribing dose of cabergoline should be 0.25 mg twice a week or 0.5 mg once a week. If bromocriptine is used, the starting dose is 1.25 mg after dinner or at bedtime for 1 week, then increasing to 1.25 mg twice a day (after breakfast and after dinner or at bedtime to reduce nausea and fatigue). After 1 month of a dopamine agonist, the patient should be evaluated for side effects and a serum prolactin level should be obtained. With a normal prolactin level, gonadal function will probably return within a few months. The dopamine agonist should typically be discontinued with pregnancy as pregnancy increases prolactin physiologically.
Treatment of a macroadenoma is essential when the tumor is large enough to cause neurologic symptoms, such as visual impairment or headache, and is preferable when it is invasive or when there are enlarging microadenomas since they are likely to continue to grow and become symptomatic. About 95% of microadenomas have not been shown to increase in size during 4-6 years of observation.6
Transsphenoidal surgery should be considered when there is:
- Persistent hyperprolactinemia and/or size of the adenoma, with associated symptoms or signs despite several months of dopamine agonist treatment at high doses.
- Presence of a giant lactotroph adenoma (e.g., >3 cm) with pregnancy desired including those whose adenoma responds to a dopamine agonist – to avoid significant growth during pregnancy while off medication.
Data from over 6,000 pregnancies suggest that the administration of bromocriptine during the first month of pregnancy does not harm the fetus.7
Discontinuing treatment
Three scenarios may allow for cessation of dopamine agonist therapy. The first is when a patient has had a normal serum prolactin test following 2 years of low-dose dopamine agonist. Another is the patient who had hyperprolactinemia and a microadenoma that responded to treatment with a normal prolactin level and no further evidence of an adenoma by MRI for at least 2 years. Lastly, the patient who had a macroadenoma prior to treatment and a subsequent normal serum prolactin level without an adenoma for at least 2 years.
Like the management of thyroid dysfunction, our field must be aware of prolactin disorders for early detection, prompt referral, and appropriate management to minimize long-term consequences.
Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
References
1. Bayrak A et al. Fertil Steril. 2005 Jul;84(1):181-5.
2. Carter JN et al. N Engl J Med. 1978 Oct 19;299(16):847-52.
3. Sachson R et al. N Engl J Med. 1972;287:972.
4. Singh SP and Singh TP. Ann Endocrinol (Paris). 1984;45(2):137-41.
5. Valassi E et al. J Clin Endocrinol Metab. 2010 Mar;95(3):1025-33.
6. Sisam DA et al. Fertil Steril. 1987 Jul;48(1):67-71.
7. Molitch ME. Best Pract Res Clin Endocrinol Metab. 2011 Dec;25(6):885-96.
Because of the increasing popularity and success of in vitro fertilization, the field of reproductive endocrinology and infertility has steadily morphed toward the treatment of infertility. Nevertheless, a physician board certified in reproductive endocrinology and infertility is the referring physician of choice regarding prolactin disorders and gynecologists should be familiar with the symptoms and sequela of prolactin elevations. This month’s column will address when to obtain a serum prolactin and how to appropriately manage hyperprolactinemia.
Of all the anterior pituitary hormones (adrenocorticotropic hormone, follicle-stimulating hormone, growth hormone, luteinizing hormone, prolactin, thyroid-stimulating hormone ), prolactin is the only one under tonic inhibition by dopamine. Disturbances in this dopaminergic pathway result in elevated serum prolactin. The normal range for prolactin is approximately 5-20 ng/mL.
In the nonpregnant state, little is known regarding the purpose of prolactin, which is produced by the anterior pituitary cluster of cells called lactotrophs. To prepare the breast for postpartum lactation, increases in prolactin are necessary and sustained throughout pregnancy. Second to pregnancy, amenorrhea can occur in 10%-20% of cases of hyperprolactinemia. Outside of pregnancy, elevations in prolactin result in hypogonadism, through gonadotropin-releasing hormone suppression, resulting in infertility (48%), headache (39%), oligomenorrhea (29%) and galactorrhea (24%).1 Most hypogonadal symptoms are more likely to occur with prolactin levels greater than 100 ng/mL, whereas infertility and ovulation dysfunction can occur with mild to moderate hyperprolactinemia, respectively. Prolonged amenorrhea can risk bone mineral density loss.
While the focus of our discussion is the effect of prolactin on women, men with hyperprolactinemia can experience hypogonadotropic hypogonadism with resultant decreased libido, impotence, infertility, gynecomastia, or, rarely, galactorrhea.2
The three Ps – physiological, pharmacologic, pathological
Physiological causes of hyperprolactinemia include rising estradiol during the late follicular phase and into the secretory phase of the menstrual cycle or while taking combined oral contraception, nipple stimulation, pregnancy, lactation, meals, sleep, and stress.
Drugs can interrupt the dopaminergic pathway, thereby elevating serum prolactin but usually not above 100 ng/mL, except for the antipsychotic drug risperidone, which can cause marked elevation up to 300 or even 400 ng/mL. Medications that can cause hyperprolactinemia are estrogens, neuroleptic drugs such as risperidone, metoclopramide, antidepressant drugs, cimetidine, methyldopa, and verapamil.
A pituitary MRI can diagnose an adenoma, that is, a collection of cells in the pituitary that are responsible for hyperprolactinemia and is named based on its size. Microadenomas are less than 1 cm and are typically associated with serum prolactin values below 200 ng/mL. Macroadenomas can worsen while a patient is on combined oral contraception and during pregnancy; fortunately, this is not the case with a microadenoma.
Hypothyroidism can elevate serum prolactin since thyrotropin releasing hormone is known to stimulate prolactin secretion.3 Consequently, when a patient presents with both hypothyroidism and hyperprolactinemia, thyroid replacement should be initiated for thyroid regulation and potential restoration of prolactin levels. If hyperprolactinemia persists, then further evaluation is required. Chronic renal impairment can also elevate prolactin levels due to decreased clearance.
Management
The appropriate evaluation of hyperprolactinemia consists of a history to disclose medications, identify galactorrhea, and visual changes. Because of an adenoma compressing the optic chiasm, partial blindness may occur where vision is lost in the outer half of both the right and left visual field, called bitemporal hemianopsia. Mild elevations in prolactin should be tested at a time when physiological influences are at a minimum, that is, during menses, fasting, and in late morning.4 Persistent elevations should be appropriately evaluated rather than by using the empiric “shotgun” approach of prescribing a dopamine agonist. Laboratory testing for repeated elevations in prolactin includes a pituitary MRI looking for a mass in the hypothalamic-pituitary region that interrupts dopamine suppression.
Treatment of hyperprolactinemia begins with a dopamine agonist and is indicated when there is hypogonadism or intolerable galactorrhea. Cabergoline is the first choice because of effectiveness (reduced adenoma size in greater than 90% of patients) and lesser side effects, particularly nausea, than bromocriptine. Dopamine agonists, such as bromocriptine and cabergoline, belong to the category of ergot-derived dopamine agonists and have been used to treat Parkinson’s disease. At high doses used to treat Parkinson’s, cabergoline is associated with an increased risk of valvular heart disease. In the United States, pergolide was voluntarily withdrawn from the market in March 2007 because of this risk. At the lower doses generally used for the treatment of hyperprolactinemia, cabergoline is probably not associated with excess risk.5
Newer dopamine agonists are known as nonergot. These are pramipexole, ropinirole, rotigotine, and apomorphine. They have not been associated with a risk of heart damage and can be prescribed.
The initial prescribing dose of cabergoline should be 0.25 mg twice a week or 0.5 mg once a week. If bromocriptine is used, the starting dose is 1.25 mg after dinner or at bedtime for 1 week, then increasing to 1.25 mg twice a day (after breakfast and after dinner or at bedtime to reduce nausea and fatigue). After 1 month of a dopamine agonist, the patient should be evaluated for side effects and a serum prolactin level should be obtained. With a normal prolactin level, gonadal function will probably return within a few months. The dopamine agonist should typically be discontinued with pregnancy as pregnancy increases prolactin physiologically.
Treatment of a macroadenoma is essential when the tumor is large enough to cause neurologic symptoms, such as visual impairment or headache, and is preferable when it is invasive or when there are enlarging microadenomas since they are likely to continue to grow and become symptomatic. About 95% of microadenomas have not been shown to increase in size during 4-6 years of observation.6
Transsphenoidal surgery should be considered when there is:
- Persistent hyperprolactinemia and/or size of the adenoma, with associated symptoms or signs despite several months of dopamine agonist treatment at high doses.
- Presence of a giant lactotroph adenoma (e.g., >3 cm) with pregnancy desired including those whose adenoma responds to a dopamine agonist – to avoid significant growth during pregnancy while off medication.
Data from over 6,000 pregnancies suggest that the administration of bromocriptine during the first month of pregnancy does not harm the fetus.7
Discontinuing treatment
Three scenarios may allow for cessation of dopamine agonist therapy. The first is when a patient has had a normal serum prolactin test following 2 years of low-dose dopamine agonist. Another is the patient who had hyperprolactinemia and a microadenoma that responded to treatment with a normal prolactin level and no further evidence of an adenoma by MRI for at least 2 years. Lastly, the patient who had a macroadenoma prior to treatment and a subsequent normal serum prolactin level without an adenoma for at least 2 years.
Like the management of thyroid dysfunction, our field must be aware of prolactin disorders for early detection, prompt referral, and appropriate management to minimize long-term consequences.
Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
References
1. Bayrak A et al. Fertil Steril. 2005 Jul;84(1):181-5.
2. Carter JN et al. N Engl J Med. 1978 Oct 19;299(16):847-52.
3. Sachson R et al. N Engl J Med. 1972;287:972.
4. Singh SP and Singh TP. Ann Endocrinol (Paris). 1984;45(2):137-41.
5. Valassi E et al. J Clin Endocrinol Metab. 2010 Mar;95(3):1025-33.
6. Sisam DA et al. Fertil Steril. 1987 Jul;48(1):67-71.
7. Molitch ME. Best Pract Res Clin Endocrinol Metab. 2011 Dec;25(6):885-96.
Because of the increasing popularity and success of in vitro fertilization, the field of reproductive endocrinology and infertility has steadily morphed toward the treatment of infertility. Nevertheless, a physician board certified in reproductive endocrinology and infertility is the referring physician of choice regarding prolactin disorders and gynecologists should be familiar with the symptoms and sequela of prolactin elevations. This month’s column will address when to obtain a serum prolactin and how to appropriately manage hyperprolactinemia.
Of all the anterior pituitary hormones (adrenocorticotropic hormone, follicle-stimulating hormone, growth hormone, luteinizing hormone, prolactin, thyroid-stimulating hormone ), prolactin is the only one under tonic inhibition by dopamine. Disturbances in this dopaminergic pathway result in elevated serum prolactin. The normal range for prolactin is approximately 5-20 ng/mL.
In the nonpregnant state, little is known regarding the purpose of prolactin, which is produced by the anterior pituitary cluster of cells called lactotrophs. To prepare the breast for postpartum lactation, increases in prolactin are necessary and sustained throughout pregnancy. Second to pregnancy, amenorrhea can occur in 10%-20% of cases of hyperprolactinemia. Outside of pregnancy, elevations in prolactin result in hypogonadism, through gonadotropin-releasing hormone suppression, resulting in infertility (48%), headache (39%), oligomenorrhea (29%) and galactorrhea (24%).1 Most hypogonadal symptoms are more likely to occur with prolactin levels greater than 100 ng/mL, whereas infertility and ovulation dysfunction can occur with mild to moderate hyperprolactinemia, respectively. Prolonged amenorrhea can risk bone mineral density loss.
While the focus of our discussion is the effect of prolactin on women, men with hyperprolactinemia can experience hypogonadotropic hypogonadism with resultant decreased libido, impotence, infertility, gynecomastia, or, rarely, galactorrhea.2
The three Ps – physiological, pharmacologic, pathological
Physiological causes of hyperprolactinemia include rising estradiol during the late follicular phase and into the secretory phase of the menstrual cycle or while taking combined oral contraception, nipple stimulation, pregnancy, lactation, meals, sleep, and stress.
Drugs can interrupt the dopaminergic pathway, thereby elevating serum prolactin but usually not above 100 ng/mL, except for the antipsychotic drug risperidone, which can cause marked elevation up to 300 or even 400 ng/mL. Medications that can cause hyperprolactinemia are estrogens, neuroleptic drugs such as risperidone, metoclopramide, antidepressant drugs, cimetidine, methyldopa, and verapamil.
A pituitary MRI can diagnose an adenoma, that is, a collection of cells in the pituitary that are responsible for hyperprolactinemia and is named based on its size. Microadenomas are less than 1 cm and are typically associated with serum prolactin values below 200 ng/mL. Macroadenomas can worsen while a patient is on combined oral contraception and during pregnancy; fortunately, this is not the case with a microadenoma.
Hypothyroidism can elevate serum prolactin since thyrotropin releasing hormone is known to stimulate prolactin secretion.3 Consequently, when a patient presents with both hypothyroidism and hyperprolactinemia, thyroid replacement should be initiated for thyroid regulation and potential restoration of prolactin levels. If hyperprolactinemia persists, then further evaluation is required. Chronic renal impairment can also elevate prolactin levels due to decreased clearance.
Management
The appropriate evaluation of hyperprolactinemia consists of a history to disclose medications, identify galactorrhea, and visual changes. Because of an adenoma compressing the optic chiasm, partial blindness may occur where vision is lost in the outer half of both the right and left visual field, called bitemporal hemianopsia. Mild elevations in prolactin should be tested at a time when physiological influences are at a minimum, that is, during menses, fasting, and in late morning.4 Persistent elevations should be appropriately evaluated rather than by using the empiric “shotgun” approach of prescribing a dopamine agonist. Laboratory testing for repeated elevations in prolactin includes a pituitary MRI looking for a mass in the hypothalamic-pituitary region that interrupts dopamine suppression.
Treatment of hyperprolactinemia begins with a dopamine agonist and is indicated when there is hypogonadism or intolerable galactorrhea. Cabergoline is the first choice because of effectiveness (reduced adenoma size in greater than 90% of patients) and lesser side effects, particularly nausea, than bromocriptine. Dopamine agonists, such as bromocriptine and cabergoline, belong to the category of ergot-derived dopamine agonists and have been used to treat Parkinson’s disease. At high doses used to treat Parkinson’s, cabergoline is associated with an increased risk of valvular heart disease. In the United States, pergolide was voluntarily withdrawn from the market in March 2007 because of this risk. At the lower doses generally used for the treatment of hyperprolactinemia, cabergoline is probably not associated with excess risk.5
Newer dopamine agonists are known as nonergot. These are pramipexole, ropinirole, rotigotine, and apomorphine. They have not been associated with a risk of heart damage and can be prescribed.
The initial prescribing dose of cabergoline should be 0.25 mg twice a week or 0.5 mg once a week. If bromocriptine is used, the starting dose is 1.25 mg after dinner or at bedtime for 1 week, then increasing to 1.25 mg twice a day (after breakfast and after dinner or at bedtime to reduce nausea and fatigue). After 1 month of a dopamine agonist, the patient should be evaluated for side effects and a serum prolactin level should be obtained. With a normal prolactin level, gonadal function will probably return within a few months. The dopamine agonist should typically be discontinued with pregnancy as pregnancy increases prolactin physiologically.
Treatment of a macroadenoma is essential when the tumor is large enough to cause neurologic symptoms, such as visual impairment or headache, and is preferable when it is invasive or when there are enlarging microadenomas since they are likely to continue to grow and become symptomatic. About 95% of microadenomas have not been shown to increase in size during 4-6 years of observation.6
Transsphenoidal surgery should be considered when there is:
- Persistent hyperprolactinemia and/or size of the adenoma, with associated symptoms or signs despite several months of dopamine agonist treatment at high doses.
- Presence of a giant lactotroph adenoma (e.g., >3 cm) with pregnancy desired including those whose adenoma responds to a dopamine agonist – to avoid significant growth during pregnancy while off medication.
Data from over 6,000 pregnancies suggest that the administration of bromocriptine during the first month of pregnancy does not harm the fetus.7
Discontinuing treatment
Three scenarios may allow for cessation of dopamine agonist therapy. The first is when a patient has had a normal serum prolactin test following 2 years of low-dose dopamine agonist. Another is the patient who had hyperprolactinemia and a microadenoma that responded to treatment with a normal prolactin level and no further evidence of an adenoma by MRI for at least 2 years. Lastly, the patient who had a macroadenoma prior to treatment and a subsequent normal serum prolactin level without an adenoma for at least 2 years.
Like the management of thyroid dysfunction, our field must be aware of prolactin disorders for early detection, prompt referral, and appropriate management to minimize long-term consequences.
Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
References
1. Bayrak A et al. Fertil Steril. 2005 Jul;84(1):181-5.
2. Carter JN et al. N Engl J Med. 1978 Oct 19;299(16):847-52.
3. Sachson R et al. N Engl J Med. 1972;287:972.
4. Singh SP and Singh TP. Ann Endocrinol (Paris). 1984;45(2):137-41.
5. Valassi E et al. J Clin Endocrinol Metab. 2010 Mar;95(3):1025-33.
6. Sisam DA et al. Fertil Steril. 1987 Jul;48(1):67-71.
7. Molitch ME. Best Pract Res Clin Endocrinol Metab. 2011 Dec;25(6):885-96.
