Prolactinoma

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Prolactinoma
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A prolactinoma is a tumor (adenoma) of the pituitary gland that produces the hormone prolactin. It is the most common type of functioning pituitary tumor. [1] Symptoms of prolactinoma are due to abnormally high levels of prolactin in the blood (hyperprolactinemia), or due to pressure of the tumor on surrounding brain tissue and/or the optic nerves. Based on its size, a prolactinoma may be classified as a microprolactinoma (<10mm diameter) or a macroprolactinoma (>10mm diameter).

Contents

Signs and symptoms

The most common symptoms at the time of diagnosis often differ between males and females. Women tend to experience more symptoms related directly to prolactin levels, such as amenorrhea and galactorrhea. By contrast, men frequently exhibit fertility issues and hormonal disruptions, such as a loss of libido, but are also more likely to show signs of the tumor compressing their brain tissue, such as headaches, vision changes, and other symptoms outlined below. [2]

The symptoms due to a prolactinoma are broadly divided into those that are caused by increased prolactin levels or mass effect. Those that are caused by increased prolactin levels are: [2] [3]

Those that are caused by mass effect are: [2]

Infertility

A prolactinoma can cause infertility, temporary or permanent, in both male and female patients. [2] [6] It is one of the most common causes of infertility in women, with some sources estimating as much as 20% of female infertility being caused by hyperprolactinemia. It represents a smaller proportion of male infertility. However, among people who have prolactinomas, males are more likely to experience infertility, as their tumors are often more aggressive and more frequently cause hypogonadism. [6]

Causes

Prolactinoma is most frequently a sporadic tumor, occurring in people without any concrete risk factors or family members with similar conditions. [2] [6] In a minority of cases, genetics predispose the patient to having one or more pituitary gland tumors during their lifetime. Most cases of prolactinoma have no known causes or risk factors. [6]

Pathogenesis

Though most pituitary tumors are sporadic, some genetic syndromes include increased risk for pituitary adenomas including Multiple endocrine neoplasia type 1 (caused by a mutation in the MEN1 gene), multiple endocrine neoplasia type 4 (MEN4 gene), Carney complex, and Familial isolated pituitary adenoma (FIPA). [2] Despite their frequent association with genetic syndromes that cause multiple cancers in affected body tissues, the large majority of prolactinomas are monoclonal in origin (originating from a single cell developing a random mutation), even in cases where the tumor begins producing multiple distinct hormones aside from prolactin. [7] [2]

A micro-prolactinoma usually does not grow to become a macro-prolactinoma, and also does not often become metastatic. As such, it is considered a benign tumor, even if it causes symptoms due to excess prolactin. However, it is still recommended that patients with known microprolactinomas should receive an MRI and visual field assessment every 6 to 12 months, to detect unexpected progression and expansion of the tumor before it becomes an emergency. [2]

Splicing factor 3B1

Among cases of sporadic prolactinoma, in patients with no family history of pituitary tumors, the splicing factor 3B1 gene (SF3B1) has been found as a common causative mutation. This mutation, most commonly a missense mutation replacing a single amino acid, has also been identified in some familial cases of prolactinoma. However, it is more commonly a somatic mutation, occurring later in life in someone who was not born with the mutated gene. This gene is responsible for splicing a wide variety of RNA products inside the cell, and a mutation of it can thus cause the creation of numerous abnormal proteins as RNA templates are produced in unpredictable ways. [8]

Sporadic cases of prolactinoma which are not related to a mutation of SF3B1 remain poorly understood. However, many studies show a link between estrogen and prolactinoma. This is theorized to be related to why prolactinomas are more common in women than men. [8]

Vision problems and headaches

While headaches are a symptom common to any tumor within the cranium, vision problems are especially frequent in pituitary adenomas because the pituitary gland rests over the optic chiasm. As the tumor grows, it begins to compress one or both optic nerves, depending on the size and direction of growth. This is an example of mass effect. As such, smaller tumors which may produce excess prolactin or other hormones may not cause any vision problems, while still having major symptomatic effects on the body. [2] [6]

Other causes of elevated prolactin

The majority of moderately raised prolactin levels (up to 5000 mIU/L) are not due to microprolactinomas but other causes. The effects of some prescription drugs are the most common. Other causes are other pituitary tumours and normal pregnancy and breastfeeding. [9]

Diagnosis

Prolactinoma is often one of the first diagnoses considered by a physician when a patient presents with symptoms of hyperprolactinemia. [8] Specifically, the presence of several of these symptoms in the same person are indicative of elevated prolactin: [10]

If these symptoms occur with the simultaneous presence of mass effects, particularly vision problems or severe neurological symptoms such as seizures or coma, aggressive prolactinoma is highly likely. [6] [8] A patient with these symptoms should immediately undergo MRI to assess the size and extent of the tumor. MRI is also useful in patients with smaller tumors, as it can be used to monitor the tumor for signs of growth, allowing a surgical intervention to be performed before it becomes a medical emergency. [2]

Imaging

All patients with hyperprolactinemia should receive MRI imaging to determine the size and characteristics of the tumor. [2] [8] [10] Prolactinomas have somewhat variable appearance on MRI, most commonly appearing hypointense on T1 weighted MRI, and heterogenous or hyperintense on T2 weighted MRI. If MRI is not available, other imaging techniques may be used if they can examine the region around the sella turcica in sufficient detail. [10] Identification of pituitary tumor on MRI, with accompanying symptoms, is considered a definitive diagnosis of prolactinoma. [8]

Unlike macroprolactinomas which compress the optic nerves, microprolactinomas are usually not large enough to be seen on MRI. However, the addition of gadolinium contrast enhancement can make them much easier to detect. Thus, evaluation of a suspected prolactinoma usually uses this form of contrast enhancement. [8] Notably, this contrast can also visualize a pituitary gland with no disease at all, so precise measurement of the gland's size and shape is essential. [2]

Biochemical testing

Elevated prolactin levels in the patient's serum are indicative of hyperprolactinemia, but are not specific to prolactinoma, meaning that other diseases causing similar symptoms could produce the same test results. Similarly, tests that use dopamine agonists to suppress prolactin production are not able to rule out other diagnoses. [2] As a result, biochemical testing is used only in a supplementary role, and MRI is the only definitive diagnostic tool available. [8] [10] Dopamine agonist testing can, however, be used to determine the effectiveness of DAs like bromocriptine as a potential non-surgical treatment option. [8]

Treatments

The goal of treatment is to return prolactin secretion to normal, reduce tumor size, correct any visual abnormalities, and restore normal pituitary function. The impact of stress should be ruled out before the diagnosis of prolactinoma is given. Exercise can significantly reduce stress and, thereby, prolactin levels. In the case of very large tumors, only partial reduction of the prolactin levels may be possible. [11]

Medications

Dopamine is the chemical that normally inhibits prolactin secretion, so clinicians may treat prolactinoma with drugs that act like dopamine such as bromocriptine and cabergoline. [12] This type of drug is called a dopamine agonist. [12] These drugs shrink the tumor and return prolactin levels to normal in approximately 80% of patients. Both bromocriptine and cabergoline have been approved by the Food and Drug Administration for the treatment of hyperprolactinemia. Bromocriptine is associated with side-effects such as nausea and dizziness and hypotension in patients with already low blood pressure readings. To avoid these side-effects, it is important for bromocriptine treatment to start slowly. [13]

Bromocriptine treatment should not be interrupted without consulting a qualified endocrinologist. Prolactin levels often rise again in most people when the drug is discontinued. In some, however, prolactin levels remain normal, so the doctor may suggest reducing or discontinuing treatment every two years on a trial basis. Recent studies have shown increased success in remission of prolactin levels after discontinuation, in patients having been treated for at least 2 years prior to cessation of bromocriptine treatment. [14]

Cabergoline is also associated with side effects such as nausea and dizziness, but these may be less common and less severe than with bromocriptine. However, people with low blood pressure should use caution when starting cabergoline treatment, as the long half-life of the drug (4–7 days) may inadvertently affect their ability to keep their blood pressure within normal limits, creating intense discomfort, dizziness, and even fainting upon standing and walking until the single first dose clears from their system. As with bromocriptine therapy, side effects may be avoided or minimized if treatment is started slowly. If a patient's prolactin level remains normal for 6 months, a doctor may consider stopping treatment. Cabergoline should not be interrupted without consulting a qualified endocrinologist.[ citation needed ]

Other dopamine agonists that have been used less commonly to suppress prolactin include dihydroergocryptine, ergoloid, lisuride, metergoline, pergolide, quinagolide, and terguride. [12]

Surgery

Surgery should be considered if medical therapy cannot be tolerated or if it fails to reduce prolactin levels, restore normal reproduction and pituitary function, and reduce tumor size. If medical therapy is only partially successful, this therapy should continue, possibly combined with surgery or radiation treatment. [15]

The results of surgery depend a great deal on tumor size and prolactin level. The higher the prolactin level the lower the chance of normalizing serum prolactin. In the best medical centers, surgery corrects prolactin levels in 80% of patients with a serum prolactin less than 250 ng/ml. Even in patients with large tumors that cannot be completely removed, drug therapy may be able to return serum prolactin to the normal range after surgery. Depending on the size of the tumor and how much of it is removed, studies show that 20 to 50% will recur, usually within five years.[ citation needed ]

Prognosis

People with microprolactinoma generally have an excellent prognosis. In 95% of cases, the tumor will not show any signs of growth after a 4 to 6-year period.[ citation needed ]

Macroprolactinomas often require more aggressive treatment otherwise they may continue to grow. There is no way to reliably predict the rate of growth, as it is different for every individual. Regular monitoring by a specialist to detect any major changes in the tumor is recommended.[ citation needed ]

Osteoporosis risk

Hyperprolactinemia can cause reduced estrogen production in women and reduced testosterone production in men. Although estrogen/testosterone production may be restored after treatment for hyperprolactinemia, even a year or two without estrogen/testosterone can compromise bone strength, and patients should protect themselves from osteoporosis by increasing exercise and calcium intake through diet or supplementation, and by avoiding smoking. Patients may want to have bone density measurements to assess the effect of estrogen/testosterone deficiency on bone density. They may also want to discuss testosterone/estrogen replacement therapy with their physician.[ citation needed ]

Pregnancy and oral birth control

If a woman has one or more small prolactinoma, there is no reason that she cannot conceive and have a normal pregnancy after successful medical therapy. The pituitary enlarges and prolactin production increases during normal pregnancy in women without pituitary disorders. Women with prolactin-secreting tumors may experience further pituitary enlargement and must be closely monitored during pregnancy. However, damage to the pituitary or eye nerves occurs in less than one percent of pregnant women with prolactinoma. In women with large tumors, the risk of damage to the pituitary or eye nerves is greater, and some doctors consider it as high as 25%. If a woman has completed a successful pregnancy, the chances of her completing further successful pregnancies are extremely high.[ citation needed ]

A woman with a prolactinoma should discuss her plans to conceive with her physician, so she can be carefully evaluated prior to becoming pregnant. This evaluation will include a magnetic resonance imaging (MRI) scan to assess the size of the tumor and an eye examination with measurement of visual fields. As soon as a patient is pregnant, her doctor will usually advise that she stop taking bromocriptine or cabergoline, the common treatments for prolactinoma. Most endocrinologists see patients every two months throughout the pregnancy. The patient should consult her endocrinologist promptly if she develops symptoms — in particular, headaches, visual changes, nausea, vomiting, excessive thirst or urination, or extreme lethargy. Bromocriptine or cabergoline treatment may be renewed and additional treatment may be required if the patient develops symptoms from growth of the tumor during pregnancy.[ citation needed ]

At one time, oral contraceptives were thought to contribute to the development of prolactinomas. However, this is no longer thought to be true. Patients with prolactinoma treated with bromocriptine or cabergoline may also take oral contraceptives. Likewise, post-menopausal estrogen replacement is safe in patients with prolactinoma treated with medical therapy or surgery.[ citation needed ]

Epidemiology

Autopsy studies indicate that 6-25% of the U. S. population have small pituitary tumors. [16] Forty percent of these pituitary tumors produce prolactin, but most are not considered clinically significant. Clinically significant pituitary tumors affect the health of approximately 14 out of 100,000 people. In non-selective surgical series, this tumor accounts for approximately 25-30% of all pituitary adenomas. [17] Some growth hormone (GH)–producing tumors also co-secrete prolactin. More than 90% of prolactinoma is microprolactinomas, which are much more common than macroprolactinomas. [18]

See also

Related Research Articles

<span class="mw-page-title-main">Prolactin</span> Protein family and hormone

Prolactin (PRL), also known as lactotropin and mammotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pituitary gland in response to eating, mating, estrogen treatment, ovulation and nursing. It is secreted heavily in pulses in between these events. Prolactin plays an essential role in metabolism, regulation of the immune system and pancreatic development.

Amenorrhea or amenorrhoea is the absence of a menstrual period in a female who has reached reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses during childhood and after menopause.

<span class="mw-page-title-main">Hyperprolactinaemia</span> Medical condition

Hyperprolactinaemia also known as Hyperprolactinemia is a condition characterized by abnormally high levels of prolactin in the blood. In women, normal prolactin levels average to about 13 ng/mL, while in men, they average 5 ng/mL. The upper normal limit of serum prolactin is typically between 15 to 25 ng/mL for both genders. Levels exceeding this range indicate hyperprolactinemia.

A prolactin cell is a cell in the anterior pituitary which produces prolactin in response to hormonal signals including dopamine, thyrotropin-releasing hormone and estrogen, which are stimulatory. Prolactin is responsible for actions needed for body homeostasis, the development of breasts, and for lactation. The inhibitory effects of dopamine override the stimulatory effects of TRH in non-pregnant, non-lactating sexually mature females. Depending on the sex of the individual, prolactin cells account for 20% - 50% of all cells in the anterior pituitary gland. The inhibitory effects of dopamine override the stimulatory effects of TRH in non-pregnant, non-lactating sexually mature females. Other regulators include oxytocin and progesterone.

Anovulation is when the ovaries do not release an oocyte during a menstrual cycle. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause. Chronic anovulation is a common cause of infertility.

<span class="mw-page-title-main">Hypopituitarism</span> Medical condition

Hypopituitarism is the decreased (hypo) secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. If there is decreased secretion of one specific pituitary hormone, the condition is known as selective hypopituitarism. If there is decreased secretion of most or all pituitary hormones, the term panhypopituitarism is used.

<span class="mw-page-title-main">Pituitary adenoma</span> Tumor of the pituitary gland

Pituitary adenomas are tumors that occur in the pituitary gland. Most pituitary tumors are benign, approximately 35% are invasive and just 0.1% to 0.2% are carcinomas. Pituitary adenomas represent from 10% to 25% of all intracranial neoplasms and the estimated prevalence rate in the general population is approximately 17%.

Galactorrhea or lactorrhea is the spontaneous flow of milk from the breast, unassociated with childbirth or nursing.

<span class="mw-page-title-main">Pickardt syndrome</span> Rare form of tertiary hypothyroidism

Pickardt syndrome denotes a rare form of tertiary hypothyroidism that is caused by interruption of the portal veins connecting hypothalamus and pituitary.It was characterized in 1972 and 1973 by Renate Pickardt and Rudolf Fahlbusch.

Witch's milk or neonatal milk is milk secreted from the breasts of some newborn human infants of either sex. Production of neonatal milk by infants usually resolves itself and does not require treatment unless it is caused by an underlying condition or medications. It is thought to be caused by the exposure to an elevated level of estrogen to infants during pregnancy or decreased exposure of estrogen to infants after birth. Its production also may be caused by certain medications. The composition of neonatal milk is similar to maternal milk for most of their components except for fats and one type of antibody.

<span class="mw-page-title-main">Cabergoline</span> Chemical compound

Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levels, prolactinomas, Parkinson's disease, and for other indications. It is taken by mouth.

<span class="mw-page-title-main">Dopamine agonist</span> Compound that activates dopamine receptors

A dopamine agonist is a compound that activates dopamine receptors. There are two families of dopamine receptors, D1-like and D2-like. They are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the D2-like family includes D2, D3 and D4 receptors. Dopamine agonists are primarily used in the treatment of the motor symptoms of Parkinson's disease, and to a lesser extent, in hyperprolactinemia and restless legs syndrome. They are also used off-label in the treatment of clinical depression. Impulse control disorders are associated with the use of dopamine agonists for whatever condition.

<span class="mw-page-title-main">Hyperpituitarism</span> Medical condition

Hyperpituitarism is a condition due to the primary hypersecretion of pituitary hormones; it typically results from a pituitary adenoma. In children with hyperpituitarism, disruption of growth regulation is rare, either because of hormone hypersecretion or because of manifestations caused by local compression of the adenoma.

Pituitary apoplexy is bleeding into or impaired blood supply of the pituitary gland. This usually occurs in the presence of a tumor of the pituitary, although in 80% of cases this has not been diagnosed previously. The most common initial symptom is a sudden headache, often associated with a rapidly worsening visual field defect or double vision caused by compression of nerves surrounding the gland. This is often followed by acute symptoms caused by lack of secretion of essential hormones, predominantly adrenal insufficiency.

<span class="mw-page-title-main">Acromegaly</span> Human disease that results in excess growth of certain parts of the body

Acromegaly is a disorder that results in excess growth of certain parts of the human body. It is caused by excess growth hormone (GH) after the growth plates have closed. The initial symptom is typically enlargement of the hands and feet. There may also be an enlargement of the forehead, jaw, and nose. Other symptoms may include joint pain, thicker skin, deepening of the voice, headaches, and problems with vision. Complications of the disease may include type 2 diabetes, sleep apnea, and high blood pressure.

Galactorrhea hyperprolactinemia is increased blood prolactin levels associated with galactorrhea. It may be caused by such things as certain medications, pituitary disorders and thyroid disorders. The condition can occur in males as well as females. Relatively common etiologies include prolactinoma, medication effect, kidney failure, granulomatous diseases of the pituitary gland, and disorders which interfere with the hypothalamic inhibition of prolactin release. Ectopic (non-pituitary) production of prolactin may also occur. Galactorrhea hyperprolactinemia is listed as a “rare disease” by the Office of Rare Diseases of the National Institutes of Health. This means that it affects less than 200,000 people in the United States population.

Hypogonadotropic hypogonadism (HH), is due to problems with either the hypothalamus or pituitary gland affecting the hypothalamic-pituitary-gonadal axis. Hypothalamic disorders result from a deficiency in the release of gonadotropic releasing hormone (GnRH), while pituitary gland disorders are due to a deficiency in the release of gonadotropins from the anterior pituitary. GnRH is the central regulator in reproductive function and sexual development via the HPG axis. GnRH is released by GnRH neurons, which are hypothalamic neuroendocrine cells, into the hypophyseal portal system acting on gonadotrophs in the anterior pituitary. The release of gonadotropins, LH and FSH, act on the gonads for the development and maintenance of proper adult reproductive physiology. LH acts on Leydig cells in the male testes and theca cells in the female. FSH acts on Sertoli cells in the male and follicular cells in the female. Combined this causes the secretion of gonadal sex steroids and the initiation of folliculogenesis and spermatogenesis. The production of sex steroids forms a negative feedback loop acting on both the anterior pituitary and hypothalamus causing a pulsatile secretion of GnRH. GnRH neurons lack sex steroid receptors and mediators such as kisspeptin stimulate GnRH neurons for pulsatile secretion of GnRH.

<span class="mw-page-title-main">Prolactin modulator</span> Drug class

A prolactin modulator is a drug which affects the hypothalamic–pituitary–prolactin axis by modulating the secretion of the pituitary hormone prolactin from the anterior pituitary gland. Prolactin inhibitors suppress and prolactin releasers induce the secretion of prolactin, respectively.

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Female fertility agents are medications that improve female’s ability to conceive pregnancy. These agents are prescribed for infertile female who fails to conceive pregnancy after 1-year of regular and unprotected sexual intercourse. The following will cover the advancements of female fertility agents, major causes of female infertility. Next, it emphasizes on common female fertility agents in terms of their mechanism of action, side effects, fetal consideration and clinical application and ended up by the introduction of supplements and herbal medicines for female infertility.

References

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  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 Melmed, Shlomo; Jameson, J. Larry (2022). "Chapter 380: Pituitary Tumor Syndromes". Harrison's Principles of Internal Medicine (21st ed.). New York: McGraw Hill. ISBN   978-1264268504.
  3. ↑ "Prolactinoma - PubMed Health". Ncbi.nlm.nih.gov. Retrieved 2012-05-28.
  4. ↑ "Gynecomastia". The Lecturio Medical Concept Library. September 2020. Retrieved 24 July 2021.
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  7. ↑ Ma, Wenbin; Ikeda, Hidetoshi; Yoshimoto, Takashi (2002-07-15). "Clinicopathologic study of 123 cases of prolactin-secreting pituitary adenomas with special reference to multihormone production and clonality of the adenomas". Cancer. 95 (2): 258–266. doi:10.1002/cncr.10676. ISSN   0008-543X. PMID   12124824.
  8. 1 2 3 4 5 6 7 8 9 Fukuhara, Noriaki; Nishiyama, Mitsuru; Iwasaki, Yasumasa (2022-07-24). "Update in Pathogenesis, Diagnosis, and Therapy of Prolactinoma". Cancers. 14 (15): 3604. doi: 10.3390/cancers14153604 . ISSN   2072-6694. PMC   9331865 . PMID   35892862.
  9. ↑ Mancini T, Casanueva FF, Giustina A (March 2008). "Hyperprolactinemia and prolactinomas". Endocrinology and Metabolism Clinics of North America. 37 (1): 67–99, viii. doi:10.1016/j.ecl.2007.10.013. PMID   18226731.
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  11. ↑ "Prolactinoma". National Institute Of Diabetes And Digestive And Kidney Diseases. Retrieved 24 July 2021.
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  13. ↑ "Prolactinoma". National Institute Of Diabetes And Digestive And Kidney Diseases. Retrieved 24 July 2021.
  14. ↑ Bronstein MD (March 2006). "Potential for long-term remission of microprolactinoma after withdrawal of dopamine-agonist therapy". Nat Clin Pract Endocrinol Metab. 2 (3): 130–1. doi:10.1038/ncpendmet0135. PMID   16932269. S2CID   10873443.
  15. ↑ "Prolactinoma". National Institute Of Diabetes And Digestive And Kidney Diseases. Retrieved 24 July 2021.
  16. ↑ McDowell BD, Wallace RB, Carnahan RM, Chrischilles EA, Lynch CF, Schlechte JA (March 2011). "Demographic differences in incidence for pituitary adenoma". Pituitary. 14 (1): 23–30. doi:10.1007/s11102-010-0253-4. PMC   3652258 . PMID   20809113.
  17. ↑ Gandhi, Chirag D.; Post, Kalmon D. (2003-01-01). "PrL-Secreting Pituitary Adenomas". BC Decker.{{cite journal}}: Cite journal requires |journal= (help)
  18. ↑ "Macroprolactinoma: a diagnostic and therapeutic update". academic.oup.com. 2013-01-16. p. 495-504. Retrieved 2022-11-04.
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