Advances in nursing care for hyperprolactinemia

Excessive PRL forms feedback to the hypothalamus and organizes the release of gonadotropin-releasing hormone (GnRH), inhibiting the secretion of pituitary follicle-stimulating hormone (FSH) and luteinizing hormone (LH), causing them to reduce or lose their secretion rhythm. FSH and LH secretion peaks cannot appear in the middle of the menstrual cycle. Insufficient FSH secretion leads to incomplete development of ovarian follicles, and then ovulation disorders occur. In severe cases, the ability to ovulate can be completely lost. After ovulation, patients with hyperprolactinemia can inhibit the production of progesterone by granulosa cells due to high PRL levels, resulting in luteal insufficiency and increasing the risk of early miscarriage. On the other hand, excessive PRL levels reduce the ovarian response to FSH and LH, and women experience low estrogen status, which manifests as low libido or dyspareunia, and men have sexual dysfunction and semen abnormalities.

2 Causes

2.1 Increased sources of PRL

Prolactin adenoma is the most common cause of hyperprolactinemia. Prolactin levels > 250 ng/mL often indicate an adenoma ≥ 1 cm. Adrenal adenoma and ectopic cancer (such as bronchial carcinoma, renal cancer) may also have elevated PRL.

2.2 Idiopathic PRL increase

After excluding drugs, hypothyroidism, renal insufficiency, and polycystic ovary syndrome, MRI examination of patients can diagnose idiopathic HPRL if no pituitary or parasellar tumors are found. However, some scholars believe that some patients with idiopathic HPRL may have prolactin microadenomas with a tumor diameter of less than 3 mm, but they cannot be found due to the low resolution of MRI.

2.3 Decreased prolactin secretion inhibitory factor leads to excessive PRL secretion

Enlarged tumors (craniopharyngioma, glioma, etc.), empty sella syndrome, meningitis, craniocerebral trauma, brain radiotherapy, etc. can all affect the secretion and transmission of prolactin-inhibiting factor (PIF), thereby causing an increase in PRL.

2.4 Endocrine disorders

When renal insufficiency, liver cirrhosis and other conditions affect the stability of the systemic endocrine system, PRL will increase. When primary thyroid function is low, TRH secretion increases to stimulate the secretion of thyrotropin and prolactin cells in the anterior pituitary. Polycystic ovary syndrome increases the sensitivity of prolactin cells through the stimulation of estrogen. In patients with polycystic ovary syndrome, those with hyperprolactinemia have more obvious insulin resistance, which should be paid attention to.

2.5 Reflex PRL elevation

Hypothalamic dysfunction, chest wall trauma, surgery, burns, herpes zoster, etc.

3 Clinical manifestations

About 85% of patients experience irregular menstruation, and 69% experience galactorrhea, which is collectively called amenorrhea-galactorrhea syndrome. Women may suffer from infertility and early pregnancy miscarriage due to ovulation disorders or corpus luteum insufficiency. Some patients may experience reduced vaginal discharge and decreased libido due to low estrogen levels in the body. Men may experience oligospermia, lack of libido or impotence, osteoporosis, and low muscle mass.

Patients with prolactin microadenomas generally have no obvious symptoms, while macroadenomas can cause headaches, vomiting, dizziness, and even visual field loss due to compression of other brain tissues in the sella turcica. Giant invasive prolactin adenomas are extremely rare, and bleeding is occasionally seen as the first symptom, which is easy to misdiagnose in clinical work.

4 Treatment according to etiology

4.1 Idiopathic HPRL

For idiopathic hyperprolactinemia with only a slight increase in PRL and no obvious clinical symptoms (regular menstruation, normal ovulation, no galactorrhea and no impact on normal life), no treatment is required, and regular follow-up should be performed to observe clinical manifestations and changes in PRL. For patients with more obvious clinical symptoms, long-term medication is not necessary. Generally, medication should be stopped after one year to observe the PRL situation and then treated. Thirty percent of idiopathic HPRL patients can return to normal prolactin levels on their own after a few years. A small number of patients will develop pituitary tumors after 10 to 20 years, so long-term follow-up should be paid attention to for patients with idiopathic HPRL.

4.2 Prolactinoma

Adenoma volume <10mm is microadenoma, 10~40mm is macroadenoma, and >40mm is giant adenoma. Patients with prolactin adenoma should take medication for a long time, which can cause some adenomas to shrink, degenerate or stop growing. In the long-term follow-up of patients with prolactin microadenomas, it was found that 90% to 95% of the tumor size did not progress, so controlling the tumor size is not the treatment goal but should focus more on the patient's clinical manifestations. For prolactin microadenomas with mild clinical symptoms and no infertility, follow-up observation of clinical manifestations and PRL changes can be selected; for prolactin microadenomas with obvious clinical symptoms, after two consecutive years of dopamine receptor agonist treatment, prolactin levels remain normal, and MRI shows only tiny residual tumors, consider stopping drug treatment. However, the recurrence rate after discontinuation of medication is very high, and MRI follow-up is required.

4.3 Women with HPRL who are planning to become pregnant or are pregnant

Patients who want to have children should wait until the PRL level is stable for a period of time before trying to get pregnant. For patients with prolactin macroadenomas, especially women who have not yet given birth, Qin Fuchuang and others do not recommend the routine use of dopamine receptor agonists. Surgical treatment is beneficial to the recovery of gonadal axis function and improves the patient's endocrine level. In the past, it was believed that surgical treatment itself would cause pituitary function damage, but for experienced surgeons, it is generally not the case unless the pituitary function is already damaged before surgery. Active observation should be carried out after surgery to reduce complications. Complications mainly include hypothalamic dysfunction syndrome and anterior pituitary insufficiency syndrome. After the use of dopamine receptor agonists after surgery until the PRL level is stable, they are encouraged to actively prepare for pregnancy.

For those who cannot successfully ovulate and become pregnant with dopamine receptor agonists alone, dopamine receptor agonists should be used as the main agent in combination with other ovulation-inducing drugs. Ovulation-inducing drugs can be clomiphene citrate, human menopausal gonadotropin (HMG), etc. Wang Huiyu conducted a clinical drug control study on such patients with fertility requirements and found that compared with the simultaneous use of bromocriptine and ovulation-inducing drugs, the effect of bromocriptine treatment first and then ovulation-inducing treatment after the prolactin level returns to normal is more ideal.

Melmed et al. believe that if the pre-pregnancy tumor is less than 1 cm, the drug should be discontinued during pregnancy because the tumor is unlikely to progress; if the pre-pregnancy tumor is larger than 1 cm, dopamine receptor agonists should continue to be used during pregnancy to prevent tumor expansion. In the past, there was controversy over whether to use dopamine receptor agonists during pregnancy. Auriemma et al. analyzed the data of 143 HPRL women who used dopamine receptor agonists during pregnancy from 1997 to 2008 and found that the use of cabergoline during pregnancy did not increase the miscarriage rate and fetal malformation rate. Moreover, 68% of patients' conception was associated with normal serum prolactin levels. Breastfeeding during lactation does not increase the recurrence rate of HPRL. Stalldecke et al. also believed that no increase in adverse outcomes was found in exposure to cabergoline during pregnancy, but believed that this conclusion requires a large sample study to ensure its safety.

Macroprolactinoma during pregnancy does not increase pregnancy complications, but the risk is higher if it increases in size during pregnancy. Monitoring should still be strengthened during pregnancy, and the visual field should be checked regularly (20, 28, and 38 weeks of pregnancy). If there are abnormalities such as headaches and visual field defects, MRI examinations should be performed in time. Dopamine receptor agonists should be added if the headache is progressive and cannot be relieved. Surgical resection should be performed if drug treatment cannot relieve it.

4.4 Macroprolactinemia

There are three forms of PRL in human blood: monomeric PRL, large PRL and macroprolactin (M-PRL). M-PRL cannot bind to target cells through the capillary wall due to its large relative molecular weight (15,000-17,000), and thus cannot exert biological effects. Most patients with M-PRLemia do not have amenorrhea and galactorrhea syndrome and can give birth normally. If M-PRLemia is not considered, all patients with hyperprolactinemia will be treated, which may lead to excessive suppression of monomeric PRL in patients with M-PRLemia, thereby causing luteal insufficiency. In clinical work, routine PRL level measurement in patients with M-PRLemia is easily confused with high monomeric PRLemia, so M-PRL needs to be measured separately.

5. Selection and use of dopamine receptor agonists

5.1 Bromocriptine (trade name: Bromocriptine)

Non-specific dopamine receptor agonist. Some patients taking the drug orally may experience adverse reactions such as nausea, vomiting, dizziness, and postural hypotension. The dosage should be increased gradually from a small dose to an effective maintenance dose. For patients who cannot tolerate oral administration, vaginal administration can be chosen. 97% to 99% of the drug can be absorbed through the vagina and avoid liver metabolism, thus significantly reducing adverse reactions.

5.2 Cabergoline (trade name: Nogoline)

Selective dopamine D2 receptor agonist. It is stronger than bromocriptine in terms of the effects of inhibiting PRL and restoring gonadal function and drug tolerance. In an international multicenter study, the efficacy of cabergoline and bromocriptine was compared in 459 women with HPRL. The first 8 weeks were double-blind studies, and the next 16 weeks were open studies. The dose was adjusted at any time according to needs. Results: 83% of the cabergoline group and 85% of the bromocriptine group had normal PRL values ​​(P<0.01), 72% and 52% of the ovulation and pregnancy were restored (P<0.01), 68% and 78% of the patients complained of side effects (P=0.03), and the frequency of nausea was 31% and 50% respectively (P<0.01). However, due to its high price (cabergoline is about 0.3mg/d, 250 yuan/mg; bromocriptine is about 2.5mg/d, 1.5 yuan/mg), it is not widely used.

6Surgery and radiotherapy

Surgical treatment should be considered for patients with prolactinoma who have obvious visual impairment, are intolerant to or ineffective with drug treatment, and strongly request surgery. Distinguishing normal tissue from adenoma tissue during surgery is the key to successful surgery. Qin Fuchuang et al. [9] found in clinical surgery that adenomas that were not treated with drugs before surgery were light red or grayish white and soft in texture. After drug treatment, adenomas in patients became fibrotic and tough, while normal pituitary tissue was yellow and tough. In addition, long-term medication may increase the toughness of the tumor, making surgery difficult and leading to tumor residue. Therefore, in clinical work, the timing of medication should be weighed according to the fertility requirements of prolactinoma patients, the volume of the adenoma, and whether there is invasive space occupation to determine the timing of surgery.

Radiotherapy is generally not used alone, but is often used for patients with residual tumors after surgical treatment, large invasive tumors, or as an adjuvant treatment for patients who cannot tolerate surgery. However, it may induce other tumors or damage peripheral nerves.

7 Conclusion

Hyperprolactinemia should be treated individually according to its different causes. For patients with mild clinical symptoms and no impact on the quality of life, treatment can be expected, but regular follow-up is required. For patients with prolactinoma, medication or surgical treatment should be selected according to the size of the adenoma and symptoms of brain tissue compression, and the correct timing of surgery should be grasped. Patients who are allowed to undergo drug treatment should regularly test prolactin levels to adjust the dosage. Those who cannot tolerate or have excessive side effects can try vaginal medication. Patients with hyperprolactinemia during pregnancy can choose whether to take medication based on prolactin levels. There is no evidence that the use of dopamine receptor agonists during pregnancy will increase the miscarriage rate or fetal malformations. Patients with prolactinomas ≥10 mm during pregnancy should take medication to prevent adenoma expansion during pregnancy.