bubble_chart Overview

Hyperprolactinemia (HPRL) refers to a syndrome caused by internal and external environmental factors, characterized by elevated PRL levels (≥25 ng/ml), amenorrhea, milk regurgitation, anovulation, and infertility. Over the past two decades, significant progress has been made in the study of PRL's physiological generation and transformation. Advances in PRL radioimmunoassays, cranial CT, and MRI diagnostic techniques have improved the diagnosis of HPRL, with its incidence also showing an increasing trend. Meanwhile, the introduction of the prolactin-inhibiting drug bromocriptine (Bromocriptine, Parlodel) and the development of transsphenoidal microsurgery have brought new prospects to the diagnosis and treatment of HPRL.

bubble_chart Etiology

The pulsatile release of PRL and its circadian rhythm play an important regulatory role in mammary gland development, lactation, and ovarian function. PRL secretion is dually regulated by hypothalamic PRL-RH and PRL-IH. During a normal ovulatory menstruation cycle, PRL is consistently under the tonic inhibitory regulation of CNS hypothalamic dopaminergic neurotransmitters and PRL-IH. Once this regulatory balance is disrupted, HPRL occurs. HPRL can be caused by physiological or pathological factors.

I. Physiological hyperprolactinemia

(1) Nighttime and sleep (2–6 AM).

(2) Late follicular phase and luteal phase.

(3) Pregnancy: Levels increase ≥10 times compared to non-pregnant states.

(4) Lactation: Acute, short-term, or sustained increases in secretion due to massage or nipple suckling.

(5) Puerperium: 3–4 weeks.

(6) Hypoglycemia.

(7) Exercise and stress stimuli.

(8) Sexual intercourse: Markedly elevated during orgasm.

(9) Fetus and neonate (≥28 gestational weeks to 2–3 weeks postpartum).

II. Pathological hyperprolactinemia

(1) Hypothalamic-pituitary disorders

1. Tumors:

Non-functional—craniopharyngioma, sarcoid-like disease (sarcoid), glioma.

Functional—PRL adenoma 46%; GH adenoma 22–31%. PRL-GH adenoma 5–7%; ACTH adenoma & Nelson's syndrome 4–15%. Multihormonal adenoma 10%; undifferentiated tumor 19–27%.

2. Inflammation: Basal meningitis, subcutaneous nodule, syphilis, actinomycosis.

3. Destruction: Injury, surgery, arteriovenous malformation, granulomatosis (Hand-Schüller-Christian syndrome).

4. Empty sella syndrome.

5. Pituitary stalk disorders, injury, or tumor compression.

6. Psychological trauma and stress.

7. Parkinson’s disease.

(2) Primary and/or secondary hypothyroidism.

1. Pseudohypoparathyroidism.

2. Hashimoto’s thyroiditis.

(3) Ectopic PRL secretion syndrome: Undifferentiated bronchogenic lung cancer, adrenal carcinoma, embryonal carcinoma.

(4) Adrenal and kidney diseases: Addison’s disease, chronic renal failure.

(5) Polycystic ovary syndrome.

(6) Liver cirrhosis.

(7) Gynecological and obstetric surgeries: Artificial late abortion, induced labor, dead fetus, hysterectomy, tubal ligation, oophorectomy.

(8) Local stimulation: Nipple inflammation, rhagades, chest wall trauma, herpes zoster, subcutaneous nodule, surgery.

(9) Iatrogenic-drug factors:

1. Insulin-induced hypoglycemia.

2. Sex hormones (estrogen-progestin contraceptives).

3. Synthetic TSH-RH.

4. Anesthetics: Morphine, methadone, methionine enkephalin.

5. Dopamine receptor blockers: Phenothiazines, haloperidol, metoclopramide, domperidone, pimozide, sulpiride.

6. Dopamine reuptake blockers: Nomifensine.

7. CNS dopamine degraders: Reserpine, alpha-methyldopa.

8. Dopamine conversion inhibitors: Apomorphine.

9. Monoamine oxidase inhibitors.

10. Diphenyl nitrogen derivatives: dibenzoxazole nitrogen, carbamoyl nitrogen, iminodibenzyl, imipramine, amitriptyline, phenytoin, diazepam, and clonazepam.

11. Histamine and histamine H₁, H₂ receptor antagonists: serotonin, amphetamines, hallucinogens, H₁ receptor antagonists (meclizine, pyribenzamine), H₂ receptor antagonists (cimetidine).

(10) Idiopathic.

bubble_chart Pathological Changes

1. Tumor-induced hyperprolactinemia
2. Postpartum hyperprolactinemia
3. Idiopathic hyperprolactinemia
4. Iatrogenic hyperprolactinemia

bubble_chart Clinical Manifestations

1. Menstrual disorders: Primary amenorrhea 4%, secondary amenorrhea 89%, scanty or infrequent menstruation 7%. Dysfunctional uterine bleeding and luteal phase defects 23-77%.
2. Milk regurgitation: Typical HPRL manifests as amenorrhea-galactorrhea syndrome, occurring in 20.84% of non-tumor cases and 70.58% of tumor cases. Simple milk regurgitation occurs in 63-83.55% of cases. Milk regurgitation may be spontaneous or expressed upon breast compression, appearing watery, serous, or milky. Breasts are mostly normal, though some may present with lobular hyperplasia or macromastia.
3. Infertility: 70.71% primary or secondary, caused by anovulation, luteal phase defects, or luteinized unruptured follicle syndrome (LUFS).

bubble_chart Auxiliary Examination

(1) Sella Turcica Tomography: The normal anteroposterior diameter of the sella turcica in women is <17mm，深度<13mm、面積<130mm², and the volume is <1100mm³. CT should be performed if the following signs are observed: ① Ballooning enlargement; ② Double floors or duplicated sellar floor; ③ High/low-density areas or heterogeneous density within the sella; ④ Saucer-like pattern; ⑤ Hyperostosis or calcification above the sella; ⑥ Osteoporosis of the anterior or posterior clinoid processes or vacuolar changes within the sella; ⑦ Bone erosion.

(2) Computed Tomography (CT) and Magnetic Resonance Imaging (MRI): Precise localization and radiological measurement of intracranial lesions.

(3) Contrast Imaging: Includes intercavernous sinus venography, pneumoencephalography, and vasoencephalography.

Ophthalmic Examination: Includes visual acuity, visual field, intraocular pressure, and fundus examination to determine whether there are signs of intracranial tumor compression.

bubble_chart Diagnosis

1. Medical History

Focus on understanding the history of menstruation, marital and reproductive history, the initial causes and triggers of amenorrhea and milk regurgitation, systemic diseases, and the history of medication related to HPRL.

2. Physical Examination

Conduct a general physical examination. Pay attention to signs such as acromegaly and myxedema. Gynecological examination should assess for atrophy of sexual organs and signs, as well as organic sexually transmitted diseases. Breast examination should note size, shape, the presence of lumps, inflammation, and milk regurgitation (by gently squeezing the breasts with both hands). Observe the characteristics and quantity of any discharge.

3. Endocrine Function Tests

(1) Pituitary function: FSH and LH are decreased, while the LH/FSH ratio is increased. PRL is elevated (≥25 ng/ml). It is generally considered <100ng/ml多為功能性。≧100mg/ml應注意排除PRL腺瘤。腫瘤越大PRL越高。如腫瘤直徑d≦5mm，PRL為171±38ng/ml；d=5～10mm 206±29ng/ml；≧10mm485±158ng/ml。巨大腺瘤出血壞死時PRL可不升高。

that it should be noted: currently, clinical PRL radioassay kits only measure small-molecule PRL (MW 25,000) and cannot detect large/very large-molecule PRL (MW 50,000–100,000). Therefore, in cases with obvious clinical symptoms but normal PRL levels, so-called occult hyperprolactinemia—i.e., large/very large-molecule hyperprolactinemia—cannot be ruled out.

(2) Ovarian function tests: E₂, P are decreased, and T is increased.

(3) Thyroid function tests: In cases of HPRL combined with hypothyroidism, TSH is elevated, while T₃, T₄, and PBI are decreased.

(4) Adrenal function tests: In cases of HPEL combined with Cushing’s syndrome and virilization, T, △⁴dione, DHT, DHEA, and 17KS are elevated, and plasma cortisol is increased.

(5) Pancreatic function tests: In cases of HPRL combined with diabetes or acromegaly, insulin, blood glucose, glucagon, and glucose tolerance tests should be performed.

4. Prolactin Function Tests

(1) Prolactin Stimulation Tests

1. Thyrotropin-releasing hormone test (TRH test): In normal women, a single intravenous injection of 100–400 μg TRH results in a 5–10-fold increase in PRL and a 2-fold increase in TSH within 15–30 minutes. No increase is observed in cases of pituitary tumors.

2. Chlorpromazine test: Chlorpromazine, through receptor mechanisms, inhibits norepinephrine uptake and dopamine conversion, promoting PRL secretion. In normal women, intramuscular injection of 25–50 mg leads to a 1–2-fold increase in blood PRL within 60–90 minutes, lasting for 3 hours. No increase is observed in cases of pituitary tumors.

3. Metoclopramide test: This drug is a dopamine receptor antagonist that promotes PRL synthesis and release. In normal women, intravenous injection of 10 mg results in a ≥3-fold increase in PRL within 30–60 minutes. No increase is observed in cases of pituitary tumors.

(2) Prolactin Suppression Tests

1. L-Dopa test: This drug is a dopamine precursor that generates DA via decarboxylase, inhibiting PRL secretion. In normal women, oral administration of 500 mg leads to a significant decrease in PRL within 2–3 hours. No decrease is observed in cases of pituitary tumors.

2. Bromocriptine test: This drug is a dopamine receptor agonist that strongly inhibits the synthesis and release of PRL. In normal women, oral administration of 2.5–5.0 mm results in a ≥50% reduction in PRL within 2–4 hours, lasting for 20–30 hours. Functional HPRL and PRL adenomas show significant decreases, while the reductions in GH and ACTH are less pronounced compared to the former two.

bubble_chart Treatment Measures

1. Treatment of Causes and Primary Diseases

For example, eliminating adverse mental stimuli, discontinuing medications that cause HPRL, and actively treating primary diseases such as pituitary tumors, hypothyroidism, Cushing's syndrome, etc.

2. Anti-Prolactin—Bromocriptine Therapy

Bromocriptine is a semi-synthetic ergot alkaloid derivative and a dopamine receptor agonist. It promotes the synthesis and secretion of PRL-IH and inhibits PRL synthesis and release through receptor mechanisms. It also directly acts on pituitary tumors and PRL cells to suppress tumor growth and inhibit the secretion of PRL, GH, TSH, and ACTH.

Bromocriptine therapy is suitable for all types of HPRL and is the first-line treatment for pituitary adenomas (micro/macro adenomas), especially for young infertility patients desiring pregnancy. The dose is 2.5–7.5 mg/d, administered orally. Other anti-prolactin drugs include L-Dopa, CV205-502, and vitamin B₆, etc. For details, refer to the "Anti-Prolactin" section in the endocrine therapy chapter.

3. Ovulation Induction Therapy

This is suitable for HPRL, anovulatory infertility, and cases where bromocriptine alone fails to induce ovulation and pregnancy. It involves a comprehensive approach primarily using bromocriptine in combination with other ovulation-inducing drugs: ① Bromocriptine-CC-hCG; ② Bromocriptine-hMG-hCG; ③ GnRH pulse therapy combined with bromocriptine, etc. The combined therapy can reduce the dosage of anti-prolactin drugs, shorten the treatment cycle, and improve ovulation and pregnancy rates.

4. Surgical Therapy

This is suitable for macro adenomas with compressive symptoms, drug-resistant tumors, cases where bromocriptine therapy is ineffective, and tumors secreting multiple pituitary hormones (e.g., chromophobe adenomas).

Current trans-sphenoidal microsurgery is safe, convenient, and effective, with outcomes comparable to bromocriptine therapy. Combining bromocriptine before and after surgery can enhance efficacy. The drawbacks of surgery include: difficulty in complete resection or injury due to the lack of a clear tumor capsule or boundaries, potentially leading to cerebrospinal fluid rhinorrhea and secondary hypopituitarism.

5. Radiotherapy

This is suitable for non-functional tumors of the hypothalamic-pituitary system and cases where drug and surgical treatments are ineffective. Radiotherapy methods include deep X-ray, ⁶⁰Co, α-particle, and proton radiation. Other options include isotope implantation (e.g., ⁹⁰Yttrium or ¹⁹⁸Gold) into the pituitary gland.

bubble_chart Complications

1. Low estrogen response: Seen in cases of prolonged amenorrhea, such as hot flashes, palpitation, spontaneous sweating, vaginal dryness, dyspareunia, decreased libido, etc.
2. Changes in vision and visual field: Occurs when pituitary tumors affect the optic chiasm, leading to decreased vision, headache, dizziness, hemianopia, and blindness, as well as functional impairment of cranial nerves II, III, and IV. Fundus edema and exudation may also be present.
3. High androgen response: Grade II obesity, seborrhea, acne, and hirsutism.
4. Acromegaly: Seen in PRL-GH adenomas when GH levels are elevated.
5. Myxedema: Occurs when combined with hypothyroidism.
6. Diabetes and abnormal glucose tolerance test results.