Neurogenic hyperprolactinemia

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Hyperprolactinemia refers to the most widely-spread pituitary-hypothalamic endocrine disorders. An increased prolactin level can be a symptom of diseases of various origin. The pathology prevalence rates vary considerably in different populations. Thus, in Belarus the hyperprolactinemia prevalence rate is 24.06 people per 100,000 of population, and among the patients with pituitary adenoma – 45.47 people per 100,000. In women of reproductive age tumors syn-thetizing prolactin are found 10 times more frequently than in men [1]. In total population of Japanese the abovementioned pathology is 0.4%, and among those under the care of family planning clinic this value reaches 5% [2]. Hyperprolactinemia is responsible for a quarter of cases of secondary amenorrhea, which can result in women’s infertility [3]. Hyperprolactinemia in infertile women amounts to 30-40% of cases [4]. Polycystic ovarian syndrome, pituitary adenoma, medicamentous hyperprolactinemia and infertility were the most widely spread causes of hyperprolactinemia when tested in India [5].

Neurogenic hyperprolactinemia progresses during the stimulation of afferent nerves in the chest region and is quite rare [2]. This results in the necessity to carefully revise this pathology to avoid the incorrect diagnosis when detecting the increased prolactin content in the blood serum.

Prolactin secretion

The main purpose of prolactin is to prepare the mammary gland tissue for lactation during pregnancy. The prolactin secretion by anterior pituitary gland complies with circadian rhythms and is under the inhibitory action of hypothalamus due to one or several prolactin-inhibitory factors (PIF) penetrating the pituitary gland via the pituitary-hypothalamic portal vessels. Dopamine is synthesized in hypothalamus arcuate nucleus and serves as the main physiological PIF acting upon the dopamine D2- and D4-recep-tors on the surface membranes of lactroph cells. The disorder of dopamine transport to lactroph receptors or medicamentous blocking of endogenic dopamine result in moderate increase in prolactin synthesis.

Thyrotropin-releasing hormone, vasoactive intestinal peptide, estrogen and oxytocin can stimulate prolactin production. The increased hormone concentrations are observed during ovulation. The monomeric prolactin with the molecular mass of 23 kDa is the prevailing form, while the dimeric one (45-60 kDa) and macroprolactin (150-170 kDa, complex of IgG and monomeric prolactin) cover less than 20% of the whole prolactin [2, 6]. The prolactin receptor is a single membrane-bound protein of the superfamily of cytokine receptors and is structurally and functionally similar to the growth hormone receptor. It is expressed in a pituitary gland, as well as in a mammary gland, ovary, endometrium, heart, lungs, thymus, spleen, liver, pancreas gland, kidneys, adrenal glands, skeletal muscles, brain, skin, osteoblasts [7, 8]. It has been recently demonstrated that prolactin can be produced by the central nerve system, adipose tissues, immune system tissues, mammary glands and prostatic gland [9].

Prolactin effects

High prolactin levels are connected with the deteriorated progress of metabolic diseases. Prolactin increase during pregnancy and lactation contributes to satisfying metabolic needs during the pregnancy [10, 11]. Prolactin stimulates the appetite, leads to the gained weight, increased leptin and insulin resistance: this results in the increased glucose content in the blood necessary for embryo development [10, 12-16]. The indicated effects help maintaining homeostasis in the system “mother-fetus”. Regardless of its origin cause, the increased prolactin content is connected with such pathologies as obesity, insulin resistance, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), endothelial dysfunction [11, 17, 18]. High prolactin levels can increase the breast cancer formation risk in women and resistance to endocrine therapy [19]. Hyperprolactinemia in women can be the cause of infertility due to the decreased kiss-peptin production and suppression of pulsatile ejection of gonadotropin-releasing hormone (GRH), which induces the production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Kiss-peptin introduction can be used to regain GRH synthesis at infertility with hyperprolactinemia [20, 21].

The bone mass is lost secondarily in relation to the decreased content of sex hormones mediated by hyperprolactinemia. The spinal column density decreas- es by 25% in women and is not always restored after the prolactin level normalization [22].

Possible causes of hyperprolactinemia

The causes of hyperprolactinemia are mainly divided into physiological, pharmacological and pathological (Table 1) [2].

Table 1. Causes of hyperprolactinemia

CAUSES

Physiological

Pregnancy, lactation, stress, sleep, coitus, physical exercises

Pathological

Systemic diseases – primary hypothyroidism, adrenal insufficiency, polycystic ovarian syndrome, renal insufficiency, liver cirrhosis, pseudocyesis, epileptic attacks

Hypothalamus diseases – tumors (craniopharyngiomas, dysgerminomas, meningiomas, etc.), infiltrative disorders (histiocytosis, sarcoidosis, etc.), metastasizing, scull irradiation, Rathke’s pocket cysts, etc.

Pituitary gland diseases – prolactinomas, acromegaly, thyro-tropinomas, Cushing disease, infiltrative disorders, metastasizing, lymphocytic hypophysitis, empty sella syndrome, etc.

Stalk disorder – gastritis, craniocerebral trauma

Neurogenic prolactinomas – chest damage (burns, chest surgeries, thoracotomy, nipple trauma), spinal damage (cervical ependymoma, spinal disease, external tumors), breast stimulation, etc.

Idiopathic

Prolactin ectopic production – renal cell carcinoma, ovary teratomas, gonadoblastomas, non-Hodgkin’s lymphoma, cervical cancer, colorectal adenocarcinoma, etc.

Macroprolactinemia induced by medications

Neuroleptic agents – phenothiazines, butyrophenones, thioxanthenes, risperidone, molindone, amilsupride, quetiapine, olanzapine

Antidepressants – tricyclic (amitriptyline, desipramine, clomipramine), MAO-inhibitors (pargyline, chlorgyline), selective serotonin reuptake inhibitors (fluoxetine, citalopram, paroxetine)

Antihypertensive medications – verapamil, а-methyldopa, reserpine, labetalol

Antispasmodic medications – phenytoin

Pro-kinetic agents – metoclorpramide, domperidone

Other groups – estrogens, anesthetics, cimetidine, opiates, methadone, morphine, apomorphine, heroin, cocaine, marijuana, alcohol, sibutramine, etc.

The most frequent cause of hyperprolactinemia is prolactinoma originating from lactotroph cells of anterior pituitary gland: they constitute about 40% of all chromophobe adenomas. 90% of such tumors are microadenomas, the rest (> 1 сm in diameter) are macroadenomas [9]. Not only the prolactin level detection (threshold is >250 ng/ml) is used to diagnose the prolactinoma but also its ratio to the tumor volume. At the same time, even a relatively low prolactin content can indicate prolactin-juvenile tumors [23, 24, 25]. Taking into account the hyperprolactinemia progress pathogenesis, the dopamine agonists (bromocriptine, cabergoline, chinagolidum) are successfully used in the treatment process [3].

Neurogenic hyperprolactinemia

Breast feeding and breast sexual stimulation result in reflexive prolactin release conditioned by the excitation of spinal cord afferent nerves. The same mechanism is realized after traumas, injuries, chest integrity damage (mastectomy, thoracotomy, herpes zoster, burns, etc.), spinal cord integrity damage (cervical ependymoma, syringomyelia, spinal disease, external tumors) and after nipple piercing, although the latter is not always confirmed as a causative factor [2, 26].

Hyperprolactinemia after the chest burns has a neurogenic nature since burn wounds are sensitive to touching and the pathological stimulation of sucking reflex takes place. The nerve impulses proceed further along the intercostal nerves to the spinal column posterior segment and then upwards – to hypothalamus where the dopamine release is suppressed. M. Van Heerden et al. described the clinical case of a 28-year-old woman who suffered chest (and mammary glands) burns as a result of domestic abuse. The patient was hospitalized for the first time in May 2018: she underwent the skin transplantation and was dismissed for ambulatory treatment. In September of the same year she was hospitalized again for the sepsis and the starting transplant rejection: the patient was treated with antibiotics, rebandaged. The wound sepsis caused the third hospitalization in February 2019, high prolactin content was detected in the blood (3537 mcg/l, reference interval – 4.8-23.3 mcg/l), galactorrhea was observed. After macroprolactin exclusion, the monomeric prolactin content was 249.5 mcg/l. The prescription of a wide range of laboratory-instrumental diagnostic procedures (including head MRT) allowed excluding all common causes of galactorrhea and hyperprolactinemia. The prolactin level was successfully decreased with the help of pharmacological therapy comprising dopamine agonists, and the patient was dismissed without prescription of any medications [27]. The cases of galactorrhea were also reported in 3 months after the dismissal from the burn unit and good response to the therapy. Despite the treatment, hypertrophic scars and callosities can develop in patients. The time of hyperprolactinemia development correlates with the time of collagen deposition and scar deformation/compression [28].

The chest irritation with infection caused by herpes-zoster virus (HZV) is one of the reasons of neurogenic hyperprolactinemia development. This problem can be especially urgent in the elderly age when HZV infection is often activated [29]. Anorgasmia developed on the background of hyperprolactinemia and any other sexual dysfunction of elderly people can influence their mental health and enhance depression and anxiety. The mechanism contributing to HZV infection possible cause of hyperprolactinemia consists in the irritation of intercostal nerves leading to prolactin release. Sarah Moslehi et al. described the clinical case of a 98-year-old patient with evident hyperprolactinemia on the background of extreme depression. The patient took in mirtazapine due to bad mood that did not improve her mental health. Sleeplessness, loss of appetite, inability to relax due to constant strain were observed. Few weeks before the specialist examination, the patient got herpes zoster. Besides, she complained of anorgasmia during self-stimulation that initiated the depression and anxiety. The stress brought the woman to suicide attempt in the form of intentional overdose of pills and stabbing herself. After that she was taken to psychiatric hospital. The prescription of antidepressants did not produce the desired effect. The search for organic reasons of the available disorders allowed revealing the increased prolactin level (1068 ml/u) that was considered as the cause of anorgasmia and enhanced hair growth on the face. Besides, the patient complained of the chest pain typical for herpes zoster exacerbation. Lactorrhea and engorgement of mammary glands were not observed. The laboratory markers of the functions of liver, kidneys, thyroid gland and general blood analysis were within the age-appropriate norm. The brain MRT did not reveal any pathologies. During the examination, the erythematous rash spreading onto the nipples was observed on the chest skin. The patient was assigned aripiprazole, an antipsychotic drug, which does not significantly increase the prolactin level. The clinicians came to the conclusion that hyperprolactinemia in the patient was secondary in relation to HZV infection, which was accompanied by gross lesion of the breast right part and spread onto the nipple. After the herpetic infection remission the prolactin level became normal and anorgasmia disappeared [30].

A similar mechanism of hyperprolactinemia development is engaged at chest trauma. Four cases of galactorrhea, hyperprolactinemia and amenorrhea in four women accompanied by spinal cord damage and chest paraplegia were reported in one publication. Galactorrhea was developed within 1-6 months after the trauma. After a short period of therapy three women refused from the treatment despite the preserved galactorrhea. One woman had galactorrhea for over 2 years [31].

Studying the profile of a 76-year-old man with the spinal cord trauma, M.R. Safarinejad demonstrated the decreased levels of LH, FSH and testosterone in the blood serum of such patients. 5 patients with the damage level Т8-Т11 had hyperprolactinemia. Besides, patients with damage level Т8-Т11 demonstrated the highest frequency of hormonal disorders, while at damage level Т12-L5 it was the lowest. Thus, it was demonstrated that a spinal cord trauma is accompanied by the change in the neutrotransmitter tonus and the probability of hypogonadism and hyperprolactinemia development is higher at low thoracic damage [32].

The increased prolactin level and galactorrhea can be induced by a breast surgery, including implant installation and reduction mammoplasty [33]. The breast implant installation results in neurogenic stimulation of prolactin secretion. A breast-enlarging surgery refers to the most popular plastic surgery. The registered cases of transitory hyperprolactinemia and galactorrhea after such surgeries are reported. The increased prolactin level can be preserved within 2 years after the surgery without any additional causes. Both retromuscular and retroglandular implant location resulted in the increased monomeric prolactin concentration in the blood [34]. 34 cases connected with mammoplasty are considered in the literature review by J. Bouhassira et al. Hyperprolactinemia was detected in 60% of women during the examination in the post-surgical period. In the average, galactorrhea developed after 12.6 days. Galactocele was detected in 65% of patients during UST [35]. Galactorrhea and hyperprolactinemia stable to bromocriptine treatment can develop in women with mammary implants. In such case, only the removal of implants results in the elimination of undesirable phenomena [36].

O. Mestak et al. described the clinical case of a 46-year-old woman who underwent the reduction mammoplasty. The patient was admitted to the plastic surgery unit with the diagnosis “macromastia”. In the past medical history – puerperal mastitis, allergy to nitrofurantoin, smoking. The breast was reduced by the method of rotation and bulging of areola on upper lateral peduncle placing the areola edges within 22 cm from the sternal notch. The breast was reduced by 470 g on the right and 400 g on the left, the areolas were bulged out by 8 and 9 cm on the right and left, respectively. Rendon’s drains were installed in the end of the surgery. The patient was prescribed 1 g of oxacillin each 12 hours within 7 days. Mastopathy with lobular hyperplasia was revealed during the histologic examination. There were no incipient post-surgical complications. The patient was dismissed in 7 days, however, the darkened areolas without feeding indications were observed in 14 days after the surgery. Dry necrosis of both areolas was further developed. The increased ESR was detected in the patient after 3 weeks, although there was no fever. Both areolas were removed in 4 weeks after the surgery when the breast became hard and painful. Hyperprolactinemia (67.9 mg) and galactorrhea were developed in the patient after 6 weeks. The authors expressed the idea that the stimulation of intercostal nerves initiates the excitation of the hypothalamic center controlling the lactation ways engaged in the puerperal period. Other laboratory indices were normal. The Turkish saddle X-ray photograph, UST and MRT of mammary glands did not demonstrate any deviations. 2.5 mg of bromocriptine 2 times a day were prescribed. After 4 months the prolactin concentration normalized and galactorrhea finished in 5 months after the surgery. The areolomammillary complex was reconstructed in 1 year after the first surgery [37]. According to the authors, the post-surgical stress could result in the increased prolactin and cortisol levels, and the elevated cortisol level increased the sensitivity of mammary glands’ cells to prolactin.

We could not find publications describing typical examples of syringomyelia complicated by hyperprolactinemia. Nevertheless, S. van Uum et al. described the case of the patient with post-surgical chromophobic adenoma and syringomyelia with very high prolactin levels in the blood associated in several years. A 50-year-old woman was hospitalized in 2000 with operated chromophobic adenoma complaining of pains and sensitivity disorder in the legs. 30 years before that she had undergone the transcranial surgery on the pituitary gland with the subfrontal approach regarding the chromophobic adenoma. The prolactin level was initially measured in 1974 and was 180 mg/l (the norm upper limit is 20 mg/l). In 1978 the eye disorder emerged and the second transcranial surgery on the pituitary gland was conducted resulting in hypopituitarism. The patient was assigned the replacement therapy, including bromocriptine 5 mg/day, however, the prolactin level remained increased. The brain and spinal cord MRT in 1993 did not reveal anomalies of the sellar area, however, it detected multiple small areas of increased density around the medulla oblongata and spinal cord, as well as between the cerebellum and peduncle of the brain. These changes were attributed to lipidol, which was used during the previous myelo-graphic investigations. As there were no complaints, the bromocriptine intake was stopped that resulted in the prolactin level increase from 650 mg/l up to 1280 mg/l. In 1998 the patient started to feel numbness and strain in the fourth and fifth fingers of the left foot. Additional symptoms emerged and progressed in 1999: pain in the left infrascapular region, feeling of cold from the waist down with leg tingling, spontaneous jerking motions of the legs, urination disorder with urge urinary incontinence. The patient took in cortisone acetate 37.5 mg/day, levothyroxine 0.05 mg/ day and the combination of estradiol and norgestrel. The prolactin level increased up to 7858 mg/l. Hypes-thesia below Т9 level and knee and ankle hyporeflexia were observed, Romberg’s test result was positive. In general, the symptomatology reflected the spinal cord lesion at the middle thoracic level. Further examination (MRT, cerebral spinal fluid analysis, etc.) allowed revealing the thoracic syringomyelia at the level Т7-Т8, as well as the vast leptomeningeal lesion (prolactinoma metastases) slightly constricting the brain stem. The occipital cervical decompression and salvage procedures were conducted. The patient took in 0.5 mg of carbegoline 2 times a day. After a month the prolactin level was below 300 mg/l, then it reached normal values, which were registered during the whole monitoring period (26 months). In this case, the main contribution to the prolactin high level in the blood serum was made by prolactin but the worsening effect of the thoracic spine syringomyelia activating the neurogenic way of prolactin level increase cannot be excluded [38].

Cases of hyperprolactinemia association with nipple piercing were described as early as in the beginning of 2000-s [39, 40]. One publication described the clinical picture of a 22-year-old man with two-sided nipple piercing and left-sided mastitis developed after that. When the prolactin level reached 40.3 ng/ml, the rings were removed. The patient took in antibiotics. The prolactin level decreased gradually to 5.6 ng/ml, however, the left breast enlargement was preserved. After some time, the patient underwent the aesthetic reduction surgery on the left breast. In the course of histological examination, the fibroepithelial nonma-lignant focus was detected [39]. In another publication a 20-year-old woman hospitalized with the breast pain and two-sided purulent discharge from the nipples in three weeks after the piercing was described. The infectious manifestations were eliminated after the cephalexin course. Nevertheless, after two weeks the woman was hospitalized again with two-sided spontaneous galactorrhea. The prolactin level was 218 mcg/l, the urinary test result for pregnancy was negative. The prolactin level normalized after the rings were removed [40]. It should be noted that in both cases the nipples inflamed that could produce an additional irritating effect and trigger the neurogenic mechanism of prolactin level increase. Later, G. Sun et al. demonstrated that when there is no accompanying infection during the nipple piercing, the prolactin content in the blood serum does not exceed normal values [26].

Conclusion

Cases describing neurogenic hyperprolactinemia are insufficiently presented in domestic and foreign publications. The reason for this consists, on the one hand, in their rare distribution in the population, including patients with hyperprolactinemia, and, on the other hand, in the lack of understanding the pathogenetic mechanisms of this pathology realization. As demonstrated in the above examples, these mechanisms activate the afferent impulses proceeding to the thoracic spine and which, going up to hypothalamus, block the release of dopamine suppressing the prolactin synthesis. The prolactin level increases due to the inhibitory action decrease. According to this mechanism, the majority of pathological processes in the chest wall affecting mammary glands can result in hyperprolactinemia. The diagnostics of the considered group of diseases is based, first of all, on the exclusion of the most widely-spread clinical options leading to the increased prolactin level. The life record data and revealing of the pathological focus in the chest and/ or spinal cord are extremely important. Neurogenic hyperprolactinemia is successfully eliminated by prescribing dopamine agonists, as well as by the main disease treatment.

Conclusions:

• 1.    The irritation of nerve endings of nipples, intercostal nerves, spinal pathology can serve as a trigger mechanism of neurogenic hyperprolactinemia.

• 2.    The neurogenic hyperprolactinemia diagnostics is based on excluding the most common causes of prolactin level increase, revealing pathology in the chest wall region, defining the prolactin level in the blood serum.

• 3.    The main treatment of neurogenic hyperprolactinemia is connected with the causative factor elimination and prescription of dopamine agonists.