Clinical cases: hyperprolactinemia in men and women at different periods of life. Who should be treated, with what and for how long?

Prolactin has other functions:

• The hormone helps women overcome excessive stress during breastfeeding;
• Increases insulin synthesis in the pancreas, thereby participating in the absorption of nutrients;
• Regulates the immune system, allowing the fetus to develop in the uterine cavity without rejection reactions and inflammation;
• Provides achievement of orgasm.

During lactation, prolactin levels increase, and this is a normal condition. If the hormone exceeds normal levels in other periods not associated with childbirth, we are talking about the development of pathology. In this case, you need to consult a doctor, undergo an examination and begin timely therapy. The consequence of hyperprolactinemia in women is frigidity and infertility, in men - impotence and infertility. This is due to the active participation of prolactin in the functioning of the reproductive system. These are just some of the possible complications of this pathological condition.

At CELT you can consult an endocrinologist.

• Initial consultation – 3,500
• Repeated consultation – 2,300

Make an appointment

Prevention

To avoid the development of pathology, it is necessary to eliminate factors that contribute to an increase in prolactin production.

If it is necessary to use drug therapy, especially psychotropic drugs, you should pay close attention to their side effects.

The choice of oral contraceptives should always be made by a doctor based on the results of the examination.

In order to promptly diagnose possible relapses, patients with hyperprolactinemia need to be observed by a specialist.

Etiology of hyperprolactinemia

The following diseases lead to an increase in prolactin:

• Pathologies of the hypothalamus (tumors, infections, injuries);
• Diseases of the pituitary gland (tumors, “empty sella” syndrome);
• Hypothyroidism (decreased functionality of the thyroid gland);
• Use of medications (antidepressants, contraceptives, antiemetics and other substances);
• Uterine fibroids and polycystic ovary syndrome;
• Cirrhosis of the liver;
• Renal failure, chronic form;
• Various injuries to the chest, including herpes viral infection.

In addition, there are causes of hyperprolactinemia that are not associated with diseases - stress and excessive physical activity. These factors can lead to a physiological increase in hormone levels.

PsyAndNeuro.ru

Hyperprolactinemia (HPRL), an increase in serum prolactin levels, is one of the most common side effects associated with antipsychotic therapy. Most often, HPRL develops when taking “typical” antipsychotics, as well as some “second generation” antipsychotics, such as paliperidone, risperidone and amisulpride [1]. GPRL is found in 30-70% of patients taking them continuously [2], and up to 80% in those taking these drugs short-term (especially in young people) [3].

Elevated prolactin levels over many years of treatment can lead to the development of osteoporosis, low estrogen levels, increased risk of cardiovascular disease, and possibly increased risk of breast and endometrial cancer [4]. In addition to harming health, HPPD can increase stigma by causing sexual dysfunction or gynecomastia in men, which also significantly affects adherence to therapy [5].

Prolactin is a polypeptide hormone secreted by lactotrophic cells of the anterior pituitary gland according to circadian rhythms. The maximum level of prolactin is achieved after 4 hours of night sleep, and the minimum level is reached 6 hours after waking up [6]. Circulating prolactin levels are the result of a complex balance of stimulatory and inhibitory factors mediated by various neurotransmitters and hormones that directly or indirectly affect lactotroph cells. The main function of these cells is to initiate the secretion of breast milk, and the most important physiological stimuli for the secretion of prolactin are breastfeeding, increased estrogen levels, sleep, sexual intercourse and stress.

Prolactin secretion is inhibited by dopamine, secreted by tuberoinfundibular neurons, when binding to D2 receptors in the membranes of lactotroph cells. Antipsychotics that block dopamine D2 receptors interfere with the natural action of dopamine, causing prolactin levels to increase [4]. Other factors such as GABA, somatostatin, acetylcholine and norepinephrine also have an inhibitory effect on prolactin secretion, although it is much weaker than that of dopamine.

Normal prolactin levels are considered to be less than 530 mU/L for women and less than 430 mU/L for men. There are three degrees of severity of elevated prolactin levels: mild - less than 1000 mU/L, moderate - from 1000 to 1600 mU/L and severe - more than 1600 mU/L [7].

The severity of HPLC correlates with the fact that the degree of hypogondism is proportional to the increased level of prolactin. The most common non-physiological cause of HPPD is the use of medications, among which antipsychotics occupy a leading position.

As mentioned at the beginning of the article, the most common causes of HPPD are risperidone, paliperidone, amisulpiride, as well as most “first” generation antipsychotics (especially haloperidol and fluphenazine) [1, 8]. In contrast, other “atypical” antipsychotics, such as aripiprazole, asenapine, clozapine, quetiapine and ziprasidone, are most beneficial in increasing serum prolactin levels [9].

Clinical manifestations of GRPD induced by antipsychotic therapy are the same as in mentally healthy people with GRPD. It is not always possible to diagnose symptoms of HPLC in the short term, because they become obvious only some time after the start of treatment. Often patients themselves do not report their complaints, for example, with sexual dysfunctions, for fear of misunderstanding.

In women, high levels of prolactin in the blood often cause hyperestrogenism with anovulatory infertility and menstrual irregularities. Thus, some women experience changes in menstrual flow, and menstruation itself may become irregular, even disappearing completely (amenorrhea). Women who are not pregnant or breastfeeding may begin to leak breast milk - galactorrhea. The prevalence of galactorrhea in patients with schizophrenia receiving antipsychotic therapy is estimated to range from 10% to 50%. Galactorrhea is more common in premenopausal women than in men and in postmenopausal women. Breast pain is also a common symptom, especially when prolactin levels first begin to rise, as prolactin promotes tissue changes in the mammary glands (galactorrhea and gynecomastia are a consequence of prolactin's proliferative effects on epithelial cells). Some women may lose libido (interest in sex), and intercourse itself may become painful due to dryness of the vaginal mucosa [4].

In men, the most common symptoms of HPPD are decreased libido, sexual dysfunction, erectile dysfunction, infertility and gynecomastia. Gynecomastia has been found in men taking risperidone with normal prolactin levels, indicating prolactin receptor hypersensitivity [10]. Because men don't have a reliable indicator like menstruation to signal a problem, many men with HPLC wait a long time to see a doctor. Men also often fail to recognize the gradual loss of their sexual function or libido. Only after treatment do some men realize that they had a problem with sexual function [4].

In the long term, HPLC can lead to the development of osteoporosis, low estrogen levels, increased risk of cardiovascular disease, and possibly increased risk of breast and endometrial cancer [4].

There is limited evidence that HPRL directly affects lipid and carbohydrate metabolism [11]. An association between HPLC and dyslipidemia has been described; Prolactin receptors are expressed in adipose tissue, where prolactin reduces lipoprotein lipase activity and inhibits adiponectin secretion, leading to insulin resistance.

A recent study of a female population without psychiatric diagnoses suggests that HPPD has a direct negative impact on cognitive function [12], which may occur due to low levels of gonadal steroids. It was also noted that in men, low testosterone levels were associated with poorer memory and visuospatial ability [13].

Most professional endocrinology communities agree that a single blood test to determine prolactin levels is sufficient to make a diagnosis, provided that the venipuncture site has not been previously injured [14]. The blood sampling process can be performed at any time during the day, with the patient lying down an hour after waking up or eating.

If the initial test results show high prolactin levels, it is necessary to exclude the secondary nature of HPLC due to high levels of circulating macroprolactin

(large prolactin molecules, usually formed by the combination of prolactin and IgG antibodies, or glycosylation of monomeric prolactin), which can lead to the picture of pseudoprolactinemia. This phenomenon occurs in 20-40% of patients with HPLC.

If macroprolactin has been excluded as a cause and HPRL has been confirmed, it is necessary to stop taking the antipsychotic for 72 hours, or replace it with another drug that does not cause a rise in prolactin and is similar in effectiveness for the patient. Then the blood test for prolactin must be repeated. If HPRL persists or cannot be alleviated by drug withdrawal, MRI or high-precision CT of the pituitary gland is recommended to exclude prolactinoma [4].

For the early detection of hyperprolactinemia and associated symptoms, a number of recommendations have been proposed that should be considered when working with patients requiring long-term antipsychotic treatment.

1. It is necessary to collect a detailed primary history. The doctor should pay attention to the history of osteoporosis, breast cancer, prolactinoma in the patient and his relatives, information about the menstrual cycle and the desire to become pregnant in women, and also evaluate the presence of galactorrhea or gynecomastia.
2. The patient should be informed about the manifestations of HPLC after it has been diagnosed through laboratory testing.
3. It is important to systematically determine prolactin levels in all patients taking antipsychotic therapy (before starting therapy and after 3 months of treatment, as well as after 3 months from increasing the dose).
4. If the patient has already been previously diagnosed with HPLC, then it is necessary to evaluate the status of gonadal hormones by determining the basal levels of luteinizing and follicle-stimulating hormones, as well as testosterone with prolactin, to exclude hypogonadism.
5. Carefully identify the clinical symptoms of HPLC, especially in those patients who will not complain themselves.
6. If HPLC has been detected in patients who have been on antipsychotic therapy for more than 5 years, bone density testing should be performed to assess the risk of osteoporosis [4].

The approach to treatment of HPLC depends on the severity of clinical manifestations

and their impact on the patient's life. The advantages and disadvantages of continuing the same treatment or initiating a new therapeutic strategy must be carefully weighed.

In the case of mild (less than 1000 mU/L) or moderate (1000 to 1600 mU/L) HPLC with clinical manifestations, a therapeutic intervention adapted to each specific case is required. For example, reducing the dose (primarily), changing the antipsychotic, or adding a drug with the ability to lower prolactin levels (aripiprazole).

In cases of severe HPLC (more than 1600 mU/L), therapeutic intervention is always required, even if there are no clinical manifestations, due to the risk of developing osteoporosis, cardiovascular disease, and possibly breast or endometrial cancer in the medium and long term [4].

In modern clinical recommendations for the management of patients with HPLC caused by antipsychotic therapy, scientists and doctors do not consider the use of drugs with a prolactin-inhibiting effect as the first choice method, but do not deny this possibility in cases where other methods of correction are ineffective [15, 16]. For this purpose, dopamine agonists are used in endocrinological practice: bromocriptine - 2.5-7.5 mg per day, in 2-3 doses, cabergoline - 0.5-1 mg per week, in 2 doses [16].

In this connection, leading Russian experts in the field of endocrinological psychiatry, taking into account the difficulties in selecting antipsychotic therapy and the reluctance at times to change an effective antipsychotic, propose the following algorithm of actions [16]:

1) Reducing the dose of antipsychotic;

2) Prescribing cabergoline or bromocriptine;

3) Use of another antipsychotic, in particular quetiapine;

To an endocrinologist in your city, or to a specialist in endocrinological psychiatry:

Gorobets Lyudmila Nikolaevna

— Doctor of Medical Sciences, Professor, Head of the Department of Psychiatric Endocrinology of the National Medical Research Center for PN named after. V.P. Serbsky (Moscow)

Mazo Galina Elevna

— Doctor of Medical Sciences, Chief Researcher, Head of the Department of Endocrinological Psychiatry of the National Medical Research Center for Psychiatry named after V.M. Bekhtereva (St. Petersburg).

Prepared by: Kasyanov E.D.

Sources:

1 – Bushe C, Shaw M, Peveler R. A review of the association between antipsychotic use and hyperprolactinaemia. J Psychopharmacol. 2008;22:46-55

2- Cookson J, Hodgson R, Hiram JW. Prolactin, hyperprolactinaemia and antipsychotic treatment: a review and lessons for treatment of early psychosis. J Psychopharmacol. 2012;26:42-51.

3 – Laita P, Cifuentes A, Doll A, Llorente C, Cortés I, Parellada M, et al. Antipsychotic-related abnormal involuntary movements and metabolic and endocrine side effects in children and adolescents. J Child Adolesc Psychopharmacol. 2007;17:487-502.

4 – Angel L. Montejoa, Celso Arango et. al. Spanish consensus on the risks and detection of antipsychotic drug-related hyperprolactinaemiaia. Rev Psiquiatr Salud Ment (Barc.). 2016;9(3):158-173

5 – DiBonaventura M, Gabriel S, Dupclay. A patient perspective of the impact of medication side effects on adherence: results of a cross-sectional national survey of patients with schizophrenia. BMC Psychiatry. 2012;12:20.

6 – Frantz AG. Prolactin. N Engl J Med. 1978;298:201-7

7 – Serri O, Chik CL, Ur E. Diagnosis and management of hyperprolactinemia. CMAJ. 2003;169:575-81.

8 – Rao VA, Bishop M, Coppen A. Clinical state, plasma levels of haloperidol and prolactin: a correlation study in chronic schizophrenia. Br J Psychiatry. 1980;137:518–21.

9 -Svestka J, Synek O, Tomanová J. Differences in the effect of second-generation antipsychotics on prolactinaemia: 6 weeks open-label trial in female in-patients. Neuro Endocrinol Lett. 2007;28:881-8.

10 – Pratheesh PJ, Praharaj SK, Srivastava A. Euprolactinemic gynecomastia and galactorrhea with risperidone—fluvoxamine combination. Psychopharmacol Bull. 2011;44:70—3.

11 – Ben-Jonathan N, Hugo ER, Brandebourg TD, LaPensee CR. Focus on prolactin as a metabolic hormone. Trends in endocrinology and metabolism. TEM. 2006;17:110-6.

12 – Henry JF, Sherwin BB. Hormones and cognitive functioning during late pregnancy and postpartum: a longitudinal study. Behav Neurosci. 2012;126:73-85

13 – Pinsky M, Hellstrom W. Hypogonadism, ADAM, and hormone replacement. Ther Adv Urol. 2010;2:99-104

14 – Melmed S, Casanueva FF, Hoffman RA, Kleinberg LD, Montori MV, Schlechte AJ, et al., Endocrine Society. Diagnosis and treatment of hyperprolactinemia: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:273-88.

15 – Peveler RC, Branford D., Citrome L. et al. Antipsychotics and hyperprolactinaemia: clinical recommendations // J. Psychopharmacol.—2008.—Vol. 22.—R. 98-103.

16 – Gorobets L.N., Mazo G.E. Drug correction of neuroleptic hyperprolactinemia. Review of psychiatry and medical psychology named after V.M. Bekhterev | №2, 2017

Hyperprolactinemia Clinic

There are certain signs, the presence of which indicates hyperprolactinemia. Knowing about them, you can independently suspect pathology. You should consult a doctor if the following symptoms appear:

• Delayed menstruation (in case of pathology in women);
• The appearance of milk in the mammary glands (both women and men);
• Acne;
• Frigidity;
• Decreased interest in sexual life;
• Psycho-emotional disorders;
• Increase in the size of the mammary glands (in both sexes);
• Decreased testosterone in the blood (in men);
• Excessive hair growth (in women);
• Excess body weight.

The most obvious sign of an increase in hormone levels is the appearance of milk in the mammary glands, provided that you are not pregnant or breastfeeding. It is necessary to consult a doctor so that he can either diagnose the pathology immediately or give a referral for examination to clarify the diagnosis.

Pathogenesis

Excessive levels of prolactin in the blood through a negative feedback mechanism suppresses the secretion of GnRH in the hypothalamus, which leads to a decrease in the production of luteinizing and follicle-stimulating hormones. As a result, deficiency of sex hormones develops, hypoplasia of the external genitalia (hypogonadism), active proliferation of the secretory apparatus of the mammary gland, increased lactogenesis and lactation (galactorrhea), especially in women.

Long-lasting hyperprolactinemia stimulates bone resorption processes, which reduces its mineral density (osteoporosis). Leptin resistance, adiponectin deficiency and hypogonadism contribute to the deposition of fat in subcutaneous fat and an increase in the content of cholesterol fractions in the serum. There is moderate hyperproduction of androgens in the reticular zone of the adrenal cortex.

Diagnostics

Diagnosis of hyperprolactinemia implies, first of all, a thorough history taking, in particular, questioning about current or previous drug therapy.

Laboratory diagnosis includes determining the level of the hormone prolactin in the blood. Venous blood is taken in the morning, always on an empty stomach. The optimal period of time during which blood should be collected is days 5-8 of the menstrual cycle. If the concentration of the hormone is higher than normal, the doctor will prescribe three blood samples to make sure there is a pathological increase in prolactin.

A decrease in thyroid hormone levels may be one of the causes of hyperprolactinemia. Computed tomography of the brain with a targeted examination of the sella turcica shows the condition of the pituitary gland. Magnetic resonance imaging of the brain also allows one to evaluate the anatomical and physiological features of the hypothalamic-pituitary system. If you consult a doctor in a timely manner, hyperprolactenemia and associated complications can be treated. Therefore, it is important to monitor your well-being, do not hesitate to visit a doctor when the first signs of the disease appear, and follow all the recommendations of a specialist in diagnosis and treatment.

Treatment

The treatment regimen is developed individually, based on the results of the examination, taking into account the woman’s desire to restore fertility. Medication, surgery, and radiation therapy may be used.

Conservative therapy

As a first step in treating drug-induced hyperprolactinemia, it is recommended to discontinue the drug if clinically possible. Otherwise, the drug should be replaced with a similar one that does not cause hyperprolactinemia.

As a rule, drugs aimed at reducing prolactin production are used to treat hyperprolactinemia. Cabergoline is currently recognized as the drug of choice.

Often, the use of medications helps not only to reduce prolactin, but also to reduce the volume of the pituitary tumor in patients with micro- and macroadenomas. Since conservative therapy is often sufficient, surgical treatment is not required in the vast majority of cases.

The duration of treatment may vary. Sometimes it is possible to achieve positive results only after several years. The effectiveness of therapy should be regularly assessed.

If hyperprolactinemia is associated with hypothyroidism or other endocrinopathies, the patient may be indicated for combination therapy for the identified diseases.

Surgery

Indications for surgical intervention are:

• large size macroadenomas, when the tumor spreads beyond the sella turcica and the patient shows signs of visual impairment;
• pituitary apoplexy - a sharp increase in tumor volume caused by hemorrhage;
• poor drug tolerance;
• pituitary adenomas (micro- and macroadenomas), the conservative treatment of which did not produce results.

Radiation therapy

This method is currently practically not used in the treatment of hyperprolactinemia.

In general, the success of therapy is assessed based on the following criteria:

• normalization of prolactin levels;
• reduction in tumor size according to the results of computed tomography and/or MRI;
• normalization of the patient’s cycle and restoration of fertility (if the woman is of reproductive age).

Hyperprolactinemia and pregnancy

Elevated prolactin leads to infertility. The question arises: can a woman become pregnant, safely give birth to a baby and feed him with breast milk? After all, prolactin regulates the functioning of the reproductive system. A woman can become pregnant only if the hormone is slightly higher than normal - no more than 27 ng/ml or 540 mU/l. In other cases, conception is impossible.

Hyperprolactinemia leads to the following pathological conditions:

• To disruption of the menstrual cycle or to the complete cessation of menstruation (amenorrhea);
• Anovulation is a cycle disorder in which the egg does not mature in the follicle and does not leave the ovary. Actually, this is the main obstacle to successful conception.
• Progesterone deficiency, as a result of which a woman cannot bear a child.

Do not forget that directly during gestation, prolactin increases, which is a natural physiological process. The increase in the amount of the hormone begins already from 5-7 weeks of pregnancy, then there is a significant increase in its level, which is also typical for the postpartum period. This is especially true in cases where the baby is fed with breast milk, because it is prolactin that significantly influences this process. Subsequently, in the absence of pathology, the numbers gradually normalize, and the hormone reaches a normal value for the body.

Prolactin is divided into several fractions:

• Small is the active fraction of prolactin that binds to receptors.
• The big one is several times less active than the small one.
• Big-big – even less active prolactin.
• Glycolyzed – this fraction is characterized by the absence of any activity; it does not bind to receptors.

Laboratories often determine the total amount of prolactin. It can be increased, but the woman still manages to get pregnant. How does this work? The fact is that hyperprolactinemia causes infertility only if the concentration of the active fraction of prolactin increases. Statistics show that in 30% of women, the pathology is caused by an increased level of inactive or low-active fractions, which means there is a chance of getting pregnant.

Therefore, it is necessary to conduct a detailed examination by qualified specialists, and then undergo treatment, the main purpose of which is to normalize the menstrual cycle and prolactin levels.

Norm prolactin

The normal level of prolactin in the blood is no more than 15 ng/ml, it is secreted in impulses - on average there can be about fourteen emissions per day. It reaches its maximum levels in the morning (somewhere between 5 and 7 am), and after waking up it begins to decline - within a few hours it becomes minimal. These data may change due to various factors. For example, if a woman is breastfeeding, the level of prolactin in her body increases and becomes higher than the generally accepted norm. Among other things, the secretion of this hormone depends on the levels of others, such as estrogens, thyroid hormones, etc. Even the slightest changes in the production of these hormones leads to a sharp jump in prolactin levels. Psychoemotional and physical stress, uncontrolled or exceeding the required dosage of taking certain medications, surgery, previous injuries, and much more can also increase prolactin levels.

There are two types of designations for the content of prolactin in the blood: nanograms/liter - ng/l and international milli-units/liter - mIU/l. The first method is used most often - ng/l. Norms for prolactin levels:

• in adult women this figure should be - 64 - 395 mIU/l or 1* - 29 ng/l
• in men - 78 - 380 mIU/l or 1* - 18 ng/l

But in women, these readings can vary depending on the phase of the menstrual cycle: during the follicular phase they are 252 - 504 mIU/l, during the periovulatory phase - 361 - 619 mIU/l, and in the luteal phase - 299 - 612 mIU/l.