Acute psychotic episodes as well as psychotic relapses are treated effectively with antipsychotic drugs. Most patients with confirmed diagnoses of psychiatric disorders need to undergo antipsychotic drug therapy throughout their whole lives [
This review aims to summarize the effects of antipsychotic agents on prolactin levels and menstruation and investigate the frequency of hyperprolactinaemia and menstrual abnormalities that affect female patients, depending on the selected antipsychotic therapy. It also indicates the need for further research on these adverse effects, the severity of which is not always reported in a clinically meaningful way to experts.
A great number of studies have investigated antipsychotic medication and its important effects on human endocrine function. In everyday practice, there are drugs that reduce hypothalamic dopamine secretion and pituitary activation and result in hyperprolactinaemia [
Conventional antipsychotic agents and some, but not all, of the marketed novel agents, elevate serum prolactin levels via inhibition of dopamine action at
Typical antipsychotic drugs block nonselective dopamine
The primary therapeutic target of traditional antipsychotics was the decrease of symptom intensity and the prevention of psychotic recurrence. However, clinicians had to accept hyperprolactinaemia as an implication and a biological marker that came with the drug’s efficacy. Data changed in clinical practice after the introduction of novel antipsychotics, which represent an advance in the treatment of psychotic disorders and have a lower tendency to induce hyperprolactinaemia. It has been suggested that the antagonism of
The majority of clinical adverse effects of hyperprolactinaemia involves the reproductive system and is attributed to prolactin direct relation with several tissues as well as indirect suppression of pulsatile gonadotropin secretion, leading to gonadal dysfunction. Hyperprolactinaemia deregulates systems and processes affected by the pituitary and gonadal hormones (Figure
Reasons for hyperprolactinaemia and its side effects.
When antipsychotics produce hyperprolactinaemia, menstrual abnormalities like anovulation, irregular menses or amenorrhea occur [
Physiological status of GnRH pulsatile secretion.
The great response of prolactin in women of a reproductive age, who are not nursing or pregnant, leads to the inhibition of the normal pulsatile secretion of gonadotropin-releasing hormone (GnRH) of the hypothalamus. These, not so frequent, pulses of GnRH result in regular menses, on the one hand, but impaired follicular growth on the other. Greater impairment of pulsatile GnRH secretion leads to an anovulatory stage with menses being too frequent, too heavy, or infrequent. Further restraining of pulsatile GnRH secretion provokes deficient secretion of LH and FSH, in amounts not adequate to induce a proper ovarian response. That provokes a hypoestrogenized amenorrheic cycle and side reactions of estrogen deficiency—comparable to what occurs during menopause or infertility [
Despite the fact that various studies described how antipsychotics lead to menstrual irregularities, sometimes it remained unclear whether menstrual dysfunction was the benign sequale of treatment or it was secondary to the disease. Prior to the introduction of antipsychotic medication, psychotic women were found to have abnormal menses. Amenorrhea is combined with infertility; thus, psychotic illness was supposed to be an indirect, natural contraceptive for female patients [
Studies in women with schizophrenia proved that they exhibit greater infertility rates compared to healthy females. Some studies support that a high percentage of menstrual irregularity and estrogen deficiency cannot be fully explained by antipsychotic induced prolactin elevation [
In order to perform this review numerous studies related to the topic were sought and selected. Most articles were electronically found via databases and citations. Manual research of references was also conducted. The research was carried out using Medline, PsychInfo, Cochrane library, and Scopus and focusing on dates from 1954 to 2010. Studies of each database were extracted and examined. Access to electronic databases was conducted by using the following sequence: #1- menstru* OR reproduct* OR amenorrhea OR hyperprolactinaemia OR prolactin OR endocrin* OR fertility, #2- disorder* OR abnormalit*, #3- #1 AND #2, #4- antipsychotic* OR neuroleptic*, #5- psychot* OR psychos* OR schizophren*, #6- #4 AND #5, #7- #3 AND #6. Words with * are root terms (we use the beginning of the word so as more related words can be identified). Selection and examination of the studies were performed and 78 of them were reviewed for the needs of this paper.
Prolactin—PRL is a single chain peptide hormone, structurally and evolutionarily homologe to growth hormone GH, as PRL gene on chromosome 6 has 40% similarity to the pituitary GH gene located on chromosome 17 [
The normal levels of prolactin in serum are below 25
Hyperprolactinaemia can be defined as an increase in circulating prolactin levels and represents the most common abnormality of pituitary hormones met in clinical practice. There are several reasons responsible for hyperprolactinaemia [
Menstrual dysfunction was historically defined in association with bleeding patterns (menorrhagia, amenorrhea, oligomenorrhea, polymenorrhea), but now definitions based on ovarian function (anovulation, luteal deficiency) are also used. Another group of menstrual disorders is defined in terms of pain (dysmenorrhea) and onset of bleeding (premenstrual syndrome) [
The term neuroleptics, introduced by Delay in 1955, is not widely accepted. In this paper, we are going to focus on the traditional antipsychotic drugs haloperidol, chlorpromazine, and flupenthixol that along with some of the atypical antipsychotics like risperidone and amisulpride cause an elevation of prolactin levels and menstrual irregularities. Novel antipsychotic agents like clozapine, paliperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, and zotepine, which do not result in hyperprolactinaemia, are also under the scope of this review. However, the terms “prolactin-sparing” and “prolactin-elevating” that will be used in this review and also describe these drugs are believed to be incomplete, because they may lead clinicians to believe that agents like olanzapine and quetiapine can never induce significant hyperprolactinaemia [
A number of 78 articles were examined and included in our study. Endocrine disorders in women provoke several problems like galactorrhea and menstrual disturbances which are responsible for fertility problems [
First, Polishuk and Kulcsar in 1956 [
Typical antipsychotics, acting as nonselective antagonists of prolactin receptors, are regarded as the most common medications related to hyperprolactinaemia. They lead to acute and persistent increase of prolactin levels [
The classical antipsychotic drug
According to Ghadirian et al. (1982) [
Most atypical antipsychotic medications do not elevate serum prolactin levels, in contrast to risperidone which is the exception and leads to a significant increase of prolactin, to a level similar to older antipsychotics [
Risperidone does not completely cross the blood-brain barrier and as a result, tights longer and heavier with
The prevalence of menstrual side effects such as amenorrhea in patients on risperidone is reported to be 1%–10% [
Feldman and Goldberg (2002) reported that there is no association between clozapine induced menstrual irregularities and weight gain [
The prevalence rate of hyperprolactinaemia in patients on olanzapine has been found to be 68% [
Furthermore, olanzapine treatment improved reproductive comorbid symptoms. Specifically, two out of three women that switched to olanzapine therapy developed a resolution of menstrual disorders opposite to women with menstrual irregularities and prestudy therapy, who continued to have the problem. Additionally, Sawamura et al. conducted a study among Japanese psychotic patients and confirmed gender differences in olanzapine induced prolactin elevation [
Benzamides are considered to belong to atypical agents but they were introduced during the 1960’s.
Amisulpride is regarded to be the antipsychotic with the maximal tendency to cause hyperprolactinaemia. Paparrigopoulos et al. (2007) found that the prevalence rate of hyperprolactinaemia was 100% and this was observed more in women than in men [
Amenorrhea develops in about 4% of women treated with amisulpride. Menstrual irregularities after usage of amisulpride were also reported in another study [
Frequency of antipsychotic induced hyperprolactinaemia and menstrual abnormalities according to different studies.
Antipsychotic agents | Prevalence rates of hyperprolactinaemia | Prevalence rates of menstrual abnormalities |
---|---|---|
All antipsychotic agents | (i) 15%–50% [ | |
(ii) 22%–50% [ | ||
(iii) 15%–97% [ | ||
| ||
All typical antipsychotic agents | (i) 33–35% (depot agents) [ |
|
(ii) 47% [ |
||
(iii) 68% [ |
||
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Haloperidol | 72% (2 weeks therapy)—60% (6 weeks therapy), [ |
(i) 91% [ |
(ii) 17% [ | ||
| ||
Risperidone | (i) 72%–100% (oral treatment) |
(i) 1%–10% (Amenorrhea) [ |
(ii) 53%–67% (intramuscular injection), [ | ||
(iii) 88% [ | ||
0%–5% [ |
(ii) 8%–48% [ | |
| ||
Clozapine | (i) Double rates of risperidone [ |
|
(ii) No difference [ |
||
Paliperidone | (iii) 68% [ |
|
(iv) 40% [ |
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(v) 28% [ |
||
(vi) 24% [ |
||
Olanzapine | (i) 0% [ |
No symptoms [ |
(ii) 14% [ | ||
(iii) 22% [ | ||
<5% [ |
||
| ||
Quetiapine | 100% [ |
|
| ||
Aripiprazole | 0% [ | |
| ||
Amisulpride | (i) 41% (amenorrhea) [ | |
(ii) No adequate data [ | ||
| ||
Ziprasidone | 0% [ | |
| ||
Zotepine | No adequate data [ |
Regular, periodical menstruation represents for women an aspect of normality, an indicator of female fertility, and a way to “clean” their bodies [
Nevertheless, menstruation plays an important role in women’s lives and any abnormalities interfere with their fertility and quality of life. Especially concerning psychotic women, menstrual disturbances can also influence their compliance to therapy. Therefore, clinicians should examine all aspects before prescribing any medication.
In order to asses a woman with hyperprolactinaemia, the clinician should first discover which treatment with antipsychotics resulted in it. Magnetic Resonance Imaging—MRI is the examination of choice so as to investigate the pathological structure in the hypothalamo-pituitary region. If there is any contraindication for MR imaging, then computed tomography scan with contrast, administered intravenously, is the best option [
However, it is worth mentioning that this assessment is often limited to a few questions about clinical manifestations of hyperprolactinaemia and clinicians underestimate hyperprolactinaemia and its side reactions. Another complicating factor is macroprolactinaemia, where a molecular complex of an immunoglobulin G and prolactin is formed. Macroprolactin is biologically inactive as it is restricted to the vascular system but may lead to asymptomatic, falsely elevated prolactin levels [
In order to evaluate amenorrhea, a medical history should be carefully taken so as to know if any genital anomalies, thyroid disorders, weight gain, or loss have been observed. Physical examination should be conducted to check for anatomical causes, as well as urine tests to exclude pregnancy. Menstrual status and history is not always adequately documented. Sometimes, the disturbances in menstruation cannot be apparent in short studies. Women might feel stressed and not comfortable to reveal information about reproductive side effects and clinicians might not have the appropriate scales to find out more information [
Clinicians should be certain about the severity of symptoms and whether they contributed to hyperprolactinaemia or not. Current antipsychotic therapy can be switched to prolactin sparing agents like olanzapine [
Bromocriptine should be prescribed with attention as it resolves amenorrhea but has been found to cause gastrointestinal implications and hypotension [
Prevalence of hyperprolactinaemia and menstrual disturbances varies not only among antipsychotic agents but also among different researchers (Table
Menstrual disturbances like amenorrhea usually recover after prolactin levels have been normalized. However, they can no longer be regarded as a necessary but rather a troublesome consequence of an effective antipsychotic remedy. More studies need to be conducted related to the usage of dopamine agonists and combination therapies for the treatment of prolactin elevation. Clinicians should take into account menstrual abnormalities when they cure women of reproductive age. New antipsychotic agents should be designed to lead to fewer side reactions and improve the lives of psychiatric patients.
Antipsychotic induced hyperprolactinaemia is an interesting and important topic and many authors have worked on this. Thus, our review tried to summarize most of the data related to this topic, but may have failed to include all the sources available in the literature.
The authors declare that there is no conflict of interests in connection with the preparation of this paper.