Download Menstrual Irregularities and Sex Hormones in Female Patients

Original Article
Clinical Psychopharmacology and Neuroscience 2010;8(1):21-25
pISSN 1738-1088 / eISSN 2093-4327
Copyrightⓒ 2010, Korean College of Neuropsychopharmacology
Menstrual Irregularities and Sex Hormones in Female Patients Treated with
Conventional Antipsychotics for more than 5 Years
Jihyeon Kim, Suyeon Kim, Sohee Kim, Sohyun Choi
Yongin Mental Hospital, Yongin, Korea
Objective: This study was designed to observe the menstrual patterns of female chronic psychiatric patients treated with anti-
psychotic drugs and to assess prolactin and estradiol levels to determine the relationship among prolactin, menstrual irregularities
and sex hormones.
Methods: Sixty female inpatients who had been treated with antipsychotics for more than 5 years participated in this study.
The first day of each menstrual cycle during a 6-month period was recorded after menstruation was confirmed by nursing staff.
Blood samples were taken at an early follicular phase for menstruating patients and randomly for amenorrheic patients to assess
prolactin and estradiol levels.
Results: Of the 60 subjects, 12 experienced regular and 23 experienced irregular menstruation. Twenty-five patients were
amenorrheic. Hyperprolactinemia was found in 80% of all subjects. The amenorrheic group showed higher prolactin levels, and
these levels were correlated with dosage of antipsychotics. Estradiol was lower than 10 pg/ml (undetectable) in 77% of the patients
but was exceptionally high in a few participants.
Conclusion: About 80% of participants experienced menstrual disturbance, hyperprolactinemia, or hypoestrogenism. These findings suggest that hypothalamic-pituitary-ovarian axis dysfunction was very common in chronic psychiatric patients receiving
long-term treatment with antipsychotic medication and should be considered in clinical practice.
KEY WORDS: Antipsychotics; Menstruation; Prolactin; Estradiol.
INTRODUCTION
hormones (LH) and GnRH. Suppressed release of GnRH
modifies normal secretion of LH and follicle-stimulating
hormones (FSH), and thus alters the normal production
and secretion of estradiol in ovaries, resulting in hypo6-8)
estronized amenorrheic cycles.
The rate of menstrual irregularities among patients taking typical antipsychotic drugs has been reported at
9-13)
However, most studies
26-78% in previous studies.
thus far have been performed with only a limited number
of subjects and with a retrospective design, restricting
their ability to reveal the actual patterns of menstruation
during the treatment with antipsychotic medication. In
some studies, women with irregular menses did not differ
in their prolactin levels or neuroleptic dosages from women with regular menses.13-15) However, small sample sizes
and/or lack of clear definitions of regular, irregular, and
amenorrheic menstrual cycles limit interpretation of these
results. Many patients with schizophrenia spectrum disorders take antipsychotic medication for decades; thus the
long-term effects of the medications on the hypothalamus-pituitary-ovarian (HPO) axis should also be considered in clinical practice. Only a few studies have exam-
It is well known that antipsychotic drugs can cause increased prolactin levels, which can lead to decreased
1-3)
blood estrogen. Prolactin is a peptide hormone secreted
by the anterior pituitary gland, a process primarily controlled by tonic dopamine inhibition. Dopamine is secreted from the hypothalamus into the pituitary portal venous system, where prolactin secretion is inhibited via D2
receptors on the surface of the lactotrophs of the anterior
pituitary gland. Typical antipsychotic drugs increase
blood prolactin levels by blocking the dopamine in this tubero-infundibular track.4,5) Hyperprolactinemia inhibits
normal pulsatile secretion of gonadotropin-releasing hormones (GnRH) from the hypothalamus, interferes with
the action of GnRH on the pituitary gland, and interferes
with the positive feedback from estradiol to lutenizing
Received: May 15, 2009 / Revised: July 23, 2009
Accepted: September 15, 2009
Address for correspondence: Jihyeon Kim, MD
Yongin Mental Hospital, 4 Sangha-dong, Yongin 446-769, Korea
Tel: +82-31-288-0114, Fax: +82-31-288-0180
E-mail: [email protected]
21
22
J.H. Kim, et al.
ined the long-term effects of neuroleptic drugs on prolactin and sex hormones.13,16)
This prospective study evaluated the long-term effects
of antipsychotic medications on prolactin, sex hormones,
and menstruation by directly observing menstrual cycles
and measuring hormones in psychiatric patients receiving
maintenance treatment.
The objectives of this study were:
1. To describe the patterns of menstruation in female inpatients treated with conventional antipsychotics.
2. To examine the relationship among prolactin, menstrual irregularities, and sex hormones.
METHODS
Subjects
The sample consisted of female inpatients admitted at
Yongin Mental Hospital receiving conventional (typical)
antipsychotics for at least five years. The age limit for patients with irregular menstruation or amenorrhea was under 45 years, but we included all patients who menstruated
regularly irrespective of their age. Exclusion criteria included pregnancy, taking oral contraceptives, alcohol or
substance abuse, and chronic diseases such as diabetes
and hypertension. Patients requiring a change in either the
kind or the dosage of their antipsychotic agents during the
study were also excluded from the analysis.
Methods
Written informed consent was received from all participants. The study protocol was approved by the local
ethics committee at Yongin Mental Hospital. The menstrual cycles were observed, and the first day of each menstruation was recorded for each patient for 6 months.
Demographic data were obtained by chart reviews and
brief interviews. Regular menstruation was defined as
more than four regular cycles (cycles of 21-35 days) during a 6-month period, whereas amenorrhea was defined as
the absence of menstruation for more than three cycles;17)
the remaining participants were placed in the irregular
menstruation group. At the sixth month, prolactin and estradiol levels were measured. Blood samples were taken
during the early follicular phase (days 1-3) for menstruating patients (regular and irregular groups) and randomly
for amenorrheic patients, at 6-7 AM. The samples were
centrifuged and frozen at −60°C. Prolactin and estradiol
were measured by chemiluminescent immunoassay (Bayer Advia 1650).
Analysis
The analysis was conducted with SPSS version 11.5 for
Windows. One-way analysis of variance and t-tests were
used for comparisons, with Bonferroni’s test for post-hoc
analysis of difference. We used Pearson’s correlation coefficients to evaluate the relationship between variables; a
p-value of ＜0.05 was considered statistically significant.
Prolactin levels were log-transformed due to the skewed
distribution.
RESULTS
Sixty patients, whose antipsychotic medications remained unchanged during the period of this study, were
observed for 6 months. Most participants were under 45
years of age, and two patients, aged 50 and 51, were also
included because they menstruated regularly. The mean
age of the subjects was 37.4 years. The subjects were all
ethnically Korean. The clinical diagnoses included schizophrenia (n=40), schizoaffective disorder (n=7) and mental
retardation (n=13). Forty-one patients were taking one antipsychotic agent and the remaining 19 were taking two
agents. Medications included haloperidol, chlorpromazine, perphenazine, sulpiride, bromperidol, nemonapride,
trifluoperazine, and cis-clopenthixol. The mean dosage
was 14.1±9.7 in haloperidol-equivalent dose.18,19) Fortyone patients were taking adjunctive medications such as
benzodiazines (lorazepam and/or clonazepam), lithium,
tegretol, and/or valproate.
Menstrual Cycles
Twelve participants experienced regular and 23 experienced irregular menstrual cycles. The remaining 25 patients were amenorrheic. Among the regular group, only
five patients had steady and regular menstrual cycles
throughout the 6-month study period. Nineteen of the 25
patients in the amenorrheic group did not menstruate during the 6 months of the study. The patterns of irregularity
were unpredictable and could not be defined as simply
oligomenorrheic. The various patterns of irregularity included; skipping two cycles after three regular cycles, experiencing more than four cycles of shortened length (＜
21 days), having two regular cycles before and after three
amenorrheic cycles, and having regular cycles with one
shortened cycle that was less than 20 days in length. No
differences in doses of antipsychotic agents and diagnoses
were found among the groups (F=0.401, p=0.672) but the
average age of the amenorrheic group was higher than that
of the other two groups (F=5.178, p=0.09) (Table 1).
Menstrual Irregularities and Sex Hormones in Patients Receiving Long Term Antipsychotics Treatment
Table 1. Demographic data and daily dosages of antipsychotic
agents
Table 2. Hormone levels of the three groups
Regular
Irregular
Amenorrheic
menstruation menstruation
group
group
group
(n=25)
(n=12)
(n=23)
Age
Dosage
(Hal Equiv., mg/day)
34.0±5.8
14.7±8.7
36.6±6.0
12.7±10.0
39.9±5.1*
15.1±10.1
23
Prolactin (ng/ml)
E2 (pg/ml)
Regular
menstruation
group
(n=12)
Irregular
menstruation
group
(n=23)
Amenorrheic
group
(n=25)
59.5±40.5
27.0±76.8
59.6±44.9
23.3±71.2
93.9±51.0*
18.2±41.3
*p＜0.01
Hal Equiv, haloperidol equivalent; *p＜0.05
DISCUSSION
Patients receiving sulpiride were more likely to demonstrate amenorrhea than were patients on other antipsychotic medications. Of the 14 patients taking sulpiride,
10 (71%) were amenorrhoeic. However, the menstrual
cycles of two patients taking sulpiride were shortened so
that they experienced seven and eight cycles during the
6-month study period. Even with the shortened regular
menstrual patterns, the serum prolactin levels of these two
patients were high (135.0 and 59.1 ng/ml), and the estradiol levels were lower than 10 pg/ml in both cases.
Endocrine Functions
The mean prolactin level (73.9±49.1 ng/ml) was higher
than the normal value for non-pregnant women (2.8-29.2
ng/ml). Hyperprolactinemia, defined as ＞30 ng/ml, was
found in 50 patients (80% of all subjects). The amenorrheic group had significantly higher prolactin levels
(F=4.353, p=0.017) (Table 2) than did the menstruating
groups but we found no significant differences between
regular and irregular menstruation groups. Ninety-two
percent of amenorrheic patients had hyperprolactinemia.
Serum prolactin levels were correlated with the dosages of
antipsychotic agents (r=0.445, p＜0.01). Age and the
number of combined medications were not correlated
with prolactin levels. Prolactin levels were significantly
higher in patients taking sulpiride (t=2.83, p=0.006). The
mean estradiol level was 21.9 pg/ml, which seemed to be
the normal range for the early follicular phase. However,
the standard deviation was ±60.8 pg/ml. The estradiol levels of 46 patients (77%), were below the sensitivity level
(＜10 pg/ml) and those of four patients were over 100
pg/ml. No specific medication was associated with high or
low estradiol levels. The four patients with high estradiol
levels were taking chlorpromazine, haloperidol, cis-clopenthixol, and a combination of chlorpromazine and
trifluoperazine.
This study demonstrated a prevalence of menstrual
problems (irregular menstruation or amenorrhea) in female patients receiving conventional antipsychotic agents
of 80% (48/60). Prolactin levels were correlated with the
dosages of antipsychotics, and estradiol levels were undetectable in 77% of the subjects.
The rate of menstrual problems was higher than that re9-13)
ported by previous studies.
Only 8% (5/60) of the subjects had six regular menstrual cycles during the 6-momth
period of this study. As mentioned above, irregular menstruation was more than just oligomenorrhea. Some patients had regular cycles after skipping 1-2 cycles or had
intermittent shortened, or prolonged cycles interspersed
among regular cycles. Considering that previous studies
obtained data from patients’ self-reports and thus depended on subjects’ memories, it is possible that some irregularly menstruating patients were categorized into the
regular group.
In this study, menstrual irregularity was observed in
most patients, and alternating between regular and irregular menstruation occurred without any changes in dosage
or in types of antipsychotic agents. In the hyperprolactonemic state, patients had either oligomenorrhea or
menorrhagia, which suggests a disruption in the HPO
axis.
The levels of estradiol also supported the instability of
the HPO axis. Of the 60 patients followed, 46 showed values of estradiol below the sensitive level, but the E2 levels
of four patients (one regular, two irregular, and one amenorrheic) were as high as those found in the mid-follicular
or ovulation phase (144-319 pg/ml). Three of these gave
samples on days 1-3 of their menstrual cycle, as
scheduled. When data from these outliers were omitted,
E2 levels were undetectable during the early follicular
phase in 87.5% of the female patients who had taken antipsychotic medication for more than 5 years. Of those patients with estradiol below sensitivity levels, 70.8% were
20)
amenorrheic. Reicher-Rossler et al. found that estradiol
24
J.H. Kim, et al.
serum levels were markedly reduced and fluctuation
throughout the cycle were dampened in acute female
schizophrenic patients with a history of regular menstrual
20)
cycles. Their study did not, however, observe the irregular fluctuations in estradiol level observed in this study.
The effect of long-term medication on the HPO axis might
not have emerged in that study because the patients were
acute. Serial hormonal assessments performed throughout
the cycles of chronic patients will be helpful in illuminating the long-term effects of hyperprolactinemia on the
HPO axis.
Serum prolactin levels were significantly higher in the
amenorrheic group, but no significant differences between regular and irregular groups were observed in these
levels. Although the criteria used to define regular and irregular menstruation were generally accepted, the demarcation between the two was not clear-cut for the majority of the subjects. Therefore, at present, it is probably
best to attribute the above finding to an error in grouping
rather than to accept it at face value. Differences in prolactin levels between all menstruating subjects and those
in the amenorrheic group were significant accordfing to
the t-test results (t=−2.974, p=0.004). Smith et al.13)
showed that most individuals reporting unaltered menstrual functioning while taking antipsychotic medication
were not actually ovulating.13) Given the irregularity of the
menstrual cycles and the low estradiol levels of the subjects in the regular group of this study, we were able to
conclude that most patients receiving long-term treatment
with conventional antipsychotic agents showed altered
HPO axis functioning, irrespective of whether they were
menstruating.
No significant differences in the dosages of antipsychotic agents were found between groups, but sulpiride
was more likely to be used by patients in the amenorrheic
group. Student’s t-tests showed that serum prolactin levels
were higher among those taking sulpiride. Consistent with
prior studies,10,13,21) a correlation between serum prolactin
levels and dosages of antipsychotic agents was observed.
No differences in the dosages of antipsychotics among the
three groups suggests that the class of antipsychotic agent
was more powerful than was the dosage in increasing prolactin and causing menstrual difficulties.
This study has several limitations. First, the amenorrheic group was older than were the other two groups.
Therefore, it could be suggested that the study included
patients who had transitioned to menopause. This is unlikely, given that the mean age of menopause is 51 years
and the perimenopausal transition begins at 47.5 years, on
average. In this study, the mean age of the amenorrheic
group was 39.9±5.1. The rate of early menopause, defined
as menopause before the age of 40, in the general pop22)
ulation is 1%, which suggests that the possibility that
our data were contaminated by including postmenopausal
subjects is very small.
Second, the duration of menstruation and the amount of
menstrual blood were not considered in assessments of
menstrual regularity. Because every first day of menstruation was considered as the beginning of a normal cycle,
cases of irregular cycles or amenorrhea could have been
underestimated.
Third, data about the menstrual patterns of the patients
before treatment with antipsychotic medication was initiated depended on the patients’ memories.
Fourth, the patients were not homogeneous in that those
with mental retardation were included. The data from
these 13 patients, however, did not seem to affect the results of this study. Mentally retarded patients were evenly
distributed among the three groups (four regular, five irregular, and four amenorrheic), and the prolactin levels remained significantly higher in the amenorrheic group
when data from patients with schizophrenia only were
analyzed.
Finally, the effect of combined medication should be
considered in interpreting the data. Long-term administration of antidepressants might produce serum prolactin
concentration but other psychotropic drugs such as lithium, valproic acid, buspirone, carbamazepine, and benzodiazepines are only rarely associated with symptomatic
hyperprolactinemia or do not produce clinically important
changes in prolactin concentration.23) Therefore, it might
be reasonable to conclude that the serum prolactin levels
and menstrual patterns of the subjects were not affected by
the combined medications.
In conclusion, this study has shown that the elevation of
serum prolactin associated with antipsychotic agents was
related to menstrual disturbances in women. The rate of
menstrual disturbances found in this study was 80%; however, the actual rate could be higher. The patterns of menstruation were irregular and unpredictable in most patients. Serum estradiol was below the sensitivity level in
77% of patients but exceptionally high in a few participants. Taken together, these findings suggest that dysfunction in the HPO axis is very common in the context of
the chronic use of antipsychotic agents. Serial hormonal
assessments performed throughout the cycle, combined
with observations of the patterns of menstruation are
needed to obtain additional information about the effects
Menstrual Irregularities and Sex Hormones in Patients Receiving Long Term Antipsychotics Treatment
of long-term treatment with antipsychotics on the HPO
axis. The long-term impact of hyperprolactinemia and/or
hypoestrogenemia represents one reason that patients
with schizophrenia develop osteoporosis, which can lead
to clinical fractures with minor trauma. Menstrual disturbances can also cause infertility, failure of contraception, or undetected pregnancy. Although clinically important, menstruation is not an issue that patients tend to
raise voluntarily. Clinicians who prescribe antipsychotic
agents, both typical and atypical, should be aware of the
possibility of hyperprolactinemia, which is prevalent
among female schizophrenic patients.
Acknowledgments
This work was supported by the research fund of Yongin
Mental Hospital.
■
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