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Antipsychotic-induced amenorrhea

Article in Journal of Mental Health · October 2011

DOI: 10.3109/09638237.2011.586741 · Source: PubMed

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Journal of Mental Health,
October 2011; 20(5): 484–491

REVIEW

Antipsychotic-induced amenorrhea

MARY V. SEEMAN

Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

Abstract
Background. Many antipsychotic drugs used to treat schizophrenia can cause amenorrhea in a
significant proportion of women. The overall impact of this side effect has been little studied.
Aim. To review the literature on the meaning of menstruation to women.
Method. This is a literature review of the meanings of menstruation to women in general, to women
of different cultures, and to women with schizophrenia.
Results. Many women feel ambivalent with respect to menstruation. Its loss can produce difficulties
for women suffering from schizophrenia, such as failure to use contraception, pseudocyesis, denial of
pregnancy, erroneous perception of early menopause, or loss of the feeling of femininity.
Conclusion. Attempts should be made to avoid the antipsychotic side effect of amenorrhea.

Keywords: Menstruation, amenorrhea, schizophrenia, antipsychotic, side effect

Introduction
Hormonal side effects of antipsychotic medication, such as amenorrhea, can complicate the
lives of women, and yet they have been relatively neglected in both research and clinical
practice (Knegtering et al., 2003). While women universally complain about ‘‘the curse’’
(Morrison et al., 2010), many see a positive side to menstruation, and its loss due to the
effects of antipsychotics can lead to negative sequelae.

The role of antipsychotic medication in amenorrhea

The mechanism by which antipsychotics stop menstruation is not totally understood, but
hyperprolactinemia secondary to dopamine blockade is central (Wieck & Haddad, 2002,
2003). Although many drugs raise prolactin levels, this occurs more commonly with
antipsychotics than with any other class of drugs (Madhusoodanan et al., 2010). Elevated
prolactin leads to disturbances in the secretion of gonadotrophin-releasing hormone, which,
in turn, results in menstrual irregularities and amenorrhea (Perkins, 1999).
Hyperprolactinemia is induced mainly by first-generation antipsychotic drugs, amisul-
pride, and risperidone, although most antipsychotic agents in current use cause some degree
of hyperprolactinemia (Madhusoodanan et al., 2010).

Correspondence: Mary V. Seeman, Professor Emerita, Department of Psychiatry, University of Toronto, 250 College St., Toronto,
ON M5T 1R8, Canada. E-mail: mary.seeman@utoronto.ca

ISSN 0963-8237 print/ISSN 1360-0567 online Ó 2011 Informa UK, Ltd.

DOI: 10.3109/09638237.2011.586741
 Amenorrhea 485

Rates of amenorrhea among women treated with antipsychotics vary depending on the type
of antipsychotic used and also on the dose, age, and sex (Montgomery et al., 2004; Smith
et al., 2002). The higher the dose, the more likely the amenorrhea. Features of the illness
itself, such as stress, concomitant medication, or unrelated medical conditions, may also play
a causal role (Yasui-Furukori et al., 2010). Younger age in women (i.e. premenopause)
correlates with a higher prolactin level (Halbreich & Kahn, 2003; Montgomery et al., 2004).
At equal doses of antipsychotics over prolonged periods, women are more likely to develop
hyperprolactinemia than men, and their level of prolactin rises to a significantly higher
degree (Kinon et al., 2003; Smith et al., 2002). The overall prevalence of symptomatic
hyperprolactinemia is at least 50% in women treated with antipsychotics. With first-
generation antipsychotics, 91% of female patients used to report changes in menstrual cycles
(Ghadirian et al., 1982), although menstrual irregularities can sometimes predate treatment
(Bergemann et al., 2005).
Nevertheless, the elevation of baseline prolactin in drug-treated psychiatric patients is
more likely to be a consequence of drug effects than of the illness itself (Haddad & Wieck,
2004). During antipsychotic treatment, prolactin levels can rise as much as 10-fold.
Hyperprolactinemia is manifested in many symptoms: gynecomastia, galactorrhea, sexual
dysfunction, hirsutism, infertility, and oligomenorrhea, in addition to amenorrhea. (Haddad
& Wieck, 2004; Hummer & Huber, 2004; Montejo, 2008).
In a recent study of 60 female psychiatric patients treated with first-generation
antipsychotics for over 5 years, Kim et al. (2010) found that 12 experienced regular periods
and 23 experienced irregular menstruation. Twenty-five patients were amenorrheic.
Hyperprolactinemia was found in 80%, with the amenorrheic group showing the highest
prolactin levels.

Aim
Because menses are so often lost in women with schizophrenia treated with antipsychotic
medication, the aim of this study is to understand the loss and to alert clinicians to potential
consequences. This article is a narrative review of scholarly papers on the meanings of menses.
The papers were selected by entering the search terms ‘‘menstruation’’ and ‘‘menses’’ in
association with ‘‘meaning’’ and ‘‘attitude’’ and, subsequently, ‘‘menstruation’’ and
‘‘menses’’ in association with ‘‘schizophrenia’’ and ‘‘antipsychotics’’ into Google Scholar
for the years 2000–2010. Relevant papers were searched for further references. Examples of the
positive meanings that menses can have for some women were taken, with permission, from the
online site, Museum of Menstruation (http://www.mum.org/stopmen.htm).1 This is a popular
site where English-speaking women from all over the world have, since the year 2000, been
addressing the question, ‘‘Would you stop menstruating indefinitely?’’

Examples of positive associations with menstruation

Although most entries at the Museum of Menstruation site express negative views about
menses, there are interesting examples of positive views. Many statements reflect the general
view that menstruation represents femininity and fertility. Some women write in that regular
menses are a proof of health. For others, there is magic in the connection between menses
and lunar cycles, e.g. ‘‘I think menstruation is also surrounded by magic. I believe the close
affinity with the moon it is not a mere coincidence.’’ There are several comments about
menstruation reflecting youth and feminine power, e.g. ‘‘It sets us apart from men in a big
empowering way.’’
486 M. V. Seeman

Views of menstruation in the academic literature

In the academic literature, as on the website, women mainly view menstruation negatively,
using terms such as ‘‘failure,’’ ‘‘waste,’’ and ‘‘debris’’ (Roberts, 2004; Schooler et al.,
2005). Of 227 stories written by women, Beausang and Razor (2000) identified 85 that
talked of menstrual experiences, and of those, only 11 described menarche as a positive
experience. Twelve percent of women undergraduate students in 2003 reported deliberately
suppressing their menstrual periods with birth control pills (Johnston-Robledo et al., 2003).
On specific questioning, over two-thirds of a sample of 221 women expressed interest in
reducing menstrual pain and menstrual discharge by taking a contraceptive that would
decrease the number of annual menstrual cycles (Andrist et al., 2004).
A study conducted in Brazil, however, revealed considerable ambivalence. Although
regarded as a nuisance, menstruation was still associated in the participants’ minds with
femininity, youth, fertility, and health (Estanislau do Amaral et al., 2005). The three aspects
of menstruation that respondents mentioned most often as losses after a hysterectomy were
the following: the use of menstrual cyclicity as a regulator; a feeling of connection to other
menstruating women; and the ability to redeploy menstruation for emotional needs, such as
using it as a reason to rest or to allow expression of anger (Elson, 2002). In a study of 30
women with polycystic ovaries who experienced irregular or absent periods, the researchers
found pervasive reports of feeling ‘‘freakish,’’ ‘‘abnormal,’’ and not ‘‘proper’’ women
(Kitzinger & Willmott, 2002). The women in the study expressed feeling ‘‘different’’ from
other women and less ‘‘feminine.’’
There is cultural specificity to a woman’s view of menstruation (Britton, 1996; World
Health Organization, 1999). Menstrual blood has been seen as both pollutant and cure,
simultaneously sacred and cursed. It is estimated that about half the world’s cultures today
celebrate menarche as an important communal event, an index of womanhood and potential
fertility, marking the transformation from girl to woman (Beausang & Razor, 2000). Native
tribal traditions emphasize that menstruation opens a woman to vision, wisdom, and insight.
During a woman’s ‘‘moon’’ or menstrual period, hormonal changes are said to bring about
heightened vulnerability and a special awareness of the natural ebb and flow of life. (Brooke
Medicine Eagle, 1991). In African traditions, menstrual blood is considered special because
it carries in it a living being (Umeora & Egwuatu, 2008).
In Australia, most young women have thought of menstruation as inconvenient or
embarrassing (Abraham et al., 1985). Recent work, however, shows that there is a counter-
culture group of women in Australia who consider menstruation a spiritual phenomenon, a
sacred female experience that empowers women (Moloney, 2010). In Mexico, the cultural
stereotype of menstruation is a negative one (Marván & Trujillo, 2010; Marván et al., 2002).
In the United States, girls’ attitudes and expectations about menstruation are also negatively
biased (Stubbs, 2008). Forty percent of women in the United States, as in Western Europe,
would stop their period if they could (Aubeny, 2007; Edelman et al., 2007).

Women with schizophrenia

Women with schizophrenia have not often been asked how they feel about menstruation. In
one small clinical study, nearly 78% of women respondents in a schizophrenia clinic
endorsed menses as being important to them with respect to most of the following domains:
fertility, sexual functioning, attractiveness, the aging process, and general health (Zhang-
Wong & Seeman, 2002). In general, not menstruating was experienced as not being
‘‘normal,’’ an important identity for these women to achieve.
 Amenorrhea 487

Drug-induced amenorrhea is probably responsible for the low fertility among women
with schizophrenia. The lowest first-child fertility rate is among women with
schizophrenia (Laursen & Munk-Olsen, 2010). If menstruation is equated with youth,
health, femininity, spirituality, and power, then its loss will have negative psychological
effects. Women with schizophrenia experiencing drug-induced amenorrhea sometimes
make the erroneous assumption that, since they are not menstruating, they cannot
become pregnant. As a consequence, they may stop using contraception or fail to insist
that their male partners do so. In a study conducted in Australia, of the 51% of mentally
ill women who reported being sexually active in the 12 months preceding the survey,
57% never used condoms (Davidson et al., 2001). This may be a reflection of the
disorganization that frequently accompanies schizophrenia, but the most frequently
endorsed reason for not using birth control measures among women with schizophrenia
is that they do not anticipate having sex and, if they do, they do not expect to get
pregnant (Solari et al., 2009). Such reasons are neither specific to schizophrenia nor are
they a necessary consequence of amenorrhea, but there is a strong association in most
women’s minds between menses and fertility; lack of menses and sterility (Morrison
et al., 2010).
When menstrual periods stop, some women with psychotic illness may assume or even
insist that they are pregnant, despite negative test results. Ahuja et al. (2008a) described
12 patients with antipsychotic-induced hyperprolactinemia, six of whom wrongly believed
they were pregnant (four were delusional), a conviction that was associated temporally
with raised prolactin levels and that resolved when these levels returned to normal. One
44-year-old woman presented with a delusion of twin pregnancy. Modification of her
antipsychotic medication was associated with a fall in serum prolactin and with the
disappearance of the delusion of pregnancy (Ahuja et al., 2008b). Pseudocyesis, or
delusional pregnancy, is a syndrome that occurs not uncommonly in women with
psychosis, especially in older women who have not had children but who desperately
want to (Dubravko, 2010). Amenorrhea induced by antipsychotics raises the risk for the
delusion.
Women experiencing antipsychotic-induced amenorrhea who do become pregnant may
deny their pregnancy even when their abdomen enlarges and when the fetus begins to
move. Denied pregnancies occur in 1 in 475 births (Beier et al., 2006). The
phenomenon is relatively common in mothers with psychotic disorders, a finding that
has been partly attributed to the fact that Child Protection agencies may have removed
previous children from the home, and women to whom this has happened are reluctant
to invest emotionally in a subsequent baby (Spielvogel & Hohener, 1995). Denial during
pregnancy is dangerous because it deprives the woman of much needed prenatal care
(Shah & Christopherson, 2010). It leaves her unprepared for labor and delivery and for
the difficult task of parenting, and it raises the risk for filicide (Ostler & Kopels, 2010;
Solari, 2010).
Some women who stop menstruating may wrongly assume that they are menopausal. This
may lead to unwanted pregnancy at a relatively late age, a potentially serious problem for
women with few familial or social supports. The mere fact of believing one has prematurely
entered into menopause is distressing to women (Boughton, 2002).
Gender identity, a classical issue in schizophrenia, is affected by amenorrhea. Twenty
percent of all patients with schizophrenia are said to experience sexual delusions, among
them the conviction of having changed sex (Borras et al., 2007). The literature reports many
cases of delusional pseudotranssexualism, reinforced by antipsychotic-induced side effects
such as hirsutism and amenorrhea (Baltieri et al., 2009; Urban, 2009).
488 M. V. Seeman

Clinical implications
Prevention of drug-induced amenorrhea consists of monitoring prolactin levels (Torre &
Falorni, 2007) and, in all patients on first-generation antipsychotics or risperidone, keeping
the dose of medication low, spacing the time between depot injections, or changing the
antipsychotic drug to one less likely to cause amenorrhea, e.g. aripiprazole, clozapine,
olanzapine, quetiapine, or ziprasidone (Lee et al., 2006; Miller, 2004; Takahashi et al.,
2003). Among atypical antipsychotics, amisulpride and risperidone are the worst offenders
(Haddad & Sharma, 2007). Patients with hyperprolactinemia 4100 ng/ml should have an
MRI to exclude prolactinoma (Haddad & Wieck, 2004; Miller, 2004). Dopamine agonists
can be used to lower prolactin levels, and they appear to be safe in this population
(Aydin et al., 2010; Lee et al., 2010). The optimal treatment of antipsychotic-induced
hyperprolactinemia and amenorrhea is not yet established (Bostwick et al., 2009), but being
forewarned about the possibility that the treatment will cause amenorrhea and what that
might mean makes coping easier (Berterö, 2003). Women need to know that drug-induced
amenorrhea does not necessarily abolish fertility and that amenorrhea does not mean
pregnancy; neither does it mean menopause and old age. Personal and cultural meanings
need to be explored. Women with psychotic illnesses may be especially vulnerable to
misinterpretations, so that issues that evoke emotional reactions need to be addressed clearly
and frequently. As eloquently expressed by Powell (2001), understanding the significance of
a side effect allows the therapist enter into a wider discussion of personal meaning. Exploring
reactions to bodily changes can yield important clues to a patient’s inner life.

Conclusion
Antipsychotic-induced amenorrhea is not a rare event among women treated for
schizophrenia. Because menstruation is associated with fertility, youth, attractiveness,
health, and normality, because it is often imbued with magical or spiritual significance, its
absence can be experienced as distressing and can be readily misinterpreted. In women with
psychosis, the misinterpretation can lead to delusions of sex change, pseudocyesis, denial of
pregnancy, and false assumptions of infertility or early menopause. Amenorrhea is sometimes
preventable, sometimes treatable, but always addressable in the sense that personal and
cultural meanings can, and should, be explored within the therapeutic relationship.

Declaration of interest: The author reports no conflicts of interest. The author alone is
responsible for the content and writing of the paper.

Note
1. Permission to use quotes from the site was obtained from Mr. Harry Finley, 31 August 2010.

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