Psychiatr News August 17, 2007
Volume 42, Number 16, page 15
© 2007 American Psychiatric Association
Genes Linked to Mood Symptoms of Premenstrual Dysphoric Disorder
Jun Yan
Why do some women have severe mood swings and anxiety before
menstruation? Researchers find a genetic piece of the puzzle.
Researchers have linked specific genetic polymorphisms in ESR1, the
estrogen receptor alpha gene, to premenstrual dysphoric disorder (PMDD) in a
new study to be published in an upcoming issue of Biological
Psychiatry.
The finding not only helps explain the individual differences and
hereditary component of the disorder, but sheds light on the neurohormonal
mechanisms in mood regulation.
According to criteria outlined in the appendix of the DSM-IV-TR,
PMDD is characterized by markedly depressed mood, anxiety, and/or irritability
in the last week of the luteal phase of most menstrual cycles in the prior
year. The symptoms diminish shortly after menstruation and must be severe
enough to cause impairment in normal function.
The condition is currently not included in the main text of
DSM-IV-TR but is listed among criteria sets that are deemed to
require further study. However, the U.S. Food and Drug Administration has
approved drug treatment, including fluoxetine (marketed under the brand name
Sarafem), sertraline (Zoloft), paroxetine controlled-release (Paxil CR), and
the oral contraceptive drospirenone and ethinyl estradiol combination (Yaz)
for this particular indication. PMDD affects about 5 percent to 8 percent of
women and is associated with substantial morbidity, according to the authors
of the study.
The underlying cause of PMDD is presumed to be hormonal but has not been
clearly mapped out. Women with menstrual cycle—related mood disorders do
not have abnormal levels of progesterone or estradiol. Other than reproductive
hormones, several neurotransmission systems involving serotonin, gamma-amino
butyric acid (GABA), and beta-endorphin have also been suspected. Notably,
previous family and twin studies have suggested a significant genetic
component in PMDD.
There are two types of estrogen receptors: alpha (coded by the gene ESR1)
and beta (coded by the gene ESR2). Both types play critical roles in a variety
of neurological pathways. In this study, researchers analyzed three genes:
ESR1, ESR2, and COMT (the gene for catechol-O-methyltransferase—an
enzyme involved in estrogen metabolism). A number of single nucleotide
polymorphisms (SNPs) commonly found in these genes were tested for their
presence in women with PMDD and a group of control subjects. Ninety-one women
who met the diagnostic criteria of PMDD as specified in DSM-IV and 56
women with no history of menstrual cycle–related mood changes were
included and gave blood samples for genetic study.
Women in both groups were Caucasian, with an average age of approximately
40 and were similar in other demographic and socioeconomic characteristics.
Women included in the PMDD group were free of other mood disorders within two
years of the study to prevent factors that might confound the analyses.
Four SNPs, all located in intron 4 of the ESR1 gene, were significantly
associated with the PMDD group, compared with the control group. (An intron is
the DNA sequence in a gene that is not transcribed into messenger RNA for
protein synthesis.)
In a subanalysis, the researchers further excluded 29 women in the PMDD
group with a history of major depression (although no subject in the study had
a major depressive episode within the previous two years) to study the
remaining "pure" PMDD subjects. These remaining women still had a
statistically significant association with the SNPs in the ESR1 gene compared
with the control group. No significant association with the PMDD group was
observed in the polymorphisms tested in the ESR2 (coding for estrogen receptor
beta) and COMT genes. This finding does not rule out the possibility that both
genes have a role in PMDD pathogenesis.
"This study suggests an involvement of genes for physiologically
meaningful receptors in PMDD. Patients do not have abnormal levels of
estrogen, but rather an abnormal response to normal hormone levels. Our study
findings help explain this paradox and also implicate estrogen receptor alpha,
which we know is relevant in arousal, as possibly mediating the abnormalities
in the steroid signaling pathways and giving rise to affective disorders that
are associated with reproductive steroids," said David Rubinow, M.D.,
one of the authors of the study and the Assad Meymandi Professor and chair of
psychiatry at the University of North Carolina at Chapel Hill.
He cautioned, however, that variations in a single gene are likely to
contribute to only a small part of the mechanism for the disorder, which may
involve other genes and mediators and complex interaction among these
components. The various types of PMDD treatments have suggested several
relevant neurological pathways, including selective serotonin reuptake
inhibitors, gonadotropin-releasing hormone agonists (for example, leuprolide,
buserelin), ovulation-suppressing contraceptives, and benzodiazepines/GABA
modulators such as alprazolam and buspirone.
Rubinow also pointed out that the sample size of this study was small and
that the women in the control group were free of any psychiatric history or
menstrual cycle–related symptoms. The different profiles between the
PMDD and control groups in the ESR1 gene may reflect a genetic variation in
the control group that results in resistance to neuroactive hormone-related
mood disorders. "Large-scale, population genomic analyses have to be
done to demonstrate what is the norm and what is the variation," he
said.
The study was supported by funds from the Intramural Research Program at
the National Institute of Mental Health.
An abstract of "Risk for Premenstrual Dysphoric Disorder Is
Associated With Genetic Variation in ESR1, the Estrogen Receptor Alpha
Gene" is posted at
<www.journals.elsevierhealth.com/periodicals/bps/article/PIIS0006322306015587/abstract>.
Get information about faster international access.
Privacy Policy
Copyright © 2007
American Psychiatric Association.
All rights reserved.
Home
| Search
| Current Issue
| Past Issues
| Subscribe
| All APPI Journals
| Help
| Contact Us
| 
