2004 Psychiatric Times. All rights reserved.

Other Hormones on Behavior

by Leslie Knowlton
Psychiatric Times August 1999 Vol. XVI Issue 8

To address the influence of estrogen and other hormones on behavior, Lyn Harper Mozley,
Ph.D., assistant professor of psychology in psychiatry at the University of Pennsylvania, is
examining olfaction in healthy women and in women with schizophrenia across the life span.
She discussed her project at the 10th annual scientific symposium of the National Alliance for
Research on Schizophrenia and Depression (NARSAD), held in New York. NARSAD is
funding Mozley's work with a Young Investigator Award.
Mozley is involved with the Mental Health Clinical Research Center for schizophrenia within
the university's department of psychiatry. "My mentors there, Ruben Gur [Ph.D.] and Raquel
Gur [M.D., Ph.D.], have been interested in gender differences for some time," she said. "But
this is really our first effort looking into women's health, and it's a very energetic and
intensive effort."
Mozley said the evidence for a relationship between estrogen and psychosis comes from
studies of gender differences in schizophrenia, as well as studies that examined clinical
symptomatology associated with the menstrual cycle (Lindamer et al., 1997).
"Studies show that women tend to be diagnosed with schizophrenia about two to 10 years
later than men," Mozley said. "Another gender difference is that after the age of 40 to 45,
when there is reduced estrogen, women are more likely to be diagnosed with schizophrenia
than are men. This observation led researchers to hypothesize that estrogen has some
protective effect on premenopausal women, perhaps in the form of a raised vulnerability
threshold for schizophrenia. And, later in life, at the time of menopause, there may be an
increased risk of developing schizophrenia."
Mozley said Lindamer et al. looked at gender differences in age of onset. They loooked at
almost 200 outpatients with schizophrenia, who ranged in ages from 35 to 97.
"When age of onset of schizophrenia was considered, results indicated that at less than 25
years of age, more men than women developed the illness, 51% compared to 37%," Mozley
reported. "But after age 45, it was 37% in women compared to 16% in men."
The authors also noted that in another sample of older patients with schizophrenia, females
had significantly more severe positive symptoms than males, added Mozley.
"In younger patients, it's been shown that women have a later age of onset and fewer negative
symptoms [Kopala et al., 1995]," she said. "Women are more responsive to neuroleptic
treatment, sometimes [require] lower doses of medication, have a less severe course of illness,
and tend to have better social functioning than men."

With regards to the menstrual cycle, Mozley said it appears that clinical symptoms, such as
thought disorder, are reduced when levels of estrogen are higher, and that symptoms are
exacerbated with lower estradiol levels around the time of menstruation.
"This finding regarding the relationship between symptoms and menstrual status is consonant
with the notion that estrogen acts as a neuroleptic, since positive symptoms have been
associated with increased dopa-mine activity," Mozley said. "In addition, some authors have
reported that women with schizophrenia tend to be admitted to the hospital during the lowestrogen phase of their menstrual cycles. Women with schizophrenia also tend to have more
relapses postpartum and postmenopausally, and fewer relapses during pregnancy, when
estrogen levels are higher. Furthermore, symptoms can also improve during pregnancy. This
finding might be somewhat disorder-specific, in that the relapse rate for women with
schizophrenia after childbirth is lower than [the relapse rate] for those with affective
disorders."
Mozley next addressed the issue of olfaction and schizophrenia specific to gender.
"There are also sex differences in olfactory identification," she explained, citing Kopala et al.
"Men with schizophrenia tend to have more impaired ability to identify odors than women
[with schizophrenia do], even though their acuity, or their thresholds, are not impaired. Based
on animal work, Kopala speculated that the functional specialization of the orbital frontal
cortex, and perhaps the amygdala and hippocampus, might take place at different rates in
males and females. These structures, in addition to a few others, are traversed by the olfactory
pathway, so they're very much implicated in olfaction. These are regions that are also rich in
dopamine pathways, as well as estrogen receptors."
As noted by the Kopala et al.study , Mozley continued, the assessment of olfaction in women
with schizophrenia might be used as a means to identify subgroups of women with
abnormalities in brain regions involved in olfaction.
"So we're really looking at olfaction as a probe to get at the potential role of estrogen in
schizophrenia," she said.
Mozley said her project is in many ways a replication of Kopala et al.'s pioneering study that
examined the relationship between estrogen and olfaction in healthy women and in women
with schizophrenia.
"One difference [between her study and ours] though, is that although she measured levels of
estrogen, she didn't really control for where women were hormonally in their menstrual
cycle," said Mozley.
In the Kopala et al. study, premenopausal women were tested at day 1 of their menstrual
cycles and 14 days later. The postmenopausal women were tested on an arbitrary day 1, and
again two weeks later.
"One of the difficulties with doing that sort of study in the premenopausal women is that even
though you have two women with normal cycles, they might not be at the same place in their
cycles, hormonally, at day 14," said Mozley. "So my study represents a modification in that
I'm asking the premenopausal women to monitor their ovulationI'm testing premenopausal
women on the first day of their menstrual cycles and again 24 to 36 hours after ovulation.

Postmenopausal women will be tested on day 1 and two weeks later. As you can see, it's really
almost two studies in one, looking at olfaction in the menstrual cycle in healthy women, but
then also comparing women with schizophrenia to healthy women."
Mozley explained that following the Kopala et al. study, her major hypotheses are that women
with schizophrenia will be impaired in olfactory identification relative to healthy women, and
that premenopausal women, regardless of diagnosis, will likely have better olfactory
identification than the postmenopausal women, presumably because of a decrease in estrogen
postmenopausally. Another hypothesis is that women with schizophrenia will have lower
levels of circulating estradiol than controls.
Mozley said her study will ultimately include 30 women with schizophrenia and 30 healthy
volunteers. Each group will include 15 premenopausal and 15 postmenopausal women. Blood
will be drawn to assess hormonal levels. The primary olfaction measure is a scratch-and-sniff
test that measures olfactory identification, the University of Pennsylvania Smell Identification
Test (UPSIT).
"It's a standardized, forced-choice test in that you scratch the odor and give people four
choices, such as [asking] 'does this smell most like pine, gasoline, menthol or licorice?'"
Mozley said. "Odor detection thresholds are also measured, and an additional task, the Picture
Identification Test, is given as a control for the non-olfactory, cognitive aspects of the
UPSIT."
Mozley said that in addition to trying to link estrogen levels to olfaction across the menstrual
cycle, she will also attempt to evaluate neurotransmitter systems more directly.
"My husband, P. David Mozley [M.D., associate professor of nuclear medicine and psychiatry
at the university], is studying the dopamine transporter system in healthy aging, as well as
various disorders," she explained.
"We're also hoping to have these same subjects participate in his studies involving SPECT
[single photon emission computerized tomography] imaging of dopamine transporter function
on the same days. That will enable us to directly link dopamine to hormone levels and
olfaction in the same women."
Addressing treatment implications, Mozley said: "At this point, there has really not been a lot
of research done looking at augmenting neuroleptic treatment with estrogen. A few case
studies have generally shown estrogen augmentation to be beneficial. A study which involved
more patients [Kulkarni et al., 1996] found that, in combination with standardized neuroleptic
treatment, estrogen was initially more helpful in reducing positive symptoms than medication
alone. However, after two months, there was no difference in terms of positive
symptomatology between the two treatment groups."
In conclusion, Mozley noted that she, Raquel Gur and their colleagues are also planning
longitudinal treatment studies.
"These are aimed at examining the effects of estrogen within the context of standardized
medication protocols, as well as neuropsychological remediation and psychosocial skills
training in women with schizophrenia," she said. "All this work is part of our efforts to
include more interventional research."

References
Kopala LC, Good K, Honer WG (1995), Olfactory identification ability in pre- and
postmenopausal women with schizophrenia. Biol Psychiatry 38(1):57-63.
Kulkarni J, de Castella A, Smith D et al. (1996), A clinical trial of the effects of estrogen in
acutely psychotic women. Schizophr Res 20(3):247-252.
Lindamer LA, Lohr JB, Harris MJ, Jeste DV (1997), Gender, estrogen, and schizophrenia.
Psycho-pharmacology Bull 33(2):221-228.
Further Reading
Hafner H, an der Heiden W, Behrens S et al. (1998), Causes and consequences of the gender
difference in age of onset of schizophrenia. Schizophr Bull 24(1):99-113.
Hallonquist JD, Seeman MV, Lang M, Rector NA (1993), Variation in symptom severity over
the menstrual cycle of schizophrenics. Biol Psychiatry 33(3):207-209.
McEwen BS, Woolley CS (1994), Estradiol and progesterone regulate neuronal structure and
synaptic connectivity in adult as well as developing brain. Exp Gerontol 29(3-4):431-436.
Seeman MV, Lang M (1990), The role of estrogens in schizophrenia gender differences.
Schizophr Bull 16(2):185-194.
Sherwin BB (1998), Estrogen and cognitive functioning in women. Proc Soc Exp Biol
Medicine 217(1):17-22.