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INNOSC Theranostics and
Pharmacological Sciences The Takotsubo syndrome: A gender disparity

predominance. This theory is in line with the concept inflammation emerges as a pathophysiologic factor. Stronger
of decreased magnitude of inter-hemispheric cortical immune responses to foreign and self-antigens are observed
lateralization in premenopausal women compared to men in women than in men, providing an explanation regarding
and postmenopausal women. Decrease of endogenous the higher prevalence of most autoimmune diseases among
female sex steroid levels in postmenopausal women leads women. There have been some investigations suggesting
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to reduced influence of estrogens on the left hemisphere, that CUMS leads to the development of GC receptor
which is believed to have parasympathetic predominance. resistance, which results in its upregulation and failure to
This results in sympathovagal imbalance, increasing inhibit the inflammatory response.
sympathetic system activity in postmenopausal women, Notably, it has been demonstrated that the sexually
rendering postmenopausal women more susceptible to dimorphic effects of GC are linked to inflammatory diseases
sympathetically mediated syndromes such as TTS.
that differ in frequency between genders. With the use
4.3. Role of GCs in modulation of stress response of experimental rat models and gene editing techniques,
the Cidlowski group demonstrated that the underlying
GCs are hormones produced in response to stress to inflammatory components seem to play a crucial role in
control inflammatory and immunosuppressive responses the recognized gender difference of the prevalence of
as well as the growth and function of CNS, intermediate many major diseases. They emphasized that inflammation
metabolism, vascular tone, and – most importantly – is a reflection of the balance between pro- and anti-
the process of programmed cell death. The GR acts inflammatory signals and looked into the responses
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as a mediator for their action. Hence, GR expression is that are specific to gender. They discovered sex-specific
proposed as a stress-related surrogate marker for a diverse GC-regulated genes in a number of canonical pathways
range of stress situations, including post-traumatic stress linked to the development and susceptibility to pertinent
disorder and chronic stress. 51
diseases with prevalence differences between genders.
Of note, stress can have negative effects and cause Specifically, they opine that either the anti-inflammatory
diseases in people who exhibit poor self-regulation, properties of GC are more potent in men or their absence
such as increased inflammation: it was convincingly may encourage the onset of specific illnesses in women.
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presented that male rats exposed to CUMS showed In a different article, the same group described a priming
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elevated expression of GR in response to CUMS. Malta mechanism in female mice in homeostatic condition that
et al.’s study emphasizes that GR is involved in regulating causes them to respond to an inflammatory stimulus
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CUMS responses, which are dependent on GC and more quickly. This mechanism causes the female mice to
NE signaling in male rats. The authors provide specific express more of the proinflammatory genes that are most
evidence that the 14-day treatment of CUMS to male rats frequently regulated. This idea is supported by research
resulted in a persistent hyperactivity of the HPA axis, as from other groups, which recently suggested that CUMS
demonstrated by an increase in plasmatic corticosterone might lead to the development of GR upregulation and
and hypertrophy of the adrenal glands. These effects were resistance impairing the suppression of inflammation. 1
dependent on the increased release of GCs and NE that
were generated during each stress session. GR protein 5. Conclusion
levels were shown to be elevated in key brain regions Chronic unpredicted mild stress is reportedly to exert
linked to HPA regulation and behavior after exposure to a potentially bigger influence on TTS development
CUMS. In a recent study, these findings were expanded than previously thought. Specifically, it pertains to the
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by measuring blood hormone and hormone receptor levels relationship between the aforementioned reduction in GR
of TTS female patients. While more research is required to
1
investigate additional CUMS-related brain GR expression and beta-adrenergic receptor sensitivity and persistent
patterns in TTS patients or animal models, these findings psychological stress. GC resistance may cause the HPA axis
clearly indicated that TTS-prone postmenopausal females to be dysregulated and GR to be overexpressed. Increased
have a higher corticosteroid response as compared to GC levels and long-term immunosuppression with elevated
healthy individuals, providing a molecular perspective on levels of peripheral proinflammatory markers may be
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the gender disparity in stress response. caused by dysregulated negative feedback. As a result, the
parasympathetic nervous system becomes less active and
4.4. Role of GCs and gender aspects in modulation the sympathetic nervous system becomes more active.
of inflammation The HPA axis’s GC negative feedback appears disrupted
In addition to physical and emotional triggers, female in TTS, causing the GCs to maintain at elevated levels in
gender, and age-related deficiency of female sex hormones, the system and sustaining their activation in a gender-

Volume 7 Issue 4 (2024) 5 doi: 10.36922/itps.3142