Exploring the Impact of Progesterone-Enriched Contraceptives on Mood Disorders and Suicide Risk: Insights from Neuroactive Steroids in the Human Hypothalamus


Neuroactive steroids have long been recognized for their pivotal role in modulating various biological functions within the human hypothalamus, impacting both health and disease states. This intricate relationship extends to the modulation of specific stress-related neuropeptide and neurotransmitter systems, suggesting a complex interplay between hormonal fluctuations and mental health outcomes. Recent advancements in the field have shed light on the dynamic and biphasic relationship between progesterone levels and suicide risk, unveiling a nuanced understanding of hormonal influences on suicidal behaviors.

Clinical and forensic studies have highlighted a notable pattern in the prevalence of suicidal behaviors among fertile women during the peri-menstrual period—a time characterized by elevated peripheral progesterone levels. This trend is mirrored in menopausal and amenorrheic women, where a decrease in peripheral progesterone levels has been observed. These findings are further corroborated by a nationwide prospective analysis, which reported an increased risk of suicide among contraception users, correlating with higher proportions of progesterone in contraceptives. Intriguingly, women who had attempted suicide repeatedly exhibited higher plasma levels of progesterone, but not estrogen, pointing towards a specific role of progesterone in modulating suicidal tendencies.

Despite these correlations, research directly investigating the effects of progesterone on the human central nervous system, specifically in the context of suicidal behaviors, had been lacking. Progesterone exerts its regulatory functions on neural responses through the progesterone receptor (PR), a mechanism that underpins its potential impact on mood and behavior. An MRI study has even linked oral contraceptive use to reduced hypothalamic volumes in healthy women, suggesting structural brain changes associated with progesterone modulation.

To delve deeper into the role of progesterone and PR in mood disorders and suicide, this study embarked on a comprehensive examination of the distribution of PR within the human hypothalamus, considering factors such as age and sex. The investigation extended to understanding the neurobiological signatures of PR in glial and peptidergic neurons, with a specific focus on the infundibular nucleus (INF)—a region dense in PR and critical in stress regulation.

The INF houses two distinct neuronal populations: pro-opiomelanocortin (POMC)-expressing neurons and neuropeptide Y (NPY)-expressing neurons. Both types play significant roles in mood disorders and suicidality. POMC+ neurons, in particular, have been implicated in depressive-like behaviors and the regulation of mood through preclinical stress studies. The interaction between selective serotonin reuptake inhibitors (SSRIs) and serotonin receptor 2A antagonists on ARC POMC+ neurons suggests a therapeutic pathway in psychiatric disorders. Similarly, NPY-expressing neurons have been associated with depression in rodent models, showing decreased levels in critical brain regions that are reversible by SSRIs and electroconvulsive therapy, indicating a potential antidepressant effect.

TABLE 1 – The Infundibular nucleus (INF)

The Infundibular nucleus (INF), a critical region within the human hypothalamus, plays a pivotal role in mood regulation and stress response, hosting two key neuronal populations that significantly influence these processes: pro-opiomelanocortin (POMC)-expressing neurons and neuropeptide Y (NPY)-expressing neurons. Each of these neuronal types contributes to the neurobiological underpinnings of mood disorders and suicidality through distinct pathways and mechanisms. Understanding their roles offers valuable insights into potential therapeutic targets for treating these conditions.

Pro-opiomelanocortin (POMC)-Expressing Neurons

POMC neurons are integral to the body’s stress response and mood regulation mechanisms. POMC is a precursor polypeptide that undergoes enzymatic cleavage to produce several important molecules, including adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormones (α-MSH, β-MSH), and β-endorphin, which are involved in stress response, energy homeostasis, and pain and immune modulation.

Role in Mood Disorders and Suicidality

  • Depressive-Like Behaviors: POMC+ neurons have been implicated in the regulation of depressive-like behaviors through their involvement in the stress response pathway. The release of POMC-derived peptides, particularly β-endorphin, plays a role in the body’s natural pain and stress relief mechanisms, suggesting a link between POMC activity and mood regulation.
  • Regulation of Mood: The modulation of mood by POMC+ neurons is likely mediated through their interaction with various neurotransmitter systems, including the serotonin system. β-Endorphin, for example, can influence mood by modulating dopaminergic and serotonergic neurotransmission, pathways often dysregulated in mood disorders.

Therapeutic Pathway

  • SSRIs and Serotonin Receptor 2A Antagonists: The interaction between selective serotonin reuptake inhibitors (SSRIs) and serotonin receptor 2A (5-HT2A) antagonists on ARC POMC+ neurons suggests a potential therapeutic pathway in psychiatric disorders. SSRIs increase serotonin levels in the synaptic cleft, potentially enhancing the mood-regulating effects of POMC-derived peptides. 5-HT2A receptor antagonists may further modulate this pathway by altering the responsiveness of POMC+ neurons to serotonin, thereby influencing mood and stress responses.

Neuropeptide Y (NPY)-Expressing Neurons

NPY is a 36-amino acid peptide neurotransmitter widely distributed in the brain, known for its roles in anxiety, stress response, food intake, and energy homeostasis.

Role in Depression

  • Depression in Rodent Models: NPY-expressing neurons have been associated with depression, with studies in rodent models showing that decreased levels of NPY in critical brain regions are linked to depressive-like behaviors. This is particularly evident in the prefrontal cortex and limbic structures, areas involved in emotion regulation.
  • Antidepressant Effects: The potential antidepressant effects of NPY are highlighted by observations that levels of NPY can be normalized in depressed animal models through treatments with SSRIs and electroconvulsive therapy (ECT). This normalization suggests a direct role of NPY in modulating depressive states, possibly through its effects on stress resilience and neuroplasticity.

SSRIs and Electroconvulsive Therapy

  • SSRIs: The mechanism by which SSRIs exert their antidepressant effect on NPY-expressing neurons may involve the normalization of serotonergic neurotransmission, which, in turn, could influence NPY expression or release. This normalization process may help restore the balance in neural circuits dysregulated in depression.
  • Electroconvulsive Therapy (ECT): ECT, a procedure often used for treatment-resistant depression, has been shown to increase NPY levels in the brain. The mechanism is not fully understood but may involve the induction of neuroplastic changes and enhancement of neurogenesis, processes in which NPY is known to play a role.

The distinct yet interconnected roles of POMC and NPY-expressing neurons in the INF highlight the complexity of the hypothalamic regulation of mood and stress responses. POMC neurons, through their production of peptides like β-endorphin, and NPY neurons, through their regulation of stress and emotional responses, offer critical insights into the neurobiological foundations of mood disorders and suicidality. Targeting these pathways pharmacologically, through the use of SSRIs, 5-HT2A antagonists, or interventions like ECT, represents a promising avenue for developing more effective treatments for these debilitating conditions. Understanding these mechanisms in greater detail will be essential for advancing our ability to intervene in mood disorders and reduce suicidality.

Given these observations, the study hypothesized a significant role for progesterone in modulating mood disorders and suicidal behaviors through its effect on PR-expressing, stress-related neurons. By examining the distribution of PR and its co-expression in hypothalamic nuclei, particularly in the context of mood disorders, death ideation, and suicidal behaviors, this research aimed to uncover the cellular mechanisms underpinning the association between progesterone levels and mental health outcomes. The quantification of POMC+ and NPY+ neurons and their co-localization with PR in the INF among individuals with mood disorders and controls offered a novel insight into the neurobiological basis of mood regulation and suicidality, paving the way for targeted therapeutic interventions.

Comprehensive Analysis of Hormonal Contraceptives: Progestin-Only and Combined Estrogen-Progestin Formulations

Hormonal contraceptives have revolutionized family planning and reproductive health since their introduction over six decades ago. Today, they are utilized by approximately 150 million individuals worldwide, signifying their widespread acceptance and the pivotal role they play in women’s health. The landscape of hormonal contraception is diverse, encompassing progestin-only formulations and combined estrogen-progestin contraceptives, each tailored to meet various health and lifestyle needs. This article delves into the intricacies of these contraceptives, focusing on their components, mechanisms of action, and the broader implications on users’ health and well-being.

Progestin-Only Contraceptives: A Closer Look

Progestin-only contraceptives (POCs) represent a crucial category within hormonal birth control options, offering an alternative to those who may not tolerate estrogen. These include progestin-only pills (POPs), intrauterine devices (IUDs), contraceptive implants, and injections, each containing specific types of synthetic progestins such as desogestrel, drospirenone, levonorgestrel, and etonorgestrel, respectively. Medroxyprogesterone acetate stands out in the injectable form, showcasing the diversity in progestin use and its tailored application to meet different contraceptive needs.

The progestin-only approach contrasts with combined oral contraceptives (COCs), which marry progestins with estrogen, typically ethinylestradiol. However, advancements in COCs have seen the inclusion of bio-identical estrogens like estetrol or estradiol-valerate, which are metabolized into estradiol, providing a more natural hormonal balance.

Mechanisms of Action: Synthetic Progestins

Synthetic progestins mimic the action of endogenous progesterone but with unique pharmacological profiles. Their primary mechanism involves activating nuclear progesterone receptors while exhibiting anti-estrogenic effects, such as downregulating estrogen receptor expression and reducing endogenous estradiol production. This dual action underscores the intricate balance synthetic progestins maintain within the hormonal milieu, influencing various physiological processes from reproductive health to mood and cognition.

Progestins’ binding affinity to nuclear steroid hormone receptors plays a significant role in their efficacy and safety profile. These affinities vary across different types, with implications for their agonistic and antagonistic potential towards receptors like androgen, glucocorticoid, and mineralocorticoid receptors. Such variability underscores the importance of choosing the appropriate progestin formulation to align with individual health profiles and contraceptive goals.

Furthermore, synthetic progestins differ from natural progesterone in their metabolic pathways and impacts on neurotransmitter signaling, particularly concerning the GABA-A receptor. This distinction is crucial for understanding the nuanced effects of progestins on mood and cognitive functions, as well as their potential neuroprotective properties mediated through alternative receptors such as mPRs and PGMRCs.

The Impact on Brain and Behavior

The influence of hormonal contraceptives extends beyond reproductive health, affecting neurological and behavioral outcomes. Studies indicate that hormonal contraceptives can lead to both positive and negative mood alterations, with a subset of users experiencing depressive symptoms. Cognitive effects are also noted, with some evidence pointing to improvements in verbal memory. These findings highlight the need for personalized contraceptive strategies to minimize adverse effects and optimize well-being.

Recent research has shed light on how hormonal contraceptives may alter brain structure and function, pointing to changes in gray matter volume, cortical thickness, and brain connectivity. Understanding these changes is key to unraveling the complex interactions between contraceptive hormones and brain health. It necessitates an interdisciplinary approach, combining human neuroimaging studies with preclinical research to map the brain systems responsive to contraceptive steroids.

Looking Forward: Research Directions and Clinical Implications

The quest to fully comprehend the effects of contraceptive progestins on the brain and behavior is ongoing. Identifying the cellular and molecular mechanisms underlying observed changes in neuroimaging parameters could pave the way for more effective and side-effect-free contraceptive options. This endeavor requires a systematic review of how contraceptive progestins, both alone and in combination with estrogens, influence neurogenesis, synaptogenesis, myelination, and neurotransmitter signaling.

As we continue to explore the intricate relationship between hormonal contraceptives and brain health, it’s clear that a personalized approach to contraceptive care is paramount. By understanding individual sensitivities and responses to different hormonal formulations, healthcare providers can tailor contraceptive methods to better suit each person’s unique physiological and psychological profile. This tailored approach not only aims to optimize contraceptive efficacy but also to enhance overall quality of life for those using hormonal contraceptives.

TABLE 2. Hormonal contraceptives currently in use. 

currently the standard of care The table lists only synthetic steroid combinations – variations in concentrations and recommended intake regimen (21+7, 24+4, 28+0) are available. Oral administration often requires a pro-drug, i.e. the physiologically active progestin is listed in brackets.

Empty CellProgestinEstrogen
InjectionsMedroxyprogesterone acetateN/A
POPs – third generationDesogestrel (→ Etonorgestrel)N/A
POPs – fourth generationDrospirenoneN/A
COCs – first generationChlormadinone acetateEthinylestradiol
Cyproterone acetateEthinylestradiol
COCs – second generation1LevonorgestrelEthinylestradiol
COCs – third generationGestodenEthinylestradiol
Desogestrel (→ Etonorgestrel)Ethinylestradiol
Norgestimat (→ Norelgestromin)Ethinylestradiol
COCs – fourth generationDienogestEthinylestradiol
Nomegestrol acetateEstradiol valerate

Neuroimaging Insights: The Impact of Contraceptive Hormones on the Human Brain

The intersection of hormonal contraception and neuroimaging has opened a new frontier in understanding how these ubiquitous medications influence the human brain. A surge of research, culminating in recent years, has provided mixed yet fascinating insights into the effects of contraceptive hormones on brain structure and function. This article synthesizes findings from key neuroimaging studies, including a seminal meta-analysis and subsequent studies up to 2022, to elucidate the nuanced impacts of contraceptive hormones, particularly combined oral contraceptives (COCs), on the brain.

The Landscape of Neuroimaging Studies on Hormonal Contraceptives

A comprehensive meta-analysis by Broennick et al. (2020) identified 33 neuroimaging studies focusing on the brain’s response to hormonal contraceptives, a number that expanded with five additional studies and one PET study published thereafter. These studies reveal a complex picture, likely influenced by the cross-sectional nature of the majority, which introduces potential sampling biases. Such biases may obscure whether observed brain differences are pre-existing, a result of previous contraceptive use, or directly attributable to current contraceptive use.

Specificity of Progestins and Study Designs

A critical limitation within this body of research is the frequent omission of specific progestins used in hormonal contraceptives, which muddles the interpretation of results. This specificity is crucial, as different progestins can have varied effects on the brain. Thus, this article focuses on longitudinal neuroimaging studies and cross-referencing results from cross-sectional studies that identified the type of progestin used, offering a clearer understanding of hormonal contraceptives’ impacts on brain structure and activity.

Frontal Cortex: A Region of Interest

Studies have pinpointed the prefrontal cortex as a significant area of interest, particularly concerning levonorgestrel (LNG)-containing COCs. Findings from controlled trials suggest that COC use, especially in women with previous negative affective responses, can lead to reduced activity and cortical thickness in several prefrontal areas. These changes are associated with decreased emotional responsiveness and mood worsening, highlighting the sensitivity of some women to the emotional effects of LNG. The exploration into whether LNG impacts neurogenesis, synaptogenesis, or neurotransmitter content in frontal brain areas is ripe for further investigation.

Amygdala and Salience Network: Emotional Processing and Connectivity

The amygdala, critical for emotional processing, also shows significant changes with COC use, including reduced gray matter volume and connectivity with the dorsolateral prefrontal cortex. Such modifications suggest alterations in how emotional stimuli are processed and may reflect broader changes in the brain’s salience network, which includes the anterior cingulate cortex and bilateral insula. This network’s reactivity to emotional stimuli and its connectivity patterns appear to be modulated by COC use, potentially influencing mood and emotional responsiveness.

Hippocampus and Parahippocampus: Memory and Spatial Navigation

While no longitudinal studies have directly linked COC use to changes in hippocampal volumes or activation, the extension of observed amygdala changes into the parahippocampal gyrus warrants attention. The hippocampus, known for its plasticity and sensitivity to hormonal fluctuations, presents an intriguing target for future research on contraceptive formulations’ effects. Mixed results from various studies on hippocampal volume changes with COC use call for more nuanced investigations, particularly regarding how specific progestins interact with ethinylestradiol.

The body of neuroimaging research on hormonal contraceptives is growing, yet challenges remain in disentangling the specific effects of different contraceptive formulations on the brain. The variability in study designs, contraceptive formulations, and the individual biological response to these medications underscores the need for more targeted and longitudinal research. Understanding the mechanisms through which hormonal contraceptives influence brain structure and function will not only advance our scientific knowledge but also guide more personalized and effective contraceptive choices for individuals worldwide. As we move forward, bridging the gap between neuroimaging findings and clinical outcomes will be crucial in optimizing contraceptive use for both efficacy and mental health.

Discussion – Progesterone Receptors and Suicidality: Unraveling the Role of the Human Hypothalamus in Mood Disorders

The human hypothalamus is a critical regulator of mood and stress, yet the specific pathophysiological mechanisms differentiating suicidality from mood disorders (MD) remain elusive and highly debated. This discussion presents groundbreaking insights into the role of progesterone receptors (PR) within the hypothalamus, particularly in relation to suicide. By closely examining the distribution and function of PR in peptidergic neurons, this study illuminates the complex interplay between hormonal changes and psychiatric conditions, offering new perspectives on the neurobiological underpinnings of suicide.

Key findings from this research reveal that hypothalamic PR-containing cells are predominantly concentrated in nuclei adjacent to the third ventricle, exhibiting a stable pattern across sexes and throughout the lifespan. This study highlights the co-expression of PR in various peptidergic neurons and neural progenitors, indicating a broader regulatory role of progesterone in hypothalamic function. Notably, an increase in POMC+ neurons within the infundibular nucleus (INF) was observed in suicide completers with MD, primarily attributed to PR/POMC co-expressing neurons. Conversely, the study found a marked reduction in NPY+ neurons in the INF among patients with MD, with no significant changes in PR/NPY co-expressing neurons. Additionally, a gender-specific reduction in NPY expression was observed in males but not females with MD, suggesting sex-specific neurobiological pathways in mood regulation.

These findings significantly advance our understanding of the endogenous opioid system’s role in suicide, proposing that progesterone-mediated alterations in hypothalamic peptides are crucial to the molecular basis of psychopathology associated with suicide. The study meticulously outlines the distribution of PR+ cells throughout the human lifespan, drawing parallels with animal studies and emphasizing the multifaceted influence of progesterone on neuroendocrine regulation. This widespread PR distribution suggests a potential pathway through which peripheral progesterone could influence emotional and metabolic integration within the brain.

The study also explores the association between progesterone and neurogenesis, evidenced by PR’s co-localization with neural progenitors in the subventricular zone (SVZ). This finding underscores progesterone’s involvement in adult neurogenesis, further linking hormonal activity to brain function and mood regulation. The elevated expression of POMC in the context of suicide ideation and behavior highlights the significant impact of progesterone on the endogenous opioid system, suggesting a mechanism through which progesterone modulates POMC synthesis and influences suicidal behaviors.

This research not only underscores the critical role of PR in the hypothalamus but also sheds light on the complex neurobiological mechanisms underlying mood disorders and suicidality. By identifying increased numbers of PR/POMC+ neurons in patients with MD and suicidal tendencies, the study offers novel insights into the potential therapeutic targets for addressing these psychiatric conditions. Furthermore, the distinct patterns of NPY expression in relation to MD and gender point to the need for tailored approaches in the treatment and understanding of mood disorders.

Despite the groundbreaking nature of these findings, the study acknowledges limitations, including the absence of menstrual cycle data and the small sample size restricted by the specificity of legal euthanasia cases. Additionally, the lack of categorization regarding the method of suicide and the potential influence of antidepressants on the findings are noted as areas requiring further investigation.

In conclusion, this comprehensive examination of PR in the human hypothalamus reveals its significant association with suicidality, particularly through the modulation of POMC+ neurons in patients with MD. The identification of specific neuronal subpopulations affected by progesterone offers a deeper understanding of the molecular mechanisms driving mood disorders and suicide. This study highlights the importance of considering hormonal influences in the development of psychiatric treatments, especially for women using hormonal contraception with high progesterone concentrations.

reference link :

  • https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-024-01733-y
  • https://www.sciencedirect.com/science/article/pii/S0091302223000080


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