graph LR
Lifestyle_Modification["Lifestyle Modification"]
Pasteurized_Akkermansia_muciniphila_MucT_Supplementation["Pasteurized Akkermansia muciniphila MucT Supplementation"]
High_Calorie_Diet["High-Calorie Diet"]
LEP["LEP"]
MC4R["MC4R"]
Energy_Imbalance["Energy Imbalance"]
POMC["POMC"]
Obesogenic_Environment["Obesogenic Environment"]
Post_Weight_Loss_Weight_Regain["Post-Weight-Loss Weight Regain"]
Increased_Body_Mass_Index["Increased Body Mass Index"]
Intestinal_Barrier_Dysfunction_and_Metabolic_Endotoxemia["Intestinal Barrier Dysfunction and Metabolic Endotoxemia"]
LEPR["LEPR"]
GLP_1_GIP_Dual_Agonists["GLP-1/GIP Dual Agonists"]
Chronic_Low_Grade_Inflammation["Chronic Low-Grade Inflammation"]
Depletion_of_Mucosal_Symbiont_Akkermansia_muciniphila["Depletion of Mucosal Symbiont Akkermansia muciniphila"]
GLP_1_Receptor_Agonists["GLP-1 Receptor Agonists"]
Orlistat["Orlistat"]
Hypothalamic_Dysregulation["Hypothalamic Dysregulation"]
Bariatric_Surgery["Bariatric Surgery"]
Efficient_Intestinal_Energy_Harvest["Efficient Intestinal Energy Harvest"]
Naltrexone_Bupropion["Naltrexone-Bupropion"]
Depletion_of_Mucosal_Symbiont_Akkermansia_muciniphila --> Intestinal_Barrier_Dysfunction_and_Metabolic_Endotoxemia
Intestinal_Barrier_Dysfunction_and_Metabolic_Endotoxemia --> Chronic_Low_Grade_Inflammation
Efficient_Intestinal_Energy_Harvest --> Energy_Imbalance
Post_Weight_Loss_Weight_Regain --> Increased_Body_Mass_Index
High_Calorie_Diet --> Energy_Imbalance
Obesogenic_Environment --> Increased_Body_Mass_Index
Lifestyle_Modification --> Energy_Imbalance
GLP_1_Receptor_Agonists --> Hypothalamic_Dysregulation
GLP_1_Receptor_Agonists --> Energy_Imbalance
GLP_1_Receptor_Agonists --> Post_Weight_Loss_Weight_Regain
GLP_1_GIP_Dual_Agonists --> Energy_Imbalance
GLP_1_GIP_Dual_Agonists --> Post_Weight_Loss_Weight_Regain
Bariatric_Surgery --> Hypothalamic_Dysregulation
Bariatric_Surgery --> Energy_Imbalance
Orlistat --> Efficient_Intestinal_Energy_Harvest
Orlistat --> Post_Weight_Loss_Weight_Regain
Naltrexone_Bupropion --> Hypothalamic_Dysregulation
Pasteurized_Akkermansia_muciniphila_MucT_Supplementation --> Post_Weight_Loss_Weight_Regain
Pasteurized_Akkermansia_muciniphila_MucT_Supplementation --> Efficient_Intestinal_Energy_Harvest
Pasteurized_Akkermansia_muciniphila_MucT_Supplementation --> Intestinal_Barrier_Dysfunction_and_Metabolic_Endotoxemia
MC4R --> Hypothalamic_Dysregulation
LEP --> Hypothalamic_Dysregulation
LEPR --> Hypothalamic_Dysregulation
POMC --> Hypothalamic_Dysregulation
style Lifestyle_Modification fill:#fce7f3
style Pasteurized_Akkermansia_muciniphila_MucT_Supplementation fill:#fce7f3
style High_Calorie_Diet fill:#dcfce7
style LEP fill:#f3e8ff
style MC4R fill:#f3e8ff
style Energy_Imbalance fill:#dbeafe
style POMC fill:#f3e8ff
style Obesogenic_Environment fill:#dcfce7
style Post_Weight_Loss_Weight_Regain fill:#dbeafe
style Increased_Body_Mass_Index fill:#fef3c7
style Intestinal_Barrier_Dysfunction_and_Metabolic_Endotoxemia fill:#dbeafe
style LEPR fill:#f3e8ff
style GLP_1_GIP_Dual_Agonists fill:#fce7f3
style Chronic_Low_Grade_Inflammation fill:#dbeafe
style Depletion_of_Mucosal_Symbiont_Akkermansia_muciniphila fill:#dbeafe
style GLP_1_Receptor_Agonists fill:#fce7f3
style Orlistat fill:#fce7f3
style Hypothalamic_Dysregulation fill:#dbeafe
style Bariatric_Surgery fill:#fce7f3
style Efficient_Intestinal_Energy_Harvest fill:#dbeafe
style Naltrexone_Bupropion fill:#fce7f3
graph LR
FSHR["FSHR"]
Circadian_Disruption_and_Epigenetic_Reprogramming_in_Granulosa_Cells["Circadian Disruption and Epigenetic Reprogramming in Granulosa Cells"]
Hypothalamic_Pituitary_Dysregulation["Hypothalamic-Pituitary Dysregulation"]
Hyperandrogenism["Hyperandrogenism"]
INS["INS"]
Granulosa_Cell_Apoptosis_via_PCSK9_Lipid_Dysregulation["Granulosa Cell Apoptosis via PCSK9-Lipid Dysregulation"]
Gut_Microbiome_Dysregulation_and_Gut_Ovarian_Axis_Inflammation["Gut Microbiome Dysregulation and Gut-Ovarian Axis Inflammation"]
Granulosa_Cell_Ferroptosis_Autophagy_Crosstalk["Granulosa Cell Ferroptosis-Autophagy Crosstalk"]
Adiposity_Amplified_Insulin_Resistance["Adiposity-Amplified Insulin Resistance"]
Population_Specific_Metabolic_vs._Inflammatory_Dysregulation["Population-Specific Metabolic vs. Inflammatory Dysregulation"]
IGF1R["IGF1R"]
Oxidative_and_Endoplasmic_Reticulum_Stress["Oxidative and Endoplasmic Reticulum Stress"]
Chronic_Low_Grade_Inflammation["Chronic Low-Grade Inflammation"]
NFKB1["NFKB1"]
Intrinsic_Post_Receptor_Insulin_Signaling_Defect["Intrinsic Post-Receptor Insulin Signaling Defect"]
Ovulatory_Dysfunction["Ovulatory Dysfunction"]
INSR["INSR"]
LHCGR["LHCGR"]
IRF1["IRF1"]
Hyperandrogenism --> Intrinsic_Post_Receptor_Insulin_Signaling_Defect
Hyperandrogenism --> Adiposity_Amplified_Insulin_Resistance
Hyperandrogenism --> Hypothalamic_Pituitary_Dysregulation
Hyperandrogenism --> Ovulatory_Dysfunction
Hypothalamic_Pituitary_Dysregulation --> Hyperandrogenism
Intrinsic_Post_Receptor_Insulin_Signaling_Defect --> Hyperandrogenism
Intrinsic_Post_Receptor_Insulin_Signaling_Defect --> Ovulatory_Dysfunction
Adiposity_Amplified_Insulin_Resistance --> Hyperandrogenism
Adiposity_Amplified_Insulin_Resistance --> Chronic_Low_Grade_Inflammation
Oxidative_and_Endoplasmic_Reticulum_Stress --> Granulosa_Cell_Ferroptosis_Autophagy_Crosstalk
Gut_Microbiome_Dysregulation_and_Gut_Ovarian_Axis_Inflammation --> Chronic_Low_Grade_Inflammation
Granulosa_Cell_Ferroptosis_Autophagy_Crosstalk --> Ovulatory_Dysfunction
Circadian_Disruption_and_Epigenetic_Reprogramming_in_Granulosa_Cells --> Granulosa_Cell_Ferroptosis_Autophagy_Crosstalk
Granulosa_Cell_Apoptosis_via_PCSK9_Lipid_Dysregulation --> Ovulatory_Dysfunction
LHCGR --> Population_Specific_Metabolic_vs._Inflammatory_Dysregulation
FSHR --> Population_Specific_Metabolic_vs._Inflammatory_Dysregulation
INS --> Population_Specific_Metabolic_vs._Inflammatory_Dysregulation
INSR --> Population_Specific_Metabolic_vs._Inflammatory_Dysregulation
IGF1R --> Population_Specific_Metabolic_vs._Inflammatory_Dysregulation
NFKB1 --> Population_Specific_Metabolic_vs._Inflammatory_Dysregulation
IRF1 --> Population_Specific_Metabolic_vs._Inflammatory_Dysregulation
style FSHR fill:#f3e8ff
style Circadian_Disruption_and_Epigenetic_Reprogramming_in_Granulosa_Cells fill:#dbeafe
style Hypothalamic_Pituitary_Dysregulation fill:#dbeafe
style Hyperandrogenism fill:#dbeafe
style INS fill:#f3e8ff
style Granulosa_Cell_Apoptosis_via_PCSK9_Lipid_Dysregulation fill:#dbeafe
style Gut_Microbiome_Dysregulation_and_Gut_Ovarian_Axis_Inflammation fill:#dbeafe
style Granulosa_Cell_Ferroptosis_Autophagy_Crosstalk fill:#dbeafe
style Adiposity_Amplified_Insulin_Resistance fill:#dbeafe
style Population_Specific_Metabolic_vs._Inflammatory_Dysregulation fill:#dbeafe
style IGF1R fill:#f3e8ff
style Oxidative_and_Endoplasmic_Reticulum_Stress fill:#dbeafe
style Chronic_Low_Grade_Inflammation fill:#dbeafe
style NFKB1 fill:#f3e8ff
style Intrinsic_Post_Receptor_Insulin_Signaling_Defect fill:#dbeafe
style Ovulatory_Dysfunction fill:#dbeafe
style INSR fill:#f3e8ff
style LHCGR fill:#f3e8ff
style IRF1 fill:#f3e8ff
name: com_Obesity__Polycystic_Ovary_Syndrome
creation_date: "2026-08-27T00:00:00Z"
curation_status: CANDIDATE
notes: >-
Split out of `kb/disorders/Polycystic_Ovary_Syndrome.yaml`'s `environmental:`
block (dismech#8296, dismech#8551). That entry listed `Obesity` as an exposure
with the note "Exacerbates insulin resistance and hyperandrogenism", but
obesity is a first-class `Disease` entry in its own right
(`kb/disorders/Obesity.yaml`) and ECTO has no term that would bind it as an
exposure.
Directionality is BIDIRECTIONAL rather than A_BEFORE_B, which is the
substantive difference from `com_Obesity__Heart_Failure`. The sources describe
a self-reinforcing cycle: obesity-induced insulin resistance worsens the
features of PCOS, and PCOS-associated androgen excess promotes visceral
adiposity in turn. Asserting a direction here would pick one arm of a loop the
literature explicitly declines to break.
Two qualifiers worth keeping visible. Obesity is neither necessary nor
sufficient for PCOS, and the association is not universal across national,
cultural and ethnic groups, so this is a modifier relationship rather than a
causal prerequisite. And visceral adiposity specifically, which is common in
women with PCOS whether or not they are obese by body-mass index, is what the
amplifying effect tracks -- so a body-mass-index-defined obesity entry
understates the relationship in lean patients.
disease_a:
slug: Obesity
preferred_term: obesity disorder
term:
id: MONDO:0011122
label: obesity disorder
disease_b:
slug: Polycystic_Ovary_Syndrome
preferred_term: polycystic ovary syndrome
term:
id: MONDO:0008487
label: polycystic ovary syndrome
directionality: BIDIRECTIONAL
effect_direction: RISK
hypotheses:
- description: >-
Obesity and polycystic ovary syndrome reinforce one another through insulin
resistance. Adiposity-driven insulin resistance amplifies ovarian and
adrenal androgen production and worsens ovulatory dysfunction, while
androgen excess promotes visceral fat deposition and further impairs insulin
sensitivity, closing the loop.
evidence:
- reference: PMID:20591140
reference_title: "Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Importantly, PCOS has unique interactions with the ever increasing obesity prevalence worldwide as obesity-induced insulin resistance significantly exacerbates all the features of PCOS."
explanation: >-
States the mechanism and direction the original environmental note
asserted: obesity acts on PCOS through insulin resistance, and does so
across the syndrome's features rather than one of them.
- reference: PMID:40580384
reference_title: The Efficacy of Various Weight Loss Strategies in Alleviating Polycystic Ovary Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The bidirectional relationship between PCOS and obesity contributes to a self-reinforcing and deleterious cycle."
explanation: >-
The basis for typing this association BIDIRECTIONAL rather than picking a
direction. Cited for the directionality claim specifically, not for the
weight-loss interventions the review evaluates.
- description: >-
The amplifying effect tracks visceral adiposity rather than body weight as
such, and obesity is a modifier of the phenotype rather than a prerequisite
for it.
evidence:
- reference: PMID:30445140
reference_title: "Characteristics of obesity in polycystic ovary syndrome: Etiology, treatment, and genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Obesity, particularly visceral adiposity which is common in obese and non-obese women with PCOS, amplifies and worsens all metabolic and reproductive outcomes in PCOS."
explanation: >-
Locates the effect in visceral adiposity, which is present in lean women
with PCOS as well, so a body-mass-index-defined entry understates the
relationship.
- reference: PMID:30445140
reference_title: "Characteristics of obesity in polycystic ovary syndrome: Etiology, treatment, and genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Obesity is neither necessary nor sufficient for the PCOS phenotype, and the association of PCOS with obesity is not universal, with national, cultural, and ethnic differences."
explanation: >-
Bounds the claim. PARTIAL because it qualifies the association rather than
supporting it: obesity modifies the phenotype without being required for
it, and the strength of the association varies by population.
association_signals:
- source: LITERATURE
method: LITERATURE_ASSOCIATION
population: >-
Women with polycystic ovary syndrome, as summarised across reported series;
the range is wide because ascertainment and diagnostic criteria differ
between them, which is the same population-dependence the second hypothesis
above records.
directionality: BIDIRECTIONAL
effect_direction: RISK
statistics:
metrics:
- metric_type: PREVALENCE
metric_value: 40.0
notes: >-
Lower bound of the reported overweight-or-obese proportion among women
with PCOS; the upper bound is 85%. Recorded as a co-occurrence
prevalence, not a directed risk estimate: this association is typed
BIDIRECTIONAL, so neither arm has a forward cohort measurement here, and
the figure says how often the two are seen together rather than how much
either raises the other.
evidence:
- reference: PMID:40352401
reference_title: "PCOS and Obesity: Contraception Challenges."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A significant proportion of women with PCOS, ranging from 40 to 85%, are either overweight or obese."
explanation: >-
Quantifies how often the two co-occur. The width of the range is itself
informative and consistent with the qualifier above that the association
is not universal across populations.