Trial Outcomes & Findings for Characterizing the Neural Substrates of Irritability in Women: an Experimental Neuroendocrine Model (NCT NCT04051320)

Last Updated: 2023-08-25

Results Overview

This outcome measure determines the extent to which irritability is characterized by dysfunctional threat processing during reproductive hormone challenge relative to baseline in HS+ and HS- by examining threat attention bias assessed during the visual dot-probe paradigm. The Visual Dot-Probe Paradigm asks participants to detect a target stimulus that is embedded in a matrix of distracting stimuli (e.g., a target stimulus, an angry face, might be embedded in a matrix of neutral distractor faces). Attention biases are inferred from faster response times to detect a threatening stimulus in a matrix of neutral stimuli relative to response time to detect neutral stimuli in neutral matrices. Thus, positive times reflect attention bias toward threat, whereas negative times reflect attention bias away from threat.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

23 participants

Primary outcome timeframe

up to 6 weeks

Results posted on

2023-08-25

Participant Flow

Participant milestones

Participant milestones
Measure	Hormone Sensitive Women (HS+) Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets	Hormone Insensitive Women (HS-) Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets
Overall Study STARTED	13	10
Overall Study COMPLETED	13	10
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Characterizing the Neural Substrates of Irritability in Women: an Experimental Neuroendocrine Model

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Hormone Sensitive Women (HS+) n=13 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets	Hormone Insensitive Women (HS-) n=10 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets	Total n=23 Participants Total of all reporting groups
Age, Continuous	34.81 years STANDARD_DEVIATION 6.46 • n=5 Participants	37.15 years STANDARD_DEVIATION 2.82 • n=7 Participants	35.77 years STANDARD_DEVIATION 5.31 • n=5 Participants
Sex: Female, Male Female	13 Participants n=5 Participants	10 Participants n=7 Participants	23 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) White	10 Participants n=5 Participants	10 Participants n=7 Participants	20 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	13 Participants n=5 Participants	10 Participants n=7 Participants	23 Participants n=5 Participants

PRIMARY outcome

Timeframe: up to 6 weeks

Population: All available data are reported. Data are missing for participants who had insufficient time to complete the task or due to computer malfunction.

Outcome measures

Outcome measures
Measure	Hormone Sensitive Women (HS+) n=10 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone sensitive women were those who experienced at least a 30% increase in negative mood symptoms as defined by the IDAS during hormone addback.	Hormone Insensitive Women (HS-) n=9 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone Insensitive women did not experience a 30% increase in negative mood symptoms during hormone addback.
Mean Threat Processing Bias During Visual Dot-probe Paradigm Over Time Baseline (Visit 3)	-0.57 attention bias in milliseconds Standard Deviation 18.92	36.92 attention bias in milliseconds Standard Deviation 110.98
Mean Threat Processing Bias During Visual Dot-probe Paradigm Over Time Hormone Addback (Visit 6)	-9.04 attention bias in milliseconds Standard Deviation 31.57	-42.35 attention bias in milliseconds Standard Deviation 102.99

PRIMARY outcome

Timeframe: up to 6 weeks

Population: Participants exceeding the motion threshold and those completing the task incorrectly were excluded.

This outcome measure determines the extent to which irritability is characterized by dysfunctional threat processing during reproductive hormone challenge relative to baseline in HS+ and HS-. By examining amygdala-medial prefrontal cortex (PFC) Blood-oxygen-level-dependent (BOLD) connectivity in response to threatening faces on the implicit emotion face processing fMRI task in HS+ (compared with HS-) during hormone challenge relative to baseline. The implicit emotion face processing task asks participants to identify the gender of angry, happy, and fearful faces at 50%, 100% and 150% emotion intensity presented in random order for 2000 milliseconds followed by jittered fixation. Trials appear in 3 blocks, generating 30 trials of each emotion at each intensity and 90 neutral face emotion trials.

Outcome measures

Outcome measures
Measure	Hormone Sensitive Women (HS+) n=11 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone sensitive women were those who experienced at least a 30% increase in negative mood symptoms as defined by the IDAS during hormone addback.	Hormone Insensitive Women (HS-) n=6 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone Insensitive women did not experience a 30% increase in negative mood symptoms during hormone addback.
Mean Right Amygdala-medial Prefrontal Cortex BOLD Connectivity During Implicit Emotion Face Processing Task Over Time Baseline (Visit 3)	0.0174 arbitrary units Standard Deviation 0.0606	0.0533 arbitrary units Standard Deviation 0.0338
Mean Right Amygdala-medial Prefrontal Cortex BOLD Connectivity During Implicit Emotion Face Processing Task Over Time Hormone Addback (Visit 6)	-0.0114 arbitrary units Standard Deviation 0.0751	0.00804 arbitrary units Standard Deviation 0.0943

PRIMARY outcome

Timeframe: up to 6 weeks

Population: Participants exceeding the motion threshold and those completing the task incorrectly were excluded.

This outcome measure determines the extent to which irritability is characterized by dysfunctional threat processing during reproductive hormone challenge relative to baseline in HS+ and HS-. By examining amygdala-medial prefrontal cortex (PFC) connectivity in response to threatening faces on the implicit emotion face processing fMRI task in HS+ (compared with HS-) during hormone challenge relative to baseline. The implicit emotion face processing task asks participants to identify the gender of angry, happy, and fearful faces at 50%, 100% and 150% emotion intensity presented in random order for 2000 milliseconds followed by jittered fixation. Trials appear in 3 blocks, generating 30 trials of each emotion at each intensity and 90 neutral face emotion trials.

Outcome measures

Outcome measures
Measure	Hormone Sensitive Women (HS+) n=11 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone sensitive women were those who experienced at least a 30% increase in negative mood symptoms as defined by the IDAS during hormone addback.	Hormone Insensitive Women (HS-) n=6 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone Insensitive women did not experience a 30% increase in negative mood symptoms during hormone addback.
Mean Left Amygdala-medial Prefrontal Cortex BOLD Connectivity During Implicit Emotion Face Processing Task Over Time Baseline (Visit 3)	0.0247 arbitrary units Standard Deviation 0.0653	0.0213 arbitrary units Standard Deviation 0.0374
Mean Left Amygdala-medial Prefrontal Cortex BOLD Connectivity During Implicit Emotion Face Processing Task Over Time Hormone Addback (Visit 6)	-0.0192 arbitrary units Standard Deviation 0.0893	0.00111 arbitrary units Standard Deviation 0.0884

PRIMARY outcome

Timeframe: up to 6 weeks

This outcome measure determines the extent to which HS+ is characterized by reactive aggression during hormone addback relative to baseline in the target population. Reactive aggression will be defined as the number of point subtractions the participant makes during the Point Subtraction Aggression Paradigm. Point Subtraction Aggression Paradigm measures relational aggression (approach behavior) in response to frustration. In the task, participants are asked to press a button to accrue money or press another button to subtract money from a (fictional) partner at no direct gain to themselves. Frustration is induced by periodic subtractions of their own money, which is attributed to the partner.

Outcome measures

Outcome measures
Measure	Hormone Sensitive Women (HS+) n=13 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone sensitive women were those who experienced at least a 30% increase in negative mood symptoms as defined by the IDAS during hormone addback.	Hormone Insensitive Women (HS-) n=10 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone Insensitive women did not experience a 30% increase in negative mood symptoms during hormone addback.
Mean Reactive Aggression During Hormone Addback Over Time Baseline (Visit 3)	103.08 Number of subtraction responses Standard Deviation 121.68	129.20 Number of subtraction responses Standard Deviation 105.76
Mean Reactive Aggression During Hormone Addback Over Time Hormone Addback (Visit 6)	34.62 Number of subtraction responses Standard Deviation 44.84	54.90 Number of subtraction responses Standard Deviation 71.85

PRIMARY outcome

Timeframe: up to 6 weeks

Population: Participants exceeding the motion threshold were excluded as were those with signal loss.

This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the right amygdala in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance.

Outcome measures

Outcome measures
Measure	Hormone Sensitive Women (HS+) n=11 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone sensitive women were those who experienced at least a 30% increase in negative mood symptoms as defined by the IDAS during hormone addback.	Hormone Insensitive Women (HS-) n=9 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone Insensitive women did not experience a 30% increase in negative mood symptoms during hormone addback.
Mean BOLD Activation of the Right Amygdala During the Affective Posner Task Over Time Baseline (Visit 3)	-0.04544 Arbitrary Units Standard Deviation 0.100148	0.037334 Arbitrary Units Standard Deviation 0.137479
Mean BOLD Activation of the Right Amygdala During the Affective Posner Task Over Time Hormone Addback (Visit 6)	0.022654 Arbitrary Units Standard Deviation 0.071363	-0.15643 Arbitrary Units Standard Deviation 0.089792

PRIMARY outcome

Timeframe: up to 6 weeks

Population: Participants exceeding the motion threshold were excluded.

This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the left amygdala in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance.

Outcome measures

Outcome measures
Measure	Hormone Sensitive Women (HS+) n=12 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone sensitive women were those who experienced at least a 30% increase in negative mood symptoms as defined by the IDAS during hormone addback.	Hormone Insensitive Women (HS-) n=9 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone Insensitive women did not experience a 30% increase in negative mood symptoms during hormone addback.
Mean BOLD Activation of the Left Amygdala During the Affective Posner Task Over Time Baseline (Visit 3)	0.005316917 Arbitrary Units Standard Deviation 0.10109272	-0.009866667 Arbitrary Units Standard Deviation 0.12208237
Mean BOLD Activation of the Left Amygdala During the Affective Posner Task Over Time Hormone Addback (Visit 6)	-0.047401917 Arbitrary Units Standard Deviation 0.19032614	-0.086876444 Arbitrary Units Standard Deviation 0.11792679

PRIMARY outcome

Timeframe: up to 6 weeks

This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the right caudate in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance.

Outcome measures

Outcome measures
Measure	Hormone Sensitive Women (HS+) n=13 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone sensitive women were those who experienced at least a 30% increase in negative mood symptoms as defined by the IDAS during hormone addback.	Hormone Insensitive Women (HS-) n=10 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone Insensitive women did not experience a 30% increase in negative mood symptoms during hormone addback.
Mean BOLD Activation of the Right Caudate During the Affective Posner Task Over Time Baseline (Visit 3)	-0.069919077 Arbitrary Units Standard Deviation 0.11155759	0.061407 Arbitrary Units Standard Deviation 0.15720728
Mean BOLD Activation of the Right Caudate During the Affective Posner Task Over Time Hormone Addback (Visit 6)	0.045146154 Arbitrary Units Standard Deviation 0.1320315	0.0058011 Arbitrary Units Standard Deviation 0.15927022

PRIMARY outcome

Timeframe: up to 6 weeks

Population: Participants with signal loss were excluded.

This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the left caudate in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance.

Outcome measures

Outcome measures
Measure	Hormone Sensitive Women (HS+) n=12 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone sensitive women were those who experienced at least a 30% increase in negative mood symptoms as defined by the IDAS during hormone addback.	Hormone Insensitive Women (HS-) n=10 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone Insensitive women did not experience a 30% increase in negative mood symptoms during hormone addback.
Mean BOLD Activation of the Left Caudate During the Affective Posner Task Over Time Baseline (Visit 3)	-0.043943333 Arbitrary Units Standard Deviation 0.19455199	0.0077258 Arbitrary Units Standard Deviation 0.18794868
Mean BOLD Activation of the Left Caudate During the Affective Posner Task Over Time Hormone Addback (Visit 6)	0.059099917 Arbitrary Units Standard Deviation 0.09144575	-0.049988 Arbitrary Units Standard Deviation 0.17179757

PRIMARY outcome

Timeframe: up to 6 weeks

Population: Participants with signal loss were excluded.

This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the right putamen in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance.

Outcome measures

Outcome measures
Measure	Hormone Sensitive Women (HS+) n=13 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone sensitive women were those who experienced at least a 30% increase in negative mood symptoms as defined by the IDAS during hormone addback.	Hormone Insensitive Women (HS-) n=9 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone Insensitive women did not experience a 30% increase in negative mood symptoms during hormone addback.
Mean BOLD Activation of the Right Putamen During the Affective Posner Task Over Time Baseline (Visit 3)	-0.007560692 Arbitrary Units Standard Deviation 0.09339182	0.002542222 Arbitrary Units Standard Deviation 0.17117375
Mean BOLD Activation of the Right Putamen During the Affective Posner Task Over Time Hormone Addback (Visit 6)	0.036225385 Arbitrary Units Standard Deviation 0.1357793	-0.080736333 Arbitrary Units Standard Deviation 0.08070693

PRIMARY outcome

Timeframe: up to 6 weeks

This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the left putamen in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance.

Outcome measures

Outcome measures
Measure	Hormone Sensitive Women (HS+) n=13 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone sensitive women were those who experienced at least a 30% increase in negative mood symptoms as defined by the IDAS during hormone addback.	Hormone Insensitive Women (HS-) n=10 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone Insensitive women did not experience a 30% increase in negative mood symptoms during hormone addback.
Mean BOLD Activation of the Left Putamen During the Affective Posner Task Over Time Baseline (Visit 3)	-0.001223462 Arbitrary Units Standard Deviation 0.11938667	0.0383029 Arbitrary Units Standard Deviation 0.2004158
Mean BOLD Activation of the Left Putamen During the Affective Posner Task Over Time Hormone Addback (Visit 6)	0.048155385 Arbitrary Units Standard Deviation 0.13830948	-0.021029 Arbitrary Units Standard Deviation 0.17785651

PRIMARY outcome

Timeframe: up to 6 weeks

Population: Participants with signal loss were excluded.

This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the right nucleus accumbens in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance.

Outcome measures

Outcome measures
Measure	Hormone Sensitive Women (HS+) n=12 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone sensitive women were those who experienced at least a 30% increase in negative mood symptoms as defined by the IDAS during hormone addback.	Hormone Insensitive Women (HS-) n=9 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone Insensitive women did not experience a 30% increase in negative mood symptoms during hormone addback.
Mean BOLD Activation of the Right Nucleus Accumbens During the Affective Posner Task Over Time Baseline (Visit 3)	0.044384167 Arbitrary Units Standard Deviation 0.17318851	0.052685333 Arbitrary Units Standard Deviation 0.13130308
Mean BOLD Activation of the Right Nucleus Accumbens During the Affective Posner Task Over Time Hormone Addback (Visit 6)	-0.005181667 Arbitrary Units Standard Deviation 0.16825616	-0.006394444 Arbitrary Units Standard Deviation 0.21780392

PRIMARY outcome

Timeframe: up to 6 weeks

Population: Participants with signal loss were excluded.

This outcome measure determines the extent to which HS+ is characterized by BOLD activation of the left nucleus accumbens in response to frustrative non-reward (FNR) in the Affective Posner Task during hormone addback relative to baseline in the target population. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance.

Outcome measures

Outcome measures
Measure	Hormone Sensitive Women (HS+) n=11 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone sensitive women were those who experienced at least a 30% increase in negative mood symptoms as defined by the IDAS during hormone addback.	Hormone Insensitive Women (HS-) n=10 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone Insensitive women did not experience a 30% increase in negative mood symptoms during hormone addback.
Mean BOLD Activation of the Left Nucleus Accumbens During the Affective Posner Task Over Time Baseline (Visit 3)	-0.028451818 Arbitrary Units Standard Deviation 0.13242342	0.0691907 Arbitrary Units Standard Deviation 0.24951478
Mean BOLD Activation of the Left Nucleus Accumbens During the Affective Posner Task Over Time Hormone Addback (Visit 6)	0.031632727 Arbitrary Units Standard Deviation 0.25999277	-0.072512 Arbitrary Units Standard Deviation 0.16302971

SECONDARY outcome

Timeframe: Endpoint (week 6)

Population: All available data are reported. Data are missing for participants who had insufficient time to complete the task or due to computer malfunction.

This outcome measure determines the extent to which irritability is characterized by dysfunctional reward processing during reproductive hormone challenge in HS+ and HS- by examining the correlation between the Inventory of Depressive and Anxiety Symptoms (IDAS) Ill Temper (i.e., irritability) Scale and threat attention bias.

Outcome measures

Outcome measures
Measure	Hormone Sensitive Women (HS+) n=10 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone sensitive women were those who experienced at least a 30% increase in negative mood symptoms as defined by the IDAS during hormone addback.	Hormone Insensitive Women (HS-) n=9 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone Insensitive women did not experience a 30% increase in negative mood symptoms during hormone addback.
Correlation Between the Inventory of Depressive and Anxiety Symptoms (IDAS) Ill -0.8Scale and Threat Attention Bias	-0.35 correlation coefficient Interval -0.8 to 0.36	0.11 correlation coefficient Interval -0.6 to 0.72

SECONDARY outcome

Timeframe: Endpoint (week 6)

Population: Participants exceeding the motion threshold and those completing the task incorrectly were excluded.

This outcome measure determines the extent to which irritability is characterized by dysfunctional reward processing during reproductive hormone challenge in HS+ and HS- by examining the correlation between the IDAS Ill Temper (i.e., irritability) Scale and amygdala-medial PFC connectivity in HS+.

Outcome measures

Outcome measures
Measure	Hormone Sensitive Women (HS+) n=11 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone sensitive women were those who experienced at least a 30% increase in negative mood symptoms as defined by the IDAS during hormone addback.	Hormone Insensitive Women (HS-) n=6 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone Insensitive women did not experience a 30% increase in negative mood symptoms during hormone addback.
Correlation Between the Inventory of Depressive and Anxiety Symptoms (IDAS) Ill Temper Scale and Right Amygdala-medial Prefrontal Cortex (PFC) BOLD Connectivity.	-0.57 correlation coefficient Interval -0.87 to 0.05	-0.08 correlation coefficient Interval -0.84 to 0.78

SECONDARY outcome

Timeframe: Endpoint (week 6)

Population: Participants exceeding the motion threshold and those completing the task incorrectly were excluded.

This outcome measure determines the extent to which irritability is characterized by dysfunctional reward processing during reproductive hormone challenge in HS+ and HS- by examining the correlation between the IDAS Ill Temper (i.e., irritability) Scale and amygdala-medial PFC connectivity in HS+.

Outcome measures

Outcome measures
Measure	Hormone Sensitive Women (HS+) n=11 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone sensitive women were those who experienced at least a 30% increase in negative mood symptoms as defined by the IDAS during hormone addback.	Hormone Insensitive Women (HS-) n=6 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone Insensitive women did not experience a 30% increase in negative mood symptoms during hormone addback.
Correlation Between the Inventory of Depressive and Anxiety Symptoms (IDAS) Ill Temper Scale and Left Amygdala-medial Prefrontal Cortex (PFC) BOLD Connectivity.	-0.13 correlation coefficient Interval -0.68 to 0.51	0.49 correlation coefficient Interval -0.53 to 0.93

SECONDARY outcome

Timeframe: Endpoint (week 6)

This outcome measure determines the degree of irritability and reactive aggression in HS+ during hormone addback and its relationship to the target population. Irritability will be defined as score on the IDAS Ill Temper Scale. Reactive aggression will be defined as the number of point subtractions the participant makes during the Point Subtraction Aggression Paradigm. The Point Subtraction Aggression Paradigm measures relational aggression (approach behavior) in response to frustration. In the task, participants are asked to press a button to ac

Outcome measures

Outcome measures
Measure	Hormone Sensitive Women (HS+) n=13 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone sensitive women were those who experienced at least a 30% increase in negative mood symptoms as defined by the IDAS during hormone addback.	Hormone Insensitive Women (HS-) n=10 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone Insensitive women did not experience a 30% increase in negative mood symptoms during hormone addback.
Correlation Between Irritability and Reactive Aggression During Hormone Addback	0.18 correlation coefficient Interval -0.42 to 0.66	0.03 correlation coefficient Interval -0.61 to 0.65

SECONDARY outcome

Timeframe: Endpoint (week 6)

Population: The a priori hypothesis focused on the HS+ group only.

This outcome measure determines the degree of subcortical (amygdala, caudate, putamen, and nucleus accumbens) activation in HS+ during hormone addback and it's relationship to the target population. The activation in amygdala and ventral striatum (caudate, putamen, nucleus accumbens) regions of interest (ROIs) will be assessed during the Affective Posner Task. The Affective Posner Task tests whether HS+ is characterized by reduced subcortical activation in response to frustration. This task is divided into 3 runs: during Run 1 (practice run), participants receive accurate feedback about their performance on the task and do not win or lose money; during Run 2, participants receive accurate feedback about their performance and win or lose 50 cents per trial; and during Run 3 (frustration), participants are told they must respond accurately to win money, but participants are given feedback that they responded too slowly on 60% of accurate trials, regardless of their performance.

Outcome measures

Outcome measures
Measure	Hormone Sensitive Women (HS+) n=13 Participants Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone sensitive women were those who experienced at least a 30% increase in negative mood symptoms as defined by the IDAS during hormone addback.	Hormone Insensitive Women (HS-) Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets Hormone Insensitive women did not experience a 30% increase in negative mood symptoms during hormone addback.
Correlation Between Irritability Subcortical Activation in HS+ During Hormone Addback	0.47 correlation coefficient Interval -0.11 to 0.81	—

Adverse Events

Hormone Sensitive Women (HS+)

Serious events: 0 serious events

Other events: 12 other events

Deaths: 0 deaths

Hormone Insensitive Women (HS-)

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Crystal Schiller, PhD

University of North Carolina at Chapel Hill

Phone: 919-966-5243

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Hormone Sensitive Women (HS+) n=13 participants at risk Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets	Hormone Insensitive Women (HS-) n=10 participants at risk Participants will take leuprolide acetate (lupron) via intramuscular injection, for 2 months. Participants will take 2 mg of estradiol twice daily and 200 mg of progesterone twice daily for 2 weeks. Leuprolide Acetate 3.75 MG/ML: 3.75 mg/month leuprolide acetate intramuscular injection Estradiol 2 Mg tablet: 2 mg estradiol tablet Micronized progesterone: 200 mg micronized progesterone tablets
Gastrointestinal disorders Bloating	23.1% 3/13 • Number of events 3 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	30.0% 3/10 • Number of events 3 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Musculoskeletal and connective tissue disorders Low back pain	15.4% 2/13 • Number of events 2 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	10.0% 1/10 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Musculoskeletal and connective tissue disorders General musculoskeletal pain	15.4% 2/13 • Number of events 4 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	0.00% 0/10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Reproductive system and breast disorders Cramps	15.4% 2/13 • Number of events 2 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	0.00% 0/10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
General disorders Headache	53.8% 7/13 • Number of events 7 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	40.0% 4/10 • Number of events 4 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Vascular disorders Migraine	15.4% 2/13 • Number of events 2 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	10.0% 1/10 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Vascular disorders Occular migraine	7.7% 1/13 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	0.00% 0/10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
General disorders Fatigue	61.5% 8/13 • Number of events 9 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	40.0% 4/10 • Number of events 5 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Musculoskeletal and connective tissue disorders Arm soreness (Lupron IM injection)	23.1% 3/13 • Number of events 3 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	40.0% 4/10 • Number of events 4 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Musculoskeletal and connective tissue disorders Arm soreness (COVID vaccine IM injection)	0.00% 0/13 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	20.0% 2/10 • Number of events 2 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Reproductive system and breast disorders Hot flashes	69.2% 9/13 • Number of events 10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	80.0% 8/10 • Number of events 8 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Infections and infestations Fever (COVID-19 infection)	7.7% 1/13 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	0.00% 0/10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Infections and infestations Anosmia (COVID-19 infection)	7.7% 1/13 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	0.00% 0/10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Infections and infestations COVID-19 Infection	7.7% 1/13 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	0.00% 0/10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Respiratory, thoracic and mediastinal disorders Dry cough (Seasonal allergies)	7.7% 1/13 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	0.00% 0/10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Gastrointestinal disorders Gastrointestinal upset	23.1% 3/13 • Number of events 3 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	40.0% 4/10 • Number of events 4 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Psychiatric disorders Mood swings	7.7% 1/13 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	0.00% 0/10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Reproductive system and breast disorders Spotting	46.2% 6/13 • Number of events 6 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	20.0% 2/10 • Number of events 2 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Psychiatric disorders Intrusive thoughts	7.7% 1/13 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	0.00% 0/10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Psychiatric disorders Anxiety	23.1% 3/13 • Number of events 5 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	30.0% 3/10 • Number of events 3 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Psychiatric disorders Anhedonia	15.4% 2/13 • Number of events 2 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	0.00% 0/10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Psychiatric disorders Depressed mood	15.4% 2/13 • Number of events 2 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	0.00% 0/10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Psychiatric disorders Irritability	30.8% 4/13 • Number of events 4 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	30.0% 3/10 • Number of events 3 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Psychiatric disorders Low libido	7.7% 1/13 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	0.00% 0/10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Metabolism and nutrition disorders Weight gain	23.1% 3/13 • Number of events 3 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	20.0% 2/10 • Number of events 2 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Injury, poisoning and procedural complications Concussion	7.7% 1/13 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	0.00% 0/10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Psychiatric disorders Early insomnia	15.4% 2/13 • Number of events 2 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	0.00% 0/10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Psychiatric disorders Late insomnia	0.00% 0/13 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	10.0% 1/10 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Reproductive system and breast disorders Breast tenderness	7.7% 1/13 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	20.0% 2/10 • Number of events 2 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Metabolism and nutrition disorders Decreased appetite	7.7% 1/13 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	0.00% 0/10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Metabolism and nutrition disorders Increased appetite	0.00% 0/13 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	10.0% 1/10 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Nervous system disorders Dizziness	46.2% 6/13 • Number of events 7 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	10.0% 1/10 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Psychiatric disorders Difficulty concentrating	7.7% 1/13 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	0.00% 0/10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Psychiatric disorders Emotional sensitivity	30.8% 4/13 • Number of events 4 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	10.0% 1/10 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Psychiatric disorders Insomnia	7.7% 1/13 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	0.00% 0/10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Gastrointestinal disorders Heartburn	7.7% 1/13 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	0.00% 0/10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Musculoskeletal and connective tissue disorders Hematoma (IM injection)	7.7% 1/13 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	0.00% 0/10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Reproductive system and breast disorders Yeast infection	7.7% 1/13 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	0.00% 0/10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Skin and subcutaneous tissue disorders Hormonal acne	7.7% 1/13 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	0.00% 0/10 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Skin and subcutaneous tissue disorders Hair loss	0.00% 0/13 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	10.0% 1/10 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Reproductive system and breast disorders Cervical mucus	0.00% 0/13 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	20.0% 2/10 • Number of events 2 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Gastrointestinal disorders Diarrhea	0.00% 0/13 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	10.0% 1/10 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Infections and infestations Fever	0.00% 0/13 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	10.0% 1/10 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Musculoskeletal and connective tissue disorders Hip pain	0.00% 0/13 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	20.0% 2/10 • Number of events 2 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Renal and urinary disorders Frequent urination	0.00% 0/13 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	10.0% 1/10 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Psychiatric disorders Vivid dreams	0.00% 0/13 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	10.0% 1/10 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.
Psychiatric disorders Passive suicidal ideation	0.00% 0/13 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.	10.0% 1/10 • Number of events 1 • From Study visit 3 (intervention start) through visit 7 (Follow-Up), a total of approximately 9 weeks.