Acute Aggression After Progesterone Discontinuation in a Young Female

Background: Although cyclical Case Presentation: We report a case of a 23-year old hospitalized African female diagnosed with complex post-traumatic stress disorder (PTSD), bipolarity and history of alcohol use disorder, who developed signicant behavioral aggression within a short time of removing her progestin (progesterone) implant. The association between abrupt behavioral deterioration and discontinuation of the contraceptive implant was further supported by resolution of patient’s aggression after 3 days of starting a long-acting progesterone contraceptive, medroxyprogesterone acetate, instead of the progestin implant to prevent non-adherence. This, to our knowledge, is the rst case to document relationship between discontinuation of a progesterone contraceptive and aggressive behavior in a patient with signicant trauma and psychiatric history.

stress disorder (PTSD), bipolarity and history of alcohol use disorder, who developed signi cant behavioral aggression within a short time of removing her progestin (progesterone) implant. The association between abrupt behavioral deterioration and discontinuation of the contraceptive implant was further supported by resolution of patient's aggression after 3 days of starting a long-acting progesterone contraceptive, medroxyprogesterone acetate, instead of the progestin implant to prevent non-adherence. This, to our knowledge, is the rst case to document relationship between discontinuation of a progesterone contraceptive and aggressive behavior in a patient with signi cant trauma and psychiatric history.

Discussion & Conclusion:
This may be the rst documented case of behavioral aggression in a young African female after removal of a progesterone implant followed by resolution of aggression after initiating a long acting progesterone injection. Although several studies, mostly in animals, have shown a link between progesterone levels and aggression, there are no reports of aggression concerning contraceptive use of progesterone. Such aggression may be rare in healthy subjects but may be more common in a psychiatrically vulnerable patient with signi cant trauma history.

Background
The psychiatric effects of progesterone and its metabolite allopregnanolone are well-known in anxiety (1), premenstrual syndrome, dysmenorrhea (2), and post-partum depression (3,4). However, the evidence for progesterone's role in behavioral aggression is not as clear and is primarily based on animal data (5).
Although the studies in post-partum depression were not designed to investigate aggression, the authors provided plausible mechanism of action behind brexenalone's e cacy in post-partum depression (3,4).
Brexenalone, an intravenous formulation of allopregnanolone, is a positive allosteric modulator of inhibitory GABA-A receptors (3). Being a PAM for GABA-A receptors, brexenalone increases the inhibitory feedback from GABA interneurons to dampen the excessive and excitotoxic glutamatergic activity observed during post-partum depression (6,7). The glutamatergic dysregulation has been associated across other symptom domains, including psychosis (8) and behavioral aggression (9). Thus, it is possible to experience behavioral dysregulation in response to glutamate surge following abrupt discontinuation progesterone contraceptives.

Case Presentation
The patient is a 23-year-old single African refugee female with complex PTSD, unspeci ed bipolar disorder, and alcohol use disorder in early remission, who was initially hospitalized in a community hospital for suicidal thoughts and alcohol intoxication, followed by readmission to a state psychiatric facility for severe agitation. The medical records revealed similar suicidal behavior in the recent past after excessive alcohol intake, resulting in repeated emergency visits at a local hospital. Based on the medical records, patient developed complex PTSD after her family was killed in front of her eyes during ethnic violence. The patient was reported to suffer from ashbacks, nightmares, and panic attacks, particularly when she heard any gunshots. However, there was no history of psychosis. The severity of her PTSD and alcohol intoxication was the main reason that the patient visited the local emergency department several times before she had to be hospitalized, rst to a community hospital, later to be transferred to a state psychiatric facility for further treatment. Medications at admission included uoxetine, 60 mg/day, prazosin 2 mg/day, and perphenazine 8 mg two times/day, later augmented with divalproex sodium 500 mg two times day (recent levels 91mcg/mL) to address bipolarity. However, patient was found to signi cant extrapyramidal symptoms and hyperprolactinemia, both of which resolved after patient was gradually cross-titrated from perphenazine to quetiapine 300 mg at bedtime and became stable enough to initiate discharge planning. However, a couple of weeks before her potential discharge, patient secretly removed her progestin implant, as she wanted to become pregnant despite being educated about the teratogenic effects of divalproex sodium. This was followed by extreme aggression towards staff and other patients as re ected by seclusion and restraint events every day for ten consecutive days. Initially the treatment team failed to nd any reason for this sudden onset of aggressive behavior without any changes in patient's medication or environment, but a few days later, staff discovered the removal of her progestin implant after nding bloodstained gauze in patient's room. When confronted, patient admitted taking out the implant. At this time, the patient was started on a long-acting injectable (LAI) progesterone contraceptive, medroxyprogesterone acetate, to prevent future nonadherence. Within three days, patient returned to baseline non-aggressive behavior and was eventually discharged from the state psychiatric facility after a week.

Discussion & Conclusions
This, to our knowledge, is the rst case to report acute aggression after the discontinuation of progesterone (progestin) implant followed by resolution of aggression within three days of initiating medroxyprogesterone acetate (progesterone LAI) in a young African female. This onset of action is consistent with the time medroxyprogesterone acetate required to change cervical mucus (10). Because progesterone can easily cross the blood-brain barrier, the central effects may be seen in a similar timeline as the peripheral effects. It is interesting to note therapeutic levels of divalproex sodium did not prevent sudden onset of behavioral aggression in this patient, which suggests that allosteric modulation may differ with the direct GABAergic effects of valproic acid. The diagnosis of complex posttraumatic stress disorder (PTSD) may also be of relevant to the acute aggression observed in this patient. Decreased levels of progesterone have been associated with fear, learning de cits, and higher PTSD symptomatology, as well as heightened intensity and the duration of adrenergic response under stress (11). In addition, individuals with low plasma GABA levels are also prone to develop PTSD after traumatic experience (12). Furthermore, administration of progestin implant may have boosted mood-stabilizing effects of valproate in our patient, who was diagnosed with unspeci ed bipolar disorder. This view is supported not only by the mood stabilization reported with progesterone (13), but also improvement in bipolar depression with pregnenolone in a clinical trial (14). With regard to alcohol, the patient was sober since her admission for about three months at the state hospital facility, which makes alcohol a less likely contributor to aggression in this patient.
The ndings from this study are based on a single patient and should be interpreted with caution. However, clinicians should consider complex psychiatric effects of progesterone and its metabolite, allopregnanolone, beyond contraception, especially in patients with a complex psychiatric history. Careful counseling and close follow-up are recommended for patients with psychiatric disorders, such as premenstrual dysphoric disorder, seeking these contraceptive methods.

Declarations
Ethics approval and consent to participate: This case report is based on a single patient's clinical observations and retrospective analysis of her chart. This case report does not have any personal health identi cation information.
Consent for publication: verbal consent was obtained Availability of data and materials: no formal data were created for this single patient case report Competing interests: none Funding: none