Exploring Safety in Gender-Affirming Hormonal Treatments: An Observational Study on Adverse Drug Events Using the Food and Drug Administration Adverse Event Reporting System Database

Abstract

Background:

People with gender dysphoria are treated with hormone therapy for gender reassignment. The indication of this therapy was initially for the opposite sex, and information on potential adverse drug reaction (ADR) is lacking.

Objective:

To describe ADR associated with gender transition medication in transgender individuals reported to the US Food and Drug Administration Adverse Event Reporting System (FAERS) database.

Methods:

Data from the FAERS database up to June 2023 were examined, focusing on reports of gender transition medication use in the context of gender dysphoria. The ADRs were categorized using the Medical Dictionary for Regulatory Activities at both Preferred Term and System Organ Class (SOC) levels. Descriptive statistics summarized report counts, medication types, indications, and ADR severity.

Results:

For individuals assigned female at birth undergoing gender transition to male (transgender men), 82 reports (230 ADRs) were analyzed, with an average age of 29.5 years. Transgender hormonal therapy was cited in 72% of reports, predominantly from the United States (67.1%). A striking 88% were categorized as serious ADRs, primarily SOC injury, poisoning, and procedural complications (26.5%), followed by psychiatric disorders (14.8%) and nervous system disorders (12.2%). Among those assigned sex male at birth transitioning to female (transgender women) (81 reports, 237 ADRs), mean age was 33.3 years, with 58% indicating use for gender dysphoria. A significant proportion (53.6%) were serious ADRs, primarily SOC: injury, poisoning, and procedural complications (26.6%).

Conclusions and Relevance:

The FAERS data reveal significant ADRs in transgender individuals using hormone therapy, sometimes unintended for their recipient gender. Population-level studies are crucial to enhance transgender health care. Spontaneous surveillance databases like FAERS illuminate off-label ADRs, urging health care providers to approach hormone therapies with informed caution.

Keywords

transgender persons transgender health drug-related side effects and adverse reactions adverse drug reaction reporting systems drug toxicity

Background

Transgender and gender nonconforming individuals represent a unique population whose gender identities diverge from traditional associations with their biological sex.¹ This group includes transgender, trans, gender nonbinary, and gender incongruent persons who may identify outside the binary gender construct or experience fluid gender identities beyond male and female.²

The medical community’s understanding of the health needs for this group has evolved over time. Recent medical nomenclature has shifted from “transsexualism” to the more inclusive “gender incongruence of adolescence and adulthood.”^3,4 The latest edition of the primary manual for diagnosing mental disorders defines “gender dysphoria” as significant distress or impairment arising from a deep-seated desire to identify as another gender.⁵ However, it is critical to note that not everyone within this spectrum experiences such dysphoria.³

Many individuals seeking to align their physical attributes with their gender identity opt for transition or gender affirmation procedures. These typically involve hormones such as estrogens or testosterone, which induce secondary sexual characteristics of their self-identified gender while suppressing natural hormone production.^6,7 While hormone therapy (HT) offers therapeutic benefits, data on its safety and potential adverse effects in populations not using them as replacement therapies remain scant. The differential efficacy and safety patterns between sexes are crucial to understand, particularly in the context of adverse drug reactions (ADRs).^8,9 For instance, the ADRs associated with sexual dysfunction (SD) significantly vary between sexes for drugs such as antidepressants and antihypertensives.¹⁰ Recognizing this variability is essential for comprehending the potential ADRs in transgender individuals undergoing HT, as their physiological changes could alter drug responses in ways distinct from those observed in cisgender populations. Previous studies on estrogen use in transgender women indicate increased risks of heart attack and ischemic stroke.^11,12 However, the potential negative impact on cardiovascular health from testosterone use in transgender men is not as clearly established.^6,13,14 There are also concerns about how preexisting comorbidities affect the development of ADRs and potential oncological risks with HT.¹⁵ A study of the French Pharmacovigilance Database (FPVD) has begun cataloging ADRs related to gender-affirming HT.¹⁵ To deepen our understanding, there is a pressing need for more extensive research. Thus, we turn to the US Food and Drug Administration Adverse Event Reporting System (FAERS) for a broader analysis.¹⁶

Analyzing ADRs for drugs used in individuals opposite to their indicated sex is crucial. Patients deserve comprehensive information when deciding and selecting a therapeutic pathway for sex reassignment. Importantly, the safety of these medications hinges on the fact that clinical trials for these treatments have predominantly been conducted on patients of the other sex. To date, only a few cohort studies, primarily in Europe, have addressed this gap.¹⁴

Objective

The objective of this study is to describe the ADRs associated with gender-affirming HT. Through this comprehensive analysis, we aspire to enrich our knowledge of the safety landscape of these treatments and offer invaluable insights for both clinicians and patients.

Methods

Study Design and Data Source

This is an observational safety study utilizing the FAERS database to explore the nature and prevalence of ADRs related to HT in individuals undergoing gender transition. The FAERS gathers voluntary reports of adverse events from health professionals and consumers. Each report details a suspected drug, accompanying medications, and their intended use. The ADRs in FAERS are categorized using the Preferred Terms (PT) from the Medical Dictionary for Regulatory Activities (MedDRA) terminology.¹⁷

Population and Drug Exposure

Our primary targets for this investigation were several key medications known for their role in gender transitioning processes.^18-20 In the case of individuals assigned male at birth for treatment transitions, we scrutinized oral estradiol, anti-androgens (spironolactone, cyproterone, bicalutamide), GnRH agonists (leuprolide), and finasteride. For individuals assigned female at birth, we primarily focused on testosterone, especially its enanthate and cypionate forms. These drugs were chosen due to their established efficacy and prevalent use in gender transitioning procedures.¹⁹ To guarantee the comprehensive nature of our study, we delved into the FAERS data by considering both the generic and US brand names of these medications.

We selected reports with the opposite sex of the transgender transformation, that is, female sex and medications for transgender men and male sex for transgender women medications. Further refinement of our data was accomplished by selecting reports that labeled the indication of the therapies with specific PT related to transgender HT. These PTs included “Transgender Hormonal Therapy,” “Gender Dysphoria,” “Transgender Operation,” and “Gender Reassignment Therapy.”

Data Curation and Outcomes

We then extracted relevant patient information from each report selected to June 6, 2023. This encompassed details such as indication, suspect product active ingredients, reactions, outcome severity, recipient’s age and weight, and country of occurrence, among other factors. While these data facilitated the identification of reports potentially associating these variables with the reported ADRs, it is important to note that FAERS data are not structured to confirm causality or investigate correlation.

For comprehensive data extraction, we conducted 2 interconnected queries. The first aimed to pinpoint transgender women (sex male) and transgender men (sex female) cases related to the mentioned HT. This was done by merging the sex criterion with androgens for females and estrogens and/or progestin for males. The second query executed an extensive full-text search of the recognized reports using the abovementioned PTs for the indication. Reports with the same literature reference, age, ADRs, outcomes, reporting date, and same medications involved were eliminated as duplicates.

The FAERS categorized patient medical history, indications, and ADR using the PT from the MedDRA terminology.¹⁷ These terms are single medical concepts for a symptom, sign, disease diagnosis, therapeutic indication, investigation, surgical or medical procedure, and medical social or family history characteristic (eg, agoraphobia). We grouped the PT into the MedDRA highest level of hierarchy classification, System Organ Class (SOC), as this level groups by etiology, manifestation site, or purpose (eg, psychiatric disorders).¹⁷

Statistical Analysis

Using descriptive statistics, we aimed to provide a complete and detailed overview of the ADRs present in the database. All analyses were conducted with Microsoft Excel Office Professional Plus 2019. All ADRs, categorized at the MedDRA PT level, were consolidated per MedDRA (English version 26.0).

Ethics Statement

Our study was granted a waiver due to the fact that FAERS complies with all US Government security standards and protections regarding health information. Consequently, using FAERS data do not necessitate institutional review board (IRB) approval or adherence to informed consent requirements.

Results

We separately examined the reports for female individuals transitioning to male (transgender men), and for male individuals transitioning to female (transgender women), as the individuals noted with the ADR.

Individuals Transitioning to Male

For transgender men, of the 150 reports associated with testosterone products for gender reassignment, 82 (54.7%) remained after duplicate exclusion. The average age of these individuals was 29.5 years (SD = 11.5), with most reports originating from the United States (55, 67.1%). Notably, a substantial portion of the reports were deemed serious (72, 87.8%), with 2 deaths (2.4%) and 25 hospitalizations (30.5%). A detailed breakdown can be found in Table 1.

Table 1.

Characteristics of the Reports for Testosterone With a Gender Reassignment Indication in Transgender Men (Female to Male).

Product: Testosterone	N = 150 (%)
Duplicates
Exclusion of literature duplicates	N = 51 (34)
Exclusion same age, ADR, and month/year of reporting	N= 17 (11.3)
Total FAERS reports for transgender men	82 (100)
Age (mean, SD)	29.5 (11.5)
Missing	26 (31.7)
Country where the event occurred
USA	55 (67.1)
Other	24 (29.3)
Missing	3 (3.6)
Reporter
Health care professional	72 (87.8)
Consumer	10 (12.2)
Reason for use^a
Transgender operation	4^b (4.9)
Transgender hormonal therapy	59 (71.9)
Gender reassignment therapy	9 (11)
Gender dysphoria	11 (13.4)
Severity (serious)	72 (87.8)
Outcomes^a
Death	2 (2.4)
Hospitalized	25 (30.5)
Life-threatening	4 (4.5)
Disable	3 (3.6)
Other outcomes	65 (79.3)
Nonserious	10 (12.2)
Adverse drug reactions
Total	230
Per report (mean, SD)	2.8 (2.0)
Min-max	1-14

Abbreviations: ADR, adverse drug reaction; FAERS, Food and Drug Administration Adverse Event Reporting System; SD, standard deviation.

Could be more than one, % over the total, not adding 100%

Two reports each encompassed dual indications: product use for unknown indication and transgender operation.

In the transgender men–related reports, a total of 230 ADRs were identified. The most commonly reported ADRs belonged to the SOC “injury, poisoning, and procedural complications” (61, 26.5%), succeeded by “psychiatric disorders” (34, 14.82%) and “nervous system disorders” (28, 12.2%). Within the “injury, poisoning, and procedural complications” SOC, the predominant PT was “off-label use of the product” (44, 72.1%). Under the “psychiatric disorders” SOC, the most frequent ADRs were “anxiety” (4, 11.8%), “depression” (3, 8.8%), and “suicidal ideation” (3, 8.8%). Among those classified under “nervous system disorders,” “idiopathic intracranial hypertension” was the predominant ADR (18, 64.3%). The SOC “neoplasms (benign, malignant, and unspecified, including cysts and polyps)” constituted 11% of the reported ADRs, with breast cancer being the most common (12, 48%). This was followed by the SOC “reproductive system and breast disorders” accounting for (17, 7.4%) of the reports. A detailed breakdown of ADRs by PT and SOC for transgender men individuals is available in Table 2.

Table 2.

Adverse Drug Reactions (ADRs) in Transgender Men (Female to Male) Using Testosterone.

System Organ Class term	N = 230	% of all ADRs
Preferred Term		% by SOC group
Injury, poisoning, and procedural complications	61	26.5
Off-label use	44	72.1
Product use in unapproved indication	6	9.8
Product use issue	6	9.8
Overdose	2	3.3
Product prescribing error	1	1.6
Skin ulcer	1	1.6
Scar	1	1.6
Psychiatric disorders	34	14.8
Anxiety	4	11.8
Depression	3	8.8
Suicidal ideation	3	8.8
Affect lability	2	5.9
Dissociative identity disorder	1	2.9
Suicide attempt	2	5.9
Euphoric mood	1	2.9
Self-destructive behavior	2	5.9
Anger	2	5.9
Gender dysphoria	2	5.9
Suicidal behavior	1	2.9
Aggression	1	2.9
Agoraphobia	1	2.9
Antisocial behavior	1	2.9
Depressed mood	1	2.9
Dermatillomania	1	2.9
Emotional disorder	1	2.9
Emotional distress	1	2.9
Homicidal ideation	1	2.9
Trichotillomania	1	2.9
Disorientation	1	2.9
Dissociation	1	2.9
Nervous system disorders	28	12.2
Idiopathic intracranial hypertension	18	64.3
Intracranial pressure increased	3	10.7
Mental impairment	2	7.1
Chronic inflammatory demyelinating polyradiculoneuropathy	1	3.6
Somnolence	1	3.6
Spontaneous cerebrospinal fluid leak syndrome	1	3.6
Transient ischemic attack	2	7.1
Neoplasms benign, malignant, and unspecified (incl. cysts and polyps)	25	10.9
Apocrine breast carcinoma	1	4
Breast cancer	2	8
Breast cancer stage I	1	4
Cervix carcinoma stage IV	1	4
Hepatocellular carcinoma	1	4
Intraductal proliferative breast lesion	1	4
Invasive breast carcinoma	1	4
Invasive ductal breast carcinoma	4	16
Metastasis to uterus	1	4
Ovarian cancer stage II	3	12
Ovarian endometrioid carcinoma	4	16
Pituitary tumor benign	1	4
Prostate cancer	1	4
Squamous cell carcinoma of the cervix	1	4
Tubular breast carcinoma	2	8
Reproductive system and breast disorders	17	7.4
Endometrial hyperplasia	2	11.8
Adnexal torsion	3	17.6
Ovarian necrosis	3	17.6
Prostatic disorder	1	5.9
Amenorrhea	2	11.8
Uterine cervical metaplasia	2	11.8
Vaginal hemorrhage	1	5.9
Enlarged clitoris	1	5.9
Erectile dysfunction	1	5.9
Vaginal disorder	1	5.9
Eye disorders	11	4.8
Papilledema	9	81.8
Blindness	1	9.1
Visual impairment	1	9.1
General disorders and administration site conditions	11	4.8
Metaplasia	3	27.3
Condition aggravated	2	18.2
Death	1	9.1
Drug ineffective	1	9.1
Drug ineffective for unapproved indication	1	9.1
Fatigue	1	9.1
Granuloma	1	9.1
Impaired self-care^a	1	9.1
Vascular disorders	7	3.0
Atherosclerotic plaque rupture	2	28.6
Deep vein thrombosis	1	14.3
Ischemia	1	14.3
Susac syndrome	1	14.3
Embolism venous	1	14.3
Hot Flush	1	14.3
Investigations	6	2.6
Weight decreased	1	16.7
Weight increased	1	16.7
Blood testosterone decreased	1	16.7
Body mass index increased	1	16.7
Body height increased	1	16.7
Quality of life decreased	1	16.7

Classification according to the Medical Dictionary for Regulatory Activities classification levels: System Organ Class (SOC) and subclassified by Preferred Term. Only showing those with SOC N > 5.

Abbreviation: ADR, adverse drug reaction.

This Preferred Term is from MEdDRA 25.0 version; it does not exist anymore in MedDRA 26.0 version.

Bold values are for the main MedDRA categories.

Individuals Transitioning to Female

For individuals transitioning to female, we identified 120 reports associated with indications for gender reassignment therapy. Of these, 39 (32.5%) were duplicates, due to the inclusion of multiple drugs from the therapeutic list for gender reassignment. The most frequently mentioned product was estradiol (35, 29.2%), followed by leuprolide (33, 27.5%). Bicalutamide and goserelin were each mentioned in only one report.

Transgender women had an average age of 33.3 years (SD = 18.9). Of the total reports, 45 (53.6%) classified the ADR as serious. One report mentioned a fatality, and 9 (11.1%) indicated hospitalization, factors that contributed to the classification of the adverse reaction as serious. A detailed breakdown of these ADR reports for transgender women is presented in Table 3.

Table 3.

Characteristics of the Reports for Treatments With a Gender Reassignment Indication in Transgender Women (Male to Female).

Products	N = 120 reports (%)
Estradiol cyproterone	17 (14.1)
Finasteride	10 (8.3)
Bicalutamide	1 (0.8)
Spironolactone	23 (19.2)
Estradiol	35 (29.2)
Leuprolide	33 (27.5)
Goserelin	1 (0.8)
Duplicates
Exclusion same ID, containing several of the drugs of interest	16 (13.3)
Exclusion literature	15 (12.5)
Exclusion same age, ADR, and month/year of reporting	8 (6.7)
Total FAERS reports for transgender women	81 (100)
Age (mean, SD)	33.3 (18.9)
Missing	30 (35.7)
Country where the event occurred
USA	54 (66.7)
Other	24 (29.6)
Missing	3 (3.7)
Reporter
Health care professional	54 (66.7)
Consumer	24 (29.6)
Missing	3 (3.7)
Reason for use^a
Transgender hormonal therapy	16 (19.7)
Gender reassignment therapy	20 (24.7)
Gender dysphoria	47 (58)
Other reasons indicated
Hormone suppression therapy	1
Hormone therapy	3
Off-label use	1
Precocious puberty	1
Product used for unknown indication	4
Weight increased	1
Hypersensitivity	1
Invasive ductal breast carcinoma	1
Severity (serious)	45 (53.6)
Outcomes^a
Death	1 (1.2)
Hospitalized	9 (11.1)
Life-threatening	4 (4.9)
Disable	1 (1.2)
Other outcomes	37 (45.7)
Adverse drug reactions
Total	237
Per report (mean, SD)	2.9 (2.2)
Min-max	1-13

Abbreviations: ID, identification; ADR, adverse drug reaction; FAERS, Food and Drug Administration Adverse Event Reporting System; SD, standard deviation.

Could be more than one, % over the total, not adding 100%.

Bold values are for the main MedDRA categories.

In total, 237 ADRs were reported for these individuals. A significant portion (63, 26.6%) were categorized under the SOC “injury, poisoning, and procedural complications,” with “off-label use” being the predominant PT at 40 reports (63.5%). Eleven percent of the ADRs fell under the SOC “general disorders and administration site conditions.” Almost 10% were classified under the SOC “neoplasms (benign, malignant, and unspecified, including cysts and polyps),” with “meningioma” and “prolactin-producing pituitary tumor” being the most commonly reported PTs at 7 (26.1%) and 4 (17.4%) mentions, respectively. A comprehensive list of ADR for transgender women individuals is available in Table 4.

Table 4.

Adverse Drug Reactions (ADRs) in Transgender Women (Male to Female) Classification According to the Medical Dictionary for Regulatory Activities Classification Levels: System Organ Class and Subclassified by Preferred Term.

System Organ Class term	N = 237	% of all ADRs
Preferred Term		% by SOC group
Injury, poisoning, and procedural complications	63	26.6
Incorrect dose administered	1	1.6
Incorrect route of product administration	1	1.6
Intercepted product preparation error	4	6.3
Medication error	1	1.6
Off-label use	40	63.5
Overdose	1	1.6
Product dispensing error	1	1.6
Product dose omission issue	3	4.8
Product use complaint	1	1.6
Product use in unapproved indication	6	9.5
Product use issue	1	1.6
Wrong technique in product usage process	3	4.8
General disorders and administration site conditions	26	11
Application site dermatitis	1	3.8
Application site discoloration	1	3.8
Application site dryness	1	3.8
Application site erythema	1	3.8
Application site exfoliation	1	3.8
Application site rash	1	3.8
Asthenia	1	3.8
Condition aggravated	3	11.5
Drug ineffective	1	3.8
Drug ineffective for unapproved indication	2	7.7
Fatigue	2	7.7
Feeling abnormal	1	3.8
Injection site erythema	1	3.8
Injection site mass	1	3.8
Injection site pain	4	15.4
Injection site rash	1	3.8
Injection site swelling	1	3.8
Unevaluable event	1	3.8
Unmasking of previously unidentified disease	1	3.8
Neoplasms benign, malignant and unspecified (incl. cysts and polyps)	23	9.7
Acoustic neuroma	1	4.3
Breast cancer	1	4.3
Inflammatory myofibroblastic tumor	1	4.3
Invasive ductal breast carcinoma	1	4.3
Meningioma	6	26.1
Meningioma benign	1	4.3
Metastases to bone	1	4.3
Metastases to liver	1	4.3
Nonsecretory adenoma of pituitary	1	4.3
Prolactin-producing pituitary tumor	4	17.4
Seminoma	2	8.7
Testicular seminoma (pure)	1	4.3
Testicular cancer	1	4.3
Tumor hemorrhage	1	4.3
Psychiatric disorders	21	8.9
Agitation	1	4.8
Anhedonia	1	4.8
Anxiety	2	9.5
Apathy	1	4.8
Delusion	1	4.8
Depression	7	33.3
Drug abuse	1	4.8
Emotional distress	1	4.8
Gender dysphoria	2	9.5
Insomnia	1	4.8
Irritability	1	4.8
Psychotic behavior	1	4.8
Suicide attempt	1	4.8
Product issues	19	8.0
Device leakage	1	5.3
Liquid product physical issue	1	5.3
Product adhesion issue	7	36.8
Product odor abnormal	1	5.3
Product packaging issue	1	5.3
Product taste abnormal	1	5.3
Product use issue	4	21.1
Syringe issue	3	15.8
Nervous system disorders	17	7.2
Aphasia	1	5.9
Cerebrovascular accident	1	5.9
Cognitive disorder	1	5.9
Disturbance in attention	1	5.9
Dizziness	1	5.9
Dysstasia	1	5.9
Facial paralysis	1	5.9
Facial paresis	1	5.9
Headache	3	17.6
Hemiparesis	1	5.9
Memory impairment	1	5.9
Migraine	1	5.9
Paresthesia	1	5.9
Transient ischemic attack	1	5.9
Tremor	1	5.9
Investigations	12	5.1
Blood glucose abnormal	1	8.3
Blood glucose increased	1	8.3
Blood estrogen increased	1	8.3
Blood testosterone decreased	1	8.3
Blood testosterone increased	3	25.0
Drug level above therapeutic	1	8.3
Hepatic enzyme abnormal	1	8.3
Hepatic enzyme increased	1	8.3
Magnetic resonance imaging abnormal	1	8.3
Pulmonary function test decreased	1	8.3
Musculoskeletal and connective tissue disorders	12	5.1
Arthralgia	2	16.7
Back pain	1	8.3
Chondrocalcinosis	1	8.3
Joint noise	1	8.3
Muscle disorder	1	8.3
Muscle spasms	1	8.3
Muscle twitching	1	8.3
Muscular weakness	1	8.3
Myalgia	1	8.3
Systemic lupus erythematosus	1	8.3
Tendonitis	1	8.3
Endocrine disorders	6	2.5
Hyperprolactinemia	6	100
Respiratory, thoracic, and mediastinal disorders	6	2.5
Pulmonary embolism	3	50
Asthma	1	16.6
Dysphonia	1	16.6
Throat tightness	1	16.6

Abbreviations: ADR, adverse drug reaction; SOC, System Organ Class.

Note. Only showing those with SOC N > 5.

Bold values are for the main MedDRA categories.

Discussion

Individuals undergoing gender reassignment due to gender dysphoria often report ADRs from these treatments to the FAERS. Based on data up until June 2023, we observed that transgender men are usually in their 20s, while transgender women tend to be in their 30s. A substantial portion of the ADRs reported for both transgender men and women were serious, with off-label use of these products emerging as the most commonly reported ADR.

The results highlight that HTs for gender reassignment are predominantly administered off-label. Although these therapies are originally approved for addressing hormone-related conditions in one gender, they are repurposed to assist individuals in transitioning to that gender—a purpose not officially endorsed on their labels.^21,22

On excluding ADRs categorized within the SOC “injury, poisoning, and procedural complications” (eg, “off-label use”) and those under “general disorders and administration site conditions” (like “application site erythema”), distinct trends emerged. Transgender men predominantly reported idiopathic intracranial hypertension and breast cancer as ADRs. In contrast, meningioma and depression were the most common ADRs for transgender women.

The ADRs for hormone treatments are described on the drug labels, but they typically pertain to the opposite sex of those transitioning for gender reassignment. For instance, common ADRs for testosterone products in males include erythrocytosis, acne, oily skin, sleep-disordered breathing, breast tenderness, and infertility.²³ Our analysis of the FAERS database concurs with previously noted findings, revealing reports of skin, blood, and respiratory disorders associated with testosterone use in female individuals. The link between testosterone and prostate cancer remains a topic of debate. Notably, while transgender men should not theoretically experience prostate-related issues due to the absence of a prostate, we encountered 3 reports alluding to prostate disorders.²⁴

The potential risk of breast cancer in transgender men presents a critical concern when considering testosterone prescriptions. The relationship between long-term testosterone exposure and cancer risk in transgender men remains largely unexplored. To date, fewer than 20 cases have been documented, highlighting the pressing need for more extensive studies on this matter.²³ According with FAERS gender reassignment reports, there were a total of 12 ADRs of breast cancer among transgender men using testosterone. Testosterone use has also been linked to cardiovascular events in men, even at low testosterone concentrations.²⁵ In our analysis, vascular disorders, encompassing thrombotic events and ischemic conditions, constituted 3% of the reported ADRs.

Several therapeutic agents are available for transgender women, with options extending beyond estrogens. Spironolactone, an androgen receptor–blocking potassium-sparing diuretic, is frequently used to initiate feminization. Notably, high doses can lead to serious adverse effects, including hyperkalemia, as well as symptoms such as polyuria and orthostatic hypotension.²⁶ In the FAERS reports concerning transgender women, all 4 documented cases of hyperkalemia were linked to spironolactone use.

The use of estrogens in female populations, especially during childbearing and menopause ages, has been associated to a higher rate of cardiovascular events, especially among smokers and those with bad lipid profiles.^27,28 Although our research revealed only 2 ADRs grouped as cardiac disorders and 7 (3%) were grouped as vascular disorders. This could potentially mirror the adverse lipid profile effects induced by estrogens.

The cardiovascular field is particularly notable for its research from a sex perspective, as notable differences in health outcomes have been observed between sexes.^29-31 It is imperative to consider sex in drug development. An underrepresentation of one sex in clinical trials can lead to disparities in both efficacy and safety outcomes.^32,33 In some cases, such imbalances have even prompted the withdrawal of Food and Drug Administration–approved treatments. In our study, vascular disorders appeared more frequently in transgender men (7 cases, 3%) than in transgender women (2 cases, 0.8%). However, cardiac disorders were almost equally reported for both groups (0.9% for transgender men and 0.8% for transgender women). While higher rates of cardiovascular events in transgender women undergoing sex reassignment treatments have been documented, the findings regarding transgender men remain ambiguous due to a lack of substantial evidence.¹¹

As more individuals with gender dysphoria seek gender reassignment treatments, ADRs concerning sexual and reproductive health have become prominent. Our study, using the FAERS database, has highlighted issues such as clitoral enlargement and erectile dysfunction in transgender men individuals and galactorrhea in transgender women individuals. The evolving health care landscape mandates enhanced care for diverse populations, especially transgender individuals. This care must not only address their immediate physical and psychological needs but also anticipate the long-term effects of gender reassignment therapies.³⁴ Given the recent success of uterine transplants in the United States for women with uterine factor infertility, there is potential to further enhance the reproductive health options available to transgender women.³⁵

There is a pressing need for clinicians to receive more comprehensive training in the area of gender dysphoria. Historically, this topic has not been adequately represented in medical school curricula, resulting in a knowledge gap. It is imperative that physicians gain a more in-depth understanding of gender reassignment treatments and their potential adverse effects. Such knowledge would empower clinicians to engage in informed discussions with their transgender patients, facilitating a balanced consideration of the benefits and risks associated with gender reassignment treatments.¹⁸

Our analysis, improved by recent research, indicates that ADR profiles prevalent in cisgender populations may not be entirely applicable to transgender individuals undergoing HT. Studies on drug-induced SD underscore the variance in drug reactions across sexes, thereby highlighting the imperative for personalized treatment strategies.¹⁰ For instance, drugs such as testosterone and spironolactone frequently used in gender-affirming therapies exhibit divergent ADR patterns in transgender individuals compared with cisgender counterparts. This underlines the importance of tailored pharmacotherapy, considering the unique physiological and hormonal alterations associated with gender transition.⁹ As evidenced by our findings, all these medications are prescribed off-label, with none specifically indicated for gender reassignment on their labels. Individuals seeking these therapies confront numerous challenges, from barriers to accessing treatments to a scarcity of health care professionals trained in gender-affirming care.³⁶ It is imperative that the therapeutic objectives for patients considering HT are clearly defined before commencing treatment. This underlines the essential need for thorough knowledge and understanding for both patients and their health care providers.

Limitations

While FAERS database is a rich source of information, it also possesses certain limitations, which are common to other spontaneous reporting databases.^37,38 Despite our rigorous curation, cleaning, and normalization process applied to FAERS reports, issues such as missing data and potential duplication of reports cannot be completely eliminated. Furthermore, the voluntary nature of these reports may lead to underreporting, thus potentially underestimating the actual incidence of adverse events. In addition, establishing a definitive causal link between the adverse events and gender-affirming hormonal treatments is challenging, due to the nature of the reports. The data should, therefore, be interpreted with caution, considering these significant constraints.

In addition, our study focused specifically on reports indicating transgender HT, as defined by selected PT. While this approach ensured targeted analysis, it also introduces a limitation in terms of the scope of our investigation. The PTs used—“Transgender Hormonal Therapy,” “Gender Dysphoria,” “Transgender Operation,” and “Gender Reassignment Therapy”—were chosen to align with our study’s focus but may have excluded relevant reports that did not use these specific terms. Therefore, there could be additional ADRs related to transgender HT that were not captured in our analysis.

We did not conduct a disproportionality analysis to compare ADR prevalence with other drugs, focusing instead on detailing ADRs specific to transgender HT. While this analysis could add perspective, its absence does not undermine our study’s contributions to understanding these ADRs. Future research could explore this comparative aspect.

Conclusions and Relevance

This study offers initial insights into the safety of gender reassignment therapies, highlighting potential adverse outcomes of hormone treatments. However, due to the limitations of the FAERS database, including voluntary submission and inability to establish causality, these findings should be interpreted cautiously. Our review contributes to the dialogue on treatment safety, suggesting the need for further research and refinement of therapeutic strategies for individuals undergoing gender transition. We advocate for future, robust studies to validate our preliminary findings and support the development of personalized care approaches for transgender and gender nonconforming individuals.

Footnotes

Author Contributions

AG-L planned the study design, analyzed the data, and wrote the first draft of the manuscript. LV-Z planned the study design, wrote the protocol, and retrieved and conducted the data curation. Both authors approved the final version of the manuscript.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethics Approval

FAERS complies with all US Government security standards and protections concerning health information. FAERS does not require IRB approval or informed consent requirements.

ORCID iD

Ainhoa Gomez-Lumbreras

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