We invite clinicians, researchers, and public health stakeholders concerned about the unchecked, off-label use of estrogen in vulnerable populations to co-sign this petition as a matter of ethical and regulatory accountability. Sign the petition here.

Subject: Citizen Petition under 21 CFR §10.30 Requesting FDA Review of the Off-Label Use of Estrogen in Gender Transition Care for Biologically Male Patients.

Dear Commissioner,

I respectfully submit this Citizen Petition under 21 CFR §10.30 requesting that the Food and Drug Administration (FDA) take regulatory action regarding the off-label use of estrogen-containing drugs in biologically male patients for the purpose of gender transition (also referred to as transfeminine or male-to-female hormone therapy).

I am a licensed and certified Physician Assistant (PA-C) with a Master of Clinical Health Services and a former Registered Nurse with frontline experience in intensive care and hospital medicine through the COVID-19 pandemic. My professional concerns are informed not only by clinical practice but also by personal experience advocating for a family member who has been prescribed estrogen for gender transition despite significant psychiatric and developmental vulnerabilities.

Estrogen is being prescribed off-label to biological male individuals for gender transition despite limited long-term safety data.   A significant proportion of these individuals present with autism, trauma, or psychiatric comorbidities, all of which heighten their cognitive and emotional vulnerability. Autism Spectrum Disorder (ASD) is especially prevalent in this group and is often associated with rigid thinking, poor abstract reasoning, and sensory sensitivities that can make puberty distressing and lead to misattributed gender dysphoria.

Also, these individuals frequently have co-occurring depression, anxiety, borderline personality disorder, and dissociative symptoms—all of which impair identity formation and increase susceptibility to suggestion. Informed consent is often inadequate.

ACTION REQUESTED

I am requesting that the FDA:

  1. Drug Safety Communication: Issue a formal Drug Safety Communication and require labeling changes for all estrogen-containing drugs to explicitly identify the off-label use of estrogen in biologically male individuals for gender transition as not FDA-approved and associated with serious risks.
  2. Safety Review and REMS Evaluation: Conduct a comprehensive safety review of estrogen when used off-label for gender transition in biologically male patients, including reevaluation of Risk Evaluation and Mitigation Strategies (REMS).
  3. Labeling and Medication Guide: Require a Medication Guide specifically addressing the use of estrogen in gender transition for biologically male individuals, highlighting risks including cardiovascular events, infertility, sexual dysfunction, hepatic effects, and cancer.
  4. Prescribing Surveillance:Urgently investigate the prevalence and clinical context in which biological male patients—especially those with developmental or psychiatric vulnerabilities such as autism, trauma histories, or severe mental illness—are being prescribed off-label estrogen for gender transition. These prescriptions are often made without adequate informed consent, long-term safety data, or prior therapeutic exploration. In many cases, gender dysphoria may reflect transient distress or trauma-related identity confusion, not a fixed or intrinsic condition. The absence of proper safeguards and psychological assessment in these high-risk populations represents a serious breach of ethical and medical standards.

Autistic individuals often experience:

  • Concrete thinking and rigid ideation, making exploration of identity more binary and less flexible.
  • Poor interoception and difficulties with abstract self-perception, limiting their ability to grasp the concept of a stable gender identity or understand irreversible medical interventions.
  • Sensory processing difficulties, which may intensify during puberty and lead to misattributed gender dysphoria when in fact the distress stems from physical or hormonal changes associated with typical development.

Vulnerable Population Safeguards: Implement safeguards for vulnerable populations, including:

  • Those with Autism spectrum disorder (ASD), severe psychiatric or developmental disorders.
  • Mandatory documentation of capacity to consent and fertility preservation counseling,

STATEMENT OF GROUNDS

  • Diagnostic ambiguity in autistic individuals who present with gender dysphoria symptoms.
  • That GD in these individuals may reflect cognitive rigidity, obsessive interests, or atypical identity development rather than stable transgender identity.
  • The need for extended diagnostic evaluations and individualized approaches before initiating irreversible treatment.
  • That no conclusions could be drawn about optimal diagnostic procedures or treatment outcomes for this population.
  1. Infertility and Testicular Damage

A pivotal study by Matoso et al. (2018) evaluated 85 orchiectomy specimens from biologically male-to-female patients undergoing gender confirmation surgery. It found:

  • 80% had spermatogenic arrest at the spermatogonia level, indicating irreversible infertility.
  • Histological findings consistent with estrogen exposure included:
    • Decreased seminiferous tubule diameter
    • Germ cell hypoplasia
    • Aspermatogenesis
    • Leydig cell hypoplasia or absence
    • Epididymal epithelial hyperplasia with fibrosis

Source: Matoso et al., Human Pathology, 2018;76:91–99.

A 2023 review also found that fertility preservation is inconsistently offered and often poorly understood by patients. Many regret the loss of reproductive capacity after transition.

Source: Bayar E et al., Human Fertility, 2023. DOI: 10.1080/14647273.2022.2163195.

  1. Cardiovascular Risk

A 2018 cohort study by Getahun et al., published in Annals of Internal Medicine, found significantly increased risk of acute cardiovascular events in transgender women using estrogen compared to matched cisgendered men and women:

  • Venous thromboembolism (VTE) risk increased significantly, especially after two years of estrogen use.
  • Increased incidence of ischemic stroke.

Source: Getahun D, Nash R, Flanders WD, et al. Ann Intern Med. 2018;169(4):205–213.

  1. Sexual Dysfunction

Estrogen therapy in biologically male patients can cause loss of libido, erectile dysfunction, and anorgasmia. These outcomes are frequently underreported but have been documented in transgender care literature. These effects are typically not reversible, especially when concurrent with infertility-inducing testicular changes.

Source: Wiepjes CM, Nota NM, de Blok, et al 2018 Journal of Endocrinological Investigation

  1. Cancer Risk

Male breast cancer risk increases with estrogen exposure. Although still rare, the long-term cancer risk from off-label estrogen exposure in biologically male patients has not been adequately studied. The potential for hepatic adenomas and other estrogen-sensitive tumors also warrants further investigation.

Source: de Blok CJM, Wiepjes CM, Nota NM, et al. Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands. BMJ. 2019;365:l1652. doi:10.1136/bmj.l1652

  1. Hepatic Dysfunction

Estrogens are known to impact liver function and may induce hepatic enzyme abnormalities or hepatic tumors.  This risk is magnified in off-label settings where long-term protocols are inconsistent.

Source: Ash NS, Schiano TD, Safer JD, et al. Obliterative portal venopathy during estrogen therapy in a transgender woman: a case report. Livers. 2024;4(3):314–319. doi:10.3390/livers4030022

  1. Hyperlipidemia and Metabolic Changes

Estrogen can cause adverse changes in lipid profiles, including elevated triglycerides and altered HDL/LDL ratios, increasing cardiovascular risk.

Source: Garg P, et al. Lipid profiles and hypertriglyceridemia among transgender and gender diverse adults on gender-affirming hormone therapy. J Clin Lipidol. 2022;17(9):e209–e220. doi:10.1016/j.jacl.2022.11.010

  1. Psychiatric Vulnerability and Neurodevelopmental Disorders

Emerging literature indicates a disproportionately high prevalence of gender dysphoria among individuals with diagnosed Autism Spectrum Disorder (ASD), raising urgent concerns about diagnostic clarity and the adequacy of informed consent protocols for this neurodiverse subgroup. International data consistently show that 5–26% of patients presenting to gender clinics have diagnosed ASD, with many centers reporting rates in the 8–12% range. Critically, these figures reflect only those with formal diagnoses—leaving out an unknown, potentially large number of individuals with undiagnosed autism.

Given the established challenges that autistic individuals face in processing abstract concepts, long-term consequences, and social pressures, the appropriateness of irreversible medical interventions such as sterilization must be seriously questioned. Are we truly safeguarding the autonomy and well-being of neurodiverse patients—or are we medicalizing a population whose developmental profile renders them especially vulnerable to misinterpretation, suggestion, and harm?

A landmark 2016 narrative review by Van Der Miesen, Hurley, and De Vries, published in the International Review of Psychiatry, affirmed that co-occurring gender dysphoria and ASD is both common and poorly understood. This intersection deserves far more caution—not fast-tracking to irreversible outcomes. The review emphasizes:

Source: Van Der Miesen AIR, Hurley H, De Vries ALC. Int Rev Psychiatry. 2016;28(1):70–80.

These findings suggest that vulnerable patients–particularly those with ASD–are at elevated risk of misdiagnosis and inappropriate treatment, Estrogen use in this population raises significant questions about medical ethics, informed consent and long-term safety especially in neurodivergent populations.

ENVIRONMENT OF CLINICAL PRACTICE: LACK OF INFORMED CONSENT AND REGULATORY OVERSIGHT

Estrogen is routinely prescribed off-label to biologically male individuals for gender transition, including vulnerable young adults. Frequently:

  • Fertility preservation is not discussed.
  • Psychiatric comorbidities are minimized.
  • Irreversible consequences are not clearly explained.

As both a clinician and mother, I have seen firsthand how these shortcomings are affecting patients and families.

ENVIRONMENT OF PROFESSIONAL GUIDELINES: LACK OF FDA ALIGNMENT

Professional guidelines (WPATH SOC8, Endocrine Society) endorse estrogen for transfeminine patients, but these remain off-label and unsupported by long-term RCTs. The Cass Review found that clinical guidelines for gender-affirming interventions frequently cite one another in a circular manner, with WPATH and the Endocrine Society relying on each other’s conclusions to legitimize their own. In medicine, where patient welfare depends on rigorous, unbiased evidence, such self-reinforcing citation practices are not merely sloppy—they are ethically indefensible. The FDA must uphold drug safety and labeling standards independently.

CONCLUSION

The off-label use of estrogen in biologically male individuals for gender transition is widespread and under-regulated. It presents serious, often irreversible risks and lacks consistent safety protocols, especially for vulnerable populations. Immediate FDA action is warranted to ensure proper regulation, informed consent, and patient safety.

ENVIRONMENTAL IMPACT

This petition does not involve actions that would significantly affect the quality of the human environment and is categorically excluded under 21 CFR §25.30.

ECONOMIC IMPACT

Economic impact information will be submitted upon request by the Commissioner.

CERTIFICATION

The undersigned certify that, to the best of their knowledge and belief, this petition includes all information and views on which the petition relies, including any unfavorable data known to the petitioners.

Respectfully submitted,

Rachel Ragosta, PA-C, RN
reragosta@gmail.com

Kallie Fell, MS, BSN, RN
CBC, Executive Director
Paul Ramsey Institute, Program Director
Venus Rising, Host
Kallie.Fell@cbc-network.org
cbc-network.org

 

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