Abstract
Background:
Danazol is a synthetic progestin with androgenic effects that is approved by the Food and Drug Administration for treatment of endometriosis, benign fibrocystic breast disease, and hereditary angioedema. In recent years, increasing numbers of transgender and nonbinary individuals seeking menstrual suppression have been offered danazol due to its potential to both induce amenorrhea and cause reversible androgenic side effects including pigmentation of vellus hairs and voice changes, which may be desirable in this population. There are currently no studies assessing use of danazol within the transgender population for menstrual suppression.
Objective:
This study’s primary aim was to evaluate the use of danazol as a menstrual suppression agent in transgender patients.
Design:
This was a retrospective multisite cohort study of all individuals who had been on danazol at two tertiary care centers between 2000 and 2022.
Methods:
All patients prescribed danazol were identified using a search of the electronic medical records. For demographic purposes, comparisons were made between those who did and did not use danazol for the purpose of menstrual suppression. A detailed chart review was then performed to analyze the experiences of menstrual suppression in transgender and nonbinary patients.
Results:
Most transgender and nonbinary patients on danazol for menstrual suppression remained on it at their most recent follow-up visit, and many charts noted improvements in gender dysphoria, pelvic pain, dysmenorrhea, endometriosis, and heavy menstrual bleeding. Most transgender patients achieved amenorrhea.
Conclusion:
Danazol may be a reasonable option for menstrual suppression in transgender and nonbinary patients. Our findings show its potential to not only induce amenorrhea but cause desired androgenic symptoms and improve gender dysphoria, pelvic pain, dysmenorrhea, endometriosis, and heavy bleeding. While the androgenic effects of danazol are less desirable in cisgender populations, it is an attractive option for menstrual suppression in transgender and nonbinary patients.
Plain language summary
Danazol has previously been used to help treat pain and bleeding related to endometriosis. However, danazol can have certain androgenic side effects (acne, deepening of the voice) that cisgender women (individuals who were assigned female at birth and identify with the female gender) often find undesirable, but that could be desirable in transgender patients seeking to affirm their gender by stopping periods. Our study looked at danazol use for period suppression, as well as for other reasons. We found that most transgender patients using danazol for period suppression found it to be successful and remained on it at follow-up appointments, and that many transgender patients saw improved gender dysphoria, pelvic pain, pain during periods, endometriosis, and heavy period bleeding. These findings suggest that danazol may be a good option for menstrual suppression in transgender individuals as any experienced androgenic effects may help with gender dysphoria, whether individuals are not yet ready to start testosterone or do not desire testosterone therapy at all.
Introduction
Danazol was originally developed in 1963 as a synthetic steroid hormone. It was approved by the Food and Drug Administration (FDA) in 1976 for the treatment of pelvic pain and menstrual suppression in endometriosis, and was subsequently approved for pain associated with benign fibrocystic breast disease and hereditary angioedema.1,2 Taken as an oral capsule, danazol has a complex and multi-pronged mechanism of action as a weak androgen, antigonadotropin, and antiestrogen. 3 Danazol has also historically had a number of off label uses including use for the treatment of immune thrombocytopenic purpura, aplastic anemia, and pre-menstrual syndrome/dysphoric disorder but is not used as a contraceptive.4 –6
Androgens are a group of steroid hormones associated with virilization. Androgens arise from the adrenal gland and gonads (ovaries and testes), of which testes typically produce far higher amounts. This group of hormones includes testosterone, dihydrotestosterone, androstenedione, and dehydroepiandrosterone (DHEA). As a weak androgen, danazol has the potential for a number of side effects that may be undesirable in cisgender women (women who were assigned female at birth) seeking treatment for endometriosis. These include hirsutism, deepening of the voice, and acne.7,8 As a result, while known for menstrual suppression in the context of endometriosis, danazol has largely fallen out of favor for endometriosis treatment in deference to other treatment modalities such as gonadotropin-releasing hormone agonists, combined hormonal contraceptives, and other less androgenizing agents. 9 However, androgenic side effects are not undesirable in all populations.
In recent years, there have been increasing numbers of individuals who as identify as transgender and nonbinary seeking menstrual suppression.10 –15 Danazol has been offered as an option for these individuals, alongside progestin and combined estrogen and progestin methods, due to its potential for amenorrhea and, often desired, weakly androgenic side effects. 14 This novel approach to its use allows transgender individuals to both achieve menstrual suppression and potentially improve gender dysphoria when they are not yet ready or able to start gender-affirming testosterone treatments, or potentially are uninterested in doing so but still open to androgenic effects. Danazol may also be an interim option for individuals who live in states that have outlawed gender-affirming hormones for minors, given that its intended purpose is typically treatment for a variety of hormonally linked conditions in cisgender women where menstrual suppression may be a goal.
While randomized controlled trials have been performed showing danazol’s efficacy for use in endometriosis, 16 to date there have not been any studies about its use for primary menstrual suppression in the transgender population. This study’s aim was to evaluate the novel use of danazol as a menstrual suppression agent in the transgender community. Our hypotheses were that transgender patients would be unlikely to discontinue danazol due to androgenic side effects and that menstrual suppression would be successfully achieved.
Methods
This was a retrospective multisite cohort study of all individuals who were sex-assigned female at birth who had been on danazol at two tertiary care referral centers between 2000 and 2022. Participants were identified by the hospital clinical research informatics team, who identified all patients who were sex-assigned female at birth with a prescription for danazol in the electronic medical record (EMR) using a prescription code. Gender identity is routinely assessed by clinicians in clinics where menstrual suppression is offered and was abstracted from provider notes. Where a separate gender was not reported, individuals were presumed to be cisgender females. This study was institutional review board (IRB) approved at both Boston Children’s Hospital (IRB-P00044004) and Penn State Health Children’s Hospital (00021705) and deemed exempt at both institutions, which also waived the requirement for informed consent. All data were deidentified prior to analysis. In addition, we followed the STROBE Guidelines when preparing this article.
The data abstraction design was devised by a team of researchers with expertise in reproductive health, endometriosis, menstrual suppression, and gender-affirming care. Each patient’s EMR was reviewed for demographics, including gender identity (coded as girl/woman, boy/man, nonbinary, or those who identified as another gender identity and then categorized as cisgender or transgender/nonbinary), ethnicity, race, insurance type, parity, sexual orientation, and all indications for danazol. In addition, it was recorded if the patient was sexually active, had a history of any penile-vaginal sex, was using any concomitant hormonal medications at the start of danazol, and had any comorbidities.
Demographics of all patients receiving danazol were compared to determine if they differed for patients using it for menstrual suppression as opposed to for other indications. For those whose primary indication for using the danazol was menstrual suppression, and who were not on any other concomitant hormones, additional data were abstracted from the EMR. These included any documented contraindications to estrogen, any prior menstrual suppression or menstrual management hormone use, and the length of time with any menstrual suppression. The effects of danazol on indications for menstrual suppression were documented as of the most recent follow-up within the study window (based on clinical documentation from the most recent clinical visit) along with any side effects, the highest dose of danazol documented, and if the patient was still on danazol. Data abstraction for individuals who were no longer taking danazol included their reason for discontinuing danazol and any subsequent forms of menstrual suppression or management.
Statistical analysis
Descriptive statistical analyses were performed. Continuous data are presented as medians and interquartile range (IQR), and categorical data are summarized using frequencies and percentages. Denominators are presented to indicate the amount of data included in obtaining each value due to the varying amount of missing data across variables. All analyses were performed using Stata (version 17.1, StataCorp LLC, College Station, Texas). The research team included cisgender and transgender researchers.
Results
The final sample included 107 patients who had been prescribed danazol at the time of initial data abstraction. Table 1 shows the demographic characteristics of these patients. The majority of the sample identified as White (N = 81, 75.7%), Non-Hispanic (N = 83, 77.6%), and boys/men (N = 60, 56.1%). The median age of danazol initiation for the total sample was 17 years (IQR = 15–24), and the median duration of danazol use was 17 months (IQR = 7–364). The median age for those taking danazol for menstrual suppression was 17 (IQR = 15–18), compared with a median age of 19.5 (IQR = 15–26) for those using danazol for other indications. For the 105 patients with follow-up data from their most recent follow-up visit, the most common primary indication for danazol was menstrual suppression (N = 43, 41%).
Demographic table of all patients on danazol.
IQR: interquartile range.
Patients may have had more than one.
Pain in the pelvis not specifically described as dysmenorrhea or endometriosis.
Included all forms of abnormal uterine bleeding (e.g. oligomenorrhea, irregular menstruation, and intermenstrual spotting) except for heavy menstrual bleeding.
Any hormonal medication which impacts menstrual function including combination estrogen and progestin contraceptives, progestin-only medications, and testosterone.
Table 2 shows the characteristics of only those patients who were prescribed danazol for menstrual suppression (N = 46), as well as the specific characteristics for those who identified as transgender (N = 39). The majority of patients taking danazol for menstrual suppression identified as White (N = 36, 78.3%), Non-Hispanic (N = 33,73.3%), and boys/men (N = 33, 71.7%) and were privately insured (N = 33, 73.3%). Of note, only seven cisgender patients used danazol for menstrual suppression.
Characteristics of those using danazol for menstrual suppression.
IQR: interquartile range.
Both the menstrual suppression and danazol use history for these 46 patients, and differences in history between the transgender and non-transgender patients, are detailed in Table 3. Of patients with follow-up data, 19 (41.3%) had prior menstrual suppression therapy, with similar percentages between transgender and non-transgender patients (N = 16, 41% and N = 3, 42.9%, respectively). Non-transgender patients had a higher median age at danazol initiation (22, IQR = 21–35) compared with transgender patients (17, IQR = 15–18). The duration of use for all patients on danazol for menstrual suppression was 19 months (IQR = 10–35), with transgender patients having a longer median duration of use (23 months, IQR = 12–37) compared with non-transgender patients (10 months, IQR = 5–15).
Menstrual suppression history including danazol use.
IQR: interquartile range.
Pain in the pelvis not specifically described as dysmenorrhea or endometriosis.
Includes concerned about increased obsessive-compulsive disorder symptoms (1), oncology treatment initiation (1), “didn’t like the way it felt” (1), caused self-reported seizures (1) as reasons provided by transgender and nonbinary individuals; hallucinations (1), and still experiencing pelvic pain (1) both reasons by cisgender individuals.
Thirty-four of the 46 patients (73.9%) using danazol for menstrual suppression had gender dysphoria as an indication, making it the most common indication in the cohort and 79.3% saw resolution or improvement in symptoms at follow-up (N = 23). The second most common indication was dysmenorrhea (N = 20, 43.5%). At follow-up, a larger proportion of transgender patients reported improvements or resolution in dysmenorrhea (N = 11, 78.6%) than non-transgender patients (N = 1, 50%). For patients with endometriosis as an indication (N = 12), 100% of transgender patients (N = 5) and 50% of non-transgender patients (N = 2) saw an improvement or resolution of endometriosis at follow-up. In addition, 80% of transgender patients with follow-up data (N = 4) reported improvement in heavy menstrual bleeding, while 100% of non-transgender patients (N = 1) reported no change in heavy menstrual bleeding symptoms. Of transgender patients who had pelvic pain prior to danazol initiation (N = 9), 85.7% (N = 6) became pain-free compared with 25% of non-transgender patients (N = 1).
At follow-up, 84.9% of transgender patients (N = 28) reported becoming amenorrheic, compared with 40% of non-transgender patients (N = 2). The median dose of danazol at which amenorrhea occurred was 400 mg daily (IQR = 200–400). In transgender patients, the median was 400 mg daily (IQR = 200–400), and in non-transgender patients, the median was 200 mg daily (IQR = 200–200). For patients in which amenorrhea occurred on danazol, the median time it took to achieve was 3 months (IQR = 1–4). Specifically, the median time to amenorrhea in transgender patients in those experiencing it was 3 months (IQR = 1–3), compared with 1 month in non-transgender patients (IQR = 1–1). In addition, 31.4% of patients at follow-up (N = 11) reported experiencing androgenic symptoms on danazol—all of which were transgender patients. The median dose at which androgenic symptoms were noted was 400 mg (IQR = 400–400), and the median time to experiencing androgenic symptoms was 5 months (IQR = 3–6). The most common androgenic symptom experienced was acne (N = 7, 15.2%), followed by voice change (N = 6, 13%). Other reported side effects included weight gain (N = 3, 6.5%), hot flashes or sweats (N = 2, 4.4%), elevated transaminases (N = 1, 2.2%), tiredness (N = 1, 2.2%), decreased size of breasts (N = 1, 2.2%), and headaches (N = 1, 2.2%).
Of those with follow-up data, 57.8% of transgender patients (N = 19) were still on danazol at the most recent follow-up, versus 16.7% of non-transgender patients (N = 1). The median duration of danazol use for those who discontinued was 12 months, compared with a median duration of 25 months for those who did not discontinue during the study window. The most common reason for the discontinuation of danazol in the transgender patients with follow-up data was a transition to testosterone, which was reported by six patients (15.4%). The most common reasons for discontinuation in non-transgender individuals were ongoing bleeding in three patients (42.9%) and “Other” in three patients (42.9%). Other reasons for discontinuation included concerns about thinning hair, an increase in obsessive-compulsive disorder (OCD) symptoms, concerns that the medication caused seizures, a bone marrow transplant, hallucinations, a continued presence of pelvic pain, and a statement that a patient didn’t like the way it made them feel.
Discussion
In our multisite study of transgender and nonbinary individuals using danazol for menstrual suppression, many individuals reported clinical improvement. Clinicians have used many methods for menstrual suppression in transgender and nonbinary patients in addition to, or instead of, gender-affirming testosterone.10 –15 These include intrauterine devices, oral contraceptive options, hormone patches, depot progesterone, and GnRH agonists. 9 While these options are all effective to various degrees in different individuals, there remains an ongoing need for alternatives. 14 Though danazol may not be well known to younger clinicians, as it has largely been replaced with GnRH as a treatment for endometriosis, fibrocystic breast disease, and hereditary angioedema, one of its on-label uses is menstrual suppression in the context of endometriosis. Although an off-label use, based on our data, danazol may be a useful option for transgender patients seeking menstrual suppression who may not feel its potential androgenic side effects are a deterrent.
In our study, the majority of those who had gender dysphoria as an indication for danazol saw improvement with use. Almost all of the transgender patients in our cohort also became amenorrheic on danazol. In addition, most transgender patients experiencing pelvic pain, dysmenorrhea, endometriosis, and heavy menstrual bleeding symptoms reported improvements in symptoms during follow-up visits after starting danazol. Their higher rates of reported resolution of symptoms compared with the, albeit smaller, cisgender cohort may be attributable to the longer duration of danazol use in the transgender population, the longer median duration of use in transgender patients compared with cisgender patients, and/or the difference in dosage of danazol between transgender and cisgender patients.
Recent studies have found that, while other menstrual suppression options are effective and satisfactory to some degree, breakthrough bleeding and other potential undesired side effects still occur.9,14,17,18 As amenorrhea occurred on danazol for the majority of our transgender and nonbinary patients, danazol seems to be a plausible option for menstrual suppression.12,14 However, there is a need for studies with longer follow-up periods, as it is possible that some patients who experienced menstrual suppression on danazol might eventually experience breakthrough bleeding.
In most of the transgender and nonbinary patients in our cohort, amenorrhea occurred at relatively low total daily dosing. The median dosing (400 mg/day) was equal to or lower than the recommended dose for mild endometriosis (two 100 or 200 mg tablets twice daily), moderate to severe endometriosis (400 mg tablets twice daily), and hereditary angioedema (200 or 300 mg tablets twice daily). 19
More than one third of transgender and nonbinary patients in our cohort experienced androgenic symptoms on danazol, with the most common being acne and voice changes. Perhaps for this reason, a larger percentage of transgender and nonbinary patients were found to still be on danazol at their most recent follow-up visit when compared with non-transgender patients. Danazol may be an appealing option for individuals who desire menstrual suppression and are either ambivalent about or would welcome androgenic effect.
As a weak androgen, not all individuals will experience virilization on danazol, and those who do are unlikely to experience the same rapidity and degree of virilization as seen on testosterone. Danazol may, therefore, be a good option for patients who seek less virilization than what can be experienced on testosterone. Not every transgender or nonbinary individual has the same gender embodiment goals. 20 For example, nonbinary patients may not want as many physical changes as transgender men and may not desire many of the effects of gender-affirming testosterone, but they may still seek menstrual suppression and appreciate the possibility of mild virilization. 21 Danazol may serve as a useful option for such individuals as well as for those who want the benefits of testosterone but are unable to access it for various reasons. For these individuals, as well as those who would like to experiment with reversible effects prior to initiation of testosterone therapy, danazol may fill a clinical niche not addressed by other medications in wide use in gender-affirming health care.22,23
Our study is limited by its retrospective nature, small sample size, and predominantly White sample, which may affect generalizability. There is also limited follow-up for some patients, which affects our capacity to discuss long-term effects. In addition, danazol was provided by multiple clinicians according to their own clinical practice patterns, which likely influenced starting doses as well as decisions about if, when, and how to increase dosing. Data derived from this study were based on clinical documentation, and as such the absence of documentation does not guarantee that a certain effect did not occur. In addition, the outcomes of interest (i.e. symptom improvement, and side effects) were not standardized and were subject to interpretation and clinical documentation. Transgender individuals may have also been more likely to desire androgenic symptoms and as such may have been more likely to report these in clinical follow-up compared with their cisgender peers, leading to attention bias. Of note, current guidelines do not require serum laboratory monitoring alongside danazol dosing; however given its androgenic potential, future studies may benefit from understanding the short- and long-term effects of danazol on serum testosterone and liver function. Strengths of this study include its multi-center data, evaluation of current clinical practices, and assessment of multiple indications for danazol use.
Conclusion
Our data suggest that danazol may be a plausible option for menstrual suppression in transgender and nonbinary patients. The fact that most transgender and nonbinary patients remained on danazol at follow-up, and that many saw improvements in/resolution of gender dysphoria on danazol, is promising. In addition, the potential for androgenic effects, alongside improved symptoms of pelvic pain, gender dysphoria, dysmenorrhea, endometriosis, and heavy menstrual bleeding, may make it a more attractive option than other currently available treatments for the suppression of menses in this population. It is also possible that, for minors who wish to start gender-affirming hormones but are restricted from doing so by local legislation, danazol may work as an interim menstrual suppression option until they are able to access desired care.
Supplemental Material
sj-docx-1-whe-10.1177_17455057241265081 – Supplemental material for Danazol’s use for menstrual suppression in transgender individuals: A retrospective multi-site cohort study
Supplemental material, sj-docx-1-whe-10.1177_17455057241265081 for Danazol’s use for menstrual suppression in transgender individuals: A retrospective multi-site cohort study by Ava Scatoni, Zaine Roberts, Elizabeth R Boskey, Steven Staffa, Rosemary Claire Roden, Emile Redwood and Frances Grimstad in Women’s Health
Footnotes
References
Supplementary Material
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