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To describe time to cessation of menses in adolescent and young adult transgender males with testosterone and/or other hormonal therapies
Design
Retrospective chart review
Setting
Tertiary children's hospital
Participants
Patients, aged 10-24, who began gender-affirming hormonal therapy between January 2013 and January 2019 (n = 220)
Intervention(s)
None
Main Outcome Measure(s)
Time to cessation of menses
Results
Most patients identified as transgender male or transmasculine (211/220, 95.9%), with an average age of 15.8 (±1.9) years. Approximately 53.6% (118/220) of patients reported regular menstrual cycles; 18.2% (40/220) reported irregular cycles. Median time to cessation of menses for all patients was 182 days. Patients treated with testosterone alone (n = 105) reported a median time to cessation of menses of 151 days. Patients who concurrently began testosterone and norethindrone acetate (NETA) (n = 5) had a median time to cessation of menses of 188 days, compared with 168 days for those on testosterone and depot medroxyprogesterone acetate (DMPA, n = 15). In 15 patients who began testosterone, a progestin therapy was later added to induce menstrual suppression, and the median time to cessation of menses was 168 days (+DMPA, n = 4) or 56 days (+NETA, n = 11). Patients treated with NETA (n = 14) or depot leuprolide (n = 11) reported a median time to cessation of menses of 78 days or 77 days, respectively. Considerable variability in prescribing patterns was noted in the remaining 36.4% of patients (n = 80).
Conclusion
Patients used a variety of different hormonal regimens for menstrual suppression. Less than half achieved cessation of menses within 6 months. NETA and depot leuprolide users reported the most rapid cessation of menses.
Transgender identity and experiences of violence victimization, substance use, suicide risk, and sexual risk behaviors among high school students - 19 states and large urban school districts, 2017.
Increasingly, patients present to health care providers requesting gender-affirming hormonal regimens to treat gender dysphoria, the distress caused by discordance between a person's gender identity and their sex assigned at birth.
Among patients with “persistent and well-documented” gender dysphoria, broadly accepted clinical guidelines published by the Endocrine Society and the World Professional Association for Transgender Health emphasize that hormonal therapies can minimize psychological distress and produce in patients desired physical and emotional changes.
For patients on the transmasculine spectrum—including transgender males who identify as male and transmasculine patients whose gender is masculine or who express themselves in a masculine way but might not always identify as male—menstruation can worsen gender dysphoria.
Hormone therapies other than testosterone can suppress menstruation in patients not on testosterone therapy or can be used in conjunction with gender-affirming hormones in cases of persistent bleeding on testosterone.
Additionally, hormone therapy in the form of contraception is essential to prevent unintended pregnancy. Unintended pregnancy in transgender patients has the potential to worsen feelings of gender dysphoria and creates potential teratogenic risk with circulating testosterone exposure to a female fetus.
Most studies examining the effects of testosterone and other hormonal therapies on menstruation focus on the adult population. In adults, testosterone induces amenorrhea in most patients (55-96%) within 6 months of initiating hormone therapy, although amenorrhea can be dose dependent and take up to 12 months to achieve.
One study evaluating transgender youth and menstrual cessation found that 85% of participants achieved amenorrhea in 6 months, with an average time of 2.9 months and few adverse effects. However, this study was limited to a sample of 36 youth who received subcutaneous injection of testosterone and therefore might not be generalizable to other testosterone therapies.
Another study examined breakthrough bleeding in TGDY on testosterone therapy for at least 1 year. Twenty-five percent of patients in this cohort experienced at least 1 episode of breakthrough bleeding after 1 year of treatment. Use and type of menstrual suppression did not differ between those who experienced breakthrough bleeding and those who did not; the authors concluded that there was no superior method in stopping breakthrough bleeding on testosterone.
Ultimately, limited data exist on the time to cessation of menses in the TGDY population across different prescribing practices. This study aimed to address this gap by assessing time to cessation of menses in transgender males on testosterone with and without additional hormonal therapies.
Materials and Methods
An IRB-approved (#18-2427) retrospective chart review was performed assessing transgender male or transmasculine patients, aged 10-24 years, seen at a tertiary children's hospital between January 1, 2013, and January 1, 2019. Subjects were identified by searching the institution's electronic health record with ICD-10 codes for gender dysphoria and cross-referenced for prescription hormonal medications as outlined below. The search identified 304 unique records; patients reporting female gender identity (n = 9), premenarchal (n = 8) or amenorrheic patients (n = 37), and those lost to follow-up (n = 30) were excluded from the final sample. The final analytic sample consisted of 220 patients who started hormonal therapies, including testosterone (cypionate or enanthate injections, patch, gel), norethindrone acetate (NETA), combined hormonal contraceptives (CHC), depot medroxyprogesterone acetate (DMPA), levonorgestrel-intrauterine system (LNG-IUS), etonogestrel implant, and depot leuprolide (DL).
Deidentified data were abstracted and stored in a secure REDCap database. Data included demographic characteristics (eg, age, race, ethnicity, sex assigned at birth, and gender identity), clinical characteristics (eg, body mass index [BMI], age at menarche, hormone therapy regimens, and menstrual bleeding patterns before and after the start of hormone therapy), sexual history, and contraceptive needs (if applicable).
The primary outcome was time to cessation of menses. In this study, cessation of menses was defined as the patient-reported absence of menses for at least 1 month (30 days) or longer. This definition was informed by our reliance on patient-reported bleeding with assessments of bleeding patterns at 30-day intervals. Secondary outcomes included rates of sexual history collection, contraceptive discussion, and unintended pregnancy. IMB SPSS 27 was used to compute descriptive statistics and Kaplan-Meier estimates for the median time to amenorrhea.
Results
Demographic and Clinical Characteristics
The sample median age was 15.8 (± 1.9) years. All patients were assigned female at birth, and most identified as transgender male or transmasculine (95.9%). The remainder identified as gender fluid or nonbinary (2.7%), male (0.5%), or something else (1%). Approximately 72% of the sample identified as Caucasian, and 16% reported Hispanic/Latino ethnicity (see Table 1).
Table 1Demographic and Clinical Characteristic of Patients (N = 220)
The sample median BMI was 22.8 kg/m2 (± 5.4 IQR). For patients with a reported age at which they began menstruating (n = 169), the median age at menarche was 12 years (± 1.3 IQR). About half of the sample (53.6%, n = 118) reported regular menstrual cycles before their first visit; 18.2% (n = 40) reported irregular cycles, and in 28.2% (n = 62), cycle frequency was not documented in the patients’ records. Sexual history was not taken in over half of appointments (56.8%, n= 125). Patients reported a spectrum of sexual attraction, most commonly to “females” (18.2%, n = 40). Whereas 2.7% (n = 6) engaged in penile-vaginal sex, for 54.5% of patients (n= 120), previous intercourse was not documented in the patients’ records. Similarly, contraception was discussed with only 5 patients (2.3%) (see Table 1: “Demographic and Clinical Characteristics of Patients”).
Hormonal Methods Prescribed
Table 2 reports the hormonal methods prescribed. A total of 185 patients started a single therapy (148 of whom remained on a single therapy throughout the study period, whereas 37 later added an additional hormonal method or methods). Thirty-five patients initiated a combination of hormone therapies, 5 of whom later added an additional hormonal method or methods.
For the 148 patients who started testosterone therapies (cypionate or enanthate injections, patch, gel), 105 started and remained on testosterone alone; 16 started testosterone and later added additional hormonal therapies including LNG-IUS (n = 1), medroxyprogesterone acetate (DMPA, n = 4), or norethindrone acetate (NETA, n = 11); and 27 patients initiated testosterone alongside an additional therapy (eg, combined oral contraceptives [COCs], DMPA, or NETA), 3 of whom later added an additional method (NETA or DMPA).
Patients Prescribed Other Hormonal Therapies
A total of 25 patients started with DMPA alone; 3 patients started DMPA in combination with another therapy, and later, 13 added an additional therapy. Sixteen patients initiated NETA, 2 later adding additional hormonal methods. Seven patients started NETA in combination with another method. Three patients were initially prescribed NETA alone or in combination and later added additional therapies.
Eleven patients initiated and remained on DL alone. Thirteen total patients began COCs: 9 started COCs alone, and 4 started COCs with another method or methods. Later, 4 COC users added testosterone, and 1 added DL. Two patients started with an LNG-IUS (later adding testosterone or COCs), and 1 patient started an etonogestrel implant (see Table 2: “Hormonal Methods Prescribed”).
Cessation of Menses
Patients reported a wide range of days to cessation of menses. The median time to cessation of menses for the full sample was 182 days. For patients treated with testosterone alone throughout the study period (n = 105), the median time to cessation of menses was 151 days. Patients who started concurrently on testosterone and NETA (n = 5) reported a median time to cessation of menses of 188 days. Those who started testosterone in combination with DMPA (n = 15) reported a median of 168 days. Patients who started DMPA (n= 4) after the initiation of testosterone reported a median time to cessation of menses of 168 days, compared with 56 days when NETA was added (n = 11).
Patients treated with DMPA alone throughout the study period (n = 13) reported a median time of 182 days to cessation of menses, compared with patients treated with NETA alone throughout the study period (n = 14) or DL alone throughout the study period (n= 11) reporting median times of 78 and 77 days, respectively (see Table 3: “Time to Cessation of Menses” and Fig. 1: “Days to amenorrhea by hormonal method”).
Table 3Time to Cessation of Menses
Time to cessation of menses
Median days (95% CI)
All patients, n = 220
182 (148.1-215.9)
Testosterone only, n = 105
151 (107.7-194.3)
Testosterone and depo medroxyprogesterone acetate (DMPA) initiated together, n = 15
168 (97.3-238.7)
Testosterone and norethindrone acetate (NETA) initiated together, n = 5
Fig. 1. Daysto cessation of menses by method. In this figure, the “+” indicates that a method was added later, whereas the “&” indicates a concurrent initiation. Colors in the first line graph indicate when a method was added.
Little is known regarding the effects of testosterone on menstrual suppression, particularly in TGDY. Previous studies indicate that intramuscular injections of testosterone induce amenorrhea in up to 97% of adult patients within 6 months of initiating therapy,
However, our data indicate that less than half of patients receiving a variety of gender-affirming hormone therapies achieved cessation of menses within 6 months. On testosterone alone, despite a median time to cessation of menses of 151 days, only 59% achieved amenorrhea within 6 months. The method that led to cessation of menses with the shortest time interval was DL, with a median time of 77 days to cessation of menses, followed by NETA at 78 days.
Nakamura et al suggested an initial dose-dependent response to cessation of menses that levels out after 6 months. In this study of 138 participants on 3 different doses of testosterone therapy, more than half (54.5%) of patients on 250 mg every 2 weeks achieved amenorrhea within a month, compared with 11.1% on 125 mg every 2 weeks. Most of the patients (96.6% on 250 mg every 2 weeks and 92.7% on 125 mg every 2 weeks), however, achieved amenorrhea at 6 months.
In another study of 74 transgender men starting on low-dose testosterone therapy (20-40 mg every week), 55% had cessation of menses within 6 months and an additional 32% by 6-12 months.
Our data on cessation of menses are not stratified by type of testosterone or dose, which is a limitation of the study, thus making interpretation of amenorrhea rates challenging.
Amenorrhea for patients on testosterone therapy could be due to endometrial atrophy and/or ovulatory suppression by inhibition of the hypothalamic pituitary ovarian axis.
Society of Family Planning clinical recommendations: contraceptive counseling for transgender and gender diverse people who were female sex assigned at birth.
Continued menstruation or breakthrough bleeding might be due to low testosterone levels due to late/missed injections or changes in regimen. Other causes of persistent bleeding include endometrial atrophy, withdrawal from menstrual suppression, structural uterine pathology, or non-uterine pathology, such as vulvovaginal atrophy, urinary tract infection, and infection.
After appropriate evaluation and management, medical options for management of bleeding include adjustment of testosterone dose, use of a nonhormonal menstrual reduction agent, or use of hormonal suppression.
In alignment with studies on breakthrough bleeding in transgender and gender-diverse patients on testosterone, our data demonstrate considerable variability in prescribing patterns, which suggests complexity when adolescents present with bleeding and how they are managed.
For patients not satisfied with menstrual control after initiating testosterone, these data reveal a wide variety of practice and prescribing patterns, with differing results on cessation of menstruation. For instance, when NETA was added to testosterone, the median time to cessation of menses was an additional 56 days, and when DMPA was added to testosterone, 168 days. These data suggest that patients might achieve cessation of menses quicker with addition of NETA, as opposed to DMPA. Similarly, when NETA was used alone for menstrual suppression, the median time to cessation of menses was shorter than when DMPA was used alone (78 days and 182 days, respectively).
In this cohort, sexual histories and contraceptive needs were either discussed or documented infrequently. Intentional discussions regarding contraception and pregnancy prevention in transgender youth are particularly important given the increased risk of early sexual debut, unintended pregnancy, and risk of sexually transmitted infections in sexual minority adolescents.
Transgender identity and experiences of violence victimization, substance use, suicide risk, and sexual risk behaviors among high school students—19 states and large urban school districts, 2017.
Conversations regarding effective contraception in individuals on testosterone therapy are needed as testosterone does not reliably suppress ovulation.
Medical providers serve as an important resource for sex education to transgender youth, especially considering the paucity of relevant information for gender-diverse or sexually diverse individuals in formal sex education settings.
This study adds to the limited literature looking at bleeding patterns in TGDY and highlights the complexity in management. Data revealing gaps in documentation of gynecological and sexual history emphasize a need for more comprehensive assessment and management of reproductive health concerns in TGDY.
The study is limited by a relatively small sample size of predominantly white patients and is further limited by the retrospective study design, which might have overestimated time to menstrual cessation. Additionally, options for documenting gender identity and sexual health in the medical record were limited during the study period to providers specifically inquiring and documenting in the medical notes and have since been improved by introducing a Sexual Orientation and Gender Identity intake form. More studies are needed to determine if the differences detected in time to cessation of menses are significant. Prospective studies examining hormonal regimens, and correlating with serum testosterone levels, would provide invaluable guidance to providers for the management of persistent or breakthrough bleeding in TGDY.
In conclusion, the patients in this cohort used a variety of different hormonal regimens for menstrual suppression. Less than half of patients achieved cessation of menses within 6 months, suggesting that adolescents might need more time on hormonal therapy before menstruation stops. NETA and DL resulted in the shortest time to cessation of menses and are therefore promising options for menstrual suppression in TGDY.
Disclosures
Author 6 is a consultant for Neurocrine Biosciences, Inc.
Acknowledgments
None
References
Herman JL
Flores AR
Brown TNT
Wilson
et al.
Age of Individuals Who Identify as Transgender in the United States.
Transgender identity and experiences of violence victimization, substance use, suicide risk, and sexual risk behaviors among high school students - 19 states and large urban school districts, 2017.
Society of Family Planning clinical recommendations: contraceptive counseling for transgender and gender diverse people who were female sex assigned at birth.
Transgender identity and experiences of violence victimization, substance use, suicide risk, and sexual risk behaviors among high school students—19 states and large urban school districts, 2017.
Represents number and percentage of patients who added another method of hormonal therapy.
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