Study selection

In total, 3315 articles were identified from the search, 34 of which were deemed eligible for this article [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48]. Figure 1 displays the PRISMA diagram for the current study. According to the PRISMA guidelines, reasons for title/abstract exclusions are not required. However, reasons for full-text exclusion are required [11]. We followed the established PRISMA guidelines and reasons for full-text exclusion are presented in Fig. 1.

Fig. 1

PRISMA diagram of study selection

Patient characteristics

In total, 3990 patients receiving gender-affirming hormones are represented in this systematic review. The 34 included articles reported race, ethnicity, and gender inconsistently. In total, eight studies reported race and/or ethnicity. However, among these, a significant amount of race and/or ethnicity data was missing (42%). Table 1 provides data on race/ethnicity and gender of included participants reported employing the terms used in the included articles. Among studies reporting mean age, the mean age ranged from 13.7 to 54.8. Among studies reporting minimum and maximum ages, the age ranged from 4.7 to 70.

Table 1 Gender and race/ethnicity of included participantsStudy information

In general, the number of publications increased each year (from 1986 to 2023), with the highest proportion of articles published in 2021 (18%). Most articles were cohort studies (65%) and had received funding (50%). Most studies were conducted in Ontario (41%), with Toronto being the most frequently studied city (29%). Study information is presented in Table 2.

Table 2 Study information for included articlesOutcomes measured

Physiologic parameters were reported in 62% of studies. Patient-reported outcomes were reported in 50% of the studies; however, among these studies, PROMs were used in only 32% of them. The actual PROMs administered across these studies were inconsistent. Table 3 provides an overview of outcomes measured and PROMs used across included articles. Table 4 provides an overview of clinical and endocrinological parameters of gender-affirming hormone therapy from the included articles. Details of these parameters and outcomes are discussed below.

Table 3 Overview of outcomes measured and PROMs used across articlesTable 4 Clinical and endocrinological parameters of gender-affirming hormone therapy from included articlesOutcomes after gender-affirming hormone treatment organized by treatment receivedTestosterone treatment

In total, nine studies focused on testosterone treatment [16, 28, 40,41,42,43,44,45,46]. Among these studies, four measured physiologic parameters, two measured physiologic parameters and provider-reported outcomes, one measured patient-reported outcomes, and two measured physiologic parameters and patient-reported outcomes.

In terms of physiologic parameters, in one study, Obiezu et al. [40] treated patients with testosterone, 250 mg intramuscularly, every 2 weeks and collected serum and urine samples to measure testosterone, PSA (prostate-specific antigen), and hK2 (human glandular kallikrein) [40]. They found that testosterone administration significantly increased PSA in serum and urine and hK2 in urine by the fourth month of treatment [40]. In another study, Miller et al. [16] examined the effects of testosterone therapy on histological examination following hysterectomy [16]. They identified marked atrophy of the cervical epithelium, which could mimic dysplasia, and variable degrees of atrophy of the endometrium [16]. They also determined that ovaries showed occasional corpora lutea, indicating that ovulation may occur despite testosterone therapy [16]. In another study, Kogachi et al. [44] described a case of a patient on testosterone cypionate, 100 mg intramuscularly per week, who developed transient obscuration of vision, headache, dizziness, and “ear popping” [44]. The patient had papilledema and elevated cerebrospinal fluid opening pressure. The patient was diagnosed with idiopathic intracranial hypertension and was managed with endovascular stenting, without reduction to testosterone therapy. The authors discussed the role of hormones in the associations between transverse sinus stenosis and increased intracranial pressure [44]. In another study, Nayman et al. described a case of a patient on testosterone, 70 mg per week, who developed transient obscuration of vision and frontal headache. The patient, who also had papilledema and elevated cerebrospinal fluid opening pressure, was diagnosed with idiopathic intracranial hypertension and was managed with acetazolamide and reduction of testosterone therapy [46]. In another study, Oberc et al. [45] described a case of a patient who was on testosterone and developed a painless palpable mass in the right breast, which was found to be a granular cell tumor (GCT) [45]. The authors commented that such tumors are rare and poorly understood, particularly in transgender individuals, in whom they have not been previously documented and that they may mimic other benign or malignant lesions [45]. In another study, Fung et al. [28]. described a case of a patient on testosterone who developed gynecomastia [28],. The authors underlined that clinicians should be aware that transgender boys undergoing testosterone therapy may develop gynecomastia and that adjustment of testosterone therapy could lead to improvements [28].

In terms of patient-reported outcomes, in one study, Taillefer et al. [43] demonstrated that the most desired outcomes of testosterone therapy in transmasculine individuals was increased body/facial hair (69% of study sample) and voice deepening/Adam’s apple growth (52% of study sample) [43]. These effects were reached in 80% of reports at 12 months, continuing to increasing steadily across the 24-month follow-up period [43]. In another study, Wilson et al. [42] investigated self-reported pre-injection anxiety, peri-injection pain, and post-injection pain for intramuscular (IM) testosterone versus subcutaneous testosterone [42]. The study found that the subcutaneous route was preferred by participants and that it resulted in similar testosterone concentration to that of the intramuscular route [42]. In another study, Todd et al. [41] described two cases of testosterone therapy that had a positive impact on headache frequency and intensity [41].

Estrogen and antiandrogen treatments

In total, ten studies focused on estrogen and/or antiandrogen treatment [17,18,19, 21,22,23, 25, 26, 38, 39]. Among these studies, six measured physiologic parameters, three measured patient-reported outcomes, and one measured physiologic parameters and provider-reported outcomes.

In terms of physiologic parameters, in one study, Fung et al. [18] compared different doses of cyproterone acetate combined with estrogen and found that lower doses (25 mg) were as effective as higher doses (≥ 50 mg) in suppressing testosterone concentrations to achieve the normal female range when used in combination with recommended estrogen therapy [18]. In another study, Prior et al. [22] examined the effects of spironolactone combined with low-dose estrogen. They compared a group of patients who were treatment-naïve with a group of patients who had previously received high-dose estrogen monotherapy. They noted a significant decrease in testosterone concentrations of both groups relative to their baselines. They also observed decreased male pattern hair loss and breast development [22]. In another study, Armstrong et al. [25] explored the effects of antiretroviral therapy on feminizing hormone therapy. Comparing patients on antiretroviral therapy with those not on antiretroviral therapy, they noted no significant differences in serum estradiol and testosterone concentrations between the two [25]. In another study, Fung et al. [39] studied the effects of spironolactone versus cyproterone acetate (CPA) on serum high-density lipoprotein (HDL). They found that spironolactone use increases HDL concentration, whereas CPA decreases HDL concentrations [39]. In another study, Obiezu et al. [38] examined the effects of cyproterone acetate, alone or in combination with estrogen, on plasma and urinary PSA and hK2 concentration. They found that CPA, both alone and in combination with estrogen, suppresses > 90% of plasma and urinary PSA and hK2 concentration after 4 or 12 months of therapy [38]. In another study, Cohen et al. [19] investigated associations between hormone therapy and auditory cerebral specialization for speech and non-speech stimuli. They found that cisgender women and transgender women exhibited similar patterns in verbal and nonverbal tasks, with a right ear advantage for verbal tasks and without a left ear advantage for nonverbal tasks, which was also exhibited in cisgender men. The authors suggest the possible role of hormones in right hemispheric cognitive processing [19]. In another study, Lam et al. [21] describe a case of a patient with asthma and cystic fibrosis who experienced a decrease in lung function with an increase in estrogen [21].

In terms of patient-reported outcomes, one study by Davies and Johnston [26] was involved in developing a PROM, the Trans Voice Questionnaire [26]. In another study, Wassersug et al. investigated the effects of antiandrogen therapy and estrogen therapy, noting an overall improvement in mental health outcomes [17]. The study found that antiandrogen and/or estrogen therapy was seen as the critical step in committing to and consolidating gender transition [17].

Puberty blockers (with or without testosterone or estrogen)

In total, eight studies focused on puberty blockers [20, 24, 29,30,31,32, 37, 48]. Among these studies, two measured physiologic parameters, one measured physiologic parameters, patient-reported outcomes, and provider-reported outcomes, four measured patient-reported outcomes, and one measured on patient-reported outcomes and provider-reported outcomes.

In terms of physiologic parameters, in one study, Waldner et al. [37] examined the effects of gonadotropin-releasing hormone agonist (GnRHa) (specifically, leuprolide acetate) on the QT interval. They noted no significant increase of the QT interval [37]. In another study, Navabi et al. [29] studied the effects of GnRHa on bone mass and body composition. They observed a reduction in bone mineral density (without evidence of fractures) and a redistribution of body fat in gynoid and android pattern, respectively [29]. In another study, Khatchadourian et al. [30] scrutinized the effects of GnRHa followed by hormone therapy. The use of both was well tolerated overall; however, of those using GnRHa, one developed an abscess, another a headache and leg pain, and another significant weight gain. Conversely, among those using hormones, seven developed severe acne, three mild dyslipidaemia, one androgenetic alopecia, and one mood swings [30].

In terms of patient-reported outcomes, in one study, Zucker et al. [31] explored the decision-making process around recommendations for puberty blockers, recognizing the role of demographic, behavioral, and psychosexual measures on these recommendations. The studied noted that having more cross gender-behavior, more self-reported gender dysphoria, and lower behavior problem scores, among some other measures, is associated with recommendations for puberty blockers [31]. In another study, Bauer et al. [32] investigated the idea of rapid onset gender dysphoria, which suggests that some adolescents suddenly experience gender dysphoria due to societal influences. The study found no significant associations between recency of gender knowledge and mental health issues. In fact, the study found that recent gender knowledge was associated with lower anxiety and lower marijuana use [32]. In another study, Heard et al. [20] examined the experiences of children and adolescents accessing gender-affirming care, including puberty blockers and hormones, in Manitoba. They reported that 70% of individuals had to provide some education to a healthcare provider regarding their needs as a transgender patient. In addition, they reported that 65% of individuals had been told that their healthcare provider did not possess adequate knowledge about transgender-related care to provide it. In another study, Silva et al. [