J Clin Med.
2020 Jun; 9(6): 1609.
Hormonal Handling Strategies Tailored to Non-Binary Transgender Individuals
Mario Maggi
2Department of Experimental, Clinical and Biomedical Sciences, Careggi University Hospital, 50139 Florence, Italy; [email protected]
Received 2020 Apr 16; Accepted 2020 May 18.
Abstract
Introduction: To appointment no standardized hormonal treatment protocols for non-binary transgender individuals have been described in the literature and at that place is a lack of information regarding their efficacy and safety. Objectives: To suggest possible treatment strategies for non-binary transgender individuals with non-standardized requests and to emphasize the importance of a personalized clinical approach. Methods: A narrative review of pertinent literature on gender-affirming hormonal treatment in transgender persons was performed using PubMed. Results: New hormonal treatment regimens exterior those reported in current guidelines should be considered for non-binary transgender individuals, in order to better psychological well-being and quality of life. In the nowadays review we suggested the utilize of hormonal and not-hormonal compounds, which—based on their mechanism of activeness—could be used in these cases depending on clients’ requests. Decision: Requests for an individualized hormonal treatment in non-binary transgender individuals stand for a hereafter challenge for professionals managing transgender health care. For each case, clinicians should balance the benefits and risks of a personalized not-standardized treatment, actively involving the person in decisions regarding hormonal treatment.
Keywords:
non-binary, transgender, gender-affirming hormonal handling, personalized medicine
one. Introduction
Gender identity is an attribute of the internal sense of cocky of each private, which can exist masculine, feminine, a mix of both or neither [one]. For nearly people, the assigned sexual activity at nativity is coinciding with gender identity and we refer to these individuals as cisgender. On the other hand, transgender is an umbrella term that describes the broad spectrum of individuals who transiently or persistently identify with a gender different from their natal gender [ii,3].
In many cultures gender identity has been looked at through a binary lens with only two possible choices: male person or female. This conceptualization takes the name of gender binarism, according to which biological sexual activity and gender identity are categorized in two mutually exclusive forms of masculine and feminine, following the supposed dualism existing in nature. The binary conception of gender has been extended too to the transgender experience, describing an identification with the opposite gender as the merely possible selection for people with gender incongruence (i.eastward., gender dysphoria according to the DSM 5, Diagnostic and statistical manual of mental disorders) [3]. Accordingly, the term transwomen has been traditionally used to draw individuals assigned male at birth (AMAB) who identify as women, whereas transmen has been used for individuals assigned female at birth (AFAB) who identify every bit men.
In Western clinical models, gender identity has been categorized co-ordinate to this binary concept. In line with that, in contempo years biomedical research has mainly focused on the validation of standardized gender-affirming hormonal treatments capable of inducing nearly complete masculinization or feminization. Indeed, the two major goals of gender-affirming hormonal handling were classically employed to (i) suppress endogenous sex hormone secretion, equally determined by the person’s genetic/gonadal sexual practice, and (ii) maintain sex activity hormone levels within the physiologic range for the person’due south affirmed gender [4].
However, the traditional view of gender binarism has started to exist questioned by several epidemiological studies highlighting a significant prevalence (1.9–ii.8%) of gender non-conformity [5,six] in the general population (although gender non-conformity does non necessarily imply a non-binary gender identity). This aspect has been specifically assessed in a recent Dutch report [7] exploring gender identity in a grouping of 415 transgender individuals. The study revealed a high prevalence of not-binary gender identity (xviii.3%) in the evaluated sample. According to this dimensional perspective, professionals dealing with transgender wellness must ensure individualized and flexible interventions during a gender-affirming path, when this is requested [ii,four]. This recommendation also includes hormonal treatments that should exist tailored as much every bit possible to the person’s needs, across the dichotomic goals of a traditional binary model [8]. In item, AFAB transgender individuals may request partial masculinization or AMAB transgender individuals may desire partial femininization, mayhap without affecting sexual function [9]. At the same fourth dimension, not-binary transgender individuals may require gender-affirming surgery (i.e., mastectomy in AFAB transgender individuals) before the start of hormonal treatment.
To engagement, there are no prove-based protocols for standardized treatment in non-binary individuals and the correlated long-term risks of these regimens remain unknown. Furthermore, possible treatment strategies in not-binary transgender individuals have not even so been explored in the electric current literature. In line with that, the aims of the present review are (i) to propose for the starting time time treatment strategies for non-binary transgender individuals with non-standardized requests and (ii) to emphasize the importance of a personalized clinical arroyo. In social club to respond to individualized and different clients’ requests, clinicians should combine dissimilar hormonal formulations, bearing in mind their mechanism of activity, efficacy and prophylactic.
2. Methods
The methodology used in this narrative review consisted of a careful analysis of literature regarding hormonal and non-hormonal compounds which could be used in not-binary transgender individuals. Nosotros considered both review and original manufactures regarding different compounds’ categories, focusing on studies conducted on the transgender population. A computerized search was performed independently by ii authors using PubMed. Search terms included gender-affirming hormonal treatment, non-binary, transgender, anti-androgens, hirsutism handling, androgens, estrogens, androgenic-anabolic steroids and gonadotropin-releasing hormone agonists (GnRHa). In addition, reference sections of the identified articles were evaluated for further relevant publications. Only English publications were selected. Studies resulting from the same search terms were selected in accord with the aims of the present review and the clinical interest for the reader.
iii. Hormonal Compounds
three.ane. Estrogens
In AMAB transgender individuals, estrogens are required to induce desired female person secondary sexual characteristics. Among available compounds, 17-β-estradiol represents the near normally used, since the synthetic estrogen ethinyl estradiol has been associated with increased cardiovascular and thromboembolic risks [ten,11]. The common dosage of estrogen during gender-affirming hormonal treatment is ii or three times equally high equally the recommended doses for hormone replacement therapy in postmenopausal women, with a goal of serum estradiol and testosterone of 100–200 pg/mL (or 367–734 pmol/L) and less than l ng/dL (or 1.seven nmol/L), respectively [four]. The aforementioned goals are those requested by trans women who want to reach a complete feminization with suppression of male person sexual characteristics. For this reason, in non-binary AMAB individuals information technology could be necessary to adjust these goals depending on patients’ requests. On the other hand, non-binary AMAB individuals requesting full feminization (i.due east., breast development, torso composition, skin tenderness) and preservation, at the same fourth dimension, of erectile role can benefit from only-estrogens treatment or estrogens combined with depression dosages of cyproterone acetate (10mg/daily or 25 mg on alternative days) or with 5α-reductase inhibitors (Figure 1).
Flowchart reporting possible handling options in non-binary transgender individuals. The figure includes hormonal/not-hormonal compounds and other strategies (i.e., procedures and surgical interventions) that could be proposed to non-binary transgender individuals on the ground of their requests. Variable dosages of hormonal compounds are discussed in the text. AMAB: assigned male at nascence; AFAB: assigned female at birth; GnRH: gonadotropin-releasing hormone CPA: cyproterone acetate; IUD: intrauterine device.
3.2. Androgens
In AFAB transgender individuals, testosterone is used to induce virilizing furnishings. Amidst bachelor compounds, the most usually prescribed are injectable testosterone esters, long acting testosterone undecanoate and testosterone gel and patches, with no differences regarding brusk-term safety and satisfaction [12]. In binary AFAB people requesting complete virilization, regimens of testosterone treatment follow the general principle of hormone replacement treatment of male hypogonadism, with the aim to attain testosterone values in the normal male range (generally 320 to yard ng/dL or 11 to 34.7 nmol/L) [4]. However, in non-binary AFAB individuals requesting partial masculinization, information technology may be possible to adjust the dose of testosterone or add other hormonal preparations in social club to model the effects of androgens on the torso (Figure ane). When the main goal is represented by body limerick changes (i.e., musculus mass increment) and vocalization deepening, but facial and body hair increase is non desired, testosterone handling tin can be combined with 5α-reductase inhibitors or definitive hair removal. In fact, in the hair follicle, testosterone is converted by 5α-reductase enzyme into 5α-dihydro-testosterone (DHT), which subsequently regulates dermal physiology through intracrine and paracrine manners [13]. Finasteride, by inhibiting 5α-reductase type 2, interferes with DHT action and results in constructive treatment of androgenetic alopecia, thus its use (1 mg/daily) could be extended to this awarding. Furthermore, several studies conducted on cisgender women have shown that finasteride is as effective as spironolactone or flutamide in treating hirsutism, due to the ability to block the conversion of testosterone into DHT in the hair follicle [14].
Other options may include nandrolone, an anabolic steroid administered via intramuscular injection, which is not every bit optimal a substrate for 5α-reductase as testosterone, just it has a stronger effect compared to the testosterone on target tissues devoid of 5α-reductase activeness (e.g., muscular tissue) [15]. Indeed, nandrolone can be theoretically used in not-binary AFAB individuals requesting masculinization of body shape (i.e., increased muscle mass) with a limited increment in facial and body hair. Regarding the safety profile of this compound, data are limited by the fact that nigh observations come up from the setting of androgenic-anabolic steroid (AAS) abuse [16,17], thus their applicability to appropriate medical therapy is express [eighteen]. In this setting, concerns most cardiomyopathy and coronary artery disease chance emerged [19], although associated with the administration of nandrolone at extremely higher dosages [xx]. Furthermore, nandrolone employ does not seem associated to hepatotoxicity, since, every bit an injectable oil, it is non subject to first-laissez passer hepatic metabolism.
3.iii. Progestogens
Historically, progestogens have been used as boosted antiandrogenic handling, since they feed back to the hypothalamus lowering luteinizing hormone (LH) and testosterone levels and compete for the 5α-reductase enzyme, which converts testosterone into DHT [21]. Moreover, some trans women may request progesterone to enhance breast development. A recent opinion [22] suggests the use of oral micronized progesterone in trans women in order to endorse feminizing effects during gender-affirming hormonal treatment, maybe by promoting ductal branching within the breast [23], and to prevent negative long-term cardiovascular and bone effects. However, to date there are no clinical studies that support a positive effect of progestogens on breast development in transgender persons [24]. Current guidelines [4] recommend against routine progestogen utilise in gender transition. In fact, evidence from studies conducted on cisgender women taking progesterone suggests an increased hazard of thromboembolism and stroke [25,26]. Finally, progestogens may induce water memory leading to weight gain and elevation of blood pressure level [27].
Apart from this, progestins, such equally lynestrenol 5–10 mg/daily, medroxyprogesterone acetate 5–x mg/daily or norethindrone 15 mg/daily, can find awarding in AFAB transgender individuals to stop menses when testosterone alone is not sufficient [4,28]. Additionally, progestins can be used for non-binary AFAB individuals reporting high distress towards period just requesting none or partial masculinization. For this purpose, progestin agents can be used alone or in combination with low doses of testosterone. Culling options to accomplish this goal are represented by GnRH agonists, endometrial ablation [4,29] or, specially when reversible contraception is desired, a progesterone-releasing intrauterine device (IUD) [30] (Effigy 1).
iii.4. Other Androgen Lowering Therapies
Antiandrogens include different compounds able to inhibit androgen secretion or action, mainly used in AMAB transgender people in gild to reduce typical male characteristics and to achieve required serum estradiol levels.
Cyproterone acetate (CPA) is ane of almost common antiandrogens used in Europe. CPA competes with androgens for bounden to the androgen receptor (AR) and inhibits adrenal steroidogenesis [31]. In addition, it exerts a negative hypothalamic feedback through its progestogenic properties, leading to a reduction of testicular androgen secretion. Traditionally, the recommended dose of CPA for AMAB transgender people ranged from 50 to 100 mg/daily [4]. Since CPA is highly lipophilic, it accumulates in the subcutaneous adipose tissue, and therefore, a lower dose or assistants on alternate days tin be used to reduce androgen levels [32]. The main critical issues regarding the utilise of CPA business organisation its hepatotoxicity and the potential increased risk of meningiomas, which are hormone-sensitive tumours expressing progesterone receptors [33,34]. However, in the transgender population, only a transient elevation of liver enzymes has been reported [35], and no significant differences have been observed between trans women under hormonal treatment and those not receiving gender-affirming hormones [36].
Spironolactone (100–300 mg/daily) is commonly prescribed in the United states, where CPA is not available. Spironolactone is an antagonist of the mineralocorticoid receptor with antiandrogenic properties, mainly exerted past blocking the AR [37]. A recent study [38] demonstrated that spironolactone 200 mg daily is effective in reducing testosterone levels in AMAB transgender individuals into the cisgender female range, with an interval of nine months required to achieve a steady-state of testosterone. The heterogeneity of this effect was mainly explained by the torso mass index (BMI), with individuals with a lower BMI having higher testosterone levels. Notwithstanding, this evidence may be limited by the co-assistants of estradiol in the whole sample. Likewise, other authors did not observe any effect of spironolactone on testosterone levels [39]. Furthermore, spironolactone use is limited by the chance of hyperkalemia, hypotension and gastrointestinal bleeding [40].
Other options may include nonsteroidal antiandrogens, such as flutamide (50–75 mg/daily) and bicalutamide (25–50 mg/daily), which cake the AR and, therefore, reduce androgens action. On the other hand, these compounds increase gonadotropin secretion, compromising the reduction of circulating testosterone levels observed with steroidal antiandrogens. The lack of information about their efficacy and safety in the transgender population, as well equally the high adventure of hepatotoxicity described in ciswomen, do not allow their utilise to be recommended [41].
Among the 5α-reductase inhibitors, finasteride and dutasteride can be used in selected cases leveraging their chapters to inhibit the conversion of testosterone into 5α-dihydro-testosterone (DHT). Fifty-fifty if some concerns related to sexual dysfunction and depression risk are reported in the literature in cisgender men [42,43], their efficacy and prophylactic on handling in this population of androgenetic alopecia has been reported [44,45], thus they could be considered to stop male person pattern hair loss in binary AMAB transgender individuals.
GnRHa, such every bit triptorelin, leuprorelin and goserelin, represent an effective culling to reduce testosterone levels, through the down-regulation of GnRH receptor in the pituitary. They are considered extremely safe, although their use is limited by the loftier cost. Potential new alternatives to GnRHa are GnRH antagonists, which practise non accept the criticality of the initial “flare” in gonadotropic axis activation, but their use in transgender population is still express [4].
Androgen lowering compounds tin can be included among hormonal treatment strategies in both not-binary AFAB and AMAB people (Effigy 1). Indeed, in the case of AMAB agender persons—wishing merely to benumb masculine characteristics, without inducing whatever feminization—only nonsteroidal or steroidal anti-androgens can exist considered. The choice between decreasing androgen production (with steroidal antiandrogens) or simply androgen peripheral activeness (with nonsteroidal ones) may be based on private phenotypical goals. Equally androgen-deprivation therapy results in a deleterious effect on bone mineral density [46], a lower dosage of estrogens can be discussed with clients. However, no information are available regarding long-term disquisitional effects when estrogen levels during gender-affirming hormonal treatment do not reach the usual therapeutic goal for binary transgender individuals. Theoretically, nonsteroidal antiandrogens practise non compromise estrogen synthesis, because testosterone levels are high and aromatase activity is all the same efficient. Moreover, some AFAB transgender individuals tin do good from testosterone therapy combined with 5α-reductase inhibitors or from treatment with nandrolone (an androgenic chemical compound less prone to 5α reduction) in example they wish merely a partial virilization (i.e., voice deepening and lean mass increase without facial and body hair increase).
4. Non-Hormonal Compounds and Other Strategies
Several not-hormonal compounds can be prescribed to attune the effects of hormonal treatment in non-binary transgender individuals.
Minoxidil is a topical treatment approved for androgenetic baldness, available at 2% and 5% solution preparations. This drug is a peripheral vasodilator, opening potassium channels located on the polish muscles of the peripheral artery [47]. Through its metabolite, minoxidil sulfate, it stimulates the growth of follicle keratinocytes and prolongs the anagen phase [48]. Although information technology is considered to be safe and benign, the most common reported side effects of minoxidil are irritant contact dermatitis and hypertrichosis. Topical application did not generally prove systemic effects such equally hypotension and abnormal middle rate [49]. Minoxidil is generally used topically twice per day in the treatment of androgenetic baldness. For this kind of application, information technology can be prescribed in AFAB transgender people experiencing androgenetic alopecia during treatment with conventional doses of testosterone [l]. Moreover, minoxidil lotion (3%) has likewise been demonstrated superior to placebo in significantly increasing hair count in cisgender population later on 16 weeks of treatment [51]. Thus, its application tin can be recommended every bit an additional treatment to testosterone in binary AFAB transgender people to promote beard growth. In improver, minoxidil application can be suggested to not-binary AFAB individuals desiring bristles development merely non (or not consummate) body male person shaping (e.g., lean mass increase, voice pitch changes).
Topical eflornithine reduces the rate of hair growth through the irreversible inhibition of ornithine decarboxylase, an enzyme which is essential for follicular polyamine synthesis. Eflornithine usually takes from half-dozen to viii weeks to give noticeable results and is a lifelong therapy, since pilus growth resumes once treatment is discontinued [52]. For this reason, eflornithine is generally used in conjunction with other therapies. Indeed, two randomized controlled trials demonstrated that eflornithine can ameliorate the efficiency of standard laser hair removal in cisgender people [53,54]. Eflornithine’s topical utilize, combined with oral anti-androgens and laser hair removal, tin can further promote hair removal in binary AMAB transgender people. Moreover, eflornithine can be offered as a treatment to reduce facial and body hair in non-binary transgender individuals not wanting sexual role impairment or body feminization, which usually result from traditional hormonal treatment (with antiandrogens or estrogens).
Furthermore, permanent methods of hair reduction may be proposed to AMAB transgender people. These include photoepilation, which is capable of treating big areas merely requires the presence of pigmented terminal hair, and electrolysis, generally used to treat small areas regardless of hair pigmentation [52]. Similarly to eflornithine, these options can exist discussed with not-binary AMAB individuals desiring only hair reduction.
Finally, in case the available compounds exercise not allow the desired goals to be accomplished, surgical interventions tin be proposed. Mastectomy and lipofilling may represent an pick for non-binary AFAB individuals requesting trunk shape changes without masculinization, while chest augmentation can be offered to non-binary AMAB individuals, somewhen in addition to low estrogen dosages.
5. Conclusions
Non-binary transgender individuals represent a growing body of clients referring to specialized gender clinics. In fact, requests for non-standardized hormonal treatments are increasing. In the near futurity, clinicians dealing with transgender health care will have to face up these requests more frequently and be aware of the need to implement truly individualized hormonal handling. On the other manus, there is a lack of data in the literature regarding possible therapeutic strategies and their efficacy and safety. For this reason, our goal was to provide a guide for clinicians in gild to meliorate run across the requests of non-binary transgender individuals. Clinicians must bear in mind that these treatment strategies are currently not included in the international guidelines [two,4], but they may play a crucial role in better responding to non-binary transgender individuals’ needs and therefore reduce distress and improve quality of life. It will exist important to define the necessary biochemical thresholds of sex hormones to achieve the desired sexual characteristics and to avoid adverse effects related to hypogonadism. In fact, to date, this information is scarce in the available literature [55]. For all these reasons, it is important that future research volition focus on the specific health issues in this population.
Writer Contributions
Conceptualization, C.C. and A.D.F.; methodology, A.D.F. and C.C.; writing—original draft preparation, C.C. and A.R.; writing—review and editing, A.D.F., M.M., J.R.; supervision, A.D.F., J.R., M.G. All authors take read and agreed to the published version of the manuscript.
Disclosure
None of the authors reports fiscal human relationship with commercial interests.
Conflicts of Interest
The authors have no disharmonize of interest.
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356977/#:~:text=Mastectomy%20and%20lipofilling%20may%20represent,addition%20to%20low%20estrogen%20dosages.
