（机器翻译uscf的激素化疗指南

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女性化激素治疗概述

主要作者：

玛德琳 B. 多伊奇，医学博士，公共卫生硕士

出版日期：

六月 17， 2016

介绍

女性化激素治疗的目标是发展女性第二性征，并抑制/最小化男性第二性征。一般影响包括乳房发育（通常到Tanner阶段2或3），面部和身体皮下脂肪的重新分布，肌肉质量减少，体毛减少（在较小程度上，面部毛发），汗水和气味模式的变化，以及头皮脱发的停止和可能的逆转。性和性腺影响包括勃起功能降低、改变、精子数量和射减少或缺失以及睾丸大小减小。女性化激素治疗也会带来情绪和社会功能的变化。一般的治疗方法是将雌激素与雄激素阻滞剂联合使用，在某些情况下还使用孕激素。

雌 激素

用于女性化治疗的主要雌激素类别是17-β雌二醇，这是一种“生物相同”的激素，因为它在化学上与来自人类卵巢的激素相同。一般方法类似于阿格纳达尔（即特纳综合征）或绝经状态中的雌激素替代治疗，但会有一些剂量调整。17-β 雌二醇（或简称雌二醇）最常通过透皮贴剂、口服或舌下含片或注射结合酯（戊酸雌二醇或环戊丙酸雌二醇）给药给跨性别女性。尚未对戊酸注射雌二醇或环戊丙酸进行结局研究，可能是因为它们在跨性别护理环境之外的现代使用并不常见;由于这种有限的使用，制造商几乎没有动力生产这种药物，并且据报道短缺。雌二醇的其他给药途径，如透皮凝胶或喷雾剂，是为治疗更年期血管舒缩症状而制定的，虽然在一些跨性别女性中方便有效，但在其他情况下，这些途径可能无法达到生理女性范围内的血液水平。专业药房也存在复合外用乳膏和凝胶;如果要使用这些，建议处方者咨询复合药剂师，以了解个别制剂的具体细节和剂量。注射用复方戊二醇或环丙酸酯也存在，在短缺时期可能是一种替代方法，或者对于那些必须为处方支付现金的人来说更具成本效益。

结合马雌激素（Premarin®）过去曾被使用，但由于多种原因不推荐使用，包括无法准确测量血液水平以及一些血栓形成和心血管风险增加的建议。[1，2] 马雌激素是从怀孕的导尿马的尿液中获得的;没有证据表明这些雌激素优于生物同质性人雌二醇。对生产方法提出了伦理问题马雌激素（链接是外部的）.乙炔雌二醇是一种用于避孕制剂的合成雌激素，与血栓形成风险增加有关。[3，4] 在避孕方面，乙炔雌二醇具有更一致和可靠的周期控制，因此耐受性更好，平衡了静脉血栓栓塞的潜在增加风险。[5]在性别肯定的情况下，不需要周期或出血调节，因此不需要使用乙炔雌二醇及其固有风险（分级：T O S）。

雌激素的副作用可能包括偏头痛、情绪波动、潮热和体重增加。

抗雄激素 - 常用方法

抑制睾酮的产生和阻断其作用有助于抑制/最小化男性第二性征。不幸的是，这些特征中的许多在出生青春期结束时是永久性的，并且是不可逆转的。雄激素阻滞剂允许使用较低的雌二醇剂量，与先前用于影响垂体促性腺激素抑制的超生理雌激素水平（和相关风险）相反。[6]

螺内酯是美国最常用的雄激素阻滞剂螺内酯是一种保钾利尿剂，在较高剂量下还具有直接的抗雄激素受体活性以及对睾酮合成的抑制作用。[6] 在接受脱发治疗的非跨性别女性中，每天 200 毫克的剂量已被描述为安全的， 尽管据报道剂量高达 400 毫克/天没有负面影响.[7] 高钾血症是最严重的风险，但当采取预防措施避免在肾功能不全的个体中使用时，以及在服用血管紧张素转换酶抑制剂或 ARB 类药物的人中谨慎使用和频繁监测时，这种情况非常罕见。由于其利尿作用，患者可能会出现自限性多尿、多饮或直立性停滞。

5-α还原酶抑制剂包括非那雄胺和度他雄胺。非那雄胺阻断 5-α 还原酶 2 型和 3 型介导的睾酮转化为强效雄激素二氢睾酮。[8] 非那雄胺 1 毫克每日被 FDA 批准用于男性型秃发， 而 5mg 剂量被批准用于前列腺肥大的管理.[9] 度他雄胺 0.5mg 更有效地阻断类型 1 同工酶， 它存在于毛囊皮脂腺单位， 因此可能具有更显着的女性化作用.由于这些药物既不阻断睾酮的产生也不阻断，因此它们的抗雄激素作用低于完全阻断。对于不能耐受或有使用螺内酯禁忌证的患者，5-α 还原酶抑制剂可能是一个不错的选择。5-α 还原酶抑制剂也可作为单药用于寻求部分女性化的患者，或用于在完全雄激素阻滞或睾丸切除术后继续表现出男性化特征或脱发的患者。

Antiandrogens - other approaches

Antiandrogens can also be used alone to bring reduced masculinization and minimal breast development, or in those patients who wish to first explore reduced testosterone levels alone, or in those with contraindications to estrogen therapy. In the absence of estrogen replacement, some patients may have unpleasant symptoms of hot flashes and low mood or energy. Long term full androgen blockade without hormone replacement in men who have undergone treatment for prostate cancer results in bone loss, and this effect would also be expected to occur in transgender individuals.[10] In addition to titrating dosing to both clinical effect and testosterone levels as guided by patient goals, monitoring hormone levels to insure suppressed gonadotropins (luteinizing hormone [LH] and follicle stimulating hormone [FSH]) levels may serve as a surrogate marker to indicate adequate sex hormone levels for maintaining bone density in such patients (Grading: T O W).[11]

In many countries, cyproterone acetate, a synthetic progestogen with strong anti-androgen activity is commonly used. Cyproterone has been associated with uncommon episodes of fulminant hepatitis.[12] Bicalutamide, a direct anti-androgen used for the treatment of prostate cancer, also has a small but not fully quantified risk of liver function abnormalities (including several cases of fulminant hepatitis); while such risks are acceptable when considering the benefits of bicalutamide in the management of prostate cancer, such risks are less justified in the context of gender affirming treatment.[13] No evidence at present exists to inform such an analysis.

在一些患者中，使用标准方案可能难以甚至不可能完全阻断雄激素。在最大抗雄激素剂量且药物依从性良好的情况下，睾酮持续升高的情况下，应考虑自主内源性产生（即肿瘤）以及未公开的外源性睾酮（即维持勃起功能）。睾丸肿瘤的评估应通过阴囊检查以及血清人绒毛膜促性腺激素 （hCG）、乳酸脱氢酶 （LDH）、甲胎蛋白 （AFP） 水平升高以及可能的阴囊影像学检查进行。[14] 一旦排除了这些原因，其他选择可以包括促性腺激素释放激素类似物 （GnRH） 或睾丸切除术。GnRH类似物通常用于需要青春期延迟的围青春期跨性别青年的护理，[15]并且在跨性别成年人的护理中也有描述。[16] 使用GnRH类似物的缺点主要与获得保险的成本和困难有关，以及需要重复注射，每天多次鼻腔喷雾剂或手术植入。睾丸切除术可能是不希望保留性腺的跨性别女性的理想选择;这种简短、廉价的门诊手术只需要几天的恢复时间，并不排除未来的阴道成形术。

**孕激素：**目前还没有关于孕激素在女性化激素治疗方案中的作用的精心设计的研究。许多跨性别女性和提供者都报告说，使用孕激素改善了乳房和/或乳晕发育、情绪或。[17，18] 没有证据表明在跨性别护理环境中使用孕激素是有害的。实际上，一些患者可能对孕激素反应良好，而另一些患者可能会发现对情绪的负面影响。虽然孕激素通过促性腺激素的中枢阻断具有一定的抗雄激素作用，但理论上也存在孕激素直接雄激素作用的风险。此类包括微粉化生物同质性黄体酮（Prometrium）以及许多合成孕激素。在跨性别护理的背景下，最常用的合成孕激素是口服醋酸甲羟孕酮（Provera）。

虽然妇女健康倡议（WHI）对使用甲羟孕酮的情况下患心血管疾病和乳腺癌的风险存在担忧，但由于多种原因，这些担忧可能不适用于跨性别护理。首先，跨性别女性患乳腺癌的风险可能低于非跨性别女性。其次，WHI的这一分支涉及在更年期妇女样本中使用结合马雌激素与甲羟孕酮联合使用，其中一些妇女在激素开始时长达绝经后10年。第三，虽然具有统计学意义，但WHI研究结果的临床意义充其量是微妙的。该研究旨在评估更年期激素治疗在预防慢性疾病中的作用。结合马雌激素加甲羟孕酮组的实际发现是每10 000人年增加7例心脏事件，8例中风，8例肺栓塞和8例浸润性乳腺癌的绝对风险过高，总体死亡率没有变化。[19]因此，WHI的这一臂被提前停止，并得出结论，联合更年期激素治疗不适用于预防慢性疾病。

在性别肯定护理方面，WHI的研究结果存在许多差异：人群往往更年轻，不使用马雌激素，重点是性别肯定干预措施，这些干预措施对心理健康和生活质量有许多好处，而不是预防。**考虑到人口统计学和治疗目标的这些差异，总体风险的极小增加，死亡率缺乏差异，以及最近与其他形式的雌激素的令人放心的数据，跨性别女性使用孕激素的风险可能很小，甚至不存在（分级：NT O M）。**注射甲羟孕酮醋酸酯（Depo-Provera®）在跨性别女性中不太常用。其他合成孕激素可根据处方限制的需要使用;一些证据表明，去甲孕酮衍生的孕激素（炔诺酮、诺孕酮）可能增加静脉血栓栓塞的风险。[20]

Table 1. Estrogen preparations and dosing (Grading: T O M) 1. 可作为标准美国药典 （USP） 以及复合产品提供
2. 初始低剂量，适用于希望（或因病史需要）低剂量或缓慢上滴定的患者。
3. 最大效果不一定需要最大剂量;因此，最大剂量不一定代表目标剂量或理想剂量。剂量增加应基于患者反应和监测的激素水平。
Estradiol oral/sublingual 1mg/day 2-4mg/day 8毫克/天 如果>2mg建议分次投标给药
经皮雌二醇 50微克 100微克 100-400微克 最大单贴剂剂量为100mcg。更改频率取决于品牌/产品。一次超过 2 个贴片对患者来说可能很麻烦
戊酸雌二醇肌内注射一个 <20毫克肌注q2周 20毫克肌注q2周 40毫克肌注每2周 对于周期性症状，可分为每周注射一次
环戊丙酸雌二醇肌内注射 <2毫克Q 2周 2毫克肌注q2周 5毫克肌注q2周 对于周期性症状，可分为每周注射一次

表 2.孕激素制剂和剂量（分级：T O M） 1. 可作为标准美国药典 （USP） 以及复合产品提供
2. Initial-low dosing for those who desire (or require due to medical history) a low dose or slow upward titration.
3. Maximal effect does not necessarily require maximal dosing; as such maximal doses do not necessarily represent a target or ideal dose. Dose increases should be based on patient response and monitored hormone levels.
醋酸甲羟孕酮（普罗维拉） 2.5毫克千克仑 5-10毫克千克/耳赤糖
微粉化黄体酮 100-200毫克千克仑

Table 3. Androgen blocker preparations and dosing (Grading: T O M) 1. Available as standard U.S. Pharmacopeia (USP) as well as compounded products
2. Initial-low dosing for those who desire (or require due to medical history) a low dose or slow upward titration.
3. Maximal effect does not necessarily require maximal dosing; as such maximal doses do not necessarily represent a target or ideal dose. Dose increases should be based on patient response and monitored hormone levels.
Spironolactone 25mg qd 50mg bid 200mg bid
Finasteride 1mg qd 5mg qd
Dutasteride 0.5mg qd

Many patients are eager to begin maximal feminizing hormone therapy and are opposed to the idea of a slow upward titration. Weak evidence suggests that initiation of estrogen therapy at lower doses and titrating up over time may result in enhanced breast development in transgender women. The estrogen receptor agonist activity of spironolactone may play a role in reduced breast development due to premature breast bud fusion. As such an escalating regimen beginning with low dose estrogen only, and titrating up over several months, and then adding spironolactone may be an alternative approach,[17] consistent with management practices in children with delayed pubertal onset (Grading: T O W). Upward titration of spironolactone can also help minimize side effects such as orthostasis or polyuria. It is recommended that providers discuss these considerations with patients before initiation of hormones in order to make an informed decision.

Table 4. Laboratory monitoring for feminizing hormone therapy * In first year of therapy only
** Used to calculate bioavailable testosterone(link is external); monitoring bioavailable testosterone is optional and may be helpful in complex cases (see text)
BUN/Cr/K+ Only if spiro used X X X X X
Lipids No evidence to support monitoring at any time; use clinician discretion Based on USPSTF guidelines
A1c or glucose No evidence to support monitoring at any time; use clinician discretion Based on USPSTF guidelines
Estradiol X X X
Total Testosterone X X X X
Sex Hormone Binding Globulin (SHBG)** PRN
Albumin** PRN
Prolactin Only if symptoms of prolactinoma

Overview of titration and monitoring

The interpretation of hormone levels for transgender individuals is not yet evidence based; physiologic hormone levels in non-transgender people are used as reference ranges. However, estrogen levels in non-transgender women may not be associated with specific secondary sex characteristics (i.e. higher estrogen levels in non-transgender women are not necessarily associated with larger breasts), and specific phenotypical end points are likely multifactorial and particularly dependent on genetics and the age at which gender affirming hormone therapy is begun. Titration upwards of dose should be driven by patient goals, in the context of clinical response, hormone level monitoring, and safety monitoring (e.g. presence of risk factors such as smoking, renal function and K+ in patients using spironolactone). A general approach for titration would include increasing of both estrogen and antiandrogen dosing until the estrogen dose is in the female physiologic range. Once this has been achieved, titration efforts can focus on increasing androgen blockade. There can be several approaches to titration of androgens. One approach is to continue increasing estrogen until it reaches the upper limit of the female physiologic range. The drawback for this approach is that patients may begin to experience estrogenic side effects as described below. Another approach is to maintain current physiologic estrogen dosing and titrate upward on antiandrogens and/or addition of a progestogen.

Some providers choose to omit the use of hormone level testing and only monitor for clinical progress or changes. The risk of this approach is that if hormone levels (particularly testosterone) have not reached the target range, but progress is judged as appropriate based on clinical exam, a suboptimal degree of feminization is possible, and the presence of supraphysiologic levels would also be obscured. Conversely, Endocrine Society guidelines recommend monitoring of hormone levels every 3 months.[21] In practice this is not realistic and not likely to add value once a stable dosing has been achieved. A prospective study of transgender women taking 4mg/day divided dose oral estradiol or 100mcg transdermal estradiol, plus 100-200mg/day divided dose spironolactone found that all women achieved physiologic estradiol levels, though only 2/3 of the women achieved female range testosterone levels.[22] Some gender-nonconforming/nonbinary patients may prefer to maintain estradiol or testosterone levels in an intermediate range. Regardless of initial dosing scheme chosen, dosing may be titrated upwards over 3-6 months. Check estradiol and testosterone levels at 3 and 6 months and titrate dose accordingly. For those patients using spironolactone, check renal function and K+ at 3 months and 6 months, then q 6-12 months. While laboratory monitoring of hormone levels may seem complex, it is of similar difficulty to the monitoring of other similarly complex lab-monitored conditions managed by primary care providers, such as thyroid disorders, anticoagulation, or diabetes.

Once hormone levels have reached the target range for a specific patient, it is reasonable to monitor levels yearly, or only as needed as described below. As with other situations involving maintenance of hormone therapy (menopause, contraception), annual visits are sufficient for transgender women on a stable hormone regimen. Other reasons for measuring hormone levels in the maintenance phase include significant metabolic shifts such as the onset of diabetes or a thyroid disorder, substantial weight changes, subjective or objective evidence of virilization, or new symptoms potentially precipitated or exacerbated by hormone imbalances such as hot flashes or migraines. Such patients may also require more frequent office visits to manage coexisting conditions. Increased frequency of office visits may also be useful for patients with complex psychosocial situations to allow for the provision of ancillary or wraparound services.

Current Endocrine Society recommendations include the measurement of only total testosterone and estradiol. This is consistent with Endocrine Society recommendations that only total testosterone be monitored in non-transgender men being managed for testosterone deficiency, except in cases of borderline testosterone levels. However, since testosterone is of particular concern is insuring maximal feminization, the calculation of bioavailable testosterone in transgender women may still be of value. Specifically, exogenous estrogens (especially oral) may be associated with elevated levels of sex hormone binding globulin (SHBG); such elevations can vary from person to person and across regimens. As such in cases of patient concern or persistent virilized features in the presence of a female-range total testosterone, calculation of the bioavailable testosterone may help fine tune hormone regimens for optimal effect.

Interpretation of laboratory results requires special attention in the context of transgender care. Numerous sources publish target ranges for serum estradiol, total estrogens, free, total and bioidentical testosterone, and sex hormone binding globulin. However, these specific ranges may vary between different laboratories and techniques. Furthermore, the interpretation of reference ranges supplied with lab result reports may not be applicable if the patient is registered under a gender that differs from their intended hormonal sex. For example, a transgender woman who is still registered as male will result in lab reference ranges reported for a male; clearly these ranges are not applicable for a transgender woman using feminizing hormone therapy. Hormone levels for genderqueer or gender nonconforming/nonbinary patients may intentionally lie in the mid-range between male and female norms. Providers are encouraged to consult with their local lab(s) to obtain hormone level reference ranges for both ‘male’ and ‘female’ norms, and then apply the correct range when interpreting results based on the current hormonal sex, rather than the sex of registration.

Monitoring estradiol levels

Historically estrogen levels have been monitored using the total serum estradiol. The 2009 Endocrine Society Guidelines recommend monitoring serum estradiol and maintaining levels at the mid-cycle range for non-transgender women.[21] This recommendation is based on expert opinion only and may be overly conservative, and hormone levels are often not easy to tightly control.[23] Providers are encouraged to review the specific estradiol reference ranges for their local lab estradiol assays, as these can vary. There is no evidence that higher estradiol levels in patients with adequate androgen suppression results in additional feminization or breast development. Maintaining estrogen levels in the physiologic range for menstruating non-transgender women minimizes risks and side effects, and makes sense clinically. Note that the use of conjugated estrogens (Premarin®) or ethinyl estradiol (found in most combined oral contraceptives) are not accurately measured by estradiol assays and will typically result in low measured levels.

In patients who have been using self-administered conjugated estrogens, or ethinyl estradiol, it is reasonable to check a total estrogens level, which may provide a more accurate estimate in these cases. This assay also measures minor estrogens such as estriol and estrone. There is some evidence that the use of oral estradiol results in higher serum levels of estrone due to first pass hepatic metabolism, as compared to parenteral forms.[24,25] This may explain dose independent reasons why some patients “feel different” on different forms of estrogen.

Monitoring testosterone levels

Testosterone levels can be difficult to measure in non-transgender men due to rapid fluctuations in levels, relating to pulsatile release of gonadotropins, with higher levels in the morning hours. Free testosterone represents the portion of testosterone unbound to serum proteins and depends on levels of sex hormone binding globulin (SHBG). While free testosterone can be measured, assays are unreliable.[26] Consensus is lacking on the role of free vs. total testosterone levels; total testosterone levels are reliable and readily available, however they do not describe the actual bioavailable testosterone level. Bioavailable testosterone is free testosterone plus testosterone weakly bound to albumin.[27] SHBG is elevated in the presence of estrogen, and in particular with exogenous estrogen supplementation, more so with oral estrogen than with parenteral routes due to first pass hepatic activity.[28] For transgender care, The Endocrine Society recommends monitoring of the total testosterone level, with a target range of <55ng/dl .[21] Calculation of the bioavailable testosterone(link is external) may help guide dosing, and can be calculated from the total testosterone, albumin, and SHBG levels.[29] A general reference range for bioavailable testosterone is >72ng/dl (2.5nmol/L).[30-32]

Monitoring gonadotropin levels

When indicated, measuring of gonadotropins (luteinizing hormone: LH and follicle stimulating hormone: FSH) can be done using the local lab ranges for eugonadal state as a reference.

Monitoring hormone levels in patients using injected estrogen

Pharmacokinetic studies of injected estrogen have been limited. Two earlier studies only examined single-dose pharmacokinetics and are therefore unable to be applied to steady-state dosing.[33] Studies of estradiol levels in the context of a monthly combined injectable contraceptive of 5mg estradiol cypionate and 25mg medroxyprogesterone acetate found peak levels 2-4 days after injection, maximum estradiol levels of approximately 250 pg/ml, and trough levels of approximately 50pg/ml.[34,35] These findings suggest that injected estradiol in the middle of the dosing ranges recommended here will result in physiologic estradiol levels, and that use of more frequent dosing will reduce peak-trough effect. When measuring hormone levels in patients using injected forms of estradiol, a mid-cycle level is often sufficient, however if the patient is experiencing cyclic symptoms such as migraines or mood swings, peak (1-2 days post injection) and trough levels of both estradiol and testosterone may reveal wide fluctuations in hormone levels over the dosing cycle; in these cases, consider changing to an oral or transdermal preparation, or reducing the injection interval (with concomitant reduction in dose, to maintain the same total dose administered over time). A single study suggests similar pharmacokinetics when estradiol is injected subcutaneously, rather than intramuscular.[34]

Interpreting sex-specific, non-hormone labs

Alkaline phosphatase, hemoglobin and hematocrit (H&H), and creatinine may vary depending on the patient’s current sex hormone configuration. Several factors contribute to these differences, bone mass, muscle mass, number of myocytes, presence or lack of menstruation, and the erythropoietic effect of testosterone. While transgender women do not menstruate, those with female-range hormone levels will lack the erythropoietic effects of male-range testosterone, and it may be reasonable to use the female-range lower limit of normal when interpreting H&H. Conversely, the lack of menstruation, and potential for pulsatile undetected androgen activity in those with retained gonads make it reasonable to use the male-range upper limit of normal for H&H. Using the male-range upper limit of normal for alkaline phosphatase and creatinine may also be appropriate for transgender women due to retained bone and muscle mass or myocyte counts, respectively. This is of particular importance in transgender women using spironolactone who are registered as female, and may have a lab result flag showing an abnormal elevated creatinine. In these cases the provider should reference the male normal ranges for their lab.[19]

Table 5. Lower and upper limits of normal to use when interpreting selected lab tests in transgender women using feminizing hormone therapy|Creatinine|Not defined|Male value|
| — | — | — |
|Hemoglobin/Hematocrit|Female value|Male value|
|Alkaline Phosphatase|Not defined|Male value|

Individualized dosing based on patient centered goals

Some patients may desire limited hormone effects or a mix of masculine and feminine sex characteristics. Examples include retention of erectile function with otherwise maximum feminization, or minimal feminizing effects with the exception of body or facial hair elimination or breast growth. While manipulation of dosing regimens and choice of medication can allow patients to achieve this goal, it is important to have a clear discussion with patients regarding expectations and unknowns. Specifically, it is not possible to select in advance an exact hormone regimen that will predictably allow patients to arrive at a specified configuration of sex characteristics. Furthermore, individual genetic and physiologic variation can result in wide variations in both blood levels and response to therapy between different individuals using the same route and dose. The best approach in these cases is to start with low doses and advance slowly, titrating to effect. At the same time, response to hormone therapy is also individualized and measures such as breast growth are variable in both degree and time course. Likely predictive factors of speed and degree of feminization include genetics, age at initiation of therapy, and body habitus.[17] Patients should be counseled on typical timeframes for changes and advised to avoid making comparisons to the experiences of others. Anecdotal sources suggest that maximal feminization may occur within 2-5 years.[36]

Specific considerations and conditions

Tobacco use:

Tobacco use in combination with estrogen therapy is associated with an increased risk of venous thromboembolism. All transgender women who smoke should be counselled on tobacco risks and cessation options at every visit. Many transgender women may be unable or unwilling to quit smoking; this should not represent an absolute contraindication to estrogen therapy. After an in depth and careful informed consent discussion, it is reasonable to prescribe estrogen using a harm reduction approach, with a preferred route of transdermal estrogen. Aspirin 81mg/day can be considered as an additional preventive measure in smokers, though no evidence exists to allow and informed assessment of the risk/benefit ratio between VTE prevention and gastrointestinal hemorrhage (Grading: X C W). Transdermal estrogens are preferred to minimize risk (Grading: T O S).

Loss of erectile function:

Sildenafil (Viagra) and tadalafil (Cialis) can be used for preservation of erectile function at any stage or with any feminizing hormone regimen, in consideration of the typical contraindications and precautions when using this class of medication. Individual results may vary. It is reasonable check both total and bioavailable testosterone levels, and consider reduction of androgen blockade to allow an increase in testosterone, depending on patient goals.

Low libido:

A study of sexual desire in transgender women found that 83% never or rarely experience spontaneous sexual desire, 76% never or rarely experience responsive sexual desire, and 22% meet the criteria for Hypoactive Sexual Desire Disorder (HSDD) by experiencing both of these in a way which results in personal or relational distress. This study also found decreases in sexual desire after genital surgery.[37] Another study found a rate of HSDD in transgender women of 34%, compared to 23% in non-transgender women. This study found no correlation between sexual desire and testosterone levels in the transgender women, though a significant correlation was found between hormones and desire in non-transgender women.[38] An unpublished study found positive correlations between libido and testosterone levels in transgender women treated with testosterone, but no effect when treated with dehydroepiandrosterone sulfate (DHEA-S).[39] As such it remains unclear if HSDD relates to androgen blockade or post-gonadectomy hormonal changes, or due to anatomical, functional and psychological changes associated with hormone therapy or genital surgery.

Post-gonadectomy:

Since estrogen dosing should be based on physiologic female levels, no reduction in estrogen dosing is required after gonadectomy. Some patients may choose to use a lower dose, which is appropriate as long as dosing is adequate to maintain bone density. Adequacy of dosing in those on low estrogen replacement post gonadectomy may be assessed by following LH and FSH levels (Grading: T O W).[11]

Older transgender women:

Older transgender women initiating therapy may have less rapid and a lesser degree of changes. Due to higher levels of co-occurring conditions in older individuals, there may also be higher risk of adverse effects. Nevertheless a large number of women have started hormones at advanced ages and safety and satisfaction have been reported as acceptable.[40] There is no evidence to support continuation or cessation of hormones for older transgender women.

Since the mean age of menopause in the U.S. is 49,[41] it is reasonable in transgender women who have undergone gonadectomy to consider stopping hormone therapy around age 50. Expected effects of this may be similar to non-transgender women experiencing menopause. Transgender women who retain their gonads but withdraw hormone therapy may experience return of virilization. A discussion of the pros and cons of this approach, with individualized and shared decision making is recommended.

Pituitary adenoma (prolactinoma) and galactorrhea:

Prolactin elevations and growth of pituitary prolactinomas are theoretical risks associated with estrogen therapy; several cases have been reported.[42] However, with the administration of physiologic doses of estrogen, there is no clear basis for an increased risk of prolactinomas in comparison to the population background rate in non-transgender women. Furthermore, Endocrine Society guidelines for the management of incidental prolactinomas are expectant management only, in the absence of suggestive visual or other symptoms (significant galactorrhea, headaches).[43] Routine screening with serum prolactin levels in asymptomatic transgender women would not have an impact on management, and could result in costs or harm if further workup if pursued. As such it is recommended that prolactin be checked only in cases of visual disturbances, excessive galactorrhea, and be considered in cases of new onset headaches. It is noted that some transgender women experience a minimal amount of galactorrhea early in their hormone therapy course. The presence of non-bloody minimal galactorrhea from more than one duct and/or bilateral is almost certainly physiologic and would not warrant further evaluation.

Venous thromboembolism:

Data from studies of menopausal women suggest no increased risk of venous thromboembolism with the use of transdermal estradiol.[44] There are some data suggestive of increased thrombogenicity and cardiovascular risk when conjugated equine estrogens (Premarin) are used.[1,2] Data on the risk associated with oral 17-beta estradiol are mixed, with some suggesting no increased risk and others suggesting a 2.5 - 4 fold increased risk.[20,44] Even in the case of a 2.5 fold increase, the background rate for VTE in the general population is very low (1 in 1000 to 1 in 10,000), so the absolute risk increase is minimal.[3] There is weak evidence that sublingual administration of oral estradiol tablets might reduce thromboembolic risk due to a bypass of hepatic first pass, with one study showing 13 fold increase in peak estradiol blood levels but similar 24 hour area-under-the-curve.[45] A study of sublingual estradiol for the management of post-partum depression found that it was well tolerated, and the increased pulsatile nature of this route may more closely mimics natural ovarian estrogen secretion.[46] Sublingual administration requires insuring that the estradiol tablets are micronized; while most commonly available estradiol tablets are micronized, specifying as such on the written prescription (or consulting with the dispensing pharmacist) is recommended.

There is also some limited evidence to suggest that the risk of VTE in menopausal women may be driven more by the choice of progestogen, and that pregnane derived progestogens such as medroxyprogesterone in combination with oral estradiol does not confer an increased risk, while norpregnane derived progestogens such as norethindrone may increase risk by 80% when used with oral estradiol.[20] Prior studies reporting a 20 to 40 fold increased risk of VTE in transgender women involved the use of high doses (100-200mcg/day) of thrombogenic ethinyl estradiol in a mix of smokers and non-smokers.[47,48] A retrospective cohort of Dutch transgender women found no increased risk in VTE once ethinyl estradiol was replaced by bioidentical estradiol as the standard regimen.[49]

Insufficient evidence exists to definitively guide estrogen therapy in transgender women with risk factors or with a personal history of prior VTE, either on or off estrogen. A report of 11 transgender women with a history of activated protein C resistance (the mechanism of action implicated in the hypercoagulable state associated with the Factor-V Lieden mutation) using transdermal estradiol without anticoagulation found no clotting events after a mean of 64 months of therapy.[50]

Figures 1-5 describe the approach to various scenarios of VTE history or risk factors and estrogen use. The decision to initiate episodic (i.e. before long airplane flights) or long term anticoagulation or antiplatelet therapy should be considered in the context of risks associated with major gastrointestinal or intracranial hemorrhage. Routine VTE prophylaxis with aspirin in unselected transgender populations is not recommended. Routine screening for prothrombotic mutations is not recommended in the absence of risk factors.[50] Regardless of the circumstances, estrogen therapy should not be administered in patients with significant risk factors for or history of VTE who continue to smoke tobacco.

Figure 1. Approach to management of estrogen in patients with a personal history of VTE

This figure outlines the estrogen management approaches for patients with a personal history of VTE.

This figure outlines the estrogen management approaches for patients with a personal history of VTE.

  1. Patients with positive prothrombotic mutations or other evidence of hypercoagulative state should begin anticoagulation as per current guidelines for nontransgender patients. Begin transdermal estrogen after informed consent discussion.
  2. For patients without positive prothrombotic mutations or evidence of hypercoagulative state, determine if there is a clear external cause for VTE such as long bone fracture, immobility, or tobacco use. If yes, continue with standard approach to estrogen therapy once external cause has been resolved. If no, consider episodic or long-term anticoagulation or antiplatelet therapy on a case-by-case basis, using the same criteria as for nontransgender patient.

Figure 2. Approach to management of estrogen in patients with a family history of VTE but no personal history of VTE

Approach to management of estrogen in patients with a family history of VTE but no personal history of VTE. Treat as nontransgender patients. Consider treatment per guidelines.

Approach to management of estrogen in patients with a family history of VTE but no personal history of VTE. Treat as nontransgender patients. Consider treatment per guidelines.

Figure 3. Approach to patient using oral or injected estrogen at time of first diagnosis of VTE

Discusses decision points related to determining cause of VTE and use of anticoagulation agents before beginning transdermal estrogen therapy.

Discusses decision points related to determining cause of VTE and use of anticoagulation agents before beginning transdermal estrogen therapy.

Figure 4. Approach to patient using transdermal estradiol at time of first diagnosis of VTE

Discusses decision points for treatment of patients taking transdermal estradiol at time of first diagnosis of VTE and whether to consider longterm anticoagulation or anti-platelet therapy.

Discusses decision points for treatment of patients taking transdermal estradiol at time of first diagnosis of VTE and whether to consider longterm anticoagulation or anti-platelet therapy.

Figure 5. Approach to patients with known hypercoagulative state who use transdermal estradiol and present with acute VTE

Decision tree for patients with known hypercoagulative state who present with acute VTE and use transdermal estaradiol.

Decision tree for patients with known hypercoagulative state who present with acute VTE and use transdermal estradiol. Those already anitcoagulated should consider lifelong avoidance of estrogen therapy. Others should begin long-term anticoagulation therapy unless contraindicated.

Autoimmunity:

There is a certain but incompletely defined linkage between sex hormones and autoimmune conditions. Testosterone has been associated with overall immune suppression, and autoimmune conditions are more common in non-transgender women than men.[51] Testosterone deprivation results in an increased Th1:Th2 ratio.[52] However the relationship is more complex, as demonstrated by the paradoxical improvements seen in multiple sclerosis during pregnancy.[51] In transgender women who have undergone orchiectomy or have full androgen blockade, some evidence suggests that supplementation with dehydroepiandrosterone (DHEA) may counteract some of the shift toward autoimmunity.[53] Patients with autoimmune conditions should be informed that their condition could potentially worsen (or improve) once feminizing therapy has begun. Hormone dosing should begin low and advance slowly, monitoring for worsening symptoms, and in collaboration with any specialists who may be managing the autoimmune condition.

Migraine:

Migraines have a clear hormonal component and may be exacerbated by estrogen therapy. Patients with a history of migraines should consider starting with a low dose and titrating upward as tolerated. Oral or transdermal estrogen may be preferred to the potentially cyclic levels associated with injected estrogen.[54] While migraine with aura is associated with an increased risk of stroke in women using oral contraceptives,[55] it is not clear if this risk translates to the use of bioidentical estradiol.

Mental health conditions:

While hormones may contribute to mood disorders (such as in premenstrual dysphoric disorder or postpartum depression), there is no clear evidence that estrogen therapy is directly associated with the onset of or worsening of mental health conditions. In fact one study found that transgender women experience improvements in social functioning and reduced anxiety and depression once estrogen therapy is begun.[56] Mental health conditions in transgender women should be approached with a broad differential diagnosis as in any other patient. It may be advisable to avoid injected estrogen due to the potentially cyclic levels, which could bring about or worsen existing mood symptoms.

Estrogen therapy in patients with a prior history of cancer:

An active estrogen-sensitive cancer is a contraindication to estrogen therapy. For patients with a prior history of estrogen sensitive cancer (breast, pituitary), consultation with an oncologist is recommended. While androgen deprivation is a mainstay of treatment for advanced prostate cancer, it is unclear if estrogen therapy may confer an independent protection or increased risk of prostate cancer.[57] PSA should be considered unreliable in those using antiandrogen or estrogen therapy due to the high risk of false negative tests.

Perioperative use of feminizing hormones:

No direct study of the risk of perioperative venous thromboembolism in users of bioidentical estrogens has been conducted. Guidelines from two British professional organizations make a weak recommendation to discontinue menopausal hormone therapy in the perioperative period, however both acknowledge that this may not be needed in the setting of proper prophylaxis (i.e. heparin or compression devices).[58] Studies of perioperative ethinyl estradiol in users of hormonal contraception have mixed findings and are wrought with confounding and methodological limitations.[59] Many surgeons insist that transgender women discontinue estrogen for several weeks before and after any gender affirming procedure.[60,61] These recommendations may appear as benign to the surgeon; however to the transgender woman undergoing a life and body-altering procedure simultaneous with gonadectomy, sudden and prolonged complete withdrawal of estrogens can have a profound impact. Postoperative depression is a nontrivial concern and may have some basis in the drastic hormone shifts, including cessation of estrogens, experienced in the perioperative period. There is no evidence to suggest that transgender women who lack specific risk factors (smoking, personal or family history, excessive doses or use of synthetic estrogens) must cease estrogen therapy before and after surgical procedures, in particular with appropriate use of prophylaxis and an informed consent discussion of the pros and cons of discontinuing hormone therapy during this time. Possible alternatives include using a lower dose of estrogen, and/or changing to a transdermal route if not already in use.[62]

About consent forms for hormone therapy:

Informed consent is a process which occurs between a patient and a provider. The process should include an individualized discussion of the risks, benefits, unknowns, alternatives, and risk of no treatment. We are no longer recommending the use of consent forms for hormone therapy. Many other common interventions such as contraception or HIV pre-exposure prophylaxis do not involve the use of consent forms, and rely on a discussion and shared decision making between patient and provider. If the informed consent process is properly documented in the chart, consent forms do not likely provide any additional legal protections to the provider. Elimination of consent forms helps to demystify and destigmatize hormone therapy. Providers can use the information provided in these guidelines to frame their individualized discussions with patients.

Hormone therapy information for patients

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