Lab Value Changes in Transgender Females

For our next edition of transgender laboratory medicine, we will explore how transgender women use hormone therapy to physically transition to their affirmed female gender. While transgender men just take testosterone, transgender women take both estradiol and an anti-androgen. In the United States, that anti-androgen is spironolactone.

Figure 1. I was amazed in freshman biology by how structurally similar these hormones were and how they lead to such dramatically different phenotypes. Spironolactone is quite a bit different with the same cholesterol backbone. Credit Wikipedia

Estradiol is administered either as an oral pill, an injectable liquid or a transdermal patch. The estradiol pills are the cheapest option as they have been made generic for use as birth control. The transdermal can be the easiest to use, but is also the most expensive version and may not deliver as much estradiol as the other routes. Oral estradiol usually starts in adults at a low-dose (2 mg) then is titrated up to 4-6 mg and rarely up to 8mg. The end-point of estradiol titration is not to reach a certain hormone level, but to achieve desired physical traits. Endocrine guidelines do suggest keeping estradiol levels below peak physiologic levels (200 pg/mL).While little evidence currently exists for side effects of supraphysiologic estradiol, blood clots are a serious known side effect.

Part of the reason for anti-androgens in treating transgender women, is that even in women, testosterone levels are orders of magnitude higher. Spironolactone is primarily used as a glucocorticoid analog to block the mineralocorticoid receptor in the kidney to induce diuresis while retaining potassium. The structure of spironolactone is similar enough totestosterone that it also binds the androgen receptor and blocks the effect of testosterone. While enlarged breasts are considered a side effect in heart failure patients, it is an intended effect of spironolactone in transgender women. While hyperkalemia (high potassium) is a well known adverse effect of spironolactone, it seems to manifest more in patients with co-morbid conditions such as heart or kidney failure rather than in healthy patients.2

Table 1. This table describes the time frame of physical traits that manifest in transgender women while taking feminizing hormone therapy. Based on Hembree et al. 2017 (1).

For feminizing hormone therapy, red blood cell indices are the one of the most responsive laboratory parameters. The hemoglobin, hematocrit, and RBC number are all seen to decrease during hormone therapy in transgender women. A previous study of 55 transgender women3 showed that hemoglobin levels decreased significantly from cis-gender male levels to be not significantly different from cis-gender female hemoglobin. With a larger patient group, we were able to confirm this previous finding of decreased hemoglobin, but transgender women’s hemoglobin levels are still significantly different from individuals with sex-assigned female at birth (Figure 2).

Figure 2. A. Figure from Roberts et al 2014. B. TW= Transgender women, Baseline TW= TW with no history of hormone therapy, Baseline TM= transgender men with no history of hormone therapy. ***p<0.0001 Data expressed as interquartile range with median (box) and 2.5th to 97.5th percentile (whiskers).

Roberts et al also found that creatinine levels remain closer to cisgender male levels compared to cisgender female creatinine values3. This brought up the concept that not all lab values change predictably to the reference interval of the opposite gender. We further confirmed this finding in our larger cohort, but we further found a significant difference in transgender women from their baseline levels (Figure 3).

Figure 3. A. Figure from Roberts et al 2014. B. TW= Transgender women, Baseline TW= TW with no history of hormone therapy, Baseline TM= transgender men with no history of hormone therapy. ***p<0.0001 Data expressed as interquartile range with median (box) and 2.5th to 97.5th percentile (whiskers).

Overall, red blood cell and creatinine levels change the most in transgender women taking hormone therapy, but they don’t go as far as being comparable to lab values of individuals of the opposite sex assigned at birth. Our summary of this data will be published soon and interested labs can note what we found to be the central 95th percentile of common lab values including those presented here. I will go into greater detail about some unexpected effects of hormone therapy in following blog posts. I hope you’re looking forward to it as much as I am!

References

  1. Hembree WC,Cohen-Kettenis PT, Gooren L, Hannema SE, Meyer WJ, Murad MH, et al. Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society*Clinical Practice Guideline. J Clin Endocrinol Metab. 2017
  2. Roberts TK, Kraft CS,French D, Ji W, Wu AHBB, Tangpricha V, et al. Interpreting Laboratory Results in Transgender Patients on Hormone Therapy. Am J Med. 2014;127:159–62.
  3. Plovanich M, Weng QY,Mostaghimi A (2015). “Low Usefulness of Potassium Monitoring Among Healthy Young Women Taking Spironolactone for Acne”. JAMA Dermatol. 151 (9):941–4. 

-Jeff SoRelle, MD is a Molecular Genetic Pathology fellow at the University of Texas Southwestern Medical Center in Dallas, TX. His clinical research interests include understanding how the lab intersects with transgender healthcare and advancing quality in molecular diagnostics.

Lab Value Changes in Transgender Males

For patients with gender dysphoria, the Endocrine Society has endorsed the use of hormone therapy to promote secondary sexual characteristics of the desired gender. These guidelines were first established in 2007 and revised last year, and gave the first evidence guided recommendations for clinicians treating transgender patients.

For transgender males, testosterone by itself is prescribed as an injectable oil-based solution. These doses are given as intramuscular injections- usually into the thigh. If that’s too painful, subcutaneous injections have been shown to have similar efficacy. The doses given to transgender males is much higher (50-100mg/ injection) than that given to men with testosterone deficiency (30-50 mg/ injection). Primarily because the men have more testosterone to start with. Also, whereas topical testosterone gel may be sufficient for men with “low T,” it doesn’t seem to provide enough testosterone to transgender males and is quite expensive, so it is generally not used.

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Image 1. Picture of testosterone cypionate vial from mcguffmedical.com. This is used for intramuscular injections.

Upon starting testosterone injections, the frequency of injections is every one to two weeks. However, the onset of physical secondary sexual characteristics takes 3-6 months to begin. After about 3 years, most of the changes to occur will have manifested. These physical changes are outlined in the table below. You’ll notice how certain traits like cessation of menses and fat redistribution start within the first 6 months whereas muscle growth and voice change take effect after 6 months. Also, the time certain effects take maximal effect varies; the voice doesn’t deepen further after 2 years, but hair growth continues to increase through 5 years.

Physical Effect Begins Maximal Effect
Facial/body hair growth 6-12 mo 4-5y
Skin oiliness/acne 1-6mo 1-2y
Scalp hair loss 6-12 mo
Increased muscle mass 6-12 mo 2-5y
Fat redistribution 1-6mo 2-5y
Cessation of menses 1-6mo
Deepening of voice 6-12 mo 1-2y

Table 1. Timeframe of physical traits that manifest in transgender males while taking testosterone hormone therapy. Based on Hembree et al. 2017 (1).

 

Just as hormone therapy induces physical manifestations of secondary sexual characteristics for transgender men, we would suspect that internal aspects of physiology are affected too.  Values measured by the laboratory provide meaningful insight into how our body and its different organ systems are functioning. Accordingly, the Endocrine Society also recommended laboratory monitoring of transgender patients starting hormone therapy.

  1. Measure Testosterone and hemogoblin/ hematocrit every 3 months for the 1st year, then 1-2x/ year afterwards.
  2. Monitor Lipids at regular intervals

Previous studies have monitoring these lab values found consistent increases in hemoglobin and hematocrit (2,3). This is due to the stimulation of erythropoiesis by testosterone (4).  While excessive testosterone could lead to polycythemia (excessive RBCs in the blood), it is not a commonly described complication in transgender patients. Some summary results from our study for hemoglobin and hematocrit are shown in Figure 1A, which shows a clear shift in levels.

However, reports on lipids have been varied LDL and triglyceride changes (2,3). The only consistent finding was that HDL decreased in transgender males taking testosterone (2,3). In our study, we found triglycerides were increased with decreased HDL (Figure 1B). The take-away is that because cardiovascular cut-offs are based on risk and not a reference range, patients and clinicians will have to be aware of these possible metabolic changes.

Creatinine, when it was checked, increases for transgender males (5). We found creatinine was strongly increased in our study to become similar to baseline creatinine in transgender women before taking hormone therapy (Figure 1C). This topic as it relates to glomerular filtration rate is very complex and will be discussed further in a future post.

To illustrate lab value changes in transgender men, I’ll direct you to data that I found in a large study of over 300 transgender patients including about 80 transgender men. The completed manuscript is not currently available but will be printed soon:

Nov 2

However, this does not mean Cisgender male reference intervals are adequate for transgender men. This topic needs further exploration and ideally a prospective trial to be performed in a controlled manner. A double-blind study would not be possible as it would be unethical to perform.

References

  1. Hembree WC, Cohen-Kettenis PT, Gooren L, Hannema SE, Meyer WJ, Murad MH, et al. Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society* Clinical Practice Guideline. J Clin Endocrinol Metab. 2017
  2. Wierkx K, et al. Cross-Sex Hormone Therapy in Trans Persons is Safe and Effective at Short-Time Follow-Up: Results from the European Network for the Investigation of Gender Incongruence. J Sex Med, 2014. 11(8):1999-2011.
  3. Mueller A, Kiesswetter F, Binder H, Beckmann MW, Dittrich R. Longer-term administration of testosterone undecanoate every 3 months for testosterone supplementation in female-to-male transsexuals. J Clin Endocrinol Metab. 2007
  4. Paller CJ, Shiels MS, Rohrmann S, Menke A, Rifai N, Nelson WG, et al. Association Between Sex Steroid Hormones and Hematocrit in a Nationally Representative Sample of Men. J Androl. 2012 33(6): 1332-1341.
  5. Fernandez JD, Tannock LR. Metabolic Effects of Hormone Therapy in Transgender Patients. Endocr Pract. 2016;22:383–8.

 

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-Jeff SoRelle, MD is a Molecular Genetic Pathology fellow at the University of Texas Southwestern Medical Center in Dallas, TX. His clinical research interests include understanding how the lab intersects with transgender healthcare and advancing quality in molecular diagnostics.

Laboratory Medicine for Transgender Patients: An Introduction

Welcome to a new series where I’ll explore the role of lab medicine in the care of transgender patients! Many of you may be asking yourself, “Why should I care? I’m in the lab far separated from these dicey patient care issues.” However, the lab plays important roles as the patient moves through the healthcare setting. Everywhere from name confirmation by phlebotomists and before blood transfusion to sex-specific reference intervals, the lab interacts with the healthcare of transgender patients in important ways. With more transgender patients presenting for clinical management, and more clinicians armed with hormone therapy guidelines created and endorsed by the Endocrine Society, it will be expected for laboratory professionals to know how to manage these patients too.

For me, my first encounter with transgender healthcare through the laboratory was during my clinical chemistry rotation when the lab paged me about a very high estradiol value 10 times higher than the upper limit of normal. I found that the patient was a transgender woman taking excessive hormone doses. Their doctor counseled them and persuaded them to stick with their prescribed dose, because the risks of supraphysiologic estrogen is not known. While we were glad the patient didn’t have an estrogen secreting tumor, I wondered how this hormone therapy may affect other aspects of their health and physiology as reflected by lab values.

After a literature review, I found there were few studies that addressed changes in lab values with hormone therapy. Those papers I found had limited numbers of patients, so I decided to find the answers for myself. Subsequently, I (along with two medical students) studied a large number of patients attending transgender specific clinics.  I’ll discuss our findings as a part of this series.

For now, I’ll go over terminology so everyone can be on the same page. Many of us are likely unfamiliar with the experiences of transgender individuals and don’t realize how what appears to be a verbal misstep can be offensive. The first distinction to make is the difference between sex assigned at birth and gender. Sex is assigned at birth to a child, often based on external anatomy. Gender is the set of behaviors and roles that society or culture assigns to a person that ranges from masculine to feminine. However, gender identity is a deeply held internal sense of whether you consider yourself male, female, both or neither. This is distinct from sexual orientation, which one colleague explains: “orientation is who you go to bed with, gender expression is what you go to bed wearing, and gender is who you go to bed as.” When one’s gender identity is concordant with their sex assigned at birth, they are called cisgender; whereas, discordance between sex assigned at birth and gender identity is termed transgender (I think of cis and trans stereochemistry in organic chemistry). The process of using medical or surgical interventions to transition is referred to as gender-affirming hormone therapy or gender-affirming surgery.

The easiest way to address someone whose preferred name doesn’t match their sex in their record is to address them as they appear: use female pronouns if they are dressed as a woman and male pronouns if they are dressed as a man. And if you’re not comfortable with that, a simple “How would you like to be addressed?” is appreciated. I will go into the importance and challenges of legal sex/name and pronouns in the electronic health record in a later discussion.

To round out the topic of terminology, I’d also like to mention a few terms that should be avoided. “Transgendered” adds an unnecessary “-ed” as transgender is already an adjective. It is further confusing, because it makes the word sound past tense (we wouldn’t say “lesbianed,” for example). Rather, a person undergoes gender transition as they accept and express their gender identity through a set of social, physical, medical or legal changes (sometimes call gender affirmation process). Using terms like pre-op/ post-op/ sex change overly emphasizes the role of surgery in the process, and thus gender transition is more inclusive. Similarly, asking for someone’s “real name” overly emphasizes their legal name and there are limited situations where that would be necessary to use. Derogatory terms include tranny, hermaphrodite, or transvestite and shouldn’t be used even when referring to people who are intersex or wear clothes of the opposite sex.

Thanks for making it all the way through this first post, I look forward to hearing any questions you have and exploring this topic together further!

References

  1. Goldstein Z, Corneil TA, Greene DN. When Gender Identity Doesn’t Equal Sex Recorded at Birth: The Role of the Laboratory in Providing Effective Healthcare to the Transgender Community. Clinical Chemistry 2017; 63(8):1342-1352.
  2. Rosendale N, Goldman S, Ortiz GM et al. Acute Clinical Care of Transgender Patients. JAMA Intern Med. Published online August 27, 2018.
  3. Roberts TK, Kraft CS, French D et al. Interpreting laboratory results in transgender patients on hormone therapy. Am J Med. 2014;127(2):159-62.

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-Jeff SoRelle, MD is a Molecular Genetic Pathology fellow at the University of Texas Southwestern Medical Center in Dallas, TX. His clinical research interests include understanding how the lab intersects with transgender healthcare and advancing quality in molecular diagnostics.

Challenges in Transgender Healthcare

Transgender healthcare is a topic that doesn’t get a lot of attention. Healthcare providers receive little to no formal training in this area, and this population is one of the most under served groups in the United States. The authors of the recent Lab Medicine paper Challenges in Transgender Healthcare: The Pathology Perspective wrote a blog on this topic for Oxford University Press. Check out obstacles in transgender healthcare to learn some of the issues providers and patients face.