Tag: transgender

TRANSforming Healthcare: The Role of The Laboratory

In 2006, an international group of human rights experts assembled in Yogyakarta, Indonesia to address patterns of discrimination and abuse of individuals related to sexual orientation and gender identity. This document, The Yogyakarta Principles: Principles on the application of

international human rights law in relation to sexual orientation and gender identity, has been widely accepted as setting the standards for fundamental human rights for all, with specific attention to sexual orientation and gender identify. It is worth studying, as it articulates rights in many domains of everyday life. Of direct relevance to our Profession are Principle #12, The Right to Work; Principle number #17, The Right to the Highest Attainable Standard of Health; and Principle #18, Protection from Medical Abuses.1  It is the goal to “Adopt the policies, and programmes of education and training, necessary to enable persons working in the healthcare sector to deliver the highest attainable standard of healthcare to all persons, with full respect for each person’s sexual orientation and gender identity.”

Because the medical laboratory provides critical data for patient management, laboratory professionals and pathologists must be able to evaluate laboratory and biopsy results wisely and appropriately.  Yet we often lack fundamental and essential information necessary to support optimal and personalized care for patients on cross-sex hormones.

The number of individuals who self-identify as transgender has risen significantly in the past decade. Transgender people face discrimination, harassment, abuse, and denial of legal rights. They often feel unsafe, and a high proportion face bullying at school or at work. The Centers for Disease Control (CDC) estimates that about 2% of high school students in the U.S. identify as transgender; among them, 35% attempt suicide. Transgender adults are twice as likely of being homeless, four times more likely to live in poverty, four times as likely as being HIV-infected, and twice as likely to be unemployed compared to the general population.2 Individuals without access to appropriate care may purchase hormones from unreliable sources, so that the dose, drug contents, and potential side-effects are poorly controlled or even toxic.

Healthcare systems often fail the transgender community. First, given the high rate of poverty, unemployment, and homelessness, access to basic health services is not available for many individuals. Second, even in those healthcare institutions that serve the uninsured, appropriate services are often lacking, including the absence of knowledgeable providers and the lack of cultural competency in the institution. The few academic hospitals with services and clinics oriented to serving transgender patients struggle to provide optimal care, because there are important gaps in knowledge regarding how best to care for transgender patients. Many health care clinics and professionals lack training in asking all patients “What pronouns do you prefer to use in referring to yourself?” This is a straightforward way to acknowledge gender diversity and sets the first stage of a potentially trusting relationship.


Examples abound regarding information gaps in managing patients on cross-sex hormones. For instance, there are only a handful of papers in the literature addressing care of elderly patients, and little is known about the risks or health benefits of long-term cross-sex hormone use. For children who elect to start puberty blockers so that their development in adolescence is more appropriate to their self-identified gender, long-term effects on bone health are poorly understood. A number of laboratory tests have different reference ranges for “men” and “women,” such as n-telopeptide as a marker of bone turnover. Most labs have not established appropriate reference ranges for patients on cross-sex hormones, nor are there good long-term studies to help guide management of bone health in this setting. And there may be times when the managing health care professionals do not realize that a patient is taking cross-sex hormones.

Patient identifiers are often incomplete. Many patients on cross-sex hormones have not had surgery to remove their gonads. Therefore, a trans-man can present to the Emergency Room with severe abdominal pain, but those managing his care may not suspect ovarian torsion, ectopic pregnancy, or other conditions of the fallopian tubes, ovaries, uterus, and cervix. Similarly, trans-women may have testes and prostates. Most patient registration systems lack the ability to record sex chromosomes and gender identity separately. Also, many individuals identify as non-binary; some are not taking cross-sex hormones at all. These factors affecting presentation are currently captured poorly. If at all, in the medical record but may have profound implications for care. Otherwise, implicit biases can adversely affect patient care.

Finally, we all have work to do to ensure that our patients and colleagues feel welcomed and respected in our labs, training programs, and hospitals. One important step is for each of us to gain self-awareness of our attitudes and biases, and to educate ourselves. A good starting place is Gupta’s article in Lab Medicine;3 another is the book Trans Bodies, Trans Selves by psychologist Laura Erickson-Schroth.4 Second, we must continue to foster inclusive workplaces, to stand up when we witness abuses or so-called “microagressions.” Third, we must work directly with patients to hear their concerns, and to provide the information needed regarding our lab results and pathology reports. We must respond to the gaps identified by our patients, do the research necessary to get better answers, and partner with other health care professionals to address the needs of our patients.

References

  1. The Yogyakarta Principles. 2017. https://yogyakartaprinciples.org/
  2. Meerwijk EL, Sevelius J. Transgender population size in the United States- a Meta-Regression of Population-Based Probability Samples. Am J Public Health 2017; 107(2):e1-e8. PMID 28075632
  3. Gupta S, Imborek KL, Kraswoski MD. Challenges in transgender healthcare: the pathology perspective. Lab Medicine 2016;47:3;180–188.
  4. Erickson-Schroth L. Trans Bodies, Trans Selves: A Resource for the Transgender Community. 2014, Oxford University Press.

-Dr. Upton is board certified in Anatomic Pathology and Cytology and directed an autopsy service and forensic pathology fellowship program at Beth Israel Deaconess Medical Center in Boston, Massachusetts. She has also practiced cytopathology and general surgical pathology, and has focused on genitourinary pathology, head and neck pathology, and gastroenterology (GI) and liver pathology. From 1982-85 and 1987-2002, Dr. Upton lived in Boston and taught at Tufts, Boston, and Harvard Universities. Since 2002, she has been at the University of Washington in Seattle, where she formerly directed the GI and Hepatic Pathology Service the Pathology Residency Program and the UW GI and Hepatic Pathology Fellowship. Currently Emeritus Professor of Pathology, she continues to practice Surgical Pathology, Autopsy Pathology, and Cytopathology, and she is one of the specialists at UW in the areas of GI, liver, and pancreatic pathology.

Keeping Abreast of the Times

Hello again everyone and welcome back! Pardon the absolutely cheesy title, but this month I’d like to share parts of a clinical case and discuss some pretty important topics in pathology practice in 2021. While last month’s brief primer on the Cures Act is a definite part of the future of medicine, there are a lot of things developing in our profession—and we should all keep up!

*** Disclaimer: Please note that if/when I share cases or clinical content, they are not current, already signed out, completed and done in compliance full patient privacy guidelines. Always. ***

So let’s dive right in. A rather young male patient was sent to us from an outside facility for mildly painful, uncomfortable bilateral breast lumps. He was noted to have bilateral gynecomastia clinically and was to be evaluated via mammogram and localized needle biopsy. An ultrasound guided core needle biopsy of the left breast was collected from a mass identified on mammography.

Figure 1. Not the typical visual presentation noted on mammography. Biopsy clip marking the location of where the core biopsies were obtained. Male patients can have histologically identical cases of breast carcinoma when compared to females and are often associated with germline mutations, high-risk BRCA1 & 2 status, and Klinefelter syndromes.

Most commonly, when evaluating gynecomastia in a male and considering the diagnostic algorithms including malignancy one worries most about ductal carcinoma: invasive, unspecified type and ductal carcinoma in situ (DCIS) pretty much round off the differential for male breast cancer. Important rule outs include clinical, hormone-related gynecomastia or otherwise relating to germ-line or chromosomal abnormalities (i.e. XXY in Klinefelter), myofibroblastoma, or unrelated distant metastases. So without too much clinical information or history—since this was an outside referral—the differential of potential considerations was pretty short therein.

The biopsy was completed shortly after mammography and was signed out as: fibroadenoma.

Wait. What?

Fibroadenomas are benign and, along with potentially malignant phyllodes tumors, come from mammary tissue, demonstrate biphasic cellular components of benign epithelium (or low-grade stroma).

Translation: to have one of these entities you need mammary tissue, specifically terminal ductal/lobular units to form the necessary architecture changes.

Simpler translation: fibroadenomas need breast tissue to be fibroadenomas.

Okay, there definitely appears to be breast tissue here to form this entity, however, it is incredibly rare for a male patient (outside of the previously mentioned conditions) to have anatomically functional lobular units. With the other etiologies ruled out, further investigation into the patient’s history was warranted. It was discovered that this patient, although male by indication on referring paperwork, actually identified as female and was on gender affirming hormone therapy for several years. A considerably simple explanation for the confounding biopsy result.

Transgender medicine and transgender pathology considerations have been talked about more in recent years than ever before. While these patients have always existed, societal changes in the last decade alone have brought to light many disparities in medical care and practice habits overall. Here on Lablogatory, there have been between 20-30 mentions of transgender patients since 2018 with entire pieces dedicated to transgender endocrinology, clinical chemistry, etc. Specific examples have included the complicated intersection of transgender care and electronic medical records, various lab values in trans patients, and an excellent overview of laboratory medicine and trans patients by Dr. Jeff SoRelle. There he discusses approaches, literature, and—most importantly—the purposeful vocabulary of transgender medicine as an empowering and informative practice.


Image 2. A 2016 paper in Laboratory Medicine highlights this patient population’s challenges to quality and equity in healthcare and establishes that gatekeepers to data—including us—should consider new ways to create inclusive laboratory medicine practices to maintain our high standard of care. Read it here.

While, this case was rather straightforward after the discovery of the patient’s history of gender affirming therapy, there are still several critical points to highlight here. First, it’s critically important in the setting of medical care to correctly and compassionately include gender identity in patient records—within the caveat of appropriate confidentiality and patient autonomy. Patient care, health management, and diagnostic efforts like ours may rely on a simple biological indication of how this patient presents and experiences their identity with relation to their clinical course. This further strengthens relationships between trans patients and their primary care providers, as well as non-patient-facing specialists like us who often put pieces of the puzzle together without an entire history at our disposal. How does this impact patient care? Simple: a trans male patient may always carry a residual indolent risk of breast cancer, while a trans female patient may need to be included in future mammogram screening. The bottom line should consider treating who you have, and screening with what you have to. Since this patient was sent because of breast lumps, as a male patient a biopsy report of “fibroadenoma” would be exceedingly rare and confounding because of normal physiology outside of specific genetic conditions. But with the right information at the right time, better patient-centered care is possible.

Finally, as a note about proper terminology, vocabulary, and available guidelines in the literature, there is both a paucity of effective transgender medical guidelines as well as a poor grasp on the terminology. Dr. SoRelle does a fantastic job with a short vocabulary outline, but we should all do better. The experiences of our trans patients is challenging to say the least, so as we continue to become stronger and closer advocates for patients in pathology and laboratory medicine, we must become familiar with their experience and advocate for the progress of inclusive medical care.

Trans patients are special, and we are specialists.

Making sure they received the highest level of care alongside all our other patients should be guaranteed. Whether in our clinical chemistry labs or surgical pathology sign outs, we already know how to create an environment of accuracy and enduring inclusion for all our patients—let’s keep it going!

Thank you for reading, I’ll see you next time!

–Constantine E. Kanakis MD, MSc, MLS(ASCP)CM is a first-year resident physician in the Pathology and Laboratory Medicine Department at Loyola University Medical Center in Chicago with interests in hematopathology, transfusion medicine, bioethics, public health, and graphic medicine. He is a certified CAP inspector, holds an ASCP LMU certificate, and xxx. He was named on the 2017 ASCP Forty Under 40 list, The Pathologist magazine’s 2020 Power List and serves on ASCP’s Commission for Continuing Professional Development, Social Media Committee, and Patient Champions Advisory Board. He was featured in several online forums during the peak of the COVID pandemic discussing laboratory-related testing considerations, delivered a TEDx talk called “Unrecognizable Medicine,” and sits on the Auxiliary Board of the American Red Cross in Illinois. Dr. Kanakis is active on social media; follow him at @CEKanakisMD.

When Gender Goes Awry in Electronic Health Records

For most people working in laboratory medicine, their first encounter with transgender patients likely arose from an issue involving the Electronic Health Record (HER). For me, I was called into the reference lab, because an abnormally high estradiol result was found by the referring lab. They were concerned this might be coming from a hormone secreting tumor, but inspection of the patient’s record revealed they had been taking higher than recommended doses of their feminizing hormones.

Today I will share stories from issues that arise in EMR when gender doesn’t equal sex. While these may not specifically happen to all of you, I hope they can be informative or help you anticipate future problems.

Transgender issues came up at one of our institutions when providers were getting dozens of messages in their in-baskets about new flagged lab results for multiple patients. This is very annoying, because they have to address each of these messages or they are out of compliance with the hospital. An investigation revealed that all of the patients involved were transgender patients. In order to get estradiol, sold as oral contraception pills, the pharmacy had to administratively change their sex in the EHR for approval, then change it back.

This moved their corresponding reference ranges out of sync, which triggered a new results flag. Changing the sex back triggered other flags and more messages. This was finally resolved after a committee was convened and several meetings occurred, but no one would have anticipated this type of issue arising from a simple action to get patients their medicine.

Sometimes transgender patients have their sex changed legally. If an EHR only includes one sex entry instead of gender and sex assigned at birth, then certain lab errors may prevent processing of important samples. The pregnancy test for a transgender man could be auto-rejected. This can be an issue even for providers in front of the patient as was recently reported in a case to the NEJM about a transman who was mistaken as obese instead of pregnant and miscarried their child.

Similarly, a prostate biopsy from a transgender woman could be auto-rejected by a surgical pathology system as an inappropriate specimen type for the patient. Even further, an EHR could fail to prompt a provider from making a prostate cancer risk assessment in a transgender woman, which could result in improper screening.

I would recommend that EHR includes three separate fields (sex assigned at birth, gender, and legal sex) to fully recognize transgender patients and provide optimal personalized healthcare to them.

References

  1. Gupta S, Imborek KL, Krasowski MD. Challenges in Transgender Healthcare: The Pathology Perspective. Lab Med. 2016 Aug; 47(3):180-188.
  2.  Stroumsa D, Roberts EFS, Kinnear H, Harris LH. The Power and Limits of Classification – A 32-YearOld Man with Abdominal Pain. N Engl J Med. 2019 May 16;380(20):1885-1888. doi:10.1056/NEJMp1811491.

-Jeff SoRelle, MD is a Chief Resident of Pathology 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 improving genetic variant interpretation.

The Paperwork of Transgender Care

I don’t think anyone enjoys filling out the paperwork at a doctor’s office. For transgender individuals, this can be an experience that ranges from irksome to offensive. Most intake forms don’t allow for expression of their gender identity. Furthermore, confusion on gender and sex can create real confusion and healthcare failures in several places that laboratory medicine encounters a transgender individual.

Arguably the first place the lab encounters a transgender patient is via the phlebotomist. These professional collectors of blood must confirm two patient identifiers, which are often name and date of birth. The “name” used is the legal name. Using a transgender person’s “dead name” (name given at birth) represents a gender they do not want to be associated with and can be a very offensive experience. “Isn’t it obvious that name is not what I look like?”

While names can be legally changed, this happens with varying difficulty and legal cost in different states. A solution is to improve training of phlebotomists to explain the necessity of confirming a legal name so lab results are properly matched to the patient. Additionally, front-desk intake workers should be similarly trained to interact with transgender patients when recording demographic information. This can be aided by electronic health records (EHR) becoming more flexible and inclusive of the gender diversity.

Traditionally, EHR would only include one field for SEX: M or F.

Several in the laboratory community have asked how many different gender options should be included? Facebook included up to 71 options in 2017. That’s a big step up from the 2 traditional EHRs are built around.

The World Professional Association for Transgender Health (WPATH) executive committee in 2011 outlined the recommended fields to include in EHR: preferred name, sex assigned at birth, gender, and pronoun preference. EHRs are evolving and can be flexible depending on the user requirements. At my program, we use EPIC at 3 different different sites (children’s, county and university hospitals) and each has a different version.

From what I’ve seen preferred name is an easy addition and would not interfere with functions of the EHR or Laboratory Information Systems (LIS), which is the Lab’s version of EHR.

If the field for sex assigned at birth is different from gender, then it would clear up any confusion about whether the person is transgender and then they should be addressed by the pronouns matching the gender. While there is a spectrum of genders, only transgender males and transgender females are of a high enough prevalence to have medically relevant recommendations. Plus, if a system at least starts here, they could expand further as necessitated by their population.

EHR could include preferred pronouns, but I haven’t seen this implemented in an EHR yet. Ideally, you would just use the pronouns that match the intended appearance of the individual (ma’am to someone wearing a dress, etc.).

Lastly, I think Legal sex should be added to the EHR as well. One of our hospitals has this and it makes several processes easier such as processing hormone medication.

Legal (or administrative) sex, sex assigned at birth, and gender data fields provide the clearest and simplest picture of a patient and should be a minimum for labs making recommendations for changes to HER.

Next month I will describe in greater detail the issues that can arise in the lab when gender or sex are entered incorrectly in the system for transgender patients and how this can negatively affect care delivery.

References

  1. Deutsch MB, Green J, Keatley J, Mayer G, Hastings J, Hall AM, World Professional Association for Transgender Health EMR Working Group. Electronic medical records and the transgender patient: recommendations from the World Professional Association for Transgender Health EMR Working Group. J Am Med Inform Assoc. 2013 Jul-Aug; 20(4):700-3.
  2. Gupta S, Imborek KL, Krasowski MD. Challenges in Transgender Healthcare: The Pathology Perspective. Lab Med. 2016 Aug; 47(3):180-188.

-Jeff SoRelle, MD is a Chief Resident of Pathology 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 improving genetic variant interpretation.

Hormone Blockers = Blood Letting for Female Athlete with high T?

Caster Semenya celebrates as she wins gold in the women’s 800 meters in the Commonwealth Games on April 13, 2018, on Australia’s Gold Coast (1). Jason O’Brien/Getty Images

I will continue this month along the thread of last month’s post, which addressed the controversy surrounding South African female mid-distance runner Caster Semenya. Caster has won many international mid-distance races (400-800m), but she has been suspected of naturally producing higher levels of testosterone.

Since last month, I’ve learned the reason for the higher testosterone is uncertain: it could be due to natural production (hyperandrogenism) or rumors of her being intersex1. Regardless, what I will discuss here is how the proposed actions of the International Olympic Committee would be expected to affect Semenya’s performance. Specifically, how would lowering testosterone levels affect her athletic performance?

Last month, we saw that muscle mass might be expected to decrease, but this may not affect athletic performance significantly.

Another important effect of testosterone is on red blood cell levels including hemoglobin, which by carrying oxygen to muscle is a central part of calculating VO2max. VO2max is maximal oxygen consumption. This is strongly linked to performance in cardiovascular athletic events.

Mid-distance running requires a large cardiovascular capacity. Maybe not the same level of Tour-de-France long distance bikers in the Alps, but still substantial. As a runner that feels pretty proud at having run a sub-3 minute 800m, I can say Caster’s feat of running it in less than 2 minutes is incomprehensible. From the burning feeling in my lungs and thudding, maximum heart rate at the end of the half-mile, I can attest that this event requires substantial cardiovascular efficiency.

Maximal oxygen consumption (VO2max) by exercising skeletal muscle is principally limited most by cardiac output and oxygen-carrying hemoglobin levels. This has been shown quite convincingly in a series of experiments in the 1950’s-70’s2,3 that probably wouldn’t be approved by the IRBs of today charged to protect research subject rights.

First, transfusing blood increased hemoglobin concentration and similarly the VO2max and exercise endurance of participants.  (This practice was exploited most notably later on in the Tour de France).  In other studies3, blood was removed from participants before assessing their exercise tolerance (10% loss of hemoglobin à 13% reduction in VO2max). Another study removed 400mL, 800mL and 1,200mL over several days, which decreased hemoglobin by 10%, 15%, and 18% respectively. There was a concomitant decrease in endurance time (-13%, -21%, -30%) and VO2max as well (-6%, -10%, -16%)3.  A summary of blood transfusion and hemodilution studies is shown in Figure 1 from Otto JM et al4.

Figure 1. Reproduced from Otto JM et al (4)

In transgender women (gender incongruent with sex assigned male at birth), hormone therapy to increase estrogen levels (oral estradiol) and block testosterone (anti-androgen: spironolactone) reduces hemoglobin by 9% on average (from 15.2 g/dL to 13.9 g/dL)5. I would expect a smaller decrease for Semenya as she will likely not get a full dose hormone regimen used for transgender transition and because her testosterone levels wouldn’t be as high as biologic males’.  However, she would still be expected to have lower hemoglobin- similar to donating a half or whole unit of blood. If hemoglobin decreased even just 5%, that could affect her performance substantially when the difference between competitors boils down to seconds in mid-distance races.

Arguably, forced blood donation could produce the same effects as testosterone-lowering therapy. But it would be far too dramatic to suggest something like bloodletting by the International Olympic Committee.

In the end, I don’t feel qualified to say what should be done in this case. All I can say is that I don’t think lowering Caster Semanya’s testosterone levels will have the intended effect of decreasing muscle mass. On the other hand, it would decrease hemoglobin levels tempering her performance. But who should determine the point where her hormone levels should be? There is such a strong biologic connection between hormone levels and physiology that manipulating them for athletic fairness could be akin to playing puppeteer.

References

  1. North, Anna. ““I am a woman and I am fast”: what Caster Semenya’s story says about gender and race in sports” Vox. May 3, 2019
  2. BALKE B, GRILLO GP, KONECCI EB, LUFT UC. Work capacity after blood donation. J Appl Physiol. 1954 Nov; 7(3):231-8.
  3. Ekblom B, Goldbarg AN, Gullbring B. Response to exercise after blood loss and reinfusion. J Appl Physiol. 1972 Aug; 33(2):175-80.
  4. Otto JM, Montgomery HE, Richards T. Haemoglobin concentration and mass as determinants of exercise performance and of surgical outcome. Extrem Physiol Med. 2013; 2: 33.
  5. SoRelle JA, Jiao R, Gao E et al. Impact of Hormone Therapy on Laboratory Values in Transgender Patients. Clin Chem. 2019; 65(1): 170-179.

-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.

Sex Hormones in Competitive Athletics

Image 1. Photo from NBC News.

Given my previous work in lab value changes in transgender individuals on hormone therapy, I was recommended to consider discussing the case of Olympic mid-distance runner, Caster Semenya. Although she is not transgender, this professional runner from South Africa has won her last 30 races and been scrutinized for her muscular build as having potentially higher levels of testosterone, a condition called hyperandrogenism. The International Olympic Committee’s (IOC) regulations require testosterone levels to be below a certain threshold for female athletes. 

While no competitor can achieve great victories without hard work and practice, there are certainly examples of outliers whose genetics give them an advantage. However, I don’t think we would endorse shortening Michael Phelps’ arms or lobotomizing chess master Bobby Fisher to decrease their inborn advantages for a level playing field.

But this gets into an area of ethics that I’m not an expert on, so instead I will stick to my area of science and examine what evidence may exist to support the IOC’s policy. Then I will extrapolate the results from our study of transgender individuals to see if hormone regulation may impact contributions to athleticism. The most strongly shifted lab values in hormone therapy for transgender individuals are red blood cells (including oxygen-carrying hemoglobin) and creatinine (byproduct of muscle used to monitor kidney function, but also reflects total muscle mass).

Once looking more closely at this topic, I realized there is a lot to say about the contributions of 1) muscle mass and 2) red blood cells to athleticism. So, I will discuss muscle mass this month and wait until next month to discuss hemoglobin levels (including athletic performance by blood removal/ doping).

Mid-distance running, which is Caster Semenya’s sport, is a mix of anaerobic and aerobic activity. This means having more muscle would be advantageous. This is supported by a study that was commissioned by the IAAF (International Association of Athletics Federation), which shows a 1.8-2.6% increased competitive advantage in short distance track events (400m, 800m and, 400m hurdles)1. However, this study had several limitations. First, the sample size was quite low with only 22 female athletes. Next, they use a p-value of 0.05 for significance without correction for multiple hypothesis testing (21 hypotheses tested representing each event), which increases the likelihood of a false positive result by chance.

What makes me curious is whether following the International Olympic Committee’s recommendations of lowering testosterone levels would even have a meaningful impact and improve competitiveness?

From my research, I know that adding testosterone to individuals assigned female at birth to transition to transgender males (TM ) does substantially increase creatinine (p<0.005, Figure 1)2 to male levels (baseline TW). This is likely not due to changes in kidney function (although this has not yet been proven), but rather due to increased muscle mass.

Figure 1.

However, the inverse is not quite true for transgender women who take combinations of estrogen for feminization and spironolactone to block the effects of testosterone. In these patients, we see a slight decrease in the creatinine (TW). While this decrease is statistically significant, the range is not clinically different from male creatinine levels. This concurs with the observations that musculature in transgender women does not change substantially upon taking hormone altering medication.

A more rigorous examination of muscle mass, performed by MRI measurement, determined that after 1 year of hormone therapy testosterone increased muscle mass in transgender men to biological male levels3, similar to our observations of creatinine. Further, they saw a significant reduction in muscle mass from baseline of transgender women on hormone therapy for 12 months, but it was still much higher than the muscle mass of biologic females4.

Therefore, were Casten Semenya to take testosterone blocking medication, I suspect there would be little impact on her overall muscle mass. Which is one of, if not the explicit purpose of taking testosterone lowering medicine. The strength of my conclusions is limited by the fact that we don’t know Casten Semenya’s testosterone levels, and furthermore a hyperadrogenic female is not the same as a male-to-female transgender woman.

As mentioned above, I will continue this discussion next month with an exploration of how testosterone lowering therapy could affect red blood cell levels, which would affect athletic performance differently.

References

  1. Bermon S and Garnier P. Serum androgen levels and their relation to performance in track and field: mass spectrometry results from 2127 observations in male and female elite athletes. British Journal of Sports Medicine. 2017; 51(17): 1309-1314.
  2. SoRelle JA, Jiao R, Gao E et al. Impact of Hormone Therapy on Laboratory Values in Transgender Patients. Clin Chem. 2019; 65(1): 170-179.
  3. Gooren LJ, Bunck MC. Transsexuals and competitive sports. Eur J Endocrinol. 2004; 151(4): 425-9.
  4. Jones BA, Arcelus J, Bouman WP, Haycraft E. Sport and Transgender People: A Systematic Review of the Literature Relating to Sport Participation and Competitive Sport Policies. Sports Med. 2017;47(4):701-716.

-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.

Potassium Levels in Transgender Women

For transgender women, taking pills of estradiol is insufficient to counteract the endogenous levels of testosterone produced by their bodies. To counteract the undesired testosterone, anti-androgens are employed. These include cyproterone acetate (approved only in Europe) or spironolactone. Spironolactone is a potassium sparing diuretic that could have unintended consequences like gynecomastia.1 This effect comes from off-target binding of spironolactone to the androgen receptor. Like the intended spironolactone target (mineralocorticoid receptor), the androgen receptor localizes to the nucleus when activated and acts as a transcription factor. Taking daily high doses of spironolactone (100mg- 300mg daily) has been shown to be safe,1 but can increase Potassium levels. In a cohort of 55 transgender women, potassium was actually not higher (Figure 1).2 This was the first time a study had rigorously measured electrolytes like potassium in transgender patients. Current guidelines recommended checking electrolyte levels in transgender women taking spironolactone.3 Full electrolytes were included for 126 TW in our study and what we found was not what we were expecting.4

Figure 1.

We found no increased potassium levels in TW who had taken hormone therapy for at least 6 months (p>0.05). However, we did see a decrease in sodium which is consistent with the diuretic effect (p<0.0001, Figure 2).

Figure 2.

We wondered if variability in spironolactone dosing could explain why no significant potassium change was found. Luckily, we had a large number of patients who were taking various doses of spironolactone for comparison. One-way ANOVA with Tukey post-hoc tests revealed no difference in potassium levels (p>0.05)- even between the lowest (0mg daily) and highest dose (200-300 mg daily) (Figure 3). While the sodium level trended to decrease with higher spironolactone, it was not statistically significant.

Figure 3.

One reason that potassium levels did not increase is a difference in study populations. The original population studied for spironolactone involved patients with heart failure and hypertension whereas our study’s population was mostly in their 20’s and 30’s with very few co-morbid conditions.

Although sodium levels are decreased, they did not fall below the lower limit of normal (135 mmol/L). Low sodium would put transgender women at risk of dizziness and syncope (passing out) from low blood pressure. Thus, the takeaway is: sodium should be clinically monitored as it can decrease in transgender women.

References

  1. Clark E. Spironolactone Therapy and Gynecomastia. JAMA. 1965;193(2):163-164.
  2. Roberts TK et al.  Interpreting Laboratory Results in Transgender Patients on Hormone Therapy. The American Journal of Medicine. 2014; 127(2): 159-162.
  3. 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
  4. SoRelle JA, Jiao R, Gao E et al. Impact of Hormone Therapy on Laboratory Values in Transgender Patients. Clin Chem. 2019; 65(1): 170-179.

-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.

Albumin Values in Transgender Men and Women

This month our study results were published in a special edition of Clinical Chemistry describing how laboratory values in transgender men and women when taking hormone therapy. While retrospective, we hope that this information will help improve transgender medicine.

There were many interesting results found in the study and I hope to describe bits of them in greater detail each month.

We wondered what we might find if we took a broad, unbiased approach comparing all laboratory parameters commonly measured by physicians. Just because there are no sex-specific differences in analytes, changes could still occur secondary to exogenous hormone use.

Albumin, which is the principle protein in our blood, was found to be decreased in transgender women after taking at least 6 months of estradiol therapy (p<0.0001)1. This was unexpected, because one reference range for albumin is used for cisgender males and females.

Frequently, changes in lab values move in opposite directions for transgender patients taking estradiol vs. testosterone (ex. hemoglobin goes up with testosterone and down with estradiol). We wondered if a similar opposite change might occur in albumin for transgender men taking testosterone. However, there was no change in albumin levels from baseline for transgender men.

The cause of decreased albumin was not readily available, but several factors could be influential. Albumin levels reflect the long term nutritional status of a patient as it has a long half life for turnover (t½= 3-4 weeks). Thus, the change in albumin could reflect a dietary change in transgender women. However, in the chart review there was nothing to suggest a substantial change in diet. While several of the patients would go on diets and lose weight, the weight loss was (unfortunately) often short lived (< 1 year). Looking towards a more objective reflection of dietary changes, the body mass index was nearly the same for transgender women pre-hormone therapy vs. while on hormone therapy (BMI: 27 vs 29, p>0.05).

Some studies have shown an increased prevalence of disordered eating behaviors among transgender individuals2, which could affect overall nutritional status as reflected in albumin. However, this should be controlled for by the control group, which is just transgender patients who haven’t taken hormones previously. 

Another consideration is that body composition changes in transgender patients such that transgender women lose lean mass and have an increase in body fat percent3. Although this could affect the metabolic profile (which it didn’t in our study), changes in fat percent don’t explain altered albumin levels.

Albumin levels are also low in patients with chronic liver disease, but this would be inconsistent with the patients’ medical history or other lab results. Frank nephrotic syndrome is unlikely as there were no reports of this disease within our population, but we did not have data on urinalysis, so we can’t say for certain.

One study did show that males (TW baseline equivalent) have higher albumin than females at younger ages (<60 y.o.) that equilibrates in later decades4. This sex-specific difference shows how estradiol decreases albumin to cisgender female levels. However, the reverse effect (increased albumin) does not occur with testosterone in transgender males. This demonstrates how sex-specific reference intervals cannot be simply reversed for transgender patients.

In a normal set of outpatients in the UK, oral contraception use (which includes estradiol) in women decreased their albumin levels by 0.2 g/dL, which is a smaller magnitude than found in our study, but supports a hormonal basis for sex-specific differences in albumin4.

Although the decrease in albumin for our cohort was not clinically significant (did not pass lower limit of normal albumin reference interval), it would be important to monitor albumin levels in older or elderly transgender females on hormone therapy. Elderly patients are at increased risk of hypoalbuminemia, especially when hospitalized5.

Summary:

  1. Albumin is decreased in transgender women taking estradiol therapy.
  2. Albumin levels do not fall below normal ranges.
  3. This could be more important in older or elderly transgender patients who are already at risk of hypoalbuminemia.

References

  1. SoRelle JA, Jiao R, Gao E et al. Impact of Hormone Therapy on Laboratory Values in Transgender Patients. Clin Chem. 2019; 65(1): 170-179.
  2. Diemer EW, Grant JD, Munn-Chernoff MA et al. Gender Identity, Sexual Orientation, and Eating-Related Pathology in a National Sample of College Students. J Adolesc Health. 2015; 57(2):144-9.
  3. Auer MK, Cecil A, Roepke Y et al. 12-months metabolic changes among gender dysphoric individuals under cross-sex hormone treatment: a targeted metabolomics study. Sci Rep. 2016; 6: 37005.
  4. Weaving G, Batstone GF, Jones RG. Age and sex variation in serum albumin concentration: an observational study. Annals of Clinical Biochemistry 2016, Vol. 53(1) 106–111.
  5. Cabrerizo S, Cuadras D, Gomez-Busto F et al. Serum albumin and health in older people: Review and meta analysis. Maturitas. 2015; 81(1):17-27.

-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 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).1 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:

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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.

 

SoRelle Picture

-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.