Parallel Lives: Endocrine Research & Gender Affirmation

Two studies from ENDO 2019 shed new light on gender dysphoria for patients undergoing gender-affirming surgery (GAS). A study of transgender women demonstrated the importance of hormone replacement after GAS while another study of transgender men showed that preserving ovarian reserve could allow for future reproduction.

The road to gender affirmation just got smoother, thanks to research from two studies presented at ENDO 2019. Millions of transgender people experience gender dysphoria, the profound incongruence between the gender a person is assigned at birth and the gender with which that person identifies. Gender affirming surgery (GAS) and cross-sex hormone therapy (CSHT) help to ease some of that conflict by better aligning the outward body and the inner self.

Although making that alignment happen can be fraught with obstacles, researchers are finding ways to hurdle them and bring both transgender women (male to female) and transgender men (female to male) closer to living the lives they want to lead.

Optimal Brain Function in Transgender Women

In “The Effects of Estradiol on The Resting-State Functional Connectivity of Transwomen Following Gender Affirming Surgery,” lead researcher Maiko Abel Schneider, PhD, of McMaster University in Hamilton, Ontario, Canada, and team looked at what happens to the brain during the transient period of hypogonadism that transgender women experience after undergoing GAS. Although estradiol is typically administered prior to GAS, many transgender women discontinue it post-surgery, possibly due to inconvenience, cost, or other factors. “My question was, if these individuals don’t institute estradiol after surgery, and they don’t have testosterone due to the gonadectomy, what would happen to the brain in the short term?” Schneider says. “So, we aimed to figure out how important it would be to replace estradiol instead of having no sex hormones after surgery.”

“Fertility issues should be addressed in transgender men, preferably before hormonal treatment initiation, but also subsequently, according to the patient’s wishes.” – Yona Greenman, MD, chair, Institute of Endocrinology and Metabolism, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel

Furthermore, although CSHT is known to affect brain anatomy and connectivity before the completion of GAS, investigation of these effects has, until now, been lacking. Schneider and team therefore evaluated the impact of CSHT on resting-state functional connectivity (rs-FC) in 18 post-GAS transgender women following GAS, using 3T functional magnetic resonance imaging (fMRI) both 30 days after CSHT washout and then again at 60 days following estradiol reinstitution. They used two approaches. First, they tested paired brain areas that they hypothesized would exhibit changes in connectivity patterns pre- and post-estradiol institution, specifically, the thalamus and the sensory motor cortex. As a second approach, they used a machine-learning algorithm, itself a two-step analysis, to identify which areas of the whole brain were more or less activated.

For part one of the study, they found that estradiol increased the coupling of the thalamus — the relay center for sensory and motricity stimuli — with the somatosensory cortex — the motor command high cortical areas of the brain. “When we tested the amount of oxygen that was consumed in these areas, we are looking for how similarly they are working — how connected they are. Our conclusion here is that replacing estradiol is important because it might avoid long-term clinical symptoms of hypogonadism that might be related to the ‘decoupling’ between those respective brain areas,” Schneider says. “There’s a lot of concern in menopause for mood disorders, fine motor asymmetry and lack of motor control, emotion regulation, or other maladaptive functioning of the brain if estradiol is not replaced after ovarian failure, which usually doesn’t occur until after age 50. Transgender women, on the other hand, face a potentially much longer period without sex hormones if they don’t replace them.

For part two of the study, the whole brain analysis, they identified brain regions that were more or less activated when replacing estradiol and found that the subcallosal gyrus (midbrain region) had a decreased activation in parts of the anatomical region when estradiol was replaced estradiol. Next, they looked at with which other regions of the brain this medial cluster region was connected or disconnected. “We found that after replacing estradiol, not only was activation within this region of the brain lower than other areas, we also found that this region was decoupled form another medial frontal region that is also involved in emotions,” Schneider explains.

The team’s next step will be working with clinical trials to test a larger sample size for a longer term as well as different types and formulations of hormones (e.g., oral versus transdermal formulations, pure estradiol versus estradiol plus progestin), and a long-term comparison of clinical effects, not just a 30 days of hypogonadism versus replacing sex hormones. “We expect similar results — that replacing sex hormones will be healthier for the brain and that brain aging can be delayed with hormone replacement therapy in transgender women, which could be potentially translated to menopausal women,” Schneider says. “This might be a good opportunity to translate knowledge, not only knowledge for the transgender population but also for non-transgender women.”

Fertility in Transgender Men

In “Evidence for Preserved Ovarian Reserve in Transgender Men Receiving Testosterone Therapy: Anti-Mullerian Hormone Serum Levels Decrease Modestly After One Year of Treatment,” lead investigator, Yona Greenman, MD, chair of the Institute of Endocrinology and Metabolism at Tel Aviv-Sourasky Medical Center in Israel, and team studied markers of ovarian reserve in a cohort of 52 transgender men. Although successful pregnancies in transgender men have been reported, this study is the first to look closely at how long-term testosterone therapy affects fertility, a very important consideration for transgender men.

Of the cohort, 32% were in a stable relationship, 17% expressed desire to have children, 50% were unsure about future parenthood, and 7% had already undergone fertility preservation procedures (egg retrieval and cryopreservation).

In the course of 12 months of treatment, participants received either intramuscular injections of 250 mg of testosterone enanthate about every three weeks, with dose adjustments depending on serum levels of testosterone, or transdermal treatment with daily testosterone gel application. Researchers took blood samples to measure anti-Müllerian hormone (AMH), gonadotropins, and sex steroid serum levels as well as determined endometrial thickness and antral follicular count by pelvic ultrasound at baseline and at the 12-month treatment mark.

In the 32 participants for whom complete data was available, AMH levels decreased slightly from about 5.65 ng/ml at baseline to about 4.89 ng/ml, and antral follicular count and endometrial thickness did not change. As the researchers expected, testosterone levels increased from about 0.84 ng/ml to 7.0 ng/ml, and estradiol levels decreased from about 90.8 pg/ml to 55.4 pg/ml during therapy. These changes brought a concomitant decrease in luteinizing hormone level from about 7.56 mIU/ml to 3.8 mIU/ml, but not a significant decrease in follicle-stimulating hormone level. “According to our data, fertility seems to be preserved during the first year of testosterone treatment,” Greenman says.

However, what this ultimately means for fertility potential remains to be explored. Said Greenman: “Our plan now is to analyze the whole cohort, which was enlarged since our report at ENDO 2019,” Greenman says. “In addition, we collected data from patients being treated for different periods of time in our department. This will be a cross-sectional analysis in which we will see if there is any correlation between AMH levels and treatment length.”

“There’s a lot of concern in menopause for mood disorders, fine motor asymmetry and lack of motor control, emotion regulation, or other maladaptive functioning of the brain if estradiol is not replaced after ovarian failure, which usually doesn’t occur until after age 50. Transgender women, on the other hand, face a potentially much longer period without sex hormones if they don’t replace them.” – Maiko Abel Schneider, PhD, McMaster University, Hamilton, Ontario, Canada

An incidental finding of the current study was that 9% of participants who initially were sexually attracted to women became bisexual during testosterone treatment. This, too, might become a future area of exploration.

The bottom line is that this is an area of tremendous significance for individuals and couples and has implications for the clinicians who treat them. “Fertility issues should be addressed in transgender men, preferably before hormonal treatment initiation, but also subsequently, according to the patient’s wishes,” Greenman says.

-Horvath is a freelance writer based in Baltimore, Md. She wrote about the link between obesity and precocious puberty in boys in the July issue.