Changing Demographics in Transgender Individuals Seeking Hormonal Therapy: Are Trans Women More Common Than Trans Men?

Introduction: The number of individuals seeking sex hormone therapy for gender dysphoria has been increasing. The prevalence gender dysphoria has recently been estimated as high as 390 to 460 per 100,000 with a consistently greater prevalence of trans women (MTF) than trans men (FTM). We report here the changing demographics encountered in our experience over the past 2 decades. Methods: We collected data on individuals receiving hormonal therapy in the transgender clinic at Albany Medical Center in upstate New York from 1990 to 2017. We analyzed temporal changes in the number, age, and gender identity of transgender individuals. Results: Through June 2017, a total of 421 transgender individuals were seen who initiated hormonal therapy after 1990. Over the past 25 years, there has been a significant increase in the number of individuals seen. The mean age at initiation has remained higher in MTF than in FTM but has decreased steadily in both groups with the overall average dropping <30 years since 2015 (27.5±10.6). Since 1990, there has been a steady increase in the percentage of FTM such that it is now equivalent to MTF. Conclusion: Consistent with many reports, we are seeing an increasing number of gender dysphoric individuals seeking hormonal therapy. The age at initiation has been dropping over the past 25 years, and we have seen a steady increase in the number of FTM such that the incidence now equals that of MTF. Possible reasons for these changes are discussed.

The Effect of Efavirenz on Estradiol Metabolism in Transgender Women.

The goal of hormonal therapy in treating gender dysphoria is to maintain cross-sex hormone levels in the normal physiological range for the desired gender. Estrogen is the mainstay of hormonal therapy for male to female transgender patients. Efavirenz, a non-nucleoside reverse-transcriptase inhibitor, has been one of the most commonly prescribed antiretroviral therapies (ARTs). However, this regimen has also given rise to the most clinically significant drug-drug interactions between ARTs and hormone-based contraceptives. We discuss here three transgender HIV-positive women in whom efavirenz effected the metabolism of orally administered estradiol (and probably medroxyprogesterone).

Hormonal Treatment of Transgender Women with Oral Estradiol.

Purpose: Maintaining cross-sex hormone levels in the normal physiologic range for the desired gender is the cornerstone of transgender hormonal therapy, but there are limited data on how to achieve this. We investigated the effectiveness of oral estradiol therapy in achieving this goal. Methods: We analyzed data on all transgender females seen in our clinic since 2008 treated with oral estradiol. We looked at the success of achieving serum levels of testosterone and 17-ß estradiol in the normal range on various doses of estradiol (with and without antiandrogens spironolactone and finasteride). Results: There was a positive correlation between estradiol dose and 17-ß estradiol, but testosterone suppression was less well correlated. Over 70% achieved treatment goals (adequate 17-ß estradiol levels and testosterone suppression) on 4 mg daily or more. Nearly a third of patients did not achieve adequate treatment goals on 6 or even 8 mg daily of estradiol. Spironolactone, but not finasteride, use was associated with impairment of obtaining desired 17-ß estradiol levels. Spironolactone did not enhance testosterone suppression, and finasteride was associated with higher testosterone levels. Conclusions: Oral estradiol was effective in achieving desired serum levels of 17-ß estradiol, but there was wide individual variability in the amount required. Oral estradiol alone was not infrequently unable to achieve adequate testosterone suppression. Spironolactone did not aid testosterone suppression and seemed to impair achievement of goal serum 17-ß estradiol levels. Testosterone levels were higher with finasteride use. We recommend that transgender women receiving estradiol therapy have hormone levels monitored so that therapy can be individualized.

Type B Insulin Resistance Masquerading as Ovarian Hyperthecosis.

Context: Hyperinsulinemia can lead to pathologic ovarian growth and androgen production. Case Description: A 29-year-old woman developed an autoantibody to the insulin receptor (type B insulin resistance), causing extreme insulin resistance and hyperinsulinemia. Testosterone levels were elevated to the adult male range. Treatment with gonadotropin-releasing hormone (GnRH) analog led to normalization of testosterone, despite persistent extreme insulin resistance. Conclusions: This case demonstrates that gonadotropins are necessary for insulin to cause pathologic ovarian androgen production. Suppression of gonadotropins with GnRH analogs may be a useful therapeutic option in patients with severe hyperandrogenism or ovarian enlargement because of hyperinsulinemia.

Lipid regulation in lipodystrophy versus the obesity-associated metabolic syndrome: the dissociation of HDL-C and triglycerides.

CONTEXT: There is an inverse relationship between triglycerides and high-density lipoprotein cholesterol (HDL-C) in insulin resistance, such that improvement in insulin resistance decreases triglycerides and increases HDL-C. Patients with lipodystrophy have extreme insulin resistance with high triglycerides and low HDL-C. Leptin replacement in lipodystrophy leads to a marked decrease in triglycerides (∼60%). OBJECTIVE: Our objective was to study the effects of metreleptin on triglycerides and HDL-C in lipodystrophy in contrast to changes in triglycerides and HDL-C in interventions for the obesity-associated metabolic syndrome. DESIGN, SETTING, AND PATIENTS: This open-label nonrandomized study at the National Institutes of Health included 82 patients with various forms of lipodystrophy. INTERVENTION: Metreleptin (0.06-0.24 mg/kg/d) was administered for 24 months in lipodystrophy. MAIN OUTCOME MEASURES: Serum triglycerides and HDL-C were measured. RESULTS: At baseline, lipodystrophy patients had low HDL-C (30 ± 1 mg/dL) and high triglycerides (961 ± 220 mg/dL) with an inverse relationship between the two (R = -0.37, P = .0006). There was no change in HDL-C with metreleptin despite major improvement in triglycerides, and individual changes in triglycerides only weakly predicted HDL-C change. On linear regression, in obesity, a decrease of 0.1 mg/dL in log(triglycerides) was associated with a 4.2 mg/dL rise in HDL-C, whereas in lipodystrophy, a decrease of 0.1 mg/dL in log(triglycerides) was associated with only a 0.6 mg/dL rise in HDL-C. CONCLUSIONS: The normal reciprocal relationship between triglyceride and HDL-C change seen in response to interventions for the obesity-associated metabolic syndrome is quantitatively different from that seen in lipodystrophy in response to metreleptin. Further work is needed to understand HDL-C regulation in this condition.

Effects of leptin replacement therapy on pancreatic ß-cell function in patients with lipodystrophy.

OBJECTIVE Leptin administration is known to directly modulate pancreatic ß-cell function in leptin-deficient rodent models. However, human studies examining the effects of leptin administration on ß-cell function are lacking. In this study, we examined the effects (16-20 weeks) of leptin replacement on ß-cell function in patients with lipodystrophy. RESEARCH DESIGN AND METHODS In a prospective, open-label, currently ongoing study, we studied the effects of leptin replacement on ß-cell function in 13 patients with congenital or acquired lipodystrophy. Insulin secretory rate (ISR) was calculated by C-peptide deconvolution from plasma glucose and C-peptide levels measured during oral glucose tolerance tests (OGTTs) performed at baseline and after 16-20 weeks of leptin replacement. ß-Cell glucose sensitivity and rate sensitivity were assessed by mathematical modeling of OGTT. RESULTS There was a significant decrease in triglycerides, free fatty acids, and glycosylated hemoglobin levels (A1C) after leptin therapy. Patients with lipodystrophy have high fasting and glucose-stimulated ISR. However, leptin therapy had no significant effect on fasting ISR, total insulin secretion during OGTT, ß-cell glucose sensitivity, rate sensitivity, or insulin clearance. CONCLUSIONS In contrast to the suppressive effects of leptin on ß-cell function in rodents, 16-20-week treatment with leptin in lipodystrophy patients did not significantly affect insulin secretion or ß-cell function in leptin-deficient individuals with lipodystrophy.