Volume 6, Number 2, 2002
New Onset of Type 2 Diabetes Mellitus with Feminizing Hormone Therapy: Case Series
Jamie Feldman, M.D., Ph.D.
The effects of hormone therapy on glucose tolerance in male-to-female transgender patients have not been specifically addressed in the medical literature. Three cases of new onset type 2 diabetes mellitus during the course of feminizing therapy are examined in light of current literature regarding sex hormones and glucose tolerance. Feminizing therapy may contribute to the onset of diabetes in male-to-female patients with concomitant risk factors. Further research is needed to evaluate the effect of feminizing regimens on glucose tolerance, and to elucidate which patients may benefit from regular screening during the course of therapy.
Keywords: type 2 diabetes mellitus, estrogen, transgender.
Diabetes mellitus (DM) affects over 7% of the adult US population, and the risk increases with age, obesity, and inactivity (American Diabetes Association, 2001). However, the effects of hormone therapy on glucose tolerance in male-to-female transgender patients have not been specifically addressed in the medical literature. Male-to-female patients often present for feminizing therapy over the age of 40, and thus carry independent risk factors for diabetes (Blanchard, 1994; van Kesteren et al., 1997). Feminizing hormone therapy itself can result in increased weight and body fat, contributing to glucose intolerance. This presentation will review three cases of new onset type 2 diabetes mellitus during the course of feminizing therapy. These cases will be examined in light of the current literature on sex hormones and glucose tolerance and their application to the transgender setting.
Beginning in autumn 1998, 117 transgender patients have received ongoing cross-gender hormone therapy at the University of Minnesota’s Center for Sexual Health (CSH). Seventy-four of these patients were male-to-female, with an average age of 41. All patients receive a full history, physical exam, and baseline labs prior to the onset of hormone therapy. These lab tests include a casual glucose, along with a HgbA1C if there is a personal or family history of glucose intolerance. Casual and/or fasting glucoses, in addition to other labs, are checked every three to six months during the first year of treatment, then every six to twelve months thereafter1. These labs are tracked across the course of treatment. Abnormal results are followed up either at CSH or in coordination with the patient’s primary care clinic. All medications, chronic medical conditions, and new diagnoses are tracked across the course of hormone treatment.
Between 1998 and 2001, three male-to-female patients developed new onset diabetes mellitus type 2 during the course of feminizing therapy, diagnosed by fasting glucoses greater than 126 mg/dl on at least two occasions (American Diabetes Association 2001 criteria). While the incidence of type 2 diabetes varies with ethnicity and age, the United States incidence is estimated at 3.7 per 1000 annually (Centers for Disease Control, 1997). Thus, the appearance of three cases in three years in this population is greater than expected.
All patients were white, between the ages of 41 and 53, and were significantly obese. Only one patient had a family history of type 2 diabetes, none in first degree relatives. Of note, all cases had hypertension and baseline hypertriglyceridemia (with or without high cholesterol), suggestive of the metabolic syndrome2.
This 41-year-old patient began hormone therapy with CEE (conjugated equine estrogen) .625 mg po daily. Other medications included atenolol and fluoxetine. The estrogen dose was increased over the course of seven months to 5 mg daily. Spironolactone 75 mg po daily, and norethindrone 5 mg po daily were added sequentially during this time (Table 2).
The patient gained 12 pounds (5.5 kg). She remained normoglycemic until approximately ten months into hormone therapy, when she was found to have elevated fasting glucoses on two occasions. Diabetic education and home glucose monitoring were instituted. Transdermal estradiol .1 mg weekly replaced oral estrogen in the regimen without significant impact on glycemic control. Glycemic data are summarized in Table 3.
Of note, the patient’s triglycerides increased from 214 to 566, coincident with the onset of hyperglycemia. TSH levels were normal during this period. Initially the patient’s diabetes was diet controlled, but her HgbA1C values continued to rise, coincident with increased doses of estrogen needed for feminization. Norethindrone was discontinued without significant impact on her glycemic control. She is currently on metformin 1500 mg po daily, transdermal estradiol .1 mg, and gemfibrozil for lipid management, atenolol, and fluoxetine.
This 48-year-old patient presented with a history of Wolf-Parkinson-White syndrome and depression, for which she took digoxin, quinidine, and sertraline. Her physical exam prior to starting hormones also revealed hypertension and hyperlipidemia, with a total cholesterol of 234 and triglycerides of 430. Simvastatin was begun for lipid control, but later discontinued due to gastrointestinal intolerance.
Despite a subsequent change from oral to transdermal estrogen (estradiol .1 mg patch), her HgbA1C values increased, although her fasting glucoses temporarily improved. The patient was initially started on metformin, but suffered gastrointestinal intolerance. Pioglitazone 15 mg po qd was then initiated for diabetic control, with subsequent normalization of the HbgA1C at 5.2%. The patient is currently maintained on pioglitazone, transdermal estrogen, spironolactone 200 mg po qd, finasteride 5 mg po qd, in addition to her initial chronic medications.
This 52-year-old patient presented with a history of untreated hypertension, and minimal contact with any primary care physician over the past decade. She does have a maternal aunt with type 2 diabetes, and a daughter with type 1 diabetes. In addition to her hypertension, she was found to have hypercholesterolemia, with a total cholesterol of 259 and LDL of 159. Spironolactone 50 mg po qd was begun for both feminizing and hypertensive management, with transdermal estradiol .05 mg q week added one month later. The estrogen dose was increased to .1mg, the spironolactone increased to 100 mg qd, and finasteride 5 mg po qd was added to the regimen within two months. The patient gained 22 pounds (10 kg) over the course of eight months, and developed elevated glucoses at that time (Table 3). The patient had limited follow-up, both at CSH and with a primary care physician, but has had a steadily increasing HgbA1C, at 6.3% at 12 months and 6.8% at eighteen months after initiating hormones. She has been attempting diet control of her diabetes, but with erratic medical follow-up. Her weight is now stable. Her hormone regimen is currently transdermal estradiol .1 mg q week, spironolactone 200 mg po qd, and finasteride 5 mg po qd.
The association between feminizing hormone therapy and alterations in glucose metabolism among transgender patients has not been well characterized. Multiple retrospective studies do not report an increase in diabetes with hormone therapy (van Kesteren et al., 1997; Schlatterer et al., 1998). Early type 2 diabetes is often asymptomatic, requiring glucose testing to detect, and it is unclear whether these studies specifically looked for diabetes. One longitudinal study (Meyer et al., 1986) showed no increase in diabetes. However, the study was not specifically designed for diabetes detection, and may not have had adequate power (N=60). Giltay et al. (1998) report increased insulin levels to transgender estrogen administration, though without change in insulin sensitivity (Giltay et al., 1998). There are no published studies directly examining insulinsensitivity or the response to glucose challenge in the transgender setting.
With the paucity of transgender-specific data, one may look to other settings for information. Oral contraceptive (OC) doses, in combination with endogenous estrogen and progestin production in women, can approximate feminizing therapy. The interaction between oral contraceptives and glucose tolerance has been studied. Russel-Briefel et al. (1987) demonstrated a 15.4% decreased glucose tolerance among oral contraceptive users. However two large, prospective studies (Chasan-Taber et al., 1997; Rimm et al., 1992) showed no increase in type 2 DM among current users, and a possible slight increase among past OC users. These studies suggest that although glucose tolerance may be affected by exogenous estrogen/progestin, its clinical impact is minimal. The applicability of these studies to the transgender setting is limited, however. Male-to-female patients presenting for hormone therapy are often older than women presenting for OCs, and may present with additional risk factors for diabetes. A study of glucose tolerance among hyperandrogenic women on oral contraceptives demonstrated a significant reduction in glucose tolerance and the development of diabetes in two of the sixteen women (Nader, Riad-Gabriel, and Saad, 1997). Thus, the presence of endogenous androgens may play an important role in glucose metabolism in the transgender setting.
The effects of estrogen and progestins on glucose tolerance have also been examined among post-menopausal women on hormone replacement therapy. Oral hormone replacement therapy, particularly combined estrogen and progesterone, appear to reduce glucose tolerance and increase insulin resistance. Transdermal estrogen may lessen this effect (Godsland et al., 1993; Espeland et al., 1998). However, prospective study (Manson et al., 1992) demonstrated no significant increase in diabetes with hormone replacement. The application of this data, however, is limited by the increased age and significantly lower hormones doses compared to the male-to-female transgender population.
Table 4 outlines the serum estradiol levels in the pre-menopausal and post-menopausal setting, as well as in response to common exogenous estrogens.
Adapted from O’Connell M., 1995 and Lobo R.A., 1987
Finally, one can examine the effects of sex steroids on glucose metabolism among type 2 diabetics. Glycemic control and insulin sensitivity varies during menstrual cycle (Gonzalez-Ortiz et al., 1998), and progestins in oral contraceptives or hormone replacement therapy may adversely affect glycemic control (Harvengt, 1992; Godsland et al., 1993). However, women with well-controlled diabetes demonstrate no change in glycemic control with estrogen replacement or oral contraceptives (Petersen et al., 1995; Fineberg, 2000; Cornu et al., 2000). Of note, male diabetics have lower testosterone levels, while female diabetics have higher testosterone and estradiol levels (Goodman-Gruen and Barrett-Connor, 2000; Christiensen et al., 1997).
In summary, there is little transgender specific evidence on glucose tolerance or diabetes with feminizing therapy. Evidence among women suggests estrogen and progestins affect glucose tolerance without increasing the risk of diabetes, but the applicability of these data to the transgender setting is limited. Sex steroid differences in male and female diabetics suggest further complexity in understanding the interaction of estrogen and progestins in the male-to-female patient.
Thus, health care providers should be aware of the risk of type 2 diabetes older, obese patients. Baseline screening should be strongly considered for patients with risk factors for diabetes or evidence of glucose intolerance. Feminizing therapy itself may increase the risk of diabetes among these patients, suggesting the need for periodic monitoring, perhaps every six months. Eliminating the use of progestins, minimizing estrogen doses, and aggressively managing weight gain may reduce the risk of diabetes during feminization. Finally, these three cases illustrate the need for specific research to clarify and minimize diabetes risk in a variety of feminizing regimens. Specific research is needed to identify which patients truly need to be screened, as well as the frequency of monitoring for glucose intolerance.
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