Severe Vasomotor Symptoms Post-Oophorectomy Despite Testosterone Therapy in a Transgender Man: A Unique Case Study.

Vasomotor symptoms (VMS), such as hot flashes and night sweats, are intense and rapid sensations of internal heat, peripheral vasodilation, and profuse sweating that can be debilitating. They occur as a result of central norepinephrine discharge and narrowing of the core body thermoneutral zone with dropping brain estrogen levels in women and men. Therapy options for the treatment of VMS in postmenopausal women have been widely studied. However, we address treatment strategies for VMS that occur in some transgender men who have undergone oophorectomy. A 35-year-old female-to-male transgender man presented with symptoms of severe and frequent VMS that began shortly after total hysterectomy and oophorectomy. The patient was treated with a stable dose of testosterone for gender affirmation, and previous attempts to increase his testosterone dose did not relieve the VMS. In addition to his testosterone therapy, 0.025 to 0.0375 mg, twice per week, of transdermal estradiol was added to his hormonal regimen. Addition of estradiol completely relieved the VMS, and masculinization was not affected. Discontinuation of estradiol led to the recurrence of VMS at the same severity as previously experienced, which was associated with a low level of serum estrogen. VMS in a transgender man taking testosterone were successfully treated with the addition of transdermal estradiol.

1. Case Report

A 35-year-old transgender man (natal female with a male gender identity) presented for continuation of testosterone therapy and severe and frequent vasomotor symptoms (VMS) that began after hysterectomy and oophorectomy. The patient measured 162.6 cm in height and weighed 77.3 kg (body mass index 26.59). He reported the severity of the hot flashes was significantly interfering with his daily quality of life. He reported having a hot flash at least once an hour, >10 times a day, and sometimes during the night (>50 VMS/week). He reported no extraordinary social or economic stressors. The patient is a plumber and lives with his wife and son. A previous provider had increased testosterone therapy from 100 mg IM every 2 weeks to 150 mg IM testosterone cypionate every 2 weeks with no improvement in symptoms, as well as worsening of his acne. The patient’s testosterone level was 853 ng/mL (male testosterone reference range: 240 to 950 ng/dL) at that time (not a trough level). His testosterone dose was subsequently reduced back to his prior regimen. Next, his testosterone regimen was split into weekly doses (50 mg IM testosterone weekly) to avoid peaks and troughs. Nonetheless, his symptoms of hot flashes persisted on a regular basis. A nonhormonal treatment option was pursued with a serotonin-norepinephrine reuptake inhibitor (venlafaxine 75 mg daily). However, he discontinued venlafaxine after a few days as a result of intolerable side effects of drowsiness and jitteriness. The efficacy of nonhormonal and hormonal therapies in natal (cis) postmenopausal women was discussed with the patient, and he asked to try estrogen despite the lack of evidence for its use for VMS in transmen. An estradiol transdermal patch of 0.025 mg/week was started with substantial improvement in symptoms, but the effects only lasted ∼3 days. The patch frequency was increased to 0.025 mg, twice a week, with continued improvement of symptoms throughout the week. The increase of the dose to 0.0375 mg, twice a week, led to the complete resolution of hot flashes. Testosterone dosing was continued at 50 mg IM testosterone cypionate every week. Laboratories performed while the patient was on testosterone and estradiol showed trough levels of testosterone between 388 and 851 ng/dL over the subsequent 6 months (reference range for testosterone in females: <60 ng/dL; males: 240 to 950 ng/dL). Estradiol levels were checked at one time point during this period of symptom remission on dual therapy and were 4.3 ng/dL (reference range for estradiol in females: 30 to 40 ng/dL; males 1 to 6 ng/dL). A period of estrogen therapy interruption as a result of insurance coverage issues led to the recurrence of hot flashes that were of the same intensity as before estrogen initiation within 48 hours of therapy interruption. Laboratories drawn during this window confirmed a low level of circulating estradiol (0.9 ng/dL).

2. Discussion

Treatment of hot flashes in a transgender man who has undergone oophorectomy is reported here with a case of the successful use of hormonal therapy in a transgender man taking testosterone. Treatment strategies involving an increased dose of testosterone, the splitting of the testosterone dose, or the use of a serotonin-norepinephrine reuptake inhibitor were not successful. In contrast, the addition of transdermal estradiol was extremely effective at stopping his symptoms of debilitating hot flashes.

This case highlights the effects of dual estrogen and testosterone therapy in a transgender man. In natal men, elevated levels of estrogen have been found in the setting of obesity as a result of increased aromatization of testosterone to estradiol [1]. Furthermore, data from Low T Centers across the United States have shown high levels of estradiol in men who use injectable testosterone therapy [2]. However, in our patient, treatment with testosterone alone did not relieve VMS. There is some evidence that in natal men exogenous estrogen does not cause harm [3]. Treatment of cis males with estrogen has been in practice for the goal of chemical castration in prostate cancer. These doses typically are given as 30 mg of estradiol every 1 to 2 weeks. Side effects associated with this treatment include gynecomastia and dermatological problems (pruritis, eczema, and urticaria) [4, 5]. Increased cardiovascular events and venous thromboembolism events that were previously reported with estrogen use have decreased with a change of the route of estrogen administration from oral to parenteral or transdermal [6]. In androgen-suppressed men, antiandrogen hormone therapy, such as estrogens and progestins, has shown therapeutic efficacy for the treatment of hot flashes [7, 8]. In women, estrogen remains the gold standard for elimination of VMS [9]. However, not all patients are candidates for therapy. A randomized double-blind trial that compared medroxyprogesterone with oral estrogen for treatment of VMS found that they were equally effective at treating VMS in women immediately postoophorectomy [10]. Furthermore, unlike estrogen, oral micronized progesterone does not cause a withdrawal increase in VMS [11, 12]. Therefore, medroxyprogesterone appears to be an effective alternative to treat VMS and would have been another potential option in our patient. We chose to continue to treat our patient with estradiol, given his very low circulating estradiol levels, even for the male reference range. Testosterone was dosed with the goal of the maintenance of testosterone levels within the range for his affirmed sex. In our patient, the addition of estradiol presented a particularly unique challenge, because treatment with his gonadal/genetic sex hormone appears to contradict the goal of providing gender-affirming hormone therapy. In this clinical case, the provision of a small dose of estradiol eliminated his VMS but also resulted in levels of estrogen within the normal range for males, his affirmed sex. Since initiation of estradiol over 1 year ago, he has not experienced gynecomastia or other reported undesirable side effects.

Here, we report a case of treatment of VMS in a transgender man without ovaries with his genetic/gonadal sex hormones to alleviate severe and frequent VMS associated with surgical menopause. We agree with the recent clinical practice guidelines put forth by the Endocrine Society for the treatment of those with gender dysphoria, which recommends a thorough discussion with the patient in determining the medical necessity of including both an oophorectomy with a total hysterectomy as part of gender-affirming surgery [13]. As part of this discussion, we recommend that potential adverse effects of complete depletion of gonadal hormones, including symptoms of hot flashes, also be discussed with patients who are contemplating oophorectomy as part of gender-reaffirming surgery.