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Bee Bennett, photographed in Casper, Wyoming, in 2016.

Randi Hutter Epstein

Bee Bennett, photographed in Casper, Wyoming, in 2016.

Randi Hutter Epstein

is a medical writer, lecturer at Yale University, writer in residence at Yale Medical School, and adjunct professor at Columbia University Graduate School of Journalism. Her articles have appeared in , , and , among others. Her latest book is (2018).

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Mel Wymore started taking testosterone just before menopause hit. As it turned out, he and his son went through puberty together. His son developed an Adam’s apple and a deeper voice first. ‘I trailed him,’ Mel said.

Mel, an engineer and community activist in New York City, had been divorced for nearly 10 years when he made the decision to start transitioning his appearance. ‘I sat down with the kids, and I pulled out an album of my childhood. I said: “You guys know that I’m not the typical mom because I date women, and you’ve seen me cut my hair short, and I’m discovering there is a boy inside of me that I’ve been hiding. I’m going to let that boy out.”’

Mel switched to a masculine wardrobe, restyled his hair into a traditional man’s cut, and wrapped his breasts to flatten them. ‘One of the first things I did was bind my breasts. It was such a relief to get rid of the bras and to masculate my feminine qualities.’

His children were supportive; they were 12 and 15 at the time. But Mel said they had no idea what was to come. Nor did he.

Mel, like others in the transgender community, believed with a deep-seated conviction that his female anatomy did not conform to the way he felt inside. That is not the same as sexual orientation, which is about desire. People in the trans community like to say that sexual orientation is whom you want to go to bed with; gender identity is who you go to bed as.

According to global surveys, between 0.3 and 0.6 per cent of people worldwide consider themselves transgender. A 2016 questionnaire in the United States yielded similar results, which would give a figure of at least 1.4 million transgender adults in the US. These numbers do not take into account people who are afraid to admit how they feel. It’s no surprise that the rate of people who identify as transgender appears to be higher in places with anti-discrimination laws.

Despite changes in MIC with amlodipine in the reduction group, no significant changes in ejection fraction were observed in these patients compared with patients treated with placebo ( Table 2 ). Absolute and relative changes in LIC were not significant in any of the study arms. In the reduction group, in which patients significantly reduced MIC, no significant differences in final LIC were seen at 12 months (11.7 [95% CI, 5.5-22.7] for amlodipine vs 13.1 [95% CI, 4.9-22.5] for placebo, P = .98). There was no significant change in serum ferritin values across the groups by the end of the study.

At 6 months, a subgroup of patients underwent MRI scans to assess MIC and LIC. Although not reaching statistical significance, the amlodipine-treated arm in the reduction group showed changes in MIC when compared with the placebo arm at this time point (−0.18 vs −0.06 mg/g, respectively, P = .16). In patients with MIC >1.16 mg/g (n = 7), median MIC at 6 months was significantly lower than baseline values (2.1 mg/g vs 2.6 mg/g, median difference −0.76 [95% CI, −1.14 to .31] mg/g, P = .047) in patients receiving amlodipine, with no significant differences in MIC in the placebo arm. No significant changes were observed in ejection fraction, LIC, or serum ferritin at this time point.

No patient died or was admitted because of cardiovascular complications during the trial. Four mild adverse events were reported in the amlodipine arm vs none in the placebo arm (13% vs 0%, P = .11; supplemental Table 3). Three patients (10%) in the amlodipine arm had their initial dose of 5 mg/day reduced to 2.5 mg/day because of mild ankle edema (2 patients) and dizziness (1 patient). All events subsided with dose reduction. One patient developed a mild cutaneous allergic reaction and stopped the medication after 15 days of use while continuing in the study. No significant cases of hypotension or bradycardia occurred in either of the groups during follow-up.

Discussion

The results of this study show that oral amlodipine reduces myocardial iron overload when added to standard iron chelation in TM patients with myocardial siderosis, subject to some statistical limitations. Amlodipine has been used as an antihypertensive agent for several decades in both adults and children with a well-known safety profile, low cost, and wide availability globally. This may suggest that our findings could be broadly applicable even at locations with more limited resources or experience, where a higher proportion of patients with myocardial siderosis are geographically situated. Because patient inclusion in this trial occurred in multiple sites and with few limiting inclusion or exclusion criteria, we believe that our findings can be generalized to a large percentage of patients with TM.

We found that amlodipine lowered levels of myocardial iron but did not affect iron storage in the liver or serum ferritin, which is compatible with the mechanisms by which the drug blocks iron uptake. Most of the hepatic and serum ferritin-bound iron does not depend on active uptake by voltage-gated channels, so blocking calcium channels was not expected to affect liver or ferritin-bound iron kinetics. One important aspect of the drug is that because of its long half-life of approximately 50 hours, at steady-state there are relatively small variations in plasma concentrations between doses. Therefore, the pharmacokinetics of amlodipine makes it suitable for single dosing any time of the day, allowing for continuous blockade of channels and thus possible prevention of labile plasma iron entrance into cell at all times.

Although we did not specifically evaluate iron excretion, blockade of calcium channels appears to increase the iron transport within the kidney by prolonging the activity of divalent metal transporter-1 channels and would favor the use of amlodipine especially with longer follow-ups. Although this mechanism of iron excretion is acknowledged, the majority of iron excreted will always be substantially derived by chelation. The allowed changes in chelation strategies during the trial might also have affected the differences observed in iron concentration in each of the organs studied. However, there were no significant differences in chelator strategies in the beginning of the study or in the proportion of patients changing chelators in each arm during follow-up. Supplemental Table 2 shows that most of the changes observed were from minor dose adjustments of current drugs and not substantial changes including switching of drugs or combination vs monotherapy modifications. If biases had indeed occurred, they would also favor treatment with amlodipine, considering that fewer patients in the treatment arm of the reduction group ended the study receiving combination therapy vs the placebo arm, despite the improvement of MIC only in the former. A separate analysis per iron chelator type would also be very interesting, but we thought this would not be feasible in this study because of the acknowledged sample size.

The reduction of 21.3% in MIC observed in patients with initial iron concentrations above the normal mean value represents a decrease of −0.26 mg/g in myocardial iron in 1 year and confirms the findings from the previous human pilot trial that showed an increase of 30% in heart T2*. This result is also in line with the experimental data that demonstrated that voltage-gated calcium-channel blockade appears to be very effective in the heart, reducing 45% of the iron uptake in mouse myocardial cells. In patients with more significant myocardial siderosis using the more clinically common cutoff for myocardial iron overload (T2* <20 ms, MIC >1.16 mg/g), this reduction was −0.92 mg/g, a greater drop than previously observed in patients with comparable initial MIC levels treated exclusively with iron chelators, in whom changes have been reported in the range of −0.26 to −0.89 mg/g. Interestingly, comparable reductions in MIC after 1 year of treatment had only been shown with either high-dose combination iron chelation therapy or intravenous, continuous deferoxamine. In patients with baseline myocardial T2* <20 ms that received amlodipine, despite the significant MIC reduction observed, only 25% of patients received combination therapy (vs 50% in the placebo group) and none received intravenous treatment, again suggesting a lack of bias in the chelation regimens interfering with the results. The findings on this group, despite the limited number of patients, reinforce the results found in the larger reduction group.

Limitations of this trial include the short observation period and the relatively small number of patients included to assess whether the addition of oral amlodipine can decrease the incidence of cardiovascular events in this population. Although our sample size calculation was based on previous experimental and pilot studies, that stratification was done after randomization, no block randomization was performed, and each subgroup was analyzed separately may have led to underpowering and possibility of confounders. This design imperfection has to be taken into account when analyzing our results, although we tried to circumvent these limitations by demonstrating the treatment–effect interactions and performing adequate statistical treatment to the data despite the reduced numbers. Previous randomized controlled studies in this area are relatively few and the number of patients in these studies is in accordance with our sample size as well. Nevertheless, we believe that the results, presented along with previous studies, allow us to reach the conclusions regarding the benefits of amlodipine.

One important clinical limitation that might have been affected by the reduced sample size was the observation that amlodipine did not increase left ventricular ejection fraction even in the reduction group. The relatively low prevalence of reduced ejection fraction or severe myocardial siderosis upon trial enrollment, limiting the power of the study to assess these outcomes, might have led to this lack of improvement because patients already started the trial with relatively high ejection fraction values with small ranges for improvement. Despite that, previous studies have established MIC as a strong and consistent surrogate for clinical outcomes with even small reductions of MIC associated with improved clinical outcomes. Future trials with patients, preferably with a higher degree of myocardial overload or even with established heart failure, might help indicate whether amlodipine can also improve global ventricular function. Patients who might benefit more from this therapy are exactly included in this group, as suggested by our results in the group with a T2* <20 ms (MIC >1.16 mg/g).

In the prevention groups, although there was no change in MIC in these patients, our data cannot rule out the possibility that extended use of amlodipine might prevent myocardial iron accumulation with a longer observation period. Although a T2* of 20 ms has traditionally been used as a clinical cutoff for relative normality, in practice the normal mean 1.5 T T2* value in the heart is considered 35 ms (corresponding to a MIC of 0.59 mg/g). Our rationale for choosing 35 ms as the stratification cutoff in this study was based on these normal human levels and on the median values for this entire cohort of patients of 34.1 ms (95% CI, 30.9-36.4 ms). In agreement with that, a recent study showed that patients with apparently normal T2* from 20 ms to 35 ms could present with lower myocardial native T1 values, which are associated with higher iron deposits in the myocardium, while no patient with a T2* >35 ms had abnormal T1 numbers. Therefore, although there would still be an expected improvement from 20 ms to 35 ms because abnormal iron deposition seems to be present, no further increases in T2* should be anticipated after those values are reached—when iron concentrations are very close to the normal threshold and other factors interfere with T2* relaxation time. Preventing an increase in MIC in patients with these initially normal values would certainly be desirable, and future studies with the use of amlodipine in longer follow-ups might address that hypothesis. Finally, future studies may also help investigate whether amlodipine can prevent iron overload or help iron removal in endocrine organs that also absorb iron through voltage-gated channels, particularly considering the close association of cardiac siderosis with endocrine complications and the correlation of pancreas and MICs.

In conclusion, the use of oral amlodipine in addition to standard chelation therapy can reduce myocardial iron more effectively than iron chelation alone in patients with TM and myocardial siderosis, and may be useful in patients with a cardiac T2* below 35 ms.

Authorship

Contribution: J.L.F was the principal investigator for the trial; S.R.L., M.P.A.V., K.Y.F., A.P., O.R.C., F.F.C., and S.T.S. were involved in the design of the trial; L.A.B.F. was involved in the analysis of the magnetic resonance imaging data; S.R.L., M.P.A.V., K.Y.F., G.R.B., D.M.T., T.H., and D.A.M. were involved in data collection and patient follow-up; and all authors contributed to the interpretation of the results and review of the manuscript.

Conflict-of-interest disclosure: J.L.F. reports personal fees from Novartis AG and Sanofi Aventis and nonfinancial support from Siemens AG, outside the submitted work. The remaining authors declare no competing financial interests.

Correspondence: Juliano L. Fernandes, Jose Michel Kalaf Research Institute, Av Jose de Souza Campos 840, Campinas, SP 13092-123, Brazil; e-mail: jlaraf@terra.com.br .

Acknowledgments

The authors are grateful for the assistance of ABRASTA (Brazilian Thalassemia Association) for help with patient communication and support and acknowledge the work of nurse Suzamar Braga Cabral in assembling part of the clinical database for the study.

This study was supported by the governmental funding agency Fundacao de Amparo a Pesquisa do Estado de São Paulo and the Sultan Bin Khalifa Translational Research Scholarship.

Footnotes

The online version of this article contains a data supplement.

Those who have had a sense of mission and accomplished great tasks have not necessarily had the full light of the gospel. Abraham Lincoln, who aspired to be a “most humble instrument in the hands of the Almighty” in the preservation of freedom in the United States, [43] was gravely concerned with the danger of a major defeat on northern soil in 1862 during the Civil War, and he sought the Lord in prayer. Making a solemn pledge before God that he would free the slaves if Lee were driven back, he issued the famous Emancipation Proclamation on September 22, following the Union victory at Fredericksburg. [44] Did the Lord raise up a Churchill to counter a Hitler? Winston S. Churchill was appointed British prime minister on May 10, 1940, the same day Adolf Hitler unleashed the might of the German Army and Air Force in the invasion of Holland and Belgium. “I was conscious of a profound sense of relief,” wrote Churchill. “I felt as if I were walking with Destiny, and that all my past life had been but a preparation for this hour.” [45] In the great plan of God, whom He “puts into the game” at any given moment may be decisive. God, the most intelligent being of the universe (see Abraham 3:18–19), is not only the great scientist but also the great manager and coach.

Migration of peoples. An eleventh means used by the Lord to accomplish His purposes is the migrations of peoples. To understand this, we must understand the covenants made to Abraham regarding his seed: that they would be holders of the priesthood and bearers of the gospel and that through them all the nations of the earth would be blessed (see Abraham 2:9–11). The children of Israel, through whom those promises continued, were warned that if they did not keep the commandments and statutes of God, they would be scattered among every nation, but they were promised that they would be gathered in, both to the knowledge of the gospel and to their lands of inheritance, in the last days (see Deuteronomy 28–30). Elder Bruce R. McConkie has stated: “‘If a complete history of the house of Israel were written, it would be the history of histories, the key of the world’s history for the past twenty centuries’ (Compendium 85) and more, for Israel has been scattered among all the nations of the earth and has acted as a leavening and enlightening influence wherever her scattered remnants have found lodgement ( Articles of Faith , 314–27).” [46]

The scattering of the house of Israel has taken place by a variety of means. The Jews mingled with neighboring people to some degree, and numerous small groups moved to near and far. As a people, the Jews were twice scattered, first by the Babylonians in about 585 BC, and then, the remnant having been reestablished in Palestine, again by the Romans with the sacking of Jerusalem in AD 70. Expelled from parts of western Europe in the late Middle Ages, many found refuge in Poland, from which significant numbers migrated to the United States toward the end of the nineteenth century in response to Russian persecution. Made in Italia Diamante Suede Heel auJYbXyD

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