In this module, we will review the initiation and maintenance of transfeminine hormone therapy for transgender patients. The objectives for this module are to recognize the treatment regimens for transfeminine individuals and to recognize the potential risks of those regimens and ways to mitigate those risks. The thing to note for transfeminine hormone treatment is that while estradiol levels are relatively similar between men and women, testosterone levels are 10 times greater for men than for women. The result therefore is the current approach to therapy for transfeminine individuals is a blockade of some sort to that testosterone or that androgen in order to lower the levels from a typical male level to a typical female level. Also, key is to avoid a hypogonadism situation which would expose the transgender woman to bone loss. Therefore, estrogen is included as part of the regimen. As you'll see as we proceed through this module, estrogen actually serves a dual role in transgender women who are treated medically, both to be the sex steroids that is protecting bones and to feed back centrally in order to act as part of the mechanism to suppress the testosterone. On this slide, I've listed typical estrogen regimens and their doses. But I would like to accentuate two points. The first point I want to make on this slide is to observe the doses of the conventional products both the 17 beta estradiol, the pure estradiol that can be given orally to transgender women and is the most common oral preparation given along with conjugated estrogens. Some of you may know of the latter under the brand name Premarin that is used for postmenopausal women. Notice that the doses that are used for transgender women are larger than the doses that are typically reported to be given to non-transgender women. I will point out that there isn't very significant monitoring of non-transgender women given estrogens and so it is possible that these are the more appropriate doses that should be used for all women, non-transgender women as well. But for those of us who are used to the lower numbers, we should recognize that numbers like these up to six milligrams or perhaps, even eight or even 10 milligrams of estradiol along with comparable numbers for conjugative estrogens, 7.5 milligrams or even 10 milligrams a day would not be unusual. The second point that I want to make is in regard to ethinyl estradiol, the main estrogen in birth control pills which had been the main estrogen used for transgender women. That turns out to be the best established estrogen in terms of its thrombogenesis risk. That is the one that is most associated with thrombosis or with blood clots. When we switched in the recent past to other estrogen preparations, the incidence of clot formation in transgender women seems to have decreased substantially and so the take-home message and recommendation from the Endocrine Society guidelines from 2017 is to avoid ethinyl estradiol as an estrogen preparation in treating transgender women. On this slide, I have listed the non-oral estrogen regimens, injectable and transdermal. I really can't say that there are data that argue strongly one way or another for your choice of estrogen product. But for the purposes of this module, I simply present all of the options and only tell you to avoid ethinyl estradiol. The estrogen treatment strategy includes estrogens to protect bone. But what I want to accentuate with this slide is a point I made a little earlier in the module which is to say that estrogen's feedback on the hypothalamus and the pituitary and act as part of the regimen that suppresses the testosterone which is an important goal of the hormone strategy for transgender women. The Endocrine Society guidelines point out that thromboembolic disease is the most concerning risk for estrogen therapy because it is the best established and potentially the most catastrophic especially if it results in pulmonary embolism or stroke. But while catastrophic, the actual risk is quite small. Data for transgender women are few but the best study to look at this topic prospectively is one from the journal for sexual medicine where just shy of 700 transgender women were followed over two years with oral estradiol and there was only one recorded thrombotic event among all of these individuals. In terms of numbers, the best paper is from Annals of Internal Medicine from the summer of 2018 where nearly 5,000 transgender individuals and nearly 100,000 non-transgender individuals were compared, and it was observed that regardless of the controls and regardless of the number of years of follow up, there was an increased risk of thrombosis in the treated transgender women that is relative to non-transgender men and relative to non-transgender women and then both at two years of follow up and at eight years of follow-up. The risk is significant and it is relatively large but the total number of events across this entire study was just shy of 150. So, while the risk seems to be present, it does not seem to be that high for a given individual. Indeed, when we look at older literature, the most important thing to observe is with data from Louis Guerin in the Netherlands where with ethinyl estradiol, they observed a six to eight percent incidence of thrombotic events. When their program switched to estradiol alone as their estrogen of choice, they could no longer observe an increase in that venous thromboembolism and that is with a patient cohort of over 2,000 transgender women. Although the difference observed with great numbers of women over a very extended period of time suggests that the difference really is there. Even though with a relatively large clinic, the difference is too small to identify a specific difference relative to individuals not being treated. So, the transgender regimen includes estrogens but also includes anti-androgens with a thought process being that they will facilitate using a slightly lower dose of estrogen and the thought being that perhaps, that will be modestly protective of this clotting risk even if the clotting risk is small. The agent of choice in United States is spironolactone and the only thing to notice here is that the dose required may be higher than is usual for blood pressure in the order of 100 to 400 milligrams per day with about 200 milligrams a day being the usual that is observed. Other anti-androgens are OK conceptually, including GnRH agonists such as leuprolide and progestins such as cyproterone acetate, which is used in Europe, although I would like to critique the ladder, and I will do so over the next few slides. For spironolactone, it is known that at pharmacologic levels, even though the purpose of spironolactone is to block the mineralocorticoid receptor, there is activity blocking the androgen receptor too. Therefore, the effect of testosterone is diminished. In addition, there is the observation that clinically, there is a decrease in testosterone in individuals receiving spironolactone. There is a small literature suggesting that metabolites of spironolactone can have that effect in vitro, which would support the clinical observation. With regard to progestins, it's true that they feed back negatively and lower testosterone. There is some reference to data where there is better areola development, although these data are not well controlled. Alternatively, progestins can be associated with some degree of virilization. So, the testosterone level may be lower, but the progestin may actually be having the testosterone effect which would not be getting your patient where she wants to be. Contrasts that with spironolactone, which may be a weaker anti-androgens and have less impact on lowering the levels, but also is known to have a downstream impact of blocking the androgen receptor so that your patient will be enjoying more benefit than would appear from the numbers. The most recent data on the subject of progestins that are transgender specific are from Europe, where it's observed that women receiving cyproterone acetate have slightly increased prolactin levels, which then go away when they no longer use that particular progestin. So, the concern about prolactin increases with transfeminine regimens, which exist in the guidelines, maybe owing to that particular progestin and not actually to the estrogen. If we think about it, the logic of progestins historically is to protect the endometrial lining, that is, the lining of the uterus in women with a uterus. So, we use them along with estrogens in post-menopausal women who still have their uterus intact. However, for post-menopausal women who have had a hysterectomy, their uterus removed for whatever reason, we give pure estrogen and we observe that there is less breast cancer and less heart disease in those women who take estrogen alone than those who take the combination product of estrogen plus progestins. This suggests that we would avoid progestins if we could. Transgender women, who have no uterus of course, therefore, should be avoiding progestin by that logic. Five-Alpha reductase inhibitors are popular among our patients. You will recall that they simply block conversion of testosterone to dihydrotestosterone in some tissues. This is not relevant in someone who is otherwise appropriately treated and has a female level testosterone to begin with. One could expect modest protection of scalp hair in individuals who have male levels of testosterone, but one would not predict much impact on someone who has female levels of testosterone circulating. GnRH agonists, which are also called puberty blockers, act centrally to shut down the entire reproductive access. It's a very clear mechanism, and they are effective. Safety in the very long term has not been established, although when we use these agents for fertility and for puberty blockade over a number of years in both circumstances, they appear quite safe. There is also the matter of them being costlier than other agents and that they need to be given by injection instead of as pills. When we observe bone density in individuals receiving GnRH agonists alone, we observe a decrement in bone density, which is not necessarily restored when they receive sex steroids later. In this particular graph, over on your left, you will observe baseline Z-scores; then in the middle bars, Z-scores for individuals who were given GnRH agonist alone; and then on the right, when these individuals receive sex steroids. Observe that they do not have a complete return to baseline. So, there is some concern for hypogonadism if a GnRH agonist is used alone. So, for transfeminine regimens, the main monitoring is of testosterone, to see if your patient is at goal. Estrogen-sensitive indexes should be monitor also, as well as potassium if you are using spironolactone as your primary adjunctive treatment to lower your estrogen dose if you can. Other cardiac-sensitive indexes, such as lipid profile and hemoglobin A1c, can make sense depending upon your patient. Prolactin sits in the Endocrine Society guidelines, but I would like to talk about that one since there are some new data since those guidelines came out. Then, importantly, tissues must be monitored independently of the gender identity of your patient. So, for transgender women, that would include a prostate. Remember that even if your patients have had a vaginoplasty, that is, genital reconstructive surgery, and the prostate is left intact, and some monitoring must be left in place for that prostate cancer concern. Then, of course, bone health monitoring is necessary for individuals who have had prolonged periods off of sex steroids for whatever reason. Monitoring for prolactin still sits in the Endocrine Society guidelines, as noted on this slide. But data following the United States regimen, where estrogen is supplemented with spironolactone as the adjunctive anti-androgen, demonstrates no change in prolactin levels that can be attributed to the transfeminine hormone regimen. So, it may be the case that the prolactin bumps that have been observed in the past will relate to the cyproterone acetate, that is, the progestin used in Europe, and that the American regimen does not result in a requirement to monitor prolactin levels. The only pitfalls that are well established for transfeminine hormone therapy are hypogonadism with its known risk to bone and possible metabolic concerns. In the case where there may be super-physiologic doses, too much estrogen, that is, then there is a thrombosis risk that is dose-response related, that that thrombosis risk will be unnecessarily accentuated with increased doses that are not achieving any known benefit. In this module, we reviewed the typical transfeminine hormone regimens along with monitoring strategies for some of the risks associated with those regimens. Thank you for joining me.