Hormones and Thrombosis, heart attack, stroke risk - sources?

[anjaq]

Hello.

I have run into this quite a few times and want to know where it comes from. A common conception is that "hormone therapy" means one has an increased risk of thrombosis, heart diseases, heart attack, stroke. For that reason many have to stop hormone treatment before any surgeries, others cannot get hormone treatment if they have risk factors like a heart attack or thrombosis in the past.

Now as I understand it, women usually have less risk of heart attacks or strokes and only a slightly increased risk of thrombosis compared to men, so I dont see the hormones in the body to be the problem with this. Any other woman cannot stop her body from producing hormones before a surgery or after a heart attack either.

My educated guess is now that this concept comes from certain ways of "hormone" treatment, which often include non-bioidentical substances instead of hormones. Ethinylestradiol or Progestins are examples, Premarin - horse estrogens - another one. Also included are antiandrogens of various sorts. All of this is lumped together into "hormone therapy" and my thought is that it is not the hormones in the blood that cause these risks, but rather a) the other stuff besides bioidentical hormones that is added and b) the way hormones are delivered. Mainly because the oral route increases total estrogen to up to 10 times the level of estradiol, which is the effective estrogen for hormone therapy and also the only one analyzed regularly.

does anyone have knowledge on where this concept of hormone treatment increasing all of these risks comes from?

Thanks

[Jenna Marie]

It actually comes largely from cis women, believe it or not - exogenous hormones have risks that endogenously produced hormones do not. Cis girls and women typically have to stop birth control or HRT before surgery, too... and since very little has been studied about trans HRT, there's an overriding presumption that the risks, etc. are similar to those of extensively studied cis women.  (This may not be true, but it's probably safer to assume that than the reverse, so doctors tend to err on the side of caution.)

[jesse]

estrogen has been demonstrated to increase the risk of blood clotting factors in the liver on the first pass  http://www.trans-health.com/2003/androgens-under-the-hood/ this link is a full discussion on the topic this risk extends to females as well which is why injections are preferable or if taking oral medication under the tongue dissolving of it to avoid the liver.  source from transgender hormone therapy primer by Dr Vasquez "Estrogens have long been tied to problems with circulation and blood clots. Studies have shown that estrogen encourages the production of blood clotting factors in the liver. THIS IS IMPORTANT. If you are a woman, trans or non-trans, taking estrogen replacement, please pay attention to the symptoms of blood clotting that your physician should have warned you about when s/he prescribed them to you. Blood clots can be very dangerous, even fatal.

What does this have to do with oral drugs? Drugs that are consumed orally undergo an initial pass through the liver. As I mentioned above, the liver is the place in which the clotting factors in question are produced. Injectable preparations do not pass through the liver in the same way, and therefore they do not have the same degree of risk for clotting."

[anjaq]

Thanks. Both your posts support the theory I was descibing - that it is not estrogen (or progesterone) which is part of a hormone therapy that causes these risk factors, but that these studies and assumptions (and precautions) are based largely (if not solely?) on oral administration of estrogens. Most that I have found written so far was referencing to oral contraceptives (some of which contain Ethinylestradiol or Cyproterone Acetate or other Progestins which is a different chapter in any case) or oral hormone replacement.
I would find it saddening that some people are denied hormone therapy completely (so sad!) and others need to make a many week long stressful break which brings the body out of balance right before a big surgery - based mainly on the fact that oral contraceptives are increasing risk factors in women. Could it be that easy and simply taking patches, Gel or injectables and avoiding progestins, Ethinylestradiol and Antiandrogens would mean one can avoid these risk factors?

[Eva]

Hi Anjaq I can tell you when I had my VFS I didnt stop anything and they had my complete list of meds... I take EV injections, spiro, dutasteride and bio identical P... They just said stop the spiro and dutas the night before and the date of my surgery... I was OK

Now I have FFS booked and they are saying to stop ALL HRT including spiro two weeks before and a week after surgery Not real excited about that at all , especially being pre op

[ReDucks]

I was told 1-2 days after to restart.  I am off since 1/1, and while I understand the silliness of it (women don't have hysterectomy b4 surgery) I'm ok following the rules.  nothing bad happened over the past 2 weeks from stopping, and I don't feel it is likely I will "educate" anyone on this so why fight it?

the micro-surgery affects such small vessels that I don't think any studies have addressed clotting at this micro a level.  studies about mortality and major complications would never pick up a clot that in VFS may be more impactful than in a less critical and undamaged area.  my $.02

[HughE]

According to this page:

http://www.hrpca.org/estrogens.htm

(which is actually about DES in prostate cancer treatment, but should be equally applicable outside that) 

"the use of an estrogen should MANDATE anti-coagulation when the estrogen is given orally. This is because oral use of estrogenic compounds results in AT3 deficiency and this increases the risk of thrombosis. This potential adverse effect is prevented by the use of Coumadin (warfarin).   It is not prevented by aspirin."
AT3 deficiency:  AT3 is a vitamin - K - dependent glycoprotein which inactivates various coagulation  factors, including thrombin. AT3 = Antithrombin III.

I've seen similar things said elsewhere too - all oral estrogens (even EV) carry an increased risk of thromboembolism, due to first pass effects in the liver.

In general, you get a lot less side effects from hormones via IM injection than orally, more consistent absorbtion and less stress on the liver. With transdermal hormones you avoid the first pass effects too, although there's still a lot more variability in absorbtion than via the IM route (and creams, gels and patches tend to cost a lot more too).

Unfortunately, doctors tend to go with what's most convenient for them, which is handing out tablets.

[Cindy]

I'm on implants, you don't go off implants for surgery, but surgeons like to wait until E is low, same for ciswomen and elective surgery.  Most surgeons like to reduce risk in anyway they can for any procedure.

[Lara1969]

Pregnant do have very high level of hormons. During pregnancy the high levels are not associated with a higher risk of clodding and strokes. Although in the week after birth the risk is much higher than normal. Therefor a sharp drop of the level may increase risks.

It seems to me that a high level of bio-identical hormons is not risky if there is no genetic disposition.

Lara

[PrincessDayna]

WEll, im my EV, and then again in my EC, there is a pamphlet in each little box, and it holds the warning statement and statistics on it as well as age groups in the study they used- on each of your mentioned issues. If no one posts this stuff up tomorrow and I remember- I will be sure to post that info for you! <3

[Ruth Ruthless]

According to this page:

http://www.hrpca.org/estrogens.htm

(which is actually about DES in prostate cancer treatment, but should be equally applicable outside that) 

"the use of an estrogen should MANDATE anti-coagulation when the estrogen is given orally. This is because oral use of estrogenic compounds results in AT3 deficiency and this increases the risk of thrombosis. This potential adverse effect is prevented by the use of Coumadin (warfarin).   It is not prevented by aspirin."
AT3 deficiency:  AT3 is a vitamin - K - dependent glycoprotein which inactivates various coagulation  factors, including thrombin. AT3 = Antithrombin III.

I've seen similar things said elsewhere too - all oral estrogens (even EV) carry an increased risk of thromboembolism, due to first pass effects in the liver.

In general, you get a lot less side effects from hormones via IM injection than orally, more consistent absorbtion and less stress on the liver. With transdermal hormones you avoid the first pass effects too, although there's still a lot more variability in absorbtion than via the IM route (and creams, gels and patches tend to cost a lot more too).

Unfortunately, doctors tend to go with what's most convenient for them, which is handing out tablets.

I eat lots of fruits and vegetables, including lots of greens so I often get 6-7 times the required daily intake of vitamin K, can the body make AT3 from vitamin K or is AT3 just dependant on K and needs to be in the body as well?

Also, I recently switched to gel and my e levels have been lower than with pills. So you're saying I get the same health benefit of injections but less actual e levels than I would with injection? Also, isn't there a danger to getting lots of e at once from injection instead of daily bit by bit?

[HughE]

I eat lots of fruits and vegetables, including lots of greens so I often get 6-7 times the required daily intake of vitamin K, can the body make AT3 from vitamin K or is AT3 just dependant on K and needs to be in the body as well?

I've read elsewhere that all oral estrogens raise the risk of clotting due to first pass effects in the liver, and that excerpt just provides what sounds like a plausible explanation for why it happens. All I know about it is what's said in that page (which I'd originally come across in the course of trying to find out more about the link between DES and transsexuality).

Also, I recently switched to gel and my e levels have been lower than with pills. So you're saying I get the same health benefit of injections but less actual e levels than I would with injection? Also, isn't there a danger to getting lots of e at once from injection instead of daily bit by bit?

I'm not on full female HRT myself, and for me, the nonprescription hormone creams you can buy online have been enough, so I haven't explored the option of injectabl E or P. However, from what I've seen other people saying, you get the most bang for your buck with HRT from injections, and as long as you inject at least once a week, fairly stable hormone levels too. Injectable E isn't in the form of free estradiol, it's in ester form (either estradiol valerate or estradiol cypionate). The ester isn't an active hormone itself, instead it's an inactive compound that gradually breaks down in your body and only then releases its estradiol. So you don't get a sudden spike in E levels from it, instead the E is released gradually over the course of about a week to 10 days. As long as you inject it at least once a week then your hormone levels from it are apparently fairly stable. Progesterone has a shorter half life, so if you add an injectable form of that to your HRT, you need to inject it 2 or 3 times a week to get stable levels.

From what I've seen people saying, pills seem to cause a lot of problems with inconsistent absorbtion and hormone levels all over the place, plus you've got the risk of blood clots as well. I gather that gels and patches tend to end up costing a lot more than injectable EV and EC, they're more hassle and some people don't absorb them very well. Most trans folk I've seen talking about it who've tried all the different options seem to end up on injectable EV or EC.

[Ruth Ruthless]

Sticking a needle in me without doctor supervision seems a lot more scary and hassle than applying gel. Is there commonly a service where you can go to your local health care facility and they inject it for me?

[Ruth Ruthless]

I just asked a trans woman in my country, and she said they do the injections if I want, but they don't import or help pay for the injectable hormones. So I'd have to buy it myself and pay the full price. :\

[jessical]

< Link removed by moderator >

Talking to my Doctor about it she has never seen a case of blood clotting when the person was just on HRT.  But she has seen cases where there were other contributing medication, or the person was a smoker.

There seems to be great variation on this from surgeons and what they want the person to do, and how long.  For example I had my gallbladder removed in October.  They asked me if I did oral estradiol (I do patches), and if I smoke (I do not), and they were completely fine with me staying on HRT.  But for GCS surgeries it very common request.  I would like to understand why that is.

[Ruth Ruthless]

Perhaps longer recovery and more blood loss that can clot?

[Sabine]

echoing jessical from same source.

From July, 2014. It's a medical abstract, but you can follow it back. It addresses some of this discussion specifically for MTF.

< Link removed by moderator >

CHICAGO — Cross-sex hormone treatment of transgender adults leads to very few long-term side effects, according to the authors of the largest study to date to examine this issue.

More than 2000 patients from 15 US and European centers participated in the retrospective study, called Comorbidity and Side Effects of Cross-Sex Hormone Treatment in Transsexual Subjects, and nearly 1600 received at least 1 year of follow-up, the authors reported.

"Our results are very reassuring," principal investigator Henk Asscheman, MD, PhD, who heads HAJAP, his clinical research company in Amsterdam, the Netherlands, told Medscape Medical News. "There are mostly minor side effects and no new [adverse events] observed in this large population."

Speaking at ICE/ENDO 2014 last week, where he presented the initial results of the research, Dr. Asscheman said the data confirm findings from smaller studies published in the past decade.

"The take-home message," he said, "is that when using the guidelines from the Endocrine Society ["Endocrine Treatment of Transsexual Persons"], you are not going to see a lot of comorbidities with cross-sex hormone treatment...."


however:

..."The primary serious side effect, venous thromboembolism, occurred in 1% of persons undergoing male-to-female (MTF) transgender transition and was due to estrogen treatment.

"Dr. Asscheman said although this incidence is still high, it is lower than reported in the past."

As for the general expectation based on study of Cis women pre (meaning using HT as part of contraception)  and post menopausal HT, here is another source:

< Link removed by moderator >

Hormone Therapy and the Risk of Venous Thromboembolism

Holly L. Thacker

[extract, but the rest of the piece is helpful]

"Pathophysiology [this is in contraception]

"The factors and mechanism by which female hormones lead to a prothrombotic state are complex and not fully understood. Procoagulant factors include modest increases in the levels of factor VII, factor VIII, factor X, prothrombin, and fibrinogen, with associated decreases in the anticoagulant proteins including antithrombin and protein S. Using a thrombin-generation assay, it has been noted that women taking HC actually develop activated protein C resistance, which might provide an explanation for the increased thrombotic risk associated with HC users who are carriers of factor V Leiden mutation. It appears that the newer progestins, such as Desogestrel, might further activate protein C resistance.... "



[POST menopausal:]

Postmenopausal hormone therapy and venous thromboembolism

Some of the most recent evidence regarding the risk of VTE and PHT came from the terminated estrogen-progestin arm and estrogen-only arm of the WHI. Although the development of VTE was not one of the primary outcomes of this trial, multivariate analysis showed it to be the most significant risk. The use of PHT increased the risk of VTE twofold, which means PHT users have 34 VTE events annually per 10,000 women ver-sus 16 VTE events per 10,000 women who are not PHT users. The risk of VTE with PHT persisted throughout the 5-year study and was notably less in the estrogen-only arm (women with hysterectomy not needing a progestin).6

The ESTHER (EStrogen and THromboEmbolism Risk) study group, a French case-controlled study, reported that oral but not transdermal PHT estrogen was associated with increased risk of VTE in postmenopausal women.7 Their data suggest but do not confirm that transdermal estrogen may be safer than oral estrogen with respect to VTE risk. The original publication from the WHI indicated an increased risk for cardiovascular disease in PHT users. However, after central adjudication, these data did not show any significant increased risk for cardiovascular disease in PHT users. Obesity and oral HT in the context of inherited hypercoagulabilty in-creases risk of VTE while mutations carriers for factor V Leiden and PGM in the context of normal body mass index and transdermal HT do not appear to have any higher risk for VTE compared with mutation carrier controls not on any HT.

The estrogen formulations used in the postmenopausal state are used at a much lower dose than those used in HC and appear to have significantly lower biologic potency than HC. Although transdermal PHT is reported to be safer with respect to VTE, transdermal HC is reported to increase the risk of VTE at 4 to 8 per 10,000 women compared with 2 to 5 per 10,000 women using oral HC. This increase may be related to the higher total estrogen exposure. The SERM raloxifene (Evista), which is approved to prevent and treat postmenopausal osteoporosis, has been reported to increase the risk VTE twofold.

Early studies of PHT showed a slight increase in the risk of venous thrombosis, but subsequent studies did not repeat those findings. Only since the 1990s has a series of studies demonstrated that PHT users have a twofold to fourfold increased risk of venous thrombosis, and that PHT, regardless of duration of use, increases thrombosis risk. As with HC, studies have shown that the risk of VTE is highest during the first year of use.
Pathophysiology

The hemostatic effects of estrogens in oral PHT are similar to those in HC. All estrogens (oral or transdermal) seem to increase the levels of procoagulant factors VII, X, XII, and XIII and to decrease anticoagulant factors such as protein S and antithrombin, leading to a more procoagulant state not balanced by fibrinolytic activity.

Summary

    Any hormonal therapy, including hormonal contraception, postmenopausal hormone therapy, and selective estrogen receptor modulators (estrogen agonist estrogen antagonist), increases the risk for venous thromboembolism.
   
Factor V Leiden mutation, the most common cause of congenital hypercoagulability, increases the risk of venous thromboembolism. Factor V Leiden mutation with any hormone therapy increases the risk of VTE in a multiplicative fashion. However, most women with factor V Leiden who use hormone therapy do not suffer from venous thromboembolism. Transdermal PHT compared with oral PHT may have a more favorable risk-benefit ratio with respect to VTE.
   
Careful and individual risk-to-benefit analysis is needed in any woman needing hormone therapy.




As for method of delivery (from another source):

Does the route of administration for estrogen hormone therapy impact the risk of venous thromboembolism? Estradiol transdermal system versus oral estrogen-only hormone therapy.
Laliberté F1, Dea K, Duh MS, Kahler KH, Rolli M, Lefebvre P.
Author information
Abstract
OBJECTIVE:

The aim of this study was to quantify the magnitude of risk reduction for venous thromboembolism events associated with an estradiol transdermal system relative to oral estrogen-only hormone therapy agents.
METHODS:

A claims analysis was conducted using the Thomson Reuters MarketScan database from January 2002 to October 2009. Participants 35 years or older who were newly using an estradiol transdermal system or an oral estrogen-only hormone therapy with two or more dispensings were analyzed. Venous thromboembolism was defined as one or more diagnosis codes for deep vein thrombosis or pulmonary embolism. Cohorts of estradiol transdermal system and oral estrogen-only hormone therapy were matched 1:1 based on both exact factor and propensity score matching, and an incidence rate ratio was used to compare the rates of venous thromboembolism between the matched cohorts. Remaining baseline imbalances from matching were included as covariates in multivariate adjustments.
RESULTS:

Among the matched estradiol transdermal system and oral estrogen-only hormone therapy users (27,018 women in each group), the mean age of the cohorts was 48.9 years; in each cohort, 6,044 (22.4%) and 1,788 (6.6%) participants had a hysterectomy and an oophorectomy at baseline, respectively. A total of 115 estradiol transdermal system users developed venous thromboembolism, compared with 164 women in the estrogen-only hormone therapy cohort (unadjusted incidence rate ratio, 0.72; 95% CI, 0.57-0.91; P = 0.006). After adjustment for confounding factors, the incidence of venous thromboembolism remained significantly lower for estradiol transdermal system users than for estrogen-only hormone therapy users.
CONCLUSIONS:

This large population-based study suggests that participants receiving an estradiol transdermal system have a significantly lower incidence of venous thromboembolism than do participants receiving oral estrogen-only hormone therapy.

[Amy Chislett]

I had the seemingly odd experience of finasteride along with my marginal kidneys causing me atrial fibrillation.  I'm a little ticked at my doctor for not heads upping me on this.