Transdermal Estradiol Reduces Risk of Venus Thromboembolism in Menopausal Hormone Replacement Therapy

Matched cohort study looks at risk reduction of using transdermal estrogen vs. oral in menopausal hormone therapy. (1) 

     In this matched cohort study of incidence of VTE in women using menopausal HRT, investigators attempted to quantify the risk reduction for VTE events associated with transdermal relative to oral estrogens.  Claims records from a health insurance database of 30 million people living in the US were reviewed over the period of January 2002 - October 2009 for patients who had received at least two dispensings of a transdermal or oral estradiol and were over age 35.  Users of other estrogens such as vaginal or injections and those with a prior VTE were excluded.  At total of 27,018 women were enrolled in each cohort.  Interestingly while only 22.4% of women in each cohort had undergone hysterectomy, a minority of the women were using a progestagen.  Primary outcome measures were the overall VTE risk as well as hospitalization-related VTE, as measured by incidence rate.

     Mean drug exposure times were 391 days for transdermal estrogen and 401 days for oral estrogens.    A total of 115 VTE events were encountered in the transdermal group vs. 164 in the oral group; a statistically significant difference.  Further analysis revealed more pronounced statistically significant reductions in VTE incidence among hospitalized women and reductions in PE incidence.

Comments:
 

     Yet another study highlighting the likely benefits of transdermal HRT with respect to VTE risk.  While this study did not compare incidence to a control population, overall VTE incidence in both cohorts was slightly higher than reported baseline incidences.  This raises the possibility of an overall skewing of the sample population, though it may not affect internal validity of the results.  It is noteworthy that the average times on HRT was just over 1 year in both cohorts;  given that the risk of VTE is highest in the first year of HRT, this may explain such skewing.  Further studies should compare oral vs. transdermal VTE incidences in those on longer term HRT when the overall VTE risk is lower, and specifically in transgender populations.  

     It is possible that there might be a skewing of results toward higher incidences of VTE as the investigators included all oral estrogen forms including conjugated equine estrogens in the oral therapy arm.

 

References:

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1) Laliberté F, Dea K, Duh MS, Kahler KH, Rolli M, Lefebvre P. Does the route of administration for estrogen hormone therapy impact the risk of venous thromboembolism? Estradiol transdermal system versus oral estrogen-only hormone therapy. Menopause. 2011 Oct;18(10):1052–9.

Transdermal Estrogen Safe With Respect to Venous Thromboembolism?

Oral estrogen shows increased risk of VTE, but transdermal does not in a French prospective cohort. (1)

     Several studies have suggested that route of estrogen administration can affect risk of venous thromboembolism (VTE) in women using postmenopausal hormone replacement therapy (HRT).  The authors reviewed data from a prospective cohort of French teachers born between years 1925 and 1950 who completed biennial self-administered questionnaires on a range of health issues.  In those who self-reported a thromoboembolic event, follow-up questions as well as a query of the subject’s physician(s) futher populated the data on such events.  Death certificates were reviewed for deceased subjects and revealed 68 additional events (all PE). Thromboembolic events (deep vein thrombosis (DVT) or pulmonary embolism (PE)) were included if they were diagnosed by an imaging procedure.  Exclusion criteria for events included superficial vein thromboses, upper-extremity DVT, central retinal vein obstruction and recurrent events.  Subject exclusion criteria were history of cancer, VTE prior to study period, recurrent VTE, or nonidopathic VTE. 

     A total of 549 incidents of VTE (415 DVT, 134 PE) were identified in 80,308 women who met inclusion criteria out of the total study enrollment of 98,995.  Of those 549 women with a VTE during the study perior, 181 were never users, 66 were past users, and 255 were current users of HRT.  An additional 47 women were using “other” or “unknown” treatments.  Progestagens were used in all but 26 of the women using HRT (micronized progesterone – 47, pregnane deriviatives – 91, norpregnane derivatives – 69, nortestosterone derivatives – 22).

     Mean age at the start of follow-up period was 54, with women followed over an average of 10.1 years.  The hazard ratio for VTE with oral estrogen use was 1.7 (95% CI: 1.1-2.8) and with transdermal estrogens was 1.1 (95% CI: 0.8-1.8).  Use of a norpregnane derivative was independently associated with an increased risk of VTE (HR 1.8, 95% CI: 1.2-2.7), while other progestagens were not. 

Comments:


     The investigators have obtained results consistent with prior studies (ESTHER) that suggest transdermal estrogens with or without a non-norpregnane progestagen may be safe with respect to VTE.  The current study has a number of limitations; it was a self-reporting survey with a non-trivial exclusion of almost one-fifth of respondents.  While 9.9% of respondents reported tobacco use (a known risk factor for VTE in HRT), the authors did not report prevalence of smokers in each arm of the study.  Since this was simply an observational cohort study, patients at higher risk of VTE based on their individual physician’s clinical impression may have guided the use of HRT type and route or may have prevented the use of HRT all together.  Lastly the study was funded by the manufacturer of a transdermal estrogen product. Nevertheless this study is yet another in a growing series of investigations which suggest that estrogen route and progestagen type can impact VTE risk.  While these results can not be generalized to transgender populations, they are suggestive and are helpful for guiding future research.  

     It is possible that there may be a skewing towards a higher incidence of VTE as the investigators did not separate out users of 17-beta estradiol vs. conjugated equine estrogens (Premarin).

References:

1) Canonico M, Fournier A, Carcaillon L, Olié V, Plu-Bureau G, Oger E, et al. Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism. Arteriosclerosis, thrombosis, and vascular biology. 2010;30(2):340–5

 

Transgender Men and HIV

Of 59 transmen presenting for HIV screening at public health clinics in San Francisco, none tested positive.  However the sample may not be representative of the population. (1)    

     Transgender men (transmen) may be at risk for HIV infection.  Transmen may have male sexual partners and therefore be identified as men who have sex with men (MSM).  Transmen may also have sex with transgender women (transwomen).  HIV prevalences in San Francisco, USA have been found to be 24% among MSM and 35% among transwomen.  Historically only a few cases of HIV in transmen have been reported in San Francisco.  The authors aimed to identify the prevalence of HIV among those transmen presented to one of 17 public health clinics in San Francisco during 2009.  These sites perform 25% of all HIV tests in the city.

     A total of 64 HIV tests were performed on 59 unique self-identified transmen in 2009 at these sites, representing 0.4% of all tests performed.  Median age was 27, with 79% ages 18-37.  Whites comprised 73% of the sample and 64% identified as gay/lesbian/queer.  With respect to sexual practices in the prior 12 months, 61% had a male sexual partner (51% vaginal receptive, 19% anal insertive, 39% anal receptive), 63% had female partners (55% vaginal or anal sex) and 47% had transgender partners (42% vaginal or anal sex); 44% had 6 or more sexual partners in the prior year.  Unprotected vaginal or anal sex was reported by 63% in the past 12 months, with 10% reporting having had vaginal or anal sex with a known HIV+ person.  None of the subjects tested positive for HIV (98% negative, 2% missing).

Comments:

     This study demonstrates a number of interesting findings.  First it confirms what is already anecdotally well known; that transmen have a range of sexual partners, practices and orientations.  It also demonstrates an absence of HIV in a population of transmen who are actively engaging in a variety of high risk behaviors.  This absence suggests that transmen are still in a “pre-epidemic” phase with respect to HIV and that there is substantial opportunity to develop HIV prevention measures targeting this population.  It also raises the question if there are factors (anatomical, functional, behavioral) that alter transmale succeptability to HIV infection to a level lower than that of other populations. 

     The study also has a number of limitations.  The study population was primarily white transmen between the ages of 18-35, and only comprised of 25% of all HIV tests performed in San Francisco during the study period.  Barriers may exist for younger transmen or transmen of color to accessing HIV testing at any location.  Older transmen may be more likely to have insurance and a primary care provider and seek testing at a private office.  Some transmen may not self-identify themselves when completing a survey.

     The study demonstrates the complexities and pitfalls of data collection on transgender populations.  The survey used contains numerous flaws and oversights with respect to demographics and sexual practices.  For example, sexual activity with a transgender person is not broken down by transmale/transfemale.  It is unclear if respondents identified transgender partners by their affirmed gender, their transgender status, or both.  It is assumed that by “man” and “woman” the researchers intended to refer to cisgender men and women – such assumptions are counter to the “two-step” recommendation for data collection (Step 1: “What was the sex you were assigned at birth?”; Step 2: “What is your gender identity?”) which allows a more complete and culturally sensitive collection of data.  Anal and vaginal sex with a transgender person or a woman (presumably cisgender) were grouped together and not qualified by insertive or receptive relative to the subject.  Further study with a greater level of detail with respect to demographics and sexual practices as well as a wider catchment of age ranges and ethnicities is essential to identify and manage HIV risks in transgender men.

References:


1) Chen S, McFarland W, Thompson HM, Raymond HF. Transmen in San Francisco: What do We Know from HIV Test Site Data? AIDS and Behavior. 2010 Dec 9;15(3):659–62

Hormone-treated transsexuals report less social distress, anxiety and depression

     Cross sectional, descriptive study of transsexuals in Spain suggests that cross-sex hormone therapy reduces symptoms of anxiety and depression, as well as social anxiety. (1)

     Most studies of the efficacy of trans related medical practices on reducing anxiety and depression have focused on surgical procedures.  Limited quantitative data exist on the role cross-sex hormone therapy (csHT) may play in reducing anxiety and depression independent of surgical interventions (THJC Nov 5, 2011).  This team of investigators at a single gender specialty center in Barcelona, Spain conducted a cross sectional, descriptive study of measures of anxiety, depression and social anxiety in 120 FTM and MTF transsexuals currently receiving csHT and 67 on a waiting list who were not yet treated.  Social anxiety was measured using the Social Anxiety and Distress Scale (SADS) and anxiety and depression were measured using the Hospital Anxiety and Depression Scale, both of which have been validated in Spanish.

     Results demonstrated that csHT was assosciated with lower scores of anxiety and depression as well as social anxiety.  A subgroup analysis of transsexuals on csHT who had also had a surgical intervention vs. those who had not showed no difference in scores on any of the scales.  Interestingly, scores of anxiety and depression as well as social anxiety were within control ranges across all respondent groups.

Comments:

     That csHT independent of surgical status is associated with reduced symptoms of anxiety and depression and social anxiety is no surprise to clinicians experienced in working with transsexuals.  More longitudinal study in this area is important since in many cultures and settings csHT is the only intervention that is available or desired.  It is interesting that transsexuals both pre- and receiving csHT had anxiety, depression and social anxiety scores within the control ranges;  While this might be the case in this population in Barcelona, a liberal city in a nation with a strong environment of LGBT rights and government-funded trans care, the results found here may not be applicable in other dissimilar settings.  Furthermore, the population studied was almost exclusively heterosexual (i.e. trans women attracted to men and trans men attracted to women) and may represent a group more conforming to gender binaries than a larger umbrella trans population.

References:

1) Gómez-Gil E, Zubiaurre-Elorza L, Esteva I, Guillamon A, Godás T, Cruz Almaraz M, et al. Hormone-treated transsexuals report less social distress, anxiety and depression. Psychoneuroendocrinology [Internet]. 2011 Sep 19 [cited 2012 Jan 2];Available from: http://www.ncbi.nlm.nih.gov/pubmed/21937168

Vaginal Prolapse, Pelvic Floor Function, and Related Symptoms 16 Years After Sex Reassignment Surgery in Transsexuals

     Cross sectional study of 52 MTF patients assessing for prolapse and related bladder, bowel and sexual problems found 3.8% of patients having prolapse warranting surgical repair, 47% with voiding difficulties, and 75% reporting that sexual complaints in some way interfered with their enjoyment of life.  (1)

     Pelvic organ prolapse affects 50% of non-transsexual parous women over age 50, though not all women with clinical signs of prolapse are symptomatic.  The authors aimed to assess the prevalence of pelvic organ prolapse in a cross sectional study of post-vaginoplasty MTF transsexual patients with a median age of 57 (range 39-69 years) under care at a single Swiss tertiary referral gynecology & endocrinology service.  The medial postoperative time was 16 years (range 13-29 years).  49 patients had undergone scrotal inversion and 3 patients had undergone sigmoideocolpoplasty at 14 different surgical centers distributed between Switzerland, the UK, France, the US and Thailand.  Objective measurement by a single examiner using the International Continence Society - Pelvic Organ Prolapse scoring (ICS-POP) and subjective symptom survey using the Sheffield Pelvic Organ Prolapse Quality-of-Life Questionnaire (SPS-Q) were conducted.

     7.5% of patients were found on exam to have an ICS-POP score greater than 2, with 3.8% of patients requiring surgical repair.  47% of patients reported voiding difficulties, 24.6% reported urgency, 17% urge incontinence, and 23% stress incontinence.  With respect to sexual satisfaction, 22.6% reported "never" and 26.4% reported "occasionally".  The paper includes a discussion of various anatomical considerations in pelvic surgery on transsexuals and also looked at outcomes in 3 FTM patients.

Comments:

     This paper is useful in reminding us that vaginoplasty is not a risk-free procedure, and that a non-trivial percentage of patients will experience bothersome urinary and sexual symptoms that can impact quality of life.  Primary care providers and surgeons should discuss known and unknown risks and percentages during the informed consent process prior to surgery.  These data are also useful in the ongoing development of government policies which allow changing legal documents to reflect the affirmed gender without requiring surgical intervention;  As more data emerge showing that surgery can be associated with substantial morbidity, the justification of surgery as a requirement for changing documents becomes weaker.

     The paper has several strengths and several weaknesses.  Using a single examiner eliminates inter-examiner reliability issues with respect to ICS-POP scoring.  At the same time, decision to perform pelvic surgical repair in cases of prolapse is more often guided by patient symptomatology and response to conservative treatment.  The study sample was rather large, but skewed towards an older population with an average age of 57.  The study population also represented an all-comer population from surgeons in a range of countries, but individual outcomes by surgeon or country were not reported.  Being a tertiary referral center, referral bias may have caused a higher prevalence of pathology in the study population.  The ICS-POP and SPS-Q scales have not been validated in transsexuals, and given the discussed anatomical differences may not be applicable or clinically relevant.  Comparisons are made to the prevalence of pelvic symptoms in parous non-transsexual women;  Weather or not this comparison is applicable vs. comparisons between groups of transsexual women by age or surgical technique, or comparison with pre- or non-op transsexual women are subjects to ponder.

References:

1) Kuhn A, Santi A, Birkhäuser M. Vaginal prolapse, pelvic floor function, and related symptoms 16 years after sex reassignment surgery in transsexuals. Fertil. Steril. 2011 Jun;95(7):2379–82.

Selective Estrogen Receptor Modulators (SERMs) for Uterine Leiomyomas (Cochrane Review)

     Cochrane Review of limited studies on the use of SERMs for uterine fibroid symptoms shows no clear evidence supporting this practice. (1)

     Uterine fibroids are known to respond to hormonal factors such as estrogens and progesterone.  Some hypothesize that a reduction in estrogen levels could improve fibroid symptomatology.  SERMS are mixed estrogen agonists/antagonists, and the SERM raloxifene specifically blocks estrogen action in breast and uterine tissue while stimulating receptors in bone and maintaining estrogenic effect on lipids.

     This Cochrane Review sought randomized controlled trials (RCT's) of women aged 18 to 45 with a diagnosis of uterine fibroids that included a raloxifene treatment arm.   Only three studies were identified, all of which had methodological limitations and data quality issues.  Adverse effects were not tracked by any of the studies.  The authors concluded that there exists insufficient evidence to support the use of SERMs in the management of uterine fibroids.


Comment:

     Transgender men receiving testosterone replacement who have not undergone oopherectomy may or may not have complete suppression of the hypothalamic-pituitary axis (HPA).  This combined with peripheral aromitization of exogenous testosterone may lead to persistantly elevated estrogen levels.  Unlike in transgender women, where testosterone blockade is central to hormonal reassignment regimens, cross gender HRT in trans men has not historically included blockers or other agents to manipulate estrogen levels.

     While most trans men do well clinically with testosterone only, a minority may present with a constellation of symptoms including abdominal or pelvic cramping, vaginal spotting, and bleeding or failed induction of amenorrhea.  Anecdotal clinician reports suggest that these patients tend to have serum estrogen levels above the normal male range, raising the question of weather or not estrogen level manipulation might improve these symptoms.

     The use of SERMs for uterine fibroids is essentially attempting to acheive similar outcomes of reduced estrogenic activity on the uterus while protecting bone health.  Bone health outcomes in trans men is an area of debate and limited evidence;  In theory, SERMs could offer relief to those trans men experiencing symptoms believed to be related to estrogen excess while reducing risks to bone health that might be seen with aromatase inhibitors or oopherectomy.   The increased risks of stroke, thromboembolic disease and hot flashes seen with SERMs in women may be mitigated in trans men by the presence of exogenous testosterone.

     This inconclusive Cochrane Review of limited quality studies does nonetheless bring to light the possible role of SERMs in the manipulation of estrogen levels and how this role might be applicable in the treatment of trans men.   Further study in this area as well as the use of aromatase inhibitors would be useful to assess their role in trans men on testosterone.

References:

1) Wu T, Chen X, Xie L. Selective estrogen receptor modulators (SERMs) for uterine leiomyomas. Cochrane Database Syst Rev. 2007;(4):CD005287. 

The Effects of Hormonal Gender Affirmation Treatment on Mental Health in Female-to-Male Transsexuals

     Results of an online, self-reported survey of a population of predominantly young, white, and educated female-to-male transsexuals demonstrated improved quality of life and reduced prevalence of mood disorders with the administration of testosterone. (1)

     Little data exist on the effects of cross gender HRT (cHRT) alone with respect to satisfaction and quality of life outcomes or the effect of cHRT on the prevalence of mood disorders in transgender persons.  Much of the existing data on these measures focuses on surgical interventions.  The authors distributed a self-reported survey to female-to-male (FTM) transsexuals via online discussion groups, measuring symptoms of depression, anxiety and stress as well as current perceived social support and health-related quality of life. The authors hypothesized that cHRT in FTM transsexuals reduced reported symptoms of depression, anxiety and stress and improved perceived social support and health-related quality of life.

     A total of 448 responses were collected, of which 369 were complete and met the minimum age requirement of 18 years.  The sample had an average age of 28, was predominantly white (76%), and educated (88% at least some college),  with 85% living in the US and 50% reporting sexual attraction to both men and women.  Sixty-six percent of respondents were on cHRT, and 41% of respondents had undergone male chest reconstruction (all but 7 of whom were also on cHRT).

     FTM transsexuals receiving cHRT reported statistically significantly lower levels of depression, anxiety and stress and higher levels of perceived social support and health-related quality of life.  Interestingly FTM transsexuals not on cHRT in this sample reported depression, anxiety, stress close to the control range.  Both groups reported lower than average perceived social support.  Both groups reported health-related quality of life higher than the control average.

Comment:

     This groundbreaking study looks at cHRT as a specific intervention with respect to mental health outcomes and quality of life measures.  Most outcome-based research on transgender populations have been focused on surgical interventions.  Looking at cHRT alone as an intervention that improves quality of life and mental health outcomes has significant implications for healthcare systems that offer limited (or no) access to more expensive surgical procedures which require additional resources and highly skilled surgeons, as well as for transgender persons who may simply not want to pursue genital surgery for a variety of reasons.

     One additional result of note is that 50% of respondents reported a sexual attraction to both men and women, further supporting the growing awareness of diversity of sexual orientations in transgender persons.

     One limitation mentioned by the authors is that the use of a psychological screening process to gain access to cHRT in some cases may color the differences between the cHRT and non-cHRT populations.  In fact, transsexuals with more severe mood symptoms may be more likely to be denied cHRT; Data on the reason(s) that the non-cHRT users were in fact not on cHRT would be helpful.  Additionally, nearly 62% of the cHRT users had undergone chest reconstruction while only 6% of the non-cHRT users had done so;  A subgroup analysis around this variable would have been helpful in determining any confounding of the results from this high prevalence of chest surgery in the study sample, as well as evaluating any incremental effects between cHRT alone and cHRT + chest surgery.  Nevertheless, chest reconstruction in its most rudimentary form is a much less painful, costly and specialized procedure than phalloplasty and as such these data are still quite relevant in the context of resources, availability and individual patient desires.

     It is interesting that respondents reported higher perceived social support on cHRT;  Was this simply an issue of perception, or was the actual provided support higher once on cHRT?  Additional study would be useful to determine the role of the former and the latter and to determine the community and societal factors driving this difference.   It is also interesting that FTM transsexuals not on cHRT reported levels of mood disorders not far from general population controls and that across all respondents reported health-related quality of life was higher than average.   This along with the somewhat homogeneous, white, educated sample limits the applicability of this study across other demographics;  Nonetheless it is a welcome addition to the nascent field of research on transgender persons undergoing cHRT alone and will hopefully lead to more study in this area.

References:

1) Colton Meier SL, Fitzgerald KM, Pardo ST, Babcock J. The Effects of Hormonal Gender Affirmation Treatment on Mental Health in Female-to-Male Transsexuals. Journal of Gay & Lesbian Mental Health. 2011 Jul;15(3):281-299.