Bone mass in young adulthood following gonadotropin-releasing hormone analog treatment and cross-sex hormone treatment in adolescents with gender dysphoria.

CONTEXT: Sex steroids are important for bone mass accrual. Adolescents with gender dysphoria (GD) treated with gonadotropin-releasing hormone analog (GnRHa) therapy are temporarily sex-steroid deprived until the addition of cross-sex hormones (CSH). The effect of this treatment on bone mineral density (BMD) in later life is not known. OBJECTIVE: This study aimed to assess BMD development during GnRHa therapy and at age 22 years in young adults with GD who started sex reassignment (SR) during adolescence. DESIGN AND SETTING: This was a longitudinal observational study at a tertiary referral center. PATIENTS: Young adults diagnosed with gender identity disorder of adolescence (DSM IV-TR) who started SR in puberty and had undergone gonadectomy between June 1998 and August 2012 were included. In 34 subjects BMD development until the age of 22 years was analyzed. INTERVENTION: GnRHa monotherapy (median duration in natal boys with GD [transwomen] and natal girls with GD [transmen] 1.3 and 1.5 y, respectively) followed by CSH (median duration in transwomen and transmen, 5.8 and 5.4 y, respectively) with discontinuation of GnRHa after gonadectomy. MAJOR OUTCOME MEASURES: How BMD develops during SR until the age of 22 years. RESULTS AND CONCLUSION: Between the start of GnRHa and age 22 years the lumbar areal BMD z score (for natal sex) in transwomen decreased significantly from -0.8 to -1.4 and in transmen there was a trend for decrease from 0.2 to -0.3. This suggests that the BMD was below their pretreatment potential and either attainment of peak bone mass has been delayed or peak bone mass itself is attenuated.

Breast cancer development in transsexual subjects receiving cross-sex hormone treatment.

INTRODUCTION: Transsexual people receive cross-sex hormones as part of their treatment, potentially inducing hormone-sensitive malignancies. AIM: To examine the occurrence of breast cancer in a large cohort of Dutch male and female transsexual persons, also evaluating whether the epidemiology accords with the natal sex or the new sex. MAIN OUTCOME MEASURE: Number of people with breast cancer between 1975 and 2011. METHODS: We researched the occurrence of breast cancer among transsexual persons 18-80 years with an exposure to cross-sex hormones between 5 to >30 years. Our study included 2,307 male-to-female (MtF) transsexual persons undergoing androgen deprivation and estrogen administration (52,370 person-years of exposure), and 795 female-to-male (FtM) subjects receiving testosterone (15,974 total years of exposure). RESULTS: Among MtF individuals one case was encountered, as well as a probable but not proven second case. The estimated rate of 4.1 per 100,000 person-years (95% confidence interval [CI]: 0.8-13.0) was lower than expected if these two cases are regarded as female breast cancer, but within expectations if viewed as male breast cancer. In FtM subjects, who were younger and had shorter exposure to cross-sex hormones compared with the MtF group, one breast cancer case occurred. This translated into a rate of 5.9 per 100,000 person-years (95% CI: 0.5-27.4), again lower than expected for female breast cancer but within expected norms for male breast cancer. CONCLUSIONS: The number of people studied and duration of hormone exposure are limited but it would appear that cross-sex hormone administration does not increase the risk of breast cancer development, in either MtF or FtM transsexual individuals. Breast carcinoma incidences in both groups are comparable to male breast cancers. Cross-sex hormone treatment of transsexual subjects does not seem to be associated with an increased risk of malignant breast development.

A long-term follow-up study of mortality in transsexuals receiving treatment with cross-sex hormones.

OBJECTIVE: Adverse effects of long-term cross-sex hormone administration to transsexuals are not well documented. We assessed mortality rates in transsexual subjects receiving long-term cross-sex hormones. DESIGN: A cohort study with a median follow-up of 18.5 years at a university gender clinic. Methods Mortality data and the standardized mortality rate were compared with the general population in 966 male-to-female (MtF) and 365 female-to-male (FtM) transsexuals, who started cross-sex hormones before July 1, 1997. Follow-up was at least 1 year. MtF transsexuals received treatment with different high-dose estrogen regimens and cyproterone acetate 100 mg/day. FtM transsexuals received parenteral/oral testosterone esters or testosterone gel. After surgical sex reassignment, hormonal treatment was continued with lower doses. RESULTS: In the MtF group, total mortality was 51% higher than in the general population, mainly from increased mortality rates due to suicide, acquired immunodeficiency syndrome, cardiovascular disease, drug abuse, and unknown cause. No increase was observed in total cancer mortality, but lung and hematological cancer mortality rates were elevated. Current, but not past ethinyl estradiol use was associated with an independent threefold increased risk of cardiovascular death. In FtM transsexuals, total mortality and cause-specific mortality were not significantly different from those of the general population. CONCLUSIONS: The increased mortality in hormone-treated MtF transsexuals was mainly due to non-hormone-related causes, but ethinyl estradiol may increase the risk of cardiovascular death. In the FtM transsexuals, use of testosterone in doses used for hypogonadal men seemed safe.

Combined hysterectomy/salpingo-oophorectomy and mastectomy is a safe and valuable procedure for female-to-male transsexuals.

INTRODUCTION: Sex reassignment surgery is an important step for transsexuals, since it is known to help the patients to live more easily in their gender role and to significantly increase quality of life. AIMS: To critically evaluate our experience with the combined procedure of hysterectomy, bilateral salpingo-oophorectomy, and bilateral mastectomy for female-to-male (FtM) transsexual patients. METHODS: Thirty-two FtM transsexuals who underwent hysterectomy, bilateral salpingo-oophorectomy, and bilateral mastectomy in one single operative setting. MAIN OUTCOME MEASURES: Operating time and complications, both intra-and postoperatively. RESULTS: Patients were 30.0 ± 5.8 years of age, with a body mass index of 24.8 ± 3.5 kg/m(2). The majority of patients underwent hysterectomy and bilateral salpingo-oophorectomy by laparoscopy (31/32, 96.9%). The median operating time was 222.5 minutes (inter-quartile range [IQR] 190-270 minutes). The median postoperative stay was eight days (IQR, 7-9 days). Postoperative adverse events were found in five patients (15.6%), including breast hematomas as the most frequent complication (4/32, 12.5%). In one patient (1/32; 3.1%), conversion from laparoscopy to laparotomy was necessary, which was considered an adverse event. None of our patients required reoperation or readmission to the hospital. CONCLUSION: Combined hysterectomy/salpingo-oophorectomy, and bilateral mastectomy in a single operating session seems a safe, feasible, and valuable procedure for FtM transsexuals.

Immunohistochemical examinations of sex hormone receptors in benign vocal fold lesions.

BACKGROUND: Acquired benign vocal fold lesions are among the most common causes of voice problems. Since the local impact of estrogen and progesterone receptors in laryngeal tissue is discussed controversially, the presence of sex hormone receptors in benign vocal fold alterations needs to be clarified. GOAL OF THE STUDY: To investigate the expression of estrogen-alpha receptors (ER-alpha), estrogen-beta receptors (ER-beta), progesterone receptors (PR) and androgen receptors (AR) in acquired benign vocal fold alterations. METHODS: Laryngeal epithelial specimens of 14 patients (13 female, 1 male) taken intraoperatively were investigated using immunohistochemistry in order to objectify ER-alpha, ER-beta, PR and AR. Macroscopically and histopathologically diagnosed edemas of Reinke's space (n = 10), vocal fold polyps (n = 3) and vocal fold nodules (n = 1) were enrolled in this study. RESULTS: No specific nuclear immunohistochemical staining could be seen in the biopsies taken. Only unspecific staining patterns could be observed. CONCLUSION: Sex hormone receptors could not be detected in the specimens tested, thus, any direct influence of sex hormones on the development of benign vocal fold lesions is rather unlikely. The results of this study confirm the impact of vocal fold stress and biomechanical abnormalities on their development due to voice overstraining and abuse.

Implanon versus medroxyprogesterone acetate: effects on pain scores in patients with symptomatic endometriosis--a pilot study.

BACKGROUND: Implanon has been reported to be effective in the treatment of dysmenorrhea. We compared the therapeutic efficacies of depot medroxyprogesterone acetate (DMPA) and Implanon with regard to pain relief in women with endometriosis. STUDY DESIGN: In a clinical research center at a university hospital, 41 patients with dysmenorrhea, nonmenstrual pelvic pain and dyspareunia associated with histologically proven endometriosis were included in an open, prospective, randomized, controlled clinical trial. Twenty-one women were assigned by computer-generated randomization to receive Implanon, and 20 women to receive DMPA. As main outcome measures of this pilot study, we evaluated pain improvement quantified according to visual analog scale score, side effects, vaginal bleeding patterns, withdrawal rate and overall degree of satisfaction. RESULTS: During a follow-up period of 1 year, we ascertained a clear improvement in pain intensity for both treatment options. After 6 months, the average decrease in pain was 68% in the Implanon group and 53% in the DMPA group. The side-effects profile and the overall degree of satisfaction after study termination were comparable for both treatment options. CONCLUSION: Concerning pain relief, the therapeutic efficacy of the contraceptive implant Implanon is not inferior to that of DMPA in symptomatic endometriosis.

Hypoactive sexual desire in transsexual women: prevalence and association with testosterone levels.

OBJECTIVE: An unknown proportion of transsexual women (defined as post-operative male-to-female transsexuals on oestrogen replacement) experience hypoactive sexual desire disorder (HSDD). It has been suggested that the absence of ovarian androgen production together with oestrogen treatment-related increase in sex hormone-binding globulin (SHBG) levels could be leading to HSDD, due to low levels of biologically available testosterone. This study wishes to document the HSDD prevalence among transsexual women and the possible association to androgen levels. DESIGN: Cross-sectional study. METHODS: Transsexual women (n=62) and a control group of ovulating women (n=30) participated in this study. Questionnaires measuring sexual desire (sexual desire inventory) and relationship and sexual satisfaction (Maudsley Marital Questionnaire) were completed. Serum levels of total testosterone, LH and SHBG were measured in blood samples obtained at random in transsexual women and in the early follicular phase in ovulating women. RESULTS: The transsexual group had lower levels of total and calculated free testosterone (both P<0.001) than the ovulating women. HSDD was reported in 34% of the transsexual and 23% of the ovulating women (P=0.30). Both groups reported similar levels of sexual desire (P=0.97). For transsexual women, no significant correlation was found between sexual desire and total (P=0.64) or free testosterone (P=0.82). In ovulating women, these correlations were significant (P=0.006, resp. P=0.003). CONCLUSIONS: HSDD is reported in one-third of transsexual women. This prevalence is not substantially different from controls, despite markedly lower (free) testosterone levels, which argues against a major role of testosterone in this specific group.

Association of the protein Z intron F G79A gene polymorphism with recurrent pregnancy loss.

OBJECTIVE: To investigate the association of the common protein Z (PZ) intron F G79A gene polymorphism with recurrent early pregnancy loss (RPL) and its gene-gene interaction with known thrombophilic risk factors for RPL. DESIGN: Case control study. SETTING: University clinic. PATIENT(S): We enrolled 49 women with a history of two consecutive or three to six nonconsecutive pregnancy losses between the 8th and 12th weeks of gestation and 48 age-matched parous controls without a history of pregnancy complications. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Allele frequencies of the PZ intron F G79A polymorphism and its gene-gene interaction with known risk factors for RPL. RESULT(S): Fourteen case subjects (28.6%) and 24 control subjects (50.0%) carried at least one A allele. This was associated with a significant reduction of the relative risk for recurrent pregnancy loss (odds ratio [OR] 0.4, 95% confidence interval [CI] 0.2-0.9; adjusted OR 0.3, 95% CI 0.1-0.8). Coexistence of any thrombophilic risk factor studied with the 79A allele resulted in a clear reduction of the primal relative risk for recurrent pregnancy loss. CONCLUSION(S): The isolated presence of the PZ intron F 79A allele as well as the combination with known thrombophilic risk factors was protective against RPL between the 8th and 12th weeks of gestation.

Towards the expression of sex hormone receptors in the human vocal fold.

BACKGROUND: The human larynx is assumed to be a steroid receptor target organ. There are only very limited data on the evidence of steroid receptors in the vocal folds, although voice alterations due to hormonal influence and treatment have been found. GOAL OF THE STUDY: To investigate the expression of estrogen alpha, progesterone, and androgen receptors in human vocal folds (vocalis muscle, glands, lamina propria, epithelium). METHODS: Immunohistochemically, vocal fold cadaver specimens of 15 autopsied patients (6 women, 9 men), which were taken approximately 4 to 8 hours postmortem were investigated. Furthermore, one (male) vocal fold biopsy obtained intraoperatively during a laryngectomy was tested. RESULTS: No specific immunohistochemical staining for the different types of steroid hormones investigated could be observed in either the postmortem taken biopsies nor the intraoperatively one. However, several unspecific staining patterns could be observed. CONCLUSION: The results of this study contradict recently published data and question the expression of sex hormone receptors in the vocal folds. Main causes of false interpretations of unspecific staining are discussed.

Role of the vaginally administered aromatase inhibitor anastrozole in women with rectovaginal endometriosis: a pilot study.

In the present nonrandomized pilot study we determined the role of the vaginally administered aromatase inhibitor anastrozole (0.25 mg anastrozole/d for 6 months) in the treatment of women with histologically proven rectovaginal endometriosis. In a series of 10 patients, dysmenorrhea, physical and social functioning, but not chronic pelvic pain and dyspareunia, improved during therapy.

Progesterone-receptor index in meningiomas: correlation with clinico-pathological parameters and review of the literature.

For recurrent and untreatable meningiomas alternative therapies, such as anti-progesterone treatment, have been sought. However, the few clinical studies have not determined progesterone receptor (PgR) expression in most cases, and studies correlating quantitative PgR expression (PgR index) with clinico-pathological variables are scarce. The aim of our study was to assess the PgR indices in a consecutive series of meningiomas and correlate these values with clinico-pathological parameters. We analyzed immunohistochemically 82 consecutive meningioma specimens (73 primary and nine recurrent tumors) for PgR and Ki-67 antigen (MIB-1). The male/female ratio was 1:1.7, and median age at the time of surgery was 57 years (range 29-77 years). The series comprised 55 grade I (subtyped as 36 meningothelial, seven fibrous, nine transitional, two psammomatous, and one angiomatous), 23 grade II, and one grade III meningiomas. Nuclear immunostaining for PgR was positive in 56 meningioma specimens (71%). PgR index was 21.4+/-2.8% (mean +/- SE; range 0-79%). Significantly higher expression was found in male patients in the age group <50 years than in those > or = 60 years and in grade I meningothelial meningiomas than in fibrous and transitional subtypes. There was a trend to lower PgR indices in non-benign meningiomas. Cell proliferation rate (MIB-1 index) was 4.4 +/- 0.4% (mean +/- SE; range 0.3-15.4%). Significantly higher MIB-1 indices were found in male than female patients,in recurrent than primary and in grade II than grade I meningiomas. We observed a trend to higher PgR indices in meningiomas with MIB-1 index <5%. In sum, the highest PgR index in our series was observed in patients under the age of 50 years with WHO grade I meningiomas of the meningothelial subtype and low cell proliferation indices. If hormonal therapy has a direct action on the PgR, these patients should respond best to anti-progesterone treatment. We conclude that PgR index is variable in meningioma, depending on clinical parameters and histopathological features. Stratification of anti-progesterone therapy trials on the basis of PgR index should be considered.

Elevated coagulation factor VIII and the risk for recurrent early pregnancy loss.

Inherited and acquired thrombophilia are associated with recurrent pregnancy loss. Recently, an increased risk for thromboembolic disease was described for patients with elevated coagulation factor VIII, but it is unknown whether there is also an association to early pregnancy loss. We therefore evaluated the relation between recurrent early pregnancy loss and levels of coagulation factor VIII. We enrolled 49 unrelated Caucasian women with a history of 2-6 early pregnancy losses and 48 healthy controls, who had delivered at least one term infant and had never experienced pregnancy loss. We determined factor V Leiden-, G20210A prothrombin-, MTHFR C677T- and A1298C-gene mutations, levels of antithrombin, protein C, protein S, factor VIII, C-reactive protein and antiphospholipid antibodies. There was a significantly higher rate of pregnancy losses in women with Antiphospholipid Syndrome (p = 0.043). Furthermore, plasma levels of coagulation factor VIII were significantly higher in cases than in controls (130.5 IU/dl +/- 25.4 vs 119.5 IU/dl +/- 24.1; p = 0.032) and appeared independent of C-reactive protein (R = 0.146, p = 0.323 in cases; R = -0.028, p = 0.850 in controls). The relative risk for recurrent pregnancy loss in women with factor VIII levels above 151 IU/dl (90(th) percentile of controls) was 2.5 (0.7 - 8.9, 95 percent confidence interval), for levels above 156 IU/dl (95(th) percentile of controls) 3.9 (0.8 - 20.0, 95 percent confidence interval). Elevated maternal plasma levels of coagulation factor VIII tend to be associated with an increased risk for recurrent early pregnancy loss.

Voice impairment and menopause.

OBJECTIVE: Menopause rating scales still do not regard voice impairment as a genuine climacteric symptom, although voice changes are frequently reported. The purpose of this study was both to register and differentiate voice alterations and disorders in menopausal women. DESIGN: A total of 107 women between 37 and 71 years of age who were rated as postmenopausal according to their hormonal status answered a questionnaire on voice changes and vocal discomfort. RESULTS: Of this group, 49 women mentioned voices changes, and 35 of those women associated these changes with subjective discomfort, whereas 58 women mentioned neither voice changes nor discomfort. Sixteen of the women who mentioned voice changes and eight who did not participated in a comprehensive investigation, which included completion of the Klimax questionnaire, a head and neck examination, videostroboscopy, perceptual evaluation of voice sound, voice range profile measurements, and voice dysfunction index determination. CONCLUSIONS: Voice changes during menopause might be a common problem seen in clinical practice. Therefore, an additional systematic registration of voice impairment in future menopause rating scales should be considered if further studies confirm our findings of a high prevalence of voice complaints associated with menopause. Severe menopausal voice impairments, even without other climacteric symptoms, should be regarded as an indication for phoniatric examination.

Plasminogen activator inhibitor 1 4G/5G polymorphism and coagulation factor XIII Val34Leu polymorphism: impaired fibrinolysis and early pregnancy loss.

BACKGROUND: A successful outcome of pregnancy depends on proper placental formation. In the very beginning of this process, trophoblast invasion and fibrin deposition into the wall of the decidual veins play an important part. Two polymorphisms, coagulation factor XIII (FXIII) Val34Leu and plasminogen activator inhibitor 1 (PAI-1) 4G/5G, interfere with fibrin cross-linking and regulation of fibrinolysis and may therefore contribute to early pregnancy loss. METHODS: We enrolled 49 unrelated Caucasian women with a history of two consecutive or three to six nonconsecutive early pregnancy losses and 48 unrelated parous healthy controls without a history of pregnancy loss and evaluated them for the following genetic variants: the factor V Leiden and prothrombin G20210A gene mutations, the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms, and the PAI-1 4G/5G and FXIII Val34Leu polymorphisms. RESULTS: For the isolated occurrence of PAI-1 4G/5G or FXIII Val34Leu, we found no statistically significant difference between cases and controls. For homozygosity of either or compound carrier status of both mutations, the overall relative risk for early pregnancy loss was significantly increased (odds ratio = 2.4; 95% confidence interval, 1.1-5.5; P = 0.032). We observed no statistically relevant association of any of the other tested mutations with early pregnancy loss. CONCLUSION: Homozygosity for PAI-1 4G or FXIII 34Leu polymorphisms as well as compound carrier status is associated with early pregnancy loss.

Interleukin-1 receptor antagonist polymorphism in women with peritoneal adhesions.

Interleukin (IL)-1 has been shown to induce peritoneal adhesions. We determined the IL-1 receptor antagonist (IL-1RN) genotype with respect to the two most common variant alleles IL-1RN*2 and IL-1RN*3 in Caucasian women with peritoneal adhesions. One hundred seven women with surgically verified peritoneal adhesions and 79 controls without peritoneal adhesions served as controls. Univariate analysis showed an increased risk for peritoneal adhesions for Caucasian women carrying the mutant IL-1RN*2 allele (OR: 2.1; 95% CI: 1.3-3.4; P = 0.004). Multiple logistic regression analysis demonstrated an increased risk for peritoneal adhesions, which is independent of previous abdominal surgery and endometriosis. Our data suggest that IL-1RN*2 allele carriers have an increased risk for adhesion formation.