A novel quantitative computer-assisted drug-induced liver injury causality assessment tool (DILI-CAT).

BACKGROUND AND AIMS: We hypothesized that a drug's clinical signature (or phenotype) of liver injury can be assessed and used to quantitatively develop a computer-assisted DILI causality assessment-tool (DILI-CAT). Therefore, we evaluated drug-specific DILI-phenotypes for amoxicillin-clavulanate (AMX/CLA), cefazolin, cyproterone, and Polygonum multiflorum using data from published case series, to develop DILI-CAT scores for each drug. METHODS: Drug specific phenotypes were made up of the following three clinical features: (1) latency, (2) R-value, and (3) AST/ALT ratio. A point allocation system was developed with points allocated depending on the variance from the norm (or "core") for the 3 variables in published datasets. RESULTS: The four drugs had significantly different phenotypes based on latency, R-value, and AST/ALT ratio. The median cyproterone latency was 150 days versus < 43 days for the other three drugs (median: 26 for AMX/CLA, 20 for cefazolin, and 20 for Polygonum multiflorum; p<0.001). The R-value for the four drugs was also significantly different among drugs (cyproterone [median 12.4] and Polygonum multiflorum [median 10.9]) from AMX/CLA [median 1.44] and cefazolin [median 1.57; p<0.001]). DILI-CAT scores effectively separated cyproterone and Polygonum multiflorum from AMX/CLA and cefazolin, respectively (p<0.001). As expected, because of phenotypic overlap, AMX/CLA and cefazolin could not be well differentiated. CONCLUSIONS: DILI-CAT is a data-driven, diagnostic tool built to define drug-specific phenotypes for DILI adjudication. The data provide proof of principle that a drug-specific, data-driven causality assessment tool can be developed for different drugs and raise the possibility that such a process could enhance causality assessment methods.

Are cytostatic drugs in surface waters a potential threat?

Cytostatic drugs are pharmaceuticals administered to cancer patients under chemotherapy. Their occurrence in surface waters has been reported worldwide, increasing environmental and human health concerns. This work addresses a question of worldwide interest: are these hazardous pharmaceuticals in surface waters a potential threat? For the first time, this study brings information on the presence of cytostatic drugs in Portuguese rivers. Furthermore, cutting-edge data on the occurrence of two cytostatic drugs is provided; up to the authors' best knowledge, flutamide and mycophenolate mofetil have never been monitored in worldwide surface waters. Nine out of thirteen cytostatic drugs were detected in Portuguese rivers. Despite bicalutamide being the cytostatic most frequently detected, the highest concentration was recorded for cyproterone (19 ± 3 ng/L). Three different scenarios were considered to estimate the risks from the exposure of humans to cytostatic drugs via surface waters. Two scenarios are associated with bathing practices in rivers, particularly in the spring and summer seasons (river beaches): (i) the exposure to cytostatic drugs by dermal contact with contaminated water and (ii) the exposure by accidental ingestion of contaminated water, which is less likely but also occurs. The third exposure scenario is related to (iii) the long-life consumption of drinking water produced from river water capture, under worst-case conditions, i.e. negligible degradation of cytostatic drugs at drinking water treatment plants. It was concluded that the third exposure context to cytostatics could represent a risk to children, if the highest concentration ever reported in the literature for cyclophosphamide in surface waters is considered. Still, attending to the carcinogenicity of some of these compounds (e.g., cyclophosphamide, chlorambucil, etoposide and tamoxifen), health risks might always be expected, regardless of the contamination level. Furthermore, health risks associated with synergic effects and/or long-term exposures cannot be ruled out, even for the remaining cytostatics/exposure contexts.

Systemic hormonal contraception and risk of venous thromboembolism.

INTRODUCTION: The increased risk of venous thromboembolism associated with the use of hormonal contraception is well recognized, but evidence regarding hormonal contraception containing natural estradiol is limited. This study aimed to assess the associations between the patterns of use of different systemic hormonal contraceptives and the risk of venous thromboembolism during 2017-2019. MATERIAL AND METHODS: All fertile-aged women (15-49 years) living in Finland in 2017 and using hormonal contraception in 2017 and their 1:1 age- and residence-matched controls not using hormonal contraception in 2017 (altogether 587 559 women) were selected from the Prescription Centre. All incident venous thromboembolism cases during 2018-2019 and their 4:1 age-matched controls were further analyzed in a prospective nested case-control design to assess the associations between the use (starting, stopping, continuous vs no use) of different hormonal contraception types and venous thromboembolism. RESULTS: Altogether, 1334 venous thromboembolism cases occurred during the follow-up period (incidence rate 1.14 per 1000 person-years, 95% confidence interval [CI] 1.08-1.20), with an incidence rate ratio of hormonal contraception vs no hormonal contraception use of 1.42 (95% CI 1.27-1.58). Compared with non-use, starting the use of gestodene and ethinylestradiol (adjusted odds ratio [aOR] 2.85; 95% CI 1.62-5.03), drospirenone and ethinylestradiol (aOR 1.55; 95% CI 0.98-2.44), desogestrel and ethinylestradiol (aOR 1.97; 95% CI 0.99-3.92), and transdermal patch releasing norelgestromin and ethinylestradiol (aOR 5.10; 95% CI 1.12-23.16), as well as continuing the use of gestodene and ethinylestradiol (aOR 2.60; 95% CI 1.61-4.21), drospirenone and ethinylestradiol (aOR 1.55; 95% CI 1.02-2.37), cyproterone-acetate and estrogen/ethinylestradiol (aOR 1.66; 95% CI 1.06-2.61), and vaginal ring releasing etonogestrel and ethinylestradiol (aOR 3.27; 95% CI 1.95-5.48) were associated with venous thromboembolism risk. Regarding the type of estrogen, the highest risk was associated with current use (vs non use in the previous 180 days) of ethinylestradiol-containing preparations (aOR 2.20; 95% CI 1.82-2.65), followed by estradiol-containing preparations (aOR 1.39; 95% CI 1.04-1.87) with no risk for progestin-only hormonal contraception. Current use of estradiol-containing preparations was not associated with venous thromboembolism risk after exclusion of cyproterone-acetate and estrogen/ethinylestradiol (aOR 1.05; 95% CI 0.66-1.66). CONCLUSIONS: An increased risk of venous thromboembolism is associated with ethinylestradiol-containing combined preparations. The use of estradiol-containing combined preparations confers only a slightly increased risk, possibly driven by cyproterone-containing combined oral contraceptives, whereas the use of progestin-only contraception is not associated with venous thromboembolism.

First case of cyproterone acetate induced multiple meningiomas in identical female twins: A case report.

Meningiomas are the most common tumors of the central nervous system. Most meningiomas are benign and occur mainly in middle-aged women. Only a few cases of meningiomas in identical twins have been reported. Cyproterone acetate (Androcur® Bayer Healthcare SAS) (CPA) is an antiandrogenic progestin used to treat female hirsutism in some countries including France. We report a case of identical twin sisters who developed multiple, atypically located meningiomas in the setting of long-term CPA use. Eighteen-month follow-up showed spontaneous decrease of meningiomas after cessation of CPA. This case illustrates CPA's ability to induce development of atypically located meningiomas that differ even between identical twins, confirms benefit of surgical abstention, and raises questions regarding security of use of CPA.

Anti-Androgenic Effects Comparison Between Cyproterone Acetate and Spironolactone in Transgender Women: A Randomized Controlled Trial.

BACKGROUND: Spironolactone and cyproterone acetate are commonly used in feminizing hormone therapy to achieve the goal of female range testosterone level; however, the data on the efficacy comparing between these two anti-androgens are scarce. AIM: To compare the anti-androgenic effects between spironolactone and cyproterone acetate as the component of feminizing hormone therapy among transgender women population. METHODS: The study was single-blinded randomized controlled trial involved 52 transgender women from two transgender health clinics. Each participant received oral estradiol valerate 4 mg/day combined with anti-androgen, spironolactone 100 mg/day or cyproterone acetate 25 mg/day, depending on which group they were randomized to. Clinical and biochemical variables were obtained at baseline and at 12 weeks of feminizing hormone therapy. MAIN OUTCOME MEASURES: The change of testosterone level from baseline. Other changes including free testosterone, estradiol, prolactin and lipid profile after the therapy. RESULTS: After a 12 weeks of feminizing hormone therapy, the change of testosterone level in the cyproterone acetate group [558.0 ng/dL (IQR 352.0 to 783.3)] was significantly higher than the spironolactone group [226.2 ng/dL (IQR,-4.3 to 480.1)](p value <0.001). Testosterone and calculated free testosterone in the cyproterone acetate group were significantly lower than the spironolactone group. Consequently, a proportion of the participants who achieved the female range testosterone (<50 ng/dL) was significantly higher in cyproterone acetate group (90%) compared to the spironolactone group (19%). Serious adverse effects observed in cyproterone acetate users were drug-induced liver injury and asymptomatic hyperprolactinemia. CLINICAL IMPLICATIONS: The data on the differences between the two anti-androgen could be benefit for the transgender health-care providers in medication selection and adverse-effects counseling. STRENGTHS & LIMITATIONS: The study design was randomized controlled trial and controlled the estrogen component by prescribed the same type and dose for each participant. However, the study was suffered from the confound feminizing effects from previous hormone therapy and the high drop-out rate. CONCLUSION: For feminizing hormone therapy, cyproterone acetate had a higher testosterone suppression efficacy than spironolactone. Burinkul S, Panyakhamlerd K, Suwan A, et al. Anti-Andorgenic Effects Comparison Between Cyproterone Acetate and Spironolactone in Transgender Women: A Randomized Controlled Trial. J Sex Med 2021;18:1299-1307.

Low-Dose Cyproterone Acetate Treatment for Transgender Women.

BACKGROUND: Transgender women with intact gonads receive lifelong hormonal treatment to suppress physiologic androgen production, the optimal efficacious and safe cyproterone acetate (CPA) dose has not been established. AIM: To assess the effectiveness and safety of low-dose (10-20 mg/day) compared with high-dose (50-100 mg/day) CPA treatment. METHODS: We conducted a historical cohort study of transgender women treated at a tertiary center for transgender health. OUTCOME MEASURES: Serum levels of testosterone, estradiol, prolactin, gonadotrophins, liver enzymes, and lipids. RESULTS: There were 38 transgender women in the low-dose group and 26 in the high-dose group. Age (median 24.9 years, interquartile range [IQR] 21-30 vs 25 years, IQR 19-35) and follow-up time (median 12 months, IQR 6-23 vs 15 months, IQR 12-36) were similar in the low- and high-dose groups, respectively. Serum gonadotropins and testosterone were suppressed to a similar level at all time points in both groups. Prolactin levels increased significantly in both groups, however, with a more substantial increase in the high- vs the low-dose group (804 ± 121 vs 398 ± 69 mIU/ml at 12 months, respectively, P = .004). Total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels were not significantly affected by the dose. CLINICAL IMPLICATIONS: We suggest an adjustment of current clinical practice guidelines to recommend lower doses of CPA for the treatment of transgender women. STRENGTHS & LIMITATIONS: This is the first demonstration that low-dose CPA treatment of transgender women is effective. Limitations include a relatively small sample and retrospective study design. CONCLUSION: Low-dose CPA treatment of transgender women is as effective as high-dose treatment and possibly safer. Zohar NE, Sofer Y, Yaish I, et al. Low-Dose Cyproterone Acetate Treatment for Transgender Women. J Sex Med 2021;18:1292-1298.

Reduction in use of cyproterone/ethinylestradiol (Diane-35 and generics) after risk minimization measures in the Netherlands, UK and Italy.

OBJECTIVES: To study the effect of risk minimization measures taken in 2013 for cyproterone acetate/ethinylestradiol (CPA/EE) on initiation, concomitant use of other hormonal contraceptives (HC) and potential indications. STUDY DESIGN: This retrospective study included data on CPA/EE use in 2011-2017 from the Netherlands, UK, and Italy. RESULTS: The initiation rate of CPA/EE decreased by 44%-91% between 2011 and 2017. Proportions with concomitant use of other HC (<3%) and approved indications did not change over time. CONCLUSION: Apart from a strong reduction in CPA/EE use following risk minimization measures, no major changes were observed regarding concomitant use of other HC or potential reasons for use.

Anti-androgenic therapy in young patients and its impact on intensity of hirsutism, acne, menstrual pain intensity and sexuality - a preliminary study.

OBJECTIVES: Using anti-androgenic contraception is one of the methods of birth control. It also has a significant, non-contraceptiveimpact on women's body. These drugs can be used in various endocrinological disorders, because of their abilityto reduce the level of male hormones.The aim of our study is to establish a correlation between taking different types of anti-androgenic drugs and intensity ofhirsutism, acne, menstrual pain intensity and sexuality. MATERIAL AND METHODS: 570 women in childbearing age that had been using oral contraception for at least three monthstook part in our research. We examined women and asked them about quality of life, health, direct causes and effects ofthat treatment, intensity of acne and menstrual pain before and after. Our research group has been divided according tothe type of gestagen contained in the contraceptive pill: dienogest, cyproterone, chlormadynone and drospirenone. Additionally,the control group consisted of women taking oral contraceptives without antiandrogenic component. RESULTS: The mean age of the studied group was 23 years ± 3.23. 225 of 570 women complained of hirsutism.The mean score for acne intensity before the use of contraception was 2.7 ± 1.34. The mean score for acne intensity after3 months of using contraception was 1.85 ± 1.02 (p < 0.001). 192 women reported excess hairiness in one or more areabefore treatment. Mean value based on Ferriman-Gallway scale before the treatment was 6.23 ± 6.21 and 5.39 ± 5.6 afterthe treatment (p < 0.001). CONCLUSIONS: All groups of drugs effectively reduced pain and acne severity. Cyproterone and drospirenone turned outas the most effective drugs in treating hirsutism. Surprisingly, according to our research, dienogest does not have anyimpact on body hairiness.

[Efficacy and metabolic safety of long-term treatment with ethinyl oestradiol/cyproterone and desogestrel/ethinyl oestradiol tablets in women with polycystic ovary syndrome].

OBJECTIVE: To evaluate the efficacy and metabolic safety of long-term treatment with ethinyl oestradiol/cyproteroneand desogestrel/ethinyl oestradiol tablets in women with polycystic ovary syndrome (PCOS). METHODS: Women with PCOSfrom West China Second Hospital of Sichuan University enrolled between September, 2011 and August, 2013 were randomlyallocated to receive either ethinyl oestradiol/cyproterone tablets (Group A, n=355) or desogestrel/ethinyl oestradiol tablets(Group B, n=357) for a prospective observation period of 6 months. Women with insulin resistance also received metformin. Atbaseline, 3 months, and 6 months, the patients were evaluated for menstruation, acne score, body mass index (BMI), waist-tohip ratio (WHR), plasma levels of sex hormones, fasting blood glucose (FPG), HOMA-insulin resistance index (HOMA-IR), serum lipid, ovarian volume, and the number of ovarian follicles. RESULTS: All the patients had a regular menstrual cycle aftertreatments. Testosterone level, acne score, LH/FSH, ovarian volume, and the number of follicles decreased significantly afterthe treatments without significant differences between the two groups. Significant increases were noted in TG, TCh, LDL, HDL, and AIP, and HDL level in group A as compared with group B (P < 0.001). FPG decreased in both groups, and wassignificantly lower in group B at 6 months (P < 0.05). BMI and WHR decreased in all the patients with insulin resistance aftercombination treatment with metformin (P < 0.05), but increased significantly in patients without insulin resistance (P < 0.05). Ingroup A, HOMA- IR significantly increased in patientswithout insulin resistance at 3 months (P < 0.05), whereas asignificant increase was not observed until 6 months ingroup B (P < 0.05). CONCLUSIONS: Both ethinyl oestradiol/cyproterone tablets and desogestrel/ethinyl oestradioltablets can relieve the symptoms of PCOS, but it isadvisable to assess the risk of cardiovascular diseasebefore the treatments.

Differential Effects of Cyproterone Acetate vs Spironolactone on Serum High-Density Lipoprotein and Prolactin Concentrations in the Hormonal Treatment of Transgender Women.

INTRODUCTION: Spironolactone and cyproterone acetate (CPA) are the two main antiandrogen medications used in feminizing hormone therapy in transgender women. Previous studies have suggested that these two agents might have opposite effects on high-density lipoprotein (HDL) level when used in this context, and limited data have suggested CPA increases prolactin more than spironolactone. AIM: To compare the effects of spironolactone and CPA on HDL and prolactin serum concentrations in transgender women. METHODS: A retrospective chart review was conducted at three clinical sites in Toronto, Ontario, Canada. Patients were selected if they (i) identified as a transgender woman, (ii) had newly started spironolactone or CPA with estrogen or restarted spironolactone or CPA after a washout period of at least 6 months, and (iii) had not used other antiandrogens within the previous 6 months. MAIN OUTCOME MEASURES: HDL and prolactin concentrations between the two treatment groups at baseline and at 12 months. RESULTS: Eighty-two patients were included in the spironolactone group and 31 patients were included in the CPA group. Baseline HDL and prolactin levels were not significantly different between the two groups. At 12 months, HDL increased by 0.10 mmol/L (SD = 0.24) in the spironolactone group but decreased by 0.07 mmol/L (SD = 0.21) in the CPA group (P = .002). The difference remained significant after adjusting for baseline HDL, use of lipid-lowering drugs, and age. The change in prolactin was +3.10 µg/L (SD = 5.70) in the spironolactone group and +11.8 µg/L (SD = 8.63) in the CPA group (P < 0.001). This difference also remained significant after adjusting for baseline prolactin level. CONCLUSION: These data suggest that spironolactone use in transgender women increases HDL levels and that CPA has the opposite effect. CPA also is associated with a larger increase in prolactin. These factors should be considered when choosing between these two antiandrogen agents.

Pills-related severe adverse events: A case report in Taiwan.

OBJECTIVE: To review and evaluate the potential adverse effects of these oral contraceptives (OCP) to overweight women. CASE REPORT: A 19-year-old college student, with a body mass index (BMI) of 35.2 kg/m(2), who received 2 months of OCP containing cyproterone and ethinyl estradiol for polycystic ovary syndrome (PCOS)-related menstrual problems was complicated with a thromboembolism-related life-threatened disease. After intensive care, including the use of an extracorporeal membrane oxygenation system, thrombolytic treatment, anticoagulant, and inferior vena filter, she recovered well without significant sequelae. CONCLUSION: This case illustrates the risk of using OCPs, especially for those containing cyproterone and ethinyl estradiol components, as a treatment for menstrual problems in young women with PCOS and a high BMI.

[Intra cranial meningiomas and long term use of cyproterone acetate with a conventional dose in women. A report of two cases of tumor decrease after treatment withdrawal]. / Méningiomes intracrâniens et utilisation prolongée d'acétate de cyprotérone à dose conventionnelle chez la femme: à propos de deux cas de régression tumorale après arrêt du traitement.

The action of synthetic progestogens, prescribed at a conventional dose in women, for a meningioma, is still poorly understood, and could be related to progesterone receptors. We report two cases illustrating multiple meningiomas with stabilization or tumor reduction after withdrawal of cyproterone acetate originally prescribed for a long term period. We also review the influence of synthetic progestogens on meningiomas, particularly the impact of treatment withdrawal.

Ethinylestradiol + cyproterone: back in France for acne and hirsutism, despite frequent off-label prescription.

Following a European review, products containing the ethinylestradiol + cyproterone combination are back on the French market for women with acne (as second-line treatment) or hirsutism. Yet experience has shown that frequent off-label prescription of this combination for contraceptive purposes exposes many women to an unjustified risk of thromboembolism.

Combined oral contraceptives: venous thrombosis.

BACKGROUND: Combined oral contraceptive (COC) use has been associated with venous thrombosis (VT) (i.e., deep venous thrombosis and pulmonary embolism). The VT risk has been evaluated for many estrogen doses and progestagen types contained in COC but no comprehensive comparison involving commonly used COC is available. OBJECTIVES: To provide a comprehensive overview of the risk of venous thrombosis in women using different combined oral contraceptives. SEARCH METHODS: Electronic databases (Pubmed, Embase, Web of Science, Cochrane, CINAHL, Academic Search Premier and ScienceDirect) were searched in 22 April 2013 for eligible studies, without language restrictions. SELECTION CRITERIA: We selected studies including healthy women taking COC with VT as outcome. DATA COLLECTION AND ANALYSIS: The primary outcome of interest was a fatal or non-fatal first event of venous thrombosis with the main focus on deep venous thrombosis or pulmonary embolism. Publications with at least 10 events in total were eligible. The network meta-analysis was performed using an extension of frequentist random effects models for mixed multiple treatment comparisons. Unadjusted relative risks with 95% confidence intervals were reported.Two independent reviewers extracted data from selected studies. MAIN RESULTS: 3110 publications were retrieved through a search strategy; 25 publications reporting on 26 studies were included. Incidence of venous thrombosis in non-users from two included cohorts was 0.19 and 0.37 per 1 000 person years, in line with previously reported incidences of 0,16 per 1 000 person years. Use of combined oral contraceptives increased the risk of venous thrombosis compared with non-use (relative risk 3.5, 95% confidence interval 2.9 to 4.3). The relative risk of venous thrombosis for combined oral contraceptives with 30-35 µg ethinylestradiol and gestodene, desogestrel, cyproterone acetate, or drospirenone were similar and about 50-80% higher than for combined oral contraceptives with levonorgestrel. A dose related effect of ethinylestradiol was observed for gestodene, desogestrel, and levonorgestrel, with higher doses being associated with higher thrombosis risk. AUTHORS' CONCLUSIONS: All combined oral contraceptives investigated in this analysis were associated with an increased risk of venous thrombosis. The effect size depended both on the progestogen used and the dose of ethinylestradiol. Risk of venous thrombosis for combined oral contraceptives with 30-35 µg ethinylestradiol and gestodene, desogestrel, cyproterone acetate and drospirenone were similar, and about 50-80% higher than with levonorgestrel. The combined oral contraceptive with the lowest possible dose of ethinylestradiol and good compliance should be prescribed-that is, 30 µg ethinylestradiol with levonorgestrel.

Effects of metformin or an oral contraceptive containing cyproterone acetate on serum c-reactive protein, interleukin-6 and soluble vascular cell adhesion molecule-1 concentrations in women with polycystic ovary syndrome.

The aim of the present study was to evaluate the effects of commonly used treatment regimens such as metformin (MET) or an oral contraceptive pill (OC) containing ethynyloestradiol and cyproterone acetate (EE-CPA) on surrogate serum CVD risk factors and markers of endothelial dysfunction (CRP, IL-6, sVCAM) in women with PCOS.This study was conducted in a crossover design in order to compare the effects of 2 different treatment regimens in the same subject and has been registered under the number NCT01798875 in the ClinicalTrials.gov registry.42 women with PCOS (age range 18-36 years, median BMI 24.9) were randomly assigned to treatment with MET (850 mg bid) or EE-CPA containing OC for 4 months. After 2 months washout period, treatments were crossed over.Treatment with and OC increased significantly serum CRP concentrations (from 0.77 mg/l [95% CI: 0.70; 2.18] to 1.70 mg/l [95% CI: 1.65; 3.69], P<0.001). Treatment with MET slightly reduced serum CRP levels, but this difference did not reach statistical significance (P=0.08). 4 months treatment with MET or EE-CPA had no effect on serum IL-6 and sVCAM-1 concentrations (P>0.05).Treatment with EE-CPA containing OC for 4 months in women with PCOS significantly raises serum CRP. Since this rise was not accompanied by the increase in serum concentrations of IL-6, which is the most potent and effective stimulant of hepatic CRP production, we can speculate that this effect is caused by the liver first-pass effect of oral oestrogen administration. If this in turn can confer, cardiovascular risk among these women warrants further -studies.

[The enigma of quaternary prevention in Primary Care. When and when not to do it (presentation of two cases)]. / El enigma de la prevención cuaternaria en atención primaria. Cuándo hacer y cuándo no hacer (a propósito de 2 casos).

Quaternary prevention has been commonly defined with the "primum non nocere" of classical texts by many authors. The daily life of our primary care consultations are full of patients in which we wondered if we try to obtain the benefit of our intervention will exceed the damage we cause him to intervene. Patients with multiple comorbidities, polypharmacy and complex are common in our consultations and it is becoming more difficult to move the balance of our actions, diagnostic or therapeutic benefit to the side. Through 2 cases often move to the reflection of this problem. Quaternary prevention must also be present in our daily activities.

Hormonal treatment reduces psychobiological distress in gender identity disorder, independently of the attachment style.

INTRODUCTION: Gender identity disorder may be a stressful situation. Hormonal treatment seemed to improve the general health as it reduces psychological and social distress. The attachment style seemed to regulate distress in insecure individuals as they are more exposed to hypothalamic-pituitary-adrenal system dysregulation and subjective stress. AIM: The objectives of the study were to evaluate the presence of psychobiological distress and insecure attachment in transsexuals and to study their stress levels with reference to the hormonal treatment and the attachment pattern. METHODS: We investigated 70 transsexual patients. We measured the cortisol levels and the perceived stress before starting the hormonal therapy and after about 12 months. We studied the representation of attachment in transsexuals by a backward investigation in the relations between them and their caregivers. MAIN OUTCOME MEASURES: We used blood samples for assessing cortisol awakening response (CAR); we used the Perceived Stress Scale for evaluating self-reported perceived stress and the Adult Attachment Interview to determine attachment styles. RESULTS: At enrollment, transsexuals reported elevated CAR; their values were out of normal. They expressed higher perceived stress and more attachment insecurity, with respect to normative sample data. When treated with hormone therapy, transsexuals reported significantly lower CAR (P < 0.001), falling within the normal range for cortisol levels. Treated transsexuals showed also lower perceived stress (P < 0.001), with levels similar to normative samples. The insecure attachment styles were associated with higher CAR and perceived stress in untreated transsexuals (P < 0.01). Treated transsexuals did not expressed significant differences in CAR and perceived stress by attachment. CONCLUSION: Our results suggested that untreated patients suffer from a higher degree of stress and that attachment insecurity negatively impacts the stress management. Initiating the hormonal treatment seemed to have a positive effect in reducing stress levels, whatever the attachment style may be.