Comparative effects of the antioxidant glutathione with metformin and Diane-35 on hormonal, metabolic, and inflammatory indicators in a DHEA-induced PCOS rat model.

OBJECTIVE: Comparison of hormonal, metabolic and inflammatory markers of glutathione with metformin and Diane-35 in a rat model of PCOS induced by dehydroepiandrosterone. METHODS: Twenty-five female rats were randomized into four groups. Group 1 was administered a subcutaneous dose of 0.2 ml saline/day. Group 2 was given 0.2 ml of 1% carboxymethyl cellulose (CMC)/day orally for 28 days. A PCOS model was established with DHEA in rats. Group 3 was given 4.5 mg/kg/day of Diane-35 orally dissolved in 1% CMC for 28 days. Group 4 was given 300 mg/kg/day of metformin orally dissolved in 1 ml of saline for 28 days, and Group 5 was administered 100 mg/kg of glutathione intraperitoneally on days 35, 42, and 49. On day 56, the rats were sacrificed. Serum markers and follicle count were examined. RESULTS: Serum IL-6, hs-CRP, insulin, testosterone, SHBG, and MDA values were significantly lower in the glutathione group than in the PCOS group (p = 0.0006, p = 0.023, p = 0.0082, p = 0.0007, p = 0.0048, and p < 0.0001, respectively).The number of all follicles was similar between the control and glutathione groups (p < 0.05). When we compared the other groups with the PCOS group, the number of primary, secondary, atretic, and cystic follicles was significantly lower in the metformin and glutathione groups. The number of primordial and antral follicles was significantly higher than in the PCOS group. CONCLUSIONS: Glutathione plays anti-inflammatory and antioxidant roles, similar to metformin, by lowering serum IL-6, insulin, testosterone, CRP, and MDA levels; decreasing atretic/cystic follicle count; and improving antral follicle count and folliculogenesis in PCOS patients.

Physician Awareness of the Safe Use of Cyproterone Acetate in Europe: A Survey on the Effectiveness of Additional Risk Minimization Measures.

BACKGROUND: Cyproterone acetate (CPA) is a synthetic progesterone derivative introduced in the 1970s and prescribed as antiandrogenic therapy for inoperable prostate cancer, sexual deviations in men, and signs of androgenization in women. In 2020, the CPA summary of product characteristics (SmPC) was revised to include an updated special warning and precaution about (1) the risk of meningioma with increasing cumulative dose and (2) contraindication in patients with meningioma or history of meningioma. A Direct Healthcare Professional Communication (DHPC) was distributed. The European Medicine Agency's Pharmacovigilance Risk Assessment Committee requested that marketing authorization holders in Europe conduct a survey to assess physicians' knowledge of the updated key safety information. The primary objective of this study was to measure physicians' awareness (i.e., did they receive and review the revised SmPC and DHPC) and level of knowledge and understanding of the key safety information pertaining to the restricted use of CPA monotherapy because of the risk of meningioma. METHODS: This cross-sectional web-based survey was administered to dermatologists, endocrinologists, gynecologists, urologists, oncologists, psychiatrists, and general practitioners in France, Germany, Poland, Spain, and the Netherlands who had prescribed CPA monotherapy in the previous 12 months to assess awareness of the risk of meningioma associated with CPA monotherapy. RESULTS: Of the 613 physicians who participated, 85% correctly indicated that CPA monotherapy should be prescribed with the lowest effective dose, 75% correctly indicated that the risk of meningioma increases with increasing cumulative CPA monotherapy doses, and 73% correctly indicated that treatment with CPA-containing products must be stopped permanently if a patient is diagnosed with meningioma. Overall, 40% of physicians reported having received the DHPC, and 42% reported having received the revised SmPC. CONCLUSIONS: Despite low recall of receipt of the updated SmPC and DHPC, most physicians surveyed are aware of the meningioma risk and actions to mitigate the risk.

Effects and plasma proteomic analysis of GLP-1RA versus CPA/EE, in combination with metformin, on overweight PCOS women: a randomized controlled trial.

PURPOSE: Polycystic ovary syndrome (PCOS) is characterized by reproductive dysfunctions and metabolic disorders. This study aims to compare the therapeutic effectiveness of glucagon-like peptide-1 receptor agonist (GLP-1RA) + Metformin (Met) versus cyproterone acetate/ethinylestradiol (CPA/EE) + Met in overweight PCOS women and identify potential proteomic biomarkers of disease risk in women with PCOS. METHODS: In this prospective, open-label randomized controlled trial, we recruited 60 overweight PCOS women into two groups at a 1:1 ratio to receive CPA/EE (2 mg/day: 2 mg cyproterone acetate and 35-µg ethinylestradiol,) +Met (1500 mg/day) or GLP-1 RA (liraglutide, 1.2-1.8 mg/day) +Met (1500 mg/day) for 12 weeks. The clinical effectiveness and adverse effects were evaluated, followed by plasma proteomic analysis and verification of critical biomarkers by ELISA. RESULTS: Eighty(80%) patients completed the study. Both interventions improved menstrual cycle, polycystic ovaries, LH(luteinizing hormone) and HbA1c(hemoglobin A1c) levels after the 12-week treatment. GLP-1RA + Met was more effective than CPA/EE + Met in reducing body weight, BMI (Body Mass Index), and waist circumference, FBG(fasting blood glucose), AUCI(area under curve of insulin),TC (Total Cholesterol), IL-6(Interleukin-6) and improving insulin sensitivity, and ovulation in overweight women with PCOS, with acceptable short-term side effects. CPA/EE + Met was more effective in improving hyperandrogenemia, including T(total testosterone), LH, LH/FSH(Luteinizing hormone/follicle-stimulating hormone), SHBG(sex hormone-binding globulin) and FAI (free androgen index). By contract, GLP-1RA+Met group only improved LH. Plasma proteomic analysis revealed that the interventions altered proteins involved in reactive oxygen species detoxification (PRDX6, GSTO1, GSTP1, GSTM2), platelet degranulation (FN1), and the immune response (SERPINB9). CONCLUSIONS: Both CPA/EE+Met and GLP-1RA + Met treatment improved reproductive functions in overweight PCOS women. GLP-1RA + Met was more effective than CPA/EE + Met in reducing body weight, BMI, and waist, and improving metabolism, and ovulation in overweight women with PCOS, with acceptable short-term side effects. CPA/EE + Met was more effective in reducing hyperandrogenemia. The novel plasma biomarkers PRDX6, FN1, and SERPINB9, might be indicators and targets for PCOS treatment. TRIAL REGISTRATION CLINICALTIALS. GOV TRIAL NO: NCT03151005. Registered 12 May, 2017, https://clinicaltrials.gov/ct2/show/NCT03151005 .

No effects of the antiandrogens cyproterone acetate (CPA), flutamide and p,p'-DDE on early sexual differentiation but CPA-induced retardation of embryonic development in the domestic fowl (Gallus gallus domesticus).

Because a wide range of environmental contaminants are known to cause endocrine disorders in humans and animals, in vivo tests are needed to identify such endocrine disrupting chemicals (EDCs) and to assess their biological effects. Despite the lack of a standardized guideline, the avian embryo has been shown to be a promising model system which responds sensitively to EDCs. After previous studies on the effects of estrogenic, antiestrogenic and androgenic substances, the present work focuses on the effects of in ovo exposure to p,p'-DDE, flutamide and cyproterone acetate (CPA) as antiandrogenic model compounds regarding gonadal sex differentiation and embryonic development of the domestic fowl (Gallus gallus domesticus). The substances were injected into the yolk of fertilized eggs on embryonic day one. On embryonic day 19 sex genotype and phenotype were determined, followed by gross morphological and histological examination of the gonads. Treatment with flutamide (0.5, 5, 50 µg/g egg), p,p'-DDE (0.5, 5, 50 µg/g egg) or CPA (0.2, 2, 20 µg/g egg) did not affect male or female gonad development, assessed by gonad surface area and cortex thickness in both sexes and by the percentage of seminiferous tubules in males as endpoints. This leads to the conclusion that antiandrogens do not affect sexual differentiation during embryonic development of G. gallus domesticus, reflecting that gonads are not target organs for androgens in birds. In ovo exposure to 2 and 20 µg CPA/g egg, however, resulted in significantly smaller embryos as displayed by shortened lengths of skull, ulna and tarsometatarsus. Although gonadal endpoints were not affected by antiandrogens, the embryo of G. gallus domesticus is shown to be a suitable test system for the identification of substance-related mortality and developmental delays.

Biotransformation of cyproterone acetate, drospirenone, and megestrol acetate in agricultural soils: Kinetics, microbial community dynamics, transformation products, and mechanisms.

The occurrence of biologically active synthetic progestins in agricultural soils is of growing concern due to their potential to disrupt the endocrine function of aquatic fish in nearby surface waters. This study investigated the biotransformation outcomes of cyproterone acetate (CPA), drospirenone (DRO), and megestrol acetate (MGA) in four agricultural soils. The biotransformation data were fitted to a first-order decay model (R2 = 0.93-0.99), with half-lives and first-order decay coefficients ranging from 76.2-217 h and 9.10 × 10-3-3.20 × 10-3 (h-1), respectively. Abundant biotransformation products (TPs) were generated during incubation, with the number and yields varying across the four soils. 1,2-Dehydrogenation was the main transformation pathway of DRO in the four soils (yields of 32.3-214 %). Similarly, 1,2-dehydrogenation was the most relevant transformation pathway of MGA in the four soils (yields of 21.8-417 %). C3 reduction was the major transformation pathway of CPA in soils B, C, and D (yields of 114-245 %). Hydrogenation (yield of 133 %) and hydroxylation (yield of 21.0 %) were the second major transformation pathway of CPA in soil B and C, respectively. In particular, several TPs exhibited progestogenic and antimineralocorticoid activity, as well as genotoxicity. The high-throughput sequencing indicated that interactions between microorganisms and soil properties may affect biotransformation. Spearman correlation and bidirectional network correlation analysis further revealed that soil properties can directly interfere with the soil sorption capacity for the progestins, thus affecting biotransformation. In particular, soil properties can also limit or promote biotransformation and the formation of TPs (i.e., biotransformation pathways) by affecting the relative abundances of relevant microorganisms. The results of this study indicate that the ecotoxicity of synthetic progestins and related TPs can vary across soils and that the assessment of environmental risks associated with these compounds requires special consideration of both soil properties and microbial communities.

Different kinds of oral contraceptive pills in polycystic ovary syndrome: a systematic review and meta-analysis.

OBJECTIVE: To compare between different combined oral contraceptive pills (COCPs) as part of the update of the International Evidence-Based Guidelines on the Assessment and Management of polycystic ovary syndrome (PCOS). DESIGN: A systematic review and meta-analysis was performed, Prospero CRD42022345640. METHODS: MEDLINE, EMBASE, All EBM, CINAHL, and PsycINFO was searched on July, 8, 2022, for studies including women with PCOS, comparing 2 different COCPs in randomized controlled trials. RESULTS: A total of 1660 studies were identified, and 19 randomized controlled trials (RCTs) were included.Fourth-generation COCP resulted in lower body mass index (BMI) (mean difference [MD] 1.17 kg/m2 [95% confidence interval {CI} 0.33; 2.02]) and testosterone (MD 0.60 nmol/L [95% CI 0.13; 1.07]) compared with third-generation agents, but no difference was seen in hirsutism.Ethinyl estradiol (EE)/cyproterone acetate (CPA) was better in reducing hirsutism as well as biochemical hyperandrogenism (testosterone [MD 0.38 nmol/L {95% CI 0.33-0.43}]) and BMI (MD 0.62 kg/m2 [95% CI 0.05-1.20]) compared with conventional COCPs.There was no difference in hirsutism between high and low EE doses. No evidence regarding natural estrogens in COCP was identified. CONCLUSION: With current evidence, combined regimens containing an antiandrogen (EE/CPA) may be better compared with conventional COCPs in reducing hyperandrogenism, but EE/CPA will not be recommended as a first-line COCP treatment by the pending PCOS guideline update, due to higher venous thrombotic events (VTE) risk in the general population. Later-generation progestins offer theoretical benefits, but better evidence on clinical outcomes is needed in women with PCOS. TRIAL REGISTRATION: The protocol for the systematic review was registered prospectively in Prospero, CRD42022345640.

Dose-Dependent Protective Effect of Hygrophila auriculata Seeds on Cyproterone Acetate-Induced Testicular Dysfunction.

Infertility affects 15% of global population. This study was designed to search out the most effective dose of chloroform fraction of hydro-ethanolic extract of Hygrophila auriculata seed to ameliorate cyproterone acetate (CPA)-treated male subfertility. The rats were made subfertile by CPA at the dose of 2.5 mg/100gm body weight for 45 days. The male subfertility represented by low sperm concentration, less motile, less viable, and less hypo osmotic tail swelled spermatozoa in CPA-treated group. Serum LH, FSH, and testosterone levels were significantly decreased in CPA-treated group in respect to control. Androgenic key enzyme Δ5,3ß-HSD, 17ß-HSD activities and gene expression pattern were also decreased significantly in respect to control. These antispermatogenic and antiandrogenic activities of CPA were significantly recovered after the treatment of Hygrophila auriculata at the dose of 2.5 mg, 5mg, and 10 mg/100gm body weight. CPA also generate oxidative free radical that indicated by altered catalase, superoxide dismutase, and peroxidase activities and protein expression pattern along with conjugated diene and thiobarbituric acid reactive substance levels in testis. Expression pattern of Bax and Bcl2 genes were deviated from control after CPA treatment. Significant diminution of body weight, organo-somatic indices, and SGOT, SGPT activities were observed in CPA-treated group. All these biomarkers significantly recovered towards control after the treatment of Hygrophila auriculata at different doses. More significant recovery was observed in 5 mg and 10 mg of chloroform fraction-treated group and 5 mg dose, i.e., the minimum therapeutic dose to recover the CPA-induced subfertility.

Women consuming oral contraceptives containing cyproterone acetate and ethinylestradiol show a higher risk of thyroid cancer than nonusers.

This study explored whether the risk of thyroid cancer in Asian women is associated with consumption of oral contraceptives (Diane-35). We conducted a population-based, retrospective cohort study using the Taiwan National Health Insurance Research Database. From the database, 9865 women aged 18 to 65 years who were prescribed Diane-35 between 2000 and 2012 were included in the Diane-35 group, and 39,460 women who were not prescribed Diane-35 were included in the comparison group and were frequency-matched by age and index year. Both groups were followed until 2013 to calculate the incidence of thyroid cancer. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazard model. The median (standard deviation) follow-up duration was 7.08 (3.63) and 7.04 (3.64) years in the Diane-35 and the comparison group, respectively. The incidence of thyroid cancer was 1.80-fold higher in the Diane-35 group than in the comparison group (2.72 vs 1.51 per 10,000 person-years). The cumulative incidence of thyroid cancer was significantly higher in the Diane-35 group than in the comparison group (log-rank test, P = .03). An elevated hazard ratio of thyroid cancer was observed in the Diane-35 group than in the comparison group (HR: 1.91, 95% CI: 1.10-3.30). In subgroup analysis, patients aged 30 to 39 years showed a higher hazard ratio of developing thyroid cancer after consuming Diane-35 than those in the comparison group (HR: 5.58, 95% CI: 1.84-16.91). The study provides evidence that women aged 30 to 39 years consuming Diane-35 are at increased risk of thyroid cancer. Nevertheless, a larger population with a longer follow-up may be necessary to confirm causality.

Respective roles of Pik3ca mutations and cyproterone acetate impregnation in mouse meningioma tumorigenesis.

Despite their rarity, PIK3CA mutations in meningiomas have raised interest as potentially targetable, ubiquitous mutations owing to their presence in sporadic benign and malignant tumors but also in hormone-related cases. Using new genetically engineered mouse models, we here demonstrate that Pik3ca mutations in postnatal meningeal cells are sufficient to promote meningioma formation but also tumor progression in mice. Conversely, hormone impregnation, whether alone or in association with Pik3ca and Nf2 mutations, fails to induce meningioma tumorigenesis while promoting breast tumor formation. We then confirm in vitro the effect of Pik3ca mutations but not hormone impregnation on the proliferation of primary cultures of mouse meningeal cells. Finally, we show by exome analysis of breast tumors and meninges that hormone impregnation promotes breast tumor formation without additional somatic oncogenic mutation but is associated with an increased mutational burden on Pik3ca-mutant background. Taken together, these results tend to suggest a prominent role of Pik3ca mutations over hormone impregnation in meningioma tumorigenesis, the exact effect of the latter is still to be discovered.

Metabolic and Dietary Factors in Acne Vulgaris and Evaluation of the Acne Vulgaris Treatment with Oral Contraceptive-Based Therapies in Young Adult Women.

The etiopathogenesis of acne is complex, as several endo- and exogenous factors that affect the sebaceous-hair unit are involved in the development of acne lesions. The main aim of the study was to evaluate selected metabolic parameters before treatment. Another goal of the study was to determine the correlation between selected metabolic and dietary parameters and the severity of acne before treatment. The third objective was to assess the severity of acne before and after treatment, considering the type of treatment used. The final objective was to assess the relationship between the difference in acne severity before and after treatment, considering the type of treatment used and factors of dairy or sweets intake. 168 women participated in the study. The patients belonged to two groups: the study group (99 patients with acne vulgaris) and the control group (69 patients without skin lesions). The study group was divided into subgroups according to the treatment used: contraceptive preparation, contraceptive preparation and cyproterone acetate, and contraceptive preparation and isotretinoin preparation. We found that LDL levels and consumption of sweets correlated with acne severity. The mainstay of acne treatment is contraceptive treatment (ethinylestradiol and drospirenone). The effectiveness of the three contraceptive-based treatments was confirmed by observing the severity of acne. There were no significant correlations between the difference in acne severity before and after treatment with the three treatments and factors of dairy or sweet consumption.

Opposed evolution of the osseous and soft parts of progestin-associated osteomeningioma after progestin intake discontinuation.

OBJECTIVE: Numerous studies have confirmed a strong association between progestins and meningiomas and the regression and/or stabilization of meningiomas after discontinuation of treatment. Osteomeningiomas represent a small subgroup of meningiomas that appear to be more common among progestin-related meningiomas. However, the specificity of the behavior of this subset of meningiomas after discontinuation of progestin has not yet been assessed. METHODS: Thirty-six patients (mean age 49.5 years) who presented with at least one progestin-related osteomeningioma (48 tumors total) were identified from a prospectively collected database of patients and had been referred to our department for meningioma and had documented use of cyproterone acetate, nomegestrol acetate, and/or chlormadinone acetate. Hormonal treatment was stopped at the time of diagnosis for all the patients, and the clinical and radiological evolution of this subgroup of tumors was evaluated. RESULTS: For half of the 36 patients, treatment was prescribed for signs of hyperandrogenism, such as hirsutism, alopecia, or acne. Most lesions were spheno-orbital (35.4%) or frontal (31.2%). Although the tissular part of the meningioma shrank in 77.1% of cases, the osseous part exhibited discordant behavior with 81.3% showing volume progression. The combination of estrogens, as well as the prolonged duration of progestin treatment, seems to increase the risk of progression of the osseous part after treatment discontinuation (p = 0.02 and p = 0.028, respectively). No patient required surgical treatment at diagnosis or during the study. CONCLUSIONS: These results show that while the soft intracranial part of progestin-related osteomeningioma tumor is the most likely to regress after treatment discontinuation, the bony part is more likely to increase in volume. These findings suggest the need for careful follow-up of these patients, especially those with tumors near the optical apparatus.

Circulating follistatin concentrations in adolescent PCOS: Divergent effects of randomized treatments.

Purpose: Follistatin is a glycoprotein that represses members of the transforming growth factor-ß superfamily including activin. Higher follistatin levels have been associated with an increased risk for type 2 diabetes and with polycystic ovary syndrome (PCOS). In non-obese adolescent girls with PCOS, insulin sensitization results in a healthier endocrine-metabolic outcome than oral contraception (OC); we assessed whether those differences are underscored by changes in serum follistatin concentrations. Methods: Circulating follistatin, endocrine-metabolic markers and hepato-visceral fat were measured longitudinally in 72 girls with PCOS [age, 16 years; body mass index (BMI), 23 Kg/m2] randomized to receive PioFluMet [pioglitazone (7.5 mg/d), metformin (850 mg/d) and flutamide (62.5 mg/d), n=17]; EE-CA [an OC containing 35 µg ethinylestradiol (EE) and 2 mg cyproterone acetate (CA), n=17]; SPIOMET [Spironolactone (50 mg/d), pioglitazone (7.5 mg/d) and metformin (850 mg/d), n=18], or EE-LNG [an OC containing 20 µg EE and 100 mg levonorgestrel (LNG), n=20]. Twenty-eight age- and BMI-matched healthy girls served as controls. Results: Pre-treatment follistatin levels were similar in PCOS and controls. OCs raised serum follistatin after 6 months (6.8-fold vs 2.5-fold for EE-CA and EE-LNG, respectively). Neither SPIOMET nor PioFluMet changed follistatin levels. Follistatin correlated negatively with high-molecular weight adiponectin and positively with mean serum insulin concentrations during an oral glucose tolerance test at baseline, and with liver fat after 6 months. Conclusion: In girls with PCOS, follistatin levels rise significantly after 6 months on OCs and this increase associates to a worsening of markers of insulin resistance and to changes in liver fat.

Incidence of hypertension in young transgender people after a 5-year follow-up: association with gender-affirming hormonal therapy.

In order to assess the risk of hypertension development, we performed a retrospective analysis of the clinical records of consecutive transgender patients who began gender-affirming hormonal therapy in our Outpatient Gender Identity Clinic with <30 years of age and had a follow-up >5 years. 149 transgender women treated with estradiol and 153 transgender men treated with testosterone were included; 129 of the transgender women received also androgen blockers (54 spironolactone, 49 cyproterone acetate and 26 LHRH agonists). The annual incidence of hypertension in young transgender men (1.18%) seemed comparable to that of the general population. In young transgender women, it seemed higher (2.14%); we found that the choice of androgen blocker had a remarkable effect, with a highly significant increase in patients treated with cyproterone acetate (4.90%) vs. the rest (0.80%); the adjusted hazard-ratio was 0.227 (p = 0.001). Correlation, logistic regression and mediation analyses were performed for the associations of the available clinical variables with the increase in systolic blood pressure and the onset of hypertension, but besides the use of cyproterone acetate, only the ponderal gain was found significant (Spearman's r: 0.361, p < 0.001); with a 36.7% mediation effect (31.2-42.3%). Cyproterone acetate has additional known risks, such as meningioma; although we cannot conclusively prove that it has a role in the development of hypertension, we conclude that the use of cyproterone acetate for this indication should be reconsidered.

Changes in Serum Testosterone and Adrenal Androgen Levels in Transgender Women With and Without Gonadectomy.

BACKGROUND: Initiating feminizing gender-affirming hormone therapy (GAHT) in transgender women causes a steep decline in serum testosterone. It is unknown if testosterone concentrations change further and whether adrenal androgen levels change during feminizing GAHT and after gonadectomy. This limits clinical decision making in transgender women with symptoms attributed to GAHT or gonadectomy. METHODS: Transgender women (n = 275) initiating estradiol and cyproterone acetate (CPA) were included at baseline, and had follow-up visits after 3 months, 12 months, and 2 to 4 years. During follow-up, 49.5% of transgender women underwent a gonadectomy. Total testosterone (TT), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and androstenedione (A4) were measured using liquid chromatography tandem mass spectrometry. RESULTS: After 3 months of GAHT, mean TT, calculated free testosterone (cFT), and A4 decreased by 18.4 nmol/L (95% CI, -19.4 to -17.4, P < 0.001 [ie, -97.1%]), 383 pmol/L (95% CI, -405 to -362, P < 0.001 [ie, -98.3%]), and 1.2 nmol/L (95% CI, -1.4 to -1.0, P < 0.001 [ie, -36.5%]), respectively, and remained stable thereafter. DHEA and DHEAS decreased by 7.4 nmol/L (95% CI, -9.7 to -5.1 [ie, -28.0%]) and 1.8 µmol/L (95% CI, -2.2 to -1.4 [ie, -20.1%]), respectively, after 1 year and did not change thereafter. After gonadectomy, CPA therapy is stopped, which induced no further change in TT, cFT, DHEA, DHEAS, and A4 compared with those who did not undergo gonadectomy. CONCLUSIONS: Our findings confirm that after an initial drop, testosterone levels in transgender women remain stable. Adrenal androgens decrease in the first year of CPA and estrogen supplementation and remain unchanged after gonadectomy. Androgens did not change after gonadectomy and cessation of CPA. Correlates with clinical symptoms remain to be elucidated.

Gender confirmation hormonal treatment use in young Polish transgender binary and non-binary persons.

INTRODUCTION: Gender confirmation hormonal treatment (GCHT) is a cornerstone of medical treatments for persistent gender dysphoria, which is expected and required by many transgender binary and non-binary individuals. Many protocols have been published, and the qualification process is guided by the World Professional Association for Transgender Health Standards of Care. The standards and other documents such as the Endocrine Society Clinical Practice Guideline provide gender confirmation hormonal care also for minors. However, the issue of starting these treatments in younger populations is still marked by controversy. This preliminary study aimed to inquire into GCHT (medications used, timing of its initiation, its tolerance, and sources of information on the treatment) in a convenience sample of young Polish transgender binary and non-binary persons. MATERIAL AND METHODS: A total of 166 adult transgender participants answered our online questionnaire between November 2020 and December 2021. The population was divided into 2 groups: assigned male at birth (AMB, n = 37) and assigned female at birth (AFB, n = 126). Subsequently, division into binary and non-binary was applied to these groups. RESULTS: Most patients (91.9% AMB and 92.2% AFB) did not use gender confirmation medical treatments before the age of 18 years. The most common medication used for GCHT before the age of 18 was cyproterone acetate for AMB and testosterone for AFB. When asked about their opinion on the timing (age) of initiating GCHT, 73.1% of the AMB and 59.2% of the AFB participants shared the view that it had been initiated much too late. By far the most common source of information on GCHT and gender confirmation surgery (GCS) was the Internet (92.2%). CONCLUSIONS: These treatments (including pubertal blocking) seem to be rarely commenced in Poland before the age of 18 years. In adults, treatment consists mostly of either testosterone or oestradiol, and cyproterone acetate and, more seldom, spironolactone are used as antiandrogens in persons assigned male at birth. In turn, gonadotropin-releasing hormone agonists are barely used at all. Specialists need to be more aware that withholding treatment in minors with gender dysphoria is not a health-neutral option. Gonadotropin-releasing hormone agonists should also be more often considered as an alternative to cyproterone acetate in the context of long-term safety.

Adverse effects of gender-affirming hormonal therapy in transgender persons: Assessing reports in the French pharmacovigilance database.

Limited data are available on adverse drug reactions (ADRs) of gender-affirming hormone therapy (HT), mainly due to the lack of population-based studies with adequate controls, thus making spontaneous reporting systems a valuable tool to detect potential side reactions. In this nationwide retrospective study, we aimed to analyze ADRs related to gender-affirming HT reported in the French pharmacovigilance database (FPVD). We requested all the individual case safety reports related to gender-affirming HT recorded in the FPVD before May 27, 2020. We excluded previously published cases and those where gender-affirming HT was not the suspected drug. A total of 28 reports of ADRs were identified. Six concerned transgender men (21-40 years) and 22 transgender women (22-68 years). In transgender men taking testosterone enanthate, all reported ADRs were cardiovascular events, with pulmonary embolism in 50% of cases. Median time to onset (TTO) was 34 months. In transgender women, antiandrogens, mainly cyproterone acetate, were involved in 68% of cases, and estrogens in 77% of cases, mostly in association with progestin or cyproterone acetate. Meningiomas were the principal ADRs, followed by cardiovascular events, with a median TTO of 5.3 months. Our data show a previously unreported, non-negligible proportion of cases indicating cardiovascular ADRs in transgender men younger than 40 years. In transgender women, cardiovascular events were the second most frequent ADR. Further research is necessary to identify risk factors that might help to the individualization of treatment strategies. There is a necessity to increase awareness, implement preventive and education measures.

Survey on the Prescription Patterns of Pharmacological Agents in Individuals Who Have Committed Sexual Offenses During Forensic Outpatient Treatment in Germany: How Many Discontinue Testosterone Lowering Medication Under Parole?

BACKGROUND: The number of individuals who sexually offended, and who are continued to be treated with pharmacological agents to reduce sex drive after their release from prison or forensic psychiatry, are not known. Furthermore, figures on the number of those who stop their sexdrive supressing antiandrogen treatment in the outpatient setting are unknown as well. This is of central importance though as it might be associated with an increased risk of recidivism. AIM: To assess prescription patterns as well as adherence to pharmacological treatment in outpatient clinics in Germany for individuals who have sexually offended and were released from prison or forensic psychiatric hospital. METHODS: A self-constructed online survey assessing the pharmacological treatment modalities was sent by e-mail to n = 103 forensic outpatient clinics in Germany. Thirty-three (32.0%) completed the questionnaire and reported about 834 patients. OUTCOMES: Prevalence of the use of different pharmacological agents in the treatment of individuals convicted for sexual offenses as well as the number of patients who have discontinued testosterone-lowering medication (TLM). RESULTS: Among all institutions, 22.4% (n = 187) of individuals received pharmacological treatment, with 40.1% receiving gonadotropin-releasing-hormone-agonists, 26.2% antipsychotics, 24.6% selective serotonin reuptake inhibitors, 6.4% cyproterone acetate, and 2.7% a combination of gonadotropin-releasing-hormone-agonists and cyproterone acetate. A significant positive correlation was found between the number of patients released from a forensic-psychiatric hospital and the number of patients treated with TLM. Within 1 year 8.6% (n = 16) stopped their TLM during or at the end of the supervision period, most of them against treatment providers advice. CLINICAL IMPLICATIONS: Substantial regional differences indicate uncertainties regarding the prescription of pharmacological agents for outpatients who have committed sexual offences in Germany. The discontinuiation of TLM within the first year of treatment against treatment providers advise in a substantial proportion of patients could be associated with a serious risk for reoffending. STRENGTHS & LIMITATIONS: The present survey captures prevalences of the pharmacotherapy in forensic aftercare facilities for individuals who have offended sexually, and is the first to record the number of discontinuations. This is a cross-sectional survey covering only 1 country, but includes a large number of individuals. CONCLUSION: Even though the number of treated individuals has increased in prisons, the majority of pharmacological treatment is still provided by forensic hospitals, which then translates into the outpatient setting. The number of those who stop taking such medication is a highly relevant topic for both forensic treatment providers and legal decision makers Sauter J, Rettenberger M, Briken P, et al. Survey on the Prescription Patterns of Pharmacological Agents in Individuals Who Have Committed Sexual Offenses During Forensic Outpatient Treatment in Germany: How Many Discontinue Testosterone Lowering Medication Under Parole?. J Sex Med 2022;19:1147-1155.

Risk of intracranial meningioma with three potent progestogens: A population-based case-control study.

BACKGROUND AND PURPOSE: A dose-dependent association between the use of cyproterone acetate (CPA) and intracranial meningioma has been identified but data for other potent progestogens are scarce. The association was assessed between intracranial meningioma surgery and exposure to three potent progestogens: CPA (≥25 mg/day), nomegestrol acetate (NOMAC) (3.75-5 mg/day) and chlormadinone acetate (CMA) (2-10 mg/day). METHODS: In this nationwide population-based case-control study, cases underwent surgery for intracranial meningioma in France from 2009 to 2018. They were matched to five control subjects for sex, year of birth and area of residence. Progestogen exposure was defined as progestogen use within the year before surgery for cases or the same date for their controls. RESULTS: In total, 25,216 cases were included (75% women, median age 58 years). Progestogen exposure was noted for 9.9% of cases (2497/25,216) and 1.9% (2382/126,080) of controls, with an odds ratio (OR) of 6.7 (95% confidence interval [CI] 6.3-7.1). The OR was 1.2 (1.0-1.4) for short-term use (<1 year) and 9.5 (8.8-10.2) for prolonged use. A strong association was identified for prolonged use of CPA (OR = 22.7, 95% CI 19.5-26.4), NOMAC (OR = 6.5, 95% CI 5.8-7.2) and CMA (OR = 4.7, 95% CI 4.5-5.3). Progestogen exposure increased the risk of meningioma for all histological grades and anatomical sites, particularly for the anterior and middle skull base: OR = 35.7 (95% CI 26.5-48.2) and 23.9 (95% CI 17.8-32.2) for CPA. The estimated number of attributable cases was 2124 (95% CI 2028-2220) (212/year). CONCLUSION: A strong association between prolonged exposure to potent progestogens and surgery for meningioma was observed. The risk increased from CMA to NOMAC to CPA. Individuals should be informed of this risk.

Hormone Concentrations in Transgender Women Who Self-Prescribe Gender Affirming Hormone Therapy: A Retrospective Study.

BACKGROUND: Self-prescribed gender-affirming hormone therapy (GAHT) is common practice among transgender women, especially in resource-limited countries, yet the effectiveness of each GAHT regimen to achieve female range sex hormone concentrations is not known. AIM: To describe the use and sex hormone concentrations of various GAHT regimens among transgender women who self prescribe in Thailand. METHODS: This was a retrospective study in a community-based setting. Five hundred and 27 records of transgender women taking GAHT who were receiving care at a community health center between January 1, 2018, and December 31, 2020 were included for the analysis. MAIN OUTCOME MEASURES: Blood total testosterone and estradiol concentration after at least a 6-month period of GAHT. RESULTS: Multiple GAHT regimens were identified including oral estradiol valerate (EV), transdermal 17ß-estradiol gel, injectable EV with hydroxyprogesterone caproate, injectable estradiol benzoate with progesterone, oral EV with cyproterone acetate (CPA), and oral contraceptive pills (OCPs). The most common GAHT regimen used by 49.1% of the participants was OCPs that contained 0.035 mg of ethinyl estradiol and 2 mg of CPA. Only 25.2% of this group had female range testosterone concentrations (<50 ng/dL). Oral EV and CPA were used by 23.1% of the participants. Most of them used 12.5 mg of CPA and 47.7% of this group had female range testosterone concentrations. There was no statistical significance between mean testosterone concentrations in CPA 12.5 and 25 mg groups, (P = .086). CLINICAL IMPLICATIONS: The inadequate sex hormone levels found in these commonly self-prescribed GAHT regimens provide information regarding the efficacy and safety of GAHT regimens for health care providers working with transgender women in a community-based setting. STRENGTHS AND LIMITATIONS: This study reflected a real-world situation and provided hormonal profiles among transgender women taking self-prescribed GAHT. However, issues in recall, medical literacy, and adherence to the medication may limit the results. CONCLUSION: Combined hormonal contraceptive pill was a commonly used GAHT regimen in Thai transgender women who self prescribe GAHT. However, this regimen was not effective to decrease testosterone concentrations to the recommended range of less than 50 ng/dL. Overall, self-prescription of GAHT does not appear to be effective in reaching target sex hormone concentrations. Including health care providers in the prescription and monitoring of GAHT may be a more effective approach in the delivery of GAHT. Salakphet T, Mattawanon N, Manojai N, et al. Hormone Concentrations in Transgender Women Who Self-Prescribe Gender Affirming Hormone Therapy: A Retrospective Study. J Sex Med 2022;19:864-871.