Antonietta Costantino

Male Hormonal Contraception: A Double-Blind, Placebo-Controlled Study

BACKGROUND This study was performed to assess spermatogenesis suppression and safety of a new combination of an etonogestrel (ENG) implant combined with testosterone undecanoate (TU) injections for male contraception. This is the first large placebo-controlled study for male hormonal contraception. DESIGN AND STUDY SUBJECTS In this double-blind, multicenter study, we randomly assigned 354 healthy men to receive either a low- or high-release ENG implant sc combined with im TU injections (750 mg every 10 or 12 wk or 1000 mg every 12 wk) or placebo implant and injections. Treatment duration was 42 or 44 wk and posttreatment follow-up at least 24 wk. RESULTS Overall, spermatogenesis was suppressed to 1 million/ml or less at wk 16 in 89% of men, with approximately 94% in two high-release ENG groups. Suppression was maintained up to the end of the treatment period in 91% of men. For all men who completed the treatment period, 3% never achieved 1 million/ml or less. Median recovery time to a sperm concentration above 20 million/ml was 15 wk (mean 17 wk, 95% confidence interval 16-18 wk). Treatment was well tolerated. As compared with the placebo group, more men in the active treatment groups reported adverse events such as weight gain, mood changes, acne, sweating, or libido change. For both spermatogenesis suppression and safety, differences were small between the active treatment groups. CONCLUSIONS The combination of an ENG implant with TU injections is a well-tolerated male hormonal method, providing effective and reversible suppression of spermatogenesis. Although the results are good, there is still room for improvement, possibly by adjusting the dose regimen or changing the mode of application.

Cross-sex hormone administration changes pain in transsexual women and men.

Abstract Chronic pain is gender‐related, since there is a clear predominance of one sex with respect to the other in most pain syndromes. Gonadal hormones are known to affect the occurrence and incidence of pain. Transsexuals receive cross‐sex hormones to develop and maintain somatic characteristics of the opposite sex: male to female transsexuals (MtF) are administered estrogens and anti‐androgens, while female to male transsexuals (FtM) are administered androgens. Hence, these subjects represent a model to study the relationship between sex hormones and pain. Questionnaires dealing with sociodemographic data and pain (occurrence, frequency, duration, intensity, location and associated symptoms) were administered to both MtF and FtM transsexuals under hormone treatment for sex reassignment for at least 1 year. Forty‐seven MtF and 26 FtM completed the questionnaires. Fourteen of the 47 MtF (29.8%) reported painful conditions, which in 11 subjects were not present before the beginning of hormone treatment. Pain consisted mainly of headaches and breast and musculoskeletal pain. Five subjects suffered from more than one pain condition. Sixteen of the 26 FtM (61.5%) reported pain. In 11 subjects, the pain was present before the beginning of hormone intake, and in 6 of them it improved after testosterone administration. These data suggest that marked changes in sex hormones affect the occurrence of pain in a high percentage of humans but not in all of them. Whether these effects are due to peripheral or central actions of sex steroids is unknown.

Prevalence of sexual dysfunction among postmenopausal women with and without metabolic syndrome.

INTRODUCTION The metabolic syndrome (MetS) is a multifactorial disease characterized by the co-occurrence of impaired glucose tolerance/diabetes, central obesity, high levels of triglycerides, low levels of high-density lipoprotein, and hypertension. Its prevalence is higher in menopausal women. We, and others, have recently shown that female sexual dysfunction (FSD) affects menopausal women. Whether the presence of MetS may be linked to a higher risk of FSD in menopausal women is unknown. AIMS THE AIMS OF OUR STUDY WERE (i) to evaluate the prevalence of FSD in women with MetS (based on National Cholesterol Education program-Adult Treatment Panel III 2009 criteria) in comparison with healthy controls and (ii) to evaluate the influence of singular components of MetS on female sexual function. METHODS The Female Sexual Function Index (FSFI) questionnaire, the Female Sexual Distress Scale (FSDS), and The Middlesex Hospital Questionnaire were administered to 103 postmenopausal women with MetS and 105 healthy postmenopausal controls (HC). Female sexuality was defined as dysfunctional when FSFI score was <23 and FSDS was >15. MAIN OUTCOME MEASURES FSFI and FSDS were completed by women with and without MetS. RESULTS The prevalence of women with sexual dysfunction was higher in MetS women than HC (39/103 [37.9%] vs. 20/105 [19%], P = 0.003). The prevalence of both pathological scores in every FSFI domain and FSDS score was higher in MetS women than HC. The logistic regression, considering age and the length of relationship as a common starting point, shows that higher levels of triglycerides are linked to a higher risk of presenting FSD (odds ratio = 2.007 95% confidence interval [1.033-3.901]) in the whole population. CONCLUSIONS Our preliminary results suggest that prevalence of FSD is higher in women with MetS in comparison with healthy controls. Higher levels of triglycerides are linked to a higher risk of presenting FSD.

Small Variations in Crucial Steps of TUNEL Assay Coupled to Flow Cytometry Greatly Affect Measures of Sperm DNA Fragmentation

Techniques for assessing sperm DNA damage are numerous and various. There are 2 main types of assay: direct and indirect. The former directly detects the amount of sperm DNA damage, whereas the latter reveals the effects of an exogenous insult on sperm chromatin. In addition, even considering the same type of technique, different strategies to reveal or quantify sperm DNA damage, or both, are used. Finally, these techniques, except for sperm chromatin structure assay (SCSA), lack standardized protocols to which all users can adhere to minimize interlaboratory variations. In this study, we investigated the effects of some of the many ways the terminal deoxynucleotidyl transferase-mediated fluorescein-dUTP nick end labeling (TUNEL) assay is performed when measuring sperm DNA fragmentation by flow cytometry. In addition, by using an established procedure, we determined the precision of the technique by calculating intra-assay coefficients of variation (CVs). We found that concentration of the fixative, the time of storage of fixed samples, the fluorochrome used to label DNA breaks, and the method used to analyze flow cytometric data all greatly affect the measures of sperm DNA fragmentation. In particular, we found that treatment with paraformaldehyde produced additional damage in most samples, suggesting that TUNEL also can be considered an indirect assay when performed in semen samples treated with such a fixative reagent. We also showed that 2 different methods used to analyze data yielded results that, albeit correlating, were different and associated differently to semen quality. On the contrary, the TUNEL assay, as measured here, showed low intraassay CVs, resulting in a quite precise technique when performed in established conditions.

Effects of Testosterone Undecanoate Administered Alone or in Combination with Letrozole or Dutasteride in Female to Male Transsexuals

INTRODUCTION Testosterone undecanoate (TU) has potential as androgen therapy for ovariectomized female to male (FtM) transsexual subjects; however, the long-term physiologic effects of TU treatment, the significance of testosterone (T), and the T metabolites dihydrotestosterone (DHT) and estradiol (E) on specific outcome parameters are currently unknown. AIM The aim of this study was to investigate the long-term treatment of TU with regard to bone metabolism, body composition, and lipid profile in FtM subjects, and to evaluate the relationship between observed effects and circulating levels of T, E, and DHT. MAIN OUTCOME MEASURES Circulating follicle-stimulating hormone, luteinizing hormone, T, E, DHT, and lipid concentrations were measured, as well as bone metabolism, body composition, and insulin resistance. METHODS This was a 1-year, randomized treatment, open-label, uncontrolled safety study. Fifteen ovariectomized FtM subjects from an outpatient clinic were divided into three groups to receive TU 1,000 mg alone or in combination with oral administration of letrozole (L) 2.5 mg/die or dutasteride (D) 0.5 mg/die for a period of 54 weeks. RESULTS TU alone and TU + D treatments were successful in terms of hormone adjustment, did not result in any adverse effects, and were well-tolerated. Bone mineral density decreased by an average of 0.9 g/cm(2) in the TU + L group, and the addition of D resulted in a failure to gain lean mass. CONCLUSIONS This study confirmed that TU is a successful and safe treatment for FtM subjects. These data indicate that E has an important role in bone metabolism and that DHT may play a role in muscle metabolism.

A Prospective Study on Sexual Function and Mood in Female-to-Male Transsexuals During Testosterone Administration and After Sex Reassignment Surgery

Testosterone administration in female-to-male transsexual subjects aims to develop and maintain the characteristics of the desired sex. Very little data exists on its effects on sexuality of female-to-male transsexuals. The aim of this study was to evaluate sexual function and mood of female-to-male transsexuals from their first visit, throughout testosterone administration and after sex reassignment surgery. Participants were 50 female-to-male transsexual subjects who completed questionnaires assessing sexual parameters and mood. The authors measured reproductive hormones and hematological parameters. The results suggest a positive effect of testosterone treatment on sexual function and mood in female-to-male transsexual subjects.

Effects of Three Different Testosterone Formulations in Female-to-Male Transsexual Persons

INTRODUCTION Gender dysphoria is characterized by a strong discomfort with the gender assigned at birth and the urge to live as a member of the opposite gender. The acquisition of phenotypic features of the desired gender requires the use of cross-sex hormones. Female-to-male (FtM) transsexual persons are treated with testosterone to induce virilization. AIM The aim of the study was to assess the effects of three different testosterone formulations on body weight and composition and metabolic and bone parameters. METHODS Forty-five FtM transsexuals were randomly assigned to receive testoviron depot (i.m.: 100 mg/10 days; n = 15), testosterone gel (50 mg/die; n = 15), and testosterone undecanoate (i.m.: 1,000 mg every 6 weeks for the first 6 weeks and then every 12 weeks, n = 15). FtM individuals were studied before, at week 30, and at week 54 of testosterone treatment. MAIN OUTCOME MEASURES Anthropometric, metabolic, bone, hematological, and biochemical parameters were evaluated at baseline and after 12 months of treatment. RESULTS Lean body mass significantly increased and fat mass decreased in all groups. No modifications were reported in fasting insulin and insulin sensitivity index. High-density plasma lipoprotein levels declined significantly and low-density lipoprotein concentrations increased significantly in the three groups. The activated partial thromboplastin time and factor I did not change while prothrombin time significantly increased in all groups. At week 54, all subjects were amenorrheic and time to amenorrhea did not differ between the three groups. Current general life satisfaction was increased in all subjects after 1 year of treatment. CONCLUSIONS One-year testosterone administration in FtM transsexuals appears to be very safe with no differences among the testosterone formulations used. Our study is preliminary, and the detection of subtle or long-term differences in the effects of the three formulations may require further larger and longer term studies in this and other populations.

Androgen receptor expression in the human vagina under different physiological and treatment conditions

Recent data report an important role of testosterone (T) in modulating female sexual responses, but little is known about the expression and distribution of androgen receptor (AR) in the human vagina. Therefore, the aims of our study were to evaluate the expression of AR in the human vagina in premenopausal (PrM) and menopausal (M) women and in T-treated women. Vaginal biopsies were obtained from PrM and postmenopausal women and from women with gender identity disorder (female to male (FtM)) receiving exogenous T. AR gene and protein expression levels in vaginal tissues were determined by real-time PCR and western blot analysis, respectively, whereas the localization of AR in vaginal mucosa and stroma was performed by immunohistochemistry. ARs were detected by immunostaining both in the mucosa and stroma. In vaginal mucosa, AR density score decreases with age but does not change with T administration. In stromal tissue, AR density score does not change with age but significantly increases with T administration (P<0.01). AR protein expression was significantly increased in FtM subjects (P<0.001). The expression of AR messenger RNA (mRNA) evaluated by Real-time PCR showed a significantly higher mRNA expression in FtM versus M patients (P<0.01) and in PrM versus M subjects (P<0.05). In conclusion, we found AR protein and mRNA expression both in the epithelium and stroma of the human vagina in all groups of women. A negative correlation exists between age and AR expression in the vaginal mucosa. T administration increases AR expression in both the mucosa and stroma.

Long-term influence of combined oral contraceptive use on the clinical course of relapsing–remitting multiple sclerosis

OBJECTIVE To assess the long-term effects of combined oral contraceptives (COCs) on the clinical course of relapsing-remitting multiple sclerosis (RRMS), focusing on disability progression and evolution to secondary-progressive multiple sclerosis (SPMS). DESIGN Retrospective and exploratory study. SETTING Academic medical center. PATIENT(S) A total of 174 women with clinically confirmed MS; of these, 33 had evolved to SPMS at the time of enrollment in the study, whereas 141 still had a relapsing-remitting form of disease. INTERVENTION(S) Women were interviewed to obtain gynecologic and obstetric history. MAIN OUTCOME MEASURE(S) Expanded Disability Status Scale (EDSS); Multiple Sclerosis Severity Score (MSSS); annualized relapse rate; evolution to SPMS. RESULT(S) Mean±SD duration of disease was 14.3±9.8 years. Compared with non-users of COCs, COC users had lower EDSS scores and MSSS only in the subset of the population with prior or current immunomodulatory treatment. Nonuse of COCs was a predictor of disease evolution in SPMS, whether treated or not with immunomodulatory drugs. The annualized relapse rate was not influenced by COC use. No differences in EDSS scores and evolution to SPMS depending on COC formulation were detected. CONCLUSION(S) Our results suggest that COC use is associated with a less severe disease and less severe evolution. Whether different doses or types of progestin may have different effects remains to be defined.

Recent advances in hormonal male contraception

Hormones inhibit fertility in men by suppressing sperm production. Testosterone-enanthate induced azoospermia has proven to provide optimal contraceptive protection. Preliminary studies have shown that testosterone alone or androgen-progestin combinations induce profound sperm suppression in the Eastern and white populations, respectively. Thus, these regimens may represent viable options for male contraception. New long-acting androgen formulations represent a major advancement in this field, allowing for the development of more acceptable and effective regimens.