Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.

An Endo-European Reference Network guideline initiative was launched including 16 clinicians experienced in endocrinology, pediatric and adult and 2 patient representatives. The guideline was endorsed by the European Society for Pediatric Endocrinology, the European Society for Endocrinology and the European Academy of Andrology. The aim was to create practice guidelines for clinical assessment and puberty induction in individuals with congenital pituitary or gonadal hormone deficiency. A systematic literature search was conducted, and the evidence was graded according to the Grading of Recommendations, Assessment, Development and Evaluation system. If the evidence was insufficient or lacking, then the conclusions were based on expert opinion. The guideline includes recommendations for puberty induction with oestrogen or testosterone. Publications on the induction of puberty with follicle-stimulation hormone and human chorionic gonadotrophin in hypogonadotropic hypogonadism are reviewed. Specific issues in individuals with Klinefelter syndrome or androgen insensitivity syndrome are considered. The expert panel recommends that pubertal induction or sex hormone replacement to sustain puberty should be cared for by a multidisciplinary team. Children with a known condition should be followed from the age of 8 years for girls and 9 years for boys. Puberty induction should be individualised but considered at 11 years in girls and 12 years in boys. Psychological aspects of puberty and fertility issues are especially important to address in individuals with sex development disorders or congenital pituitary deficiencies. The transition of these young adults highlights the importance of a multidisciplinary approach, to discuss both medical issues and social and psychological issues that arise in the context of these chronic conditions.

Sexual functioning, sexual esteem, genital self-image and psychological and relational functioning in women with Mayer-Rokitansky-Küster-Hauser syndrome: a case-control study.

STUDY QUESTION: Do sexual functioning, sexual esteem, genital self-image and psychological and relational functioning in women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome differ from a comparison group of women without the condition? SUMMARY ANSWER: In comparison to controls, women with MRKH with a non-surgically or surgically created neovagina did not differ in psychological and relational functioning but reported lower sexual esteem and more negative genital self-image, intercourse-related pain, clinically relevant sexual distress and sexual dysfunction, with sexual esteem levels strongly associated with sexual distress and sexual dysfunction. WHAT IS KNOWN ALREADY: Studies on sexual functioning measured with standardized questionnaires in women with MRKH syndrome compared with women without the condition have yielded contradictory results. Factors associated with sexual functioning in this patient population have rarely been investigated. STUDY DESIGN, SIZE, DURATION: Between November 2015 and May 2017, 54 women with MRKH syndrome with a neovagina and 79 age-matched healthy women without the condition were enrolled in this case-control study. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants had to be at least 18-years old and had to live in a steady heterosexual relationship. Women with MRKH syndrome were asked to participate by their (former) gynecologists at three university hospitals and by MRKH peer support group. Controls were recruited via advertisement in local newspapers and social media. Standardized questionnaires were administered to assess sexual functioning, sexual esteem, genital self-image and psychological and relational functioning. MAIN RESULTS AND THE ROLE OF CHANCE: Women with MRKH syndrome with a surgically or non-surgically created neovagina reported significantly more pain during intercourse (P < 0.05, d = 0.5), but did not differ in overall sexual functioning from control women. More women with MRKH syndrome reported clinically relevant sexuality-related distress (P < 0.05, odds ratio (OR): 2.756, 95% CI 1.219-6.232) and suffered a sexual dysfunction (P < 0.05, OR: 2.654, 95% CI: 1.088-6.471) in comparison with controls. MRKH women scored significantly lower on the sexual esteem scale (SES) (P < 0.01, d = 0.5) and the female genital self-image scale (FGSIS) (P < 0.01, d = 0.6) than controls. No significant differences were found between the two groups regarding psychological distress, anxiety and depression, global self-esteem and relational dissatisfaction. Sexual esteem was significantly associated with the presence of clinically relevant sexual distress (ß = 0.455, P = 0.001) and suffering a sexual dysfunction (ß = 0.554, P = 0.001) and explained, respectively, 40% and 28% of the variance. LIMITATIONS, REASONS FOR CAUTION: Given the nature of the study focusing on sexual functioning, a potential selection bias cannot be excluded. It is possible that those women with the most severe sexual and/or psychological disturbances did or did not choose to participate in our study. WIDER IMPLICATIONS OF THE FINDINGS: The study results add new data to the very limited knowledge about psychosexual functioning of women with MRKH syndrome and are of importance for more adequate counseling and treatment of these women. STUDY FUNDING/COMPETING INTEREST(S): The research was financially supported by the Dutch Scientific Society of Sexology (Nederlandse wetenschappelijke Vereniging Voor Seksuologie). The funding was unrestricted, and there was no involvement in the conduct of the research. There are no conflicts of interest to declare.

Association of prenatal phenobarbital and phenytoin exposure with genital anomalies and menstrual disorders.

BACKGROUND: Animal studies demonstrated that early exposure to phenobarbital decreases reproductive function. This study investigates whether prenatal exposure to these anticonvulsants affects human genital tract development. METHODS: Genital anomalies at birth were studied retrospectively in 90 phenobarbital-exposed, 108 phenobarbital plus phenytoin-exposed, and 198 matched control infants. Of this group, 72 drug-exposed males, 75 drug-exposed females, and 147 matched control subjects participated in a follow-up and were interviewed at age 19-35. Differences between groups were tested by chi-square and t-tests. RESULTS: A total of 15% of the phenobarbital-exposed boys versus 2.8% control boys had undescended testes at birth. More anticonvulsant-exposed (24%) than control males (11%) had received medical treatment for genital anomalies. Anticonvulsant-exposed females more often had irregularities in menstrual cycles (31% vs. 17%) and bleeding (15% vs. 3%) and reported more problems during pregnancy. CONCLUSIONS: Prenatal exposure to anticonvulsants seems to induce minor genital anomalies and may affect reproductive function.

Association of prenatal phenobarbital and phenytoin exposure with small head size at birth and with learning problems.

UNLABELLED: Small head size has been observed in prenatally anticonvulsant-exposed neonates. In infancy, cognitive impairments were revealed. It is presently unknown whether these impairments are permanent or disappear after puberty. We studied the link between the prenatal influence of anticonvulsants on brain development and cognitive functioning in adulthood: a retrospective study on head size and a follow-up assessing cognitive capacities among adults who had been included in the retrospective study. The retrospective study comprised 172 exposed and 168 control neonates, matched with respect to age, sex and their mothers' age. Prenatally phenobarbital + phenytoin-exposed neonates had a significantly smaller occipitofrontal circumference (OFC) than prenatally phenobarbital-monotherapy-exposed and control neonates (mean difference of 0.7 cm). In the follow-up, no difference in cognitive functioning was found between the exposed and the control groups. Most of the prenatally anticonvulsant-exposed subjects had normal intellectual capacity. However, 12% of the exposed subjects versus 1% of the controls had persistent learning problems. In addition, more of the exposed subjects were mentally retarded. There was no clear relationship between learning problems and small OFC, maternal epilepsy or unfavourable family climate. CONCLUSIONS: We conclude that the combination of phenobarbital + phenytoin affects the fetal OFC. The smaller OFC does not seem to be related to cognitive functioning in adulthood, but learning problems and mental retardation proved to be more prevalent among exposed subjects. Phenobarbital and phenytoin may therefore affect cognitive capacity but only in infants who are susceptible to this particular influence of the drugs.

Twenty-year follow-up of antenatal corticosteroid treatment.

OBJECTIVE: To study late side effects of antenatal corticosteroid treatment on health and sexual development in subjects 20 to 22 years old. METHODS: A follow-up study among young adults whose mothers had, because of a threatening delivery, participated in a randomized, double-blind, placebo- controlled trial of betamethasone to prevent neonatal respiratory distress syndrome. Measurements were taken on general health, growth, development in puberty, reproductivity, genital or gynecological complaints, gender development, sexual orientation, sex-specific cognitive functioning, and psychoneuroticism. In addition, some measurements were performed on family diseases, socioeconomic status, and education. RESULTS: No differences were found between the corticosteroid-treated and placebo groups as to medical or psychological variables. In general, the subjects were healthy and had normal intellectual capacities. Groups did not differ on gender development, sexual orientation, sex-specific cognitive functioning, and psychoneuroticism. Systolic blood pressure was significantly lower in the corticosteroid group, but the groups did not differ as to diastolic blood pressure. CONCLUSIONS: Our 20-year follow-up study indicates that 1 course of antenatally administered corticosteroid to prevent respiratory distress syndrome does not have adverse effects up to adulthood.

Prenatal exposure to anticonvulsants and psychosexual development.

Animal studies have shown that prenatal exposure to the anticonvulsant drugs phenobarbital and phenytoin alters steroid hormone levels which consequently leads to disturbed sexual differentiation. In this study, possible sequelae of prenatal exposure to these anticonvulsants on gender development in humans were investigated. A follow-up study was carried out in phenobarbital- and phenytoin-exposed subjects and control subjects matched for age, sex, and the mothers' ages. Subjects were born in the Academic Medical Center between 1957 and 1972. Out of 243 exposed and 222 control subjects who were asked to volunteer, 147 exposed subjects (72 male, 75 female) and equal numbers of their matched control subjects participated in the follow-up study. They were interviewed and were asked to fill out questionnaires on gender role behavior, gender development, and sexual orientation. As a group, exposed and control subjects did not differ with respect to gender role behavior, although higher numbers of prenatally anticonvulsant-exposed subjects reported current or past cross-gender behavior and/or gender dysphoria. Three prenatally anticonvulsant-exposed subjects were transsexuals and had undergone sex reassignment surgery, a remarkably high rate given the rarity of transsexualism. In addition, two exposed males had exclusively homosexual experiences, whereas none of the control males reported exclusive homosexual behavior. The groups did not differ in attainment of pubertal psychosexual milestones.

Studies on long-lasting consequences of prenatal exposure to anticonvulsant drugs.

Based on neonatal examination at birth, it has been estimated that epileptic women have a 2-3 times greater risk of giving birth to an infant with congenital anomalies. But anticonvulsant drugs may also have more subtle influences on the developing foetus which are not visible at birth but only emerge later in life. Evidence for these functional teratogenic influences has been provided by animal research and follow-up studies in young children. This article discusses these findings in human and animal studies. In addition, the outline of a study carried out at the Department of Obstetrics and Neonatology, Academic Medical Centre, Amsterdam, is described. In this study cognitive functioning, fertility and gender role behaviour of young adults, who had been prenatally exposed to barbiturates and/or hydantoins was examined.