Pubertal development and premature ovarian insufficiency in patients with APECED.

OBJECTIVE: To determine the natural course of pubertal development, growth during puberty, and development of POI in females with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also called autoimmune polyendocrine syndrome type I. DESIGN: Longitudinal follow-up study. METHODS: A national cohort of females with APECED aged ≥12 years were followed during 1965-2018. Attainment of adult height was defined when patients' height increased less than 1 cm per year. Diagnosis of POI was based on delayed puberty or POI symptoms with amenorrhea, and/or FSH ≥40 IU/L. RESULTS: Altogether 40 women with APECED were followed up to the average age of 37.3 (range: 14.6-61.9) years; 16 females (40%) were ≥ 40 years. Pubertal development started spontaneously in 34 patients and 29 had spontaneous menarche. POI developed in 28 patients (70%) at the median age of 16.0 years (range: 11.3-36.5), and in 20 of them (71%) before attaining adult height. In 11 cases puberty was induced or completed by hormonal therapy. Patients with POI were significantly shorter at menarche, but adult heights did not differ from non-POI females. Patients with POI had more often primary adrenocortical insufficiency (93% vs 58%, P = 0.017) and ovarian antibodies (81% vs 30%, P=0.003) compared to those with normal ovarian function (n = 12). CONCLUSIONS: POI developed in the majority of patients with APECED, often before or shortly after menarche. Timely commencement of hormonal replacement therapy is important to ensure optimal pubertal development and growth. The possibility of fertility preservation before development of POI in APECED patients should be further studied.

The immune response to a two-dose schedule of quadrivalent HPV vaccine in 9-13 year-old girls: Is it influenced by age, menarche status or body mass index?

HPV vaccines are highly immunogenic. A two-dose schedule for 9-14 year-old is recommended. However, no data exist regarding the impact of age, menarche status and body mass index (BMI) on the immune response to a two-dose schedule. In this post-hoc analysis, we present antibody titers to HPV6/11/16/18 in 9-13 year-old girls participating in a randomized clinical trial and assigned to receive two doses of quadrivalent HPV vaccine at 6 months interval (NCT00501137). Antibody titers were measured at month 7 and 24 of the study by using a competitive Luminex immunoassay (cLIA).Both, at Month 7 and 24 the GMTs for four HPV genotypes were similar across the age bands, and did not vary significantly by menarche status. Overweight and obese girls had lower GMTs. More than 99% of girls remained seropositive for HPV 6/11/16 and 89% for HPV18 at month 24. Comprehensive data in overweight and obese vaccines are warranted.

Puberty in females enhances the risk of an outcome of multiple sclerosis in children and the development of central nervous system autoimmunity in mice.

BACKGROUND: For reasons that remain unclear, three times more women develop multiple sclerosis (MS) than men. This preponderance among women is evident only after 12 years of age, implicating pubertal factors in the risk of MS. OBJECTIVE: To investigate the influence of female puberty on central nervous system (CNS) autoimmunity. METHODS: We examined the relationship between age of menarche on MS outcomes in 116 female children (< 16 years old) whom presented with incident 'acquired demyelinating syndromes' (ADS) and were followed prospectively in the national Canadian Pediatric Demyelinating Disease Study, from 2004-2013. Furthermore, we directly investigated the effects of puberty on susceptibility to experimental autoimmune encephalomyelitis (EAE) in two groups of female mice that differed only in their pubertal status. RESULTS: In the ADS children, a later age of menarche was associated with a decreased risk of subsequent MS diagnosis. This relationship persisted, after accounting for patient age at ADS presentation and the presence of ≥1 T2 lesions on brain magnetic resonance imaging (MRI), with a hazard ratio (HR) of 0.64; and additional factors that associate with MS outcomes in ADS children, including low vitamin D levels. Furthermore, we found female mice that had transitioned through puberty were more susceptible to EAE than age-matched, pre-pubertal mice. CONCLUSION: Puberty in females enhances CNS autoimmune mechanisms that lead to MS in humans and EAE in mice.

Premenarchal and postmenarchal girls with insulin-dependent diabetes mellitus: ovarian and other organ-specific autoantibodies, menstrual cycle.

STUDY OBJECTIVE: To estimate various organ-specific autoantibodies and detect other endocrine autoimmune disorders and menstrual cycle characteristics in girls with Type 1 insulin dependent diabetes mellitus (IDDM). DESIGN: Prospective cohort study from 1993 to 1998, duration 4.5 years. SETTING: Diabetes & Endocrine Clinic of the University Hospital, Motol, Prague. PATIENTS: 53 IDDM girls (group A--43 postmenarchal, group B--10 premenarchal), 15.5 +/- 2.5 (8-19) years old, 6.2 +/- 4.3 years after IDDM onset. MAIN OUTCOME MEASURES: Ovarian autoantibodies directed to ooplasm, zona pellucida, membrana granulosa, theca folliculi interna, and lutein cells, insulin autoantibodies, thyroid peroxidase and thyroglobulin autoantibodies. Menstrual cycle character, endocrine glands disturbance. Diabetes control, body mass index, duration of IDDM. RESULTS: Ovarian autoantibodies in at least one of the followed structures were found in 67.9% of the IDDM girls. In the control group of 21 healthy girls of corresponding age, the positive findings in lutein cells were found in only 4.8% of the girls (P < 0.01 versus IDDM girls). The lutein cells commonly associated with theca folliculi interna cells were the most frequent immunopositive structures in diabetic girls (P < 0.05 versus another positive ovarian autoimmune structure). Autoantibodies directed to ovarian steroid producing cells were frequent in IDDM patients with both irregular and normal menstrual cycles. Irregular menstrual cycles were diagnosed in 27.9% of IDDM girls, polymenorrhea in half of them, and oligomenorrhea in the remainder. Diabetes control in our patients (glycosylated hemoglobin HbA1c in postmenarchal girls 10.1 +/- 2.0%) did not differ between those with regular and those with irregular menstrual cycles. Over a follow-up period one-third of the girls with oligomenorrhea and a long-term noncompliance (HbA1c 13.5%) developed secondary amenorrhea. Insulin autoantibodies were found in 67.8%, thyroid peroxidase autoantibodies in 12.5%, and thyroglobulin autoantibodies in 10.4% of the IDDM girls. Autoimmune thyroiditis was diagnosed in 5 IDDM patients (9.4%); hypothyroidism developed in 3 of them. Menstrual cycle was irregular in 4 of the 5 girls with autoimmune thyroiditis (polymenorrhea in 1, oligomenorrhea in another 3 girls). CONCLUSIONS: An increased incidence of various circulating autoantibodies may be markedly demonstrated in IDDM girls. Their reproductive function might have an important relationship to an evidence of ovarian autoantibodies. Menstrual cycle disturbances could be linked to the poor diabetes control, to the presence of ovarian and other autoantibodies, and also to other autoimmune disease.