State of the Art Review: Emerging Therapies: The Use of Insulin Sensitizers in the Treatment of Adolescents with Polycystic Ovary Syndrome (PCOS)

PCOS, a heterogeneous disorder characterized by cystic ovarian morphology, androgen excess, and/or irregular periods, emerges during or shortly after puberty. Peri- and post-pubertal obesity, insulin resistance and consequent hyperinsulinemia are highly prevalent co-morbidities of PCOS and promote an ongoing state of excess androgen. Given the relationship of insulin to androgen excess, reduction of insulin secretion and/or improvement of its action at target tissues offer the possibility of improving the physical stigmata of androgen excess by correction of the reproductive dysfunction and preventing metabolic derangements from becoming entrenched. While lifestyle changes that concentrate on behavioral, dietary and exercise regimens should be considered as first line therapy for weight reduction and normalization of insulin levels in adolescents with PCOS, several therapeutic options are available and in wide use, including oral contraceptives, metformin, thiazolidenediones and spironolactone. Overwhelmingly, the data on the safety and efficacy of these medications derive from the adult PCOS literature. Despite the paucity of randomized control trials to adequately evaluate these modalities in adolescents, their use, particularly that of metformin, has gained popularity in the pediatric endocrine community. In this article, we present an overview of the use of insulin sensitizing medications in PCOS and review both the adult and (where available) adolescent literature, focusing specifically on the use of metformin in both mono- and combination therapy

Epidemiologic and mucosal immunologic aspects of HPV infection and HPV-related cervical neoplasia in the lower female genital tract: A review

Human papillomavirus (HPV) infections are known to play an important role in the pathogenesis of cervical neoplasia. Considering the morbidity and mortality of cervical cancer, infection with HPV can be regarded as a worldwide problem, especially in developing countries. Currently, many studies focus on the development of both prophylactic and therapeutic HPV vaccines. Crucial for these vaccination protocols to be successful is that they will result in a long-lasting ability to generate an immune response that will eliminate the virus. HPV transmission and subsequent infection is a local event in the lower female genital tract and therefore the efficacy of vaccines against this locally transmitted infection can be best assessed by parameters of local immunity. In this review we describe both the epidemiology of HPV-related cervical neoplasia and the general aspects of mucosal immunity in the female genital tract while focusing on the local humoral immunity in HPV-related cervical neoplasia

Antibodies against human papillomavirus type 16 and 18 E6 and E7 proteins in cervicovaginal washings and serum of patients with cervical neoplasia

Serum antibodies against the E6 and E7 proteins of human papillomavirus (HPV) 16 and 18 are associated with cervical cancer. The aim of this study was to investigate the presence of local antibodies against HPV in cervicovaginal washings (CWs). In this study antibodies against the native HPV16 and HPV18 E6/E7 proteins were detectable in CWs (48%) and sera (29%) from patients with cervical cancer (n = 21) utilizing a sandwich protein enzyme-linked immunosorbent assay (ELISA). In paired CWs and sera from patients with cervical intraepithelial neoplasia (n = 38) and from healthy women (n = 22) no antibodies against these proteins were found. In 10 of 11 patients, the antibody response corresponded with the HPV type in the cervical smear and/or tumor tissue, which indicates the HPV type specificity of the assay. In 7 of 11 patients with antibody reactivity against HPV16 or HPV18 E6 and/or E7 proteins a higher level of antibody reactivity in the CWs than in the paired serum samples was found at similar inputs of total IgG. This suggests that the antibodies in the CWs against the investigated HPV proteins in these patients were locally produced

IgG antibodies against human papillomavirus type 16 E7 proteins in cervicovaginal washing fluid from patients with cervical neoplasia

Little information is available about the cervicovaginal mucosal antibodies against human papillomavirus (HPV) proteins. In this study specific IgG antibodies against HPV 16 E7 protein were determined in paired samples of cervicovaginal washing fluid and serum from patients with cervical cancer (n = 22), cervical intraepithelial neoplasia (CIN) (n = 38), healthy individuals (n = 22), and serum from children (n = 41) by a radioactive immunoprecipitation assay (RIPA). HPV 16 E7 specific IgG antibodies were found in cervicovaginal washings (n = 8) and in sera (n = 8) of the patients with cervical cancer. About 60% of the patients with HPV 16 positive cervical cancer had HPV 16 E7 specific IgG antibodies. Titration studies showed that the IgG antibody reactivity in cervicovaginal washings was higher than in the paired serum samples of six patients with cervical cancer (P < 0.001). In the CIN group we found no IgG reactivity in the serum, but in five patients we found a low IgG reactivity in the cervicovaginal washings. No IgG reactivity was found in cervicovaginal washings and sera from healthy individuals and sera from children. HPV 16 E7 specific IgG antibodies seem to be locally produced in a number of patients with HPV 16 positive (pre)malignant cervical lesions. For more definitive evidence for the local production of these antibodies immunostaining should be performed to demonstrate the presence of specific anti-HPV 16 E7 IgG producing plasma cells in the cervical epithelium

Differences in cytokine mRNA profiles between premalignant and malignant lesions of the uterine cervix

The aim of this study was to assess the expression of cytokine transcripts, reflecting the type of ongoing immune responses at the site of human papillomavirus (HPV) infection, in relation to the development of cervical neoplasia. To this end reverse transcription-polymerase chain reaction (RT-PCR) was performed for interferon (IFN)γ, interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12 (p35 and p40), and transforming growth factor (TGFβ1) in snap-frozen cervical biopsies, which were tested for the presence of high risk HPV DNA and histologically classified from normal to invasive carcinoma (n = 40). IFNγ, IL-10 and IL-12 (p35 and p40) transcripts were found to be expressed at significantly lower frequencies in invasive carcinoma as compared with premalignant biopsies (P=0.006, P=0.007 and P=0.002, respectively). IFNγ and IL-10 mRNA were associated with the presence of the IL-12 p35 and p40 transcripts (P=0.008 and P<0.00001, respectively). These results were consistent with a locally reduced cellular (type 1) immunity correlating with HPV-induced invasive cervical carcinoma