Tissue sensitivity to thyroid hormones may change over time.

INTRODUCTION: Patients with congenital hypothyroidism (CH) may transiently show a certain degree of pituitary resistance to levothyroxine (LT4) which, however, normalizes subsequently. However, in some individuals, thyroid-stimulating hormone (TSH) fails to normalize despite adequate LT4 treatment. METHODS: Nine patients with CH followed in three Academic Centre who developed over time resistance to thyroid hormones underwent extensive biochemical and genetic analyses. These latter were performed by Sanger sequence or targeted next-generation sequencing technique including a panel of candidate genes involved in thyroid hormone actions and congenital hypothyroidism (CH): THRA, THRB, DIO1, DIO2, SLC16A2, SECISBP2, DUOX2, DUOXA2, FOXE1, GLIS3, IYD, JAG1, NKX2-1, NKX2- 5, PAX8, SLC26A4, SLC5A5, TG, TPO, TSHR. RESULTS: All patients displayed a normal sensitivity to thyroid hormone (TH) in the first years of life but developed variable degrees of resistance to LT4 treatment at later stages. In all cases, TSH normalized only in the presence of high free thyroxine levels. Tri-iodothyronine suppression test followed by thyrotrophin-releasing hormone stimulation was performed in two cases and was compatible with central resistance to THs. This biochemical feature was present independently on the cause of CH, being observed either in patients with an ectopic (n = 2) or eutopic gland (n = 3) or in case of athyreosis (n = 1). None of the patients had genetic variants in genes involved in the regulation of TH actions, while in two cases, we found two double heterozygous missense variants in TSHR and GLIS3 or in DUOX2 and SLC26A4 genes, respectively. CONCLUSIONS: We report CH patients who showed an acquired and unexplainable pituitary refractoriness to TH action.

The levelling-off of the secular trend of age at menarche among Italian girls.

OBJECTIVE: The main aim of this study was to verify whether the secular trend stopped in Italy by comparing the results of a 1990-2000 birth cohort versus a 1980-1990 birth cohort of Italian young women. The results were used to speculate about age at menarche as adaptive response to non-genetic factors. METHODS: In 2016, a study was set on 413, 18-to-26 year-old women (1990-2000 birth cohort) attending two Italian Universities by web-based, self-reported questionnaires. Previously in 2000, a research including 3,783 high school female students (1980-1990 birth cohort) was led. The age at menarche distribution was performed by Kaplan-Meier analysis. The comparison between the findings of the two birth cohorts was performed by Wilcoxon sum-rank test. Mixed models analysis was applied to evaluate the effect of cohort and socio-economic status on age at menarche. RESULTS: 1990-2000 cohort's age at menarche median was 12.44y (95%CI 12.37; 12.59y). There was no significant difference with age at menarche of the previous cohort (p = 0.56). Consistently, the advance of age at menarche in comparison to the mothers' one was not significantly different between the two cohorts (-0.27y±0.10y vs -0.25y±0.03y, p = 0.33). The socio-economic level was not significantly associated with menarcheal age. CONCLUSIONS: The findings of this study confirm that, like in other developed countries, the advance of age at menarche has stopped in Italy, consistently with the stop of the improvement of socio-economic conditions. Further studies are needed to explore the differential effect of each non-genetic factor to outline future scenarios of human sexual maturation. TRIAL REGISTRATION: the Comitato Etico per la Sperimentazione Clinica (CESC) della Provincia di Padova of the Veneto Region (Italy), n°3993/U16/16.

Menstrual Cycle and Headache in Teenagers.

OBJECTIVE: This population-based study on school-aged girls aimed to estimate the rate of peri-menstrual headache, evaluate headache pain pattern during the menstrual cycle, and verify its relationships with physical, psychosocial and life-style factors. METHODS: The students (n = 4973) fulfilled a self-administered questionnaire on demographic and behavioral characteristics, menarche, menstrual pattern and features including headache and dysmenorrhea. The prevalence of headache and the mean pain intensity score at the three menstrual cycle phases (premenstrual, menstrual, in-between period) were estimated, both overall and by gynecological year. Furthermore, the prevalence of three different patterns of headache (peri menstrual/mid-cycle/acyclic) was evaluated, together with the mean pain intensity score. RESULTS: The overall prevalence of headache at least once at any time during the menstrual cycle was 64.4%. At multivariable logistic analysis, gynecological age (OR 1.07; 95%CI 1.03-1.12), middle social level (1.24; 1.01-1.55, compared to high social level), physical activity (0.67; 0.51-0.89), oral contraceptive use (1.34; 1.04-1.73) and dysmenorrhea (2.30; 1.54-3.42) were significantly associated with headache. Among girls with headache, 83.4% had peri-menstrual headache (44.6% premenstrual, 38.8% menstrual), 3.5% mid-cycle headache and 13.2% acyclic headache. The gynaecological age and dysmenorrhea were significantly associated with the headache pattern (p = 0.03 and p < 0.0001, respectively). CONCLUSIONS: This study suggests that peri-menstrual headache is highly prevalent among adolescents. In girls, the headache rate linearly raises with higher gynecological age; menses-related painful syndromes, such as headache and dysmenorrhea, are strongly interrelated. The anamnesis and monitoring of menstrual health should be mandatory when taking care of girls with headache.

Age at Menarche and Menstrual Abnormalities in Adolescence: Does it Matter? The Evidence from a Large Survey among Italian Secondary Schoolgirls.

OBJECTIVE: To explore the independent role of age at menarche on menstrual abnormalities among adolescents. METHODS: The present study was a multicenter cross-sectional study on a large sample (n = 3782) of Italian girls aged 13-21 y attending secondary school who already had menarche. Girls were asked to fill in a questionnaire on menarcheal age and menstrual features during the latest three menses. The gynecological age was computed as the difference between age at the survey and the age at menarche. Main outcome measures were: prevalence of oligomenorrhea, polymenorrhea, menstrual cycle irregularity, abnormal bleeding length and dysmenorrhea. Irregularity in the recent past and since menarche was also studied. Multiple logistic models were used to identify any independent association between each abnormal feature and age at menarche or gynecological age. Adjusted ORs and 95%CI were performed. RESULTS: After adjusting for covariates, menarcheal age was not independently associated with polymenorrhea (OR = 0.81; 95%CI 0.63-1.04), oligomenorrhea (OR = 1.16; 95%CI 0.94-1.43), menstrual cycle irregularity (OR = 0.99; 95%CI 0.86-1.14), abnormal bleeding length (OR = 0.96; 95%CI 0.87-1.06) and dysmenorrhea (OR = 1.03; 95%CI 0.85-1.24). The multivariate analysis suggests that the higher prevalence of oligomenorrhea and menstrual cycle irregularity among the girls who were older at menarche might be purely explained by their younger gynecological age. CONCLUSIONS: No evidence of any independent influence of age at menarche on menstrual abnormalities among young girls was shown by the investigation. The findings suggest that, after menarche, adolescent girls' menstrual health should be checked to monitor the endocrine system maturation and to early intercept latent disorders becoming symptomatic.

Primary Dysmenorrhea in Adolescents: Prevalence, Impact and Recent Knowledge.

BACKGROUND AND OBJECTIVES: Dysmenorrhea is commonly categorized into two types; primary and secondary. Primary dysmenorrhea (PD) is the focus of this review. PD is defined as painful menses with cramping sensation in the lower abdomen that is often accompanied by other symptoms, such as sweating, headache, nausea, vomiting, diarrhea, and tremulousness. All these symptoms occur just before or during the menses in women with normal pelvic anatomy. In adolescents the prevalence of PD varies between 16% and 93%, with severe pain perceived in 2% to 29% of the studied girls. Several studies suggest that severe menstrual pain is associated with absenteeism from school or work and limitation of other daily activities. One-third to one-half of females with PD are missing school or work at least once per cycle, and more frequently in 5% to 14% of them. The wide variation in the prevalence rates may be attributed to the use of selected groups of subjects. Many risk factors are associated with increased severity of dysmenorrhea including earlier age at menarche, long menstrual periods, heavy menstrual flow, smoking and positive family history. Young women using oral contraceptive pills (OCP) report less severe dysmenorrhea. The considerably high prevalence of dysmenorrhea among adolescents verified that this condition is a significant public health problem that requires great attention. SUMMARY OF MAIN RESULTS: Many methodological problems are encountered during quantifying and grading severity of pain related to dysmenorrhea. Quantifying and assessment tools depend on women's self-reporting with potential bias. There is a scarcity of longitudinal studies on the natural history of dysmenorrhea as well as the possible effects of many modifiable risk factors. In addition, the duration of follow-up in the available studies is relatively short. Therefore, several aspects are still open for research. Medical treatment for dysmenorrhea includes anti-inflammatory drugs (NSAIDs), OCP or surgical intervention. The efficacy of conventional treatments using NSAIDs and OCP is high. However, failure rate may reach up to 20% to 25%, besides the occurrence of drug-associated adverse effects. Only 6% of adolescents receive medical advice to treat dysmenorrhea while 70% practice self-management. Unfortunately, some girls even abuse these medications (non-therapeutic high doses) for quick pain relief. The persistence of dysmenorrhea despite the use of OCP and/or NSAIDs drugs is a strong indicator of an organic pelvic disease. This condition mandates an appropriate referral to a gynecologist with proper laparoscopic diagnosis of endometriosis and/or other pelvic diseases. CONCLUSIONS: Dysmenorrhea is an important health problem for adolescents, school and occupational as well as practitioners that adversely affects the daily activities and quality of life for adolescent women. The accurate prevalence of dysmenorrhea is difficult to establish due to the variety of diagnostic criteria and the subjective nature of the symptoms. In adolescents, moderate to severe dysmenorrhea that affects lifestyle and does not respond to medical treatment requires professional attention and proper diagnosis of possible underlying pelvic disease. Therefore, adolescent care providers should be more knowledgeable and actively involved in the care of dysmenorrhea.

Onset of menstrual cycle and menses features among secondary school girls in Italy: A questionnaire study on 3,783 students.

PREMISE: Healthcare professionals need updated information about what is the range of "normal" variation of menstrual cycle features to support young girls and their parents in managing reproductive health, and to detect diseases early. MATERIALS AND METHODS: This cross-sectional study aimed to provide an updated picture of age at menarche and main menstrual cycle characteristics and complaints in an Italian population-based sample of 3,783 adolescents attending secondary school. Girls filled in a self-administered anonymous questionnaire including questions about demography, anthropometry, smoking and drinking habits, use of contraceptive, socioeconomic status, age at menarche, menstrual pattern, and physical/psychological menstrual complaints. Mean age at menarche and prevalence of polymenorrhea (cycle length < 21 days), oligomenorrhea (cycle length > 35 days), irregularity, dysmenorrhea, and of physical/psychological complaints were computed. Factors associated with age at menarche and menstrual disturbances were explored by using multiple logistic models. RESULTS: The girls' mean age was 17.1 years (SD 1.4 years) and the mean age at menarche was 12.4 years (SD 1.3 years); menarche occurred with two monthly peaks of frequency in July-September and in December-January (P < 0.0001). Age at menarche was significantly associated with geographic genetics (as expressed by parents' birth area), mother's menarcheal age, BMI, family size, and age at data collection. The prevalence of polymenorrhea was about 2.5%, oligomenorrhea was declared by 3.7%, irregular length by 8.3%, while long bleeding (>6 days) was shown in 19.6% of girls. Gynecological age was significantly associated with cycle length (P < 0.0001) with long cycles becoming more regular within the fourth year after menarche, while frequency of polymenorrhea stabilized after the second gynecological year. Oligomenorrhea and irregularity were both significantly associated with long menstrual bleeding (adjusted OR = 2.36; 95% CI = 1.55-3.60, and adjusted OR = 2.59; 95% CI = 1.95-3.44, respectively). CONCLUSIONS: The findings of the study support the levelling-off of secular trend in menarche anticipation in Italy and confirm the timing in menstrual cycle regularization. The study provides updated epidemiological data on frequency of menstrual abnormalities to help reproductive health professionals in managing adolescent gynecology.

Menstrual pattern and menstrual disorders among adolescents: an update of the Italian data.

BACKGROUND: The most striking event in the whole process of female puberty is the onset of menstruation. To our knowledge, no large population-based studies have been performed on the topic of menstrual health among Italian adolescents in recent years. The aims of this study were to produce up-to-date information on the menstrual pattern of Italian girls attending secondary school, and to estimate the prevalence of menstrual cycle abnormalities in this population. METHODS: This was a cross-sectional study on a population-based sample of Italian adolescents aged 13-21 years attending secondary school. Only girls who had already started menstruating were requested to participate. Information was collected by means of a questionnaire that included items on the girls' demographic details, anthropometrics, smoking and drinking habits, use of contraceptive pills, and socioeconomic status. The questions on the girls' menstrual pattern concerned their age at menarche, duration of the most recent menstruation intervals (<21, 21-35, >35 days, variable), average days of bleeding (<4, 4-6, >6 days), and any menstrual problems and their frequency. RESULTS: A total of 6,924 questionnaires were administered and 4,992 (71%) were returned. One hundred girls failed to report their date of birth, so 4,892 subjects were analyzed. The girls' mean age was 17.1 years (SD ±1.4); their mean age at menarche was 12.4 (±1.3) years, median 12.4 years (95%CI 12.3-12.5). In our sample population, 3.0% (95%CI 2.5%-3.4%) of the girls had menstruation intervals of less than 21 days, while it was more than 35 days in 3.4% (95%CI 2.9%-3.9%). About 9% of the girls (95%CI 7.7%-9.4%) said the length of their menstruation interval was currently irregular. Short bleeding periods (<4 days) were reported in 3.2% of the sample population (95%CI 2.7%-3.7%), long periods (>6 days) in 19% (95%CI 17.9%-20.1%). Menstruation-related abdominal pain was reported by about 56% of our sample. About 6.2% of the girls (95%CI 5.4%-7.0%) were suffering from dysmenorrhea. CONCLUSIONS: In conclusion, to the best of our knowledge, this is one of the largest studies on menstrual patterns and menstrual disorders among Italian adolescent girls. Adolescent girls referring persistent oligomenorrhoea, in first two years from menarche, had a higher risk for developing a persistent menstrual irregularity. They had longer bleeding periods (>6 days) and this has practical implications because it makes these adolescents potentially more susceptible to iron deficiency anemia. Clinicians need to identify menstrual abnormalities as early as possible in order to minimize their possible consequences and sequelae, and to promote proper health information.We recommend that adolescents should be encouraged to chart their menstrual frequency and regularity prospectively from the menarche onwards.

Update on age at menarche in Italy: toward the leveling off of the secular trend.

PURPOSE: To update the information on age at menarche in the Italian population and to verify the influence of genetic, nutritional, and socioeconomic factors on menarcheal age. Recent studies suggest that the magnitude of the secular trend toward an earlier age at menarche is slackening in industrialized countries. METHODS: This multicenter study was conducted on a large, population-based sample of Italian high school girls (n = 3,783), using a self-administered questionnaire. The questionnaire was used to gather information on the girls, including demography, anthropometry, menarcheal date, regularity of menses, behavioral habits, and physical activity. The questionnaire was also used to gather information on parents, including demography and mothers' and sisters' menarcheal ages. The median age at menarche and its 95% confidence interval were estimated by means of Kaplan-Meier survival analysis. To identify the independent predictive factors of age at menarche, multivariate mixed-effects models were applied. RESULTS: The median age at menarche of the subjects was 12.4 years (95% confidence interval: 12.34-12.46). The girls had their first menses approximately one-quarter of a year (median-0.13) earlier than did their mothers (p < .0001). Among all variables, parents' birth area, body mass index, family size, and the mother's menarcheal age were significantly and independently associated with age at menarche. CONCLUSIONS: This study confirmed the reduction in the trend toward earlier menarche in Italy. The results also confirmed that genetic and nutritional factors are strong markers for early menarche. Currently, socioeconomic factors do not seem to play as significant a role as in the past.

Changes in serum insulin-like factor 3 during normal male puberty.

CONTEXT: Insulin-like factor 3 (INSL3) is produced by the Leydig cells, and in adults, its secretion is dependent on the state of differentiation of these cells, which, in turn, is dependent on LH. However, the secretion and regulation of INSL3 during puberty is unknown. OBJECTIVE: Our objective was to evaluate INSL3 concentrations during normal male puberty and the relation of INSL3 to LH, FSH, and testosterone. DESIGN AND SETTING: We conducted a cross-sectional study from January to December 2005 at academic clinics. PATIENTS: Participating in the study were 75 healthy male subjects aged 9.5-17.5 yr, homogeneously distributed into five pubertal groups of 15 according to Tanner stages. MAIN OUTCOME MEASURES: We assessed mean testicular volume and LH, FSH, testosterone, and INSL3 concentrations in relation to age and pubertal stage. RESULTS: We observed an increase of INSL3 and LH levels from Tanner stage 2 to 4, and an increase of FSH from stage 2 to 3. Testosterone levels increased from stage 3 to 4. No differences were seen for all measured hormones between stages 4 and 5. The increase in INSL3 seemed therefore to anticipate the increase in testosterone. However, INSL3 plasma concentrations at pubertal stages 4 and 5 are about one fourth of adult levels, whereas FSH, LH, and testosterone reached adult levels by stage 4. Positive significant correlations were found between INSL3 and LH for all pubertal stages. CONCLUSIONS: This study provides information on the physiological dynamics of INSL3, showing that the serum concentrations of this hormone increased progressively throughout puberty under the differentiating action of LH on Leydig cells. INSL3 is therefore confirmed to represent a marker of Leydig cell differentiation and function. However, a prolonged exposure to LH seems to be necessary to reach INSL3 concentrations of adults. A possible use of INSL3 in puberty disorders is promising.

McCune-Albright syndrome: persistence of autonomous ovarian hyperfunction during adolescence and early adult age.

Gonadal hyperfunction is the most frequent endocrine dysfunction in females with McCune-Albright syndrome (MAS). Peripheral precocious puberty is usually the first MAS manifestation in children, characterized by episodes of hypersecretion of estrogens with a consequent reduction in gonadotropin secretion. Little is known about the course of this endocrine disease in adolescence and during young adult life. The aim of this study was to evaluate ovarian function in 10 females with MAS (age 11.4-20.1 years) to detect the persistence of autonomous ovarian hyperfunction throughout and following adolescence, after at least 1 year wash out of any treatment for precocious puberty. LH, FSH, estradiol, prolactin, androgen secretion, ovarian and breast sonography in luteal and follicular phases of some menstrual cycles were evaluated. We demonstrated the persistence of some ovarian autonomy, documented by hyperestrogenism and/or low or absent gonadotropin secretion and/or ovarian cysts.

Insulin sensitivity in growth hormone-deficient children: influence of replacement treatment.

OBJECTIVE: In adults, excessive GH secretion may lead to secondary diabetes mellitus, while prolonged GH treatment may accelerate the onset of type 2 diabetes mellitus in predisposed children. The aim of the study was to evaluate insulin sensitivity (IS) and glucose tolerance (GT) in a group of GH-deficient children treated with GH for a period of 6 years. PATIENTS AND DESIGN: One hundred and twenty-eight children (40 females, 88 males) were included in the study. At the beginning of treatment chronological age was 8.9 +/- 3.2 years, height standard deviation score (SDS) -2.43 +/- 0.90 and body mass index (BMI) SDS 0.18 +/- 1.60. At the end of the study chronological age was 13.0 +/- 2.9 years, height SDS -1.24 +/- 1.27 and BMI SDS 0.23 +/- 1.54. GH was administered at a mean weekly dosage of 0.3 mg/kg, injected subcutaneously over 6-7 days. GT was assessed according to the criteria of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. IS was evaluated with the quantitative insulin sensitivity check index (QUICKI). RESULTS: No cases of impaired GT or diabetes were recorded during the follow-up period. IS, already lower than in controls before starting treatment with GH, decreased significantly during the first year of therapy (QUICKI: 0.346 +/- 0.033 vs. 0.355 +/- 0.044, P < 0.05), with no further decrease in the following years. No correlation was found between QUICKI, BMI, years of treatment and onset of puberty. CONCLUSIONS: GH treatment in GH-deficient children does not lead to an impaired GT or type 2 diabetes mellitus, although it does significantly decrease IS.

Insulin sensitivity in Turner's syndrome: influence of GH treatment.

OBJECTIVE: Excessive GH secretion may lead to secondary diabetes mellitus, while prolonged GH treatment may accelerate the onset of type 2 diabetes mellitus in predisposed individuals. Turner's syndrome (TS) patients are a population at risk since they have reduced glucose tolerance (GT) spontaneously and because they are usually treated with high doses of GH. DESIGN AND METHODS: The aim of the study was to evaluate insulin sensitivity (IS) and glucose tolerance (GT) in a group of TS patients treated with GH for a period of 6 years. Forty-seven TS girls were included in the study. GH was administered at a mean weekly dosage of 0.35 mg/kg, injected subcutaneously over 6-7 days. GT was assessed according to the criteria of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. IS was evaluated with the quantitative insulin sensitivity check index (QUICK-I). RESULTS: No significant increase of impaired GT was observed in the patients during the follow-up period, while a reduced IS was detected. IS in TS patients was already lower than in prepubertal controls (P<0.001) before starting treatment and further decreased during the first year of therapy (P<0.05), and then remained stable over the following years. No correlation was found between QUICK-I, body mass index, years of treatment, onset and duration of puberty. One patient became diabetic during the course of treatment. CONCLUSIONS: GH treatment in TS girls does not significantly increase the prevalence of impaired GT or type 2 diabetes mellitus, while it does, however, decrease IS.

Molecular analysis of the GNAS1 gene for the correct diagnosis of Albright hereditary osteodystrophy and pseudohypoparathyroidism.

Pseudohypoparathyroidism (PHP) is a heterogeneous disease characterized by PTH resistance and classified as types Ia, Ib, Ic, and II, according to its different pathogenesis and phenotype. PHP-Ia patients show Gsalpha protein deficiency, PTH resistance, and typical Albright hereditary osteodystrophy (AHO). Heterozygous mutations in the GNAS1 gene encoding the Gsalpha protein have been identified both in PHP-Ia and in pseudopseudohypoparathyroidism (PPHP), a disorder with isolated AHO. A single GNAS1 mutation may be responsible for both PHP-Ia and PPHP in the same family when inherited from the maternal and the paternal allele, respectively, suggesting that GNAS1 is an imprinted gene. To evaluate whether molecular diagnosis is a useful tool to characterize AHO and PHP when testing for Gsalpha activity and PTH resistance is not available, we have performed GNAS1 mutational analysis in 43 patients with PTH resistance and/or AHO. Sequencing of the whole coding region of the GNAS1 gene identified 11 mutations in 18 PHP patients, eight of which have not been reported previously. Inheritance was ascertained in 13 cases, all of whom had PHP-Ia: the mutated alleles were inherited from the mothers, who had AHO (PPHP), consistent with the proposed imprinting mechanism. GNAS1 molecular analysis confirmed the diagnosis of PHP-Ia and PPHP in the mutated patients. Our results stress the usefulness of this approach to obtain a complete diagnosis, expand the GNAS1 mutation spectrum, and illustrate the wide mutation heterogeneity of PHP and PHP-Ia.