High DHEAS in girls and metabolic features throughout pubertal maturation.

CONTEXT: An association between premature adrenarche and metabolic syndrome at presentation has been described. Our aim was to assess whether the presence of high dehydroepiandrosterone sulphate (DHEAS [HD]) at the adrenarche determines the risk of metabolic syndrome during puberty, taking into account body mass index (BMI) and birth weight. DESIGN: Prospective observational. PATIENTS: Five hundred four girls from the Growth and Obesity Chilean Cohort Study were followed from birth through puberty. At age ~7, subjects were classified by DHEAS concentrations into the HD (>75th percentile) or normal DHEAS (ND, ≤75th percentile) subgroups. MEASUREMENTS: Anthropometrics, semiannual clinical pubertal staging and hormonal and metabolic levels. The relationships among DHEAS at age ~7, metabolic syndrome, and each of its components independently, were analyzed by linear and logistic regression models during puberty and 1-year postmenarche, adjusted by confounders. RESULTS: Girls with HD at 7 years exhibited higher BMI, more central fat and higher serum androgen and insulin like growth factor (IGF)-I levels throughout puberty. Also, girls with HD had a greater prevalence of hyperglycemia at B2 and B4 breast stages, and of low HDL at B4. At 1 year after menarche, HD girls had a higher prevalence of metabolic syndrome, and those with BMI > 1 SD score had a higher metabolic score and insulin levels than ND girls with similar BMI. CONCLUSIONS: Our observations suggest that girls with HD at the age of adrenarche may be at greater risk for metabolic syndrome at adolescence, especially in those who are overweight or obese. Our results emphasize the importance of lifestyle interventions for childhood overweight and obesity among girls with HD.

Contraception for Adolescents and Young Women with Type 2 Diabetes-Specific Considerations.

PURPOSE OF REVIEW: This article reviews how to address contraception in young women with type 2 diabetes (T2D). The presence of obesity and comorbidities associated with insulin resistance increases the risk of thromboembolic disease and adverse cardiovascular outcomes. RECENT FINDINGS: Recent studies have shown that adolescents with T2D are at high risk of unintended pregnancy with poor outcomes for the mother and offspring. Adolescents with T2D without severe obesity, micro- or macrovascular disease, or other cardiovascular risk factors can use any contraceptive method. However, only nonhormonal or progestin-only methods may be used when morbid obesity, severe hypertension, micro- or macrovascular disease, or multiple cardiovascular risk factors are present. The medical team must provide preconceptional counseling and contraception to reduce adolescent pregnancies in young women with T2D. Progestin-only or nonhormonal long-acting reversible contraception (LARC) should be recommended for women with T2D with compliance issues or adverse cardiovascular risk profiles.

Phenotypic continuum between Waardenburg syndrome and idiopathic hypogonadotropic hypogonadism in humans with SOX10 variants.

PURPOSE: SOX10 variants previously implicated in Waardenburg syndrome (WS) have now been linked to Kallmann syndrome (KS), the anosmic form of idiopathic hypogonadotropic hypogonadism (IHH). We investigated whether SOX10-associated WS and IHH represent elements of a phenotypic continuum within a unifying disorder or if they represent phenotypically distinct allelic disorders. METHODS: Exome sequencing from 1,309 IHH subjects (KS: 632; normosmic idiopathic hypogonadotropic hypogonadism [nIIHH]: 677) were reviewed for SOX10 rare sequence variants (RSVs). The genotypic and phenotypic spectrum of SOX10-related IHH (this study and literature) and SOX10-related WS cases (literature) were reviewed and compared with SOX10-RSV spectrum in gnomAD population. RESULTS: Thirty-seven SOX10-associated IHH cases were identified as follows: current study: 16 KS; 4 nIHH; literature: 16 KS; 1 nIHH. Twenty-three IHH cases (62%; all KS), had ≥1 known WS-associated feature(s). Moreover, five previously reported SOX10-associated WS cases showed IHH-related features. Four SOX10 missense RSVs showed allelic overlap between IHH-ascertained and WS-ascertained cases. The SOX10-HMG domain showed an enrichment of RSVs in disease states versus gnomAD. CONCLUSION: SOX10 variants contribute to both anosmic (KS) and normosmic (nIHH) forms of IHH. IHH and WS represent SOX10-associated developmental defects that lie along a unifying phenotypic continuum. The SOX10-HMG domain is critical for the pathogenesis of SOX10-related human disorders.

Long-acting contraception in adolescents and young women with type 1 and type 2 diabetes.

Adolescent pregnancy is a major public health problem worldwide. Adolescents living with diabetes are not aware of the risks of unplanned pregnancy and the high rate of fetal and maternal complications when gestation occurs in women with significant hyperglycemia. These data highlight the significance of pregnancy prevention in young women with diabetes. Long-acting reversible contraceptives (LARCs), which include subdermal progestin implants and hormonal and nonhormonal intrauterine devices (IUDs), have been recommended by the American College of Obstetricians Gynecologists and the American Academy of Pediatrics as a first-line contraceptive option for adolescents and young women. This article reviews LARC options for adolescents and young women with type 1 (T1D) and type 2 (T2D) diabetes as well as the possible complications and side effects.

Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency.

Inactivating mutations in chromodomain helicase DNA binding protein 7 (CHD7) cause CHARGE syndrome, a severe multiorgan system disorder of which Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a minor feature. Recent reports have described predominantly missense CHD7 alleles in IGD patients, but it is unclear if these alleles are relevant to causality or overall genetic burden of Kallmann syndrome (KS) and normosmic form of IGD. To address this question, we sequenced CHD7 in 783 well-phenotyped IGD patients lacking full CHARGE features; we identified nonsynonymous rare sequence variants in 5.2% of the IGD cohort (73% missense and 27% splice variants). Functional analyses in zebrafish using a surrogate otolith assay of a representative set of these CHD7 alleles showed that rare sequence variants observed in controls showed no altered function. In contrast, 75% of the IGD-associated alleles were deleterious and resulted in both KS and normosmic IGD. In two families, pathogenic mutations in CHD7 coexisted with mutations in other known IGD genes. Taken together, our data suggest that rare deleterious CHD7 alleles contribute to the mutational burden of patients with both KS and normosmic forms of IGD in the absence of full CHARGE syndrome. These findings (i) implicate a unique role or preferential sensitivity for CHD7 in the ontogeny of GnRH neurons, (ii) reiterate the emerging genetic complexity of this family of IGD disorders, and (iii) demonstrate how the coordinated use of well-phenotyped cohorts, families, and functional studies can inform genetic architecture and provide insights into the developmental biology of cellular systems.

Elevation of C-reactive protein during the luteal phase in healthy adolescents.

INTRODUCTION: Variations in inflammatory markers have been reported in adult women during the luteal phase, but whether these findings are observed during adolescence is unknown. We postulate that higher ultrasensitive C-reactive protein (usCRP) and lower 2-hydroxyestrone (2OHE) levels, an estrogen metabolite with cardioprotective actions, are present during the luteal phase in young women. AIM: To evaluate usCRP levels during the menstrual cycle and to determine its association with 2OHE and 16α-hydroxyestrone (16OHE) in adolescents. METHODS: Healthy postmenarcheal adolescents (N = 37) were studied during one menstrual cycle in follicular phase (FP) and luteal phase-like period (LP-L). RESULTS: Elevations in usCRP levels in the LP-L were observed in the entire group and in anovulatory cycles (1.9 ± 1.1 mg/L in FP to 2.5 ± 1.8 mg/L in LP-L; p < 0.0001). Increases in estrone, estradiol, free and bioavailable estradiol, testosterone, usCRP and 2OHE levels were observed in LP-L compared with FP (p < 0.01), with a borderline elevation in IFG-I levels (p = 0.06). CONCLUSIONS: We report an elevation of usCRP and 2OHE levels during the luteal phase in healthy adolescents. Elevations of this inflammatory marker in anovulatory adolescents without an increase in 2OHE may play a role in metabolic risks associated with chronic anovulation.

Hirsutism and oligomenorrhea are appropriate screening criteria for polycystic ovary syndrome in adolescents.

We evaluated the association of hirsutism and oligomenorrhea (persistent menstrual cycles > 45 days) as screening criteria for the detection of biochemical hyperandrogenism (BH) and polycystic ovaries (PCOM) during adolescence and determined which androgens, granulosa cell hormone, ultrasonographic parameters have the best association with polycystic ovary syndrome (PCOS). Hirsute girls with oligomenorrhea (N = 26 Hirs/Oligo group) and non-hirsute girls with regular cycles (N = 63, C group) were studied. Prevalence of BH and PCOM, diagnostic performance of androgens and ultrasound parameters for PCOS diagnosis were analyzed. BH and PCOM prevalence were higher in the Hirs/Oligo girls than in the C girls (76.9% versus 25.5%; 92.3% versus 33.3%, respectively; p < 0.0001). A complete PCOS phenotype (Hirs/Oligo with BH and PCOM) was observed in 73.1% of the Hirs/Oligo group. The presence of both BH and PCOM was observed in 7.9% of the C group. The parameters with the best diagnostic performance were free androgen index ≥6.1, testosterone ≥2.4 nmol/L, follicle number ≥12 and ovarian volume ≥10 ml anti-Müllerian hormone (AMH) exhibited a low diagnostic accuracy. Hirsutism and persistent menstrual cycle over 45 days are highly associated with BH and PCOM suggesting that the presences of both criteria are necessary for the diagnosis of PCOS during adolescence.

Subdermal Progestin Implant and an Oral Combined Hormonal Contraceptive in Youth with Type 1 Diabetes.

STUDY OBJECTIVE: To determine the metabolic effects of the subcutaneous etonogestrel implant compared with an oral contraceptive in adolescents and young adults (AYAs) with type 1 diabetes (T1D) on body weight, body composition, glucose, lipids, and C-reactive protein levels. METHODS: This was a non-randomized, interventional, prospective study. Thirty-nine AYAs with T1D participated; 20 used the implant (Implant-T1D), and 19 used an oral combined contraceptive (OC-T1D). Body composition, HbA1c, intermittent continuous glucose monitoring, lipids, and high-sensitivity C-reactive protein (hsCRP) levels were evaluated. RESULTS: All participants were followed for at least 12 months, and 26 completed the 24-month follow-up. No women discontinued the intervention due to adverse effects. Body weight increased by 0.8 ± 3.5 and 1 ± 2.9 kg in the OC-T1D and the Implant-T1D group at 12 months and by 2.6 ± 3.9 and 3.3 ± 3.6 kg at 24 months, respectively. OC-T1D and Implant-T1D had similar HbA1c, mean interstitial glucose levels, and time in range throughout the study; no significant difference over time was observed. hsCRP levels increased in both groups and were associated with BMI and HbA1c (P < .001 for both variables). Women in the OC-T1D group had higher total cholesterol, HDL-C, and triglyceride levels compared with the Implant-T1D. CONCLUSION: Glucose levels were similar in youth using the subdermal progestin implant and an OC. However, both AYA groups showed increased BMI, fat mass, and subclinical inflammation. Changes in lipid levels were associated with the OC method. These data highlight the importance of weight gain prevention in young women with T1D using hormonal contraception.

[Screening of Neisseria gonorrhoeae and Chlamydia trachomatis using techniques of self collected vaginal sample in young women]. / Experiencia con un método de autotoma de muestra vaginal para la detección de infección por Chlamydia trachomatis y Neisseria gonorrhoeae en mujeres jóvenes.

INTRODUCTION: Chlamydia trachomatis and Neisseria gonorrhoeae are responsible for 3-10% of sexually transmitted diseases in adolescents. 75% are asymptomatic. International standards recommend annual screening for C. trachomatis in sexually active women under 26 years. Self-collected vaginal swab is one of the less invasive screening methods, it is well accepted by patients and rarely used in our country. AIM: To determine the frequency of C. trachomatis and n. gonorrhoeae by a self-sampling method of vaginal swab and its acceptability in a group of adolescents and young adults. PATIENTS AND METHODS: Women 18 to 25 years old. Vaginal samples were processed by nucleic acid amplification tests, Gen Probe APTIMA Combo2. Data were collected on sexual behavior and perception of self-sampling by survey. RESULTS: We studied 344 patients with an average age of 21.7 years. Detection of C. trachomatis was positive in 7.9% women and it was not found in any of the patients studied for N. gonorrhoeae. 98% considered self-sampling instructions easy to understand, 87.5% felt comfortable taking the sample. CONCLUSIONS: Prevalence of C. trachomatis in the study population was similar to that described in other national and international studies. N. gonorrhoeae was not found in this series, which is consistent with literature reports. The self-sampling technique of vaginal sample was well accepted by the patients. However, they were anxious about the quality of the sample. According to our results, it is important to emphasize the importance of annual detection of these pathogens and that self-sampling technique is a valid alternative.

Prevalence of Deleterious Variants in MC3R in Patients With Constitutional Delay of Growth and Puberty.

CONTEXT: The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth, and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than noncarriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown. OBJECTIVE: This work aimed to determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH). METHODS: We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterized the signaling properties of all nonsynonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice-breaking in the UK Biobank cohort. RESULTS: MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 [2.2%]; OR = 4.17; P = .001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 [0.6%]; OR = 1.15; P = .779). In 246 328 women from the UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (aged ≥16 years) vs normal age at menarche (OR = 1.66; P = 3.90E-07). CONCLUSION: We have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.

Contraception, and pregnancy in adolescents with type 1 diabetes: a review.

Adolescence is a critical period for girls with type 1 diabetes mellitus (T1D). Reproductive issues, such as menstrual abnormalities, risk of an unplanned pregnancy, and contraception, should be addressed during this phase of life. This paper reviews several reproductive issues that are important in the care of adolescents, including pubertal development, menstrual abnormalities, ovulatory function, reproductive problems, the effects of hyperglycemia, contraception, and treatment of an unplanned pregnancy. A review of the literature was conducted. A MEDLINE search January 1966 to March 2011 was performed using the following MESH terms: puberty, menarche, ovary, polycystic ovary syndrome, menstruation, contraception, contraception-barrier, contraceptives-oral-hormonal, sex education, family planning services, and pregnancy in adolescence. This literature search was cross-referenced with an additional search on diabetes mellitus-type 1, diabetes complications, and pregnancy in diabetes. All published studies were searched regardless of the language of origin. Bibliographies were reviewed to extract additional relevant sources.

Infantile/Capillary Hemangioma of the Uterine Corpus: A Rare Cause of Abnormal Genital Bleeding.

BACKGROUND: Infantile hemangiomas are vascular anomalies. However, they rarely cause genital bleeding. Here, we present the case of a young female with an endocavitary hemangioma who presented with abnormal uterine bleeding (AUB). CASE: The patient was an 8-year-old female with genital bleeding. Transabdominal pelvic ultrasound showed a 20-mm highly vascularized focal intrauterine endocavitary lesion. Vascular computerized tomography excluded vascular anomalies. Magnetic resonance imaging suggested a hemangioma. Minimally invasive open surgery was performed to remove the lesion. Subsequent pathology analyses confirmed an infantile/capillary hemangioma. CONCLUSIONS: Infantile hemangiomas are vascular anomalies that should be considered potential causes of AUB in early puberty. The study of these cases should include pelvic ultrasound and vascular magnetic resonance imaging. Experienced surgeons can successfully accomplish fertility-sparing surgical procedures. SUMMARY: We describe an unusual case of peripubertal AUB caused by an endocavitary capillary hemangioma. Management included fertility-sparing surgery and the complete resolution of symptoms.

Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women With Hypothalamic Amenorrhea.

CONTEXT: Functional hypothalamic amenorrhea (HA) is a common, acquired form of hypogonadotropic hypogonadism that occurs in the setting of energy deficits and/or stress. Variability in individual susceptibility to these stressors, HA heritability, and previous identification of several rare sequence variants (RSVs) in genes associated with the rare disorder, isolated hypogonadotropic hypogonadism (IHH), in individuals with HA suggest a possible genetic contribution to HA susceptibility. OBJECTIVE: We sought to determine whether the burden of RSVs in IHH-related genes is greater in women with HA than controls. DESIGN: We compared patients with HA to control women. SETTING: The study was conducted at secondary referral centers. PATIENTS AND OTHER PARTICIPANTS: Women with HA (n = 106) and control women (ClinSeq study; n = 468). INTERVENTIONS: We performed exome sequencing in all patients and controls. MAIN OUTCOME MEASURE(S): The frequency of RSVs in 53 IHH-associated genes was determined using rare variant burden and association tests. RESULTS: RSVs were overrepresented in women with HA compared with controls (P = .007). Seventy-eight heterozygous RSVs in 33 genes were identified in 58 women with HA (36.8% of alleles) compared to 255 RSVs in 41 genes among 200 control women (27.2%). CONCLUSIONS: Women with HA are enriched for RSVs in genes that cause IHH, suggesting that variation in genes associated with gonadotropin-releasing hormone neuronal ontogeny and function may be a major determinant of individual susceptibility to developing HA in the face of diet, exercise, and/or stress.

High DHEAS Level in Girls Is Associated with Earlier Pubertal Maturation and Mild Increase in Androgens throughout Puberty without Affecting Postmenarche Ovarian Morphology.

OBJECTIVE: To assess whether the presence of high DHEAS (HD) at 7 years determines different timing, sequence, and rate of pubertal events, and whether it is associated with adrenal and/or ovarian hyperandrogenism and changes in ovarian morphology throughout puberty. METHODS: In a longitudinal study of 504 girls, clinical evaluation was performed every 6 months after 7 years of age to detect Tanner stages; hormonal and anthropometric measurements were conducted at thelarche (B2), breast Tanner 4 (B4), and 1 year after menarche; ultrasonographic evaluation was also performed after menarche. The girls were classified as HD if their DHEAS level was >42.1 µg/dL (>75th percentile) around 7 years. RESULTS: HD around 7 years is associated with a younger age at thelarche, pubarche, and menarche. Girls with HD had higher androstenedione and total testosterone levels, and a higher free androgen index (FAI), and lower levels of antimüllerian hormone (AMH) at B2, and higher levels of androstenedione and FAI at B4 and after menarche. All these results were significant even after adjusting for body mass index, age at first DHEAS determination, and birth weight. One year after menarche, polycystic ovarian morphology was detected in 7.6 and 7.3% of the HD and the normal DHEAS group, respectively. Ovarian volume was correlated with AMH, testosterone, androstenedione, and LH but not with DHEAS around 7 years. CONCLUSION: Prepubertal HD in normal girls was associated with earlier thelarche, pubarche, and menarche, and a mild androgen increase throughout puberty. We believe continuous follow-up of this cohort is important to prospectively address the interrelationships between biochemical adrenarche and early growth as determinants of ovarian function.

Age at Pubertal Development in a Hispanic-Latina Female Population: Should the Definitions Be Revisited?

STUDY OBJECTIVE: To assess pubertal events in a Hispanic female population and to create normograms of puberty. DESIGN: Longitudinal. SETTING: University facility. PARTICIPANTS: Five hundred forty-nine girls from the Growth and Obesity Chilean Cohort study. INTERVENTIONS: Follow-up twice a year beginning at age 6 years. MAIN OUTCOME MEASURES: Breast development, pubic hair development, and age. Breast development (B2, B3, and B4) and pubarche (P2) were determined. Age at menarche was obtained from the adolescents and their mothers. Age and growth velocity at peak height velocity were calculated. RESULTS: In girls, B2, B3, and B4 occur at median ages of 9.2, 10.2, and 10.9 years, respectively. The median age at P2 was 9.7 years. The mean age at peak height velocity and the growth velocity were 10.6 years (SD = 1.1) and 8 cm/y, respectively. The mean age at menarche was 11.9 years (SD = 1.1); only 2.8% (15 /530) of girls experienced menarche after 14 years and 1.9% before 10 years. The mean interval time between B2 and menarche was 2.5 ± 1.0 years. Transient thelarche occurred in 8.6% of girls. CONCLUSION: This longitudinal cohort shows that thelarche occurred 1.2 months later than previously reported in cross-sectional studies. Conversely, we found that pubic hair appeared 12 months earlier and menarche occurred 9 months earlier than previously reported. These findings are important in setting normalcy data and avoiding unnecessary clinical consultations.

Ovarian Function in Adolescents Conceived Using Assisted Reproductive Technologies.

STUDY OBJECTIVE: To compare ovarian function between adolescents conceived using assisted reproductive technology (AcART) and adolescents who were conceived spontaneously (AcSP). DESIGN: Multicenter study of ovarian function in AcART because of male or tubal infertility. SETTING: University Hospital. PARTICIPANTS: We evaluated 22 AcART and 53 AcSP at 1-2 years after menarche. The participants were born at term (≥37 weeks of gestation) with normal birth weights (≥2500 g) from singleton pregnancies. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Differences in ovulation, reproductive hormones, and ovarian morphology. RESULTS: AcART had an older age of menarche than that of AcSP, even after adjusting for maternal age at menarche, gestational age, and birth weight (P = .027). AcART had lower incidence of ovulation (P = .021) and higher luteinizing hormone serum levels (P = .01) than those of AcSP. The incidence of oligomenorrhea and the cycle length were similar between AcART and AcSP. AcART had levels of anti-Müllerian hormone, inhibin B, follicle-stimulating hormone, estradiol, and androgens similar to those of AcSP. The ovarian morphology, ovarian volume, and follicle counts were similar in both groups. CONCLUSION: AcART had later menarche, lower ovulation rates, and higher luteinizing hormone levels than those of AcSP. Future studies should investigate whether these findings are indicative of a risk of ovarian dysfunction later in life for AcART.

Discordance in the Dependence on Kisspeptin Signaling in Mini Puberty vs Adolescent Puberty: Human Genetic Evidence.

Context: Hypothalamic kisspeptin signaling plays a critical role in the initiation and maintenance of reproductive function. Biallelic mutations in the coding sequence of KISS1R (GPR54) have been identified in patients with idiopathic hypogonadotropic hypogonadism, but it is unknown whether biallelic variants can also be associated with related reproductive disorders. Case Description: A missense homozygous variant (c.890G>T p.R297L) in KISS1R was identified in a child who presented with microphallus and bilateral cryptorchidism. This variant has been reported to reduce, but not abolish, postreceptor signaling in vitro. Biochemical evaluation during the neonatal period revealed low testosterone levels. By 11 years and 8 months, the boy began demonstrating increases in testicular volume. By 17 years and 3 months, his testicular volume was 20 mL; his penile length was 7.3 cm; and he had adult levels of circulating gonadotropins and testosterone. Conclusion: This case report associates biallelic loss-of-function mutations in KISS1R with normal timing of adolescent puberty. Because these coding sequence variants occurred in a patient with microphallus and cryptorchidism, they demonstrate different levels of dependence of the hypothalamic-pituitary-gonadal cascade on kisspeptin signaling at distinct times in the reproductive life span. The suppression of the hypothalamic-pituitary-gonadal cascade during early life but not adolescence suggests that the mini puberty of infancy depends more on kisspeptin-induced, gonadotropin-releasing hormone-induced luteinizing hormone secretion than does adolescent puberty.

New Diagnostic Criteria of Polycystic Ovarian Morphology for Adolescents: Impact on Prevalence and Hormonal Profile.

BACKGROUND: The ultrasonographic criteria used to identify polycystic ovarian morphology (PCOM) during adolescence have changed over time. Recently, a Worldwide Pediatric Consensus (PedC) defined PCOM using stricter criteria than the previous recommendations of the Rotterdam Consensus (RC) and Androgen Excess-Polycystic Ovarian Syndrome Society (AES/PCOS) criteria. The aim of this study was to determine the prevalence of PCOM in healthy adolescents according to the 3 reported diagnostic criteria and compare the hormonal profile in females with and without PCOM based on the PedC criteria. METHODS: Nonobese adolescents (n = 102) with regular menstrual cycles were studied. Transabdominal ultrasound and hormonal profiles were assessed during the follicular phase. PCOM was defined on the basis of the 3 published criteria. RESULTS: On the basis of the PedC, RC, and AES/PCOS criteria, PCOM was diagnosed in 13, 34, and 24% of adolescents, respectively. Adolescents with and without PCOM according to the PedC criteria had similar androgen levels. Serum anti-Müllerian hormone (AMH) levels were elevated in adolescents with PCOM, irrespective of the criteria used. CONCLUSIONS: Use of the new PedC diagnostic criteria for PCOM results in a lower prevalence of this ultrasonographic pattern in adolescents, but this condition is not associated with hyperandrogenism. Elevated AMH is associated with PCOM in adolescents regardless of the criteria used to determine the ultrasonographic pattern.

When genetic load does not correlate with phenotypic spectrum: lessons from the GnRH receptor (GNRHR).

CONTEXT: A broad spectrum of GnRH-deficient phenotypes has been identified in individuals with both mono- and biallelic GNRHR mutations. OBJECTIVE: The objective of the study was to determine the correlation between the severity of the reproductive phenotype(s) and the number and functional severity of rare sequence variants in GNRHR. SUBJECTS: Eight hundred sixty-three probands with different forms of GnRH deficiency, 46 family members and 422 controls were screened for GNRHR mutations. The 70 subjects (32 patients and 38 family members) harboring mutations were divided into four groups (G1-G4) based on the functional severity of the mutations (complete or partial loss of function) and the number of affected alleles (monoallelic or biallelic) with mutations, and these classes were mapped on their clinical phenotypes. RESULTS: The prevalence of heterozygous rare sequence variants in GNRHR was significantly higher in probands vs. controls (P < 0.01). Among the G1-G3 groups (homozygous subjects with successively decreasing severity and number of mutations), the hypogonadotropic phenotype related to their genetic load. In contrast, subjects in G4, with only monoallelic mutations, demonstrated a greater diversity of clinical phenotypes. CONCLUSIONS: In patients with GnRH deficiency and biallelic mutations in GNRHR, genetic burden defined by severity and dose is associated with clinical phenotype. In contrast, for patients with monoallelic GNRHR mutations this correlation does not hold. Taken together, these data indicate that as-yet-unidentified genetic and/or environmental factors may combine with singly mutated GNRHR alleles to produce reproductive phenotypes.