The authors hypothesized that mutations in genes involved in idiopathic hypogonadotropic hypogonadism would be associated with functional hypothalamic amenorrhea, a reversible disorder commonly ...triggered by stress. Variants in such genes were detected in patients with hypothalamic amenorrhea.
Reproduction is an energetically costly process for women, and defense mechanisms have evolved that temporarily inhibit reproduction under adverse conditions. Stressors such as weight loss,
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excessive exercise,
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eating disorders,
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and psychological distress
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suppress the hypothalamic–pituitary–gonadal axis by inhibiting hypothalamic pulsatile secretion of gonadotropin-releasing hormone (GnRH).
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This frequent cause of female infertility is diagnosed as functional hypothalamic amenorrhea, defined as the absence of menses, low or normal gonadotropin levels, and hypoestrogenemia without organic abnormality.
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Hypothalamic amenorrhea is associated with a spectrum of abnormal GnRH-secretion patterns, and administration of exogenous pulsatile GnRH can restore functionality of the hypothalamic–pituitary–gonadal axis.
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The exquisite sensitivity . . .
Autoimmune oophoritis presents in adolescents as a component of autoimmune polyendocrine syndrome type I or type II. Autoimmune oophoritis can be diagnosed in women with primary ovarian insufficiency ...in the presence of adrenal cortical or steroid cell antibodies, and/or antibodies to adrenal and ovarian steroidogenic enzymes. The ovaries are cystic macroscopically, with a lymphocytic infiltrate in the steroidogenic theca cells. The immune infiltrate results in low estradiol levels and a compensatory increase in FSH levels. Granulosa cells are spared, and inhibin A and B levels are normal to high. Treatment is aimed at symptom relief with further investigation needed to assess treatment options such as immunosuppression.
Muscle inflammation and fibrosis underlie disuse-related complications and may contribute to impaired muscle recovery in aging. Cellular senescence is an emerging link between inflammation, ...extracellular matrix (ECM) remodeling and poor muscle recovery after disuse. In rodents, metformin has been shown to prevent cellular senescence/senescent associated secretory phenotype (SASP), inflammation, and fibrosis making it a potentially practical therapeutic solution. Thus, the purpose of this study was to determine in older adults if metformin monotherapy during bed rest could reduce muscle fibrosis and cellular senescence/SASP during the re-ambulation period. A two-arm controlled trial was utilized in healthy male and female older adults (n = 20; BMI: <30, age: 60 years+) randomized into either placebo or metformin treatment during a two-week run-in and 5 days of bedrest followed by metformin withdrawal during 7 days of recovery. We found that metformin-treated individuals had less type-I myofiber atrophy during disuse, reduced pro-inflammatory transcriptional profiles, and lower muscle collagen deposition during recovery. Collagen content and myofiber size corresponded to reduced whole muscle cellular senescence and SASP markers. Moreover, metformin treatment reduced primary muscle resident fibro-adipogenic progenitors (FAPs) senescent markers and promoted a shift in fibroblast fate to be less myofibroblast-like. Together, these results suggest that metformin pre-treatment improved ECM remodeling after disuse in older adults by possibly altering cellular senescence and SASP in skeletal muscle and in FAPs.
Abstract
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.
To determine age-based criteria for polycystic ovary morphology.
Cross-sectional, case-control design.
Outpatient setting.
Women with polycystic ovary syndrome (PCOS) defined by hyperandrogenism and ...irregular menses (n = 544) and controls with regular menses and no evidence of hyperandrogenism (n = 666) participated. Parameters were tested in a second cohort of women with PCOS (n = 105) and controls (n = 32) meeting the same criteria.
Subjects underwent a pelvic ultrasound documenting ovarian volume and maximum follicle number in a single plane.
A receiver operating characteristic curve was constructed to determine the ovarian volume and follicle number with the best sensitivity and specificity to define PCOS for age groups at approximately 5-year intervals from age 18 to >44 years.
The best sensitivity and specificity were obtained using a threshold volume of 12 mL and 13 follicles for ages ≤24 years, 10 mL and 14 follicles for ages 25–29 years, 9 mL and 10 follicles for ages 30–34 years, 8 mL and 10 follicles for ages 35–39 years, 10 mL and 9 follicles for ages 40–44 years, and 6 mL and 7 follicles for ages >44 years. Data from a second cohort confirmed the need to decrease volume and follicle number with increasing age to diagnose PCOS. Polycystic ovary morphology was most accurate at predicting the PCOS diagnosis for women ages 30–39 years.
The ovarian volume and follicle number threshold to define polycystic ovary morphology should be lowered starting at age 30.
We hypothesized that body mass index (BMI) and DNA variants would predict age at menarche in polycystic ovarian syndrome (PCOS).
Subjects aged 18–45 years with PCOS defined by the National Institutes ...of Health criteria (n=522) and controls with regular menstrual cycles and no hyperandrogenism (n=472) were studied.
Age at menarche was compared between PCOS cases and controls and examined as a function of multiple parameters.
There was a strong inverse relationship between BMI and age at menarche in PCOS (r=–0.32, p=5×10
). The chromosome 6 rs7759938-T variant was associated with earlier age at menarche in women with PCOS (12.60±0.09 vs. 13.41±0.23 years; genotype TT vs. CC; p=0.006). Age at menarche was predicted by PCOS status (β=0.512, p<0.001), reported weight group at 10–14 years (β=–0.432, p<0.001), current BMI (β=–0.0202, p=0.01), and genotype (β=0.169, p=0.02).
Age at menarche in women with PCOS is influenced by BMI and genetic variants near
Context:
Primary ovarian insufficiency (POI), or premature ovarian failure, results from ovarian follicle depletion with a consequent elevation of FSH levels before age 40 years. We identified a ...family in which 9 women in 3 consecutive generations developed menopause at approximately age 30 years. We hypothesized a genetic cause with a dominant mode of inheritance.
Design:
This was a family-based genetic study and a replicate group of women with POI.
Setting:
The study was conducted at an academic medical center.
Patients:
Seven affected women and an obligate carrier and 7 unaffected family members were genotyped. The genes of interest were also sequenced in 38 unrelated women with POI.
Intervention:
The DNA from 7 family members was subjected to whole-exome sequencing. The genotypes of interest were confirmed and genotypes of additional family members and unrelated women with POI were determined using Sanger sequencing.
Main Outcome Measure:
A high-impact, deleterious variant that segregated appropriately with POI in the family was required.
Results:
A heterozygous stop codon (Ser429X) was identified in the eukaryotic translation initiation factor 4E nuclear import factor 1 (eIF4ENIF1) in the proband and all affected women but not in the unaffected family members. The chance that such a high-impact, deleterious variant would segregate appropriately among the affected and unaffected relatives by chance is very low (P < .05). There were no additional mutations identified in eIF4ENIF1 or eIF4E in 38 unrelated women with POI.
Conclusion:
Data demonstrate a new gene associated with dominantly inherited POI. These results highlight the importance of translation initiation factors and their regulators in ovarian function.
Polycystic ovary syndrome (PCOS) is a heterogeneous disorder because of the variable criteria used for diagnosis. Therefore, International Classification of Diseases 9 (ICD-9) codes may not ...accurately capture the diagnostic criteria necessary for large scale PCOS identification. We hypothesized that use of electronic medical records text and data would more specifically capture PCOS subjects.
Subjects with PCOS were identified in the Partners Healthcare Research Patients Data Registry by searching for the term "polycystic ovary syndrome" using natural language processing (n = 24,930). A training subset of 199 identified charts was reviewed and categorized based on likelihood of a true Rotterdam PCOS diagnosis, i.e. two out of three of the following: irregular menstrual cycles, hyperandrogenism and/or polycystic ovary morphology. Data from the history, physical exam, laboratory and radiology results were codified and extracted from notes of definite PCOS subjects. Thirty-two terms were used to build an algorithm for identifying definite PCOS cases and applied to the rest of the dataset. The positive predictive value cutoff was set at 76.8 % to maximize the number of subjects available for study. A true positive predictive value for the algorithm was calculated after review of 100 charts from subjects identified as definite PCOS cases with at least two documented Rotterdam criteria. The positive predictive value was compared to that calculated using 200 charts identified using the ICD-9 code for PCOS (256.4; n = 13,670). In addition, a cohort of previously recruited PCOS subjects was submitted for algorithm validation.
Chart review demonstrated that 64 % were confirmed as definitely PCOS using the algorithm, with a 9 % false positive rate. 66 % of subjects identified by ICD-9 code for PCOS could be confirmed as definitely PCOS, with an 8.5 % false positive rate. There was no significant difference in the positive predictive values using the two methods (p = 0.2). However, the number of charts that had insufficient confirmatory data was lower using the algorithm (5 % vs 11 %; p < 0.04). Of 477 subjects with PCOS recruited and examined individually and present in the database as patients, 451 were found within the algorithm dataset.
Extraction of text parameters along with codified data improves the confidence in PCOS patient cohorts identified using the electronic medical record. However, the positive predictive value was not significantly different when using ICD-9 codes or the specific algorithm. Further studies are needed to determine the positive predictive value of the two methods in additional electronic medical record datasets.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Spontaneous thelarche and isolated menses occur in female GnRH deficiency; sequence variants in FRFR1, GNRHR, PROKR2, and KAL1 are the most commonly associated genetic abnormalities.
Context:
GnRH ...deficiency is a rare genetic disorder of absent or partial pubertal development. The clinical and genetic characteristics of GnRH-deficient women have not been well-described.
Objective:
To determine the phenotypic and genotypic spectrum of a large series of GnRH-deficient women.
Design, Setting, and Subjects:
Retrospective study of 248 females with GnRH deficiency evaluated at an academic medical center between 1980 and 2010.
Main Outcome Measures:
Clinical presentation, baseline endogenous GnRH secretory activity, and DNA sequence variants in 11 genes associated with GnRH deficiency.
Results:
Eighty-eight percent had undergone pubarche, 51% had spontaneous thelarche, and 10% had 1–2 menses. Women with spontaneous thelarche were more likely to demonstrate normal pubarche (P = 0.04). In 27% of women, neuroendocrine studies demonstrated evidence of some endogenous GnRH secretory activity. Thirty-six percent (a large excess relative to controls) harbored a rare sequence variant in a gene associated with GnRH deficiency (87% heterozygous and 13% biallelic), with variants in FGFR1 (15%), GNRHR (6.6%), and PROKR2 (6.6%) being most prevalent. One woman had a biallelic variant in the X-linked gene, KAL1, and nine women had heterozygous variants.
Conclusions:
The clinical presentation of female GnRH deficiency varies from primary amenorrhea and absence of any secondary sexual characteristics to spontaneous breast development and occasional menses. In this cohort, rare sequence variants were present in all of the known genes associated with GnRH deficiency, including the novel identification of GnRH-deficient women with KAL1 variants. The pathogenic mechanism through which KAL1 variants disrupt female reproductive development requires further investigation.
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