Health-related quality of life in women with primary ovarian insufficiency: a scoping review of the literature and implications for targeted interventions.

STUDY QUESTION: What is known about health-related quality of life (HR-QoL) in women with idiopathic primary ovarian insufficiency (POI)? SUMMARY ANSWER: Women with POI have a range of unmet psychosocial needs relating to three interrelated themes: 'diagnostic odyssey', 'isolation and stigma' and impaired 'ego integrity'. WHAT IS KNOWN ALREADY: Prior studies have reported increased depressive symptoms, diminished sexual function and altered body image/self-concept in women with POI. STUDY DESIGN, SIZE, DURATION: A systematic scoping review (11 databases) on HR-QoL in POI including published quantitative, qualitative and mixed-methods studies as well as unpublished gray literature (i.e. unpublished dissertations) through June, 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: After removing duplicates, 1244 articles underwent title and abstract review by independent reviewers. The remaining 72 relevant articles underwent dual full text review to determine inclusion criteria yielding 24 articles (100% concordance) for data extraction. Findings were summarized in tables by methodology and recurrent HR-QoL themes/sub-themes were mapped to define key aspects of HR-QoL in POI. Promoters of active coping were charted at the individual, interpersonal and healthcare system levels. Targets for tailored interventions supporting active coping and improved HR-QoL were mapped to the Theory of Planned Behavior (TPB). MAIN RESULTS AND THE ROLE OF CHANCE: Three interrelated themes affecting HR-QoL in POI emerged from the data synthesis. First, the theme 'diagnostic odyssey' comprised sub-themes of uncertainty, lack of control, knowledge gaps, discontinuous care and negative clinical interactions. The second theme 'isolation and stigma' included sub-themes of guilt, shame, concealment, feeling labeled as infertile, lack of social support and unsympathetic clinicians. The third theme, impaired 'ego integrity' captured sub-themes of decreased sexual function, altered body image, psychological vulnerability and catastrophizing. Targets promoting active coping at the individual (n = 2), interpersonal (n = 1) and healthcare system (n = 1) levels were mapped to the TPB to inform development of tailored interventions supporting active coping and improved HR-QoL in POI (i.e. narrative intervention, co-creating patient-facing materials, peer-to-peer support and provider resources). LIMITATIONS, REASONS FOR CAUTION: No studies using a POI-specific HR-QoL instrument were identified. No interventional studies aimed at improving HR-QoL in POI were identified. Only articles published in English were included in the study. WIDER IMPLICATIONS OF THE FINDINGS: Women with POI frequently have impaired HR-QoL related to the life-altering infertility diagnosis. The range of unmet psychosocial needs may be relevant for informing interventions for other populations with infertility. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development 'Massachusetts General Hospital-Harvard Center for Reproductive Medicine' (1 P50 HD104224-01 NICHD). The authors have no conflicts to declare. REGISTRATION NUMBER: N/A.

Correction: Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.

[This corrects the article DOI: 10.1371/journal.pgen.1007813.].

Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.

Identification of subjects with polycystic ovary syndrome using electronic health records.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A genetic basis for functional hypothalamic amenorrhea.

BACKGROUND: Functional hypothalamic amenorrhea is a reversible form of gonadotropin-releasing hormone (GnRH) deficiency commonly triggered by stressors such as excessive exercise, nutritional deficits, or psychological distress. Women vary in their susceptibility to inhibition of the reproductive axis by such stressors, but it is unknown whether this variability reflects a genetic predisposition to hypothalamic amenorrhea. We hypothesized that mutations in genes involved in idiopathic hypogonadotropic hypogonadism, a congenital form of GnRH deficiency, are associated with hypothalamic amenorrhea. METHODS: We analyzed the coding sequence of genes associated with idiopathic hypogonadotropic hypogonadism in 55 women with hypothalamic amenorrhea and performed in vitro studies of the identified mutations. RESULTS: Six heterozygous mutations were identified in 7 of the 55 patients with hypothalamic amenorrhea: two variants in the fibroblast growth factor receptor 1 gene FGFR1 (G260E and R756H), two in the prokineticin receptor 2 gene PROKR2 (R85H and L173R), one in the GnRH receptor gene GNRHR (R262Q), and one in the Kallmann syndrome 1 sequence gene KAL1 (V371I). No mutations were found in a cohort of 422 controls with normal menstrual cycles. In vitro studies showed that FGFR1 G260E, FGFR1 R756H, and PROKR2 R85H are loss-of-function mutations, as has been previously shown for PROKR2 L173R and GNRHR R262Q. CONCLUSIONS: Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism are found in women with hypothalamic amenorrhea, suggesting that these mutations may contribute to the variable susceptibility of women to the functional changes in GnRH secretion that characterize hypothalamic amenorrhea. Our observations provide evidence for the role of rare variants in common multifactorial disease. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00494169.).

Heterozygous Eif4nif1 Stop Gain Mice Replicate the Primary Ovarian Insufficiency Phenotype in Women.

We created the c.1286C>G stop-gain mutation found in a family with primary ovarian insufficiency (POI) at age 30 years. The Eif4enif1 C57/Bl6 transgenic mouse model contained a floxed exon 10-19 cassette with a conditional knock-in cassette containing the c.1286C>G stop-gain mutation in exon 10. The hybrid offspring of CMV- Cre mice with Eif4enif1 WT/flx mice were designated Eif4enif1 WT/ Δ for simplicity. A subset of female heterozygotes ( Eif4enif1 WT/ Δ ) had no litters. In those with litters, the final litter was earlier (5.4±2.6 vs. 10.5±0.7 months; p=0.02). Heterozygous breeding pair ( Eif4enif1 WT/ Δ x Eif4enif1 WT/ Δ ) litter size was 60% of WT litter size (3.9±2.0 vs. 6.5±3.0 pups/litter; p <0.001). The genotypes were 35% Eif4enif1 WT/flx and 65% Eif4enif1 WT/ Δ , with no homozygotes. Homozygote embryos did not develop beyond the 4-8 cell stage. The number of follicles in ovaries from Eif4enif1 WT/ Δ mice was lower starting at the primordial (499±290 vs. 1445±381) and primary follicle stage (1069±346 vs. 1450±193) on day 10 (p<0.05). The preantral follicle number was lower starting on day 21 (213±86 vs. 522±227; p<0.01). Examination of ribosome protected mRNAs (RPR) demonstrated altered mRNA expression. The Eif4enif1 stop-gain mice replicate the POI phenotype in women. The unique mouse model provides a platform to study regulation of protein translation across oocyte and embryo development in mammals.

The male reproductive system in classic galactosemia: cryptorchidism and low semen volume.

Previous studies examining reproductive parameters in men with galactosemia have inconsistently demonstrated abnormalities. We hypothesized that men with galactosemia may demonstrate evidence of reproductive dysfunction. Pubertal history, physical examination, hormone levels and semen analyses were examined in 26 males with galactosemia and compared to those in 46 controls. The prevalence of cryptorchidism was higher in men with galactosemia than in the general population [11.6% vs. 1.0% (95%CI: 0.75-1.26; p <0.001)]. Testosterone (461±125 vs. 532± 33 ng%; p=0.04), inhibin B (144±66 vs. 183±52 pg/mL; p=0.002) and sperm concentration (46±36 vs. 112±75×10(6) spermatozoa/mL; p=0.01) were lower and SHBG was higher (40.7±21.5 vs 26.7±14.6; p=0.002) in men with galactosemia compared to controls. Semen volume was below normal in seven out of 12 men with galactosemia. Men with galactosemia have a higher than expected prevalence of cryptorchidism and low semen volumes. The subtle decrease in testosterone and inhibin B levels and sperm count may indicate mild defects in Sertoli and Leydig cell function, but does not point towards severe infertility causing reproductive impairment. Follow-up studies are needed to further determine the clinical consequences of these abnormalities.

Cigarette smoking, nicotine levels and increased risk for metabolic syndrome in women with polycystic ovary syndrome.

Women with polycystic ovary syndrome (PCOS) are at risk for metabolic syndrome, which may be exacerbated by smoking. We hypothesized that smoking worsens androgen levels and the metabolic profile in women with PCOS. PCOS smokers (n = 47) and non-smokers (n = 64) and control smokers (n = 30) and non-smokers (n = 28), aged 18-45 years, underwent anthropomorphic measurements, pelvic ultrasound and blood sampling. Smokers had higher cotinine (801 ± 83 versus <11 nmol/L; smokers versus non-smokers, respectively; p < 0.001) and nicotine levels (37 ± 4 versus <12 µmol/L; p < 0.001). Triglyceride levels were higher in women with PCOS who smoked compared to non-smokers (1.55 ± 0.18 versus 0.95 ± 0.08 mmol/L; p < 0.001), even when adjusted for BMI. Metabolic syndrome was more common in smokers with PCOS compared to non-smokers with PCOS and smokers who were controls (28.6 versus 3.6%; p = 0.02). There were no differences in reproductive parameters including androgen levels. Cotinine (r = 0.3; p < 0.001) and nicotine levels (r = 0.2; p = 0.005) correlated with triglycerides. Nicotine levels also correlated with pulse rate (r = 0.2; p = 0.02) and waist:hip ratio (WHR; r = 0.2; p = 0.02). Taken together, smoking may worsen the already high risk for metabolic syndrome in women with PCOS.

DIS3 Variants are Associated With Primary Ovarian Insufficiency: Importance of Transcription/Translation in Oogenesis.

CONTEXT: A genetic etiology accounts for the majority of unexplained primary ovarian insufficiency (POI). OBJECTIVE: We hypothesized a genetic cause of POI for a sister pair with primary amenorrhea. DESIGN: The study was an observational study. Subjects were recruited at an academic institution. SUBJECTS: Subjects were sisters with primary amenorrhea caused by POI and their parents. Additional subjects included women with POI analyzed previously (n = 291). Controls were recruited for health in old age or were from the 1000 Genomes Project (total n = 233). INTERVENTION: We performed whole exome sequencing, and data were analyzed using the Pedigree Variant Annotation, Analysis and Search Tool, which identifies genes harboring pathogenic variants in families. We performed functional studies in a Drosophila melanogaster model. MAIN OUTCOME: Genes with rare pathogenic variants were identified. RESULTS: The sisters carried compound heterozygous variants in DIS3. The sisters did not carry additional rare variants that were absent in publicly available datasets. DIS3 knockdown in the ovary of D. melanogaster resulted in lack of oocyte production and severe infertility. CONCLUSIONS: Compound heterozygous variants in highly conserved amino acids in DIS3 and failure of oocyte production in a functional model suggest that mutations in DIS3 cause POI. DIS3 is a 3' to 5' exoribonuclease that is the catalytic subunit of the exosome involved in RNA degradation and metabolism in the nucleus. The findings provide further evidence that mutations in genes important for transcription and translation are associated with POI.

Disuse-induced muscle fibrosis, cellular senescence, and senescence-associated secretory phenotype in older adults are alleviated during re-ambulation with metformin pre-treatment.

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.

Environmental and genetic factors influence age at menarche in women with polycystic ovary syndrome.

OBJECTIVE: We hypothesized that body mass index (BMI) and DNA variants would predict age at menarche in polycystic ovarian syndrome (PCOS). SUBJECTS: 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. METHODS: Age at menarche was compared between PCOS cases and controls and examined as a function of multiple parameters. RESULTS: There was a strong inverse relationship between BMI and age at menarche in PCOS (r=-0.32, p=5 x lO(-11)). 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 (beta = 0.512, p < 0.001), reported weight group at 10-14 years (beta = -0.432, p < 0.001), current BMI (beta = -0.0202, p = 0.01), and genotype (beta = 0.169, p = 0.02). CONCLUSIONS: Age at menarche in women with PCOS is influenced by BMI and genetic variants near LIN28B.

Causal and Candidate Gene Variants in a Large Cohort of Women With Primary Ovarian Insufficiency.

CONTEXT: A genetic etiology likely accounts for the majority of unexplained primary ovarian insufficiency (POI). OBJECTIVE: We hypothesized that heterozygous rare variants and variants in enhanced categories are associated with POI. DESIGN: The study was an observational study. SETTING: Subjects were recruited at academic institutions. PATIENTS: Subjects from Boston (n = 98), the National Institutes of Health and Washington University (n = 98), Pittsburgh (n = 20), Italy (n = 43), and France (n = 32) were diagnosed with POI (amenorrhea with an elevated follicle-stimulating hormone level). Controls were recruited for health in old age or were from the 1000 Genomes Project (total n = 233). INTERVENTION: We performed whole exome sequencing (WES), and data were analyzed using a rare variant scoring method and a Bayes factor-based framework for identifying genes harboring pathogenic variants. We performed functional studies on identified genes that were not previously implicated in POI in a D. melanogaster model. MAIN OUTCOME: Genes with rare pathogenic variants and gene sets with increased burden of deleterious variants were identified. RESULTS: Candidate heterozygous variants were identified in known genes and genes with functional evidence. Gene sets with increased burden of deleterious alleles included the categories transcription and translation, DNA damage and repair, meiosis and cell division. Variants were found in novel genes from the enhanced categories. Functional evidence supported 7 new risk genes for POI (USP36, VCP, WDR33, PIWIL3, NPM2, LLGL1, and BOD1L1). CONCLUSIONS: Candidate causative variants were identified through WES in women with POI. Aggregating clinical data and genetic risk with a categorical approach may expand the genetic architecture of heterozygous rare gene variants causing risk for POI.

Genetics of Polycystic Ovary Syndrome: What is New?

Polycystic ovary syndrome (PCOS) is a complex genetic disorder with many genetic loci contributing small risk. Large genome-wide association studies identified 21 genetic risk loci for PCOS in European and Han Chinese women. The genetic architecture is similar across PCOS diagnostic categories. The next wave of analysis will incorporate large genotyped datasets linked to medical records, increasing numbers and ethnic subsets. The resulting genetic risk loci can then be used to create robust genetic risk scores enhanced with clinical information, environment and lifestyle data for a precision medicine approach to PCOS diagnosis and treatment.

Practical Approach to Hyperandrogenism in Women.

The approach to hyperandrogenism in women varies depending on the woman's age and severity of symptoms. Once tumorous hyperandrogenism is excluded, the most common cause is PCOS. Hirsutism is the most common presenting symptom. The woman's concern about her symptoms plays an important role in the management of disease. Although measurement of testosterone is useful in identifying an underlying cause, care must be taken when interpreting the less accurate assays that are available commercially. Surgical resection is curative in tumorous etiologies, whereas medical management is the mainstay for non-tumorous causes.

PRL Mutation Causing Alactogenesis: Insights Into Prolactin Structure and Function Relationships.

CONTEXT: Isolated prolactin deficiency is a rare disorder manifesting as absence of puerperal lactation. We identified a 2-generation family with 3 women experiencing alactogenesis. OBJECTIVE: We hypothesized a heterozygous genetic mutation. METHODS: This was a family-based study. Two generations of women (proband, sister, and niece) with puerperal alactogenesis and one control were studied. Prolactin levels in the 3 women ranged from 0.618 to 1.4 ng/mL (range, 2.8-29.2 ng/mL). All the women had regular menstrual cycles during their reproductive years. The niece required fertility treatment to become pregnant and the proband and sister underwent menopause before age 45 years. Prolactin gene (PRL) exons 1 to 5 were sequenced. We sought a heterozygous, deleterious gene variant with functional consequences. RESULTS: We identified a heterozygous mutation (c.658C > T) changing CGA to TGA (p.Arg220Ter) in exon 5 of the prolactin gene. Transfection of PRL containing the stop gain mutation resulted in similar intracellular prolactin levels compared to PRL wild type, but little detectable immunoactive or bioactive prolactin in conditioned medium. Prolactin secretion was also impaired by a PRL stop gain mutation deleting both of the terminal cysteine amino acids (c.652A > T; p.Lys218Ter). CONCLUSION: This is the first report of a PRL mutation causing familial prolactin deficiency and alactogenesis. The loss of the terminal cysteine resulted in failure of prolactin secretion. Secretion was not rescued by deleting the penultimate cysteine, with which it forms a disulfide bond. These data suggest that the PRL C terminal is critical for protein secretion.

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.

Single nucleus multi-omics regulatory landscape of the murine pituitary.

To provide a multi-omics resource and investigate transcriptional regulatory mechanisms, we profile the transcriptome, chromatin accessibility, and methylation status of over 70,000 single nuclei (sn) from adult mouse pituitaries. Paired snRNAseq and snATACseq datasets from individual animals highlight a continuum between developmental epigenetically-encoded cell types and transcriptionally-determined transient cell states. Co-accessibility analysis-based identification of a putative Fshb cis-regulatory domain that overlaps the fertility-linked rs11031006 human polymorphism, followed by experimental validation illustrate the use of this resource for hypothesis generation. We also identify transcriptional and chromatin accessibility programs distinguishing each major cell type. Regulons, which are co-regulated gene sets sharing binding sites for a common transcription factor driver, recapitulate cell type clustering. We identify both cell type-specific and sex-specific regulons that are highly correlated with promoter accessibility, but not with methylation state, supporting the centrality of chromatin accessibility in shaping cell-defining transcriptional programs. The sn multi-omics atlas is accessible at snpituitaryatlas.princeton.edu.

Recombinant human prolactin for the treatment of lactation insufficiency.

CONTEXT: Lactation insufficiency has many aetiologies including complete or relative prolactin deficiency. Exogenous prolactin may increase breast milk volume in this subset. We hypothesized that recombinant human prolactin (r-hPRL) would increase milk volume in mothers with prolactin deficiency and mothers of preterm infants with lactation insufficiency. DESIGN: Study 1: R-hPRL was administered in an open-label trial to mothers with prolactin deficiency. Study 2: R-hPRL was administered in a randomized, double-blind, placebo-controlled trial to mothers with lactation insufficiency that developed while pumping breast milk for their preterm infants. PATIENTS: Study 1: Mothers with prolactin deficiency (n = 5). Study 2: Mothers of premature infants exclusively pumping breast milk (n = 11). DESIGN: Study 1: R-hPRL (60 µg/kg) was administered subcutaneously every 12 h for 28 days. Study 2: Mothers of preterm infants were randomized to receive r-hPRL (60 µg/kg), placebo or r-hPRL alternating with placebo every 12 h for 7 days. MEASUREMENTS: Change in milk volume. RESULTS: Study 1: Peak prolactin (27·9 ± 17·3 to 194·6 ± 19·5 µg/l; P < 0·003) and milk volume (3·4 ± 1·6 to 66·1 ± 8·3 ml/day; P < 0·001) increased with r-hPRL administration. Study 2: Peak prolactin increased in mothers treated with r-hPRL every 12 h (n = 3; 79·3 ± 55·4 to 271·3 ± 36·7 µg/l; P < 0·05) and daily (101·4 ± 61·5 vs 178·9 ± 45·9 µg/l; P < 0·04), but milk volume increased only in the group treated with r-hPRL every 12 h (53·5 ± 48·5 to 235·0 ± 135·7 ml/day; P < 0·02). CONCLUSION: Twice daily r-hPRL increases milk volume in mothers with prolactin deficiency and in preterm mothers with lactation insufficiency.

Publisher Correction: Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Healthy Post-Menarchal Adolescent Girls Demonstrate Multi-Level Reproductive Axis Immaturity.

Context: Menstrual irregularity after menarche has been attributed to immature estrogen positive feedback activity (E+FB) but data are conflicting. Objective: To determine the hypothalamic-pituitary-ovarian contributions to menstrual irregularity in adolescents. Methods: Twenty-three healthy girls [aged 12.8 to 17.6 years; 0.4 to 3.5 years postmenarche; body mass index (BMI) percentile, 41.0 to 99.3] underwent serial hormone measurements and pelvic ultrasounds during two consecutive menstrual cycles. Hormones and follicle growth were compared with 65 adult historic controls with ovulatory cycles (OVs). Results: Girls had anovulatory cycles (ANOVs; 30%), OVs with a short luteal phase (short OVs; 22%), or OVs with normal luteal phase (normal OVs; 48%) without differences in cycle length, chronologic or gynecologic age, or BMI. Adolescents showed a spectrum of E+FB [midcycle LH adjusted for preovulatory estradiol (E2)]; only normal OV girls were comparable to adults. All OV girls had lower E2, progesterone, and gonadotropins during the luteal phase and luteal-follicular transition compared with adults. Normal OV girls also had lower follicular phase LH and FSH levels, a longer follicular phase, a slower dominant follicle growth rate, and smaller estimated preovulatory follicle size than adults. Follicular phase E2 and inhibin B levels were lower in normal OV girls than in adults even after adjusting for differences in FSH and follicle size. Conclusions: Early postmenarchal girls with normal OVs demonstrate mature E+FB but continue to have lower gonadotropin levels, diminished ovarian responsiveness, and decreased corpus luteum sex steroid synthesis compared with adults, indicating that reproductive axis maturity requires coordinated development of all components of the hypothalamic-pituitary-ovarian axis.