Higher Follicle-stimulating Hormone Levels Research Articles

Follicle-Stimulating Hormone (FSH) Levels During Androgen Deprivation Therapy Are Not Associated With Survival or Development of Castration-Resistant Prostate Cancer

Background Follicle-stimulating hormone (FSH) dysregulation plays a potential role in prostate cancer progression. The objective of this study was to evaluate whether higher FSH levels during androgen deprivation therapy (ADT) for recurrent prostate cancer could predict the development of castration-resistant prostate cancer (CRPC), prostate cancer-specific survival (CSS), and overall survival (OS). Methods Serum FSH levels were measured in cryopreserved samples of the continuous ADT arm of the PR.7 trial, supplemented with analogous samples from a large contemporaneous biobank. Univariate and multivariate analyses assessed the relationship between FSH tertiles and time to CRPC, as well as CSS, and OS. Results A total of 172 patients were included in our analysis. Of these, 54 patients (31%) developed CRPC during the 9-year follow-up. Median FSH for the tertiles was 4.35, 6.13, and 11.32 mIU/mL. FSH tertiles were not significantly associated with the time to CRPC, or with CSS or OS. FSH levels were not a significant prognostic factor for these oncologic outcomes. Conclusion As previously reported, the use of gonadotropin-releasing hormone (GnRH) antagonists for ADT has significantly more suppression of FSH levels than GnRH agonists. Our results do not suggest that differences in circulating FSH 1 year following ADT initiation influence long-term oncologic outcomes or development of CRPC.

High levels of FSH before puberty are associated with increased risk of metabolic syndrome during pubertal transition.

SummaryBackgroundDuring perimenopause, the rise in serum follicle‐stimulating hormone (FSH) is associated with increased adiposity, insulin resistance (IR), and metabolic syndrome (MetS). However, data for the pubertal period, which is characterized by increasing FSH levels and changing body composition, are limited.ObjectivesTo investigate the relationships between FSH and anthropometric changes, IR markers, and development of MetS in the peripubertal period.MethodsUppsala Longitudinal Study of Childhood Obesity (ULSCO) is an ongoing study that aims to understand the factors contributing to childhood obesity and the development of obesity‐related diseases. We analysed the subset of participants who were prepubertal at the first visit (n = 95, 77 with obesity). Mean follow‐up time was 3.0 ± 1.4 years.ResultsHigher serum FSH levels at the first visit were associated with an increased likelihood of elevation in body mass index (BMI SDS) (p = 0.025, OR = 16.10) and having MetS (p = 0.044, OR = 4.67) at the follow‐up. We observed nonlinear relationships between varying serum FSH levels and markers of adiposity and IR, especially in girls. At the first visit, when girls were prepubertal, FSH was negatively associated with BMI (β = −0.491, p = 0.005) and positively associated with sex hormone‐binding globulin (SHBG) (β = 0.625, p = 0.002). With the progression of puberty, negative associations between BMI and SHBG disappeared while FSH became positively associated with HOMA‐IR (β = 0.678, p = 0.025) and fasting insulin (β = 0.668, p = 0.027).ConclusionsHigher serum FSH levels in prepubertal children were associated with an increased risk of MetS development during pubertal transition. Along with nonlinear associations between varying serum FSH levels and IR markers, our results might imply a relationship between FSH and IR of puberty.

Prognostic Value of Follicle-Stimulating Hormone Levels in Predicting Survival in Men With Idiopathic Pulmonary Arterial Hypertension.

The objective of the study was to assess the association between changes in plasma follicle-stimulating hormone (FSH) and the potential effect on idiopathic pulmonary arterial hypertension (IPAH) in male patients. A total of 116 male patients with IPAH and 53 healthy controls were included from XX Hospital. Plasma FSH concentration was assessed in all participants. Receiver operating characteristic curves were used to assess the mortality risk. Kaplan–Meier curve and Cox regression analyses were used to predict the value of FSH on the survival rate of male IPAH patients. The plasma FSH concentration in the IPAH group was significantly higher than that in the control group (p = .017). Nonsurvivors had significantly higher levels of FSH than survivors (p < .0001). FSH levels were positively correlated with World Health Organization Functional Class, mean pulmonary artery pressure, and pulmonary vascular resistance (PVR; p = .023, p < .0001, and p < .0001, respectively) and negatively correlated with 6-min walk distance (6MWD) and cardiac output (CO; p = .004 and p = .010). Cox regression model analysis showed that the levels of FSH were also the independent factors of mortality in male IPAH patients (p < .0001). The IPAH patients with higher FSH levels had higher PVR, lower 6MWD, CO, and a lower survival rate (p = .042, p = .003, p = .029, and p < .0001, respectively). Therefore, we identified that increased FSH levels were associated with disease severity in male patients with IPAH and independently predicted risk of disease and poor survival rate.

Comparative characteristics of patients with infertility when applying melatonin in complex preparation for assisted reproductive technologies

Оbjective of the study was to conduct a retrospective comparative characterization of patients with infertility who took or did not take melatonin with assisted reproductive technologies (ART).Materials and methods. In our study, we examined 89 women. The first (control) group included 13 healthy women oocyte donors who got pregnant on their own and gave birth to their own healthy children, the second group - 33 patients with infertility, who took 3 mg of the preparation "Vita-melatonin" produced by "Kyiv Vitamin Plant" at the same time before bedtime, two weeks before and during ovulation stimulation, the third group - 43 patients with infertility who did not take melatonin preparation before and during ovulation stimulation. There were no women who worked night shifts among the patients. Medical documentation of women of the control group and those with infertility, data of gynecological, ultrasound examination, hormones blood were analyzed. Ultrasound examination of the pelvic organs was performed on all patients with the device "Mindray DC-80 X-Insight", and measurements were performed using a transvaginal sensor. The thickness and structure of the endometrium were evaluated, and the number of antral follicles (NAF) ranging in size from 2 to 10 mm was counted in each ovary. All patients were tested for serum levels of the anti-mullerian hormone (AMG), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), prolactin (PRL), progesterone (P), thyroid-stimulating hormone (TSH), triiodothyronine (T4).Results. The average age of women in the first (control) group was 27.08 ± 12.38 years, the second (taking melatonin) - 33.12 ± 8.18 years, the third (not taking melatonin) - 30.95 ± 7.07 years &gt; 0.05), i. e. the age of the patients of the examined groups was equal. It should be noted that in the studied patients of both groups, the occurrence of primary infertility exceeded secondary infertility 2.7 times in the second group (p &lt; 0.05) and 1.7 times in the third (p &lt; 0.05). Infertility factors such as reduced ovarian reserve, habitual miscarriage and infertility of unknown origin were more common in patients of the second group, and endometriosis, tubal factor and male factor in the third, although the difference was not significant. The available extragenital pathology did not differ in the patients of the examined groups. The number of antral follicles was significantly higher in both ovaries of women in the control group compared with patients of the second and third groups. While the thickness of the endometrium did not differ significantly in groups, although in women of the control group it was slightly less. Regarding the study of hormonal status, it should be noted that we did not find a significant difference in the levels of hormones in the blood of women we examined. Exceptionally, there was a significant difference (p &lt; 0.001) in progesterone content between the second (0.62 ± 0.052 nmol/l) and third (181.63 ± 13.87 nmol/l) groups. Also, the patients of the third group had significantly (p &lt; 0.05) higher levels of FSH in blood (8.25 ± 0.63 mUn/ml) compared with the control group (4.93 ± 0.69 mUn/ml).Conclusions. The examined women in the control group, as well as infertility patients who received melatonin two weeks before the expected menstruation and during ovulation stimulation, and infertility patients who did not receive this preparation in similar programs, did not differ in age, occurrence of primary and secondary infertility, the factor that led to infertility, concomitant extragenital pathology, ovarian reserve and hormone levels of the reproductive panel. That is, they were equal in our study.

Effects of acute severe acute respiratory syndrome coronavirus 2 infection on male hormone profile, ACE2 and TMPRSS2 expression, and potential for transmission of severe acute respiratory syndrome coronavirus 2 in semen of Asian men

ObjectiveTo confirm if severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be detected in semen of men with acute coronavirus disease 2019 and if their male hormone profile (testosterone, follicle-stimulating hormone, luteinizing hormone, sex hormone binding globulin, and free androgen index) is adversely affected during the acute phase of infection and any relation to the ACE2 and/or TMPRSS2 expression in human semen.DesignClinical study.SettingNational University Hospital, Singapore.Patient(s)Asian men aged 21–55 years who were admitted to National University Hospital, Singapore, with a laboratory-confirmed diagnosis of SARS-CoV-2 infection via nasopharyngeal swab in the acute phase of the infection, within 2–14 days of the development of symptoms or contact history, were recruited for the study.Intervention(s)Blood was collected in the morning to assess the male hormone profile. Human semen were obtained by masturbation and sent to the molecular diagnostic laboratories to detect the presence of SARS-CoV-2 RNA and assess the ACE2 and TMPRSS2 expression.Main Outcome Measure(s)Male hormone profile level and expression of SARS-CoV-2 RNA, ACE2, and TMPRSS2 in human semen.Result(s)A total of 63 men of Asian ethnicities agreed to participate in the study. Subsequently, 65% of recruited men had completely normal levels of male hormone profile. Moreover, 27% were noted to have higher luteinizing hormone levels between 6.6 and 16.1 IU/L (normal range, 0.8–6.1 IU/L), and 10% had higher follicle-stimulating hormone levels between 13.6 and 41.6 IU/L (normal range, 1.5–12.4 IU/L); all had normal testosterone levels. No SARS-CoV-2 RNAs were detected in all human semen. The ACE2 and TMPRSS2 expression was undetectable in 26 samples, whereas 23 samples only had a detectable TMPRSS2 expression and 4 only had an ACE2 expression. The remaining 3 expressed both ACE2 and TMPRSS2.Conclusion(s)Severe acute respiratory syndrome coronavirus 2 could not be found in the semen of a cohort of young to middle-aged Asian men with mild acute SARS-CoV-2 infection. However, there was a detectable expression of ACE2 and TMPRSS2 in semen, although not causal, and it may be correlated to changes in male hormone profiles and male age.

Primary hypothyroidism as a predictor of the hypogonadism development

Background. Human lifestyle significantly affects human health and reproductive functions. The presence of hypothyroidism negatively impacts the health, activity, and reproductive status. This study was aimed to assess hormonal status, metabolic and anthropometric parameters in men of active reproductive age with primary hypothyroidism. Materials and methods. Totally 60 males with primary hypothyroidism were included in the study. Acomparative analysis of hormonal, anthropometric, and metabolic parameters in 60 men with hypothyroidism (basic group) and 25 men without hypothyroidism and other chronic somatic diseases (control group) was performed. The mean age of the subjects was 42.4±2.7 years. Results. It has been established that hypothyroidism was accompanied by an increase in serum concentrations of cholesterol and low-density lipoprotein cholesterol in comparison with control group (25 men without hypothyroidism) indicating metabolic disturbance. The data shows the significant effect of hypothyroidism on testosterone and follicle-stimulating hormone (FSH) serum concentration but not on luteinizing hormone, estradiol levels. Patients with hypothyroidism had lower circulating testosterone and higher FSH level in comparison with the controls. The reproductive hormone changes in men with hypothyroidism can result in deleterious effects on sexual functions including erectile dysfunction, reduced libido, and alteration in spermatogenesis. Conclusions. In men with hypothyroidism, changes in hormonal status have been found, which manifested in a decrease in testosterone and an increase in the blood level of follicle-stimulating hormone. The effect of hypothyroidism on the blood level of other hormones (luteinizing, estradiol, cortisol) has not been established. Hypothyroidism in men is accompanied by changes in lipid metabolism (increased levels of total cholesterol and low-density lipoprotein cholesterol).

Nomogram to predict pregnancy outcomes of emergency oocyte freeze-thaw cycles.

Background:Existing clinical prediction models for in vitro fertilization are based on the fresh oocyte cycle, and there is no prediction model to evaluate the probability of successful thawing of cryopreserved mature oocytes. This research aims to identify and study the characteristics of pre-oocyte-retrieval patients that can affect the pregnancy outcomes of emergency oocyte freeze-thaw cycles.Methods:Data were collected from the Reproductive Center, Peking University Third Hospital of China. Multivariable logistic regression model was used to derive the nomogram. Nomogram model performance was assessed by examining the discrimination and calibration in the development and validation cohorts. Discriminatory ability was assessed using the area under the receiver operating characteristic curve (AUC), and calibration was assessed using the Hosmer–Lemeshow goodness-of-fit test and calibration plots.Results:The predictors in the model of “no transferable embryo cycles” are female age (odds ratio [OR] = 1.099, 95% confidence interval [CI] = 1.003–1.205, P = 0.0440), duration of infertility (OR = 1.140, 95% CI = 1.018–1.276, P = 0.0240), basal follicle-stimulating hormone (FSH) level (OR = 1.205, 95% CI = 1.051–1.382, P = 0.0084), basal estradiol (E2) level (OR = 1.006, 95% CI = 1.001–1.010, P = 0.0120), and sperm from microdissection testicular sperm extraction (MESA) (OR = 7.741, 95% CI = 2.905–20.632, P < 0.0010). Upon assessing predictive ability, the AUC for the “no transferable embryo cycles” model was 0.799 (95% CI: 0.722–0.875, P < 0.0010). The Hosmer–Lemeshow test (P = 0.7210) and calibration curve showed good calibration for the prediction of no transferable embryo cycles. The predictors in the cumulative live birth were the number of follicles on the day of human chorionic gonadotropin (hCG) administration (OR = 1.088, 95% CI = 1.030–1.149, P = 0.0020) and endometriosis (OR = 0.172, 95% CI = 0.035–0.853, P = 0.0310). The AUC for the “cumulative live birth” model was 0.724 (95% CI: 0.647–0.801, P < 0.0010). The Hosmer–Lemeshow test (P = 0.5620) and calibration curve showed good calibration for the prediction of cumulative live birth.Conclusions:The predictors in the final multivariate logistic regression models found to be significantly associated with poor pregnancy outcomes were increasing female age, duration of infertility, high basal FSH and E2 level, endometriosis, sperm from MESA, and low number of follicles with a diameter >10 mm on the day of hCG administration.

The role of reproductive hormones and anovulation in moderating the relationship of phthalates with fecundability

BACKGROUND AND AIM: Phthalates are endocrine disruptors that may inhibit folliculogenesis and we previously observed a relationship of metabolites of DEHP, DEP and BzBP with reduced fecundability. Estrogen supplementation may additionally mitigate phthalate-associated follicular atresia. Thus, we aimed to evaluate whether the impact of phthalates on achieving pregnancy was modified by their relationship with endogenous reproductive hormones and anovulation. METHODS: The EAGeR trial (2007-2011) enrolled 1,228 women attempting pregnancy with a history of pregnancy loss and followed them for up to 6 menstrual cycles or throughout pregnancy if they became pregnant. Twenty phthalate metabolites were measured in a 3-day pooled urine sample at the beginning of the first menstrual cycle of follow-up. Hormone levels were assessed during the follicular phase, ovulation and the luteal phase in the first two cycles. Cycles were considered anovulatory in the absence of a surge in luteinizing hormone (LH). Generalized estimating equations assessed risk of anovulation and generalized linear models change in hormone levels, adjusting for urinary creatinine and individual characteristics. Modification of the relationship of DEHP, DEP, and BzBP with fecundability by quartiles of estradiol was evaluated using discrete-time Cox proportional hazards models, incorporating interaction terms. RESULTS:We observed no clear relationship between phthalates and anovulation. Phthalates were associated with lower levels of estradiol and higher levels of follicle-stimulating hormone across the menstrual cycle, and higher pregnanediol and LH in the luteal phase. We observed the strongest association of metabolites of DEHP and DEP with fecundability among women in the lowest quartile of estradiol during the follicular phase (e.g. DEP fecundability odds ratio [FOR] 0.70, 95% CI 0.55, 0.91 for quartile 1 vs. FOR 0.95, 95% CI 0.76, 1.18 for quartile 4, p-interaction = 0.036). CONCLUSIONS:Reproductive hormones may play a role in the relationship of phthalates with fecundability among couples trying to conceive. KEYWORDS: Phthalates, Female reproductive outcomes

Proposed age-stratified reference intervals of FSH derived from normozoospermic men

Objective: To demonstrate that serum follicle-stimulating hormone (FSH) in men rises with age, and to explore FSH reference intervals of age-related partitioning. Methods: Men aged 20-50 years (n=1 190) underwent semen analysis according to World Health Organization (2010) methods. Serum was frozen prior to measurement of FSH by using the Siemens ADVIA Centaur® XP immunoassay system. FSH central 95% intervals after logarithmic transformation based on age were derived from 1 037 normozoospermic men. These were then applied to oligozoospermic and azoospermic men. Men producing azoospermic semen samples were further classified as having non-obstructive azoospermia by clinical diagnostic criteria, including genetic analysis and surgical exploration. Results: Serum FSH in normozoospermic men increased with age (P&lt;0.05), and reference intervals were determined with 10-year brackets: 21-30 years [(1.0-8.2) IU/L], 31-40 years [(1.4-9.5) IU/L], 41-50 years [(1.9-12.0) IU/L]. The proportion of oligozoospermic men with normal FSH concentrations was less than the normozoospermic men, which in turn was lower among azoospermic men (both P&lt;0.01). The azoospermic men were further broken down according to the nature of the azoospermia as either obstructive or non-obstructive azoospermia, and 86.4% (38/44) men with non-obstructive azoospermia had elevated serum FSH concentrations whereas only 6.7% (1/15) men with obstructive azoospermia had high FSH levels, and this was significantly different (P&lt;0.01). Conclusions: FSH concentrations increase in men between 20-50 years, and clinical interpretation of serum FSH results in men must be made by using age-based reference intervals.

Tributyltin and high‐refined carbohydrate diet lead to metabolic and reproductive abnormalities, exacerbating premature ovary failure features in the female rats

Exposure to the obesogen tributyltin (TBT) alone or high carbohydrate diet (HCD) alone leads to obesity and reproductive complications, such as premature ovary failure (POF) features. However, little is known about interactions between TBT and nutrition and their combined impact on reproduction. In this study, we assessed whether acute TBT and HCD exposure results in reproductive and metabolic irregularities. Female rats were treated with TBT (100 ng/kg/day) and fed with HCD for 15 days and metabolic and reproductive outcomes were assessed. TBT and HCD rats displayed metabolic impairments, such as increased adiposity, abnormal lipid profile and triglyceride and glucose (TYG) index, worsening adipocyte hypertrophy in HCD-TBT rats. These metabolic consequences were linked with reproductive disorders. Specifically, HCD-TBT rats displayed irregular estrous cyclicity, high follicle-stimulating hormone (FSH) levels, low anti-Müllerian hormone (AMH) levels, reduction in ovarian reserve, and corpora lutea (CL) number, with increases in atretic follicles, suggesting that HCD-TBT exposure exacerbated POF features. Further, strong negative correlations were observed between adipocyte hypertrophy and ovarian reserve, CL number and AMH levels. HCD-TBT exposure resulted in reproductive tract inflammation and fibrosis. Collectively, these data suggest that TBT plus HCD exposure leads to metabolic and reproductive abnormalities, exacerbating POF features in female rats.

The Spectrum of Chromosomal Abnormalities and Endocrine Profile of Male Infertility with Nonobstructive Semen Abnormality: A Case-Control Study.

Background:Primary infertility is a common occurrence which affects approximately 15% of couples who desire to begin their family. Chromosomal abnormalities are well-established causes of pregnancy loss but may also have a role in explaining the cause of male infertility, especially with nonobstructive semen abnormalities. Hence, awareness regarding safety of artificial reproductive technology in these individuals due to underlying sperm aneuploidy is required.Aims:The aims of the study are to determine the prevalence of chromosomal abnormalities in primary infertile males with nonobstructive semen abnormalities and correlate with their endocrine profile.Study Design:A case–control study, in which 100 males with primary infertility and non-obstructive semen abnormalities were evaluated for chromosomal abnormality and hormonal profile; and were compared with 50 healthy males with normal semen analysis and at least one biological child.Materials and Methods:Blood T-lymphocytes were cultured using RPMI-1640 medium for obtaining metaphases and chromosomal analysis.Statistical Analysis:SPSS software and Student's t-test were used. A p < 0.05 was considered statistically significant.Results:Azoospermia (81%) was the most common nonobstructive semen abnormality. Overall prevalence of major chromosomal abnormalities and polymorphic variants was 16% and 7%, respectively. Klinefelter syndrome was the most common sex chromosomal numerical abnormality seen in 6.17% of cases with azoospermia. All healthy control males had 46, XY karyotype. Higher levels of follicle-stimulating hormone and luteinizing hormone and lower levels of testosterone along with testicular volumes were observed in infertile males with abnormal karyotype (p < 0.05).Conclusion:Primary infertile males with nonobstructive semen abnormality have high frequency of chromosomal aberrations, which justify the requirement of cytogenetic testing in these patients.

Compensated hypogonadism in men with sickle cell disease.

To evaluate the prevalence of hypogonadism in a population of men with SCD and characterize its aetiology. Sickle cell disease (SCD) is associated with the development of hypogonadism, but there is still controversy regarding its aetiology and clinical implications. We performed a cross-sectional study of 34 men with SCD aged > 18 years. Sociodemographic and clinical data, including anthropometric measurements (weight, height and BMI), were obtained. Early morning, blood samples were collected and total testosterone (TT), free testosterone (FT), luteinizing hormone (LH), follicle stimulating hormone (FSH), a complete blood count and haemoglobin electrophoresis were measured. Eugonadism was defined as T≥300ng/dL and LH≤9.4mUI/mL; primary hypogonadism as T< 300 ng/dL and LH>9.4mUI/mL; secondary hypogonadism as T<300ng/dL and LH≤9.4mUI/mL; and compensated hypogonadism as T≥300ng/dL and LH>9.4mUI/mL. Median age was 33 (26-41) years, and SS genotype was the most frequent (73.5%). The prevalence of eugonadism, compensated hypogonadism and secondary hypogonadism was 67.5%, 26.4% and 5.88%, respectively. No men with primary hypogonadism were identified in our sample. Those with compensated hypogonadism had also higher FSH levels (>7.8mUI/mL, P<.0001). In our study population of men with SCD, a high prevalence of compensated hypogonadism was identified, which is a controversial and distinct clinical entity that warrants monitoring and further research.

Controlled ovarian hyperstimulation for poor ovarian responders undergoing in vitro fertilisation/intracytoplasmic sperm injection: a protocol for systematic review and Bayesian network meta-analysis

IntroductionControlled ovarian hyperstimulation (COH) is the routine regimen used to generate a sufficient number of follicles during in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatment. Poor ovarian response...

In-Vitro Fertilization Outcome Predictors in Women With High Baseline Follicle-Stimulating Hormone Levels: Analysis of Over 1000 Cycles From A Tertiary Center.

Objective:The present study aimed to evaluate reproductive outcomes and determine the predictors of clinical pregnancy and live birth in women with elevated baseline follicle-stimulating hormone (FSH) levels, who have undergone intracytoplasmic sperm injection (ICSI) treatment.Methods:This retrospective study included 1011 ICSI cycles of women with high baseline FSH levels (> 10 IU/L), from a tertiary university IVF center between 2010 and 2015. Logistic regression analysis was performed to evaluate the prognostic factors of clinical pregnancy and live birth.Results:Among the 1011 ICSI cycles, the clinical pregnancy and live birth rates per oocyte retrieval were 19.5% and 14.3%, respectively. The live birth rates were 21.1% and 1.7% in women aged ≤30 years and those aged ≥40 years, respectively. In addition, the live birth rate was 1.47-fold higher in women from whom >3 oocytes were retrieved, compared to those from whom ≤3 oocytes were retrieved (p=0.047). Logistic regression analysis indicated that the age categories ≤30y, 36-39y and ≥40y, level of baseline FSH (≥20 IU/L) and the ovarian response (≤3 or >3 oocytes retrieved) were significantly associated with live birth.Conclusions:Our study indicated that age, baseline FSH level, and ovarian response are independent predictive factors for clinical pregnancy and live birth among women with baseline FSH levels >10 IU/L.

Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations.

Loss-of-function mutations of makorin RING finger protein 3 (MKRN3) are the most common monogenic cause of familial central precocious puberty (CPP). To describe the clinical and hormonal features of a large cohort of patients with CPP due to MKRN3 mutations and compare the characteristics of different types of genetic defects. Multiethnic cohort of 716 patients with familial or idiopathic CPP screened for MKRN3 mutations using Sanger sequencing. A group of 156 Brazilian girls with idiopathic CPP (ICPP) was used as control group. Seventy-one patients (45 girls and 26 boys from 36 families) had 18 different loss-of-function MKRN3 mutations. Eight mutations were classified as severe (70% of patients). Among the 71 patients, first pubertal signs occurred at 6.2 ± 1.2 years in girls and 7.1 ± 1.5 years in boys. Girls with MKRN3 mutations had a shorter delay between puberty onset and first evaluation and higher follicle-stimulating hormone levels than ICPP. Patients with severe MKRN3 mutations had a greater bone age advancement than patients with missense mutations (2.3 ± 1.6 vs 1.6 ± 1.4 years, P = .048), and had higher basal luteinizing hormone levels (2.2 ± 1.8 vs 1.1 ± 1.1 UI/L, P = .018) at the time of presentation. Computational protein modeling revealed that 60% of the missense mutations were predicted to cause protein destabilization. Inherited premature activation of the reproductive axis caused by loss-of-function mutations of MKRN3 is clinically indistinct from ICPP. However, the type of genetic defect may affect bone age maturation and gonadotropin levels.

FSHB and FSHR gene variants exert mild modulatory effect on reproductive hormone levels and testis size but not on semen quality: A study of 2020 men from the general Danish population.

Spermatogenesis depends on stimulation by follicle-stimulating hormone (FSH) which binds to FSH receptors (FSHR) on testicular Sertoli cells. Three FSH-related single-nucleotide polymorphisms (SNPs), FSHB -211G>T (rs10835638), FSHR -29G>A (rs1394205) and FSHR 2039A>G (rs6166) affect FSH action, and have been suggested to affect testicular function, but the evidence is uncertain. To describe the associations between the three SNPs and testicular function in a large and well-characterised cohort of men from the general population. A cross-sectional study of 2020 Danish men unselected regarding testicular function. Outcome variables were semen parameters, reproductive hormones and testis size. Genotyping was done by competitive allele-specific quantitative PCR. Differences in genotype frequencies were tested by chi-square test and associations between genotypes and outcomes were assessed by multivariate linear regressions. The SNPs affected serum FSH; carriers of the variant affecting FSH secretion (FSHB -211G>T) had lower FSH levels while carriers of variants affecting receptor expression (FSHR -29G>A) and receptor sensitivity (FSHR 2039A>G) had higher FSH levels. Carriers of FSHB -211G>T had lower calculated free testosterone/LH ratio. Although both FSHB -211G>T and FSHR 2039A>G were associated with smaller testis size, no clear association was detected in relation to any semen parameters, except a lower total number of morphologically normal spermatozoa in the heterozygous carriers of the FSHB -211G>T DISCUSSION AND CONCLUSION: The studied polymorphisms have only minor modulating influence on testis size and function in healthy men. We detected subtle effects of the three SNPs on FSH levels, but also effects of FSHB -211G>T on calculated free testosterone/LH ratio, compatible with altered Leydig cell function. Thus, the role of these FSH-related polymorphisms is complex and modest in men with normal testicular function, but the possible importance of FSH polymorphisms in men with impaired testicular function should be evaluated in future studies in more detail.

Correlation of progesterone levels on the day of oocyte retrieval with basal hormonal status and the outcome of ART

This study aimed to assess whether basal hormonal levels can predict the levels of progesterone (P4) on the day of oocyte retrieval (OR) and examine the impact of P4 levels on the day of OR on the outcome of assisted reproduction. One hundred sixty-four patients that were enrolled in the assisted reproduction procedure were classified according to their P4 levels on the OR day (< 2 ng/ml vs. ≥ 2 ng/ml). Patients who had P4 levels < 2 ng/ml had significantly higher follicle stimulating hormone (FSH) levels and significantly lower anti-Mullerian hormone (AMH) levels. More than half of patients with P4 levels < 2 ng/ml on the OR day got pregnant and delivered healthy infants. There was a significant correlation between lower FSH values and higher P4 values at OR and between higher AMH values and higher P4 values on the day of OR. Regression analysis showed that high FSH levels are the most important factor that can reliably imply lower P4 levels on OR day. Our study confirmed that lower basal FSH levels can predict the levels of P4 on the OR day. Moreover, lower levels of P4 on the day of OR are associated with a positive outcome in assisted reproduction.

Prediagnostic circulating levels of sex hormones and survival in esophageal adenocarcinoma.

Sex hormonal differences may contribute to the strong male predominance in esophageal adenocarcinoma (EAC), but whether sex hormone levels influence survival in EAC is unstudied. Our study aimed to assess associations between prediagnostic sex hormone levels and survival in EAC. In a population‐based cohort study, 244 male EAC patients from the Janus Serum Bank Cohort in Norway were followed up through 2018. Associations between prediagnostic serum levels of 12 sex hormone measures and disease‐specific mortality were assessed using multivariable Cox regression, providing hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age, calendar year, body mass index, tobacco smoking, physical activity and surgical resection. Higher levels of sex hormone‐binding globulin (SHBG) indicated decreased disease‐specific mortality (HR 0.68, 95% CI 0.44‐1.07, highest vs lowest tertile). In stratified analyses by surgery, such associations remained in nonoperated patients (HR 0.58, 95% CI 0.35‐0.96, highest vs lowest tertile), but not in operated patients. Higher levels of follicle‐stimulating hormone (FSH) were associated with increased disease‐specific mortality in an exposure‐response pattern; HRs for the middle and highest tertiles vs the lowest tertile were 1.35 (95% CI 0.89‐2.05) and 1.61 (95% CI 1.06‐2.43), respectively. No clear associations were observed with serum levels of dehydroepiandrosterone sulfate, luteinizing hormone, prolactin, testosterone, 17‐OH‐progesterone, progesterone, estradiol, androstenedione, testosterone:estradiol ratio or free testosterone index. These findings suggest that higher endogenous levels of SHBG and lower levels of FSH may increase the survival in EAC. The other 10 examined sex hormone measures may not influence the survival.

High follicle-stimulating hormone levels accelerate cartilage damage of knee osteoarthritis in postmenopausal women through the PI3K/AKT/NF-κB pathway.

Osteoarthritis is the main cause of pain and disability in the elderly, with the most commonly affected joint being the knee. The prevalence of knee osteoarthritis (KOA) is significantly increased in postmenopausal women, although the mechanisms underlying KOA remain unclear. The present study aimed to investigate the association between follicle-stimulating hormone (FSH) and postmenopausal women with KOA aged between 50 and > 70 years, as well as explore its underlying molecular mechanisms. Here, we report that the 50-60 years age group had the highest level of serum FSH. Compared to the low FSH group (< 40 mIU·mL-1 ) in the same age group, the high FSH group (> 40 mIU·mL-1 ) showed more severe cartilage damage. Furthermore, phosphorylated (p)-phosphoinositide 3-kinase (PI3K)/PI3K, p-AKT/AKT and p-nuclear factor kappa B (NF-κB)/NF-κB levels were significantly higher in the high FSH group compared to the low FSH group. Immunofluorescence experiments showed that FSH stimulation promoted the translocation of NF-κB p65 into the nucleus, and decreased type II collagen and aggrecan in ATDC5 cells. Moreover, we used western blotting in ATDC5 cells to demonstrate that FSH decreased type II collagen and increased p-PI3K/PI3K, p-AKT/AKT, p-NF-κB/NF-κB and p-IKB/IKB in a concentration-dependent manner. Our results suggest that increased FSH levels are associated with KOA for postmenopausal women aged 50-60 years and that high FSH levels might damage the cartilage tissues through the PI3K/AKT/NF-κB pathway.

Fluorescence-assisted sequential insertion of transgenes (FASIT): an approach for increasing specific productivity in mammalian cells

Currently, the generation of cell lines for the production of recombinant proteins has the limitation of unstable gene expression due to the repeat-induced gene silencing or the loss of transgene copies resulting from recombination events. In this work, we developed a new strategy based on the sequential insertion of transgenes for generating stable clones producing high levels of a chimeric human follicle-stimulating hormone (hscFSH). Gene insertion was done by transducing HEK-293 cells with a lentiviral vector containing a bicistronic transcriptional unit for expressing hscFSH and GFP genes. Clone selection was performed by flow cytometry coupled to cell sorting, and the GFP gene was further removed by CRE-mediated site-specific recombination. High-producing clones of hscFSH were obtained after three rounds of lentiviral transduction. Expression levels increased in a step-wise manner from 7 to 23 pg/cell/day, with a relatively constant rate of 7 pg/cell/day in each round of transduction. The GFP gene was successfully removed from the cell genome without disturbing the hscFSH gene expression. Clones generated using this approach showed stable expression levels for more than two years. This is the first report describing the sequential insertion of transgenes as an alternative for increasing the expression levels of transformed cell lines. The methodology described here could notably impact on biotechnological industry by improving the capacity of mammalian cells to produce biopharmaceuticals.