bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recovery of Male Reproductive Endocrine Function Following Prolonged Injectable Testosterone Undecanoate Treatment
Authors: Shankara-Narayana Nandini , Desai Reena , Conway Ann , Stuckey Bronwyn Gwenneth Ann , Inder Warrick John , Grossmann Mathis , Yeap Bu Beng , McLachlan Robert Ian , Lam Ly P , Bracken Karen , Wittert Gary Allen , Handelsman David J 
Published: May 2021

Abstract
Background: Exogenous androgen treatment suppresses the hypothalamo-pituitary testicular (HPT) axis causing reduced serum LH, FSH and testosterone (T). Recovery of male reproductive endocrine function in past androgen abusers takes 9-18 months with persistent mild lowering of serum T. The natural history of recovery of HPT axis following prolonged injectable testosterone undecanoate (TU) treatment at standard dose is not known. Therefore, the Runoff Study investigated the rate and extent of reproductive hormone recovery over 12 months following cessation of 2 years of TU treatment in the Testosterone for Diabetes Mellitus (T4DM) Study, while men remain blinded to treatment allocation. Methods: T4DM participants without pathological hypogonadism (n=1007) were randomised to TU or Placebo (P) injections every 3 months for 2 years with 303 subsequently volunteering to enter the Runoff study at 12 weeks after last injection. Before T4DM study unblinding, they provided blood samples and validated sexual function questionnaires (PDQ, IIEF-15) at entry (3 months after last injection), 6, 12, 18, 24, 40 and 52 weeks later. Serum steroid profile (T, DHT, E2, E1) was measured batchwise by LCMS and serum LH, FSH and SHBG by immunoassays. Results: Runoff study participants in both groups were similar and did not differ from all T4DM participants. As expected, at entry to Runoff serum T was higher in TU-treated men but at all timepoints from 12 weeks onwards serum T and SHBG remained consistently 11% and 13%, respectively, lower in TU-treated than in P-treated men. Similarly, at entry sexual function scores were higher in TU-treated men but subsequently no different from P-treated men. Serum LH and FSH recovered slowly with the median time to reach their own pre-treatment baseline of serum LH was 51.1 weeks [95% CI 50.4 – 53.0 weeks] and for serum FSH was 52.7 weeks [51.0 – 60.9 weeks]. Conclusion: After stopping 2 years of standard dose injectable TU treatment in men without pathological hypogonadism, recovery of testicular endocrine function is eventually complete but slow with serum gonadotropin recovery taking on 12 months since the last dose. Persistent mild, proportionate reduction in serum SHBG and T reflects lasting exogenous T effects on hepatic SHBG secretion rather than signifying androgen deficiency. This suggests that recovery from androgen-induced HPT axis suppression depends primarily on time since cessation rather than dose or duration of androgen exposure.
The Hypothalamic-Pituitary-Testicular Axis in Exceptionally Old Men
Authors: Aleksic Sandra , Desai Dimpi , Ye Kenny , Duran Sally , Gao Tina , Crandall Jill P , Atzmon Gil , Barzilai Nir , Milman Sofiya 
Published: May 2021

Abstract
Introduction: As life expectancy continues to increase and more men reach the extremes of age, it is important to understand the physiology of the aging hypothalamic-pituitary-testicular (HPT) axis and its role in health. While prior studies primarily focused on men younger than age ninety, we studied a unique cohort enriched for men with exceptional longevity to characterize the age-related trends in male sex-hormones, the etiology of the observed changes in the HPT axis, and its relationship with metabolic dysfunction and survival at the extremes of age. Methods: This is a cross-sectional study of community-dwelling Ashkenazi Jewish men (n = 427), age range 50-106 years. Longitudinal follow-up for vital status was conducted for men age ≥ 88 at enrollment (n = 86). Measurements included serum total testosterone (TT) by LC/MS, LH, SHBG, lipids, glucose and BMI. Free testosterone (FT) was calculated according to Vermeulen et. al. A change-point linear regression model was applied to describe the age trend of TT. Multivariable linear regression adjusted for comorbidities tested the associations between metabolic parameters and TT. The association between survival and TT was evaluated with the age-adjusted Cox proportional hazards model. Age-specific cutoffs for TT and LH were used to define primary and secondary hypogonadism. Results: The change point model was a significantly better fit for the data compared to the straight-line model (p = 0.004), indicating that TT significantly declines after age 88 years. Men age &lt; 88 years had higher average TT (401 ± 162 vs. 278 ± 178 ng/dL, p &lt; 0.001), FT (6.3 ± 2.0 vs. 3.3± 2.1 pg/mL, p &lt; 0.001), and lower LH (4.3 [3.0 - 6.1] vs. 14.6 [7.2 - 25.5] mIU/mL, p &lt; 0.001), compared to men age ≥ 88 years. The prevalence of primary and secondary hypogonadism was 2% and 11%, respectively, in men age &lt; 88 years, and 30% and 11%, among men age ≥ 88 years (p &lt; 0.001). A multivariable linear regression analysis revealed interactions between age, dichotomized at the change-point of 88 years, and metabolic parameters. Models stratified at age 88 demonstrated an inverse association between TT and BMI (p = 0.02), serum triglycerides (p = 0.007), and random glucose levels (p = 0.02) among men age &lt; 88; whereas a positive association was noted between TT and HDL cholesterol (p = 0.009) in this group. In men age ≥ 88 years, TT was not associated with any of the metabolic parameters or overall survival. Conclusions: Low testosterone in men with exceptional longevity is largely a result of primary testicular failure that occurs around age 88 and is accompanied by preserved hypothalamic-pituitary response with no associated metabolic dysfunction or effect on survival. This is in contrast to younger men, whose low T typically results from hypothalamic-pituitary dysfunction and is associated with metabolic derangements.
Effect of Diet on Mental Health on Those Suffering With Premenstrual Syndrome
Authors: Ramirez Francisco E , Hunter Jennifer 
Published: May 2021

Abstract
Objective: This study documents the effects that various dietary factors have on mental health among those suffering with premenstrual syndrome (PMS). DESIGN/Methods: N=3231 participants from around the world took an 85 question questionnaire that assessed depression and anxiety using the DSM-5 [The Diagnostic and Statistical Manual of Mental Disorders Volume 5] criteria, as well as various dietary patterns. Depression was classified as: Less than 7 none, 7 to 10 mild, 11 to 19 moderate and more than 20 severe.
Results: From n=3231 that took the test, n=1330 reported suffering from PMS. The average age from the n=1330 group was 35.1 ST 12.2.
Regarding meat n=1002 reported not eating meat twice a week, they had an average depression of 12 and SD of 7.7, n=328 eating meat twice a week they had a depression of 13.6 and SD of 7.3.
Regarding cheese n=720 reported not eating cheese more than twice a week, they had an average depression of 11 and SD 7.6, n=610 were eating cheese twice a week and had a depression of 14 and SD 7.5.
Regarding folate N=597 were eating folate rich foods at least 3 times a week, they had an average depression of 10.1 SD 7.5, n=356 were eating irregularly folate rich food less than 3 times a week they had a depression of 13.1 SD 7.2, n=377 did not eat folate eat rich food at least 3 times a week they had a depression of 15.2 and SD 7.3.
Regarding fish n=134 were eating fish more than twice a week they had an average depression of 12.6 and SD 7.4, n=1196 were not eating fish twice a week they had a depression of 12.3 SD 7.7
Regarding whole foods n=225 were eating more than 5 portions of fruits, vegetables and whole grain each day had an average depression of 9.6 SD 7.6, those that were eating 3 to 4 portions (n=453) had a depression of 10.8 SD 7.6, those eating 1 or 2 portions (n=512) had a depression of 14.1 SD 7.6, those eating less than 1 portion daily (n=140) had a depression of 15.2 SD 6.9. Regarding alcohol n=132 were drinking alcohol more than twice a week they had an average depression of 16.5 SD 7.2, n=1198 were not drinking alcohol more than twice a week they had a depression of 11.9 SD 7.6.
Conclusions: It seems that among those suffering from PMS eating fruits, vegetables, whole grains, and folate rich foods was related to less depression symptoms while alcohol, meat and cheese consumption was related to worse depression maybe due to a hormonal effect. It seems fish didn’t have an effect.
Wnt2b Is Essential for Adrenocortical Progenitor Cell Fate and Zona Glomerulosa Identity in Vivo
Authors: Little Donald W , Borges Kleiton S , Basham Kaitlin J , O’Connell Amy E , LaPensee Christopher R , Breault David T , Hammer Gary D 
Published: May 2021

Abstract
Dysregulation of normal adrenal structure and function contributes to a spectrum of diseases from hypoplasia to cancer. Peripheral adrenocortical progenitor cells in the zona glomerulosa (zG) centripetally migrate and differentiate to replenish steroidogenic cells of the zG and the inner cortex over time. Both the fate of progenitor cells and aldosterone production by steroidogenic cells in the zG are regulated by Wnt/β-catenin signaling, but the cell-specific effects of individual WNT ligands in the adrenal cortex are not fully understood. To further characterize Wnt signaling components crucial for progenitor cell fate and zG identity, we analyzed mouse adrenals using single molecule in situ hybridization, which revealed the previously unknown expression of Wnt2b exclusively in the adrenal capsule. Wnt2b is co-expressed in the capsule with the Wnt signaling potentiator Rspo3, the loss of which causes zG depletion and reduced adrenal size in mice. Therefore, we hypothesized that capsular WNT2B activates Wnt signaling in the underlying zG to maintain the undifferentiated state of progenitor cells. To define the role of WNT2B in these processes, we first generated whole body Wnt2b knockout (KO) mice, which exhibit complete zG loss, as defined by known markers of zG identity (β-catenin and DAB2). To more fully determine the mechanism by which Wnt2b deletion results in zG loss, we crossed Wnt2b-floxed and capsule-specific Gli1-CreERT2 mice to generate a Wnt2b conditional knockout (cKO) model and study the effects of Wnt2b loss on the zG during homeostasis of the adult adrenal cortex. Gli1-CreERT2 activation by tamoxifen in 6-week-old mice significantly decreased Wnt2b expression and resulted in a lower adrenal-to-body weight ratio in Wnt2b cKOs compared to controls four weeks later. Adrenocortical proliferation (Ki67) was also significantly decreased in Wnt2b cKO mice, suggesting that WNT2B may promote progenitor cell self-renewal. To characterize the consequences of WNT2B loss on canonical Wnt signaling, we assessed activation of β-catenin, the primary Wnt signaling effector. High β-catenin activity in the zG observed in wild-type mice was disrupted in Wnt2b cKO mice, together with markedly reduced expression of adrenocortical Wnt target genes Axin2 and Wnt4. In addition, Wnt2b loss resulted in downregulation of steroidogenic genes Cyp11b2 and Hsd3b6. Together, these data reveal that capsule-derived WNT2B is required for zG differentiation and maintenance, potentially through activating adrenocortical Wnt/β-catenin signaling and downstream target gene expression involved in both progenitor cell fate and steroid-producing cell function. Studies to more fully elucidate the dynamic effects of WNT2B on the adrenal zG are ongoing as they have important implications for adrenal homeostasis and disease, including both primary adrenal failure and neoplasia.
The Effect of Estetrol/Drospirenone on Ovarian Function Is Similar to a Well-Established Combined Oral Contraceptive: Results From a Phase 2 Study
Authors: Duijkers Ingrid J M , Klipping Christine , Jost Maud , Bastidas Adriana , Foidart Jean Michel F 
Published: May 2021

Abstract
Background: Combined oral contraceptives (COCs) often contain ethinylestradiol (EE), an estrogen known to be associated with several side effects including venous thromboembolism. Estetrol (E4) is a native estrogen synthesized by the human fetal liver during pregnancy. Results from a phase 2 dose-finding study showed that E4 15 mg in combination with drospirenone 3 mg (E4/DRSP) resulted in a good bleeding profile and cycle control. Here, we present phase 2 results showing the effect of E4/DRSP on ovarian function. Study Design: A single-center, randomized, open-label, parallel study was conducted in healthy young volunteers with proven ovulatory cycles. Study subjects received either E4 15 mg/DRSP 3 mg (n=41) or EE 20 µg/DRSP 3 mg (n=41) in a 24/4-day regimen for three consecutive cycles. Both in cycle 1 and 3, serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH), estradiol and progesterone levels were determined, and follicular size and endometrial thickness were measured every three days using transvaginal ultrasound. Ovarian function was assessed using the Hoogland score, which considers follicular size and estradiol/progesterone levels. Return of ovulation was determined after treatment cessation. Safety and tolerability were assessed by monitoring adverse events (AEs), vital signs, physical and gynecological examination, clinical laboratory parameters, 12-lead electrocardiogram and echocardiogram. Results: No ovulations were reported during the use of E4/DRSP, while three ovulations occurred in two subjects in the EE/DRSP group. In both groups, most participants had no ovarian activity according to the Hoogland score. In cycle 1, Hoogland scores and follicular diameters were similar in both groups. In cycle 3, these parameters were slightly less suppressed in the E4/DRSP group when compared to EE/DRSP. While mean FSH and LH concentrations were less inhibited by E4/DRSP, mean estradiol and progesterone concentrations and endometrial thickness were similarly suppressed in both groups. Return of ovulation occurred on average 15.5 days after discontinuation of E4/DRSP intake. The number of frequently reported AEs considered to be related to study medication was similar for both treatment groups except for breast pain (11 subjects in the E4/DRSP group versus 4 subjects with EE/DRSP). Most related AEs were of mild or moderate intensity. Three subjects discontinued due to an AE, one with E4/DRSP (severe stress, emotional lability), and two with EE/DRSP (emotional lability, depressed mood). Other safety assessments did not show significant abnormalities. No serious AEs were reported. Conclusions: The combination of E4 15 mg and DRSP 3 mg results in adequate ovulation inhibition and ovarian function suppression, which is similar to a well-established COC containing EE/DRSP. E4/DRSP is considered safe and well-tolerated.
The Impact of the Covid-19 Pandemic on Women’s Reproductive Health
Authors: Owens Lisa A , Phelan Niamh , Behan Lucy Ann A 
Published: May 2021

Abstract
Background: The Covid-19 pandemic has profoundly affected the lives of the global population. It is known that periods of stress and psychological distress can affect women’s menstrual cycles. We, therefore, performed an observational study of women’s reproductive health over the course of the pandemic. Materials & Methods: An anonymous digital survey was shared by the authors via social media in September 2020. All women of reproductive age were invited to complete the survey. Results: 1031 women completed the survey. The mean age was 36.7 ± 6.6 years. 693/70% reported recording their cycles using an app or diary. 233/23% were using hormonal contraception. 441/46% reported a change in their menstrual cycle since the beginning of the pandemic. 483/53% reported worsening premenstrual symptoms, 100/18% reported new menorrhagia (p=0.003) and 173/30% new dysmenorrhea (p&lt;0.0001) compared to before the pandemic. 72/9% reported missed periods who not previously missed periods (p=0.003) and the median number of missed periods was 2 (IQR 1-3). 17/21% of those who ‘occasionally’ missed periods pre-pandemic missed periods ‘often’ during the pandemic. 467/45% reported a reduced libido. There was no change in the median cycle length (28 days) or days of bleeding (5) but there was a wider variability of cycle length (p=0.01) and a 1-day median decrease in the minimum (p&lt;0.0001) and maximum (p=0.009) cycle length. Women reported a median 2kg increase in self-reported weight and a 30-minute increase in median weekly exercise. 517/50% of women stated that their diet was worse and 232/23% that it was better than before the pandemic. 407/40% reported working more and 169/16% were working less. Women related a significant increase in low mood (p&lt;0.0001), poor appetite (p&lt;0.0001), binge eating (p&lt;0.0001), poor concentration (p&lt;0.0001), anxiety (p&lt;0.0001), poor sleep (p&lt;0.0001), loneliness (p&lt;0.0001) and excess alcohol use (p&lt;0.0001). Specific stressors reported included work stress (499/48%), difficulty accessing healthcare (254/25%), change in financial (201/19%) and living (169/16%) situation, difficulties with homeschooling children (191/19%), family or partner conflict (170/16%), family illness or bereavement (156/15%), and difficulties accessing or providing childcare (99/10%). Conclusions: The Covid-19 pandemic has significantly impacted the reproductive health of women. The long term health implications of this are yet to be determined and future studies should address this.
Vitamin D and TSH: Do Their Level Impact on IVF outcomes?
Authors: Negreiros Ricardo , Negreiros Luis , Rosado Victor , Cavalcanti Leonardo , Rosado Bernardo , Machado Breno , Bianco Bianca , Assunção Viviane 
Published: May 2021

Abstract
Abstract: There is a positive correlation between serum 25 (OH) Vit D concentrations below 30 ng/ml and the incidence of preterm delivery, while higher levels can bring benefits to pregnancy. Although studies agree that TSH levels affect fertility, in euthyroid women (0.5&lt;TSH&lt;4.5), the serum concentration of this hormone still has a dubious effect on gestational outcomes. In order to study the relationship between vitamin D, TSH levels and pregnancy endpoint, a retrospective cohort study was conducted that considered 520 women who had undergone In-Vitro Fertilization (IVF). Patients were grouped regarding TSH values in mIU/L: 0.5-2.49 (Group 1) (n=416) and 2.5-4.5 (Group 2) (n=104), the serum levels of 25 (OH) Vit D within them were dichotomized in subgroups: &lt;30 ng/mL (Group 1, n=212; Group 2, n=49) and &gt;30 ng/mL (Group 1, n=204; Group 2, n=55). Primary endpoint was clinical pregnancy (the presence of the gestational sac and fetal heartbeat by ultrasound) and secondary outcomes were miscarriage and gestacional age (preterm or full-term pregnancy). The rate of clinical pregnancy in group 1 was significantly higher in patients with 25 (OH) Vit D &lt;30 ng/ml (51.9%) than 25 (OH) Vit D &gt;30 ng/ml (42.2%) according to the chi-square test and Fisher’s exact test (p&lt;0.05 all). There was no significant difference in group 2 (p=0.35), with percentages of 49% and 40% in the respective subgroups. Moreover, no statistical difference between the abortion rates was seen in 25 (OH) Vit D subgroups in groups 1 (p=0.71) and 2 (p=0.52). When gestational age rates were measured, the percentage of full-term pregnancies was lower in patients with 25 (OH) Vit D &lt;30 ng/ml (Group 1=62.6%; Group 2=57.9%), compared to those with 25 (OH) Vit D &gt;30 ng/ml (Group 1=77.6%; Group 2=78.9%), however, only the subgroups in the TSH category between 0.5-2.49 mUI/L showed a statistically significant difference (p&lt;0,05). The Spearman test identified a weak positive correlation between 25 (OH) Vit D and gestational age (ρ=0.218; p&lt;0.05). The findings indicate lower frequency of clinical pregnancy in patients with TSH between 0.5-2.49 mIU/L and 25 (OH) Vit D &gt;30 ng/ml. In addition, variations in 25 (OH) Vit D, in both TSH groups, do not suggest interference in miscarriage rates. Furthermore, higher serum concentrations of 25 (OH) Vit D seem to be involved with an increase in the prevalence of full-term births, an important finding to guide the procedures for IVF.
A Prospective Cross-Over Study of Tissue Glucocorticoid Metabolism in Patients With Adrenal Insufficiency: The Effects of Dual-Release Hydrocortisone Therapy
Authors: Dineen Rosemary Anne , Martin-Grace Julie , Saeed Ahmed Khalid Mohamed , Taylor Angela Elizabeth , Shaheen Fozia , Schiffer Lina , Gilligan Lorna , Frizelle Isolda Mary , Gunness Anjuli , Garrahy Aoife , Hannon Anne marie , O’Reilly Michael William , Smith Diarmuid , McDermott John , Marie-Louise Healy , Agha Amar , Pazderska Agnieszka , Gibney James , Behan Lucy-Ann , Arlt Wiebke , Thompson Chris John , Sherlock Mark 
Published: May 2021

Abstract
Background: Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Within tissues, cortisol (F) availability is under the control of the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). We hypothesize that GC metabolism is altered in patients with AI due to the non-physiological pattern of current immediate-release hydrocortisone (IR-HC) replacement therapy. The use of once-daily dual-release hydrocortisone (DR-HC) preparation (Plenadren®) offers a more physiological cortisol profile and may alter GC metabolism in vivo.Study Design and Methods: Prospective cross-over study assessing impact of 12 weeks of DR-HC on tissue GC metabolism (using urinary steroid metabolomics, serum cortisol generation curves and adipose tissue biopsies) in 51 patients with AI (primary and secondary) and compared to age-and BMI-matched controls. Results: Patients with AI (n=51) receiving immediate-release HC (IR-HC) had a higher median 24-hour excretion of urinary cortisol compared to healthy controls [72.1µg/24hrs (IQR 43.6–124.2) vs 51.85 (35.5–72.3), p=0.02],with a lower global activity of 11β-HSD2 and higher activity of 5-alpha reductase. Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary F and total GC metabolite excretion, which was most significant in the evening on diurnal urine sampling. There was an increase in global 11β-HSD2 activity. Hepatic 11β-HSD1 activity was not significantly altered post-DR-HC but there was a significant reduction in gene expression of 11β-HSD1 in subcutaneous adipose tissue. Conclusion: Using comprehensive in-vivo techniques we have demonstrated significant abnormalities in glucocorticoid metabolism in patients with AI. This is driven by dysregulation in the pre-receptor enzyme activity controlling tissue-specific GC availability, which can be improved following treatment with DR-HC.