Showing papers by "Christina Wang published in 2022"

Associations Between Prenatal Urinary Biomarkers of Phthalate Exposure and Preterm Birth: A Pooled Study of 16 US Cohorts.

Abstract: Importance Phthalate exposure is widespread among pregnant women and may be a risk factor for preterm birth. Objective To investigate the prospective association between urinary biomarkers of phthalates in pregnancy and preterm birth among individuals living in the US. Design, Setting, and Participants Individual-level data were pooled from 16 preconception and pregnancy studies conducted in the US. Pregnant individuals who delivered between 1983 and 2018 and provided 1 or more urine samples during pregnancy were included. Exposures Urinary phthalate metabolites were quantified as biomarkers of phthalate exposure. Concentrations of 11 phthalate metabolites were standardized for urine dilution and mean repeated measurements across pregnancy were calculated. Main Outcomes and Measures Logistic regression models were used to examine the association between each phthalate metabolite with the odds of preterm birth, defined as less than 37 weeks of gestation at delivery (n = 539). Models pooled data using fixed effects and adjusted for maternal age, race and ethnicity, education, and prepregnancy body mass index. The association between the overall mixture of phthalate metabolites and preterm birth was also examined with logistic regression. G-computation, which requires certain assumptions to be considered causal, was used to estimate the association with hypothetical interventions to reduce the mixture concentrations on preterm birth. Results The final analytic sample included 6045 participants (mean [SD] age, 29.1 [6.1] years). Overall, 802 individuals (13.3%) were Black, 2323 (38.4%) were Hispanic/Latina, 2576 (42.6%) were White, and 328 (5.4%) had other race and ethnicity (including American Indian/Alaskan Native, Native Hawaiian, >1 racial identity, or reported as other). Most phthalate metabolites were detected in more than 96% of participants. Higher odds of preterm birth, ranging from 12% to 16%, were observed in association with an interquartile range increase in urinary concentrations of mono-n-butyl phthalate (odds ratio [OR], 1.12 [95% CI, 0.98-1.27]), mono-isobutyl phthalate (OR, 1.16 [95% CI, 1.00-1.34]), mono(2-ethyl-5-carboxypentyl) phthalate (OR, 1.16 [95% CI, 1.00-1.34]), and mono(3-carboxypropyl) phthalate (OR, 1.14 [95% CI, 1.01-1.29]). Among approximately 90 preterm births per 1000 live births in this study population, hypothetical interventions to reduce the mixture of phthalate metabolite levels by 10%, 30%, and 50% were estimated to prevent 1.8 (95% CI, 0.5-3.1), 5.9 (95% CI, 1.7-9.9), and 11.1 (95% CI, 3.6-18.3) preterm births, respectively. Conclusions and Relevance Results from this large US study population suggest that phthalate exposure during pregnancy may be a preventable risk factor for preterm delivery.

Hormonal Male Contraception: Getting to Market

Abstract: Rates of unplanned pregnancies are high and stagnant globally, burdening women, families and the environment. Local limitations placed upon contraceptive access and abortion services exacerbate global disparities for women. Despite survey data suggesting men and their partners are eager for expanded male contraceptive options, efforts to develop such agents have been stymied by a paucity of monetary investment. Modern male hormonal contraception, like female hormonal methods, relies upon exogenous progestins to suppress the hypothalamic-pituitary-gonadal axis, in turn suppressing testicular testosterone production and sperm maturation. Addition of an androgen augments gonadotropin suppression, more effectively suppressing spermatogenesis in men, and provides androgenic support for male physiology. Previous contraceptive efficacy studies in couples have shown that hormonal male methods are effective and reversible. Recent efforts have been directed at addressing potential user and regulatory concerns by utilizing novel steroids and varied routes of hormone delivery. Provision of effective contraceptive options for men and women is an urgent public health need. Recognizing and addressing the gaps in our contraceptive options and engaging men in family planning will help reduce rates of unplanned pregnancies in the coming decades.

Standards in semen examination: publishing reproducible and reliable data based on high-quality methodology

Abstract: Abstract Biomedical science is rapidly developing in terms of more transparency, openness and reproducibility of scientific publications. This is even more important for all studies that are based on results from basic semen examination. Recently two concordant documents have been published: the 6th edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen, and the International Standard ISO 23162:2021. With these tools, we propose that authors should be instructed to follow these laboratory methods in order to publish studies in peer-reviewed journals, preferable by using a checklist as suggested in an Appendix to this article.

Treatment of Cushing's Disease with Pituitary-Targeting Seliciclib.

Abstract: CONTEXT Preclinical studies show seliciclib (R-roscovitine) suppresses neoplastic corticotroph proliferation and pituitary adrenocorticotrophic hormone (ACTH) production. OBJECTIVE To evaluate seliciclib as an effective pituitary-targeting treatment for patients with Cushing's disease (CD). DESIGN Two prospective, open-label, phase 2 trials. SETTING Tertiary referral pituitary center. PATIENTS Adult patients with de novo, persistent, or recurrent CD. INTERVENTION Oral seliciclib 400 mg twice daily for 4 consecutive days each week for 4 weeks. MAIN OUTCOME MEASURES Primary endpoint in the proof-of-concept single-center study was normalization of 24-hour urinary free cortisol (UFC; ≤ 50 µg/24 h) at study end; in the pilot multicenter study, primary endpoint was UFC normalization or ≥50% reduction in UFC from baseline to study end. RESULTS Sixteen patients were consented and 9 were treated. Mean UFC decreased by 42%, from 226.4 ± 140.3 µg/24 h at baseline to 131.3 ± 114.3 µg/24 h by study end. Longitudinal model showed significant UFC reductions from baseline to each treatment week. Three patients achieved ≥50% UFC reduction (range, 55% to 75%), and 2 patients exhibited 48% reduction; but none achieved UFC normalization. Plasma ACTH decreased by 19% (p = 0.01) in patients who achieved ≥48% UFC reduction. Three patients developed grade ≤2 elevated liver enzymes, anemia, and/or elevated creatinine, which resolved with dose interruption/reduction. Two patients developed grade 4 liver-related serious adverse events that resolved within 4 weeks of seliciclib discontinuation. CONCLUSIONS Seliciclib may directly target pituitary corticotrophs in CD and reverse hypercortisolism. Potential liver toxicity of seliciclib resolves with treatment withdrawal. The lowest effective dose requires further determination.

In vitro propagation of XXY human Klinefelter spermatogonial stem cells: A step towards new fertility opportunities

Abstract: Klinefelter Syndrome (KS) is characterized by a masculine phenotype, supernumerary sex chromosomes (47, XXY), and impaired fertility due to loss of spermatogonial stem cells (SSCs). Early testicular cryopreservation could be an option for future fertility treatments in these patients, including SSCs transplantation or in vitro spermatogenesis. It is critically essential to adapt current in vitro SSCs propagation systems as a fertility option for KS patients. KS human testicular samples (13,15- and 17-year-old non-mosaic KS boys) were donated by patients enrolled in an experimental testicular tissue banking program. Testicular cells were isolated from cryopreserved tissue and propagated in long-term culture for 110 days. Cell-specific gene expression confirmed the presence of all four main cell types found in testes: Spermatogonia, Sertoli, Leydig, and Peritubular cells. A population of ZBTB16+ undifferentiated spermatogonia was identified throughout the culture using digital PCR. Flow cytometric analysis also detected an HLA-/CD9+/CD49f+ population, indicating maintenance of a stem cell subpopulation among the spermatogonial cells. FISH staining for chromosomes X and Y showed most cells containing an XXY karyotype with a smaller number containing either XY or XX. Both XY and XX populations were able to be enriched by magnetic sorting for CD9 as a spermatogonia marker. Molecular karyotyping demonstrated genomic stability of the cultured cells, over time. Finally, single-cell RNAseq analysis confirmed transcription of ID4, TCN2, and NANOS 3 within a population of putative SSCs population. This is the first study showing successful isolation and long-term in vitro propagation of human KS testicular cells. These findings could inform the development of therapeutic fertility options for KS patients, either through in vitro spermatogenesis or transplantation of SSC, in vivo.

Dimethandrolone, a Potential Male Contraceptive Pill, is Primarily Metabolized by the Highly Polymorphic UDP-Glucuronosyltransferase 2B17 Enzyme in Human Intestine and Liver

Abstract: Dimethandrolone undecanoate (DMAU), an oral investigational male hormonal contraceptive, is a prodrug that is rapidly converted to its active metabolite, dimethandrolone (DMA). Poor and variable oral bioavailability of DMA after DMAU dosing is a critical challenge to develop it as an oral drug. The objective of our study was to elucidate the mechanisms of variable pharmacokinetics of DMA. We first identified DMA metabolites formed in vitro and in vivo in human hepatocyte incubation and serum samples following oral DMAU administration in men, respectively. The metabolite identification study revealed two metabolites, DMA-glucuronide (DMA-G; major) and the androstenedione analog of DMA (minor), in the hepatocyte incubations. After oral DMAU administration, only DMA-G was detected in serum, which was >100-fold compared with DMA levels, supporting glucuronidation as the major elimination mechanism for DMA. Next, 13 clinically relevant UDP-glucuronosyltransferase (UGT) enzymes were tested for their involvement in DMA-G formation, which revealed a major role of UDP-glucuronosyltransferase 2B17 (UGT2B17) isoform with a smaller contribution of UGT1A9 in DMA-G formation. These data were confirmed by dramatically higher DMA glucuronidation rates (>200- and sevenfold) in the high versus the null UGT2B17-expressing human intestinal and liver microsomes, respectively. Since human UGT2B17 is a highly variable enzyme with a 20%–80% gene deletion frequency, the in vitro data suggest a major role of UGT2B17 polymorphism on the first-pass metabolism of DMA. Further, considering DMA is a selective and sensitive UGT2B17 substrate, it could be used as a clinical probe of UGT2B17 activity. SIGNIFICANCE STATEMENT Dimethandrolone (DMA) is an active metabolite of dimethandrolone undecanoate (DMAU), an investigational male hormonal contraceptive. Previous studies have indicated poor and inconsistent bioavailability of DMAU following oral administration. This study found that UDP-glucuronosyltransferase 2B17–mediated high intestinal first-pass metabolism is the key mechanism of variable DMA bioavailability.

ODP644 Oral Dosing of Progestogenic Androgens for Male Contraception Show Low Serum Testosterone and High Acceptability in Placebo-Controlled Trials

Abstract: Abstract A promising development in hormonal male contraception (HMC) is a class of bifunctional prodrugs that combine both androgenic and progestogenic activities into a single molecule. Examples of these prodrugs currently being studied are dimethandrolone undecanoate (DMAU) and 11β-methyl-19-nortestosterone-17β-dodecylcarbonate (11β-MNTDC) (1, 2). The inactive prodrugs are cleaved to release active drug over a 24-hour timeframe, providing once-a-day dosing. As potent androgens, these steroids suppress gonadotropin secretion, leading to markedly decreased serum testosterone production and circulating levels. Low testosterone levels might lead to unpleasant symptoms of hypogonadism if DMAU and 11β-MNTDC are not providing sufficient and effective androgenicity. Therefore, we examined the impact of the novel progestogenic androgens on serum testosterone levels and acceptability of varying dosages of these oral prodrugs in a secondary analysis of two Phase 1 placebo-controlled trials. Healthy male participants were randomized to take two or four oral pills of active drug or placebo per day. As DMAU and 11β-MNTDC share similar mechanisms of action and tolerability, we examined the association of dosage as well as testosterone concentrations on combined drug acceptability versus placebo. Survey respondents across the two trials (39 DMAU, 30 11β-MNTDC, 28 combined placebo group) shared similar baseline demographics. After seven days of usage, testosterone levels for those using either prodrug dropped to levels below 100 ng/dL while testosterone levels for those using the placebo (400-600 ng/dL) remained within the reference. Recipients of either DMAU or 11β-MNTDC reported greater willingness to use the active prodrug in the future (75%), compared to placebo recipients (46.4%, p=0. 007). Throughout the 28-day oral pill usage, while average testosterone levels during the period of suppression (day 7 to 28) were very low, they were significantly higher in the 200 mg group than in the 400 mg group (92.7 ng/dL vs. 49.6 ng/dL, p-value <0. 001). Participants using 2 pills (200 mg, n=33) versus 4 pills (400 mg, n=35) of active drug did not report a significant difference in general satisfaction, willingness to use in the future, or recommendation of the study pill to other men (p=0.85, p=0.48, p=0.60). In placebo-controlled trials, men randomized to use active, daily oral progestogenic androgen prodrugs reported greater acceptability with their respective regimens than did men who received placebo pills despite low serum testosterone levels. Oral hormonal male contraceptive pill prototypes, DMAU and 11β-MNTDC, significantly suppress serum testosterone while providing sufficient androgenicity to be acceptable to most men. (1) Thirumalai et al. J Clin Endocrinol Metab. 2019; 104: 423-32. (2) Yuen et al. J Clin Endocrinol Metab. 2020;105. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Occupation and Semen Parameters in a Cohort of Fertile Men

Abstract: Workplace exposures may have subclinical effects on semen parameters in several heretofore not described, occupations. Results highlight occupational groups, including physical sciences and law enforcement, where risks to male reproduction have been less well described, and the need for attention to these occupations as sources of male infertility. Objective We examined associations between occupation and semen parameters in demonstrably fertile men in the Study for Future Families. Methods Associations of occupation and workplace exposures with semen volume, sperm concentration, motility, and morphology were assessed using generalized linear modeling. Results Lower sperm concentration and motility were seen in installation, maintenance, and repair occupations. Higher exposure to lead, and to other toxicants, was seen in occupations with lower mean sperm concentrations (prevalence ratio for lead: 4.1; pesticides/insecticides: 1.6; solvents: 1.4). Working with lead for more than 3 months was associated with lower sperm concentration, as was lead exposure outside of work. Conclusions We found evidence in demonstrably fertile men for reduced sperm quality with lead, pesticide/herbicide, and solvent exposure. These results may identify occupations where protective measures against male reproductive toxicity might be warranted.

PMON267 Comparison Between Single Time Point Testing and 24-Hour Average Concentration of Total Testosterone in Hypogonadal Men Treated with an Oral Testosterone Undecanoate Softgel (JATENZO®)

Abstract: Abstract In 2019, a novel, first-in-class testosterone (T) replacement therapy (TRT), oral testosterone undecanoate (TU) was approved by the U.S. FDA for the treatment of male hypogonadism. During clinical trials, dose adjustments were based on 24-hr average T concentration (Cavg) because single T measurements were considered less accurate. Subsequent, concordance analyses for this oral TU product have shown that a single total T value 6-hrs after the morning oral TU dose best corresponds to Cavg. Nonetheless, a conversion factor for T values obtained at other post-dose time points would be useful for healthcare providers (HCPs) and ease potential scheduling challenges for patients. Consequently, the relationship between other T sampling time points and Cavg was examined to determine if a reliable conversion factor could be derived to help HCPs monitor a patient's serum T concentration at times other than 6-hrs after oral TU administration. Hypogonadal men, age 18–65 y/o, were recruited into a randomized, open-label, multicenter, dose-titration trial. Overall, 166 men were randomized into the oral TU arm. Dose titration was based on Cavg calculated from serial pharmacokinetic (PK) samples. There were three pre-designated PK visits, to individualize the appropriate TU dose and to achieve a eugonadal T Cavg by the final study visit. Ratios between different timepoints and Cavg were determined for PK samples following morning drug administration. Overall, 87.3% (95% CI: 81.3%, 92.0%) of hypogonadal men had a final Cavg in the eugonadal range, with a mean serum total T = 488.7 ± 154.5 ng/dL (16.95 ± 5.37 nmol/L). Pooled values from all PK days demonstrated a linear relationship between T concentrations at 4, 6, and 9-hrs and Cavg (p < 0.0001). Visit and time of sampling interaction were not statistically significant (p >> 0.50), indicating consistency in results among PK visits and among sampling timepoints. A factor was derived to enable conversion of T values assessed at a time other than 6-hrs (post oral TU dose) into a close approximation of Cavg: 1/[1.870–0.14×(hours after AM dose)]. Therefore, a sample drawn at 4-hrs after the morning oral TU dose would be multiplied by 0.75; while one drawn at 8-hrs would be multiplied by 1.33. Hence, T Cavg can be approximated after morning JATENZO administration if a blood sample cannot be collected precisely 6-hrs thereafter. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Poor and variable oral bioavailability of dimethandrolone (DMA), an investigational male hormonal contraceptive, is likely associated with UGT2B17 mediated first‐pass metabolism

Abstract: Dimethandrolone (DMA), an active metabolite of dimethandrolone undecanoate (DMAU) is a novel derivative of 19‐nortestosterone that is undergoing clinical investigation as an experimental male hormonal contraceptive.1 However, poor and variable oral bioavailability of DMAU including dramatic food‐effect2 may decrease its potential use by oral route. Moreover, DMA to DMAU serum concentration ratios revealed that food significantly alters the first‐pass metabolism of DMAU or DMA (Fig. 1A). Thus, the objective of this study was to investigate intestinal and hepatic metabolism of the active metabolite, DMA, to understand its poor bioavailability. We first detected and elucidated the structures of DMA metabolites formed in human hepatocyte incubations and in serum samples after oral administration in men using nano‐liquid chromatography high‐resolution mass spectrometry. The accurate mass and the mass fragmentation data confirmed DMA (m/z 303.2318) analogues of androstenedione (m/z 301.2162) and glucuronide (m/z 479.2639) in the human hepatocyte incubation, however, only DMA‐glucuronide was detected in the serum samples following an oral dose of 400 mg DMAU. DMA‐glucuronide serum concentration was >100‐fold higher than DMA levels, revealing glucuronidation as the major elimination mechanism for DMA. The targeted metabolomics of DMA revealed that unlike testosterone, DMA is not metabolized by other androgen metabolizing enzymes such as aromatase and 5‐α‐ and 5‐β‐ reductases, likely due to the absence of the C19‐methyl group.3,4 Next, to identify UGT isoforms involved in DMA metabolism, thirteen clinically‐relevant UGT enzymes (UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B10, 2B15, and 2B17) were screened for their capacity to metabolize DMA. Only UGT2B17 and UGT1A9 were able to metabolize DMA to DMA‐glucuronide. Finally, since UGT2B17 is a highly variable enzyme (>3000‐fold variability) with highly prevalent gene deletion, an enzyme kinetic experiment was performed in human intestinal microsomes (HIM) samples with known UGT2B17 expression. The kinetics data revealed >200‐fold higher maximum reaction velocity (Vmax) in the high UGT2B17‐expressing HIM samples as compared to the null expressors (Fig. 1B). Proteomics‐informed modeling estimated the intestinal fractional contributions (fm) of UGT2B17 in DMA glucuronidation to be 0.996, 0.994, and 0.0 in the high, average, and null expressors of UGT2B17, respectively. These data suggest that genetic variations in UGT2B17 and its high‐intestinal abundance are the potential reasons for the variable first‐pass metabolism and oral pharmacokinetics of DMA, whereas UGT1A9, which is expressed in the liver and kidney, likely decreases fm, UGT2B17 in DMA metabolism after intramuscular dosing.