Restoring testosterone levels by adding dehydroepiandrosterone to a drospirenone containing combined oral contraceptive: II Clinical effects

Objectives: Combined oral contraceptives (COCs) decrease androgen levels, including testosterone (T), which may be associated with sexual dysfunction and mood complaints in some women. We have shown that co-administration of dehydroepiandrosterone (DHEA) to a drospirenone (DRSP) containing COC restored total T levels to baseline and free T levels by 47%. Here we describe the effects on sexual function, mood and quality of life of such an intervention. Study design: This was a randomized, double-blind, placebo-controlled study in 99 healthy COC starters. A COC containing 30 μg ethinylestradiol (EE) and 3 mg DRSP was used for 3 cycles, followed by 6 cycles of the same COC combined with 50 mg/day DHEA or placebo. Subjects completed the Moos Menstrual Distress Questionnaire (MDQ), the McCoy Female Sexuality Questionnaire (MFSQ) and the short form of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Safety and tolerability, including effects on skin were evaluated. Results: The addition of DHEA induced small, but significant improvements compared to placebo in the MDQ score for: Autonomic reactions during the menstrual (- 2.0 vs 0.71; P = 0.05) and the pre-menstrual phase (- 3.1 vs 2.9; P = 0.01); and for Behavior during the inter-menstrual phase (- 1.4 vs 3.6; P = 0.02). A significant difference was found in the MDQ score for arousal during the pre-menstrual phase in favor of placebo (- 5.0 vs 1.0; P = 0.01). There were no statistically significant differences between groups for the MSFQ and Q-LES-Q scores. DHEA co-administration resulted in an acceptable safety profile. DHEA negated the beneficial effect of the COC on acne according to the subjects' self-assessment. Conclusions: Co-administration with DHEA did not result in consistent improvements in sexual function, mood and quality of life indicators in women taking EE/DRSP. Retrospectively, the 50 mg dose of DHEA may be too low for this COC. Implications: A well-balanced judgment of the clinical consequences of normalizing androgens during COC use may require complete normalization of free T

Restoring testosterone levels by adding dehydroepiandrosterone to a drospirenone containing combined oral contraceptive: I Endocrine effects

Objectives: Combined oral contraceptives (COCs) decrease testosterone (T) levels. This study investigated restoration of T and other androgen concentrations during COC use by co-administration of dehydroepiandrosterone (DHEA). Study design: In this randomized, double-blind, placebo-controlled study in 99 new COC starters (18-35 years old with BMI range 18-34 kg/m2), a COC containing 30 μg ethinylestradiol (EE) and 3 mg drospirenone (DRSP) was used for 3 cycles, followed by 6 cycles of the same COC combined with either 50 mg/day DHEA or placebo. Total T, albumin, sex hormone-binding globulin (SHBG), DHEA-sulfate (DHEA-S), Δ4-androstenedione (AD), 3α-androstanediol glucuronide (ADG) and estradiol (E2) were measured, whereas free T and the free T index (FTI) were calculated. Assessments took place at baseline (no COC use), after the run-in period (COC use alone) and during the treatment period (DHEA or placebo). Results: During COC use alone androgen levels decreased, especially total T by 62% and free T by 86%, and SHBG increased by 243%. Total T increased with DHEA compared to placebo (change from end of run-in period to end of treatment period: 1.3 ± 1.2 nmol/L vs 0.0 ± 0.4 nmol/L; P < 0.0001), and was restored to baseline levels. Free T and the FTI increased significantly (P < 0.0001), but the free T level was still 53% below baseline levels. DHEA-S, AD and ADG increased significantly to levels above baseline (P < 0.0001 for each). DHEA had no effect on SHBG, albumin and E2. Conclusions: An EE/DRSP containing COC strongly suppressed endogenous androgen concentrations in all users. The addition of 50 mg DHEA to a COC regimen containing EE/DRSP restored total T to baseline levels, but free T levels were restored by only 47% as most of the T remains bound to SHBG. Implications: When using a COC that increases SHBG considerably, a daily dose of 50 mg DHEA is insufficient to normalize free T levels completely

A tumor cell specific Zona Pellucida glycoprotein 3 RNA transcript encodes an intracellular cancer antigen

BackgroundExpression of Zona Pellucida glycoprotein 3 (ZP3) in healthy tissue is restricted to the extracellular Zona Pellucida layer surrounding oocytes of ovarian follicles and to specific cells of the spermatogenic lineage. Ectopic expression of ZP3 has been observed in various types of cancer, rendering it a possible therapeutic target.MethodsTo support its validity as therapeutic target, we extended the cancer related data by investigating ZP3 expression using immunohistochemistry (IHC) of tumor biopsies. We performed a ZP3 transcript specific analysis of publicly available RNA-sequencing (RNA-seq) data of cancer cell lines (CCLs) and tumor and normal tissues, and validated expression data by independent computational analysis and real-time quantitative PCR (qPCR). A correlation between the ZP3 expression level and pathological and clinical parameters was also investigated.ResultsIHC data for several cancer types showed abundant ZP3 protein staining, which was confined to the cytoplasm, contradicting the extracellular protein localization in oocytes. We noticed that an alternative ZP3 RNA transcript, which we term ‘ZP3-Cancer’, was annotated in gene databases that lacks the genetic information encoding the N-terminal signal peptide that governs entry into the secretory pathway. This explains the intracellular localization of ZP3 in tumor cells. Analysis of publicly available RNA-seq data of 1339 cancer cell lines (CCLs), 10386 tumor tissues (The Cancer Genome Atlas) and 7481 healthy tissues (Genotype-Tissue Expression) indicated that ZP3-Cancer is the dominant ZP3 RNA transcript in tumor cells and is highly enriched in many cancer types, particularly in rectal, ovarian, colorectal, prostate, lung and breast cancer. Expression of ZP3-Cancer in tumor cells was confirmed by qPCR. Higher levels of the ZP3-Cancer transcript were associated with more aggressive tumors and worse survival of patients with various types of cancer.ConclusionThe cancer-restricted expression of ZP3-Cancer renders it an attractive tumor antigen for the development of a therapeutic cancer vaccine, particularly using mRNA expression technologies

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Bleeding Pattern and Cycle Control With Estetrol-Containing Combined Oral Contraceptives: Results From a Phase II, Randomised, Dose-Finding Study (FIESTA)

peer reviewe

OPERATION BREADBASKET: A U.S. VIRGIN ISLANDS COMMUNITY OUTREACH AND ASSISTANCE PARTNERSHIP PROGRAM

Operation Breadbasket was a program of the Virgin Islands Farmers Cooperative (VIFC).The primary goal of this program was to reverse the 45-year decline of agricultural production in the U.S. Virgin Islands by reducing the risk of farming through training and community outreach. The technical staff of the University of the Virgin Islands (UVI) Cooperative Extension Service, UVI Agricultural Experiment Station, UVI Small Business Development Center, Virgin Islands Department of Agriculture and the Virgin Islands Bureau of Internal Revenue partnered with the VIFC to conduct risk management training in vegetable crop and small livestock production, farm business development and income tax preparation. The nature of the training was hands-on, onsite; practical applications, instructions and demonstrations for the purpose of having the producer reduce risk, and utilize improved sustainable production methods. Training was conducted on various farms on the island of St. Croix. On each of the farms an assessment was conducted to evaluate and strengthen the producer's knowledge of their farm operations and the utilization of emerging technologies and practices. The program used seven crops (watermelon, tomato, eggplant, okra, cucumber, bell pepper and cantaloupe), small livestock production (sheep, goats and pigs), improved forage management, farm business planning, recordkeeping and tax preparation to provide the participants with the tools needed to successfully manage an efficient farming enterprise. The training was intended to help transition limited resource, socially disadvantaged farmers into productive and profitable farmers through the creation of new farming enterprises and the increased availability of high-quality, locally-grown food. The program provided practical training in farm management, financial management, marketing, production, crop insurance and other risk management tools to educate U.S. Virgin Islands farmers on how to increase their production and income. The program trained producers in various methods of sustainable farming to reduce risks and increase crop, livestock and forage production. The program sought to use the agriculture training as a means to: create a social and economic stimulus while improving the image of farming to attract and develop new farmers. The anticipated outcome is an improvement in our local food system, food security, and overall quality of life in the territory

Reported jealousy differs as a function of menstrual cycle stage and contraceptive pill use: a within-subjects investigation

Previous research suggests that female jealousy is sensitive to hormonal variation and, more specifically, potentially moderated by estrogen levels. Here, we tracked self-reported jealousy using a within-subjects design, comparing jealousy when the same women were regularly cycling and using hormonal contraceptives. Results show that fertile cycle phases are associated with higher levels of jealousy than nonfertile cycle phases in both single and partnered women. However, patterns of jealousy reported when using hormonal contraceptives, as compared to when regularly cycling, differed between single and partnered women. In single women, levels of jealousy while on the pill fell between those reported when fertile and nonfertile but were not significantly different from either. In partnered women, levels of jealousy while using the pill were significantly higher than those reported during the nonfertile cycle phase and similar to those during the brief period of fertility. We discuss possible reasons for differences between single and partnered women in reported jealousy while using the pill. This research is the first to definitively show that a psychological characteristic, for example, jealousy, may be influenced differentially by endogenous hormones vs. exogenous hormones administered via hormonal contraceptives

Maintaining physiologic testosterone levels during combined oral contraceptives by adding dehydroepiandrosterone: II. Effects on sexual function. A phase II randomized, double blind, placebo-controlled study

To evaluate the effect of combined oral contraceptives (OCs) on sexual function, either alone or together with DHEA. An exploratory randomized, double-blind, placebo-controlled, comparative, crossover study was conducted in 81 OC users. Subjects discontinued their OC for one cycle before being randomized for 10cycles to a 30μg ethinyl estradiol (EE)/levonorgestrel (LNG) OC or a 30μg EE/drospirenone (DRSP) OC, along with daily use of 50mg dehydroepiandrosterone (DHEA) or placebo during 5 OC cycles before crossing over from DHEA to placebo or the reverse for another 5cycles. First the effect on sexual function of 5 OC cycles + placebo was compared to baseline. Then, the effect of 5 OC cycles + DHEA was compared to the OC+placebo. Results regarding endocrine changes have been published separately. Primary efficacy outcomes of the current study were genital response (measured by vaginal pulse amplitude [VPA]) and sexual feelings (measured by the subjective self-assessment questionnaire [SSAQ]) to self-induced erotic fantasy and visual sexual stimuli in a laboratory setting and measures of desire and arousability using a sexual function diary (SFD). Secondary efficacy outcomes were the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale Revised (FSDS-R). Eighty-one women were enrolled and 74 women completed the study. Five cycles of OC+placebo resulted in a significant decline compared to baseline of four out of six SFD self-ratings of sexual desire and arousability with both OCs. The LNG OC also resulted in significant declines in the FSFI scores (baseline vs LNG OC+placebo: Total score, 28.7±3.7 vs 25.6±7.4; Arousal, 5.0±0.7 vs 4.5±1.4; Lubrication, 5.2±0.9 vs 4.6±1.7; Pain, 4.9±0.9 vs 4.5±1.4), but no changes were observed using the DRSP OC. In the laboratory setting, five cycles of OC+DHEA showed no significant differences with placebo except for a significant increase in genital sensations (SSAQ) during erotic fantasy (OC+placebo vs OC+DHEA: 3.3±1.4 vs 3.6±1.5; p <.05). No significant changes were observed for genital response (VPA) and the other two variables of the SSAQ assessed after visual erotic stimulus exposure. Using the SFD, 5 out of 10 variables showed a significant improvement with DHEA. Partner's initiative was rejected less often with OC+DHEA compared to placebo (OC+placebo vs OC+DHEA: 1.1±1.5 vs 0.8±1.0; p <.05). Women with free testosterone levels in the upper quartile during DHEA co-administration showed significantly better effects on sexual arousal and desire compared to the three lower quartiles (lower vs upper quartiles: Sexual arousability: 25.0±19.8 vs 41.2±29.0; Sexual desire: 5.6±3.7 vs 9.6±8.0; Desire for sex with partner: 4.9±3.1 vs 8.6±7.4; Number of sex fantasies: 3.0±3.2 vs 5.5±4.4; all p <.05). In this exploratory study, OC use was associated with decreases in some measures of sexual functioning, whereas others remained unchanged. Maintaining or restoring physiological testosterone concentrations by the co-administration of DHEA to the OC may prevent these effects on sexuality, particularly in women with relatively high, but physiologic levels of free testosterone during DHEA co-administration. The results of this exploratory study warrant further testing of the hypothesis that restoration and/or preservation of physiologic testosterone levels during OC use by co-administration of DHEA has favorable effects on those aspects of sexual function compromised by OC