Surrogate post-coital testing for contraceptive efficacy against human sperm activity in the ovine vaginal model†

Zhu, Yong; Saada, Jamal I.; Shrestha, Bhawana; Lai, Sam; Villarreal, Paula; Pyles, Richard B.; Vargas, Gracie; Moench, Tom; Vincent, Kathleen L.

doi:10.1093/biolre/ioaa221

Cited by 5 publications

(4 citation statements)

References 18 publications

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“…Another distinction is the estrus cycle experienced by sheep rather than the menstrual cycle observed in humans. As previously described (20,21,24,29), the ovine estrus cycle actually has noted similarities to the menstrual cycle with a rise in estradiol after stimulation by FSH from GnRH, an LH surge stimulating ovulation/estrus, and a rise in progesterone from the corpus luteum after ovulation. The additional qualities of the ovine vaginal vault, such as accommodation of human-size devices and applicant volumes, as well as greater similarity in epithelial thickness and anatomical structure, support the use of sheep as well as continued study of the vaginal environment to advance the utility of the model.…”

Section: Discussionmentioning

confidence: 67%

“…Although N9 is considered safe for use as a contraceptive agent, it has been shown to cause reversible disruption of the vaginal epithelium and is considered a reference standard for vaginal safety studies; ( 3 ) BZK 2%, which also has a spermicidal capacity similar to N9 and is sold in contraceptive suppositories and creams. BZK is well-known to cause tissue injury at higher concentrations in women in clinical studies; therefore, it is considered a known irritant for vaginal safety studies at concentrations ranging from 0.2 to 2% that have been shown to cause disruption of the mucosal epithelial barrier and inflammation in sheep ( 21 , 22 , 28 ).…”

Section: Resultsmentioning

confidence: 99%

“…Further, the suitability of sheep as a large animal model for evaluation and testing of the performance of human size intravaginal devices including vaginal rings for sustained delivery of emerging non-vaccine biological preventatives, (e.g. tenofovir), as well as application of several OTC and experimental compounds is indicated by recent reports (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Finally, in addition to standard histopathology of tissues after euthanasia, there are now refined repeated measure methods for ovine vaginal irritation inspection, namely, optical coherence tomography (OCT), colposcopy, and tissue sampling by repeat biopsy.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of the Ovine Vaginal Microbiome and Inflammation Patterns as an Improved Testing Model of Human Vaginal Irritation

Pyles

Miller

Maxwell

et al. 2021

Front. Reprod. Health

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The development of therapies targeted to improve the health of women has utilized direct vaginal delivery as a more effective and less toxic method of protection from HIV and other pathogens. Vaginal applicants and delivery devices that provide sustained effects have been met with increasing acceptability, but the efficacy and toxicity outcomes have not been successfully predicted by preclinical in vitro studies and animal modeling. We have explored the utilization of sheep as a model for testing the safety of vaginal applicants and devices based on spatial and structural similarities to the human vagina. As recently noted by the FDA, an additional safety measure is an impact on the vaginal microbiome (VMB) that is known to contribute to vaginal health and influence pathogen susceptibility and drug metabolism. To advance the utility of the sheep vaginal model, we completed a thorough molecular characterization of the ovine VMB utilizing both next-generation sequencing (NGS) and PCR methods. The process also created a custom PCR array to quantify ovine VMB community profiles in an affordable, higher throughput fashion. The results from vaginal swabs (>475 samples) collected from non-pregnant crossbred Dorset and Merino ewes treated with selected vaginal applicants or collected as sham samples established 16 VMB community types (VMB CTs). To associate VMB CTs with eubiosis or dysbiosis, we also completed custom ELISAs for six cytokines identifying IL1B, IL8, TNFa, and CXCL10 as useful markers to support the characterization of ovine vaginal inflammation. The results indicated that Pasteurella, Actinobacillus, Pseudomonas, Bacteroides, Leptotrichia, and E. coli were common markers of eubiosis (low inflammatory marker expression), and that Haemophilus, Ureaplasma, and Corynebacterium were associated with dysbiosis (high cytokine levels). Utilizing the optimized workflow, we also confirmed the utility of three commonly used vaginal applicants for impact on the VMB and inflammatory state, producing a dataset that supports the recommendation for the use of sheep for testing of vaginal applicants and devices as part of preclinical pipelines.

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Section: Discussionmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Characterization of the Ovine Vaginal Microbiome and Inflammation Patterns as an Improved Testing Model of Human Vaginal Irritation

Pyles

Miller

Maxwell

et al. 2021

Front. Reprod. Health

Self Cite

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“…Anatomically, the ewe has been well studied (56)(57)(58). The ewe's cervix and vagina share similar length and epithelial layer thickness compared to that of humans (59), supporting the use of ewes to test the safety of contraceptive products such as microbicidal vaginal rings (60), and the efficacy of spermicides (61). In addition, the ram deposits semen vaginally (62), not directly in the uterus like in the rat models also used in reproductive and contraceptive research (63).…”

Section: Discussionmentioning

confidence: 99%

Topical reinforcement of the cervical mucus barrier to sperm

Schimpf

Caldas-Silveira

Katchan³

et al. 2022

Sci. Transl. Med.

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Close to half of the world’s pregnancies are still unplanned, reflecting a clear unmet need in contraception. Ideally, a contraceptive would provide the high efficacy of hormonal treatments, without systemic side effects. Here, we studied topical reinforcement of the cervical mucus by chitosan mucoadhesive polymers as a form of female contraceptive. Chitosans larger than 7 kDa effectively cross-linked human ovulatory cervical mucus to prevent sperm penetration in vitro. We then demonstrated in vivo using the ewe as a model that vaginal gels containing chitosan could stop ram sperm at the entrance of the cervical canal and prevent them from reaching the uterus, whereas the same gels without chitosan did not substantially limit sperm migration. Chitosan did not affect sperm motility in vitro or in vivo, suggesting reinforcement of the mucus physical barrier as the primary mechanism of action. The chitosan formulations did not damage or irritate the ewe vaginal epithelium, in contrast to nonoxynol-9 spermicide. The demonstration that cervical mucus can be reinforced topically to create an effective barrier to sperm may therefore form the technological basis for muco-cervical barrier contraceptives with the potential to become an alternative to hormonal contraceptives.

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