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Open access

Gisele Montano, Pat Clough, Todd Schmitt, Michelle Davis, Karen Steinman, Justine O’Brien, and Todd Robeck

To gain more knowledge about the influence of hormone regulation on follicle development, ovarian ultrasounds were performed, and urinary hormone profiles were determined in ovulating and non-ovulating female bottlenose dolphins (n  = 15) following estrus synchronization with altrenogest. Ovarian ultrasounds were conducted daily, post-synchronization to describe follicular recruitment in relation to the endocrine profile. Follicle sizes were grouped into very small (VSM), small (SM), medium (MD) and large (LG). In ovulating females, two follicular waves were identified, and follicular deviation toward establishing a dominant follicle only occurred during the second wave. For non-ovulating females, only the first wave was observed. For all urinary hormones, the non-ovulating group presented significantly lower concentrations of follicle-stimulating hormone (uFSH), luteinizing hormone (uLH), estrone conjugates (uE1-C) and estriol (uE3) but similar progestagen and cortisol concentrations compared to the ovulating group. Concentrations of uE1-C and uE3 and the numbers of MD and LG follicles significantly (P < 0.05) increased, while uFSH concentrations significantly (P < 0.05) decreased as ovulation approached. Urinary LH significantly increased concurrently with increasing numbers of LG follicles and decreasing numbers of SM follicles. The characterization of follicular development and its relationship with hormone assessment complements our understanding of follicular recruitment post-synchronization in bottlenose dolphins and provides new information concerning differences between ovulating and non-ovulating females in response to an estrous synchronization protocol.

Lay summary

Many species of fresh and saltwater dolphins and porpoises are facing increasing pressure for food and habitats due to human activities. One of the primary aspects that can be affected by such activities is reproduction. The bottlenose dolphin has been successfully bred in zoos and aquariums for at least 70 years, and they can be trained for several voluntary behaviors that enable medical examinations. Therefore, they represent a unique resource for research and understanding of normal dolphin reproduction. In this research, voluntary ultrasound exams and urine samples from 15 female dolphins were used to describe changes in their ovaries. The resulting descriptions and comparisons provide insight into the unique ovarian physiology of bottlenose dolphins and into the differences between animals after treatment. This information adds to the body of knowledge which one day may be used for developing advanced reproductive techniques to help preserve endangered species of dolphins.

Open access

Nicola Tempest, Madeleine France-Ratcliffe, Hannan Al-Lamee, Evie R Oliver, Emily E Slaine, Andrew J Drakeley, Victoria S Sprung, and Dharani K Hapangama

Optimisation of lifestyle factors such as smoking and alcohol is encouraged to improve fecundability rates in the fertility setting. Currently, routine fertility consultations do not involve counselling or imparting advice regarding habitual physical activity (PA) and/or structured exercise, despite data showing that vigorous PA can be associated with delayed time to pregnancy. Therefore, this study aimed to determine habitual PA in a sample of women attending the one-stop infertility (OSI) clinic. In total, 250 women attending a large tertiary level NHS fertility unit prospectively completed a questionnaire anonymously over a period of 9 months. The participants (mean age: 34 ± 5 years, mean BMI: 29 ± 7 kg/m2) habitual PA levels varied from vigorous exercise on ≥5 days/week (8%, n  = 17) to no moderate or high-intensity activities across the whole week (66%, n  = 29). A majority of women reported no structured exercise (72%, n  = 179). No association was identified between any domain of PA and BMI, age, alcohol units, regular periods, or time spent trying to conceive (P > 0.05). The participants habitual PA levels varied widely and no association between any domain of PA and background of the women was identified. No existing evidence and/or guidelines to explicitly inform women attempting to conceive regarding recommended PA levels are available, despite PA being a modifiable, affordable, and feasible lifestyle choice with the possible potential to improve fertility. A large-scale, clinical trial assessing the effects of PA on fecundability is warranted to gain insight into the potential of this lifestyle factor to improve fertility outcomes and to explore the underlying biological mechanisms involved.

Lay summary

Infertility affects approximately one in seven couples with many and varied causes, including lifestyle factors such as smoking, alcohol, and diet. Lifestyle changes are low-cost unimposing options to implement in routine fertility care. Information on regular physical activity is not currently enquired from women and no agreement regarding the best levels of exercise exists for fertility patients. In this study, we aimed to determine the exercise habits of women attending the OSI clinic. In total. 250 women attending OSI clinic over a period of 9 months completed a questionnaire collecting data on their exercise habits. The levels of physical activity performed varied widely from vigorous exercise on ≥5 days/week to no moderate or high-intensity activities across the whole week. A majority of women did no structured exercise (72%). These novel data highlight the variations in form, type and intensity of exercise women who attend OSI clinics perform. Currently, there is no existing evidence and/or guidelines to explicitly inform women attempting to conceive regarding the recommended physical activity levels. Physical activity is a modifiable, affordable, and feasible lifestyle choice that is not currently acknowledged in the fertility setting and has the potential to improve fertility.

Open access

Mike Armour, Jodie Avery, Mathew Leonardi, Leesa Van Niekerk, Marilla L Druitt, Melissa A Parker, Jane E Girling, Brett McKinnon, Antonina Mikocka-Walus, Cecilia H M Ng, Rebecca O’Hara, Donna Ciccia, Katherine Stanley, and Subhadra Evans

Graphical abstract

Abstract

Endometriosis is a common yet under-recognised chronic disease with one in nine (more than 830,000) women and those assigned female at birth diagnosed with endometriosis by the age of 44 years in Australia. In 2018, Australia was the first country to develop a roadmap and blueprint to tackle endometriosis in a nationwide, coordinated manner. This blueprint is outlined in the National Action Plan for Endometriosis (NAPE), created from a partnership between government, endometriosis experts and advocacy groups. The NAPE aims to improve patient outcomes in the areas of awareness and education, clinical management and care and research. As researchers and clinicians are working to improve the lives of those with endometriosis, we discuss our experiences since the launch of the plan to highlight areas of consideration by other countries when developing research priorities and clinical plans. Historically, major barriers for those with endometriosis have been twofold; first, obtaining a diagnosis and secondly, effective symptom management post-diagnosis. In recent years, there have been calls to move away from the historically accepted ‘gold-standard’ surgical diagnosis and single-provider specialist care. As there are currently no reliable biomarkers for endometriosis diagnosis, specialist endometriosis scans and MRI incorporating artificial intelligence offer a novel method of visualisation and promising affordable non-invasive diagnostic tool incorporating well-established technologies. The recognised challenges of ongoing pain and symptom management, a holistic interdisciplinary care approach and access to a chronic disease management plan, could lead to improved patient outcomes while reducing healthcare costs.

Lay summary

Endometriosis is a chronic disease where tissue like the lining of the uterus is found in other locations around the body. For the 830,000 people living with endometriosis in Australia, this often results in an immense burden on all aspects of daily life. In 2018, Australia was the first country to introduce a roadmap and blueprint to tackle endometriosis in a nationwide coordinated manner with the National Action Plan for Endometriosis. This plan was created as a partnership between government, endometriosis experts and advocacy groups. There are several other countries who are now considering similar plans to address the burden of endometriosis. As researchers and clinicians are working to improve the lives of those with endometriosis, we share our experiences and discuss areas that should be considered when developing these national plans, including diagnostic pathways without the need for surgery, and building new centres of expertise in Endometriosis and Pelvic Pain.

Open access

Vanessa Caroline Fioravante, Alana Rezende Godoi, Victória Mokarzel de Barros Camargo, Patricia Fernanda Felipe Pinheiro, Marcelo Martinez, Carlos Roberto Padovani, and Francisco Eduardo Martinez

Graphical abstract

Abstract

The relationship between adolescent ethanol uses and its impacts throughout life are not conclusive. Thus, we evaluated if the low and high consumption of ethanol at postpuberty interferes with the reproduction and ethanol-naive offspring and if the effects are dose-related. Female and male rats were divided into three groups: low drinker (L), high drinker (H) and control (C). The L and H groups were exposed to ethanol up to 10 % from 65 to 80 days with withdrawal after this period. The ethanol consumed by low drinkers was 1.41 ± 0.21 g/kg/day and by high drinkers 4.59 ± 0.45 g/kg/day. The study was conducted in two phases. The first phase verified the reproductive capacity in adulthood on generations (litter size and sex ratio). Data were collected over 10 years. The second phase analyzed the parent reproductive parameters (body weight, reproductive organ weight, sperm parameters and estrous cycle) and the pup development. We observed a reduced litter size in both drinker groups. Gestational body weight gain and feed consumption were lower in L and H. We observed an alteration in reproductive organs weight in both sexes of H. Females presented a longer estrous cycle duration. Males presented an increase in abnormal sperm, a decrease in sperm count and accelerated transit time. The ethanol-naive offspring development was also impaired. We conclude that low and high postpubertal alcohol use impairs long-term reproductive parameters, even after alcohol withdrawal. There is also impaired ethanol-naive offspring. Besides, the effects are dose-related.

Lay summary

The effects of alcohol use have been reported in several studies. However, better knowledge about early alcohol use and its impact on reproduction in adulthood, after abstinence and on ethanol-naive offspring could help improve preventive measures and mechanisms of action. One of the methods used was retrospective analysis which allows to evaluate the effects of postpubertal ethanol use on the reproductive capacity of rats over generations. Despite our limitations, we verified that the post-adolescent period acts as a susceptibility window, and lifestyle at this age modulates the long-term reproductive parameters. The early ethanol use impairs reproduction function since sperm parameters and the estrous cycle have been altered. The dose of alcohol also contributes to damage on the drinkers’ reproduction and on the physical development of ethanol-naive offspring. Future studies are necessary to identify the mechanism involved in long-term alcohol use effects, even in withdrawal, as well as ethanol-naive offspring outcomes.

Open access

Nkoyenum Pamela Olisa, Lisa Campo-Engelstein, and Sarah Martins da Silva

Infertility is a time-consuming and exhaustive process, which disproportionally affects women. Although concerns have been raised about deficiencies in the clinical evaluation of infertile men, there are currently little published data documenting this. A SurveyMonkey questionnaire was therefore created to capture the current clinical practice of fertility specialists working in in vitro fertilisation clinics. Responses were collected from May to July 2021. A total of 112 clinicians completed the pilot survey with respondents from Europe (n = 49; 43.8%), Africa (n = 39, 34.8%), North America (n = 6; 5.4%), Asia (n = 16; 14.3%), South America (n = 1; 0.9%) and Australasia (n = 1; 0.9%). Forty-one percent of fertility specialists (45/110) reported taking only a brief medical history and 24% reported that they never routinely examined infertile male patients. Fifty-four percent of fertility specialists also reported issues getting men to undertake diagnostic semen analysis. Treatment for male infertility spanned assisted reproductive technology (ART), with themes of individualised medicine influencing treatment recommendations. Of the clinicians, 48.2% clinicians reported using empirical medical therapy for unexplained male infertility. Notably, 3.6% respondents recommended testosterone treatment, despite the likely negative impact on spermatogenesis. However, high levels of opportunistic general health advice were reported, including discussion of life exposures thought to be important for male reproductive health. This study adds novel evidence and highlights current deficiencies in clinical practice relating to male infertility. Evaluation of the infertile male using simple medical tools (detailed history taking and clinical examination) has the potential to identify treatable or reversible conditions and should be an immediate focus for education and improvement in reproductive medicine. Investment in research and development is much needed in the field of andrology to develop effective non-ART treatment options for male infertility.

Lay summary

Poor sperm quality (male infertility) significantly reduces the chance of natural conception and accounts for half of all cases of infertility, yet affected men are frequently overlooked when couples seek fertility investigations and treatment. Despite a growing awareness of men’s issues and a need to improve patient experience, there is very little documented about how fertility specialists (clinicians) routinely assess and treat male infertility. This study used a SurveyMonkey® questionnaire to capture current clinical practice, with 112 respondents from around the world. Forty-one percent of clinicians did not routinely consider male medical history in detail and 24% never routinely examined infertile men. This should be a focus for improvement in clinical care. As expected, fertility treatment recommended for male infertility was mostly in vitro fertilisation and intracytoplasmic sperm injection, where a single sperm is injected into each mature egg. However, 48.2% of clinicians also reported prescribing unproven medical therapy for unexplained male infertility. Of concern, a few clinicians routinely recommended testosterone treatment, which is likely to harm sperm production. However, advice regarding general health was universally delivered.

Open access

Emmanuel Amabebe, Henry Ogidi, and Dilly O Anumba

Graphical abstract

Abstract

The phenomenal extracellular matrix (ECM) remodelling of the cervix that precedes the myometrial contraction of labour at term or preterm appears to share some common mechanisms with the occurrence, growth, invasion and metastasis of cervical carcinoma. Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that are pivotal to the complex extracellular tissue modulation that includes degradation, remodelling and exchange of ECM components, which contribute to homeostasis under normal physiological conditions such as cervical remodelling during pregnancy and puerperium. However, in cancer such as that of the uterine cervix, this extensive network of extracellular tissue modulation is altered leading to disrupted cell–cell and cell–basement membrane adhesion, abnormal tissue growth, neovascularization and metastasis that disrupt homeostasis. Cervical ECM remodelling during pregnancy and puerperium could be a physiological albeit benign neoplasm. In this review, we examined the pathophysiologic differences and similarities in the role of MMPs in cervical remodelling and cervical carcinoma.

Lay summary

During pregnancy and childbirth, the cervix, which is the barrel-shaped lower portion of the womb that connects to the vagina, gradually softens, shortens and opens to allow birth of the baby. This process requires structural and biochemical changes in the cervix that are stimulated by enzymes known as matrix metalloproteinases. Interestingly, these enzymes also affect the structural and biochemical framework of the cervix during cervical cancer, although cervical cancers usually occur after infection by human papillomavirus. This review is intended to identify and explain the similarities and differences between the structural and chemical changes in the cervix during pregnancy and childbirth and the changes seen in cervical cancer.

Open access

Noble K Kurian and Deepak Modi

Graphical abstract

Abstract

Group B Streptococcus (GBS) is an opportunistic pathogenic bacterium which upon colonization in the female reproductive tract can cause preterm births, fetal injury, and demise. Several determinants for GBS pathogenesis have been explored so far through the studies using animal models ranging from mice to non-human primates. The results from these experimental data have identified outer membrane vesicles, β-hemolysin, hyaluronidase, and Cas9 of GBS as major virulence factors leading to preterm births. Most of these factors drive inflammation through activation of NLRP3 and elevated production of IL1-β. However, the absence of one of the factors from the pathogen reduces but does not completely abolish the pathogenesis of GBS suggesting the involvement of more than one factor in causing preterm birth. This makes further exploration of other virulence factors of GBS pathogenesis important in gaining an insight into the mechanistic basis of GBS-mediated preterm births.

Lay summary

Group B Streptococcus (GBS) is a pathogenic bacteria whose infection in the reproductive tract during pregnancy can cause premature delivery. This bacterial infection is one of the major causes of death of mother and baby during pregnancy, and the bacteria is prevalent in all parts of the world. This makes the research on GBS so important and many of the mechanisms behind GBS infection during pregnancy still remain unexplored. In this review, we have outlined how various animal models contributed in finding the mechanism of GBS pathogenesis. The review also focuses on compiling various virulence factors which makes GBS pathogenic in the vulnerable. Understanding the mechanisms of infection by GBS will be crucial in developing drugs and vaccines to protect against the harmful effects of the bacteria.

Open access

Carlos H Miyashira, Fernanda Reali Oliveira, Marina Paula Andres, Julian A Gingold, and Mauricio Simões Abrão

The objective of this study was to systematically review the literature on the human microbiome in association with endometriosis. PubMed/Medline, Cochrane, and Embase databases were searched for literature published from 1986 to August 2021. All human studies that assessed the microbiome using 16S rRNA sequencing or shotgun sequencing in women with endometriosis were included. Two reviewers independently abstracted data from the selected articles into tables. To assess the quality of included studies, the National Institutes of Health Study Quality Assessment Tools were utilized. This review included 12 case–control studies. Included studies compared the microbiome from various anatomical sources (fecal, vaginal, cervical, peritoneal, endometrial, and intra-lesional) between patients with endometriosis and a heterogeneous set of control patients. Study quality ranged from poor to good, with 8 of 12 studies rated fair. Multiple studies reported a different distribution of bacteria among women with endometriosis across anatomical sites, but the results were highly heterogeneous. Pseudomonas was overrepresented in peritoneal fluid among women with endometriosis across multiple studies but was also observed to be increased in vaginal, endometrial, and intra-lesional samples. Among bacteria noted across different anatomical samples, Gardnerella was found to be increased in cervical but decreased in endometrial, fecal, and vaginal samples of patients with endometriosis, while Atopium was found to be decreased in vaginal and cervical samples from patients with endometriosis. Sphingobium was found to be increased in vagina, endometrium, and peritoneal fluid from patients with endometriosis. Streptococcus was found to be increased in peritoneal, endometrial, and cervical samples from women with endometriosis. Microbiomal comparisons stratified by endometriosis stage or site of endometriosis involvement were limited and highly heterogeneous.

Lay summary

The microbiome, a group of bacteria found in a particular place in the body, has been shown to vary when patients have some diseases, such as cancer or inflammatory bowel disease. Less is known about the microbiome in patients with endometriosis. This review looked at existing studies comparing the bacteria found in patients with endometriosis and others without. Twelve studies were found that assessed the bacteria from swabs collected from different places, including the vagina, cervix, endometrium, peritoneum, feces, and endometriosis lesions themselves. Most of the studies found higher or lower levels of specific bacteria at each of these places, but the findings were often inconsistent. The findings were probably limited by the small numbers of patients involved and variations in the groups studied. More research is needed to find out which bacteria are over- and underrepresented in patients with endometriosis and where they are found.

Open access

Fiona Hartley, Arwa Alageel, Ruth Appeltant, Nicki Gray, Emmanouela Repapi, Dagan Wells, Suzannah A Williams, and Joanna Poulton

Graphical abstract

Abstract

Mitochondrial quality is implicated as a contributor to declining fertility with aging. We investigated mitochondrial transcripts in oocytes and their associated cumulus cells from mice of different ages using RNA-seq. Mice aged 3 weeks, 9 weeks, and 1 year were superovulated, and 48 h later, oocyte cumulus complexes were collected by follicle puncture. We did not detect any major differences that could be attributed to aging. However, mitochondrial RNA transcripts which deviated from the consensus sequence were found at a higher frequency in cumulus cells than in their corresponding oocyte. Previous investigations have shown that variation in the sequence of mtRNA transcripts is substantial, and at least some of this can be accounted for by post-transcriptional modifications which impact base calling during sequencing. Our data would be consistent with either less post-transcriptional modification in mitochondrial RNA from oocytes than cumulus cells or with lower mtDNA mutational load.

Lay summary

Women become less fertile as they age. Shortage of energy contributes to this, caused by a decline in the quality of mitochondria (the powerhouses of the cell) in the egg. Genes are the blueprint for the cell. They are made of DNA which is copied into an RNA message, or instructions, for making proteins. We counted differences in the RNA message of developing eggs and the cells that support them during development (cumulus cells). We compared the number of these differences in mice of different ages. These age groups represent mice had not reached puberty, those of prime reproductive age, and old mothers. We did not find any differences linked to the age of the mice. However, we did find differences between the egg and the cumulus cells. In most cases, there were lower levels of mutations in eggs than there were in cumulus cells.

Open access

Kirsten S Wilson, Desheng Li, Iain Valentine, Alan McNeilly, Simon Girling, Rengui Li, Yingmin Zhou, Lynn Vanhaecke, W Colin Duncan, and Jella Wauters

Graphical abstract

Abstract

Giant pandas are mono-estrus seasonal breeders, with the breeding season typically occurring in the spring. Successful fertilization is followed by an embryonic diapause, of variable length, with birth in the late summer/autumn. There is a need for additional understanding of giant panda reproductive physiology, and the development of enhanced biomarkers for impending proestrus and peak fertility. We aimed to determine the utility of non-invasive androgen measurements in the detection of both proestrus and estrus. Urine from 20 cycles (−40 days to +10 days from peak estrus) from 5 female giant pandas was analyzed for estrogen, progestogens and androgens (via testosterone and DHEA assays), and hormone concentrations were corrected against urinary specific gravity. Across proestrus, estrogens increased while progestogens and androgens decreased – at the point of entry into proestrus, androgens (as detected by the testosterone assay) decreased prior to progestogens and gave 4 days advanced warning of proestrus. At the time of peak estrus, androgens (as detected by the DHEA assay) were significantly increased at the time of the decrease in estrogen metabolites from the peak, acting as an alternative confirmatory indicator of the fertile window. This novel finding allows for enlargement of the preparative window for captive breeding and facilitates panda management within breeding programmes. Androgens allow an enhanced monitoring of giant panda estrus, not only advancing the warning of impending proestrus, but also prospectively identifying peak fertility.

Lay summary

Giant pandas have one chance at pregnancy per year. The 2-day fertile window timing varies by year and panda. This is monitored by measuring the level of estrogens in the urine, which increase, indicating an upcoming fertile period. After 1–2 weeks of increase, estrogens peak and fall, marking the optimal fertile time. We tested other hormones to see if we can predict the fertile window in advance, and the specific fertile time with more accuracy. In 20 breeding seasons from 5 females, we found androgens, usually thought of as male hormones, had an important role. Testosterone gives 4 days advanced warning of estrogens increasing. DHEA identified peak estrogen and the fertile time before needing to see a confirmed decrease in estrogen itself. Therefore, androgens help improve monitoring of the giant panda breeding season, giving early warning of fertility, key in facilitating captive breeding and giant panda conservation.