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Open access

The impact of COVID-19 on the assessment and management of ectopic pregnancies

Bethany Chung, Charlotte Greene, Alice Pearson, Lisa M Starrs, and W Colin Duncan

Lay Summary

During the COVID-19 pandemic, the public delayed seeking medical help, which may have affected the impact of having an ectopic pregnancy. An ectopic pregnancy is when pregnancy tissue grows outside its normal position in the womb, and it can be life-threatening. It can be treated by non-surgical or surgical options, and any delay in seeking help can reduce the options for treatment and increase the need for more urgent management. We wanted to assess whether there were differences in the presentation and management of ectopic pregnancies in a major teaching hospital between 2019 (pre-COVID-19) and 2021 (COVID-19 period). We found that the pandemic did not cause a delay in seeking medical help or cause worse outcomes. In fact, immediate surgical treatment and time in the hospital were less during COVID-19, perhaps because of a desire to avoid admission to hospital. One outcome of COVID-19 is reassurance that we can safely use more non-surgical treatments for ectopic pregnancies.

DOI:
https://doi.org/10.1530/RAF-22-0073
Volume 4: Issue 1
Open access

New perspectives on fertility in transwomen with regard to spermatogonial stem cells

Jennifer Dabel, Florian Schneider, Joachim Wistuba, Sabine Kliesch, Stefan Schlatt, and Nina Neuhaus

Objective

Germ cells of transwomen are affected by gender-affirming hormone therapy (GAHT). Fertility will be lost after surgical intervention; thereby, fertility preservation becomes an increasingly imortant topic. This study investigated if the absolute number of spermatogonia in transwomen is comparable at the time of gender-affirming surgery (GAS) to that in pre-pubertal boys.

Methods

We carried out a retrospective study of testicular tissues from 25 selected subjects, which had undergone a comparable sex hormone therapy regimen using cyproterone acetate (10 or 12.5 mg) and estrogens. As controls, testicular biopsies of five cisgender adult men (aged 35–48 years) and five pre-/pubertal boys (5–14 years) were included. Testicular tissues were immunohistochemically stained for MAGE A4-positive cells, the most advanced germ cell type. The number of spermatogonia per area was assessed. Clinical values and serum hormone values for FSH, LH, testosterone, free testosterone, estradiol and prolactin were determined on the day of GAS for correlation analyses.

Results

Round spermatids were the most advanced germ cell type in 3 subjects, 5 had an arrest at spermatocyte stage, while 17 showed a spermatogonial arrest. On average, testicular tissues of transwomen contained 25.15 spermatogonia/mm3, a number that was significantly reduced compared to the two control groups (P < 0.01, adult 80.65 spermatogonia/mm3 and pre-/pubertal boys 78.55 spermatogonia/mm3). Linear regression analysis revealed that testes with higher weight and high LH contained more spermatogonia.

Conclusion

Irrespective of treatment dose or duration, spermatogenesis was impaired. Spermatogonial numbers were significantly reduced in transwomen compared to the control groups.

Lay summary

When transwomen go through treatment to confirm their gender, their germ cells are affected. They lose their fertility after surgery, so fertility preservation becomes an important topic. We carried out a study looking at tissue from testes of 25 people who had been through the same sex hormone therapy until surgery. Blood samples were also taken. As controls, samples were taken from the testes of cisgender boys and adult men. On average, the samples from the testes of transwomen contained a smaller number of early sperm cells compared to the two control groups. Regardless of the dose or length of hormone treatment, the fertility of transwomen was significantly reduced so that counseling about fertility preservation should be offered before hormone therapy.

DOI:
https://doi.org/10.1530/RAF-22-0022
Volume 4: Issue 1
Open access

Nitric oxide synthase phosphorylation in fetoplacental endothelium is enhanced by agonism of Piezo1 mechanosensor in small for gestational age babies

L C Morley, M Debant, H J Gaunt, N A B Simpson, and D J Beech

Lay summary

Friction caused by blood flowing across cells that line blood vessels (endothelial cells) activates sensors of mechanical force. This produces nitric oxide (NO) which widens placental blood vessels, enabling more blood flow to the baby. This study sought to determine whether the mechanical sensor, Piezo1, is important for NO production in fetoplacental endothelial cells (FpECs) and whether the steps in this pathway are different in small for gestational age (SGA) babies, where placental blood flow is often altered. We showed that in healthy FpECs, blood flow increased NO signalling. We suggest that in SGA babies, FpECs have an increase in baseline levels of NO signalling, suggestive of a compensatory drive. Treating healthy and SGA cells with a Piezo1 chemical activator, Yoda1, upregulated NO signalling. This shows that Piezo1 is linked to NO and that in SGA, FpECs have the capacity to further increase NO. Further research will establish whether Piezo1 enhancement leads to increased blood flow in the placenta. If so, Piezo1 could be a new target for developing treatments to prevent poor growth of babies in the womb.

DOI:
https://doi.org/10.1530/RAF-22-0100
Volume 4: Issue 1
Open access

Revealing the uterine blood vessel network via virtual pathology

Tsafrir S Kolatt, Yoel Shufaro, Shlomo Mashiach, Bernard Czernobilsky, Sarit Aviel-Ronen, Liat Apel-Sarid, Mazal Dahan, and Yuval Or

Graphical abstract

Abstract

Background

The distribution of the blood vessel network at any point in time in any body tissue may provide valuable information with regard to the tissue condition, whether it is in a growth, declining or recovery phase as well as giving insights as to its angiogenesis functionality. The blood vessel three-dimensional network of the endometrium goes through a process of change over a relatively short period of 4 weeks on average. It is well accepted that angiogenesis within the endometrium is closely related to the success or failure of the implantation of the embryo.

Objective and rationale

Our study aims to present a method to follow the three-dimensional evolution of the superficial blood vessel distribution in the endometrium throughout the uterine cycle.

Method

This method utilizes differences in the observed broadband colors of the blood vessels in order to assess their depth coordinate below the endometrial tissue surface. We implemented the method using microscopic images of fresh, ex vivo, endometrial samples of different cycle days to obtain the statistical evolution track of the superficial blood vessel population in both human and animal (swine) samples.

Outcomes

In human samples, we observed a systematic and consistent trend in the blood vessel diameter distribution at different tissue depths. We demonstrate that the magnitude of this trend evolves throughout the course of the female cycle.

Wider implications

This method has the potential to further our understanding of the mechanisms of angiogenesis in tissues other than the endometrium. We propose that this method may also contribute to more precise endometrial dating and may assist in more accurate determination of embryo transfer timing within in vitro fertilization treatments.

Lay summary

The inner lining tissue of the womb (uterus) is called the endometrium, and it undergoes significant changes during the menstrual cycle.

The endometrium blood vessel network goes through rapid changes during the cycle.

We have developed a new method to measure this through surface imaging of the endometrium.

We use samples of endometrial tissues collected at different dates in the cycle to show how useful this method is in evaluating the development of the endometrium.

The method may also be used to investigate different processes of generating new blood vessels and may help to support dating the development of the endometrium.

Our work offers a non-invasive or minimally invasive method which reveals the three-dimensional blood vessel network and may be used to help in a variety of diagnoses. For example, this method may be used to see how receptive the uterus is during in vitro fertilization treatment.

DOI:
https://doi.org/10.1530/RAF-22-0135
Volume 4: Issue 1
Open access

Sperm cryopreservation for impaired spermatogenesis

G Hughes and S Martins da Silva

Sperm cryopreservation for men with severely impaired spermatogenesis is one of the commonest reasons for short-term sperm storage, usually in advance of fertility treatment. Cryopreservation is generally very effective, although not all spermatozoa survive the process of freezing and thawing. This review considers various aspects of freezing sperm, including an overview of methods, appropriate use of cryoprotectants and practical considerations, as well as oxidative stress and mechanisms of cell cryodamage.

Lay summary

Cryopreservation involves freezing of cells or tissues to preserve them for future use. Sperm cryopreservation for men with a very low sperm count is one of the commonest reasons for short-term sperm storage, usually in advance of fertility treatment. Cryopreservation is generally very effective, although not all sperm cells survive the process of freezing and thawing. This review covers various aspects of freezing sperm, including consideration of methods used and mechanisms of cell damage.

DOI:
https://doi.org/10.1530/RAF-22-0106
Volume 4: Issue 1
Open access

Survey of endocrinologists managing recovery from anabolic androgenic steroid induced hypogonadism

Bonnie Grant, Anjali Pradeep, Suks Minhas, Waljit S Dhillo, Richard Quinton, and Channa N Jayasena

Lay summary

Anabolic steroids (also known as ‘steroids’) are banned drugs like testosterone, which make muscles bigger in men. These drugs are dangerous because they stop the testes from making natural testosterone and can cause heart attacks. Men stopping steroids have very low testosterone, which makes them feel weak, depressed, suicidal, infertile, and unable to have erections. We surveyed over 100 doctors to find out how they treat men giving up steroids. We report that doctors differ widely in the way they treat these men. Most doctors simply advise men to wait for the natural recovery of testosterone levels to happen. But 20% of doctors give men drugs to boost testosterone and make men feel better. Unfortunately, many patients had not recovered by the time of our survey. In summary, our survey highlights differences and limitations in the treatment of men giving up steroids. The use of steroids is increasing rapidly among young men, so we recommend further work to improve the treatment of men who are motivated to give up steroids.

DOI:
https://doi.org/10.1530/RAF-22-0097
Volume 4: Issue 1
Open access

Epigenetics, ovarian cell plasticity, and platelet-rich plasma: Mechanistic theories

E Scott Sills and Samuel H Wood

Ovarian platelet-rich plasma (PRP) is claimed to restore the fertility potential by improving reserve, an effect perhaps mediated epigenetically by platelet-discharged regulatory elements rather than gonadotropin-activated G-protein coupled receptors, as with stimulated in vitro fertilization (IVF). The finding that fresh activated platelet releasate includes factors able to promote developmental signaling networks necessary to enable cell pluripotency tends to support this theory. The mechanistic uncertainty of intraovarian PRP notwithstanding, at least two other major challenges confront this controversial intervention. The first challenge is to clarify how perimenopausal ovarian function is reset to levels consistent with ovulation. Perhaps a less obvious secondary problem is to confine this renewal such that any induced recalibration of cellular plasticity is kept within acceptable physiologic bounds. Thus, any ‘drive’ to ovarian rejuvenation must incorporate both accelerator and brake. Ovarian aging may be best viewed as a safeguard against pathologic overgrowth, where senescence operates as an evolved tumor-suppression response. While most ovary cells reach the close of their metabolic life span with low risk for hypertrophy, enhanced lysosomal activity and the proinflammatory ‘senescence-associated secretory phenotype’ usually offsets this advantage over time. But is recovery of ovarian fitness possible, even if only briefly prior to IVF? Alterations in gap junctions, bio-conductive features, and modulation of gene regulatory networks after PRP use in other tissues are discussed here alongside early data reported from reproductive medicine.

DOI:
https://doi.org/10.1530/RAF-22-0078
Volume 3: Issue 4,
Pages:
C44–C51
Open access

Expression of polycystic ovary syndrome candidate genes in bovine fetal and adult ovarian somatic cells

Menghe Liu, Katja Hummitzsch, Nicole A Bastian, Monica D Hartanti, Helen F Irving-Rodgers, Richard A Anderson, and Raymond J Rodgers

Polycystic ovary syndrome (PCOS) is an endocrine metabolic disorder that appears to have a genetic predisposition and a fetal origin. The fetal ovary has two major somatic cell types shown previously to be of different cellular origins and different morphologies and to differentially express 15 genes. In this study, we isolated the somatic gonadal ridge epithelial-like (GREL) cells (n  = 7) and ovarian fetal fibroblasts (n  = 6) by clonal expansion. Using qRT-PCR, we compared the gene expression levels of PCOS candidate genes with previous data on the expression levels in whole fetal ovaries across gestation. We also compared these levels with those in bovine adult ovarian cells including fibroblasts (n  = 4), granulosa cells (n  = 5) and surface epithelial cells (n  = 5). Adult cell types exhibited clear differences in the expression of most genes. In fetal ovarian cells, DENND1A and ERBB3 had significantly higher expression in GREL cells. HMGA2 and TGFB1I1 tended to have higher expression in fetal fibroblasts than GREL cells. The other 19 genes did not exhibit differences between GREL cells and fetal fibroblasts and FBN3, FSHB, LHCGR, FSHR and ZBTB16 were very lowly expressed in GREL cells and fibroblasts. The culture of fetal fibroblasts in EGF-containing medium resulted in lower expression of NEIL2 but higher expression of MAPRE1 compared to culture in the absence of EGF. Thus, the two fetal ovarian somatic cell types mostly lacked differential expression of PCOS candidate genes.

Lay summary

Polycystic ovary syndrome (PCOS) is one of the most common reproductive problems. The cause is not known so there are no specific treatments or prevention strategies. We know it can be linked to issues that occur in the womb and that some people may be more likely to get PCOS due to their genetic makeup. Our recent studies showed that many of the genes linked to PCOS were found to be switched on in the fetal ovary and are likely to be involved in the development of the fetal ovary. In order to improve our understanding of PCOS, we need to identify the type of cells in the fetal ovary where these genes are switched on. In this study, we examined the PCOS genes in two types of cells that mature as the fetal ovary develops and found very little difference between them but bigger differences to their mature adult counterparts.

DOI:
https://doi.org/10.1530/RAF-22-0068
Volume 3: Issue 4,
Pages:
273–286 (14 total)
Open access

Extracellular vesicles from seminal plasma to improve fertilizing capacity of bulls

Anna Lange-Consiglio, Emanuele Capra, Noemi Monferini, Simone Canesi, Giampaolo Bosi, Marina Cretich, Roberto Frigerio, Valentina Galbiati, Federica Bertuzzo, Francesco Cobalchini, Fausto Cremonesi, and Bianca Gasparrini

Extracellular vesicles (EVs) contained in seminal plasma, vehicle RNA, proteins, and other molecules able to influence the biological function of sperm. The aim of this study was to improve the fertilizing capacity of male gametes of low-fertility bulls using EVs isolated by ultracentrifugation from the seminal plasma of a bull of proven fertility. After a dose–response curve study, 10×106 sperm of low-fertility bulls were co-incubated for 1 h with 400×106 EVs/mL. In addition, it has been verified that the incorporation of EVs, which takes place in the sperm midpiece, is maintained for 5 h and even after cryopreservation. Subsequently, the spermatozoa of low-fertility bulls, with EVs incorporated, were used for the in vitro production of embryos. The rate of blastocyst at seventh day yield in vitro, with the use of sperm with EVs incorporated, increased by about twice the yield obtained with the same sperm in the absence of EVs: bulls having an average embryonic yield of 6.41 ± 1.48%, 10.32 ± 4.34%, and 10.92 ± 0.95% improved their yield to 21.21 ± 1.99%, 22.17 ± 6.09%, and 19.99 ± 5.78%, respectively (P < 0.05). These encouraging results suggest that it might be possible to keep breeding bulls with poor fertility. Further studies will be needed to evaluate the in vivo fertility of sperm treated with EVs and understand how the content of EVs is involve in the sperm–vesicle interaction and in the improved sperm performance.

Lay summary

Sperm can fertilize eggs after they mature as they move through the tube in the testes. As they move, the sperm communicate with the lining of the tubes, thanks to small sacs which are made by the tube itself. These sacs contain many molecules that may play a part in the mechanisms that help sperm fertilize eggs. In veterinary medicine, as with humans, there are fertile and less-fertile individuals. It is possible that the sacs of the semen from a bull which is known to be fertile are different to those from a bull with low fertility. For this reason, sacs from bulls with proven fertility were mixed with sperm from the less-fertile bulls to test in the laboratory how the sperm was able to fertilize eggs and produce embryos. The results show that, in the laboratory, the number of embryos produced is doubled. This suggests it would be possible to improve the fertility of people who are less fertile.

DOI:
https://doi.org/10.1530/RAF-22-0037
Volume 3: Issue 4,
Pages:
313–327 (15 total)
Open access

Multivariable analysis to determine risk factors associated with abortion in mares

J M Roach, J C Arango-Sabogal, K C Smith, A K Foote, K L Verheyen, and A M de Mestre

Risk factors associated with equine reproductive efficiency have been identified along with those associated specifically with early pregnancy loss (EPL). In contrast, no studies have reported risk factors associated with abortion (loss between days 70 and 300 post-cover). Given the causes of abortion differ from those of EPL, likely too will the risk factors. A retrospective cohort study was carried out to identify risk factors associated with abortion in UK- and Irish-based Thoroughbreds, collecting data on 20 exposure variables over a 5-year period. A generalized linear mixed model was utilized to evaluate the associations between exposure variables and abortion, with clustering of observations accounted for at the mare and farm level. Variables with a likelihood ratio test (LRT) P value < 0.2 were entered into the model in a forward stepwise approach. Pregnancy outcome was available on 4439 pregnancies from 2510 mares. Having had two or more prior abortions (odds ratio (OR): 7.91, 95% CI: 2.86, 21.88), conceiving on the second or subsequent covered estrous cycle (OR: 1.84, 95% CI: 1.22, 2.78) and conceiving multiple conceptuses (OR: 1.68, 95% CI: 1.02, 2.76) were associated with an increased risk of abortion compared to null parous, first estrous cycle covers and singleton conceptions, respectively. Increasing paternal age (OR: 0.95, 95% CI: 0.90, 0.99) was associated with a decreasing risk of abortion. Mare and farm variance were not significant in the final model, LRT P = 0.43. These findings provide evidence-based data to inform Thoroughbred breeding management practices to help mitigate abortion risk.

Lay summary

This is the first study to identify the risk factors (characteristics which change the chance of an event) for abortion (miscarriage between days 70 and 300 of pregnancy) in the horse. Statistical models were used to account for the interactions between 20 different factors. The factor which increased the mare’s risk of having an abortion the most was when she had had two or more abortions prior to the pregnancy. Additionally, when the mare was initially pregnant with twins but one of those pregnancies was reduced, the remaining pregnancy was at an increased risk of aborting. Older mares were not at an increased risk of abortion like in humans; however, pregnancies fathered by older stallions were less likely to abort than those from younger stallions. The findings of this study can inform horse breeding practices to help reduce the chance of an abortion.

DOI:
https://doi.org/10.1530/RAF-22-0087
Volume 3: Issue 4,
Pages:
301–312 (12 total)