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Current Challenges and Future Prospects in Human Reproduction and Infertility

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A special issue of Medicina (ISSN 1648-9144). This special issue belongs to the section "Obstetrics and Gynecology".

Deadline for manuscript submissions: 31 May 2024 | Viewed by 12242

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Dr. Laurie Henry

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Guest Editor

Center for Reproductive Medicine, University of Liege, Boulevard du 12ème de Ligne 1, 4000 Liege, Belgium
Interests: oncofertility; fertility preservation; implantation failure; ovulatory disorders; endometriosis; infertility; IVF

Prof. Dr. Michelle Nisolle

E-Mail Website
Guest Editor

Obstetrics and Gynecology Department, University of Liege, 4000 Liège, Belgium
Interests: endometriosis; adenomyosis; reproductive surgery; gynecology of childhood and adolescence; malformations of the genital system; uterine myomas

Special Issue Information

Dear Colleagues,

Reproduction is a vast field of human physiology that remains partly mysterious. Although it can be medicalized to varying degrees, from intrauterine insemination to in vitro fertilization with or without pre-implantation genetic testing, failures are unfortunately frequent and can be tragic for the individuals concerned. The genetic recombination between the oocyte and the spermatozoon at the time of fertilization and the implantation of the embryo in the endometrium are the main black boxes of human reproduction.

Reproductive specialists are constantly looking for ways to enhance the assisted reproductive technologies in order to improve the results obtained while limiting the heaviness of the treatments, particularly their impact on the couple but also on the desired child.

Another important aspect of reproduction is the prevention of infertility. This is especially true as the age of women at first conception continues to increase while individuals are subjected to pollutants and other endocrine disruptors which, combined with a sometimes-inappropriate lifestyle, will alter the chances of conception. Another facet of this fertility preservation concerns the prevention of the toxic effects of certain treatments, such as chemotherapy, but also ovarian surgery. Indeed, preservation of ovarian tissue is challenging for infertile patients suffering from ovarian endometriosis. Different surgical procedures aiming to avoid ovarian reserve damage are nowadays possible.

Given the complexity of this topic and its impact on clinical practice and public health, Medicina is launching a Special Issue entitled Current Challenges and Future Prospects in Human Reproduction and Infertility.

Dr. Laurie Henry
Prof. Dr. Michelle Nisolle
Guest Editors

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Keywords

fertility preservation
embryology
implantation
fertility
human reproduction
reproductive surgery

Published Papers (9 papers)

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Research

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17 pages, 1091 KiB

Open AccessArticle

Risk Factors of Thrombophilia-Related Mutations for Early and Late Pregnancy Loss

by Ema Borsi, Ovidiu Potre, Ioana Ionita, Miruna Samfireag, Cristina Secosan and Cristina Potre

Medicina 2024, 60(4), 521; https://doi.org/10.3390/medicina60040521 - 22 Mar 2024

Viewed by 680

Abstract

Background and Objectives: This retrospective cohort study investigates the role of genetic thrombophilia in pregnant women experiencing early pregnancy loss compared to those with late pregnancy loss. Materials and Methods: Participants were categorized into early and late pregnancy loss groups based on gestational age. A total of 156 patients were included, out of which 103 had early-trimester pregnancy losses and 96 had multiple miscarriages. Results: The study revealed a synergistic effect of Factor V Leiden (FVL G1691A) and Methylenetetrahydrofolate Reductase (MTHFR C677T) mutations (coefficient 3.42). Prothrombin (PT) G20210A and β-Fibrinogen 455 G>A mutations exhibited a significant interaction (coefficient 1.98). Additionally, MTHFR A1298C and Plasminogen Activator Inhibitor-1 (PAI-1 4G/5G) mutations showed a significant interaction (coefficient 1.65). FVL G1691A and Endothelial Protein C Receptor (EPCR) allele A1/A2 mutations also demonstrated a significant association (coefficient 2.10). Lastly, MTHFR C677T and Glycoprotein IIb/IIIa T1565C mutations interacted significantly (coefficient 1.77). Risk factor analysis identified several mutations associated with early pregnancy loss, including PAI-1 4G/5G homozygous (OR 3.01), FVL G1691A heterozygous (OR 1.85), and MTHFR A1298C heterozygous (OR 1.55). Both homozygous and heterozygous MTHFR C677T mutations were significant risk factors (OR 2.38; OR 2.06), as was PT G20210A homozygous mutation (OR 1.92). The PAI-1 4G/4G homozygous variant posed a risk (OR 1.36). Late pregnancy loss was associated with MTHFR A1298C homozygous mutation (OR 3.79), β-Fibrinogen 455 G>A heterozygous mutation (OR 2.20), and MTHFR A1298C heterozygous mutation (OR 2.65). Factor XIII G1002T heterozygous mutation (OR 1.18) and PAI-1 4G/5G homozygous mutation (OR 2.85) were also significant risk factors. EPCR allele A1/A2 (OR 1.60) and A2/A3 (OR 1.73) mutations were identified as significant risk factors for late pregnancy loss. Furthermore, FVL G1691A homozygous mutation, PT G20210A homozygous mutation, MTHFR C677T heterozygous mutation, MTHFR A1298C heterozygous mutation, and EPCR allele A1/A2 were identified as significant risk factors for multiple miscarriage. Conclusions: This study highlights significant interactions and risk factors related to genetic thrombophilia mutations in different types of pregnancy loss, contributing valuable insights for miscarriage management guidelines. Full article

(This article belongs to the Special Issue Current Challenges and Future Prospects in Human Reproduction and Infertility)

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10 pages, 481 KiB

Open AccessArticle

Evaluation of the Impact of Letrozole in Combination with the GnRH Antagonist Ovarian Stimulation Protocol in Patients Expected to Have a Poor Ovarian Response (POSEIDON Groups 3 and 4)

by Bulut Varlı, Yavuz Emre Şükür, Eda Üreyen Özdemir, Batuhan Özmen, Murat Sönmezer, Bülent Berker, Cem Atabekoğlu and Ruşen Aytaç

Medicina 2024, 60(3), 407; https://doi.org/10.3390/medicina60030407 - 28 Feb 2024

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Abstract

Background and Objectives: The objective of this study was to evaluate the impact of adjuvant letrozole administration during ovarian stimulation using the gonadotropin-releasing hormone (GnRH) antagonist protocol on treatment outcomes in women categorized into POSEIDON groups 3 and 4. Materials and Methods: This retrospective cohort study analyzed data from patients classified into POSEIDON groups 3 and 4 who underwent fresh embryo transfer subsequent to intracytoplasmic sperm injection following a GnRH antagonist stimulation protocol between January 2017 and December 2021. Patients were divided into two groups: the GnRH-LZ group, who received letrozole at a dosage of 5 mg/day for five consecutive days, and the GnRH-ant group, who did not receive adjuvant letrozole. The primary outcome measure of the study was a comparative analysis of live birth rates between the two groups. Results: A total of 449 patients were deemed suitable for final analysis and were allocated into two groups: 281 patients in the GnRH-ant group and 168 patients in the GnRH-LZ group. Live birth rates were found to be comparable in both groups (11% vs. 9%, p = 0.497). Letrozole administration significantly reduced the total amount of gonadotropins required (2606.2 ± 1284.5 vs. 3097.8 ± 1073.3, p < 0.001), the duration of ovarian stimulation (11.2 ± 3.9 vs. 10.2 ± 3, p = 0.005), and the serum peak estradiol concentration (901.4 ± 599.6 vs. 463.8 ± 312.3, p < 0.001). Conclusions: Adjuvant letrozole administration did not demonstrate a significant impact on live birth rates among women categorized into POSEIDON groups 3 and 4. However, this approach may offer potential cost reductions by diminishing the necessity for exogenous gonadotropins and shortening the duration of ovarian stimulation. Full article

(This article belongs to the Special Issue Current Challenges and Future Prospects in Human Reproduction and Infertility)

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9 pages, 1391 KiB

Open AccessCommunication

A Pilot Prospective Study Evaluating the Effect of Curcuma-Based Herbal Food Supplement on the Outcome of In Vitro Fertilization in Patients Testing Positive for Four Immunological Biomarkers

by Renato Colognato, Incoronata Laurenza, Gabriele Ersettigh, Giada Antonia Aiello, Marta Carnovali, Massimo Mariotti and Nicoletta Maxia

Medicina 2024, 60(2), 204; https://doi.org/10.3390/medicina60020204 - 25 Jan 2024

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Abstract

Background and Objectives: Inflammation and oxidative stress have been described to reduce the chance for pregnancy instauration and maintenance. NOFLAMOX, a recently developed herbal preparation with recognized antioxidant and anti-inflammatory properties, can represent an interesting treatment to increase the chance of pregnancy, both physiological or after in vitro fertilization (IVF). The aim of this study was to assess NOFLAMOX’s effect; a population with unexplained infertility was screened for the recently described IMMUNOX panel based on four immunological biomarkers with a prospective study approach. Materials and Methods: Patients with unexplained infertility and positive for at least one of the biomarkers of the IMMUNOX panel were included in this study and treated with NOFLAMOX for three months prior to an IVF cycle. Results: Eighty-six patients (n = 86) were screened with the IMMUNOX panel and the forty-seven (54.5%) found positive were included in this study. In more detail, 11 were positive for TNFα (23.4%), 18 (38.3%) for glycodelin (GLY), 29 (61.7%) for Total Oxidative Status (TOS), and 32 (68.1%) for Complement Activity Toxic Factor (CATF). After three months of treatment, a significant reduction in the number of IMMUNOX-positive patients was observable, with 26 patients who turned IMMUNOX-negative displaying a quantitative statistically significant variation of 100% (11/11), 38.9% (7/18), 65.5% (18/29), and 75% (24/32), for TNFα, glycodelin, TOS, and CATF, respectively. Followed in the subsequent IVF cycle, this NOFLAMOX-treated population showed a pregnancy rate of 42.3% compared to the 4.7% of the IMMUNOX-positive group of patients. Conclusions: Taken together, the results of this study suggest that NOFLAMOX could represent an interesting option for those patients with unexplained infertility of inflammatory/oxidative origin. Further studies are needed to confirm these results and explore possible strategies to restore fertility in women with immune-mediated sterility. Full article

(This article belongs to the Special Issue Current Challenges and Future Prospects in Human Reproduction and Infertility)

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11 pages, 554 KiB

Open AccessArticle

Impact of Assisted Reproduction Techniques on Adverse Maternal Outcomes and on the Rate of Hospitalization in Maternal Intensive Care

by Julie Collée, Laure Noel, Laurence Seidel, Frédéric Chantraine, Michelle Nisolle and Laurie Henry

Medicina 2023, 59(11), 2030; https://doi.org/10.3390/medicina59112030 - 17 Nov 2023

Viewed by 884

Abstract

Background and Objective: The aim of this retrospective cohort study is to evaluate the impact of assisted reproductive treatment (ART) on adverse maternal outcomes and the rate of hospitalization in maternal intensive care (MIC) in a tertiary university center in Liege, Belgium. Materials and Methods: This is a retrospective cohort study comparing two groups, 6557 patients who achieved pregnancy spontaneously and 330 patients who achieved pregnancy after ART, between January 2020 and December 2022. These patients were followed in the academic obstetrics department of Citadelle Hospital, Liège. The database of the ART center was compared with the database of the delivery unit to determine the cohort of patients who conceived after ART. Adverse maternal outcomes and MIC hospitalization rates were compared with between spontaneous pregnancies and ART groups. ART groups were also compared with each other. Results: The rate of hospitalization in maternal intensive care for patients who achieved pregnancy spontaneously was 12.1%, compared to 17.3% after ART. Comparing the rate of pre-eclampsia, 3.5% of spontaneous pregnancies were complicated by pre-eclampsia, while after ART, 10.9% of patients developed this complication during pregnancy. This rate was higher after IVF (12%) compared to intrauterine insemination and particularly after frozen embryo transfer (FET) in artificial cycle (17.9%). The birthweight of newborns after ART was also analyzed. A significant difference was obtained when comparing fresh embryo transfer with FET. Conclusions: Our study confirmed that FET in artificial cycle is a risk factor for pre-eclampsia and that fresh embryo transfer is associated with a higher rate of newborns with a lower percentile of birthweight. Our data showed that the rate of MIC hospitalization was significantly higher after ART but did not differ between groups. Full article

(This article belongs to the Special Issue Current Challenges and Future Prospects in Human Reproduction and Infertility)

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13 pages, 1579 KiB

Open AccessArticle

The Prediction of IVF Outcomes with Autologous Oocytes and the Optimal MII Oocyte/Embryo Number for Live Birth at Advanced Maternal Age

by Jelena Havrljenko, Vesna Kopitovic, Aleksandra Trninic Pjevic, Stevan Milatovic, Tatjana Pavlica, Nebojsa Andric and Kristina Pogrmic-Majkic

Medicina 2023, 59(10), 1799; https://doi.org/10.3390/medicina59101799 - 10 Oct 2023

Viewed by 1334

Abstract

Background and Objectives: Delayed childbearing in advanced age might be associated with a low prognosis for achieving pregnancy. Therefore, it is important to establish a predictive tool that will optimize the likelihood of a live birth at advanced age. Material and Methods: The retrospective study was conducted at the Ferona Fertility Clinic in Novi Sad (Republic of Serbia), between January 2020 and May 2021. The survey included 491 women aged ≥35 who met the inclusion criteria and who were subjected to an IVF (in vitro fertilization) treatment cycle. Results: The average number of retrieved oocytes, MII (metaphase II) oocytes, and developed embryos significantly decreased in advanced age. Age was also found to have a significant adverse effect on pregnancy and live birth rates. In women aged ≥35, 10/12 MII oocytes or 10/11 embryos are required for reaching an optimal live birth rate/cumulative live birth rate. Optimal CLBR (cumulative live birth rate) per one oocyte was achieved when 9 MII oocyte were retrieved. Conclusions: The study indicates that the cut-off for increased risk is ≥42 year. However, despite low live birth rates, autologous IVF for these women is not futile. An increase in the number of retrieved mature oocytes and a generation of surplus cryopreserved embryos could reinforce LBR (live birth rate) and CLBR. Clinicians should be very cautious in counseling, as autologous IVF may only be applicable to women with good ovarian reserve. Full article

(This article belongs to the Special Issue Current Challenges and Future Prospects in Human Reproduction and Infertility)

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20 pages, 15714 KiB

Open AccessArticle

The mTOR Inhibitor Rapamycin Counteracts Follicle Activation Induced by Ovarian Cryopreservation in Murine Transplantation Models

by Jules Bindels, Marlyne Squatrito, Laëtitia Bernet, Michelle Nisolle, Laurie Henry and Carine Munaut

Medicina 2023, 59(8), 1474; https://doi.org/10.3390/medicina59081474 - 16 Aug 2023

Viewed by 1509

Abstract

Background and Objectives: Ovarian tissue cryopreservation followed by autotransplantation (OTCTP) is currently the only fertility preservation option for prepubertal patients. Once in remission, the autotransplantation of frozen/thawed tissue is performed when patients want to conceive. A major issue of the procedure is follicular loss directly after grafting mainly due to follicle activation. To improve follicular survival during the OTCTP procedure, we inhibited the mTOR pathway involved in follicle activation using rapamycin, an mTOR inhibitor. Next, we compared two different in vivo models of transplantation: the recently described non-invasive heterotopic transplantation model between the skin layers of the ears, and the more conventional and invasive transplantation under the kidney capsule. Materials and Methods: To study the effects of adding rapamycin during cryopreservation, 4-week-old C57BL/6 mouse ovaries, either fresh, slow-frozen, or slow-frozen with rapamycin, were autotransplanted under the kidney capsule of mice and recovered three weeks later for immunohistochemical (IHC) analysis. To compare the ear with the kidney capsule transplantation model, fresh 4-week-old C57BL/6 mouse ovaries were autotransplanted to either site, followed by an injection of either LY294002, a PI3K inhibitor, vehicle control, or neither, and these were recovered three weeks later for IHC analysis. Results: Rapamycin counteracts cryopreservation-induced follicle proliferation, as well as AKT and mTOR pathway activation, in ovaries autotransplanted for three weeks under the kidney capsule of mice. Analyses of follicle proliferation, mTOR activation, and the effects of LY294002 treatment were similar in transplanted ovaries using either the ear or kidney capsule transplantation model. Conclusions: By adding rapamycin during the OTCTP procedure, we were able to transiently maintain primordial follicles in a quiescent state. This is a promising method for improving the longevity of the ovarian graft. Furthermore, both the ear and kidney capsule transplantation models were suitable for investigating follicle activation and proliferation and pharmacological strategies. Full article

(This article belongs to the Special Issue Current Challenges and Future Prospects in Human Reproduction and Infertility)

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11 pages, 613 KiB

Open AccessArticle

Effects of Selective Serotonin Reuptake Inhibitor Treatment on Ovarian Reserves in Patients with Depression

by Soner Gök, Berfin Can Gök, Erkan Alataş, Hande Senol and Osman Zülkif Topak

Medicina 2023, 59(3), 517; https://doi.org/10.3390/medicina59030517 - 07 Mar 2023

Cited by 1 | Viewed by 1782

Abstract

Background and Objectives: The goal of this study was to investigate the effect of selective serotonin reuptake inhibitor treatment on the ovarian reserves of women of reproductive age with major depressive disorder. Materials and Methods: The current study is a prospective controlled trial including 48 women with major depressive disorder and 48 age-matched healthy controls. Ovarian reserve tests are performed prior to treatment and after six cycles of selective serotonin reuptake inhibitor treatment in the major depressive disorder group. Serum follicle-stimulating hormone, luteinizing hormone, estradiol, and anti-Müllerian hormone levels were evaluated from blood samples, and endometrial thickness, total antral follicle count, and volume of both ovaries were assessed using transvaginal ultrasonography. Results: When the first measurements were compared, menstrual duration and menstrual bleeding increased (p = 0.007 and 0.005, respectively) and luteinizing hormone decreased (p = 0.045) in the major depressive disorder group, while follicle-stimulating hormone, estradiol, anti-Müllerian hormone, endometrial thickness, total antral follicle count, and mean ovarian volume did not differ significantly between groups (p > 0.05). When the major depressive disorder group’s first and final measurements were compared, follicle-stimulating hormone, estradiol, and endometrial thickness increased (p = 0.05, 0.0001, and 0.005, respectively), luteinizing hormone remained constant (p = 0.541), and anti-Müllerian hormone and total antral follicle count decreased (p = 0.024 and 0.042, respectively). Conclusions: In this study, we observed that the ovarian reserve test results of patients diagnosed with major depression for the first time after 6 months of SSRI treatment were significantly different from the results of the pretreatment and control groups. Full article

(This article belongs to the Special Issue Current Challenges and Future Prospects in Human Reproduction and Infertility)

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Review

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16 pages, 1061 KiB

Open AccessReview

Exploring Hormone Therapy Effects on Reproduction and Health in Transgender Individuals

by Efthalia Moustakli and Orestis Tsonis

Medicina 2023, 59(12), 2094; https://doi.org/10.3390/medicina59122094 - 29 Nov 2023

Cited by 1 | Viewed by 1784

Abstract

Transgender individuals often face elevated mental health challenges due to gender dysphoria, but gender-affirming treatments such as surgery and hormone therapy have been linked to significant improvements in mental well-being. The potential influence of time and circadian rhythms on these treatments is prevalent. The intricate interplay between hormones, clock genes, and fertility is profound, acknowledging the complexity of reproductive health in transgender individuals. Furthermore, risks associated with gender-affirming hormonal therapy and potential complications of puberty suppression emphasize the importance of ongoing surveillance for these patients and the need of fertility preservation and family-building options for transgender individuals. This narrative review delves into the intricate landscape of hormone therapy for transgender individuals, shedding light on its impact on bone, cardiovascular, and overall health. It explores how hormone therapy affects bone maintenance and cardiovascular risk factors, outlining the complex interplay of testosterone and estrogen. It also underscores the necessity for further research, especially regarding the long-term effects of transgender hormones. This project emphasizes the critical role of healthcare providers, particularly obstetricians and gynecologists, in providing affirming care, calling for comprehensive understanding and integration of transgender treatments. This review will contribute to a better understanding of the impact of hormone therapy on reproductive health and overall well-being in transgender individuals. It will provide valuable insights for healthcare providers, policymakers, and transgender individuals themselves, informing decision-making regarding hormone therapy and fertility preservation options. Additionally, by identifying research gaps, this review will guide future studies to address the evolving healthcare needs of transgender individuals. This project represents a critical step toward addressing the complex healthcare needs of this population. By synthesizing existing knowledge and highlighting areas for further investigation, this review aims to improve the quality of care and support provided to transgender individuals, ultimately enhancing their reproductive health and overall well-being. Full article

(This article belongs to the Special Issue Current Challenges and Future Prospects in Human Reproduction and Infertility)

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9 pages, 9295 KiB

Open AccessCase Report

Endometrial Osseous Metaplasia—A Rare Cause of Infertility with Unknown Etiology

by Vlad Iustin Tica, Iulia Postolache, Madalina Boșoteanu, Mariana Aschie, Irina Tica, Cristian Ionut Orasanu, Roxana Cleopatra Penciu, Andrei Adrian Tica, Liliana Steriu, Rudy Leon De Wilde and Oana Sorina Tica

Medicina 2023, 59(10), 1803; https://doi.org/10.3390/medicina59101803 - 10 Oct 2023

Cited by 1 | Viewed by 1838

Abstract

Background: Osseous tissue in the endometrium is a rare find, and it is most often discovered when the patient presents with infertility. It is frequently associated with dysmenorrhea and abnormal menstrual bleedings. Although its etiology remains unclear, in almost all described cases until now, the patient has an obstetrical history. Case report: In this report, we present a unique case of endometrial osseous metaplasia in a 27-year-old primary infertile patient. The transvaginal ultrasound revealed a 18/13/7 mm hyperechoic endometrial mass with posterior acoustic shadowing and no flow on color Doppler. A hysteroscopic examination found a polygonal calcification on the endometrial posterior face of the uterine cavity, in the corporeal isthmic region, which was extracted. The histopathological evaluation revealed microscopic elements compatible with endometrial calcification. The patient had a good postoperative course and the complex endocrinologic, immunologic and electrolytical investigation failed to prove any abnormality. Follow-up transvaginal ultrasound examinations revealed no modifications. Three years later, the patient conceived spontaneously, had an uneventful pregnancy and delivered a full-term fetus. Conclusion: We assumed that this entity can be a serious cause of infertility since the patient had a long history of (primary) infertility and its resection made the pregnancy’s occurrence possible. Finally, since neither history of abortion or chronic inflammation nor any abnormal laboratory test were noticed, we concluded that the etiology of this entity remained unclear. Full article

(This article belongs to the Special Issue Current Challenges and Future Prospects in Human Reproduction and Infertility)

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