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Challenges in Diagnosis and Treatment of Infertility—2nd Edition
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Challenges in Diagnosis and Treatment of Infertility—2nd Edition

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Reproductive Medicine & Andrology".

Deadline for manuscript submissions: 27 July 2026 | Viewed by 7759

Special Issue Editor

Prof. Dr. Konstantinos A. Zikopoulos

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Guest Editor
Assisted Reproduction Unit, Department of Obstetrics and Gynaecology, Faculty of Medicine, University of Ioannina, 45500 Ioannina, Greece
Interests: research and practice in gynecology endocrinology and medical assisted reproduction
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the second edition of “Challenges in Diagnosis and Treatment of Infertility” (https://www.mdpi.com/journal/jcm/special_issues/233D25OURQ).

The diagnosis and treatment of infertility are challenging due to issues related to the precision required to address individual medical needs and personalized assisted reproduction applications. Age-related or gamete-depletion-related subfertility raises concerns about best practice modalities to warrant early diagnoses and prompt treatments to avoid further fertility loss or a significant reduction in patients’ chances to conceive. Lately, technical advances in preimplantation diagnostic approaches, especially via the introduction of NGS, have offered novel insights into the genetic makeup of preimplantation embryos and even the clinical exploitation of mosaic embryos. Additionally, the treatment outcomes of cell therapies and growth factors showed significant improvements in the regeneration of ovaries and the uterus following the advent of PRP therapy. Furthermore, in all cases, technological innovations such as minimally invasive or non-invasive preimplantation genetic diagnosis improved the prognosis of ART and the prospects for a wider application. It is thus important to closely monitor progress in the evaluation and treatment protocol for fertility. This Special Issue of the Journal of Clinical Medicine focuses on the recent clinical advances in fertility preservation diagnosis and treatment, as well as the improvement of prospects for the conception of and reduction in the time to pregnancy.

Prof. Dr. Konstantinos A. Zikopoulos
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • fertility
  • regeneration
  • age-related infertility
  • preimplantation diagnosis
  • precision assessment
  • individualized fertility needs
  • clinical diagnosis
  • in vitro fertilization

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Related Special Issue

Published Papers (3 papers)

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Research

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19 pages, 1226 KB  
Article
Fertility Outcomes in Men with Nonobstructive Azoospermia Due to Hypogonadotropic Hypogonadism After Gonadotropin Therapy
by Athanasios Zachariou, Athanasios Zikopoulos, Eleftheria Markou, Sotirios Koukos, Grigorios Daligaros, Sotirios Skouros, Fotios Dimitriadis, Michael Chrisofos, Nikolaos Sofikitis and Aris Kaltsas
J. Clin. Med. 2026, 15(3), 1204; https://doi.org/10.3390/jcm15031204 - 3 Feb 2026
Viewed by 151
Abstract
Background/Objectives: Hypogonadotropic hypogonadism (HH) is an uncommon but treatable cause of non-obstructive azoospermia (NOA). Fertility can often be restored with gonadotropin therapy. This study evaluated spermatogenic and reproductive outcomes in men with HH-related NOA managed by stepwise gonadotropin therapy, microdissection testicular sperm extraction [...] Read more.
Background/Objectives: Hypogonadotropic hypogonadism (HH) is an uncommon but treatable cause of non-obstructive azoospermia (NOA). Fertility can often be restored with gonadotropin therapy. This study evaluated spermatogenic and reproductive outcomes in men with HH-related NOA managed by stepwise gonadotropin therapy, microdissection testicular sperm extraction (microTESE) for persistent azoospermia, and assisted reproduction when indicated. Methods: A retrospective cohort study included 35 men treated between 2010 and 2022. Human chorionic gonadotropin (hCG), with or without follicle-stimulating hormone (FSH), was administered to induce spermatogenesis. Outcomes included sperm appearance in the ejaculate, microTESE sperm retrieval rate in persistent azoospermia, and pregnancy and live birth outcomes after natural conception or in vitro fertilization with intracytoplasmic sperm injection (IVF-ICSI) when required. Results: Mean gonadotropin therapy duration was 12.0 months (range 6–24). Sperm appeared in the ejaculate in 27/35 men (77%). The remaining 8/35 (23%) underwent microTESE, with sperm retrieved in 7/8 (88%). Seven couples proceeded to IVF-ICSI, undergoing 11 cycles that yielded 6 clinical pregnancies (55% per cycle) and 5 live birth deliveries, including 2 twin pregnancies. Among responders, 13 natural pregnancies occurred, resulting in 13 live birth deliveries, including 2 twin pregnancies. Overall, 18/35 men (51%) achieved biological fatherhood, corresponding to 18 live birth delivery events (4 twin and 14 singleton deliveries) and 22 newborns. Conclusions: In men with HH-related NOA, exogenous gonadotropin therapy is expected to induce spermatogenesis in most patients. MicroTESE provides high sperm retrieval rates for those without ejaculatory sperm. Through an integrated approach of hormonal induction, microsurgical sperm retrieval, and assisted reproduction, approximately half of patients may ultimately achieve biological fatherhood in longer-term follow-up, depending on baseline severity and partner factors. Full article
(This article belongs to the Special Issue Challenges in Diagnosis and Treatment of Infertility—2nd Edition)
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13 pages, 987 KB  
Article
Flow Cytometric Assessment of Sperm DNA Fragmentation by TUNEL and Acridine Orange: Methodological and Clinical Insights
by Mohamed Abdelkarim, Nadine Ghannem, Khadija Kacem-Berjeb, Sana Chtourou, Linda Debbabi, Anis Fadhlaoui, Mounir Ben Mefeteh, Fethi Zhioua, Marouen Braham and Nozha Chakroun
J. Clin. Med. 2026, 15(2), 403; https://doi.org/10.3390/jcm15020403 - 6 Jan 2026
Viewed by 435
Abstract
Background/Objectives: Male infertility contributes to nearly half of global infertility cases, yet conventional semen analysis is insufficient to predict assisted reproductive technology (ART) outcomes such as intracytoplasmic sperm injection (ICSI). Sperm DNA fragmentation (SDF) is a promising biomarker of genomic integrity, but clinical [...] Read more.
Background/Objectives: Male infertility contributes to nearly half of global infertility cases, yet conventional semen analysis is insufficient to predict assisted reproductive technology (ART) outcomes such as intracytoplasmic sperm injection (ICSI). Sperm DNA fragmentation (SDF) is a promising biomarker of genomic integrity, but clinical implementation remains hindered by methodological heterogeneity. This study compared two SDF assays—TUNEL and Acridine Orange (AO)—regarding their correlations with semen parameters and ICSI outcomes. Methods: Sixty men undergoing ICSI were prospectively enrolled. SDF was analyzed using two flow cytometric assays: TUNEL (detecting DNA strand breaks) and AO (assessing chromatin instability). Semen quality and ICSI outcomes (fertilization, cleavage, blastulation, and embryo utilization rates) were evaluated. Statistical analyses included Spearman’s rank correlation and Mann–Whitney tests. Results: Median SDF levels were significantly higher by TUNEL than AO (17.2% vs. 10.15%; p = 0.0065). Inter-assay correlation was weak (r = 0.299, p = 0.01). AO-derived SDF correlated positively with age (r = 0.311, p = 0.02), while TUNEL showed no such trend. Neither assay correlated significantly with semen parameters or ICSI outcomes, although AO tended to associate with lower motility and slightly reduced top-quality embryo rates. Conclusions: TUNEL and AO capture distinct facets of sperm DNA damage. Their limited correlation and lack of predictive value for ICSI outcomes highlight the need for assay-specific interpretation and standardization. Integration of SDF with additional biomarkers and oocyte factors may enhance its clinical utility. Full article
(This article belongs to the Special Issue Challenges in Diagnosis and Treatment of Infertility—2nd Edition)
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Review

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16 pages, 1309 KB  
Review
Premature Ovarian Insufficiency and Diminished Ovarian Reserve: From Diagnosis to Current Management and Treatment
by Lara Houeis, Jacques Donnez and Marie-Madeleine Dolmans
J. Clin. Med. 2025, 14(21), 7473; https://doi.org/10.3390/jcm14217473 - 22 Oct 2025
Viewed by 4467
Abstract
Premature ovarian insufficiency (POI) and diminished ovarian reserve (DOR) are two related conditions characterized by a reduced ovarian reserve. Their etiologies are multifactorial, encompassing iatrogenic causes such as chemotherapy, pelvic surgery, or radiotherapy, as well as non-iatrogenic factors including genetic and chromosomal abnormalities, [...] Read more.
Premature ovarian insufficiency (POI) and diminished ovarian reserve (DOR) are two related conditions characterized by a reduced ovarian reserve. Their etiologies are multifactorial, encompassing iatrogenic causes such as chemotherapy, pelvic surgery, or radiotherapy, as well as non-iatrogenic factors including genetic and chromosomal abnormalities, environmental exposures, autoimmune mechanisms and idiopathic sources. Early recognition of these conditions is essential, as timely and appropriate management can significantly impact both reproductive potential and long-term health. In women with POI, hormone replacement therapy is required to prevent the detrimental effects of estrogen deficiency on wellbeing and overall health, while in women with DOR, management focuses on counseling, fertility preservation when pregnancy is not an immediate goal, and strategies to optimize assisted reproductive outcomes when conception is desired. In addition, emerging research into ovarian rejuvenation offers promising new avenues for future therapeutic approaches. This review summarizes current knowledge on the pathophysiology, diagnosis, and management of POI and DOR, while highlighting innovative developments in reproductive medicine. Full article
(This article belongs to the Special Issue Challenges in Diagnosis and Treatment of Infertility—2nd Edition)
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