{"paper_id":"59ec4586-d467-4431-a13b-61ef9cd9a9f6","body_text":"Mansour  Beni-Suef Univ J Basic Appl Sci           (2023) 12:81  \nhttps://doi.org/10.1186/s43088-023-00416-2\nREVIEW\nInfertility diagnosis and management\nHend Abd El‑halim Mansour1*   \nAbstract \nBackground One of the most stressful problems for married couples is infertility, which is a widespread health issue. \nIt has been defined as a profound life‑changing problem that comes with severe psychological stress despite the fact \nthat it is not fatal. The rate of infertility among couples is gradually rising due to postponing childbearing, which \nis brought on by several social and economic causes.\nMain body Depending on the cause, the length of the couple’s struggle, and the ages of the partners, infertility can \nbe treated medically, surgically, or with modern reproductive assistance (in vitro fertilisation, intrauterine insemination, \nintracytoplasmic sperm injection, and nanotechnology). Fertility issues can be a stressful circumstance in a person’s \nlife with serious psychological repercussions. Hypogonadotropic hypogonadism, hyperprolactinemia, ciliary disorders, \ncystic fibrosis, infections, systemic diseases, and diseases connected to lifestyle are the factors that impair fertility \nin both sexes. Female infertility may be caused by premature ovarian insufficiency, polycystic ovary syndrome, endo‑\nmetriosis, uterine fibroids, and pelvic inflammatory disease. Testicular and post‑testicular deficits can cause male infer‑\ntility. Other potential contributing factors include consanguinity, endocrine disrupting substances, and the observed \nsemen reduction throughout time.\nConclusion One in eight females between the ages of 15 and 49 receives assistance with conception. Although suc‑\ncess rates vary by age and diagnosis, many couples receiving treatment for infertility can achieve their fertility objec‑\ntives with the help of a precise diagnosis, efficient therapy, and shared decision‑making. The term “assisted reproduc‑\ntive technology” can facilitate egg fertilisation and aid implantation of the fertilised egg in the uterine lining.\nKeywords Infertility, Causes of female and male infertility and “assisted reproductive technology” (ART) for infertility\n1  Background\nThe inability to become pregnant after participating in \nregular, protected sexual activity for at least a year is a \nsign of infertility, a disease of the male or female repro -\nductive system. After a year of unprotected sexual activ -\nity, infertility is the inability to get pregnant [1]. In the \nUSA, 10–15% of married couples have infertility [2]. \nMale and female spouses both contribute equally to the \ninfertility, with the other factors being a result of their \njoint efforts [3]. The motivation for having children is \nthe formation of a new family unit which essential to a \nperson’s instinct for survival [4]. Having fertility prob -\nlems can be a stressful situation in a person’s life with \nnegative psychological effects. The qualified clinician \nshould be aware of and comprehend the heavy burdens \nand frustrated demeanour of the infertile person. Most \nadults are motivated to discuss their sexual problems, \nissues, and behaviours if the interview is conducted in a \npolite, confidential, professional, and non-judgmental \nmanner. Throughout the past few decades, significant \nadvancements have been made in the field of male infer -\ntility. Procedures for diagnosis and treatment have both \nmade important related improvements. Due to the fact \nthat many infertile couples suffer from many causes of \ninfertility, you will likely both need to see a doctor [4]. \nMale infertility is most frequently brought on by issues \nwith the ejection of semen, a lack of sperm or low sperm \ncounts, or irregular sperm shape (morphology) and \nOpen Access\n© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which \npermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line \nto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory \nregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this \nlicence, visit http://creativecommons.org/licenses/by/4.0/.\nBeni-Suef University Journal of\nBasic and Applied Sciences\n*Correspondence:\nHend Abd El‑halim Mansour\nhendmansour.sci.g@azhar.edu.eg\n1 Zoology and Entomology Department, Faculty of Science (for Girls), \nAl‑Azhar University, P .O. 11884, Nasr City, Cairo, Egypt\n\nPage 2 of 20Mansour  Beni-Suef Univ J Basic Appl Sci           (2023) 12:81 \nmotility (motion). Women who are infertile can develop \na variety of diseases that affect their ovaries, uterus, fallo -\npian tubes, and endocrine systems, among other organs. \nPrimary or secondary infertility is both possible. If at \nleast one prior pregnancy was successful, a person has \nsecondary infertility, whereas primary infertility is when \na pregnancy has never been successful. When a couple \nregularly engages in unprotected sexual activity yet is \nunable to conceive, every seventh couple may have trou -\nble getting pregnant. 84% of couples who engage in regu -\nlar, unprotected intercourse will spontaneously become \npregnant (every two or three days) within a year. For cou-\nples who have spent more than three years attempting to \nconceive, the likelihood of becoming pregnant naturally \nin the following year is 1 in 4, or less [1].\n2  Main text\n2.1  Types of infertility\nMany factors can contribute to infertility. For one in four \nmarriages, the reason is unknown.\n2.1.1  Female infertility\nThe female is to blame for infertility in roughly 45% of \ninfertile marriages. Male factor infertility affects 30% of \ncases, while the remaining 25% go undiagnosed.\n• Fertilised oocytes (10–15%) split, but fail to implant.\n• Implanted ova (42%) are successful in suppressing \nthe subsequent menstrual cycle.\n- Women have abortion (24%) in 4th week of pregnancy \n[5, 6].\n2.1.1.1 Ovulation issues may arise from \n• Thyroid issues associated with polycystic ovarian syn -\ndrome (PCOS): Ovulation premature ovarian failure, \nin which the ovaries cease to function before the age \nof 40, can be avoided by both an overactive thyroid \ngland and an underactive thyroid gland.\n• Scarring from surgery: During pelvic surgery, the fal -\nlopian tubes, which join the ovaries to the womb, \nmay be hurt or scarred. Moreover, some cervical sur-\ngeries shorten the womb’s neck or leave scars behind \n(the cervix).\n• A cervical mucus issue: cervix’s mucous thins during \novulation to make it easier for sperm to get through. \nConception may be more difficult if there is a mucus \nissue.\n• Fibroids: Fertility may be impacted by non-cancerous \ngrowths called fibroids which develop in or near the \nuterus. They may occasionally stop a zygote from \nadhering to the fallopian tube or uterus.\n• Endometriosis: Little fragments of the endome -\ntrium, the lining of the womb, begin to grow in \nother locations, such as the ovaries, in endometrio -\nsis. Infertility issues may result from this harm to \nthe fallopian tubes or the ovaries.\n• Inflammatory illness of the pelvis: is an infection \nof the upper female genital tract, which includes \nthe ovaries, fallopian tubes, and wombs known as \npelvic inflammatory disease (PID). Often, a sexu -\nally transmitted infection is the culprit. PID has \nthe potential to scar and injure the fallopian tubes, \neffectively blocking an egg’s descent into the womb.\n• Sterilisation: If a woman decides she does not want \nto have any more children, she may elect to be ster -\nilised. To prevent an egg from entering the womb, \nthe fallopian tubes are blocked during sterilisation. \nSterilisations are rarely reversible, and even if they \nare, you might not be able to conceive.\n-Medicines and drugs: Your fertility may be impacted by \nthe side effects of certain medications and pharmaceu -\nticals, including the following:\n• Non-steroidal anti-inflammatory drugs (NSAIDs): \nIt may be more challenging to get pregnant if you \nuse NSAIDs like ibuprofen or aspirin frequently or \nin excessive doses.\n• Chemotherapy: Ovarian failure is a side effect of \nseveral chemotherapy drugs that prevents your \novaries from functioning properly. Anti-neuroleptic \ndrugs and antipsychotic drugs, which are frequently \nprescribed to cure schizophrenia, can occasionally \nresult in infertility or missed periods.\n• Spironolactone: a medication used to treat oedema \n(fluid retention); after stopping spironolactone, in \nabout two months, fertility should resume. Illicit \nsubstances like marijuana and cocaine can have a \nmajor negative impact on fertility and make ovula -\ntion more challenging.\n2.1.1.2 Fallopian tubes problems Infection or injury \nto the fallopian tubes is one of the most frequent rea -\nsons of infertility in women. The majority of the time, \none or both tubes may be obstructed, preventing the \nmovement of eggs, spermatozoa, or embryos from the \novary to the uterus. Harm to the mucosal lining, partial \nobstruction, and adhesions are also frequent. The lat -\nter are distinguished by tissue strands that emerge from \nsick places and maintain the tubes’ stability and ability \nto move, such as when picking up an ovum, for example \n[7].\n\nPage 3 of 20\nMansour  Beni-Suef Univ J Basic Appl Sci           (2023) 12:81 \n \n2.1.1.3 Uterine problems While a woman is pregnant, \nthe uterus, also known as the womb, is where the baby \ndevelops. Bleeding between cycles or after intercourse \nmay be the first indicator of uterine problems. Uterine \ndifficulties are ailments that impact the uterus or any \nother portion of your reproductive system. There are \nseveral potential causes, including hormonal imbal -\nances, cancer, fibroids, polyps, and infections during \npregnancy. Uterine fibroids, endometriosis, uterine pro -\nlapse, and uterine tuberculosis are a few frequent uter -\nine conditions. In two more uterine conditions, tissue \nthat ordinarily borders the uterus grows in an unnatural \nlocation. It expands external to the uterus in endome -\ntriosis. It develops in the outer walls of the uterus during \nadenomyosis. Painkillers might be useful. In addition, \nthere are surgical and hormonal therapies.\n2.1.2  Male infertility\n30% of infertile couples caused by male infertility. Most \noften, oligospermia, or a lack of spermatozoa in the \nsemen or sperm of poor quality or motility, is the issue. \nSurgery for azoospermia, or no sperm production, is \nfar less prevalent [7 ].\n2.1.2.1 Semen and sperm Low-grade sperm, the fluid \nthat contains sperm that is ejaculated while having sex, \nis a common factor in male infertility. Among the poten -\ntial causes of anomalous semen are: not enough sperm. \nSperm that are not moving properly or that are very low \nin number will make it more difficult for them to swim to \nthe oocyte. Sometimes aberrant sperm have odd shapes, \nwhich makes it more difficult for them to migrate and \nfertilise an oocyte. There are many unexplained cases \nof anomalous semen. Although there is a connection \nbetween elevated scrotal warmth and decreased semen \nquality, it is unknown whether donning baggy under -\nwear increases fertility.\n2.1.2.2 Testicles Sperm are produced and kept in the \ntestis. The quality of the semen may be significantly \nimpacted by damage to them. This might happen if testis \nare infected, have cancer, have undergone surgery, have \na congenital deformity, or have been injured. It can also \nhappen if one or both of the testis have not descended \ninto the scrotum.\n2.1.2.3 Sterilisation Some men decide to undergo \na vasectomy. It entails severing and closing up the vas \ndeferens, which transports sperm from your testicles, to \nensure that your semen is devoid of sperm. It is possible \nto undo a vasectomy; however, this rarely results in suc -\ncess.\n2.1.2.4 Ejaculation disorders Some men may have \ntrouble passing semen during ejaculation (intercourse) \ndue to ejaculation issues.\n2.1.2.5 Hypogonadism Low levels of testosterone, the \nmale sex hormone essential for the production of sperm, \nare referred to medically as hypogonadism. Drug abuse, \ncancer, or the rare condition known as Klinefelter syn -\ndrome (which contains an extra female chromosome) \ncould all be to blame.\n2.1.2.6 Medicines and drugs Many types of medicines \nmay cause infertility issues. These include:\n• Sulfasalazine : is an anti-inflammatory medication \nused to treat conditions like rheumatoid arthritis \nand Crohn’s disease. It may momentarily suppress \nsperm counts, but as soon as stop using it, they \nshould start to rise again.\n• Anabolic: Illegal use of anabolic steroids is common \nto increase sports performance and muscle mass; \nprolonged use of these drugs can lower sperm qual -\nity and motility.\n• Chemotherapy: therapies using herbs and some \nherbal medicines, such as root preparations of the \nChinese herb Tripterygium wilfordii, have been \ndemonstrated to affect testicle size or sperm pro -\nduction. Chemotherapy drugs sometimes cause a \nconsiderable reduction in sperm production.\n• Illegal drugs : Semen quality may be impacted by \ndrugs like cocaine and marijuana.\n2.1.3  Unexplained infertility\nWhen neither spouse can pinpoint the source, this is \nthe situation. See your doctor about the next steps if \nthe root of your fertility issues has not yet been iden -\ntified. The National Institute for Health and Care \nExcellence (NICE) recommends making IVF therapy \navailable to women with unexplained infertility who \nhave not conceived after two years of engaging in fre -\nquent unprotected sexual contact. More information \non unexplained infertility can be found in the NICE \nrecommendations.\n2.2  Diagnosis\n2.2.1  Female examination\nQuestions about menstruation and related factors, mar -\nriage and childbirth histories, and high-risk factors that \nmay affect the fallopian tube or pelvic environment \nshould all be carefully questioned in order to ascertain \n\nPage 4 of 20Mansour  Beni-Suef Univ J Basic Appl Sci           (2023) 12:81 \nthe likelihood of ovulatory dysfunction or aberrant pelvic \nfactors [8].\n2.2.1.1 Physical examination In both general and \ngynaecological exams, take the following into considera -\ntion:\n• A general assessment primarily focuses on a patient’s \ngrowth and nutritional state, including thyromegaly, \nskin changes, secondary sex features, weight, height, \nand body fat distribution.\n• It is necessary to confirm the following. The position, \nsize, texture, shape, and mobility of the uterus, the \npubic hair pattern, the size of the clitoris, the pres -\nence of abnormal vaginal secretion, whether the cer -\nvix is smooth without abnormal secretion, whether \nthe accessory area is thickening, massing, or ten -\nder, and whether the aforementioned symptoms are \nnoticeable [14].\n2.2.1.2 Ovulatory function Up to 40% of female infertil-\nity is caused by ovulatory disorder, which will be found \nin 15% of all infertile couples [8]. Ovulatory dysfunc -\ntion is most frequently brought on by polycystic ovarian \nsyndrome, obesity, weight gain or loss, intense activity, \nthyroid issues, and hyperprolactinemia. Even though a \nwoman’s cycle usually lasts longer than 25  days, irregu -\nlar menstrual cycles, periods that last less than 21  days \nor more than 35 days, or complaints of abnormal uterine \nbleeding or amenorrhea may cause ovarian cancer to be \nsuspected [9]. Usually, ovulation happens 14 days before \nto the start of menstruation. A postovulatory serum pro -\ngesterone level that is measured in the anticipated mid -\nluteal phase, roughly one week before to the anticipated \nmenses, may be used to identify ovulation in cases when \nthe menstrual history is lacking or unclear. Seventy per \ncent of women with anovulation have polycystic ovarian \nsyndrome (PCOS), which is the condition’s most preva -\nlent cause [10]. Along with PCOS, obesity has been linked \nto anovulation; women with a body mass index (BMI; \ncalculated as weight in kilogrammes divided by height in \nmetres squared) greater than 27 are at a higher risk of ano-\nvulatory infertility than women with a BMI in the normal \nrange (relative risk: 3.1 [95% CI 2.2–4.4]; absolute rates \nwere not provided in the American Society for Reproduc-\ntive Medicine guideline) [11]. Additional causes include \nthyroid illness (2–3%), pituitary disease (13%), increased \nandrogens from an adrenal tumour or hyperplasia (2%), \nidiopathic chronic ovulation (7–8%), and functional \nhypothalamic amenorrhea (induced, for example, by \nunderweight, eating disorders, or extreme exercise). Ano-\nvulatory infertility is more frequent in patients with eating \ndisorders than in women without eating disorders (16.2% \nvs. 5.6%; n = 271) [12, 13]. Any of the following techniques \nmay be used to assess ovulatory function:\n• A woman’s menstrual history can be sufficient.\n• Repeated measures of basal body temperature (BBT) \noffer an easy and affordable way to assess ovulatory \nfunction. The seven days before the mid-cycle surge \nin BBT are when fertility is at its peak in cycles being \ntracked by BBT. Women with more modest ovulatory \nfailure may be identified by (10 days of temperature \nelevation). The test can get boring and is unable to \naccurately pinpoint the ovulation time. As a result, \nfor the majority of infertile women, BBT is no longer \nregarded as the best or recommended tool for evalu -\nating ovulatory activity [8].\n• Serum progesterone levels provide a reliable and \nunbiased evaluation of ovulatory function if they are \nmeasured at the appropriate time in the cycle. Given \nthe range of natural variation in ovulatory cycles (e.g. \ncycle day 21), a blood progesterone measurement \nshould normally be performed around a week before \nthe anticipated start of the following menses rather \nthan on any specific cycle day. Progesterone concen -\ntrations greater than 3  ng/mL provide suspect but \nreliable evidence of recent ovulation. The criterion is \nunreliable because of the pulsatile nature of corpus \nluteum progesterone secretion and the potential for \nup to sevenfold fluctuations in serum concentration \nover a few hours, even though higher threshold val -\nues (such as R10 ng/mL) have frequently been used \nto evaluate the quality of luteal function [8].\n• Several commercial “ovulation predictor kits” that \nmeasure urinary luteinising hormone (LH) can be \nused to identify the mid-cycle LH spike, which takes \nplace one to two days before ovulation. Urinary LH \ndetection is an indirect indicator of ovulation and \naids in identifying the time of greatest fertility, which \nis the day of the LH surge and the two days that fol -\nlow. Particularly when the test is performed on mid -\nday or evening urine samples, results frequently \nclosely match the peak in serum LH. Accuracy, usa -\nbility, and dependability of products varies, and test -\ning can result in both false positive and false negative \nresults [8]. Progesterone-induced secretory endome -\ntrium can be seen during endometrial biopsy (EBM) \nand histology, which supports ovulation. The lack of \nprecision and accuracy, as well as the inability to dis -\ntinguish between fertile and infertile women, has led \nto the conclusion that histologic endometrial dating \nis not a valid diagnostic tool. Therefore, it is no longer \nrecommended to test an infertile woman’s ovulatory \nor luteal function, and endometrial biopsy should \n\nPage 5 of 20\nMansour  Beni-Suef Univ J Basic Appl Sci           (2023) 12:81 \n \nonly be carried out when a specific endometrial \ncondition (such neoplasia or chronic endometritis) \nis strongly suspected [8]. Transvaginal ultrasonog -\nraphy has the ability to count the growing follicles, \ncount their size, and count putative ovulation and \nluteinisation indications. The abrupt collapse of the \npre-ovulatory follicle, loss of clearly defined follicu -\nlar boundaries, appearance of internal echoes, and a \nrise in the volume of the cul de sac fluid are some of \nthese symptoms. The method should typically only \nbe used for women in circumstances where simpler \napproaches are unable to offer the essential informa -\ntion due to the cost and practical challenges involved \n[8].\n• TSH and prolactin measurements in the serum can \nidentify hyperprolactinemia and/or thyroid prob -\nlems, which may require specialised care [8].\n• In amenorrheic women, measurements of serum \nfollicle-stimulating hormone (FSH) and estradiol can \ndistinguish between those who have hypothalamic \namenorrhea (low or normal FSH, low estradiol), \nwhich will require exogenous gonadotropin stimula -\ntion to induce ovulation, and those who have ovarian \nfailure (high FSH, lowest estradiol), who may be can -\ndidates for oocyte donation [8].\n2.2.1.3 Ultrasound examination \n• Pelvic ultrasound examination: This requires placing \na particular instrument into the vagina as opposed \nto a typical, external ultrasonography. It projects an \nimage of the uterus and other reproductive organs \non a screen using high-frequency sound waves. The \ndoctor can then spot any structural issues or fibroids \nthat might be preventing pregnancy. This is normally \ndone two weeks prior to the patient’s period and is \nnot [15].\n• Hysterosalpingography (HSG): A radiopaque dye is \ninjected into the uterine cavity via a catheter during a \nfluoroscopic examination to evaluate the morphology \nof the cavity and the patency of the fallopian tubes. \nThe test is typically planned for the time period \nright after monthly menstruation and before ovula -\ntion. HSG should not be done if there is an adnexal \ntumour, pelvic inflammatory disease, a history of \nectopic pregnancy, an allergy to a radiocontrast dye, \nor an iodine allergy. During an HSG, congenital \nanomalies, intrauterine polyps, submucous leiomyo -\nmas, surgical alterations, and synechiae may be dis -\ncovered. Among the tubal abnormalities are peritubal \nadhesions, polyps, hydrosalpinx, salpingitis isthmica \nnodosum, and proximal or distal tubal blockage [15].\n• Sonohysterography (SHG): Investigations using SHG \ncan be conducted to look into issues like irregular \nuterine bleeding, infertility, and recurrent miscar -\nriage. SHG can be used to examine the uterus’s archi-\ntecture. This can be done in women who have uterine \ncongenital abnormalities (birth defects), prior to and \nduring uterine surgery, or to find issues that develop \nlater in life, like polyps or possible scar tissue inside \nthe uterus. SHG might also be used to investigate \nuterine anomalies discovered during a standard ultra-\nsound. SHG is often performed following the end of \nthe menstrual cycle. It may be done at any time in \nwomen who are not menstruation (such as those \ntaking drugs to suppress the menstrual cycle, post -\nmenopausal women, etc.). An ultrasound examina -\ntion utilising a probe inserted in the vagina starts the \nprocess. The uterus is then filled with sterile saline \n(salt water) using a thin catheter that is inserted via \nthe cervix using a speculum. The uterus is filled with \nsaline solution, which helps define the uterine walls \nand cavity. This reveals abnormalities in the uterus, \nsuch as fibroids, polyps, or scar tissue [16].\n• Laparoscopy: In this minimally invasive procedure, \nyour fallopian tubes, ovaries, and uterus are exam -\nined by inserting a thin viewing equipment through \na small incision made beneath your navel. Endome -\ntriosis, scarring, blockages or abnormalities of the \nfallopian tubes, as well as issues with the ovaries and \nuterus, may all be discovered during a laparoscopy \n[17].\n2.2.2  Protocols used for evaluation of infertile males\n60% of cases involving couples of reproductive age who \nare experiencing fertility-related problems are either \ndirectly or indirectly related to male infertility [18, 19]. \nMale infertility assessment is frequently undervalued or \ndelayed. The effectiveness, danger, and expense of follow-\ning therapy are all improved with a coordinated evalua -\ntion of the infertile male utilising established protocols. \nThe ability to recognise and treat reasons of male infer -\ntility that were previously incurable has been made pos -\nsible by recent developments in assisted reproductive \ntechniques (ART). It is crucial that patients are correctly \nidentified and evaluated in order to make the best use of \nthe techniques that are currently available and enhance \ntherapeutic outcomes. In a perfect world, this prelimi -\nnary evaluation would also be affordable and available. \nWe provide information on the wise use of current diag -\nnostic techniques and better understand the aetiology of \nthe best appropriate treatment for the existing disease by \nproviding a practical description of the main features of \nmale infertility evaluation [19]. A male’s initial evaluation \n\nPage 6 of 20Mansour  Beni-Suef Univ J Basic Appl Sci           (2023) 12:81 \nis based primarily on histology, a physical examina -\ntion, and sperm analysis. Semen analyses and acquiring \na reproductive history, including a sexual history, are \nimportant procedures that are generally accepted. The \nfollowing details should be included in the reproduc -\ntive history, according to the ASRM [19]: Sexual history \n(including STDs), sexual frequency and timing, length \nof infertility, prior fertility, childhood ailments, previous \nsurgeries, drugs, and allergies, as well as exposure to gon-\nadotoxins, such as heat and chemical toxins, are all fac -\ntors [19, 20].\n2.2.2.1 Physical examination Secondary sexual features \nsuch skeletal proportions, hair pattern, and muscular \nmass are observed during a thorough physical assess -\nment. The genitalia should receive special consideration \nwith regard to testicular size and the disparity in devel -\nopment between the two sides. The vas should be easily \nperceptible and the epididymis should not be swollen or \nindurated. Congenital vas absence is typically identifiable \nand may be linked to renal abnormalities. When a patient \nis standing, large varicoceles may be readily visible along \nthe spermatic cord, whereas minor ones may only be per-\nceptible during Valsalva. Varicoceles should easily decom-\npress when the patient is supine if there is no obstruction \nto internal spermatic venous drainage in the retroperito -\nneal region. Prostate needs to Varicoceles should be sim -\nple to decompress when the patient is lying supine if there \nis no obstruction to internal spermatic venous drainage \nin the retroperitoneal region. A little, non-tender prostate \nshould be palpable in the rectal area. Unsuitable urethral \nmeatus placement or stenosis may prevent proper semen \ndeposition in the vagina [14].\n2.2.2.2 Laboratory examination \n• Hormonal examination: To ascertain the general hor-\nmonal system balance and the precise stage of sperm \nproduction, measure the levels of testosterone and \nFSH (follicle-stimulating hormone). If preliminary \ntesting reveals a need for them, additional hormonal \ntests, such as those for prolactin and serum LH, may \nbe performed [20].\n• Seminal examination: Semen analysis should be per -\nformed 2–3 times for the male partner of an infer -\ntile relationship in order to establish baseline data. \nThe test needs to be given every time at the same \ntime, 2–7  days after ejaculation. The result and the \nclinical characteristics should be carefully analysed \ntogether. Any individual can go through a wide range \nof changes. The range of each measure is therefore \nsimply used as a guide when evaluating the fertility \nof males, and it is not the main determinant in diag -\nnosing infertility. Males with results over the bottom \nbound of the reference range are not strictly sterile. \nIn addition, each laboratory should define its own \nreference range based on sperm concentration in \nconsideration of the variations between areas or lab -\noratories. The following categories apply to individu -\nals with oligozoospermia:\n• The mild-to-moderate level of sperm concentra -\ntion is defined as the range of 5–15 106/mL for \n2–3 consecutive standard semen analyses.\n• Serious level: 1–106 sperm per millilitre of semen \nfor 2–3 consecutive standard semen examinations. \n(3) The sperm concentration reaches a severe level \nof less than 1 106/mL after two to three consecu -\ntive standard semen examinations.\n• Cryptozoospermia is a condition in which sper -\nmatozoa are only visible in sediment pellets during \ncentrifugation and not in fresh semen samples [19, \n21, 22].\n2.2.2.3 Ultrasound examination In cases of male infer -\ntility, ultrasound is typically always the first imaging test \nperformed. Evaluation aims to determine testicular mor -\nphology, efferent duct patency, and prostatic abnormali -\nties. Moreover, erectile dysfunction may be evaluated [23].\n• Scrotal ultrasound: The examination makes use of a \nhigh-frequency (7–12  MHz) linear array transducer \nthat is long enough to measure the testis longitudi -\nnally. The patient is examined while lying flat. The \ntestes should be routinely evaluated in orthogonal \ntransverse and longitudinal planes, as well as through \ncolour Doppler evaluation and volume measures. \nThe formula for measuring volume is typically: \nlength*height*width*0.51. In general, a single tes -\nticular volume of 12–15 ml and a combined volume \n(both testes) > 30 ml are regarded as normal [18].\n• Transrectal ultrasound: Transrectal ultrasound, \nwhich provides high-resolution imaging of the pros -\ntate, seminal vesicles, and vas deferens, is the advised \nmethod for identifying congenital and acquired \nabnormalities associated in the pathophysiology of \nobstructive azoospermia. The terminal vas deferens, \nseminal vesicles, ejaculatory duct, and prostate are all \nthoroughly examined in the axial and sagittal planes \n[23].\n• Moderate and dynamic colour Doppler penis ultra -\nsound: Penile ultrasonography is utilised to iden -\ntify the underlying physical causes of erectile dys -\nfunction. They include difficulties with the venous \nocclusive system, artery input, and anomalies in the \n\nPage 7 of 20\nMansour  Beni-Suef Univ J Basic Appl Sci           (2023) 12:81 \n \npenile’s structure. Due to the small risk of priapism, \ninformed consent must be obtained before to intra -\ncavernosal prostaglandin injection [23].\n• Magnetic resonance imaging techniques (MRI): help \ndetect prostatic cysts and evaluate the vas deferens, \nseminal vesicles, and ejaculatory ducts. This makes \ntriplanar T2-weighted spin echo imaging with [long \nrepetition time (TR)/long echo time (TE)] the ideal \nmethod and short TR/short TE T1-weighted turbo \nspin echo images with a slice thickness of 3–4  mm \nused to get high-resolution images of the triplanar \n[20, 23].\n2.2.3  Other examinations\n• After an orgasm, checking your pee. With the excep -\ntion of people who have hypoplasia of the bilateral \nspermaducts or clinical signs of hypogonadism, it \napplies to people who do not excrete semen or who \nhave post-orgasmic semen volumes of less than \n1 mL.\n• Anti-sperm antibodies in seminal plasma should only \nbe used as a reference for immunological infertility \nand not as a stand-alone criterion.\n• Genetic testing: Patients with severe oligozoo -\nspermia or azoospermia may benefit from Y chro -\nmosome microdeletion testing and karyotype analy -\nsis. Patients whose azoospermia is accompanied by \nunilateral or bilateral spermaduct agenesis may ben -\nefit from CFTR gene testing. Patients with suspected \nKallmann syndrome may benefit from Kal gene test -\ning.\n• Patients with hyperprolactinemia and insufficient \ngonadotropin secretion can benefit from imaging \nassessment of the hypothalamus-pituitary area.\n• Diagnostic testicular biopsy is advised for individu -\nals with azoospermia to assess the testis’ capacity \nto generate sperm and determine if their condition \nis obstructive or non-obstructive [14]. WHO 2021’s \nminimum amount for procreative semen:\nVolume of semen (mL): 1.4 (1.3–1.5)\nTotal number of sperm (106 per ejaculate): 39 (35–40)\nThe motility (%) 42 (40–43)\nProgression of motility (%) 30 (29–31)\nMotility that does not advance (%) 1 (1–1)\nImmobile sperm (%) 20 (19–20)\nEnergy (%) 54 (50–56)\nStander forms (%) (3.9–4)\n2.3  Infertility treatment\nInfertility treatment is dependent on understanding the \ncausing of infertility, the time which couple spent with \ninfertility, the age of partners. Certain infertility causes \nare unfixable. Couples can frequently still conceive \neven when a spontaneous pregnancy does not occur \nby using assisted reproductive technology. Treatment \nfor infertility may require tremendous time, effort, and \nfinancial obligations [24].\n2.3.1  Medical treatment of infertility\nAmong the drugs used by both men and women include \ngonadotropins, follicle-stimulating hormone (FSH), \nhuman chorionic gonadotropin (hCG), gonadotro -\npin-releasing hormone (GnRH) analogues, aromatase \ninhibitors, and metformin [24].\n2.3.1.1 Clomiphene citrate By stimulating the pitui -\ntary gland to generate more FSH and LH when taken \norally, this medication promotes ovulation by encourag -\ning the development of an ovarian follicle that contains \nan egg. In most cases, this is the first line of treatment \nfor women under the age of 39 without PCOS. Pitui -\ntary gland in the brain secretes more follicle-stimulat -\ning hormone (FSH) and LH when clomiphene is taken \n(luteinising hormone). This causes the ovarian follicle to \ndevelop more quickly, which starts the ovulation pro -\ncess [25]. Some side effects of Clomiphene include:\n• Flushing (extremely common)\n• “Mittelschmerz” (pain and heightened sensitivity \nassociated with ovulation)\n• blurred, double, or “traces” vision (a complication \nwhich may cause treatment to be discontinued)\n• Sadness (requiring discontinuation in severe cases)\n• Nausea\n• Breast sensitivity\n• Headache\n• Vaginal aridity\n• Clomiphene may have a negative effect on oestro -\ngen production in 20% of patients, which inhibits \nthe uterine lining from thickening at the proper \nperiod and causes greater sensitivity, commonly \nknown as “mittelschmerz” .\n• Double, fuzzy, or “traces” vision (a complication \nwhich may cause treatment to be discontinued) \nMoodiness (which, in extreme circumstances, \nrequires abstinence) (requiring discontinuation in \nsevere cases). Only one egg is ovulated during a \ntypical menstrual cycle. The ovaries frequently gen -\nerate two or three eggs per cycle when clomiphene \nis used. Clomiphene is taken orally for five days, \n\nPage 8 of 20Mansour  Beni-Suef Univ J Basic Appl Sci           (2023) 12:81 \nand only the month it is administered has any effect \n[25].\n2.3.1.2 Gonadotropins These intravenous therapies \nencourage the ovary to release many eggs. Human meno-\npausal gonadotropin, often known as HMG (Menopur), \nand FSH are examples of gonadotropin medicines. \nHuman chorionic gonadotropin (Ovidrel, Pregnyl), a \ndifferent gonadotropin, is used to develop the eggs and \ncause their release at the time of ovulation. There are \nworries that using gonadotropins increases the chance \nof conceiving multiples and having a baby too soon [26]. \nAs gonadotropins are the same as human pituitary FSH, \nadministering them to the body would stimulate the for -\nmation of ovarian follicles. The main method for increas-\ning fertility is to stimulate several follicles, which results \nin the production of numerous eggs [27]. FSH and lute -\ninising hormone (LH) cooperate to promote folliculogen-\nesis and ovulation in humans. They help ovarian output \nby controlled ovarian stimulation (COS). The quantity \nof oocytes created during IVF [28]. Medication for gon -\nadotropins is administered subcutaneously via injection \n(i.e. under the skin with a very small needle). A significant \nincrease in the expression of proapoptotic cell genes in the \nstratum granulosum layer is produced by supplementing \nwith highly purified human menopausal gonadotropin \n(HP-hMG), which contains hCG-driven LH bioactivity, \naccording to studies. This suggests that HP-hMG may \nplay a key role in the developmental competence of the \noocyte [ 29]. These medications cannot be given orally \nsince doing so would cause the digestive system to break \ndown the protein hormones. Gonadotropins are available \nas pre-mixed cartridges that fit into a self-injection device \nor as a powder that is mixed with sterile water. Once it is \nverified that a specific number of mature eggs have grown \nin the ovarian follicles, medication must be taken every \nday. We are aware that the idea of self-injection might be \nfrightening for many individuals. Nurses in fertility clin -\nics encourage patients to inject themselves with ovulation \nstimulants and pharmaceutical companies also offer edu -\ncational films for this matter [26]. Throughout the course \nof therapy, patients undergo routine ultrasound examina-\ntions to count and measure the size of egg follicles in each \novary and make sure the ovaries are receiving the right \namount of stimulation. Patients receive an injection of \nHCG (human chorionic gonadotropin), commonly known \nas Ovidrel, when it is determined that the follicles have \ngrown sufficiently and the eggs within should be mature. \nThis hormone starts ovulation, the release of the egg, and \nthe growth of the corpus luteum, both of which are nec -\nessary for progesterone production. Typically, ovulation \nhappens 38 to 44 h following the HCG injection [26, 30]. \nAccording to the Centres for Disease Control, there were \n32.3 twin births per 1000 live births, or 3% of all live births, \na high record. Since 1980, when the rate was 18.9 per 1000 \nlive births overall, there has been a 71% increase. Accord-\ning to the study, 43% of pregnancies resulted from assisted \nreproductive technologies, 38% from ovulation-inducing \nmedicines, and 20% from spontaneous conception. Better \npredictors of multiple gestations should be developed due \nto concerns about the obstetrical and neonatal dangers \nassociated with multiple pregnancy [31]. Among the via -\nble pregnancies that arise with gonadotropin-IUI, there is \na significant chance of high-order multiple birth (11.6%). \nThe risk would not be reduced to tolerable levels by stop-\nping cycles with increased estradiol levels (> 1200 pg/mL) \nor an excessive number of developing follicles (5) [32].\n2.3.2  Surgical treatment\n2.3.2.1 Male surgical Obstructive azoospermia (OA) \nis present in 20% of men who seek infertility treatment. \nAbout 40% of these individuals, or 21, have post-tes -\nticular obstruction, because the epididymis is bilaterally \nrestricted, as well as the seminal or ejaculatory ducts. In \npost-ejaculate urine and semen, OA is the absence of sper-\nmatozoa and spermatogenetic cells. FSH levels, testicular \nsize, and epididymal hypertrophy were all within normal \nlimits in men with OA. The vas deferens can occasionally \nbe missing due to birth defects or recent surgery. Anoma-\nlies of the ejaculatory, vassal, or epididymal ducts, prior \nvasectomy procedures, and OA are possible reasons [33].\n• Varicocele repair: In up to 35% of cases, varicocele \nis thought to be the cause of or a contributing fac -\ntor to male infertility or subfertility. The mechanisms \nunderlying the detrimental effects of varicocele on \nmale fertility are the subject of numerous hypoth -\neses. Hypoxia, stasis, raised testicular temperature, \nan increase in spermatic vein catecholamine causing \ntesticular underperfusion, and enhanced oxidative \nstress are some of the proposed mechanisms. Nev -\nertheless, none of them adequately explains the vari -\nable impact of varicocele on male fertility and human \nspermatogenesis. There is considerable controversy \nover the link between varicocele and infertility. The \nincidence of this illness is undoubtedly higher among \ninfertile males, though. Furthermore, there is a cor -\nrelation between varicocele and decreased testicular \nsize and semen characteristics, and improvements in \nsemen quality and pregnancy rates following varico -\ncelectomy provide compelling evidence of a cause-\nand-effect relationship. Notwithstanding these facts, \nit is still not apparent why most men with varicocele \nare still able to conceive and why their reproductive \n\nPage 9 of 20\nMansour  Beni-Suef Univ J Basic Appl Sci           (2023) 12:81 \n \nstatus does not always become better following ther -\napy [33].\n• Vasovasostomy: Up to 6% of male vasectomy patients \nare thought to eventually seek reversal surgery \n(Fig.  (6)). According to a review of the literature, a \nmicroscopic vasovasostomy produces better out -\ncomes than a macroscopic or loupe-magnification \nprocedure. After vasovasostomy, sperm return to the \nejaculate occurs without the use of ART, pregnancy \nis achieved in 70–95% of individuals. The interval \nin years between a vasectomy and a vasovasostomy \naffects the rate of sperm recovery and conception. \nAccording to Silber, males who had five years or less \nwith an obstruction increased the likelihood of pro -\nductive intervals. Despite being statistically insig -\nnificant, the pregnancy rate appeared to decline with \nblockage duration while the patency rate did not \nseem to change obviously. The rate of pregnancy is \nalso significantly influenced by the age of the female \nspouse [25].\n• Vasoepididymostomy: Candidates for vasoe -\npididymostomy should be patients who have epididy-\nmal blockage without any other anatomical anoma -\nlies. For the epididymal obstructive azoospermic \nmale, microscopic vasoepididymostomy is regarded \nas the best option. Many methods for effective anas -\ntomosis have been documented since the invention of \nmicrosurgical tools and suture material [33]. Patency \ncan be restored in 70–90% of people with microsur -\ngical treatments; however, only 50% of people have \ntheir fertility returned. Individual patient character -\nistics and intraoperative variables affected the surgi -\ncal success rate. Unilateral vasoepididymostomy has \na low success rate, but bilateral surgery is expected \nto up the overall patency rate. In comparison to \nthe caudal epididymis, In the caput epididymis, the \nepididymal tubules’ luminal widths are narrower. \nThe vasoepididymostomy site has been linked to the \npatency rate in various studies compared to the cau -\ndal epididymis, the caput epididymis has epididymal \ntubules with a smaller diameter. The caudal vasoe -\npididymostomy has a higher patency rate than the \ncaput. For vasoepididymostomy patients, sperm \ncollection and cryopreservation during surgery is \nadvised to prevent surgical and pregnancy failure. \nMen having vasoepididymostomy should have their \nsperm cryopreserved intraoperatively to increase \ntheir postoperative reproductive choices [25].\n• Sperm retrieval techniques in obstructive azoo -\nspermia (OA): In the case of congenital problems, \nsurgery can frequently open blocked tubes in the \ngenital system or create connections that never \nformed. The experts specialise in delicate proce -\ndures to safely and successfully restore your sperm \nflow if you have obstructive azoospermia. There is \nfrequently a backup plan if surgical reconstruction \nis not an option. The experts are able to remove \nsperm from the:\n• Testis\n• Epididymis, the nearby tube where sperm develop.\n• Vas deferens, the tube that transports sperm from \nthat location. With the patient, the experts will \nthoroughly go through the possibilities and assist \nin making a choice. If surgery is an option, there \nare two kinds: endoscopic surgery and microsur -\ngery.\n• Microsurgery: is a time-tested method with a \nrich history. The specialists have specialised fel -\nlowship training, which entails studying for a \nfurther year to specialise in this treatment, to \nperform it. Prior to surgery general anaesthetic \nwill used to sleep totally. The patient’s scrotum \nis cut in a minor incision by the physician. Then \ncarefully removes the obstruction or replaces \nthe lost connection, then meticulously stitches \nup the wound using powerful magnification and \nspecialised tools. Use microsurgery to fix issues \nwith the vas deferens and the epididymis.\n• Endoscopic surgery: Uses a tiny incision and is a \nminimally invasive procedure. Prior to surgery\n• general anaesthesia is used to put someone to \nsleep entirely and local anaesthetic is added for \ncomfort.\n• The surgeon guides themselves by viewing the \nsurgical site through a special scope (extremely \nthin, flexible tube equipped with a camera, light, \nand magnification). The urethra is carefully \nthreaded with the scope, preventing the need for \nan incision. Carefully remove the obstruction. \nProblems in the ejaculatory duct, the tube from \nwhich sperm escape into the urethra and com -\nbine with fluid to produce semen, are fixed with \nendoscopic surgery [34].\n• Surgically removing an epididymal obstruction \nand retrieving sperm: sometimes the epididymis \ngets clogged, which interferes with proper \nsperm ejaculation. If this is the root of the prob -\nlem with infertility, the blockage can be removed \nsurgically. The option of sperm extraction via \nsurgery if:\n• Possess a blockage that prevents sperm from \nescaping\n• Being born missing the tube that removes sperm \nfrom a testicle (vas deferens)\n\nPage 10 of 20Mansour  Beni-Suef Univ J Basic Appl Sci           (2023) 12:81 \n• Have undergone a vasectomy or a vasectomy \nreversal that failed\n• Both treatments are performed as outpatient \nprocedures under local anaesthesia and last a \nfew hours [25].\n2.3.2.2 Female surgical There are various surgical \ntechniques that can be utilised to examine reproduc -\ntive issues and support fallopian tube surgery. You could \nrequire surgery to have your fallopian tubes repaired if \nthey are scarred or clogged. Your fallopian tubes’ scar \ntissue can be removed surgically to make it simpler for \neggs to travel through. The degree of your fallopian \ntubes’ damage will determine how successfully the pro -\ncedure goes. Ectopic pregnancy, which happens when \nthe fertilised egg implants outside the uterus, is one of \nthe potential negative effects of tubal ligation. PCOS, \nfibroids, and endometriosis are the condition in which \nsome of the womb lining begins to protrude outside the \nuterus. Cysts, which are fluid-filled sacs, are frequently \nremoved or destroyed during laparoscopic surgery to \ntreat endometriosis. Submucosal fibroids, which are tiny \ngrowths in the uterus, may also be removed using it. If \novulation medication has not been successful for PCOS \npatients, a quick surgical technique termed laparoscopic \novarian drilling may be utilised. This entails vaporising a \nportion of the ovary with heat or a laser [35].\n• Fimbrioplasty: It is carried out to cure fimbrial phi -\nmosis, which is a partial occlusion of the fallopian \ntube’s distal end. Although the tube is patent, sticky \nbands around the terminal end. Usually, the tube’s \nlongitudinal folds are still present. The peritoneal \nadhesive bands that encircle the fimbria are cut \napart during a fimbrioplasty. Stretching the tube \nand releasing modest degrees of fimbrial agglutina -\ntion are accomplished by gently inserting an alli -\ngator laparoscopic forceps into the tubal ostium, \nopening the forceps, and then removing them. Fol -\nlowing laparoscopic fimbrioplasty, after two years \nof follow-up the rate of ectopic pregnancy was \n23%, the rate of live births was 37%, and the rate \nof intrauterine pregnancy was 51%. The pregnancy \nand fecundity rates after laparoscopic fimbrioplasty \nwere 40 and 4 per cent, respectively, compared to \n56 and 16 per cent after salpingostomy, according \nto another study that found identical outcomes \nafter either procedure. Ectopic pregnancy rates \nwere generally around 5%. Salpingostomy results \nappear to be similar to those of fimbrioplasty. The \nlatter approach produces tubules that are more \nnormally shaped [35].\n• Terminal salpingostomy: To treat the hydrosalpinx-\nrelated tubal blockage, a terminal salpingostomy \nis performed. The effectiveness of treatments to \nincrease fertility is typically low, but it also depends \non factors including ampullary dilatation, the exist -\nence of mucosal folds, the proportion of ciliated cells \nin the fimbrial end, and peritubal adhesions. After \nsalpingostomy, there is a 30% average pregnancy rate \nand a 5% ectopic pregnancy rate. However, the likeli -\nhood of pregnancy can range from 0% in cases where \nthe tube is rigid and thick without rugae to 80% in \ncases where tubal damage is absent or limited as \ndetermined by a hysterosalpingogram, salpingoscopy, \nor surgical inspection [36].\n• Fallopian tube surgery: You might require surgery to \ntreat obstructed or scarred fallopian tubes. In order \nto facilitate egg passage through fallopian tubes, scar \ntissue might be removed surgically. The degree of the \nfallopian tube damage will determine whether the \nprocedure is successful. An ectopic pregnancy, in \nwhich the zygote implants outside the uterus, is one \nof the potential negative effects of tubal ligation [37].\n• Endometriosis: Endometriosis is the condition in \nwhich some of the womb lining begins to protrude \noutside the uterus. Cysts, which are fluid-filled \nsacs, are frequently removed or destroyed during \nlaparoscopic surgery to treat endometriosis. Sub -\nmucosal fibroids, which are tiny growths in the \nuterus, may also be removed using it. If ovulation \nmedication does not work for polycystic ovary syn -\ndrome (PCOS), a quick surgical technique called \nlaparoscopic ovarian drilling may be utilised. In \norder to do this, a portion of the ovary must be \ndestroyed using heat or a laser. When endometrio -\nsis is identified during a laparoscopy, surgical endo -\nmetriosis therapy is frequently carried out. By an \nincision just below the navel, a lighted telescope is \ninserted to observe the pelvic cavity during a lapa -\nroscopy operation. The doctor may remove ovarian \ncysts, endometriosis nodules, and adhesions dur -\ning laparoscopy. While treating recurring endo -\nmetriosis with the intention of protecting future \nfertility, laparoscopy is frequently employed [38]. \nEndometriosis can occasionally be so severe that \nextensive surgery is necessary to remove both the \nendometriosis and adhesions. The excision of the \ncomplete ovarian cyst with its wall is preferable to \njust emptying the endometriotic cyst for relieving \npain and preventing recurring cysts. After child -\nbearing is finished, hysterectomy (removal of the \nuterus) along with ovarian removal can be used \nto effectively treat endometriosis. More than 90% \nof women experience complete pain relief from \n\nPage 11 of 20\nMansour  Beni-Suef Univ J Basic Appl Sci           (2023) 12:81 \n \nendometriosis following this surgery. There may be \na higher likelihood that the symptoms may return \nand that additional surgery would be necessary if \none or both ovaries are maintained. After the ova -\nries are removed during a hysterectomy, hot flashes \nand other menopausal symptoms can be lessened if \nlow-dose hormone treatment (oestrogens or pro -\ngestins) is used [38].\n2.4  Reproductive assistance\n2.4.1  Artificial insemination (In vitro fertilisation, IVF)\nIs the fusing together in a laboratory dish of a woman’s \noocyte and a man’s sperm. Zygote mature in  vivo and \nembryos give rise to pregnancy in the uterus; however, \nthe phrase “in vitro” refers to outside of a living crea -\nture [39]. IVF may be the best option for women whose \nfirst-line reproductive treatments have failed. It was \ninitially created for women whose fallopian tubes were \nnot functioning due to tubal factor infertility [40– 42]. \nThe following are some typical cases of female infertil -\nity where artificial insemination may be a reasonable \noption:\n• Endometriosis,\n• Infertility brought on by ageing,\n• Irregular menstrual cycle,\n• Genetic disease risk,\n• Unknown infertility,\n• male partner enable to produce any sperm,\n• Non-functional fallopian tube\n• Bilateral tubal ligation of women,\n• Anti-sperm antibodies,\n• Females who experienced three failed attempts at \nconception.\n• Less ovarian function (it suggests that women of \nreproductive age have fewer oocytes of lower quality \nand number) [43].\n- Typical female infertility scenarios where assisted repro-\nductive techniques (ART) may be a viable option include: \nIVF and intrauterine insemination (IUI) are advised in \ncases of male infertility, idiopathic infertility, or when \nthere are considerable aberrant sperm parameters but \nsome normal spermatozoa. In the majority of cases, preg-\nnancy rates rise to between 40 and 50% following. When \nthe sperm are dead (a positive result on the sperm viabil -\nity staining or hypoosmotic swelling test), intrauterine \ninsemination procedures should not be employed. IVF \nwith ICSI should be utilised instead, according to abnor -\nmal functional sperm tests (such capacitation, acrosomal \nresponse, and sperm penetration assays) [44, 45].\n2.4.1.1 IVF technique  \n• Stimulation of the ovaries under control: Ovar -\nian stimulation is the first step in the IVF process. \nThere have been a variety of protocols used, from \nno stimulation to varied degrees of ovarian stimu -\nlation utilising letrozole, clomiphene citrate, and \nexogenous gonadotropins (FSH and LH). In gon -\nadotropin-releasing hormone (GnRH) analogues, \nthe woman’s LH surge is inhibited throughout \nIVF cycles, allowing the medical staff to time egg \nretrieval. Blood levels of E2 can detect any neces -\nsary changes to the stimulation regimen, while \ntransvaginal ultrasonography tracks follicle devel -\nopment [46]. When using a natural cycle for IVF, \nthe egg is removed before the mid-cycle LH surge \nor the release of LH is prevented by using a GnRH \nantagonist (GnRHant). The LH surge is replaced \nwith hCG once the primary follicle reaches its \nmature size. The cycle-to-cycle pregnancy rate is \nroughly 8% since the annualised pregnancy rate is \n21% after three cycles and can reach 44% in couples \nwho suffer with male factor infertility. IVF cycles \ninitiated voluntarily are less common because of \nthe lower clinical pregnancy rate [47]. The vast \nmajority of IVF treatments harvest 10–20 oocytes \nwith ovarian stimulation. There are two primary \nmethods: a GnRHant cycle or a prolonged luteal \nGnRH agonist (GnRHa) cycle. Beginning on cycle \nday 21 of the previous month, the extended luteal \nGnRHa regimen entails daily administration of \n0.1 mg of GnRHa. The pituitary consequently stops \nsecreting LH (and FSH) during ovarian stimulation, \nand the GnRHa is maintained until the injection \nof hCG. Starting on cycle day 2, gonadotropins are \nprovided at doses ranging from 75 to 450 IU daily. \nDose modifications are made in response to fol -\nlicular development and estradiol levels. Three or \nmore follicles must be at least 18 mm in size before \nthe hCG injection is given. Gonadotropins (75 to \n450  IU) must be given daily starting on cycle day \n2 or 3 according to the GnRHant protocol. When \nthe lead follicle diameter reaches 14 mm or on the \nsixth day of ovarian stimulation, the GnRHant is \ninitiated to suppress the natural LH surge. 18 mm \nhCG is injected once three or more follicles have \ndeveloped [46]. With or without gonadotropins, the \nbare minimum stimulation protocol uses the selec -\ntive oestrogen receptor modulator (SERM) clomi -\nphene citrate or the aromatase inhibitor letrozole. \nThe pair will pay less or nothing when gonadotro -\npin stimulation is minimised. The percentage of live \nbirths is slightly lower (49% vs. 63% vs. extended \n\nPage 12 of 20Mansour  Beni-Suef Univ J Basic Appl Sci           (2023) 12:81 \nGnRHa method) with the lowest stimulation regi -\nmen, but multiple pregnancies and ovarian hyper -\nstimulation syndrome are far less prevalent [48, 49].\n• Oocyte retrieval: 34 to 36  h after hCG treatment, \nmature oocytes are recovered, regardless of the \nstimulation regimen. Using intravenous sedation \nand ultrasound-guided transvaginal aspiration, \noocyte retrieval is carried out. The ovaries are exam -\nined using a vaginal ultrasonography probe, and the \naccompanying needle guide helps the physician pre -\ncisely place the needle into each follicle to aspirate \nthe oocyte and follicular fluid [46].\n• Embryo fertilisation: The oocytes are fertilised using \neither insemination or ICSI. To prepare the semen \nsample, the sperm are separated by density centrifu -\ngation and washed in high protein media to encour -\nage capacitation, which is a necessary step for sperm \nto become fertile. An oocyte is incubated with fifty \nto one hundred thousand sperm for 12 to 18 h. ICSI, \nin which one immobilised oocyte is directly injected \nby sperm, may be necessary for male factor infertility. \nAs a result, there is no requirement for the sperm to \nenter the zona pellucida, a glycoprotein matrix that \nencloses the oocyte [46].\n• Embryo transfer: Embryos that have undergone fer -\ntilisation are implanted either during the blastocyst \nstage (5 days after fertilisation) or the cleavage phase \n(3  days after fertilisation). Since fewer embryos are \nrequired to accomplish the blastocyst stage transfer, \nit increases the number of live births per cycle and \ndecreases the number of multiple gestations [50]. \nThe disadvantage of transferring embryos at the \nblastocyst stage is that there may be fewer embryos \navailable for transfer due to the loss of embryos that \ndid not survive in culture until day 5. Embryos are \ntransplanted into the uterus via a catheter inserted \nthrough the cervix under transabdominal ultrasound \nguidance. The embryos are separated from the uter -\nine fundus by 1 to 2 cm. To ensure that each embryo \nwas successfully implanted in the uterus and that \nnone were left in the catheter following the transfer, \nthe catheter is checked under a microscope. How \nmany embryos are transferred depends on several \nfactors, including patient preference, maternal age, \nembryo quality, and stage. More than two blastocysts \nshould not be transferred into women under the age \nof 37, three blastocysts should not be transferred into \nwomen between the ages of 38 and 40, and four or \nmore should not be transferred into women between \nthe ages of 41 and 42, according to the American \nSociety for Reproductive Medicine [46]. More cleav -\nage stage embryos may be transferred due to the \nlower chance of successful implantation; however, \nthe maximum number of embryos that may be trans-\nferred is two for women under the age of 35, three for \nthose between the ages of 35 and 37, four for those \nbetween the ages of 38 and 40, and five or fewer \nfor those between the ages of 41 and 42. Progester -\none supplementation is started on the day of oocyte \nretrieval or embryo transfer in order to maximise \nembryo implantation and a continuous pregnancy. \nCryopreserved extra healthy embryos are kept for \nfuture use [46].\n• Chances of success: The age of the woman receiving \ntreatment and the underlying cause of her infertility \nboth affect the likelihood that IVF will be success -\nful. A successful pregnancy is more likely to occur \nin younger women. IVF is typically not advised for \nwomen beyond the age of 42 since it is believed that \nthe likelihood of a successful pregnancy is very low. \nThe proportion of IVF procedures that resulted in a \nlive birth in 2019 was:\n• Women under 35 (32%)\n• Women aged 35 to 37 (25%)\n• Women aged 38 to 39 (19%)\n• Women aged 40 to 42 (11%)\n• Women aged 43 to 44 (5%)\n• Women aged over 44 (4%) [51].\n2.4.2  Donation\nTo assist intended parents in becoming parents, gam -\nete and embryo donation involves using their own eggs, \nsperm, or embryos. The word “intended parent” refers \nto the people who will raise the kids. A woman (donor) \ndonates her eggs to a different woman (receiver) so that \nthe recipient can have a child. A male can help a person \nor a couple have a child by donating his sperm through \nthe process of sperm donation. Sperm are released after \nejaculation and are found in the fluid called semen. Intra-\nuterine insemination, which involves injecting donated \nsperm into a woman’s reproductive system, and labo -\nratory fertilisation of mature eggs both employ donor \nsperm (in vitro fertilisation). Third-party reproduction \nrefers to the use of donated sperm.\n2.4.2.1 Egg donation uses in \n• Couples who desire to have a biological child using \nthe male’s sperm but the woman has low quality or \nno eggs,\n• Ladies with an intact uterus but no ovaries,\n• Females who do not want to impart genetic traits to \ntheir offspring,\n• Females age over 42.\n\nPage 13 of 20\nMansour  Beni-Suef Univ J Basic Appl Sci           (2023) 12:81 \n \n2.4.2.2 Egg donation process The egg donor receives \nhormone injections to promote lot of eggs ovulation. In \naddition to the one egg that women naturally generate \neach month, the injections enable many eggs to mature at \nsimultaneously. When her eggs are mature and ready to \nbe removed, her fertility specialist plans the surgery. The \negg donor is given a sedative before an ultrasound-guided \nneedle is used to puncture each mature follicle and collect \nan egg. Several eggs will be fertilised in a laboratory using \nthe recipient’s partner’s sperm or a chosen donor’s sperm. \nThe method in question is in  vitro fertilisation (IVF). \nAfterwards, an embryo is implanted into the recipient’s \nuterus (fertilised egg).\n2.4.2.3 Sperm donor screening There is no foolproof way \nto ensure that DI will not spread infectious diseases. How-\never, the following suggestions should significantly reduce \nthese dangers, along with accurate information of the \ndonor’s background and the specific exclusion of those \nwith a high risk of HIV and other STIs. Medical back -\nground: Consult the “Donor Eligibility Medical Question-\nnaire” list. Performing a “FDA Donor Eligibility Physical \nExam” to assess physical health. Perform the laboratory \ntest outlined under “FDA Donor Eligibility Laboratory \nTesting” within 7 days of semen production [52, 53].\n2.4.2.4 Selection of sperm donors An assurance of excel-\nlent health and typical results from a semen analysis is \ngiven to a donor. The simplest requirements for normal \nsemen quality can typically be employed, despite the \nfact that there are no globally accepted norms. B genetic \nanalysis: The donor should undergo the requisite genetic \ntesting, as is covered in the section of this document on \ngenetic counselling. The donor should be of legal adult \nage in their state and young enough to minimise risks to \nthe offspring associated with a high paternal age, such as \nautism, ideally R21 year donors [54].\n2.4.2.5 Donor screening for  oocytes There is no way \nto completely stop pathogenic viruses from spreading \nthrough donor oocytes. These dangers should be signifi -\ncantly reduced by the donor’s history and the targeted \nexclusion of persons with a high risk of obtaining HIV and \nother STIs. Performing a “FDA Donor Eligibility Physical \nExam” to assess physical health. For details on medical \nhistory and “FDA Donor Eligibility Laboratory Testing” \nwithin 30 days of or up to 7 days after acquisition labora -\ntory testing, consult the “FDA Donor Eligibility Medical \nQuestionnaire” list [52, 53].\n2.4.2.6 Donor selection for  oocytes Oocyte donors \nshould be between the ages of 21 and 34, and they must \nbe of legal drinking age in their state. Donors who are \n34  years of age should reveal their age to the recipient \nduring the discussion regarding cytogenetic risks and the \neffect of donor age on pregnancy rates. Donors must be \nin good health and have no past illnesses that might be \ninherited. Proven fertility in the donor is preferable but \nnot required. Pelvic ultrasonography is suggested for \nassessing the anatomy of the pelvis, including the ovaries, \nand counting the number of antral follicles. To predict \nthe response to oocyte stimulation, additional testing of \nserum ovarian reserve indicators is necessary. All donors \nshould get a psychoeducational evaluation and counsel -\nling from a licenced mental health practitioner. The donor \nshould go through the proper genetic testing [53].\n2.4.2.7 Ethical considerations and  potential emotional \nimplications associated with  third‑party reproduc ‑\ntion Gene relatedness is less significant than the quality \nof the parent–child bond, according to the general con -\nclusion reached by children and families who benefit from \ngamete donation. However, for some people, finding the \ndonor and other “donor relations” does seem to be signifi-\ncant. This leads to a paradox where genetic relatedness is \npresumed to be significant for the link to the donor and \n“donor siblings” but negligible for parent–child ties and \nchild adjustment. It stands to reason that views on the rel-\native (in)importance of genetic relatedness have evolved \nover time. A vital part of identification that children have \na right to understand, whether for moral, psychological, \nor medical reasons, is the genetic link between a child \nborn through donor conception and their donor. This \nrelationship was formerly regarded to be “best forgotten” , \nbut it is now being highlighted as a crucial aspect of iden-\ntity. The genetic link between a child and their donor is \nmade more relevant by donor identification techniques \nalone. These “genetic” relationships have societal mean -\ning, much to how people who share a donor are referred \nto as “half siblings” . This approach has implications for \nboth empirical research and ethical discussions in terms \nof how questions concerning gamete donation and infor -\nmation sharing are phrased. How much weight is given to \nthe complex genetic links involved is also influenced by \nthe rules governing donor conception [55, 56].\n2.4.3  Intrauterine insemination (IUI)\nFor patients with ovulatory problems, unexplained infer -\ntility, cervical or male factor infertility, a handful of clin -\nics use therapeutic intrauterine insemination (IUI) using \npartner spermatozoa as a first line of treatment [57]. It is \na reproductive technique used by couples who have tried \nunsuccessfully to conceive for at least a year. With an IUI \nprocedure, sperm is injected into a woman’s uterus to \naid with fertilisation (the joining of the sperm and egg). \nCohen [58] is the first paper on intrauterine insemination \n\nPage 14 of 20Mansour  Beni-Suef Univ J Basic Appl Sci           (2023) 12:81 \n(IUI) which was published. Since then, sperm prepara -\ntion, timing monitoring for pre-ovulatory periods, and \nhCG-induced ovulation (hCG) have all contributed to \nadvancements in IUI. Additionally, IUI has been used \nwith ovarian stimulation using clomiphene citrate (CC) \nor gonadotrophins. Despite not having the designation \nof an ART, it is regularly used, frequently as an empirical \ntreatment, for a variety of infertile indications [59]. The \npurpose of IUI is to increase the quantity of sperm that \nenters the fallopian tubes, hence raising the possibility \nof conception. IUI gives the sperm a head start, giving it \nan advantage, but a sperm still needs to travel indepen -\ndently to the egg and fertilise it. Comparatively speak -\ning to in vitro fertilisation, it is a less invasive and more \naffordable choice. Low sperm count or reduced sperm \nmotility is the most frequent causes of IUI. However, any \nof the following conditions may also be treated with IUI, \nincluding infertility:\n• Females have pelvic infections,\n• Cervical mucus problems,\n• Cervical scar tissue from previous surgeries that \nmight prevent sperm from entering the uterus\n• Endometriosis,\n• Dysfunction of ejaculation,\n• IUI is not recommended for the following patients,\n• The presence of the fallopian tubes disease,\n• Unknown infertility.\n2.4.3.1 Procedures and insemination methods \n• Ovarian stimulation: On cycle days three through \nseven, the women received either 50 or 100  mg of \nclomiphene citrate. Following that, they received \ndaily doses of 1–2 ampoules (75–150  IU) of HMG. \nOn cycle days 9 to 13, vaginal ultrasonography \nwas used to assess the ovarian and endometrial \nresponses. When at least one follicle had a mean \ndiameter of.16 mm, HCG (Pregnyl; Organon or Pro -\nfasi; Serono) in the dosage range of 5000–10,000 IU \nwas administered. The standard IUI procedure was \ncarried out 36 h following the HCG injection.\n• Semen preparation: At the clinic, your partner’s \nsperm is harvested. The low-quality sperm are sepa -\nrated from the sample of sperm by washing, which \nkeeps only the best sperm that appear normal and are \nvery active. If a concentrated sample of healthy sperm \nis used, the likelihood of conception is increased. You \nwill be watched for ovulation symptoms (release of \nan egg). In order to stimulate the ovaries, increase \negg production, and increase your chances of getting \npregnant, doctors may also advise you to take medi -\ncation. Usually, IUIs are carried out a day or two after \novulation has been detected. The sperm suspension \nmay be placed in the Fallopian tube, uterus, perito -\nneum, or cervix. The method that is applied most \nfrequently is IUI. Typically without the use of imag -\ning guidance, a small catheter is utilised to transfer \na sperm solution containing between 0.2 and 0.5 ml \ninto the uterus. With a 4  ml inseminate with Fallo -\npian tube sperm perfusion (FSP), the inseminate has \nthe potential to partially or completely fill the perito -\nneal cavity in addition to the uterine cavity and Fal -\nlopian tubes [60]. For frozen semen, IUI is preferable \nto intracervical insemination (ICI) since, after six \ninsemination cycles, it raises the likelihood of a live \ndelivery by two (OR 1.98; 95% CI 1.02–3.86) [61]. \nFSP outperformed IUI in two investigations includ -\ning patients with unexplained infertility. There is not \nenough evidence to say that FSP is any better than \nIUI for other indicators [62, 63].\n• Timing of insemination: It is possible to inseminate \nonce, several times, or not at all in the days leading \nup to the ovulation. The vast majority of published \nstudies use insemination 32–36  h following hCG \ntherapy. Given that it is widely believed that timing \ninsemination in relation to ovulation is important for \nan optimum success rate, it is really surprising that \nso little study has been done to find the appropriate \ntime for insemination [64]. A thorough review found \nno variation in pregnancy rates per couple with two \ninseminations compared to one [63].\n• Procedure: A hormone called human gonadotro -\npin hormone is administered during the process to \nrelease the eggs. With a catheter, your doctor admin-\nisters the sample of semen directly into the uterus \n(long tube). You will be need to stay on your back for \na short while after the treatment. The entire treat -\nment takes little time and may only cause little dis -\ncomfort.\n2.4.3.2 Risks \n• Infection: There is a very small chance that the sur -\ngery will result in an infection.\n• Spotting: Sometimes a little vaginal bleeding occurs \nas a result of inserting the catheter in the uterus. \nUsually, this has no impact on a woman’s odds of get-\nting pregnant.\n• Multiple pregnancy: IUI by itself does not put \nwomen at a higher risk of having twins, triplets, or \nmore pregnancies. However, there is a considerable \nincrease in the likelihood of multiple pregnancies \nwhen used in conjunction with ovulation-inducing \n\nPage 15 of 20\nMansour  Beni-Suef Univ J Basic Appl Sci           (2023) 12:81 \n \ndrugs. Premature labour and low birth weight are \ntwo risks that are higher for multiple pregnancies \nthan for single pregnancies\n2.4.3.3 Chances of  success with  IUI This relies on a \nvariety of factors, including:\n• Infertility causes,\n• Females age,\n• The quantity and calibre of the man’s sperm (using \nfresh sperm leads to higher conception rates than \nusing frozen sperm)\n• Fertility medicines. It is best to discuss your unique \npossibilities of success with your fertility team \nbecause there are many various elements at play. \nIUI is a straightforward, low-tech process that has \nthe potential to be less expensive than other forms \nof fertility therapy. Although it increases your \nchances of getting pregnant, IUI is not guaran -\nteed to be successful because each person’s body is \nunique.\n2.4.3.4 Results Before performing a home pregnancy \ntest, wait two weeks. Testing too soon could result in the \nfollowing outcome:\n• False-negative: The test result may be negative even \nthough you are actually pregnant if pregnancy hor -\nmones have not yet reached detectable levels.\n• False-positive: The chemical that remains in your sys-\ntem after taking an ovulation-inducing medication, \nsuch as HCG, may signify pregnancy even if you are \nnot pregnant. A blood test, which is more sensitive \nin identifying pregnancy hormones after fertilisa -\ntion, may be recommended by your doctor a couple \nof weeks following the findings of your at-home kit. \nIf IUI does not work, you might try it again before \ntrying any other reproductive treatments. The same \ntherapy is usually given for three to six months to \nboost the likelihood of conception.\n• 4–4 Intracytoplasmic sperm injection (ICSI): Infertil -\nity in couples who were unable to conceive naturally \nwith subzonal insemination of the oocytes or normal \nin  vitro fertilisation (TVF) has recently been docu -\nmented as being aided by intracytoplasmic sperm \ninjection (ICSI) [65]. A single live sperm is injected \ninto the core of a human egg. The majority of these \ninfertile couples experienced severe male factor \ninfertility, and the ejaculate’s motile sperm count \nwas occasionally insufficient for the couples to be \naccepted into an IVF programme.\n2.4.3.5 Mechanism of ICSI IVF allows for both standard \nand ICSI fertilisation of an egg. In a laboratory dish, the \negg is placed close to 50,000 or more swimming sperm \nduring classical IVF. When one of the sperm enters the \ncytoplasm of the egg, fertilisation takes place. In the ICSI \nprocedure, a single sperm is injected into the centre of the \negg using a tiny needle called a micropipette. After ferti -\nlisation, whether via traditional IVF or ICSI, the fertilised \negg (now known as an embryo) develops in a laboratory \nfor one to five days before being implanted into the wom-\nan’s uterus (womb).\n- ICSI aids in overcoming issues with fertility such as:\n• Regardless of the sperm’s health, traditional IVF has \nnot been able to successfully fertilise eggs,\n• The sperm may experience difficulties affixing to the \negg,\n• Male reproductive tract blockage,\n• Low sperm count to perform IVF or IUI,\n• The eggs are in vitro matured,\n• Eggs that had previously been frozen are used.\n2.4.3.6 Procedure \n• Sperm collection: If masturbation is not an option for \nsperm acquisition, they are surgically retrieved from \na testis by making a small incision. When sperm can -\nnot be expelled from the ejaculate or when there is \na difficulty with sperm development, this treatment \nmay be used. Doctors advise men who have few or \nno sperm in their semen (not because of a blockage) \nto seek genetic testing to search for issues that could \nharm their offspring before beginning ICSI.\n• Ovulation and egg retrieval: To prepare for a ther -\napy utilising your own eggs, you must receive daily \nshots and spend the two weeks prior to the egg col -\nlection under strict surveillance. The multiple egg \nproduction in your ovaries is stimulated by partners \nadministering gonadotropin or follicle-stimulating \nhormone (FSH) injections at home. Superovulation \nis the term for this. Your doctor will monitor your \nblood oestrogen levels after the first week and use \nultrasound to evaluate whether eggs are developing \nin the follicles. Your dosage may change during the \nsecond week in accordance with the outcomes of \ntests and ultrasounds. If the follicles have reached full \ndevelopment, an injection of human chorionic gon -\nadotropin (hCG) is given to promote the maturity of \nthe follicles. The developed eggs must be harvested \nafter 34 to 36 h.\n• Sperm injection and transfer: An egg is held in posi -\ntion using a glass object. One sperm is inserted into \n\nPage 16 of 20Mansour  Beni-Suef Univ J Basic Appl Sci           (2023) 12:81 \nthe egg via a thin glass tube. Eggs are examined to \nsee if they have been fertilised after being cultured \nin the laboratory for an entire night. The eggs that \nhave undergone successful fertilisation or have had \nthree to five days to continue developing are cho -\nsen after incubation. A small, flexible tube (cath -\neter) is introduced into the cervix to deliver one or \nmore to the uterus. Based on your age and other \nfactors about you, your doctor will advise on the \nrecommended number of embryos to transfer. The \nremaining embryos could be preserved for later use \n[66].\n• The most often studied oocyte morphologies \ninclude the meiotic spindle, CC, ZP , PS, vacuoles \nor refractile entities, form, granulation, and viscos -\nity of cytoplasm. Which of these forms is ideal for \noocyte selection is a topic of continuing discus -\nsion. Based on numerous morphological investiga -\ntions, it seems plausible to identify oocytes with \na higher probability for growing into competent \nearly embryos. If there are no restrictions, such as \nthe patient’s age, the quantity of harvested oocytes, \nor previous ART failures, the oocytes with clear or \nmoderately granular cytoplasm, narrow PS, PB in \nan intact appearance, normally appearing meiotic \nspindles and CC, and colourless and birefringent \nZP should be selected for the initial ART applica -\ntion. It is noteworthy that in order to assess these \nmorphological criteria, many ART facilities are \nrequired to take part in a sizable sample of homo -\ngeneous cases. To more accurately predict the \noocytes of high quality, advanced technologies like \ngenomes, transcriptomics, proteomics, and metab -\nolomics can be used in conjunction with morpho -\nlogical studies [67].\n• Another frequently used method in the treat -\nment of infertility is the selection of competent \nembryos, which helps to improve success rates and \ndecrease the likelihood of multiple pregnancies. \nThe embryos created by IVF or ICSI can be chosen \nbased on their physical features and, in rare circum -\nstances, preimplantation genetic testing for ane -\nuploidy analysis if acquiring oocytes for fertilisation \nis not restricted. Evaluations of the early embryos \nusing morphokinetic, metabolomic, proteomic, \nepigenetic, and genomic data are also being taken \ninto consideration in order to choose the best early \nembryos. The morphological criterion for identify -\ning competent oocytes might be used even when its \ntherapeutic usefulness is less than expected when \na case only produces a small number of oocytes \nbecause of poor reproductive features or regulatory \nlimits [68].\n2.4.3.7 Result ICSI is frequently successful when \npaired with in vitro fertilisation and eggs of high qual -\nity for men who have inadequate or no sperm in the \nejaculate. ICSI, which takes sperm from the testicles, is \nthought to be the cause of 25–30% of pregnancies.\n2.4.3.8 Risks  \n• The same risks for in vitro fertilisation,\n• Ovarian hyperstimulation can caused by Superovu -\nlation,\n• The embryos number implanted in a female uterus \nhas a direct correlation with her risk of conceiving \nmultiples. High-risk pregnancies include multiple \nbirths for both the mother and her foetuses.\n2.4.4  Nanotechnology as a treatment of infertility\nNanotechnology has changed human infertility treat -\nments because pregnancy rates after ART increased \nfrom 6 to 35% during the last four decades [66]. By \nincluding antioxidants, small compounds, and growth \nfactors into the culture medium, it has been shown that \nbettering in vitro culture conditions can enhance gam -\nete/embryo survival and developmental potential [68]. \nTraditional medication delivery and tissue engineering \nboth use nanotechnology [69]. It provides the oppor -\ntunity to create tools specifically designed to enhance \nin  vitro growing systems. From 1 to 100  nm in size, \nnanomaterials are composed of rather large surfaces. \nBecause of their large loading capacity, stability, and \nselective affinities, they may be a helpful method for \ndelivering drugs into gametes and embryos [68].\n2.4.4.1 Male infertility and  nanotechnology The use \nof nanoparticles has improved sperm selection, semen \nsexing, and cryopreservation in a number of farm ani -\nmal species [70– 72]. It is critical to stress that a nano -\nparticle’s size, surface volume, composition, shape, and \nsurface functionalisation are all crucial elements in \nhow effective they are when exposed to sperm [73– 75]. \nAnother method that could boost male fertility is the \nuse of magnetic iron oxide nanoparticles [76].\n• Semen quality is improved by separating damaged \nsperm cells from semen using a specific aptamer \npaired with superparamagnetic nanoparticles. Also, \nthe removal of apoptosis and acrosome-reacted \nspermatozoa by conjugating magnetic nanoparti -\ncles with annexin or lectins was successful [77].\n\nPage 17 of 20\nMansour  Beni-Suef Univ J Basic Appl Sci           (2023) 12:81 \n \n• Silver nanoparticles in pig sperm function as an anti -\nbacterial agent for semen preservation and storage, \nproviding an alternative to using antibiotics [78].\n• Sperm structure, including membrane integrity and \nmitochondrial activity, are positively impacted by \nzinc inclusion nanoparticles in the semen extender. \nThese factors preserve ATP , which is necessary for \nsperm functioning, viability, acrosome reaction, and \nmovement needed to reach and pierce the egg [79, \n80].\n• Cryopreserved semen’s sperm quality can be \nimproved using nanoparticle-based techniques. \nCerium oxide  (CeO2), zinc oxide (ZnO), and sele -\nnium nanoparticles, for example, showed that by \nreducing ROS formation and membrane lipid peroxi-\ndation, they may maintain the viability and motility \nof spermatozoa when added to freezing solutions [70, \n80]. Timing is crucial since prolonged exposure to sil-\nver nanoparticles in human sperm led to DNA dam -\nage, structural flaws, and an increase in ROS pro -\nduction. In addition, employing magnetic iron oxide \nnanoparticles may improve male fertility [66].\n2.4.4.2 Female infertility and nanotechnology \n• To speed up the development of embryos, Zn nano -\nparticles are added to in vitro maturation conditions. \nThis increases the activity of the enzyme superoxide \ndismutase (SOD) in cumulus cells, reduces DNA \ndamage, and reduces apoptosis in COC. Superoxide \nis converted into oxygen and hydrogen peroxide by \nthe enzymes catalase (CAT) and SOD. Reactive oxy -\ngen species (ROS) and reactive nitrogen species lev -\nels are regulated by SOD to lessen the potential toxic-\nity of these molecules [80].\n• Inhibition of Connexin-43 (CX43) production by \nfullerenol nanoparticles caused the transzonal pro -\njections (TZPsfif ) to retract, which hampered TZP-\ndependent transport and accelerated the return \nof meiosis in rat oocytes. These researchers also \nobserved that CX43 and EGFR were disseminated \nperinuclearly in granulosa cells, illuminating how \nfullerenol nanoparticles can stop the resumption of \noocyte meiosis [81, 82].\n• As an oxidative stressor, linoleic acid decreases \nthe proportion of bovine oocytes that reach the \nmetaphase II stage, the frequency of fully expanded \ncumulus cells, and the proportion of blastocysts. It \nis interesting to note that adding 10 mg/ml chitosan \nnanoparticles to the COC maturation media fully \nreduced the oxidative effects of linoleic acid on the \nnuclear maturation of oocytes, cumulus cell pro -\nliferation, and blastocyst rate. Chitosan nanopar -\nticle concentrations of 60 and 100  mg/ml reduced \nthe percentage of completely expanded cumulus \ncells and the developmental competence of bovine \noocytes, demonstrating the toxicity’s dose-depend -\nent character [83].\n• The intracellular glutathione concentration and \nDNA integrity of cumulus cells were also increased \nby the addition of nanoselenium and nano-ZnO \nnanoparticles during the in  vitro maturation of \nbovine COCs. Cultured cells need increased glu -\ntathione levels to handle oxidative stress properly \n[83, 84].\n• The body’s primary antioxidant, glutathione, aids \nin the preservation of all other antioxidants. It is a \nnaturally occurring antioxidant that can be found \nin varying amounts in both male and female gam -\netes. Its significance in preserving the biological \nvalue of germ cells has been verified, and it has \nalso been linked to the process of fertilisation and \nearly embryo development. The good news is that \nglutathione may both be recycled by the body and \ndestroyed if conditions are right. Glutathione can \nreduce oxidative stress by halting the production \nof dangerous free radicals in the reproductive sys -\ntem. It performs the role of the cell’s primary anti -\noxidant. Low glutathione levels are an unmistakable \nsign of illness and impending death. Glutathione \ndeficit has been associated to ovarian cancer and \neven early ovarian ageing. Autoimmune disor -\nders, one of the factors that affect fertility, may be \naffected by glutathione. Higher levels of glutathione \nin a woman’s follicle were linked to increased rates \nof fertilisation in IVF patients [85]. Egg quality is \ndependent on glutathione because it protects eggs \nfrom oxidative stress during folliculogenesis. In \nfact, studies have demonstrated that oocytes with \ngreater intracellular glutathione levels develop \nstronger and healthier embryos. According to \nanother study, women’s ovaries have higher intra -\ncellular glutathione levels when they are younger \n[86]. Egg health, one of the cells most impacted by \nageing, may benefit from glutathione’s antiaging \nantioxidant properties, according to earlier studies \nEggs are one of the cells most impacted by ageing. \nGlutathione production has a significant role in the \nprotective effect of follicle-stimulating hormone on \nembryonic development [85].\n• Cumulus cells from bovine COCs that underwent \nin  vitro maturation in the presence of copper and \nZnO nanoparticles had greater intracellular glu -\ntathione levels, which contributed to improved \nembryo development [83].\n\nPage 18 of 20Mansour  Beni-Suef Univ J Basic Appl Sci           (2023) 12:81 \n3  Conclusion\nBetween the ages of 15 and 49, one in eight females \nreceives aid with conception. With the aid of an accu -\nrate diagnosis, effective therapy, and shared deci -\nsion-making, many couples receiving treatment for \ninfertility can achieve their fertility goals; however, \nsuccess rates vary by age and diagnosis. Today, owing \nto technology, there are several options to help people \nwith varied fertility issues. Your particular situation \nand the cause of your infertility will determine the best \nsolutions for you. Both partners may mix different sorts \nof therapy at times when only one partner needs treat -\nment. In fertility treatments, hormone and ovulation-\nsupporting drugs are often employed, occasionally in \nconjunction with minor surgical operations. The term \n“assisted reproductive technology” (ART) can facilitate \negg fertilisation and aid implantation of the fertilised \negg in the uterine lining. The aforementioned makes it \nevident that infertility has grown to be one of the most \nsignificant issues that society faces, so we must look for \ncutting-edge, innovative, and affordable solutions to \naddress this issue.\nAbbreviations\nPCOS  Polycystic ovarian syndrome\nPID  Pelvic inflammatory disease\nNSAIDs  Non‑steroidal anti‑inflammatory drugs\nNICE  National Institute for Health and Care Excellence\nBBT  Basal body temperature\nLH  Luteinising hormone\nEBM  Endometrial biopsy\nTSH  Thyroid‑stimulating hormone\nFSH  Follicle ‑stimulating hormone\nHSG  Hysterosalpingography\nSHG  Sonohysterography\nART   Assisted reproductive techniques\nMRI  Magnetic resonance imaging techniques\nWHO  World Health Organization\nhCG  Human chorionic gonadotropin\nGnRH  Gonadotropin‑releasing hormone\nHMG  Human menopausal gonadotropin\nOA  Obstructive azoospermia\nIVF  In vitro fertilization\nGnRH  Gonadotropin‑releasing hormone\nICSI  Intracytoplasmic sperm injection\nIUI  Intrauterine insemination\nCC  Clomiphene citrate\nART   Assisted reproductive technology\nFSP  Fallopian tube sperm perfusion\nICI  Intracervical insemination\nCeO2  Cerium oxide\nZnO  Zinc oxide\nAcknowledgements\nThe author gratefully acknowledges the late Prof. Dr. Fatma Ahmed Mohamed \nEid, Professor of Cytochemistry and Histology, and Dr. Al‑Shaimaa Mohsen \nSadek Ahmed, Lecturer of Parasitology, Zoology Department, Faculty of Sci‑\nence, Al–Azhar University (Girls branch) for their constant, continuous support, \nstanding next to me, teaching me the basics of writing scientific research and \npublishing.\nAuthor contributions\nHend Abd El‑halim Mansour was responsible for paper idea and contributed \nto writing and revision and publication.\nFunding\nThere was no external funding for this study itself, and the author had full \naccess to all of the data in this study.\nAvailability of data and materials\nNot applicable.\nDeclarations\nEthics approval and consent to participate\nNot applicable.\nConsent for publication\nI agree.\nCompeting interests\nThe author declares that he has no competing interests.\nReceived: 12 May 2023   Accepted: 22 August 2023\nReferences\n 1. 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