Genetic Characteristics of Oocytes and Somatic Cells of Ovarian Follicles in Humans_Crimson Publishers

Genetic Characteristics of Oocytes and Somatic Cells of Ovarian Follicles in Humans by Bezerra FTG in Investigations in Gynecology Research & Womens Health_Scholarly articles for women's health journal

Mini Review

Since most of the RNAs/proteins that support the initial phases of embryogenesis are accumulated during oocyte growth [1], knowledge about the effects of oocyte quality on embryo development plays a crucial role in the development of adequate assisted reproduction techniques. In this sense, understanding the requirements of oocytes recovered from different sized follicles is very important to optimize IVM and IVF of oocytes, which can have an excellent impact on the number of embryos produced in vitro. It will also allow analysis of the developmental potential of oocytes at different stages of development, the pattern of gene expression, the epigenetic modifications and the cytogenetic disorders in various domestic species, including humans [2].

Influence of oocyte and follicle sizes on oocyte maturation

In human oocytes, gain of meiosis ability starts at the antral follicle stage, while its size reaches up to 100-120μm. Theoretically, antral follicles with diameter of 2.0-5.0mm contain oocytes with nuclear and cytoplasmic competence [3]. However, the minimum size of follicles required for developmental competence in humans is estimated to be 5.0-7.0mm in diameter [4]. It is possible that the selection of the dominant follicle induces changes in the remaining follicles that are detrimental for subsequent oocyte fertilization and embryonic development. Fadini et al. [5] reported that follicles of up to 12mm in size at the time of oocyte retrieval have not compromised their outcome. Taken together, the above information proposes that the molecular events that are triggered according to follicular and oocyte development influence oocyte maturation.

Gene expression in oocytes from follicles of different sizes

It is well known that while the oocyte progresses in growth and development, it acquires maternal stores (mRNAs and proteins) which are essential to support the development of the embryo during the early cleavage stages [6]. Under in-vitro conditions, the dynamic micro RNA (miRNA) profile changes are partly attributed to the in-vitro maturation environment or ingredients used, while under in-vivo conditions, the miRNA profile is affected by physiological conditions, like the age. In humans, treatment of metaphase I (MI) human oocytes with insulin-like growth factor 1 activates the expression of miR-133a, miR-205-5p and 145 miRNAs and suppresses 200 others, including miR-152 and miR-142-5p [7]. In the same context, [8] demonstrated that YTHDF2 post-transcriptionally regulates transcript dosage during oocyte maturation and act as determinant of mammalian egg quality. Several studies have correlated the oocyte ATP content and its developmental competence, both in humans [9].

Characteristics of somatic cells of follicles at different sizes

Within an antral follicle, the oocyte is surrounded by several layers of cumulus and mural granulosa cells. It is known that the characteristics of these cells vary according to the size of the follicle and this can directly affect the ability of the enclosed oocyte to undergo maturation. A study with humans [10] showed that the morphology of CCs collected from follicles smaller than 12.0mm is different from those retrieved from mature follicles of standard IVF. Immature oocytes rescued from smaller antral follicles are usually embedded in more compact cumulus cells [10]. The number of dispersed CCs increases with duration of human chorionic gonadotrophin (HCG) priming and growing of follicular size in IVM program [11]. The patterns of CCs are divided into three groups: dispersed, compacted and sparse. Dispersed CCs have an expanded CC and multiple layers of corona cells. A GV oocyte that is completely masked with many layers of corona cells is considered as compacted CCs, while very few coronal cells exist in sparse CCs [3]. Comparison of different patterns of COCs reveals a significant increase in COCs with dispersed cumulus cells during oocyte maturation and blastocyst formation [3].

References

1. Biase FH, Cao X, Zhong S (2014) Cell fate inclination within 2-cell and 4-cell mouse embryos revealed by single-cell RNA sequencing. Genome Res 24(11): 1787-1796.
2. Sirard MA, Richard F, Blondin P, Robert C (2006) Contribution of the oocyte to embryo quality. Theriogenology 65(1): 126-136.
3. Son WY, Chung JT, Dahan M (2011) Comparison of fertilization and embryonic development in sibling in vivo matured oocytes retrieved from different sizes follicles from in vitro maturation cycles. J Assist Reprod Genet 28(6): 539-544.
4. Trounson A, Anderiesz C, Jones G (2001) Maturation of human oocytes in vitro and their developmental competence. Reproduction 121(1): 51-75.
5. Fadini R, Canto MB, Mignini RM, Brambillasca F, Comi R, et al. (2009) Effect of different gonadotrophin priming on IVM of oocytes from women with normal ovaries: a prospective randomized study. Reprod Biomed Online 19(3): 343-351.
6. Li L, Zheng P, Dean J (2010) Maternal control of early mouse development. Development 137(6): 859-870.
7. Xiao G, Xia C, Yang J, Liu J, Du H, et al. (2014) MiR-133b regulates the expression of the Actin protein TAGLN₂ during oocyte growth and maturation: a potential target for infertility therapy. PLoS ONE 9(6): e100751.
8. Ivanova I, Much C, Giacomo M, Azzi C, Morgan M, et al. (2017) The RNA m⁶A reader YTHDF₂ Is essential for the post-transcriptional regulation of the maternal transcriptome and oocyte competence. Mol Cell 67(6): 1059-1067.
9. Blerkom J, Davis P, Lee J (1995) ATP content of human oocytes and developmental potential and outcome after in vitro fertilization and embryo transfer. Hum Reprod 10(2): 415-424.
10. Yang Y, Kanno C, Sakaguchi K, Yanagawa Y, Katagiri S, et al. (2017) Extension of the culture period for the in vitro growth of bovine oocytes in the presence of bone morphogenetic protein-4 increases oocyte diameter but impairs subsequent developmental competence. Anim Sci J 88(11): 1686-1691.
11. Pincus G, Enzmann EV (1935) The comparative behavior of mammalian eggs in vivo and in vitro: I. the activation of ovarian eggs. J Exp Med 62(5): 665-675.

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Adult Ovarian Granulosa Cell Tumor: Role of Systemic Chemotherapy and Surgical Treatment_Crimson Publishers

 Adult Ovarian Granulosa Cell Tumor: Role of Systemic Chemotherapy and Surgical Treatment by Nour Tashtush in Investigations in Gynecology Research & Womens Health_Scholarly articles for women's health journal

Abstract

Ovarian granulosa cell tumors (GCT) are rare ovarian neoplasms. The main treatment for GCT is surgical. The volume of operation depends on the stage of the disease and the age of the patient. The possibility of maintaining fertility in patients of reproductive age in the early stages of the disease and the feasibility of lymphadenectomy are discussed. The positive effect of repeated cytoreductive operations for relapse was demonstrated. Role of chemotherapy in the treatment of GCT, due to the rarity of GCT and the late recurrence of the disease, is still not defined. Adjuvant chemotherapy is not shown to protect against relapse in patients with adult type (AGCT). Hormone therapy is considered to be a promising direction for the palliative treatment of AGCT relapses.

Keywords: Granulosa cell tumors; Relapse; Surgical treatment; Fertility-saving treatment; Chemotherapy; Hormone therapy; Aromatase inhibitors

Introduction

Ovarian tumors are a heterogeneous group of tumors, including epithelial and non-epithelial ovarian tumors. Non-epithelial ovarian tumors account for approximately 10% of all ovarian cancers, including malignant germ cell tumors and and sex cord-stromal tumors. Sex cord-stromal tumors consist of a heterogeneous group of neoplasms with diverse clinicopathological features and biological behavior. GCT are rare sex cord-stromal tumors. Their frequency is approximately 3%-5% of all malignant ovarian tumors, and the incidence is from 0.6 to 2.1 cases per 100000 women per year [1]. According to the histological features, GCT are divided into two types: adult and juvenile [2]. Both adult and juvenile types GCT, due to the uncertainty of their malignant potential, until recently, according to the 2003 WHO histological classification, were referred to borderline tumors due to the relatively high 5-and 10-year survival [3]. In the 2014 WHO histological classification, GCOS were divided into borderline, which included the GCT of the juvenile type, and the malignant GCT of the adult type [4].

Despite the definition of AGCT not as borderline, but as low-grade malignant tumors, there are no specific recommendations for the surgical and drug treatment in such patients. This is primarily due to the late recurrence of the disease, requiring long-term follow-up of patients, as well as the rarity of these tumors and conflicting data on prognosis factors.

Surgical treatment

The main treatment is surgery (hysterectomy with bilateral salpingoophorectomy). It was shown significant positive effect of full staging at an early stage and primary treatment in a specialized clinic on the indicator of five-year relapse-free survival [5]. Multivariate analysis of multicenter retrospective study with data on 102 patients with AGCT of an adult type did not find the effect of surgical treatment options on the recurrence rate of the disease [6]. Fertility-saving unilateral salpingooophorectomy is one of the options for surgical treatment in young patients with stage IA [7,8]. Stage of the disease is an independent prognostic factor for the occurrence of a relapse of the disease [9,10]. For advanced disease it is recommended to perform optimal interval cytoreduction after chemotherapy, but lymphodissection is not recommended because according to the authors it did not affect the recurrence rate of the disease, and metastases were not found in histological examination of the removed lymph nodes [5].

Drug treatment

The role of drug treatment in AGCT is under discussion. Increasing of relapse-free survival and time to progression has been reported in high-risk patients receiving adjuvant chemotherapy [11,12]. Other studies have not found a positive effect of chemotherapy on relapse rates, even in the early stages of AGCT [13,14]. In AGCT patients with stage IC, there were no differences in relapse-free survival between patients with or without adjuvant chemotherapy [14]. Adjuvant chemotherapy is not shown to protect against relapse in patients with adult type AGCT [8]. The most widely used first-line adjuvant treatment regimen in patients with AGCT is BEP regimen. Platinum-based chemotherapy is currently used for patients with advanced stages or a recurring disease, with a total response rate of 63% to 80%. Combination chemotherapy with taxes and platinum appears to be a suitable regimen for further research [15]. The gynecological oncology group (GOG) is currently conducting a randomized phase II trial, the results of which are expected in 2024, by comparing the effect of the TC regimen with the BEP regimen on progressive survival in adult GCT patients (ClinicalTrials.gov Identifier NCT01042522). It is expected that the TC regimen may be associated with relatively lower toxicity and similar non-progressive survival compared to the BEP regimen.

Hormone therapy based on progestogens (megestrol) and gonadotropin-releasing hormone agonists [16-18] is considered to be a promising direction for the palliative treatment of GCT relapses. It was also shown promising results of the use of aromatase inhibitors in relapses of AGCT [19,20]. The efficacy of targeted therapy, particularly, mTOR inhibitors and tyrosine kinase inhibitors in the treatment of GCT, is currently being investigated [21,22].

Discussion

GCT are rare low-grade malignant sex cord-stromal tumors with indolent behavior. The etiology of GKO, like most ovarian epithelial tumors, is unknown. GKO of the ovaries are distinguished by their ability to secrete sex steroid hormones (estrogens), and glycoprotein hormone inhibin, which are used in the clinic as tumor markers. So, the majority of patients are diagnosed at early stage [6,23]. The main risk factors of AGCT include nulliparity, fatness, oral contraceptives and family cancer history. The recent studies provided powerful evidences that fork head box protein L2 (FOXL2), PI3K/AKT signaling pathway, TGF-β signaling pathway, Notch signaling pathway and etc. were involved in granulosa cell tumor through influencing cell proliferation and apoptosis [24]. More and more clinical data show that FOXL2 mutation is the main factor in AGCT. So, understanding the FOXL2 regulation mechanism is instrumental to develop new prevention and therapy methods [25]. The main treatment is surgery [6-8]. Most clinicians agree that in patients of a young and young age with stage IA disease can be limited to unilateral adnexectomy with adequate surgical staging, which allows these women to maintain reproductive function [7,8]. At the pre- and postmenopausal age, preference is given to radical surgery in the amount of extirpation of the uterus with appendages and removal of the momentum with mandatory optimal surgical staging [5,6,8,9,15]. Stage of the disease is an independent prognostic factor for the occurrence of a relapse of the disease [9,10]. Adjuvant chemotherapy is not shown to protect against relapse in patients with adult type AGCT [8]. High recurrent rate is the most critical factor for GCT death. At present, the most important problem lies in the early diagnosis and prevention of recurrence. Studies showed that hormones play a critical role in the pathogenesis and treatment of GCT, especially in some ineffective cases for radiotherapy and chemotherapy [24,25]. Targeting drugs for signal pathway in the subsequent chemotherapy can significantly improve the survival rate of patients [21,22,24,25].

Conclusion

There were not found significant difference in the overall and relapse-free survival of patients with ovarian AGCT, depending on the options of surgical and drug treatment they underwent. Additional multicenter randomized trials are needed to clarify the effectiveness of the various options for surgical and drug treatment of adult GCT patients.

References

1. Bryk S, Pukkala E, Martinsen JI, Kallio LU, Tryggvadottir L, et al. (2017) Incidence and occupational variation of ovarian granulosa cell tumours in Finland, Iceland, Norway and Sweden during 1953-2012: A longitudinal cohort study. BJOG 124(1): 143-149.
2. Young R (2005) Sex cord-stromal tumors of the ovary and testis: their similarities and differences with consideration of selected problems. Modern Pathology 18: 81-91.
3. Tavassoli FA, Devilee P (2003) Pathology and genetics of tumours of the breast and female genital organs. In: Tavassoli FA, Devilee P (Eds.), World Health Organization Classification of Tumours. IARC press, France, p. 432.
4. Kurman RJ, Carcangiu ML, Herrington CS, Young RH (2014) WHO classification of tumours of female reproductive organs. IARC, Lyon, France.
5. Mangili G, Ottolina J, Gadducci A. Giorda G, Breda E, et al. (2013) Long-term follow-up is crucial after treatment for granulosa cell tumours of the ovary. Br J Cancer 109(1): 29-34.
6. Lee IH, Choi CH, Hong DG, Song JY, Kim YJ, et al. (2011) Clinicopathologic characteristics of granulosa cell tumors of the ovary: A multicenter retrospective study. J Gynecol Oncol 22(3): 188-195.
7. Iavazzo C, Gkegkes ID, Vrachnis N (2015) Fertility sparing management and pregnancy in patients with granulosa cell tumour of the ovaries. Journal of obstetrics and gynaecology: The journal of the Institute of Obstetrics and Gynaecology 35(4): 331-335.
8. Wang D, Xiang Y, Wu M, Keng S, Jiaxin Y, et al. (2018) Is adjuvant chemotherapy beneficial for patients with FIGO stage IC adult granulosa cell tumor of the ovary? Journal of Ovarian Research 11: 25.
9. Park JY, Jin KL, Kim DY, Kim JH, Kim YM, et al. (2012) Surgical staging and adjuvant chemotherapy in the management of patients with adult granulosa cell tumors of the ovary. Gynecol Oncol 125(1): 80-86.
10. Thomakos N, Biliatis I, Koutroumpa I, Sotiropoulou M, Bamias A, et al. (2016) Prognostic factors for recurrence in early stage adult granulosa cell tumor of the ovary. Arch Gynecol Obstet 294(5): 1031-1036.
11. Munem A, Bahrani B, Mehdi I, Kamona A, Nadas AM, et al. (2012) Aromatase inhibitors--a viable option for recurrent granulosa cell tumour of ovary: overview and case report. J Pak Med Assoc 62(5): 505-507.
12. Meisel JL, Hyman DM, Jotwani A, Zhou Q, Rustumd NR, et al. (2015) The role of systemic chemotherapy in the management of granulosa cell tumors. Gynecol Oncol 136(3): 505-511.
13. Nosov V, Silva I, Tavassoli F, Adamyan L, Eisner R, et al. (2009) Predictors of recurrence of ovarian granulosa cell tumors. Int J Gynecol Cancer 19(4): 628-633.
14. Mangili G, Ottolina J, Cormio G, Loizzi V, Iaco P, et al. (2016) Adjuvant chemotherapy does not improve disease-free survival in FIGO stage IC ovarian granulosa cell tumors: The MITO-9 study. Gynecol Oncol 143(2): 276-280.
15. Colombo N, Parma G, Zanagnolo V, Insinga A (2007) Management of ovarian stromal cell tumors. Journal of Clinical Oncology 25(20): 2944-2951.
16. Briasoulis E, Karavasilis V, Pavlidis N (1997) Megestrol activity in recurrent adult type granulosa cell tumour of the ovary. Ann Oncol 8(8): 811-812.
17. Kauppila A, Bangah M, Burger H, Martikainen H (1992) GnRH agonist analog therapy in advanced/recurrent granulosa cell tumors: Further evidence of a role of inhibin in monitoring response to treatment. Gynecol Endocrinol 6(4): 271-274.
18. Hardy RD, Bell JG, Nicely CJ, Reid GC (2005) Hormonal treatment of a recurrent granulosa cell tumor of the ovary: Case report and review of the literature. Gynecol Oncol 96(3): 865-869.
19. Korach J, Perri T, Beiner M, Davidzon T, Fridman E, et al. (2009) Promising effect of aromatase inhibitors on recurrent granulosa cell tumours. Int J Gynecol Cancer 19(5): 830-833.
20. AlHilli MM, Long HJ, Podratz KC, Gamez JN (2012) Aromatase inhibitors in the treatment of recurrent ovarian granulosa cell tumors: Brief report and review of the literature. J Obstet Gynaecol Res 38(1): 340-344.
21. Rico C, Laguë MN, Lefèvre P, Tsoi M, Devillers A, et al. (2012) Pharmacological targeting of mammalian target of rapamycin inhibits ovarian granulosa cell tumor growth. Carcinogenesis 33(11): 2283-2292.
22. Jamieson S, Fuller PJ (2015) Tyrosine kinase inhibitors as potential therapeutic agents in the treatment of granulosa cell tumors of the ovary. Int J Gynecol Cancer 25(7): 1224-1231.
23. Khosla D, Dimri K, Pandey AK, Mahajan R, Trehan R (2014) Ovarian granulosa cell tumor: Clinical features, treatment, outcome, and prognostic factors. N Am J Med Sci 6(3): 133-138.
24. Yang AD (2018) Ovarian adult-type granulosa cell tumor: Focusing on endocrine-based therapies. International Journal of Endocrine Oncology 5(2).
25. Li J, Bao R, Peng S, Zhang C (2018) The molecular mechanism of ovarian granulosa cell tumors. J Ovarian Res 11(1): 13.

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Prevention of Pelvic Floor Disorders After Vaginal Birth_Crimson Publishers

Prevention of Pelvic Floor Disorders After Vaginal Birth by Nour Tashtush in Investigations in Gynecology Research & Womens Health_Scholarly articles for women's health journal

Abstract

Vaginal birth is the main risk factor in the development of pelvic floor disorders. Pelvic floor muscle training (PFMT) can prevent prolapse symptoms at 2 years after intervention and could reduce the uptake of treatment. Also, results indicated that PFMT increases the chance of improvement in prolapse stage by 17% compared to no treatment.

Keywords: Vaginal birth; Prolapse; Physical therapy; Pelvic floor muscle strength

Abbreviations: PFMT: Pelvic Floor Muscle Training; TRA: Transverses Abdominis

Introduction

Epidemiological studies have consistently identified vaginal birth as the main risk factor in the development of pelvic floor disorders. Women who deliver vaginally are 2.8 times more likely to develop stress urinary incontinence and 5.5 times more likely to have pelvic organ prolapse than women who undergo cesarean delivery [1]. The aim of this review article is to assess the importance of pelvic floor training in preventing pelvic floor disorders.

Discussion

Pelvic organ prolapse is the symptomatic descent of one or more of the anterior vaginal wall, posterior vaginal wall, the uterus (cervix), or the apex of the vagina from the normal anatomical position, caused by herniation through deficient pelvic fascia or weaknesses or deficiencies in the ligaments or muscles that support the pelvic organs [2]. 5-10 years after a first birth, pelvic floor disorders were dramatically increased among women with a history of at least one operative vaginal birth [3]. Women with normal vaginal delivery and mediolateral episiotomy had the weakest pelvic muscles and nulliparous women had the strongest pelvic muscles [4].

Pelvic floor muscle training can prevent prolapse symptoms at 2 years after intervention and could reduce the uptake of treatment. Therefore, women should be recommended to undertake pelvic floor muscle training even before they have bothersome symptoms. The intervention should be encouraged on the basis of it being safe and done easily by most women [2]. Another conservative method: Pelvic floor physical therapy which targets the muscles, nerves, ligaments, connective tissue, lymphatic system, and joints inside and a rounding the pelvic girdle and focuses on addressing mobility and function. Pelvic floor physical therapists use internal or external therapies such as myofascial release, connective tissue manipulation, joint and scar tissue mobilization. Manual therapy uses palpation to loosen spastic muscles and lengthen tightened tissue to provide relief from pain. Therapies such as neuromuscular electrical stimulation and biofeedback use technology to help women gain functional awareness of the pelvic floor better coordinate muscle contractions and improve endurance to promote maximal functioning [5].

Randomized trials were done to assess the benefit of conservative methods in preventing pelvic prolapse, including six trials. Four trials compared pelvic floor muscle training (PFMT)with no intervention, and two trials compared pelvic floor muscle training plus surgery to surgery alone. PFMT compared to no intervention was found in individual trials to improve prolapse symptoms. Data on prolapsed severity was combined from two trials and results indicated that PFMT increases the chance of improvement in prolapse stage by 17% compared to no treatment. Pelvic floor muscle function appeared to be improved with PFMT in two out of three trials which measured this. Bladder symptoms were improved with PFMT in two out of three trials measuring this; bowel symptoms were measured in one trial, and an improvement with PFMT was found. The two trials which looked at the benefit of PFMT in addition to surgery, were small but of good quality. Findings were contradictory: women benefited from PFMT, in terms of urinary symptoms and pelvic floor muscle strength, in one trial but not the other [6].

Urinary incontinence is associated significantly with pelvic floor disorders, one of the studies on the effect of pelvic floor muscle exercise on quality of life in women with stress urinary incontinence and its relationship with vaginal deliveries has shown Both the combined training of the pelvic floor muscle (PFM) and the synergistic transverses abdominis (TRA) muscle, and the isolated PFM exercises improve the quality of life of women with stress urinary incontinence. Nonetheless, the combined PFM and TRA muscle physiotherapy is more effective. The exercises for the PFM and the synergistic muscle give better results in women who have given birth fewer than three times than isolated PFM exercises [7]. According to the previous mentioned studies, we assure the importance of pelvic floor muscle training as an effective conservative method in preventing and treating pelvic floor disorders.

Conclusion

Vaginal birth has encountered many cases of pelvic floor disorders that are resulted from the weakening of pelvic floor, so we conclude that preventing measures should be started immediately after the first vaginal birth which include pelvic muscle training and physical therapy that showed positive results as compared to no intervention.

References

1. Howard D, Makhlouf M (2016) Can pelvic floor dysfunction after vaginal birth be prevented? Int Urogynecol J 27(12): 1811-1815.
2. Hagen S, Glazener C, McClurg D, Macarthur C, Elders A, et al. (2017) Pelvic floor muscle training for secondary prevention of pelvic organ prolapse (PREVPROL): A multicentre randomized controlled trial. Lancet 389(10067): 393-402.
3. Handa L, Blomquist JL, Knoepp LR, Hoskey KA, McDermott KC, et al. (2011) Pelvic floor disorders 5-10 years after vaginal or cesarean childbirth. Obstet Gynecol 118(4): 777-784.
4. Afshari P, Dabagh F, Iravani M, Abedi P (2016) Comparison of pelvic floor muscle strength in nulliparous women and those with normal vaginal delivery and cesarean section. Int Urogynecol J 28(8): 1171-1175.
5. Lawson S, Sacks A (2018) Pelvic floor physical therapy and women’s health promotion. J Midwifery Womens Health 63(4): 410-417.
6. Hagen S, Stark D (2011) Conservative prevention and management of pelvic organ prolapse in women. Cochrane Database Syst Rev, Issue 12: CD003882.
7. Magdalena P, Ciećwież S, Brodowska A, Starczewski A, Rutkowska JN, et al. (2018) The effect of pelvic floor muscles exercise on quality of life in women with stress urinary incontinence and its relationship with vaginal deliveries: a randomized trial. BioMed Research International 2019: 1-7.

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