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Pathology Jan 2018Sex cord-stromal tumours of the ovary include many of the most morphologically intriguing ovarian neoplasms and albeit many of them are rare, they factor into the... (Review)
Review
Sex cord-stromal tumours of the ovary include many of the most morphologically intriguing ovarian neoplasms and albeit many of them are rare, they factor into the differential diagnosis more often than their frequency might suggest. The most common malignant form, the adult granulosa cell tumour, may grossly simulate various surface epithelial neoplasms. Microscopically, confusion with endometrioid carcinoma may occur because the cords and microfollicles of the granulosa cell tumour may be mimicked by endometrioid carcinoma and the latter may have pale nuclei with nuclear grooves. Thorough sampling generally resolves this differential and if not immunohistochemistry aids. Although the adult granulosa cell tumour typically has cells with scant cytoplasm in some cases the tumour cells are luteinised and others have cells with abundant pale cytoplasm. A reticulum stain may be of great aid in indicating whether cells of the type just noted are of granulosa or theca nature. Variations in the morphology of the juvenile variant of granulosa cell tumour that can be diagnostically challenging include those that have a macronodular pattern with scant follicular differentiation, those with marked sclerosis, and those that are unusually pleomorphic. The uncommon but histologically varied Sertoli-Leydig cell tumour is considered, emphasis being placed on the most recently described variant, the retiform pattern, with its potential to mimic surface epithelial neoplasms and even mixed mesodermal tumours. Considering the usual young age of the patient may be paramount in making this tumour come to the mind of the pathologist. The rare pure Sertoli cell tumour is briefly noted as is the sex cord tumour with annular tubules, well known because of its association in some cases with Peutz-Jeghers syndrome. Most do not have that association, however, but have their own interesting features including a greater than average risk, among sex cord stromal tumours, of nodal metastasis and progesterone production, and an occasional development from them of an otherwise typical Sertoli cell tumour. The stromal family includes the common fibroma which is challenging when it is cellular with some mitotic activity and the approach to such neoplasms is reviewed. Emphasis in the consideration of thecoma is placed on its typical cytological features and the overlap with what may be seen in some adult granulosa cell tumours. The review concludes with three fascinating pure stromal tumours all described within the last several decades: the sclerosing stromal tumour, the unusual luteinised thecoma associated with sclerosing peritonitis and the microcystic stromal tumour. The first is sometimes misdiagnosed when pure stromal neoplasms of other types are vascular and may have pseudolobules and it is essential that the pseudolobules of the sclerosing stromal tumour contain a haphazard admixture of fibroblasts and weakly luteinised cells. The remarkable tumours associated with peritonitis exhibit brisk mitotic activity but appear not to have a metastatic potential; they can cause significant problems because of the sclerosing peritonitis. The microcystic stromal tumour may mimic a steroid cell tumour or thecoma but unlike them is inhibin and calretinin negative, and stains for CD10 and β-catenin. It often shows bizarre nuclei atypia but limited mitotic activity and appears to be clinically benign on the basis of still limited experience.
Topics: Biomarkers, Tumor; Diagnosis, Differential; Female; Granulosa Cell Tumor; Humans; Immunohistochemistry; Ovarian Neoplasms; Ovary; Sex Cord-Gonadal Stromal Tumors
PubMed: 29132723
DOI: 10.1016/j.pathol.2017.09.007 -
Drugs Aug 2022Linzagolix (Yselty) is an orally administered, selective, non-peptide small molecule gonadotrophin releasing hormone (GnRH) receptor antagonist that is being developed... (Review)
Review
Linzagolix (Yselty) is an orally administered, selective, non-peptide small molecule gonadotrophin releasing hormone (GnRH) receptor antagonist that is being developed by Kissei Pharmaceutical for the treatment of uterine fibroids and endometriosis in women of reproductive age. Linzagolix binds to and blocks the GnRH receptor in the pituitary gland, modulating the hypothalamic pituitary-gonadal axis and dose-dependently reducing serum luteinising hormone and follicle-stimulating hormone production and serum estradiol levels. In June 2022, linzagolix was approved for the treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age in the EU. Linzagolix is under regulatory review the USA for this indication and is in phase 3 clinical development in the treatment of pain associated with endometriosis. This article summarizes the milestones in the development of linzagolix leading to this first approval for the treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age.
Topics: Adult; Carboxylic Acids; Endometriosis; Estradiol; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leiomyoma; Luteinizing Hormone; Pharmaceutical Preparations; Pyrimidines; Receptors, LHRH
PubMed: 35997940
DOI: 10.1007/s40265-022-01753-9 -
Reproductive Biology Mar 2018Premature rise of progesterone during the late follicular phase in stimulated IVF cycles is a frequent event and its effect on the endometrial receptivity and on the ART... (Review)
Review
Premature rise of progesterone during the late follicular phase in stimulated IVF cycles is a frequent event and its effect on the endometrial receptivity and on the ART (Assisted Reproductive Technique) - outcome has become a matter of intense debate and research. An emerging body of evidence demonstrates that premature progesterone rise does have a negative impact on the outcome of the ART-success. Until now, the exact cause of progesterone elevation is not fully clear, however lately published studies points to the fact, that premature progesterone elevation might be caused by enhanced FSH stimulation. The impact of elevated peripheral progesterone levels seems to be mainly on the endometrium and the window of implantation, leading to an asynchrony between the endometrium and the developing embryo. Hence, new data show additional an influence on the embryo quality. This review aims to summarize the up-to-date knowledge on the causes of premature progesterone rise during hormonal stimulation, on its influence on endometrial receptivity and embryo quality, on the impact on pregnancy and live birth rates as well as on the possible strategies to prevent this event or to deal with premature progesterone elevation in case it could not be avoided.
Topics: Animals; Birth Rate; Dose-Response Relationship, Drug; Drug Resistance; Embryo Transfer; Endometrium; Female; Fertility Agents, Female; Humans; Infertility, Female; Luteinization; Ovulation Induction; Practice Guidelines as Topic; Pregnancy; Progesterone; Reproductive Techniques, Assisted; Up-Regulation
PubMed: 29317175
DOI: 10.1016/j.repbio.2018.01.001 -
Vitamins and Hormones 2018GATA4 and GATA6 are the sole GATA factors expressed in the ovary during embryonic development and adulthood. Up today, GATA4 and GATA6 are the only transcription factors... (Review)
Review
GATA4 and GATA6 are the sole GATA factors expressed in the ovary during embryonic development and adulthood. Up today, GATA4 and GATA6 are the only transcription factors that have been conditionally deleted during ovarian development and at each major stage of follicle maturation. The evidence from these transgenic mice revealed that GATA4 and GATA6 are crucial for follicles assembly, granulosa cell differentiation, postnatal follicle growth, and luteinization. Thus, conditional knockdown of both factors in the granulosa cells at any stage of development leads to female infertility. GATA targets impacting female reproduction include genes involved in steroidogenesis, hormone signaling, ovarian hormones, extracellular matrix organization, and apoptosis/cell division.
Topics: Aging; Animals; Apoptosis; Embryonic Development; Extracellular Matrix; Female; Follicular Atresia; GATA Transcription Factors; Gene Expression Regulation, Developmental; Humans; Luteinization; Menstrual Cycle; Models, Biological; Oogenesis; Ovary; Ovulation; Reproduction
PubMed: 29544631
DOI: 10.1016/bs.vh.2018.01.014 -
Theriogenology Sep 2021Although prostaglandins are important in the ovulation process, a precise role for prostaglandin F2α (PGF) has not been elucidated. This study aimed to evaluate the...
Although prostaglandins are important in the ovulation process, a precise role for prostaglandin F2α (PGF) has not been elucidated. This study aimed to evaluate the regulation of PGF receptor mRNA (PTGFR) in granulosa cells and the local effect of PGF on ovulation and luteinization. In Experiment 1, using samples collected in vivo before (Day 2), during (Day 3) and after (Day 4) follicular deviation, expression of PTGFR in bovine granulosa cells was more abundant in the dominant follicle after deviation than in subordinates (P < 0.05). However, the expression of PTGFR was not regulated (P = 0.1) in preovulatory follicles at different time-points (0, 3, 6, 12 and 24 h) after ovulation induction with GnRH. In Experiment 2, to assess the role of systemic PGF treatment on luteinization and vascularization of preovulatory follicles, flunixin meglumine (FM), a nonsteroidal anti-inflammatory drug, was used to inhibit endogenous prostaglandin synthesis. Cows with preovulatory follicles were induced to ovulate with GnRH (0 h) and allocated to three groups: Control, with no further treatment; FM, treated with 2.2 mg/kg FM im 17 h after GnRH treatment; and FM + PGF, treated with FM 17 h after GnRH, followed by 25 mg dinoprost tromethamine (PGF) 23 h after GnRH treatment. FM injection was able to reduce the concentration of PGF in the follicular fluid (FF) (P < 0.001). However, contrary to our hypothesis, color Doppler ultrasound evaluations revealed decreased vascular flow in FM + PGF group (P < 0.05), and no effect of the treatments on intrafollicular P4 and E2 concentrations 24 h after GnRH. The prostaglandin metabolite (PGFM) concentrations in the FF were greater in cows receiving systemic PGF (P < 0.001), which prompted us to further check its role on ovulation. Therefore, in Experiment 3, in a final attempt to demonstrate the local effect of PGF on ovulation, cows with preovulatory follicles received an intrafollicular injection (IFI) of PBS (Control) or 100 ng/mL purified PGF (PGF group). PGF treatment did not affect the time of ovulation after IFI (66 ± 6.4 and 63 ± 8.5 h for control and PGF, respectively; P > 0.05), further suggesting that it has no direct effect in the ovulatory process. Based on our findings, we concluded that FM decreased PGF synthesis within the follicle, whereas PGF treatment decreased follicular vascularization. In addition, the in vivo model of intrafollicular injection evidenced that PGF alone is not able to locally induce ovulation.
Topics: Animals; Cattle; Dinoprost; Female; Gonadotropin-Releasing Hormone; Luteinization; Ovarian Follicle; Ovulation; Progesterone
PubMed: 34004368
DOI: 10.1016/j.theriogenology.2021.05.008 -
Methods in Molecular Biology (Clifton,... 2018Culture of granulosa cells has for long provided a useful tool to understand the molecular processes underlying ovarian follicle development. Among all species...
Culture of granulosa cells has for long provided a useful tool to understand the molecular processes underlying ovarian follicle development. Among all species investigated, cattle have become an excellent model for in vitro studies on follicular biology, both because of their resemblance with humans in terms of follicular biology and the importance of reproductive failure as a cause of lost productivity in the dairy industry. In this chapter, we describe up-to-date methods for the harvesting of granulosa cells from bovine ovaries collected post-mortem, as well as procedures for both culturing granulosa cells in an undifferentiated state and inducing their luteinization in vitro, and for the efficient transfection of granulosa cells with oligonucleotide sequences for the purpose of investigating the function of specific genes in vitro.
Topics: Animals; Cattle; Cell Culture Techniques; Cell Differentiation; Cell Separation; Cells, Cultured; Female; Granulosa Cells; Luteinization; Models, Biological
PubMed: 29959704
DOI: 10.1007/978-1-4939-8600-2_8 -
Journal of Assisted Reproduction and... Oct 2018Premature luteinization (PL) affects 12.3-46.7% of fresh in vitro fertilization cycles, and there is accumulating evidence confirming its negative effect on success... (Review)
Review
PURPOSE
Premature luteinization (PL) affects 12.3-46.7% of fresh in vitro fertilization cycles, and there is accumulating evidence confirming its negative effect on success rates. However, despite its clinical significance, PL is poorly understood and defined. This narrative review aims to provide a fresh look at the phenomenon of PL by summarizing the existing evidence and re-evaluating fundamental issues.
METHODS
A thorough electronic search was conducted covering the period from 1978 until January 2018 in PubMed, Embase, and Medline databases, and references of relevant studies were cross-checked. Meeting proceedings of the European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine were also hand searched.
RESULTS
In the curious case of PL, one should go back to the beginning and re-consider every step of the way. The pathogenesis, definition, measurement methods, clinical implications, and management strategies are discussed in detail, highlighting controversies and offering "food for thought" for future directions.
CONCLUSIONS
Authors need to speak the same language when studying PL in order to facilitate comparisons. The terminology, progesterone cut-off, measurement methods and days of measurement should be standardized and globally accepted; otherwise, there can be no scientific dialog. Future research should focus on specific patient profiles that may require a tailored approach. Progesterone measurements throughout the follicular phase possibly depict the progesterone exposure better than an isolated measurement on the day of hCG. Adequately powered randomized controlled trials should confirm which the best prevention and management plan of PL is, before introducing any strategy into clinical practice.
Topics: Chorionic Gonadotropin; Female; Fertilization in Vitro; Gonadotropin-Releasing Hormone; Humans; Luteinization; Ovulation Induction; Pregnancy; Pregnancy Rate; Premature Birth; Progesterone
PubMed: 30051348
DOI: 10.1007/s10815-018-1264-8 -
Frontiers in Endocrinology 2023Spermatogenesis is a multi-step process of male germ cell (Gc) division and differentiation which occurs in the seminiferous tubules of the testes under the regulation... (Review)
Review
Spermatogenesis is a multi-step process of male germ cell (Gc) division and differentiation which occurs in the seminiferous tubules of the testes under the regulation of gonadotropins - Follicle Stimulating Hormone (FSH) and Luteinising hormone (LH). It is a highly coordinated event regulated by the surrounding somatic testicular cells such as the Sertoli cells (Sc), Leydig cells (Lc), and Peritubular myoid cells (PTc). FSH targets Sc and supports the expansion and differentiation of pre-meiotic Gc, whereas, LH operates Lc to produce Testosterone (T), the testicular androgen. T acts on all somatic cells e.g.- Lc, PTc and Sc, and promotes the blood-testis barrier (BTB) formation, completion of Gc meiosis, and spermiation. Studies with hypophysectomised or chemically ablated animal models and hypogonadal (hpg) mice supplemented with gonadotropins to genetically manipulated mouse models have revealed the selective and synergistic role(s) of hormones in regulating male fertility. We here have briefly summarized the present concept of hormonal control of spermatogenesis in rodents and primates. We also have highlighted some of the key critical questions yet to be answered in the field of male reproductive health which might have potential implications for infertility and contraceptive research in the future.
Topics: Male; Mice; Animals; Spermatogenesis; Testis; Sertoli Cells; Gonadotropins; Follicle Stimulating Hormone; Luteinizing Hormone; Mammals
PubMed: 37124741
DOI: 10.3389/fendo.2023.1110572 -
Frontiers in Endocrinology 2022Feedback from oestradiol (E2) plays a critical role in the regulation of major events in the physiological menstrual cycle including the release of gonadotrophins to... (Review)
Review
Feedback from oestradiol (E2) plays a critical role in the regulation of major events in the physiological menstrual cycle including the release of gonadotrophins to stimulate follicular growth, and the mid-cycle luteinising hormone (LH) surge that leads to ovulation. E2 predominantly exerts its action oestrogen receptor-alpha (ERα), however, as gonadotrophin releasing hormone (GnRH) neurons lack ERα, E2-feedback is posited to be indirectly mediated upstream neurons. Kisspeptin (KP) is a neuropeptide expressed in hypothalamic KP-neurons that control GnRH secretion and plays a key role in the central mechanism regulating the hypothalamic-pituitary-gonadal (HPG) axis. In the rodent arcuate (ARC) nucleus, KP is co-expressed with Neurokinin B and Dynorphin; and thus, these neurons are termed 'Kisspeptin-Neurokinin B-Dynorphin' (KNDy) neurons. ARC KP-neurons function as the 'GnRH pulse generator' to regulate GnRH pulsatility, as well as mediating negative feedback from E2. A second KP neuronal population is present in the rostral periventricular area of the third ventricle (RP3V), which includes anteroventral periventricular (AVPV) nucleus and preoptic area neurons. These RP3V KP-neurons mediate positive feedback to induce the mid-cycle luteinising hormone (LH) surge and subsequent ovulation. Here, we describe the role of KP-neurons in these two regions in mediating this differential feedback from oestrogens. We conclude by considering reproductive diseases for which exploitation of these mechanisms could yield future therapies.
Topics: Kisspeptins; Neurokinin B; Dynorphins; Luteinizing Hormone; Gonadotropin-Releasing Hormone; Neurons
PubMed: 36479214
DOI: 10.3389/fendo.2022.951938