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Background The use of progestin (P) during ovarian stimulation is effective in blocking the luteinizing hormone (LH) surge in women with normal ovarian reserve, however, its effects have not been determined in poor responders. This study aimed to explore the follicular dynamics in P-primed minimal stimulation in poor responders. Methods A total of 204 infertile women with diminished ovarian reserve were allocated into the medroxyprogesterone acetate (MPA) group or the natural-cycle control group in an alternating order. MPA (10 mg) was administered daily beginning from the early follicular phase and a low dose of hMG was added in the late follicular phase if the serum FSH level was lower than 8.0mIU/ml. When a dominant follicle reached maturity, triptorelin 100 μg and hCG 1000 IU were used for trigger, and oocytes were retrieved 34-36 h later.All viable embryos were cryopreserved for subsequent frozen embryo transfer. Natural cycle IVF was used as controls. Results Compared with the natural cycle group, the MPA group exhibited a larger pre-ovulatory follicle (18.7 ± 1.8 mm vs 17.2 ± 2.2 mm), a longer follicular phase (13.6 ± 3.6 days vs 12.3 ± 3.2 days), and higher peak oestradiol values (403.88 ± 167.16 vs 265.26 ± 122.16 pg/ml), while maintaining lower LH values ( P  < 0.05). The incidences of spontaneous LH surge and premature ovulation decreased significantly (1.0% vs 50%; 2% vs. 10.8%, respectively; P  < 0.05). A greater number of oocytes and viable embryos were harvested from the MPA group than from the natural cycle group ( P  < 0.05). Moreover,the clinical pregnancy rate was slightly higher in the MPA group than in the natural cycle controls, but the difference was not significant (11.8% vs 5.9%, P  > 0.05). Conclusion This study supported the hypothesis that P-primed minimal stimulation achieved ovulation control of the dominant follicle and did not adversely affect the quality of oocytes in poor responders. Therefore, P-priming is a promising approach to overcome premature ovulation in minimal stimulation for poor responders. Trial registration ChiCTR-OCH-14004176 . Registered on January 8, 2014.

In the mammalian ovary, progressive activation of primordial follicles from the dormant pool serves as the source of fertilizable ova. Menopause, or the end of female reproductive life, occurs when the primordial follicle pool is exhausted. However, the molecular mechanisms underlying follicle activation are poorly understood. We provide genetic evidence that in mice lacking PTEN (phosphatase and tensin homolog deleted on chromosome 10) in oocytes, a major negative regulator of phosphatidylinositol 3-kinase (PI3K), the entire primordial follicle pool becomes activated. Subsequently, all primordial follicles become depleted in early adulthood, causing premature ovarian failure (POF). Our results show that the mammalian oocyte serves as the headquarters of programming of follicle activation and that the oocyte PTEN-PI3K pathway governs follicle activation through control of initiation of oocyte growth.

PurposeThe aim of this study was to determine the autoimmune effects of ankylosing spondylitis (AS) on the fertility potential of women by evaluating ovarian reserves of AS patients.MethodsA total of 104 patients, 52 in the AS group (study group) and 52 in the control group were included in the study. Ovarian reserve was evaluated by serum anti-Müllerian hormone (AMH) levels, antral follicle count (AFC) and baseline serum follicle-stimulating hormone (FSH) levels.ResultsThe mean serum AMH levels were significantly lower in the study group when compared to the controls (2.203 ± 1.110 vs. 1.188 ± 0.891, p < 0.001). In addition, the mean AFC was also significantly lower in the study group. (10.67 ± 1.81 vs. 9.54 ± 2.50, p = 0.009). Mean FSH levels were calculated to be 6.72 ± 1.14 in the study group and 7.21 ± 1.22 in the control group. The difference was not statistically significant (p = 0.781).ConclusionThis study shows that AS like several other autoimmune conditions has an adverse effect on the female fertility potential. Therefore, an early start and long-term management of AS patients who have fertility desire is recommended. Serum AMH levels can be used in monitoring ovarian reserve and in early detection of reproductive decline of AS patients.ClinicalTrial NumberNCT04209881.

Background Cryopreservation and transplantation of ovarian tissue (OTCTP) represent a promising fertility preservation technique for prepubertal patients or for patients requiring urgent oncological management. However, a major obstacle of this technique is follicle loss due to, among others, accelerated recruitment of primordial follicles during the transplantation process, leading to follicular reserve loss in the graft and thereby potentially reducing its lifespan. This study aimed to assess how cryopreservation itself impacts follicle activation. Results Western blot analysis of the PI3K/PTEN/Akt and mTOR signalling pathways showed that they were activated in mature or juvenile slow-frozen murine ovaries compared to control fresh ovaries. The use of pharmacological inhibitors of follicle signalling pathways during the cryopreservation process decreased cryopreservation-induced follicle recruitment. The second aim of this study was to use in vitro organotypic culture of cryopreserved ovaries and to test pharmacological inhibitors of the PI3K/PTEN/Akt and mTOR pathways. In vitro organotypic culture-induced activation of the PI3K/PTEN/Akt pathway is counteracted by cryopreservation with rapamycin and in vitro culture in the presence of LY294002. These results were confirmed by follicle density quantifications. Indeed, follicle development is affected by in vitro organotypic culture, and PI3K/PTEN/Akt and mTOR pharmacological inhibitors preserve primordial follicle reserve. Conclusions Our findings support the hypothesis that inhibitors of mTOR and PI3K might be an attractive tool to delay primordial follicle activation induced by cryopreservation and culture, thus preserving the ovarian reserve while retaining follicles in a functionally integrated state.

Purpose Empirical treatment options for unexplained infertility treatment include controlled ovarian stimulation (COS) with clomiphene citrate, letrozole or gonadotropins followed by intrauterine insemination (IUI). Achieving consistent multifollicular development with letrozole generally requires addition of gonadotropins. However, the cost and discomfort of injections remains a drawback of this regimen. Therefore, there is a need for evolving newer cost-effective regimens for COS/IUI using orally administered drugs like letrozole. Methods Sixty couples with unexplained infertility (on standard infertility investigations) visiting the infertility clinic at a tertiary centre in North India were randomized into two groups. Group A COS was done by step-up protocol of letrozole from day 2 or 3 of menstrual cycle, starting with 2.5 mg and increased by 2.5 mg per day for next 3 days (2.5 mg, 5 mg, 7.5 mg, 10 mg). Group B COS was done with combination of letrozole and hMG (human menopausal gonadotropin). Starting from day 2 or 3 of menses, tablet letrozole 2.5 mg twice a day was given for 5 days. Intramuscular injection of hMG 150 IU was given every alternate day starting from day 7 and titrated according to the response. HCG was given when leading follicle was 17 mm and IUI done 36 h after HCG. Results Twenty-eight couples in letrozole step-up group (group A) and 30 couples in letrozole plus hMG group (group B), completed follow up for 44 and 55 cycles, respectively. Mean numbers of follicle ≥ 16 mm in both groups were comparable: 1.74 (± 0.83) in group A and 1.94 (± 0.68) in group B ( p  = 0.178). Ovulation rate of 90.9% (40/44) was achieved in group A, whereas it was 100% (55/55) in group B ( p  = 0.022), although there was no significant difference in clinical pregnancy rate per patient, which was 3/28 (10.7%) in group A versus 5/30 (16.67%) in group B ( p  = 0.707). The mean (SD) cost of medicines was significantly lower in group A Rs. 345.00 (00) compared to group B Rs. 2148.64 (515.67) [ p  < 0.0001]. There was one case each of hyperstimulation and multiple pregnancies in group B, while none in group A. Conclusion It is possible to achieve multifollicular development with use of novel letrozole step-up protocol, even without addition of gonadotropins, at significantly lower cost.

Background Costs of in vitro fertilisation (IVF) are high, which is partly due to the use of follicle stimulating hormone (FSH). FSH is usually administered in a standard dose. However, due to differences in ovarian reserve between women, ovarian response also differs with potential negative consequences on pregnancy rates. A Markov decision-analytic model showed that FSH dose individualisation according to ovarian reserve is likely to be cost-effective in women who are eligible for IVF. However, this has never been confirmed in a large randomised controlled trial (RCT). The aim of the present study is to assess whether an individualised FSH dose regime based on an ovarian reserve test (ORT) is more cost-effective than a standard dose regime. Methods/Design Multicentre RCT in subfertile women indicated for a first IVF or intracytoplasmic sperm injection cycle, who are aged < 44 years, have a regular menstrual cycle and no major abnormalities at transvaginal sonography. Women with polycystic ovary syndrome, endocrine or metabolic abnormalities and women undergoing IVF with oocyte donation, will not be included. Ovarian reserve will be assessed by measuring the antral follicle count. Women with a predicted poor response or hyperresponse will be randomised for a standard versus an individualised FSH regime (150 IU/day, 225-450 IU/day and 100 IU/day, respectively). Participants will undergo a maximum of three stimulation cycles during maximally 18 months. The primary study outcome is the cumulative ongoing pregnancy rate resulting in live birth achieved within 18 months after randomisation. Secondary outcomes are parameters for ovarian response, multiple pregnancies, number of cycles needed per live birth, total IU of FSH per stimulation cycle, and costs. All data will be analysed according to the intention-to-treat principle. Cost-effectiveness analysis will be performed to assess whether the health and associated economic benefits of individualised treatment of subfertile women outweigh the additional costs of an ORT. Discussion The results of this study will be integrated into a decision model that compares cost-effectiveness of the three dose-adjustment strategies to a standard dose strategy. The study outcomes will provide scientific foundation for national and international guidelines. Trial registration NTR2657

Background The role of ovarian reserve markers as predictors of the controlled ovarian stimulation (COS) response in intracytoplasmic sperm injection (ICSI) cycles in women with endometriosis has been much debated. The aim of the present study is to assess the predictability of ovarian reserve markers for the number of mature oocytes (MII) retrieved and to assess the pregnancy rate and live birth rate in women with advanced endometriosis. Methods Two hundred eighty-five infertile women who had laparoscopy followed by a first ICSI cycle were recruited in this prospective study. One hundred ten patients were diagnosed with endometriosis stage III-IV (group 1), and 175 patients had no endometriosis (group II). Sixty-three patients in group 1 had no history of previous endometrioma surgery (group Ia), and 47 patients had a history of previous endometrioma surgery (group Ib). Results The number of mature oocytes retrieved was significantly lower in women with advanced endometriosis than in women with no endometriosis. The number of mature oocytes retrieved in women with and without endometriosis was best predicted by antral follicle count (AFC) and age, whereas only AFC was a predictor in women with previous endometrioma surgery (odds ratio: 0.49; 95% confidence interval: 0.13-0.60). Women with endometriosis had a lower rate of live births than the control group, but this difference was not statistically significant; the number of live births was significantly lower in those with previous endometrioma surgery. Conclusions The best predictor of the COS response in ICSI was AFC, followed by age. Women receiving ICSI following surgery for ovarian endometrioma had a poorer clinical outcome and lower rate of live births compared with those with endometriosis but no previous surgery and the control group.

Purpose This study aimed to induce follicular wave emergence (FWE) using pharmacological (recombinant hCG administration) or mechanical (aspiration of dominant follicle) interventions in infertile women. Methods Sixteen infertile women (≤35 years) with indications for in vitro fertilization due to tubal and/or male factor infertility were randomized into three groups: control ( n  = 6), pharmacological ( n  = 5) and mechanical ( n  = 5) groups. Women in both experimental groups underwent serial transvaginal sonograms (TVS) from menstrual cycle day 10 until identification of a dominant follicle ≥15 mm. Women in the pharmacological group received 250 μg of recombinant-hCG to induce ovulation, and resumed serial TVS 2 days later. In the mechanical group, dominant and subordinate follicles ≥10 mm were aspirated, and daily TVS was resumed on the following day. An increased pool of follicles ≥5 and ≤9 mm after interventions characterized FWE. Women in the control group underwent ovulation induction (OI) with 150 IU/day of recombinant follicle-stimulating hormone started on menstrual cycle day 3 (D3). OI was started on the day of FWE in the experimental groups. Endometrial asynchrony with development of the embryo was expected in the experimental groups. Therefore, all viable embryos were cryopreserved and transferred in an endometrial-stimulated cycle. Results The number of follicles ≥5 and ≤9 mm increased after the interventions in both experimental groups ( p  < .001), indicating induction of FWE. OI outcomes were similar among the groups. Conclusions The pharmacological and mechanical interventions are efficient in inducing FWE; outcomes of OI synchronized with FWE should be further investigated.

Primordial follicle assembly in the mouse occurs during perinatal ages and largely determines the ovarian reserve that will be available to support the reproductive life span. The development of primordial follicles is controlled by a complex network of interactions between oocytes and ovarian somatic cells that remain poorly understood. In the present research, using single-cell RNA sequencing performed over a time series on murine ovaries, coupled with several bioinformatics analyses, the complete dynamic genetic programs of germ and granulosa cells from E16.5 to postnatal day (PD) 3 were reported. Along with confirming the previously reported expression of genes by germ cells and granulosa cells, our analyses identified 5 distinct cell clusters associated with germ cells and 6 with granulosa cells. Consequently, several new genes expressed at significant levels at each investigated stage were assigned. By building single-cell pseudotemporal trajectories, 3 states and 1 branch point of fate transition for the germ cells were revealed, as well as for the granulosa cells. Moreover, Gene Ontology (GO) term enrichment enabled identification of the biological process most represented in germ cells and granulosa cells or common to both cell types at each specific stage, and the interactions of germ cells and granulosa cells basing on known and novel pathway were presented. Finally, by using single-cell regulatory network inference and clustering (SCENIC) algorithm, we were able to establish a network of regulons that can be postulated as likely candidates for sustaining germ cell-specific transcription programs throughout the period of investigation. Above all, this study provides the whole transcriptome landscape of ovarian cells and unearths new insights during primordial follicle assembly in mice.

Vitrification is a well-accepted procedure for cryopreservation of gametes and embryos. Less is known, however, about its performance in preserving ovarian tissue, for which slow freezing is the current convention. Increasing interest is being focused on vitrification, but there are as yet no standard protocols for its use with ovarian tissue. In part, this is because of the variety of cell types and complex nature of ovarian tissue. We performed a meta-analysis of 14 studies that compared vitrification with slow freezing for cryopreservation of ovarian tissue. In the pooled analysis, there was no significant difference between the two methods in terms of the proportion of intact primordial follicles, but vitrification was associated with significantly less DNA damage. Secondary endpoints included the number of stromal cells, significantly higher with vitrification, and primordial follicle density, which did not differ between the two methods. The present meta-analysis suggests that vitrification may be more effective than slow freezing, with less primordial follicular DNA strand breaks and better preservation of stromal cells. These advantages should lead to improved ovarian function after transplantation.