Cholesterol uptake or trafficking, steroid biosynthesis, and gonadotropin responsiveness are defective in young poor responders

Bildik, Gamze; Esmaeilian, Yashar; Hela, Francesko; Akin, Nazlı; İltumur, Ece; Yusufoglu, Sevgi; Yildiz, Ceren Sultan; Yakın, Kayhan; Öktem, Özgür

doi:10.1016/j.fertnstert.2022.01.024

Cited by 15 publications

(10 citation statements)

References 44 publications

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“…Resveratrol can increase mitochondrial mass in human granulosa cells (GC) through a mechanism involving reduction of voltage-dependent potassium currents, intracellular calcium homeostasis, and regulation of mitomiRNAs (28, 29). Women with reduced ovarian responsiveness exhibit reduced mitochondrial mass, cholesterol uptake capacity and expression of enzymes involved in steroidogenesis, such as StAR (Steroidogenic Acute Regulatory), 3-betahydroxysteroid dehydrogenase (3-beta-HSD) and aromatase, compared with normal responders (30). Low expression of these enzymes leads to a reduced estrogen and progesterone production even after OS.…”

Section: Discussionmentioning

confidence: 99%

The impact of Resveratrol on the outcome of the in vitro fertilization: a pilot randomized controlled trial

Conforti,

Iorio,

Girolamo

et al. 2024

Preprint

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Background Resveratrol is a natural polyphenolic compound present in plants and red wine with many potential health benefits. This compound has various anti-inflammatory and anti-tumor properties and can improve cellular mitochondrial activity. This pilot trial was designed to evaluate the effect on the outcome of IVF of Resveratrol supplementation in women > 35 years with good ovarian reserve (AMH > 1.2 ng/ml). Women were randomized to receive or placebo or Resveratrol (150 mg twice per day) for three months preceding the ovarian stimulation (OS). All patients were stimulated with a starting dose of recombinant FSH ranging between 150 and 300 IU according to age and ovarian reserve. GnRH antagonist flexible protocol was adopted for pituitary suppression. Triggering was performed with urinary hCG (10.000 IU). Results The study was conducted between January 2019 and December 2022 with aa total of 37 cases and 33 controls were recruited. A statistically significant increase in the follicle output rate (FORT) and follicle-to oocyte index (FOI) in women treated with resveratrol was observed compared with control group (0.92 versus 0.77 [p = 0.02], and 0.77 versus 0.64 [p = 0.006], respectively). No statistically significant differences in the number of oocytes retrieved, biochemical pregnancy, clinical pregnancy and live birth rates were observed between groups. Conclusions Preliminary results from this study indicate that pre-treatment with resveratrol may improve ovarian sensitivity to exogenous FSH, which in turn may decrease the risk of hypo-response to OS.

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Section: Discussionmentioning

confidence: 99%

The impact of Resveratrol on the outcome of the in vitro fertilization: a pilot randomized controlled trial

Conforti,

Iorio,

Girolamo

et al. 2024

Preprint

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“…The demographic characteristics of the patients are summarized in Supplementary Table S1 . Primary luteinized granulosa cells (GCs) were obtained from follicular aspirates of the patients ( n = 95) during the oocyte retrieval procedure as described previously [ 9 , 13 – 15 ]. Ovarian stimulation with gonadotropin hormones was performed with the same protocol (recombinant FSH and gonadotropin-releasing hormone antagonist) in all patients.…”

Section: Methodsmentioning

confidence: 99%

“…Patient-derived ovarian corpus luteum (CL) tissue samples, primary luteinized granulosa cells, and immortalized mitotic non-luteinized granulosa cell line (HGrC1) were used to study the role of autophagy in progesterone (P 4 ) and estrogen (estradiol:E 2 ) synthesis arms of steroidogenesis, respectively. CL and luteinized GCs are frequently used by our group and other researchers to study ovarian biology, steroidogenesis and luteal phase characteristics of IVF cycles [ 9 , 13 , 15 – 19 ]. To investigate the role of autophagy in estrogen synthesis of the steroidogenic pathway, we utilized mitotic human granulosa cell line HGrC1, which is a non-luteinized granulosa cell line expressing enzymes related to steroidogenesis, such as steroidogenic acute regulatory protein (StAR), aromatase and gonadotropin receptors.…”

Section: Methodsmentioning

confidence: 99%

Autophagy regulates sex steroid hormone synthesis through lysosomal degradation of lipid droplets in human ovary and testis

et al. 2023

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Autophagy is an evolutionarily conserved process that aims to maintain the energy homeostasis of the cell by recycling long-lived proteins and organelles. Previous studies documented the role of autophagy in sex steroid hormone biosynthesis in different animal models and human testis. Here we demonstrate in this study that sex steroid hormones estrogen and progesterone are produced through the same autophagy-mediated mechanism in the human ovary in addition to the human testis. In brief, pharmacological inhibition and genetic interruption of autophagy through silencing of autophagy genes (Beclin1 and ATG5) via siRNA and shRNA technologies significantly reduced basal and gonadotropin-stimulated estradiol (E2), progesterone (P4) and testosterone (T) production in the ex vivo explant tissue culture of ovary and testis and primary and immortalized granulosa cells. Consistent with the findings of the previous works, we observed that lipophagy, a special form of autophagy, mediates the association of the lipid droplets (LD)s with lysosome to deliver the lipid cargo within the LDs to lysosomes for degradation in order to release free cholesterol required for steroid synthesis. Gonadotropin hormones are likely to augment the production of sex steroid hormones by upregulating the expression of autophagy genes, accelerating autophagic flux and promoting the association of LDs with autophagosome and lysosome. Moreover, we detected some aberrations at different steps of lipophagy-mediated P4 production in the luteinized GCs of women with defective ovarian luteal function. The progression of autophagy and the fusion of the LDs with lysosome are markedly defective, along with reduced P4 production in these patients. Our data, together with the findings of the previous works, may have significant clinical implications by opening a new avenue in understanding and treatment of a wide range of diseases, from reproductive disorders to sex steroid-producing neoplasms, sex steroid-dependent malignancies (breast, endometrium, prostate) and benign disorders (endometriosis).

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“…This very close relationship between androgen production and folliculogenesis was the rationale of the study conducted by Prof Okten's team in Turkey (16). The main objective here was to perform an extended analysis of the steroidogenic capacity of human luteinized granulosa cells obtained in young patients who experimented hypo-response to ovarian stimulation related to poor ovarian reserve.…”

Section: Relationship Between Ovarian Sensitivity To Fsh and Steroido...mentioning

confidence: 99%

“…Therefore, to validate the interest of a long-term hCG priming, the authors suggested to design a new study with the collection of follicular fluid from antral follicles before and immediately after priming in order to measure androgen levels and Androgen receptor and FSH receptor expression in small follicles (58). Additionally, these negative results should be interpreted in light of the data reported by Okten's team (16). Indeed, the significant deficit in basal / stimulated ovarian steroidogenesis reported in young poor responders could definitely explained the absence of positive effect of hCG administration.…”

Section: Stimulation Of Androgen Production (Lh-hcg-aromatase Inhibit...mentioning

confidence: 99%

Subtle perturbations of ovarian steroidogenesis in patients classified as Poseidon Group 3. Which consequences for therapeutic strategy?

Hugues

2024

Front. Endocrinol.

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The optimal strategy for stimulation of young women with a low ovarian reserve is still a challenging issue because the physio-pathogeny of this disorder is often unknown. As androgen production by the ovary plays a crucial role in folliculogenesis, it was tempting to speculate that subtle perturbations in ovarian steroidogenesis might participate to the low responsiveness to gonadotrophins. Indeed, in vitro analysis of human luteinized granulosa cells has recently provided evidence for some enzymatic deficits in steroidogenesis and altered response to gonadotrophins. Therefore, improving androgen environment of women classified in Poseidon Group 3 should be considered. In this clinical situation, the potential benefit of androgen supplementation or stimulation of theca cells by LH-activity products are respectively discussed.

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Cholesterol uptake or trafficking, steroid biosynthesis, and gonadotropin responsiveness are defective in young poor responders

Cited by 15 publications

References 44 publications

The impact of Resveratrol on the outcome of the in vitro fertilization: a pilot randomized controlled trial

The impact of Resveratrol on the outcome of the in vitro fertilization: a pilot randomized controlled trial

Autophagy regulates sex steroid hormone synthesis through lysosomal degradation of lipid droplets in human ovary and testis

Subtle perturbations of ovarian steroidogenesis in patients classified as Poseidon Group 3. Which consequences for therapeutic strategy?

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