Granulosa cells are significant components of ovarian follicles. They are somatic support cells that surround and sustain the developing oocyte while orchestrating every stage of follicle maturation. Far from passive bystanders, they are metabolically active conductors of hormone synthesis, follicular development, and reproductive timing. Derived from the ovarian surface epithelium, granulosa cells proliferate in sync with the oocyte, forming a multilayered follicular environment that shapes fertility from a foundational level.
Follicular Formation and Specialization
Initially, in primordial cells (the most immature stage of ovarian follicles), granulosa cells present as flattened precursors. As the follicle matures into primary and secondary stages (progressive phases in folliculogenesis marked by oocyte growth and granulosa cell proliferation), these cells transition into a cuboidal shape, denoting their increased metabolic and steroidogenic activity [1]. The transition from a monolayer to a stratified structure leads to two distinct cell populations: mural granulosa cells and cumulus granulosa cells.
Mural granulosa cells line the follicular wall and are essential for producing estradiol (a key estrogen that helps thicken the uterine lining and regulate the menstrual cycle). They express follicle-stimulating hormone (FSH) receptors and play a key role in the conversion of androgens into estrogens via the aromatase enzyme (CYP19A1) [2–3]. Meanwhile, cumulus cells form a cluster surrounding the oocyte, and are fundamental in the oocyte’s maturation and development. This occurs through paracrine signaling and metabolic transfer, while maintaining gap junctional communication. These interactions allow bidirectional signaling, with oocyte-derived growth differentiation factor 9 (GDF9) and bone morphogenic protein 15 (BMP15) [4–5].
Endocrine Coordination
Granulosa cells respond to key hormones, FSH (follicle-stimulating hormone) and LH (luteinizing hormone), to help guide the stages of follicle development. In the early phases, FSH tells granulosa cells to produce aromatase, an enzyme that helps make estrogen. They also produce anti-Müllerian hormone (AMH), which helps control how many follicles start to grow at once and protects the long-term egg supply [6–7]. By the time the follicle matures, granulosa cells have generated receptors for LH. This allows them to prepare for and wait for the LH surge that triggers ovulation. This surge sets off a cascade of genetic switches that push the follicle towards ovulation and prepare it for the next phase [8–9]. After ovulation, granulosa cells change into luteal cells, start making progesterone (a hormone essential for preparing the uterus for implantation and supporting early pregnancy), and stop producing estrogen.
The Ovulatory Switch
The LH surge plays a critical role in the transition of granulosa cells from a proliferative state to pro-ovulatory agents during the ovulatory process. This surge sets off a chain reaction of events that activate enzymes, like matrix metalloproteinases (MMPs), which break down parts of the follicle wall [10]. This remodeling process is essential because it allows the mature egg to be released from the follicle during ovulation. This transformation is closely regulated, involving exact changes in cytoskeleton configuration, extracellular matrix digestion, and vascular recruitment to promote rupture as well as luteinization.
From Harmony to Dysfunction
When granulosa cells malfunction, reproductive outcomes suffer. Conditions such as polycystic ovary syndrome (PCOS) involve granulosa cells showing disrupted follicle-stimulating hormone (FSH) signaling and elevated androgen levels, leading to follicular arrest, which is a crucial factor in women’s reproductive health and fertility [11]. In another condition, premature ovarian insufficiency (POI), depleted or apoptotic granulosa cells halt early to cease the reproductive function. Finally, granulosa cell tumors serve as a different pathological state characterized by uncontrolled proliferation of cells and excessive estrogen production, which objectifies their powerful endocrine role within ovarian physiology [12].
These cells have served as critical biomarkers of assisted reproductive technologies (ART), with their gene expression profiles and steroidogenic activities reflecting an oocyte’s potential embryo quality. For example, changes in hormone expression of hormones like estradiol were found to impact oocyte maturation and the subsequent development of embryos [13]. Their gene expression, steroid profiles, and sensitivity to gonadotropins have served as biomarkers for oocyte quality and embryo potential. This has offered critical insights into IVF outcomes.
Orchestrating More Than Ovulation
Outside of the ovary, granulosa cells play a crucial role in managing systemic hormonal balance. Their secretion of estrogen and progesterone regulates uterine preparedness, influences the hypothalamic-pituitary-ovarian axis, and impacts broader metabolic and cardiovascular health. Any dysfunction or loss of granulosa cell activity affects numerous organs, highlighting their importance as hormonal monitors, not merely as facilitators of fertility.
In conclusion, while the contributions of granulosa cells may still not be fully understood, they are essential for every successful ovulation and potential pregnancy. They orchestrate whole reproductive processes, from arranging the egg sac to maintaining hormonal homeostasis, and nurturing the oocyte as it transitions into progesterone-producing luteal cells. In fertility research and clinical settings, these cells are seen not just as tools for reproduction but also as potential therapeutic targets for hormonal imbalances, ageing issues, and infertility challenges. Subtle yet essential, granulosa cells shape the hormonal symphony behind every ovulation and pregnancy.
Recognizing and appreciating the labs working in this space
- Pepin Lab: Massachusetts General Hospital, Boston, MA, USA https://www.pepinlab.com/ , LinkedIn: https://www.linkedin.com/in/david-pepin-02762133/ , X: @pepinlab
- Telfer Lab: University of Edinburgh, Edinburgh, Scotland https://www.research.ed.ac.uk/en/persons/evelyn-telfer
- Suh Lab: Columbia University, New York, NY, USA https://www.yousinsuhlab.org/
- Conley Lab: University of California, Davis, CA, USA https://www.vetmed.ucdavis.edu/faculty/alan-conley, FB: https://www.facebook.com/UCDavisVetMed, IG: @ucdavisvetmed , X: @ucdavisvetmed
- Walton Lab: University of Queensland, St Lucia, Australia https://biomedical-sciences.uq.edu.au/research/groups/reproductive-growth-factors , FB: https://www.facebook.com/uniofqld, LinkedIn: https://www.linkedin.com/school/university-of-queensland/, IG: @uniofqld, X:@uqnews
- Garcia-Guerra Lab: Ohio State, Columbus, OH, USA https://u.osu.edu/osurepro/research/
- Seli Lab: Yale School of Medicine, New Haven, CT, USA https://medicine.yale.edu/profile/emre-seli/ , IG: @seli.lab
- So-Youn Kim Lab: University of Nebraska Medical Center, Omaha, NE, USA https://www.unmc.edu/obgyn/research/academic-research/kim/index.html, FB: https://www.facebook.com/unmccom, X: @UNMCCOM
- Clark Lab: UCLA, Los Angeles, CA, USA https://clark.mcdb.ucla.edu/research/
- Pisarska Lab: Cedars-Sinai, Los Angeles, CA, USA https://www.cedars-sinai.edu/health-sciences-university/research/labs/pisarska.html , FB: https://www.facebook.com/CedarsSinaiHealthSciencesUniversity/, LinkedIn: https://www.linkedin.com/company/cedars-sinai-health-sciences-university/ , IG: @cedarssinaihsu
References
- Wang XL, Wu Y, Tan LB, et al. Follicle-stimulating hormone regulates pro-apoptotic protein Bcl-2-interacting mediator of cell death-extra long (BimEL)-induced porcine granulosa cell apoptosis. J Biol Chem. 2012;287(13):10166–10177. doi:10.1074/jbc.M111.293274
- Matsui T, Manabe N, Goto Y, Inoue N, Nishihara S, Miyamoto H. Expression and activity of Apaf1 and caspase-9 in granulosa cells during follicular atresia in pig ovaries. Reproduction. 2003;126(1):113–120. doi:10.1530/rep.0.1260113
- Wang X, Li C, Wang Y, Li L, Han Z, Wang G. UFL1 Alleviates LPS-Induced Apoptosis by Regulating the NF-κB Signaling Pathway in Bovine Ovarian Granulosa Cells. Biomolecules. 2020;10(2):260. Published 2020 Feb 9. doi:10.3390/biom10020260
- Maeda A, Goto Y, Matsuda-Minehata F, Cheng Y, Inoue N, Manabe N. Changes in expression of interleukin-6 receptors in granulosa cells during follicular atresia in pig ovaries. J Reprod Dev. 2007;53(4):727–736. doi:10.1262/jrd.19011
- Nakayama M, Manabe N, Inoue N, Matsui T, Miyamoto H. Changes in the expression of tumor necrosis factor (TNF) alpha, TNFalpha receptor (TNFR) 2, and TNFR-associated factor 2 in granulosa cells during atresia in pig ovaries. Biol Reprod. 2003;68(2):530–535. doi:10.1095/biolreprod.102.004820
- Aghssa MM, Tarafdari AM, Tehraninejad ES, et al. Optimal cutoff value of basal anti-mullerian hormone in iranian infertile women for prediction of ovarian hyper-stimulation syndrome and poor response to stimulation. Reprod Health. 2015;12:85. Published 2015 Sep 10. doi:10.1186/s12978–015–0053–4
- Yucel Cicek OS, Gezer S, Cakir O, Hekimoglu Gurbuz R. Extremely high anti-Mullerian hormone levels detected during infertility workup revealing sex cord tumor with annular tubules and underlying Peutz-Jeghers syndrome: A case report. J Obstet Gynaecol Res. 2022;48(2):492–496. doi:10.1111/jog.15107
- Ren YA, Liu Z, Mullany LK, Fan CM, Richards JS. Growth Arrest Specific-1 (GAS1) Is a C/EBP Target Gene That Functions in Ovulation and Corpus Luteum Formation in Mice. Biol Reprod. 2016;94(2):44. doi:10.1095/biolreprod.115.133058
- Jin H, Won M, Park SE, Lee S, Park M, Bae J. FOXL2 Is an Essential Activator of SF-1-Induced Transcriptional Regulation of Anti-Müllerian Hormone in Human Granulosa Cells. PLoS One. 2016;11(7):e0159112. Published 2016 Jul 14. doi:10.1371/journal.pone.0159112
- Naredi N, Singh SK, Sharma R. Does Perifollicular Vascularity on the Day of Oocyte Retrieval Affect Pregnancy Outcome in an In Vitro Fertilization Cycle?. J Hum Reprod Sci. 2017;10(4):281–287. doi:10.4103/jhrs.JHRS_43_17
- Mao Z, Fan L, Yu Q, et al. Abnormality of Klotho Signaling Is Involved in Polycystic Ovary Syndrome. Reprod Sci. 2018;25(3):372–383. doi:10.1177/1933719117715129
- Nishimura H, Ikawa Y, Kajikawa E, et al. Maternal epigenetic factors in embryonic and postnatal development. Genes Cells. 2023;28(6):422–432. doi:10.1111/gtc.13024
- Yang G, Yao G, Xu Z, et al. Expression Level of ADAMTS1 in Granulosa Cells of PCOS Patients Is Related to Granulosa Cell Function, Oocyte Quality, and Embryo Development. Front Cell Dev Biol. 2021;9:647522. Published 2021 Apr 12. doi:10.3389/fcell.2021.647522
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DR. CHRISTY KESTNER
Content Editor The League of Extraordinary Cell Types, Sci-Illustrate Stories
Dr. Christy Kestner holds a PhD in Neuroimmunology from the Medical University of South Carolina (MUSC), where she studied how complement drives pathological conditions related to neuroinflammation and brain injury (stroke and traumatic brain injury), as well as approaches to reduce harmful complement activation. She later conducted postdoctoral research in oncology therapeutic development, investigating new drug targets for pancreatic cancer. Dr. Kestner currently works as a scientific and medical writer, creating educational content and op-eds for science and health communication platforms. She also runs her own science communication platform, Brain & Beyond, aimed at translating complex research into accessible content. Passionate about science storytelling, she is dedicated to making immunology and neuroscience both accurate and engaging for diverse audiences.
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The League of Extraordinary Cell types
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