Investigation into the ovary spurred by OTC, has demonstrated that our traditional description of the ovarian anatomy is inadequate as research in the field progresses. One obstacle to the advancement of knowledge in female fertility and reproduction is that there is a paucity of distinction between the different cellular and anatomical compartments of the ovary. In May-June 2021, Dr. Gomez-Lobo convened scientists from around the U.S. for several Division of Intramural Research (DIR) supported Ovarian Tissue Nomenclature Workshop meetings. Experts in reproductive endocrinology, gynecologic oncology, radiology, pathology, bioinformatics, and ovarian tissue research, met and created workgroups to further delineate ovarian follicle description, tissue ontology, and the 3-D description of the ovary. Resulting recommendations will establish the new national and international classification standards for ovary research which will allow for clearer evaluation of the function of the ovary at a gross and sub-anatomic level.
Workshop recommendations:
Workshop Sub-Groups
Gross Anatomy Workgroup Recommendations
The Ovarian Gross Anatomy Working Group recommended use of a three-dimensional (3D) regional model of the ovary based on the organ’s macroscopically visible structures and major points of fixation.
Sub-anatomy Workgroup Recommendations
The Subanatomy Working Group reviewed the current ontology of the ovary and proposed updates to the Uberon classification by referencing histologic features with a revised list of subanatomic structures, including cell types and extracellular features.
Follicle Workgroup Recommendations
The Follicle Classification Working Group recommended the expansion of the current classification system to include six stages of preantral follicles, five stages of antral follicles, three categories of abnormal preantral follicles, abnormal antral follicles, multi-oocytic follicles, and follicle variations of unknown significance (FVUS).
Table 1. Follicular morphological characteristics used in classification system
| Follicle Classes | Morphologic Characteristics | ||
|---|---|---|---|
| Preantral Follicle | Preantral Follicles with Normal Morphology | Primordial ovarian follicle | Oocyte surrounded by a continuous or an incomplete single layer of squamous granulosa cells. ~ 40 μm. |
| Transitional primordial ovarian follicle | Oocyte surrounded by a continuous or incomplete single layer consisting of both squamous and cuboidal granulosa cells. | ||
| Primary ovarian follicle | Oocyte surrounded by a complete single layer of cuboidal granulosa cells. ~ 40 μm. | ||
| Transitional primary ovarian follicle | Oocyte surrounded by reorganizing cuboidal granulosa cells that exist in a partial single and double layer; zona pellucida and theca layer may be visible. | ||
| Secondary ovarian follicle | Oocyte surrounded by 2-3 layers of cuboidal granulosa cells surrounded by the theca interna layer. Zona pellucida present. | ||
| Multilayer ovarian follicle | Oocyte surrounded by >3 layers of cuboidal granulosa cells with outer layer of theca cells. Zona pellucida present. | ||
| Preantral Follicle with Abnormal Morphological Features | Preantral Follicles with abnormal morphological features of oocyte [AMF-o] | Preantral follicles with vacuoles in oocyte and/or containing degenerating oocytes. | |
| Preantral Follicles with abnormal morphological features of granulosa cells [AMF-g] | Preantral follicles with vacuoles in granulosa cells and/or containing degenerating granulosa cells. | ||
| Preantral Follicles with abnormal morphological features in both oocytes and granulosa cells [AMF-og] | Preantral follicles with vacuoles in both oocytes and granulosa cells and/or containing both degenerating oocytes and granulosa cells. | ||
| Antral Follicle | Antral Follicles with Normal Morphology | Cumulus-enclosed oocyte in a fluid-filled space (antrum) surrounded by multiple layers of mural granulosa cells separated by a basement membrane from the adjacent layer of theca interna cells and the outermost layer of theca externa cells. Measured either histologically or on ultrasound. | |
| Early antral | Antral follicle with diameter < 2 mm on histology or imaging. ~ 100 μm. | ||
| Pre-selection | Antral follicle with diameter 2-5 mm on histology or imaging | ||
| Selection | Antral follicle with diameter 6-9 mm on histology or imaging | ||
| Dominance | Antral follicle with diameter 10-15 mm on histology or imaging | ||
| Ovulatory | Antral follicle with diameter 16-28 mm on histology or imaging. ~ 140 μm (“preovulatory”) | ||
| Atretic Antral Follicle with Normal Morphology | Antral follicle of any stage wherein granulosa cells proximal to the antrum detach from the mural layers that appear as single or multiple cells within the antrum; these granulosa cells typically have pyknotic nuclei; follicle may contain an oocyte with abnormal morphology. | ||
| Antral Follicle with Abnormal Morphological Features | Antral follicles containing a subset of atretic-appearing granulosa cells enclosing an oocyte with normal morphology. | ||
| Corpus Luteum (CL) and derivatives | CL of the Menstrual Cycle | Generally separated from the cortex by a thin band of medullary stromal cells. Yellow in appearance with a granulosa lutein layer, theca lutein layer, endothelium, and macrophages. | |
| CL of Pregnancy | Generally separated from the cortex by a thin band of medullary stromal cells. Contains a granulosa lutein layer and RNA is gathered into large rod-shaped clumps at the margin of the cytoplasm (unclear which type of cells) | ||
| Corpora Albicans (corpora albicantia) | Small white scars typically present in the medulla. Generally separated from the cortex by a thin band of medullary stromal cells. | ||
| Corpora Atretica | Generally separated from the cortex by a thin band of medullary stromal cells. | ||
| Hemorrhagic Anovulatory Follicle | When the preovulatory follicle fails to rupture or ovulate the oocyte and the antrum gets increasingly filled with blood. | ||
| Luteinized Unruptured Follicle | Oocytes trapped within CLs and expanded cumulus oocyte complexes within unruptured antral follicles, phenotypes consistent with failed ovulation. Found in reproductively older mice, mares, and monkeys. Humans? | ||
| Multioocytic follicles | ≥2 oocytes surrounded by squamous or cuboidal granulosa cells; represent germ cell cysts that have failed to breakdown. | ||
| Follicle Variations of Unknown Significance (FVUS) | Follicles that do no fit any above definition; i.e. large primordial follicles as observed in prepubertal ovaries. | ||
| Tangential | |||
A. Primordial: Oocyte surrounded by a continuous or an incomplete single layer of squamous granulosa cells. B. Transitional Primordial: Oocyte surrounded by a continuous or incomplete single layer consisting of both squamous and cuboidal granulosa cells. C. Primary: Oocyte surrounded by a complete single layer of cuboidal granulosa cells. D. Transitional Primary: Oocyte surrounded by reorganizing cuboidal granulosa cells in a partial single and double layer; zona pellucida and theca layer may be visible. E. Secondary: Oocyte surrounded by 2-3 layers of cuboidal granulosa cells with outer layer of theca cells. F. Multilayer: Oocyte surrounded by >3 layers of cuboidal granulosa cells with outer layer of theca cells G. Abnormal Morphological features of the oocyte (AMF-o): Vacuoles in oocyte and/or containing degenerating oocytes. H. Abnormal Morphological features of granulosa cells (AMF-g): Vacuoles in granulosa cells and/or containing degenerating granulosa cells. I. Abnormal morphological features in both oocytes and gcs (AMF-og): Vacuoles in both oocytes and granulosa cells and/or containing both degenerating oocytes and granulosa cells. J. Multi-oocytic: ≥2 oocytes surrounded by squamous or cuboidal granulosa cells; represent germ cell cysts that have failed to breakdown. K: Early Antral Follicle (<2mm diameter). L: Pre-selection Antral Follicle (2-5mm diameter). M: Selection Antral Follicle (6-9 mm diameter). N: Atretic Antral with Normal Morphology. O: Atretic Antral with Abnormal Morphology. P: Corpus Luteum. Q,R: Tangential cut. S: Tangential antral follicle cut. T: Capillary. U: Cross section of ovary. Example of calculating follicle density by using 1mm depth of the cortex to calculate area.
Workshop Participants
| Name | Affiliation |
|---|---|
| Christina Annunziata, MD, PhD | National Cancer Institute |
| G Thomas Brown, MD, PhD | Artificial Intelligence Resource; National Cancer Institute |
| Alan H DeCherney, MD | Reproductive Endocrinology and Infertility; Eunice Kennedy Shriver National Institute of Child Health and Human Development |
| Tazim Dowlut-McElroy, MD | Pediatric and Adolescent Gynecology Program; Eunice Kennedy Shriver National Institute of Child Health and Human Development |
| Francesca E Duncan, PhD | Department of Obstetrics and Gynecology; Feinberg School of Medicine, Northwestern University |
| Veronica Gomez-Lobo, MD | Pediatric and Adolescent Gynecology Program; Eunice Kennedy Shriver National Institute of Child Health and Human Development |
| Clarisa R Gracia, MD | Division of Reproductive Endocrinology and Infertility/Fertility Preservation; University of Pennsylvania Perelman School of Medicine |
| Stefan Gysler, MD | Division of Gynecologic Oncology; University of Pennsylvania Perelman School of Medicine |
| Lisa M Halvorson, MD | USMA-Bayer Pharmaceuticals (Current Affiliation) Affiliation at time of workshop: Gynecologic Health and Disease Branch; Eunice Kennedy Shriver National Institute of Child Health and Human Development |
| Tracy Harrison, MD | Reproductive Sciences; University of California San Diego |
| Junhyong Kim, PhD | University of Pennsylvania Perelman School of Medicine |
| Monica M Laronda, PhD | Stanley Manne Children's Research Institute, Ann & Robert H Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University |
| Richard D LeDuc, PhD | Children's Hospital Research Institute of Manitoba |
| Hong Lou, MD | Pediatric and Adolescent Gynecology Program; Eunice Kennedy Shriver National Institute of Child Health and Human Development |
| Marla Lujan, PhD | Division of Nutritional Sciences; Cornell University |
| Jacqueline Y Maher, MD | Pediatric and Adolescent Gynecology Program; Eunice Kennedy Shriver National Institute of Child Health and Human Development |
| Kathleen O’Neill, MD, MSTR | Division of Reproductive Endocrinology and Infertility; University of Pennsylvania Perelman School of Medicine |
| Kutluk H Oktay, MD, PhD | Department of Obstetrics, Gynecology, and Reproductive Sciences; Yale University School of Medicine |
| Stephanie A Pangas, PhD | Department of Pathology and Immunology; Baylor College of Medicine |
| Alison Pouch, PhD | Departments of Radiology & Bioengineering: University of Pennsylvania Perelman School of Medicine |
| Rebecca Rakow-Penner, MD, PhD | Department of Radiology; University of California San Diego |
| Julie Rios, MD | Reproductive Endocrinology and Infertility; University of Pittsburgh (Present affiliation) |
| Erin Rowell, MD | Associate Professor of Surgery; Northwestern University Feinberg School of Medicine |
| Lauren E Schwartz, MD | Department of Pathology; University of Pennsylvania Perelman School of Medicine |
| James Segars, MD | Reproductive Science and Women’s Health Research; Johns Hopkins University |
| Ariella Shikanov, PhD | Department of Biomedical Engineering, Department of Obstetrics and Gynecology; University of Michigan |
| Susan Taymans, PhD | Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health |
| Candace Tingen, PhD | Gynecologic Health and Disease Branch; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health |
| Elizabeth L Tsui, BS | Stanley Manne Children's Research Institute, Ann & Robert H Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University |
| Mary B Zelinski, PhD | Oregon National Primate Research Center; Oregon Health & Science University |
Publications
- Tsui EL, O'Neill KE, LeDuc RD, Shikanov A, Gomez-Lobo V, Laronda MM. Creating a common language for the subanatomy of the ovary. Biol Reprod. 2022 Oct 29:ioac199. doi: 10.1093/biolre/ioac199. Epub ahead of print. PMID: 36308436.
- O'Neill KE, Maher JY, Laronda MM, Duncan FE, Leduc RD, Lujan ME, Oktay KH, Pouch AM, Segars JH, Tsui EL, Zelinski MB, Halvorson LM, Gomez-Lobo V. Anatomic Nomenclature and 3D Regional Model of the Human Ovary: Call for a New Paradigm. Am J Obstet Gynecol. 2022 Sep 30:S0002-9378(22)00795-5. doi: 10.1016/j.ajog.2022.09.040. Epub ahead of print. PMID: 36191605.
BACK TO TOP