The Ovary:
Ovaries are where oogenesis occurs in the female reproductive tract. The ovaries are paired with one lying on either side of the uterus. When a female reaches sexual maturity, her ova are released by a process known as ovulation that is ultimately controled by a series of hormone fluctuations characterizing the menstral cycle. The major hormones that control ovary hormone production and activity are luteinising hormone (LH) and follicle stumilating hormone (FSH) (Young et al, 2000).
Origin of the Tissue:
The development of the ovary tissue begins at approximately 5 weeks following fertilization. At this time the coelomic epithelium thickens to form a genital ridge. This thickened epithelium continues to proliferate as well as the adjacent mesenchyme. The yolk sac endoderm is formed by primordial germ cells known as oogonia that undergo mitosis. Only about 1 third of these cells make it to full term, the rest undergo atresia. At 3-4 months gestation these oogonia switch from mitosis to meiosis becoming primary oocytes arrested in meiotic prophase. By this time the ovary is a recognizable structure, it has a definite cortex, contains pregranulosa cells and is penetrated by vascular connective tissue. The pregranulosa cells then surround germ cells forming primordial follicles and folliculargenesis begins in the inner cortex of the ovary, extending to the outer cortex in the early neonate (Wagenen et al., 1965).
Histology:
Surface Epithelium:
- single, focally pseudostratified layer of modified peritoneal cells.
- Cell Shape: flat, cuboidal, columnar or a mixture in different areas
of one ovary.
- Epithelial cells separated from stroma by a basement membrane.
- Gylcogen and acidic and neutral mucopolysaccharides (long
unbranched polysaccharides with a repeating disaccharide unit)
in epithelial cells.
- Apical region is dome shaped covered by either microvilli,
cilia or pinocytotic vesicles.
- The cytoplasm contains numerous free ribosomes, polysomes, intermediate filaments and mitochondria (Mills, 2007).
- Lateral surfaces of epithelial cells are joined by junctional complexes, desmosomes and desmosomal-tonofilament complexes (Ferenczy et al., 1974).
Stroma:
- Composed of a cortex and a medulla with a poorly defined boundary.
- Contains spindle-shaped cells with very little cytoplasm.
- Cytoplasmic lipid droplets present especially in late reproductive or postmenopausal ovaries (Fienberg et al., 1965).
- Cells are located in a reticulum network containing collagen in various abundances.
- Luteinized stromal cells are present in the medulla with abundant cytoplasm and are increased in pregnancy and after menopause (Mills, 2007). 
Primordial Follicles:
- At birth a female has approximately 400,000 primordial follicles in the cortex of the ovary.
- Atresia and folliculogenesis then begin decreasing this number till menopause at which there is none left. Minor exceptions occur in which few follicles remain after menopause accounting for post menopausal bleeding caused by sporadic ovulation (Dawood et al., 1980).
- Primordial follicles contain the centrally located primary oocyte surrounded by a single layer of mitotically active granulosa cells (Mills, 2007).
Maturing Follicles:
- Maturing follicles appear during the luteal phase of the menstrual cycle.
- During each cycle only one follicle will mature (dominant follicle) and its oocyte released in ovulation.
- Other follicles eliminated by atresia.
- Maturation is characterized by the transition from a flattened granulosa cell to a columnar or cuboidal shape as well as an enlargement of the oocyte (Primary follicle).
- Granulosa cells surrounding the oocyte undergo mitosis and form concentric layers (Mills, 2007). 
- An eosinophilic, acellular Zona Pellucida then develops surrounding the centralized oocyte (Ferenczy et al., 1974).
- Granulosa cells secrete mucopolysaccharide-rich fluid during mature follicle development that forms a large cavity within the follicle known as an antrum. The oocyte enlarges also and is located at one pole of the follicle and protrudes into the antrum surrounded by the cumulus oophorus. The cumulus oophorus is composed of granulosa cells. This mature follicle may also be refered to as the Graafian follicle (Mills, 2007).
Ovulation:
- In the late stages of follicular development the oocyte encased in the zona pellucida and a thin layer of granulosa cells known as the corona radiata are released from the protruding cumulus oophorus into the antrum.
- At this stage the preovulatory follicle is at its maximum size (15-25mm) and it protrudes from the ovary surface where the stroma and epithelial cells degenerate.
- The oocyte in the preovulatory follicle enters telophase of meiosis I and is thereafter known as a secondary oocyte.
- The secondary oocyte is then expelled into the peritoneal cavity. The secondary oocyte then begins meiosis II arresting in metaphase until it is fertilized by a sperm (Balboni, 1983 and Mills, 2007).
Corpus Luteum of Menstration:
- Following ovulation, the release of the oocyte from the ovulatory follicle, if fertilization does not occur this collapsed follicle becomes the Corpus Luetum of Menstration. This structure fills with a blood clot and acts as an endocrine organ for a brief period of time (Mills, 2007).
- The anterior pituitary at this time is secreting Luteinizing Hormone (LH) which induces an increase in granulosa cell size.
- These granulosa cells then secrete progesterone which helps prepare the endometrium for implantation of a fertilized egg.
- Since Progesterone creates a negative feedback on the secretion of luteinizing hormone, if fertilization does not occur, after about 14 days the corpus luteum becomes the functionless corpus albicans.
- If fertilization does occur however Human Chorionic Gonadotrophin (HCG) functions just as LH, maintaining the corpus luteum until the placenta takes over the role of progesterone secretion (Young et al., 2000).
Ovarian Pathology: Granulosa Cell Tumor
In the human population, sex cord-stromal tumors account for just 10% of all ovarian tumors, with the stromal cells – thecal or granulosa – as the cell of tumour origin. Of the sex-cord stromal class of ovarian tumour, approximately half of the cases are derived from granulosa cells (GC) that surround the oocyte (Young et al., 2003). Unlike ovarian tumors derived from the surface epithelium that appear primarily in older women, GC tumors can appear in both pre-pubertal girls and post-menopausal women.
Clinical Presentation:
· Abnormal uterine bleeding.
· Abdominal pain.
· Menstrual irregularities when occurrence in the reproductive age group.
· Postmenopausal women: bleeding and or a pelvic or abdominal mass.
· Can be associated with endometrial hyperplasia (excessive proliferation of endometrial cells).
· Breast enlargement (over production of estrogen from tumor may be the cause).
· Juvenile cases - precocious puberty, breast development, increased pubic hair, advanced growth and bone age.
· Can metastasis, most commonly to lymph node, lungs, liver and brain. · Have a strong tendency to reoccur, often several years (up to 25) after initial diagnosis.
(Koukourakis et al., 2008).
Pathology:
Granulosa cell tumors are solid tumors and are often cystic. Cysts are filled with either serous fluid or clotted blood. The appearance is often dependent on the amount of lipid present in the lesion but can rage from yellow to grey. These tumors can exhibit a wide range of differentiation (Koukourakis et al., 2008).
Granulosa cell tumor from a 44 year old female. In this figure you can see the yellow colored tumor that has broken through the ovary surface (link to source).
Cut surface of a granulosa cell tumor, showing a hemorrhagic cyst common of these tumors (link to source).
Prognostic Factors:
· Due to the extended follow up that these tumor occurrences require because of their nature to reoccur up to 25 years after initial diagnosis, this data is hard to collect.
· 10 year survival rate is between 60-90% however the 25 year survival rate decreases to 40- 60%.
· Prognostic factors also depend on what stage of the disease you present with. As stage increases (I-IV) the percent survival rate decreases.
Treatment:
1. Surgical Management
2. Radiation Therapy
3. Chemotherapy
For more information on Granulosa Cell Tumors of the ovary please refer to the following helpful papers found through PubMed:
References:
Balboni GC. Structural changes: ovulation and luteal phase. In: Serra GB,
ed. The Ovary. New York: Raven Press; 1983:123-141.
Dawood MY, Strongin M, Kramer EE, Wieche R. Recent ovulation in a
postmenopausal woman. Int J Gynaecol Obstet 1980;18:192-194.
Ferenczy A, Richart RM. Female Reproductive System: Dynamics of Scan and
Transmission Electron Microscopy. New York: John Wiley & Sons; 1974.
Fienberg R, Cohen RB. A comparative histochemical study of the ovarian
stromal lipid band, stromal theca cell, and normal ovarian follicular apparatus.
Am J Obstet Gynecol 1965;92:958-969.
Koukourakis V et al. Granulosa cell tumor of the ovary: Tumor Review. Integr Cancer Ther 2008;(3):204-15.
Mills, Stacey E. Histology for Pathologists. 3rd ed. Lippincott Williams & Wilkins, 2007.
Van Wagenen G, Simpson ME. Embryology of the Ovary and Testis in Homo Sapiens
and Macaca Mulatta. New Haven: Yale University Press; 1965.
Reeves G. Specific stroma in the cortex and medulla of the ovary. Cell type
and vascular supply in relation to follicular apparatus and ovulation. Obstet
Gynecol 1971;37:832-844.
Van Wagenen G, Simpson ME. Embryology of the Ovary and Testis in Homo Sapiens
and Macaca Mulatta. New Haven: Yale University Press; 1965.
Young, Barbara, and John W. Heath. Wheater's Functional Histology A Text and Colour Atlas. 4th ed. Spain: Churchill Livingstone, 2000.
Young JL, Jr., Cheng Wu X, Roffers SD, Howe HL, Correa C, Weinstein R. Ovarian cancer in children and young adults in the United States, 1992-1997. Cancer 2003;97(10 Suppl):2694-700.
