Well, time flies like an arrow but fruit flies like a banana…
(By the way, that doesn’t look like a fruit fly on the right. To me, it looks like a common house fly. But I digress.)
Seems like just last week when I wrote a post about the embryonic differentiation and development of ovaries and testes, the genes that control these processes and what happens when the genetics go awry. But actually, it was almost a year ago.
Now, it’s finally time to talk about normative functioning of the human ovary which is, hopefully, a prelude to a discussion about Polycystic Ovary Syndrome (PCOS) in trans men.
So what does the human ovary look like? According to Gray’s Anatomy – The Classic Collector’s Edition:
The ovaries are of a grayish-pink color, and present either a smooth or puckered, uneven surface. They are each about an inch and a half in length, three-quarters of an inch in width, and about a third of an inch thick, and weigh from one to two drachms.
Wait, what’s a drachm?
Anyway, in the photomicrograph below you can see the cross-section of an ovary from an adult primate, which is very similar to a human ovary. You can see two “zones” of the organ: an outer cortex where the follicles are mainly located and an inner medulla made up of mostly stroma. The hilum, the structure that anchors the ovary, is where the blood and lymph vessels and nerves enter the organ.
As you can see in the photomicrograph, the follicles, which contain the eggs, are in different stages of development in the adult. As a refresher on these structures, here is a description of their embryonic development from a previous post:
By approximately 28 weeks in the fetal stage, most of the follicles are present and are no longer organized in cords. The follicles form when somatic cells (i.e. cells that are not germ cells) aggregate in a single layer around the oocytes in the embryonic ovaries. At this stage, they’re known as “primordial follicles” and they reside in mostly the cortex, although some can be found deeper in the embryonic ovary, closer to the medulla which has grown and become even more vascularized with blood vessels. In this phase of development, the layer of cells around the oocytes differentiate into granulosa cells which communicate with the oocytes and stop meiosis in the immature eggs.
By the late fetal stage, the human ovary is stocked with 5 to 6 million oocytes that are arrested partway through meiosis and reside in primordial follicles that are made up of a single cell envelope of granulosa cells. By the time of birth, the number of oocytes has dropped to approximately 2 million.
And so at birth, the ovarian cortex contains oocytes (immature eggs) that are arrested part way through meiosis and are encased in primordial follicles. How do the primordial follicles get to the different stages that we see in the photomicrograph above, and why is this important?
To answer that, I hope you don’t mind that I skip over puberty and just talk about the different stages of follicle development in the adult ovary, called folliculogenesis, where the ultimate goal is the ovulation of a mature ovum (egg) at the proper time in the menstrual cycle and in the proper hormonal milieu. To quote Gregory F. Erickson (2002):
The follicles in the cortex are present in a wide range of sizes representing various stages of folliculogenesis. The goal of folliculogenesis is to produce a single dominant follicle from a pool of growing follicles. There are four major regulatory events involved in this process: recruitment, preantral follicle development, selection and atresia [i.e. regression and death].
… Recognition that only a few follicles become dominant beautifully demonstrates the fundamental principle that folliculogenesis in mammals is a highly selective process … In women, the process is long, requiring almost one year for a primordial follicle to grow and develop to the ovulatory stage.
The cartoon below illustrates the different stages of folliculogenesis in the human. At the beginning is the primordial follicle which we have already discussed, a couple million of which are present in the ovarian cortex at birth.
To go from primordial to primary stage, the follicle must undergo the first major regulatory event, recruitment, which sends the quiescent follicles into a pool of growing follicles. In the transition from primordial to primary follicle, the single layer of flattened, squamous granulosa cells surrounding the oocyte divide and differentiate into a single layer of cuboidal-shaped granulosa cells. These cells send processes into the oocyte so that they are connected and can communicate with each other, forming a “metabolically and electrically coupled unit” (Erickson, 2002). The oocyte grows and differentiates and forms an outer “shell” called the zona pellucida. This process constitutes the second major regulatory event, preantral follicle development.
The development from primary to secondary follicle involves division of the granulosa cells so that they form between two and ten layers of stratified epithelium around the oocyte. A basement laminae forms around the outer layer of granulosa cells, which is like a collagen capsule of sorts.
Two important events occur during the growth of a secondary follicle. One is the development of the theca cells, the theca interna (inner layer) and theca externa (outer layer) around the basal laminae. The second, which occurs in parallel, is the formation of small blood vessels which, for the first time, bring blood to the developing follicle, and in so doing, deliver nutrients, remove waste products and expose it to hormones.
The delivery of hormones to the follicle at this stage is important for continued development. To quote Erickson (2002) again:
At the endocrine level, folliculogenesis is regulated by a central nervous system, anterior pituitary, and ovary cascade mechanism. Specialized hypothalamic [a part of the brain] neurons secrete pulses of gonadotropin-releasing hormone (GnRH) into the portal blood vessels [of the pituitary], which acts on the gonadotrophs [cells in the anterior pituitary] to cause a pulsatile release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which act on ovarian follicle cells to control folliculogenesis. Although GnRH, FSH, and LH are critically important in regulating folliculogenesis, hormones and growth factors, which are themselves products of the follicle, can act locally to modulate (amplify or attenuate) FSH and LH action.
It’s the delivery of the gonadotropins to the follicle, in part, that cause it to differentiate further and become steroidogenic. (More on that later, in the next post.)
At this point, the follicle has a basement laminae, theca interna and externa layers, and a stratified epithelium of granulosa cells surrounding a zona-encapsulated, fully grown oocyte. It moves to the tertiary stage of folliculogenesis by developing a cavity called an antrum in a process called cavitation.
In the early tertiary follicle, fluid begins to accumulate among the granulosa cells near one “pole” of the oocyte. The fluid-filled cavity is called an antrum, and the follicle is, at this point, known as an antral follicle or graafian follicle.
As the follicular fluid in the graafian follicle accumulates, the antrum expands and the follicle grows and is arbitrarily classified based on size:
Small graafian follicle: 1-6 mm
Medium graafian follicle: 7-11 mm
Large graafian follicle: 12-17 mm
Preovulatory graafian follicle: 18-23 mm
Also during this process, the next major regulatory event occurs, that of selection, where the graafian follicle either develops down the path to ovulation as a healthy, dominant follicle, or it becomes atretic and eventually degenerates through the process of atresia.
If a graafian follicle is selected to become a dominant follicle, the granulosa and theca cells continue to divide via mitosis as the follicular fluid accumulates. If a graafian follicle is atretic, mitosis of the granulosa cells and accumulation of follicular fluid both cease. The atretic graafian follicle may grow from the small to medium stage but cannot increase in size beyond that because cellular division and fluid production are no longer occurring.
In a healthy, dominant graafian follicle, the granulosa cells undergo proliferation and differentiation that are dependent upon their position within the follicle. (Click on the image to enlarge it.)
In the graafian follicle, the granulosa cells and oocyte exist as a mass of precisely shaped and precisely positioned cells. The spatial variation creates at least four different granulosa cell layers or domains: the outermost domain is the membrana granulosa, the inner most domain is the periantral, the intermediate domain is the cumulus oophorus, and the domain juxtaposed to the oocyte is the corona radiata. A characteristic histologic property of the membrana domain is that it is composed of a pseudostratified epithelium of tall columnar granulosa cells, all of which are anchored to the basal lamina.
The location and differentiation of the different granulosa cells will become important when we talk about ovulation in the next post.
Going back to the first image above, we can see that the adult human ovary has a collection of follicles at different stages in the pool of growing follicles. I have not discussed the known mechanisms that orchestrate the recruitment, development, selection and atresia of multiple follicles that are ongoing at any one time. Many mechanisms driving these processes are not currently known, but they are regulated such that at the time of ovulation, there is only one dominant follicle that is ready to ovulate (except in the case of fraternal twins, when there are two dominant follicles that ovulate, three in the case of fraternal triplets, and so on).
As mentioned above, the entire process, from primordial to preovulatory dominant follicle, takes almost one year in the human, with the greatest amount of time being needed in the preantral stages, as outlined in the following figure. (Click the image to enlarge it.)
In this post, we have had a relatively high-level overview of the anatomy of the human ovary and the process of folliculogenesis. In the next post, we will consider steroid production and ovulation to wrap up the discussion about normative ovarian function as a prelude to looking at ovarian function in trans men.
Erickson GF, 2002. “Follicle Growth and Development.” In: Gynecology and Obstetrics, Sciarra JJ, ed, Vol 5, Chapter 12 (and references and images therein).
Bloom W, Fawcett DW, 1975. A Textbook of Histology. WB Saunders, Philadelphia.
Erickson, GF, 1987. The ovary: Basic principles and concepts. In: Endocrinology and Metabolism, 3rd edition, Felig P, Baxter JD, Broadus AE, Frohman LA, eds., New York: McGraw Hill.
Erickson, GF, 1995. The ovary: Basic principles and concepts. In: Endocrinology and Metabolism, Felig P, Baxter JD, Frohman L, eds., New York: McGraw Hill.
Gougeon A, 1986. Dynamics of follicular growth in the human: a model from preliminary results. Hum Reprod 1986 1:81-87.