The Human Ovary: Steroidogenesis & Ovulation

When we last considered the human ovary, we were discussing a bit of anatomy and a lot of folliculogenesis. We learned about the different steps and changes that ovarian follicles undergo as they develop or become atretic.

With the information from that previous post in mind, we will now consider the functional aspects of the ovary, those being production of steroids and ovulation of a mature egg.

Steroidogenesis
In order to talk about steroid production by the ovary, we need to talk about the brain first. There are two parts of the brain responsible for control of reproduction, the pituitary gland and the hypothalamus.  The pituitary is a tri-lobed structure situated mid-brain at the base, nestled in a protective pocket in the bone of the skull.  The two main functional parts of the pituitary gland are the anterior and posterior lobes, with the intermediate lobe being non-functional in humans.

Cross section of the human brain showing the pituitary gland. From "Gray's Anatomy"

It is the hypothalamus of the brain that controls the pituitary gland via two different means for the two main lobes.  The posterior lobe of the pituitary is composed of neural tissue and is in communication with the hypothalamus via neurosecretory neurons that reside in the hypothalamus and send axons through the median eminence and pituitary stalk into the posterior lobe.

The communication of the brain with the anterior pituitary is by a capillary plexus, a blood portal system that delivers neuroendocrine signals from the hypothalamus through the median eminence and pituitary stalk directly to the endocrine (hormone-producing) tissue of the anterior lobe.

Hypothalamic-hypophyseal blood portal system. From Reeves, 1987.

I’m not going to go into a lot of detail about all of the hormones the pituitary gland produces and what bodily functions and mechanisms are controlled by this small yet very important endocrine gland; you can read that information here.

Instead, I’m going to focus on the hypothalamic/anterior pituitary/ovarian axis that orchestrates reproductive function in females, with the direct control of the anterior lobe by the hypothalamus being modified by hormones from the ovary in a feedback loop mechanism.  (The hypothalamus and anterior pituitary are also important for reproduction in males, which will not be covered in this post.)

Two glycoprotein hormones that are produced by the anterior lobe of the pituitary and important for ovarian function are  Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH).  These are gonadotropic hormones in that they are trophic (stimulatory) to the gonads, specifically the ovary for the goals of the current discussion.  (FSH and LH also have actions in the testes of the male.)

The production and secretion of the gonadotropin hormones from the pituitary are under the control of Gonadotropin Releasing Hormone (GnRH) from the hypothalamus.  (As a side note, GnRH analogs are used as puberty blockers in trans children, but that’s a topic for another post.)

We’ve already heard a little bit about the stimulation of gonadotropin production by GnRH in the previous post about the ovary, the one dealing with folliculogenesis.  We also learned that FSH acts upon the granulosa cells of the follicles, stimulating them to proliferate and differentiate, pushing follicular development from secondary to tertiary and finally to Graafian follicles.  (Hence the name of the hormone.)  But what about LH, what does it do, and how do FSH and LH stimulate steroidogenesis in the follicles?

Well, both FSH and LH are required for ovarian steroidogenesis because estrogen production actually occurs in two different cell types, the theca interstitial cells and the granulosa cells, which are under control by the two different gonadotropins as part of the Two-Cell, Two-Gonadotropin Concept.  This is a bit simplified because other hormones and factors are involved (such as insulin, for example), but basically, LH stimulates the theca interstitial cells to produce androgen which is then converted to estrogen by the granulosa cells under the stimulation of FSH.

In order to see this in more detail, let’s first look at steroidogenesis in the ovarian follicle starting with the pathway in the thecal cells.

Androgen Biosynthesis, from Arici & Hochberg, 2002.

The pathway above requires several different enzymes that are located in the theca cells:  P450 side chain cleavage (P450scc, which converts cholesterol to the first steroid in the pathway), 3-beta-hydroxysteroid dehydrogenase/isomerase (3β-HSD/isom) and P450-c17-lyase (P450c17).

The expression of these enzymes in the theca cells begins when the follicle starts to develop an antrum during differentiation from the tertiary to the antral stage.  In conjunction with expression of these steroidogenic enzymes, the theca cells start to produce androgen, mainly in the form of androstenedione as mentioned in the figure legend above.

Next, the androstenedione goes to the granulosa cells and is aromatized by P450-aromatase enzyme (P450arom) to estrone which is then converted to estradiol by the enzyme 17-beta-hydroxysteroid dehydrogenase (17β-HSD).

Conversion of androgen to estrogen in the granulosa cells, from Arici & Hochberg, 2002.

Expression of 17β-HSD in granulosa cells appears to be constitutive (automatic) in follicles from the primary stage all the way to preovulatory Graafian follicles.  It’s the expression of aromatase, stimulated by FSH in the putative dominant follicle when it is approximately 1 mm in diameter, that results in the production of estradiol.  And so, with the growth of the dominant follicle, there is an increase in steroid production.

Follicle Growth, Steroid Production and Gonadotropins, from Erickson, 2002.

Ovulation
And so now that we understand all the players – the gonadotropins FSH and LH from the pituitary, steroids from the ovary and the process of folliculogenesis – how do these all work together to result in ovulation?

We know from our discussion of folliculogenesis that cohorts of follicles are growing all the time in the ovary, but only one follicle will become dominant during each menstrual cycle, with others in its cohort becoming atretic and regressing.

During folliculogenesis, FSH from the pituitary is increasing to stimulate follicular growth.  Once the dominant follicle is selected, estradiol production begins to increase as the follicle grows (as shown above).  In the human, this period is called the Follicular Phase and occurs during the first 14 days of the 28-day menstrual cycle.  As estradiol produced by the follicle increases, it feeds back to the pituitary to decrease FSH release, causing all antral follicles except the dominant one to become atretic due to lack of sufficient support by FSH.

Follicle recruitment, selection & atresia. From McGee & Hsueh, 2000.

Also during the Follicular Phase of the cycle, GnRH from the hypothalamus stimulates LH release from the pituitary in a pulsatile fashion which induces androgen production by thecal cells as mentioned above.  As the dominant follicle grows and its production of estradiol increases, the estradiol reaches peak concentrations at mid-cycle and, in a positive feedback loop, stimulates a huge surge in gonadotropin release by the pituitary.  It is the gonadotropin surge that is responsible for a number of well-coordinated biological processes at this time.

→  FSH stimulates the final morphological changes in the pre-ovulatory follicle.  It grows to its largest size and protrudes from the ovarian surface while enzymes are produced within the follicle that digest the stigma, point where the egg will be released at ovulation.
→ FSH acts on the cells of the cumulus oophorus, the special granulosa cells that surround the oocyte/egg and causes the entire complex of cells to expand.
→ FSH and estradiol both act on the granulosa cells to induce expression of LH receptors.
→ LH induces changes in the steroidogenic machinery of the follicle, inhibiting androgen production (and thereby cutting estrogen production as well), which results in the production of progesterone.
→ LH acts on the oocyte, which has been locked in early meiosis since birth, and stimulates it to undergo the first meiotic division, thereby rendering it ready for fertilization.
→ LH stimulates rupture of the stigma and release (ovulation) of the cumulus cell mass containing the oocyte from the follicle into the oviduct.
→ LH induces a complete morphological change of the ruptured follicle to a new structure called the corpus luteum (CL), which is Latin for “yellow body,” and stimulates it to produce progesterone.  (A CL can be seen in cross-section of the ovary shown in the micrograph at the top of this post.)

Plasma concentrations of steroid hormones and gonadotropins during the menstrual cycle. From Groome et al., 1996.

So what then is the ultimate goal for all of these biological processes?  To deliver a mature egg to the oviduct, the site of fertilization.

If the egg is fertilized (by a sperm cell), the resulting embryo makes its way down the oviduct to the uterus which has already been prepared to accept it.  The estradiol that was produced by the follicle during the Follicular Phase induced a buildup of the endometrium, the lining of the uterus, so that it becomes a receptive and supportive environment for the embryo to implant.

After the gonadotropin surge, the progesterone from the CL maintains the endometrium in its pregnancy-ready state during the second half of the menstrual cycle, the Luteal Phase.  If an embryo arrives and implants into the uterine endometrium, it sends signals back to the ovary to maintain the CL and its production of progesterone during pregnancy.  If no embryo implants, the CL regresses and progesterone production falls, thereby removing support for the endometrial lining which is subsequently sloughed during the process of menstruation and the cycle starts over again.

Cycle of the uterine endometrium (shown in the upper panel in cross-section) and hormones. From Shepperson & Vernon, 2002.

Next Posts
With the material covered in this post and the previous post about folliculogenesis, we now have a foundation of information that we can use to consider the next topic in this series, Polycystic Ovary Syndrome (PCOS).  The discussion on PCOS will then be a prelude to the discussion about PCOS in trans men.

–ATM

References – The information provided above was taken from the following references and the references therein:

Arici A & Hochberg RB, 2002, Steroidogenesis. In:  Gynecology and Obstetrics, Sciarra JJ, ed, Vol 5, Chapter 1.

Erickson GF, 2002, Follicle Growth and Development.  In:  Gynecology and Obstetrics, Sciarra JJ, ed, Vol 5, Chapter 12.

Ferin M, 2002, The Hypothalamic-Hypophyseal-Ovarian Axis and the Menstrual Cycle.  In:  Gynecology and Obstetrics, Sciarra JJ, ed, Vol 5, Chapter 6.

Images:

Arici A & Hochberg RB, 2002, Steroidogenesis. In:  Gynecology and Obstetrics, Sciarra JJ, ed, Vol 5, Chapter 1.

Erickson, GF, 1986.  Analysis of follicle development and ovum maturation.  Semin Reprod Endocrinol 4:233.

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.

Gray H, 1901, Gray’s Anatomy, The Classic Collector’s Edition, Pick TP & Howden R, eds, Bounty Books, New York, p 660.

Groome NP, Illingworth PJ, O’Brien M et al., 1996, Measurement of dimeric inhibin B throughout the human menstrual cycle.  J Clin Endocrinol Metab 81:1401.

McGee EA & Hsueh AJ, 2000, Initial and cyclic recruitment of ovarian follicles. Endocr Rev 21:200.

Reeves JJ, 1987, Endocrinology of Reproduction.  In:  Reproduction in Farm Animals, 5th Edition, Hafez ESE, ed, Lea & Febiger, Philadelphia, pp 89.

Shepperson D & Vernon M, 2002.  In: Endometriosis: A Key to Healing Through Nutrition, Harper Collins, pp 370.

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8 Responses to The Human Ovary: Steroidogenesis & Ovulation

  1. j says:

    Oh thank you so much for this. I always wanted to know. It’s very complicated. But I did understand something. So Thank you.

  2. Fei says:

    Both this post and the previous folliculogenesis post are very well written, the process is described in detail but easy to understand ! Thanks for the nice work!!

  3. Fe!Y says:

    One question though, I noticed that on Wiki it says both LH and FSH are suppressed by the increase level of estrogen prior to ovulation, whereas in your post, LH is increased by positive feedback of increase in estrogen. I understand that wiki is not an academic reference, but could you please clarify? Cheers!

    • Both are correct. The rising estrogen during the follicular phase suppresses GnRH, LH and FSH in a feedback loop. Then, just hours before ovulation, the increasing estrogen from the dominant, preovulatory follicle actually stimulates the massive GnRH/LH surge from the brain that induces ovulation. Hope that helps to explain the difference.

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