Physiology, Ovulation


Article Author:
Julie Holesh


Article Editor:
Megan Lord


Editors In Chief:
Tod Aeby


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Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
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Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
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Ahmad Malik
Mark Pellegrini
James Hughes
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Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
4/21/2019 12:21:11 PM

Introduction

The typical female pelvis has two ovaries, one on either side of the uterus. Each ovary is attached to the uterus by its utero ovarian ligament, and to the pelvic sidewall by the infundibulopelvic ligament, which carries the ovarian vessels. Ovaries contain oocytes, or eggs, which are female gametes. Females are born with a lifetime supply of immature oocytes, each ovary containing one million to two million eggs. While the number of eggs declines with time, within a typical female lifespan, about 300 to 500 eggs mature and progress through ovulation, the process of mature egg release from the ovary into the adjacent fallopian tube, through which the egg is carried into the uterus. The ovaries are not directly attached to the fallopian tubes, and either fallopian tube may pick up an egg from either ovary.[1][2][3]

Hormones involved in ovulation include:

Gonadotropin-releasing hormone (GnRH) is a tropic peptide hormone made and secreted by the hypothalamus. It is a releasing hormone that stimulates the release of FSH and LH from the anterior pituitary gland. Low-frequency GnRH pulses are responsible for FSH secretion whereas high-frequency pulses are responsible for LH secretion.

Follicle-Stimulating Hormone (FSH) is a gonadotropin synthesized and secreted from the anterior pituitary gland in response to GnRH. It is involved in reproductive processes of both males and females. FSH stimulates the growth and maturation of immature oocytes into mature (Graafian) follicles before ovulation. 

Luteinizing Hormone (LH) is a gonadotropin synthesized and secreted by the anterior pituitary gland in response to GnRH. Like FSH, LH is involved in reproductive processes in both males and females. When follicle maturation is complete, an LH surge triggers ovulation.

Progesterone is a steroid hormone that is responsible for preparing the endometrium for uterine implantation of the fertilized egg. If a fertilized egg implants, the corpus luteum secretes progesterone in early pregnancy until the placenta develops and takes over progesterone production for the remainder of the pregnancy.

Estrogen is a steroid hormone that is responsible for the growth and regulation of the female reproductive system and secondary sex characteristics. Estrogen is produced by the granulosa cells of the developing follicle and exerts negative feedback on LH production in the early part of the menstrual cycle. However, once estrogen levels reach a critical level as oocytes mature within the ovary in preparation for ovulation, estrogen begins to exert positive feedback on LH production, leading to the LH surge. Estrogen also has many other effects which are important for bone health and cardiovascular health in premenopausal patients, which will be discussed in another article. 

Issues of Concern

The most common cause of female infertility in the United States is ovulatory dysfunction, in which a variety of hormonal factors interfere with the complex sequence of hormonal events required to trigger ovulation. Problems can occur at any point in this pathway (hypothalamus, pituitary, ovary) and can lead to failure to ovulate. The most common cause of chronic ovulatory dysfunction in the United States is Polycystic Ovarian Syndrome, or PCOS, which interferes with ovulation at multiple points.[4]

Cellular

Granulosa cells surround the oocyte. They respond to follicle-stimulating hormone (FSH) released by the anterior pituitary by converting androgens to estrogen.

Theca cells appear as the follicle matures, and produce androgens which are subsequently converted to estrogens by the granulosa cells.

The oocyte is the actual female gamete contained within the follicle.

Development

The prepubertal ovary contains primordial follicles, which consists of an oocyte surrounded by a single layer of granulosa cells. Following puberty, the anterior pituitary begins to secrete FSH and LH in response to GnRH release from the hypothalamus, and the dormant cells in the ovary begin to secrete steroid hormones in response.

Organ Systems Involved

The hypothalamus secretes GnRH in a pulsatile fashion, which triggers FSH and LH release from the anterior pituitary. These, in turn, act on the granulosa and theca cells in the ovary to stimulate follicle maturation and trigger ovulation.

Mechanism

Follicular Development

A large number of primordial follicles begin the process of maturation into primary follicles. When this happens, the granulosa cells which surround the oocyte "plump up" and become active. The zona pellucida develops at this stage as well, and separates the oocyte from the granulosa cells. The zona pellucida in the protective casing through which sperm must penetrate in order to fertilize the egg following ovulation.

A subset of these primary follicles is recruited to the secondary follicle stage, during which the theca cells appear and begin to secrete androgens, which the granulosa cells convert into estrogens.

Development of primary and secondary follicles is independent of FSH. The time that it takes to complete this process varies, but is thought to be longer than one menstrual cycle.

Next, the follicle develops a fluid-filled cavity surrounding the oocyte known as an antrum. It is now referred to as an antral, or Graafian follicle, and can now be seen on ultrasound as a small, fluid-filled cyst on the ovary. The follicular phase of the menstrual cycle occurs when the antral follicle, now dependent on FSH, develops into a preovulatory follicle in preparation for ovulation. The occurs on day one to 14 of a typical 28-day cycle, in which day one is the first day of full, red flow (not spotting). The antral follicle becomes dependent on FSH, and begin to compete with each other for FSH. The antral follicles secrete the hormones estrogen and inhibin, which exert negative feedback on FSH, thus "turning off" their neighboring antral follicles. One follicle will begin to grow larger than the others, and the remaining follicles will undergo atresia (more on that later). 

The majority of the follicles which began the process of maturation will undergo atresia (radical apoptosis of all cells within the follicle, including the oocyte) at some point during this process, leaving only one (rarely more) mature follicle to ovulate. If more than one follicle ovulates in a given cycle, this leads to non-identical multiple gestations, such as fraternal twins.

Ovulation

Ovulation occurs at about day 14 of a typical 28-day cycle. Estrogen levels rise as a result of increasing estrogen production by hormonally active cells within the follicle. Estrogen levels reach a critical point at which estrogen begins to exert positive feedback on the hypothalamus and pituitary, leading to an LH surge. The LH surge increases intrafollicular proteolytic enzymes, weakening the wall of the ovary and allowing for the mature follicle to pass through.

The surge also causes the luteinization of thecal and granulosa cells which increases progesterone levels and begins the development of the corpus luteum.  Once the follicle is released, it is caught by the fimbriae of the fallopian tubes. The oocyte remains in metaphase of meiosis II. It will complete meiosis II after fertilization.

Luteal Phase

The luteal phase lasts from day 14 to 28 of a typical cycle.  It begins with formation of the corpus luteum and ends in pregnancy or luteolysis (destruction of the corpus luteum). FSH and LH stimulate what remains of the mature follicle after ovulation to become the corpus luteum. The corpus luteum grows and secretes progesterone and some estrogen, which make the endometrium more receptive to implantation. If fertilization does not occur, progesterone and estrogen levels fall, and the corpus luteum dies. These falling hormone levels stimulate FSH to begin recruiting follicles for the next cycle. If fertilization does occur, human chorionic gonadotropin (hCG ) produced by the early placenta preserves the corpus luteum, maintaining progesterone levels until the placenta is able to make sufficient progesterone to support the pregnancy.

Related Testing

Home ovulation predictor kits work by measuring urine LH levels, to detect the LH surge which precedes ovulation.

Mid-luteal progesterone testing can also be used and determines in retrospect whether ovulation occurred by testing for progesterone produced by the corpus luteum.

Clinical Significance

Multiple endocrine disorders can lead to disruption of the hypothalamic-pituitary-ovarian axis, leading to ovulatory dysfunction and therefore infertility.[5][6][7][8]


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Physiology, Ovulation - Questions

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Physiology, Ovulation - References

References

Kara E,Dupuy L,Bouillon C,Casteret S,Maurel MC, Modulation of Gonadotropins Activity by Antibodies. Frontiers in endocrinology. 2019;     [PubMed]
Laven JSE, Follicle Stimulating Hormone Receptor (FSHR) Polymorphisms and Polycystic Ovary Syndrome (PCOS). Frontiers in endocrinology. 2019;     [PubMed]
Gilbert RO, Symposium review: Mechanisms of disruption of fertility by infectious diseases of the reproductive tract. Journal of dairy science. 2019 Apr;     [PubMed]
Toosy S,Sodi R,Pappachan JM, Lean polycystic ovary syndrome (PCOS): an evidence-based practical approach. Journal of diabetes and metabolic disorders. 2018 Dec;     [PubMed]
Dosouto C,Haahr T,Humaidan P, Advances in ovulation trigger strategies. Panminerva medica. 2019 Mar;     [PubMed]
Weiss NS,Kostova E,Nahuis M,Mol BWJ,van der Veen F,van Wely M, Gonadotrophins for ovulation induction in women with polycystic ovary syndrome. The Cochrane database of systematic reviews. 2019 Jan 16;     [PubMed]
Mikhael S,Punjala-Patel A,Gavrilova-Jordan L, Hypothalamic-Pituitary-Ovarian Axis Disorders Impacting Female Fertility. Biomedicines. 2019 Jan 4;     [PubMed]
Pundir J,Charles D,Sabatini L,Hiam D,Jitpiriyaroj S,Teede H,Coomarasamy A,Moran L,Thangaratinam S, Overview of systematic reviews of non-pharmacological interventions in women with polycystic ovary syndrome. Human reproduction update. 2019 Mar 1;     [PubMed]

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