2.2: Hormonal Control of the Ovarian Cycle

Before learning the details of the hormonal control of the ovarian cycle, let’s have a brief overview of the hypothalamic-pituitary axis.

2.2.1 The Hypothalamic–Pituitary Axis

The hypothalamus is made up of a series of nuclei located at the base of the brain. The hypothalamic neurons contract synapses throughout the central nervous system. The hypothalamus is linked with the anterior pituitary gland by the portal system of blood supply. The posterior pituitary gland or neurohypophysis is like a “repository” for the hypothalamic hormones ADH and oxytocin. In fact, it contains the axonal terminals of neurons arising in the supraoptic (SO) nucleus that produces ADH and the paraventricular nucleus (PVN) that produces oxytocin in the hypothalamus. The hypothalamus produces gonadotropin-releasing hormone (GnRH), a decapeptide that stimulates gonadotropins biosynthesis and secretion: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Pulsatile GnRh input is required for the activation and maintenance of GnRh receptors; changes in GnRH pulse frequency affect the absolute levels and the ratio of LH and FSH release.

The anterior pituitary gland contains five hormone-producing cell types: gonadotrophs (LH and FSH), lactotrophs (PRL), somatotrophs (GH), thyrotrophs (TSH), and adrenocorticotrophs (ACTH). All the pituitary hormones are stimulated by hypothalamic neuroendocrine secretion, while PRL is under tonic inhibition, and its expression is primarily under inhibitory regulation by dopamine. In fact, the gonadotropins (LH and FSH) are regulated by GnRH. The biosynthesis of ACTH is stimulated by the corticotropin-releasing hormone. The secretion of TSH is induced by the thyrotropin-releasing hormone.⁹

2.2.2 Follicular Phase

In humans, follicular development from the primordial to the early tertiary follicle occurs in approximately two months. The stage of development from a tertiary follicle to ovulation of a secondary oocyte spans approximately 28 days. The hormonal regulation of follicular development involves GnRH, LH, and FSH.

2.2.2.1 Early Follicular Phase

In the early follicular phase, the ovary is least hormonally active, resulting in low serum estradiol and progesterone concentrations. Influenced by the negative feedback effects of estradiol, progesterone, and probably inhibin, there is an increase in the hypothalamus's GnRH production (in a pulsatile manner). GnRH subsequently stimulates the anterior pituitary gland to produce the gonadotropins FSH and LH (Figure 2.2.9), increasing serum follicle-stimulating hormone (FSH) concentrations by approximately 30%. At this time, LH pulse frequency increases rapidly from one pulse every four hours in the late luteal phase to one pulse every 90 min in the early follicular phase. The FSH and LH leave the pituitary through the bloodstream to the ovaries. In the ovaries, they bind to receptors on the granulosa and theca cells of the follicles.

This small increase in FSH secretion is required to recruit the next cohort of developing follicles, one of which will become the dominant and then ovulatory follicle during that cycle (hence its name of follicle-stimulating hormone).

The LH stimulates the granulosa and theca cells of the follicles to produce the sex steroid hormone estradiol, a type of estrogen. This ovarian cycle phase, when the tertiary follicles are growing and secreting estrogen, is known as the follicular phase. The more granulosa and theca cells a follicle has (the larger and more developed it is), the more estrogen it will produce in response to LH stimulation. As a result of these large follicles producing large amounts of estrogen, systemic plasma estrogen concentrations increase.

Serum anti-Müllerian hormone (AMH) has been used as a potential marker of ovarian health and aging. It is secreted by small antral follicles and correlates with the total number of ovarian antral follicles. The variability of serum AMH across the menstrual cycle appears to be minimal.

Ultrasonographically, the ovary is quiescent in the early follicular phase, except for the occasionally visible resolving corpus luteum from the previous cycle. It is possible to see small follicles of 3 to 8 mm in diameter at this time. The endometrium is relatively indistinct during menses, becoming a thin line once menses are completed. In this phase, the endometrium appears as a brightly echogenic stripe comprising the basal layer; minimal fluid can be appreciated endovaginally within the endometrium in the menstrual phase.¹⁰

2.2.2.2 Mid Follicular Phase

In the mid-follicular phase, the moderate rise in FSH secretion progressively stimulates folliculogenesis and estradiol production, leading to the progressive growth of the cohort of follicles selected. When several follicles initially grow to the antral stage (several antral follicles of 9–10 mm are visible on ovarian ultrasonography), their granulosa cells increase in size and divide, producing increasing serum concentrations of estradiol via FSH stimulation of aromatase and then inhibin A from the granulosa cells in the ovaries. The increase in estradiol production negatively affects the hypothalamus–pituitary axis, suppressing the FSH and LH concentrations as well as the LH pulse amplitude. At the same time, the GnRH pulse generator accelerates slightly to a mean LH pulse frequency of approximately one per hour (versus one per 90 min in the early follicular phase). This GnRH stimulation is probably due to the negative feedback effects of progesterone from the previous luteal phase.

Several antral follicles of 9–10 mm are visible on ovarian ultrasonography. There is a proliferation of the uterine endometrium, which thickens with an increase in the number of glands and the typical aspect of a “triple stripe” caused by increased estradiol concentrations. The endometrium's triple stripe or trilaminar appearance comprises an outer echogenic basal layer, a middle hypoechoic functional layer, and an inner echogenic stripe at the central interface.

2.2.2.3 Late Follicular Phase

In the late follicular phase, the week before ovulation, the growing follicle induces the increase of estradiol and inhibin A. This increase in estradiol is responsible for reducing the concentrations of FSH and LH because of negative feedback effects. Once the dominant follicle has been selected, FSH induces LH receptors in the ovary and increases ovarian secretion of intrauterine growth factors.

After a single dominant follicle has been selected, it increases by 2 mm per day until it reaches a mature size of 20 to 26 mm. The rest of the growing cohort of follicles gradually stop developing and undergo atresia. The uterine endometrium gradually thickens because of the rising estradiol concentrations and changes in the cervical mucus; in particular, there is an increase in the amount and “stringiness.” Stringiness refers to the stretchy quality of the cervical mucous around the time of ovulation.

2.2.3 Ovulation

Following a classic negative feedback loop, the high estrogen concentrations will stimulate the hypothalamus and pituitary to reduce the production of GnRH, LH, and FSH. Because the large tertiary follicles require FSH to grow and survive at this point, this decline in FSH caused by negative feedback leads most of them to die (atresia). Typically, only one follicle, now called the dominant follicle, will survive this reduction in FSH, and this follicle will be the one that releases an oocyte.

Scientists have studied many factors that lead to a particular follicle becoming dominant: size, the number of granulosa cells, and the number of FSH receptors on those granulosa cells all contribute to a follicle becoming the one surviving dominant follicle. When only one dominant follicle remains in the ovary, it again begins to secrete estrogen. It produces more estrogen than all developing follicles did before negative feedback. It produces so much estrogen that normal negative feedback doesn’t occur. Instead, these extremely high concentrations of systemic plasma estrogen trigger a regulatory switch in the anterior pituitary that responds by secreting large amounts of LH and FSH into the bloodstream (Figure 2.2.9).

The positive feedback loop by which more estrogen triggers the release of more LH and FSH only occurs at this point in the cycle. This large burst of LH (called the LH surge) leads to the ovulation of the dominant follicle. The LH surge induces many changes in the dominant follicle; the primary oocyte in the dominant follicle completes its first meiotic division and becomes a secondary oocyte. As noted earlier, the polar body that results from unequal cell division simply degrades. The LH surge also triggers proteases (enzymes that cleave proteins) to break down structural proteins in the ovary wall on the surface of the bulging dominant follicle. This degradation of the wall, combined with pressure from the large, fluid-filled antrum, results in the expulsion of the oocyte surrounded by granulosa cells into the peritoneal cavity. This release is ovulation and occurs approximately 36 hours after the LH surge.

At the same time, there is an increase in the secretion of plasminogen activator and other cytokines required for the ovulation process. Before the oocyte is released, the granulosa cells begin to luteinize and produce progesterone. Progesterone is responsible for reducing LH pulse that becomes less frequent by the termination of the surge. Follicular rupture and oocyte release are closely related to the LH surge; as a result, serum or urine LH measurements can be used to estimate the time of ovulation in women.

As the endometrium becomes more uniformly bright, the “triple stripe” image is lost. This is due to the impact of progesterone increase responsible for cessation of mitoses and “organization” of the glands.¹¹

2.2.4 Luteal Phase

The surge of LH also stimulates a change in the granulosa and theca cells that remain in the follicle after ovulation. This change is called luteinization (recall that the full name of LH is luteinizing hormone), and it transforms the collapsed follicle into a new endocrine structure called the corpus luteum, a term meaning “yellowish body” (Figure 2.2.9).

Instead of estrogen, the luteinized granulosa and theca cells of the corpus luteum begin to produce large amounts of the sex steroid hormone progesterone. The post-ovulatory phase of progesterone secretion is known as the luteal phase of the ovarian cycle. Progesterone triggers negative feedback at the hypothalamus and pituitary, which keeps GnRH, LH, and FSH secretions low, so no new dominant follicles develop at this time. A decrease in LH secretions results in a gradual fall in progesterone and estradiol production by the corpus luteum in the absence of a fertilized oocyte.

If the oocyte is fertilized after ovulation, it is implanted in the endometrium. The early embryo begins to produce human chorionic gonadotropin (HCG), which maintains the corpus luteum and progesterone production until the placenta can take over progesterone production. Inhibin A is also produced by the corpus luteum, and serum concentrations of inhibin A peak in the mid-luteal phase. Inhibin B secretion is virtually absent during the luteal phase. Progesterone is critical for the establishment and maintenance of pregnancy; therefore, it is a “pro-gestational hormone.” If pregnancy does not occur within 10 to 12 days, the corpus luteum will stop secreting progesterone and degrade into the corpus albicans, a nonfunctional “whitish body” that will disintegrate in the ovary over several months. In response to estradiol and progesterone decline due to the resolution of the corpus luteum, the endometrium loses the blood supply and starts to break and slough. This is called menstruation, which marks the low point for estrogen activity and is the starting point of a new cycle. Menstruation is the cyclic, orderly sloughing of the uterine lining approximately 14 days after the LH surge. Simultaneously, secondary to reduced progesterone levels, the hypothalamic–pituitary axis induces the FSH and LH secretion, and a new cycle starts with the follicular phase involving a new cohort of early tertiary follicles starting to grow and secrete estrogen.¹²

Figure 2.2.9 Hormonal regulation of ovulation. The hypothalamus and pituitary gland regulate the ovarian cycle and ovulation. GnRH activates the anterior pituitary to produce LH and FSH, which stimulate the ovaries' production of estrogen and progesterone.
Image Source: Karve, Simantini. "Anatomy and Physiology of the Female Reproductive System." Human Physiology for Allied Health Professionals, (2022). This work is openly licensed via CC BY NC SA 4.0 Creative Commons License. Available from LibreText, Skyline College.

Glossary Terms

Antidiuretic hormone (ADH)

Hypothalamic hormone that is stored by the posterior pituitary and that signals the kidneys to reabsorb water

Aromatase

Enzyme that catalyzes the desaturation (aromatization) of the ring A of C19 androgens and converts them to C18 estrogens. In this process, the 19-methyl is removed. This enzyme is membrane-bound, located in the endoplasmic reticulum of estrogen-producing cells of ovaries, placenta, testes, adipose, and brain tissues

Atresia

Absence or abnormal narrowing of an opening or passage in the body

Dopamine

One of the catecholamine NEUROTRANSMITTERS in the brain. It is derived from TYROSINE and is the precursor to NOREPINEPHRINE and EPINEPHRINE. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement

Endometrium

Inner lining of the uterus, part of which builds up during the secretory phase of the menstrual cycle and then sheds with menses

Estradiol

17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids

Follicle stimulating hormone (FSH)

Interior pituitary hormone that stimulates the production and maturation of sex cells

Folliculogenesis

Development of ovarian follicles from primordial to tertiary under the stimulation of gonadotropins

Granulosa

Supportive cells in the ovarian follicle that produce estrogen

Hypothalamus

Major region of the diencephalon that is responsible for coordinating autonomic and endocrine control of homeostasis

Inhibin

Hormone secreted by the gonads that inhibits FSH production by the anterior pituitary ischemia

Luteinization

Formation of CORPUS LUTEUM. This process includes capillary invasion of the ruptured OVARIAN FOLLICLE, hypertrophy of the GRANULOSA CELLS and the THECA CELLS, and the production of PROGESTERONE

Luteinizing hormone (LH)

Anterior pituitary hormone that triggers ovulation and the production of ovarian hormones in females, and the production of testosterone in males

Meiotic division

Type of CELL NUCLEUS division, occurring during maturation of the GERM CELLS. Two successive cell nucleus divisions following a single chromosome duplication (S PHASE) result in daughter cells with half the number of CHROMOSOMES as the parent cells

Menses

Shedding of the inner portion of the endometrium out though the vagina; also referred to as menstruation

Oxytocin

Oxytocin injection is used to begin or improve contractions during labor. Oxytocin also is used to reduce bleeding after childbirth. It also may be used along with other medications or procedures to end a pregnancy. Oxytocin is in a class of medications called oxytocic hormones

Paraventricular nucleus (PVN)

Nucleus in the anterior part of the HYPOTHALAMUS

Pituitary Gland

Bean-sized organ suspended from the hypothalamus that produces, stores, and secretes hormones in response to hypothalamic stimulation (also called hypophysis)

Plasminogen activator

Heterogeneous group of proteolytic enzymes that convert PLASMINOGEN to FIBRINOLYSIN. They are concentrated in the lysosomes of most cells and in the vascular endothelium, particularly in the vessels of the microcirculation

Primordial follicles

Least developed ovarian follicles that consist of a single oocyte and a single layer of flat (squamous) granulosa cells

Progesterone

Sex hormone important in regulating the reproductive cycle in those with ovaries and the maintenance of pregnancy

Supraoptic nucleus

Hypothalamic nucleus overlying the beginning of the OPTIC TRACT

Tertiary follicle

(also, antral follicles) Ovarian follicles with a primary or secondary oocyte, multiple layers of granulosa cells, and a fully formed antrum

Theca

Estrogen-producing cells in a maturing ovarian follicle

Tonic inhibition

form of neurotransmission usually thought to reduce the excitability of all neurons

 

Footnotes

9. Section adapted from Nappi, Luigi, Felice Sorrentino, Sorrentino, Francesca Greco, Laura Vona, Francesco Maria Zullo and Stefano Bettocchi F. "Pathophysiology of Female Reproduction and Clinical Management." This work is openly licensed via CC BY 4.0 DEED Creative Commons license. Bettocchi, C., Busetto, G.M., Carrieri, G., Cormio, L. (eds) Practical Clinical Andrology. Springer, Cham. (2023). doi.org/10.1007/978-3-031-11701-5_16.
10. Section adapted from Nappi, L. et al, 2023.
11. Section adapted from Nappi, L. et al, 2023.
12. Karve, Simantini. "Anatomy and Physiology of the Female Reproductive System." Human Physiology for Allied Health Professionals, (2022). This work is openly licensed via CC BY NC SA 4.0 Creative Commons License. Available from LibreText, Skyline College

Image Acknowledgements

Karve, Simantini. "Anatomy and Physiology of the Female Reproductive System." Human Physiology for Allied Health Professionals, (2022). This work is openly licensed via CC BY NC SA 4.0 Creative Commons License. Available from LibreText, Skyline College.