Ovarian and Uterine Cycles

1. The Ovarian Cycle

The ovarian cycle is a set of predictable changes in oocytes and ovarian follicles. During the reproductive years, it is a cycle that can be correlated with, but is not the same as, the uterine cycle, which you will learn about later in this lesson.

The ovarian cycle includes three phases: the follicular phase, ovulation, and the luteal phase. Follicular maturation occurs during the follicular phase. Ovulation is when the egg is released from the ovaries. Finally, the luteal phase is when the uterus lining thickens to prepare for pregnancy: The corpus luteum, which is a transformed follicle following ovulation that secretes progesterone, is formed (and eventually degenerates if pregnancy does not occur), and the secretion of progesterone stimulates the thickening of the uterus lining.

The process of development that we have just described, from primordial follicle to early tertiary follicle, takes approximately 2 months in humans. The final stages of development of a small cohort of tertiary follicles, ending with ovulation of a secondary oocyte, occur over a course of approximately 28 days.

As you previously learned, the ovarian cycle includes two interrelated processes: oogenesis (the production of gametes) and folliculogenesis (the growth and development of ovarian follicles). You previously learned about oogenesis. Here, you will learn more about folliculogenesis.

term to know

Ovarian Cycle

The approximately 28-day cycle of changes in the ovary consisting of a follicular phase and a luteal phase.

1a. Folliculogenesis

Recall that ovarian follicles are oocytes and their supporting cells. They grow and develop in a process called folliculogenesis, which typically leads to ovulation of one follicle approximately every 28 days, along with death of multiple other follicles. The death of ovarian follicles is called atresia and can occur at any point during follicular development.

As you have learned, a female infant at birth will have one to two million oocytes within the ovarian follicles, and this number declines throughout life until menopause, when no follicles remain. Follicles progress from primordial to primary, to secondary and tertiary stages before ovulation—with the oocyte inside the follicle remaining as a primary oocyte until right before ovulation.

Folliculogenesis begins with follicles in a resting state. These small primordial follicles are present in newborn females and are the prevailing follicle type in the adult ovary. Primordial follicles have only a single flat layer of support cells, called granulosa cells, that surround the oocyte, and they can stay in this resting state for years—some until right before menopause.

After puberty, a few primordial follicles will respond to a recruitment signal each day and will join a pool of immature growing follicles called primary follicles. Primary follicles start with a single layer of granulosa cells, but the granulosa cells then become active and transition from a flat or squamous shape to a rounded, cuboidal shape as they increase in size and proliferate. As the granulosa cells divide, the follicles—now called secondary follicles (see the image below)—increase in diameter, adding a new outer layer of connective tissue, blood vessels, and theca cells, which are cells that work with the granulosa cells to produce estrogens.

Within the growing secondary follicle, the primary oocyte now secretes a thin acellular membrane called the zona pellucida that will play a critical role in fertilization. A thick fluid, called follicular fluid, that has formed between the granulosa cells also begins to collect into one large pool, or antrum. Follicles in which the antrum has become large and fully formed are considered tertiary follicles (or antral follicles). Several follicles reach the tertiary stage at the same time, and most of these will undergo atresia. The one that does not die will continue to grow and develop until ovulation when it will expel its secondary oocyte surrounded by several layers of granulosa cells from the ovary.

key concept

Keep in mind that most follicles don’t make it to this point. In fact, roughly 99% of the follicles in the ovary will undergo atresia, which can occur at any stage of folliculogenesis.

IN CONTEXT

Ovarian Disorders

As you have learned, the ovaries are one of the most essential organs in the female reproductive system. Therefore, when they are not functioning correctly, they can cause health issues. A couple of common disorders associated with the ovaries are cysts and polycystic ovarian syndrome (PCOS).

Ovarian cysts are sacs that are typically filled with fluid and form on or in the ovaries. Cysts are generally very common in females and often go away on their own after a few months. However, they can still cause relatively mild symptoms in some individuals, such as pelvic and abdominal pain, and in some cases, they can become twisted or rupture, causing severe symptoms.

PCOS is a relatively common hormone disorder in women of reproductive age. In PCOS, there is the development of small cysts (sacs with fluid) along the ovary that have follicles within them, but the follicles are not able to release eggs as they are supposed to.

Some common symptoms of PCOS include irregular menstruation, abnormal hair growth, acne, obesity, and infertility. PCOS is also associated with some long-term complications, such as type 2 diabetes and heart disease. Although the exact causes of PCOS are not known, early diagnosis, treatment, and weight loss can lower the risks of long-term complications.

terms to know

Folliculogenesis

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

Primordial Follicles

The least developed ovarian follicles; they consist of a single oocyte and a single layer of flat (squamous) granulosa cells.

Primary Follicles

Ovarian follicles with a primary oocyte and one layer of cuboidal granulosa cells.

Secondary Follicles

Ovarian follicles with a primary oocyte and multiple layers of granulosa cells.

Tertiary Follicles

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

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2. The Uterine (Menstrual) Cycle

Now that we have discussed the maturation of the cohort of tertiary follicles in the ovary, the buildup and then shedding of the endometrial lining in the uterus, and the function of the uterine tubes and vagina, we can put everything together to talk about the three phases of the uterine cycle (also known as the menstrual cycle)—the series of changes in which the uterine lining is shed, rebuilds, and prepares for implantation.

2a. Layers of the Uterus

The wall of the uterus is made up of three layers that play important roles in the uterine cycle.

1. The most superficial layer is the serous membrane, or perimetrium, which consists of epithelial tissue that covers the exterior portion of the uterus.
2. The middle layer, or myometrium, is a thick layer of smooth muscle responsible for uterine contractions. Most of the uterus is myometrial tissue, and there are multiple layers of connective tissue and smooth muscle fibers that run horizontally, vertically, and diagonally. The internal layer even includes circular fibers, similar to the stomach. Consequently, the myometrium allows the powerful contractions that occur during labor and the less powerful contractions (or cramps) that help to expel menstrual blood during a woman’s period. Anteriorly directed myometrial contractions also occur near the time of ovulation and are thought to possibly facilitate the transport of sperm through the female reproductive tract.
3. The innermost layer of the uterus is called the endometrium. The endometrium contains a connective tissue lining, the lamina propria, which is covered by epithelial tissue that lines the lumen.

Structurally, the endometrium consists of two layers: the stratum basalis and the stratum functionalis (the basal and functional layers). The stratum basalis layer is part of the lamina propria and is adjacent to the myometrium; this layer is not shed during menses. In contrast, the thicker stratum functionalis layer contains the glandular portion of the lamina propria and the endothelial tissue that lines the uterine lumen. It is the stratum functionalis that grows and thickens in response to increased levels of estrogen and progesterone. In the luteal phase of the uterine cycle, special branches from the uterine artery called spiral arteries supply the thickened stratum functionalis. This inner functional layer provides the proper site of implantation for the fertilized egg, and—should fertilization not occur—it is only the stratum functionalis layer of the endometrium that sheds during menstruation.

did you know

Painful menstruation that occurs in the absence of a physiologic cause is called dysmenorrhea. While many people have some cramping and pain during menstruation, people with dysmenorrhea have pain so severe that it interferes with their daily life. The condition is further classified as either primary dysmenorrhea, which is typical menstrual pain that occurs before or during a period, or secondary dysmenorrhea, which is menstrual pain caused by an underlying condition (ACOG, 2022a).

Common signs and symptoms of dysmenorrhea include cramping abdominal pain that may radiate to the lower back and thighs, nausea, vomiting, fatigue, headache, and diarrhea (ACOG, 2022a). Dysmenorrhea is more prevalent in younger people, smokers, people with early menarche or a family history, and people who have never been pregnant or given birth (Hickey et al., 2023).

Recall that during the follicular phase of the ovarian cycle, the tertiary follicles are growing and secreting estrogen. At the same time, the stratum functionalis of the endometrium is thickening to prepare for a potential implantation. The post-ovulatory increase in progesterone, which you will learn characterizes the luteal phase, is key for maintaining a thick stratum functionalis. As long as a functional corpus luteum is present in the ovary, the endometrial lining is prepared for implantation.

Indeed, if an embryo implants, signals are sent to the corpus luteum (a transformed follicle that forms after ovulation and secretes progesterone) to continue secreting progesterone to maintain the endometrium and thus maintain the pregnancy. If an embryo does not implant, no signal is sent to the corpus luteum, and it degrades, ceasing progesterone production and ending the luteal phase. Without progesterone, the endometrium thins, and under the influence of prostaglandins, the spiral arteries of the endometrium constrict and rupture, preventing oxygenated blood from reaching the endometrial tissue. As a result, endometrial tissue dies, and blood, pieces of the endometrial tissue, and white blood cells are shed through the vagina during menstruation, or menses. The first menses after puberty, called menarche, can occur either before or after the first ovulation.

IN CONTEXT

Endometrial Disease: Endometriosis

Endometriosis is a disease characterized by the presence of endometrial-like tissue found outside the uterus—in the uterine tubes, on the ovaries, or even in the pelvic cavity. This condition is often very painful, especially during menstrual periods.

This tissue acts similarly to the actual lining of the uterus. With each uterine cycle, the tissue thickens, breaks down, and bleeds. However, it is growing where it does not belong, and therefore it does not leave the body.

If endometriosis is associated with the ovaries, a type of cyst called an endometrioma can be formed. Scar tissue can then form as the surrounding tissue becomes irritated. Adhesions can also form as a result of endometriosis; these are bands of fibrous tissue that can cause pelvic tissues and organs to stick together. Potential complications associated with endometriosis also include fertility problems and even infertility in some cases. Although there is not yet a cure for endometriosis, there are treatment options that can help mitigate pain and fertility-related issues.

terms to know

Perimetrium

The outer epithelial layer of the uterine wall.

Myometrium

The smooth muscle layer of the uterus that allows for uterine contractions during labor and expulsion of menstrual blood.

Endometrium

The inner lining of the uterus, part of which builds up during the secretory phase of the uterine cycle and then sheds with menses.

Menses

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

Menarche

The first menstruation in a pubertal female.

2b. Phases of the Uterine Cycle

The timing of the uterine cycle starts with the first day of menses, which is referred to as day one of a period. Cycle length is determined by counting the days between the onset of bleeding in two subsequent cycles. Because the average length of a uterine cycle is 28 days, this is the time period used to identify the timing of events in the cycle. The length of the uterine cycle varies even in the same person from one cycle to the next, typically from 21 to 32 days. However, in all instances, there are three phases of the uterine cycle: the menses phase, the proliferative phase, and the secretory phase.

The menses phase (also known as the menstrual phase) of the uterine cycle is the phase during which the lining is shed—that is, the days that the person menstruates. Although it averages approximately 5 days, the menses phase can last from 2 to 7 days, or longer.

Once menstrual flow ceases, the endometrium begins to proliferate again, marking the beginning of the proliferative phase of the uterine cycle. This is the phase where the endometrium proliferates. In a typical 28-day uterine cycle, ovulation occurs on day 14. Ovulation marks the end of the proliferative phase in the uterine cycle as well as the end of the follicular phase in the ovarian cycle.

In the uterus, progesterone from the corpus luteum begins the secretory phase of the uterine cycle, in which the endometrial lining prepares for implantation. Over the next 10 to 12 days, the endometrial glands secrete a fluid rich in glycogen. If fertilization has occurred, this fluid will nourish the ball of cells now developing from the zygote. At the same time, the spiral arteries develop to provide blood to the thickened stratum functionalis.

If no pregnancy occurs within approximately 10 to 12 days, the corpus luteum will degrade into the corpus albicans, which is a nonfunctional structure that disintegrates over time. The endometrial tissue will die, resulting in menses—or the first day of the next cycle.

terms to know

Uterine Cycle

An approximately 28-day cycle of changes in the uterus consisting of a menses phase, a proliferative phase, and a secretory phase; also, menstrual cycle.

Menses Phase

The phase of the uterine cycle in which the endometrial lining is shed.

Proliferative Phase

The phase of the uterine cycle in which the endometrium proliferates.

Secretory Phase

The phase of the uterine cycle in which the endometrium secretes a nutrient-rich fluid in preparation for implantation of an embryo.

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3. Hormonal Control of the Ovarian and Uterine Cycles

Although changes that occur during the ovarian and uterine cycles are regulated by many of the same hormones that regulate the male reproductive system, the control of reproduction in females is more complex than in males. The ovarian and uterine cycles, which occur concurrently, are regulated by hormones of the hypothalamus, pituitary, and ovaries. The ebb and flow of the hormones causes the ovarian and uterine cycles to advance. Similar to males, the anterior pituitary hormones cause the release of the hormones FSH and LH. In addition, estrogens and progesterone are released from the developing follicles. Estrogen is the reproductive hormone in females that assists in endometrial regrowth, ovulation, and calcium absorption; it is also responsible for the secondary sexual characteristics of females. These include breast development, flaring of the hips, and a shorter period necessary for bone maturation. Progesterone assists in endometrial regrowth and inhibition of FSH and LH release.

In females, FSH stimulates the development of egg cells, called ova, which develop in structures called follicles. Follicle cells produce the hormone inhibin, which inhibits FSH production. LH also plays a role in the development of ova, induction of ovulation, and stimulation of estrogen and progesterone production by the ovaries. Estrogen and progesterone are steroid hormones that prepare the body for pregnancy. Estrogen produces secondary sex characteristics in females, while both estrogen and progesterone regulate the uterine cycle.

As you have learned, the ovarian cycle governs the preparation of endocrine tissues and the release of eggs, whereas the uterine cycle governs the preparation and maintenance of the uterine lining. These cycles are coordinated over an average length of 28 days, which is regulated by various hormones.

Additionally, recall there are three phases of the uterine cycle: the menses phase, the proliferative phase, and the secretory phase. The image below shows that the menses phase occurs when progesterone, FSH, and LH levels are low. Progesterone concentrations decline as a result of the degradation of the corpus luteum, marking the end of the luteal phase of the ovarian cycle. This decline in progesterone triggers the shedding of the stratum functionalis of the endometrium (menses).

If pregnancy does not occur, levels of both estrogen and progesterone will fall, and the endometrium will grow thinner. Prostaglandins will be secreted that cause constriction of the spiral arteries, reducing oxygen supply. This results in the death of endometrial tissue, which results in menses.

watch

View the following video to learn more about uterine and ovarian cycles.

terms to know

Estrogen

A reproductive hormone in females that assists in endometrial regrowth, ovulation, and calcium absorption.

Progesterone

A predominantly female sex hormone important in regulating the female reproductive cycle and the maintenance of pregnancy.

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4. Menopause

key concept

Female fertility (the ability to conceive) peaks when people are in their 20s and is slowly reduced until 35 years of age. After that time, fertility declines more rapidly, until it ends completely at the end of menopause. Menopause is the cessation of the uterine cycle that occurs as a result of the loss of ovarian follicles and the hormones that they produce. Menopause is considered complete if an individual has not menstruated in a full year. After that point, individuals are considered postmenopausal. The average age for this change is consistent worldwide at between 50 and 52 years of age, but it can normally occur at any time in a person's 40s or 50s. Poor health, including from smoking, can lead to earlier loss of fertility and earlier menopause.

As the age of menopause approaches, depletion of the number of viable follicles in the ovaries due to atresia affects the hormonal regulation of the uterine cycle. During the years leading up to menopause, there is a decrease in the levels of the hormone inhibin, which normally participates in a negative feedback loop to the pituitary to control the production of FSH. The menopausal decrease in inhibin leads to an increase in FSH. The presence of FSH stimulates more follicles to grow and secrete estrogen. Because small secondary follicles also respond to increases in FSH levels, larger numbers of follicles are stimulated to grow; however, most undergo atresia and die. Eventually, this process leads to the depletion of all follicles in the ovaries, and the production of estrogen falls off dramatically. It is primarily the lack of estrogen that leads to the symptoms of menopause.

The earliest changes occur during the menopausal transition, often referred to as perimenopause, when a uterine cycle becomes irregular but does not stop entirely. Although the levels of estrogen are still nearly the same as before the transition, the level of progesterone produced by the corpus luteum is reduced.

This decline in progesterone can lead to abnormal growth, or hyperplasia, of the endometrium. This condition is a concern because it increases the risk of developing endometrial cancer. Two harmless conditions that can develop during the transition are uterine fibroids, which are benign masses of cells, and irregular bleeding. As estrogen levels change, other symptoms that occur are hot flashes and night sweats, trouble sleeping, vaginal dryness, mood swings, difficulty focusing, and thinning of hair on the head along with the growth of more hair on the face. Depending on the individual, these symptoms can be entirely absent, moderate, or severe.

After menopause, lower amounts of estrogen can lead to other changes. Cardiovascular disease becomes as prevalent in females as in males, possibly because estrogens reduce the amount of cholesterol in the blood vessels. When estrogen is lacking, many people find that they suddenly have problems with high cholesterol and the cardiovascular issues that accompany it. Osteoporosis is another problem because bone density decreases rapidly in the first years after menopause. The reduction in bone density leads to a higher incidence of fractures.

IN CONTEXT

Everyday Connection: Hormone Therapy

Hormone therapy (HT), which employs medication (synthetic estrogens and progestins) to increase estrogen and progestin levels, can alleviate some of the symptoms of menopause.

In 2002, the Women’s Health Initiative began a study to observe the long-term outcomes of hormone replacement therapy over 8.5 years. However, the study was prematurely terminated after 5.2 years because of evidence of a higher-than-normal risk of breast cancer in patients taking estrogen-only HT. The potential positive effects on cardiovascular disease were also not realized in the estrogen-only patients.

The results of other hormone replacement studies over the last 50 years, including a 2012 study that followed over 1,000 menopausal women for 10 years, have shown cardiovascular benefits from estrogen and no increased risk for cancer. Some researchers believe that the age group tested in the 2002 trial may have been too old to benefit from the therapy, thus skewing the results. In the meantime, intense debate and study of the benefits and risks of replacement therapy is ongoing. Current guidelines approve HT for the reduction of hot flashes or flushes, but this treatment is generally only considered when people first start showing signs of menopausal changes. It is used in the lowest dose possible for the shortest time possible (5 years or less), and it is suggested that people on HT have regular pelvic and breast exams.

term to know

Menopause

The loss of reproductive capacity caused by decreased sensitivity of the ovaries to the hormones FSH and LH.

SOURCE: THIS TUTORIAL HAS BEEN ADAPTED FROM (1) OPENSTAX “BIOLOGY 2E”. ACCESS FOR FREE AT OPENSTAX.ORG/BOOKS/BIOLOGY-2E/PAGES/1-INTRODUCTION (2) OPENSTAX “ANATOMY AND PHYSIOLOGY 2E”. ACCESS FOR FREE AT OPENSTAX.ORG/BOOKS/ANATOMY-AND-PHYSIOLOGY-2E/PAGES/1-INTRODUCTION. LICENSING (1 & 2): CREATIVE COMMONS ATTRIBUTION 4.0 INTERNATIONAL.

REFERENCES

Mayo Clinic. “Ovarian cysts”. Retrieved November 8, 2023, from www.mayoclinic.org/diseases-conditions/ovarian-cysts/symptoms-causes/syc-20353405

Mayo Clinic. “Polycystic ovary syndrome (PCOS)”. Retrieved November 8, 2023, from www.mayoclinic.org/diseases-conditions/pcos/symptoms-causes/syc-20353439