THE FEMALE REPRODUCTIVE CYCLE

Oogenesis and Follicular Development

• The formation of gametes in the ovaries is termed oogenesis
• (o¯ -o¯ -JEN-e-sis; oo- egg). 

• In contrast to spermatogenesis, which begins in males at puberty, oogenesis begins in females before they are even born. 

• Oogenesis occurs in essentially the same manner as spermatogenesis; 
• meiosis  takes place and the resulting germ cells undergo maturation.

• During early fetal development, primordial (primitive) germ cells migrate from the yolk sac to the ovaries. 
• There, germ cells differentiate within the ovaries into oogonia (o¯ -o¯ -GO¯ -ne¯ -a; singular is oogonium). 
• Oogonia are diploid (2n) stem cells that divide mitotically to produce millions of germ cells.
• Even before birth, most of these germ cells degenerate in a process known as atresia (a-TRE¯ -ze¯ -a). 

• A few, however, develop into larger cells called primary oocytes (O¯ -o¯-sı¯tz) that enter prophase of meiosis I during fetal development but do not complete that phase until after puberty. 
• During this arrested stage of development, each primary oocyte is surrounded by a single layer of flat follicular cells, and the entire structure is called a primordial follicle.

•  The ovarian cortex surrounding the primordial follicles consists of collagen fibers and fibroblast-like stromal cells. 

• At birth, approximately 200,000 to 2,000,000 primary oocytes remain in each ovary. 
• Of these, about 40,000 are still present at puberty, 
• and around 400 will mature and ovulate during a woman’s reproductive lifetime. 
• The remainder of the primary oocytes undergo atresia.

• Each month after puberty until menopause, gonadotropins (FSH and LH) secreted by the anterior pituitary further stimulate the development of several primordial follicles, although only one will typically reach the maturity needed for ovulation. 

• A few primordial follicles start to grow, developing into primary follicles. 
• Each primary follicle consists of a primary oocyte that is surrounded in a later stage of development by several layers of cuboidal and low-columnar cells called granulosa cells. 
• The outermost granulosa cells rest on a basement membrane.

• As the primary follicle grows, it forms a clear glycoprotein layer called the zona pellucida (pe-LOO-is-da) between the primary oocyte and the granulosa cells. 

• In addition, stromal cells surrounding the basement membrane begin to form an organized layer called the theca folliculi (THE¯ -ka fo-LIK-u¯ -li).

• With continuing maturation, a primary follicle develops into a secondary follicle . 
• In a secondary follicle, the theca differentiates into two layers: 

(1) the theca interna, 


     - a highly vascularized internal layer of cuboidal secretory cells that secrete estrogens and

 (2) the theca externa, 

     - an outer layer of stromal cells and collagen fibers. 

• In addition, the granulosa cells begin to secrete follicular fluid, which builds up in a cavity called the antrum in the center of the secondary follicle. 

• The innermost layer of granulosa cells becomes firmly attached to the zona pellucida 
• and is now called the corona radiata (corona = crown; radiata = radiation) 

• The secondary follicle eventually becomes larger, turning into a mature (graafian) follicle . 

• While in this follicle, and just before ovulation, the diploid primary oocyte completes meiosis I, producing two haploid (n) cells of unequal size—each with 23 chromosomes . 
• The smaller cell produced by meiosis I, called the first polar body,

            -  is essentially a packet of discarded nuclear material. 

• The larger cell, known as the secondary oocyte,              - receives most of the cytoplasm.

• Once a secondary oocyte is formed, it begins meiosis II but then stops in metaphase. 
• The mature (graafian) follicle soon ruptures and releases its secondary oocyte, a process known as ovulation.

• At ovulation, the secondary oocyte is expelled into the pelvic cavity together with the first polar body and corona radiata.

• Normally these cells are swept into the uterine tube. 

• If fertilization does not occur, the cells degenerate. 
• If sperm are present in the uterine tube and one penetrates the secondary oocyte, however, meiosis II resumes. 
• The secondary oocyte splits into two haploid cells, again of unequal size. 

• The larger cell is the ovum, or mature egg; 
•  the smaller one is the second polar body. 

• The nuclei of the sperm cell and the ovum then unite, forming a diploid zygote. 

• If the first polar body undergoes another division to produce two polar bodies, then the primary oocyte ultimately gives rise to three haploid polar bodies, which all degenerate, and a single haploid ovum. 

• Thus, one primary oocyte gives rise to a single gamete (an ovum). 

• By contrast, in males one primary spermatocyte produces four gametes (sperm).

THE FEMALE REPRODUCTIVE CYCLE

During their reproductive years, 

• nonpregnant females normally exhibit cyclical changes in the ovaries and uterus. 

• Each cycle takes about a month 
• and involves both 

                      - oogenesis and

                      -  preparation of the uterus to receive a fertilized ovum.

• Hormones secreted by

1. the hypothalamus, 
2. anterior pituitary, and 
3. ovaries 

         - control the main events. 

• The ovarian cycle is a series of events in the ovaries that occur during and after the maturation of an oocyte

• The uterine (menstrual) cycle is a concurrent series of changes in the endometrium of the uterus to prepare it for the arrival of a fertilized ovum that will develop there until birth.

•  If fertilization does not occur, ovarian hormones wane, 

          - which causes the stratum functionalis of the endometrium to slough off. 

• The general term female reproductive cycle encompasses 

a. the ovarian and uterine cycles, 

b. the hormonal changes that regulate them, 

c. and the related cyclical changes in the breasts and cervix.

Hormonal Regulation of the Female Reproductive Cycle

1. Gonadotropin-releasing hormone (GnRH) 

• secreted by the hypothalamus

• controls the ovarian and uterine cycles 

• stimulates the release of

a.  follicle-stimulating hormone (FSH) and 
b.  luteinizing hormone (LH) from the anterior pituitary. 

FSH 

• initiates follicular growth, 
• Under the influence of FSH, the androgens are taken up by the granulosa cells of the follicle and then converted into estrogens.

while LH 

• stimulates further development of the ovarian follicles. 
• LH stimulates the theca cells of a developing follicle to produce androgens.
• At midcycle, LH triggers ovulation 
• and then promotes formation of the corpus luteum, 
• the reason for the name luteinizing hormone.
• Stimulated by LH, the corpus luteum produces and secretes estrogens, progesterone, relaxin, and inhibin.

In addition, both FSH and LH 

• stimulate the ovarian follicles to secrete estrogens.

  

• At least six different estrogens have been isolated from the plasma of human females, 
• but only three are present in significant quantities: 

1. beta ( )-estradiol, 
2. estrone, and 
3. estriol. 

• In a nonpregnant woman, the most abundant estrogen is -estradiol,
• which is synthesized from cholesterol in the ovaries.

Estrogens secreted by ovarian follicles have several important functions

A.  Estrogens promote the development and maintenance of

1. female reproductive structures, 
2. secondary sex characteristics,
3. and the breasts. 

The secondary sex characteristics include

• distribution of adipose tissue in the breasts, abdomen, monspubis, and hips;
• voice pitch; 
• a broad pelvis; 
• and pattern of hair growth on the head and body.

 B. Estrogens increase protein anabolism, including the building of strong bones. 

• In this regard, estrogens are synergistic with human growth hormone (hGH).

C.  Estrogens lower blood cholesterol level, 

• which is probably the reason that women under age 50 have a much lower risk of coronary artery disease than do men of comparable age.

D.  Moderate levels of estrogens in the blood inhibit 

• both the release of GnRH by the hypothalamus 
• and secretion of LH and FSH by the anterior pituitary.

 Progesterone, 

• secreted mainly by cells of the corpus luteum,

1. cooperates with estrogens to prepare and maintain the endometrium 

• for implantation of a fertilized ovum 
• and to prepare the mammary glands for milk secretion. 

2. High levels of progesterone

• also inhibit secretion of GnRH and LH.

Relaxin 

• The small quantity of relaxin produced by the corpus luteum during each monthly cycle                           - relaxes the uterus by inhibiting contractions of the myometrium. 

• Presumably, implantation of a fertilized ovum occurs more readily in a “quiet” uterus. 

During pregnancy,

•  the placenta produces much more relaxin, 
• and it continues to relax uterine smooth muscle. 

At the end of pregnancy,

• relaxin also increases the flexibility of the pubic symphysis and
• may help dilate the uterine cervix, both of which ease delivery of the baby.

Inhibin

• is secreted by granulosa cells of growing follicles and by the corpus luteum after ovulation. 
• It inhibits secretion of FSH and, to a lesser extent, LH.

Phases of the Female Reproductive Cycle

• The duration of the female reproductive cycle typically ranges from 24 to 35 days.
• we assume a duration of 28 days and 
• divide it into four phases: 

1. the menstrual phase, 
2. the preovulatory phase, 
3. ovulation, and
4. the postovulatory phase

1. Menstrual Phase

• The menstrual phase (MEN-stroo-al), also called menstruation (men -stroo-A¯ -shun) or menses (MEN-se¯z month), 
• lasts for roughly the first 5 days of the cycle.
•  (By convention, the first day of menstruation is day one of a new cycle.)

a. EVENTS IN THE OVARIES 

Under the influence of FSH, 

• several primordial follicles develop into primary follicles 
• and then into secondary follicles. 

           - This developmental process may take several months to occur. 

• Therefore, a follicle that begins to develop at the beginning of a particular menstrual cycle may not reach maturity and ovulate until several menstrual cycles later.

b. EVENTS IN THE UTERUS 

Menstrual flow from the uterus consists
of 

• 50–150 mL of blood, 
• tissue fluid, 
• mucus, and
•  epithelial cells shed from the endometrium. 

This discharge occurs because

• the declining levels of progesterone and estrogens stimulate release of prostaglandins 

                    - that cause the uterine spiral arterioles to constrict. 

• As a result, the cells they supply become oxygen-deprived and start to die. 
• Eventually, the entire stratum functionalis sloughs off. 

• At this time the endometrium is very thin, about 2–5 mm, because only the stratum basalis remains. 
• The menstrual flow passes from the uterine cavity through the cervix and vagina to the exterior.

2. Preovulatory Phase

The preovulatory phase 

• is the time between the end of menstruation and ovulation. 

• The preovulatory phase of the cycle is more variable in length than the other phases and 
• accounts for most of the differences in length of the cycle.
•  It lasts from days 6 to 13 in a 28-day cycle.

a. EVENTS IN THE OVARIES 

• Some of the secondary follicles in the ovaries begin to secrete estrogens and inhibin. 
• By about day 6, a single secondary follicle in one of the two ovaries has outgrown all the others to become the dominant follicle. 

Estrogens and inhibin

• secreted by the dominant follicle 
• decrease the secretion of FSH, 
• which causes other, less well-developed follicles to stop growing and undergo atresia.

 Fraternal (nonidentical) twins or triplets 

• result when two or three secondary follicles become codominant 
• and later are ovulated and fertilized at about the same time.

Normally, 

• the one dominant secondary follicle becomes the mature (graafian) follicle,
•  which continues to enlarge 
• until it is more than 20 mm in diameter and ready for ovulation . 

• This follicle forms a blisterlike bulge due to the swelling antrum on the surface of the ovary. 

During the final maturation process,

•  the mature follicle continues to increase its production of estrogens .

With reference to the ovarian cycle,

•  the menstrual and preovulatory phases together are termed the follicular phase (fo¯- LIK-u¯-lar) 
• because ovarian follicles are growing and developing.

b. EVENTS IN THE UTERUS 

Estrogens liberated into the blood by growing ovarian follicles 

• stimulate the repair of the endometrium;
• cells of the stratum basalis undergo mitosis and produce a new stratum functionalis. 

As the endometrium thickens,

• the short, straight endometrial glands develop, 
• and the arterioles coil and lengthen as they penetrate the stratum functionalis. 
• The thickness of the endometrium approximately doubles, to about 4–10 mm. 

With reference to the uterine cycle, the preovulatory phase is also termed the proliferative phase 

• because the endometrium is proliferating.

Ovulation

•  the rupture of the mature (graafian) follicle and the release of the secondary oocyte into the pelvic cavity, 
• usually occurs on day 14 in a 28-day cycle. 

During ovulation, 

• the secondary oocyte remains surrounded by its zona pellucida and corona radiata.

• The high levels of estrogens during the last part of the preovulatory phase exert a positive feedback effect on the cells that secrete LH and gonadotropin-releasing hormone (GnRH) and cause ovulation, as follows 

1. A high concentration of estrogens 

• stimulates more frequent release of GnRH from the hypothalamus.
•  It also directly stimulates gonadotrophs in the anterior pituitary to secrete LH.

2.  GnRH 

• promotes the release of FSH and additional LH by the anterior pituitary.

3. LH

•  causes rupture of the mature (graafian) follicle 
•  and expulsion of a secondary oocyte about 9 hours after the peak of the LH surge.
•  The ovulated oocyte and its corona radiata cells are usually swept into the uterine tube.

• From time to time, an oocyte is lost into the pelvic cavity,
• where it later disintegrates. 

• The small amount of blood that sometimes leaks into the pelvic cavity from the ruptured follicle can cause pain, known as mittelschmerz (MIT-el-shma¯rts pain in the middle), at the time of ovulation.

• An over-the-counter home test that detects a rising level of LH can be used to predict ovulation a day in advance.

3. Postovulatory Phase


The postovulatory phase of the female reproductive cycle 

• is the time between ovulation and onset of the next menses. 

In duration,

• it is the most constant part of the female reproductive cycle
• It lasts for 14 days in a 28-day cycle, 
• from day 15 to day 28 .

a. EVENTS IN ONE OVARY 

After ovulation, 

• the mature follicle collapses,
•  and the basement membrane between the granulosa cells and theca interna breaks down. 

Once a blood clot forms from minor bleeding of the ruptured follicle, 

• the follicle becomes the corpus hemorrhagicum (hemo- blood; rrhagic-  bursting forth) . 

• Theca interna cells mix with the granulosa cells as they all become transformed into corpus luteum cells under the influence of LH. 
• Stimulated by LH, the corpus luteum secretes progesterone, estrogen, relaxin, and inhibin.

• The luteal cells also absorb the blood clot. 

• With reference to the ovarian cycle, this phase is also called the luteal phase.

• Later events in an ovary that has ovulated an oocyte depend on whether the oocyte is fertilized.

 If the oocyte is not fertilized,

• the corpus luteum has a lifespan of only 2 weeks. 
• Then, its secretory activity declines, 
• and it degenerates into a corpus albicans. 
• As the levels of progesterone, estrogens, and inhibin decrease, release of GnRH, FSH, and LH rises due to loss of negative feedback suppression by the ovarian hormones.

• Follicular growth resumes and a new ovarian cycle begins.

If the secondary oocyte is fertilized and begins to divide,

• the corpus luteum persists past its normal 2-week lifespan.
•  It is “rescued” from degeneration by human chorionic gonadotropin (hCG). 
• This hormone is produced by the chorion of the embryo beginning about 8 days after fertilization.
• Like LH, hCG stimulates the secretory activity of the corpus luteum.

• The presence of hCG in maternal blood or urine is an indicator of pregnancy and
•  is the hormone detected by home pregnancy tests.

b. EVENTS IN THE UTERUS 


Progesterone and estrogens produced by the corpus luteum 

• promote growth and coiling of the endometrial glands, 
• vascularization of the superficial endometrium, and 
• thickening of the endometrium to 12–18 mm (0.48–0.72 in.).

Because of the secretory activity of the endometrial glands, which begin to secrete glycogen, 

• this period is called the secretory phase of the uterine cycle. 

• These preparatory changes peak about one week after ovulation, at the time a fertilized ovum might arrive in the uterus. 

If fertilization does not occur,

• the levels of progesterone and estrogens decline due to degeneration of the corpus luteum. 
• Withdrawal of progesterone and estrogens causes menstruation.