Information

22.9: Disorders of the Female Reproductive System - Biology


Vaccinating Against Cancer

Can a vaccine prevent cancer? In the case of cervical cancer, it can. Cervical cancer is one of three disorders of the female reproductive system described in detail in this concept. Of the three, only cervical cancer can be prevented with a vaccine.

Cervical Cancer

Cervical cancer occurs when cells of the cervix (neck of the uterus) grow abnormally and develop the ability to invade nearby tissues or spread to other parts of the body, such as the abdomen or lungs. Figure (PageIndex{2}) shows the location of the cervix and the appearance of normal and abnormal cervical cells when examined with a microscope.

Cervical Cancer Prevalence and Death Rates

Worldwide, cervical cancer is the second most common type of cancer (after breast cancer) and the fourth most common cause of cancer death. In the United States and other high-income nations, the widespread use of cervical cancer screening has detected many cases of precancerous cervical changes and has dramatically reduced rates of cervical cancer deaths. About three-quarters of cervical cancer cases occur in developing countries, where routine screening is less likely because of cost and other factors. Cervical cancer is also the most common cause of cancer death in low-income countries.

Symptoms of Cervical Cancer

Early in the development of cervical cancer, there are typically no symptoms. As the disease progresses, however, symptoms are likely to occur. The symptoms may include abnormal vaginal bleeding, pelvic pain, or pain during sexual intercourse. Unfortunately, by the time symptoms start to occur, cervical cancer has typically progressed to a stage at which treatment is less likely to be successful.

Cervical Cancer Causes and Risk Factors

More than 90 percent of cases of cervical cancer are caused at least in part by human papillomavirus (HPV), which is a sexually transmitted virus that also causes genital warts. HPV infection can cause cervical cancer by interfering with a normal cell division. When HPV is not present, cervical cells containing mutations are not allowed to divide, so the cervix remains healthy. When HPV is present, however, cervical cells with mutations may be allowed to divide, leading to uncontrolled growth of mutated cells and the formation of a tumor.

Other risk factors for cervical cancer include smoking, a weakened immune system (for example, due to HIV infection), use of birth control pills, becoming sexually active at a young age, and having many sexual partners. However, these risk factors are less important than HPV infection. Instead, the risk factors are more likely to increase the risk of cervical cancer in individuals who are already infected with HPV. For example, among HPV-infected, current and former smokers have roughly two to three times the incidence of cervical cancer as non-smokers. Passive smoking is also associated with an increased risk of cervical cancer but to a lesser extent.

Diagnosis of Cervical Cancer

Diagnosis of cervical cancer is typically made by looking for microscopic abnormal cervical cells in a smear of cells scraped off the cervix. This is called a Pap smear. If cancerous cells are detected or suspected in the smear, this test is usually followed up with a biopsy to confirm the Pap smear results. Medical imaging (by CT scan or MRI, for example) is also likely to be done to provide more information, such as whether the cancer has spread.

Prevention of Cervical Cancer

It is now possible to prevent HPV infection with a vaccine. The first HPV vaccine was approved by the U.S. Food and Drug Administration in 2006. The vaccine protects against the strains of HPV that have the greatest risk of causing cervical cancer. It is thought that widespread use of the vaccine will prevent up to 90 percent of cervical cancer cases. Current recommendations are to be given the vaccine between the ages of nine and 26. (All sexes should be vaccinated against HPV, because the virus may also cause cancer of the penis and certain other cancers.) The vaccine is effective only if it is given before HPV infection has occurred. Using condoms during sexual intercourse can also help prevent HPV infection and cervical cancer, in addition to preventing pregnancy and sexually transmitted infections (such as HIV).

Even for those who have received the HPV vaccine, there is still a small risk of developing cervical cancer. Therefore, it is recommended that individuals with cervix continue to be examined with regular Pap smears.

Treatment of Cervical Cancer

Treatment of cervical cancer generally depends on the stage at which the cancer is diagnosed, but it is likely to include some combination of surgery, radiation therapy, and/or chemotherapy. Outcomes of treatment depend largely on how early the cancer is diagnosed and treated. For surgery to cure cervical cancer, the entire tumor must be removed with no cancerous cells found at the margins of the removed tissue on microscopic examination. If cancer is found and treated very early when it is still in the microscopic stage, the five-year survival rate is virtually 100 percent.

Vaginitis

Vaginitis is inflammation of the vagina — and sometimes the vulva, as well. Symptoms may include a discharge that is yellow, gray, or green; itching; pain; and a burning sensation. There may also be a foul vaginal odor and pain or irritation with sexual intercourse.

Causes of Vaginitis

About 90 percent of cases of vaginitis are caused by infection with microorganisms. Most commonly, vaginal infections are caused by the yeast Candida albicans (Figure (PageIndex{3})). Such infections are referred to as vaginal candidiasis. Other possible causes of vaginal infections include bacteria, especially Gardnerella vaginalis, and some single-celled parasites, notably the protist parasite Trichomonas vaginalis, which is usually transmitted through vaginal intercourse. The risk of vaginal infections may be greater in those who wear tight clothing, are taking antibiotics for another condition, use birth control pills, or have improper hygiene. Poor hygiene allows organisms that are normally present in the stool (such as yeast) to contaminate the vagina. Most of the remaining cases of vaginitis are due to irritation by — or allergic reactions to — various products. These irritants may include condoms, spermicides, soaps, douches, lubricants, and even semen. Using tampons or soaking in hot tubs may be additional causes of this type of vaginitis.

Diagnosis of Vaginitis

Diagnosis of vaginitis typically begins with symptoms reported by the patient. This may be followed by a microscopic examination or culture of the vaginal discharge in order to identify the specific cause. The color, consistency, acidity, and other characteristics of the discharge may be predictive of the causative agent. For example, infection with Candida albicans may cause a cottage cheese-like discharge with a low pH, whereas infection with Gardnerella vaginalis may cause a discharge with a fish-like odor and a high pH.

Prevention of Vaginitis

Prevention of vaginitis includes wearing loose cotton underwear that helps keep the vulva dry. Yeasts and bacteria that may cause vaginitis tend to grow best in a moist environment. It is also important to avoid the use of perfumed soaps, personal hygiene sprays, and douches, all of which may upset the normal pH and bacterial balance in the vagina. To help avoid vaginitis caused by infection with Trichomonas vaginalis, the use of condoms during sexual intercourse is advised.

Treatment of Vaginitis

The appropriate treatment of vaginitis depends on the cause. In many cases of vaginitis, there is more than one cause, and all of the causes must be treated to ensure a cure.

  • Yeast infections of the vagina are typically treated with topical anti-fungal medications, which are available over the counter. The medications may be in the form of tablets or creams that are inserted into the vagina. Depending on the particular medication used, treatment may involve one, three, or seven days of application.
  • Bacterial infections of the vagina are usually treated with antibiotics. These may be taken orally as pills or applied topically to the vagina in creams.
  • Trichomonas vaginalis infections of the vagina are generally treated with a single dose of an oral antibiotic. Sexual partners should be treated at the same time, and intercourse should be avoided for at least a week until both partners have completed treatment and been followed up by a physician.

Endometriosis

Endometriosis is a disease in which endometrial tissue, which normally grows inside the uterus, grows outside of the uterus (Figure (PageIndex{4})). Most often, the endometrial tissue grows around the ovaries, Fallopian tubes, and uterus. In rare instances, the tissue may grow elsewhere in the body. The areas of endometriosis typically bleed each month during the menstrual period, and this often results in inflammation, pain, and scarring. An estimated six to ten percent of individuals with a uterus are believed to have endometriosis. It is most common in their thirties and forties, and only rarely occurs before menarche or after menopause.

Signs and Symptoms of Endometriosis

The main symptom of endometriosis is pelvic pain, which may range from mild to severe. There appears to be little or no relationship between the amount of endometrial tissue growing outside the uterus and the severity of the pain. For many with the disease, the pain occurs mainly during menstruation. However, nearly half of those affected have chronic pelvic pain. The pain of endometriosis may be caused by bleeding in the pelvis, which triggers inflammation. Pain can also occur from internal scar tissue that binds internal organs to each other.

Another problem often associated with endometriosis is infertility, or the inability to conceive or bear children. Among patients with endometriosis, up to half may experience infertility. Infertility can be related to scar formation or to anatomical distortions due to abnormal endometrial tissue. Other possible symptoms of endometriosis may include diarrhea or constipation, chronic fatigue, nausea and vomiting, headaches, and heavy or irregular menstrual bleeding.

Causes of Endometriosis

The causes of endometriosis are not known for certain, but several risk factors have been identified, including a family history of endometriosis. People who have a genetic relationship with a person with endometriosis have about six times the normal risk of developing the disease themselves. It has been suggested that endometriosis results from mutations in several genes. It is likely that endometriosis is multifactorial, involving the interplay of several factors.

At the physiological level, the predominant idea for how endometriosis comes about is retrograde menstruation. This happens when some of the endometrial debris from a menstrual flow exits the uterus through the Fallopian tubes, rather than through the vagina. The debris then attaches itself to the outside of organs in the abdominal cavity, or to the lining of the abdominal cavity itself. Retrograde menstruation, however, does not explain all cases of endometriosis, so other factors are apparently involved. Suggestions include environmental toxins and autoimmune responses.

Diagnosis of Endometriosis

Diagnosis of endometriosis is usually based on self-reported symptoms and a physical examination by a doctor, often combined with medical imaging, such as ultrasonography. The only way to definitively diagnose endometriosis, however, is through visual inspection of the endometrial tissue. This can be done with a surgical procedure called laparoscopy, in which a tiny camera is inserted into the abdomen through a small incision (Figure (PageIndex{5})). The camera allows the physician to visually inspect the area where endometrial tissue is suspected.

Treatment of Endometriosis

The most common treatments for endometriosis are medications to control the pain, and surgery to remove the abnormal tissue. Frequently used pain medications are non-steroidal inflammatory drugs (NSAIDS), such as naproxen. Opiates may be used in cases of severe pain. Laparoscopy can be used to surgically treat endometriosis, as well as to diagnose the condition. In this type of surgery, an additional small incision is made to insert instruments that the surgeon can manipulate externally in order to burn (cauterize) or cut away the endometrial growths. In younger patients who want to have children, surgery is conservative to keep the reproductive organs intact and functional. However, with conservative surgery, endometriosis recurs in 20 to 40 percent of cases within five years of the surgery. In older patients who have completed childbearing, hysterectomy may be undertaken to remove all or part of the internal reproductive organs. This is the only procedure that is likely to cure endometriosis and prevent relapses.

Feature: My Human Body

A Pap smear is a method of cervical cancer screening used to detect potentially pre-cancerous and cancerous cells in the cervix. It is the most widely used screening test for this type of cancer, and it is very effective. The test may also detect vaginal infections and abnormal endometrial cells, but it is not designed for these purposes.

If you are sexually active, you should start receiving routine Pap smears by age 21. Because most cases of cervical cancer are caused by infection with human papillomavirus (HPV), which is a sexually transmitted infection, there is little or no benefit to screening people who have not had vaginal intercourse. Starting at age 21, general guidelines are for Pap smears to be repeated every three years until age 50, and then every five years until age 65. Screening may be discontinued after age 65 if the last three Pap smears were normal. If a person has a complete hysterectomy so they no longer have a cervix, there is also no need for further Pap smears. On the other hand, if a person has had a history of abnormal Pap smears or cancer, they will likely be screened more frequently. Pap smears can be done safely during the first several months of pregnancy and resumed about three months after childbirth. Generally, better results are obtained if Pap smears are not done during menstruation.

If you’ve never had a Pap smear, knowing what to expect may help prepare you for the procedure. The patient lies on the examining table with their feet in “stirrups” to hold the legs up and apart. An instrument called a speculum is inserted into the vagina to hold back the vaginal walls and give access to the cervix. A tiny amount of tissue is brushed off the cervix and smeared onto a microscope slide. The speculum is then removed, and the procedure is over. The slide is later examined under a microscope for abnormal cells. Some people experience light spotting or mild diarrhea after a Pap smear, but most have no lasting effects.

Pap smears are uncomfortable and may be somewhat painful for some people. there may also be a pelvic exam where doctors insert their fingers into the vagina during the Pap smear test. If you experience pain during a Pap smear, tell your health care provider. Many steps can be taken to minimize the pain, which might include using a smaller speculum, using warm instruments and a lubricant, and applying a topical anesthetic such as lidocaine to the cervix before obtaining the smear. Any pain is generally very brief, and the potential reward is worth it. Pap tests are estimated to reduce up to 80 percent of cervical cancer deaths. One of the lives saved could be your own.

Review

  1. What is cervical cancer? Worldwide, how prevalent is it, and how does it rank as a cause of cancer deaths?
  2. Identify the symptoms of cervical cancer.
  3. What are the causes of — and risk factors for — cervical cancer?
  4. What roles can Pap smears and HPV vaccines play in preventing cervical cancer cases and cervical cancer deaths?
  5. How is cervical cancer treated?
  6. Define vaginitis and identify its symptoms.
  7. What are some of the causes of vaginitis? Which cause is responsible for most of the cases?
  8. How is vaginitis diagnosed and treated?
  9. What is endometriosis, and what are its symptoms?
  10. Discuss possible causes of endometriosis.
  11. How is endometriosis treated? Which treatment is most likely to prevent the recurrence of the disorder?
  12. Which disorder below is the most likely to cause symptoms, specifically during menstruation?
    1. endometriosis
    2. cervical cancer
    3. HPV infection
    4. vaginitis
  13. True or False: Yeast infections are normally treated with antibiotics.
  14. True or False: In the absence of HPV, there are no mutated cells in the cervix.
  15. In the case of infection with Trichomonas vaginalis, why is the woman’s sexual partner usually treated at the same time?

Biogenesis and functions of circular RNAs and their role in diseases of the female reproductive system

A member of the newly discovered RNA family, circular RNA (circRNA) is considered as the intermediate product of by-product splicing or abnormal RNA splicing. With the development of RNA sequencing, circRNA has recently drawn research interest. CircRNA exhibits stability, species conservatism, and tissue cell specificity. It acts as a miRNA sponge in the circRNA-microRNA (miRNA-mRNA axis, which can regulate gene transcription and protein translation. Studies have confirmed that circRNA is ubiquitous in eukaryotic cells, which play an important role in the regulation of human gene expression and participate in the occurrence and development of various human diseases. CircRNA may be closely related to the occurrence and development of female reproductive system diseases. By analyzing the biological functions and mechanism of circRNA, we find that circRNA has certain development prospects as biomarkers of the female reproductive system diseases. The production and degradation of circRNA, biological functions, and their association with the occurrence of diseases of female reproductive system are reviewed in this article.


Consumption and effects

Over 500 different compounds are found in C. sativa, and at least 100 of these are cannabinoids.[5] Tetrahydrocannibinol (THC) is the high-inducing component of marijuana.

Cannabis is consumed as raw plant materials and extracts that are smoked or converted into edibles for ingestion.[5] Smoking is currently the most popular form of consumption but ingestion may eventually surpass smoking in popularity. According to Current Opinion in Food Science, ingestion of cannabis creates a slower, longer-lasting experience than smoking because a more psychoactive form of THC (11-hydroxy-Δ9-tetrahydrocannabinol) is created in the liver by cytochrome P-450.[5,7]

Beyond the detrimental respiratory effects of inhaling burning plant material, excess consumption of cannabis products can lead to nausea, vomiting, and disorientation.[5,8] Contaminants such as pesticides, metals, and microbial toxins are also potential sources of harm.[5]


Female External Genital Organs

The external genital organs include the mons pubis, labia majora, labia minora, Bartholin glands, and clitoris. The area containing these organs is called the vulva.

The external genital organs have three main functions:

Enabling sperm to enter the body

Protecting the internal genital organs from infectious organisms

Providing sexual pleasure

The mons pubis is a rounded mound of fatty tissue that covers the pubic bone. During puberty, it becomes covered with hair. The mons pubis contains oil-secreting (sebaceous) glands that release substances that are involved in sexual attraction (pheromones).

The labia majora (literally, large lips) are relatively large, fleshy folds of tissue that enclose and protect the other external genital organs. They are comparable to the scrotum in males. The labia majora contain sweat and sebaceous glands, which produce lubricating secretions. During puberty, hair appears on the labia majora.

The labia minora (literally, small lips) can be very small or up to 2 inches wide. The labia minora lie just inside the labia majora and surround the openings to the vagina and urethra. A rich supply of blood vessels gives the labia minora a pink color. During sexual stimulation, these blood vessels become engorged with blood, causing the labia minora to swell and become more sensitive to stimulation.

External Female Genital Organs

The area between the opening of the vagina and the anus, below the labia majora, is called the perineum. It varies in length from almost 1 to more than 2 inches (2 to 5 centimeters).

The labia majora and the perineum are covered with skin similar to that on the rest of the body. In contrast, the labia minora are lined with a mucous membrane, whose surface is kept moist by fluid secreted by specialized cells.

The opening to the vagina is called the introitus. The vaginal opening is the entryway for the penis during sexual intercourse and the exit for blood during menstruation and for the baby during birth.

When stimulated, Bartholin glands (located beside the vaginal opening) secrete a thick fluid that supplies lubrication for intercourse.

The opening to the urethra, which carries urine from the bladder to the outside, is located above and in front of the vaginal opening.

The clitoris, located between the labia minora at their upper end, is a small protrusion that corresponds to the penis in the male. The clitoris, like the penis, is very sensitive to sexual stimulation and can become erect. Stimulating the clitoris can result in an orgasm.


Diseases of the female reproductive system

Many parts of the male and female reproductive systems can be affected by cancer. In females, cancer can attack the uterus, ovaries, breast and cervix, among other organs, according to the American Cancer Society.

Many experts have seen what they refer to as the "Angelina Jolie" effect, where women are taking proactive measures by having breasts and internal reproductive organs removed if they have a family history of cancer before there are signs of the disease. "With better genetic testing and screening, we have seen a number of women who are being more proactive about their reproductive health," said Dr. Shana Wingo, who specializes on gynecologic oncology at Arizona Oncology.

Ovarian cancer tends to have a poorer outcome than other gynecological cancers, Ross noted, because it is not typically diagnosed until it has progressed significantly. "There is no standard screening available for ovarian cancer, so it is very difficult to identify it early."

Tests to detect ovarian cancer, as well as cancer of the fallopian tube, and primary peritoneal cancer are currently being studied, according to the National Cancer Institute.

There are two tests used to screen for cervical cancer. The Pap test screens for cellular changes in the cervix called cytology, while the genital human papillomavirus (HPV) test identifies the presence of infection with high-risk HPV, the strains that are linked to cervical cancer, according to Dr. Charles Dubin, an OB/GYN in Santa Monica, Calif.

A recent study published by Cancer Cytopathology, found that HPV-only screening misses more cervical cancer in women than Pap-only or co-testing, based on approximately 8.6 million women ages 30 to 65. There is approximately a three-fold improvement in the cancer detection rate of co-testing compared to HPV only.

Current guidelines recommend that women first start getting the Pap test alone when they turn 21 and repeat every three years if the test is normal until age 30. A Pap-plus-HPV test, or co-testing, is recommended for women ages 30 to 65, and if both are negative repeated every five years, regardless of whether they have received HPV vaccination. "However, there is compelling scientific evidence that co-testing every three years misses less cases of cancer and pre-cancer than every five-year co-testing," Dubin noted.

While genital HPV is typically associated with females, it is the most common sexually transmitted infection. The majority of sexually active people in the United States — male and female — will have HPV at some time in their lives, but most will not experience any symptoms. In a small portion of women, it can result in cervical cancer and genital warts in men, it can cause penile and anal cancer and genital warts, according to the NIH.

Both genders can develop sexually transmitted diseases, including genital herpes, gonorrhea and syphilis, according to the National Institutes of Health (NIH). HIV/AIDS, a disease of the immune system, is not exclusively transmitted through sexual contact sexual activity is one of the ways that the HIV virus is spread.

For females, severe menstrual cramping, or dysmenorrheal, is the most common disease of the reproductive system occurs with a woman's monthly menstrual period, according to Dr. Sheryl Ross, OB/GYN and Women's Health Specialist at Providence Saint John&rsquos Health Center.

"Severe pain before or during your period can last anywhere from one to seven days and disrupt your normal day-to-day routines at school, work and socially," Ross noted. Diagnosis is made by the patient's medical history and a pelvic exam. The best treatment includes medications that block the effects of prostaglandins and include ibuprofen and naproxen. The birth control pill also works well in treating dysmenorrhea by decreasing the blood flow, Ross noted.

Another common disorder of the female reproductive system is a vaginal yeast infection, which is caused by a yeast fungus in the vagina. Most can be successfully treated with over-the-counter medications, according to WebMD.

Endometriosis is a condition where that normally lines the inside of your uterus — the endometrium — ends up outside of uterus, most commonly in the ovaries, bowel or the tissue lining your pelvis. The endometrial tissue becomes trapped, causing pain, according to the Mayo Clinic.

Pelvic inflammatory disease can involve an infection of any of the female reproductive organs, including the uterus and ovaries. Sexually transmitted diseases, such as gonorrhea and chlamydia, are typical causes of pelvic inflammatory disease, according to the NIH. "Any of these STIs can cause serious and potentially long term reproductive problems that include chronic pelvic pain and infertility," Ross said.


Effects of Aging on the Female Reproductive System

Around menopause, changes in the genital organs occur rapidly. Menstrual cycles stop, and the ovaries stop producing estrogen . After menopause, the tissues of the labia minora (which surround the opening of the vagina and urethra), clitoris, vagina, and urethra thin (atrophy). This thinning can result in chronic irritation, dryness, and a discharge from the vagina. Vaginal infections are more likely to develop. Also after menopause, the uterus, fallopian tubes, and ovaries become smaller.

With aging, there is a decrease in the amount of muscle and connective tissue, including that in muscles, ligaments, and other tissues that support the bladder, uterus, vagina, and rectum. As a result, the affected organs may sag or drop down (prolapse), sometimes causing a feeling of pelvic pressure or fullness, difficulty urinating, loss of control of urination or bowel movements (incontinence), or pain during sexual intercourse. Women who have had many children are more likely to have such problems.

Did You Know.

Some women enjoy sexual intercourse more after menopause.

Because there is less estrogen to stimulate milk ducts, the breasts decrease in size. The connective tissue that supports the breasts also decreases, leading to sagging and contributing to changes in shape. Fibrous tissue in the breasts is replaced with fat, making the breasts less firm.

For most women, age-related changes in reproductive organs do not interfere with sexual activity or sexual pleasure after menopause. Some women enjoy sexual activity more after menopause, possibly because they are no longer concerned about becoming pregnant. In addition, after menopause, the ovaries and adrenal glands continue to produce male sex hormones. Male sex hormones help maintain the sex drive, slow the loss of muscle tissue, and contribute to an overall sense of well-being.


I. Ovary

Slide 239 Ovary, monkey, H&E View Virtual Slide

Slide 269 Ovary, monkey, PAS stain View Virtual Slide

Slide 235 Ovary, human, H&E View Virtual Slide

Slide 234 Ovary, human, H&E View Virtual Slide

Slide 234-1 Ovary, human, H&E View Virtual Slide

Slide 234-2 Ovary, human, trichrome stain View Virtual Slide

Slide 236a Ovary, human, H&E View Virtual Slide

Overview: The ovaries are paired organs situated on either side of the uterus. They are attached on one edge, the hilus, to the broad ligament of the uterus by a fold of peritoneum, the mesovarium. Using slide 239, examine the overall topography of the ovary and note the numerous vessels which enter it via the broad ligament. The inner medulla (present in most slides) is highly vascular and composed of a loose connective tissue core. Examine the outer cortex of the ovary which is composed of stroma and numerous follicles in various stages of development. In slide 239, note the layer of collagenous connective tissue, the tunica albuginea View Image just below the surface epithelium (mesothelium/serosa often misleadingly referred to as "germinal epithelium") that covers the ovary.

Examine the stroma of the cortex in slide 239 and note the whorls of closely-packed, spindle-shaped fibroblasts. The cortex also contains many oocytes (300,000- 400,000 at birth) embedded in this cortical stroma. Because of the variation in sectioning, age and stage of the cycle, you will have to study several slides in order to study all aspects of follicular development, atresia and corpus luteum formation.

Primordial & Primary Follicles: Examine several primordial follicles View Image using slide 239 or 269 and note that they consist of a large oocyte surrounded by a layer of flattened follicular cells. Next examine the appearance of primary follicles View Image in which the large oocyte is surrounded by a layer of cuboidal follicular cells (also good in slide 238). These follicular cells proliferate to form a loose multi-layer, the granulosa cell layer. A rim of neutral glycoprotein, the zona pellucida (clear zone), surrounds the oocyte separating it from the surrounding granulosa cells. Slide 269 has been stained with PAS, so that carbohydrates and connective tissue are highlighted. Using this slide, examine the zona pellucida View Image of several smaller follicles. Stromal cells form a dense sheath (theca) around the follicle.

Secondary Follicles: Examine the structure of several secondary follicles View Image and observe that between the stratified granulosa cells there are large lacunae that coalesce to form the follicular antrum. The stromal cells surrounding the follicle have differentiated to form an inner layer (theca interna) of plump cells that secrete steroid precursors and an outer layer (theca externa) composed of concentrically arranged stromal cells that provide support for the developing follicle. Slide 235 also has good theca layers (see below).

Mature/Graafian Follicle: With continued development, the follicle becomes a Graafian or ovulatory follicle View Image (This follicle is actually rather small to be a real Graafian follicle). The granulosa zone now consists of many layers of cuboidal follicular epithelial cells located at the periphery of the large, well-formed follicular antrum. The oocyte has attained its full size, is located eccentrically within the follicle in a small hillock, the cumulus oophorus which protrudes into the antrum. The zona pellucida is surrounded by a continuous layer of follicular cells, the corona radiata. Because of its size, the oocyte will not be present in every section of the follicle, but examine the other components of a tertiary follicle. The theca interna is separated from the granulosa cells by a distinct basement membrane. Theca externa cells are densely packed, spindle-shaped cells which blend with the theca interna cells and with the surrounding stroma. Note that the theca interna has a rich capillary vascular supply, particularly well demonstrated in slide 235 View Image.

Atretic Follicles: Because the contents of only one follicle are usually ovulated at a time in humans, other follicles which have been stimulated to develop must degenerate, or undergo atresia View Image. Atresia is not limited to mature follicles, but may begin at any stage in follicular development. Early atretic alterations include: clumping of the nuclear chromatin (pyknosis) and shrinkage and lysis of the cytoplasm of the oocyte, granulosa or follicular cells. Examine the pyknotic granulosa cells View Image, which are sloughed into the follicular antrum. The basement membrane that separates the granulosa cells from the theca interna may also thicken considerably to form a so-called “glassy membrane.” These changes are especially well illustrated in H&E slide 234 View Image and trichrome-stained slide #234-2 View Image. Make sure you are able to differentiate atretic changes from artifacts related to shrinkage due to fixation. Macrophages may eventually invade the center of the larger atretic follicles that are finally replaced by loose connective tissue.

Corpus Luteum: After ovulation, the follicle which housed the ovum collapses and becomes highly infolded and invaded by vessels, forming the corpus luteum View Image (yellow body). Examine slide 236a and observe that the corpus luteum appears pale and very folded. If the egg is fertilized and implants, the corpus luteum enlarges to become the corpus luteum of pregnancy. Examine the inner granulosa lutein cells View Image (formed from the remaining granulosa cells) and the outer theca lutein cells View Image which come from the remaining theca interna cells. Both cell types are polyhedral and filled with lipid droplets and have centrally located nuclei. The theca lutein cells are, however, considerably smaller, more darkly staining and have fewer lipid filled vacuoles than the granulosa lutein cells. They are found most prominently in the infoldings right up against the granulosa lutein layer. Granulosa lutein cells contain a pigment, lipochrome, which produces the yellowish color of the corpus luteum in an unfixed ovary. A central blood clot may be present in recently ovulated follicles.

Corpus Albicans: If the egg is not fertilized, the corpus luteum degenerates, and is gradually infiltrated with collagen and a few (if any) fibroblasts, forming the corpus albicans (white body) particularly evident in slide 234 stained with H&E View Image and trichrome View Image. The corpus albicans is also formed during the later half of pregnancy when the placenta takes over steroid secretion from the corpus luteum. Excellent examples of corpus albicans can be best observed in slides 234 or236.


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The origin of reproductive organs

Early in human development, during the first trimester of gestation, a fetus may have XX or XY chromosomes that indicate its sex. Yet at this stage a mass of cells known as the bipotential gonad that ultimately develops into either ovaries or testes has yet to commit to its final destiny.

While researchers had studied the steps that go into the later stages of this process, little has been known about the precursors of the bipotential gonad. In a new study published in Cell Reports and co-led by Kotaro Sasaki of Penn's School of Veterinary Medicine, an international team lays out the detailed development of this key facet of sexual determination in two mammalian models.

"Using single-cell transcriptome data, we can get a lot of information about gene expression at each developmental stage," says Sasaki. "We can define what the default process is and how it might go awry in some cases. This has never been done in traditional developmental biology. Now we can understand development in molecular terms."

Disorders of sex development (DSD) occur when internal and external reproductive structures develop differently from what would be expected based on an individuals' genetics. For example someone with XY chromosomes might develop ovaries. These conditions often affect fertility and are associated with an increased risk of germ cell tumors.

"These disorders oftentimes create psychological and physical distress for patients," Sasaki says. "That's why understanding gonadal development is important."

To understand atypical development, Sasaki and colleagues in the current study sought to layout the steps of typical development, working with a mouse model and a monkey model.

The researchers began by examining mouse embryos throughout embryonic development, using molecular markers to track the location of different proteins suspected to be involved in the formation of reproductive structures. They noticed that by day nine of a mouse's embryonic development, a structure called the posterior intermediate mesoderm (PIM) lit up brightly with the marker for a gene critical to the development of gonads, kidneys, and the hormone-producing adrenal glands, which are located adjacent to the kidneys.

Zeroing in on the PIM and its progeny cells, the team found that, by day 10.5, these also expressed a marker known to be associated with the bipotential gonad.

"People have previously studied the origin of the urogenital organs and the kidney and based on that believed that their origins were very close," Sasaki says. "So our hypothesis was that the PIM was the origin of the gonads as well as the kidneys."

To identify the origin of the gonad, they performed lineage tracing, in which scientists label cells in order to track their descendents, which indeed supported the connection between the PIM and the gonads.

To further confirm that the PIM played a similar role in an organism closer to humans in reproductive biology, the researchers made similar observations in embryos from cynomolgus monkeys. Though the developmental timing was different from the mouse, as was expected, the PIM again appeared to give rise to the bipotential gonad.

Digging even deeper into the molecular mechanism of the transition between the PIM and bipotential gonad, the researchers used a cutting-edge technique: single-cell sequencing analysis, whereby they can identify which genes are being turned on during each developmental stage.

Not only were they able to identify genes that were turned on -- many of which had never before been associated with reproductive development -- but they observed a transition state between the PIM and bipotential gonad, called the coelomic epithelium. Comparing the mice and monkey embryos, the researchers came up with a group of genes that were conserved, or shared between the species. "Some of these genes are already known to be important for the development of mouse and human ovaries and testes," Sasaki says, "and some have been implicated in the development of DSDs."

He notes that in roughly half of patients with DSDs, however, the genetic cause is unknown. "So this database we're assembling may now be used to predict some additional genes that are important in DSD and could be used for screening and diagnosis of DSDs, or even treatment and prevention."

The study also illuminated the relationship between the origin of the kidneys, adrenal glands, and gonads. "They all originate from the PIM, but the timing and positioning is different," Sasaki says.

The adrenal glands, he says, develop from the anterior portion of the PIM, or that section closer to the head and arise early, while the kidney arises later from the posterior portion of the PIM. The gonadal glands span the PIM, with some regions developing earlier and others later.

In future studies, Sasaki and colleagues would like to continue teasing out the details and stages of gonadal development. Sasaki's ultimate goal is to coax a patient's own stem cells to grow into reproductive organs in the lab.

"Some patients with DSDs don't have ovaries and testes, and some cancer patients undergo chemotherapy and completely lose their ovary function," Sasaki says. "If you could induce a stem cell to grow into an ovary in the lab, you could provide a replacement therapy for these patients, allowing them to regain normal hormone levels and even fertility. With a precise molecular map to the developing gonad in hand, we are now one step closer to the this goal."


Hermaphroditism

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Hermaphroditism, the condition of having both male and female reproductive organs. Hermaphroditic plants—most flowering plants, or angiosperms—are called monoecious, or bisexual. Hermaphroditic animals—mostly invertebrates such as worms, bryozoans (moss animals), trematodes (flukes), snails, slugs, and barnacles—are usually parasitic, slow-moving, or permanently attached to another animal or plant.

In humans, conditions that involve discrepancies between external genitalia and internal reproductive organs are described by the term intersex. Intersex conditions are sometimes also referred to as disorders of sexual development (DSDs). Such conditions are extremely rare in humans. In true gonadal intersex (or true hermaphroditism), an individual has both ovarian and testicular tissue. The ovarian and testicular tissue may be separate, or the two may be combined in what is called an ovotestis. Affected individuals have sex chromosomes showing male-female mosaicism (where one individual possesses both the male XY and female XX chromosome pairs). Most often, but not always, the chromosome complement is 46,XX, and in every such individual there also exists evidence of Y chromosomal material on one of the autosomes (any of the 22 pairs of chromosomes other than the sex chromosomes). Individuals with a 46,XX chromosome complement usually have ambiguous external genitalia with a sizable phallus and are therefore often reared as males. However, they develop breasts during puberty and menstruate and in only rare cases actually produce sperm. In 46,XX intersex (female pseudohermaphroditism), individuals have male external genitalia but the chromosomal constitution and reproductive organs of a female. In 46,XY (male pseudohermaphroditism), individuals have ambiguous or female external genitalia but the chromosomal constitution and reproductive organs of a male, though the testes may be malformed or absent.

Treatment of intersex in humans depends upon the age at which the diagnosis is made. Historically, if diagnosed at birth, the choice of sex was made (typically by parents) based on the condition of the external genitalia (i.e., which sex organs predominate), after which so-called intersex surgery was performed to remove the gonads of the opposite sex. The remaining genitalia were then reconstructed to resemble those of the chosen sex. The reconstruction of female genitalia was more readily performed than the reconstruction of male genitalia, so ambiguous individuals often were made to be female. However, intersex surgery has long-term consequences for affected individuals. Later in life, for example, the person may not be satisfied with the results of surgery and may not identify with the assigned gender. Thus, patient consent has become an increasingly important part of decisions about intersex surgery, such that surgery may be delayed until adolescence or adulthood, after patients have had sufficient time to consider their gender and are able to make informed decisions about treatment. In older individuals the accepted gender may be reinforced by the appropriate surgical procedures and by hormonal therapy.

The Editors of Encyclopaedia Britannica This article was most recently revised and updated by Kara Rogers, Senior Editor.


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