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Ovulation Disorders - View Presentation

Slide 1
This review is a general summary of ovulation disorders, disorders that usually present as irregular menstrual intervals rather than regular monthly menstrual flows. There are many different causes for these disorders and they will be discussed. Ovulation disorders can cause a variety of problems, including (1) infertility and (2) an overgrowth of the tissues that line the uterine cavity. An overgrowth of the uterine lining cells can ultimately result in cancer, or a malignant degeneration of these tissues. These problems will also be discussed.

Slide 2
In order to understand ovulation disorders, you will need to know what normally occurs during ovulation.

Normal ovulation generally causes regular monthly menstrual intervals with a consistent amount of flow and premenstrual symptoms.

Disorders of ovulation can involve the central nervous system, the hypothalamus, the pituitary gland or the ovary.

Slide 3
The normal female reproductive lifespan starts at puberty, when the first mature fertilization capable egg is released from an ovary, and it ends at menopause, when this process of ovulation stops because there are no maturation capable eggs left in the ovaries.

At puberty, there are thought to be roughly 300,000 to 400,000 eggs in the ovaries and at menopause very few or no eggs remain. A normal reproductive lifespan is about 30-40 years long, with 12 monthly cycles per year, so there are only about 300 - 400 ovulations in a normal reproductive lifespan. Therefore, during a normal human reproductive lifespan, 300-400 thousands eggs are used during 300-400 ovulations, or eggs are used at a rate of about 1,000 eggs per ovulation. This is a tremendously inefficient system.

Many biological systems are inefficient including the human male reproductive system. The need to release several million sperm during intercourse just for one sperm to find and fertilize the egg is evidence of inefficiency in the male system.

Slide 4
A complex and highly regulated series of events must occur to result in regular monthly ovulation and regular menstrual cycle intervals. These events involve the Central Nervous System, the hypothalamus, the pituitary gland, and the ovary.

The preoptic area and the arcuate nucleus of the hypothalamus respond to neurotransmitter signals in the brain and various local hormones to release the hormone, gonadotropin releasing hormone or GnRH at very specific frequencies and amplitudes. This GnRH hormone is transported to the blood vessels in an area called the median eminence and these vessels then carry the GnRH to anterior lobe of the pituitary gland.

The anterior lobe of the pituitary gland has specific receptors for the GnRH hormone that allow it to capture and respond to GnRH by releasing the gonadotropin hormones: follicle stimulating hormone or FSH and luteinizing hormone or LH into the general circulation or bloodstream. FSH and LH secretion is also tightly regulated and has normal pulse frequencies and pulse amplitudes.

FSH and LH in the blood can reach the ovary where they can find and bind to their own specific hormone receptors. These receptors are concentrated around ovarian cysts that contain an egg, called a follicle. The follicle matures from an immature follicle to a fully mature follicle predominantly under the influence of the hormone FSH (follicle stimulating hormone). The developing follicle actively produces hormones, predominantly estrogen before ovulation. The estrogen produced by the developing follicle prior to ovulation stimulates the cells that line the uterine cavity, the endometrial cells, to grow or multiply in number and this lining becomes thicker.

Once a fully mature egg has developed, the follicle is thought to send a signal to the pituitary gland in the form of high concentrations of estrogen hormone that ovulation should occur. In response, the pituitary gland releases LH in high concentrations to provide the hormonal trigger (or signal) to ovulate, which is called the LH surge. It takes about 36 hours after the onset of the LH surge for the egg to complete its final maturation steps and for the ovary to release the mature egg into the pelvis.

After ovulation, the ovarian cyst that contained the egg remains hormonally active yet it converts its hormone production from predominantly estrogen to predominantly progesterone and it is now called a corpus luteum cyst. The progesterone produced after ovulation modifies the cells that line the uterine cavity, the endometrial cells, to allow for embryo implantation and the development of a normal pregnancy. If a pregnancy does not occur within 14 days of ovulation, then the corpus luteum no longer produces progesterone and the lining is shed as the menstrual flow.

Normally, this entire process repeats itself at monthly intervals throughout the reproductive lifespan.

Slide 5
The central nervous system uses a huge number of neurotransmitters to accomplish its tasks. Normal neurotransmitter function can be disrupted by almost any mild altering drug or medication. Chronic opioid use, whether in the form of illicit drugs, like heroin, or in the form of medications, like narcotic pain medication, can easily disrupt the reproductive axis and ovulation.

Slide 6
There are several hypothalamic causes for ovulation dysfunction. Polycystic ovarian syndrome (PCOS) involves a vicious cycle of problems can be considered to originate in the hypothalamus, the pituitary gland or the ovary. This syndrome involves irregular menstrual intervals, elevated androgen (male hormone) concentrations that may result in excess male pattern hair growth or acne, and/or polycystic ovaries as seen on ultrasound examination. This is another presentation that specifically deals with the complex and important situation of PCOS that is available through The NJ Center for Fertility and Reproductive Medicine website.

Functional hypothalamic amenorrhea is a diagnosis of exclusion, meaning that the menstrual disorder has no identifiable cause. It is most often thought that neurotransmitter regulation of the hypothalamus results in an irregular GnRH pulsatility or amplitude, and that this abnormality in GnRH secretion then results in an ovulation disorder.

Structural lesions of the hypothalamus can limit the ability of GnRH from the hypothalamus to reach the pituitary gland. These structural lesions can include tumors (the most common tumor in this region is a called a craniopharyngioma) or granulomas (due to either tuberculosis or sarcoidosis). If blood work suggests a low estrogen and also a low FSH and LH concentration, then looking for a lesion using radiologic tests is considered prudent.

Stress, strenuous exercise, sudden weight loss, and malnutrition can all interfere with ovulation. It is possible that almost any significant physical or emotional stress will alter the brain's neurotransmitter levels to disrupt GnRH secretion, increase the brain's levels of natural opioids called endorphins to reduce GnRH secretion, or modify the adrenal gland's releasing hormones like CRF and ACTH to interfere with ovulation.

Medications that affect the hypothalamic release of GnRH include any medicine that alters mood or mental status, such as anti anxiety or anti depression medication.

Slide 7
Both hypothyroidism and hyperthyroidism can result in an ovulation disorder. The mechanism for these dysfunctions is not clearly understood, but most experts believe that there is an increase in circulating estrogen concentration due to reduced metabolism of estrogen in the liver. The elevated circulating estrogen concentrations can then interfere with follicle growth. Additionally, hypothyroidism causes an increase in hypothalamic TRH (which primarily releases thyroid stimulating hormone or TSH from the pituitary gland). The TRH can cause a release of the hormone prolactin and elevated prolactin concentrations can cause an ovulation dysfunction.

The way in which elevated prolactin causes a problem with ovulation is not clearly understood. Elevated prolactin concentrations result in elevated dopamine concentrations (since dopamine inhibits prolactin release) and increased dopamine is known to reduce GnRH release from the hypothalamus.

The pituitary tumor that is not related to elevated prolactin that is most likely to result in an ovulation disorder is an ACTH producing tumor, which results in excess cortisol secretion from the adrenal glands, called Cushing's syndrome. A Cushingoid appearance involves a moon facies (round face), truncal obesity (excess weight especially around the waist rather than the hips), excess fat tissue under the back of the neck between the shoulder blades (sometimes referred to by our internal medicine colleagues as a buffalo hump), muscle weakness, purple linear discoloration of the skin, easy bruising, low fracture threshold, insulin resistance or diabetes, and high blood pressure.

Blood clots or bleeding around the pituitary gland can result in permanent destruction or damage. Rarely, a severe postpartum hemorrhage can result in low blood pressure and damage to the pituitary gland, called Sheehan's syndrome. Whenever there is damage to the pituitary gland itself it is important to evaluate the other pituitary hormones to rule out such life threatening problems like adrenal insufficiency.

To understand the empty sella syndrome you must know a little about the anatomy of the pituitary gland. The pituitary gland is surrounded by a bony structure called the sella turcica and there is a diaphragm of tissue over the top of this bony container. The empty sella syndrome occurs when this diaphragm herniates into the sella turcica and cerebrospinal fluid fills most of the sella turcica while flattening the pituitary gland along its sides. This condition results in reduced pituitary FSH and LH, which then lead to an ovulation dysfunction.

Medications that affect the pituitary gland include any medication with estrogenic (estrogen like) or progestagenic (progesterone like) substances, such as oral contraceptive pills or progesterone supplements.

Slide 8
There are multiple ovarian causes for an ovulation dysfunction.

The reproductive lifespan for a given woman normally spans several decades. As a woman ages, she uses her eggs and there are fewer and fewer eggs remaining in the ovaries. It is commonly thought that a woman may use her best eggs earlier in the reproductive lifespan, which if true may account for the finding of reduced fertility and increased miscarriage rates as a woman ages.

Infertility doctors are fond of blood work that assesses ovarian reserve, or the number of eggs remaining in the ovaries, such as cycle day 3 FSH and estradiol concentrations or the clomiphene citrate challenge test. Despite the reduced reproductive potential with aging, it should be noted that I have had many patients who have successfully conceived and delivered normal babies well into their 40s.

Ovarian surgery may destroy many normal eggs adjacent to abnormal ovarian tissue that is removed. The removal of an entire ovary or a significant part of an ovary can immediately reduce the ovarian reserve.

Pelvic radiation or chemotherapy can result in months or years of anovulation. The classes of chemotherapy agents most strongly associated with long-term ovarian dysfunction are the alkylating agents. If the ovary begins to produce mature eggs and ovulate even several years after chemotherapy and radiation therapy, then the eggs that are produced are generally thought to be of normal quality.

Premature ovarian failure occurs when there is ovarian failure (menopause) prior to the age of 40 years old. Premature ovarian failure may be caused by an abnormality in one of the X chromosomes or there may be an immune disorder that doesn't allow the ovary to respond to FSH. There are occasions in which an immunological disorder goes into spontaneous remission (resolves temporarily on its own), menstrual cycles occur because ovulation can occur when the ovary can respond to FSH, and a woman can become pregnant.

There are over 13 articles in the literature that show that cigarette smoking can reduce a woman's reproductive lifespan up to 1-2 years. Cigarette smoking also increases the miscarriage rate by up to 2 fold and increases the ectopic pregnancy rate by up to 4 fold.

Pelvic infections, especially those that result in pelvic abscesses, can destroy a lot of eggs in the ovaries. These infections should be treated aggressively and as early as possible.

Decreased blood supply to the ovary can occur when an ovary twists or torsion occurs. Also when there is surgery in the vicinity of the ovary it is possible that the blood supply to the ovary is compromised. Whenever there is reduced blood supply to the ovary eggs can be damaged.

Endometriosis is a common abnormality of the female pelvis and it can reduce the ovary's response to stimulation with FSH.

Medications that affect the ovary's ability to ovulate include nonsteroidal anti-inflammatory agents, like ibuprofen, since these medications reduce prostaglandins that may be necessary for the ovary to release a mature egg.

Slide 9
Whenever I consult with a woman who has an ovulation disorder, I take time to obtain a thorough history including both a menstrual history and a medical history. The information that can be obtained during a careful history is invaluable and can often guide further evaluation.

The single most common reason for a reproductive age woman to be late for a menstrual flow is pregnancy so I always suggest a pregnancy test whenever there is an absence of flow for greater than a month.

A basal concentration of FSH, LH and estradiol is informative since these tests can determine ovarian reserve (at least roughly), they illustrate whether there is an increase in LH to FSH concentration (suggestive of PCOS), and they are all often low when dealing with stress (emotional, weight loss, extreme exercise).

TSH is my preferred screening test for thyroid disease. If the TSH is abnormally high it is repeated with thyroid hormone tests and anti-thyroid antibody levels. Prolactin concentration is also routinely tested, with follow-up as needed.

The progesterone challenge test determines whether there has been growth or thickening of the uterine lining since this lining should shed (there should be a menstrual flow) after administration of progesterone. A pregnancy test should always be done prior to this test.

Blood androgen concentrations, like free testosterone, androstenedione and DHEAS should be considered when there is a PCOS like appearance. I also screen for insulin resistance if there is a suggestion of PCOS.

If there is any significant suggestion of Cushing's syndrome, I screen with a 24 hour "urine free cortisol" level or an overnight 1mg Dexamethasone suppression test.

Radiologic tests may be advised based on the history and blood work results.

Slide 10
Treatment is strongly goal oriented.

When the ultimate goal is fertility, then ovulation induction may be the immediate goal. If a woman has 12 ovulatory cycles per year then she is at a fertility advantage compared to a woman with only 3 ovulatory cycles per year. 12 opportunities to conceive per year are more likely to result in success compared to 3 opportunities per year.

Ovulation induction may be attempted in any woman with an ovulation disorder as long as there are some eggs remaining in the ovaries that might respond.

Specific abnormalities found during the initial evaluation should be corrected whenever possible. On several occasions in my own practice, a thyroid abnormality or a prolactin abnormality is corrected and pregnancy quickly follows.

When a woman is overweight, weight reduction of only 5% can be very significant in terms of inducing ovulation.

Clomiphene citrate is the normal entry-level medication for ovulation induction. It has few complications and it is often well tolerated. There are some women who are intolerant to the side effects of clomiphene so other induction techniques should be used. About 85% of women with an ovulation disorder will respond to clomiphene citrate with either regular menses or significantly more regular menstrual intervals.

If clomiphene citrate is ineffective or the woman is intolerant to the side effects, then menotropins can be considered. These medications contain FSH as the active ingredient and are generally very effective. There are risks involved with menotropin controlled ovarian hyperstimulation, such as multiple pregnancies and ovarian hyperstimulation syndrome, and these medications need to be administered by a qualified fertility physician.

The first donor egg success was in 1983 and since this time many women with very few or no maturation capable eggs have looked to donor egg IVF for assistance. A qualified fertility physician should advice you of the appropriateness of this option if you are considering it.

Slide 11
The uterine cavity or inside of the womb is lined by a delicate and dynamic tissue called endometrium. This endometrium grows in response to estrogen to become thicker and it is organized in response to progesterone to allow for implantation and the development of a normal pregnancy.

Estrogen stimulation occurs primarily prior to ovulation and progesterone increases after ovulation. When pregnancy does not occur, the entire lining that developed for that ovulation cycle would then be shed as the menstrual flow. When there is a problem with regular ovulation and when menstrual flows occur infrequently, there can be an overgrowth of endometrium due to persistent estrogen without any progesterone (since ovulation does not occur). This can lead to a benign abnormality known as endometrial hyperplasia, or overgrowth of the uterine lining. This chronic exposure to unopposed estrogen (without progesterone) can also lead to atypical endometrial hyperplasia or endometrial carcinoma (cancer).

To minimize the increased exposure to risk of endometrial hyperplasia and carcinoma a progesterone or progesterone like medication should be administered regularly. Oral contraceptive pills (or patch) are a common and effective way of providing protection since all of the pills are predominantly progestagenic. The oral contraceptives also reduce ovarian androgen production by reducing excess LH so they may help with excess hair growth or acne. Note that the progestagen contained in the pills can also have some androgenic side effects. There are several pills with low androgenic side effects some of which, but by no means all, are listed here. Ortho tri cyclen is FDA approved for treatment of acne and is thought to have few androgenic side effects. Yasmin contains a progestagen with antimineralocorticoid and antiandrogenic actions similar to the popular medication for excess male pattern hair growth, Spironolactone. Demulen 1/50 may be used if there is persistent break through bleeding on a low dose estrogen pill and additional estrogen is desireable.

If a woman is not a candidate for the pill or is intolerant to the side effects of the pill, then intermittent use of progesterone can be useful. A common regimen is provera 10mg x 7-10 days every 1-2 months. Many gynecologists are more comfortable with just giving provera 10mg x 10 days every month on calandar days 1-10 (January 1-10, February 1-10, etc). If a woman is also intolerant to the side effects of provera then natural progesterone like prometrium usually has less side effects.

The use of metformin for endometrial protection is unproven at this time (2006)

Slide 12
The ultimate goal in the treatment of ovulation disorders is to use modern medical knowledge to help women and couples enjoy a happy and healthy family.

It was a pleasure to be able to present this information to you and I hope you have found it useful. If you are interested in being notified of other similar presentations, you can check the website for The NJ Center for Fertility and Reproductive Medicine (with links on the lower right hand corner of each slide) since a full list of narrated presentations is listed there.

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