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Hypothalamic-Pituitary-Ovarian Axis | Egg Development | Hormones During A Menstrual Cycle Hypothalamic-Pituitary-Ovarian Axis Case: 22 year old G0 with a history of regular menstrual intervals every 28-29 x 4-5 days and monthly premenstrual symptomatology until 4 months ago. About 4-5 months ago this young woman's older sister (with whom she shared a close relationship) was found to have a deadly malignancy of her blood cells (leukemia) and was given a grave prognosis (even with aggressive treatment). For the past 4 months, this otherwise healthy 22 year old has not had a menstrual flow. Question: What evaluation and treatment would be suggested? Answer: The hypothalamic pituitary ovarian (reproductive) axis involves communication between these structures that is tightly regulated. Even small disruptions in the usual amplitude and frequency of the hormones that are secreted can result in amenorrhea (an absence of menses). When amenorhea occurs suddenly the initial evaluation should consider a pregnancy test (the most common cause of missed menses in reproductive age women), a hormone evaluation for treatable hormone dysfunctions that can disrupt the reproductive axis (TSH and prolactin concentrations), gonadotropin concentrations (FSH and LH) to rule out ovarian failure, and a progesterone challenge test (short course of a progestational agent such as medroxyprogesterone acetate x 5-10 days). Many causes of amenorrhea involve a more subtle disruption in the normal communication between the hypothalamus, pituitary gland and ovaries. These imbalances can be due to many different causes, including emotional stress (as is most likely in this case), physical stress (related to starvation, surgery, illness, exercise), chronic elevation of LH (associated with PCOS), and drugs (especially those that act within the brain and alter mental status). If anovulation due to emotional stress is found to be the likely cause of this woman's lack of menses (a diagnosis of exclusion), then she should be counseled that the chronic exposure of the uterine lining (endometrium) to unopposed estrogen is potentially harmful. She should be started on a monthly course of a progestational agent (such as medroxyprogesterone acetate 10mg x 10 days every month) or an oral contraceptive pill (which is predominantly progestagenic). The anovulatory state will most likely resolve spontaneously once the stress is relieved. Case: 12 year old girl has undergone a (skeletal) growth spurt (recent more rapid increase in height), breast development (budding and increase in overall size), growth of pubic hair in the genital and axillary (arm pit) regions, and just started to menstruate every month. Question: What events appear to result in menstruation at puberty? Answer: Immediately prior to puberty, the circulating gonadotropin (FSH and LH) concentrations are low, the FSH:LH ratio is generally greater than 1 (FSH concentration is greater than LH concentration), and the hypothalamic gonadotropin releasing hormone (GnRH) concentration is also low. The initial hormonal event that has most often been associated with the onset of puberty in girls and signals impending menarche (menses) is the occurrence of intermittent pulses of LH during sleep. As puberty progresses and menses begin, the intermittent pulses of LH occur all day long (during sleep as well as during the daytime). In order for ovulation to occur, hypothalamic GnRH increases to stimulate the pituitary gland to release gonadotropins (FSH and LH), the increasing and very tightly regulated FSH and LH concentrations result in the maturation of ovarian follicles (and eggs), the ovarian follicles produce an increased amount of estradiol (estrogen), the circulating high concentrations of estradiol (are thought to) trigger a positive response within the pituitary gland that results in the LH surge, and the LH surge triggers the cascade of molecular reactions that result in ovulation. An intact and properly functioning hypothalamic-pituitary-ovarian (reproductive) system is required for spontaneous (natural cycle) ovulation throughout the entire reproductive lifespan. Case: 33 year old G0 with a history of irregular menstrual cycles every 25-40 x 5-6 days and basal body temperature charts that suggest ovulation is taking place consistently 13-15 days prior to the onset of the next menstrual cycle. Question: Does the quality (reproductive potential) of the egg relate to the time that is required "within a particular cycle" to mature and release the egg (length of the follicular phase)-- which ranges from 12-25 days for this woman? Answer: There is no data (to my knowledge) from published peer reviewed research that can be used to help answer this question. It is commonly believed that (for a particular woman) menstrual cycles with varying follicular phase duration (time from the onset of a cycle through egg maturation to ovulation) produce similar quality (reproductive potential) eggs. Many of my patients have irregular menstrual intervals, and they appear to achieve pregnancies at the same general rate of success regardless of the duration of the follicular phase. In fact, one of my patients has only a few menstrual cycles per year yet knows (from seemingly subjective symptoms) when she is about to ovulate and has become pregnant on several different occasions (resulting in several full term deliveries). The primary disadvantage (in terms of fertility) of having irregular menstrual intervals appears to be predicting the time of ovulation. If this becomes a problem, regularization of the cycles can (usually) be achieved with clomiphene citrate or the other (FSH containing) fertility medications. This can make timing of periovulatory events such as intercourse or intrauterine inseminations (when required) much more convenient and accurate. Case: 30 year old G1 P1 undergoes a cycle of controlled ovarian hyperstimulation (using FSH containing fertility medication) and intrauterine insemination (COH/IUI) for "unexplained infertility." During the COH cycle, 16 follicles developed with 11 follicles being greater than 14mm diameter at the time of hCG (trigger of ovulation). Question: Will the maturation of several ovarian follicles (and eggs) during a single COH cycle affect the eventual timing of menopause or the regularity of this woman's subsequent menstrual cycles? Answer: Ovarian follicles undergo a process of development that allows them to respond to FSH. The duration of this process is thought to be 3-6 months long. For any given menstrual cycle, only follicles (and eggs) that have undergone this developmental change will respond to the (FSH hormone) stimulation to mature. The tens of thousands of other follicles (and eggs) in the ovaries will be unaffected by circulating FSH since they did not complete this series of changes (including the development of FSH receptors). Ovarian follicles (and eggs) committed to a particular menstrual cycle (through completion of the process that allows them to respond to FSH) will either ovulate during that cycle of maturation or become degenerate (atretic). Therefore, FSH containing fertility medications simply try to optimize the maturation of eggs that are already committed to that particular menstrual cycle. Menstrual cycles that follow the COH cycle and the eventual time of menopause (complete depletion of eggs) should not be changed. Case: 26 year old G0 completes a cycle of controlled ovarian hyperstimulation (using FSH containing fertility medications) and intrauterine insemination (COH/IUI) for a moderate male factor problem. During the COH cycle, twelve follicles were noted to grow (by serial ultrasonography) but one follicle outgrew the others to have a diameter of 18mm when the next largest follicle had a diameter of 13mm. Question: The FSH containing fertility medications were initiated on the second day of the menstrual cycle, so why did the ovarian follicles develop so unevenly? Answer: In natural menstrual cycles, circulating FSH concentration increases a few days prior to the onset of menstrual flow and begins the process of ovarian follicular recruitment. The follicles that have completed the (several month process of) development that allows them to respond to FSH (and commits them to that particular cycle of maturation) then begin to mature. One of these follicles may significantly outgrow the others even as early as cycle day 2 or 3, such that it "outcompetes" the other follicles for circulating FSH and grows more rapidly. When there is a large variation in the sizes of the ovarian follicles at the end of a COH cycle, or when only 1-2 follicles fully mature despite the presence of several other growing follicles, it makes sense to consider ovarian suppression prior to the next COH cycle. Generally, a GnRH agonist (such as lupron) is initiated in the midluteal phase (about 7 days after ovulation), which should effectively suppress circulating FSH and ovarian development prior to the onset of the next cycle. This ovarian suppression should thereby increase the chances that the ovarian follicles for that upcoming cycle are at the same (baseline) level of development on cycle day 2-4. This would (hopefully) result in more even maturation of follicles when FSH containing fertility medications are administered. Hormones During a Menstrual Cycle Case: 29 year old G0 with a history of a mild male factor is undergoing controlled ovarian hyperstimulation with intrauterine insemination (COH/IUI), the follicular growth has been consistently about 1-2 mm (diameter) per day (during stimulation) with a linear rise in estradiol concentration, and now at the end of the stimulation cycle the follicular sizes and estradiol concentrations (used in monitoring) are rising at a much greater rate (seemingly in an exponential rather than a linear manner). Question: Is this apparent increase in the rate of ovarian follicular growth and estradiol concentration normal during a cycle of COH/IUI? Answer: Yes. The rate of growth of the ovarian follicles and the rise in circulating estradiol concentration is roughly linear until a day or so prior to full maturation (at about 16-18 mm diameter), at which time both increase dramatically. An encouraging sign during COH/IUI is the sudden expansion of the follicles and the increase in the rate of rise of estradiol concentration (the estradiol may double in one day), signaling egg maturity. It is important to have an experienced physician monitoring your progress during a cycle of COH/IUI. I recommend a (fellowship trained) reproductive endocrinologist since these physicians can optimally interpret the results of your ultrasound and bloodwork monitoring. Case: 34 year old G1 P1 undergoing a cycle of controlled ovarian hyperstimulation with intrauterine insemination (COH/IUI) has 8 ovarian follicles measuring about 14-15 mm in diameter (with several smaller follicles), good interval (daily) growth of follicles, and a drop in estradiol concentration from 1025 pg/mL to 800 pg/mL in the past day (without a change in the dose of FSH containing medication). Question: What is the significance of this drop in estradiol concentration and what should be recommended at this time? Answer: The estradiol concentration usually continues to rise (without decreasing) throughout most of ovarian follicular maturation and then will drop sharply immediately (about one day) prior to ovulation. This woman's drop in estradiol concentration most likely signals the onset of the LH surge and impending ovulation. One exception would be if the dosage of FSH containing medication was recently decreased, in which case the estradiol concentration often decreases due to lower production by the smaller follicles (the larger follicles continue to grow and produce estradiol). If ovulation was triggered by the woman's own LH surge this cannot be "reversed" or prevented. Therefore, I generally complete ovulation with the hCG (profasi) injection and plan an intrauterine insemination if there are follicles greater than 12-14mm diameter (size at which mature eggs commonly exist). Case: 25 year old with a history of sudden onset of debilitating pelvic pain (left greater than right), cycle day 15 (she normally has a 28-30 day menstrual interval), a negative pregnancy test, temperature of 98.2 F, normal CBC (complete blood count) bloodwork, a normal postovulatory progesterone concentration, and an ultrasound exam that was only remarkable for a 3.7 cm (diameter) complex left ovarian cystic structure. Question: What treatment options are available (appropriate) for this woman? Answer: This appears to be periovulatory pain, which is most likely due to the formation of a (normal functional) corpus luteum cyst within the ovary. These cysts often have a complex appearance on ultrasonography due to internal bleeding and clot formation. They should resolve spontaneously with the onset of the next menstrual cycle. The pain due to a corpus luteum cyst usually lasts about 1-4 days and then resolves spontaneously. It is important to rule out an ectopic pregnancy (with a negative pregnancy test) and a pelvic infection (with a normal temperature and a normal white blood count on CBC). It is also important to rule out a hemorrhagic ovarian cyst, which can bleed significantly to produce free fluid in the pelvis and abdomen (identifiable on ultrasonography and followed with serial blood counts and the woman's clinical status). If the pain recurs every month, persists beyond a few days, or is associated with bleeding into the pelvis and abdomen then more aggressive management may be required. Surgery, with laparoscopy (or laparotomy if facilities are not available to do laparoscopic surgery) are sometimes required to assess (and treat) acute and chronic pelvic pathology. Case: 31 year old G0 with a history of irregular menstrual intervals every 23-36 x 3-5 days, a normal hysterosalpingogram (normal uterine cavity and bilaterally tubal patency), and a husband with an apparent mild male factor (slightly abnormal semen analysis and unproven fertility). The couple is planning a few cycles of timed natural cycle intrauterine insemination (IUI) but has had difficulty predicting when ovulation occurs (using the commercially available home ovulation predictor kits) since the intermenstrual intervals may vary by several (up to 13) days. The couple wants to try to predict the time of ovulation using ultrasound exams and bloodwork rather than ovulation kits. Question: How can the ultrasounds and/or labwork be used to accurately predict when ovulation will occur? Answer: In general, intermenstrual interval variability may be reduced (and the cycle regularity thereby increased) with clomiphene citrate treatment. An alternative way to reduce intercycle variability is to identify when a mature egg (follicle) is present using ultrasonography and then trigger ovulation with an hCG injection. In a spontaneous (natural) menstrual cycle, the ovarian follicle normally grows to a diameter of about 18-30mm prior to ovulation, the estradiol concentration normally increases to in excess of 200 pg/mL and is generally sustained at this high concentration for greater than 48 hours (2 days), the sustained elevation in estradiol concentration is thought to trigger the LH surge (signal to ovulate), the follicle collapses during ovulation and then may reaccumulate with fluid to become the (progesterone producing) corpus luteum cyst. The growing follicle often increases (in diameter) by about 1-3 mm per day, so that the range of time (days) that it takes for an ovarian follicle to increase in diameter from 18 to 30 mm is usually several days. Because spontaneous ovulation may be triggered (via the LH surge) at any point in this time interval of several days, it is difficult to use ultrasonography (alone) to reliably predict when ovulation will naturally occur. Occasionally, ultrasound will be coupled with bloodwork to predict when ovulation is likely. The estradiol concentration can be tracked and often will be greater than 200 pg/mL for greater than 2 days prior to the LH surge. However, the exact concentration (and duration) of elevated estradiol is largely unknown. Therefore, estradiol concentrations cannot reliably predict the timing of spontaneous ovulation. Ultrasound exams and estradiol concentrations can fairly reliably identify an ovarian follicle containing a mature egg. Serial LH concentrations can then be used to identify when the LH surge has occurred. The LH concentration during the LH surge will normally increase by greater than 3 times (fold) over an established baseline (LH) concentration (for the particular woman and cycle). Thus, the baseline concentration of LH can be established with 3-4 concentrations (generally obtained 1-2 days apart) prior to identifying the mature follicle and subsequent daily LH concentrations can then identify a significant increase in LH (the LH surge). Multiple ultrasound exams, estadiol concentrations and LH concentrations are expensive. Using these somewhat cumbersome and expensive techniques to predict the timing of a spontaneous ovulation appears to be of low cost effectiveness and convenience (for the patient). An alternative is to identify the presence of a mature egg with ultrasound exams and then to trigger ovulation (with an hCG injection to simulate the LH surge). Case: 26 year old G0 with a history of irregular menstrual intervals every 65-96 x 2-5 days, a normal hysterosalpingogram (normal uterine cavity with bilateral tubal patency), a husband with a mildly abnormal semen analysis and unproven fertility (no previous pregnancies), failure to ovulate spontaneously to (up to) 100 mg clomiphene citrate per day (taken cycle days 5-9), apparent ovulation on 150 mg clomiphene citrate per day (taken cycle days 5-9) with intermenstrual intervals every 33-36 x 4 days, difficulty pinpointing the time of ovulation on clomiphene with the commercially available home LH ovulation predictor kits, now undergoing serial ultrasound exams with serial bloodwork (LH and estradiol concentrations) to determine when a mature follicle can be triggered to ovulate (with an hCG injection). At ovulation, intrauterine inseminations (IUIs) are planned due to the "mild" male factor. Question: What testing (ultrasound findings, LH concentration and estradiol concentration) is useful for this sort of patient prior to ovulation? Answer: In an ovulatory clomiphene citrate menstrual cycle, the ovarian follicle most often grows to a diameter of about 25-30mm prior to spontaneous ovulation and the estradiol concentration often increases to (far) in excess of 200-300 pg/mL (and is generally sustained at this high concentration for greater than 2 days-- at which time it may trigger the LH surge). Ovarian follicles with diameters in excess of 18 mm are generally thought to contain mature eggs during a clomiphene citrate cycle. The growing ovarian follicle(s) in a clomiphene citrate cycle often increases (in diameter) at the same rate (1-3 mm a day) as in a spontaneous (natural) ovulatory cycle. In a clomiphene citrate (or natural) cycle, I generally begin to monitor ovarian follicular development about 2-3 days prior to the "earliest expected" time of ovulation (given the woman's prior menstrual history). In this case, the shortest cycles seem to be 33 days apart so that ovulation in these short cycles might occur around cycle day 19 (14 days prior to the "next menstrual flow"). In this case, I would (therefore) generally obtain a baseline ultrasound on cycle day 16-17. I would then schedule a followup ultrasound based on the diameter of the "lead ovarian follicle." If the lead diameter on ultrasonography were less than 10 mm, I probably would bring the woman back in 3-4 days (allowing more time to grow). If the diameter were 10-12 mm, I would bring the woman back in 2-3 days. If the lead diameter were 13-15 mm, I would bring the woman back in 2 days. If the lead diameter is 16 mm or greater, I would monitor growth every day. Once the lead follicle is 18 mm diameter, I trigger ovulation with hCG. The ideal size (diameter) of the lead ovarian follicle prior to hCG injection in a clomiphene citrate cycle is somewhat controversial, and some reproductive endocrinologists suggest triggering at about 25 mm rather than 18 mm. I have had good apparent success with 18 mm so I would continue with this until there is good quality research data to support switching to another protocol. I visualize an analogy between "eggs maturing in the ovary" and "apples ripening on an apple tree." Anytime between 18 mm and 30 mm follicle diameters, the egg within the ovarian follicle may be ideally matured for subsequent fertilization. Normally, during this time period the egg will spontaneously be triggered to ovulate but the egg can also be (artificially) triggered to ovulate during this time period with an injection of hCG hormone (to mimic the LH surge). By analogy, an apple may be fully ripe on an apple tree anytime between when it changes color (to red) and when it finally will spontaneously fall from the tree's branch to the ground. However, a perfectly good apple can also be "picked" from the tree at anytime after it initially becomes ideally ripened. Triggering ovulation once a mature egg is identified allows the time of ovulation to become known fairly precisely (about 36 hours following the hCC injection) and is often very convenient for couples undergoing infertility treatments timed around ovulation. In this case, an IUI can be planned following hCG triggering of ovulation. If the ovarian follicles grow as expected (above), then the utility of bloodwork for estradiol concentration or LH concentration is minimal. If there is confusion as to whether the ovarian follicles are growing on ultrasonography, then bloodwork may add information that can be very useful. | |||||||||||||||
