| visit: www.infertilitytutorials.com |
|
Ovary | Pituitary Gland | CNS and Hypothalamus Case: 32 year old G0 undergoing an infertility evaluation (for recurrent pregnancy loss) has a midluteal phase endometrial biopsy performed (to rule out an hormonal cause) and the pathology results suggest an insufficient progesterone effect (4 day lag in endometrial stromal and glandular maturation compared to the expected level of maturation based on the time of ovulation). Question: What additional diagnostic tests would be suggested? Answer: Assessment of progesterone in the luteal phase may include basal body temperature charts, random serum progesterone assays, and the endometrial biopsy. The basal body temperature (BBT) should rise between 0.5 and 1.0 degrees Farrenheit after ovulation due to the increase in progesterone production (a significant increase in temperature usually occurs about 2-3 days after ovulation when the circulating progesterone concentration exceeds 4 ng/mL). There often is a dip (nadir) in the BBTs just prior to ovulation, which correlates roughly to the timing of the LH surge, but the occurrence and timing of this nadir is unpredictable. The length of the luteal phase (increased temperatures on BBTs) should be at least 11 days long. If there is a short luteal phase this may reflect a significant dysfunction in progesterone effect. Random serum progesterone concentrations in the luteal phase are pulsatile. Therefore, if you determine a woman’s blood progesterone concentration on three separate occasions during a given day (during the luteal phase) you most likely will obtain 3 significantly different results. This makes interpretation difficult. The endometrial biopsy is (for most infertility experts) the gold standard test to assess luteal progesterone levels since it directly looks at the effect of the progesterone on endometrial maturation (the primary concern is an insufficient progesterone effect on the lining of the uterus). A luteal phase defect (lag) occurs when the actual maturation of the uterine lining (endometrium) lags behind the expected maturation by more than 2 days. Research (is scanty but) suggests that the endometrial biopsy is abnormal in up to 30% of normal cycling (ovulating) women. The endometrial biopsy is consistently abnormal in only about 5% of normal ovulatory women having an endometrial biopsy performed in two consecutive cycles. Therefore, it is often suggested that the biopsy be repeated if initially found to be out of phase (abnormal) and treatment reserved for women with persistently abnormal endometrial biopsy results. Case: 29 year old G3 P1 S2 with 2 consecutive out of phase endometrial biopsies during the investigation for recurrent pregnancy loss. Question: Should treatment be suggested? Answer: When inadequate progesterone effect during the luteal phase of the menstrual cycle is detected it can (and should) be treated with either (1) supplemental progesterone (oral micronized progesterone, vaginal suppositories, vaginal gel applicator, or by intramuscular injection of progesterone in oil); (2) supplemental hCG (injections every few days after ovulation to enhance the ovary’s own progesterone production); or (3) clomiphene citrate (taken by mouth in the follicular (preovulatory) phase to increase the final size of the follicle prior to ovulation... so that there are more granulosa cells to then produce progesterone during the luteal phase). Supplemental progesterone is usually continued until about 10-12 weeks gestation (8-10 weeks after fertilization). The placenta takes over progesterone production from the ovarian corpus luteum during this time, so that further supplementation is usually not necessary. Case: 35 year old G1 P1 cigarette smoker has a reduced ovarian reserve on hormone assessment and subfertility. Question: If a smoker quits cigarettes does her ovarian reserve (or fertility in general) return to normal? Answer: The assessment of ovarian reserve will probably not return to normal but fertility may still improve. Cigarette smoking is associated with a number of reproductive problems. The ovarian reserve relates to the number of maturation capable eggs remaining in the ovaries and there is no known treatment to increase this number. Women are born with all of their eggs and they use this "ovarian reserve" throughout their life until no maturation capable eggs remain (resulting in menopause). One line of ongoing and very exciting research has attempted to mature eggs from human ovarian biopsy specimens "in vitro" (outside the body in the laboratory). Eventually, physicians may be able to obtain human ovarian biopsy tissue and optimize the maturation of the isolated eggs beyond what would normally be possible "in vivo" (within the body). At this time, it is thought that cigarette smoking accelerates the destruction of eggs such that chronic cigarette smokers undergo menopause 1-2 years earlier than "comparable" nonsmokers. In 1993 the American College of Obstetrician-Gynecologists released a technical bulletin (number 180) entitled "Smoking and Reproductive Health." In this bulletin it is noted that
If a couple quits smoking the restoration of fertility in terms of the ovulatory dysfunction, tubal factor, pregnancy loss rates and male factor appear to be rapid (a few months). The damage with regard to the ovarian reserve may not recover. Case: 31 year old unmarried G0 has a keen interest in future childbearing but needs chemotherapy (which most likely would disrupt ovulation for many years and possibly indefinitely) for treatment of a recognized malignancy (cancer). If the cancer is treated promptly, the long term prognosis (outcome) for the malignancy is excellent. Question: Can this woman preserve her eggs prior to the chemotherapy to increase her chances for future childbearing (using her own eggs)? Answer: Cryopreservation (preservation through freezing) of human "fertilized eggs" (preimplantation embryos) has many years of clinically established success. Most In Vitro Fertilization programs routinely offer this if there are "additional embryos" (of good quality) after a fresh embryo transfer. Cryopreservation of human (unfertilized) eggs has been attempted throughout the world over the past decade (or so) and there are case reports of reproductive success (subsequent fertilization and pregnancy) using frozen thawed (unfertilized) eggs. The success rate (in terms of pregnancy resulting from frozen thawed eggs) is very low. Two methods used to recover eggs from the human ovary are (1) egg retrieval by the (ultrasound guided) aspiration of ovarian follicles (predominantly after they have been matured with the assistance of FSH containing medications) and (2) ovarian biopsy with subsequent (experimental) in vitro maturation of eggs. In the event that a woman needs immediate therapy for an urgent medical condition (such as cancer) or if the woman does not have an accepted source of sperm (a partner with whom childbearing or childrearing is mutually desired) and wants to freeze her eggs (rather than embryos) then contacting one of the world’s leading In Vitro Fertilization research centers would be encouraged. For example, I know that at the Hospital of the University of Pennsylvania there has been an ongoing interest in freezing unfertilized human eggs for women undergoing cancer treatments. Discussing the possibility of, and the success rates for, this type of management "at the time it is needed" is important since this area of experimental medicine is rapidly developing (changing) and (hopefully) growing. Case: 26 year old G0 with a history of extensive endometriosis, infertility, severe pelvic pain (including dysmenorrhea), significant improvement in pain with the use of NSAIDs (non steroidal anti inflammatory agents such as ibuprofen), and controlled ovarian hyperstimulation (using FSH containing medication to mature multiple eggs) with intrauterine insemination. Question: Would the (pregnancy) success rate for this woman be improved if she discontinued the use of her NSAID medicine prior to her stimulation cycle? Answer: Rabbits and rodents have been used in research directed at understanding the molecular mechanisms involved in the process of ovulation. The results of studies using these animal models suggest that
The NSAID medications work by blocking the action of one of the body’s natural enzymes named cyclooxygenase. Cylcooxygenase converts arachidonic acid into prostaglandins. Therefore, the use of any of the NSAIDs is discouraged when a couple is trying to get pregnant since these medications may block the ovary’s ability to release the mature egg. NSAIDs include aspirin, ibuprofen, indomethacin, ketoprofen, naproxen, diclofenac, etodolac, mefanamic acid, oxaprozin and others. Tylenol is not an NSAID. NSAID medications have varying half lives (rates of metabolism) in the circulation (blood). Roughly, aspirin has a half life (at lower concentrations) of about 2-3 hours, ibuprofen has a half life of about 2-4 hours, and indomethacin has a half life of about 1 hour. However, these NSAID medications act (as anti inflammatory agents) by inhibiting prostaglandin synthesis by (irreversibly) inactivating cyclooxygenase (the enzyme required to convert arachidonic acid into prostaglandins) so that its course of action is longer than its concentration in the circulation. Most of these NSAID agents are normally dosed (administered) 3-4 times a day for anti inflammatory action. The woman described in this case report would be advised to discontinue her NSAID medication prior to ovulation. The amount of time required for the NSAIDs to "wear off" with respect to their inhibition of prostaglandin synthesis and the subsequent inhibition of ovulation (release of the mature egg from the ovary) is not known. If the benefit of the medication is minimal then I would suggest discontinuing the NSAIDs at the onset of the menstrual cycle (about 2 weeks prior to ovulation). If the benefit of the medication is significant (with respect to pain management) then the individual "risk to benefit" ratio needs to be considered. It is possible that (future) research will suggest that discontinuing the NSAID medications a few days prior to expected ovulation is adequate. Case: 32 year old G1 P1 with a history of (ovarian) endometriosis that was surgically treated 5 years prior to controlled ovarian hyperstimulation (COH), good ovarian reserve by available hormone assessment, and poor follicular response to FSH containing medications on multiple occasions. Question: Given this woman’s youth and the encouraging assessment of her ovarian reserve would treatment of residual or recurrent (ovarian) endometriosis be suggested to enhance the response to ovulation inducing medication? Answer: There is virtually no reliable data (information) correlating the treatment of implants of endometriosis (within the pelvis or on the surface of the ovaries) and ovarian follicular response to FSH containing ovulation inducing medications. Many reproductive endocrinologists do (anecdotally) find that women with endometriosis are more difficult to stimulate with (FSH containing) fertility drugs (less eggs are matured, more medication is required, egg or embryo quality at In Vitro Fertilization is often reduced). I suggest aggressive (laparoscopic) CO2 laser (using superpulse or optimally ultrapulse/XJ pulse if available) vaporization of endometriosis and lysis of pelvic adhesions to optimize the "pelvic factor." If this has been recently performed, I do not recommend re-operating. The recurrence rate of endometriosis is quite variable and a high percentage of women may in fact have significant recurrence within a few years of highly aggressive management (with an experienced reproductive surgeon). In this case, the woman has a known pelvic issue (endometriosis and possibly pelvic adhesions) with a reduced ovarian response to fertility medications. In Vitro Fertilization success rates are related to the woman’s age, the ovarian reserve, and her response to the fertility medications (number and quality of eggs matured). In this case, the response to the fertility medication is poor and the time since the prior treatment of endometriosis is 5 years. Therefore, I would generally suggest a pelvic evaluation (laparoscopy and possibly hysteroscopy) to optimize this pelvic factor (with aggressive treatment of any identified pathology). Following surgery, I would then allow either (1) a course of natural cycles with intercourse (if postcoital test normal and significant pathology was found and treated) or (2) another trial of (FSH containing) fertility medications to see if the response is improved. Case: 36 year old G0 interested in fertility with sudden onset of hot flashes, insomnia and amenorrhea (lack of menstrual flow). Hormonal bloodwork suggests premature ovarian failure (POF). Question: What are the chances of fertility during a natural cycle, on hormone replacement therapy, using steroid medications, or using (FSH containing) fertility medications? Answer: By convention, when ovarian failure occurs before the age of 40 it is termed "premature." These women should be started on hormone replacement medication to protect the woman from cardiovascular disease and loss of bone mineral content. For the woman with POF who is interested in fertility the chances for conception with her own eggs are slim (overall less than 3-5%). The reason that some of these women do become pregnant is unclear, but seems to be related to the ability of the ovaries to spontaneously resume ovulation for at least short periods of time. The use of steroids (glucocorticoids) to suppress an autoimmune cause for POF has significant risks and is not known to be beneficial, so I generally discourage their use. The use of FSH containing fertility medication is very involved (time consuming, expensive, stressful for most women) and rarely enhances egg development (consider that the diagnosis of POF is confirmed by finding an elevated circulating FSH concentration so that the addition of even more FSH should theoretically not really be very effective) so I generally discourage its use. Some women with POF (on no medication) will periodically resume ovulation for up to several consecutive menstrual cycles. Women with POF who are on hormone replacement therapy are not using contraceptive doses of estrogen (ie., the dose of estrogen allows ovulation to occur) so that a spontaneously occurring menstrual flow (between the usual HRT withdrawal flows) may alert the couple (and the physician) that spontaneous ovulation is taking place. For some (unknown) reason women with POF on hormone replacement therapy seem to resume spontaneous ovulation more often than women on no medication. When spontaneous ovulation does resume, serial ultrasounds to pinpoint when a mature follicle is present and then timing intercourse (with ovulation predictor kits) or more aggressively triggering ovulation with hCG (and timing intrauterine inseminations) seems reasonable. Case: 22 year old G1 P1 with a history of easy fatiguability and cold intolerance was recently diagnosed with "hypothyroidism" (elevated TSH and suppressed free T4 concentrations). Question: Given that this woman is actively interested in becoming pregnant, should she wait until she is on an adequate thyroid replacement dosage of synthroid before attempting pregnancy? Answer: Yes. Hypothyroidism is more often associated with infertility than recurrent pregnancy loss, but may be loosely associated with either condition. Establishing a normal circulating thyroid hormone concentration is therefore desirable prior to attempting pregnancy. Synthroid is the thyroid replacement drug of choice in pregnancy. Desiccated thyroid extract is available but seems to contain a disproportionately elevated concentration of T3, which can be counterproductive from the fertility (reproductive) point of view. If this woman does become pregnant before adequate thyroid replacement medication is established, she should be placed on synthroid and brought into the normal range as soon as possible. One difficulty with adjusting synthroid doses is that the circulating half life of T4 is relatively long (about a week) so that the serum steady state of T4 is really only obtained 3-4 weeks after changing to a new dose (of synthroid). Case: 28 year old G0 with recent onset of heat intolerance and (hand) tremor is diagnosed with hyperthyroidism (suppressed TSH with elevated free T4 concentrations). The anti-microsomal and anti-thyroglobulin antibody concentrations are found to be markedly elevated. Question: Given an immediate interest in fertility, should this woman delay fertility? Should she be started on antithyroid medications? Answer: Probably and No, respectively. Clinical hyperthyroidism is weakly associated with pregnancy loss. The mechanism for this association is not clear. Ideally, a woman should be euthyroid (circulating thyroid hormones in the normal range) when she becomes pregnant. The most common etiology (cause) for hyperthyroidism in a young woman is an autoimmune disorder. In these situations, the immune system produces agents (antibodies) that attack and usually eventually destroy the thyroid gland. Autoimmune thyroid disease (thyroiditis) is characterized by an elevation in the anti thyroid antibodies (called anti microsomal and anti thyroglobulin antibodies). The initial phase of autoimmune thyroiditis is the release of thyroid hormone that has been produced and stored in the thyroid gland, which results in a transient hyperthyroidism. This phase usually lasts up to a few months. The hyperthyroid phase of autoimmune thyroiditis is followed by a prolonged (life long) hypothyroid phase. This phase represents the destruction of the thyroid gland after the release and metabolism of all stored thyroid hormone. The hyperthyroid phase of autoimmune thyroiditis does not require treatment unless the patient is symptomatic. If the symptoms of hyperthyroidism do require treatment (which is uncommon) then this treatment is specifically directed at the symptoms themselves. There is really no way to supress the release of thyroid hormone from the thyroid gland since it is increased due to a destructive process (and there is no reliable treatment for the autoimmune process). The thyroid function tests should be followed (determine TSH and free T4 every couple of months) through the hyperthyroid phase and when hypothyroidism occurs then thyroid replacement medication (synthroid) should be initiated. The dose of synthroid will usually need to be adjusted over the initial 1-2 years of autoimmune hypothyroidism since the destruction of the thyroid gland is progressive. Therefore, ideally this woman would wait until the resolution of her hyperthyroid phase of autoimmune thyroiditis before attempting pregnancy. If she is not willing to do so, then she should be aware that there might be a (somewhat) elevated possibility of pregnancy loss. Case: 31 year old woman with a history of irregular menstrual intervals every 26-35 days consistently lasting 3-4 days (with presence of premenstrual symptoms) is found to have an elevated circulating prolactin concentration during an infertility evaluation. Question: Is further testing necessary and should this elevation in prolactin be treated? Answer: The prolactin concentration should be rechecked to confirm a persistent elevation in concentration. At this time, the TSH should also be checked (if not recently done) since hypothyroidism can result in hyperprolactinemia (high circulating prolactin concentration). The repeat prolactin level ideally should be drawn after the woman has been resting comfortably in a quiet location for about 15-30 minutes, since the most common reason for a mild elevation of prolactin concentration is anxiety (or stress). The simple stress associated with having your blood drawn can increase release of prolactin (elevating the circulating concentration). Other events associated with an elevation in prolactin include (1) breast stimulation (do not have the prolactin concentration evaluated immediately following a gynecologic breast examination), (2) some medications (let your infertility doctor know which medications you are taking), (3) sleep (prolactin concentrations rise at night with sleep and are relatively low in the morning so some physicians recommend an early morning level), (4) exercise (do not have the prolactin drawn immediately following strenuous exercise), (5) high protein meals (do not have the prolactin level determined immediately after a meal), and (6) pregnancy (prolactin normally rises about 10 fold over normal during pregnancy). If the prolactin concentration is persistently elevated then your doctor should consider a radiologic test to assess the brain for a structural lesion. The radiologic test of choice is controversial, with the MRI currently giving very high resolution (one of the best pictures) and the lateral coned down xray being adequate to detect large masses (and is one of the least expensive tests for this purpose). Once a persistent prolactin elevation has been confirmed and a structural defect in the brain is ruled out this woman should be treated to bring the prolactin concentration into the normal range since she is interested in fertility. The medical treatment options (medications) are almost always effective. Once the prolactin concentration has been brought into the normal range the menstrual cycle intervals often regularize and the (prolactin induced) ovulation dysfunction resolves. Case: 37 year old woman with a history of irregular menstrual intervals every 30-36 days (with presence of premenstrual symptoms and biphasic basal body temperature charts), status post (following) breast surgery to remove a solid tumor (benign), and a persistent milky discharge from her breasts. The prolactin concentration is within normal limits. Question: Should this woman consider further evaluation and treatment of this milky breast discharge? Answer: Galactorrhea (milky breast discharge not related to pregnancy) is associated with an elevated prolactin concentration only about 60% of the time. If the milky nature of the discharge is unclear then examining a drop of the discharge under a microscope can confirm that it is truly milk (by the presence of fat droplets). Prolactin that circulates in the blood exists in a number of different forms and sizes (called "isoforms"). The most bioactive form of prolactin is the monomeric (small) form, which has a molecular weight of 22,000 daltons. This small form of prolactin most often constitutes about 80% of the total circulating prolactin. Other forms of prolactin have less bioactivity, including a polymeric (big) form (with a molecular weight of about 55,000 daltons) and a larger polymeric (big-big) form (with a molecular weight over 100,000 daltons). Galactorrhea in the presence of a normal prolactin concentration is most likely due to the "most bioactive forms of prolactin" comprising a greater than normal percentage of the total amount of immunoreactive prolactin (the amount detected in the assays). Alternatively, this may be due to an increase in breast cell receptors for prolactin. The increase in prolactin in this case that is presented may be due to chronic stimulation of the breast by the presence of a surgical scar on the breast. If fertility is desired, or if the milky discharge is bothersome to the woman, then medical (drug) treatment of the excess functional (bioactive) prolactin is frequently effective. Case: 39 year old woman with highly irregular menstrual intervals every few months (with scanty irregular amount of flow), persistently elevated prolactin concentrations with normal thyroid function test results, absence of milky discharge from the breasts, normal MRI (radiologic) study of the brain, and no interest in fertility. Question: Should this woman have further evaluation and treatment? Answer: Persistent elevations of prolactin may result in low circulating estrogen concentrations and irregular or absent menstrual flow. If the woman is found to have symptoms (such as hot flashes) or signs (such as a low estradiol concentration with an elevated FSH concentration) of hypoestrogenemia then treatment is suggested. Estrogen protects women against cardiovascular disease and loss of bone mineral content. In these situations, the woman should be started on either medical (drug) management for the prolactin excess to lower the circulating prolactin concentration to normal (often found to be undesirable due to the side effects of these medications) or estrogen treatment with oral contraceptive pills (if no contraindications) or hormone replacement therapy. Case: 26 year old G0 with irregular menstrual intervals every 24-31 days (with premenstrual symptoms), a persistent elevation in prolactin concentration, FSH and LH concentrations at the lower limit of the normal range, a MRI (radiologic study) of the brain revealing "empty sella syndrome," and an interest in fertility. Question: What treatment options are available for the apparent ovulatory dysfunction given this woman’s interest in fertility? Answer: The empty sella syndrome is a disorder characterized by a congenital imperfection in the sellar diaphragm that allows for the herniation of both the subarachanoid space and cerebrospinal fluid into the sella turcica to flatten the pituitary gland and result in increased prolactin and decreased FSH and LH secretion. On radiologic imaging the sella turcica looks empty, to give the condition its name. Most women with an empty sella syndrome have no detectable endocrinologic abnormality. Treatment for this woman’s ovulatory dysfunction should initially include medical management of the elevated prolactin concentration and if not effective (at normalizing ovulation) then ovulation induction should be considered. Clomiphene citrate may be initially attempted and if ineffective then ovulation induction with FSH containing fertility medication may be required. Treating identified endocrine abnormalities and normalizing ovulation are the principal concerns with the empty sella syndrome. There is no need for surgical intervention. Case: 28 year old infertility patient with a history of regular menstrual intervals every 28-29 x 3-4 days, hypothyroidism being treated with thyroid extract, and recent normal thyroid function tests. Question: Should this woman change from her thyroid extract to synthroid given her interest in fertility? Answer: I think that she should change medication from thyroid extract to synthroid. The desiccated thyroid extract provides adequate amounts of the T4 (thyroxine) hormone but also contains T3 (thyronine). Women who replace the deficient T4 with thyroid extract also replace T3 at supraphysiologic (greater than normal) concentrations. This may be associated with a subtle but significant (in terms of fertility) ovulatory dysfunction (despite regular menstrual intervals). One of my infertility patients with hypothyroidism was on desiccated thyroid extract (stated to be "more natural" by her prescribing physician) with normal thyroid function tests for TSH and free T4. I switched her to synthroid and she became pregnant without other management within a few months. This is an isolated case (anecdotal report) based on personal experience and should not be thought of as part of a "clinical study." I believe that in fertility work it is important to be highly meticulous with respect to diagnosis and treatment. Synthroid makes more sense for fertility seeking women since the thyroid replacement (once at an adequate dose) more closely approximates normal (physiologic) levels. Case: 36 year old G1 P1 with a history of subfertility, synthroid for hypothyroidism due to Hashimoto’s thyroiditis, and recent onset of signs of hyperthyroidism (hand tremor, occassional palpitations, heat intolerance, diarrhea). Thyroid function tests reveal an elevated free T4 and suppressed TSH concentration. Question: What treatment should be suggested? Answer: The dose of synthroid is excessive and should be reduced. Followup TSH and free T4 concentrations (bloodwork) should be drawn about 4-6 weeks after adjusting the dose and further adjustments should be made as needed. The followup bloodwork needs to be drawn several weeks after an adjustment in synthroid to allow for the existing T4 to be metabolized and excreted (the circulating half life of T4 is about a week). Signs and symptoms of hyperthyroidism alerted the patient and physician to possible hyperthyroidism. In practice, women on synthroid replacement medication should have periodic (every 6 to 12 months) thyroid function testing (bloodwork) since excessive replacement results in at least biochemical hyperthyroidism (even when there are no noted symptoms). Hyperthyroidism, whether via natural production by the thyroid gland or through excess replacement, is potentially harmful. Hyperthyroidism is associated with osteoporosis (decreased bone mineral content). Thyroid hormone stimulates bone resorption to decrease overall bone mineral content. The mechanism for the increased bone resorption appears to involve direct effects of thyroid hormone on the bone as well as effects involving vitamin D, calcitonin and parathyroid hormone. Case: 24 year old G0 with a history of subfertility, an ovulatory dysfunction with irregular menstrual intervals every 26-35 days, persistently elevated prolactin concentrations with a pituitary microadenoma identified on MRI of the brain (treated with bromocriptine), normalization of both the menstrual intervals and circulating prolactin concentrations on bromocriptine, now 4-5 weeks gestation (pregnant) and still on the bromocriptine. Question: Should bromocriptine be discontinued during pregnancy? Answer: Yes. Bromocriptine crosses the placenta and readily enters the fetal (developing baby’s) circulation. Fetal prolactin production is suppressed but other fetal effects have not been reported. In one study of over 1400 pregnancies in which bromocriptine was taken in early pregnancy, there was no increase in minor or major congenital abnormalities and no increase in reported spontaneous abortions (miscarriages). Nevertheless, it is prudent to discontinue bromocriptine during pregnancy and restart the medicine only if symptoms develop or rapid tumor growth is demonstrated. Pregnant patients with pituitary macroadenomas or symptomatic microadenomas should have regular (some say monthly) visual field and neurologic exams. In the early 1980s, a metaanalysis of the available literature reported that of 275 women with pituitary prolactinomas, 215 women had microadenomas and less than 1% of these had either visual changes or radiologic evidence of tumor growth during pregnancy (5% did have headaches), and 60 women had macroadenomas with 20% of these having visual changes or radiologic evidence of growth. Therefore, the need for treatment in pregnancy is uncommon. Case: 46 year old G3 P3 with a history of persistent elevation of circulating prolactin, irregular menstrual intervals prior to treatment for excess prolactin, on bromocriptine for the past 15 years with normalization of prolactin concentrations (checked annually), and chronic nausea attributed to the bromocriptine medication. Not interested in fertility and no history of galactorrhea. Question: What are the risks and the benefits for this woman if the bromocriptine is discontinued at this time? Answer: The obvious benefits of discontinuing bromocriptine include a reduction in the side effects (which are not uncommon) associated with the medication (most significantly nausea in this woman’s case) and eliminating the need to take the medicine once or twice a day. The potential risks of discontinuing the medication include (a) a subsequent elevation of circulating prolactin concentrations, (b) the onset of galactorrhea, (c) development of hypoestrogenism (low circulating estrogen) associated with excess circulating prolactin, (d) an increase in the size (and possibly symptoms) of a pituitary prolactinoma (tumor), or (e) increasing irregularity of the menstrual intervals. If the symptoms are the primary concern for the woman, vaginal administration of bromocriptine often decreases these side effects and only requires once a day administration. Also, one can switch to one of the other dopamine agonist medications that may have less bothersome side effects (such as cabergoline). Case: 35 year old G0 with irregular menstrual intervals every couple of months, monophasic basal body temperature charts, moderate excess hair growth (along the chin and under the belly button), oily skin with occasional acne, mild excess weight, and an interest in fertility. Hormone evaluation includes an LH = 17 IU/L, FSH = 5 IU/L, TSH normal, and prolactin normal. Question: What treatment options for ovulation induction are available for this woman? Answer: This woman has many characteristics of polycystic ovarian syndrome (PCOS). The treatment of choice for ovulation induction in women with polycystic ovarian syndrome is clomiphene citrate. This is a relatively inexpensive medication that can be taken by mouth over the course of a few days during the early part (follicular phase) of the menstrual cycle, has some potentially significant side effects (hot flashes, irritability, insomnia, headaches) but rare complications (twins in about 8-10% of pregnancies, nonfunctional ovarian cyst formation is uncommon). About 85% of women with PCOS will ovulate to clomiphene citrate. If the woman does not ovulate to the initial dose used (usually 50mg per day for cycle days 5-9), then increased doses (100mg or 150mg, same regimen) can be tried. Generally, you want to use the least amount of clomiphene required to accomplish the goal of ovulation induction. If the woman is very symptomatic (has side effects) on 50 mg a day you can also try reducing the initial dose to 25 mg per day on cycle days 5-9. Women who fail to ovulate to clomiphene alone may benefit from adrenal suppression with dexamethasone (0.5mg every night until pregnant) if the DHEAS concentration in the blood is elevated, hCG (10,000 units) triggering of ovulation if a periovulatory follicle is identified, extended treatment courses (possibly with higher doses) using clomiphene, pretreatment with either a several month course of oral contraceptive pills or a GnRH agonist (like lupron) to suppress circulating LH concentrations, or addition of bromocriptine (until pregnant) if there is an elevation of prolactin or galactorrhea. Most recently, insulin sensitizing medications (such as metformin) have been used (with or without clomiphene) in obese or insulin resistant PCOS women with mixed (but overall favorable) results. For these women, treatment directed at reducing overall weight (by limiting total daily caloric intake), keeping carbohydrate intake at about 50% of ingested calories, and exercise may also help with ovulation induction. Women with PCOS who fail to ovulate to clomiphene citrate then need to consider more aggressive medical ovulation induction (with injectible FSH containing fertility medication) or surgical treatments (ovarian drilling or wedge resection). I generally avoid surgical management for this endocrinologic disorder since surgery often results in extensive scar formation around the ovaries and fallopian tubes. Case: 28 year old (elite athlete) G0 with a history of amenorrhea (lack of menses) for 8 months, training for competition level long distance (marathon) running, (immediate) interest in fertility, a normal hormone evaluation (TSH and prolactin normal, FSH and LH "low normal" concentrations), no withdrawal flow to progesterone challenge, and a normal MRI of the brain. Question: What fertility recommendations are appropriate concerning ovulation induction and pregnancy? Answer: Women elite level athletes who exercise intensely (especially running and swimming) often "turn off" their reproductive function (menstrual cycles). This is most likely due to abnormalities in the amount of GnRH, FSH and LH that are released. Ovulation induction may be attempted with clomiphene citrate, which has the primary advantage (over FSH containing fertility medications) of being relatively inexpensive and easy to take (by mouth versus injection and the monitoring required is far less time consuming). Clomiphene citrate often does not work effectively at ovulation induction in these women, so the FSH containing medications may eventually be required. Controlled ovarian hyperstimulation with FSH containing medication is generally very effective at ovulation induction for these women. Close monitoring is required and these women may be at a somewhat increased chance for ovarian hyperstimulation syndrome. The woman should realize that her ability to compete in sports will be affected if she does successfully become pregnant. Pregnant women can continue to exercise regularly and at a level of intensity that they are (physiologically) used to. As the pregnancy progresses, the level of intensity that is comfortable and safe for both the mother and the growing fetus generally decreases. Case: 37 year old G0 infertility patient with irregular menstrual intervals every few months, a history of polycystic ovarian syndrome (an elevated LH to FSH ratio, obesity, oily skin and acne, excess hair growth), and failure to ovulate to clomiphene citrate. Question: Are more aggressive treatment options for this woman’s ovulatory dysfunction reasonable? Answer: Controlled ovarian hyperstimulation (using FSH containing medication) with intrauterine insemination or surgical management of the ovaries (drilling, wedge resection) are common alternatives used to treat ovulatory dysfunctions associated with PCOS. Both of these alternatives are more aggressive than the use of clomiphene citrate so they are employed if the woman fails to ovulate to clomiphene. In this situation, these are generally considered reasonable treatment options. Controlled ovarian hyperstimulation with intrauterine insemination (COH/IUI) involves the daily administration of injectable medications for about 5-10 days, frequent monitoring of ovarian follicle (egg) development (with ultrasounds and bloodwork), triggering ovulation with another injectable medication and then timing an IUI. This option has few side effects but the potential complications are important to understand (there is an entire section on these in the infertility procedures tutorial). The complications include multiple pregnancy (the incidence of higher order multiples such as triplets or more is about 3%), need to consider (decide if you would be able to have) selective reduction (to twins), ovarian hyperstimulation syndrome (with abdominal bloating, pelvic tenderness, possible dehydration, and other related [uncommon] potentially serious associated complications), ovarian torsion, premature triggering of ovulation (LH surge), and the possibility of increasing your future risk for ovarian malignancies. COH/IUI is time consuming and expensive. The medication used can cost in excess of $500-1,000 dollars per cycle. If ovarian hyperstimulation becomes a major issue, then use of a GnRH pump is (somewhat) available and a reasonable alternative. Surgery to correct the ovulatory dysfunction associated with PCOS attempts to (selectively) destroy the (stromal) tissue within the ovaries that is responsible for (excess) androgen production. This tissue is thought to be more abundant than normal due the endocrinologic abnormality (including the elevated LH:FSH ratio) that causes the PCOS. By removing a wedge of ovary or by drilling holes into the surface of the ovary some women with PCOS will find that they resume spontaneous ovulation or are able to ovulate to less aggressive fertility medication (clomiphene citrate). The downside of surgery is that it is associated with all of the potential complications of surgery (in general), and these procedures have also been associated with (extensive) pelvic adhesion formation. These pelvic adhesions may cause an additional pelvic infertility problem. I usually suggest COH/IUI for women with PCOS since I think that the risk of pelvic adhesions is very important (and unpredictable since I have seen several women with extensive adhesions following this sort of surgery even when performed by very experienced fertility surgeons). Case: 39 year old G0 infertility patient with irregular menstrual intervals every few months, monophasic basal body temperature charts, excess hair growth along the chin and under the belly button, oily skin with occasional acne, moderate excess weight, acanthosis nigricans (brown velvety discoloration of the skin) on the back of the neck and along the inner thighs, and an interest in fertility. Hormone evaluation includes an LH = 20 IU/L, FSH = 7 IU/L, TSH normal, prolactin normal, and fasting glucose to fasting insulin ratio of less than 4.5. Clomiphene citrate failed to induce ovulation. Question: 39 year old G0 infertility patient with irregular menstrual intervals every few months, monophasic basal body temperature charts, excess hair growth along the chin and under the belly button, oily skin with occasional acne, moderate excess weight, acanthosis nigricans (brown velvety discoloration of the skin) on the back of the neck and along the inner thighs, and an interest in fertility. Hormone evaluation includes an LH = 20 IU/L, FSH = 7 IU/L, TSH normal, prolactin normal, and fasting glucose to fasting insulin ratio of less than 4.5. Clomiphene citrate failed to induce ovulation. Answer: Polycystic ovarian syndrome (PCOS) is an endocrine disorder that results in chronic anovulation. Classically, PCOS starts around puberty and is associated with hyperandrogenism (which may result in hirsutism, acne, oily skin and virilization if severe), obesity, and insulin resistance (IR). The most consistent endocrine abnormality of PCOS is a tonic elevation of LH (there is an exaggerated response to GnRH) with suppression of FSH (thought to be primarily due to increased inhibin), resulting in an increased LH:FSH ratio (often greater than 3). Tonic elevation of LH can result in excess ovarian androgen production and an arrest of ovarian follicular development. Obesity and IR may cause an ovulatory dysfunction. Insulin and Insulinlike Growth Factor-1 (IGF-1) have specific receptors in the pituitary gland and on ovarian theca cells where they are thought to enhance both pituitary LH secretion and local ovarian androgen production. Insulin resistance is increased with (a) body fat content, (b) daily caloric intake, or (c) relative percent of dietary carbohydrates, and decreased with exercise. For obese or IR PCOS women, treatment directed at (a) reducing overall weight by limiting total daily caloric intake, (b) keeping carbohydrate intake at about 50% of ingested calories, (c) exercise, and (d) insulin sensitization with medication appears to be effective, healthy and less expensive than the injectible fertility medication (controlled ovarian hyperstimulation with FSH containing medication) or surgical (ovarian drilling) alternatives. Metformin has been associated (uncommon) with lactic acidosis and is entirely excreted by the kidneys, so renal insufficiency must be ruled out prior to initiating treatment. I discontinue metformin once pregnancy is established. Case: 22 year old woman with no immediate interest in fertility, very irregular menstrual intervals every several months, no premenstrual symptoms, moderate excess weight, and mild male pattern hair growth (chin and under belly button). Question: Given that there is no immediate interest in fertility, is any treatment recommended? Answer: Yes. Anovulation (whether due to PCOS or not) is associated with unopposed estrogen stimulation of the endometrium (lining cells of the uterus) and an increased incidence of eventual endometrial carcinoma (malignant degeneration of the uterine lining). Women with a diagnosis of chronic anovulation should initially have been assessed via (bloodwork for) a hormone evaluation for TSH (a fairly sensitive thyroid screening test) and prolactin (a pituitary hormone which if elevated can result in anovulation) as well as a progesterone challenge (administration of a progestagen, often provera 5-10mg, x 5-10 days) to confirm a withdrawal flow (signifying adequate estrogen stimulation of the uterine lining). Once anovulation is diagnosed and fertility is not immediately desired, the woman should be placed on (at least) periodic progesterone to counter the potentially harmful effects of unopposed estrogen. Provera (medroxyprogesterone acetate) 10 mg for 10-14 days per month appears to be adequate (probably 10 mg of provera for 10-14 days every other month is adequate) or any of the oral contraceptive pills (all of which are predominantly progestagenic) seem to be adequate. Case: 27 year old woman with no menstrual flow for 9 months. Hormone profile was unremarkable (including LH, FSH, estradiol, TSH, prolactin, hCG). No history of recent intense stress, weight loss, binge dieting, strenuous exercise, or illicit drug use. Progesterone challenge resulted in a normal withdrawal flow. No immediate interest in fertility. Question: Is any further testing necessary and what treatments would be recommended? Answer: This woman has no identified cause for her amenorrhea, and therefore would generally be classified as "functional hypothalamic amenorrhea." The cause of "functional hypothalamic amenorrhea" is not clear, but probably has to do with an abnormal hypothalamic GnRH pulse frequency and/or amplitude. Suppression of GnRH pulsatility results in a reduction or total suppression of LH pulsatility. If fertility is not immediately desired then cycling the endometrial lining (of the uterus) with periodic progesterone (either with a monthly 10-14 day course of progestagen like provera or with oral contraceptive pills) will protect the woman from potential serious complications associated with chronic unopposed estrogen stimulation (including endometrial carcinoma). Case: 33 year old female infertility patient with amenorrhea (no menstrual flow) for 7 months. Hormone profile was unremarkable (including LH, FSH, estradiol, TSH, prolactin, hCG), and there is no history of recent intense stress, weight loss, binge dieting, strenuous exercise, or illicit drug use. Progesterone challenge resulted in a normal withdrawal flow. Question: What ovulation inducing medication would be suggested? Answer: "Functional hypothalamic amenorrhea" (amenorrhea without clear cause) is most likely due to abnormal hypothalamic GnRH pulse frequency and/or amplitude which then results in a reduction or total suppression of LH pulsatility. The effectiveness of clomiphene citrate in women with functional hypothalamic amenorrhea is unpredictable. However, clomiphene citrate is much easier to take (by mouth) and is less expensive than the FSH containing injectible medications so it is generally worth a try. I suggest clomiphene citrate (50mg daily cycle day 5-9, increasing to up to 150 mg as needed) to induce ovulation. If the clomiphene is not able to accomplish the goal of ovulation, then I suggest controlled ovarian hyperstimulation (with FSH containing medication). Controlled ovarian hyperstimulation is usually effective for ovulation induction in women with functional hypothalamic amenorrhea (even if they fail clomiphene citrate). I generally recommend an intrauterine insemination during these cycles of treatment. Case: 34 year old woman with amenorrhea (absence of menses) for 14 months, hot flashes (with insomnia and the feeling that her "skin is tightening") for about 2 years, no progesterone withdrawal flow at progesterone challenge, a suppressed estradiol (less than 20 pg/mL) with a suppressed FSH (2 IU/L), and frequent urination (with a nearly constant intense feeling of thirst). Question: Are any further tests required and what treatments are appropriate? Answer: Amenorrhea associated with a suppressed circulating estradiol concentration (which then results in absence of withdrawal flow at progesterone challenge) and a suppressed FSH concentration is possibly due to a structural lesion (including tumors or granulomas) in the brain that acts to mechanically interfere with the communication between the hypothalamus and pituitary gland. Radiologic imaging (ideally MRI of the brain) is suggested to rule out anatomic lesions in women with both low circulating estrogen and low circulating FSH concentrations. Polydipsia (excessive thirst) or polyuria (excessive excretion of urine) may be signs of diabetes insipidus (chronic excretion of large volumes of dilute urine causing dehydration and thirst which may result from inappropriate pituitary secretion of ADH = antidiuretic hormone). The structural lesions that cause hypogonadotropic (low FSH) hypogonadism (low estradiol) and amenorrhea may also interfere with the regulation of pituitary ADH secretion (and result in diabetes insipidus). If a structural lesion in the brain is identified, expert consultation with a neurosurgeon is recommended. Removal of the tumor is often necessary. Case: 18 year old woman goes away to college, has significant anxiety concerning leaving home (for the first time) as well as her performance in (an elite academic) school, and develops amenorrhea (absence of menses). Previously, menstrual intervals were every 28-30 x 4-5 days with premenstrual symptoms. TSH, prolactin, hCG, and FSH concentrations are all unremarkable. Question: Does further testing need to be performed and what treatment is suggested? Answer: Theoretically, a progesterone challenge test should be performed to confirm adequate biological function of estrogen. If there is insufficient estrogen stimulation of the lining of the uterus for a withdrawal flow, and if the FSH and LH concentrations are not elevated then consideration of a structural lesion interfering with the communication between the hypothalamus and pituitary glands should be ruled out (radiologic study of the brain). If hypothalamic hypogonadotropic (low FSH) hypogonadism (low estradiol) causes amenorrhea due to stress (as the diagnosis of exclusion after all appropriate testing has been performed), then hormone replacement therapy (to provide estrogen) should be initiated. Birth control pills are adequate and seemingly convenient for many women. Standard hormone replacement regimens such as those given to menopausal women are also fine (often 1.25 mg rather than .625 mg of premarin is used in younger women). The duration of amenorrhea is uncertain when caused by stress, and the woman often resumes normal menstrual cycling once the stress (or cause of the stress) is relieved. Case: 17 year old G0 with a very thin body habitus (5 foot 6 inches tall weighing 105 pounds), amenorrhea (lack of menses) for 11 months, high level of success in school (academically and socially), and who feels that she is "fat" despite her appearance. Progesterone challenge results in a scanty withdrawal flow. Hormone evaluation includes a normal TSH, normal free T4, low free T3, normal prolactin, "low normal" range FSH and LH, and low estradiol concentrations. No current interest in fertility. Question: What treatments would be suggested for this woman? Answer: This woman has an ideal body weight of about 130 pounds (her actual body weight is about 20% below the ideal body weight), a distorted body image in that she finds herself to be "fat," no known psychiatric abnormality, and amenorrhea. Her amenorrhea is not accounted for by the endocrine studies, history of stress or strenuous exercise, or illegal drug use. She may have a structural lesion interfering with communication between the hypothalamus and pituitary gland so a radiologic study of the brain should be performed to rule out this (unlikely) situation. Once this imaging study has been completed (and is found to be normal), the probable diagnosis of anorexia nervosa should become the focus of attention. An honest and direct discussion between the physician and patient, including the potential dangers of anorexia nervosa and the association between anorexia and menstrual irregularity, may resolve the problem. If not, prompt psychiatric counseling is important. The mortality rate with anorexia nervosa is high (5-15%) so a heightened index of suspicion is warranted. These women are typically success, appearance and achievement oriented with a tendency to be overachievers. The diagnosis is based on standard criteria, including
In addition to the historical and physical findings, laboratory evaluation may reveal
If amenorrhea persists, hormone replacement medication should be initiated. Standard doses of "premarin and provera" or oral contraceptive pills are adequate. Case: 22 year old G0 with a history of narcotics abuse, irregular menstrual intervals every 24-65 x 2-6 days, a normal hormone evaluation (TSH and prolactin), and a husband with a normal semen analysis has infertility and is seeking treatment. Question: Does the history of active narcotics abuse (most likely) affect this woman’s fertility? Answer: Yes. First of all, narcotics abuse during pregnancy can affect the developing embryo and fetus (baby) by resulting in birth defects. Therefore, I would require that this woman discontinue illicit drug use prior to initiating fertility treatments. Narcotics act on the central nervous system (CNS) at least partially by altering the behavior of neurotransmitters (specific chemical agents released by the "cells that are involved in the nervous system" (synapses) that can then affect the behavior of other synapses). These neurotransmitters are also involved in the communication occurring within the brain that directs hypothalamic function. It is the hypothalamus that largely directs the pituitary gland to subsequently release its hormones. When narcotics act to alter behavior within the brain (CNS) there is often a resulting alteration of hypothalamic function that will result in a change in pituitary FSH and LH release and this may then lead to an ovulatory dysfunction. The presence of an ovulation dysfunction in this situation is suggested by the irregularity of the menstrual cycles. | |||||||||||||||
