Ovarian Lifecycle

Normal Events

Ovulation Detection

Ovulation Dysfunction
  • Ovarian Dysfunction
  • Pituitary Dysfunction
    ¬ Hypothyroidism
    ¬ Hyperthyroidism
    ¬ Postpartum Depression
    ¬ Hyperprolactinemia
    ¬ Crushing's Syndrome
    ¬ Acromegaly
  • Hypothalamic &
      CNS Dysfunction

Clinical Evaluation

Treatment Options

A Patient Reviews her Experience
with Dr Eric Daiter.

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Pituitary Gland

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).

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