Oligomenorrhea Caused by Hypothyroidism and Hyperprolactinemia Case File
Eugene C. Toy, MD, Gabriel M. Aisenberg, MD
Case 48
A 38-year-old woman presents to your clinic for evaluation of menstrual irregularity. She states that her periods started when she was 12 years old, and they have been fairly regular ever since, coming once every 28 to 30 days. She has had three previous uncomplicated pregnancies and deliveries. However, approximately 9 months ago, her cycles seemed to lengthen, and for the last 3 months she has not had a period at all. She stopped breastfeeding 3 years ago, but over the last 3 months she noticed that she could express a small amount of milky fluid from her breasts. She had a bilateral tubal ligation after her last pregnancy, and she has no other medical or surgical history. She takes no medications except multivitamins. Over the last year or so, she thinks she has gained about 10 lb, and she feels as if
she has no energy despite adequate sleep. She has noticed some mild thinning of her hair and slightly more coarse skin texture. She denies headaches or visual changes. Her physical examination, including pelvic and breast examinations, are normal. She is not obese or hirsute. Slight whitish nipple discharge is elicited from her breasts. Her pregnancy test is negative.
▶ What is the most likely diagnosis?
▶ What is the most likely etiology for the condition?
ANSWERS TO CASE 48:
Oligomenorrhea Caused by Hypothyroidism and Hyperprolactinemia
Summary: A 38-year-old woman presents with
- Oligomenorrhea and now secondary amenorrhea, along with galactorrhea
- Weight gain, fatigue, mild thinning of her hair, and slightly more coarse skin
- No headaches or visual changes, which might suggest a pituitary adenoma
- Normal pelvic and breast examinations
- No obesity or hirsutism; last pregnancy 3 years ago and not breast-feeding
- Slight whitish nipple discharge
Most likely diagnosis: Oligomenorrhea and galactorrhea due to hypothyroidism.
Most likely etiology: Primary hypothyroidism is the most likely diagnosis, most often due to autoimmune (Hashimoto) thyroiditis.
ANALYSIS
Objectives
- Understand the differential diagnosis of secondary amenorrhea and the approach to the investigation of possible hormonal causes. (EPA 2, 3)
- Understand the interactions of the hormones involved in the hypothalamic-pituitary-gonadal axis. (EPA 12)
- Recognize the clinical features and diagnostic evaluation of hypothyroidism. (EPA 1, 3)
- Describe the treatment of hypothyroidism. (EPA 4)
Considerations
This 38-year-old woman presents with secondary amenorrhea, weight gain, fatigue, and galactorrhea despite having previously normal menses and discontinuing breastfeeding 3 years ago. Her history of fatigue, weight gain, and hair loss suggests a systemic cause of her symptoms, possibly hypothyroidism. However, her normal physical examination with lack of myxedema or bradycardia, normal reflexes, normal cognition, and nondisplaced point of maximal impulse suggest mild hypothyroidism. Lack of virilization or obesity does not exclude polycystic ovary syndrome (PCOS), but their absence makes this diagnosis less likely. Hypothyroidism alone could be the cause of the galactorrhea because elevated thryoid releasing hormone can lead to hyperprolactinemia. Prolactinomas can also cause galactorrhea as well as secondary amenorrhea, however, and should be excluded.
APPROACH TO:
Oligomenorrhea and Hypothyroidism
DEFINITIONS
AMENORRHEA: Primary—Absence of menarche by the age of 15 regardless of the presence or absence of secondary sex characteristics. Secondary—Absence of menstruation for 3 or more months in women with normal past menses.
GALACTORRHEA: Any discharge of milk-containing fluid from the breast; may be unilateral or bilateral and may appear clear, milky, or bloody.
OLIGOMENORRHEA: Menses occurring at infrequent intervals of more than 35 days or fewer than nine menses per year.
POLYCYSTIC OVARY SYNDROME: Syndrome characterized by infertility, hirsutism, obesity, and amenorrhea or oligomenorrhea and often clinically significant insulin resistance.
CLINICAL APPROACH TO OLIGOMENORRHEA
Pathophysiology
The assessment of oligomenorrhea is similar to the workup for secondary amenorrhea, with the understanding that secondary amenorrhea is present when a normally menstruating woman stops having periods for 3 consecutive months or more. The most common cause of both symptoms, and the easiest to exclude in the clinic, is pregnancy. A negative in-clinic pregnancy test should be confirmed with a serum beta-human chorionic gonadotropin (hCG). Primary amenorrhea is present when the first menses has not appeared in a girl by the age of 15 and is generally caused by a variety of genetic or congenital defects. It is commonly associated with disorders of puberty. Given this patient’s age and history, primary amenorrhea is not a consideration; thus, a diagnostic pathway for secondary amenorrhea/oligomenorrhea should be undertaken (Figure 48–1).
Problems of the Hypothalamic-Pituitary-Ovarian Axis. Excluding pregnancy and problems in the genital outflow tract, disorders of the hypothalamic-pituitary-ovarian axis account for the largest number of cases of oligomenorrhea and amenorrhea. Disorders of the hypothalamus account for the largest percentage of abnormality (> 45%); these include problems of nutrition (rapid weight loss/anorexia), excessive exercise, stress, and infiltrative diseases (eg, craniopharyngioma, sarcoidosis, histiocytosis).
PCOS. The largest single cause of oligomenorrhea is PCOS, accounting for 30% of all cases. PCOS was once thought to be a disease originating in the ovary; however, it now is known that PCOS is a much more complicated neuroendocrine disorder with evidence of estrogenization, as well as insulin resistance. The diagnosis is a clinical one (anovulation, hyperandrogenism, and small follicles on the ovary on ultrasound) after ruling out other causes. These women often have glucose intolerance and may develop metabolic syndrome. They are at risk for cardiovascular disease and endometrial cancer. Treatment for PCOS includes weight loss (via diet and exercise), oral contraceptives, androgen blockers such as spironolactone, and metformin. Clomiphene citrate or letrozole can be used as a fertility treatment to induce ovulation in patients looking to get pregnant.
Other Causes. Other important causes of amenorrhea include diseases of the pituitary, specifically neoplasms (eg, prolactinomas, functioning or nonfunctioning adenomas), which account for 18% of cases. Empty sella syndrome, caused by cerebrospinal fluid herniation into the pituitary fossa, and Sheehan syndrome, caused by severe obstetric hemorrhage and/or maternal hypotension at delivery, are important causes of atrophy and ischemia of the pituitary. If suspected, they should be investigated by magnetic resonance imaging (MRI). Finally, disorders such as premature ovarian failure (loss of all functional ovarian follicles before the age of 40), diseases of the thyroid, and adult-onset adrenal hyperplasia should be considered and investigated if supported by history and physical examination with the appropriate laboratory studies (Table 48–1).
Hypothyroidism. The history and physical examination will narrow the range of possible causes. In this patient, the history of fatigue, weight gain, and galactorrhea, along with previously normal menses and a normal physical examination, place hypothyroidism at the top of the list. In primary hypothyroidism, the hypothalamus increases thyrotropin-releasing hormone, which also stimulates prolactin secretion. Measurement of both thyroid hormone and prolactin levels would be indicated in this case. Prolactinomas are the most common functional pituitary tumors in both men and women and should be suspected if the prolactin level is markedly elevated, > 200 μg/L. If prolactin levels are markedly elevated, pituitary imaging with MRI is indicated. Hyperprolactinemia from any cause inhibits hypothalamic gonadotropin-releasing hormone (GnRH) secretion, leading to amenorrhea in women and infertility and diminished libido in men. In the workup of secondary amenorrhea, these two diagnoses are the easiest to start with because the tests are noninvasive and relatively inexpensive.
Abbreviations: ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; OCP, oral contraceptive pill; TSH, thyroid-stimulating hormone.
aPregnancy must always be suspected with oligomenorrhea or amenorrhea.
CLINICAL APPROACH TO HYPOTHYROIDISM
Pathophysiology
Hypothyroidism is defined as the insufficient production of thyroid hormone. Secondary hypothyroidism as a result of dysfunction of hypothalamic and pituitary hormone secretion is much less common but should be suspected in a patient with a history suggestive of Sheehan syndrome or with symptoms or signs of a tumor in the region of the sella. Ninety-five percent of cases of hypothyroidism are caused by primary thyroid gland failure, resulting in insufficient thyroid hormone production. In the United States, the most common cause of hypothyroidism is autoimmune (Hashimoto) thyroiditis, in which cytotoxic antibodies are produced, leading to thyroid atrophy and fibrosis. The next most common cause is surgical or radioactive iodine treatment for hyperthyroidism, or Graves disease. Worldwide, iodine deficiency is the most common cause of goitrous (enlarged thyroid) hypothyroidism, but in the United States, this is rare.
Clinical Presentation
Most hypothyroid patients present with vague and nonspecific symptoms. Elderly individuals may be suspected of having dementia or depression when the cause is really hypothyroidism. In general, symptoms of fatigue, weight gain, muscle cramping, cold intolerance, hair thinning, menstrual changes, or carpal tunnel syndrome are common and should prompt an investigation of thyroid function.
Laboratory Values. When testing outpatients for hypothyroidism, measurement of the serum thyroid-stimulating hormone (TSH) level is the most sensitive and useful test. Because most cases of hypothyroidism are caused by thyroid gland failure, the normal pituitary response is to markedly increase the TSH levels in an attempt to stimulate the failing gland. Falling levels of thyroid hormone lead to an increase in the TSH concentration. Measurement of TSH alone would be insufficient in suspected cases of pituitary disease, so measurement of the thyroid hormone level can also be performed. One should remember that almost all thyroxine (T4) circulates bound to protein, but it is the free or unbound fraction that is able to diffuse into cells and become active. Most laboratories can now measure free T4 directly, or it can be estimated by using the free thyroxine index (FTI). The FTI is calculated from measurements of total T4 and the triiodothyronine (T3) resin uptake test. When there is excess thyroid-binding globulin (TBG), as in pregnancy or oral contraceptive use, T4 levels will be high (as a consequence of the large amount of carrier protein), but T3 uptake will be low (value varies inversely with amount of TBG present). Conversely, when there is a low level of TBG, as in a hypoproteinemic patient with nephrotic syndrome, the T4 level will necessarily also be low (not much carrier protein), but the T3 uptake will be high. If both total T4 and T3 uptake are low, the FTI is low, and the patient is hypothyroid.
In mild cases, or subclinical hypothyroidism, the TSH level is mildly elevated, but the free T4 or FTI is within the normal range. Patients may be asymptomatic or report the vague and subtle symptoms of hypothyroidism, such as fatigue. About half of such patients will progress to overt hypothyroidism within 5 years. They often have some derangement of cholesterol metabolism, such as elevated total and low-density lipoprotein cholesterol. Thyroid hormone replacement can be prescribed in the cases of TSH > 10 mU/L, pregnancy, infertility, and/or strongly convincing symptoms of hypothyroidism. In clinical hypothyroidism, the TSH level is markedly elevated, and the free T4 or FTI is low.
Treatment
The overwhelming majority of patients with hypothyroidism can be treated with once-daily dosing of synthetic levothyroxine, which is biochemically identical to the natural hormone. Levothyroxine is relatively inexpensive; has a long half-life (6–7 days), which allows once-daily dosing; and gives a predictable response. Older thyroid preparations, such as desiccated thyroid extract, are available but are not favored because of the variable content of T3 and T4 in each tablet.
If there is no residual thyroid function, the daily replacement dose of levothyroxine is 1.6 μg/kg, which usually calculates to 100 to 150 μg. However, in older patients and in those with known cardiovascular disease, dosing should start at a lower level, such as 25 to 50 μg/d, and be increased at similar increments once every 4 to 6 weeks until the patient achieves a euthyroid state. Overly rapid replacement with the sudden increase in metabolic rate can overwhelm the coronary or cardiac reserve. The goal of treatment is normalized TSH, ideally in the lower half of the reference range. Patients may not experience full relief of symptoms until 3 to 6 months after normal TSH is achieved.
Complications
In severe, prolonged hypothyroidism, a syndrome termed myxedema may develop. These patients present with hypothermia, hypotension, hypoventilation, altered mental status, hyponatremia, and/or hypoglycemia. They may also have underlying adrenal insufficiency. This is a life-threatening emergency with a high mortality, even when managed aggressively with intravenous hydrocortisone (in case of underlying adrenal insufficiency) followed by intravenous levothyroxine.
CASE CORRELATION
- See also Case 49 (Adrenal Insufficiency), Case 50 (Hypercalcemia/Multiple Myeloma), Case 51 (Type 2 Diabetes Diagnosis and Management), and Case 53 (Thyrotoxicosis/Graves Disease).
COMPREHENSION QUESTIONS
48.1 A 42-year-old woman presents to your clinic for her annual physical examination. On examination, you note neck fullness. When you palpate her thyroid, it is enlarged, smooth, rubbery, and nontender. The patient is asymptomatic. You send her for thyroid function testing. Her T4, free T4, and T3 are normal, but her TSH is slightly elevated. Which of the following is the most likely diagnosis?
A. Iodine deficiency
B. Thyroid cancer
C. Hashimoto thyroiditis
D. Graves disease
E. Multinodular goiter
48.2 Which of the following laboratory tests is most appropriate to be performed to confirm your diagnosis of the patient in Question 48.1?
A. Repeat thyroid function tests
B. Thyroid ultrasound
C. Nuclear thyroid scan
D. Antithyroperoxidase (anti-TPO) antibody tests
E. Complete blood count with differential
48.3 A 19-year-old gymnast active in national competition is brought to your clinic by her mother because the daughter’s menses have ceased for the last 3 months. Prior to this, she was always regular. She denies excess dieting, although she does work out with her team 3 hours daily. Her physical examination is normal except for her body mass index of 20 kg/m2. Which of the following laboratory tests should be ordered first?
A. Thyroid function tests
B. Complete blood count
C. Luteinizing hormone (LH)/follicle-stimulating hormone (FSH)
D. Prolactin
E. Beta-human chorionic gonadotropin (beta-hCG)
48.4 A 35-year-old woman who was diagnosed with hypothyroidism 4 weeks ago presents to your clinic complaining of persistent feelings of fatigue and sluggishness. After confirming your diagnosis with a measurement of the TSH, you started her on levothyroxine 50 μg daily. She has been reading about her diagnosis on the Internet and wants to try desiccated thyroid extract instead of the medicine you gave her. On examination, she weighs 175 lb, her heart rate is 64 beats per minute (bpm) at rest, and her blood pressure is normal. Which of the following is the best explanation to be conveyed to the patient?
A. The delay in resolution of symptoms is to be expected.
B. Thyroid extract is approved by the Food and Drug Administration (FDA) but inconsistent in activity.
C. Her dose of levothyroxine should be increased.
D. She should take a multivitamin with iron for her symptoms.
ANSWERS
48.1 C. Hashimoto thyroiditis is the most common cause of hypothyroidism with goiter in the United States. It is most commonly found in middle-aged women, although it can be seen in all age groups. Iodine deficiency (answer A) is exceedingly uncommon in the United States because of iodized salt. Graves disease (answer D) is a hyperthyroid condition. Patients with multinodular goiter (answer E) usually are euthyroid. Patients with thyroid cancer (answer B) usually are also euthyroid.
48.2 D. Hashimoto thyroiditis is an autoimmune disease of the thyroid. Several different autoantibodies directed toward components of the thyroid gland will be present in the patient’s serum; however, of these, anti-TPO antibody almost always is detectable. These antibodies are the markers, not the cause, of gland destruction. On thyroid biopsy, lymphocytic infiltration and fibrosis of the gland are pathognomonic. The presence of these autoantibodies predicts progressive gland failure and the need for hormone replacement. None of the other tests (answer A, repeat thyroid function tests; answer B, thyroid ultrasound; answer C, nuclear thyroid scan; answer E, complete blood cell count with differential) will be helpful.
48.3 E. In a young woman with oligomenorrhea, pregnancy should always be the first diagnosis considered. Urine pregnancy tests are easily performed in the clinic and are highly sensitive. Serum beta-hCG can be measured to confirm a negative test. In this patient, the next most likely diagnosis is hypothalamic hypogonadism, secondary to her strenuous exercise regimen. These young women are at risk for osteoporosis and should be counseled on adequate nutrition and offered combined oral contraceptives if the amenorrhea persists. If the pregnancy test is negative, then evaluation of oligomenorrhea includes TSH (answer A), serum prolactin level (answer D), and serum LH and FSH (answer C); this patient likely has a hypothalamic dysfunction with lack of pulsatile GnRH from the excessive exercise and low body weight. Answer B (complete blood count) is not indicated in this case.
48.4 C. This patient’s thyroid replacement should be increased. She has been on thyroid replacement therapy for 4 weeks which is sufficient time for a clinical effect (answer A). The symptoms point to continued hypothyroidism. Levothyroxine is the preferred replacement hormone for hypothyroidism. The amount of hormone batch to batch and the patient dose response are believed to be more predictable than with other forms of hormone replacement, such as thyroid extract (answer B), which is made from desiccated beef or pork thyroid glands; this preparation is not FDA approved. There is no evidence that the natural hormone replacement is superior to the synthetic form. The dose of levothyroxine should be titrated to relief of symptoms, as well as to normalization of the TSH. Other medications, especially iron-containing vitamins (answer D), should be taken at different times than levothyroxine because they may interfere with absorption.
CLINICAL PEARLS
▶ The most common causes of oligomenorrhea are disorders of the hypothalamic-pituitary-gonadal axis, such as PCOS and hypothyroidism.
▶ Hypothyroidism may cause hyperprolactinemia. Hyperprolactinemia from any cause induces hypothalamic dysfunction, leading to menstrual irregularities in women and diminished libido and infertility in men.
▶ The most common cause of hypothyroidism is primary thyroid gland failure as a result of Hashimoto thyroiditis.
▶ A low free T4 or FTI and a high TSH characterize primary hypothyroidism.
▶ Synthetic levothyroxine (T4) replacement is the treatment of choice for hypothyroidism; in older patients, you need to “start low and go slow.”
▶ The goal of therapy is to normalize the TSH level in primary hypothyroid-ism and to relieve symptoms.
REFERENCES
Cooper DS. Subclinical hypothyroidism. N Engl J Med. 2001;345:260-265.
Hall JE. Menstrual disorders and pelvic pain. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, et al, eds. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw Hill; 2018:2794-2799.
Jameson JL, Mandel SJ, Weetman AP. Hypothyroidism. In: Jameson JL, Fauci AS, Kasper DL, Hauser SL, et al, eds. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw Hill Education; 2018:2698-2703.
Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association task force on thyroid hormone replacement. Thyroid. 2014;24(12):1670-1751.
Melmed S, Jameson JL. Pituitary tumor syndromes. In: Jameson JL, Fauci AS, Kasper DL, Hauser SL, et al, eds. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw Hill Education; 2018:2670-2684.
0 comments:
Post a Comment
Note: Only a member of this blog may post a comment.