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Founded by Richard C. Cabot Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor

Case 20-2010: A 32-Year-Old Woman with Oligomenorrhea and Infertility

Andrea L. Utz, M.D., Ph.D., Pamela W. Schaefer, M.D., and Matija Snuderl, M.D.

Pr e sen tat ion of C a se

From the Neuroendocrine Unit (A.L.U.) and the Departments of Radiology (P.W.S.) and Pathology (M.S.), Massachusetts General Hospital; and the Departments of Medicine (A.L.U.), Radiology (P.W.S.), and Pathology (M.S.), Harvard Medical School both in Boston; and the Pituitary Center, Vanderbilt University Medical Center, Nashville (A.L.U.). N Engl J Med 2010;363:178-86.
Copyright 2010 Massachusetts Medical Society.

Dr. Elizabeth Guancial (Medicine): A 32-year-old woman was evaluated because of oligomenorrhea and difficulty becoming pregnant. Menarche had occurred at 12 years of age and menses were regular until the patient began taking oral contraceptives at 20 years of age. At 25 years of age, she discontinued oral contraceptives and irregular menstrual cycles developed, ranging from 31 to 51 days, with menstrual flow of 7 days duration. Between the ages of 28 and 32 years, she had unprotected coitus with her husband but did not conceive. At 32 years of age, her primary care provider referred her to a gynecologist because of infertility. The patient reported that testing with over-the-counter ovulation-predictor kits did not show evidence of ovulation. Pelvic examination revealed no abnormalities. Clomiphene citrate was administered (100 mg on days 5 through 9 of the menstrual cycle). Laboratory-test results are shown in Table 1. A hysterosalpingogram was normal. Two months later, the patient was seen in the reproductive endocrine clinic of another hospital. She reported frequent acne and facial hair that she removed manually. She had no pain with menstruation and no intermenstrual bleeding. Papanicolaou smears had been normal, and there was no history of sexually transmitted diseases, use of intrauterine devices, or exposure to diethylstilbestrol. Her only medications were prenatal vitamins and folate, and results of hemoglobin electrophoresis and cystic fibrosis screening tests had reportedly been normal. Clomiphene citrate (150 mg) was administered (on days 5 through 9 of the cycle). Ultrasonography of the pelvis revealed that the endometrium was 8.8 mm thick and homogeneously echogenic; fluid and echogenic material that was thought to be blood was present in the cavity, and 5 to 10 simple cysts were present in the right ovary. Laboratory-test results are shown in Table 1. One month later, the serum level of human chorionic gonadotropin was elevated; ultrasonography revealed a single intrauterine fetus. Routine laboratory-test results were normal. The pregnancy was complicated by gestational diabetes mellitus, which was diet-controlled. After a 40-week gestation, the patient delivered a healthy infant by means of spontaneous vaginal delivery. She breast-fed her child for 12 months and had one spontaneous episode of menstrual flow during that time. Glu-

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cose intolerance persisted, but she declined treatment. She had frequent headaches, attributed to sinusitis. When the patient was 34 years of age, computed tomography (CT) of the sinuses, performed because of persistent frontal headaches and nasal discharge, revealed a lesion in the sella. Magnetic resonance imaging (MRI) performed 11 days later revealed a lesion (2.8 cm by 2.4 cm by 2.4 cm and isointense to gray matter on T1-weighted and T2-weighted images) that extended into the suprasellar region and abutted the optic chiasm, with mild compression and possible invasion of the right cavernous sinus. With the administration of contrast material, mild patchy enhancement was evident. The skull was diffusely thickened, and the frontal sinuses were prominent. Results of laboratory tests are shown in Table 1. The patient was referred to the neuroendocrinology clinic of this hospital. The patient reported decreased libido after stopping oral contraceptives, intermittent hot flashes accompanied by palpitations, and amenorrhea for almost 1 year. She had occasional floaters in her vision but no loss of peripheral vision. She had chronic pain and stiffness in the knees, shoulders, and hands, as well as occasional numbness and tingling in the hands, which had been occurring for approximately 13 years. During the same period, increasing numbers of coarse dark hairs grew on her face; darkening of the skin of the back of her neck, axilla, and groin occurred; her weight had increased 18.1 kg; and snoring, fatigue, and occasional daytime somnolence, suggestive of obstructive sleep apnea, developed. Her shoe size had increased from size 7 (European size 38) medium to size 8 (European size 39) double-wide, her ring size had also increased, and she thought that her nose had become larger. She did not have abdominal pain, nausea, vomiting, diarrhea, dizziness, chest pain, respiratory symptoms, peripheral edema, or excessive thirst or hunger or polyuria. Approximately 2 years earlier, during her pregnancy, a sharp headache, associated with visual changes, had developed during an airplane flight to another city. CT scans of the brain at a local hospital reportedly showed evidence of left frontal sinusitis. After receiving the report of the abnormal CT shortly before the present evaluation, she contacted the other facility and was told that the report of the earlier CT had described expansion of the sella turcica.
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For the previous 2 years, the patient had had intermittent episodes of acute sinusitis, treated with antibiotics and nasal spray, and seasonal environmental allergies; plantar warts had been excised, and wisdom teeth had been extracted in the past. She lived with her husband and baby, worked in academics, drank alcohol rarely, and did not smoke or use illicit drugs. She was of white and Asian ancestry. Her mother had high cholesterol and osteoporosis; her father was obese, with peripheral edema and prostatic hypertrophy; and a maternal aunt had diabetes mellitus type 2. Medications included vitamins, calcium, n3 fish oil, topical tretinoin, benzoyl peroxide, and loratadine as needed. She had no known allergies to medications. The vital signs were normal. The weight was 74.8 kg, the height 162.6 cm, and the body-mass index (the weight in kilograms divided by the square of the height in meters) 29.2. The face and nose were broad, the brow was prominent, and the teeth and jaw revealed a slight underbite; there was no macroglossia. There was facial acne, multiple skin tags, and acanthosis nigricans. The hands were large, and the fingers were thick. The remainder of the examination was normal. A diagnostic test was performed.

Differ en t i a l Di agnosis
Dr. Andrea L. Utz: This woman presented at 32 years of age with the very common condition of intermittent oligomenorrhea. The differential diagnosis for secondary oligomenorrhea and amenorrhea is broad and includes physiological causes, such as pregnancy, lactation, and menopause; anatomical causes, such as Ashermans syndrome (acquired intrauterine adhesions); and multiple causes of anovulation. This patient had evidence of anovulation.
Anovulation

Anovulation may be caused by either ovarian impairment or dysregulation of the cyclicity of gonadotropin secretion. Ovarian dysfunction is most commonly due to autoimmune destruction of the ovary, chemotherapeutic agents, pelvic irradiation, or genetic abnormalities (e.g., Turners syndrome or premutations for the fragile X syndrome). Suppression or disruption of the rhythm of gonadotropin release can be caused by lesions of the hypothalamus, lesions of the infundibulum or the pituitary or both, malnutrition or excessive energy expenditure, other hormonal dysfunction (e.g., hynejm.org july 8, 2010

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Reference Range, Adults 3rd Day of Menstrual Cycle 30th Day of Cycle 0.35.5 <32 1.6 3.0 <32 2.5 (ref for midcycle phase, 3.117.7) 12.2 272 0.54 1.92 0.52 0.41 0.9 10th Day of Cycle (after 100 mg Clomiphene on Days 59) 3rd Day of Menstrual Cycle 10th Day of Cycle (after 150 mg Clomiphene on Days 59) 32 Yr of Age, Gynecologists Office 2 Mo Later (32 Yr of Age), Reproductive Endocrine Clinic 1 Wk before Neuroendocrine Evaluation (34 Yr of Age), Other Hospital 30th Day of Menstrual Cycle 1.4
The

Table 1. Results of Laboratory Tests.*

Variable

Thyrotropin (IU/ml)

Estradiol (pg/ml)

Follicular phase, 0212; midcycle, 0480; luteal phase, 0247

Follicle-stimulating hormone (mIU/ml) 218

Follicular phase, 2.510.2; midcycle, 3.433.4; luteal phase, 1.59.1

Insulin (fasting) (U/ml)

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Testosterone (pg/ml)

100750 (women)

Free testosterone (pg/ml) Ovulatory, 0.353.75; postmenopausal, 0.141.72

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DHEA sulfate (g/ml)

0.993.40, in persons 25 to 34 years of age 1.3 (ref for follicular phase, <1; midluteal phase, 320)

Progesterone (ng/ml)

of

Follicular phase, 0.21.5; ovulatory phase, 0.83.0; luteal phase, 1.727.1

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Luteinizing hormone (mIU/ml)

Follicular phase, 1.912.5; midcycle, 8.776.3; luteal phase, 0.516.9

2.6 (ref for follicular phase, 2.412.6; ovulatory phase, 1495.6; luteal phase, 1.011.4) 20.9

1.4 (ref for follicular phase, 1.912.5; midcycle, 8.7 76.3; luteal phase, 0.516.9) 21.9 10.8 (no time given)

Prolactin (ng/ml) 521

2.826.7

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Cortisol (g/dl)

* DHEA denotes dehydroepiandrosterone, and ref reference range. To convert the values for cortisol to nanomoles per liter, multiply by 27.59. To convert the values for DHEA sulfate to micromoles per liter, multiply by 2.714. To convert the values for estradiol to picomoles per liter, multiply by 3.671. To convert the values for insulin to picomoles per liter, multiply by 6.945. To convert the values for progesterone to nanomoles per liter, multiply by 3.180. To convert the values for testosterone to picomoles per liter, multiply by 3.467. Reference values are affected by many variables, including the patient population and the laboratory methods used. They may therefore not be appropriate for all patients. Reference ranges are from the laboratory at which the testing was done.

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perprolactinemia, thyroid dysfunction, hypercortisolemia, or growth hormone excess), adrenal or ovarian neoplasms or hyperplasia, iatrogenic causes (e.g., use of estrogens, progestins, androgens, or opiates), and the polycystic ovary syndrome.1
Polycystic ovary syndrome

The criteria that have been proposed to establish a diagnosis of the polycystic ovary syndrome include oligo-ovulation or anovulation, biochemical evidence or clinical evidence (e.g., hirsutism, acne, or male-pattern alopecia) of hyperandrogenism, polycystic ovaries on ultrasonography,2 and the absence of other causes of hormonal disruption. Consensus groups continue to debate the specific criteria required to define the polycystic ovary syndrome.3,4 Disorders that can mimic the polycystic ovary syndrome include nonclassic congenital adrenal hyperplasia, hyperprolactinemia, Cushings syndrome, acromegaly, androgen-secreting tumors of the adrenal glands or ovary, syndromes of severe insulin resistance, and some medications (e.g., valproic acid and androgens).5 This patient had intermittent oligomenorrhea, and clinically she had mild hyperandrogenism symptoms. An ovarian ultrasound examination revealed 5 to 10 simple cysts on one ovary, which does not meet the Rotterdam criteria for polycystic ovaries (at least one ovary with more than 12 follicles measuring 2 to 9 mm in diameter).
Causes of Infertility

In addition to and probably related to her menstrual irregularity, this patient also had infertility. For couples, the primary causes of infertility are female anatomical abnormalities, ovulatory dysfunction, unexplained or idiopathic infertility, and male factor infertility.6 Semen analysis is the initial step in the evaluation of male infertility, and if an abnormality is uncovered, further testing of testosterone and gonadotropins is indicated.7
Evaluation of Infertility in Women

The method of assessing female infertility is similar to that of assessing oligomenorrhea but includes some additional tests. Evaluation of the patient should establish the length of the menstrual cycle; the gestational history; and the history of sexually transmitted diseases, medications, weight changes, and exercise. Initial laboratory tests generally include measurement of levels of human chorionic gonadotropin (hCG), thyrotron engl j med 363;2

pin, prolactin, day 3 follicle-stimulating hormone (FSH) and estradiol, and dehydroepiandrosterone sulfate (DHEAS), as well as free testosterone (measured by means of an accurate assay). Regular menses within a 21-to-35-day cycle often suggest ovulatory cycles. Measurement of basal body temperature and home ovulation-predictor kits can help assess the timing of ovulation. Ovulation can be confirmed by measuring the progesterone level during the midluteal phase. Hysterosalpingography is performed to assess the patency of the fallopian tubes as well as any structural abnormalities of the uterus. Other assessments considered in the evaluation are clomiphene challenge, follicular-phase ovarian ultrasonography for antral follicle assessment, and laparoscopy in some cases of endometriosis.8 This patient had normal levels of thyrotropin, prolactin, testosterone, and DHEAS; the hCG level was not measured. The luteal-phase progesterone level was 1.3 ng per milliliter (4.1 nmol per liter) (a value >6 ng per milliliter [19.1 nmol per liter] is suggestive of ovulation). Home ovulationpredictor kits did not show a rise in the level of luteinizing hormone (LH). A fasting insulin level was within the normal range but on the high side for a young, presumably healthy woman; no glucose value was provided to estimate insulin resistance. Clomiphene challenge showed low normal FSH levels and low estradiol levels at baseline and at day 10. The patient did not have a history suggestive of malnutrition or excessive exercise. The hysterosalpingogram was normal, and the endometrium was not atrophic. These results are suggestive of a pituitary abnormality that was impairing FSH production and preventing the stimulation of estradiol production, signifying possible hypogonadotropic hypogonadism. Pituitary MRI is appropriate if hypogonadotropic hypogonadism is suspected and would have been appropriate at that time for this patient. The patient spontaneously became pregnant after 4 years of infertility. During the pregnancy, gestational diabetes developed, and she continued to have impaired glucose tolerance after delivery. She breast-fed normally, which is an indication of adequate prolactin production. It was not until she presented with persistent headaches and nasal discharge that the diagnosis of a pituitary lesion was made with the use of imaging. The lesion was large, with cavernous sinus invasion and contact with the optic chiasm; the sella
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was expanded; and the calvarium was diffusely thickened. These features suggest that the lesion had been present for an extended time. In fact, CT of the head performed 2 years earlier because of a headache reportedly revealed an expanded pituitary sella.

In summary, the mass is most likely an adenoma. The thickened skull and prominent frontal sinuses provide clues to the particular type of adenoma. Dr. Utz: On the basis of the imaging scans, the most likely diagnosis is a pituitary adenoma. For any pituitary lesion, it is important to evaluate for Pituitary Lesions visual or other neurologic dysfunction from mass The differential diagnosis of a mass lesion in the effect, for hypopituitarism from disruption of norpituitary is quite broad and can be broken down mal pituitary function, and for a syndrome assointo several primary categories: neoplasms, cysts, ciated with pituitary hormone excess. hyperplasia, inflammatory or infiltrative lesions, infectious conditions, and vascular lesions. The Hypopituitarism most common abnormalities within the pituitary Assessing for hypopituitarism includes confirmasella are benign adenomas. A benign cyst, such tion of normal levels of cortisol (a random or as Rathkes cleft cyst, craniopharyngioma, men- corticotropin-stimulated cortisol level >18 g per ingioma, germinoma, or metastasis must also be deciliter [500 nmol per liter]), thyroid hormone considered. Hypophysitis can mimic a neoplastic (a normal free thyroxine level), gonadal steroids lesion on MRI scans, as can sarcoidosis and his- (regular menses in premenopausal women or a tiocytosis. Vascular lesions, such as aneurysms normal morning testosterone level in men), and of the cavernous segment of the carotid artery, growth hormone (normal results of growth horare rare but must be considered.9 mone stimulation testing). Diabetes insipidus is Dr. Pamela W. Schaefer: T1-weighted and T2-weight- rarely caused by a pituitary adenoma, but with ed MRI scans without contrast material reveal a other pituitary lesions and a suggestive clinical mass centered in the sella that is isointense to history, fluid-deprivation testing is indicated. brain parenchyma, with extension into the suprasellar cistern (Fig. 1). The sella is widened and Pituitary hormone excess syndromes remodeled without definite bone destruction. On the basis of their cell of origin, pituitary adThere is mass effect on the optic chiasm, and enomas are subdivided into prolactinomas, sothe mass may invade the right cavernous sinus matotroph adenomas (acromegaly), corticotroph without narrowing the right internal carotid ar- adenomas (Cushings disease), thyrotropin-secrettery flow void. Gradient-echo images show no evi- ing adenomas, and hormonally nonfunctioning dence of hemorrhage within the mass. After the adenomas usually derived from gonadotroph cells. administration of gadolinium, there is mild, patchy A substantial elevation in the prolactin level usuenhancement. The pituitary stalk is obscured by ally indicates that the lesion is a prolactinoma. the mass. The skull is diffusely thickened and A mild elevation in the prolactin level does not the frontal sinuses are prominent. always indicate a prolactinoma and may be a reThe features of the mass appear benign and sult of disruption of the inhibitory dopamine sigare most consistent with a pituitary adenoma. nal from the hypothalamus (known as the stalk Craniopharyngiomas are also benign masses, but effect) by any disorder that affects the pituitary they usually arise in the suprasellar region and region; alternatively, certain medications can cause extend down into the sella. They also frequently an increase in prolactin levels. Cushings synhave cysts and calcifications and usually occur drome is diagnosed on the basis of elevated levin children and in 50-to-60-year-olds. Rathkes els of 24-hour urinary cortisol, late-night salivary cleft cysts are benign and usually arise in the sella, cortisol, and dexamethasone-suppressed serum but they typically do not enhance. Malignant le- cortisol. Subsequent determination of corticotrosions such as lymphoma and metastases are usu- pin dependence and the ruling out of an ectopic ally more heterogeneous and less well circum- source of corticotropin confirm pituitary Cushscribed, and they destroy rather than remodel ings syndrome. bone. Granulomatous processes and other infecThe finding of an elevated serum level of intious and inflammatory conditions are usually sulin-like growth factor 1 (IGF-1) is suggestive of more infiltrative and are frequently associated with acromegaly, and the diagnosis is confirmed by lack of growth hormone suppression after oral basilar meningeal enhancement.
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Figure 1. MRI Scans of the Sellar Region. A T1-weighted coronal image (Panel A) and a T2 -weighted sagittal image (Panel B) show a homogeneous mass lesion centered in a widened, remodeled sella with extension into the suprasellar region (arrows). The mass is isointense to brain parenchyma and displaces the optic chiasm superiorly. It may invade the right cavernous sinus but does not narrow the internal carotid artery flow void. A gadolinium-enhanced T1-weighted coronal image (Panel C) shows patchy enhancement (arrows). An axial gradient-echo image (Panel D) shows no hemorrhage within the mass (arrows).

glucose suppression testing. Thyrotropin-secreting underbite, facial edema, macroglossia, enlarged adenomas cause elevated free thyroxine levels and hands and feet, skin tags, excessive perspiration, nonsuppressed thyrotropin levels. acne, headache, tall stature (in those in whom the disorder develops before the completion of puberAcromegaly ty), hypogonadism, insulin resistance or diabetes Acromegaly, which I believe this patient has, is mellitus, hypertension, sleep apnea, carpal tunnel due to overproduction of growth hormone. Bind- syndrome, arthralgia, cardiac hypertrophy or valing of growth hormone to hepatic receptors leads vular dysfunction, and colon polyps.10,11 This pato systemic release of IGF-1. Growth hormone and tient has many clinical features of acromegaly: IGF-1 have effects on many tissues, fluid balance, hypogonadism, skeletal changes, acne, glucose and glucose homeostasis. The diagnosis should be intolerance, sleep apnea, and arthralgias. considered in a patient with clinical findings such This patients menstrual irregularity could as prognathism, frontal bossing, deep nasolabial have been caused by hypogonadotropic hypogofolds, thickened skull, widened spacing of teeth, nadism due to disruption of normal LH and FSH
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release by the pituitary tumor mass12 or excessive growth hormone, which may have induced a polycystic ovary syndromelike anovulatory state. An excess of growth hormone increases insulin resistance, possibly because of a direct cellular effect or mobilization of free fatty acids. In a study of 14 women with active acromegaly, 50% had polycystic ovaries on ultrasonography and 43% fulfilled the Rotterdam criteria for the phenotype of the polycystic ovary syndrome.13 Women with acromegaly frequently have signs and symptoms of hyperandrogenism, with normal estrogen and testosterone levels and low sex hormonebinding globulin levels. Growth hormone or IGF-1 or both may directly affect ovarian function, or growth hormone may induce these changes indirectly by means of hyperinsulinemia.12,13 This patient most likely had active acromegaly while she was pregnant, which may have contributed to her gestational diabetes; it also probably contributed to her continued glucose intolerance. This patient had several characteristics that could have led to an earlier diagnosis of acromegaly. The presence of a hypogonadotropic hypogonadism hormonal pattern during an infertility evaluation indicates a need for pituitary MRI. Her oligo-ovulation and clinical hyperandrogenism met the criteria for the polycystic ovary syndrome phenotype, and thus this case highlights the need to consider alternative causes of the polycystic ovary syndrome phenotype. Her clinical features were suggestive of acromegaly, and measurement of the serum IGF-1 level to check for growth hormone excess was indicated, as was a test for growth hormone suppression after an oral glucose load. Untreated acromegaly diminishes survival, particularly in those with diabetes mellitus or cardiac disease.14 The initial treatment is generally surgical resection, which was probably the procedure performed in this case. Frequently, residual tumor remains after surgery, and medical management is necessary. The primary medical therapies are somatostatin analogues, a growth hormone receptor antagonist, dopamine agonists, or a combination of these. Radiation may be necessary in some cases.15 Dr. Nancy Lee Harris (Pathology): May we have the medical students diagnosis? A Harvard Medical Student: We thought that the most likely cause of this womans symptoms was a growth hormonesecreting pituitary adenoma,
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because of the sella turcica mass and the clinical features of acromegaly. Dr. Lisa B. Nachtigall (Neuroendocrinology): We thought that this patient had acromegaly caused by a growth hormonesecreting pituitary macroadenoma. The results of visual-field testing were normal. Laboratory testing showed that the IGF-1 level was slightly elevated at 574 ng per milliliter (reference range, 114 to 492). An oral glucosetolerance test for growth hormone suppression was markedly abnormal: after a 75-g load of glucose, the nadir growth hormone level was 72 ng per milliliter (normal, <1). Additional testing was done to evaluate other anterior pituitary functions, since in patients with a sellar mass, compression may cause dysfunction of any pituitary hormonal axis. Although the thyrotropin level was normal, the free thyroxine level was low, a feature consistent with central hypothyroidism. The stimulated cortisol level was normal. The LH, FSH, and estradiol levels were low, features consistent with central hypogonadotropic hypogonadism. The glycated hemoglobin level was slightly elevated, a feature suggestive of metabolic dysfunction associated with acromegaly. The prolactin level was slightly elevated (measurement was performed on a diluted sample), which could have been caused by cosecretion of prolactin and growth hormone or the effect of stalk compression by the tumor. Our preoperative diagnosis was acromegaly, with central hypothyroidism, and hypogonadotropic hypogonadism. Adrenal reserve was normal. We recommended transsphenoidal resection of the tumor, which was performed.

Cl inic a l Di agnosis
Acromegaly due to a growth hormonesecreting pituitary macroadenoma.

Dr . A ndr e a L . U t zs Di agnosis
Acromegaly due to a growth hormonesecreting pituitary macroadenoma.

Pathol o gic a l Discussion

Dr. Matija Snuderl: We received the tumor as multiple fragments of tissue measuring 2.0 by 1.5 by 0.4 cm in aggregate. Microscopical evaluation (Fig. 2A and 2B) confirmed the diagnosis of the
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Figure 2. Pathological Examination of a Specimen of the Pituitary Tumor from a Transsphenoidal Resection. A smear of the tumor (Panel A, hematoxylin and eosin) is hypercellular, with relatively uniform, medium-size neuroendocrine nuclei; however, scattered larger pleomorphic cells are noted. On a permanent section (Panel B, hematoxylin and eosin), the tumor is composed of sheets of monomorphic neuroendocrine cells with abundant pink cytoplasm, with loss of normal pituitary gland architecture. An immunohistochemical study reveals strong positivity for human growth hormone in most tumor cells (Panel C, immunoperoxidase); a few tumor cells were positive for alpha subunit and prolactin (not shown). Tumor cells show a strong diffuse fibrillary pattern of CAM 5.2 cytokeratin expression (Panel D, immunoperoxidase). The proliferation fraction with Ki67 is less than 1% (inset).

pituitary adenoma with moderate cellular pleomorphism. Immunohistochemical studies revealed that most tumor cells were reactive for human growth hormone (Fig. 2C), some tumor cells were reactive for prolactin, and occasional tumor cells were reactive for alpha subunit. Immunohistochemical staining for cytokeratin CAM 5.2 (Fig. 2D) revealed a diffuse cytoplasmic pattern of positivity. The proliferation index, assessed with Ki67 immunostaining, was less than 1% (Fig. 2D, inset). A low proliferation index and diffuse fibrillary CAM 5.2 staining pattern are associated with a lower risk of recurrence.16,17 Dr. Harris: Dr. Nachtigall, would you tell us how the patient is now? Dr. Nachtigall: At the patients 6-week postoperative follow-up, a pituitary MRI scan showed
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no evidence of a tumor. Results of visual-field tests remained normal. There was rapid diminishing or resolution of signs and symptoms of acromegaly, including carpal tunnel syndrome, joint pains and stiffness, snoring, sweating, acne, and hirsutism, and the patients ring size and shoe size decreased. Regular menstrual periods resumed. Fasting blood glucose levels were normal. The IGF-1 level was normal at 369 ng per milliliter. However, after an oral glucose-tolerance test, the growth hormone level remained elevated at 2.5 ng per milliliter (normal, <1). The rest of the patients pituitary function returned to normal, as did the glycated hemoglobin level. Because of the elevated nadir growth hormone level after the oral glucose-tolerance test, we suggested that she begin medical therapy with a low
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dose of a somatostatin analogue. Ten weeks postoperatively, we started her on 10 mg of octreotide monthly. She continued on this therapy until about 7 months postoperatively, when she wished to conceive again. Her MRI scan remained clear, and her visual fields were normal. She spontaneously conceived almost exactly 1 year postoperatively. The IGF-1 level and results of thyroidfunction, glucose, and visual-field tests remained normal throughout her pregnancy, and she delivered a healthy infant. Eight months later, however, the IGF-1 level was 646 ng per milliliter, and monthly injections of octreotide were resumed.
references
1. Practice Committee of American Soci-

The IGF-1 level is now normal, and 2.5 years after removal of the adenoma, the patient remains well.

A nat omic a l Di agnosis

Pituitary adenoma with production of growth hormone.
This case was presented at a Medical Case Conference, December 12, 2008. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank Dr. Lisa B. Nachtigall for helping to prepare the case history and for providing follow-up information.

ety for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril 2008;90:Suppl:S219-S225. 2. Balen AH, Laven JS, Tan SL, Dewailly D. Ultrasound assessment of the polycystic ovary: international consensus definitions. Hum Reprod Update 2003;9:505-14. 3. Azziz R, Carmina E, Dewailly D, et al. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 2009;91:456-88. 4. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81:19-25. 5. Kaltsas GA, Isidori AM, Besser GM, Grossman AB. Secondary forms of polycystic ovary syndrome. Trends Endocrinol Metab 2004;15:204-10. 6. Brassard M, AinMelk Y, Baillargeon

JP. Basic infertility including polycystic ovary syndrome. Med Clin North Am 2008;92:1163-92. 7. Brugh VM III, Lipshultz LI. Male factor infertility: evaluation and management. Med Clin North Am 2004;88:367-85. 8. Quaas A, Dokras A. Diagnosis and treatment of unexplained infertility. Rev Obstet Gynecol 2008;1:69-76. 9. Sam S, Molitch M. The pituitary mass: diagnosis and management. Rev Endocr Metab Disord 2005;6:55-62. 10. Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev 2004;25:102-52. 11. Melmed S. Acromegaly. N Engl J Med 2006;355:2558-73. 12. Kaltsas GA, Mukherjee JJ, Jenkins PJ, et al. Menstrual irregularity in women with acromegaly. J Clin Endocrinol Metab 1999;84:2731-5. 13. Kaltsas GA, Androulakis II, Tziveriotis K, et al. Polycystic ovaries and the

polycystic ovary syndrome phenotype in women with active acromegaly. Clin Endocrinol (Oxf) 2007;67:917-22. 14. Rajasoorya C, Holdaway IM, Wrightson P, Scott DJ, Ibbertson HK. Determinants of clinical outcome and survival in acromegaly. Clin Endocrinol (Oxf) 1994; 41:95-102. 15. Melmed S, Colao A, Barkan A, et al. Guidelines for acromegaly management: an update. J Clin Endocrinol Metab 2009; 94:1509-17. 16. Gejman R, Swearingen B, HedleyWhyte ET. Role of Ki-67 proliferation index and p53 expression in predicting progression of pituitary adenomas. Hum Pathol 2008;39:758-66. 17. Mazal PR, Czech T, Sedivy R, et al. Prognostic relevance of intracytoplasmic cytokeratin pattern, hormone expression profile, and cell proliferation in pituitary adenomas of akromegalic patients. Clin Neuropathol 2001;20:163-71.
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