Daily catheter-directed single dosing of t-PA in treatment of acute deep venous thrombosis of the lower extremity.

The strong fibrin affinity of recombinant tissue plasminogen activator (rt-PA) theoretically obviates continuous infusion or replacement of t-PA after direct intrathrombic injection. This hypothesis led the authors to evaluate single daily catheter-directed injection of rt-PA as a thrombolytic treatment for acute deep vein thrombosis of the lower extremity. Once-daily injection of rt-PA was performed in large thrombosed veins (popliteal or larger) with use of pulse-spray catheters and in small thrombosed veins in patients' calves with use of 3-4-F coaxial catheters. Patients received only full systemic anticoagulation on his/her patient care unit. This dosing regimen has been tested in 10 patients (12 legs) with a maximum dose of 50 mg per leg per day. Extensive thrombolysis was achieved in nine patients and partial thrombolysis was achieved in one patient, at an average total dose of 106 mg of rt-PA per leg. Minor bleeding was seen in three patients and no transfusions were needed. Our technique and the rationale for this pilot study is the focus of this article.

Ultrasound and sestamibi scan as the only preoperative imaging tests in reoperation for parathyroid adenomas.

BACKGROUND: In an effort to determine an efficient algorithm for the evaluation of patients with parathyroid adenomas in the reoperative setting, we explored the combination of using ultrasound scans (US) and sestamibi scintigraphy as the only preoperative imaging tests. METHODS: We analyzed the outcomes of 62 consecutive patients who were treated between January 1995 and May 1999 and who were referred for persistent primary hyperparathyroidism after initial surgical exploration, at which time no abnormal parathyroid glands had been found. Although all patients underwent US, computed tomography scan, magnetic resonance imaging, and sestamibi scan, we analyzed the success of localization and reoperation using only the results of US and sestamibi scan. RESULTS: Sixty-one patients (98%) underwent curative reoperations. The sensitivity, positive predictive value, and accuracy for US were 90%, 86%, and 84%, respectively; the corresponding values for sestamibi imaging were 78%, 94%, and 74%, respectively. In 58 of 62 cases (94%) preoperative US and/or sestamibi scan accurately identified the adenoma. In 3 patients for whom combined US and sestamibi scan were inaccurate, 1 adenoma was found by intraoperative US in the strap muscle; 1 adenoma was found by blind cervical thymectomy, and 1 adenoma was found by planned sternotomy that was based on computed tomography findings. CONCLUSIONS: This study supports an algorithm of obtaining US and sestamibi scan as the initial and perhaps only preoperative localization tests for patients with primary hyperparathyroidism after failed operation, at which time no abnormal glands had been found.

A phase 2 study of radio frequency interstitial tissue ablation of localized renal tumors.

PURPOSE: Small renal tumors are frequently detected during the screening of patients with a hereditary type of renal cancer. The development of nonsurgical treatment modalities would greatly improve quality of life in these patients. We present our experience with radio frequency interstitial tissue ablation, a heating device approved by the Food and Drug Administration for treating soft tissue tumors. MATERIALS AND METHODS: Patients underwent radio frequency interstitial tissue ablation of small renal tumors just before surgical excision. Pathological examination of the renal tumors was done to evaluate the treatment effect. Computerized tomography and renal function testing were performed before and after therapy to evaluate toxicity. RESULTS: Four patients underwent treatment of a total of 14 tumors with the radio frequency interstitial tissue ablation device just before surgical removal of the tumors. All lesions were brown after ablation, in contrast to the normal pink appearance of untreated lesions that were resected. On color Doppler ultrasound blood flow to each tumor evident before was not visualized after treatment. The Wilcoxon rank sum test demonstrated no difference preoperatively and postoperatively in blood urea nitrogen, serum creatinine, creatinine clearance or differential renal function. We identified no toxicity associated with radio frequency interstitial tissue ablation. Of the excised tumors 11 were renal cell carcinoma and 3 fibrotic hemorrhagic cysts. For renal cell carcinoma the treatment effect involved the loss of nuclear detail and nonvisualization of nucleoli. These changes were not observed in any tumors resected without radio frequency interstitial tissue ablation. The treatment effect was noted in 10 of the 11 lesions, and in 1 case the treatment effect involved 35% of the tumor. CONCLUSIONS: No toxicity was associated with radio frequency interstitial tissue ablation. Percutaneous treatment of renal tumors is planned to evaluate the treatment effect better and further evaluate toxicity.

Localization of pituitary adenomas by using intraoperative ultrasound in patients with Cushing's disease and no demonstrable pituitary tumor on magnetic resonance imaging.

OBJECT: Pituitary surgery has been reported to produce remission of Cushing's disease with preservation of pituitary function in only 60 to 70% of patients. The inability to identify an adenoma accounts for most failed sellar explorations. Most negative surgical explorations occur in patients in whom magnetic resonance (MR) imaging of the pituitary demonstrates normal findings, which happens in at least 35 to 45% of patients with Cushing's disease. METHODS: To examine the usefulness of intraoperative ultrasonography (IOUS) for identifying an adenoma in patients with no demonstrable tumor (negative findings) on pituitary MR imaging. we prospectively assessed the results of IOUS in 68 patients with a negative (59 patients) or equivocal (nine patients) MR image from a consecutive series of 107 patients with Cushing's disease (64%). We compared surgical findings and outcomes in these 68 patients with a group of 68 patients with Cushing's disease and negative findings on MR imaging in whom IOUS was not available. Intraoperative ultrasonography localized a tumor in 47 (69%) of 68 patients with negative findings on MR imaging. Surprisingly, the size of the adenomas that were detected with IOUS compared with the size of those not detected did not differ (6.8+/-3.4 mm compared with 6.1+/-2.8 mm [mean+/-standard deviation], respectively [p=0.51). In four patients, no adenoma was found at surgery or in the pathological specimen ("true negative"). In eight patients, nine abnormalities detected by IOUS that were suspected adenomas were negative on exploration ("false positive"). Thus, IOUS has a sensitivity of 73% and a positive predictive value of 84% for detecting pituitary adenomas in patients with Cushing's disease and negative findings on MR imaging. Compared with the 68 patients who did not undergo IOUS. remission after surgery was improved (61 patients [90%] compared with 57 patients [84%]), the number of tumors found on exploration was increased (61 tumors compared with 51 tumors, p=0.02), and the number of hemihypophysectomies was decreased (five compared with 15; p=0.02) with IOUS. When the groups were compared after excluding patients with prior pituitary surgery, tumors were found in 91% versus 72% (p=0.008), and remission occurred in 95% versus 87% of patients, respectively, in the groups that had or did not have IOUS. CONCLUSIONS: The IOUS is a sensitive imaging modality when used in patients with Cushing's disease in whom findings on pituitary MR imaging are negative. The improved ability to detect and localize these tumors by using IOUS positively affects surgical outcome.

Operative management of islet-cell tumors arising in the head of the pancreas.

BACKGROUND: Pancreatic islet cell tumors (ICTs) can be treated by enucleation or pancreatic resection. We reviewed our experience with ICTs in the head of the pancreas to define indications for enucleation versus pancreaticoduodenectomy. METHODS: Between January 1982 and December 1997, 48 patients underwent surgical resection for presumed ICTs of the pancreatic head. Of these, 18 were found on pathologic examination to be disease in a lymph node. Thirty patients had 32 true pancreatic head ICTs. We reviewed the operative results and postoperative courses in these patients. RESULTS: Mean diameter of the ICTs was 15 mm. Twenty-seven patients (90%) underwent successful enucleations. Three patients failed enucleation and underwent pancreaticoduodenectomy. There was no operative mortality. The median time to regular diet was 7 days. The median time to removal of all drains was 22 days. The most common complication was pancreatic fistula (15%). No patient required reoperation for treatment of a fistula. CONCLUSION: Most ICTs of the pancreatic head can be removed with enucleation, preserving pancreatic tissue and avoiding the morbidity of pancreaticoduodenectomy. The primary indication for pancreaticoduodenectomy is not the size of the lesion but its proximity to the pancreatic duct.

Sonography of gallbladder abnormalities in acromegaly patients following octreotide and ursodiol therapy: incidence and time course.

PURPOSE: We studied the effects of octreotide and ursodiol on the gallbladders of patients with acromegaly. METHODS: We performed gallbladder sonography in patients with acromegaly at various intervals during treatment. Group I (18 patients) was treated with subcutaneous injections of the somatostatin analogue octreotide. Group II (10 patients) was treated with ursodiol while receiving octreotide therapy. RESULTS: Seventy-eight percent of patients receiving octreotide developed gallbladder abnormalities: sludge in 72% (13/18) and calculi in 39% (7/18). Ursodiol reversed the gallbladder abnormalities in 7 of 10 patients. CONCLUSIONS: A majority of patients receiving octreotide develop gallbladder abnormalities. Ursodiol appears to reverse the abnormalities in most cases.

Syndrome of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas (Carney complex): breast imaging findings.

PURPOSE: To study the imaging appearances of breast lesions in female patients with Carney complex. MATERIALS AND METHODS: Seven patients with Carney complex underwent mammography (n = 5), ultrasound (US) (n = 6), or magnetic resonance (MR) imaging (n = 6) in a prospective study. Previous breast images in three patients were reviewed. Mammograms in two additional patients were retrospectively reviewed. Thus, nine patients aged 16-61 were included in this study. RESULTS: Mammograms showed well-defined, iso- or hypodense masses; most were not calcified. Two lesions contained calcifications; both were biopsy-proved ductal adenomas. US demonstrated solid, hypoechoic, well-circumscribed masses in six patients and complex cystic masses (myxoid fibroadenomas) in one patient. MR imaging with a fat-suppressed, fast spin-echo, T2-weighted sequence demonstrated high-signal-intensity lesions (n = 5). Fat-suppressed, spoiled gradient-recalled-echo MR images demonstrated hypointense lesions with variable contrast material enhancement (n = 5). Five of seven patients in the prospective review had multiple breast lesions on at least one study. Mammograms and US scans were negative in three patients each. Chest and breast MR images were negative in only one patient. CONCLUSION: Female patients with Carney complex often have multiple breast masses with variable imaging appearances that probably represent myxoid fibroadenomas or ductal adenomas. MR imaging showed the most lesions. These lesions all demonstrate benign characteristics and should not prompt multiple biopsies.

Phase I trial of photodynamic therapy in the treatment of recurrent superficial transitional cell carcinoma of the bladder.

OBJECTIVES: A Phase I trial of photodynamic therapy (PDT) in the treatment of superficial transitional cell carcinoma (TCC) of the bladder was performed. METHODS: Twenty patients with recurrent superficial TCC of the bladder after receiving a mean of 2.6 (range 1 to 6) courses of intravesical therapy were treated with PDT. The photosensitizer Photofrin II dose was 1.5 or 2.0 mg/kg. A 630-nm intravesical red laser was used to activate the photosensitizer 2 days after administration of Photofrin II. A 0.01% intralipid solution was used as a bladder-filling medium to scatter light and achieve more homogeneous light distribution. Light doses from 5.1 to 25.6 J/cm2 (total dosage 1500 to 5032 J) were used to illuminate the bladder. RESULTS: Twenty patients underwent 21 treatments with PDT. Complications included asymptomatic reflux in 4 patients. One other patient, treated at the highest total light dose, experienced bladder contraction and fibrosis. Nine patients (45%) had no tumor evident at cystoscopy, on random biopsies, or in urinary cytology at the 3-month evaluation after treatment. Four patients remained without recurrent disease for 23 to 56 months. Sixteen of 20 (80%) patients experienced recurrence, and 8 of the 16 underwent cystectomy. CONCLUSIONS: An intravenous photosensitizer dose of 1.5 mg/kg Photofrin II followed by light energy in the range of 13 J/cm2 (total light dose 2500 to 3250 J) was defined as a safe treatment parameter and resulted in tumor responses. With present technologies, administration of PDT requires careful dosimetry.

Intraarterial calcium stimulation and intraoperative ultrasonography in the localization and resection of insulinomas.

BACKGROUND: Standard imaging studies (computed tomography, magnetic resonance imaging, somatostatin receptor scintigraphy, ultrasonography, and angiography) correctly localize insulinomas in less than 50% of patients and provide no information about the feasibility of enucleation based on proximity of tumor to pancreatic duct. We reviewed our experience with intraarterial calcium stimulation (Ca-Stim) and intraoperative ultrasonography (IOUS) to localize and guide management of insulinomas. METHODS: Thirty-six patients (14 men, 22 women, median age 44 years) with insulinomas were treated between August 1989 and June 1996. Preoperative imaging studies were obtained. Patients underwent abdominal exploration with IOUS. Fourteen were evaluated by a surgeon blinded to preoperative imaging results. RESULTS: Tumors (4 to 50 mm) were resected by enucleation (67%) or partial pancreatectomy (33%); all were cured. Sensitivities of computed tomography, magnetic resonance imaging, somatostatin receptor scintigraphy, ultrasonography, angiography, and Ca-Stim in localizing insulinomas were 24%, 45%, 17%, 13%, 43%, and 94%, respectively. Tumors were identified by blinded surgical exploration with IOUS in 12 of 14 patients (86%). CONCLUSIONS: All insulinomas were identified before operation; however sensitivity of individual noninvasive tests was low (less than 50%). In contrast, Ca-Stim was correct in 94% of cases, thus allowing a focused pancreatic exploration and obviating use of blind distal pancreatectomy. IOUS can then be used to guide safe enucleation.

Phase II trial of 5-fluorouracil, leucovorin, interferon-alpha-2a, and cisplatin as neoadjuvant chemotherapy for locally advanced esophageal carcinoma.

BACKGROUND: Most patients with esophageal carcinoma present with locally advanced disease and a poor prognosis. Surgery or radiation provides palliation for locally advanced esophageal carcinoma. The role of neoadjuvant therapy remains to be defined. We administered neoadjuvant chemotherapy consisting of 5-fluorouracil (5-FU), leucovorin, interferon-alpha, and cisplatin to 11 patients with locally advanced disease. METHODS: Eleven patients with squamous cell or adenocarcinoma of the esophagus were treated peroperatively with two to three cycles of combination chemotherapy. Nine patients underwent resection with curative intent. RESULTS: Six patients received three cycles of chemotherapy, and five received two. Dose reduction was necessary for two patients. One patient achieved a pathologic complete response, histologically confirmed. Of the eleven patients, two did not undergo surgery because of progressive disease during chemotherapy. Seven of the 9 patients relapsed after surgery and 2 have been disease free for 27 months. CONCLUSIONS: The combination 5-FU leucovorin, interferon-alpha-2a, and cisplatin administered in a neoadjuvant setting resulted in a median survival of 11.8 months with a median time to relapse of 7 months.

Testicular adrenal rest tissue in congenital adrenal hyperplasia: findings at Gray-scale and color Doppler US.

PURPOSE: To study the ultrasound (US) features of scrotal adrenal rest tissue in congenital adrenal hyperplasia (CAH). MATERIALS AND METHODS: Gray-scale and color Doppler US examinations were performed of scrotal masses in eight patients. The masses were evaluated for size, location, echogenicity, sound attenuation, and vascularity. RESULTS: Seventeen intratesticular masses and one extratesticular mass were examined. All were hypoechoic except for one intratesticular mass that contained hyperechoic areas. Six masses demonstrated sound attenuation. The mediastinum testis was found in the center of 11 of the 17 intratesticular masses. At color Doppler US, six masses were hypervascular, seven were isovascular, and five were hypovascular relative to the normal testicle. All intratesticular masses contained vascular structures that entered them from the normal testis without change in course or caliber. Eleven masses showed a spoke-like pattern of converging vessels. CONCLUSION: The US features of scrotal adrenal rests assist diagnosis of CAH.

High cervical intravagal hypercellular parathyroid gland as the etiology of severe persistent primary hyperparathyroidism.

The preoperative localization and operative management of a high cervical intravagal parathyroid adenoma in a young woman with severe persistent primary hyperparathyroidism is presented. The etiology of persistent hyperparathyroidism is most frequently a missed adenoma that is often in an ectopic location; of these, undescended adenomas represent a small but important proportion. If clinical suspicion and preoperative localization procedures suggest an undescended gland, a direct surgical approach using a high cervical incision and a unilateral exploration is often successful.

Intraoperative ultrasound-directed resection of pituitary tumors.

Microadenomas of the pituitary vary in size, particularly those related to Cushing's disease. They are often not visualized on preoperative magnetic resonance (MR) imaging and may be difficult to find during surgical exploration of the pituitary. To enhance intraoperative localization of pituitary adenomas, we assessed the feasibility of using ultrasound to detect and localize pituitary tumors. Intraoperative ultrasound (IS) in the axial and sagittal planes was performed with an Intrascan system using a 12-MHz mechanically oscillating, end-firing transducer. Interpretation of the scans was performed by two individuals, who were usually blinded to the results of preoperative MR imaging or petrosal sinus sampling. Twenty-eight patients were examined. Eighteen of these patients had microadenomas (1.5-7 mm), all with Cushing's disease; nine had macroadenomas (10-20 mm), three of which were adrenocorticotropic hormone-secreting, three growth hormone-secreting, two thyroid-stimulating hormone-secreting, and one nonfunctioning; and one patient had an intrasellar craniopharyngioma. Normal sellar and parasellar structures, such as intrapituitary cysts, the intracavernous carotid arteries, and the diaphragma sella were easily visualized. Twenty-three of the 28 tumors, including 13 of the 18 microadenomas, were detected on IS (82% sensitivity). Tumors were seen as hyperechoic masses in 19 patients, mixed echogenicity in three, and isoechoic in one. In most macroadenomas IS allowed visualization of the interface between the tumor and the normal pituitary gland. These results indicate the potential of IS to aid the intraoperative localization and definition of pituitary tumors.

Medullary nephrocalcinosis in nephropathic cystinosis.

Children with nephropathic cystinosis excrete large amounts of calcium and phosphate due to renal tubular Fanconi syndrome, and also receive substantial supplements of phosphate and alkalinizing agents. Since these constitute risk factors for nephrocalcinosis, we evaluated 41 children age 2 months to 15 years with nephropathic cystinosis and good renal function by performing retroperitoneal ultrasound examinations in a blinded fashion. We also retrospectively analyzed parameters of calcium and phosphate metabolism representing 216 person-years of data on these children. Fifteen children had no evidence of medullary nephrocalcinosis, while 18 had mild nephrocalcinosis, and 8 severe nephrocalcinosis; 5 had renal stones. Mean urine calcium and phosphate concentrations increased from 1.47 mM and 5.30 mM, respectively, in children without nephrocalcinosis to 1.60 mM and 5.69 mM in children with mild nephrocalcinosis to 1.66 mM and 6.19 mM in children with severe nephrocalcinosis. Mean urine pH ranged from 7.5 to 8.1. The mean (+/- SD) age of the 26 patients with nephrocalcinosis was 9.4 +/- 3.8 years compared with 5.1 +/- 3.8 years for those without nephrocalcinosis (P < 0.005). Serum calcium, phosphate, vitamin D, and parathyroid hormone did not correlate with frequency or degree of nephrocalcinosis. We conclude that nephrocalcinosis frequently accompanies nephropathic cystinosis, can be detected by ultrasound examination, and might be managed by reducing oral replacement of phosphate, calcium, vitamin D, and citrate. Consideration should be given to truncating phosphate replacement once bone growth ceases.

Evaluation of color Doppler intraoperative ultrasound in parenchymal sparing renal surgery.

A renal parenchymal sparing surgical approach may be recommended in select patients with von Hippel-Lindau disease and renal cancer or in those with sporadic renal cancer and limited normal renal function. We performed 27 partial nephrectomies or enucleations in 17 patients with the use of intraoperative ultrasound to examine a subset of all renal lesions identified on preoperative examination. Of 24 lesions deep in the renal parenchyma that were examined, localized or identified with intraoperative ultrasound 18 were characterized as cystic and 6 as solid. The deep cystic lesions were characterized with ultrasound as benign simple cysts. Intraoperative ultrasound was used to locate and mark the line of incision over 2 impalpable solid renal cell carcinomas. Four solid renal cell tumors extended deep into the renal parenchyma where color Doppler intraoperative ultrasound helped to define the plane of dissection adjacent to vital vascular structures. Renal hypothermia was not used in 3 renal operations based on intraoperative ultrasound findings.

Use of preoperative fine-needle aspiration in patients undergoing reoperation for primary hyperparathyroidism.

BACKGROUND: Neck reexploration for primary hyperparathyroidism has a lower success rate and greater morbidity than initial exploration because of scarring and distortion of tissue planes and the possibility of a parathyroid neoplasm located in an ectopic or unusual position. Although the use of standard noninvasive imaging studies for reoperative parathyroid surgical procedure is well accepted, the use of invasive studies to localize parathyroid neoplasms, particularly percutaneous aspiration of potential lesions, is controversial. In this report we analyze the results and morbidity in patients undergoing fine-needle aspiration before neck reexploration. METHODS: From 1982 to 1993, 255 patients underwent reexploration for persistent or recurrent hyperparathyroidism at the National Institutes of Health. Of these 255 patients 42 underwent 44 preoperative fine-needle aspirations by ultrasonography or computed tomography guidance in an attempt to localize a parathyroid neoplasm. The aspirated contents were then analyzed for parathyroid hormone content. RESULTS: Of the 44 aspirations 26 (59%) were true positives with no false positives. Of 18 negative fine-needle aspirations, 11 (25%) were false negatives, and seven (16%) were true negatives. The specificity and sensitivity of percutaneous fine-needle aspiration were 100% and 70%, respectively. CONCLUSIONS: Percutaneous fine-needle aspiration for parathyroid hormone is a safe, well-tolerated technique that is highly specific and allows a directed surgical resection avoiding further invasive workup when the aspirate is positive.

Localization and operative management of undescended parathyroid adenomas in patients with persistent primary hyperparathyroidism.

BACKGROUND: Between 5% and 10% of patients who undergo cervical exploration for primary hyperparathyroidism will have persistent or recurrent hyperparathyroidism. Many of these patients have parathyroid tumors in unusual locations. One such site of ectopic parathyroid tissue is an undescended parathyroid adenoma at or superior to the carotid bifurcation. We describe our experience with the preoperative localization and surgical management of undescended parathyroid adenomas. METHODS: From 1982 to 1993 a consecutive series of 255 patients have undergone localization studies and surgical exploration for persistent or recurrent hyperparathyroidism at the Clinical Center of the National Institutes of Health. Operative strategy was determined by review of the patient's surgical history, disease reports, and data from localizing studies. Patients with an undescended parathyroid adenoma identified before the operation were examined with a direct approach high in the neck. Patients who did not have definitive preoperative localization were explored with the previous transverse cervical incision. RESULTS: Seventeen undescended parathyroid adenomas were identified in 255 patients. Thirteen (76%) of 17 patients had an undescended parathyroid adenoma precisely localized before the operation and were examined via a limited, oblique incision high in the neck anterior to the sternocleidomastoid muscle. In the 13 patients who had undergone accurate localization before the operation, the median operative time was 75 minutes compared with 235 minutes for four patients who did not have an undescended parathyroid adenoma identified before the operation and were examined via a previous transverse cervical incision. All patients were cured of their hyperparathyroidism. CONCLUSIONS: Undescended parathyroid adenomas were the cause of failed cervical exploration in 17 (7%) of 255 patients. Accurate preoperative localization of these lesions is possible in most cases with a combination of noninvasive and invasive modalities. Successful preoperative localization can convert a prolonged exploration of the neck and mediastinum into a brief, curative procedure with minimal morbidity.

Development of luteinized graafian follicles in patients with karyotypically normal spontaneous premature ovarian failure.

Despite having amenorrhea and markedly elevated serum gonadotropin levels, some women with karyotypically normal spontaneous premature ovarian failure, nevertheless, have ovarian follicles that function intermittently. Graafian follicles capable of responding to these high FSH levels are faced with high serum LH levels as well, which might induce inappropriate luteinization and prevent normal follicle function. We examined this possibility using weekly blood sampling and sonography in 65 patients. Nearly 50% of our patients demonstrated ovarian follicle function [serum estradiol, > 183 pmol/L (50 pg/mL)] during a median of 4 months of observation (range, 2-6 months). However, during this observation, only 16% achieved an ovulatory serum progesterone level [> 9.5 nmol/L (3.0 ng/mL)]. We imaged an antral follicle by sonography in over 40% of patients (27 of 65), and serum estradiol was significantly greater when an antral follicle was present. The follicles in these patients were not functioning normally, however. In contrast to normal women, patients with ovarian failure had poor correlation between follicle diameter and serum estradiol. We biopsied these antral follicles in 6 patients and found luteinized Graafian follicles in all cases. Therefore, luteinized Graafian follicles account for at least 60% of the antral structures imaged (95% confidence limit). Thus, inappropriate luteinization of Graafian follicles appears to be a major pathophysiological mechanism in patients with karyotypically normal spontaneous premature ovarian failure.