Endocrine function and oocyte retrieval after autologous transplantation of ovarian cortical strips to the forearm.

CONTEXT: In reproductive-age women, one of the common adverse effects of chemotherapy and radiotherapy is premature ovarian failure. In addition, a significant number of women experience early menopause due to oophorectomy performed for benign indications. OBJECTIVE: To develop an ovarian transplantation technique to preserve endocrine function in women undergoing sterilizing radiotherapy and/or chemotherapy, or oophorectomy. DESIGN AND SETTING: Case study of 2 patients in New York who received autologous ovarian transplantation (patient A, November 1999; patient B, April 2000) to the forearm prior to pelvic radiotherapy or after oophorectomy. PARTICIPANTS: Patient A is a 35-year-old woman with stage IIIB squamous cell cervical carcinoma and patient B is a 37-year-old woman with recurrent benign ovarian serous cysts. MAIN OUTCOME MEASURES: Follicular development evident by ultrasound examination; cyclical production of estradiol and progesterone; restoration of serum follicle-stimulating hormone, luteinizing hormone, and testosterone levels to nonmenopausal range; and disappearance of menopausal symptoms. RESULTS: Menopause was confirmed immediately after the transplantation in both patients by serum follicle-stimulating hormone measurements (patient A, 47 mIU/mL; patient B, 50.7 mIU/mL). In patient A, follicle development was noted by physical and ultrasound examinations approximately 10 weeks after the transplantation. The mean (SE) follicle-stimulating hormone and luteinizing hormone levels decreased to 8.6 (0.4) mIU/mL and 12.8 (0.8) mIU/mL, respectively. The peripheral estradiol levels showed cyclical variation (mean [SE], 115 [9.2] pg/mL [422 (33.8) pmol/L), and during the 18-month follow-up, a dominant follicle developed each month. The estradiol levels from the right cubital vein were consistent with ovarian vein measurements (mean [SE], 1069 [269] pg/mL [3924 (987.5) pmol/L]). Percutaneous oocyte aspirations yielded a mature oocyte. In patient B, ovarian function was demonstrated by ultrasound visualization of a 9-mm follicle by 6 months after transplantation. Thereafter, the patient had spontaneous menstruation every 25 to 28 days. Ovulation was further confirmed by midluteal progesterone measurements (range, 7-10.1 ng/mL; mean [SE], 8.5 [0.9] ng/mL). Patient B's ovarian graft was still functional 10 months after the transplantation. CONCLUSIONS: Subcutaneous ovarian transplantation appears to be a relatively simple, novel technique to preserve endocrine function in women undergoing sterilizing cancer therapy or surgery.

The practice of surgical staging and its impact on adjuvant treatment recommendations in patients with stage I endometrial carcinoma.

A survey of American gynecologic oncologists was undertaken to assess their compliance with current surgical staging criteria in patients with early endometrial carcinoma. One hundred forty-four members of the Society of Gynecologic Oncologists responded to the survey. Respondents treated an average of 22 new cases annually. Tumor grade and intraoperative determination of depth of myometrial invasion were demonstrated to influence the frequency of lymphatic dissection. In grade 1, 2, and 3 lesions, 76, 60, and 34% of responders, respectively, indicated that depth of invasion influenced their decision to perform lymphadenectomy. In addition, depth of invasion was important in determining type and extent of lymphatic resection. Further, the impact of pathologic lymph node status on postoperative adjuvant radiation therapy recommendations was evaluated for various stratifications of endometrial adenocarcinoma confined to the corpus. The greatest differences in treatment recommendations were noted in the 50-66% invasion category. For grade 1 and 2 cancers, adjuvant therapy recommendations were reduced by 23 and 16% respectively when comparing pelvic and combined therapy versus none and vaginal therapy. The effect of surgical staging data on clinical decisions is clearly evident. The knowledge of pathologically negative lymph node status reduces the recommendation for postoperative adjuvant radiotherapy in patients with adenocarcinoma otherwise confined to the uterine corpus.

The effect of naproxen on fever in patients with advanced gynecologic malignancies.

The antipyretic action of naproxen has been reported as sufficiently selective for neoplasm-related fever such that the use of this agent has been recommended to distinguish neoplastic from infectious fever. The antipyretic effect of naproxen was evaluated in gynecologic oncology patients with advanced pelvic malignancies and fever without obvious source of infection (suspected neoplastic fever). Naproxen (250 mg orally every 8 hr) was given to 12 patients with (i) a daily temperature greater than 38.3 degrees C, (ii) fever for at least 3 days, (iii) no evidence of infection on physical exam, (iv) negative results of blood and urine cultures, and (v) a chest roentgenogram negative for pneumonia. Ten of the 12 patients initially received a minimum of 3 days of empiric antibiotic therapy without resolution of fever. Within 24 hr of starting naproxen therapy, 10 patients' (83%) fever responded: Eight patients (80%) had a complete lysis of fever and two had partial lysis (20%). Temperature response was accompanied by subjective improvement in patient malaise and fatigue. Naproxen therapy was continued for 5-7 days in these patients, and chemotherapy was administered to those patients scheduled to receive it. Two patients did not respond to naproxen therapy in 24 hr; thus, it was stopped and the fever workup was continued. Of these two patients, one was eventually diagnosed with bacteremia after multiple negative blood cultures and initially no response to antibiotics. Naproxen is clinically useful in the palliation of fever-related symptoms in gynecologic oncology patients with suspected neoplastic fever. Naproxen may also allow the limitation of extensive fever workups and prolonged empiric antibiotic therapy in these patients, and prevent delays in systemic therapy or supportive care.

Abnormal cervical cytology in adolescents. A 15-year experience.

The onset of sexual activity at a young age (< 17 years) has been identified in several studies as the most important epidemiologic risk factor in the development of cervical intraepithelial neoplasia (CIN). In characterizing the natural history of CIN, investigators have indicated that a percentage of such lesions progress to invasive carcinoma if left untreated. CIN in adolescents was first reported in 1961. The subsequently reported CIN prevalence rates in sexually active, medically indigent teenage populations have increased over time, temporally paralleling increasing early sexual activity among teenagers. In our 15-year experience with abnormal cervical cytology in adolescents, all grades of CIN were observed. Fully 13% of patients had histologically proven CIN 3, a preinvasive lesion. Given reports of an increase in cervical cancer in young women (< 35 years old), the findings of this and similar studies mandate routine cervical cytologic screening in all sexually active teenage girls.

CYP19 (aromatase cytochrome P450) gene expression in human malignant endometrial tumors.

C19 steroids are converted to estrogens in a number of human tissues by the aromatase enzyme complex, which consists of aromatase cytochrome P450 (P450arom; product of the CYP19 gene) and NADPH-cytochrome P450 reductase. Aromatase activity has been previously demonstrated in endometrial tumors. In the present study, we investigated CYP19 gene expression and its regulation in endometrial tumor samples (n = 9). Using a specific method of competitive polymerase chain reaction after reverse transcription, varying levels of P450arom transcripts were detected in all endometrial adenocarcinomas (n = 8) and one mixed Müllerian tumor studied. No correlations were observed between P450arom transcript levels and histological type of the tumor, grade, myometrial invasion, stage of the disease, or patient age. We have recently demonstrated that the tissue-specific regulation of CYP19 gene transcription is in part the consequence of alternative promoter use. The use of each promoter gives rise to a P450arom transcript with a unique untranslated 5'-end. We analyzed the untranslated first exons in 5'-terminals of P450arom transcripts in endometrial adenocarcinomas using a specific reverse transcription-polymerase chain reaction/Southern hybridization method we recently developed. Our findings indicated the gonadal-type (promoter II) and one of the adipose stromal cell-type (I.3) promoters were primarily used for P450arom expression in adenocarcinomas. On the other hand, distribution of transcripts specific for I.3, I.4 (another adipose-type promoter), and promoter II in one mixed Müllerian tumor was uniform. Placental promoter (I.1)-specific P450arom transcripts were not detected in endometrial tumors. As P450arom transcripts were detected in all endometrial malignancies studied, whereas they were not demonstrable in the disease-free endometrium, activation or failure of inhibition of aromatase expression in these tumors may serve to promote neoplastic proliferation.

Abnormal cervical cytology in pregnancy: a 17-year experience.

OBJECTIVE: To evaluate the safety and accuracy of colposcopy and colposcopically directed biopsy in pregnant women with abnormal cervical cytology. METHODS: A retrospective analysis of 612 gravidas with abnormal cervical cytology was conducted. Colposcopy and directed biopsy were performed using standard techniques. Two patients underwent diagnostic conization during the second trimester. One hundred twelve patients had procedures that provided a final specimen. Endocervical curettage was omitted. The transformation zone was fully visualized in all patients by the 20th week of gestation. Directed cervical biopsy was performed on the following patients: 1) with colposcopic evidence of invasion or cervical intraepithelial neoplasia (CIN) III, 2) with discordancy between colposcopy and cytology, 3) electing termination of pregnancy, and 4) whose anticipated reliability was even remotely questioned. RESULTS: A colposcopically directed biopsy was performed in 449 patients (73%). Ninety-one patients (15%) did not have biopsies because of normal colposcopic findings, and the remaining 72 patients (12%) had either CIN I or II. Thirty-nine of these patients (6%) were lost to follow-up. Colposcopically directed biopsy and colposcopic impression had a 95% concordancy within one degree of severity; however, 14% of CIN I colposcopic impressions and 54% of normal colposcopic findings turned out to be CIN III and CIN I or II, respectively. Ninety-five percent of the biopsy diagnoses correlated with the final pathology to within one degree of severity. CONCLUSION: The data confirm previous findings that colposcopically directed biopsy is a safe and reliable method of evaluating pregnant patients with abnormal cervical cytology.

Endothelin-1 gene expression and biosynthesis in human endometrial HEC-1A cancer cells.

In this study, evidence was obtained that endothelin-1 (ET-1) is produced by an established endometrial cancer (HEC-1A) cell line. PreproET-1 mRNA is present in HEC-1A cells, and immunoreactive endothelin is secreted into the medium of these cells maintained in culture. Cycloheximide treatment of these cells caused superinduction of preproET-1 mRNA. Transforming growth factor-beta acts in these cells to increase the levels of preproET-1 mRNA. This effect of transforming growth factor-beta on preproET-1 mRNA accumulation was accompanied by an increase in the amount of immunoreactive endothelin secreted into the culture medium. ET-1, added to the culture medium, did not act as a mitogen in HEC-1A cells. We speculate that ET-1 (which is known to stimulate fibroblast proliferation) produced by endometrial adenocarcinoma cells may participate in the angiogenic process that occurs during the establishment of this carcinoma in vivo.

Endothelin-1 gene expression and protein biosynthesis in human endometrium: potential modulator of endometrial blood flow.

We present evidence that endothelin-1 (ET-1) is produced by two distinct cell types (other than vascular endothelial cells) in human endometrial tissue. The supportive findings of this investigation are summarized as follows: 1) prepro-ET-1 mRNA is present in endometrial tissue and in separated endometrial stromal and glandular epithelial cells in culture; 2) immunoreactive ET is secreted into the medium of isolated endometrial stromal cells and glandular epithelium maintained in culture; and 3) the level of prepro-ET-1 mRNA in endometrial tissues obtained at the premenstrual-menstrual phase of the endometrial cycle is greater than that in tissues from the proliferative or early and midsecretory phases. We also found that transforming growth factor-beta and interleukin-1 alpha act to increase the levels of prepro-ET-1 mRNA in endometrial stroma cells in monolayer culture. We speculate that ET-1 derived from endometrial stromal cells may act on the adventitial surface of contiguous spiral arterioles of the endometrium to modulate endometrial blood flow.