Khaled Zeitoun

Treatment of severe postmenopausal endometriosis with an aromatase inhibitor

OBJECTIVE To treat an unusually aggressive case of recurrent postmenopausal endometriosis. DESIGN Case report. SETTING University of Texas Southwestern Medical Center (Dallas, Texas). PATIENT(S) A 57-year-old woman who presented with recurrent severe endometriosis after hysterectomy and bilateral salpingo-oophorectomy. INTERVENTION(S) Oral administration of anastrozole (an aromatase inhibitor) (1 mg/d) and elemental calcium (1.5 g/d) for 9 months. Alendronate (a nonestrogenic inhibitor of bone resorption), 10 mg/d, was added to this regimen. MAIN OUTCOME MEASURE(S) Reduction in size of endometriotic lesion, pain relief, tissue levels of aromatase P450 messenger RNA, bone density. RESULT(S) Circulating levels of estradiol-17beta were reduced to approximately 50% of the baseline value after the onset of treatment with anastrozole. Pain rapidly decreased and completely disappeared after the 2nd month of treatment. The 30 x 30 x 20-mm bright red polypoid vaginal lesion was reduced to a 3-mm gray tissue by the end of 9 months of treatment. Markedly high pretreatment levels of aromatase P450 messenger RNA in the endometriotic tissue became undetectable in a specimen obtained from a repeated biopsy after 6 months of treatment. Bone density of lumbar spine decreased by 6.2% after 9 months of treatment. CONCLUSION(S) This is the first description of the use of an aromatase inhibitor in the treatment of endometriosis. The short-term results were extraordinarily successful in elimination of pain and near-complete eradication of implants associated with severe endometriosis not responsive to other therapy. We conclude that the recently developed potent aromatase inhibitors are candidate drugs in the treatment of endometriosis that is resistant to standard regimens.

Aromatase: a key molecule in the pathophysiology of endometriosis and a therapeutic target☆

OBJECTIVE To provide a clinically useful model illustrating the molecular aberrations affecting estrogen biosynthesis and metabolism in endometriosis and to discuss the therapeutic role of aromatase inhibitors. DESIGN Literature review. RESULT(S) Several molecular aberrations were found in endometriotic lesions (in contrast to eutopic endometrium) that favor increased local concentrations of E2. Endometriotic stromal cells aberrantly express aromatase, which converts C19, steroids to estrogens. Aromatase activity in these cells is stimulated by prostaglandin (PG)E2. Estrogen stimulates cyclooxygenase-2, giving rise to increased PGE2 formation. Thus, this positive feedback loop produces increasing quantities of E2 and PGE2 in endometriosis. The lack of aromatase expression in eutopic endometrium is maintained by binding of an inhibitory transcription factor, COUP-TF, to the aromatase promoter. In endometriosis, however, an aberrantly expressed factor, SF-1, displaces COUP-TF to bind to this same promoter and activates aromatase expression and thus local estrogen biosynthesis. Additionally, endometriotic glandular cells are deficient in 17beta-hydroxysteroid dehydrogenase type 2, which converts E2 to estrone in the eutopic endometrium in response to P. Deficiency of this enzyme in endometriosis impairs the inactivation of E2 and may be a consequence of insensitivity to P. CONCLUSION(S) Molecular aberrations that increase local E2 concentrations may be important in the etiology of endometriosis. These molecules may be targeted to develop novel therapeutic strategies. The clinical relevance of aromatase expression in endometriosis was shown recently by the successful treatment of an unusually aggressive case of postmenopausal endometriosis with use of an aromatase inhibitor.

Use of Crinone vaginal progesterone gel for luteal support in in vitro fertilization cycles.

OBJECTIVE To investigate the efficacy and safety of intravaginal Crinone 8% (Columbia Research Laboratories, Miami. FL) versus IM progesterone for luteal phase support after IVF-ET. DESIGN Prospective open trial with comparison to historical controls. SETTING University hospital. PATIENT(S) Two hundred six women undergoing IVF-ET. INTERVENTION(S) One hundred patients received Crinone vaginal progesterone gel (90 mg once daily) and 106 patients received IM progesterone (50 mg once daily) beginning on the evening of oocyte retrieval. MAIN OUTCOME MEASURE(S) Pregnancy and miscarriage rates, and midluteal serum progesterone levels. RESULT(S) Positive beta-hCG pregnancy rates, clinical pregnancy rates per transfer, and ongoing pregnancy rates were similar for the Crinone and IM progesterone groups. Women who received Crinone had higher rates of biochemical pregnancy loss but lower rates of clinical pregnancy loss (i.e., spontaneous abortion) than women who received IM progesterone. Midluteal serum progesterone concentrations were significantly higher in the IM progesterone group (94.3+/-8.8 ng/mL versus 57.7+/-7.4 ng/mL). Several women who received Crinone had vaginal bleeding 11-13 days after oocyte retrieval. CONCLUSION(S) For all age categories, positive beta-hCG and ongoing pregnancy rates were similar when Crinone or IM progesterone was given for luteal phase support in IVF-ET cycles, despite lower serum progesterone concentrations and higher rates of biochemical pregnancy loss with Crinone. Although the results of this study support the use of Crinone as an acceptable alternative for luteal support after IVF-ET, differences in bleeding patterns and rates of biochemical pregnancy loss demonstrate the need for a prospective randomized study.

Expression of dioxin-related transactivating factors and target genes in human eutopic endometrial and endometriotic tissues

OBJECTIVE Although an association between dioxin exposure and endometriosis has been proposed, the effects of this environmental toxin on human endometriosis are not known. To understand the potential underlying molecular mechanisms we studied the expressions of cytochrome P-450 genes (CYP1A1, CYP1A2, and CYP1B1 ), which are induced by dioxin, and the expressions of cytosolic receptor for dioxin, aryl hydrocarbon receptor, and its nuclear translocator, aryl hydrocarbon receptor nuclear translocator protein, in endometriotic and eutopic endometrial tissues. STUDY DESIGN Levels of transcripts of CYP1A1, CYP1A2, CYP1B1, aryl hydrocarbon receptor, and aryl hydrocarbon receptor nuclear translocator protein were determined by a quantitative reverse transcriptase-polymerase chain reaction and Southern blot assay in total ribonucleic acid samples from endometriotic and eutopic endometrial tissues. Eutopic endometrial tissue samples (n = 33) and endometriotic tissue samples (n = 10) were obtained at the time of uterine curettage and laparoscopy from disease-free women and from patients with endometriosis. Portions of these eutopic endometrial and endometriotic tissues were obtained simultaneously from the same patients (n = 8 pairs of samples). Levels of transcripts of CYP1A1, CYP1A2, CYP1B1, aryl hydrocarbon receptor, and aryl hydrocarbon receptor nuclear translocator protein were determined in endometrial and endometriotic tissues during follicular and luteal phases of the cycle and in cultured endometriotic stromal cells treated with forskolin, phorbol diacetate, medroxyprogesterone acetate,and serum. RESULTS Transcripts of dioxin receptor, its nuclear translocator, and two dioxin-induced target genes (CYP1A2 and CYP1B1) were demonstrated during follicular and luteal phases of the cycle in both eutopic endometrial tissues and tissues affected by pelvic endometriosis, with no readily detectable differences between these tissues. On the other hand, levels of transcripts of another dioxin-induced gene, CYP1A1, were found to be strikingly higher in endometriotic tissues than in the eutopic endometrium. Mean levels in endometriotic tissues were 8.7 times those found in eutopic endometrium. Various hormonal treatments of endometriotic stromal cells did not significantly alter these levels. CONCLUSION We demonstrated for the first time the expression of dioxin-related transcription factors aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator protein and target genes CYP1A1, CYP1A2, and CYP1B1 in endometriotic tissues and stromal cells. Strikingly elevated CYP1A1 transcripts in endometriosis may give rise to significantly increased P-4501A1 enzyme activity and thus promote the development and growth of endometriosis by either activating procarcinogens or inducing the formation of catechol estrogens or both. In fact, the proposed link between dioxin exposure and endometriosis may be explained in part by the up-regulation of the CYP1A1 gene expression in endometriotic tissues.

Is There an Increased Risk of Stroke Associated with Oral Contraceptives

In the last few years several studies were published about the relationship between oral contraceptive use, estrogen dose, different types of progestogens, cigarette smoking and the risk of stroke.There is a persistent association between the use of oral contraceptives containing more than 50μg of ethinylestradiol and the risk of stroke. Also, cigarette smoking seems to be a strong additive risk factor, especially in women >35 years old even with lower doses (≤30μg) of estrogen.Unlike oral contraceptives containing >50μg of estrogen, currently there is no convincing evidence that the use of oral contraceptives containing <50μg in the absence of smoking is associated with any meaningful increase in the risk of ischaemic or haemorrhagic stroke.Progestogenonly pills are not associated with an increased risk of stroke. A specific type of progestogen in combined pills was associated with an increased risk of stroke in a few studies. Data regarding this issue is, however, inconsistent and controversial and needs further investigation.There were few if any studies that have addressed the effects of new types of progestogens (i.e. norgestimate, norgestrel or gestodene) and formulations containing 20μg of ethinylestradiol. At the present time we find no reason to alter the current practice in prescribing oral contraceptives. We do concede, however, that there might be a slight causal relationship between use of oral contraceptives containing <50μg of ethinylestradiol and stroke that did not reach statistical significance. This relationship is rare and should be viewed in context with the many benefits of oral contraceptives. Underlying risk factors for stroke such as factor V Leiden mutation and other thrombophilias might explain the role of oral contraceptiveinduced stroke.