The association of variants in the FTO gene with longitudinal body mass index profiles in non-Hispanic white children and adolescents.

OBJECTIVE: To investigate possible age-related changes in associations between polymorphisms in the fat mass and obesity-associated (FTO) gene and higher body mass index (BMI). DESIGN AND SUBJECTS: Multilevel mixed regression models were used to examine associations between four FTO variants and longitudinal BMI profiles in non-Hispanic white and African American children and adolescents 8-17 years of age from two different longitudinal cohort studies, the Bogalusa Heart Study (BHS) and Project HeartBeat! (PHB). In the BHS, there were 1551 examinations of 478 African Americans and 3210 examinations of 1081 non-Hispanic whites; in PHB, there were 971 examinations of 131 African Americans and 4458 examinations of 505 non-Hispanic whites. RESULTS: In African Americans, no significant FTO associations with BMI were found. In non-Hispanic whites, linkage disequilibrium among all four variants made haplotype analysis superfluous, so we focused on the single-nucleotide polymorphism, rs9939609. In longitudinal multilevel models, the A/A genotype of rs9939609 was associated with higher BMI in non-Hispanic whites in both cohorts at all ages. A significant age-by-genotype interaction found only in the BHS cohort predicted that in those with the A/A genotype, BMI would be ∼0.7 kg m(-2) higher at age 8 and ∼1.6 kg m(-2) higher at age 17 than in those with A/T or T/T genotypes. The design of PHB limited follow-up of any single individual to 4 years, and may have reduced the ability to detect any age-by-genotype interaction in this cohort. CONCLUSIONS: The A/A genotype of rs9939609 in the FTO gene is associated with higher longitudinal BMI profiles in non-Hispanic whites from two different cohorts. The association may change with age, with the A/A genotype being associated with a larger BMI difference in late adolescence than in childhood, though this was observed only in the BHS cohort and requires verification.

Fourteen-year experience with laparoscopic ventrosuspension in patients with retroverted and retroflected uterus and pelvic pain syndromes.

BACKGROUND: In women with a retroverted uterus, who have dyspareunia, chronic pelvic pain, or dysmenorrhea, laparoscopic ventrosuspension of the uterus has been reported effective in achieving symptom relief. STUDY OBJECTIVE: To critically review our experience with our method of laparoscopic ventrosuspension. DESIGN: Cohort study (Canadian Task Force classification II-3). SETTING: Tertiary care center. PATIENTS: Sixty-three women who had undergone laparoscopic ventrosuspension for treatment of pain syndromes during 1995 through 2008. INTERVENTIONS: Laparoscopic ventrosuspension, and a questionnaire about the long-term outcome of the operation. MEASUREMENTS AND MAIN RESULTS: There were no adverse events except for 2 repeat operations within 3 postoperative days. Forty-nine women (77.8%) answered the questionnaire about long-term outcome, and in these patients, significant pain relief was achieved (p <.001). Pain levels decreased, based on a numeric rating scale, from a mean (SD) of 6.35 (1.92) to 0.97 (1.40) in patients without endometriosis, and from 6.93 (2.09) to 3.80 (2.08) in those with endometriosis. Of 34 patients without endometriosis, 1 (2.9%) stated that the operation had not led to symptom relief, compared with 4 of 15 (26.7%) with endometriosis (p = .03). CONCLUSION: Laparoscopic ventrosuspension is clearly beneficial in women with a retroverted and retroflected uterus who have pelvic pain syndromes, even in the long term.

Villous mucinous cystadenoma of the appendix in a postmenopausal woman.

OBJECTIVE: To present the case of a postmenopausal woman, who was suspected of having an ovarian cyst. Instead, a cystadenoma of the appendix was discovered during laparoscopy. METHODS: A 64-year-old postmenopausal nulliparous woman was admitted to our hospital because of a cystic lesion, which had been detected in the course of a routine gynecological examination. The patient underwent vaginal ultrasound, magnetic resonance tomography, and laparoscopy. RESULTS: During vaginal ultrasound, a dumbbell-shaped anechogenic cystic structure 70 x 32 x 22 mm in diameter was found in the region of the right adnexa. Magnetic resonance tomography revealed no additional information. During diagnostic laparoscopy, the cystic lesion was found to be a distended appendix. A laparoscopic appendectomy was performed. Subsequent histological analysis revealed a villous mucinous cystadenoma of the appendix with low-grade intraepithelial neoplasia. CONCLUSION: Gynecologists should routinely consider this disease in the differential diagnosis of right lower dumbbell abdominal cysts. Eleven percent to 20% of mucoceles are caused by mucinous cystadenocarcinomas, which carry the risk of peritoneal tumor implantation caused by rupture or laparoscopic resection. Therefore, it should be mandatory that a general surgeon be involved in the laparoscopic procedure and the conversion to laparotomy for resection of the structure.

Prevention of recurrent bacterial urinary tract infections by intravesical instillation of hyaluronic acid.

OBJECTIVE: To evaluate the efficacy of vesical instillation of hyaluronic acid against recurrent urinary tract infections. METHODS: Twenty women with a history of recurrent urinary tract infections each received 9 intravesical instillations of hyaluronic acid over 6 months. Their status was assessed prospectively over 47.6 weeks and compared with a retrospective review of patient charts covering 36.2+/-6.2 weeks. RESULTS: The total numbers of urinary tract infections were 67 before and 10 after treatment (p<0.001). Thirteen patients (65%) were free of recurrences until the end of the study. One had a recurrence during treatment, and 6 (30%) during follow-up. The number of infections per year per patient was reduced from 4.99+/-0.92 to 0.56+/-0.82 (p<0.001). In women with recurrences, time to recurrence was 178.3+/-25.5 days, compared with 76.7+/-24.6 days before treatment (p<0.001). CONCLUSION: Intravesical instillation of hyaluronic acid is effective in preventing recurrent urinary tract infections.

The creation of evidence in 'evidence-based' drug prevention: a critique of the Strengthening Families Program Plus Life Skills Training evaluation.

School-based curricula have become a mainstay of drug prevention policy in the United States and are increasing in popularity in other parts of the world. The promotion and dissemination of these interventions has been driven in large part by the creation of lists of programmes which, it is claimed, are grounded in scientific evidence demonstrating their effectiveness. Recently concerns have been raised about the data analysis and presentation practices used in evaluations of a number of programmes that appear on these lists. Here we examine a series of papers from an evaluation of an intervention that combined the Strengthening Families Program 10-14 and Life Skills Training Program, each of which is among the most widely advocated universal drug prevention programmes. The data analysis and presentation practices employed in the evaluation of this combined programme include one-tailed significance testing, alpha levels of 0.10, changes in outcome variables across publications and use of the post-test data as the baseline when assessing change over time. Taken together, these practices severely limit the claims that can be made about the results presented in the evaluation. Specifically, we believe that far from supporting the evaluators' claims concerning the rigour of the findings and their generalisability and public health significance, the results are very fragile, of little practical significance and quite possibly analysis-dependent.

Propolis solution for the treatment of chronic vaginitis.

OBJECTIVE: To evaluate the efficacy of 5% propolis solution in recurrent vaginitis. METHOD: Fifty-four patients with recurrent vaginal infections having undergone at least one cycle of antibiotic treatment were instructed to apply a 5% aqueous propolis solution as a vaginal douche for seven days. Vaginal smears and specific symptoms were evaluated at baseline and 14 days after treatment. Long-term well-being was assessed by telephone interview six months after follow-up. RESULT: At the follow-up, the vaginal smears of 41 patients (75.9%) had improved. Forty-seven patients (87%) reported reliefs concerning at least one complaint. Associated improvement of smear and well-being was observed in 36 women (66.7%). After 6 months, 33 patients (61.1%) were satisfied with their condition without having undergone further treatment. CONCLUSION: Propolis may have a role as an alternative treatment for chronic vaginal infection.

Estrogen increases endothelial carbon monoxide, heme oxygenase 2, and carbon monoxide-derived cGMP by a receptor-mediated system.

Carbon monoxide, a gaseous activator of soluble guanylyl cyclase formed by a subtype of the enzyme heme oxygenase designated heme oxygenase-2 in vascular endothelium, has been found to dilate blood vessels independently from nitric oxide. Because of the parallels between nitric oxide and carbon monoxide, we speculated that estrogen might affect carbon monoxide production in vascular endothelium. Endothelial cells of human origin (umbilical vein and uterine artery) were incubated for 4 or 24 h with 10(-12)-10(-6) M 17beta-estradiol. 17beta-Estradiol, at a concentration such as that attained during the ovulatory phase of the menstrual cycle (10(-10) M), administrated for 4 h led to a 2-fold increase in intracellular carbon monoxide production and heme oxygenase-2 protein levels (P < 0.05). A reporter assay, measuring the formation of cGMP as the direct product of carbon monoxide-induced activation of soluble guanylyl cyclase in endothelial cells, also revealed a 56% increase in cellular cGMP after treatment with 10(-10) M E2 17beta-estradiol (P < 0.05). By contrast, higher 17beta-estradiol concentrations had no significant respective effects due to nitric oxide synthase inhibition of carbon monoxide release. This 17beta-estradiol effect appeared to be ER dependent, as preincubation with tamoxifen (10(-6) M) blocked the stimulatory effect of 17beta-estradiol in each instance. Our preliminary data indicate a potential role for carbon monoxide as a biological messenger molecule in estrogen-mediated regulation of vascular tone.

Expression of endothelial (type III) nitric oxide synthase in cytotrophoblastic cell lines: regulation by hypoxia and inflammatory cytokines.

Expression of endothelial nitric oxide synthase (eNOS) has been localized to the villous syncytiotrophoblasts suggesting that NO release from these cells could prevent platelet adhesion and aggregation in the intervillous space. Hypoxia- or inflammation-dependent changes in the release of this vasoactive substance may result in thrombus formation and altered vascular resistance which occur in the placental bed of pre-eclamptic patients. To evaluate the influence of low-oxygen tension and inflammation on eNOS production in the trophoblast steady-state eNOS mRNA and protein levels were investigated in cytotrophoblastic BeWo and Jeg-3 cells cultured at 3.5 per cent oxygen and/or in the presence of the pro-inflammatory cytokines IL-1 and TNF-alpha. By RT-PCR and immunocytochemistry we demonstrate that BeWo cells produce eNOS mRNA and protein while eNOS polypeptide was undetectable in JEG-3 cells. In BeWo cells addition of both cytokines decreases eNOS mRNA and protein abundancies within 24 h of incubation while each substance alone had no effect. Compared to controls, the amount of eNOS transcripts was found to be elevated at low-oxygen tension, however, cNOS protein was downregulated after 24 h in the hypoxic environment, as shown by immunocytochemistry and Western blot analysis. Forskolin and methotrexate, which induce biochemical differentiation/ growth arrest in choriocarcinoma cells, stimulate eNOS mRNA and protein synthesis, but cannot overcome the decline of eNOS polypeptide levels during hypoxic incubation. It is speculated that acute hypoxia and inflammation impair eNOS/NO production of the trophoblast in vivo, which might contribute to pathological conditions of gestational diseases.

Tryptophan hydroxylase gene polymorphism (A218C) and idiopathic recurrent miscarriage.

OBJECTIVE: To investigate the frequency of a polymorphism in intron 7 of the tryptophan hydroxylase gene among women with idiopathic recurrent miscarriage and healthy controls. METHODS: In a case control study, we studied 125 women with a history of three or more consecutive pregnancy losses before 20 weeks' gestation and 137 healthy controls with at least two live births and no history of pregnancy loss. Peripheral venous puncture, DNA extraction, and polymerase chain reaction followed by restriction fragment length polymorphism analysis were used to genotype women for the presence of the A218C polymorphism in intron 7 of the tryptophan hydroxylase gene. RESULTS: Allele frequencies among women with idiopathic recurrent miscarriage and controls were 32.4% and 38.7%, respectively, for allele A (wild type) and 67.6% and 61.3%, respectively, for allele C (mutant). No association between the presence of allele C and idiopathic recurrent miscarriage was found (P = .3; odds ratio 1.31; 95% confidence interval 0.93, 1.87). Genotype frequencies also were not significantly different between the study group (C/C: 44.8%; A/C: 45.6%; A/A: 9.6%) and the control group (C/C: 37.2%; A/C: 48.2%; A/A: 14.6%; P = .2). Between women with primary and women with secondary idiopathic recurrent miscarriage, no statistically significant differences with respect to allele frequencies were observed (63% vs 62% for allele C and 31% vs 38% for allele A; P = .3). CONCLUSION: The A218C polymorphism in intron 7 of the tryptophan hydroxylase gene is not associated with idiopathic recurrent miscarriage.

Dehydroepiandrosterone in the treatment of erectile dysfunction: a prospective, double-blind, randomized, placebo-controlled study.

OBJECTIVES: In 1994, the Massachusetts Male Aging Study presented an inverse correlation of the serum levels of dehydroepiandrosterone (DHEA) and the incidence of erectile dysfunction (ED). We evaluated the efficacy of DHEA replacement in the treatment of ED in a prospective, double-blind, randomized, placebo-controlled study. METHODS: The inclusion criteria included ED, normal physical and neurologic examinations, serum levels of testosterone, dihydrotestosterone, prolactin, and prostate-specific antigen (PSA) within the normal range, and a serum DHEA sulfate level below 1.5 micromol/L. Also all patients had a full erection after a pharmacologic erection test with 10O microg prostaglandin E1; pharmacocavernosography showed no visualization in corporeal venous structures. Forty patients from our impotence clinic were recruited and randomly divided into two groups of 20 patients each. Group 1 was treated with an oral dose of 50 mg DHEA and group 2 with a placebo one time a day for 6 months. The International Index of Erectile Function (IIEF), a 15-item questionnaire, was used to rate the success of this therapy. RESULTS: Therapy response was defined as the ability to achieve or maintain an erection sufficient for satisfactory sexual performance according to the National Institutes of Health Consensus Development Panel on Impotence. DHEA treatment was associated with higher mean scores for all five domains of the IIEF. There was no impact of DHEA treatment on the mean serum levels of PSA, prolactin, testosterone, the mean prostate volume, and the mean postvoid residual urine volume. CONCLUSIONS: Our results suggest that oral DHEA treatment may be of benefit in the treatment of ED. Although our patient data base is too small to do relevant statistical analysis, we believe that our data show a biologically obvious trend that justifies further extended studies.

Interleukin 1 receptor antagonist polymorphism in women with idiopathic recurrent miscarriage.

OBJECTIVE: Proinflammatory cytokines have been described as etiologic factors in idiopathic recurrent miscarriage. We investigated the relation between idiopathic recurrent miscarriage and polymorphisms in the gene encoding for the interleukin 1 receptor antagonist, an indigenous modulator of proinflammatory immune response. DESIGN: Prospective case control study. SETTING: Academic research institution. PATIENT(S): One hundred five women with a history of three or more consecutive pregnancy losses before 20 weeks of gestation and 91 healthy, postmenopausal controls with at least two live births and no history of pregnancy loss. INTERVENTION(S): Peripheral venous puncture. MAIN OUTCOME MEASURE(S): Polymerase chain reaction was performed to identify the different alleles of the gene encoding for interleukin 1 receptor antagonist. RESULT(S): Allele frequencies among women with idiopathic recurrent miscarriage and controls were 0.34 and 0.11, respectively, for the polymorphic allele 2 (P=.002; odds ratio: 7.4, confidence interval: 2.9--10.8) and.05 and.05, respectively, for the polymorphic allele 3 (P=.6; odds ratio: 1.3, confidence interval: 0.8--2.3). Allele 2 was present in homozygous form in 9% of women with idiopathic recurrent miscarriage. In contrast, 1% of the control women were homozygous for this allele (P<.001; odds ratio: 13.5, confidence interval: 7.5--21.8). CONCLUSION(S): These data support a role for allele 2 of the gene encoding for interleukin 1 receptor antagonist as genetic determinant of idiopathic recurrent miscarriage.

Effect of hormone replacement therapy on growth hormone stimulation in women with premature ovarian failure.

OBJECTIVE: To assess the effect of oral hormone replacement therapy (HRT) on body weight, insulin-like growth factor I (IGF-I), and GH response to exogenous GHRH [corrected] in women with premature ovarian failure (POF) [corrected]. DESIGN: Controlled clinical study. SETTING: Outpatients studied in the department of endocrinology of the University Hospital in Vienna. PATIENT(S): Twenty-four women with POF (study group) and 24 volunteers with normal ovarian cycles (control group). INTERVENTION(S): Pituitary GHRH [corrected] stimulation was performed in all women at study entry and in patients with POF after 1, 6, and 12 months of standard oral HRT. Blood samples were collected from 15 minutes before to 120 minutes after GHRH administration [corrected]. Body weight also was evaluated. RESULT(S): No differences in baseline and stimulated serum GH were found either between POF women and controls or in POF women during HRT. Women with POF without HRT had significantly higher IGF-I levels; a reduction in circulating IGF-I levels occurred during HRT. Body weight remained stable. CONCLUSION(S): Our results show the following: [1] Women with POF have similar Gh secretion patterns as healthy age-matched women; [2] physiologic HRT has no impact on GHRH-induced [corrected] GH stimulation; and [3] HRT has no impact on body weight in women with POF.

Atraumatic cervical passage at outpatient hysteroscopy.

OBJECTIVE: To evaluate the efficacy of topical anesthesia routinely administered to reduce discomfort and the need for additional local anesthesia during outpatient hysteroscopy. DESIGN: Comparative observational study. SETTING: Outpatient hysteroscopy clinic in a University hospital. PATIENT(S): Three hundred patients undergoing outpatient hysteroscopy. INTERVENTION(S): Application of lidocaine spray both to the surface of the cervix and into the cervical canal before performing hysteroscopy. MAIN OUTCOME MEASURE(S): The discomfort during passage of the hysteroscope through the cervical canal, the need for additional local anesthesia, and the failure rate of outpatient hysteroscopy. RESULT(S): One hundred fifty consecutive patients receiving lidocaine spray before the hysteroscopy were compared to a control group of another 150 consecutive patients who underwent the examination without pretreatment. Women treated with spray experienced significantly less pain at insertion of the hysteroscope. Furthermore, the spray significantly reduced both the need for additional anesthesia and the rate of failed hysteroscopies due to intolerable pain. CONCLUSION(S): Topical anesthesia with lidocaine spray is a simple method to alleviate patients' discomfort during cervical passage. It is effective in reducing the need for local anesthesia and should reduce the rate of failed outpatient hysteroscopies.

Serum 3 alpha-androstanediol-glucuronide is decreased in nonhirsute women with acne vulgaris.

OBJECTIVE: To determine if acne vulgaris in women has a different pattern of androgen activity than hirsutism at the pilosebaceous unit. DESIGN: Prospective clinical study. SETTING: Outpatient clinic for gynecological endocrinology at a university hospital. PATIENT(S): Twenty women suffering from mild or moderate acne vulgaris compared with 38 controls. MAIN OUTCOME MEASURE(S): Serum androgens DHEAS, androstendione, T, including 3 alpha-androstanediol-glucuronide (3 alpha-diolG), the metabolite of 5 alpha-reductase activity. RESULT(S): Serum 3 alpha-diolG was decreased in the acne groups depending on the grade of severity. No statistically significant differences were observed between the other androgens measured in acne patients and controls. CONCLUSION(S): In contrast to hirsutism, acne is influenced directly by T and not by its 5 alpha-reduced metabolites. In female acne patients, 5 alpha-reductase activity appears to be reduced, which is reflected in decreased serum levels of 3 alpha-diolG. Consequently, 5 alpha-reductase inhibitors are most likely not promising candidates for acne therapy; a postulation that, however, requires further clinical investigation.

Computerized assessment of facial hair growth.

OBJECTIVE: To evaluate a computer-assisted technique for objective and sensitive monitoring of facial hair growth. DESIGN: Prospective study. SETTING: Department of Gynecological Endocrinology and Reproductive Medicine and Clinic for Ear, Nose, and Throat, General Hospital, University of Vienna, Vienna, Austria. PATIENT(S): Four men, three hirsute women, and three nonhirsute women. INTERVENTION(S): Using video equipment and computer software, we were able to document, analyze, and store data regarding hair growth in specific areas of interest. For digital image analysis, we used the Digi Trace System (Olympus, Vienna, Austria; Imatec, Munich, Germany). MAIN OUTCOME MEASURE(S): Hair growth within 20 days in well-defined regions of interest on the faces of hirsute and nonhirsute women and of men. RESULT(S): Hair growth on day 21 was significantly different between hirsute and nonhirsute women as well as in men. The scores for individual hair growth between day 0 and day 21 also were significantly different in hirsute women and in men. No statistically significant difference in hair growth was found within the group of nonhirsute women. CONCLUSION(S): With digital image analysis, facial hair growth, especially in hirsute women, can be calculated in a sensitive and objective manner.

A polymorphism of the interleukin-1beta gene and idiopathic recurrent miscarriage.

OBJECTIVE: Proinflammatory cytokines have been described to be involved in the pathogenesis of idiopathic recurrent miscarriage (IRM). We investigated the association between IRM and a polymorphism in exon 5 of the interleukin-1beta gene (IL1B) and interleukin-1beta (IL-1beta) serum levels. DESIGN: Case control study. SETTING: Academic research institution. SUBJECTS: One hundred thirty-one women with a history of three or more consecutive pregnancy losses before 20 weeks' gestation and 68 healthy controls with at least two live births and no history of pregnancy loss. INTERVENTIONS: Peripheral venous puncture. MAIN OUTCOME MEASURES: An IL1B exon 5 (position +3953) gene polymorphism was analyzed by PCR amplification followed by restriction fragment length polymorphism analysis. IL-1beta serum levels were analyzed by a commercially available ELISA. RESULTS: Allele frequencies in women with IRM and controls were 77.9% and 80.8%, respectively, for the E1 allele (wild type), and 22.1% and 19.2%, respectively, for the E2 allele (mutant). No association between the E2 allele and the occurrence of IRM was found (P=.57, odds ratio =.83). Genotype frequencies and IL-1beta serum levels were not significantly different between the study group and the control group. CONCLUSIONS: This is the first report on an IL1B polymorphism in IRM. Although known to alter IL-1beta expression, the investigated IL1B polymorphism is not associated with IRM and increased serum levels in a large Caucasian population.

Topical cyproterone acetate treatment in women with acne: a placebo-controlled trial.

OBJECTIVE: To evaluate the clinical and hormonal response of topically applied cyproterone acetate, oral cyproterone acetate, and placebo lotion in women with acne. DESIGN: Placebo-controlled, randomized study. SETTING: Patients were recruited from the Institute of Endocrine Cosmetics, Vienna, Austria. PATIENTS: Forty women with acne. INTERVENTIONS: Treatment with oral medication consisting of 0.035 mg of ethinyl estradiol and 2 mg of cyproterone acetate (n=12), 20 mg of topical cyproterone acetate lotion (n=12), and placebo lotion (n=16) was offered. Patients were assessed monthly for 3 months. MAIN OUTCOME MEASURES: Clinical grading according to acne severity and lesion counts as well as determinations of serum cyproterone acetate concentrations. RESULTS: After 3 months of therapy with topical cyproterone acetate, the decrease of mean facial acne grade from 1.57 to 0.67 was significantly better (P<.05) compared with placebo (which showed a change from 1.57 to 1.25), but not compared with oral medication (1.56 to 0.75) (P>.05). Lesion counts also decreased from 35.9 to 9.1 in the topical cyproterone acetate group compared with oral medication (45.4 to 15.5) (P>.05) and placebo (38.2 to 23.1) (P<.05). After topical cyproterone acetate treatment, serum cyproterone acetate concentrations were 10 times lower than those found after oral cyproterone acetate intake. CONCLUSIONS: The therapeutic effect of topically applied cyproterone acetate for acne treatment was clearly demonstrated. Topically applied sexual steroids in combination with liposomes are as effective as oral antiandrogen medication in acne treatment, while reducing the risk of adverse effects and avoiding high serum cyproterone acetate concentrations.

Tissue specificity: the clinical importance of steroid metabolites in hormone replacement therapy.

Metabolic activations or inactivations of estrogens, progesterone and androgens are important steps towards the understanding of the physiological and the pathological effects of these hormones in the female organism. Analysis of the tissue specific metabolic pathways of sex steroids will result in a better understanding of successful hormone replacement therapy on the one hand and of the occurrence of steroid hormone related side effects on the other hand. In this contribution we analyse the different mechanisms involved in the synthesis of tissue specific metabolites and discuss the therapeutical importance of these metabolites in hormone replacement therapy.

Genetic modelling of the estrogen metabolism as a risk factor of hormone-dependent disorders.

Estradiol is a pleiotropic hormone, involved in the etiology of a wide variety of diseases. Over the last decade individual genetic variability of the estradiol metabolism has been described as a significant contributor to disease susceptibility with variations depending on ethnic background. Among others, genetic variations of genes encoding cytochrome P450 (CYP) enzymes play an important role in this regard. Mutant alleles of the CYP 1A1 gene are major modulators of lung cancer risk among smokers, mediate gender differences in lung cancer susceptibility, and have been associated with an elevated risk for developing breast, prostate, colorectal, and oral squamous cell cancer. Variants of the CYP 1B1 gene modulate the risk for developing prostate, ovarian, lung, and breast cancer. Also, mutations in the CYP 1B1 gene are the major genetic determinant of congenital glaucoma. Mutant CYP 17 alleles are associated with serum and plasma levels of steroid hormones, use of hormone replacement therapy, and the development of endometrial, prostate, and breast cancer. Available data indicate that the protective effect against breast cancer of a later age at menarche is limited to wild-type CYP 17 allele carriers. Among women with the polycystic ovary syndrome, carriage of mutant CYP 17 alleles is sufficient to aggravate the clinical presentation of the disease. Molecular variants of the CYP 19 gene are associated with an increased risk for developing breast cancer, advanced breast cancer stages, and tumor aromatase production. Carriage of a mutant catechol-O-methyltransferase allele is associated with breast cancer, neurologic disorders such as Parkinson's disease, and modulates behavior among patients with schizophrenia, alcoholics and the general population. In summary, the available evidence points to genes that encode estrogen-metabolizing enzymes as strong hereditary determinants of the susceptibility to benign as well as malignant conditions.