Corrigendum to "Improving adherence to endocrine hormonal therapy among breast cancer patients: Study protocol for a randomized controlled trial" [Contemp. Clin. Trials Commun. 12 (2018) 109-115].

[This corrects the article DOI: 10.1016/j.conctc.2018.10.001.].

Improving adherence to endocrine hormonal therapy among breast cancer patients: Study protocol for a randomized controlled trial.

Adjuvant endocrine hormonal therapy (EHT) is highly effective and appropriate for nearly all breast cancer patients with hormone receptor-positive tumors, which represent 75% of all breast cancer diagnoses. Long-term use of EHT reduces recurrence rates and nearly halves the risk of death during the second decade after diagnosis. Despite the proven benefits, about 33% of women receiving EHT do not take their medication as prescribed. This causes an increase in the risk for recurrence and death. To promote adherence to EHT among breast cancer patients, this study will develop and pilot-test an intervention consisting of 1) a bilingual, culturally tailored, personalized, interactive smartphone application (app); and 2) support from a patient navigator. The control group will receive usual care. This 2-group randomized control trial will recruit 120 breast cancer patients receiving EHT at the Mays Cancer Center at UT Health San Antonio. The two-year study will have 3-time assessments (baseline, 3 and 6 months). This theory-based intervention will empower patients' self-monitoring and management. It will facilitate patient education, identification/reporting of side effects, delivery of self-care advice, and simplify communication between the patient and the oncology team. The ultimate goal of this innovative multi-communication intervention is to improve overall survival and life expectancy, enhance quality of life, reduce recurrence, and decrease healthcare cost. The anticipated outcome is a scalable, evidence-based, and easily disseminated intervention with potentially broad use to patients using EHT and other oral anticancer agents.

Veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in patients with BRCA1/2 locally recurrent/metastatic breast cancer: randomized phase II study.

Background: Homologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase inhibitors, which interfere with DNA damage repair. Veliparib, a potent poly(ADP-ribose) polymerase inhibitor, enhanced the antitumor activity of platinum agents and temozolomide in early phase clinical trials. This phase II study examined the safety and efficacy of intermittent veliparib with carboplatin/paclitaxel (VCP) or temozolomide (VT) in patients with BRCA1/2-mutated breast cancer. Patients and methods: Eligible patients ≥18 years with locally recurrent or metastatic breast cancer and a deleterious BRCA1/2 germline mutation were randomized 1 : 1 : 1 to VCP, VT, or placebo plus carboplatin/paclitaxel (PCP). Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and overall response rate (ORR). Results: Of 290 randomized patients, 284 were BRCA+, confirmed by central laboratory. For VCP versus PCP, median PFS was 14.1 and 12.3 months, respectively [hazard ratio (HR) 0.789; 95% CI 0.536-1.162; P = 0.227], interim median OS 28.3 and 25.9 months (HR 0.750; 95% CI 0.503-1.117; P = 0.156), and ORR 77.8% and 61.3% (P = 0.027). For VT (versus PCP), median PFS was 7.4 months (HR 1.858; 95% CI 1.278-2.702; P = 0.001), interim median OS 19.1 months (HR 1.483; 95% CI 1.032-2.131; P = 0.032), and ORR 28.6% (P < 0.001). Safety profile was comparable between carboplatin/paclitaxel arms. Adverse events (all grades) of neutropenia, anemia, alopecia, and neuropathy were less frequent with VT versus PCP. Conclusion: Numerical but not statistically significant increases in both PFS and OS were observed in patients with BRCA1/2-mutated recurrent/metastatic breast cancer receiving VCP compared with PCP. The addition of veliparib to carboplatin/paclitaxel significantly improved ORR. There was no clinically meaningful increase in toxicity with VCP versus PCP. VT was inferior to PCP. An ongoing phase III trial is evaluating VCP versus PCP, with optional continuation single-agent therapy with veliparib/placebo if chemotherapy is discontinued without progression, in this patient population. Clinical trial information: NCT01506609.

A pilot study of cabergoline for the treatment of metastatic breast cancer.

PURPOSE: The prolactin (PRL) receptor is over-expressed in breast cancer, and pre-clinical data indicate that it contributes to breast oncogenesis. Cabergoline is a potent dopamine receptor agonist of D2 receptors and has a direct inhibitory effect on pituitary PRL secretion. METHODS: A phase II study of cabergoline in patients with metastatic breast cancer was conducted. The primary end point of the study was to determine the clinical benefit rate (CBR) at 2 months. Eligible patients had tumors of any receptor status with no limit of prior lines of therapy. Measurable and unmeasurable diseases were allowed. Cabergoline 1 mg orally, twice weekly (1 cycle = 4 weeks) was given until disease progression or unacceptable toxicity. PRL receptor immunohistochemical staining was performed on available baseline tumor tissue; serial serum PRL levels were assessed. RESULTS: Twenty women were enrolled; 18 were evaluable for CBR. Tumor receptor status was distributed as follows: HR-any/HER2+ 2(10%), HR+/HER2- 18 (90%). The CBR was 33% (6/18), median progression free survival was 1.8 months, and median overall survival was 10.4 months. Two patients experienced disease control for over 12 months. Most common treatment-related adverse events were nausea (30%), fatigue (25%), and elevation in alkaline phosphatase (15%). Nine patients had baseline tissue for analysis; there was no association between baseline tumor PRL receptor expression and clinical benefit (p = 0.24). Change in serum PRL level and response were not correlated after 2 months of treatment (p = 0.64). CONCLUSION: Cabergoline was well tolerated, and while the ORR was low, a small subset of patients experienced extended disease control.

Clinical and genetic predictors of weight gain in patients diagnosed with breast cancer.

BACKGROUND: Post-diagnosis weight gain in breast cancer patients has been associated with increased cancer recurrence and mortality. Our study was designed to identify risk factors for this weight gain and create a predictive model to identify a high-risk population for targeted interventions. METHODS: Chart review was conducted on 459 breast cancer patients from Northwestern Robert H. Lurie Cancer Centre to obtain weights and body mass indices (BMIs) over an 18-month period from diagnosis. We also recorded tumour characteristics, demographics, clinical factors, and treatment regimens. Blood samples were genotyped for 14 single-nucleotide polymorphisms (SNPs) in fat mass and obesity-associated protein (FTO) and adiponectin pathway genes (ADIPOQ and ADIPOR1). RESULTS: In all, 56% of patients had >0.5 kg m(-2) increase in BMI from diagnosis to 18 months, with average BMI and weight gain of 1.9 kg m(-2) and 5.1 kg, respectively. Our best predictive model was a primarily SNP-based model incorporating all 14 FTO and adiponectin pathway SNPs studied, their epistatic interactions, and age and BMI at diagnosis, with area under receiver operating characteristic curve of 0.85 for 18-month weight gain. CONCLUSION: We created a powerful risk prediction model that can identify breast cancer patients at high risk for weight gain.

Behçet's disease associated with malignancies. Report of two cases and review of the literature.

OBJECTIVE: To investigate the incidence of malignancies in a cohort of Behçet's disease patients and review the world literature. METHODS: Our database of 128 patients was searched and the age standardized rate (ASR) for cancer was calculated. Furthermore, we performed a MEDLINE search from 1970 through 2003, as well as, a search in the proceedings of international conferences for cases of malignancies associated with Behçet's disease. RESULTS: Two of our 128 patients with Behçet's disease were found to have solid tumors. One male had lung cancer and the other female had kidney cancer. The ASR for cancer cases in our population was investigated and it was found to be 1,600 per 100,000 in 10 years. The ASR for cancer cases in Greece according to WHO is 272.51 per 100,000 per year and therefore 2,725 per 100,000 in 10 years. In the world literature 112 cases of malignancies associated with Behçet's disease were found: Sixty five cases were of male patients and 46 of female with 1 case of unknown gender. The solid malignancies associated with Behçet's disease included cases of bladder, breast, uterus, thyroid and stomach cancer, whereas haematological malignancies included leukemia, myelodysplastic syndrome, lymphoma, multiple myeloma, Hodgkin's disease and lymphosarcoma. The treatment administered in these patients with their disease is also reported. CONCLUSION: The age standardized rate of cancer in our population was lower than that of the general population in Greece, although the difference was not statistically significant. However, there is discrepancy in the world literature and the possibility of development of malignancies in Behçet's disease patients should not be ignored.

Adjuvant therapy of breast cancer.

In the past few years the treatment of early stage breast cancer has gone through several important changes. Both chemotherapy and hormonal therapy have been shown by large, randomized trials to offer a survival advantage. The most commonly used chemotherapeutic agents used in the US are doxorubicin and cyclophosphamide (AC). However, 3 studies have suggested that there may be an advantage in the use of taxanes in the adjuvant treatment of breast cancer. Furthermore the use of dose dense chemotherapy, incorporating AC and paclitaxel, has shown very promising results. It is well established that tamoxifen (T), a selective estrogen receptor modulator (SERM), improves overall survival (OS) in women with hormone receptor (HR) positive breast cancer. However, the results from large multicenter, randomized trials, suggest the potential superiority of aromatase inhibitors (AIs), compared to T or an advantage of sequencing T followed by an AI. The role ovarian suppression is still being investigated in patients who have received prior chemotherapy. Newer agents, such as the monoclonal antibody against the her2/neu receptor, trastuzumab, are now being studied as adjuvant therapy in early stage breast cancer. In the next few years, with the completion of several large randomized trials, we will be able to answer several questions, including the optimal way of incorporating AIs into the adjuvant therapy, the long-term sequella of using trastuzumab in the adjuvant treatment of breast cancer and the role of ovarian suppression combined with an AI in premenopausal women with breast cancer.

Treatment of Behçet's disease--an update.

OBJECTIVES: To report the experience of the investigators and review the major treatment trials conducted for Behçet's disease (BD). METHODS: A MEDLINE literature review from 1970 to date was performed on the drugs prescribed for the treatment of BD. Open and controlled clinical studies and indications for the treatment of affected organs are analyzed. RESULTS: Glucocorticoids are indicated for the treatment of BD, although no controlled studies have been reported. The combination of corticosteroids and immunosuppressant drugs is used when vital organs are involved. Nonsteroidal anti-inflammatory drugs are of little value in arthritis. In controlled trials, colchicine was efficacious for erythema nodosum and arthritis, particularly in women. Cyclosporine A has a rapid action and when combined with azathioprine is effective in patients with severe uveitis and extraocular manifestations. Chlorambucil is indicated for uveitis and meningoencephalitis. In controlled studies, azathioprine prevented unilateral uveitis from becoming bilateral and improved extraocular symptoms. Pulse cyclophosphamide combined with corticosteroids improves severe systemic vasculitis. Interferon alpha benefits ocular and extraocular manifestations, but controlled studies are lacking. Methotrexate is indicated for uveitis and arthritis, and sulfasalazine improves gastrointestinal vasculitis. In controlled trials, thalidomide was effective for mucocutaneous manifestations, but on its discontinuation the disease exacerbated. Orogenital manifestations are treated with local application of corticosteroids or other medications. CONCLUSIONS: Combination therapy is not always efficacious in controlling inflammation. The goal of management is to treat early to avoid recurrences and irreversible damage to the vital organs. With proper management of BD, loss of useful vision was reduced from 75% to 20% of the affected eyes. However, less favorable results are seen for central nervous system and large artery and vein involvement.

Renal involvement in Adamantiades-Behçet's disease. Case report and review of the literature.

A patient with Adamantiades-Behçet's disease with renal involvement is reported. This patient fulfilled the International Study Group criteria for the disease. Kidney biopsy was performed and proliferative glomerulonephritis with deposition of IgA and IgM immunoglobulins were demonstrated. Review of the literature demonstrates that renal involvement in this disease is not so rare as it was believed. Crescent formation and IgA nephropathy are infrequently observed. Treatment of renal involvement may require immunosuppressive drugs.

Recurrent epididymo-orchitis in patients with Behçet's disease.

PURPOSE: We study the clinical features of epididymo-orchitis in patients with Behçet's disease. MATERIALS AND METHODS: Of 57 men with Behçet's disease 7 had epididymo-orchitis during the course of disease. A questionnaire was applied to all cases and the clinical features were recorded. HLA class 1 was determined and a pathergy test was performed. RESULTS: All 7 patients fulfilled the international study group criteria for Behçet's disease. All patients had recurrent oral ulcers, skin lesions (folliculitis, erythema nodosum-like lesions) and uveitis, and 6 had recurrent genital ulcers, 2 arthritis, 1 vasculitis and 4 central nervous system involvement. The pathergy test was positive in 4 patients and all had B5(51). The allele B5101 was present in 6 patients and 1 had B5102. Recurrences were observed in 5 patients. Concurrent symptoms with epididymo-orchitis consisted of oral ulcers, fever, uveitis, arthritis and penile ulcer. Colchicine, glucocorticoids, nonsteroidal anti-inflammatory drugs and cyclosporine were administered. CONCLUSIONS: Epididymo-orchitis in patients with Behçet's disease is not as infrequent as believed. It was not the first manifestation of the disease but developed during followup. In any patient with epididymo-orchitis Behçet's disease should be considered, particularly in regions with a high prevalence of the disease.

Assessment of physician responses to abnormal results of bone densitometry studies.

OBJECTIVE: To assess how physicians who have ordered bone densitometry studies respond to abnormal results. METHODS: We conducted a retrospective review of cases from physicians affiliated with a community teaching hospital. The study sample consisted of 142 female patients with abnormal bone mineral density (BMD) who had been referred by 50 physicians (internists or gynecologists). A questionnaire was completed for each patient, providing data about further investigations, treatment interventions, and frequency of referral to a specialist in bone diseases. RESULTS: Of the patients diagnosed with osteoporosis on the basis of BMD studies, 20.4% had no further investigations, and 27.8% underwent only mammography. Of all the patients with osteoporosis, 10.6% received no therapy (calcium and vitamin D excluded). The majority of all patients (71.8%) received a combination of calcium and vitamin D. The most common treatment modality was hormone replacement therapy. The second most common treatment strategy was bisphosphonates. The percentage of all referrals to specialists in metabolic bone diseases was low--11.3% in the patients of internists and 14.5% in the patients of gynecologists. CONCLUSION: In this study, the information provided by bone densitometry did not affect management in a substantial percentage of patients. A considerable percentage of patients underwent no further investigations to rule out secondary causes of osteoporosis.

Dietary factors in relation to rheumatoid arthritis: a role for olive oil and cooked vegetables?

BACKGROUND: Although several studies showed that risk of rheumatoid arthritis (RA) is inversely associated with consumption of n-3 fatty acids, the one study showing that olive oil may have a protective role has not yet been confirmed. OBJECTIVE: We examined the relation between dietary factors and risk of RA in persons from southern Greece. DESIGN: We studied 145 RA patients and 188 control subjects who provided information on demographic and socioeconomic variables, prior medical and family history, and present disease status. Subjects responded to an interviewer-administered, validated, food-frequency questionnaire that assessed the consumption of >100 food items. We calculated chi-square statistics for linear trend and odds ratios (ORs) for the development of RA in relation to the consumption of olive oil, fish, vegetables, and a series of food groups classified in quartiles. RESULTS: Risk of developing RA was inversely and significantly associated only with cooked vegetables (OR: 0.39) and olive oil (OR: 0.39) by univariate analysis. A significant trend was observed with increasing olive oil (chi-square: 4.28; P = 0.03) and cooked vegetable (chi-square: 10. 48; P = 0.001) consumption. Multiple logistic regression analysis models confirmed the independent and inverse association between olive oil or cooked vegetable consumption and risk of RA (OR: 0.38 and 0.24, respectively). CONCLUSIONS: Consumption of both cooked vegetables and olive oil was inversely and independently associated with risk of RA in this population. Further research is needed to elucidate the underlying mechanisms of this finding, which may include the antioxidant properties or the high n-9 fatty acid content of the olive oil.

Dietary fat and carbohydrates are independently associated with circulating insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 concentrations in healthy adults.

PURPOSE: To evaluate and quantify the association between consumption of specific food groups/macronutrients and concentrations of serum insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3). SUBJECTS AND METHODS: Data from a comprehensive food-frequency questionnaire administered to 115 healthy subjects were used to study cross-sectionally the relationship between nutritional factors and circulating IGF-1 and IGFBP-3 concentrations. Adjustment for the effect of total energy intake and a series of epidemiologic parameters (age, sex, height, body mass index, smoking, alcohol consumption, and coffee drinking) was implemented through multivariate linear regression. RESULTS: We observed that serum levels of IGF-1 are positively associated with consumption of red meats, fats, and oils. In addition, serum levels of IGF-1 are independently and positively associated with energy intake from lipids and negatively associated with energy intake from carbohydrates. Finally, serum levels of IGFBP-3 are independently and negatively associated with energy intake from saturated fat. CONCLUSION: Serum IGF-1 and/or IGFBP-3 concentrations are associated with red meat, carbohydrate intake, and fat intake and, thus, may mediate the effect of these dietary factors on the pathogenesis of several disease states. Additional studies are needed to further quantify these associations and elucidate the underlying mechanisms.

Association of MICA gene and HLA-B*5101 with Behçet's disease in Greece.

PURPOSE: Behçet's disease (BD) is known to be associated with HLA-B51 in many different ethnic groups. Recently MICA, a member of a novel family of the human major histocompatibility complex (MHC) class I genes termed MIC (MHC class I chain-related genes), was identified near the HLA-B gene, and a triplet repeat microsatellite polymorphism was found in the transmembrane (TM) region. Because a strong association with BD of one particular MICA-TM allele, A6, was shown in a Japanese population, the present study was conducted to investigate microsatellite polymorphism in Greek patients with BD to know whether this association is generally observed in BD occurring in other populations. METHODS: Thirty-eight Greek patients with BD and 40 ethnically matched control subjects were examined for MICA microsatellite polymorphism using polymerase chain reaction (PCR) and subsequent automated fragment detection by fluorescent-based technology. RESULTS: Similar to the Japanese patients with BD, the phenotype frequency of the MICA-TM A6 allele was significantly increased in the Greek patients with BD (50.0% in control subjects versus 86.8% in BD cases), with an odds ratio (OR) of 6.60 (P = 0.0012). The MICA-A6 allele was found in a high frequency both in males and females (weighted OR = 6.68; P = 0.0017). No association was found between the A6 allele and several disease features. A strong association exists between the MICA-TM A6 allele and the B*5101 allele in both the control subjects and patients with BD (weighted OR = 44.39; P = 0.0000023). CONCLUSIONS: This study revealed in Greek patients a strong association of BD with a particular MICA-TM allele, MICA-A6, providing insight into the molecular mechanism underlying the development of BD.

Clinical features of juvenile Adamantiades-Behçet's disease in Greece.

Adamantiades-Behçet's disease (A-BD) is a chronic relapsing vasculitis of unknown etiology. This disease is relatively rare in children and only recently have series of patients been reported. The objective of this study was to describe the clinical features of the disease in juvenile patients, and to compare them with adult cases and with those juveniles reported in the literature.

Age, sex, and smoking are predictors of circulating insulin-like growth factor 1 and insulin-like growth factor-binding protein 3.

PURPOSE: Insulin-like growth factor (IGF-1) and its major binding protein (IGF-BP3) have recently been implicated in the pathogenesis of several malignancies. However, anthropometric and lifestyle predictors of these hormones have not been elucidated. Here we report the results of a cross-sectional study. SUBJECTS AND METHODS: This cross-sectional study examines the relationship of a series of epidemiologic parameters (age, sex, height, body mass index, smoking, alcohol consumption, and coffee drinking) with IGF-1 and IGF-BP3 in a sample of 130 healthy adults. RESULTS: We observed that serum levels of IGF-1 are higher, whereas levels of IGF-BP3 are lower, in men than in women. In addition, serum levels of IGF-1 are independently and negatively associated with age and positively associated with pack-year history of smoking. Finally, serum levels of IGF-BP3 are independently and negatively associated with the number of cigarettes smoked per day or pack-year history of smoking. CONCLUSION: Age, sex, and smoking are independent predictors of IGF-1 and/or IGF-BP3. The influence of these epidemiologic variables on the pathogenesis of disease states associated with IGF-1 and IGF-BP3 warrants further exploration.

Sex differences in circulating human leptin pulse amplitude: clinical implications.

Leptin, a product of fat cells, provides a signal of nutritional status to the central nervous system. Leptin concentrations have ultradian and diurnal fluctuations. We conducted this study to assess sex differences in the levels of organization of frequently sampled leptin concentrations in healthy, normal weight women and men. Leptin levels were sampled every 7 min for 24 h in 14 healthy, normal weight individuals (6 women and 8 men). The 14 leptin time series containing a total of 2898 leptin measurements were assessed by 1) algorithms that characterize statistically significant pulsatility, 2) Spectral (Fourier) analysis, 3) analysis of time intervals and variability, and 4) approximate entropy. We found that frequently sampled plasma leptin concentrations have a 24-h profile that is numerically more than twice as high in women as in men, and leptin pulse amplitude is likewise more than twice as high in women. However, healthy men and women have nearly identical concentration-independent and frequency-related 24-h and ultradian patterns. Leptin concentrations have nonrandom fluctuations over 24 h, independent of their absolute value and underlying 24-h periodicity, that are similar in men and women. Ultradian periodicities detected by Fourier time series have similar values in men and women. The strongest distinction between the sexes in the level of organization of leptin concentration is not at the level of pulse organization or oscillation frequency, but, rather, in the mass or amount of leptin released (or removed) per unit time, indicating that women might be more resistant to the effects of leptin than men. Because leptin is clinically relevant to the regulation of body weight, future studies should examine whether the relative leptin resistance exhibited by women might contribute to their increased susceptibility to disorders whose pathophysiology involves dysregulation of food intake and body weight.

Circulating insulin concentrations, smoking, and alcohol intake are important independent predictors of leptin in young healthy men.

OBJECTIVE: Leptin, an adipocyte-secreted hormone, has been shown to signal the status of energy stores to the brain, regulate energy homeostasis, and mediate the neuroendocrine response to food deprivation. Obesity is associated with increased leptin levels, and several hormones, including insulin and glucocorticoids, have been associated with leptin levels and expression in rodents. Although obesity has been strongly associated with increased leptin in humans, a significant percentage of leptin's variability remains unexplained. The role of endogenous hormones, demographic factors, or certain life-style factors in explaining the residual variability of leptin levels has not yet been clarified. We performed this cross-sectional study to document the relative importance of obesity, lifestyle factor, and endogenous hormones in determining serum leptin levels. RESEARCH METHODS AND PROCEDURES: We measured serum concentrations of insulin, cortisol, testosterone, growth hormone, and dehydroepiandrosterone sulfate; ascertained anthropometric, demographic, and lifestyle characteristics; and studied these variables in relationship to serum leptin concentrations in a sample of young healthy men. RESULTS: Obesity and alcohol intake were independently and positively associated with circulating leptin concentrations. Additionally, cigarette smoking was negatively and independently associated with leptin concentrations. Finally, serum insulin concentration was an independent hormonal determinant of circulating leptin concentrations, whereas serum testosterone was negatively associated with leptin only by bivariate analysis. DISCUSSION: We conclude that, in addition to obesity, cigarette smoking, alcohol intake, and serum insulin levels are associated with leptin levels in a population of healthy young men.

Synchronicity of frequently sampled, 24-h concentrations of circulating leptin, luteinizing hormone, and estradiol in healthy women.

Leptin, an adipocyte hormone, is a trophic factor for the reproductive system; however, it is still unknown whether there is a dynamic relation between fluctuations in circulating leptin and hypothalamic-pituitary-ovarian (HPO) axis hormones. To test the hypothesis that fluctuations in plasma leptin concentrations are related to the levels of luteinizing hormone (LH) and estradiol, we sampled plasma from six healthy women every 7 min for 24 h during days 8-11 of the menstrual cycle. Cross-correlation analysis throughout the 24-h cycle revealed a relation between release patterns of leptin and LH, with a lag of 42-84 min but no significant cross-correlation between LH and estradiol. The ultradian fluctuations in leptin levels showed pattern synchrony with those of both LH and estradiol as determined by cross-approximate entropy (cross-ApEn). At night, as leptin levels rose to their peak, the pulsatility profiles of LH changed significantly and became synchronous with those of leptin. LH pulses were fewer, of longer duration, higher amplitude, and larger area than during the day. Moreover, the synchronicity of LH and leptin occurred late at night, at which time estradiol and leptin also exhibited significantly stronger pattern coupling than during the day. We propose that leptin may regulate the minute-to-minute oscillations in the levels of LH and estradiol, and that the nocturnal rise in leptin may determine the change in nocturnal LH profile in the mid-to-late follicular phase that precedes ovulation. This may explain the disruption of hypothalamic-pituitary-ovarian function that is characteristic of states of low leptin release, such as anorexia nervosa and cachexia.