Overview

This trial is active, not recruiting.

Condition hot flashes
Treatment leuprolide acetate (lupron)
Phase phase 2/phase 3
Sponsor Hadine Joffe, MD
Start date November 2005
End date September 2007
Trial size 33 participants
Trial identifier NCT00455689, 2005P-001512

Summary

The purpose of the study is to examine the impact of hot flushes on sleep, mood, and well-being. Hot flushes (or "hot flashes") are a feeling of being overheated, and often are followed by heavy sweating, skin becoming red and hot, and discomfort. Sometimes hot flushes are followed by chills. Some women experience a rapid heart rate. Hot flushes that happen at night are called night sweats, and they may interfere with sleep.

The investigators will cause hot flushes by giving study participants a hormone medication called leuprolide (Lupron). Hormones are chemicals that are naturally produced in the body. Leuprolide is a manufactured (artificial) hormone that will make the body think that it has reached menopause temporarily. Most women begin to have hot flushes within 4 weeks after taking leuprolide.

The investigators will also evaluate changes in sleep, mood, and feelings of well-being over the course of the study. The investigators will use questionnaires to measure these changes.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation non-randomized
Intervention model single group assignment
Masking open label
Arm
(Experimental)
leuprolide acetate (lupron)
Leuprolide acetate (Lupron Depot®) 3.75-mg intramuscular injection Leuprolide is a widely used GnRH agonist that is manufactured by TAP Pharmaceutical Products. Leuprolide is indicated for treatment of endometriosis, uterine fibroids, precocious puberty, and prostate cancer, and is used off-label for in-vitro fertilization and premenstrual syndrome. In this protocol, leuprolide will be administered once during the mid-luteal phase of the menstrual cycle at a dose routinely used for treatment of endometriosis and uterine fibroids in women.

Primary Outcomes

Measure
To examine the impact of hot flushes on sleep, mood, and well-being.
time frame: Baseline and post-treatment (4 weeks after GnRH agonist)

Secondary Outcomes

Measure
To describe the hormonal dynamics after administration of a gonadotropin-releasing hormone agonist that are associated with the development of hot flushes.
time frame: Baseline and post-treatment (4 weeks after GnRH agonist)

Eligibility Criteria

Female participants from 18 years up to 45 years old.

Inclusion Criteria: - Women 18-45 years old - Premenopausal, defined as regular month menstrual cycles (every 25-35-days) for the past 6 months and corroborated by a mid-luteal phase progesterone of > 3 ng/ml - Willingness to use barrier methods of contraception during study and after completion of study until menses resume - Good general health with normal hemoglobin, prolactin, TSH, liver function tests (SGOT, SGPT, bilirubin) and renal function tests (BUN, creatinine, alkaline phosphatase) Exclusion Criteria: - Pregnancy, confirmed by serum HCG at screening visit and also by additional serum HCG testing conducted at the 3rd visit when GnRH agonist is given and in the 24 hours prior to each of the PET scans. - Breastfeeding - Hot flushes, as determined by skin-conductance monitor measurement and hot flush diary obtained after screening visit and before initiation of study medications - Hemoglobin at the screening visit less than 10 gm/dL - Abnormal liver function tests (SGOT, SGPT, or bilirubin > 2.5 times the upper limit of normal) - Abnormal renal function tests (BUN or creatinine > 2 times the upper limit of normal) - BMI > 35 kg/m2 - Previously diagnosed osteoporosis or osteopenia - Psychiatric disorder involving mood (current major depression, current dysthymia, bipolar disorder) anxiety (current panic disorder, current obsessive compulsive disorder), psychotic disorder, current anorexia nervosa, or current alcohol or substance-use disorder, as determined by administration of the Patient Health Questionnaire (PHQ) or a score >16 on the Montgomery-Åsberg Depression Rating Scale (MADRS) indicating significant depression symptoms at the screening study visit. If the PHQ suggests one of these psychiatric disorders, the Structured Clinical Interview for Diagnosis-IV (SCID)48 will be administered to ensure that potential study participants do not have one of these psychiatric disorders. Previous severe depression, as characterized by psychotic symptoms or inpatient psychiatric hospitalization for a suicide attempt in the 5 years prior to study enrollment - Previous severe depression, as characterized by psychotic symptoms or inpatient psychiatric hospitalization for a suicide attempt in the 5 years prior to study enrollment - Evidence of suicidal or homicidal ideation, as determined by PHQ and MADRS at screening visit - Sleep apnea, narcolepsy, or other diagnosed sleep disorder, as determined by clinical interview in conjunction with the Sleep Disorders Questionnaire (55, 56) administered at screening visit - Contraindication, hypersensitivity, or previous allergic reaction to GnRH agonists - Regular use of centrally active medications (antidepressants, anxiolytics, hypnotics, anticonvulsants) for at least one month - Use of hormonal medications for at least 2 months - Use of ketoconazole, clomiphene citrate, or anabolic/androgenic steroids in the preceding 3 months - Renal insufficiency - Abnormal vaginal bleeding - History of thrombo-embolism or cardiovascular disease - History of congestive heart failure or other conditions requiring sodium restriction - History of spinal cord compression - Metastatic vertebral lesions - Memory disorders - Urinary tract obstruction - History of liver, kidney, pulmonary, or metabolic disease that may put subject at risk when treated with study medication. - Contraindication to PET or MRI imaging, such as cardiac pacemaker, implanted cardiac defibrillator, brain aneurysm clips, cochlear implant, ocular foreign body, shrapnel and/or prior history of allergic reaction to dyes used with scans.

Additional Information

Official title Understanding Experimentally Induced Hot Flushes
Principal investigator Hadine Joffe, M.D., M.Sc.
Description Hot flushes are common in peri/postmenopausal women and women receiving breast cancer therapies. Every year in the United States, 1.3 million women are expected to reach menopause.(1, 2) Hot flushes occur in >85% of menopausal women, typically persisting for several years.(3) In addition, over 200,000 women are diagnosed with breast cancer in the US each year.(4) Hot flushes are the most common side effect of anti-estrogen therapies used to treat estrogen-receptor positive (ER+) breast cancer. Widely used anti-estrogen therapies are used continuously for many years, and include tamoxifen, aromatase inhibitors (AI), and gonadotropin-releasing hormone (GnRH) agonists.(5) Hot flushes persist with ongoing use of these cancer treatments.(6) The number of women with hot flushes has been increasing because many women have declined estrogen therapy since the results of the Women's Health Initiative were published and because anti-estrogen therapies are now used more widely over longer periods of time in women with breast cancer.(7) Hot flushes impair quality-of-life by producing discomfort, disrupting sleep, diminishing mood, and reducing overall well-being in menopausal women and breast cancer patients.(5, 8) They are the primary reason for discontinuation of anti-estrogen therapies.(9) Recent advances have identified non-hormonal therapies for hot flushes (e.g., serotonergic agents and gabapentin),(8, 10-16) but such agents are effective in only 60% of women with hot flushes.(8) Better therapies are needed. Current studies are limited by reliance on populations with hot flushes that vary in frequency and intensity, biases in perceptions that influence self-reporting of hot flushes,(17) and a 30% placebo-response rate.(8, 18) Utilizing an experimental model to induce hot flushes will advance the discovery of novel hot flush therapies through the use of a robust and reproducible system in which to test potential therapies. An experimental model will also permit greater understanding of the effects of novel therapies on hot flushes and of hot flushes on sleep, mood, and quality-of-life. This work will accelerate the development of more effective therapies to prevent and alleviate hot flushes, thereby improving adherence to anti-estrogen therapies in women with breast cancer and quality-of-life in all women with hot flushes. Etiology of hot flushes: Withdrawal of estrogen is central to the pathophysiology of hot flushes,(18) with estrogen possibly exerting its effects on hot flushes in the hypothalamic thermoregulatory center.(18) Evidence supporting estrogen's role derives from women in whom hot flushes occur spontaneously or iatrogenically. Hot flushes are caused by oöphorectomy or GnRH agonists, which lead to rapid estrogen withdrawal,(19) SERMs (e.g., tamoxifen), which antagonize the estrogen receptor,(5) and AI, which block peripheral conversion of androstenedione to estrone,(20, 21) the primary estrogen source in postmenopausal women.(22) GnRH agonists: GnRH agonists such as leuprolide are effective treatments for premenopausal breast cancer and prostate cancer in men, and are also used in women with endometriosis, fibroids, and infertility.(23-27) On GnRH agonist therapy, hot flushes develop within the first 2-3 weeks of treatment and are present in at least 80% of women by 4 weeks of use.(19, 28-31) An average of 1 to 6 hot flushes per day can occur while on GnRH agonist therapy, and may continue up to 3 months after discontinuation.(19, 28-31) GnRH agonists initially stimulate release of gonadal steroids (estradiol [E2], estrone [E1], leutinizing hormone [LH], follicle-stimulating hormone [FSH]) then suppress their secretion within 1-2 weeks of treatment.(19, 30, 32) E2 and E1 are suppressed to levels seen after oöphorectomy and, like LH, remain persistently suppressed, while FSH rises after 4 weeks of ongoing GnRH agonist therapy.(19, 30, 32) Osteopenia is not seen until GnRH agonists are used for 6 months.(33) Impact of hot flushes on sleep, mood, and quality-of-life: Sleep disruption is common and strongly associated with hot flushes in peri/postmenopausal women (3, 34, 35) and breast cancer patients.(5, 36) Hot flushes that occur at night (night sweats) lead to repeated, brief awakenings, abnormal sleep architecture, and poor sleep quality.(37-39) Depression symptoms occurs in 10% of perimenopausal women.(40) Depression symptoms in peri/postmenopausal women are strongly linked to hot flushes.(41, 42) Impairment of sleep, mood, and quality-of-life are also seen with GnRH agonists and AI.(43-46) However, it is not known whether sleep and mood problems that occur with GnRH agonists and AI are caused by hot flushes or are a consequence of estrogen withdrawal. Neuro-anatomical correlates of hot flushes: Hot flushes are thought to be induced by changes in estrogen that disrupt the thermoregulatory region in the hypothalamus through estrogen inputs to the hypothalamus. (3, 18) Other evidence suggests that changes in the insular cortex correlate with hot flushes.(48) However, changes in the hypothalamic and insular regions that occur in women with GnRH agonist-induced hot flushes have not been extensively investigated. Only one published study to date has utilized functional neuro-imaging to examine the neuroanatomic correlates of hot flushes.(48) Using functional MRI testing, this study found activation in the insular cortex but not the hypothalamus during an individual hot flush event. Our study will utilize PET technology to explore hypothalamic and insular changes that occur in women who develop hot flushes on leuprolide. PET Imaging of the CNS: Dr. Hall, one of the co-investigators, has used PET scan techniques to examine changes in hypothalamic activity in an estrogen infusion study. Her work has shown that estrogen negative feedback occurs in the hypothalamus and inferior thalamus.(49) These data were collected in collaboration with 2 other co-investigators on this project, Drs. Dougherty and Fischman, and demonstrate that PET scanning can be used to detect changes in hypothalamic activity that occurs when serum levels of estrogen are altered. The current study will use a similar PET scan method. Of the neuroimaging methods currently available, PET offers the best combination of resolution, sensitivity, ability to study subcortical and midline structures such as the hypothalamus, range of feasible experimental designs, and well-validated analytical tools. Early studies documented changes in regional cerebral blood flow in the presence of estrogen.(50) Previous cross-sectional studies using FDG PET have demonstrated significant effects of estrogen administration on brain regions associated with memory that are sensitive to cognitive changes in normal aging and in Alzheimer's Disease.(51-53) [18F] 2-fluoro-2-deoxy-D-glucose (18FDG) has also been used successfully to measure changes in local cerebral glucose utilization rate elicited by pharmaceutical or cognitive challenge.(54) As with native glucose, FDG is transported in brain across the capillary endothelium and cell membrane by facilitated diffusion and phosphorylated to FDG-PO4. However, FDG-PO4 does not undergo further metabolism because the cerebral activity of glucose-6-phosphatase is very low, causing no significant dephosphorylation. Thus, after intravenous injection, the local cerebral concentration of FDG rises to a plateau level that is directly proportional to glucose utilization rates.
Trial information was received from ClinicalTrials.gov and was last updated in April 2012.
Information provided to ClinicalTrials.gov by Massachusetts General Hospital.