Know Cancer

forgot password

Understanding Experimentally Induced Hot Flushes

Phase 2/Phase 3
18 Years
45 Years
Open (Enrolling)
Hot Flashes

Thank you

Trial Information

Understanding Experimentally Induced Hot Flushes

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.

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

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

- 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.

Type of Study:


Study Design:

Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label

Outcome Measure:

To examine the impact of hot flushes on sleep, mood, and well-being.

Outcome Description:

Experimentally induced hot flushes will correlate with impairment of sleep and mood.

Outcome Time Frame:

Baseline and post-treatment (4 weeks after GnRH agonist)

Safety Issue:


Principal Investigator

Hadine Joffe, M.D., M.Sc.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Massachusetts General Hospital


United States: Food and Drug Administration

Study ID:




Start Date:

November 2005

Completion Date:

October 2012

Related Keywords:

  • Hot Flashes
  • Lupron
  • Premenopausal
  • Hot flashes
  • PET
  • MRI
  • Hot Flashes



Massachusetts General Hospital Boston, Massachusetts  02114-2617