Hot flashes affect approximately 75% of postmenopausal women and 40% of perimenopausal women. Women who experience hot flashes have higher rates of sleep and mood disturbances than do women unaffected by hot flashes.1–3 Although hormone replacement therapy (HRT) is highly effective in reducing hot flashes, there is growing concern that long-term HRT is associated with an increased risk of developing breast cancer.4,5 Although the data are equivocal,6 the perception of increased breast cancer risk has influenced the decision-making of patients and physicians regarding HRT. Because about half of women who experience hot flashes will do so for 5 or more years, and up to 10% will do so for more than 15 years,1 risks from long-term HRT are relevant for this population. Most recently, HRT has been associated with increased rates of heart disease when used for primary prevention5 and has been shown not to have a role for secondary prevention of heart disease.7–9 In addition, many women have contraindications to HRT, such as those with a history of an estrogen-sensitive tumor, liver dysfunction, gall bladder disease, or a hypercoagulable state. Safe, effective, and well-tolerated alternative therapies for hot flashes are needed.
Gabapentin is a γ-aminobutyric acid analogue approved in 1994 for the treatment of seizures. Since then, gabapentin has shown efficacy in controlled studies for neuropathic pain,10,11 migraine headache,12 essential tremor,13 panic disorder,14 and social phobia.15 Recently, we reported that open-label gabapentin treatment was associated with a reduction of hot flashes in four postmenopausal women, one woman with tamoxifen-induced hot flashes, and one man with leuprolide-induced hot flashes.16
We conducted a randomized, double-blind, placebo-controlled trial to examine the effects of low dose (900 mg per day) gabapentin treatment on hot flash frequency and severity in 59 postmenopausal women. Sleep quality, mood, quality of life, and patient global impression of change were also assessed.
MATERIALS AND METHODS
Study participants were recruited by advertisements and from a local news program about alternative hot flash therapies. We enrolled 59 postmenopausal women meeting the following entry criteria: an average of seven or more hot flashes per day accompanied by sweating; amenorrhea for more than 12 months or amenorrhea for 6–12 months with a serum follicle-stimulating hormone level greater than 40 mIU/mL and estrogen less than 20 pg/mL or status post-bilateral oophorectomy for 2 months; no estrogen, progestin, leuprolide, or tamoxifen therapy within the past 2 months; no change in dose of raloxifene, clonidine, or any antidepressant therapy within the past month and no plan to change the dose in the future; no calcium channel antagonist or gabapentin therapy within the past 2 weeks; no previous allergic reaction to gabapentin; and an estimated creatinine clearance of 60 or more mL per minute. Each patient was asked at screening to describe the symptoms of their typical hot flash. Events were considered hot flashes if described as a sudden onset of heat sensation accompanied with sweating that spontaneously resolved within 1 hour. At least one daytime hot flash per day was required. Also, if more than 50% of a patient's hot flashes were associated with occurrence of migraine headaches or ingestion of particular foods or beverages, the patient was not eligible.
After a 2-week screening baseline assessment, patients were randomly assigned to 12 weeks of double-blind therapy with either gabapentin 300-mg capsules, one capsule three times daily (900 mg per day), or identically appearing placebo. This dose of gabapentin was selected based on our previous open-label findings.16 The Office of Investigational Drug Services in the Department of Pharmacy at the University of Rochester prepared all study capsules and performed the randomization via a random number table. The randomization was stratified by surgical menopause status. Patient medication containers were labeled with sequential numbers corresponding to the treatment. The treatment code was kept secure by The Office of Investigational Drug Services and was not revealed to any study personnel until after the last patient completed the open-label study.
Medication was increased over the first week as follows: one capsule at bedtime for 3 days, then one capsule twice daily for 3 days, then one capsule three times daily thereafter. Dosing could be decreased for intolerable side effects. After 12 weeks of double-blind therapy, patients had the option of enrolling in a 5-week, open-label study, during which all patients received gabapentin. The dose could be titrated up to 2700 mg per day maximum as follows: every 4 days the total daily dose was increased by 300 mg until the patient experienced satisfactory reduction of hot flashes or intolerable side effects; the dose was then maintained or decreased by 300 mg per day for the remainder of the open-label study.
Patients made four visits to the General Clinical Research Center at Strong Memorial Hospital, Rochester, New York at screening, 2 weeks later at randomization, and after 4 and 12 weeks of treatment. Serum follicle-stimulating hormone and estrogen levels were assessed at the screening visit and Week 12. Serum luteinizing hormone, complete blood count with differential and platelets, chemistry-14 panel, and phosphate levels, as well as vital signs, height, and weight were assessed at randomization and Week 12. The University's Research Subjects Review Board approved the study, and all participants provided written, informed consent at the screening visit.
Hot flash frequency and severity were recorded in a hot flash diary. A novel, real-time hot flash diary was used to help maximize accuracy in hot flash recording. Patients were instructed to carry the diary with them at all times possible and to mark down the severity of a hot flash immediately after it occurred. Both daytime and nighttime hot flashes were recorded. Each hot flash was recorded by filling in the appropriate severity “bubble” on a scale of 1 to 7.
Daily hot flash frequency was calculated by adding the number of hot flashes recorded in a week and dividing by the number of days in that week for which completed diaries were received. Daily hot flash composite score reflected both hot flash frequency and severity in one score; it was calculated by adding the hot flash severity scores over a week and dividing by the number of days for which completed diaries were received. A minimum of 4 days of recorded data in a week was needed for the week to be included in the analysis.
Diaries were filled out for 6 consecutive weeks (from screening to treatment Week 4); for two, 1-week periods during Weeks 8 and 12; and for all 5 weeks of open-label gabapentin treatment. Diaries were mailed weekly to the study's data manager in the General Clinical Research Center.
Sleep quality, mood, quality of life, and patient global impression of change were assessed at screening and Weeks 4 and 12 with the Pittsburgh Sleep Quality Index,17 the Profile of Mood States,18 the Short Form-36 Health Survey,19 and the Patient Global Impression of Change Scale,11 respectively. Adverse events were monitored at each visit, and patients were asked about adverse events during bimonthly phone contacts.
Given our inclusion criterion of 7–20 hot flashes per day, we assumed a mean daily hot flash frequency at baseline of approximately 12 in each group. We also estimated a standard deviation of the change from baseline to 12 weeks in daily hot flash frequency of 4. Under these assumptions, a sample size of 22 subjects per group was chosen to provide 90% power to detect a 33% reduction (from 12 to 8) in mean daily hot flash frequency with gabapentin, using a two-tailed t test at the 5% level of significance. Because we planned to use the Wilcoxon rank sum test instead of a t test in the primary analysis, and we anticipated that some subjects would not complete the trial, we increased the sample size to 30 subjects per group (60 total).
The primary outcome measure was the percentage change in hot flash frequency from baseline to treatment Week 12. Secondary outcome measures included the percentage change in hot flash composite score from baseline to Week 12, the Patient Global Impression of Change Scale score at Week 12, and absolute changes from baseline to Week 12 in Pittsburgh Sleep Quality Index total score, Profile of Mood States total and sub-scale scores, and Short Form-36 Health Survey subscale scores. Group comparisons of hot flash scores were also performed at other time points; P values are reported for these comparisons for descriptive purposes only and are not adjusted for multiple comparisons. The Wilcoxon rank sum test was used to compare the treatment groups regarding all outcomes, except a χ2 test was used to compare the percentages of patients having a greater than 50% reduction in hot flash composite score from baseline to Week 12. Treatment effects were estimated using the Hodges–Lehmann estimate of the group difference in population medians and its associated 95% confidence interval.20 Secondary analyses of the primary outcome variable adjusting for group differences in baseline characteristics were performed using analysis of covariance. All statistical tests were performed at the two-tailed 5% level of significance.
All hot flash analyses were performed according to the intention-to-treat principle. Analyses of the hot flash frequency and composite score data included all randomized patients. If data was missing for any week, the last available observation for that patient was imputed for that week. We repeated these analyses not using imputation for missing data, for comparison purposes; the results of these analyses did not significantly differ and hence are not reported here. Non–hot flash secondary outcome measures did not use imputation for missing data.
A total of 246 women were screened by phone conversation. Most were ineligible because of insufficient hot flash frequency or occurrence of menses within the past 6 months. Fifty-nine patients were enrolled from July to November 2000 (Figure 1), and follow-up continued until March 2001. Patient baseline characteristics are summarized in Table 1.
Of the 54 patients who completed the double-blind study, 26 of 26 (100%) and 26 of 28 (93%) of gabapentin-treated and placebo-treated patients, respectively, provided complete diary data during the 12th week of treatment. Of the 50 patients who completed the open-label gabapentin study, 20 of 24 (83%) and 26 of 26 (100%) of patients previously assigned to gabapentin and placebo, respectively, provided complete diary data during the fifth week of open-label treatment.
Low-dose gabapentin (900 mg per day) provided significant improvement in both hot flash frequency and composite score compared with placebo after 12 weeks of treatment. There was a 45% decrease in mean hot flash frequency and a 54% decrease in mean hot flash composite score from baseline in the gabapentin group, compared with a 29% (P = .02) and a 31% (P = .01) decrease in the placebo group, respectively. This difference was apparent even after the first week of treatment (Figures 2 and 3). Analyses adjusting for group differences in baseline characteristics (in particular, duration of hot flashes and Profile of Mood States Total Mood Disturbance score) did not significantly alter the results. Sixty-seven percent of gabapentin-treated patients, compared with 38% of placebo-treated patients, experienced a more than 50% reduction in hot flash composite score during Week 12 (P = .03).
Results from the open-label study showed mean reductions in hot flash frequency and composite scores during Week 17 of 54% and 61%–67%, respectively (Table 2). Seventy-two percent of patients experienced a more than 50% reduction in hot flash composite scores during Week 17. Worsening of hot flashes in the gabapentin group during Week 13 was likely due to the decreased gabapentin dose while repeating the open-label titration.
During the open-label study, patients were able to adjust their own gabapentin dosing from 300 to 2700 mg per day, based on effectiveness. Of the 54 patients who started the open-label study, 44 patients (81.5%) requested to continue gabapentin after the open-label study for the treatment of their hot flashes. Of these 44 patients, 11 (25.0%) requested a dose of 900 or less mg per day, 27 (61.4%) requested a dose between 900 and 1800 mg per day, and 6 (13.6%) requested a dose between 1800 and 2700 mg per day. Patients who requested the higher doses tended to have a higher frequency of hot flashes at baseline (data not shown).
The most common adverse events in the gabapentin group during the double-blind study were somnolence (six patients [20.0%]), dizziness (four patients [13.3%]), and rash with or without peripheral edema (two patients [6.7%]), none of which occurred in the placebo group. Onset of menses was the most common adverse event in the placebo group, occurring in three patients (10.3%), compared with two patients (6.7%) in the gabapentin group. Fifteen patients (50.0%) in the gabapentin group reported at least one adverse event, compared with eight patients (27.6%) in the placebo group. Four patients (13.3%) in the gabapentin group withdrew from the study because of dizziness, rash, heart palpitations, and peripheral edema, respectively. One patient (3.4%) in the placebo group withdrew because of diarrhea. Two patients (6.7%) in the gabapentin group temporarily decreased the dose because of dizziness and sleepiness, respectively. Higher gabapentin dosing during the open-label study was not associated with increased adverse events. Two patients previously in the placebo group withdrew from the open-label gabapentin study because of the side effects of dizziness and peripheral edema, respectively.
There were no significant differences between the groups in any of the total or subscale scores of the Short Form-36 Health Survey, Profile of Mood States, or Patient Global Impression of Change Scale measures at either Week 4 or Week 12 (Table 2). Sleep quality, measured by the Pittsburgh Sleep Quality Index, was improved in the gabapentin group at Week 4 (− 3.1 compared with − 0.9 mean point change from baseline, gabapentin versus placebo, P = .01); however, this benefit was no longer apparent at Week 12 (− 2.9 compared with − 1.2 mean point change from baseline, gabapentin versus placebo, P = .09).
Blood laboratory studies at Week 12 compared with baseline showed decreases in albumin, total protein, total bilirubin, blood urea nitrogen, and platelets in the gabapentin group compared with the placebo group (Table 3). Changes in other laboratory studies as well as in patient vital signs and weight from baseline to treatment week 12 were not significantly different between the two groups.
The results of this randomized, double-blind, placebo-controlled trial have confirmed our previous open-label findings that low-dose gabapentin is effective in treating hot flashes in postmenopausal women. A significant difference between the gabapentin and placebo groups was apparent after 12 weeks of therapy, and this difference was consistent throughout the double-blind study. Subsequent, open-label data showed that most patients (86.4%) were satisfied with moderate gabapentin doses (up to 1800 mg per day) to treat their hot flashes. The Patient Global Impression of Change Scale and Pittsburgh Sleep Quality Index non–hot flash secondary outcome variables tended to favor gabapentin treatment; however, the Profile of Mood States and Short Form-36 Health Survey did not (Table 2). Gabapentin treatment was preferred to no treatment, as 81.5% of patients requested to continue gabapentin treatment after the open-label study was completed. There were no gabapentin withdrawal symptoms reported by any patients who withdrew from the study or by any patients at study completion.
In the double-blind study, gabapentin adverse events were similar to those found in previous studies10,11 and consisted mostly of somnolence and dizziness during the initial few weeks of therapy. In our experience, gabapentin's side effects can be effectively managed by maintaining a gradual titration, as performed in this study, and by taking the medication with meals. To our knowledge, this is the first report to associate gabapentin with a significant decrease in serum total protein. Peripheral edema is a known side effect of gabapentin10 and led to two patient withdrawals from our study. It would be interesting to determine if serum protein levels are further decreased in such patients experiencing peripheral edema.
Despite patient randomization in this study, there were some group differences in patient baseline characteristics (Table 1), most notably, duration of hot flashes and Profile of Mood States Total Mood Disturbance score, both of which tended to be higher in the gabapentin group. Analyses that adjusted for these baseline characteristics did not affect the results. Although gabapentin does have clinical anxiolytic effects,14,15 it is unlikely that this mode of action accounts for the associated improvement in hot flashes because gabapentin did not affect the tension/anxiety subscale or the total mood disturbance score as measured by the Profile of Mood States (Table 2). On the other hand, gabapentin's potentially sedative side effects may have played a role in a reduced perception of nighttime hot flashes. The hot flash diary used in this study reflected a placebo effect equivalent to those reported in other recent hot flash studies using a conventional diary.21,22
Another nonhormonal, alternative hot flash therapy shown to be effective is the antidepressant venlafaxine. A recent double-blind, placebo-controlled study in breast cancer patients showed a significant benefit for venlafaxine therapy over placebo after 4 weeks of treatment.21 A majority of the patients (69%) were taking tamoxifen, which is known to cause hot flashes, making it unclear if these results can be generalized to non–tamoxifen-using, postmenopausal women with hot flashes. Also, long-term efficacy for venlafaxine may not be inferred after 4 weeks of treatment. For example, belladonna–ergotamine tartrate–phenobarbital has been shown to have significant benefit over placebo in the treatment of hot flashes after 4 weeks but to no longer be efficacious after 8 weeks of treatment.23 The US Food and Drug Administration recommends at least 12 weeks of double-blind therapy for clinical trials on hot flash therapies.24 Other alternative hot flash therapies, such as black cohosh, clonidine, soy, vitamin E, selective serotonin re-uptake inhibitors, and methyldopa have either not been studied in controlled trials, show inconsistent findings in clinical trials, or have limited efficacy and/or poor tolerability.22,25–31
Gabapentin's mechanism of action is unknown; however, modulation of calcium currents may be involved, as gabapentin has been shown to inhibit neuronal calcium currents in vitro,32 and gabapentin's binding site is known to be on the α2δsubunit of voltage-gated calcium channels.32,33 In an animal model of neuropathic pain, the gabapentin-binding site was shown to upregulate 17-fold selectively in rat dorsal root ganglion in response to peripheral nerve injury.34 This marked upregulation may be involved with gabapentin's efficacy in the treatment of neuropathic pain. Similar localized plasticity of this binding site in the central nervous system in response to the estrogen-deprived state could play a role in gabapentin's efficacy in the treatment of hot flashes. The pathophysiology of hot flashes is also unknown; however, there is evidence that elevated levels of tachykinin neurotransmitters in the arcuate nucleus of the hypothalamus are involved.35,36 The arcuate nucleus has direct connections with a central temperature regulatory center that has been implicated in hot flash physiology.37 Gabapentin binding sites have not been localized to the hypothalamus in male rats, but female species have yet to be studied. We speculate that mitigation of hypothalamic tachykinin activity is involved in gabapentin's mechanism of action in the treatment of hot flashes. Further studies are needed to address this hypothesis.
In addition, further randomized controlled trials using higher doses of gabapentin in postmenopausal women, as well as in populations with treatment-induced hot flashes caused by medications such as tamoxifen, raloxifene, or leuprolide, are merited.
1. Oldenhave A, Jaszmann LJ, Haspels AA, Everaerd WT. Impact of climacteric on well-being. A survey based on 5213 women 39 to 60 years old. Am J Obstet Gynecol 1993;168:772–80.
2. Hammar M, Berg G, Fahraeus L, Larsson-Cohn U. Climacteric symptoms in an unselected sample of Swedish women. Maturitas 1984;6:345–50.
3. Erlik Y, Tataryn IV, Meldrum DR, Lomax P, Bajorek JG, Judd HL. Association of waking episodes with menopausal hot flushes. JAMA 1981;245:1741–4.
4. Colditz GA, Hankinson SE, Hunter DJ, Willett WC, Manson JE, Stampfer MJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995;332:1589–93.
5. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321–33.
6. Bush TL, Whiteman M, Flaws JA. Hormone replacement therapy and breast cancer: A qualitative review. Obstet Gynecol 2001;98:498–508.
7. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605–13.
8. Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC, Shumaker SA, Snyder TE, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343:522–9.
9. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/ Progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49–57.
10. Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the treatment of postherpetic neuralgia: A randomized controlled trial. JAMA 1998;280:1837–42.
11. Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, Hes M, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: A randomized controlled trial. JAMA 1998;280:1831–6.
12. Mathew NT, Rapoport A, Saper J, Magnus L, Klapper J, Ramadan N, et al. Efficacy of gabapentin in migraine prophylaxis. Headache 2001;41:119–28.
13. Ondo W, Hunter C, Vuong KD, Schwartz K, Jankovic J. Gabapentin for essential tremor: A multiple-dose, double-blind, placebo-controlled trial. Mov Disord 2000;15:678–82.
14. Pande AC, Pollack MH, Crockatt J, Greiner M, Chouinard G, Lydiard RB, et al. Placebo-controlled study of gabapentin treatment of panic disorder. J Clin Psychopharmacol 2000;20:467–71.
15. Pande AC, Davidson JR, Jefferson JW, Janney CA, Katzelnick DJ, Weisler RH, et al. Treatment of social phobia with gabapentin: A placebo-controlled study. J Clin Psychopharmacol 1999;19:341–8.
16. Guttuso TJ Jr. Gabapentin's effects on hot flashes and hypothermia. Neurology 2000;54:2161–3.
17. Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: A new instrument for psychiatric practice and research. Psychiatry Res 1989;28:193–213.
18. McNair D, Lorr M, Droppleman L. Profile of Mood States: Manual. San Diego: Educational and Industrial Testing Service, 1981.
19. Ware J Jr, Snow K, Konsinski M, Gandek B. SF-36 Health Survey: Manual and interpretation guide. Boston: The Health Institute, New England Medical Center, 1993.
20. Hettmansperger T. Statistical inference based on ranks. New York: John Wiley & Sons, 1984.
21. Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, LaVasseur BI, Barton DL, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: A randomised controlled trial. Lancet 2000;356:2059–63.
22. Albertazzi P, Pansini F, Bonaccorsi G, Zanotti L, Forini E, De Aloysio D. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol 1998;91:6–11.
23. Bergmans MG, Merkus JM, Corbey RS, Schellekens LA, Ubachs JM. Effect of Bellergal Retard on climacteric complaints: A double-blind, placebo-controlled study. Maturitas 1987;9:227–34.
24. U.S. Department of Health and Human Services, Food and Drug Administration. Guidance for clinical evaluation of combination estrogen/progestin-containing drug products used for hormone replacement therapy of postmenopausal women, 1977. Available at: http://www.fda.gov/cder/guidance/old054fn.pdf
. Accessed 2002 June 3.
25. Jacobson JS, Troxel AB, Evans J, Klaus L, Vahdat L, Kinne D, et al. Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. J Clin Oncol 2001;19:2739–45.
26. Goldberg RM, Loprinzi CL, O'Fallon JR, Veeder MH, Miser AW, Mailliard JA, et al. Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol 1994;12:155–8.
27. Pandya KJ, Raubertas RF, Flynn PJ, Hynes HE, Rosenbluth RJ, Kirshner JJ, et al. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: A University of Rochester Cancer Center Community Clinical Oncology Program study. Ann Intern Med 2000;132:788–93.
28. Quella SK, Loprinzi CL, Barton DL, Knost JA, Sloan JA, LaVasseur BI, et al. Evaluation of soy phytoestrogens for the treatment of hot flashes in breast cancer survivors: A North Central Cancer Treatment Group Trial. J Clin Oncol 2000;18:1068–74.
29. Barton DL, Loprinzi CL, Quella SK, Sloan JA, Veeder MH, Egner JR, et al. Prospective evaluation of vitamin E for hot flashes in breast cancer survivors. J Clin Oncol 1998;16:495–500.
30. Stearns V, Isaacs C, Rowland J, Crawford J, Ellis MJ, Kramer R, et al. A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil) in controlling hot flashes in breast cancer survivors. Ann Oncol 2000;11:17–22.
31. Nesheim BI, Saetre T. Reduction of menopausal hot flushes by methyldopa. A double blind crossover trial. Eur J Clin Pharmacol 1981;20:413–6.
32. Stefani A, Spadoni F, Bernardi G. Gabapentin inhibits calcium currents in isolated rat brain neurons. Neuropharmacology 1998;37:83–91.
33. Gee NS, Brown JP, Dissanayake VU, Offord J, Thurlow R, Woodruff GN. The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel. J Biol Chem 1996;271:5768–76.
34. Luo ZD, Chaplan SR, Higuera ES, Sorkin LS, Stauderman KA, Williams ME, et al. Upregulation of dorsal root ganglion (alpha)2(delta) calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats. J Neurosci 2001;21:1868–75.
35. Rance NE, Young WS. Hypertrophy and increased gene expression of neurons containing neurokinin-B and substance-P messenger ribonucleic acids in the hypothalami of postmenopausal women. Endocrinology 1991;128:2239–47.
36. Abel TW, Voytko ML, Rance NE. The effects of hormone replacement therapy on hypothalamic neuropeptide gene expression in a primate model of menopause. J Clin Endocrinol Metab 1999;84:2111–8.
© 2003 The American College of Obstetricians and Gynecologists
37. Akesson TR, Simerly RB, Micevych PE. Estrogen-concentrating hypothalamic and limbic neurons project to the medial preoptic nucleus. Brain Res 1988;451:381–5.