Several studies indicate that there is a relationship between ovarian hormones and central nervous system function. Progesterone and certain metabolites of it (such as, 3α, 5α-tetrahydroprogesterone; allopregnanolone, 3α, 5β-tetrahydroprogesterone; and pregnenolone) are potent positive allosteric modulators of γ-aminobutyric acid (GABA) type A receptors (1,2). On administration, these steroids exhibit clear behavioral effects that include anxiolysis (3), sedation (4), and analgesia (5). They are anticonvulsant (6), and at large doses they induce a state of general anesthesia (7). Progesterone and 3 α reduced steroids produce a benzodiazepine-like sleep electroencephalogram profile in rats (8,9) and humans (10). Several theories have been proposed to explain the mechanism of action of inhaled anesthetics (11–13). The GABA system has been suggested as a major substrate for the anesthetic effect of inhaled anesthetics (11). The action of progesterone on inhaled anesthetic requirements has not been established in nonpregnant females. Progesterone secretion equals a few milligrams per day in the follicular phase of the menstrual cycle but increases to 20–30 mg/d in the luteal phase (14). In this study, anesthetic requirement was compared in women in the follicular phase (low progesterone levels) versus women in the luteal phase (high progesterone levels).
After approval of the ethics committee and written informed consent, 40 adult female patients undergoing ear-nose-throat surgery were included in this study. The surgeries performed were septorhinoplasty and tympanomastoidectomy. Twenty patients with menstrual cycle days from 1 to 10 (follicular group) and 20 patients with menstrual cycle days from 18 to 24 (luteal group) were included in the study. Exclusion criteria included renal, hepatic, or neurological dysfunction, alcoholism or use of benzodiazepines, anticonvulsants, or opioids, and irregular menstrual cycles.
None of the patients was premedicated. The Aspect A 2000 bispectral index (BIS) monitor (Aspect Medical Systems, Natrick, MA) was used in this study. In all cases, the BIS sensor was applied to the forehead and connected to the patient via an interface cable and digital signal converter before the induction of anesthesia along with the standard monitors. Anesthesia was standardized in all patients and induced with fentanyl 1 μg/kg, thiopental 5–7 mg/kg, and rocuronium 0.5 mg/kg. Anesthesia was maintained with sevoflurane in a mixture of nitrous oxide 2 L/min and oxygen 2 L/min, and the lungs of all patients were mechanically ventilated to maintain an ETco 2 concentration of 30–37 mm Hg. BIS was used to guide administration of sevoflurane. The BIS target range during maintenance was 40–60. No further fentanyl was given during surgery. Inspiratory and end-tidal concentrations of sevoflurane and ETco2 were measured by Dräger Cato SW-Version 2.0 (Lübeck, Germany). Heart rate (HR), noninvasive arterial blood pressure, arterial oxygen saturation (Sao2) were also measured (Dräger Cato pm 8040) and recorded during surgery. All measurements were recorded at 5-min intervals. We calculated a minimum alveolar anesthetic concentration (MAC)-h (the average value for MAC over the course of an hour) for each of the groups.
To determine the progesterone levels, a competitive chemiluminescent enzyme immunoassay method was used (IMMULITE 2000 Analyzer, Inter Medico, Markham, Ontario, Canada) and blood samples were taken from all patients before surgeries.
Data are expressed as the mean ± sd. Statistical analysis was performed using the GraphPad InStat (ver2.02; GraphPad Software, San Diego, CA). Parametric data were analyzed using a t-test. Pearson correlation analysis was used for the relationships between progesterone concentration and end-tidal sevoflurane concentration. P < 0.05 was considered as statistically significant.
The demographic characteristics of the patients in the two groups (Table 1) did not differ except for the day of the menstrual cycle and the progesterone levels. Both of these differed significantly (P < 0.001). End-tidal concentrations of sevoflurane in the follicular group exceeded those in the luteal group during the maintenance phase of anesthesia (Fig. 1). The end-tidal concentration of sevoflurane correlated with the progesterone concentrations (Fig. 2; P = 0.003).
The mean preinduction BIS values were 96.7 ± 1.2 in the follicular group and 96.7 ± 1.3 in the luteal group (P = 0.90). In both groups, BIS values during surgery were similar, being 46.1 ± 2.1 in the follicular group and 46.3 ± 2.8 in the luteal group (P = 0.78).
Progesterone levels were 0.86 ± 0.30 ng/mL in the follicular group and 7.48 ± 3.86 ng/mL in the luteal group. End-tidal sevoflurane concentrations calculated as MAC-h were 1.55 ± 0.18 in the follicular group and 1.3 ± 0.13 in the luteal group. There was a statistically significant difference between the two groups (P < 0.0001).
The hemodynamics data (mean arterial blood pressure and HR) of the patients are shown in Table 2. There were no differences in HR, noninvasive arterial blood pressure, Sao2, and ETco2 between the groups.
This study demonstrates that the increased serum progesterone concentrations found during the luteal phase of the menstrual cycle correlate with a decrease in anesthetic requirement. Progesterone is the most important progestin in humans. In addition to having important hormonal effects, it has cerebral depressant and hypnotic effects (15). It is synthesized in the ovary and adrenal from circulating cholesterol. Large amounts are also synthesized and released by the placenta during pregnancy. In the ovary, progesterone is produced primarily by the corpus luteum. Including the small contribution from the adrenal, the blood production rate of progesterone in the preovulatory phase is <1 mg/d. Progesterone levels normally increase after ovulation and peak approximately eight days after luteinizing hormone surge. Therefore, patients with menstrual cycle days from 1 to 10 and 18 to 24 were included in this study. We found that progesterone levels were 0.86 ± 0.30 ng/mL in the follicular group and 7.48 ± 3.86 ng/mL in the luteal group.
Menstrual cycle length is determined by the rate and quality of follicular growth and development, and it is normal for the cycle to vary in an individual. From age 25 to 35 years, more than 60% of cycles are between 25 and 28 days in length (16). Most women have cycles that last from 24 to 35 days, but at least 20% of women experience irregular cycles (16). Therefore, it may be difficult to predict the luteal phase. In our study, however, we determined the luteal phase by measuring the progesterone level.
BIS is a calculated multifactorial variable derived from the electroencephalogram. BIS has been proposed as a measure of the hypnotic component of anesthesia. BIS is a dimensionless variable between 0 and 100 that correlates with the degree of sedation (17,18). BIS values between 40 and 60 are proposed to indicate a sufficient depth of anesthesia excluding intraoperative awareness (19). High-frequency signals such as electrical devices, electrocardiogram, and electromyogram, potentially increase BIS (20). Conversely, a decrease of BIS after the administration of neuromuscular relaxants was suggested (21). It is a limitation of our study that we used BIS (over such a wide range) instead of MAC to determine the anesthetic requirement. Moreover, the presence of progesterone may alter the BIS value without truly altering anesthetic requirement. However, numerous studies have been published showing advantages of BIS-monitored and -guided anesthesia over standard clinical practice (22–24). In both groups, BIS values during surgery were similar, being 46.1 ± 2.1 in the follicular group and 46.3 ± 2.8 in the luteal group. The lack of monitoring of temperature is another limitation of our study because MAC for volatile anesthetics decreases by 4%–5% per degree centigrade decrease in core temperature (25,26). However, progesterone has thermogenic properties and increases basal body temperature. Basal body temperature is generally low during the follicular phase of the cycle, then modestly higher (0.2°C–0.4°C) during the luteal phase, and decreases again to baseline levels just before or after the onset of menses (27).
Animal studies demonstrate that the requirement for inhaled anesthetics is decreased by up to 40% during pregnancy (28). Reduced MAC has also been demonstrated during early pregnancy (10–12 weeks’ gestation) (29) and in the immediate (24–36 hours) postpartum period (30). The sedative effects of increased levels of progesterone were proposed as a mechanism, and rabbits given exogenous progesterone show a reduced halothane MAC (31). One study suggests that the phase of the menstrual cycle is irrelevant to MAC in Japanese women (32). This result contrasts with the results of our study in which anesthetic requirement was based on BIS. Although two studies of primarily white patients demonstrated no difference in MAC for women versus men (33,34), two studies of Japanese patients found smaller MAC values in women (35,36). We studied women in two phases of their menstrual cycles. Differences between race or study protocols may explain the contrasting results. For example, MAC is a spinally-determined anesthetic phenotype. In contrast, the BIS reflects actions on higher centers. The pain threshold varies as a function of the menstrual cycle (37), doing so in a manner that would seem inconsistent with our results. Women have a higher threshold to pain in the follicular phase than in preovulatory, luteal, or premenstrual phases. Women are most sensitive to ischemic, thermal, and pressure pain during the luteal phase (37–39). Despite a predicted increase in pain sensitivity in the luteal phase, we found a decrease in anesthetic requirement during this phase. Such a finding suggests that perception of pain does not materially influence BIS values at anesthetizing concentrations of sevoflurane plus nitrous oxide.
We conclude that increased progesterone levels during the luteal phase of the menstrual cycle decrease anesthetic requirement as defined by BIS. Our results are also consistent with a difference between anesthetic depth as measured by BIS and as measured by MAC.
1. Evans RM. The steroid and thyroid hormone receptor superfamily. Science 1998;240:889–95.
2. Paul SM, Purdy RH. Neuroactive steroids. FASEB J 1992;6:2311–22.
3. Bitran D, Shiekh M, McLeod M. Anxiolytic effect of progesterone is mediated by the neurosteroid allopregnanolone at brain GABAA
receptors. J Neuroendocrinol 1995;7:171–7.
4. Soderpalm AH, Lindsey S, Purdy RH, et al. Administration of progesterone produces mild sedative-like effects in men and women. Psychoneuroendocrinology 2004;29:339–54.
5. Nadeson R, Goodchild CS. Antinociceptive properties of neurosteroids III: experiments with alphadolone given intravenously, intraperitoneally, and intragastrically. Br J Anaesth 2001;86:704–8.
6. Herzog AG. Progesterone therapy in women with complex partial and secondary generalized seizures. Neurology 1995;45:1660–2.
7. Carl P, Högskilde S, Nielsen JW, et al. Pregnanolone emulsion: a preliminary pharmacokinetic and pharmacodynamic study of a new intravenous anaesthetic agent. Anaesthesia 1990;45:189–97.
8. Lancel M, Faulhaber J, Holsboer F, Rupprecht R. Progesterone induces changes in sleep EEG comparable to those of agonistic GABAA
receptor modulators. Am J Physiol 1996;271:763–72.
9. Lancel M, Faulhaber J, Schiffelholz T, et al. Allopregnanolone affects sleep in a benzodiazepine-like fashion. J Pharmacol Exp Ther 1997;282:1213–8.
10. Friess E, Tagaya H, Trachsel L, et al. Progesterone-induced changes in sleep in male subjects. Am J Physiol 1997;272:885–91.
11. Franks NP, Lieb WR. Molecular and cellular mechanisms of general anaesthesia. Nature 1994;367:607–14.
12. Franks NP, Lieb WR. Selective actions of volatile general anaesthetics at molecular and cellular levels. Br J Anaesth 1993;71:65–76.
13. Krasowski MD, Koltchine VV, Rick CE, et al. Propofol and other intravenous anesthetics have sites of action on the |gg-aminobutyric acid type A receptor distinct from that for isoflurane. Mol Pharmacol 1998;53:530–8.
14. Speroff L, Glass RH, Kase NG. Hormone biosynthesis, metabolism, and mechanism of action. In: Clinical gynecologic endocrinology and infertility. 6th ed. Baltimore: Lippincott Williams & Wilkins, 1999: 31–105.
15. Goldfien A. The gonadal hormones & inhibitors. In: Katzung BG. Basic & clinical pharmacology. 7th ed. Stamford, CT: Appleton & Lange, 1998:653–83.
16. Speroff L, Glass RH, Kase NG. Regulation of the menstrual cycle. In: Clinical gynecologic endocrinology and infertility. 6th ed. Baltimore: Lippincott Williams & Wilkins, 1999:200–46.
17. Glass PS, Bloom M, Kearse L, et al. Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane, and alfentanil in healthy volunteers. Anesthesiology 1997;86:836–47.
18. Sebel PS, Lang E, Rampil IJ, et al. A multicenter study of bispectral electroencephalogram analysis for monitoring anesthetic effect. Anesth Analg 1997;86:891–9.
19. Rampil IJ. A primer for EEG signal processing in anesthesia. Anesthesiology 1998;89:980–1002.
20. Hemmerling TM, Fortier JD. Falsely increased bispectral index values in a series of patients undergoing cardiac surgery using forced-air-warming therapy of the head. Anesth Analg 2002;95:322–3.
21. Bruhn J, Bouillon TW, Shafer SL. Electromyographic activity falsely elevates the bispectral index. Anesthesiology 2000;92:1485–7.
22. Johansen JW, Sebel PS, Sigl JC. Clinical impact of hypnotic titration guidelines based on EEG bispectral index (BIS) monitoring during routine anesthetic care. J Clin Anesth 2000;12:433–43.
23. Pavlin DJ, Hong JY, Freund PR, et al. The effect of bispectral index monitoring on end-tidal gas concentration and recovery duration after outpatient anesthesia. Anesth Analg 2001;93:613–9.
24. Wong J, Song D, Blansbard H, et al. Titration of isoflurane using BIS index improves early recovery of elderly patients undergoing orthopedic surgeries. Can J Anaesth 2002;49:13–8.
25. Regan MJ, Eger EI II. Effect of hypothermia in dogs on anesthetizing and apneic doses of inhalation agents: determination of the anesthetic index (apnea/MAC). Anesthesiology 1967;28:689–700.
26. Eger EI II. Age, minimum alveolar anesthetic concentration, and minimum alveolar anesthetic concentration-awake. Anesth Analg 2001;93:947–53.
27. Speroff L, Fritz MA. Female infertility. In: Clinical gynecologic endocrinology. 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2005:1013–69.
28. Palahniuk RJ, Shnider SM, Eger EI II. Pregnancy decreases the requirement for inhaled anesthetic agents. Anesthesiology 1974;41:82–3.
29. Gin T, Chan MT. Decreased minimum alveolar concentration of isoflurane in pregnant humans. Anesthesiology 1994;81:829–32.
30. Chan, MT, Gin T. Postpartum changes in the minimum alveolar concentration of isoflurane. Anesthesiology 1995;82:1360–3.
31. Datta S, Migliozzi RP, Flanagan HL, Krieger NR. Chronically administered progesterone decreases halothane requirements in rabbits. Anesth Analg 1989;68:46–50.
32. Tanifuji Y, Mima S, Yasuda N, et al. Effect of menstrual cycle on MAC (in Japanese). Masui 1988;37:1240–2.
33. Eger EI II, Laster, MJ, Gregory GA, et al. Women appear to have the same minimum alveolar concentration as men. Anesthesiology 2003;99:1059–61.
34. Wadhwa A, Durrani J, Sengupta P, et al. Women have the same desflurane minimum alveolar concentration as men. Anesthesiology 2003;99:1062–5.
35. Katoh T, Ikeda K. The effects of fentanyl on sevoflurane requirements for loss of consciousness and skin incision. Anesthesiology 1998;88:18–24.
36. Katoh T, Kobayashi S, Suzuki A, et al. The effect of fentanyl on sevoflurane requirements for somatic and sympathetic responses to surgical incision. Anesthesiology 1999;90:398–405.
37. Riley JL III, Robinson, ME, Wise EA, Price DD. A meta-analytic review of pain perception across the menstrual cycle. Pain 1999;81:225–35.
38. Veith JL, Anderson J, Slade SA, et al. Plasma beta-endorphin, pain thresholds and anxiety levels across the human menstrual cycle. Physiol Behav 1984;32:31–4.
39. Pfleeger M, Straneva PA, Fillingim RB, et al. Menstrual cycle, blood pressure and ischemic pain sensitivity in women: a preliminary investigation. Int J Psychophysiol 1997; 27:161–6.