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Increased Progesterone Production During the Luteal Phase of Menstruation May Decrease Anesthetic Requirement

Erden, Veysel, MD*; Yangn, Zehra, MD; Erkalp, Kerem, MD*; Delatioğlu, Hamdi, MD*; Bahçeci, Feyza, MD*; Seyhan, Ayşe, MD

Section Editor(s): White, Paul F.

doi: 10.1213/01.ane.0000168271.76090.63
Ambulatory Anesthesia: Research Report
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Besides having important hormonal effects, progesterone has depressant and hypnotic effects on the brain. In this study, we compared women in the follicular phase with low progesterone levels and in the luteal phase with high progesterone levels regarding their anesthetic requirements. 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. Anesthesia was induced with fentanyl and thiopental; relaxation was secured with rocuronium, and anesthesia was maintained with a mixture of nitrous oxide 2 L/min and oxygen 2 L/min plus sevoflurane. The delivered sevoflurane concentration was adjusted to sustain a constant bispectral index value that averaged 46 in both groups. To determine the progesterone levels, blood samples were taken from all patients before surgery. 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. The minimum alveolar anesthetic concentration (MAC)-hour (MAC-h) value of sevoflurane in the follicular group (1.55 ± 0.18 MAC-h) was significantly larger than in the luteal group (1.3 ± 0.13 MAC-h) (P < 0.0001). The sevoflurane requirements were larger in the follicular group during the maintenance phase of anesthesia. In conclusion, high progesterone levels during the luteal phase might be the cause of decreased anesthetic requirement.

IMPLICATIONS: The aim of this study was to determine the effect of high progesterone levels on anesthetic requirement. We measured progesterone levels before surgery and calculated the sevoflurane dose (MAC-h) required to maintain a constant bispectral index value. The dose of sevoflurane correlated inversely with serum progesterone concentrations.

*Departments of Anesthesiology and †Obstetrics/Gynecology, SSK Vakıf Gureba Hospital, Istanbul, Turkey

Accepted for publication April 15, 2005.

Address correspondence and reprint requests to Zehra Yangın, MD, Siyavuşpaşa cad. Lale sok. No: 8/20 Bahçelievler, Istanbul. Address e-mail to zehrayangin@hotmail.com or zehrayangin@yahoo.com.

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).

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Methods

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.

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Results

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).

Table 1

Table 1

Figure 1.

Figure 1.

Figure 2.

Figure 2.

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.

Table 2

Table 2

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Discussion

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.

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