1 Department of Microbiological Science and Gynaecological Science, 2 Research Group for Sexology, Section of Dept for Gynaecological Science, and 3 Institute of Otorhinolaryngology, University of Catania, Catania, Italy
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Abstract |
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Key words: menstrual cycle/olfactometry/oral contraceptives/rhinomanometry
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Introduction |
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One of the variables associated with changes in female hormonal status is oral contraceptive (pill) intake. Worldwide there are currently ~400 million contraceptive users, with ~1/6 taking the pill. Use of the pill declines with age; 75% of users are 1930 years.
Oral contraceptives influence the olfactory performance of women (Wedekind and Furi, 1997). Just before and during ovulation, women preferentially seek men who evidence phenotypic markers of genetic benefits. These subjects are defined as symmetrical men. Normally-ovulating women using a contraceptive pill show no significant preference for the scent of either symmetrical or asymmetrical men, with respect to normally-cycling women, who tend to prefer the scent of shirts worn by symmetrical men during the ovulatory phase of the cycle (Gangestad and Thornhill, 1998
). The contact between odorous substances and receptors could depend on flow quantity and trans-nasal pressure during respiration. In turn, the contact between substances and receptors could depend on the different degree of oedema of the nasal mucous during the three phases of the menstrual cycle. Accessibility of odourants to the olfactory epithelium may vary with cyclical changes in the mucus layer, thus resulting in changes in olfactory sensitivity (Mair et al., 1978
). The combined effect of these variables may convey a message of increased alertness and attention during ovulation. Threshold values are subject to large individual differences and can vary considerably. This variation may be due, in part, to the different methodologies employed by various investigators.
Several psychophysical tests are available to assess the sense of smell in a clinical setting. These tests can be useful in differential diagnosis and in assessing the extent of chemosensory loss. Tests of olfactory sensitivity employ squeezable polypropylene bottles containing pyridine (Amoore and Ollman, 1983) or butane (Cain et al., 1983
). Another test, which measures suprathreshold function, is the University of Pennsylvania Smell Identification Test (Doty, 1997
).
From previous studies, it seems that there is currently only fragmentary research being carried out on olfactory cyclicity in oral contraceptive users. Thus, rhinomanometry could be useful in evaluating the olfactory differences during oral contraceptive use, and the olfactory threshold could depend on rhinomanometric characteristics.
Any endogenous or iatrogenic hormonal modification can influence physiological and dysfunctional mechanisms, and the following study was set up to investigate ways in which the airflow and olfactory threshold change during the use of oral contraceptives with respect to the different phases of the menstrual cycle. Although the results may not be clear, it appears that there may be a cause and effect relationship among oral contraceptives and olfaction. This was the end-point. A prospective trial was set up in which the airflow and olfactory threshold changes before and after taking oral contraceptives in premenopausal cyclic women were studied.
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Materials and Methods |
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Subjects
Sixty-four healthy volunteers ranging from 1840 years (mean age 28.2 ± 4.1), who were attending the Family Planning Centre and were planning to take oral contraceptives, participated in the study. All subjects had normal body mass index (23.1 ± 1.4 kg/m2). None was using any oral contraceptive. Each woman had no subjective olfactory pathology during enrolment. Subjects with tobacco use and/or drug abuse were excluded from the study. Moreover, the women enrolled in the study did not have any dysendocrinism and no metabolic or neoplastic pathologies. Menstrual cycles were regular (mean cycle length 28.5 ± 3.1 days), with ovulation. To confirm the ovulatory cycle, sonography was performed on day 10, 12 and 15 of the cycle, and serum progesterone concentrations were measured at day 21 and 25 of the cycle. Hormone concentrations were measured by enzyme-linked immunoassorbent assay (ELISA) using commercially available kits (Roche, Monza, Italy). Menstrual cycle was defined as ovulatory when the serum progesterone was >18 IU/ml.
Clinical Testing
Each woman was referred to the Olfactology Service to evaluate both the objective and the instrumental aspects. All women underwent ear, nose and throat checks to look for inflammation of the upper airways. Screening tests using endoscopy, rhinomanometry and olfactometry were carried out.
Endoscopy was used because it can aid in the differential diagnosis of olfactory dysfunctions. We used a Pentax FNL 10S endoscope (Pentax, Asahi Optical, Osaka, Japan) with a television camera and an SWHS AG: 4700 VHS Panasonic recorder (Matsushita Electric Industrial Co., Osaka). This permitted an unobstructed view of the nasal cavity and the rhinopharynx, without using a local anaesthetic, and the subsequent recording of the images obtained. Rhinomanometry is defined as the simultaneous measurement of nasal airflow resistance (R) before and after nasal decongestion during spontaneous respiration. This resistance can be expressed by the formula R = P/V, where P is the trans-nasal pressure and V is the volume of airflow. We used a Rhinospir 164 (Sibelmed, Barcelona, Spain) for this test. To test the olfactory threshold we used the Fortunato-Niccolini olfactometer (Fortunato-Niccolini, Catania, Italy) with six different odour substances. To evaluate the sensitivity differences during the menstrual cycle, rhinomanometric and olfactometric surveys were carried out during the follicular phase (day 58), the periovular phase (day 1316) and the luteal phase (day 1823). Rhinomanometry was performed on each woman during both inhalation and exhalation, with trans-nasal pressure ranging between 300 and 300 mmHg, and with airflow ranging between 800 and 800 cm3/s.
The substances used to test olfactory sharpness with the Fortunato-Niccolini olfactometer were among the best known monomolecular substances and the most suitable for a complete investigation: anise and musk-ketone with an exclusive olfactory component; clove and pyridine which, apart from the olfactory effect, add to the stimulation of taste and trigeminal terminations; citral with an exclusive olfactory and trigeminal effect; ammonia with a prevalent trigeminal component (Fortunato et al., 1972; Murphy and Cain, 1980
; Lawless and Zwillenberg, 1983
; Keverne et al., 1986
). Each substance was used in the liquid state. Anise, musk-ketone, citral and clove were pure essences; pyridine was a pure liquid substance; ammonia was a liquid substance diluted to 22% in distilled water (Pharmacia, Milan, Italy). We considered the olfactory coefficient of each substance, which is the quantity of odorous air sufficient to reach the level of identification >5 s: 2 ml for anise, musk-ketone, citral and clove; 0.5 ml for ammonia; 1 ml for pyridine. Usually, subjects who do not perceive any substance in the range of its specific olfactory coefficient >5 s are defined as being affected by hyposmia/anosmia. The Fortunato-Niccolini olfactometer is shown in Figure 1
. Each odour was delivered to the nasal mucous during normal inspiration. Bearing in mind the different degree of edema of nasal mucous during the three phases of the menstrual cycle, the test was repeated for each of the odorous substances until the patient no longer perceived the odour, by stopping the pressure syringe system. The threshold perception was given by the smallest volume of air able to make the subject perceive the odour.
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Oral Contraceptives
After clinical testing, oral contraceptives were prescribed to each woman. Table I shows the types and formulations of the monophasic oral contraceptives containing either gestodene or desogestrel used for the subjects. During month 3 of oral contraception, rhinomanometric and olfactometric surveys were performed at day 7, 14, and 21.
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Rhinomanometric values between phases of the menstrual cycle were explored using Spearman's rank correlation. The rhinomanometric values of each phase of the menstrual cycle were compared with those obtained from the oral contraceptive intake using Wilcoxon's rank sum test. Olfactometric values obtained from each phase of the menstrual cycle were compared to the other phases by analysis of variance. Paired data t-test was used to compare each phase of the menstrual cycle to the oral contraceptive values. Finally, two-sided t-test for independent samples was used to compare the effects of the two monophasic oral contraceptives on both rhinomanometric and olfactometric aspects. All reported values are given as means ± SD. The differences were considered statistically significant for P 0.05. Each statistical analysis was carried out using a software package for TMWindows 95 (Glantz, Primer of Biostatistics, McGraw-Hill, Inc. New York, 1997).
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Results |
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Figure 2 shows both the inhalation and exhalation rhinomanometric values obtained during the menstrual cycle and during contraceptive use. For each menstrual phase and during contraceptive use, mean trans-nasal pressure with respect to the airflow value during inhalation and the exhalation time of the right nasal cavity was similar to that of the left nasal cavity (P = NS). Each woman had a higher, but not statistically significant, airflow during the periovular phase than during the follicular and luteal phases. Table II
shows the rank correlation analysis with Spearman's rank correlation coefficient of the values between the phases of the menstrual cycle. Table III
shows the Wilcoxon's rank sum statistical comparisons of inhalation and exhalation rhinomanometric values obtained during the oral contraceptive intake with those of each menstrual phase. The values of rhinomanometric surveys in pill users were statistically different from those of the luteal phase (P < 0.02), the follicular phase (P < 0.001) and the periovular phase (P < 0.001) of the menstrual cycle.
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Discussion |
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The olfactory threshold to odours seems to depend on variations of the ovarian steroids more than on the airflow and trans-nasal pressure. These events can depend on the action of the different qualitative and qualitative ovarian hormones during the menstrual ovulatory cycle.
We observed that the highest degree of olfactory sensitivity coincides with ovulation. Other authors did not find any changes in the olfactory sensitivity during the menstrual cycle, probably due to the fact that the exact time of ovulation was not determined (Amoore and Ollman, 1983; Cain et al., 1983
). We confirmed, by sonography and by measuring the serum levels of progesterone, that the menstrual cycle of each womanat the time during which the rhinomanometric and the olfactometric tests were performedwas an ovulatory one.
Our data seem to show that iatrogenic steroids, such as those contained in oral contraceptives, may affect changes in smell sensitivity. In fact, olfactory surveys emphasized that (i) smell parameters did not have any significant fluctuation with respect to those noted before pill use, during which it was possible to observe different values during the three phases of the menstrual cycle; (ii) although they were statistically different, both rhinomanometric and olfactometric values during pill use showed linear outlines similar to those of the luteal phase of the menstrual cycle. The latter aspect could emphasize the particular feature of the monophasic pills whose hormonal activities are mainly progestative, similar to the natural events of luteal phase of the menstrual cycle.
Moreover, there are changes of sexual functioning during the menstrual cycle. Women report less desire to engage in sexual activity and less frequent sexual activity during the late luteal phase than during the other phases of their menstrual cycle (Clayton et al., 1999). This could depend on female midcycle total testosterone or free testosterone peak (Morris et al., 1987
).
Among pill-users substantially lower levels of free testosterone have been observed (Brancroft et al., 1991). Both endocrine and psycho-relational elements may interact (Dei et al., 1997
). Libido depends on the free testosterone concentrations. Sex hormone-binding globulin concentrations are increased and, therefore, free testosterone concentrations seem to be affected by the use of birth control pills (DeCherney, 2000
). The Kallman syndrome, a disorder characterized by hypogonadotrophic hypogonadism and anosmia, could help in understanding the loss of libido during oral contraceptive use. The syndrome indicates the importance of smell in sexual development through the progenitor cells in the olfactory placode because LH-releasing cells of the hypothalamus arise from these cells (Goldzieher and Zamah, 1995
). The results of some studies did indeed find that the highest rate of coitus during the female cycle occurs around ovulation (Udry and Morris, 1977
). Biologically, odours probably influence reproductive processes in humans and perhaps the notion of concealed ovulation in humans needs rethinking. Pheromones could guide one's sex life (Claus and Karlson, 1983
). Thus, ovarian cycle parameters can be drastically changed by chemical cues originating from both male and female co-specifics. Nevertheless, data about the chemical signals that influence ovarian cycle are quite rare (Maiworm and Langthaler, 1990
; Wobst et al., 1998
).
Although our data have confirmed the existence of changes of olfactory sensitivity during oral contraceptive use with respect to non-using time, further studies are needed to investigate ways in which smell variations could vary the sexual life of the subject.
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Notes |
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References |
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Submitted on March 8, 2001; accepted on July 2, 2001.