Alcohol and Alcoholism Advance Access originally published online on January 31, 2007
Alcohol and Alcoholism 2007 42(2):80-83; doi:10.1093/alcalc/agl094
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MENSTRUAL CYCLE IN WOMEN ADDICTED TO ALCOHOL DURING THE FIRST WEEK FOLLOWING DRINKING CESSATION—CHANGES OF SEX HORMONES LEVELS IN RELATION TO SELECTED CLINICAL FEATURES
SKA1,*
KOWSKI2
-SYPNIEWSKA3PISKI4
1 Department of Pathobiochemistry and Clinical Chemistry, Nicolaus Copernicus University Bydgoszcz, Poland
2 Department of Psychiatry Nursing, Nicolaus Copernicus University Bydgoszcz, Poland
3 Department of Laboratory Medicine, Nicolaus Copernicus University Bydgoszcz, Poland
4 Department of Psychiatry, Collegium Medicum, Nicolaus Copernicus University Bydgoszcz, Poland
*Author to whom correspondence should be addressed at: Department of Pathobiochemistry and Clinical Chemistry, Collegium Medicum, Nicolaus Copernicus University, 9 Curie-Skodowska Street, 85-094 Bydgoszcz, Poland E-mail: augustynska{at}op.pl
Received 23 January 2006; in revised form 11 April 2006; in revised form 31 October 2006; accepted 1 November 2006
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSSTATISTICAL ANALYSISRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Aims: To assess the prevalence of hormonal dysfunction in women addicted to alcohol during first week following drinking cessation; to determine whether fluctuations of hormone levels in follicular, ovulation and luteal phases in addicted women are equal to those normally found in healthy women; to determine the association between hormonal imbalances with selected clinical features. Methods: Biochemical parameters of liver function and hormone levels were assessed in 30 women treated for 30 days in a Short Term Therapy and Detoxification Ward. The following hormones were measured: prolactin (PROL), folliculotropin (FSH), luteotropin (LH), estradiol (ES) and testosterone (TEST)—(i) after menstruation, at follicular phase, between 5th and 7th day of the cycle; (ii) around ovulation, 11-14th day of the cycle; and (iii) before menstruation, at luteal phase, between 19th and 22th day of the cycle. Results: Mean PROL levels in all three cycle phases and progesterone level in follicular phase were above, while mean TEST level was below, the reference values. Over 50% of women had abnormally increased PROL values in all phases of the cycle while decreased values of PROG or LH were found in
50% and >30% of study women. Conclusions: The menstrual cycle disturbances in alcoholic women are most prominent around the middle part of the cycle and age influences the pattern of hormonal changes. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSSTATISTICAL ANALYSISRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The issue of disorders of endocrine system and reproductive function in women with alcohol problem is often overlooked. Alcohol may interfere with the hormonal balance and reproductive function either directly, by activating or inhibiting the neurohormonal axis, or indirectly, by changing liver metabolism of the hormones (Junik and K
ubo-Gwie
dzi
ska, 2004
). Disorders of reproductive system in women with excessive alcohol consumption result from dysfunction of hypothalamus–pituitary–ovaries axis, as well as, from ovaries dysfunction and disruption of regulation mechanisms. The gonads are very sensitive to toxic influence of alcohol (Emanuele et al., 2002a and b; Junik and Kubo-Gwiedziska, 2004). In women the hypothalamus–pituitary–ovaries axis shows characteristic periodical activity known as menstrual cycle (Emanuele et al., 2002a and b; Skaba, 2003; Junik and Kubo-Gwiedziska, 2004). Sex hormones are secreted in a monthly repeated pattern and the physiological biorhythms of the hormone secretion are known (Skaba, 2003). The aims of the study were: to assess the prevalence of hormonal dysfunction in women addicted to alcohol during first week following drinking cessation, to determine whether fluctuations of hormone levels in follicular, ovulation and luteal phases in addicted women are equal to those normally found in healthy women, to determine the association between hormonal imbalances with selected clinical features.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSSTATISTICAL ANALYSISRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We studied 30 women treated for 30 days in Short Term Therapy and Detoxification Ward for Women in Bydgoszcz E.Warminski City Hospital. Their age was 36 ± 6 years, with duration of alcohol dependency of 5 ± 3 years.
Inclusion criteria were: (i) fulfilling alcohol dependency criteria according to ICD-10; (ii) informed, written consent to participate in the study; and (iii) alcohol abstinence period not longer than 7 days.
Exclusion criteria were: (i) dependency on nicotine and/or alcohol; (ii) active phase of extrahepatic disease; (iii) liver impairment other than due to alcohol (serological features of hepatotropic infection and biochemical abnormalities showing metabolic disorders); (iv) intake of hormones and contraceptives.
The amount of alcohol consumed during 30 days preceeding the study was assessed with the WHO Timeline/IDS questionnaire. The alcohol amount in the standard drink was 13.6 g of pure alcohol. In every subject biochemical parameters of liver function and hormone levels were assessed using standard laboratory procedures (Roche Hitach 912 and Elecsys 1010). The following hormones were measured, prolactin (PROL), folliculotropin (FSH), luteotropin (LH), estradiol (ES) and testosterone (TEST): (i) after menstruation, at follicular phase, between 5th and 7th day of the cycle; (ii) around ovulation, between 11th and 14th day of the cycle; and (iii) before menstruation, at luteal phase, between 19th and 22th day of the cycle. For the assessment of hormone and liver enyzmes levels, the following Roche tests were used (reference values in brackets):
- — ES II test (pg/ml): [follicular phase (ES1) 24.5–195, ovulation phase (ES2) 66.1–411, luteal phase (ES3) 40.0–261];
- — LH Luteinizing hormone test (mIU/ml): [follicular phase (LH1) 2.4–12.6, ovulation phase (LH2) 14.0–95.6, luteal phase (LH3) 1.0–11.4];
- —Progesterone II test (ng/ml): [follicular phase (PROG1) 0.2–1.5, ovulation phase (PROG2) 0.8–3.0, luteal phase (PROG3) 1.7–27];
- —Follicle stimulating hormone FSH test (mIU/ml): [follicular phase (FSH1) 3.5–12.5, ovulation phase (FSH2) 4.7–21.5, luteal phase (FSH3) 1.7–7.7];
- — TEST test (ng/ml): (0.06–0.82);
- — PROL test (µIU/ml): (72–511)
- — Aspartate amino transferase AST <31 (U/l)
- — Aspartate amino transferase ALT <32 (U/l)
- — Gamma glutamyl transferase GGT 9–39 (U/l)
- — LH Luteinizing hormone test (mIU/ml): [follicular phase (LH1) 2.4–12.6, ovulation phase (LH2) 14.0–95.6, luteal phase (LH3) 1.0–11.4];
Menstrual phases were assessed based on the clinical interview with the subjects. Study period for all women comprised one full menstrual cycle.
No liver biopsy was performed due to the early stage of abstinence and lack of medical indications for the procedure (Menon et al., 2001). The study was approved by the Local Ethics Committee and written informed consent was obtained from all subjects.
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STATISTICAL ANALYSIS |
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Results are presented as means ± SD. Significance was assessed with Student's t-test for variables not correlated, and with Chi-Squared test or Fisher's exact test (depending on the number of subgroups). The correlations were also assessed with Spearman's non-parametric analysis using statistical software SPSS 12.0.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSSTATISTICAL ANALYSISRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Characteristics of alcohol-dependent women under the study are shown in Table 1.
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Serum levels of hormones: FSH, LH, ES, TEST, PROG, PROL, in each cycle phase, are shown in Table 2. Our results show that mean PROL levels in all three cycle phases were above, progesterone level in follicular phase was above while mean LH level in ovulation phase was below the reference values for healthy women (Table 2).
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Frequency of hormone abnormalities is shown in Table 2. Over 50% of women had abnormally increased PROL values in all phases of the cycle while decreased values of PROG or LH were found in
50% and >30% of study women. Because of the high prevalence of abnormal hormone values, in further analysis the variations of hormone levels in relation to the phase of the cycle were calculated. No difference in mean levels of FSH and PROG in follicular phase in relation to their mean levels in ovulation phase was detected, as well as lack of differences in mean levels of LH and ES in the ovulation phase in relation to their mean levels in luteal phase.
Spearman's non-parametric analysis was also used, with age, time of dependence, number of drinking days during 30 days prior to the study, as independent variables and with respective hormone value as dependent variable. Results are shown in Table 3.
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The relation between hormone levels and selected clinical features (age, time of dependence, number of drinking days during 30 days prior to the study) was assessed. Significant positive correlations were found between age of subjects and FSH1 and ES in the follicular phase. The longer the duration of alcohol-dependence, the higher the TEST levels in the luteal phase.
Positive correlation was found between number of drinking days during 30 days prior to the study and ES levels in the luteal phase. ES levels increased with number of drinking days.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSSTATISTICAL ANALYSISRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The function of the hypothalamic–pituitary–ovarian axis is coordinated and the periodical changes are initiated by the hypothalamus, which generates pulses of GnRH. The target cells for GnRH are gonadotropins of pituitary glands, secreting gonadotropins acting on ovaries. Gonadotropins and ovarian steroid hormones are linked by positive and negative feedback serving as regulatory mechanisms for the whole axis (Emanuele et al., 2002a
; Skaba, 2003). Menstrual cycle can be divided into three phases: follicular, ovulation, and luteal phase. FSH stimulates ES secretion, and the ES pre-ovulation peak level is directly responsible for transitional slight FSH level decrease. The ratio LH/FSH during the follicular phase is constantly rising with distinct LH dominance in the ovulation peak. The ES peak always precedes the LH peak by 8–12 h, as well as the progesterone increase. In luteal phase substantial quantities of progesterone are synthesized by corpus luteum, with maintaining ability for estrogen synthesis.
Androstendione and TEST in serum are relatively stable with slight tendency for increase in ovulation phase. Serum PROL levels do not show such characteristic fluctuation patterns as the gonadotropins during the cycle. Its mean level is only slightly higher during the ovulation and in luteal phase in comparison with follicular phase. (Skaba, 2003).
In women the consequences of alcohol consumption may differ depending on their age (Gill, 2000). Since alcohol use in women has also been linked to earlier menopause we decided to include only women younger than 45 years. Although the results of previous studies on alcohol influence on hormonal homeostasis in alcohol-dependent women have not been unequivocal, most researchers agree that alcohol does influence the circulation and levels of sex hormones (Dorgan et al., 2001; Verkasalo et al., 2001; Register et al., 2002; Spear, 2002).
Women addicted to alcohol suffer from menstrual cycle and reproductive function dysregulation, ranging from cycle irregularities to amenorrhoea and infertility. These dysfunctions are often accompanied by hyperprolactinemia. Alcohol consumption increases PROL levels, which in turn interferes with reproductive functions. Hypersecretion of this hormone in women may increase the dysfunction of the pituitary–ovarian axis caused directly by alcohol (Frias et al., 2002).
Lack of ovulation is associated with reduction or lack of LH secretion. It is consistent with epidemiological data, showing that the increase of cycle dysfunctions is related to increased alcohol consumption. It is known that PROL increase stimulates the decrease of LH level.
Similarly alcohol may cause decrease in LH levels—disturbance of post-translative transport of LH leads to intracellular LH accumulation (Emanuele et al., 2002a and b). Alcohol may interfere with reproductive cycle by the neuroendocrine stimulation—due to decrease of IGF-1: the ability of IGF-1 to increase LH levels is blocked by alcohol. Thus alcohol can disturb the cycle by decreasing IGF-1 stimulation (Emanuele et al., 2002a and b). Our studies show that increase in PROL levels is often accompanied by decrease in LH. LH reduction (together with FSH) was observed by Verkasalo et al. (2001) who stated that both hormones decrease with increase of daily dose of alcohol. According to this author it is possible that this FSH level reduction is caused by increase of ES level, which suppresses FSH secretion. However observations have been made that levels of LH and FSH in women abusing alcohol are not significantly higher (Frias et al., 2002). Most researchers agree that moderate alcohol consumption is associated with progesterone level reduction in women (Gill, 2000). Our studies confirm this observation (Table 2).
Various studies have shown that alcohol consumption increases ES levels in pre-ovulation and luteal phases (Reichman et al., 1993; Emanuele et al., 2002a and b). It is explained by the following: influence of alcohol on sex hormones levels can be stronger when gonadotropins are high (early pregnancy, pre-ovulation LH increase); alcohol induces increase of estrogens, which is caused by dysfunction of hepatocyte metabolism: enzymatic alcohol degradation leads to a shift in NAD/NADH ratio. The accumulation of NADH disturbs the process of ES–estrone conversion. Similarly, the dysfunction can be caused by the overall red–ox state imbalance resulting from alcohol metabolism with an increase in enzymatic conversion of estrone to ES (Sarkola et al., 1999).
However, in other studies on alcohol-dependent and alcohol-abusing women no relation was found in the cycle phases between alcohol consumption and ES levels (Dorgan et al., 1994). The influence of alcohol on menstrual cycle is complex. Some studies show that alcohol consumption (30 g/day) increases the ES levels, but only in the middle of the cycle (Verkasalo et al., 2001). Similarly, Reichman et al. (1993) showed that ES increased around the ovulation phase (Wiktor et al., 2004). In other studies ES increase was observed in all the three cycle phases (Verkasalo et al., 2001). ES, depending on situation, may both stimulate and inhibit the hypophysis–pituitary axis (Emanuele et al., 2002a and b).
In our study, the cycle disturbances were most frequent in ovulation phase, with no relevant ES level deviations, more often it was decreased than increased.
Some authors observe that alcohol consumption leads to a decrease in TEST levels. Various mechanisms explaining this phenomenon have been proposed: inhibition of TEST synthesis, increase of TEST inactivation, increase of peripheral TEST conversion into ES (Emanuele et al., 2002a and b). It seems, however, that alcohol directly inhibits the synthesis and secretion of this hormone (Emanuele et al., 2002).
However, more often increase of TEST level due to alcohol consumption is observed (Emanuele et al., 2002a and b). Since TEST is known to suppress the hypothalamic-pituitary axis, this influence may explain the negative consequences on normal menstrual cycle (Emanuele et al. 2002a and b). Frias et al. (2002) as well as Sarkola et al. (2000, 2001) have observed increased TEST levels in women after acute alcohol consumption. Sarkola showed that the biggest increase occurred in women drinking alcohol while taking oral contraceptives. In women not taking contraceptives the TEST increase was most prominent in the middle of the cycle.
Alcohol can disrupt the delicate balance of the hormonal cycle responsible for normal reproductive function in women. In healthy women the hormone levels change in accordance with the menstrual cycle phase. We found the lack of change in some hormone levels between the cycle phases—it pertains to FSH in follicular and ovulation phases, and reflects the cycle dysregulation.
No relation was described between the sex hormone levels and age with regard to alcohol consumption (Verkasalo et al., 2001). In post-menopausal women no significant changes in hormone levels due to alcohol consumption were found (Verkasalo et al., 2001). Similarly, lack of significant change in TEST and progesterone levels in post-menopausal women drinking 15 or 30 g of alcohol per day was found, but significantly higher ES levels were observed (Dorgan et al., 2001). The latter observation was confirmed by other authors (Nagata et al., 1997). In post-menopausal women, no change in TEST levels was seen in some studies (Dorgan et al., 1994, 2001, Sarkola et al., 2000, 2001). Others have also shown no change of ES levels in post-menopausal women, but high synthetic estrogens levels were seen in women using oral contraceptives (Longnecker and Tseng, 1998; Purohit, 1998).
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONMETHODSSTATISTICAL ANALYSISRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The menstrual cycle disturbances related to alcohol are most prominent around the middle part of the cycle. In alcohol-dependent women approaching the menopause, age influences the pattern of hormonal changes.
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REFERENCES |
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