PERSISTENT DISTURBANCE OF THE HYPOTHALAMIC–PITUITARY–GONADAL AXIS IN ABSTINENT ALCOHOLIC MEN

Martin Hasselblatt, Christian Krieg-Hartig, Michael Hüfner1, Angelos Halaris2 and Hannelore Ehrenreich*

Department of Psychiatry and Neurology and
1 Department of Internal Medicine, Georg-August-University, and Max-Planck-Institute for Experimental Medicine, Göttingen, Germany and
2 Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MI, USA

Received 1 August 2002; in revised form 28 November 2002; accepted 11 December 2002


    ABSTRACT
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Aims: Testosterone synthesis in chronic alcoholics is affected by a variety of mechanisms. Little is known about the reversibility of these changes upon abstinence and available data on circulating hormone levels are incomplete and inconsistent. Methods: Serum concentrations of free testosterone, total testosterone, and luteinizing hormone (LH) were determined in 18 male non-cirrhotic chronic alcoholics on days 2, 22, 82 and 127 of strictly controlled abstinence, as well as in a group of 20 healthy age-matched controls. Results: Higher total testosterone concentrations were found in alcoholics on the second day of abstinence, as compared to controls (7.1 ± 1.9 vs 5.6 ± 1.4 ng/ml) and throughout the whole observation period. Correspondingly, free testosterone concentrations were increased over control levels on day 2 (40.0 ± 12.1 vs 29.7 ± 8.1 pg/ml) and stayed elevated in the presence of augmented concentrations of LH [4.5 U/l (range 1.6–9.5 U/l) vs 2.0 U/l (range 0.8–8.1 U/l)] for up to 127 days of strictly controlled abstinence. Conclusions: Sustained increases in serum free and total testosterone levels in the presence of inadequately raised LH concentrations point towards persisting disturbances of the hypothalamic–pituitary–gonadal axis in male alcoholics upon cessation of drinking.


    INTRODUCTION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Disturbances of the hypothalamic–pituitary–gonadal axis are a frequent cause of sexual dysfunction and have also been associated with depression in males (Schweiger et al., 1999Go). Both disorders substantially contribute to comorbidity in chronic alcoholics and are highly prevalent even following abstention from drinking (Fahrner, 1987Go; Schneider et al., 2001Go).

Alcohol suppresses testosterone synthesis through a variety of mechanisms thereby influencing serum testosterone concentrations. In actively drinking chronic alcoholics, low total or free serum testosterone levels have been described in the presence of increased luteinizing hormone (LH) concentrations (for review see Bannister and Lowosky, 1987Go). Although a relationship between low serum testosterone levels and withdrawal symptoms has been suggested (Ruusa and Bergman, 1996Go), the recovery and nature of alcohol-induced disturbances of the hypothalamic–pituitary–gonadal axis upon abstention from drinking remain controversial. On the one hand, normal or low total testosterone serum levels have been described during the first weeks of abstinence (Välimäki et al., 1984Go; Iranmanesh et al., 1988Go; Heinz et al., 1995Go; Iturriaga et al., 1995Go; Schiavi et al., 1995Go; Ruusa et al., 1997Go). On the other hand, the finding of increased free testosterone concentrations in the presence of high circulating LH levels has suggested an impaired endocrine feedback mechanism (Iranmanesh et al., 1988Go). In most of these studies, patients were only followed over a short period of time or documentation of abstinence or an adequate control group were missing.

These obvious discrepancies together with the unique opportunity for long-term follow-up provided by the OLITA programme [Outpatient Longterm Intensive Therapy for Alcoholics (Ehrenreich et al., 1997aGo)], prompted us to determine serum testosterone and LH concentrations in 18 male alcoholics under conditions of strictly controlled abstinence in comparison with a carefully selected control group. In addition, serum concentrations of ACTH and cortisol were also measured.


    SUBJECTS AND METHODS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
After approval of the study by the Committee for Medical Ethics of the Georg-August-University, Göttingen, Germany, informed consent for participation was obtained from 18 male alcoholics. After an in-patient detoxification period of 1–2 weeks, subjects joined the OLITA programme (Ehrenreich et al., 1997aGo), where abstinence was ascertained through daily contacts (including weekends and holidays) and daily urine analyses for alcohol. The mean age (± SD) of the subjects was 42.9 ± 8.4 years. Subjects had a history of 20 (4–25) (median, range) years of alcohol dependence according to DSM-IV criteria (American Psychiatric Association, 1994Go) with a median daily consumption of 375 g of pure alcohol over the last half year before entering the programme. Subjects displayed no signs of liver cirrhosis (confirmed by means of physical and laboratory examination and abdominal ultrasound imaging), were free of other severe or chronic illnesses and had no history of drug misuse (except for alcohol, nicotine and caffeine). They received clomethiazole, magnesium, potassium and vitamin B1 during the first week of abstinence. Starting from the third week, 50 mg of oral calcium carbimide (Dipsan®) was given daily over the first 3 months of abstinence. From the fourth month on, patients were switched to disulfiram (Antabuse®), 3 x 400 mg/week (Ehrenreich et al., 1997aGo). The control group consisted of 20 healthy male volunteers (mean age ± SD: 43.2 ± 10.8 years) with no evidence of alcohol or drug misuse. Controls were matched with patients with regard to age and cigarette consumption as closely as possible.

The prevalence of sexual dysfunction (libido, erection, ejaculation) was evaluated twice, i.e. upon study entry and upon completion of the study using a semi-structured interview. Serum hormone concentrations were determined on the second, 22nd, 82nd and 127th days of abstinence in alcoholics, as well as once in healthy controls. To control for diurnal variation of hormone levels, fasting blood samples were collected on each occasion between 07:00 and 08:00. Serum hormone concentrations were measured using commercially available assays: Coat-A-Count® Total testosterone RIA; Coat-A-Count® Free testosterone RIA; Coat-A-Count® LH RIA; Immulite® ACTH chemiluminescence assay (all from Diagnostic Products Corporation, Los Angeles, CA, USA) and the TDx/TDxFLx® Cortisol FPIA (Abbott Laboratories, Abbott Park, IL, USA). Serum activity of liver enzymes as well as albumin concentrations were determined using routine methods on days 2, 6, 18, 30, 42, 66, 97 and 127 of abstinence.

Normally distributed data are presented as means ± SD in the text, and as means ± SEM in the figures. Otherwise, data are given as medians and ranges. Parametric testing was performed by ANOVA followed by LSD test. Non-parametric testing was done by Kruskal–Wallis ANOVA followed by Mann–Whitney U-test using the Statistica software package (Statsoft Inc., Tulsa, OK, USA). Significance was considered at a P < 0.05 level.


    RESULTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Laboratory and sexual function parameters
All subjects were followed completely throughout the whole observation period, i.e. 18 weeks of strictly controlled abstinence. Serum activities of liver enzymes returned to control levels within the first ~42 days of abstinence (Table 1Go). Serum albumin concentrations did not differ significantly from control values.


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Table 1. Serum markers of liver function in abstinent male alcoholics
 
Upon study entry, only five (28%) of the subjects reported undisturbed sexual function. All other subjects (n = 13) admitted compromised sexual performance, particularly erectile dysfunction (n = 11). Libido was reported to be impaired in seven cases. These percentages remained unchanged until the end of the study, i.e. after 18 weeks of controlled abstinence.

Total serum testosterone levels
Total serum testosterone concentrations were within the normal range of the assay (2.6–15.9 ng/ml) in both patients and controls. However, as compared to controls (5.6 ± 1.4 ng/ml), significantly higher concentrations were found in alcoholics on the second day of abstinence (Fig. 1AGo) (7.1 ± 1.9 ng/ml; P < 0.01). Thereafter, values remained elevated throughout the remainder of the 18-week observation period.



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Fig. 1. Hormones of the hypothalamic–pituitary–gonadal axis in abstinent male alcoholics. Total (A) and free (B) testosterone serum concentrations in 18 alcoholics on days 2, 22, 82 and 127 of strictly controlled abstinence were compared to those in 20 healthy controls. Data are presented as means ± SEM. *P < 0.05, **P < 0.01 vs controls. Serum LH concentrations (C) are presented as individual data (circles) and medians (bars).

 
Free serum testosterone levels
Free serum testosterone concentrations were found to be above the normal range of the assay (13–40 pg/ml) in 50% of the patients on the second day of abstinence (Fig. 1BGo) (40.0 ± 12.1 vs 29.7 ± 8.1 pg/ml; P < 0.01). Values remained elevated until the end of the study (38.8 ± 7.7 vs 29.7 ± 8.1 pg/ml in controls; P < 0.05 for all time points).

Serum LH levels
On the second day of abstinence, median serum LH concentrations in alcoholics were significantly increased over controls [4.5 U/l (range 1.6–9.5 U/l) vs 2.0 U/l (range 0.8–8.1 U/l)] and remained elevated throughout the whole observation period (Fig. 1CGo,P < 0.01 for all time points).

Hormones of the hypothalamic–pituitary–adrenal axis
Only transient increases in serum cortisol (204 ± 13 vs 156 ± 43 µg/l; P < 0.01) and adrenocorticotropin (ACTH) (54.3 ± 7.9 vs 40.9 ± 4.0 pg/ml; NS) were observed on the second day of abstinence. On day 22, serum concentrations of both hormones had returned to control levels (cortisol: 174 ± 50 µg/l; ACTH: 44.5 ± 20.7 pg/ml).


    DISCUSSION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
In the present study, serum concentrations of testosterone and LH were monitored along with cortisol and ACTH in non-cirrhotic chronic alcoholics over 18 weeks of strictly controlled abstinence.

Although in agreement with previous studies (Välimäki et al., 1984Go; Ehrenreich et al., 1997bGo) reporting that increases in serum ACTH and cortisol were only transient, our findings of sustained increases in both free and total serum testosterone concentrations in the presence of inadequately raised LH concentrations imply a persisting disturbance of the hypothalamic– pituitary–gonadal axis upon cessation of drinking. The present study therefore extends previous observations obtained over up to 5 weeks of abstinence (Iranmanesh et al., 1988Go), clearly outlasting the normalization of serum liver enzyme activities. The failure of several other studies to detect any changes in total serum testosterone upon abstention from drinking (Välimäki et al., 1984Go; Iranmanesh et al., 1988Go; Ruusa et al., 1997Go) might well be explained by the omission of age-matched control groups. Although concentrations of sex hormone binding globulin (SHBG) were not determined in the present study, the concomitant increase in both free and total serum testosterone levels in the presence of unchanged serum albumin concentration strongly argues against major changes in the proportion of protein-bound testosterone upon abstention from drinking.

As documented by increased free and total testosterone serum concentrations, the direct negative effects of ethanol on gonadal testosterone synthesis (Bannister and Lowosky, 1987Go; Frias et al., 2002Go) seem to vanish rapidly upon cessation of drinking. However, despite increased serum testosterone, sexual dysfunction remained highly prevalent upon abstinence, pointing towards a relative testosterone insensitivity. This is in line with the observation that unusually high doses of androgens were needed to treat impotence successfully in abstinent chronic alcoholics (Van Thiel et al., 1983Go). To this end, the multifactorial aetiology of sexual dysfunction in alcoholics, including psychological and vascular factors, should also be kept in mind. A sustained disturbance of the testosterone-mediated adenohypophyseal negative feedback mechanism, i.e. a reduced pituitary sensitivity towards testosterone, however, may explain the persistence of inadequately high serum LH concentrations in the present study. This is in agreement with the finding of reduced hypothalamic and adenohypophyseal androgen binding sites in ethanol-fed rats (Chung, 1989Go).

It should be mentioned, however, that since no data are available on pre-abstinence hormone levels in our group of alcoholics, the pre-existence of abnormally increased hormone levels, although unlikely, cannot be entirely excluded. Another potentially interfering variable to be considered is the treatment of alcohol-dependent patients with the aldehyde dehydrogenase inhibitors, calcium carbimide and disulfiram. These compounds, however, have been shown not to affect the hypothalamic–pituitary–gonadal axis in abstinent alcoholic men (Ramirez et al., 1988Go). Other treatments, i.e. clomethiazole, magnesium, potassium and vitamin B1, were discontinued in all patients after the first week of abstinence and are therefore unlikely to explain the consistently altered hormone levels. This consistent alteration appears to be a robust finding, not even affected by the known pulsatile serum hormone profiles of LH and testosterone. In fact, in neither controls nor alcoholics was there a striking correlation between serum concentrations of LH and free testosterone at any time point. This is not unexpected considering the pulsatile release pattern of these hormones.

In conclusion, in male alcoholics, disturbances of the hypothalamic–pituitary–gonadal axis persist over months of abstinence. A relative insensitivity towards testosterone might contribute to the high prevalence of sexual dysfunction in this group of patients.


    ACKNOWLEDGEMENTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The authors would like to thank Christa Claus for expert technical assistance.


    FOOTNOTES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
* Author to whom correspondence should be addressed at: Max-Planck-Institute for Experimental Medicine, Hermann-Rein-Strasse 3, D-37075 Göttingen, Germany. Back


    REFERENCES
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 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
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