The effects of alcohol on male reproductive system

ADDIS ABABA UNIVERSITY

SCHOOL of Health Sciences

Department Of Physiology

The Effects of Alcohol on Male Reproductive System

A Review

By

Girmay Fitiwi

2012

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Acknowledgments

I would like to express my great attitude to my advisor Dr Tewabech Zewdie for her excellent

valuable and scientific comments of the manuscript. I also thank AAU digital libraries for their

full resources of journals and free internet access.

My deepest gratitude goes to Dr Getahun shibru for his excellent guiding in how to write mono-

graphic type writing.

Finally I would like thank all staffs of physiology Department, my Family and my Colleagues.

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Table of contents

Pages

Acknowledgments .... ...................................................................................................... I

Table of Contents ........................................................................................................... II

List of Acronyms ......................................................................................................... IV

List of Figures .............................................................................................................. V

Summary....................................................................................................................... VI

1. Introduction ................................................................................................................. 1

2. Consumption of Alcohol ............................................................................................ 1

3. Gender difference in alcohol consumption .................................................................. 3

4. Blood alcohol concentration ....................................................................................... 3

5. Alcohol metabolism .................................................................................................... 4

5.1 Alcohol dehydrogenase system ...................................................................... 6

5.2 Microsomal ethanol oxidazing system............................................................ 7

5.3 Catalase ........................................................................................................ 7

5.4 Aldehyde dehydrogenase .............................................................................. 7

6. Alcoholism .................................................................................................................. 8

7 .General effect of alcohol on the body .......................................................................... 9

7.1 Alcohol’s effect on the liver ........................................................................ 10

7.2 The effect of Alcohol on nervous system .................................................... 11

8 Alcohol’s Effect on Male Reproductive System ....................................................... 13

8.1 Over view of Male Reproductive System ..................................................... 13

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8.2 Hypothalamic –Pituitary –Gonadal Axis ...................................................... 14

8.3 Testosterone ................................................................................................ 16

8.4 Alcohol and the Male Hypothalamic-Pituitary axis ..................................... 17

8.5 Alcohol and Testes ...................................................................................... 19

8.5.1. Mechanisms of Alcohol Induced Testicular Injury ……………………20

9. Alcohol and Sexual Performances ……………………………………………………23

10. Conclusions and prospective studies……………………………………………….. 26

References…………………………………………………..28

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LIST of ACRONYMS

AAI Acute alcohol intoxication

ACTH Adrenocorticotropin hormone

ADH Alcohol Dehydrogenase

ALDH Acetaldehyde Dehydrogenase

BAC Blood Alcohol Concentration

CYP2E1 Cytochrome P450 type2 E1

DHEAS Dehydroepiandrosteron

EtOH Ethanol

FAS Fetal alcohol syndrome

FSH Follicular Stimulating Hormone

GnRH Gonadotropin Releasing Hormone

GABAA γ-amino butyric acid

HPG axis Hypothalamus Pituitary Gonadal axis

LTP Long Term Potentiation

LH Luteinizing Hormone

MEOS Microsomal Ethanol Oxidizing System

NAD+ Nicotinamide adenine dinucleotide

NADH Nicotinamide adenine dinucleotide, reduced form

NADP+

Nicotinamide adenine dinucleotide phosphate

NADPH Nicotinamide adenine dinucleotide phosphate, reduced form

NOS Nitrogen oxygen species

NMDA N-methyl-D-aspartic acid

ROS Reactive Oxygen Species

WHO World Health Organization

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List of Figures

Figure 1.Oxidative Pathways of Alcohol Metabolism ...................................................... 5

Figure2. Hepatic Metabolic Changes Associated to Ethanol Metabolism ........................ 8

Figure3: The Hypothalamic-Pituitary-Gonadal Axis ..................................................... 15

Figure4. Phases of Male Sexual Behavior as indicated by Mean Plasma Testosterone

Level and Sperm Production at Different Phases of Life ................................. 15

Figure 5. Schematic Diagram of the Actions of Testosterone (solid arrows) and

Dihydrotestosterone (dashed arrows) ............................................................. 17

Figure 6. The proposed neuronal pathways by which excitatory amino acids may influence the

Secretion of GnRH and in turn LH…………………………………………….18

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Summary

Chronic alcohol consumption have profound deleterious effect in male reproductive system at all

levels along the hypothalmic pituitary gonadal axis resulting in testicular dysfunction, which is

manifested by erectile dysfunction, reduced libido, gynacomatesia , impaired sperm production

and infertility.

Alcohol metabolism generates ROS, NOS and acetaldehyde and all this compounds create oxi-

dative stress, which may result in injury of leyding cells and may end up in decrease serum tes-

tosterone, testicular atrophy and reduced secondary sexual characteristics of male. In addition

Sertoli cells are affected and spermatogenesis is diminished and may end up with infertility.

Chronic Alcohol consumption affects GnRH secretion by disrupting the stimuli necessary to pro-

duce GnRH. LH is also affected by alcohol both in quantity and potency and all these altering

mechanisms may end up with gonadal dysfunction.

Key words: Acetaldehyde: Blood Alcohol Concentration: Ethanol: Hypothalamic-Pituitary-

Gonadal axis: Gonadal Dysfunction: Lipid peroxidation: Leyding cell: Oxidative stress: Testos-

terone: ROS: Gynacomastia: Testis

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1. Introduction

Alcohol consumption has been part of human civilization for millions of years (Freeman et al.,

2006). Alcoholic beverages are produced by the fermentation of yeast, sugars and starches. And

ethanol is the intoxicating ingredient in alcohol beverages. Nowadays, consumption of alcohol

increases tremendously and health related problems due to alcohol consumption is numerous.

A standard drink is defined by 12-ounce1 of beer, 5-ounce glass of wine, or 1.5 ounces of dis-

tilled spirits, which does not affect the health status of an individual. However, consumption of

alcohol in large quantity has detrimental effects on different body systems including nervous sys-

tem, cardiovascular system, reproductive system, respiratory system, endocrine system and liver

(Freeman et al., 2006). Fetal alcohol syndrome2 is another detrimental problem that frequently

happens in pregnant ladies consuming alcohol (Larkby et al., 1997).

The patterns and amounts of drinking vary between different populations and there is no clearly

single reason why different people drink to different extent. Furthermore Drinking is influenced

by factors such as genetics, social environment, culture, age, gender, accessibility, exposure and

personality (Freeman et al., 2006).

This paper attempts to review the effects of chronic alcohol consumption on male reproductive

system, especially on the hypothalamus-pituitary gonadal axis and the direct effect on testes.

2. Consumption of Alcohol

1 Ounce is a unit for measuring liquid, equal to 0.0284 of a Liter.

2 Fetal alcohol syndrome (FAS) is a collection of different defects in offspring due to alcohol

ingestion during pregnancy. The clinical definitions are small for their age, exhibit characteristic

facial anomalies, and demonstrate deficits in central nervous system development.


Around 2 billion people worldwide consume alcohol (WHO, 2004). From the 2 billion people,

approximately 76.3 million have a diagnosable alcohol use disorder, such as excessive drinking

and alcohol dependence. Worldwide, adults (age 15 years and older) consume an average of 5

liters of pure alcohol from beer, wine and spirits each year. In Africa, the adult consumption of

pure alcohol is about 4 liters of pure alcohol each year (WHO, 2004).

The WHO Global Status Report on Alcohol released in 2004 showed that in Ethiopia, 1liter of

pure alcohol is consumed per capita each year3 and Data from 2003 world health survey showed

that, 60.2 % of the total populations are life time abstainers4 , among these 56.9% are male and

63.7% are female. Furthermore it has been indicated that 9.3% of the total populations are heavy

and hazardous drinkers 5 and 4.1 % are heavy episodic drinkers

6 (Ustun TB et al., 2003).

In Ethiopia 69.4% of young people (18 up to 24 years old) are life abstainers among which

68.6% are male and 70.3% are female. Heavy episodic young people drinkers are 2% among

which 4.2% of which are male and 0.25% are female (Ustun TB et al., 2003).in Addis Ababa the

percentage of youth regular drinkers have been shown to be about 34% among which 7% of

these consumed more than 100 grams of pure alcohol per week (Betre M et al.,1997). Further-

more, in a study of 10, 468 adults of rural and semi-urban community, it was found that people

who were currently problem drinkers reported lifetime suicide attempts more often than others

(Alem K et al., 1999).

3 Annual per capita alcohol consumption= Alcohol production + alcohol imports – alcohol exp

population 15 years of age and over

4 Abstainers are defined as people who abstain from drinking alcohol, either over the year

preceeding the survey (last year abstainers) or throughout their life (lifetime abstainers).

5 According to WHO, average consumption of 40 g or more of pure alcohol a day for men and

20 g or more of pure alcohol a day for women categorized as heavy and hazardous drinker.

6 According WHO, at least once a week consumption of five or more standard drinks in one sit-

ting categorized as heavy episodic drinkers.


The unrecorded alcohol consumption in Ethiopia is estimated to be 1.0 litre pure alcohol per cap-

ita for population older than 15 for the years after 1995 (estimated by a group of key alcohol ex-

perts) (European Addiction Research, 2001).

3. Gender Difference in Alcohol Consumption

Women consume alcohol less frequently and have a lower prevalence of alcohol consumption

related problems than men, but they are more sensitive to physiological effects of alcohol than

men (Margaret Ely et al., 1999).

A given dose of alcohol results in a higher blood alcohol level (BAL) in women than in men and

it is thought that this is one reason why women suffer more physical harm from drinking the

same amount of alcohol as men (Margaret Ely et al., 1999).The risk of liver cirrhosis due to

chronic alcohol consumption has been shown to be greater for women than men (Tuyne et al.

1983).

Possible mechanisms to explain the gender difference in BAL include gender differences in the

metabolism of alcohol, the interaction of alcohol dehydrogenase (ADH) with female sex hor-

mones, decreased first pass metabolism in women because of lower levels of gastric ADH, and

more rapid metabolism of alcohol in the liver by women (Thomasson, 1995). Another potential

possible mechanism is body water content, which is the only physiological difference consistent-

ly related to peak BAL (Graham et al. 1998). Women have an average a lower volume of body

water than men, because of their lower weight and a lower proportion of lean body mass. The

lower volume of body water in women gives a smaller volume for distribution of alcohol than

man, which may account for their higher BAL at comparable quantities of alcohol consumed

(Margaret Ely et al., 1999).

4. Blood Alcohol Concentration

Blood alcohol concentration (BAC) is the amount of alcohol in blood volume and expressed in

percentage. BAC can be measured by breath, blood, saliva or urine tests. For instance, having a


BAC of 0.10 percent means that a person has 1 part alcohol per 1,000 parts blood in the body

(Freeman et al., 2006).

The effects of alcohol on various tissues depend on its concentration in the blood (BAC) over

time. BAC is determined by how quickly alcohol is absorbed, distributed, metabolized, and ex-

creted (Samir Zakhari, 2006).

The rate of rise of BAC is influenced by the rate of alcohol absorption, first pass metabolism,

rate of alcohol drinking, the presence of food in the stomach, and the type of alcoholic beverage

and genetic factors including variations in the principal alcohol-metabolizing enzymes, alcohol

dehydrogenase and aldehyde dehydrogenase (Samir Zakhari, 2006).

The elimination rate of alcohol varies widely among individuals and is influenced by factors

such as chronic alcohol consumption, diet, age, smoking, and time of day (Bennion and Li 1976;

Kopun and Propping, 1977).

5 Alcohol Metabolism

Ethanol is primarily absorbed in the duodenum and to a lesser extent in the stomach, at both

places by diffusion (Stephan Krähenbühl, 2004). It readily passes through membranes and enters

tissues, exerting its effects on the body (Susanna Apter, 2008). Only 2% to 10% of that absorbed

is eliminated through the kidneys and lungs; the rest is oxidized in the body, principally in the

liver (Charles S. Lieber, 2005).

Extra hepatic metabolism of ethanol is small. This relative organ specificity, coupled with the

high energy content of ethanol (each gram provides 29 kJ, or 7.1 kcal) and the lack of effective

feedback control of its rate of hepatic metabolism, results in a displacement of up to 90% of the

liver’s normal metabolic substrates by ethanol. The effect explains why ethanol disposal produc-

es striking metabolic imbalances like inhibition of fatty acid oxidation and gluconeogenesis, ac-

cumulation of lactic acid and ketone bodies in the liver (Charles S. Lieber, 2005).

In the hepatocyte there are three systems which are able to metabolize ethanol and these are lo-

cated in three different cellular compartments: alcohol dehydrogenase (ADH) located in the cy-

tosol, the microsomal ethanol oxidizing system (MEOS) situated in the endoplasmic reticulum


and catalase located in the peroxisomes. Each of these systems causes specific metabolic and

toxic alterations which all lead to acetaldehyde production (Juan Caballería, 2003).

In the second oxidative step, acetaldehyde is quickly metabolized to acetate by mitochondrial

acetaldehyde dehydrogenase (ALDH). Finally, the acetate produced in the liver is released into

the blood and is oxidized by peripheral tissues to carbon dioxide, fatty acids and water (Juan

Caballería, 2003).

Figure 1.Oxidative pathways of Alcohol Metabolism (Source: Juan Caballería, 2003).

The intermediate product of ethanol metabolism, acetaldehyde, is more toxic than ethanol.

A dose of 0.75g acetaldehyde/kg of body weight is lethal in mice. In contrast, an alcohol dose of

6.5g/kg of body weight is fatal only in seven out of ten cases in mice (Sussanna Apter, 2008).

The toxicity of acetaldehyde lies in its inhibitory effect on the sodium-potassium pump, protein

synthesis of the cell, and cell respiration (Tabakoff et al., 1989). In addition, acetaldehyde is

toxic, mutagenic and carcinogenic as it interferes with DNA synthesis and repair at many sites

(Salaspuro et al., 2003).


The concentration of acetaldehyde is usually kept low due to the high activity of ALDH. In indi-

viduals with reduced ALDH activity, high acetaldehyde levels after alcohol intake cause symp-

toms such as tachycardia, hypotension, nausea, and facial flushing (Sussanna Apter, 2008).

5.1 Alcohol Dehydrogenase System

Alcohol dehydrogenase is a dimeric7 zinc dependent methaloenzyme and it has five different

classes (I-V), encoded in seven genes, from ADH1 to ADH7. However, the isoenzymes, which

are important for alcohol metabolism, are of the classes I, II, IV (Jornvall H, 1995).

Class I isoenzymes have a low Km8 for ethanol, are found in the liver and consist of homo or

heterodimeric forms of three subunits: α, β, and γ, ADH1, ADH2 and ADH3, respectively. Class

II ADH is a homodimeric ππ form, ADH4, with a relatively high Km for ethanol (34 mM) and is

found in the liver. The class IV isoenzymes, ADH7, are a homodimeric σσ found in the stomach

and have a very high Km for ethanol (Juan Caballerí, 2003).

There are genetic variations for ADH2 and ADH3 encoded by different alleles9. Alleles

ADH2*1, ADH2*2 and ADH2*3 have subunits β1, β2 and β3 respectively. Alleles ADH3*1 and

ADH3*2 have subunits γ1 and γ2, respectively. The frequency of the different ADH alleles has

ethnic variations. The affinity for alcohol and the metabolic rate among the different isoenzymes

differ, and these genetic differences have been implicated in the pathogenesis of alcoholic liver

disease (Juan Caballería, 2003).

In the human stomach the presence of class I, III and IV ADH isoenzymes of both low and high

Km for ethanol has been demonstrated (Allali-Hassani, 1997). Gastric ADH is responsible for

7 Dimer is a compound formed by the combination of two simple molecules(sub units)that nor-

mally are not functional by themselves

8 Km is a measurement used to describe the activity of an enzyme. It describes the concentration

of the substance upon which an enzyme acts that permits half the maximal rate of reaction

9 Allele is one of two or more variants of certain gene. Different alleles of a gene generally serve

the same function but may produce different phenotypes


some of the ethnic and gender variations observed in alcohol metabolism which may favor its

toxicity (Juan Caballería, 2003).

5.2 Microsomal Ethanol Oxidazing System (MEOS)

The microsomal ethanol oxidazing system (MEOS) constitutes a second mechanism that is able

to oxidize alcohol. The MEOS shares many properties with other microsomal drug metabolizing

enzymes such as utilization of the cytochrome P-450, NADPH and oxygen. An increase in

MEOS activity is produced as a consequence of chronic alcohol consumption and this affects the

CYP2E1 which is the ethanol inducible fraction of the cytochrome P-450 and is also capable of

activating other hepatotoxic agents (Lieber CS, 1999).

The CYP2E1 has a high redox potential which leads to the formation of free oxygen radical, oxi-

dative stress and lipid peroxidation (DuPont I, 1998). Oxidative stress induces the activation of

Kupffer cells, increasing the expression of several cytokines such as transforming growth factor

beta, tumoral necrosis factor alpha and interleukin 1. All of this mechanism contributes to the

activation of stellate cells with the consequent increase in collagen synthesis favoring the pro-

gression of alcoholic liver disease (NietoN, 1999).

5.3 Catalase

The role of catalase in alcohol metabolism is small, and accounts for less than 2% of the total

ethanol metabolism (Salaspuro et al., 2003).

5.4 Aldehyde Dehydrogenase

Acetaldehyde is rapidly metabolized to acetate by aldehyde dehydrogenase (ALDH). There are

two classes of ALDH, ALDH1 located in the cytosol with a high Km for acetaldehyde and

ALDH2 located in the mitochondrial with a low Km for acetaldehyde and has the greatest im-

portance in the metabolism of acetaldehyde (Salaspuro et al., 2003).


ALDH2 also presents a genetic polymorphism with two alleles, ALDH2*1 and ALDH2*2, with

there also being homo and heterozygote for each. ALDH2*2 is a physiologically inactive form

(Bosron WF et al., 1993)

Figure2. Hepatic Metabolic Changes Associated to Ethanol Metabolism (Source: Juan

Caballería, 2003).

6. Alcoholism

Alcoholism is a chronic, often progressive disease which includes the development of an alcohol

addiction, a state of increased alcohol tolerance, and the presence of withdrawal symptoms dur-

ing abstinence (Apter, 2008).Genetic, psychosocial and environmental factor influence its devel-

opment and manifestations (Morse et al., 1992).


Alcoholism has been classified into two subtypes (Cloninger et al., 1981). Type 1 alcoholics

make up about 80% of all alcoholics and start consuming alcohol later in life (age of onset >25

years). It occurs in both male and female and requires environmental provocation. These types of

alcoholics experience withdrawal symptoms and loss of control and often feel guilty about their

drinking behavior (Cloninger et al., 1981).

Type 2 alcoholism, on the other hand, is hereditary and male-limited. Such types of alcoholics

generally begin drinking in early adolescence, which is concurrent with the rise of testosterone

levels (Apter, 2008).In addition they have been described as possessing personality traits such as

low harm avoidance, high sensation seeking, impulsiveness, as well as aggressive and antisocial

behavior (Apter, 2008).

Impulsive violence, suicidal and aggressive behaviors, and type 2 alcoholism have been repeat-

edly linked to low concentrations of cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-

HIAA) (Mann, 1995) , a metabolite that reflects serotonin10

turnover predominantly in the frontal

cortex (Stanley et al., 1985).

7. General Effect of Alcohol on the Body

Alcohol adversely affects multiple organs of the body. Complications due to alcohol consump-

tion can range from acute damage of the lining of the stomach to severe chronic liver damage,

sterility and loss of memory. Some complications are acute and can be reversed or treated after

stopping alcohol use, others are chronic and become irreversible and permanent.

This review attempts to explain the effect of alcohol on liver and nervous system which have an

effect on male reproductive system through metabolic clearance of testosterone and release of

neuronal transmitters or signals important for generator cells of the hypothalamus respectively.

10

Serotonin is a neurotransmitter thought to function as a behavioral inhibitor. Thus; decreased

serotonin activity is associated with increased impulsivity and aggressiveness as well as with ear-

ly-onset alcoholism among men.


7.1 Alcohol’s Effect on the Liver

The liver is particularly susceptible to alcohol-related injury because it is the primary site of al-

cohol metabolism. By products of alcohol metabolism in the liver produce free radicals and have

role in contributing alcohol-induced liver damage (Maher, 1997).

Epidemiological studies suggest that a threshold dose of alcohol must be consumed for serious

liver injury to become apparent (Mezey et al. 1988). For men, this dose amounts to 600 kg taken

chronically over many years , an intake that can be achieved by consuming approximately 72

ounces (oz) of beer, 1 liter of wine, or 8 oz distilled spirits. For women, the threshold dose is

one-fourth to one-half amount of men (Maher, 1997).

Heavy long-term alcohol consumption clearly plays a major role in the development of alcohol-

related liver damage. In addition factors like heredity, environment, or both interact to influence

the course of liver disease (Maher, 1997).

Alcohol-related liver damage can be divided into three categories: Fatty liver (hepatic steatosis),

alcoholic hepatitis and alcoholic cirrhosis (French et al., 1993). The prevalence rate of alcoholic

fatty liver is about 20% of heavy drinkers, alcoholic hepatitis and alcohol cirrhosis is about 10-

15% of people with alcohol dependence (Freeman et al., 2006).

Alcohol hepatitis is characterized by inflammation of the liver, jaundice and abdominal pain.

Scar tissue may replace healthy tissue leading to a process of fibrosis. The condition is reversible

with abstinence (Maher, 1997).

Alcoholic cirrhosis is the most advanced form of liver disease. The liver is characterized by ex-

tensive fibrosis that stiffens blood vessels and distorts the internal structure of the liver. This

damage results in severe functional impairment (Maher, 1997). The amount of alcohol consumed

and the duration of that consumption are closely associated with cirrhosis (Freeman et al., 2006).

Traditionally, these three conditions have been considered sequentially related, progressing from

fatty liver to alcoholic hepatitis to cirrhosis. However, heavy drinkers may develop alcoholic cir-


rhosis without first developing hepatitis. Moreover, alcoholic hepatitis may have a sudden onset

and a rapid course, causing death before cirrhosis can develop (Maher, 1997).

In alcoholic cirrhosis testosterone metabolism is increased through 5α-testosterone reductase

and aromatase in the liver. This, in turn, leads to an increased testosterone catabolism and turno-

ver to estrogens (Chiao and Van Thiel, 1983). So that decreased serum testosterone is associated

with loss of libido, reduced potency, shrinking in size of testes and penis, reduced or absent

sperm formation and so infertility. Furthermore, plasma SHBG is markedly raised, which reduc-

es the free fraction of plasma testosterone below normal (Green, 1977).

7.2 The Effect of Alcohol on the Nervous System

Alcohol is one of the most abused drugs that produce depression of the central nervous system

(CNS) and several morphological and physiological alterations in humans brain (Valeria Rettori

et al., 2010). Alcohol appears to act through a multitude of mechanisms, instead of a single fun-

damental process (Vengeliene et al., 2008).

Ethanol (EtOH) induces neurochemical changes in various brain areas, in particular on

GABAergic, glutamatergic, cholinergic, serotonergic and catecholaminergic neuronal systems

(Nevo and Hamon, 1995).

The primary targets are the membrane bound- ligand-gated ion channels and voltage-dependent

ion channels, such as N-methyl-D-aspartic acid (NMDA)11

, GABA, serotonin and nicotinic cho-

linergic receptors as well as L-type Ca2+ channels and Gprotein- activated inwardly rectifying

K+ channels (Vengeliene et al., 2008; Dopico and Lovinger, 2009).

11

N-methyl-D-aspartate receptors (NMDA) are glutamate-activated ligand-gated ion channels

that participate in diverse forms of synaptic plasticity as well as glutamate-dependent

excitotoxicity


Ethanol has direct effect on cell membranes rafts by nonspecific interactions with lipidic com-

ponents and therefore disrupting protein–lipid interactions (Szabo et al., 2007). Also, the mole-

cule of ethanol can easily cross the cell membranes affecting intracellular proteins such as pro-

tein kinase A and C and therefore their pathways.

The indirect effect of ethanol on a variety of neurotransmitter/ neuropeptide systems are initiated

leading to behavioral effects of alcohol, ranging from disinhibition to sedation and even hypnosis

depending on the amount of ethanol consumed (Davies, 2003, Jia et al., 2008).

Short-term alcohol consumption depresses brain function by altering the balance between inhibi-

tory and excitatory neurotransmission (Valenzuela, 1997). Specifically, alcohol can act as a de-

pressant by increasing inhibitory neurotransmission, by decreasing excitatory neurotransmission,

or through a combination of both (Valenzuela, 1997).

Alcohol’s depressant effect on neurons may be associated with some of the behavioral manifes-

tations of intoxication: Alcohol consumption is initially accompanied by decreased attention, al-

terations in memory, mood changes and drowsiness. Continued acute consumption may result in

lethargy, confusion, amnesia, loss of sensation, difficulty in breathing and death (Draski and

Deitrich, 1995). Alcohol’s excitatory actions (e.g. reduction of social inhibitions) are caused by

suppression of inhibitory neurotransmitter systems (Pohorecky, 1977).

Short-term alcohol exposure decreased LTP (long term potentiation) in the hippocampus (Bliss

and Collingridge, 1993), and has inhibitory effect on glutamate and GABA systems (Weiner et

al., 1997; Valenzuela and Harris 1997). Both evidences indicate that alcohol’s general inhibitory

effect on memory.

When alcohol consumption is abruptly reduced or discontinued, a withdrawal syndrome may fol-

low, characterized by seizures, tremor, hallucinations, insomnia, agitation, and confusion and

this syndrome represents the hyperactivity of neural adaptive mechanisms no longer balanced by

the inhibitory effects of alcohol (Metten and Crabbe, 1995).


An increased NMDA (N-methyl-D-aspartic acid) receptor activity due to chronic alcohol con-

sumption significantly increases the amount of calcium that enters nerve cells. An excess of cal-

cium within neurons produce cell toxicity or death (Hunt, 1993).

Long-term alcohol use may lead to a decrease in GABAA receptor function. In the absence of

alcohol, the reduced activity of inhibitory GABA neurotransmission might contribute to the anx-

iety and seizures of withdrawal (Valenzuela, 1997).

8 Alcohol’s Effect on Male Reproductive System

8.1 Over view of Male Reproductive System

The male testes perform two essential functions, spermatogenesis in the seminiferous tubules and

synthesis and secretion of androgens in the interstitium (Reini Bretveld et al., 2007).

The production of sexual hormones is regulated by the hypothalamus-pituitary-gonadal axis,

comprising the hormones gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH),

follicle- stimulating hormone (FSH), testosterone and inhibin B (Doug Bayliss, 2003).

LH and FSH are produced by the anterior pituitary gland under the influence of pulsatile secre-

tions of GnRH released by the hypothalamus. LH stimulates Leydig cells in the testes to produce

testosterone, which is an important hormone for spermatogenesis through the stimulation of

Sertoli cells in the seminiferous tubules. The main function of Sertoli cells is to create a favora-

ble environment for germ cell proliferation and maturation (Emanuele et al., 2001).

FSH controls spermatogenesis via direct stimulation of Sertoli cells. It also stimulates inhibin B

synthesis in the Sertoli cells. Both testosterone and inhibin B regulate GnRH and LH or FSH se-

cretion through a negative feedback loop. For normal spermatogenesis to occur, adequate func-

tioning of this endocrine regulatory system and the two testicular compartments are necessary

(Emanuele et al., 2001).


In the complex regulation of hormone production and spermatogenesis, disturbances can easily

occur by different environmental factors including alcohol consumption, pesticide exposure,

smoking, coffee and thus result in diminished or absent spermatogenesis and infertility (Reini

Bretveld et al., 2007).

8.2 Hypothalamic –Pituitary –Gonadal Axis

The hypothalamic-pituitary-gonadal axis is active in males and females during three main peri-

ods of life (Doug Bayliss, 2003).

1. in the midtrimester of the fetal period.

2. Early in the neonatal period

3. from puberty throughout the reproductive years.

During the fetal period, testosterone secretion is essential for sexual differentiation in male and

elevated levels of FSH may contribute to folliculogenesis in girls. The increased activity in the

neonatal period results from the abrupt decrease in steroid levels at birth and the resultant

disinhibition of the hypothalamic-pituitary system. In both boys and girls, increased pulsatile re-

lease of GnRH occurs mostly at night in early puberty; later on pulsatile release of GnRH occurs

throughout the 24 hour day (Doug Bayliss, 2003).

The increased GnRH release, along with enhanced pituitary responsiveness to GnRH triggers

elevated gonadotropin secretion, gonadal steroidogenesis and development of secondary sexual

characteristics. In men, testosterone levels peak following puberty, are maintained at those levels

throughout adulthood and decrease slightly with advancing age, but the ability to produce viable

gametes persists (Doug Bayliss, 2003). In women, testosterone concentrations are decreased

following menopause as the production of testosterone by the ovaries is reduced. The main

source of androgens in postmenopausal women is the adrenal cortex (Välimäki et al., 2000).


Figure 3: The Hypothalamic-Pituitary-Gonadal Axis (Source: Mary Emannele and Nicholas

Emanuele, 2001)

Figure 4. Phases of Male Sexual Behavior as indicated by Mean Plasma Testosterone Level and

Sperm Production at Different Phases of Life (Source: Doug Bayliss, 2003)


8.3 Testosterone

Testosterone, an androgenic steroid hormone derived from cholesterol, occurs more abundantly

in Circulation among men, than women (Susanna Apter, 2008). Testosterone is synthesized in

the testes among males, ovaries among females, and in the adrenal cortex in both sexes (Davis

and Tran, 2001).

Testosterone has androgenic, anabolic, and psychological effects. It is crucial for gonadal devel-

opment and secondary male characteristics, essential for normal spermatogenesis, and it contrib-

utes to general growth and protein synthesis. Testosterone also effects libido, sexual potency, and

behaviors such as aggressive and sexual behavior (Nieschlag and Behre, 2004).

The normal range of testosterone in men is large, between 10-35nmol/L (Välimäki et al., 2000,

Nieschlag and Behre, 2004). The testosterone concentration in women is around 5-10% of that in

men (Nieschlag and Behre, 2004). There are large diurnal variations in levels of testosterone in

men, with 25-50% higher concentrations in the mornings than evenings, due primarily to chang-

es in production (Välimäki et al., 2000).

The catabolism of testosterone, as well as that of other androgens, takes place mainly in the liver,

although testosterone is metabolized into other active hormones in several places of the body.

Secretion products are excreted from the body via urine and the skin (Välimäki et al., 2000).

Acute and chronic alcohol consumption has been shown to be associated with low level of tes-

tosterone (Little et al., 1992). Studies with pubertal male rats indicate that both acute and chronic

alcohol exposure result in profound testosterone suppression accompanied by lower or normal

LH and FSH levels, when elevated levels are expected (Hadley, 1988, Yen and Jaffe, 1991). This

suggests that the hypothalamic cells which produce GnRH do not respond correctly to the nega-

tive classic feedback mechanism normally provided by testosterone, when testosterone levels are

decreased. So that the detrimental effects of alcohol on reproductive system may be mediated at

all levels of the hypothalamic-pituitary gonadal axis.


Low levels of testosterone in adult men have been associated with a variety of medical problems

including accelerated osteoporosis, decreased muscle and prostate function, anemia, altered im-

mune function, and decreased reproductive ability (Klein and Duwall, 1994, Jackson and

Klerekoper, 1990, Azad et al., 1991; Berczi et al., 1981, Hadley, 1988).

Figure 5. Schematic Diagram of the Actions of Testosterone (solid arrows) and

Dihydrotestosterone (dashed arrows) (source: Doug Bayliss, 2003)

8.4 Alcohol and the Male Hypothalamic-Pituitary Axis

Acute and chronic alcohol exposures are associated with low levels of hypothalamic GnRH and

pituitary LH in adult and pubertal male rat (Cicero 1982, Salonen et al., 1992).

GnRH secretion is closely regulated by a series of complex mechanisms involving various nerve

impulses generated outside the hypothalamus. Multiple processes including opioids, neuro

transmitters and nerve signals lead to the activation of the GnRH pulse generator, the part of the

hypothalamus responsible for GnRH secretion (Gianoulakis, 1990). Alcohol could influence any

of these stimuli. However, this uppermost level of the reproductive axis, the hypothalamus,


seems to be the least vulnerable to the deleterious consequences of alcohol (Emanuele et al.,

1993).

In vitro experiments with incubation of medial basal hypothalamus (Lomniczi et al., 2000)

demonstrated that EtOH inhibited the N-methyl-D-aspartic acid (NMDA), which stimulates the

release of GnRH. Furthermore, ethanol increases the release of two neurotransmitters, β endor-

phin and GABA.

Figure 6: The proposed neuronal pathways by which excitatory amino acids may influence the

secretion of GnRH, and in turn LH (Source: Henry Urban´ski et al., 1996).

The primary action of GABA appears to be to inhibit the nitric oxide activation of cyclooxygen-

ase (Seilicovich et al., 1995), which increases the release of prostanoids, ProstaglandinE2

(Rettori et al., 1992) by activating adenylate cyclase (AC) with a consequent increase in cAMP,


evokes exocytosis GnRH granules by activation of protein kinase A. Furthermore, beta endor-

phin inhibits nitric oxide synthase activity. Therefore, ethanol inhibits release GnRH via the

above mechanism in the hypothalamus.

Alcohol affects production and secretion of LH by disrupting the function of the GnRH receptor

or its interaction with GnRH, impairing the function of protein kinaseC, decreasing the ability of

LH genetic material to bind to the parts of the cell i.e., ribosome (Salonen et al., 1992, Emanuele

et al., 1993). So that the ability of LH to stimulate leyding cells are highly diminished.

The potency of LH depends on the number and types of carbohydrates attached to the protein.

Therefore, Numerous LH variants exist with differing attached carbohydrates and differing po-

tencies. Alcohol has been shown to result in the production of less potent LH molecules. There-

fore, alcohol’s deleterious effects on LH function are qualitative as well as quantitative

(Emanuele et al., 1993).

8.5 Alcohol and Testes

The cells responsible for sperm production occupy 95 percent of the testicular volume. There-

fore, failure of spermatogenesis may be characterized by testicular atrophy associated with

oligospermia12

or azoospermia13

. In contrast, decreased production of steriod sex hormones prin-

cipally testosterone is characterized by a loss of male secondary sex characteristics, impotence,

diminished libido, and other symptoms, but usually not by an obvious reduction in testicular size

(Harlan I .et al., 1991).

Chronic alcohol consumption affects both testicular functions, which produces sexual dysfunc-

tion and impairs sperm production (yen And Jaffe, 1991). Acute and chronic ethanol ingestion

has been shown to be associated with reduced testosterone levels in humans and rat (Badr and

Bartke, 1974).In vitro, both ethanol and acetaldehyde can be shown to inhibit 17, 20-lyase activi-

ty, while chronic ethanol feeding is associated with reduced activity of 3-β-hydroxysteroid dehy-

drogenase, the rate-limiting step in steroid hormone biosynthesis (chio et al., 1981).Furthermore,

increase in the metabolic clearance rate (Steiner et al., 1996) and conversion of testosterone or

12

Oligospermia is less than 5-20 x 106 sperm cells/ml.

13 Azoospermia is less than 5 x 106 sperm cells/ml.


androsatenedione to estradiol and estrone through a process called aromatization by increased the

activity of aromatase enzyme in liver are another mechanisms for alcohol induced testosterone

inhibition.

Chronic alcohol consumption is associated with elevated estrogen level due to increased aroma-

tization of testosterone and androsatenedione in liver and fat tissue (Gordon et al., 1979). This

increased conversion may account for the elevated estrogen levels and abnormal breast enlarge-

ment observed in some heavy drinkers. For example, in the study by Lloyd and Williams (1948),

42% of males with alcoholic cirrhosis exhibited enlarged breasts.

In alcoholic men and rats fed alcohol chronically, reduced spermatogenesis caused by advanced

injury to the germ cells of the seminiferous tubules by inhibiting the testicular conversion of reti-

nol to retinal, which is essential for spermatogenesis. Ethanol inhibits retinal generation within

the testes by blocking or more appropriately, efficiently competing with retinol for alcohol dehy-

drogenase. As a result, despite retinol sufficiency, the testes become retinal deficient and sper-

matogenesis is affected adversely (Kley et al., 1975, Gavaler and van thiel, 1987).

As a result of reduced spermatogenesis, the number of germ cells within the testes declines, sem-

iniferous tubular volume declines, and gross testicular atrophy becomes evident clinically

(Gavaler and Van Thiel,1982). At the seminiferous tubular level alcohol decreases semen vol-

ume, total sperm concentration, motility of sperm, number of morphologically normal sperm and

viability of sperm (Muthusami and Chinnaswamy, 2005).

8.5.1. Mechanisms of Alcohol Induced Testicular Injury

Opioids, free radicals and intermediate toxic metabolic products of alcohol are the possible

mechanisms of alcohol induced testicular injury.

Concentrations of endogenous opioids (β-endorphin) have been shown to be increased in the in-

terstitial fluid in testis, hypothalamus, pituitary gland, and serum following alcohol intake (Ad-

ams and Cicero, 1991). Increased levels of testicular opioids (β-endorphin) suppress testosterone


production and release through autocrine or paracrine effect (Gianoulakis, 1990) and increase

apoptosis14

(Yin et al., 1999; Nanji and Hiller-Sturmhöfel, 1997). Similarly beta endorphin pro-

duced in the hypothalamus results in decrease GnRH levels (Emanuele et al., 2001). Chronic al-

cohol consumption increase estradiol level, which in turn enhance secretion of testicular opioids

((Emanuele et al., 2001).

Apoptosis at the gonadal level would result in the death of both Leydig and seminiferous cells,

leading to low testosterone and diminished sperm production. In both adult and pubertal male

rats, treatment with opioid antagonists like naloxone and naltrexone has been successful in pre-

venting alcohol-induced testosterone inhibition (Gianoulakis, 1990).

Acetaldehyde, which is the principle product of alcohol metabolism, produces highly toxic ROSs

including anion superoxide, hydrogen peroxide, hydroxyl radicals and nitrogen reactive species.

these ROSs have role in alcohol induced testicular damage by creating oxidative stress15

. In addi-

tion Acetaldehyde alters the process of testosterone production by inhibiting protein kinase C, a

key enzyme in testosterone synthesis (Anderson et al., 1985; Chiao and Van Thiel, 1983).

Alcohol consumption promotes oxidative stress and testicular damage either by enhancing the

production of free radicals or by decreasing the levels of anti oxidants (Emanuele et al., 2001).

Reactive aldehyde and hydroxyl radicals, which may be generated during metabolism of ethanol,

have the ability to attack amino acid residues of proteins, thereby forming both stable and unsta-

ble adducts with proteins and cellular constituents. As a consequence, cellular functions may be-

come disturbed together with damage to proteins, nucleic acids and lipids (Lieber Charles

S.1997; Clot Paolo et al., 1997).In addition alcohol reduces the levels endogenous antioxidants

like Glutathione reductase, superoxide Dismutase, catalase and dietary antioxidants like β-

carotene, vitamin E and vitamin C.(Maneesh M et al., 2005).

14

Apoptosis is programmed cell death, and the cells participate in the cell death process by acti-

vating a cascade of biochemical reactions that ultimately lead to cell shrinkage and fragmenta-

tion of the nucleus.

15 Oxidative stress is imbalance between ROS and antioxidants and have role in escalating cell

damage


Peroxidation injury can be attenuated with dietary supplementations of non enzymatic antioxi-

dant vitamins including vitamin C, vitamin A and vitamin E through different mechanisms. Vit-

amin C reacts rapidly with superoxide, peroxyl and hydroxyl radicals to give

semidehydroascorbate (Jacob RA etal., 1991). Vitamin A and vitamin E are lipid soluble, serve

as first line defence against peroxidation injury (Burton GW, 1994).

Another explanations for the gonadal suppression associated with alcohol is disturbance of

other hormones that have interaction with HPG axis, such as the ACTH, cortisol and prolactin

(Ogilvie and rivier, 1997). Consumption of alcohol increases production of ACTH, cortisol

(Aguirre et al., 1995) and prolactin (Ida et al., 1992) which have inhibitory effect on reproductive

system.

Alcohol has been shown to increase stress hormone levels (Corticosterone and cortisol) through

effect on paraventricular nuclei of the hypothalamus through enhanced release of CRH or by di-

rect stimulation of corticotrophins in the pituitary to release ACTH(Emanuele, 1997).However,

some people tend to increase their alcohol intake when they are stressed. This has been called the

“alcohol paradox”16

(Pohorecky, 1991; Stritzke et al., 1996). Testicular interstitial cells express

glucocorticoids receptors on their cell membranes; the binding of receptor agonists to these re-

ceptors causes a stress response in the cells and can reduce interstitial testosterone synthesis

(Välimäki et al., 1984). In addition it decreases the LH-induced cyclic adenosine monophos-

phate-production and the activity of 17α-hydroxylase17

.Thus the overall effect of releasing

stressor hormones due to alcohol consumption has inhibitory effect on male reproductive and

may end up with decreased sex steroid production, impaired libido, delayed onset of puberty and

impaired spermatogenesis.

16

Alcohol paradox defined as alcohol increases stress hormone concentrations, people appear to

use alcohol as a means of self medication to cope with stress

17 17α-hydroxylase is an enzyme catalyzing the reactions from progesterone to17α-

hydroxyprogestrone and androsatenedione.


Human and animal studies on both sexes have demonstrated that both acute and chronic alcohol

exposure leads to a stimulation of prolactin release (Emanuele et al. 1993). Alcohol induced

reduction of dopamine’s inhibitory effect as well as direct effect on the anterior pituitary can

stimulate prolactin release. Elevated prolactin frequently is associated with inhibitory effect on

reproductive system through an action on the GnRH neurons of the hypothalamus by enhance

secretion of gamma amino butyric acid, opioid, neuropeptide Y. All of which are implicated in-

hibitory effect on GnRH neurons.additionaly prolactin affect both the frequency and amplitude

of LH pulses in male and female rats (Grattan et al., 2007).

Across sectional study on the effects of acute alcohol intoxication (AAI) on the pituitary-gonadal

axis hormones, and the possible contribution of pituitary-adrenal axis hormones, beta-endorphin

and prolactin to alcohol-induced dysfunction of pituitary-gonadal axis hormones were studied in

adult men and women. Blood samples were drawn from a total of 21subjects (12 men and 9

women) age group who arrived at the emergency department with evident behavioral symptoms

of drunkenness (AAI) and a total of 27 healthy volunteers (11 men and 16 women) of same age

from 20-27 years whose alcohol consumption was nil as controls. The results demonstrated that

AAI produces a high increase in plasma prolactin, ACTH, and cortisol in adults of both sexes, a

decrease in luteinizing hormone levels only in men, an increase in DHEAS and testosterone in

women and a decrease in men. ACTH and prolactin correlated positively with cortisol, DHEAS

and testosterone in women, which suggests that prolactin and ACTH could contribute to stimu-

lated adrenal androgen production. In contrast, the decrease in testosterone and increase in beta-

endorphin in men suggests that AAI could have an inhibitory effect on testicular testosterone

mediated by beta-endorphin. These results suggest that the effect of alcohol on pituitary-gonadal

axis hormones in humans could depend on the gender and degree of sexual maturity of the indi-

vidual.

9. Alcohol and Sexual Performance

Chronic Alcohol consumption has long been recognized as an agent that can affect male erectile

function (Masters and Johnson, 1970). Since an enhancement or decrement in penile tumescence

may occur depending on the amount of alcohol ingested and length of time of exposure, it is im-


portant to characterize the entire range of responses of alcoholics and controls acutely and chron-

ically exposed to alcohol as well as during various stages of withdrawal and sobriety. The phe-

nomenon of nocturnal penile tumescence (NPT) 18

can measured the male potency or impotence

(Scott Snyder and Ismet Karacan, 1981).

In 1981 Scott Snyder and Ismet Karacan have done investigations on alcoholism and NPT, 26

sober, detoxified, chronic male alcoholics was measured during polysomnography19

. Subjects

had significantly reduced latency to tumescence, decreased number and amount of maximal pe-

nile erections, and an increased number and amount of semi-erections compared to age-matched,

nonalcoholic controls.

A variety of physiological mechanisms have been invoked to explain why alcohol affects sexual

performance in males. The effects of alcohol specifically on penile tumescence are most likely

the result of direct damage to the nervous system. A significant impairment in maximum erectile

capacity occurred in alcoholics this impairment was caused by an alteration in a nervous system

arc consisting of the cerebral contex (origin of sexual thoughts), anterior portion of the temporal

lobe (may regulate libido intensity), hypothalamus, spinal cord reflex centers (mediates erection)

and peripheral nerves (Lemere and Smith ,1973).

Positive loci for erection were found in several corticosubcortical subdivisions of the limbic sys-

tem. These loci included some paraventricular areas of the thalamus, mamillary bodies, and the

floor of the 4th ventricle. These locales are analogous in other primates (Maclean and Denison,

1963, Robison and Mishkin, 1968).The effects of chronic alcohol abuse include

neuropathological changes in these areas, contributing to impaired erectile function (Dreyfus,

1974, Weiss, 1972). Also chronic alcoholism may induce atrophy of the frontal lobes and seg-

mental enlargement of the lateral and third ventricles (Dreyfus, 1974). Since the psychic stimula-

18

NPT is a normal component of the autonomic, arousal characteristic of REM sleep and accu-

rately measure changes in penile circumference during sleep and used in the differential diagno-

sis of psychogenic and organic impotence.

19 Polysomnography is recording of physiological changes that occur during sleep.


tion thought to initiate male sexual arousal and erection may originate in those cortical areas,

chronic alcoholism may impair erectile capacity through a direct cortical effect.

The peripheral nervous system is particularly important in initiating and maintaining penile tu-

mescence. Vasodilation of the vascular system of the penis is activated by parasympathetic

nerves. Erection is maintained by vascular arteriovenous balance and sufficient blood pressure

and blood flow to the penis. The nervi erigentes, formed by the sacral, hypogastric, and pelvic

plexi, are involved in these processes (Weiss, 1972). Chronic alcoholism may result in axonal

degeneration with destruction of the axon and myelin sheath and segmental demyelination. The

distal parts of the longest and largest myelinated fibers of the crural nerves are most affected.

The anterior horn cells themselves may show chromatolysis (Victor and Adams, 1953).


10. Conclusions and Prospective Studies

Chronic Alcohol consumption has many direct and indirect effects on the male reproductive sys-

tem. It affects the reproductive regulatory mechanism i.e. the hypothalamic pituitary axis and the

gonads.

The hypothalamic preoptic and arcuate nuclei are responsible for the pulsatile release of GnRH

which stimulates the gonadotropes. GnRH neurons are affected by alcohol via enhancements of

GABA and beta endorphin secretions, which have inhibitory effect on the GnRH neurons.

The effects of alcohol on Adenohypysis of gonadotropes are multiple; it down regulates the

GnRH receptors in the gonadotropes and causes less response to GnRH, inhibits the production,

glycosylation of luteinizing hormone and decrease the potency of LH hormone.

Free radicals, acetaldehyde and other derivatives of alcohol metabolites damage leyding cell and

seminiferous tubules and hence reduce testosterone production and sperm production respective-

ly

Generally low testosterone level due to alcohol consumption may be related to:

1. Decrease secretion of LH from the gonadotropes of adenohypophysis.

2. Damage of leyding cell.

3. Increase conversion of testosterone to estradiol in liver due to increase 5α-testosterone

reductase and aromatase.

4. Increase metabolic clearance rate of testosterone.

The Sertoli cells are also affected by alcohol via decrease secretion of FSH and direct damage by

the oxidative stress, this leads to oligospermia, abnormal morphology of sperm and infertility.

In general, the main mechanism for alcohol induced testicular injury is oxidative stress, which is

responsible for the apoptosis and necrosis of leyding and Sertoli cell. Oxidative stress is created

by the imbalance between free radicals generated by metabolism of alcohol and endogenous an-

tioxidants.


Further investigation on the mechanisms of alcohol induced oxidative damage and apoptosis in

the testis, consequences of paternal alcohol exposure for their offspring are some points to indi-

cate the direction of research.

Interventions to prevent or decrease lipid peroxidation due to oxidative stress created by acetal-

dehyde and other byproducts of alcohol are applied like administration of vitamin A, which has

role in stabilizing cell membrane and antioxidant activity. Further investigation on this strategy is

mandatory.


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Health & Medicine

The effects of alcohol on male reproductive system