Metformin

In women with polycystic ovary syndrome (PCOS, discussed in Chapter 38), common symptoms are anovulation and hyperandrogenism, with infertility and high prevalence of spontaneous abortion, gestationaldiabetes and pre-eclampsia. Insulin reduction strategies are helpful in treating the associated infertility, especially simple weight reduction. In women with a high body mass index, an insulin-sensitising agent such as metformin may be used to assist ovulation and weight reduction. Metformin (500 mg orally, 3 times daily with meals, continued until the first positive pregnancy test) has been shown to be as effective as clomiphene citrate as first-line therapy of PCOS infertility. The mechanisms are not clear; however, metformin reduces hyperinsulinaemia and improves insulin sensitivity, improves cardiovascular risk factors such as high blood pressure and dyslipidaemia, reduces free fatty acids, reduces high androgen levels, promotes weight loss and overall improves the chance of ovulation and outcome of pregnancy (see review by Diamanti-Kandarakis et al [2010]).

Hormone components

The aim of most COC formulations is to mimic closely the sequence and relative levels of oestrogen and progestogen in the menstrual cycle (see Figure 38-3): oestrogen levels are low early in the cycle, high in midcycle and medium late in the cycle; progestogen levels are very low or absent until after the midcycle surge of gonadotrophins, then rise in the latter half of the cycle. Although the use of exogenous oestrogenic substances alone will inhibit ovulation, undesirable ‘break-through’ bleeding frequently occurs during the latter phase of the cycle. If oestrogen levels are increased to prevent this, severe nausea, breast tenderness and thromboembolic adverse reactions may occur. Hence progestogens are combined with oestrogens in COCs.

In the typical 21/7 COC regimen, withdrawal of the active hormones after 21 days (when 7 placebo tablets or no tablets are substituted for active tablets) precipitates the withdrawal bleed, i.e. the next menstrual cycle. Phasic dosing, i.e. varying levels of each hormone) was introduced in the belief that it might interfere less with a woman’s normal metabolism but this has not been substantiated clinically.

Note that menstruation can be effectively suppressed by continuous taking of the active tablets (see Clinical Interest Box 38-1). In some countries an ‘extended’ formulation is available with 84 hormone tablets followed by a 7-day break, which effectively causes amenorrhoea within one year in most women using this formulation. This 91-day pack reflects the fact that many women skip the inactive tablets for a couple of months at times when menstruation would be inconvenient.

Mechanisms of actions

Much research has gone into identifying the actions of the hormones that together bring about contraceptive effects. Current views are that the oestrogen component causes decreased FSH release and thus impaired selection of a dominant ovarian follicle and impaired follicle development, with consequent decreased likelihood of ovulation and decreased chance of implantation. The actions of the progestogen component are to modify the secretory activity of the uterine cervix, decrease LH release, impair ovulation and impair tubal motility, decreasing likelihood of fertilisation.

Taken together over a few cycles, oestrogen–progestogen combinations effectively inhibit secretion of hypothalamicGnRH, pituitary gonadotrophins FSH and LH and endogenous ovarian steroids. This causes production of thickened cervical mucus that impairs sperm transport; decreases endometrial proliferation, secretions and menstrual flow; and reduces likelihood of ovulation and implantation. Overall, pregnancy does not occur.

The mechanisms of action of female contraceptive methods are compared diagrammatically in Figure 40-2.

Figure 40-2 Sites of action of various contraceptive methods in the female reproductive tract (compare Figure 38-2). [ – ] = effect decreased or inhibited; GnRH = gonadotrophin-releasing hormone; IUD = intrauterine device; OCP = oral contraceptive pill.

Clinical use of oral contraceptives

Oral contraceptives are indicated for use in menstrual disorders and premenstrual syndrome as well as for contraception. In addition, they can be used for emergency contraception (described later). For detailed information on the pharmacokinetics, adverse effects, drug interactions and contraindications of the component drugs, see the drug monographs for typical oestrogens (oestradiol valerate, Drug Monograph 38-2) and progestogens (medroxyprogesterone acetate, Drug Monograph 38-3) in Chapter 38.

Before prescribing OC therapy, a prescriber should perform a thorough history and physical examination, including breast examination and a complete drug history. Teaching and monitoring of patients are also necessary; in particular, a woman needs to know:

Combined oral contraceptive formulations

Many different types of COC formulations are available, with different combinations and sequences of semisynthetic hormones selected to optimise activity and minimise adverse effects. Table 40-1 lists the compositions, doses and brand names of some typical OCs used in these methods; a typical calendar pack is shown in Figure 40-1A. However, formulations change frequently, so current reference lists should be consulted. Other concurrent medical conditions may determine the preferred drug or contraceptive method (see Table 40-2).

Table 40-1 Examples of hormonal contraceptives

Source: AMH 2010; MIMS OnLine.

Table 40-2 Recommendations for selecting a contraceptive method

^† > 15 cigarettes/day. CVA = cerebrovascular accident (stroke).

Source: AMH 2010.

Most formulations in Australia contain ethinyloestradiol (EE); the only other oestrogen used is mestranol. (New oestrogens being trialled include estetrol [not yet available in Australia or New Zealand in 2010], a steroid produced in the human liver.) Because naturally occurring pro gesterone is inactivated or extremely weak in its effect when taken orally, and must be given by injection to be effective, synthetic progestogens with stronger actions were developed. Several are used in OC preparations: norethisterone, levonorgestrel; desogestrel, gestodene or drospirenone (the latter three are less likely to have androgenic effects), or cyproterone (with antiandrogen activity). New progestogens with antiandrogenic activity undergoing trials in other countries include dienogest (currently available in Australia and New Zealand)and nomegestrol (not available in Australia or New Zealand).

Progestogen-only oral contraception

SPRMs as contraceptives

A new method undergoing trials is the use of a selective progesterone receptor modulator (SPRM) such as mifepristone, which is available in New Zealand but not Australia, (or a new drug ulipristal that is not yet marketed in Australia or New Zealand) to block receptors in the ovary and inhibit the LH surge. Daily doses of 5 mg mifepristone, or weekly doses of 25 mg, effectively inhibit pregnancies and lead to fewer bleeding days and more amenorrhoea than the progesterone-only pill.

Risk–benefit analysis

Because OC preparations are taken by millions of women for most of their reproductive lives, it is crucial that long-term safety, risks and benefits be identified. The risks need to be compared with risks associated with pregnancy and childbirth, particularly in countries where obstetric care is inadequate, and with the risks of abortion in the case of unwanted pregnancy. Major long-term studies over millions of woman–years have demonstrated that the newer low-dose OCs have many advantages over earlier preparations, and fewer risks than pregnancy (see Clinical Interest Box 40-2).

Absolute contraindications for the use of OC are: thromboembolic disease, coronary artery disease, stroke, active liver disease, oestrogen-dependent cancers, focal migraine, porphyrias and pregnancy. OC is relatively contraindicated in hypertension, diabetes, previous cholestasis, undiagnosed vaginal bleeding, elective surgery within 4 weeks, sickle cell disease and severe depression, and in women over 35 years with risks for coronary artery disease.

Common adverse reactions and drug interactions are described under ‘Oestrogens’ and ‘Progestogens’ (Chapter 38).

Combined vaginal ring

A new technique that provides controlled release of a combination of hormones is the vaginal ring that contains both a progestogen and an oestrogen (see Figure 40-1C). It is a flexible polymer ring that slowly releases EE (15 mcg/24 hours) and etonogestrel (120 mcg/24 hours). It is inserted by the woman into her vagina and left for 3 weeks, then removed; her next menstrual period usually starts within 2–3 days. A new ring is inserted 1 week after the previous ring was removed. Absorption of the steroid through the vaginal epithelium is rapid, and first-pass metabolism is avoided. Rings have now been made that continuously release hormones for up to one year. Progestogen-only rings can be used by lactating women.

The ring has the same possible adverse effects, precautions and contraindications as combined oestrogen–progestogen products taken orally in the COC pill. There are additional warnings and advice as to changing from COCs or progestogen-only products, and what the woman should do if the ring is accidentally removed, left in too long or not replaced on time.

Combined depot injections

Depot injections containing both a progestogen (either MPA or norethisterone) with an oestrogen (oestriol valerate or cypionate) have been trialled and gone into clinical use in some countries. The combined depot preparations disturb bleeding patterns less than the progestogen-only injections, and allow earlier return to ovulation after stopping use.

Progestogen-only depot preparations

Depot injections of progestogen (e.g. MPA 150 mg given IM every 3 months) have the lowest failure rate of all reversible contraceptive methods. Progestogen depots inhibit gonadotrophin secretion, thus preventing follicular maturation and ovulation, resulting in contraception. This method is suitable for women who do not want to take a daily tablet or who cannot take oestrogens. There may be a period of infertility for some months after completing the course. Adverse reactions include vaginal bleeding, irregular periods and weight gain. New formulations containing lower doses of micronised medroxyprogesterone acetate (MPA) for depot IM injection are undergoing clinical trials; the MPA is absorbed more slowly and reaches lower peak levels, with fewer adverse effects but good efficacy.

A subdermal depot implant containing a progestogen is also available, consisting of a polymer rod (4 cm long, 2 mm diameter) impregnated with 68 mg etonogestrel (see Figure 40-1 D). It is implanted using aseptic procedures under the skin of the inner aspect of the upper arm,² and is left in place for 3 years, during which there is a gradually reducing rate of release of active drug (from 60–70 to 25–30 mcg/day). The contraceptive effect is due mainly to inhibition of ovulation. It is then removed and a new rod is inserted if continuing contraception is desired. Fertility will return after removal of the implants, with rapid return to normal menstrual periods. New versions of the implant containing nestorone or nomegestrol, and biodegradable implants, are being trialled.

A plastic IUD impregnated with 52 mg levonorgestrel, a slow-release progestogen, is also available. It is useful for long-term contraception (5 years), to treat menorrhagia and to provide the progestogen content of continuous combined HRT.

Diaphragm plus spermicidal agent

An occlusive vaginal diaphragm may be used in conjunction with a spermicidal gel (containing surfactant chemicals) as a non-hormonal method of contraception. The gel is applied before placement to the surface of the diaphragm to be in contact with the cervix and around the rim. The diaphragm should remain in situ for 6–8 hours after sexual intercourse. A fresh application of spermicidal gel should be made (using an intravaginal applicator) for subsequent sexual activity during this time frame. Adverse effects may include mild irritation or dermatitis; neither diaphragms nor spermicides protect against sexually transmissible diseases. Some spermicides have been shown to damage the vaginal epithelium and potentially increase the risk of sexually-transmitted infections.

Intrauterine devices

Intrauterine devices (IUDs) impregnated with copper (see Drug Monograph 40-2 and Figure 40-1B) progestogen (levonorgestrel) are used for long-term (5–8 years) reversible contraception. They alter the intrauterine environment to decrease sperm motility and viability, inhibit nidation (attachment of the fertilised ovum in the endometrium) and inhibit or decrease ovulation and follicular development. They can cause dysmenorrhoea, pelvic inflammatory disease or uterine perforation, and the IUD can be expelled from the uterus; they do not protect against STDs.

Other methods

Other methods tested or under trial in women include continuous administration of GnRH drugs that inhibit luteinising hormone-releasing hormone; luteolytic agents, including prostaglandin F₂α; and vaccines against hCG, GnRH or sperm antigens. An anti-hCG vaccine has gone through phase 2 clinical trials, but provided effective contraception in only 60%–80% of women using it.

Phosphodiesterase type 5 inhibitors

The final common pathway leading to impotence is a lack of the vasodilator nitric oxide (NO), which normally relaxes the smooth muscle of the penile arteries and allows congestion. Sildenafil (which rapidly became renowned worldwide by its trade name Viagra) specifically improves erectile function and treats impotence (see Drug Monograph 40-3).sildenafil was the first oral medication approved for efficacy in treating impotence; later drugs in this group are tadalafil and vardenafil. Tadalafil has a significantly longer half-life (17.5 hours compared to 2–5 hours) and duration of action (12–36 hours compared to 4–5 hours).

Other drugs used to treat erectile dysfunction

Second-line drugs used to treat ED are testosterone derivatives, prostaglandins and papaverine. These must all be given by injection, hence the major advantage of oral sildenafil. Alprostadil, a synthetic form of prostaglandin E₁ (PGE₁), is given by penile injection (into the corpora cavernosa) or transurethral application; it dilates the cavernosal arteries and thus assists erectile function. Testosterone implants, IM depot injections and patches or transdermal gels are tried if the ED is due to androgen deficiency (see Drug Monograph 39-1); however, the role of testosterone in the human erectile response is not well defined. Papaverine, a smooth muscle relaxant, is given by intracavernosal injection; it relaxes all vascular components of the penile erectile system.

Bromocriptine is effective in patients in whom the cause of ED is hyperprolactinaemia. The local anaesthetic lignocaine is available in a spray formulation as a local surface penile desensitiser to be used to prevent premature ejaculation. A variety of combination therapies have also been tried, along with surgical procedures and prosthetic devices (see review by Ellsworth and Kirshenbaum [2008]).

Vasodilators

As well as the PDE5 inhibitors, other drugs with vasodilator activity may enhance the sexual response.

One of the few compounds with proven activity is yohimbine, an alkaloid derived from the West African tree Coryanthe yohimbe and related chemically to the ergot alkaloids. Yohimbine produces a competitive α-adrenergic block, leading to vasodilation, enhanced erection and increased ejaculatory reflexes. There is no convincing evidence that it acts as a sexual stimulant, and it has no medical use as it has low efficacy.

Vasodilators such as the organic nitrates (glyceryl trinitrate [see Drug Monograph 23-1]; isosorbide mononitrate) might be expected to be useful in dilating blood vessels in the penis and improving erections; however, such drugs have non-specific vasodilator actions and thus powerful adverse effects, causing headaches, hypotension and fainting, which would be counter-productive. Amyl nitrite, a drug used in the past to treat angina pectoris, is alleged to enhance sexual activity in humans and has been reported to intensify the orgasmic experience for men if inhaled at the moment of orgasm. No effect of amyl nitrite on libido has been reported, but loss of erection or delayed ejaculation may result. Women generally experience negative effects on orgasm when taking this drug.

Social drugs and psychoactive agents

The use of drugs such as morphine, heroin, cocaine, alcohol, marijuana, lysergic acid diethylamide (LSD), amphetamines and ‘designer drugs’ in the hope of aphrodisiac actions has become widespread in contemporary society (see Chapter 21). These agents can, in certain circumstances, enhance the enjoyment of the sexual experience for some people. More commonly, however, sexual function decreases. Responsiveness varies because these agents have no particular properties that specifically increase sexual potency—rather they tend to affect the user according to expectations. Thus the user’s state of mind, the amount of drug(s) consumed and the surrounding company and environment contribute considerably to the effect perceived. Like alcohol, these drugs act on the CNS to weaken inhibitions, which are often the cause of problems involving sexual behaviour. Taken in excess or too often, however, these drugs have the opposite effect and inhibit sexual drive and function. Because of these variations, researchers are sceptical of their clinical value.

Opioids such as morphine, pethidine and heroin are general CNS depressants and cause disorientation and mental confusion. They are said to have an ‘orgasmic effect’, but habitual users have low libido and impaired potency.

Marijuana (cannabis), an extract of the Cannabis sativa plant, is considered by many to be a sexual stimulant. Its effects, however, like those of alcohol, result indirectly from relaxation and release of inhibitions surrounding sexual activity. The active ingredient in marijuana is tetrahydrocannabinol. The pharmacological effects resulting from smoking marijuana depend on the expectations and personality of the user, the dose and the prevailing circumstances. Usually, the effects of marijuana are to distort time and enhance suggestibility, producing the illusion that sexual climax is prolonged. Thus the expectation that marijuana is an aphrodisiac may enhance enjoyment of the sex act. Studies of marijuana for a specific effect on sexual behaviour, however, have shown that it has no such enhancing effect. On the contrary, there is evidence that marijuana smokers have a higher incidence of decreased libido, potency and fertility than non-users do, possibly because of its oestrogenic-type effects and a decrease in release of the gonadotrophins FSH and LH. In addition, chronic intensive use of marijuana depresses plasma testosterone levels and produces gynaecomastia in some male users and decreases prolactin levels and ovulation in women. Chromosomal breaks have also been reported, with the risk of congenital abnormalities.

LSD is another drug that, although considered an aphrodisiac by some, has potentially adverse effects on sexual function and behaviour. As with marijuana, any alteration of sexual performance produced by LSD is principally subjective. This drug acts as an agonist at central 5-hydroxytryptamine (5-HT, serotonin) receptors (see Figure 21-4), causing facilitated sensory input, altered sensations and improved mood. The repeated use of LSD may produce serious psychological problems, which could overall adversely affect sexual interest or activity. Teratogenic effects have also been reported.

Amphetamines (‘speed’) have also been used to stimulate sexual function. These drugs release catecholamines from neuronal stores and inhibit their reuptake. They also have a powerful central stimulant action at dopamine and 5-HT receptors and peripheral sympathomimetic effects. The main effects are wakefulness and alertness, mood elevation, increased motor and speech activity, often elation and euphoria and decreased fatigue. The effects of ampheta mines on sexual performance, however, are inconsistent and may be attributed to overcoming feelings of shyness or inadequacy or to delaying sleep.

Nicotine is a CNS stimulant and has complex peripheral effects due to its actions at acetylcholine nicotinic receptors in autonomic ganglia and skeletal muscle. Overall, it tends to increase heart rate and vasoconstriction, inhibit spinal reflexes and increase release of ADH and oxytocin. No clear-cut acute effect of smoking on sexual functions is evident. However long-term effects are well known: statistically, 50% of men who smoke regularly from their 20s are impotent by their 50s, due to impaired cardiovascular functions.

Other drugs that may stimulate sexual behaviour

Hormones involved in the reproductive systems have effects in sexual functions; thus oestrogens and androgens may increase sexual activity in people of the appropriate sex. Oxytocin appears to have roles in mating and parenting behaviours in humans as well as in animals studied.

Premature ejaculation, the occurrence of a male orgasm too early in sexual intercourse, is a condition that impairs sexual functioning in many relationships. A topical spray or cream formulation of the local anaesthetic lignocaine is available; it is used to desensitise the surface of the penis and prolong time to ejaculation.

Levodopa, useful in treating parkinsonism by enhancing dopamine transmission in the CNS, is reported to increase libido and has caused priapism. Elderly men on levodopa have been observed to have a sexual rejuvenation, and studies with younger men complaining of decreased erectile ability have shown that levodopa increases libido and incidence of penile erections. Overall, however, these effects are short-lived and do not reflect continued satisfactory sexual function and potency. Thus levodopa is not a true aphrodisiac, but the increased sexual activity experienced by parkinsonian patients treated with levodopa may reflect improved wellbeing and partial recovery of normal sexual and motor functions impaired by Parkinson’s disease.

Vitamin E compounds (the tocopherols) act as antioxidants and have metabolic roles and have been postulated to be involved in sexual functions because deficiencies of the vitamin impair reproductive ability. Much has been said about the positive effects of vitamin E on sexual performance and ability in human beings, but beneficial effects are not proven. Because sexual performance is often influenced by mental attitude, a person who believes vitamin E improves sexual prowess may actually find improvement.

Ganglion-blocking agents

These drugs occupy nicotinic acetylcholine receptor sites at all autonomic ganglia and block the actions of released acetylcholine. They thus block all sympathetic and parasympathetic responses and effectively ‘wipe out’ the entire ANS. Because of their widespread actions and severe adverse effects, including hypotension, inhibition of gut functions, urinary retention and impairment of both erectile capability and ejaculatory function, they are no longer used. Examples were hexamethonium and mecamylamine.

Adrenergic neuron-blocking agents

Adrenergic neuron-blocking agents act by decreasing release of adrenergic transmitter (noradrenaline) and depleting transmitter stores. They thus impair sympathetic nervous system functions, causing vasodilation and hypotension as well as ejaculatory disturbances and impotence. Reserpine, a drug affecting central transmitter stores of catecholamines and 5-HT, was formerly used as an antihypertensive drug and in psychiatry, but is no longer used because of its many adverse effects.

Other antihypertensive agents

Centrally acting α₂-agonists used as antihypertensives, such as methyldopa and clonidine, have been associated with frequent reports of impotence, sexual dysfunction, dec reased libido and gynaecomastia. The α-blocker phenoxy benzamine, an effective hypotensive drug, decreases ejaculation. (This drug has been referred to as the male contraceptive: interestingly, it has been used successfully in men with premature ejaculation problems.) Beta-blockers such as propranolol and metoprolol have also been reported to cause impotence and sexual dysfunction, as have calcium channel blockers (nifedipine, verapamil) and angiotensinconverting enzyme inhibitors (like captopril)

The thiazide diuretic hydrochlorothiazide may induce sexual dysfunction through its hypotensive and vasodilator actions. Spironolactone, an aldosterone antagonist, has both diuretic and endocrine effects and has been associated with impotence, gynaecomastia and a decrease in libido.

Antipsychotic agents

The phenothiazine tranquillisers, such as chlorpromazine, prochlorperazine, thioridazine and fluphenazine, are commonly prescribed antischizophrenic agents that are thought to act by inhibiting dopaminergic transmission in the CNS. They very frequently have endocrine-type adverse effects mediated through their stimulation of prolactin release, causing gynaecomastia (in men) or galactorrhoea (in women), and through their decreased release of pituitary gonadotrophins and thus of sex hormones, causing priapism and ejaculatory disorders or impaired menstruation and ovulation. The phenothiazines are very ‘dirty’ drugs, affecting many transmitter systems (see Tables 18-1 and 18-2), and can block α-receptors (causing hypotension and ejaculatory disorders) and cholinergic receptors (causing ED). They have general CNS-depressant effects, including sedation, which may partly account for decreased sexual interest in people undergoing phenothiazine therapy. There have been some reports of enhanced libido, particularly in women. Because of the many serious adverse reactions, patient compliance with phenothiazine therapy is often low.

Other non-phenothiazine antipsychotics (neuroleptics, antischizophrenics) may cause similar adverse effects because all appear to act by inhibiting dopamine transmission. Such drugs include the thioxanthenes (flupenthixol and analogues), haloperidol and droperidol, and pimozide. The ‘atypical’ neuroleptics, clozapine and olanzapine, appear to be less problematic than all other neuroleptics in these respects.

Antidepressants

Antidepressant drugs generally elevate mood and thus may increase sexuality, as depression is often associated with diminished sexual interest, drive and activity (see Chapter 18). Unfortunately, however, antidepressants can influence sexual behaviour adversely by causing impotence, menstrual disorders, ejaculatory disturbances or gynaecomastia. All groups of antidepressants have been implicated: tricyclic antidepressants such as imipramine and amitriptyline (possibly related to their peripheral anticholinergic effects); monoamine oxidase (MAO) inhibitors such as phenelzine and moclobemide; and even the more specific selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac).

Hypnotics/sedatives

Benzodiazepine compounds (diazepam, alprazolam etc) are commonly prescribed antianxiety medications that are also useful as skeletal muscle relaxants. The sedative and relaxing effects of these drugs may account for the reported decreased interest in sexual activity, anorgasmia in men and women and ejaculation failure. Alternatively, the judicious use of benzodiazepines has been considered of value in the treatment of sexual impotence and other problems involving sexual performance where excessive anxiety was a factor in decreased sexual performance. Buspirone, a non-benzodiazepine antianxiety agent, has also been associated with reports of increased or decreased libido and (rarely) with impotence or delayed ejaculation.

Barbiturates such as phenobarbitone and thiopentone are sedative–hypnotic drugs that have general depressant effects on all nervous tissues. They are used variously as antiepileptics, sedatives or induction anaesthetics. These drugs, in prescribed dosage, produce relaxation, hypnosis and sleep, with depression of various body functions, including sexual performance and ability.

The classical antihistamines act as competitive inhibitors of histamine at H₁-receptor sites; these drugs include diphenhydramine, promethazine and chlorpheniramine. They are commonly taken as antiemetics and mild sedatives and for the control of allergy symptoms and travel sickness. Most antihistamines cause anticholinergic effects such as dry mouth, urinary retention and constipation. Continuous use of these drugs may interfere with sexual activity. The histamine H2-receptor antagonists such as cimetidine and ranitidine, used to treat peptic ulcers, have been reported to cause gynaecomastia and impotence in men in high doses; ranitidine is probably the safest drug in this respect.

Ethyl alcohol

Ethanol is, for its effects on human sexual function and behaviour, a drug of individual and unique notoriety (see Chapter 21 and Drug Monograph 21-3). Revered for centuries as a sexual stimulant and cure of all ills, alcohol is in fact a CNS depressant, but in moderate amounts may enhance sexual activity by relieving anxieties and reducing the inhibitions that often impair sexual behaviour. In the oftenquoted words of Shakespeare (the porter at the gate, in Macbeth, Act II, Scene III, in response to Macduff’s question ‘What three things does drink especially provoke?’): ‘Lechery, sir, it provokes and it unprovokes: it provokes the desire, but it takes away the performance: therefore, much drink may be said to be an equivocator with lechery: it makes him, and it mars him…’ Or, as William Osler put it (quoted by Bowman and Rand 1980): ‘Alcohol does not make people do things better, it makes them less ashamed of doing them badly’.

Beyond a certain limit, however, neither desire nor potency will overcome the depressed physical capability that alcohol causes. The CNS is more affected by alcohol than is any other system of the body. Electrophysiological studies show that alcohol first depresses the part of the brain responsible for integrating the various activities of the nervous system, causing impaired sensorimotor performance. The first mental processes affected are related to sobriety and self-restraint, producing a less inhibited and less restrained approach to sexual behaviour and other activities normally inhibited by previous training or experience. With continued consumption of alcohol, cerebral functions become depressed, reflexes become slowed, blood vessels are dilated and the capacity for sexual function is diminished. In addition, alcohol produces a potent diuretic effect, which can also interfere with sexual function.

Typically, the male alcoholic after years of chronic alcoholism experiences delayed ejaculation and impotence after drinking. Vascular changes, peripheral neuropathy and lower testosterone levels because of liver damage are thought to cause the impotence; body image changes such as testicular atrophy, ‘beer gut’ and gynaecomastia compound the problems.