9.4.7 Sequelae of extratesticular disease

Systemic disease has major effects on male reproductive health, although these are not always recognised. Management of any medical disorder should include careful consideration of the effects of illness and its treatment on androgen secretion, fertility, and sexuality. A functional reproductive system is a profoundly valued aspect of a healthy life and it is an important, albeit often unstated, expectation of medical care that reproductive function is preserved and protected. Hence, recognition of this important but easily overlooked aspect of medical care should form a part of optimal management of chronic medical illness (1).

The effects of systemic disease on male reproductive health are mediated by effects of the illness and its investigation and treatment on the testis, and its impact on hypothalamic-pituitary regulation. This is manifest by reduced androgen secretion and/or spermatogenesis with or without impaired sexual function. Androgens are responsible for the anabolic status and function of many tissues, most notably muscle, bone, haematopoietic cells, and brain. The ubiquitous tissue expression of the androgen receptor indicates widespread, often subtle, effects (2). Consequently, androgen deficiency has diverse clinical manifestations that depend upon not only the diversity of tissues involved but also the epoch of life when it begins, its severity and its chronicity. Unlike androgen deficiency commencing before puberty, postpubertal androgen deficiency leaves no distinctive physical signs and its clinical features are subtle, variable and not life-threatening. Hence, clinical features of androgen deficiency during systemic disease are readily overshadowed by the more dramatic manifestations of systemic diseases. Despite its frequency, androgen deficiency is thus an often unrecognised feature of systemic diseases in adult life (1).

Severe extratesticular illness including burns, myocardial infarction, traumatic or surgical injury, and acute critical illness depress hypothalamic-pituitary testicular function. This is evidenced by low blood testosterone and inhibin levels, accompanied by decreased or mildly increased gonadotropin levels with diminution of pulsatile luteinizing hormone secretion (3, 4). Transient biochemical androgen deficiency (‘secondary hypogonadism’), owing primarily to defective central regulation of pulsatile gonadotropin-releasing hormone (GnRH) and luteinizing hormone secretion, is a generic feature of severe acute or chronic illnesses (4). This is the most frequent manifestation of dynamic, functional, and reversible hypopituitarism due to coexisting illness, which was once misnamed the ‘sick euthyroid’ syndrome (5). The underlying generic pathogenic mechanism, termed ontogenic regression, reflects a programmed reversal of reproductive maturation due to transient environmental circumstances unfavourable to reproduction (6). The impact of diminished anabolic status on morbidity due to critical illness, particularly on the rate and extent of muscular recovery and cerebral function, remain unclear as controlled clinical studies of androgen therapy in acute or critical illness are still lacking (7).

Common features of systemic illness such as elevated cytokines, fever, weight loss, and chronic catabolism all depress testicular function and distinguishing their effects is difficult. Reproductive function in men is more refractory to effects of catabolic states such as undernutrition, trauma, and extreme physical exertion compared with women. Nutritional extremes such as anorexia nervosa and severe obesity inhibit testicular testosterone secretion, but moderate undernutrition and selective dietary cofactor deficiencies have little effect on human testicular function. Similarly, while extreme physical exertion inhibits testicular testosterone secretion, strenuous physical exercise such as among elite athletes has minimal effects on spermatogenesis. The effects of catabolic states, including decreased blood testosterone with minimal changes in gonadotropin levels, reflect primarily a widespread functional adaptation of hypothalamic function to disease states (4, 8). These hormonal changes are usually not accompanied by clinically recognisable androgen deficiency, and they are reversed by full recovery from the underlying disease.

Age is a crucial modifier of testicular response to extratesticular disease. The maturing hypothalamic pituitary testicular axis has both heightened sensitivity to negative feedback and increased susceptibility to catabolic stress, making adolescents particularly vulnerable to delayed puberty during chronic illness. Ageing men exhibit decreases in blood and tissue testosterone levels, while circulating sex hormone-binding globulin (SHBG) and gonadotropin levels increase, changes which are markedly accentuated by the coexistence of chronic illness and/or its treatment (9). These changes reflect alterations in hypothalamic function including loss of diurnal testosterone rhythm, alterations in pulsatile luteinizing hormone secretion, sensitivity to negative steroidal feedback and opioids, and testicular changes such as progressive decreases in testis size and spermatogenesis.

Therapeutic drugs may impair androgen action through distinct, and sometimes multiple, mechanisms including (1) decreasing luteinizing hormone secretion (e.g. opiates), (2) inhibiting steroidogenic enzymes (e.g. aminoglutethimide, ketoconazole), (3) increased testosterone metabolism (e.g. anticonvulsants and hepatic enzyme inducers), (4) androgen receptor antagonists (e.g. cimetidine, spironolactone, cyproterone acetate), or (5) antiandrogenic effects (digoxin, drug-induced hyperprolactinaemia). Few drugs, however, have had their potential effects on the human male reproductive system studied in detail. Smoking has modest effects on blood testosterone, spermatogenesis, sperm function, and male fertility in otherwise healthy men, but neither effects on androgen secretion nor reversal after smoking cessation are well established. Chronic heavy alcohol intake has multiple deleterious effects on the male reproductive function due to direct testicular toxicity as well as indirect effects (e.g. undernutrition, hepatic damage). Opiates interfere with hypothalamic regulation of pituitary-testicular function, culminating in reduced testosterone secretion. The effects of recreational drugs such as marijuana and cocaine on testicular function are not well understood; few studies are reported and convincing controls for confounding effects of undernutrition, multiple drug usage, psychological, and socioeconomic factors are lacking.

Fertility may be influenced by reduced spermatogenesis and, occasionally, sexual dysfunction. Disruption of spermatogenesis, indicated by reduced number and/or defective function of ejaculated sperm, is identifiable after puberty when spermatogenesis normally develops. The intense cellular and DNA replication of the germinal epithelium makes it singularly susceptible to cytotoxins such as ionizing radiation, cytotoxic and other therapeutic drugs, and environmental toxin exposure. These can produce any degree of defect in spermatogenesis from minor, reversible depression to permanent ablation. In addition, defects in spermiogenesis could produce hypofunctional (infertile) sperm, although no instances of selective defects in human spermiogenesis have yet been recognized.

Sexuality can be adversely affected by effects on libido, erection or ejaculation. These components of sexuality may be affected by the underlying illness through disturbances of the neurovascular control of erection and ejaculation, whereas libido is susceptible to the general psychological effects of ill-health and severe androgen deficiency.

Chronic renal failure causes prominent disturbances of testicular function, largely through aberrant hypothalamic regulation of pituitary gonadotropin secretion and secondary testicular effects (10). Gonadal dysfunction in uraemia manifests as delayed puberty in adolescents, and as testicular atrophy, hypospermatogenesis, infertility, impotence, and/or gynaecomastia in men. Most disturbances begin prior to inception of dialysis, and deteriorate during maintenance with peritoneal or haemodialysis. They can, however, be fully reversed by successful renal transplantation. Inhibition of both spermatogenesis and steroidogenesis, accompanied by modest to minimal reflex increases in gonadotropins and testicular histological features, are indicative of a functional hypogonadotropic state (11). The clinical features of testicular dysfunction in uraemia are the outcome of multiple factors, including impaired gonadotropin clearance rates with suboptimal reflex increases in net luteinizing hormone secretion, defects in pulsatile luteinizing hormone secretion (8), and aberrant hypothalamic opiatergic regulation of gonadotropin secretion (11). These reflect the predominance of aberrant hypothalamic regulation in the pathogenesis of human uraemic hypogonadism.

Acute renal failure is accompanied by decreased testosterone levels, with minimal changes in gonadotropin or SHBG levels. Responses to GnRH stimulation are preserved, consistent with hypothalamic (secondary) hypogonadism that is reversible following recovery of renal function.

The only effective treatment for uraemic testicular dysfunction is a well functioning renal transplant. In contrast, dialysis fails to correct, or aggravates, testicular dysfunction. Claims that adjuvant treatments, including suppression of hyperprolactinaemia, zinc supplementation, or erythropoietin, improve testicular function are not supported by well controlled studies (10). Similarly, conventional immunosuppressive regimens for renal transplantation have minimal or no deleterious effects on testicular function (11), although recent retrospective observations suggesting deleterious effects require further prospective evaluation (12). Despite the clinical and biochemical features of biochemical androgen deficiency in uraemic men with unchanged testosterone pharmacokinetics (13), there are too few well controlled studies of testosterone administration to justify testosterone replacement therapy for men with chronic renal failure. The potential pharmacological effects of testosterone synergism with erythropoietin, which may augment its hematopoietic effects, are supported by some (14) but not all (15) studies.

Acute liver disease (hepatitis) causes marked increase in circulating SHBG levels, resulting in reflex increases in blood testosterone and gonadotropin secretion. The pathophysiological significance of such transient biochemical disturbances during acute illness is unclear. Chronic liver failure causes striking hypogonadism including infertility, hypospermatogenesis, testicular atrophy, gynaecomastia, reduced body hair, and sexual dysfunction (16). Testosterone production rate is decreased, leading to lower blood testosterone levels. However, the concomitant increase in circulating SHBG levels, with a consequential fall in testosterone clearance rate, conceals the severity of the androgen deficiency. Despite subnormal blood testosterone levels, gonadotropin levels remain in the low to normal eugonadal range with diminished pulsatile luteinizing hormone secretion; this emphasizes the importance of hypothalamic dysregulation in the pathogenesis of hypogonadism in chronic liver disease. Gonadotropin levels are relatively higher among men with alcoholic liver disease, reflecting more direct testicular damage, but are markedly lowered in hepatic failure reflecting the central (hypothalamic-pituitary) effects of critical illness. Alcohol is the most common cause of cause of chronic liver disease in developed countries. The usual clinical features of chronic liver disease are therefore an amalgam of the effects of chronic liver disease per se with alcoholic toxicity. Beyond direct alcohol effects, major pathogenic factors for the reproductive effects of liver disease include the loss of hepatic parenchyma, porto-caval shunting (causing cerebral neurotransmitter disturbances), aromatase overexpression, and secondary IGF-1 deficiency, but their relative roles remain uncertain. Controlled clinical trials of pharmacological androgen therapy in men with acute or chronic liver disease failed to show any significant benefit (7, 17). Men with chronic active hepatitis requiring immunosuppression have essentially normal spermatogenesis despite azathioprine doses of up to 150 mg daily. Little information is otherwise available about spermatogenesis in other liver diseases. Testicular endocrine dysfunction is proportional to the severity of the underlying liver disease, and is reversed by successful liver transplantation (18).

Systemic iron overload, due to either genetic haemochromatosis or acquired post-transfusional iron overload, often causes hypogonadotropic hypogonadism, because of pituitary iron deposition causing relatively selective damage to gonadotropes (19). In more advanced disease, the additional effects of cirrhosis and diabetes further highlight the clinical presentation of androgen deficiency. Haemochromatosis often presents with progressive androgen deficiency in middle-aged men of Anglo-Saxon descent. The hypogonadism is rarely reversible by iron depletion, except in very early stages. This disorder is readily amenable to gonadotropin or androgen replacement therapy, with benefits in symptoms and restoring lost bone density due to androgen deficiency. Gonadotropin induction of spermatogenesis is particularly effective in genetic haemochromatosis where the onset of gonadotropin deficiency follows a normal puberty. Pulsatile GnRH therapy is ineffective; gonadotropin secretion cannot be induced since gonadotrope loss is a leading feature of the pituitary sclerosis induced by pituitary iron deposition. Systemic iron chelation is effective at reversing gonadotropin deficiency only in early, minimal iron overload, and most cases of haemochromatotic gonadotropin deficiency are not improved by iron depletion. Puberty is delayed in regularly transfused children with β thalassaemia, but prepubertal onset of iron chelation therapy enhances pubertal maturation—presumably by preventing pituitary siderosis. The development of efficient population screening, by preclinical genetic diagnosis of haemochromatosis in family members, has reduced the frequency of presentation of hypogonadism, a late manifestation of iron overload (19).

Chronic sinopulmonary infections (recurrent bronchitis, bronchiectasis, chronic sinusitis, and/or otitis media) are associated with infertility due to Young's syndrome, cystic fibrosis, and dyskinetic cilia (immotile cilia and Kartagener’s) syndromes. Both cystic fibrosis and Young’s syndrome feature obstructive azoospermia, due to congenital absence of the vas deferens (20) and epididymal obstruction by inspissated intraluminal secretion (21), respectively. In contrast, both ducts and sperm output are normal in dyskinetic cilia syndromes, but sperm are immotile due to genetic defects in axonemal function (22). Classical cystic fibrosis, caused by mutations in the CFTR gene, is also associated with delayed puberty, attributable to both chronic illness and malabsorption from exocrine pancreatic insufficiency. Nearly all (95%) men with cystic fibrosis have congenital bilateral absence of vas deferens (CBAVD), but CBAVD alone is recognized as a primarily genital variant of the condition, where most affected men are compound heterozygotes for different CFTR mutations. The most frequent mutations associated with CBAVD are the ΔF508 deletion of the CFTR gene and an intron 8 variant (IVS8–5T) (23). However, approximately 1500 other mutations have been identified, most as single nucleotide changes and many ‘private’ to a particular family. This profusion of genotypes makes comprehensive genetic screening for sporadic cases difficult, as many mutations remain undefined. Assisted reproductive techniques (ARTs) can regularly achieve paternity from testicular sperm aspiration (24), but every child is an obligate cystic fibrosis carrier and well-informed genetic counselling is essential. What determines the clinical pattern of disease (cystic fibrosis vs CABVD) remains an intriguing biological puzzle.

Chronic obstructive pulmonary disease (COPD) is associated with pubertal delay. After puberty, male reproductive function is depressed to an extent proportional to respiratory failure (25). In both settings, a central neuroendocrine response to chronic illness and its treatment is invoked. Biochemical androgen deficiency in COPD has been related to the impact of hypoxaemia, systemic inflammation, and the use of corticosteroids on hypothalamic-pituitary regulation of the testis. It may be reversible if contributory factors are ameliorated (26), consistent with an underlying ontogenic regression mechanism. Testosterone administration may reverse muscle and bone loss from long-term glucocorticoid treatment (27) or improve quality of life, but it will not improve underlying pulmonary function (28, 29).

About half of the men with sarcoidosis show hypogonadotropic hypogonadism independent of glucocorticoid usage. Neural involvement in around 5% of cases can produce hypogonadotropic hypogonadism by pituitary infiltration. The lack of specific morphological findings in the reproductive tract is consistent with the effects of a chronic disease ontogenic regression mechanism. Whether the low circulating testosterone levels contribute to the symptoms of fatigue, muscle weakness, and depressed mood seen in sarcoidosis remains to be established (30).

Obstructive sleep apnoea is associated with sexual dysfunction and lowered testosterone levels, without the changes in gonadotropin levels that would indicate a central hypogonadotropic mechanism (31). These effects are partially explained by the associated truncal obesity, but the relative contributions of hypoxia and sleep fragmentation remain to be fully defined. Testosterone administration can occasionally precipitate obstructive sleep apnoea in predisposed obese men, through blunting central respiratory control and/or narrowing upper airway structures.

Asthma is associated with pubertal delay due to chronic illness and systemic corticosteroid therapy, but has no reported effects on postpubertal male reproductive function, apart from lowered circulating total testosterone levels due to glucocorticoid-induced decreases in SHBG levels. Emphysema due to genetic α₁-antitrypsin deficiency is associated with normal testicular function and fertility (32). The late onset of severe symptoms may explain the unusually high prevalence of this deleterious genetic disease, which fails to impair genetic ‘fitness’ until after reproductive age.

The common malignancies of male reproductive life that are medically treated with curative intent include testicular (teratoma, seminoma) and haematological (Hodgkin’s and non-Hodgkin’s lymphoma) tumours and sarcomas. Treatment with combination chemotherapy and/or therapeutic irradiation virtually always causes azoospermia and infertility. The duration of azoospermia and the degree and rate of spermatogenic recovery vary according to the regimen used, from full (e.g. cisplatinum-based regimens for teratoma), partial (e.g. combination chemotherapy for sarcoma), and dose-dependent (e.g. pelvic irradiation with testicular shielding for seminoma) reversibility over several years after treatment, to essentially irreversible sterilization (e.g. mechlorethamine, vincristine, procarbazine, and prednisone, or MOPP, chemotherapy for Hodgkin’s disease, whole body irradiation for bone marrow transplantation). The testis is exceptionally sensitive to ionizing radiation, with single doses of 20 cGy causing azoospermia, and time to recovery being proportional to dose (33). In contrast to other tissues, dose fractionation enhances spermatogonial killing (34).

Cytotoxin-induced infertility could be prevented through reducing spermatogenic damage by using less toxic regimens or cytoprotective adjunct therapy, or circumvented by sperm cryostorage, testicular sperm extraction (TESE), or germ cell transplantation. In men with Hodgkin’s disease the otherwise irreversible sterilization from a standard course of MOPP is avoided by using fewer cycles of MOPP or less toxic regimens (e.g. doxorubicin, bleomycin, vinblastine and dacarbazine, or ABVD). The effective testicular irradiation dose can be greatly reduced by testicular shielding during pelvic irradiation; however, the scatter doses still easily exceed the threshold for germinal damage (<0.5% of dose). Total body irradiation (TBI), given for conditioning prior to allogeneic hematopoietic stem cell transplantation, causes severe spermatogenic damage. Spermatogenic recovery is more likely in younger men (<25 yr) who remain free of chronic graft-versus-host disease (35). Many men are rendered temporarily androgen deficient for years (36). Radioiodine treatment for thyroid cancer causes dose-dependent damage to spermatogenesis, which is transient and minor with single doses (37), but becomes sustained and severe with progressive treatment (38). Experimental hormonal cytoprotection treatments, using either steroids and/or GnRH analogues to inhibit testicular function during chemotherapy, have shown limited promise in experimental models, but preliminary human studies have been unsuccessful. Although unilateral orchidectomy for testis cancer usually has little long-term effect on sperm output or male fertility, cancer surgery impinging on pelvic autonomic nerves often disrupts erectile and/or ejaculatory failure.

Moderate testicular dysfunction is frequent in men with malignant disease even prior to cytotoxic treatment, due to fever, weight loss, diagnostic procedures, disturbed cytokine levels, and possibly other undefined factors. Although family planning is often an important issue for men of reproductive age with cancer, many young men with cancer are not well informed regarding infertility as a common side effect of cancer treatments (39). Since the advent of intracellular sperm injection (ICSI), allowing a single sperm to be utilized to fertilize an oocyte, pretreatment sperm cryostorage represents valuable ‘fertility insurance,’ and is feasible for virtually all men with at least one testis who have not completed their family (40). Although chemotherapy and radiotherapy for cancer convey theoretical teratogenic and mutagenic risks, clinical experience of fertility among cancer survivors indicates no excess of paternally-mediated fetal abnormalities, presumably indicating the efficacy of biological surveillance for nonviable fetuses (41).

Myotonic dystrophy, the most frequent inherited muscle disease of adults, is associated with reduced fertility, testicular atrophy, hypospermatogenesis, elevated gonadotropins, and low or normal testosterone levels (42). The testicular defect bears no relationship to the severity, duration or treatment of the muscular disease, nor does pharmacological testosterone therapy improve muscular strength despite increasing muscle mass (43). The relationship of testicular dysfunction to the causative mutation, a polymorphic expansion of tandem CTG triplet codon repeats (>35 copies) in the 3’ untranslated region of the myotonin protein kinase gene (19q13) causing transcriptional silencing of the flanking SIX5 allele. The loss of SIX5 results in male sterility and age dependent decrease in testicular mass (44); IVF techniques are applicable, but well informed genetic counselling is essential (45).

The genetic basis of Kennedy’s disease, a late onset, X-linked, relatively slowly progressive form of motor neurone disease, is a pathological increase (>40 copies) in CAG triplet repeats in the first exon of the androgen receptor, in a region coding for its nonbinding, C-terminal domain (45). This leads, by an unexplained mechanism, to late-onset androgen resistance—including gynaecomastia and testicular atrophy. The disease severity and age of onset are correlated with the number of tandem CAG triplet repeats. These are associated with subtle defects in androgen receptor function, but the pathogenesis of the neurotoxicity and its precise relationship to the androgen receptor mutations remains unknown.

The fragile X syndrome is the most common cause of familial mental retardation (prevalence around 1 in 4000 men) and explains the overrepresentation of men among the intellectually impaired. It is associated with moderate mental retardation, dysmorphic features, and macro-orchidism; the lattermost manifests after puberty, with testes enlarged in all dimensions (possibly due to prenatal lymphangiectasis), but functioning normally (46). The genetic basis involves acquisition of an excessive expansion of hypermethylated CCG triplet repeats (>200 vs 6–60 on the normal X chromosome) in the 5’ untranslated region of the FMPR1 gene, although the precise pathogenesis of the phenotype remains unknown (47).

Huntington’s disease is an adult onset neurodegenerative disorder characterized by motor, neuropsychiatric and cognitive abnormalities. The condition is caused by an expanded CAG trinucleotide in the HD (or HTT) gene (chromosome 4p16.3) coding for huntingtin. Men with Huntington’s disease have decreased blood testosterone and luteinizing hormone (48), but normal fertility (49). However, a postmortem examination of testes from four men with Huntington’s revealed decreased germ cell numbers, consistent with late-onset testicular dysfunction in mouse models of the disease (50). The reasons why diseases with heritable unstable DNA replication might manifest with testicular and neurological dysfunction remain unclear.

A variety of other rare genetic neurological disorders involving multiple congenital defects are associated with hypogonadotropic hypogonadism, presumably due to defective neural circuitry involving the hypothalamic GnRH neurons and/or their pulse generator. These conditions include the Prader–Labhart–Willi syndrome, characterized by mental retardation, hypotonia, short stature, and obesity, and caused by deletions or uniparental disomy of chromosome 15 (51); the Laurence–Moon–Biedl syndrome of retinitis pigmentosa, obesity, mental retardation, and polydactyly or other dysmorphic features; Friedrich’s and other cerebellar ataxia syndromes; multiple lentigines syndrome; steroid sulphatase deficiency (X linked congenital icthyosis); and other rare congenital neurological syndromes (Moebius, RUD, CHARGE, Lowe, Martsolf, Rothmund–Thompson, Borjeson–Forssman–Lehman) (52). Such patients may require androgen replacement, although social factors usually dictate that fertility, requiring gonadotropin induction of spermatogenesis, is rarely requested.

Temporal lobe epilepsy is associated with hypogonadism and sexual dysfunction. These usually respond to anticonvulsant therapy, with only a minority requiring additional androgen replacement therapy. Other forms of epilepsy per se do not appear to be associated with abnormal testicular endocrine function, although aberrations in blood testosterone and SHBG levels and hyposexuality are common in anticonvulsant treated epileptics. Anticonvulsants increase hepatic SHBG secretion, leading to decreased testosterone metabolic clearance rate and increases in blood testosterone and gonadotropins. Sperm output remains normal but morphology and motility are impaired during long-term treatment with phenylhydantoin (53, 54). Although testosterone has antiseizure effects in experimental animal models, no controlled clinical studies of the effects of androgen administration on seizure control or androgenic status have been reported.

Recent studies report an inverse correlation between Alzheimer’s disease, Parkinson’s disease or multiple sclerosis severity and blood testosterone levels. These effects are probably attributable to ageing, combined with the nonspecific effects (via the ontogenic regression mechanism) of chronic illness on hypothalamic-pituitary regulation of testicular function, in common with many other disease states. Small studies of testosterone therapy in men with early Alzheimer’s disease showed marginal improvement in spatial abilities (55), No benefit was observed in Parkinson’s disease (56), but possible neuroprotective effects were seen in multiple sclerosis (57). The effects of testosterone therapy in Alzheimer’s disease and multiple sclerosis warrant further evaluation, by well controlled and suitably powered RCT’s of testosterone replacement, controlling for nonspecific mood effects on cognition, before the clinical application of testosterone treatment can be considered justified. Similarly, lowered blood testosterone levels are also associated with major psychiatric disorders such as schizophrenia (58) or depression (59). Placebo-controlled studies, however, show no benefit of testosterone in depression (60), consistent with the lowered blood testosterone representing a biomarker for severity of underlying disease effects mediated via a neuroendocrine ontogenic regression mechanism, rather than connoting a deficiency state.

Spinal cord damage from trauma or neurological disease causes testicular dysfunction depending in severity on the level and extent of spinal cord interruption. Testicular function is disrupted by aberrant thermoregulation, recurrent ascending urinary tract infections from bladder catheterization, neurogenic dysfunction, and iatrogenic factors (diagnostic irradiation, drugs). Impotence is predominantly due to interruption of neural pathways controlling erection and emission, while libido remains appropriate for age. Conservation of sexual function depends upon the level and extent of the spinal injury. Hypospermatogenesis and testicular atrophy are usually observed in men with long-term spinal injuries, but fertility may be preserved by early sperm cryopreservation using electroejaculation coupled with artificial insemination or male-factor IVF procedures. Head injuries may cause gonadotropin deficiency, due to disruption of the pituitary portal bloodstream and/or pituitary infarction following basal skull fractures.

Coeliac disease is associated with subfertility and impaired sperm output, morphology and motility, together with elevated blood testosterone and gonadotropin levels. All are reversible upon dietary improvement of the gluten enteropathy. This distinctive endocrine pattern is suggestive of acquired androgen resistance; however, detailed studies of androgen receptor function or action are lacking.

Inflammatory bowel disease is often associated with impaired spermatogenesis, but testicular endocrine function is unaffected. Hypospermatogenesis is common in Crohn’s disease, and is possibly related to fever, chronic illness, and/or nutritional status (61). Similarly, men with ulcerative colitis taking salazopyrine exhibit impaired spermatogenesis, sperm function, and fertility (62). Routine use of salazopyrine for both acute and preventative maintenance therapy early in the course of ulcerative colitis has precluded studies of testicular function in untreated men to determine the extent of effects of ulcerative colitis per se. The effects of aminosalicylate on testicular function may be less pronounced than those of salazopyrine, but detailed comparative studies are lacking.

Peptic ulceration has no reported effects on testicular function; however, treatment with the H₂ receptor blocker cimetidine, but not ranitidine or other H₂ receptor blockers, impairs testicular function by androgen receptor antagonism unrelated to its H₂ receptor blocking activity.

Haemoglobinopathies (including sickle cell anaemia and thalassaemias) are associated with delayed puberty, while transfusion-induced iron overload leads to acquired gonadotropin deficiency functionally similar to that of genetic haemochromatosis (see above). Iron deficiency anaemia has no recognised effects on testicular function, but men with sickle cell anaemia have reportedly poor spermatogenesis (63).

Megaloblastic anaemia from folate or vitamin B₁₂ deficiencies inhibits DNA replication in the bone marrow, and might cause arrest of the germinal epithelium; however, no reports describing spermatogenesis among men with megaloblastosis are available that examine this hypothesis.

Haemophilia is associated with a striking reduction in male fertility, although whether this is explained fully by voluntary restraint of fertility is unclear, as studies of testicular function in haemophilia are not available.

Thyroid disease influences male reproductive function primarily through changes in circulating SHBG levels (64, 65), which modulates testosterone metabolic clearance rate (66). An acute rise in SHBG decreases testosterone clearance rate, leading to increased total testosterone, oestradiol, and gonadotropin levels. Meanwhile, circulating free testosterone levels are transiently reduced, and this causes gynaecomastia and reduced sexual function in a minority of cases. Hyperthyroidism increases blood SHBG, and hypothyroidism decreases it, but normalization is achieved by reinstating euthyroidism (67). Similarly, reversible defects in both sperm output and function (68) as well as erectile function (69) and other features (gynaecomastia) in men with either hyper- or hypothyroidism are rectified in the euthyroid state (70). Spermatogenesis is depressed in thyrotoxicosis and long standing hypothyroidism of prepubertal onset, but not in postpubertal hypothyroidism (71).

Congenital adrenal hyperplasia (CAH), most commonly caused by 21 hydroxylase deficiency, can confer impaired spermatogenesis and infertility (72), although most affected men are fertile even if untreated (73). Testicular dysfunction is most evident in men with poorly controlled CAH, where high blood concentrations of adrenal androgens can inhibit gonadotropin secretion. Additionally, ectopic nests of adrenal cells in the testes, subject to chronic adrenocorticotropic hormone (ACTH) stimulation, may develop into testicular adrenal rest tumours (74). Testicular adrenal rest tumours (TART) are readily visualized by ultrasonography and are more frequent among men with severe salt-losing CAH and/or poorly controlled disease. While initially responsive to ACTH suppression by glucocorticoid therapy, with severe and/or prolonged ACTH stimulation TART may become resistant to hormonal suppression, requiring testis-sparing conservative surgery. There is a risk of diagnostic confusion and needless surgery for testis cancer. In severe cases TART lead to azoospermia and testicular damage, due to seminiferous tubular obstruction.

Hypercortisolism of any origin inhibits testicular function at multiple levels of the hypothalamic-pituitary testicular axis, and leads to a reversible reduction in circulating testosterone and gonadotropin levels (75). The degree to which androgen deficiency contributes to the catabolic state and symptoms of sexual dysfunction and weakness during hypercortisolism is unclear.

The effects of diabetes mellitus on male reproductive function are primarily due to neuropathic and vascular complications of diabetes causing erectile and/or ejaculatory dysfunction. The direct effects of hyperglycaemia on testicular function are not well established. Cross-sectional studies report mildly decreased blood testosterone levels in men with type 2 diabetes mellitus, which most likely reflect multiple factors mediating the effects of chronic disease (via neuroendocrine ontogenic regression mechanisms) and obesity (via lowered SHBG). In contrast, men with type 1 diabetes mellitus have normal blood testosterone and gonadotropin levels (76). The potential beneficial effects of testosterone therapy on insulin sensitivity in men with type 2 diabetes mellitus require large studies, with healthy or obese men without diabetes mellitus as controls. A critical evaluation of the benefits and risks of adjuvant testosterone therapy in men with type 2 diabetes mellitus should also aim to reduce vascular complications. The reported relationship between the metabolic syndrome and low blood testosterone concentrations also remains inconclusive, as lowered blood testosterone concentrations may be a consequence rather than the cause of impaired metabolic status. Spermatogenesis and fertility are minimally affected in men with diabetes whose sexual function is intact. Apart from reduced semen volume, attributable to defective neurally-mediated ejaculatory function, men with diabetes have normal conventional sperm parameters. However, some increase in sperm nuclear and mitochondrial DNA damage of uncertain clinical significance has been reported (77).

Anorexia nervosa is rare in males, but when it occurs it causes profound inhibition of testicular endocrine function (78). Anorexic males show low blood testosterone levels, with low gonadotropin and poor responses to GnRH stimulation. Weight gain is associated with increasing testosterone and luteinizing hormone levels, with a positive correlation with blood leptin levels (79). The effects of moderate undernutrition or selective dietary micronutrient deficiencies (e.g. vitamins, cofactors) on human testicular function are unclear.

Obesity inhibits testicular endocrine function (80), reflecting mainly a reduction in blood SHBG concentration proportional to degree of obesity. Effects on spermatogenesis (80) and fertility (81) remain minimal, and there is little consistent evidence for obesity as a cause of male infertility. Obese boys show delayed pubertal development, with decreased blood testosterone levels for chronological age, but ultimately normal growth and normal testicular development ensue (82). The mechanism causing decreased blood testosterone and SHBG levels remains speculative, but increased circulating oestradiol levels because of aromatization by excess adipose tissue may explain the partial reversal by an aromatase inhibitor (83). The hormonal features of obesity are not accompanied by overt clinical features of androgen deficiency, and are reversed by weight reduction. Moderate obesity has little overt effect on male reproductive function, but may contribute to the decline of hypothalamus and pituitary testicular function in ageing men (84).

Autoantibodies to spermatozoa develop in about 70% of men after vasectomy, but have no apparent deleterious effects on general health (85), although they may inhibit sperm function and fertility after vasectomy reversal. Sperm autoantibodies are observed in 5 to 10% of nonvasectomized infertile men, who also have a modestly increased prevalence of other organ-specific autoantibodies. Immune complexes of unknown significance have been observed in seminiferous tubular basement membranes of infertile men.

Most autoimmune diseases have a marked (>5 to 1) female predominance (e.g. systemic lupus erythematosus, chronic active hepatitis, chronic biliary cirrhosis), which remains unexplained. Testicular involvement in immune disease is unusual apart from polyarteritis nodosa where testicular biopsy may be diagnostic. Rheumatoid arthritis causes prolonged depression of testosterone levels during flares of disease activity, with spontaneous recovery during remission (86). Testicular endocrine function is minimally affected in men with ankylosing spondylitis, systemic lupus erythematosus or osteoarthritis. Treatment of immunological diseases with cytotoxic drugs may lead to severe, dose dependent and sometimes irreversible spermatogenic damage typical of alkylating agents.

Autoimmune orchitis is a rare component of the organ-specific autoimmune cluster, and autoimmune hypophysitis causing isolated gonadotropin deficiency or panhypopituitarism is also uncommon. Amyloidosis involving the testis is rare, and usually occurs in secondary systemic amyloidosis. Massive primary infiltration causing testicular enlargement has been reported (87).

Systemic infections often influence testicular function, with or without causing orchitis. Many mechanisms are involved including the effects of fever (mediated by tumour necrosis factor-α and cytokines), weight loss, and chronic catabolism. The net effects depend on the severity and duration of the infection.

Epididymo-orchitis is rare in prepubertal boys, but occurs in 15–30% of mumps-affected pubertal or postpubertal males, with 15–30% of cases being bilateral (88). Mumps orchitis only rarely causes infertility, mostly after severe bilateral infection (89), and successful testicular sperm extraction for ICSI is feasible (90). The pathophysiological mechanisms include direct viral infection of the tubules, pressure-induced necrosis of seminiferous tubules due to parenchymal oedema within the tight testicular capsule, and the inflammatory reaction. Testicular atrophy occurs in up to half of men with mumps orchitis infection. Direct testicular damage is evident in the acute phase, with a prominent decrease in blood testosterone and reflex increase in blood gonadotropins occurring prior to testicular atrophy. Whether the treatment of mumps orchitis with interferon α-2B prevents testicular atrophy and might protect fertility requires further verification (91). However, mumps vaccination remains the best protection against mumps-induced infertility.

A characteristic example of an infectious disease influencing male reproductive health is the testicular dysfunction common in AIDS. This reflects both the stage of clinical disease and/or its treatment. Testicular endocrine function (92) and spermatogenesis (93) are unaffected in asymptomatic HIV seropositive men, but deteriorate with clinical status and treatment (94). Similar effects would be expected with comparable severe and/or chronic systemic infections, including viral hepatitis, but detailed information is lacking.

Androgen deficiency in AIDS is associated with weight loss, including loss of muscle mass, consistent with the non-specific effects of other chronic non-testicular diseases. Symptomatic androgen deficiency among HIV-positive men with advanced disease, prior to starting highly active antiretroviral therapy (HAART), is now reported at around 6% (95). An estimated 20% of these men have low blood testosterone levels (96), whereas before HAART was available androgen deficiency was reported in around 50%. Most HIV-infected men have hypogonadotropic or normogonadotropic hypogonadism, indicative of a hypothalamic-pituitary dysregulation. After symptomatic progression to AIDS, luteinizing hormone and FSH levels rise, and postmortem evaluation shows testicular atrophy (97). The relative contributions of the underlying infection or its treatment remain unclear (95). Spermatogenic damage in men with AIDS is almost universal at postmortem (98), whereas sperm output (93) is unaffected in asymptomatic, HIV seropositive men, but deteriorates with clinical status and treatment (99). HIV-associated malignancies such as lymphomas, or opportunistic infections such as toxoplasmosis, can cause mass lesions disrupting the hypothalamic-pituitary-testicular axis at all levels. Additional factors contributing to hypogonadism in HIV patients include several medications used as antiretrovirals or to prevent or treat opportunistic infections, such as ketoconazole, megestrol-acetate, ganciclovir, and spironolactone. Testosterone replacement therapy in symptomatic HIV-positive men has beneficial effects on the body composition (100), and improves the quality of life in androgen deficient men with AIDS wasting syndrome.

Hypertension (101) and antihypertensive treatments (102) have a modest effect in lowering circulating testosterone concentrations, which contributes to the decline in testosterone concentrations associated with ageing (103) and obesity (104). Such small decreases in blood testosterone levels are insufficient to account for the high frequency of sexual dysfunction in treated hypertensive men, which presumably reflect hemodynamic effects on the vascular hydraulics of erection rather than hormonal effects from hypertension and antihypertensive medication.

Epidemiological studies show that low testosterone levels are usually associated with increased rates of cardiovascular disease; however, the direction of causality in such observational studies remains unknown. Whether there are any additional factors beyond the nonspecific chronic disease effects, of moderate lowering of blood testosterone levels due to the presence of acute or chronic cardiovascular disease, remain to be established. Some, but not all, recent prospective cohort studies show that low blood testosterone levels predict cardiovascular death; however, whether blood testosterone is a passive barometer of health or an active determinant of reduced mortality cannot be decided from such observations. At pharmacological doses, testosterone has dose-dependent vasodilator properties on animal resistance arteries. Clinical trials of testosterone replacement therapy have shown modest benefits in men with coronary heart disease (105–107), and in congestive cardiac failure (108). Larger studies are required to better define the potential adjuvant benefits of testosterone in cardiovascular disease.

Psoriasis is associated with impaired spermatogenesis, which correlates with the extent and severity of the disease rather than with methotrexate or corticosteroid treatment (109).

Hereditary angioedema (HAE) is an autosomal dominant inherited disorder of the complement system caused by mutations of the C1INH gene (chromosome 11q12). It causes either deficiency (type 1 HAE) or impaired function (type 2 HAE) of the C1-esterase inhibitor. The disease is characterized by episodic oedematous attacks, mostly of hands and feet, but sometimes also involving the genitalia, trunk, face, tongue, the wall of the bowel, and the respiratory system, which can be fatal if not treated adequately (110). Synthetic 17-alpha alkylated androgens have proven beneficial effects on the clinical course of the disease (111), via an increase in circulating C1 inhibitor levels in vivo and in vitro, but the underlying testicular function has been little studied and is probably normal. This illustrates that the existence of underlying testicular dysfunction from a disorder is not a prerequisite for effective pharmacological androgen therapy for that condition.

Familial Mediterranean fever (FMF) is a chronic disease characterized by recurrent episodes of fever, peritonitis, pleuritis, and arthritis, with amyloidosis as a major long-term complication. FMF is associated with testicular germ cell arrest and oligozoospermia or azoospermia (112). Similar adverse effects on spermatogenesis are also reported in Behçet’s disease, a multisystemic inflammatory disease involving the urogenital system. Behçet’s disease features genital aphthous ulcers and cystitis, urethritis, and epididymitis, and its postpubertal onset and strong male preponderance are suggestive of a role for androgens in its pathogenesis (113). These effects are most likely to be attributable to the deleterious effects of recurrent fever on spermatogenesis (114). The potential additional effects of colchicine, an alkaloid commonly used for prevention and treatment of arthritic episodes in gouty arthritis, FMF, and Behçets disease on the testis remain speculative (115). Testicular amyloidosis is rare, occurring mostly as secondary systemic AA-amyloidosis, but massive primary testicular infiltration causing macro-orchidism (87) and hypogonadism due to amyloid deposition, with abnormal semen parameters and infertility (116), are described.

The inhibition of reproductive function during extragonadal illness may have therapeutic implications. While acute systemic illness usually impairs reproductive function, these effects are usually transient and reversible with no lasting sequelae, and therapeutic intervention is not warranted. Indeed, the activation of ontogenic regression by intercurrent illness may be an important archaic adaptive evolutionary strategy. Ontogenic regression is the programmed reversal of reproductive maturation, in an orderly manner, to facilitate reinstatement of reproductive function when the prevailing environment is more favourable (6). When prolonged, severe systemic illness may have more prominent adverse impacts on fertility, androgen status, and/or sexuality, which create bystander side effects superimposed on the underlying illness. Examples include infertility due to cytotoxin-induced spermatogenic damage, gonadotrophin deficiency due to pituitary iron deposition in haemochromatosis, and androgen deficiency during prolonged catabolic illness states.

Androgen therapy is feasible in many systemic illnesses, but evidence of efficacy, safety, and cost-effectiveness from controlled clinical trials is mostly lacking, as reviewed by Liu and Handelsman (117). Uncontrolled, short-term studies during the 1960s suggested that androgen supplementation during catabolic illness initially augmented anabolic status, but that this response was not sustained during prolonged androgen therapy. Further well controlled clinical studies in some chronic diseases may identify a useful adjunctive therapy role for testosterone.

Infertility is an increasingly common presenting problem among men with chronic medical illnesses, successfully treated with transplantation or combination cancer treatments. This includes men with organ transplants that now provide expectation of prolonged survival with good quality of life. Impaired reproductive functions, including spermatogenesis and fertility, due to underlying organ failure are usually improved or normalized with successful transplantation. Furthermore, most men now survive cancer treatment of testicular tumours, haematological malignancies, or sarcomata with an effective cure of malignancy at the cost of severe, prolonged and often irreversible testicular damage. In these men counselling about the likelihood of spermatogenic recovery, contraceptive advice, and appropriate application of assisted reproductive techniques such as pretreatment sperm cryostorage, insemination, male factor IVF/ICSI, or donor insemination should be available. Difficult psychosocial and ethical decisions may be faced regarding the responsibilities of parenthood with limited life expectancy, the risks of paternally-mediated malformations, and post-mortem insemination.

Impaired sexuality, including particularly loss of libido and erectile dysfunction, is a common feature of ageing and of most chronic diseases that accumulate in older men. New pharmacological therapies for erectile dysfunction will have an increasing place in management of erectile dysfunction associated with chronic illness. In the context of systemic illness, androgen deficiency is a rare but rewardingly treatable cause of isolated loss of libido.