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Home , Hypogonadism

European Journal of (2005) 152 501–513 ISSN 0804-4643

REVIEW Gonadal dysfunction in systemic diseases Asterios Karagiannis and Faidon Harsoulis Second Propedeutic Department of Internal Medicine, Division of Endocrinology, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece (Correspondence should be addressed to A Karagiannis, 44 Tsimiski str., Thessaloniki, 54623, Greece; Email: [email protected])

Abstract Gonadal function is significantly affected in many acute and chronic systemic diseases. As the func- tion of the testes and the is determined by the integrity of the hypothalamic–pituitary–gona- dal axis, it is obvious that a systemic disease may affect one or more levels of the axis in such a manner that the gonadal dysfunction may have various clinical and laboratory manifestations. In this brief review, the most common disturbances seen in the main systemic diseases will be discussed.

European Journal of Endocrinology 152 501–513

Testicular function in systemic diseases The pulsatile secretion of LH has been studied in cases with elevated levels and it has In acute stresses, testicular function is harmed been ascertained that the amplitude of the pulsatile indirectly via gonadotropin suppression and directly wave was reduced while the frequency remained by the action of cytokines upon the testes. In chronic normal (6). In patients with chronic renal failure, stresses, testicular dysfunction is due to primary testi- apart from the indirect testicular effect, the elevated cular failure with reduced production of LH levels are due to insufficient renal excretion (7), and semen and elevated gonadotropin levels (1). It is while concurrently there is obvious reduction of the interesting that both types of testicular dysfunction amplitude and frequency of the pulsatile waves of appear to be reversible, since studies performed in LH (8). patients after kidney or liver transplantation have In most cases of primary or secondary hypogonad- shown full recovery of testicular function (2, 3). How- ism, Leydig cells present a functional disturbance, as ever, primary and secondary hypogonadism may alter- has been demonstrated by the human chorionic gon- nate or may be superimposed. For example, a adotropin (hCG) test. Even if the baseline testosterone suppression of previously high gonadotropin levels levels are within normal limits, the rise after a maxi- occurs during the terminal stages of with mally effective dose of hCG is usually less than the the onset of hepatic coma (4). normal doubling of pretreatment levels. Defective Acute illnesses are associated with gonadotropin sup- Leydig cell function may result from altered paracrine pression and secondary testicular failure. There is a signals by damaged seminiferous tubules (9). common underlying mechanism of reduced secretion An important factor affecting sex levels and of gonadotropin-releasing hormone (GnRH) similar to more specifically the efficient relationship between the seasonal regression of reproductive function in ani- and is the level of - mals. Many toxic mechanisms are implicated, such as binding globulin (SHBG). Of the circulating testosterone fever, drugs, cytokines and stress which act in adult men, approximately 45% is bound with high directly upon the testes or indirectly upon the hypo- affinity to SHBG, 50% is loosely bound to albumin thalamus and pituitary. The type of hypogonadism and less than 4% is free (not protein bound). SHBG is may vary in proportion to the process of the illness. a carbohydrate-rich b-globulin produced by hepato- Severe starvation leads to low cytes; it binds testosterone and other steroids with (LH)/follicle-stimulating hormone (FSH) levels, which high affinity and prolongs their metabolic clearance. may rise during refeeding, causing a transient excess Because of the role of SHBG as a plasma testosterone- of estrogen production and refeeding (5). binding protein, there is a positive correlation between The hypogonadism that accompanies most chronic its level and the level of testosterone in human adult systemic diseases is primary and is characterized by male plasma. It is well known that the production of reduced testosterone levels and elevated levels of gon- SHBG by the liver is suppressed by and adotropins and inhibin B. It must be noticed that in stimulated by . An excess of estrogen increases many cases the derangement is located at both levels. serum SHBG levels, leading to reduced free testosterone

q 2005 Society of the European Journal of Endocrinology DOI: 10.1530/eje.1.01886 Online version via www.eje-online.org

Downloaded from Bioscientifica.com at 09/30/2021 12:40:28AM via free access 502 A Karagiannis and F Harsoulis EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 152 and (DHT), while the metabolic with cirrhosis present reduced and clearance of estrogen is not affected. This has been peritubular fibrosis. called the estrogen amplification effect of SHBG and The normal function of the hypothalamic–pitu- may contribute to the clinical signs of feminization in itary–gonadal axis is affected in liver diseases. The pul- conditions such as cirrhosis, senescence and thyrotoxi- satile secretion of LH and the response to GnRH and cosis, in which serum SHBG levels are elevated (10). clomiphene are reduced. As has already been men- Consequently, every factor altering SHBG levels may tioned, in late stages of cirrhosis the patients present influence the hormone changes during the process of features of feminization, suggesting altered levels of a systemic disease. sex hormones. The clinical signs of hypogonadism are The hormonal control of SHBG in plasma is complex. more pronounced in alcoholic patients due to the Table 1 lists those factors that are known to decrease or direct effect of ethanol upon the testes. In cirrhotic increase plasma SHBG levels. Only insulin and thyrox- patients, the estrogen/androgen ratio is usually ine influence SHBG levels through effects on steady- increased. The levels of testosterone and dihydroepian- state mRNA levels (11). How other factors increase or drosterone are reduced, while the levels decrease circulating SHBG levels remains unknown. are normal or slightly elevated. These alterations are The peripheral metabolism of steroids is altered in dependent on the severity of the liver disease and many forms of hypogonadism, including cirrhosis, are more pronounced in patients with higher Child– chronic renal failure, thyrotoxicosis, old age, Klinefelter Pugh score (14, 15). Several other factors may contrib- syndrome and testicular atrophy after orchitis. ute to these hormonal changes in cirrhosis, including In healthy men, the major quantity of estrogens comes hepatic overproduction of SHBG, changed SHBG iso- from the biological conversion of testosterone to estra- forms with different steroid-binding affinities, elevated diol and of androstendione to by the enzyme levels, direct suppression of Leydig cell func- aromatase, which is found in fat, muscles, kidneys tion by estrogens, increased estrogen receptors in the and liver. In clinical practice, the features of feminiza- liver and cyclic variation in the severity of the liver ill- tion, such as gynecomastia, are not directly related to ness producing the hormonal changes of refeeding the plasma estrogen levels (12). The ratio of estrogen gynecomastia (16). It must be kept in mind that the to androgen and the wide range of responsiveness of gynecomastia and impotence of cirrhotics are augmen- male breast tissue to estrogen are considered more ted by the chronic use of , a receptor important factors, as shown by the great variability in antagonist of aldosterone and testosterone, which the extent of gynecomastia in men given estrogens for reduces the testosterone levels and slightly increases metastatic prostatic cancer. Finally, in both men with the levels of estradiol. idiopathic seminiferous tubular failure and patients suf- Portocaval shunts in normal rats result in testicular fering from celiac disease with an acquired androgen atrophy manifested histologically by loss of germinal resistance or 5a-reductase deficiency, defects of andro- epithelium due to decreased mitosis and increased gen receptors have been reported as a different patho- apoptosis with loss of spermatogonia, loss of spermato- physiologic mechanism (13). zoa in the lumen of the seminiferous tubules and event- ual complete atrophy of the seminiferous tubule, which Disorders associated with testicular failure are then lined only by Sertoli cells (3). The primary event after portocaval shuntings increases estrogen- Liver disease Hepatic cirrhosis is associated with hypo- suppressing LH secretion which leads to decreased tes- gonadism and signs of feminization irrespective of the tosterone levels and hypogonadism. direct toxic effect of ethanol upon the testes. Testicular atrophy, low testosterone levels, decreased libido, infer- Alcoholism – alcoholic cirrhosis Most alcoholics, tility, reduced secondary sex hair and gynecomastia are particularly those with cirrhosis, present features of found in men with cirrhosis. Fifty percent of patients hypogonadism, such as feminization, impotence, reduced and testicular atrophy. There is a large body of data providing evidence that ethanol Table 1 Factors that influence circulating SHBG levels. reduces the testicular synthesis and serum levels of tes- Increase Decrease tosterone, in widely different experimental designs. Both acute and chronic administration of ethanol Aging Prepubertal development reduces serum levels of testosterone in rats in vivo. Like- Growth hormone deficiency wise, in vitro studies in isolated Leydig cells, isolated per- Estrogens Hyperinsulinemia Androgen deficiency Glucocorticoids fused rat testes and testicular homogenates have all Hyperthyroidism Androgens demonstrated reduced testosterone synthesis and con- Hepatitis Progestins centrations. Furthermore, acute alcohol intoxication Porphyria Hypothyroidism in normal men results in a fall in serum levels of testos- Growth hormone excess Familial terone. In a large series of clinical studies, reduced serum testosterone levels have been found in chronic

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Downloaded from Bioscientifica.com at 09/30/2021 12:40:28AM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 152 Gonadal dysfunction in systemic diseases 503 alcoholics. Most of these patients also have decompen- transferrin expression by the Sertoli cells. IGF-I admin- sated cirrhosis. On the other hand, normal serum levels istration increased the expression of this protein in Ser- of testosterone have been found in non-cirrhotic alco- toli cells of cirrhotic rats, showing a dysfunction of holics and in cirrhotic patients without hepatic decom- these cells and consequently the disruption in blood– pensation (17). testis barrier integrity. The lesion could affect cellular Several factors affect the testicular biosynthesis proliferation of spermatogenesis (24). The above find- caused by alcohol. Ethanol and its metabolite acet- ings support the conclusion that the exogenous admin- aldehyde have a direct toxic effect on Leydig cells but, istration of IGF-I may be useful for the treatment of on the other hand, there is a disruption on the hypo- testicular alterations in cirrhotic patients. thalamic–pituitary–gonadal axis. Chronic alcohol exposure decreases circulating LH levels and the Hemochromatosis Hemochromatosis in its primary response of LH to GnRH is reduced in alcoholics (18). form is a genetic disease. The hemochromatosis gene Thus disturbance of the hypothalamic–pituitary– (HLA-H) has been identified on the short arm of gonadal axis persists over months of abstinence, with chromosome 6 as a single point mutation in which sustained increases in serum free and total testosterone the amino acid cysteine at position 282 changes to a levels in the presence of inadequate raised LH concen- tyrosine. The gene product modulates the uptake of trations (19). transferrin by cells, and causes excessive iron accumu- Hyperprolactinemia is often found in male alcoholics, lation and toxicity in the pituitary and the testes (25). particularly those with cirrhosis and may participate in Half the patients have hypogonadism with testicular the pathogenesis of hypogonadism by inhibiting gon- atrophy. The main lesion is hypogonadotropic hypogo- adotropin secretion. nadism due to the unresponsiveness of LH to the Alcohol abuse can cause hypogonadism even in the administration of GnRH. The secondary hypogonadism absence of liver disease. It is interesting to note that cir- results from iron deposits in the and gonado- rhosis, acting in concert with alcohol, produces femin- tropin secretion is selectively impaired. Patients may ization, such as gynecomastia, alteration in body fat present with impotence or , with low testoster- distribution and a female escutcheon. The main mech- one, azoospermia or low semen volume and sperm anism is that both alcohol and acetaldehyde stimulate motility with normal sperm concentration (26). the adrenal cortex to increase the secretion of weak Patients with chronic anemia, especially sickle cell adrenal androgens that serve as estrogen precursors. disease and thalassemia major, and repeated transfu- Alcoholic men with chronic liver disease have elevated sions develop similar disturbances of the hypothala- circulating estradiol and estrone levels from aromatiza- mic–pituitary–testis axis and destruction of testicular tion of androstendione. Ethanol increases the activity of tissue due to interruption of the blood supply by the aromatase, which converts androgens to estrogens. sickling process (27). Patients with sickle cell anemia Successful orthotopic liver transplantation leads to and thalassemia display characteristics of prepubertal improvement of the sex hormone disturbances. Six hypogonadism mainly manifested as delayed . months after transplantation, testosterone and gonado- The accurate and effective iron chelation can reduce tropin levels return to normal values. However, in cases the prevalence of hypogonadotropic hypogonadism, of hypergonadotropic hypogonadism, with elevated preventing the iron accumulation in the pituitary (28). FSH and LH levels due to alcohol-induced gonadal injury, the testicular failure is not reversible. Finally, Chronic renal disease Chronic renal failure causes transplanted patients will permanently receive predni- major effects on the male reproductive system, notably zolone and cyclosporine which both tend to reduce tes- impairment of spermatogenesis, steroidogenesis and tosterone levels in men (17). sexual function, through effects at all levels of the hypo- An additional mechanism to explain the hypogonad- thalamic–pituitary–testicular axis. Disturbances of ism has been proposed by a series of recent studies the axis can be detected with only moderate reductions examining the role of insulin-like growth factor-I in the glomerular filtration rate and progressively (IGF-I). It is known that IGF-I levels are normal in worsen as the renal failure progresses. Approximately early stages of cirrhosis but its bioavailability seems to 50% of uremic men complain of be diminished (20). It is also known that IGF-I stimu- while an even greater percentage complain of lates testosterone synthesis and spermatogenesis (21). decreased libido and a marked decline in the frequency Its deficiency could contribute to the development of of intercourse (29, 30). In addition to the uremic hypogonadism associated with cirrhosis as supported milieu, peripheral neuropathy, autonomic insufficiency, by some experimental data in rats (22). In an experi- peripheral vascular disease, psychological and physical mental model of carbon tetrachloride-induced histo- stresses, and multiple drugs all contribute to the logically proven cirrhosis in rats, recombinant IGF-I genesis of . The disorders of the pitu- was administered for 2 weeks (23). This study showed itary–gonadal axis rarely normalize with initiation of an altered hemato-testicular barrier from an early hemodialysis or peritoneal dialysis and, in fact, often stage of cirrhosis as was suggested by the reduced progress. Transplantation leading to restoration of

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Downloaded from Bioscientifica.com at 09/30/2021 12:40:28AM via free access 504 A Karagiannis and F Harsoulis EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 152 normal renal function can reverse most of the hormo- FSH release by the pituitary normally responds to nal changes of chronic renal failure, although some feedback inhibition by inhibin, a peptide product of changes resulting from prolonged dialysis may be irre- the Sertoli cells. The plasma FSH levels tend to be high- versible (31). est in those uremic patients with the most severe Chronic renal failure is associated with impaired damage to seminiferous tubules and presumably the spermatogenesis and testicular damage, often leading lowest levels of inhibin. It has been reported that high to infertility. A decreased volume of ejaculate combined FSH levels may portend a poor prognosis for recovery with low or complete azoospermia and a low percen- of spermatogenic function after renal transplantation tage of motility has been shown in semen analysis (32). The administration of clomiphene to uremic (32). Compared with other causes of severe primary patients leads to an appropriate rise in the levels of testicular lesions, the Leydig and Sertoli cells show both LH and FSH, suggesting that the negative feedback little evidence of hypertrophy or hyperplasia, probably control on the is intact and that the sto- due to a defect in their hormonal regulation. This rage and release of by the pituitary is later effect might occur with either gonadotropin normal (34). deficiency or resistance, rather than being a cytotoxic Hyperprolactinemia is frequent in uremic patients, effect of uremia where spermatogonia would be most due to a functional disturbance in hypothalamic regu- affected (33). lation of pituitary prolactin secretion, which appears to Plasma LH, FSH and inhibin-a levels are slightly be autonomous and resistant to stimulatory or suppres- elevated along with reduced circulating total and free sive manoeuvres (41). Insulin-induced hypoglycemia testosterone levels and normal SHBG levels (34). and arginine or thyrotropin-releasing hormone infu- Although these changes are consistent with a primary sions elicit no response or only a blunted response in defect in testicular function, there is also strong evi- prolactin secretion. On the other hand, dopamine infu- dence for defective neuroendocrine regulation as an sion or the administration of L-dopa fails to decrease important functional aspect of the reproductive dys- basal prolactin levels. In chronic renal failure, function in uremia. The increase in gonadotropins is increased prolactin secretion may be related in part to largely explained by the significant reduction (,70%) the development of secondary hyperparathyroidism in renal filtration and whole body clearance rate of (42, 43). Bromocryptine can reduce plasma prolactin LH which, in the presence of decreased testosterone levels in patients with chronic renal failure, but there secretion, indicates significantly reduced LH secretion. has been an inconsistent effect on sexual potency The hCG test with a single is abnormal, but and libido (41). It should be noted that only a small the long-term administration of hCG may restore the percentage of uremic patients have prolactin levels testosterone levels, proving that testes retain their .100 ng/ml. In these cases, imaging studies of the reserve secretion (35). There is evidence of a factor in hypothalamic–pituitary region should be performed uremic serum capable of blocking the LH receptor, to exclude the presence of a microadenoma or a thus providing an explanation for the sluggish response macroadenoma. Depletion of total body zinc stores of the Leydig cell to infusion of hCG (36). Plasma levels may also play an etiologic role in uremic hyper- of estradiol are normal or low, which are consistent prolactinemia (44). with a hypogonadotropic state, because the increased In addition to the disturbances in the hypothalamic– LH levels should enhance the testicular estradiol pituitary–gonadal axis, abnormalities in the sympath- secretion (37). etic nervous system, derangements in the arterial Delayed pubertal maturation can occur in children supply or venous drainage of the penis and psycologic with chronic renal failure. Plasma LH and testosterone effects may contribute to the sexual dysfunction in levels are normal for their age but the FSH levels are uremic men. Primary depression may affect sexual elevated, suggesting damage of the germinal epithelium function and lead to reduced libido and decreased fre- while the Leydig cell function appears normal (38). quency of intercourse (45). Careful consideration of In healthy men, LH is secreted in a pulsatile manner. the patient’s medications may reveal a drug that In chronic renal failure, the number of secretory bursts could be responsible for impairing sexual function. Cen- remains normal, but the amount of LH released per trally acting drugs and b-blockers used as anti-hyper- secretory burst is reduced (39). It is unclear whether tensives are the most commonly implicated agents in this derangement is the result of a change in the pat- causing impotence. The angiotensin-converting tern of GnRH release from the hypothalamus or a enzyme inhibitors or angiotensin receptor blockers change in the responsiveness of the pituitary. Adminis- are associated with a lower incidence of impotence tration of GnRH increases LH levels to the same degree and represent a useful alternative in uremic patients as in healthy subjects; however, the peak value and with hypertension. Other drugs commonly implicated return to baseline may be delayed (40). The decreased include cimetidine, phenothiazines, tricyclic anti- metabolism of LH and GnRH may explain the observed depressants and metoclopramide. variations, since the kidneys contribute significantly to The management of sexual dysfunction in uremia the clearance of these hormones. involves a multifactorial approach. One needs to

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Downloaded from Bioscientifica.com at 09/30/2021 12:40:28AM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 152 Gonadal dysfunction in systemic diseases 505 ensure optimal delivery of dialysis and adequate nutri- elevated in obese men and urinary estrone and estra- tional intake. Optimal management of the anemia with diol production rates are positively correlated to the administration of recombinant human erythropoietin percent above ideal body weight (60). has been shown to improve sexual function in chronic The association between obesity, low testosterone renal failure (46, 47). Control of secondary hyperpar- and SHBG has received considerable attention. Many athyroidism with 1,25(OH)2 vitamin D may be of ben- studies have shown that testosterone levels are inver- efit in lowering prolactin levels and improving sexual sely correlated with insulin and C-peptide concen- function in some patients. In uremic men complaining trations (61). This association is partly through of erectile dysfunction, the first-line therapy is oral sil- SHBG, because fasting insulin correlates negatively denafil (48–50). It should be emphasized that sildenafil with SHBG levels (62). The regulation of SHBG is absolutely contra-indicated in patients using organic expression by insulin has been studied directly using nitrates for coronary artery disease, where lethal hypo- cultures of HepG2 hepatoma cells that express the tension can occur. Caution is also required in men SHBG gene (63). In these cells, adding insulin reduces using complex anti-hypertensive regimes. If sildenafil SHBG mRNA levels and protein secretion (11). This is not effective or is contra-indicated, additional options effect may be mediated by the liver-enriched transcrip- include cavernosal vasodilator pharmacotherapy (pros- tion factor, hepatocyte nuclear factor-4, which transac- taglandin E (PGE) and phentolamine, papaverine), tivates the SHBG promoter (64). intracavernous injection of alprostadil (synthetic Total testosterone levels are lower than normal in PGE1) or mechanical devices such as vacuum/constric- men with type 2 diabetes and much of this difference tion devices or implantable prosthesis. Surgical place- may result from lower SHBG (65). Several prospective ment of a penile prosthesis is considered in patients studies found that low SHBG levels predict the develop- who fail the less invasive first-line treatments. ment of type 2 diabetes (66). This finding follows logi- Administration of androgens in patients with chronic cally from the inverse correlation between SHBG and renal failure has a proven indication only for the treat- obesity (54) and insulin resistance (61) and the propen- ment of renal anemia, where it was widely applied for sity for obese and insulin-resistant individuals to more than three decades before being largely sup- develop type 2 diabetes. planted by recombinant human erythropoietin (51, Various cross-sectional and prospective studies relat- 52). Uremic patients with hyperprolactinemia may ing testosterone to cardiovascular disease end-points benefit from the administration of bromocryptine. How- are inconclusive. On the other hand, the findings of sev- ever, its usefulness has been limited by a relatively high eral studies raise the possibility that men with relatively frequency of side-effects, particularly hypotension (41). low total, particularly bioavailable (non-SHBG-bound), Finally, the administration of zinc in a zinc-deficient testosterone levels may be related to the progression uremic man may contribute to improvement of gonadal of aortic atherosclerosis compared with men with function (53). higher testosterone levels (67). The biological mechanisms by which testosterone Testosterone and the metabolic cardiovascular might influence atherosclerosis in men are unclear. A syndrome Circulating testosterone levels are reduced direct effect of testosterone on the arterial wall is plaus- in massively obese men (54) and several studies have ible given the presence of androgen receptors in vascu- confirmed that total testosterone levels decrease as lar smooth muscle and endothelial cells (68). Other body mass increases. The major reason for the low proposed mechanisms are the decrease of vascular levels are the reduced levels of SHBG but free and adhesion molecule-1 expression in human endothelial non-SHBG-bound testosterone levels are also reduced cells (68), the upregulation of high-density lipoprotein in massive obesity (55). As Leydig cell function is (HDL) receptors in macrophages (69) and finally the normal in obese subjects, the main mechanism respon- modulation of cardiovascular disease risk factors, sible are the lower mean LH levels and pulse amplitude such as blood lipids, lipoproteins, coagulation and fibri- (56). The leading hypothesis is that reduced LH pulse nolytic proteins. amplitude in obesity results from increased estrogen Several studies have found a positive association production, because estradiol suppresses the pituitary between testosterone or SHBG and HDL-cholesterol LH response to GnRH stimulation in males (57). Testos- (HDL-C) levels (70). There is a linear relationship terone is converted to estradiol by aromatase P450, the throughout the physiologic range of testosterone con- product of the CYP19 gene (58). Aromatase may be centrations, such that HDL-C increases by 1.0 mg/dl increased in obesity because of increased subcutaneous with every 100 ng/dl increase in total testosterone adipose tissue mass, or adipose-derived factors could (71). The mechanisms are not clear but one possibility upregulate aromatase in selected tissues (59). The is that testosterone increases the synthesis of apolipo- plasma estradiol in normal adult men is 20–40 pg/ml protein A-1, the major component of nascent HDL par- and its production rate in blood is 25–40 mg/24 h; ticles. There is also evidence that testosterone both of these values are higher than in postmenopausal upregulates the expression of HDL receptors (69). women. Mean serum estrone and estradiol levels are Low HDL-C is found in patients with other metabolic

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Downloaded from Bioscientifica.com at 09/30/2021 12:40:28AM via free access 506 A Karagiannis and F Harsoulis EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 152 risk factors which are referred to as the metabolic syn- autoimmunity, impaired function of joints and psycho- drome. All components of the metabolic syndrome have logical responses to chronic disease, such as depression been related to low testosterone and SHBG in epidemio- and reduced self esteem. logic studies, although it is not clear if these relation- Active rheumatic disease can cause hypogonadism in ships are truly causal or indirect. men and has been reported in patients with rheuma- Testosterone may influence the risk of cardiovascular toid arthritis (RA) and systemic lupus erythematosus diseases by affecting hemostatic function and thrombo- (SLE) (77, 78). Decreased libido, erectile dysfunction sis. The few population studies that have examined the and failure to ejaculate have been reported in 19– relationship between testosterone and plasma fibrino- 35% of men with SLE. gen, factor VII and plasminogen activator inhibitor Hypoadrogenicity has been found in men with RA type I (PAI-I) levels were inconsistent. Low levels of tes- especially in the presence of high-degree activity (79). tosterone are associated with higher concentrations of Basal serum concentrations of total testosterone, factor VII, fibrinogen and PAI-I,independent of age, cen- SHBG and LH were measured in 104 men with RA tral obesity, fasting insulin, glucose and other cardiovas- and were compared with those of 99 age-matched cular risk factors (72). Each of these factors predisposes healthy men (80). Men with RA had lower levels of to atherosclerosis and coronary vascular disease. bioavailable testosterone and a large proportion was In conclusion, total testosterone and SHBG levels are considered hypogonadal. A similar study did not find reduced in men who are obese and hyperinsulinemic any significant differences in patients with ankylosing and men with type 2 diabetes. These men have lower spondylitis (81). levels of HDL-C and triglycerides and higher levels of Some anti-rhemautic drugs carry a risk for male the thrombotic factors tissue PAI, fibrinogen and reproduction. Adverse effects include gonadotoxicity factor VII, known to predispose to atherosclerosis and and chromosomal defects. Cytotoxic drugs like metho- coronary vascular disease. Low testosterone increases trexate and cyclophosphamide infer a risk of genotoxi- the risk for developing type 2 diabetes, whereas the city either by inducing chromosomal aberrations or contribution of low testosterone to the metabolic cardio- through single gene mutations. vascular syndrome is less certain. Oligo- or azoospermia can be induced by sulfasala- Starvation Starvation has a profound suppressive zine and cyclophosphamide. It occurs rarely during effect on gonadotropin secretion and testicular func- therapy with methotrexate and is reversible after dis- tion, independent of its etiology. The main mechanism continuation of the drug. Azathioprine, cyclosporine of gonadotropin suppression is the inhibition of GnRH and colchicine do not impair male fertility. Salazo- secretion, as is apparent from the suppression of LH pyrin-induced sperm alterations are reversible after an secretion (73). Much evidence indicates that leptin, as average of 2.5 months after discontinuing the drug a signal for starvation, mediates the under-nutrition- (82). Treatment with cyclophosphamide carries the induced alterations of the reproductive axis. It has risk of irreversible infertility (83). The risk of permanent infertility after treatment with cyclophosphamide can been found, in mice, that preventing the starvation- induced fall in leptin with leptin administration sub- be avoided by the cryopreservation of sperm before stantially blunts the changes seen in the gonadal axis start of therapy. Even when sperm counts and quality in males (74). In studies in primates, it has been are reduced, sperm banking is meaningful given the shown that intravenous leptin infusion maintains LH advanced techniques of assisted reproduction which pulsatility in fasted male rhesus macaques (75), are available. thereby demonstrating the ability of leptin to counter- act the inhibitory effect of fasting on gonadotropin Miscellaneous illnesses Leydig cell function and sper- secretion. Serum testosterone levels are low with a matogenesis are frequently disturbed in miscellaneous poor response to hCG. As body weight is regained, systemic diseases, such as Hodgkin’s disease, cancer the pulsatile gonadotropin secretion is restored in a before and after chemotherapy, cystic fibrosis, chronic manner reminiscent of the changes with puberty. respiratory diseases and amyloidosis. These illnesses During the improvement in nutritional status, gyneco- usually induce low testosterone levels and normal or mastia and, rarely,spider nevi may develop. Breast devel- slightly elevated LH levels, due to the combined attack opment, called refeeding gynecomastia, was seen in the of testes and the hypothalamic–pituitary axis. After starved prisoners of World War II. surgery, or severe burn-elevated rarelyoccurs in men but appears to present the same hor- SHBG levels are seen, whereas free testosterone, mone changes as expected from studies in women, which is the biologically active fragment, is lower namely low serum LH and FSH levels and a poor response than total testosterone (84). to GnRH administration. These disturbances are normal- There is a high prevalence of low testosterone levels ized with attainment of normal weight (76). in patients with HIV infection, resulting from defects at all levels of the hypothalamic–pituitary–gonadal axis. Rheumatic diseases Rheumatic diseases disturb sexual Both hypogonadotropic and hypergonadotropic hypo- function and reproduction in a multifactorial way; gonadism has been described, the former being more

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Downloaded from Bioscientifica.com at 09/30/2021 12:40:28AM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 152 Gonadal dysfunction in systemic diseases 507 prevalent. Low testosterone levels are associated with plasma gonadotropin and estrogen levels with a adverse disease outcomes, including weight loss, dis- common mechanism of the alteration of pulsatile LH ease progression and decreased free mass and exercise secretion. A lack of increase of plasma gonadotropin capacity (85). Testosterone replacement in hypogona- has been considered to be the main finding despite dal men with HIV-associated weight loss, physiologic the shortage of inhibitory factors of ovarian origin in testosterone administration alone or in combination plasma, such as estradiol and inhibin. The disturbance with resistance training has been shown to increase of pulsatile secretion is referred either to the frequency lean body mass, muscle strength and quality of life or the amplitude of the pulse wave of LH. In severe (86). The role of higher dose testosterone therapy in cases, the frequency and the wave amplitude are both eugonadal men with HIV-associated weight loss is less significantly reduced (93). This normal function of clear, given the potential adverse effects on HDL-C the hypothalamic–pituitary axis is disturbed in con- and lack of safety data (87). ditions of prolonged exposure to chronic stress, such In thyrotoxicosis, the hypothalamic–pituitary–testis as strenuous exercise or severe emotional states. In all axis alterations are secondary, due to elevated estrogen these conditions, the stress hormones, such as cortico- levels, and consist of reduced semen, elevation of tropin-releasing hormone, adrenocorticotropin, corti- plasma testosterone and normal free testosterone sol, prolactin, oxytocin, vasopressin, epinephrine and levels (84). The issue of fertility in celiac men is norepinephrine, are elevated. These hormones inhibit poorly understood, and there are few studies available. gonadotropin secretion by various mechanisms provok- Basal serum FSH and LH concentrations are higher in ing hypothalamic anovulation. untreated celiac men than in male controls with Heavy and prolonged training for championships in Crohn’s disease (88). Plasma testosterone and free tes- women is associated with three distinct disorders of tosterone indices are high, whereas DHT levels are reproductive function, namely delayed menarche, reduced, indicating androgen resistance (89). It was luteal dysfunction and amenorrhea. In addition to recently reported that the children of celiac men had amenorrhea, these female athletes present disordered a lower birth weight than age- and sex-matched non- eating and (94). celiac children (90). It has been suggested that genetic Amenorrhea may occur in women with a definite loci outside the human leucocyte antigen complex are history of psychological and socio-economic trauma. implicated (90, 91). In depressed women, the incidence of amenorrhea is quite high and hormonal tests reveal low to normal Ovarian function in systemic diseases gonadotropin levels with normal responses to GnRH, prolonged suppression of gonadotropins in response to Chronic anovulation is a common problem in women estradiol and failure of a positive feedback response to with systemic diseases and is displayed with secondary estradiol (95). In patients with depression, the disturb- amenorrhea, oligomenorrhea or irregular episodes of ance of the hypothalamic–pituitary–ovarian axis is metrorrhagia. Chronic diseases affect regular menses similar to the hypothalamic amenorrhea caused by through various mechanisms determined by the main exercise or disordered eating (96). illness. In most cases, treatment of the underlying dis- In anorexia nervosa, severe undernutrition is associ- ease restores the normal function of the hypothala- ated with extremely low plasma and cerebrospinal fluid mic–pituitary–ovarian axis. leptin levels, low and apulsatile gonadotropins, altered GnRH is produced in the arcuate nucleus of hypo- menstrual function and amenorrhea (97). Leptin thalamus and secreted via the hypothalamic portal levels below 1.85 ng/ml have been found to be associ- vessels to the median eminence in a pulsatile fashion ated with amenorrhea in underweight females with which a is necessary presumption for the secretion of eating disorders (98). In addition, the resumption of FSH and LH by the . After depolariz- menses is associated with leptin levels above this ation of the GnRH-containing neurons, GnRH is threshold. However, in underweight patients, the secreted with a frequency which fluctuates between rapid increment in serum leptin with weight gain is 60 and 200 min in the various phases of the menstrual not concomitant with menstruation, which suggests cycle (92). The frequency of the pulsatile secretion is that the normalization of menstrual periods might defined by the feedback of the ovarian steroids and by depend on additional factors, such as the GH–IGF-I local regulatory substances of the hypothalamus, axis (99). Various experimental data strongly suggest such as norepinephrine, dopamine and b-endorphin. that leptin acts centrally to influence reproduction This fine function may be influenced by locally devel- and that a stimulatory effect is exerted over a relatively oped tumors or genetic diseases as well as by functional narrow range of leptin concentrations. Leptin stimu- disorders. The latter are the most frequent and include lates the release of GnRH from the hypothalamus. strenuous exercise, abrupt weight loss, vigorous Double labeling studies failed to demonstrate the emotional conditions and various systemic diseases. expression of the leptin receptor Ob-R in GnRH-secret- The above constitute the clinical setting of functional ing neurons. However, strong immunoreactivity for hypothalamic anovulation, characterized by reduced Ob-R has been shown in pro-opiomelanocortin and

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Downloaded from Bioscientifica.com at 09/30/2021 12:40:28AM via free access 508 A Karagiannis and F Harsoulis EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 152 neuropeptide Y, and cocaine- and amphetamine-related It has been suggested that increased plasma prolactin transport neurons in the arcuate nucleus. Together levels may impair hypothalamic–pituitary function with functional studies, these findings suggest that and contribute to sexual dysfunction and . these peptides might be involved in the stimulatory As in men with chronic renal failure, the hypersecre- effects of leptin on GnRH (100). The administration tion of prolactin appears to be autonomous, as it is of recombinant human leptin to underweight women resistant to manoeuvres designed to inhibit or stimulate or those taking strenuous exercise results in an its release. In selected cases, the administration of bro- increase in mean and pulsatile LH levels, enlargement mocryptine may help. of the ovaries and dominant follicles and estradiol The first steps for the management of sexual dysfunc- levels. Three out of eight patients had ovulatory men- tion in uremic women are to optimize delivery of dialy- strual cycles (101). sis, raise haemoglobin to 11–13 g/dl with recombinant human erythropoietin, and control the degree of sec- Systemic diseases and ovarian dysfunction ondary hyperparathyroidism with 1,25(OH)2 vitamin D. A review of the patient’s medications may reveal The metabolic syndrome Central obesity combined that a drug could be responsible for the impaired with elevated blood pressure, impaired fasting glucose, sexual function, as has been already described for high triglycerides and low HDL-C concentrations are uremic men. the main criteria for diagnosing the metabolic syn- Low estradiol levels in amenorrheic hemodialysis drome. The syndrome is called the insulin-resistant women can secondarily lead to vaginal atrophy and syndrome and increases the likelihood that one or dryness resulting in discomfort during intercourse. more abnormalities will be present (102). Polycystic These women may benefit from local estrogen therapy syndrome (PCOS) is the most common endocrine or vaginal lubricants. Administration of testosterone abnormality in premenopausal women and compelling in low doses may be effective in increasing sexual evidence indicates that the prevalence of insulin resis- desire, but is rarely used secondary to potential toxicity. tance/hyperinsulinemia is significantly increased in Successful renal transplantation is the most effective patients with this syndrome. In this instance, the clini- means to normalize sexual desire in women with cal features of PCOS result from an increase in testoster- chronic renal insufficiency (30). one secretion by ovaries that are at least normally Careful gynaecologic follow-up is recommended insulin sensitive, secondary to the higher circulating because the risk of endometrial hyperplasia and/or car- insulin concentrations seen in these patients. Conver- cinoma, associated with unopposed estrogen effects on sely, PCOS cannot be a simple function of insulin resist- the uterus, has not been assessed properly. In some ance. Nevertheless, not all insulin-resistant women patients, it may be desirable to administer a progesta- have PCOS and vice versa (103). Family studies suggest tional agent several times per year to interrupt the pro- that there is a genetic susceptibility to hyperandrogen- liferation induced by unopposed estrogen release. emia and insulin resistance in PCOS. Consistent with Because of poor pregnancy outcomes, restoring ovu- this hypothesis, there is evidence for linkage and associ- latory cycles is not a therapeutic goal in women on ation of marker locus near the insulin receptor with the chronic dialysis. For uremic women who are menstru- hyperandrogenemia phenotype (104). ating normally, birth control is recommended. In women with a well-functioning renal transplant, the Chronic renal failure The disturbances of ovarian abnormalities in can be reversed and a suc- function occur frequently in women with end-stage cessful pregnancy may be achieved. renal failure, leading to amenorrhea and infertility (105). Menstruation may present various abnormal- Liver diseases – alcoholism Alcohol abuse provokes ities, such as oligomenorrhea or menorrhagia, which profound disturbances in the hormonal status and the may occasionally require hysterectomy. In some reproductive performance of women. Chronic alcohol women, normal menses are restored after initiation of abuse is associated with hypogonadism, as manifest hemodialysis (106). Moreover, women may present by the loss of secondary sexual characteristics, amenor- decreased libido and a reduced ability to reach rhea and early , because the secretion of (45). Pregnancy might rarely occur in chronic estrogens and gonadotropin is reduced. Ovary failure renal insufficiency, but fetal wastage is significantly results in lack of ovulation and infertility (108). The increased (107). precise mechanism of alcohol action upon the hypo- The hormonal profile of uremic women includes elev- thalamic–pituitary–ovarian axis is not known and ated prolactin levels, normal FSH and modestly elevated relative studies are limited. Long-term administration LH levels, along with an increased LH/FSH ratio and of alcohol to female rats reduces ovarian size, destroys relatively low estradiol, estrone, and tes- the corpora lutea and induces changes in estrogen tosterone levels (33). The normal pulsatile release of deficiency in the uterus and the salpinxes. There are gonadotropins is disturbed, but the response to GnRH no specific studies on the effect of ethanol on is preserved and may be excessive and prolonged. women’s ovaries, even though it seems that the

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Downloaded from Bioscientifica.com at 09/30/2021 12:40:28AM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 152 Gonadal dysfunction in systemic diseases 509 addition of ethanol in cultures of theca cells inhibits the abnormalities in estrogen and progesterone levels progesterone and estradiol response (109). have been found with RA compared with controls Fifty percent of women suffering from alcoholic cir- (113, 114). Studies on androgens have been contradic- rhosis present amenorrhea. Moreover, they may pre- tory, although a meta-analysis confirmed the finding of sent oligomenorrhea, metrorrhagia or menorrhagia. lowered sulfate in premeno- In some cases with obvious signs of malnutrition, pausal women with RA (113). women manifest hypogonadotropic hypogonadism. In In a population-based study, lower numbers of births other cases, the portosystemic bypass of adrenal andro- and a reduced period of reproduction were found in gens leads to elevated estradiol and testosterone levels, women with rheumatic diseases compared with due to peripheral conversion of androgens to estrogens healthy controls (115). Two other studies have in fat and other tissues (108). In the final stages of the suggested that fertility or fecundity may be decreased disease, where there is hepatic encephalopathy, the cen- among women with RA (116, 117), whereas others tral secretion of neurotransmitters (norepinephrine, have found that fertility or fecundity do not differ dopamine) is influenced, resulting in modification of from healthy controls (112). Although fertility is the pulsatile gonadotropin secretion by the hypothala- normal in SLE, increased fetal loss either as miscarriage mus. This factor may be responsible for the hyperpro- or stillbirth has been reported (118–122). Active lupus lactinemia seen in some cases. nephritis, a previous history of fetal death and the Normal postmenopausal women who drink moder- presence of anti-phospholipid antibodies (aPLs) are ately (one drink per day or less) have higher estradiol predictive factors for pregnancy loss in lupus levels than women who do not drink. It is unclear pregnancies. whether this phenomenon is due to alcohol or to the aPLs were shown to be connected not only with preg- phytoestrogens which are contained in the alcoholic nancy losses, but with inhibition of implantation and beverages. possibly with failures of in vitro fertilization (IVF) Postmenopausal women suffering from alcoholic cir- implantation. Auto-antibodies may exert actions on rhosis have slightly higher estradiol and lower testoster- the trophoblast via interference with membrane surface one levels than control women. The underlying hemostatic reactions or by reacting with antigens or mechanism is that the conversion of androgens to cell surfaces, resulting in altered cell activity. Effects estrogens is enhanced by alcohol abuse. The elevated may include direct cellular injury or microvascular estrogen levels suppress gonadotropin secretion. How- thrombosis (123). The presumed thrombotic effects ever, despite the relatively increased levels of estrogens, have led to the use of heparin and aspirin for women alcoholic cirrhotic women have profound signs with aPLs and recurrent abortion or IVF implantation of defeminization with loss of secondary sexual failure. Despite the experimental evidence that aPLs characteristics (110). Finally, in addition to other interfere with implantation and thrombotic develop- harmful effects of alcohol on the female reproductive ment, the question as to whether some of these anti- system, it must be noticed that alcoholic pregnant bodies are mere epiphenomena remains. women are at risk of intra-uterine growth retardation Most anti-rheumatic drugs have no effects on the of their newborns (111). gonads. However, some drugs can cause reversible After successful orthotopic liver transplantation, infertility, such as the non-steroidal anti-inflammatory women achieve normal menstrual function and ferti- drugs in women and salazopyrin or methotrexate in lity. The return of menses can occur in 2 or 3 months men. Irreversible infertility has been reported after transplantation. Pregnant transplant recipients exclusively after treatment with alkylating agents, are treated with the same doses of immunosuppressive such as cyclophosphamide and chlorambucil drugs as the non-pregnant women, resulting in the (112, 124). successful outcome of the pregnancy, both for the mother and the newborn. Celiac disease Celiac disease has been ascertained to be the cause of infertility in 4–8% of women with unex- Rheumatic diseases Different rheumatic diseases can plained infertility. In some cases, fertility was restored cause specific sexual problems related to the nature of after treatment of the underlying disease. Menarche is prevailing symptoms. In primary and secondary Sjo¨g- delayed while menopause appears earlier, resulting in ren’s syndrome, decreased cervical mucus production a shorter duration of the reproductive period. Women and atrophic vaginitis can result in dyspareunia, suffering from celiac disease who do not follow a which occurs in 40–50% of patients (112). Vaginal proper diet present more frequently spontaneous abor- dryness and dyspareunia are also frequently encoun- tions and other complications of pregnancy in relation tered in women with systemic sclerosis, systemic to women following a gluten-free diet (125). The above lupus erythematosus and RA. disturbances cannot be completely interpreted by the Several studies have investigated serum concen- malabsorption of food. However, it seems that women trations of hypophyseal gonadal and adrenal hormones who do not follow a gluten-free diet have an increased in women with rheumatic diseases. No significant risk of a poor outcome of their pregnancy (90).

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