ENDOCRINE PATHOLOGY: EFFECTS ON MALE FERTILITY
R. Martin-du Pan
Infertility and Gynecologic Endocrinology Clinic,
Department of Obstetrics and Gynecology,
University Cantonal Hospital, 1211 Geneva 14, Switzerland
The incidence of primary endocrine defects in subfertile men is less than 3 per cent and is rare in men with sperm concentrations greater than 5 million per ml. When an endocrinopathy is discovered, however, specific hormonal treatment is often successful (10).
Hormonal control of spermatogenesis
Spermatogenic activity requires sufficient testosterone (T) concentration. Testosterone is produced by the Leydig cells under the influence of luteinizing hormone (LH). Its role varies between species and ages. Studies in hypophysectomized adult rats have shown that contrary to previous belief high intratesticular levels of T are not required to maintain spermatogenesis. However the T level could be critical for the final steps of spermatogenesis. Receptors for T have been detected in Leydig, Sertoli and peritubular cells but not in germ cells (32).
In men with gonadotropin insufficiency T on its own cannot maintain spermatogenesis contrary to what is observed in rats. Experimental gonadotropin deficiency can be induced in man by administration of pharmacological doses of testosterone resulting in azoospermia. In that situation selective replacement of either LH activity with human chorionic gonadotropin (hCG), or follicle-stimulating hormone (FSH) activity with FSH increased sperm count to the 20-50 million/ml range but quantitatively normal spermatogenesis was not achieved. Therefore normal levels of both FSH and LH are required to achieve quantitatively normal levels of sperm production (24).
In men with severe oligospermia due to spermatogenic damage, FSH concentration is inversely proportional to the spermatogonial population (11). It is usually believed that FSH increase in case of severe seminiferous damage is due to decrease of inhibin secretion. However normal or increased levels of inhibin have also been measured in azoospermic patients with high FSH values (7,12). It is possible that in states of spermatogenic damage, Sertoli cells produce less inhibin than activin, an FSH-releasing factor, or that the decrease in T due to concomitant Leydig cell dysfunction increases FSH levels which in turn would stimulate inhibin secretion (6).
Elevated serum FSH is a reliable indicator of germinal epithelial damage and is usually associated with severe oligospermia or azoospermia of bad prognosis. Normal spermograms and high FSH levels have however been observed after hemicastration and mumps orchitis (17,26). In cases of oligospermia, if the levels of gonadotropins are normal or increased, the administration of human menopausal gonadotropins (hMG) (3 x 150 U/week) and hCG (2 x 2500 U/week) is not more effective than a placebo (19). After i.m. injection of 150 IU of FSH, immunoreactive and bioreactive FSH peaked at 8 h. but whereas immunoreactive FSH reached baseline values after 96 hours, bioreactive FSH values were undectable 12 hours after the injection. The half life was calculated to be 24.6 h for immunoreactive FSH and 13.4 h for bioreactive FSH (16).
Clinical findings (10)
History: special attention should be paid regarding to cryptorchidism, postpubertal mumps, orchitis, testicular trauma, testicular pain and anosmia. Precocious puberty may indicate adrenogenital syndrome. Drugs and medications: anabolic steroids, cimetidine, spironolactone, cancer chemotherapy, hashish and alcohol may contribute to male infertility. Decreased libido and impotence may be due to low testosterone or increased prolactin levels.
Clinical examination: if testicular failure occurs before puberty, the patient will have features of eunuchoidism (Table 1).
The normal adult testis is 4.6 cm long (3.6-5.5) and 2.6 cm wide (2.1-3.2). with a mean volume of 18.6 ± 4.8 ml. The seminiferous tubules account for 95% of the testicular volume. A volume of 3 ml indicates a complete lack of endogenous GnRH secretion. A volume of 4 ml reflects a residual GnRH secretion.
Gynecomastia can occur in primary testicular failure (e.g. Klinefelter syndrome) and less frequently in secondary testicular failure. It is observed in liver and kidney failure and in hyperthyroidism.
Luteinizing hormone (LH) is secreted in bursts occurring every 120 min (interpulse intervals vary from 30 to 480 min. Because of the pulsatility of LH secretion and its short half life, a single LH determination has an accuracy of ±50%. Testosterone (T) is secreted episodically in response to the LH pulses with a possible lag of 40 min. Testosterone pulses are recognizable in gonadal veins but not in peripheral veins (36). Testosterone has a diurnal pattern with an early morning peak although a circadian rhythm is not observed in some normal young men and elderly men (31).
About 60% of T is bound to testosterone-binding globulin (TeBG) and 35% to albumin. The free fraction of T is increased when TeBG is decreased (obesity, hypothyroidism, acromegaly, androgen or glucocorticoid treatment). Normal T levels (but decreased free T) can be measured when TeBG is increased by estradiol (e.g. hyperthyroidism). Testosterone binds to the androgen receptor either directly or after conversion to dihydrotestosterone, which binds to the receptor more tightly than T. Quantitative or qualitative defects of androgen binding due to mutations in the androgen receptor would result in a spectrum of disorders ranging from complete testicular feminization to infertile male syndrome (14).
Bioactive LH and FSH
Twenty different forms of LH and FSH have been identified on the basis of electrophoretic separation. Gonadotropin heterogeneity reflects variable glycosylation. The more acidic LH and FSH isoforms have longer in vivo half life and display lower receptor binding and in vitro bioactivity compared with the basic isoforms. The proportion of acidic isoforms increases with advancing age or after castration, whereas more basic forms with enhanced bioactivity predominate during puberty and during the preovulatory LH surge. An increase of the Bioactive: Immunoreactive ratio for LH (B:I LH ratio) has been observed in men with primary hypogonadism, whereas the B:I LH ratio is decreased in old men, in men with psychogenic impotence and after treatment with gonadotropin releasing hormone (GnRH) agonists (33). A low B:I FSH ratio has been observed after administration of hMG (16). The 5 studies of the B:I FSH ratio in cases of normogonadotropic oligospermia compared with normal men have yielded contradictory results (9).
The measurement of the LH bioactivity is useful in 2 situations:
- In the " invisible LH ": low LH is measured by certain RIA using monoclonal antibodies (IRMA) whereas normal LH values are measured by polyclonal antibodies or bioassays (20). Inaccuracy of the dosage of LH can be suspected if FSH and sex steroid levels are normal. Dosage of testosterone is a simple way to evaluate LH bioactivity.
- " False " increase of LH RIA with low LH bioactivity and low testosterone has been observed in a case of pubertal delay due to an anomaly of the ß subunit of LH molecule. The gonadal response to the administration of hCG or LH was normal (35).
Endocrine causes of infertility
FSH and LH levels are increased with low normal or decreased levels of T. Many cases are due to a genetic cause (e.g. Klinefelter syndrome). There is no treatment of the consequent sterility except in some acquired cases (renal insufficiency, sickle cell anemia) in which zinc administration may improve sperm count (22).
FSH, LH and T levels are decreased. Eunuchoidism results from hypogonadism occurring before the age of puberty. Kallmann syndrome is due to a congenital lack of GnRH secretion. In case of hypogonadism occurring after puberty, a pituitary or hypothalamic tumor must be ruled out by a radiological examination (CT scan of the pituitary) and by evaluating prolactin serum levels.
Infertile men with hypogonadotropic hypogonadism can be successfully treated by hCG (3 x 2000 U/week for 2 months) followed by hCG + hMG (3 x 150 U/week). Previous androgen therapy will not affect their responsiveness. Fertility is more difficult to achieve in case of cryptorchidism (13). Pulsatile GnRH therapy (4-8 µg subcutaneously every 2 hours) using a portable pump together with i.m. hCG (3 x 2500 U/week) has been compared to hCG-hMG treatment in a non randomized study. The increase in testicular volume and of sperm count was achieved more rapidly in the GnRH group than in the hMG group (28). In case of a lack of response to hMG, the administration of growth hormone (3 x 4 U/week) could increase the sensitivity of the gonads to hMG, according to an uncontrolled study (30). In a hypophysectomized azoospermic patient we observed an increase of IGF-I in the sperm after administration of hCG-hMG. Adjunctive growth hormone therapy increased IGF-I in the blood but not in the sperm.
Androgen resistance syndrome
Androgen receptor deficiency has been observed in 11 to 29% of men with idiopathic oligospermia and normal phenotype (27). LH levels are slightly increased due to increased LH pulse amplitude whereas T levels are normal (28). The LH (IU) x testosterone (ng/ml) product is usually increased above 200 but may be normal (100) (1). FSH levels are slightly increased. No treatment is available.
Congenital adrenal hyperplasia
In mild forms of 21-hydroxylase deficiency, the excessive production of ACTH consecutive to the defective cortisol synthesis stimulates the production of androgenic steroids by the adrenal cortex resulting in precocious puberty and abnormal phallic enlargement (34). Gonadotropins are suppressed by the increased steroids resulting (in some cases) in oligospermia or spermatogenic arrest. 17-hydroxyprogesterone and androstenedione are increased. Fertility can be restored by glucocorticoid treatment (5).
Loss of libido associated with headaches, visual abnormalities and galactorrhea (in 14 to 33% of cases) suggests hyperprolactinemia. It is an unusual cause of infertility and prolactin should not routinely be measured in the investigation of infertility unless there is also impotence or galactorrhea and/or low T with low-normal LH. Fertility and potency can be recovered after surgical or medical treatment, for example, with bromocriptine (8,29).
Oligoasthenospermia and decreased libido have been reported in 40 to 50% of cases and gynecomastia in 20 to 40% of cases. Testosterone levels are normal or increased and there are increased levels of estradiol, LH and LH response to GnRH, but decreased response of T to hCG. There is an increased production rate of E2 and a decreased clearance of E2. Estradiol can decrease spermatogenesis by direct action on the testis (18).
Decreased spermatogenesis may occur in Cushing syndrome, or in case of iatrogenic hypercorticism. Elevated plasma cortisol may depress LH secretion and cause secondary testicular dysfunction in Cushing disease (21). Acute or chronic administration of glucocorticoids induces a decrease of testosterone without compensatory elevation of LH secretion (25). Improvement of fertility (without effect on sperm) has however been observed after prednisolone 40 to 80 mg 10 days /month for 9 months given in case of anti-sperm antibodies (15).
Slow pulsing oligospermia
Reduced LH pulse frequency was found in oligospermic patients with high FSH levels that were reversed by GnRH pulsatile administration (2). These data have not however been confirmed. Normal or increased LH pulse frequency has been observed by other groups (4,37) and FSH increase is partially due to concomitant decrease of T (6). GnRH therapy was not able to improve sperm count despite decreased FSH levels, according to different authors (3,37).
Spermatogenic arrest is diagnosed by testicular biopsy in men with normal testicular volume and FSH values. It may result in oligospermia (partial spermatogenic arrest) or azoospermia (total spermatogenic arrest). The arrest occurs usually at primary spermatocyte level. Spermatogenic arrest can be due to an endocrinopathy (adrenogenital syndrome, male pseudohermaphrodism, androgen resistance, LH abnormality), or due to toxic factors (heat, drugs, radiotherapy). Other causes would be most probably due to genetic factors, for which no treatment is available (23).
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