Department of Surgery, Division of Urology
University of North Carolina School of Medicine
Male Infertility --- Overview
The Hypothalamic-Pituitary-Gonadal Axis
Prolactin also has a complex inter-relationship with the gonadotropins, LH and FSH. In males with hyperprolactinemia, the prolactin tends to inhibit the production of GnRH. Besides inhibiting LH secretion and testosterone production, elevated prolactin levels may have a direct effect on the central nervous system. In individuals with elevated prolactin levels who are given testosterone, libido and sexual function do not return to normal as long as the prolactin levels are elevated.
The germinal cells or the spermatogenic cells are arranged in an orderly manner from the basement membrane up to the lumen. Spermatogonia lie directly on the basement membrane, and next in order, progressing up to the lumen, are found the primary spermatocytes, secondary spermatocytes and spermatids. There are felt to be 13 different germ cells representing different stages in the developmental process.
Spermatogenesis is a complex process whereby primitive stem cells or spermatogonia, either divide to reproduce themselves for stem cell renewal or they divide to produce daughter cells that will later become spermatocytes. The spermatocytes eventually divide and give rise to mature cell lines that eventually give rise to spermatids. The spermatids then undergo a transformation into a spermatozoa. This transformation includes nuclear condensation, acrosome formation, loss of most of the cytoplasm, development of a tail and arrangement of the mitochondria into the middle piece of the sperm which basically becomes the engine room to power the tail. Groups of germ cells tend to develop and pass through spermatogenesis together. This sequence of developing germ cells is called a generation. These generations of germ cells are basically in the same stage of development. There are six stages of seminiferous epithelium development. The progression from stage one through stage six constitutes one cycle. In humans the duration of each cycle is approximately 16 days and 4.6 cycles are required for a mature sperm to develop from early spermatogonia. Therefore, the duration of the entire spermatogenic cycle in humans is 4.6 cycles times 16 days equals 74 days.
Hormonal Control of Spermatogenesis
Transport-Maturation-Storage of Sperm
During emission, secretions from the seminal vesicles and prostate are deposited into the posterior urethra. Prior to ejaculation peristalsis of the vas deferens and bladder neck occur under sympathetic nervous control. During ejaculation, the bladder neck tightens and the external sphincter relaxes with the semen being propelled through the urethra via rhythmic contractions of the perineal and bulbourethral muscles. It is true that the first portion of the ejaculate contains a small volume of fluid from the vas deferens which is rich in sperm. The major volume of the seminal fluid comes from the seminal vesicles and secondarily the prostate. The seminal vesicles provide the nourishing substrate fructose as well as prostaglandins and coagulating substrates. A recognized function of the seminal plasma is its buffering effect on the acidic vaginal environment. The coagulum formed by the ejaculated semen liquefies within 20 to 30 minutes as a result of prostatic proteolytic enzymes. The prostate also adds zinc, phospholipids, spermine, and phosphatase to the seminal fluid. The first portion of the ejaculate characteristically contains most of the spermatozoa and most of the prostatic secretions, while the second portion is composed primarily of seminal vesicle secretions and fewer spermatozoa.
Fertilization normally takes place within the uterine tubes after ovulation has occurred. During the menstrual mid cycle, the cervical mucus changes to become more abundant, thinner and more watery. These changes serve to facilitate entry of the sperm into the uterus and to protect the sperm from the highly acidic vaginal secretions. Physiologic changes in the spermatozoa known as capacitation occur within the female reproductive tract in order for fertilization to occur. As the sperm cell interacts with the egg, there is initiation of new flagellar movement called hyperactive motility and morphologic changes in the sperm that result in the release of lytic enzymes and exposure of parts of the sperm's structure known as the acrosome reaction. As a result of these changes, the fertilizing sperm cell is able to reach the oocyte, traverse it's various layers, and become incorporated into the ooplasm of the egg.
Both the vas deferens and the testicular blood supply can easily be injured during hernia repair. In patients with cystic fibrosis, the vas deferens or epididymis and seminal vesicles are usually absent. Any generalized fever or illness can impair spermatogenesis. The ejaculate may be affected for three months after the event, as spermatogenesis takes about 74 days from initiation to the appearance of mature sperm. There is also a variable transport time in the ducts. Sometimes events that have occurred in the previous 3-6 months are extremely important. Sexual habits including frequency of intercourse, frequency of ejaculation, use of coital lubricants and the patient's understanding of the ovulatory cycle should be discussed. Previous infertility evaluation and treatment and the reproductive history from previous marriages should be ascertained. A history of recurrent respiratory infections and infertility may be associated with the immotile cilia syndrome, in which the sperm count is normal but the spermatozoa are completely non-motile due to ultrastructural defects. Kartagener's syndrome, which is a variant of immotile cilia syndrome, consists of chronic bronchiectasis, sinusitis, situs inversus and immotile spermatozoa. In Young's syndrome, also associated with pulmonary disease, the cilia ultrastructure is normal but the epididymis is obstructed due to inspissated material, and these patients present with azoospermia. Loss of libido associated with headaches, visual abnormalities and galactorrhea may suggest a pituitary tumor. Other medical problems that have been associated with infertility include thyroid disease, seizure disorders, and Liver disease. Interestingly it is not the seizure disorder itself that causes infertility but it is the typical treatment of it with Dilantin (phenytoin). Dilantin decreases FSH. Chronic systemic diseases such as renal disease and sickle cell disease are associated with abnormal reproductive hormonal parameters.
A careful examination of the testes is an essential part of the examination. Normal adult testes are on the average about 4.5 cm long and 2.5 cm wide with a mean volume of about 20 cc. A caliper or orchidometer may be used to measure testicular size. If the seminiferous tubules were damaged before puberty, the testes are small and firm. With postpubertal damage, they are usually small and soft.
Gynecomastia is a consistent feature of a feminizing state. Men with congenital hypogonadism may have associated midline defects such as anosmia, color blindness, cerebellar ataxia, hair lip, and cleft palate. Hepatomegaly may be associated with problems of hormonal metabolism. Proper neck examination may help rule out thyromegaly, a bruit or nodularity associated with disease. Neurologic exam should test the visual fields and reflexes.
Irregularities in the epididymis suggest a previous infection and possible obstruction. Examination may reveal a small prostate with androgen deficiency or slight tenderness (bogginess) in men with prostatic infection. Any penile abnormalities like hypospadias, abnormal curvature, phimosis, should be looked for. The scrotal contents should be carefully palpated with the patient in both the supine and standing positions. Many varicoceles are not visible and may only be discernible when the patient stands or performs the Valsalva maneuver. Varicoceles can often result in a smaller left testis, and a discrepancy in size between the two testes should arouse suspicion. Both vas deferens should be palpated, as 2% of infertile men have congenital absence of the vasa and seminal vesicles.
PRE-TESTICULAR CAUSES OF INFERTILITY
Hypothalamic disease Isolated gonadotropin deficiency (Kallmann's syndrome) Isolated LH deficiency ("Fertile eunuch") Isolated FSH deficiency Congenital hypogonadrotropic syndromes Pituitary disease Pituitary insufficiency (tumors, infiltrative processes, operation, radiation) Hyperprolactinemia Hemochromatosis Exogenous hormones (estrogen-androgen excess, glucocorticoid excess, hyper and hypothyroidism).
Kallmann's syndrome which is an isolated gonadotropin (LH and FSH) deficiency occurs in both a sporadic and familial form and although uncommon i.e. 1 in 10,000 men, it is second to Klinefelter's syndrome as a cause of hypogonadism. The syndrome is often associated with anosmia, congenital deafness, hair lip, cleft palate, craniofacial asymmetry, renal abnormalities, color blindness. The hypothalamic hormone GnRH appears to be absent. If exogenous GnRH is administered, both LH and FSH are released from the pituitary. Except for the gonadotropin deficiency, anterior pituitary function is intact. The syndrome appears to be inherited either as an autosomal recessive trait or an autosomal dominant trait with incomplete penetrance. The differential diagnosis should include delayed puberty. Kallmann's syndrome distinguishing features though are testes less than 2 cm in diameter and positive family history with the presence of anosmia. "Fertile eunuch" are individuals with isolated LH deficiency. They have eunuchoid proportions with variable degrees of virilization and gynecomastia. They characteristically have large testes and semen containing a few sperm. Plasma FSH levels are normal but both the serum LH and testosterone concentrations are low normal. The cause appears to be a partial gonadotropin deficiency in which there is adequate LH to stimulate testosterone production with resultant spermatogenesis but insufficient testosterone to promote virilization. In isolated FSH deficiency which is rare, patient's are normally virilized and have normal testicular size and baseline levels of LH and testosterone. Sperm counts range from O to a few sperm. Serum FSH levels are low and do not respond to GnRH stimulation. Congenital hypogonadotropic syndromes are associated with secondary hypogonadism and a multitude of other somatic findings. Prader-Willi syndrome is characterized by hypogonadism, hypomentia, hypotonia at birth and obesity. Laurence-Moon-Bardet-Biedel syndrome is an autosomal recessive trait characterized by mental retardation, retinitis pigmentosa, polydactyly and hypogonadism. These syndromes are felt to be due to a defect in hypothalamic deficiency of GnRH.
Pituitary insufficiency may result from tumors, infarctions, iatrogenic causes like surgery and radiation or one of several infiltrative processes. If pituitary insufficiency occurs prior to puberty, growth retardation associated with adrenal and thyroid deficiency is the major clinical presentation. Hypogonadism that occurs in a sexually mature male usually has its origin in a pituitary tumor. Decreasing libido, impotence and infertility may occur years before symptoms of an expanding tumor i.e. such as headaches, visual abnormalities, or thyroid/adrenal hormone deficiency. Once an individual has passed through normal puberty, it takes a long time for secondary sexual characteristics to disappear unless adrenal insufficiency is present. The testes will eventually become small and soft. The diagnosis is made by low serum testosterone levels with low or low normal plasma gonadotropins concentrations. Depending on the degree of panhypopituitarism, plasma corticosteroids will be reduced with plasma TSH and growth hormone levels.
Hyperprolactinemia can cause both reproductive and sexual dysfunction. Prolactin-secreting tumors of the pituitary gland whether from a microadenoma (less than 10 mm) or a macroadenoma, can result in loss of libido, impotence, galactorrhea, gynecomastia and alter spermatogenesis. Patients with a macroadenoma usually first present with visual field abnormalities and headaches. They should undergo CT or MRI scanning of the pituitary and laboratory testing of anterior pituitary, thyroid and renal function. These patients have low serum testosterone levels but basal serum levels of LH and FSH are either low or low normal and reflect an inadequate pituitary response to depressed testosterone.
Approximately 80% of men with hemochromatosis have testicular dysfunction. Their hypogonadism may be secondary to iron deposition in the liver or may be primarily testicular as a result of iron deposition in the testes. Iron deposits have also been found in the pituitary, implicating this gland as the major site of abnormality.
With regard to the role of exogenous hormones, adrenocortical tumors, Sertoli cell tumors, interstitial cell tumors of the testes may all at times be estrogen-producing. Hepatic cirrhosis is associated with increased endogenous estrogens. Estrogens act primarily by suppressing pituitary gonadotropin secretion, resulting in secondary testicular failure. Androgens can also suppress pituitary gonadotropin secretion thereby leading to secondary testicular failure. The current use of anabolic steroids by certain athletes may result in temporary sterility. Endogenous androgen excess may be due to an androgen-producing adrenocortical tumor or testicular tumor but more likely to congenital adrenal hyperplasia. As a consequence of this disease, the production of androgenic steroids by the adrenal cortex is increased, resulting in premature development of secondary sexual characteristics and abnormal phallic enlargement. The testes failed to mature because of gonadotropin inhibition and are characteristically small. In the absence of precocious puberty, the diagnosis is extremely difficult since excessive virilization is difficult to detect in an otherwise normally sexually mature man. Careful laboratory evaluation is essential. Infertility caused by documented congenital adrenal hyperplasia is treatable with corticosteroids. Physicians have used corticosteroids in individuals with idiopathic infertility, but unless these abnormalities can be documented, steroid therapy has no place.
Sometimes glucocorticoid excess (prednisone usage) is exogenous in the therapy of ulcerative colitis, asthma, or rheumatoid arthritis. The result is decreased spermatogenesis. The elevated plasma cortisone levels depress LH secretion and can cause secondary testicular dysfunction. Correction of the glucocorticoid excess results in improvement in spermatogenesis. Hyper and hypothyroidism can alter spermatogenesis. Hyperthyroidism effects both pituitary and testicular function with alterations in the secretion of releasing hormones and increased conversion of androgens to estrogens.
|- Chromosomal abnormalities (Klinefelter's syndrome, XX disorder (sex reversal syndrome), XYY syndrome)|
|- Noonan's syndrome (male Turner's syndrome)|
|- Myotonic dystrophy|
|- Bilateral anorchia (vanishing testes syndrome)|
|- Sertoli-cell-only syndrome (germinal cell aplasia)|
|- Gonadotoxins (drugs, radiation)|
|- Systemic disease (renal failure, hepatic disease, sickle cell disease)|
|- Defective androgen synthesis or action|