III. ASSESSMENT OF HYPOGONADAL PATIENTS
Hypergonadotropic hypogonadism and hypogonadotropic hypogonadism
Patients who have low serum
testosterone levels usually fall into one of two pathophysiologic classes: those with primary testicular disease (hypergonadotropic hypogonadism) or those with secondary hypothalamic-pituitary disorder (hypogonadotropic hypogonadism). These two classes can be differentiated by the measurement of serum levels of LH and FSH.
Patients who have primary Leydig cell damage exhibit diminished feedback inhibition of gonadotropin secretion resulting in high serum LH and FSH concentrations. In hypergonadotropic hypogonadism, these patients have a diminished Leydig cell reserve and a blunted
testosterone response to administered LH or to the LH-like effects of
hCG.
Patients who have low serum testosterone and low or inappropriately low-normal serum LH are classified as hypogonadotropic hypogonadism. This may result from an abnormality of either the hypothalamus or the pituitary gland. In general, this defect can be 1) structural, such as a hypothalamic or pituitary tumor, 2) secondary to the administration of drugs that inhibit the hypothalamic axis, such as tranquilizers or estrogens; 3) the congenital inability to synthesize GnRH or LH and FSH; or 4) altered hypothalamic control mechanisms such as starvation or anorexia nervosa.
EVALUATION
A. Fertility Status
Throughout early childhood, gonadotropin and testosterone levels remain low. LH and FSH levels begin increasing from approximately 6 to 8 years of age. Testosterone levels begin increasing at 10 to 12 years of age. During the reproductive years, gonadotropin and testosterone levels remain relatively constant. Later in life, testosterone levels, particularly free testosterone levels, decrease and gonadotropin concentrations rise. Degeneration of seminiferous tubules and decreased numbers of Leydig cells are thought to be partly responsible for these changes.
Male infertility may be a manifestation of a primary hormonal abnormality. Such abnormalities are rare in patients with sperm concentrations greater than 5 million sperm per milliliter. In most cases, 2-3 semen analyses spaced over a 2-3 month period are recommended to adequately assess baseline parameters. According to the World Health Organization, a normal semen analysis is defined as: 1) volume 2.0 ml or more 2) pH 7.2 or more 3) sperm concentration 20 million/ml or more 4) total sperm number per ejaculate 40 million or more 5) motility 50% or more Grade A + B 6) morphology 15% or more normal and 7) viability 75% or more. In the presence of normal spermatogenesis, FSH secretion is regulated by negative inhibition from inhibin. With primary testicular failure, inadequate Leydig and Sertoli cell function result in elevated gonadotropin levels with normal or low testosterone levels. Hypothalamic or pituitary dysfunction resulting in inadequate levels of gonadotropins causes low peripheral levels of testosterone and an absence of spermatogenesis. As a result of the pulsatile secretion of GnRH, gonadotropins are secreted episodically, resulting in variation in the serum concentrations of these hormones, particularly LH.
B. Clinical Studies
A single
test dose of GnRH does not distinguish hypothalamic from pituitary disease, however, a GnRH challenge
test preceded by a period of "priming" the pituitary gonadotrophs by repeated low-dose stimulation has been used to diagnose hypothalamic disorders. The GnRH
test with prior priming can demonstrate that low or absent LH responses to a single dose of GnRH in hypothalamic disorders can be augmented to give normal LH levels, whereas priming has no effect in pituitary disorders.
The clomiphene
test is based on the observation that an increase in FSH and LH occurs after clomiphene administration. Although the mechanism of action of clomiphene is not absolutely clear, most evidence indicates that it interferes at a hypothalamic level with steroid feedback inhibition of gonadotropin secretion. Since an intact pituitary is required for normal LH and FSH secretion, adult patients with either hypothalamic or pituitary defects will demonstrate an impaired response to clomiphene.
Patients with severe germinal-epithelial damage without concomitant loss of androgen function may show modest isolated elevation of serum FSH levels. Such an isolated increase in FSH in patients with azoospermia or severe oligospermia is believed to be due to a decrease in the production of inhibin from the germinal epithelium.
In rare instances, phenotypic male patients with clinical evidence of under-virilization may have normal, high-normal, or elevated serum testosterone levels. Such patients have a partial peripheral defect in testosterone responsiveness. Serum LH levels in such patients may be either elevated or normal, depending on whether hypothalamic response to testosterone is also impaired.
C. Endocrine
In addition to serum testosterone, LH, and FSH, serum prolactin levels should be measured in these patients. However, in men with pituitary tumors, serum prolactin concentration may be normal. Most men with prolactin-secreting tumors present with macroadenomas (greater than 1 cm). Prolactin levels in these patients are usually higher than 200 ng/ml. Hypogonadotropism, coupled with low androgen levels, is commonly found in these patients. A hypothalamic or pituitary lesion should be ruled out by computed tomography (CT) scan or magnetic resonance imaging (MRI). Impaired visual fields or severe headaches suggest the presence of a central nervous system tumor. However, mild prolactin elevation is more frequent in infertile patients. Evaluation of the central nervous system often fails to identify a tumor. These patients with idiopathic hyperprolactinemia have normal gonadotropin and testosterone levels. Indirect evidence has suggested that prolactin may have a direct detrimental effect on the testes.
Estrogen levels should be measured as estrogen excess may be endogenous or exogenous. Patients with estrogen excess may present with bilateral gynecomastia, impotence, and atrophic testes. Normal levels of plasma FSH, LH, and testosterone are usually found in cases of elevated levels of plasma estrogens. Thyroid function studies do not need to be determined unless there is clinical evidence of thyroid abnormalities. Finally, buccal smears and chromosomal analyses (karyotype) may be indicated in some patients with a history or physical findings suggestive of a genetic basis.
D. Testicular Biopsy
The testicular biopsy is performed primarily for azoospermic patients with normal-sized testes to differentiate ductal obstruction from abnormal spermatogenesis. In cases of symmetric testes, unilateral biopsies should be performed. However, in patients with asymmetric testes in which the physician suspects different lesions (such as primary testicular failure on one side and ductal obstruction on the other), bilateral biopsies or biopsy of the more normal testis may be performed. In cases of bilaterally atrophic testes associated with markedly elevated FSH values, testicular specimens usually demonstrate an absence of germ cells. Biopsies in these cases are usually unnecessary but at times may be performed to give the couple a definitive diagnosis and avoid unnecessary treatments. Similarly, biopsy is not indicated in most cases of oligospermia, since the results will not alter therapy. A biopsy very occasionally is performed to rule out partial ductal obstruction in patients with severe oligospermia, normal-sized testes, and normal FSH values. Partial ductal obstruction is suggested in these cases if the biopsy specimen demonstrates normal spermatogenesis. A testicular biopsy may be performed under local or general anesthesia. The examination should evaluate the size and number of seminiferous tubules, the thickness of the tubule basement membrane, the relative number and types of germ cells within the seminiferous tubules, the degree of fibrosis in the interstitium, and the presence and condition of Leydig cells. The testicular biopsy will determine hypospermatogenesis, maturation arrest, and general aplasia (Sertoli cell only syndrome).