Specific Therapy

Specific therapy seeks to reverse known pathophysiologic effects to improve fertility. For the most part, they are cost-effective treatments.

A. Pyospermia
The presence of elevated numbers of leukocytes in semen is termed pyospermia and has been associated with (1) subclinical genital tract infection, (2) elevated reactive oxygen species, and (3) poor sperm function and infertility. Sperm are highly susceptible to the effects of oxidative stress induced by leukocytes or infection because they possess little cytoplasm and therefore little antioxidant activity. The treatment of pyospermia is controversial in the absence of overt bacteriologic infection. It is important to evaluate the patient for sexually transmitted diseases, penile discharge, prostatitis, or epididymitis. An expressed prostatic secretion is examined for leukocytes, and urethral cultures are obtained for chlamydia and mycoplasma. The use of broad-spectrum antibiotics such as doxycycline and trimethoprim-sulfamethoxazole has been shown to reduce seminal leukocyte concentrations, improve sperm function, and increase conception. Generally, the female partner is also treated.

In pyospermia with a documented prostatic source (> 20 leukocytes per high-power field in expressed prostatic secretion), frequent ejaculation (more than every 3 days) and doxycycline may result in a more durable resolution of pyospermia (55% of treated men) than either treatment alone (5-17% resolution) (Branigan and Muller, 1994). There is increasing evidence that the antioxidant vitamins (A, C, and E) as well as glutathione and other antioxidants may help scavenge reactive oxygen species within semen and improve sperm motility in pyospermic men (Baker et al, 1996).

B. Coital Therapy
Simple counseling on issues of coital timing, frequency, and gonadotoxin avoidance can improve fertility. It is important to review the essentials of basal body temperature charting or home kits that detect the LH surge in the urine immediately (< 24 h) before ovulation. Since sperm reside in the cervical mucus for 48 h and are released continuously, it is not necessary that coitus and ovulation occur at the exact same time, a fact that can reduce the stress associated with infertility. Coitus every other day around ovulation is the best recommendation. Coital lubricants should be avoided if possible. If necessary, vegetable oils, olive oil, and petroleum jelly are the safest.

Retrograde ejaculation results from a failure of the bladder neck to close during ejaculation. Diagnosed by the finding of sperm within the postejaculate bladder urine, it can be treated with a trial of sympathomimetic medications. Approximately 30% of men will respond to treatment with some degree of antegrade ejaculation. Begun several days before ejaculation, imipramine (25-50 mg twice a day), Nasal-D (twice a day), Ornade (twice a day), or Sudafed Plus (60 mg 4 times a day) have all been used with success. The side effects associated with these medications usually limit the efficacy of this therapy. For medication failure, sperm harvesting techniques can be used with IUI to achieve a pregnancy. Premature ejaculation occurs when men ejaculate before the partner is ready. Sexual counseling combined with tricyclic antidepressants, Prozac, or other serotoninergic uptake inhibitors can be very effective.

C. Immunologic Infertility
Antisperm antibodies are a complex problem underlying male infertility. Available treatment options include corticosteroid suppression (

Table 42-17), sperm washing, IUI, IVF, and ICSI. Steroid suppression is based on the concept that an overactive immune system can be weakened to reduce antibodies on sperm. Intrauterine insemination places more sperm nearer the ovulated egg to optimize the sperm-egg environment. Pregnancy rates with this technique generally fall in the 10-15% range. Assisted reproductive technology with IVF and ICSI is very effective in this scenario. In general, if > 50% of sperm are bound with antibodies, then treatment should be offered. In addition, head-directed or midpiece-directed sperm antibodies appear more relevant than tail-directed antibodies. Since the presence of ASA is associated with obstruction in the genital tract, these lesions should be sought and corrected. There is renewed interest in the causes and possible treatments of this interesting problem, as several animal models exist that mimic the condition in humans.

D. Medical Therapy
Effective hormonal therapy can be offered to patients with diseases that predispose to infertility. Hormone therapy is effective when it is used as specific and not empiric treatment. Specific replacement therapy seeks to reverse well-established, pathophysiologic states. Empiric treatments attempt to overcome pathologic conditions that are ill-defined or have no proven treatment.

1. Hyperprolactinemia - Normal levels of prolactin in men help sustain high intratesticular testosterone levels and affect the growth and secretions of the accessory sex glands. Hyperprolactinemia abolishes gonadotropin pulsatility by interfering with episodic GnRH release. Visible lesions are generally treated with transphenoidal surgery, and nonvisible lesions are treated with bromocriptine, 5-10 mg daily, to restore normal pituitary balance.

2. Hypothyroidism - Both elevated and depressed levels of thyroid hormone alter spermatogenesis. States of thyroid dysfunction account for 0.5% of infertility cases but are very treatable. Replacement or removal of low or excessive thyroid hormone is effective treatment for infertility. As these diseases are clinically very evident, routine thyroid screening is not recommended for infertility patients.

3. Congenital adrenal hyperplasia - Most commonly, the 21-hydroxylase enzyme is deficient, and defective cortisol production results. The testes fail to mature because of gonadotropin inhibition due to excessive androgens. The diagnosis is rare and classically presents as precocious puberty; careful laboratory evaluation is essential. In both sexes, the condition and the infertility associated with it are treated with corticosteroids.

4. Testosterone excess/deficiency - Patients with Kallmann syndrome lack GnRH that stimulates normal pituitary function. Infertility associated with this condition can be very effectively treated with hCG, 1000-2000 U 3 times weekly, and recombinant FSH 75 U twice weekly, to replace LH and FSH. It is also possible to give GnRH replacement in a pulsatile manner, 25-50 ng/kg every 2 h, by a portable infusion pump. Pituitary diseases associated with testis failure are not amenable to GnRH treatment but respond well to hCG and human menopausal gonadotropin therapy. Individuals with fertile eunuch syndrome or isolated LH deficiency respond well to hCG therapy alone. One can expect to find sperm in the ejaculate beginning 9-12 months after therapy is started. Since injectable drug regimens are long, complex, and costly, it is good practice for men to cryopreserve motile sperm once achieved in the ejaculate. Anabolic steroids are a common and underdiagnosed reason for testicular failure in which excess exogenous testosterone and metabolites depress the pituitary-gonadal axis and spermatogenesis. Initially, the patient should discontinue the offending hormones to allow the return of normal homeostatic balance. Second-line therapy generally consists of “jump-starting” the testis with hCG and FSH as with Kallmann syndrome.