In 1 to 2 percent of cases, male infertility is the result of problems in an area of the brain (the hypothalamus) and or in a small gland situated just below the base of the brain known as the pituitary gland. The pituitary gland produces two gonadotropin hormones: The first is FSH that controls production of sperm (spermatogenesis) by Sertoli cells in the testes and the second, luteinizing hormone (LH) that controls male hormone production (predominantly testosterone) by testicular Leydig cells. In the woman, these same gonadotropin hormones control ovarian production of estrogen, progesterone and male hormones such as androstenedione and testosterone. A sustained reduction in FSH production, is capable of resulting in reduced sperm count, motility and morphology while a sustained reduction in LH can result in low blood testosterone levels with associated Low-Testosterone Syndrome which includes but is not limited to mood changes, reduced energy level and libido, redistribution of muscle mass, breast development (gynecomastia) and progressive demasculinization. If judiciously and selectively administered to qualifying patients, the use of oral treatment with clomiphene or the parenteral administration of gonadotropins for 3-6 months (sometimes a longer duration of therapy is needed) will often successfully reverse the male infertility in such cases. While a woman’s ovulatory cycle usually lasts about 28 days, in the man, there exists a cyclical production of sperm over a period of about 100 days. This is why any assessment of the effect of treatment administered to the man to improve sperm production requires waiting for a time period of at least 100 days. There are two basic approaches to the hormonal enhancement of sperm production:

1. Clomiphene Citrate: Clomiphene citrate is a hormone which, through its central action on the brain, stimulates the pituitary gland to produce natural FSH in large amounts. The FSH, in turn, as mentioned above, stimulates spermatogenesis. The treatment is very simple, and involves the administration of 1/2 tablet (25 mg.) of clomiphene citrate every alternate 1-2 days perform a baseline semen analysis, FSH, LH, and male hormone measurements immediately, and then to serially repeat all of these tests intermittently throughout the treatment with Clomiphene. The final assessment of response can only be made approximately 90 days after initiating therapy. This administration of clomiphene is essentially harmless to the man. He may experience some minor side effects such as spots in front of the eyes, dryness of the mouth, headaches, slight changes in mood, and rarely, hot flashes. These side effects are all reversible upon discontinuation of therapy. This having been said, it is best to confine treatment to a period of 6 months, but certainly not for longer than 12 months. Thus in cases where a significant improvement occurs in sperm parameters, it is often advisable to collect the treated man’s sperm and cryobank it for future use, thereby mitigating the need for prolonged or repeated bouts of treatment. Since clomiphene increases both FSH and LH production by the pituitary, the increase in LH ill reciprocally increase testicular testosterone output and thereby reverse symptoms associated with low testosterone syndrome.
2. Letrozole: Like clomiphene, Letrozole is also an oral agent that causes FSH and LH to be released. The mechanism of action by which it does so is similar to clomiphene. The FSH then promotes Sertoli cell activity and spermatogenesis. Thus Letrozole can supplant clomiphene for promoting spermatogenesis. The duration of treatment is the same as for clomiphene.
3. Gonadotropin Therapy: In cases where clomiphene/letrozole therapy fails or in certain situations where such treatment does not stimulate the pituitary gland, FSH can be administered directly by injection, alone, or combined with hCG. hCG functions similar to LH to further enhance the production of male hormones in cases where demasculinization is associated with reduced sperm production. These hormones must be administered 3 times per week, for a period of about 90 days, whereupon hormonal and sperm assessments are repeated to determine the effect. Such treatment is relatively harmless and side effects are minor and reversible upon discontinuation of therapy.
4. Treatment of Other Endocrine Conditions: Thyroid hormone is given in cases of hypothyroidism. Diabetes is treated with hypoglycemic agents such as Metformin or insulin, and elevated blood prolactin levels can be lowered with bromocriptine (Paroled/Dostinex) which will often effect an improvement in sperm quality.
5. Testosterone Therapy: Some doctors prescribe testosterone preparations to men with compromised sperm production and/or function. Such treatment is to be decried since it will invariably make matters worse. The reason for this is that testosterone suppresses pituitary FSH production and thus reduces sperm production and quality. It is, of course, not practical or safe to administer potent medications such as clomiphene, FSH, LH, or hCG for an indefinite period of time. Thus, in cases where the patient responds favorably to such treatment it is advisable to collect and cryostore a number of masturbation specimens for future use, so that there will always be relatively good quality sperm on hand when the fertility treatment is discontinued

Adjunct treatments:  

• Antioxidants and Vitamins: There is evidence (although anecdotal) that for males with unexplained infertility, dietary supplementation with commercially available products such as ProXeed or Proceptin (that contain a combination of non-invasive vitamins and vitamin-like agents, such as L-carnitine, acetyl carnitine, Co-enzyme Q, vitamins C and E, and fructose, citric acid, selenium and zinc), might improve sperm quality.

• Treatment of Varicocele (a collection of dilated veins in the scrotum): There are many men who have varicoceles but do not have a fertility problem. Sometimes however, sperm quality can be compromised and when that happens, occluding dilated blood vessels either by surgically tying off one or both spermatic veins (varicocelectomy), or by interventional radiological obliteration of the spermatic vein(s) can be curative

• Intrauterine insemination (IUI) might be of benefit in the treatment of “mild” male infertility, there is no conclusive evidence that it will improve pregnancy potential in cases of moderate or severe male infertility (regardless of whether the woman receives fertility drugs or not).

• Intracytoplasmic Sperm Injection (ICSI):ICSI is a procedure where fertilization is achieved through the direct injection of a single sperm into the substance of each mature egg. Until the introduction ICSI in the mid-90s, IVF was relatively unsuccessful in achieving pregnancies in cases of male infertility. ICSI changed all that. Now, IVF/ICSI is the treatment of choice for refractory, moderate or severe male infertility.

• Testicular Sperm Aspiration (TESA): The TESA process involves the introduction of a thin needle directly into the testicle(s), to aspirate sperm or directly into sperm bearing tissue and then taking hair-thin biopsy specimens for processing. Sperm so obtained is treated in the laboratory whereupon each egg is injected with a single sperm using ICSI. TESA is a procedure performed when there are no sperm in the ejaculate (azoospermia) or when the man is unable to ejaculate at all. In most cases it is done when the sperm ducts are blocked or absent but the testicles are still fully capable of producing sperm. It can also be used in non-obstructive cases of male infertility where the failure to ejaculate live sperm is due to partial testicular failure. In cases of obstructive azoospermia the fertilization rate is about 50-60% and the anticipated birth rate is similar to that achieved in the absence of male factor and no different to that seen in conventional IVF conducted on in women of comparable age. When it comes to non-obstructive azoospermia the results are much poorer. TESA is a simple, relatively low-cost, safe, and virtually pain-free procedure. Most men can literally take off a few hours for the procedure and return to normal activity immediately thereafter. In about 80% of cases, TESA procedures are done in cases of men who had a previous vasectomy. The introduction of TESA has in fact made surgical reconnection of sperm ducts (i.e. vasectomy reversal) obsolete. This is especially so because TESA is far more successful in initiating a pregnancy than is surgical reversal and because it achieves the desired end point result while leaving the vasectomy intact for future contraception.