Male Infertility: Enhancing Sperm Production
It can only be speculated as to why so much less is known about the causes and treatment of male infertility than female infertility. Perhaps it is at least in part due to the fact that men are proud and arrogant creatures by nature and are in a state of denial. Since male infertility accounts for approximately 40% of all cases of infertility, it is appropriate that we focus on this important problem.
So, what are the more common approaches to treating male factor infertility?
First let’s look at the causes:
- Anatomical Factors such as (i) collection of venous blood vessels around the testicles known as varicocele; (ii) developmental absence of the sperm ducts; (iii). previous vasectomy and, (iv) prior inflammation, most commonly resulting from sexually transmitted diseases such as Gonorrhea and Chlamydia.
- Testicular Failure due to mal-descent of the testicles prior to birth, testicular infections (e.g. mumps); mal-development of the testes, prior exposure to radiation and chemotherapy, and over-exposure to environmental toxins and heavy metals.
Anatomical defects can often be reversed surgically. However when it comes to testicular failure there is usually very little that can be one to reverse the problem.
In cases of obstructive azoospermia (absence of sperm in the ejaculate), which is most commonly seen following vasectomy, surgical reconnection can sometimes restore patency. However, even following surgical reestablishment of normal sperm ejaculation, the quality of the sperm will not necessarily be adequate to propagate a pregnancy. In fact, in many cases where a previous vasectomy or traumatic injury occurred more than five years prior, the man will produce antibodies to his own sperm. These antibodies incapacitate the sperm, thereby precluding fertilization. Testicular Sperm Extraction (TESE-see below) combined with Intracytoplasmic Sperm Injection (ICSI-see below) has become the treatment of choice such cases and the results are very good indeed.
The pituitary gland produces two important hormones that play a role in testicular function. The first is follicle-stimulating hormone (FSH), which stimulates Sertoli cells in the testicles to produce sperm. The second is luteinizing hormone (LH) which stimulates testicular Leydig cells to produce male hormones (predominantly testosterone). Reduced FSH production will result in a low sperm count, poor sperm motility and abnormal sperm morphology, collectively referred to as “oligozoospermia.” With a few notable exceptions, a reduction in FSH is not usually accompanied by a reduction in LH. Accordingly, men with poor sperm production due to a low FSH usually will have sufficient LH to insure adequate male hormone production and so avoid demasculinization.
In man, sperm production (spermatogenesis) is cyclical, taking place over a period of approximately 90 days. It follows that any treatment aimed at enhancing sperm production requires a period of approximately 3 months. Since the enhancement of testicular function must of necessity be mediated through FSH and LH it follows that in order to assess response to testicular stimulatory drugs it is necessary to get a baseline FSH, LH and male hormones produced by the testicles (i.e. testosterone, androstenedione, and dehydroepiandrosterone) as well as a semen analysis and then to re-measure these during and following the 3 month course of treatment.
Hormonal Sperm Enhancement
There are two basic approaches to the hormonal enhancement of sperm production:
- 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 day for a period of 90 days. Before treatment is initiated it is necessary to 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.
- 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.
- 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 human chorionic gonadotropin (hCG). The 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.
- Treatment of 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 bromocryptine (Parlodel) which will often effect an improvement in sperm quality.
- 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
- 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, acetylcarnitine, 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.
- Avoidance of exposure to unnecessary radiation or to dangerous chemicals.
- Avoiding tight underwear, hot baths and long bicycle rides: These are all of doubtful benefit and for all practical purposes can probably be discounted and ignored.
What about intrauterine insemination (IUI)?
While the performance of 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): The Treatment of Choice
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-90’s, 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 (TESE)
The TESE 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. TESE 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. TESE 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.
As stated, TESE is best suited to cases of obstructive azoospermia. In fact more than 80% of TESE procedures are done in cases of men who had a previous vasectomy. The introduction of TESE has in fact made surgical reconnection of sperm ducts (i.e. vasectomy reversal) obsolete. This is especially so because TESE 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.