Thursday, April 25, 2024

Male Infertility

Diagnosis and Management

What Causes Infertility in Men?

One common mistake when it comes to male infertility is the confusion between aspermia and azoospermia. Aspermia refers to a condition where there is no ejaculate during intercourse or via masturbation. This means there is no fluid coming out of the penis during intercourse. This is not to be confused with azoospermia, which is a condition where there is fluid coming out of the penis during ejaculation but there are no viable sperm cells that can initiate pregnancy.

In some cases, there might be live and viable sperm cells in the ejaculate, but they may not possess the necessary characteristics to allow for natural conception to occur, requiring additional treatments. In this section, we will discuss all forms of male infertility and mention available management options currently in use and on the horizon.

Male factor infertility can be broadly categorized in two main groups:

1- Problems making sperm, which means producing too few sperm cells or none at all. This category is further divided into the categories of obstructive azoospermia and non-obstructive azoospermia.

Obstructive azoospermia is a condition where there exists sperm production, but the channels through which the sperm is carried outside to the ejaculate are blocked/damaged or restricted for a variety of reasons. In these cases, surgical sperm extraction methods often prove successful and men with obstructive azoospermia can often have their own biological children through the use of IVF/ICSI treatment. Men who have had vasectomies also belong to this group. While they have an active production of sperm cells, the tubes which are responsible for ejecting the sperm cells out into the ejaculate have been surgically blocked.

In summary, any problem which blocks the exit of sperm cells through the penile opening despite having active sperm production is known as obstructive azoospermia. Management of obstructive azoospermia may vary from case to case and the surgical method may differ depending on where the obstruction is.

Non-obstructive azoospermia refers to problems that have to do with the production or maturation of sperm cells. In these cases, we are mostly talking about congenital disorders, genetic problems or environmental factors that cause sperm production or maturation issues. Surgical sperm retrieval can sometimes yield success when the problem is at the later stages of sperm maturation where there is active sperm production but the maturation of sperm cells stop at a point before the cells gain their capability to move outside the male genitalia. However, in most cases of non-obstructive azoospermia, the problem is lack of early production or maturation, therefore, surgical sperm extraction is not likely to provide a desired outcome. At North Cyprus IVF Center, we have been offering a “Therapeutic Stem Cell Infusion” since early 2016. This is still a highly experimental and clinical study which so far offers very promising results. Stem cell therapy involves obtaining the patient’s own stem cells and injecting them into the possible defective sites in the testes in order to stimulate cellular regeneration and differentiation into sperm cells. If having your own biological child is important and you would like to try possible medical methods before moving onto seeking “IVF treatment with Donor Sperm“, this study may be a suitable option. Please contact us to see if you qualify for this study.

2- Problems with the sperm’s ability to reach the egg and fertilize it, which could be the case where abnormal sperm shape or structure may prevent it from moving correctly. Sometimes a man is born with the problems that affect his sperm’s reproductive abilities. Other times problems start later in life due to illness or injury. The number and quality of a man’s sperm can also be affected by his overall health and lifestyle. Some things that may reduce sperm number and/or quality include:

– Alcohol
– Drugs, including anabolic steroids used in muscle training
– Environmental toxins, including pesticides and lead
– Cigarette smoking
– Health problems such as recent febrile illness or congenital/genetic problems
– Medicines
– Radiation treatment and chemotherapy for cancer, or exposure to radiation at work.
– Age

In order to understand the cause and severity of the problem, a semen analysis is very important. A semen analysis will indicate very important parameters such as sperm volume and sperm count which will in turn, tell us whether there are enough sperm cells in the ejaculate to fertilize eggs. However, having enough sperm cells is not a sufficient condition. These sperm cells will also need to have a certain level of motility, which indicates the sperm’s ability to move freely and reach the eggs for fertilization to occur in the female reproductive tract. Similarly, sperm morphology is another very important factor which shows what percent of the sperm cells have a normal structure. If a large portion of the sperm cells show abnormality, it may suggest more fundamental DNA related genetic problems with the sperm cells, which may require more advanced sperm testing to screen for DNA fragmentation issues. Another parameter is the white blood cells in the ejaculate. The number of white blood cells in the sperm sample often suggest a urinary tract infection, which may impair the sperm cells’ ability to achieve fertilization. In such cases, an antibiotic treatment may be initiated to clear the infection before pregnancy can be achieved either naturally or artificially. pH, on the other hand, is another parameter of the sperm sample which may affect reproductive function. It is important that the sperm cells maintain a relatively alkaline pH in order to survive the hostile acidic conditions on the female reproductive tract. If the sperm sample is less alkaline than it should be, it may not be able to successfully complete its journey to the fallopian tubes where it is supposed to meet the egg.

As you can see, there are many considerations when it comes to reproductive qualities of sperm cells. Therefore, a careful investigation needs to be made with respect to all these considerations. According to World Health Organization’s published standards for viability of sperm in 2010, the following parameters have been established for normal sperm:

Volume: > 2.0 ml
Concentration: >20 million/ml
Motility: > 50%
Morphology: >30% with normal morphology
White Blood Cells (Round Cells): < 1 million/ml
pH: 7.2-7.8

You should keep in mind that these values have been established for natural conception. During infertility treatments such as IUI or IVF, we can work with much lower values as we bypass some or most of the physiological processes, depending on type of treatment used.

Please make sure that you allow for 2-5 days of abstinence before you provide your sperm sample for analysis for most accurate results. This is also important prior to providing a sample before a fertility treatment. In any case, if you are required to provide a sperm sample, it is best to have an abstinence period of 2 to 5 days unless otherwise specified. Also, keep in mind that the numbers above have been established as reference values for natural conception. Therefore, if your sperm analysis shows lower numbers that the parameters set forth by WHO criteria, this does not mean that you will not be able to have child. It simply means that conceiving naturally can be very difficult.

For more information on what the numbers on a semen analysis mean, and how to categorize a sperm sample based on its parameters, please refer to our “Infertility Testing” section. In this section, you will find information about sperm classifications based on various semen parameters. In some cases, even if sperm production is not sufficient enough to produce sperm through ejaculation (as in the case of obstructive azoospermia mentioned above), minor surgical procedures like TESA, PESA and MESA can be used to retrieve sperm. These are relatively easy, quick and relatively painless procedures. If live sperm cells are found during these procedures, fertilization may be possible. However, it should be kept in mind that fertilization rates with sperm cells obtained surgically will be lower than sperm cells found in the ejaculate as surgically obtained sperm cells tend to be less mature compared to those found in the ejaculate.

Sometimes, patients with azoospermia do not necessarily know which type of azoospermia they suffer from and it might be more cost and time effective to attempt surgical sperm extraction rather than undergoing extensive and expensive testing. Normally, we recommend the surgical sperm extraction to be performed at the same time as the female partner’s egg retrieval so that the freshly obtained sperm cells can be used with the freshly obtained egg cells in an IVF cycle as a way of improving odds of success. When the outcome of the surgical sperm extraction cannot be anticipated, patients do not feel comfortable initiating their IVF cycle. What if the IVF cycle is started, the female patient underwent egg retrieval but there is no sperm to fertilize the eggs? One option is freezing the sperm sample obtained via surgical extraction to avoid having to cancel the IVF cycle. However, since the quality and maturation levels of surgically retrieved sperm cells will be lower compared to standard sperm cells, freezing surgically retrieved/extracted sperm is often not recommended. This poses a difficult dilemma and there is no right decision in such a case. What we often recommend is to plan the IVF cycle as if surgical sperm extraction is going to be successful. If successful, the IVF cycle can be completed. If not, then the patients can be given two options:

1- Freeze the eggs obtained from the female patient so that they can be used in the future (either with donor sperm, or possibly the male patient may like to try stem cell therapy and reattempt treatment with his own sperm cells- see the section below for more information about stem cell therapy at North Cyprus IVF Clinic)

2- Complete the IVF cycle using donor sperm. Please visit the relevant page for more information about IVF treatment using donor sperm. Stem cell therapy for non-obstructive azoospermia

Stem Cell Therapy : Can Azoospermia Be Treated?


Azoospermia can be divided into two categories: Obstructive azoospermia and Non-obstructive azoospermia. When there is an obstruction (as in the case of obstructive azoospermia), sperm cells are not able to come out into the ejaculate even though there is active sperm production. In such cases, surgical sperm retrieval methods are employed and sperm cells are extracted surgically. However, when azoospermia is non-obstructive, there is a sperm production/maturation problem. In non-obstructive azoospermia, surgical sperm extraction methods are not likely to yield desired outcomes. The other two alternatives are: Stem cell therapy or IVF treatment using a sperm donor.

If the patient is not yet ready to consider IVF treatment using donor sperm, an assessment cane be made whether he qualifies for our stem cell therapy. In our stem cell study, we use mesenchymal stem cells (from the patient’s own fat tissue). Fat tissue is extracted in a surgical procedure very much like liposuction. Once the fat tissue is extracted, further processing and laboratory work is in order to isoleate the mesenchymal stem cells. When stem cells are isolated, they are mixed with platelet rich plasma (prp), which is also obtained from the patient’s own blood sample. A mixture of mesenchymal stem cells and platelet rich plasma are directly injected into the testicles at four different locations, which are important for initiation and maturation of spermatogenesis.

You will be expected to stay in Cyprus for approximately 3-4 days for the stem cell therapy. This will give us enough time to run the necessary tests, obtain your blood sample, perform liposuction for the fat tissue and process all of them together for the injection. After injection with stem cells, there is a three month waiting period to observe the effect. Spermatogenesis (production and maturation of sperm cells) takes about 65 to 70 days. Therefore, anything that is likely to affect sperm cells will have an effect on the sperm sample after this period. If the semen analysis performed three months after the stem cell injection, an IVF treatment can be planned accordingly.

Please visit the relevant page on our website for more information on stem cell therapy for non-obstructive azoospermia.


Male Infertility From a Scholarly Perspective


The Role of Androgenic Anabolic Steroid Abuse on Male Infertility
By Ahmet Ozyigit

Case Study
A muscular 28 year old man attends for infertility investigations with his 27 year old partner. They have been attempting to conceive (unsuccessfully) for 3 years. All investigations of the female partner indicate that she has normal ovarian function, patent fallopian tubes and a normal endocrine profile. Initial investigations of the male partner conducted at the clinic two years before indicated that he was severely oligozoospermic or even azoospermic with < 10,000 sperm per ml of which > 90 % were of abnormal morphology by WHO (1999) criteria. The most recent follow up investigation of the male partner conducted in 2011, indicate that he has a reduced testicular volume (1.5mls) and an abnormally raised level of FSH. ICSI using a treatment plan that may include testicular sperm aspiration (TESA) is being considered. Given his muscularity, the consultant asks the man if he has been using steroids in the past twelve months. The man admits that he was taking ‘something’ provided by a friend at the gym but stopped taking ‘it’ six months ago and has no plans to restart. He then refuses to answer any more questions.

Androgenic anabolic steroid abuse may produce unwanted and sometimes irreversible changes in various organs and systems including the cardiovascular, metabolic and reproductive systems(1). Even though there exists limited literature on the precise relationship between steroid abuse and infertility, existing literature sheds some light on the issue by pointing to a number of key steroid induced common characteristics of abuse victims. The dose and time frame of steroid abuse are likely to determine the extent of the effect on reproductive function. A number of studies reveal that after cessation of steroid use, sperm characteristics may in fact return to normal levels(2,3,6) while in heavy AAS users, serum testosterone levels may not return back to normal levels(1).

One of the main problems when approaching patients with androgenic anabolic steroid (AAS) abuse is that they tend to be reluctant in providing a detailed account of their history of abuse, which makes it difficult to make an effective assessment of the potential impact on reproductive function. However, before considering more invasive treatment options, further investigation is in order.

Current Case Study Analyzed
The current case presents us with a couple with male factor infertility. The couple’s consultant at the fertility clinic notices the muscularity of the male partner and asks them about possible steroid use, which the male partner admits to using. Given the hesitance of the patient in answering any further questions regarding his substance abuse, it may be assumed that his account of the history of abuse may not be accurate. Even though the patient claims to have stopped using AAS six months prior to their consultation, a 1992 study provides evidence that half of the muscle gains through long term AAS use would be lost within two months of cessation, and would further be lost in the following months(4). If the patient’s muscularity is very well noticeable, it may be that the patient is still abusing steroids or has been until recently. In such a scenario, both the testicular volume, pituitary gonadotrophins and the sperm count are known to exhibit deviations from normal levels. Anabolic steroids are expected to suppress gonadotrophin secretion through negative feedback, which would, in turn, result in decreased serum gonadotrophins, decreased serum testosterone levels, testicular atrophy and impaired sperm, which is evidenced in most case studies investigating into the relationship between AAS abuse and male infertility(3)

Considering the likelihood of the male patient’s reluctance in telling the truth about his substance abuse, the first step in treatment would be psychological counseling where the temporary and permanent effects of long term AAS abuse would be thoroughly explained with respect to their impact on male infertility as well as other systems. Counseling would potentially convince the patient to cease AAS abuse permanently if he is seriously considering parenting a child.

A 1997 study analyzes four cases of AAS abuse and their follow up work. All four cases show low levels of pituitary gonadotrophins when first admitted to study along with findings of azoospermia and lowered testicular volume. In all four cases, patients are asked to cease using steroids and the same tests are administered after 12 and 18 months of cessation. In all four cases, improvements in pituitary gonadotrophin levels and total sperm count have been reported. Three out of four cases report a natural pregnancy in the following years(5). A 1995 study uses a 34 year old male patient with AAS abuse whose semen analysis indicates total absence of sperm during his substance use. The patient is give r-hFSH along with hCG for the duration of six months resulting in 13 million/ml sperm count and hormone levels within normal range(6). Both studies provide evidence for the reversible aspect of AAS damage.

A 2001 study by Torres-Calleja et al indicates that AAS abuse can potentially impair the percentage of morphologically normal sperm in some abuse victims(8). The resulting lower sperm count can be defined as AAS-induced hypogonadotrophic hypogonadism with associated azoospermia or oligozoospermia(2,8,15). This is in line with the current patient’s experience. However, a number of things set our patients apart from these case studies and from the findings of various literature in the field. First of all, the testicular volume of the male partner is significantly reduced, even more than other cases studied. For this end, the patient may need to undergo varicocele and epididymitis work for a possible explanation of the shrunken testes(13). Secondly, unlike the several cases presented in literature, the patient has an elevated serum FSH level, which is the opposite of what other cases have documented. However, it has been reported that with decreased testicular volume, sperm count tends to decrease and the FSH tends to increase(14). High levels of FSH in men can also point to developmental defects or testicular failure, which strengthens the possibility of chromosomal abnormality such as Klinefelters syndrome or damaged germinal epithelium. It has also been reported that severe oligozoospermic men whose sperm concentration is lower than 5 million/ml, serum FSH concentration tends to be higher than normal range(8). In order to further investigate into the possible scenarios with the current case study, a complete hormonal profile of the patient needs to be identified given that his serum testosterone and estradiol levels have not been measured. A karyotype analysis would be necessary in order to eliminate the suspicion of Klinefelters syndrome (KFS). One study has found that all its subjects with KFS had elevated plasma FSH levels while approximately one-fourth of KFS patients had Y chromosome microdeletions(9). Another recent study has found that regardless of existence of microdeletions, serum FSH level is elevated in men with severely impaired germ cell function(10). Although not every men with elevated FSH level is to have a Y chromosome microdeletion, for the sake of identification of the most appropriate method of treatment, it can be argued that diagnostic tests should be performed on men with severe oligozoospermia(11).

Given the young ages of the patients and given that the female partner’s endocrine profile and ovarian function are within normal parameters, we would argue in favor of further testing on male partner in subsequent months to observe his pituitary gonadotrophin levels and sperm count as evidence suggests that AAS damage can be reversible unless the patient has been heavily abusing. Having the subject cease AAS use and retesting in six months would be the most appropriate course of action unless his other tests mentioned previously indicate another problem. ICSI and TESA procedures would exert unnecessary emotional and financial burden as well as unnecessary medication use and invasive treatment protocols at this point.

1. Karila, T (2003) Adverse effects of anabolic androgenic steroids on the cardiovascular, metabolic and reproductive systems of anabolic substance abusers. Dissertation Medical Faculty, University of Helsinki.
2. Schurmeyer, T., Knuth, U.A., Belkien, E. et al. (1984) Reversible azoospermia induced by the anabolic steroid 19-nortestosterone. Lancet, I: 417–420.
3. Holma, P.K. (1977) Effects of an anabolic steroid (metandienone) on spermatogenesis. Contraception, 15, 151.
4. Forbes, G.B., et al. (1992). Sequence of changes in body composition induced by testosterone and reversal of changes after the drug is stopped. JAMA. 267:397-399.
5. Gazvani MR, Buckett W, Luckas MJ, Aird IA, Hipkin LJ, Lewis-Jones DI. (1997). Conservative management of azoospermia following steroid abuse. Hum Reprod, 12: 1706–8
6. Moretti, E. et al. (2007) Structural Sperm and Aneuploidies Studies in a Case of Spermatogenesis Recovery after the Use of Androgenic Anabolic Steroids,” J Assist Reprod Genet, 24:195-198.
7. Simoni M, Weinbauer GF, Gromoll J, Nieschlag E. (1999). Role of FSH in male gonadal function. Ann Endocrinol. 60: 102-6.
8. Martin-du-Pan, R.C. and Bischof, P. (1995) Increased follicle stimulating hormone in infertile men: is increased plasma FSH always due to damage epithelium? Hum. Reprod., 10, 1940–1945. 9. Mitra A, Dada R, Kumar R, Gupta NP, Kucheria K, Gupta SK.  (2006). Y chromosome microdeletions in azoospermic patients with Klinefelter’s syndrome. Asian J Androl. 8(1):81-88.
10. Kumar R, Dada R, Gupta NP, Kucheria K. (2006) Serum FSH levels and testicular histology in infertile men with non obstructive azoospermia and Y chromosome microdeletions. Ind J Urol. 22 : 332-6.
11. Foresta C, Moro E, Ferlin A (2001). Y chromosome microdeletions and alterations of spermatogenesis. Endocr Rev, 22:226-239
12. J Pundir, D K Chui, D W Lipscomb. (2008) Anabolic steroids and male subfertility. Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology. 28(8):810-811.
13. Sah P (1998). “Role of low-dose estrogen–testosterone combination therapy in men with oligospermia”. Fertility and Sterility 70 (4): 780–781
14. Bujan L, Mieusset R, Mansat A, Moatti JP, Mondinat C, Pontonnier F (1989) Testicular size in infertile men: relationship to semen characteristics and hormonal blood levels. Br J Urol 64(6), 632-63.
15. Penna, S., & Hernández, G. (2010) 75 Effects of Androgenic Anabolic Steroids (AAS) on reproductive function and lipid metabolism in Venezuelan bodybuilders. Reproductive BioMedicine Online 20:3; 30-31