Male Infertility: Fellowship in Reproductive Medicine

Introduction to male Infertility

The topic for today’s discussion in the Fellowship in In vitro fertilization (IVF) and Reproductive Medicine in Bangalore India is assessment of the infertile male. This is regarding male infertility. It is from the OG article. Definitely on subfertility, in subfertility, there will be some question on the male infertility, including the prevalence and all they are asking.

So, male infertility alone accounts for around 30% of couples with, in cases of sub fertile couple, it contributes around 30% patients undergoing IBO. And when you consider combined infertility, male plus female factor, almost 50% of the couple will have the combined factors, that is male plus female. So, the prevalence of isolated male factor is around 30% in the sub fertile couple and in the combined factors, it is around 50%.

So, majority of the cases are idiopathic. Generally, the causes of male infertility are divided into sperm production problems, then sperm transport problems and third is sexual dysfunction. In sperm production, we have primary testicular failure or varicocine, there may be genetic cause such as Klinefelter syndrome, Y chromosome microdulations, Y chromosome microdulations, then infection, chemotherapy, radiotherapy, etc.

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Causes of Male Infertility

Then sperm transport problems, it may be because of obstructive azoospermia, like congenital, bilateral absence of vas deferens or post-infection or vasectomy or there can be ejaculatory duct obstruction. And other is a sexual dysfunction like erectile dysfunction or interval ejaculation, etc. Then there are modifiable risk factors such as obesity, smoking, alcohol excess, anabolic steroids, heat exposure, environmental toxins, etc. So, lifestyle optimisation may improve parameters, but medical therapy has a limited impact on the semen quality as such.

Clinical Assessment of the Infertile Male

Now, when we are assessing the infertile male, what are the things which we need to do? We will take a detailed history examination and then we will go for the investigation. So, in history, we need to ask about the duration of infertility, sexual history, past infections such as mumps, architis, surgery, hernia repair, vasectomy, drug history, steroids, chemotherapy, any systemic illness that we need to go into the details.

And we should examine the testicular size, look for varicocine, vas deferens whether it is present or absent, and secondary sexual characters. So, these particular things are going to be very important, especially from part three point of view when there is a male infertility station. Okay.

So, from SBA EMQ point of view, there are no questions on this slide, but we should know this is a part of the evaluation. Then in investigations, we have a first line investigation is a semen analysis.

At least two samples. Simple, single sample is required if it is normal, but if there is abnormality, then you require a two sample.

Then hormonal profile, like FSH, LH, testosterone, and depending upon need, we may add prolactin also. And genetic testing for calotype and Y chromosome micro deletion.

If there is a azoospermia or severe oligospermia and scrotal ultrasound, if it is indicated, we need to do. Okay. So, these are the causes what we have discussed, causes of male infertility.

Classification of Male Infertility

Traditionally, we divide it into pretesticular, testicular and post testicular. Okay. Now, in pretesticular, we have hypothalamic disease such as gonadotropin deficiency like Kalman syndrome.

This Kalman syndrome also sometimes can be asked in the diagnosis. So, hypothalamic disease, then pituitary disease like pituitary insufficiency, tumours, radiation, surgery, hyperplatinemia, exogenous hormones like anabolic steroids, glucocorticoid excess, hyper or hypothyroidism. Especially, the use of anabolic steroids in the young population is quite high.

So, there may be some question, scenario-based question where the couple is infertile and the partner is young using this anabolic steroid. There is a part 3 station also, ASCII station also on this.

So, remember these particular points. In the testicular, there may be congenital causes such as chromosomal plant filter syndrome, that is 47 XXY, this also you should know. Then Y chromosome micro deletion, then Noonan syndrome.

Noonan is a counterpart of Turner syndrome. So, in males if it is a 45 XO, it is called as Noonan syndrome. That is the male counterpart of Turner syndrome. Okay. Then other, it could be cryptorchidism and acquired causes like injury, varicose, systemic renal failure, liver failure, chemotherapy, radiotherapy, testicular tumours and most of the cases can be idiopathic also.

And in post testicular, we have congenital causes such as cystic fibrosis, congenital absence of the vas deferens, then young syndrome and acquired like vasectomy, infection, etc. So, and sexual dysfunction can be the post testicular cause also like ejaculatory dysfunction or erectile dysfunction, diabetes, malaise, etc.

Spermatogenesis: Process and Clinical Relevance

Now, coming to the regulation of the spermatogenesis, generally the process takes around 74 to 90 days, around 3 months. This can be asked in the SBA. So, the total duration of the spermatogenesis is around 74 to 90 days.

So, we know well that spermatogonia, initially there are spermatogonia which divide by mitosis and form primary spermatocytes which are diploid in nature. They undergo meiosis and will form secondary spermatosis which are haploid in nature. And these will go under meiosis II will form the spermatids.

These are also haploid in nature. Then from spermatids, there will be formation of the mature spermatogena by a process called as spermiogenesis. And there will be condensation of the DNA, acrosome formation, tail development and loss of cytoplasm.

These are the changes which are happening. Clinical relevance is that the lifestyle changes will take around 3 months to reflect in the semen analysis. So, whatever the lifestyle changes or medical treatment we are giving, we need to give it for at least for 3 months.

Hormonal Regulation of Spermatogenesis

Now, let us see about the hormone profile, what happens in different conditions. We know the hormone control is by FSH, LH and testosterone. What does FSH do? FSH, the source is from anti-reputatory. It will act on the serotonin cells.

The target cells of FSH are serotonin cells and that will stimulate the spermatogonia proliferation and maturation. But it will not, the, it will, alone it will not complete the process of spermatogenesis. Okay.

So, FSH will act on serotonin cells, it will stimulate the spermatogonia proliferation and maturation. Okay. Then LH is also coming from anti-reputatory.

It will act on lytic cells and it will stimulate the testosterone production. Now, this testosterone is responsible for the final maturation. So, this testosterone which is coming from the lytic cell, so in the seminiferous tubules, it will, what is its function? It is essential for the spermatid maturation and completion of the spermatogenesis.

So, from spermatid to spermatogenesis is under the influence of testosterone in the seminiferous tubules. Okay. So, this is what is the hormonal control of the spermatogenesis.

Testicular Failure and Varicocele

Now, we will talk about the testicular failure. So, this can, this, when there is a testicular failure, there will be hypergonadotropic hypogonadism.

So, there will be increase in FSH and LH labels, testes will be small and there will be oligospermia or azoospermia.

So, generally the cause could be bilateral cryptorganism, plant filter syndrome, chemotherapy, radiotherapy, there may be systemic disease or it can be idiopathic in around 66 percent of cases. Under special conditions, there can be varicocele also. But varicocele in those patients who have normal semen parameters, they, there is a prevalence of around 11 percent.

So, even the semen analysis normal, these patients, 11 percent of male may have this varicocele. And abnormal semen population around 1 in 4, that is 25 percent patients may have varicocele.

So, the possible mechanism why this varicocele leads to abnormal semen, one is scrotal hyperthermia and it can alter the steroidogenesis also. However, the clinical significance of varicocele is controversial and that is why the NICE does not recommend varicocele surgery. That we have seen in the last, when we have discussed the NICE guideline

Obstructive Male Infertility

Then there is a post testicular, that is obstructive cases in which you will have the FSH which is normal, testicular size will be normal and on biopsy, spermatogenesis will also be normal. So, because the cause is post testicular. So, normal FSH, normal testicular size and normal spermatogenesis on biopsy.

Cause will be vasectomy or there can be infection like chlamydia, gonorrhoea, tuberculosis. There may be surgical trauma or there can be congenital absence of bilateral vas deferens and this post testicular cause accounts for around 41 percent of cases of azoospermia.

Age, Environmental and Lifestyle Factors

And what is the effect of age and spermatogenesis? Generally, after 35 years, there is a 50 percent reduction in pregnancy rate as compared to the young population of around less than 25 years and more than 50 years, there is a marked decline of this fertility rate. But advanced paternal age, generally increased adverse offspring outcomes, there is increased adverse offspring outcomes as the paternal age increases.

But the effect is not as consistent as we have seen with the maternal age. Then there are environmental and lifestyle factors, then there are occupational exposures, then there is a role of electromagnetic radiation and role of obesity.

So, in the environmental and lifestyle factors, it is mainly the testicular hyperthermia, sedentary lifestyle. There is no strong association or evidence of loose underwear improves the fertility. And occupational exposure of heavy metals such as lead, lead, mercury, pesticides, glycerol, ethers, then x-rays, heat, etc. For electromagnetic radiation, there is a dose dependent reduction in the semen parameters.

However, the clinical significance is not clear. Then in obesity, it is associated with a decrease in the SHBG levels, that is sex hormone binding globally, increase in oestrogen levels. It also leads to hormone imbalance and associated with increased erectile dysfunction and increasing global relevance to the obesity nowadays.

Drugs, Substances and Oxidative Stress

Then other drugs and substances, nowadays they are asking about the drugs, many questions are asked on the drugs. So, whenever there are drugs, please concentrate. So, anabolic steroids that will suppress the hypothalamus, pituitary, gonadal axis and will lead to osteospermia. Generally, it recovers in 4 to 12 months after stopping.

So, treatment is with SCG and you may add HMG also. So, even if you stop and wait for 4 to 12 months after stopping is sufficient, but the treatment is with SCG and HMG can be added. Other alcohol moderate use has got a minimal effect on spermatogenesis, but heavy use will have irreversible impairment.

Then smoking and cannabis will reduce the semen parameters and there is a strong cessation advice in suboptimal semen quality. So, if the semen parameters are abnormal, then you need to ask to stop these drugs and all.

So, recreational drugs such as cocaine, amphetamines, opiates, etcetera will decrease the libido and there can be erectile dysfunction also. Then oxidative trace and antioxidants, DNA damage is implicated in around 30 to 80 percent of cases and antioxidants such as vitamin C, vitamin E, zinc, selenium, carnitine, coenzyme Q10, etcetera, there may be improvement in the semen quality with this.