The prevalence of male hypogonadism that has been estimated, I mean to say all of the hypogonadism, it's not only hyper hypo or hypo hypo, so it's about 6 to 12% and if it is left untreated, it can lead to sexual dysfunction, infertility, anaemia, osteoporosis, fracture, myopathy, frailty, gynaecomastia and psychological issues that happen and there is also reduced quality in the life. Defining this problem as already has been discussed, that is hypogonadism means it is just impaired testicular function that can result from primary disorders or can be from the secondary disorders.

And secondary hypogonadism again can be congenital and acquired. Congenital means it can be anosmic, that is Kalman syndrome, and it can be normosmic, that is isolated hypogonatropic hypogonadism. And acquired hypogonatropic hypogonadism can be caused by other causes, that is hyperglycemia, certain drugs, infectious, pituitary lesions, trauma, pituitary and brain irradiation, and exhausting exercise, alcohol abuse, illicit drug use, systemic diseases in the form of hemochromatosis, sarcoidosis, ischiocytosis, and of the several factors what have been discussed that are responsible for the male infertility, if you see the hypogonatropic hypogonadism, that is definitely a treatable cause of infertility, maybe less number, but definitely is a treatable cause of infertility.

So most of the idiopathic hypogonatropic hypogonadism is because of the Kalman syndrome, and maybe 40 percent is just normosmic idiopathic hypogonatropic hypogonadism. Amongst all of them, two-thirds are because of this sporadic, and one-third is inherited cause. So this slide says actually we need to know something about the clinical pictures.

Everything has been discussed, but the male hypogonadism, you need to know whether it is pre-pubertal hypogonadism or post-pubertal hypogonadism. So normally any patient having pre-pubertal hypogonadism, they have a disproportionate height, like you know, stature, and they have small testes, small pennies, lack of normal squirtle ruby and pigmentation, small prostate, scanty facial, axillary pubic hair, high-pitched voice. On the other hand, the post-pubertal hypogonadism, they have a normal structure and proportions are normal.

Testicular volume may be normal to slightly low. Penile size may be normal. There is normal squirtle ruby and pigmentation.

Prostate size will be normal. There is thinning of the facial, axillary and pubic hair, and voice should be normal. But common symptoms which are common to both the hypogonadism is gynaecomastia, infertility, lack of libido, low bone mineral density, loss of muscle mass, increase in the fat, and of course, other things.

And the features of androgen deficiency, as you know, it is in the adolescent, it can be lack, delay, or suggestion of the pubertal sexual maturation. And in case of adult, of course, infertility is a major issue and loss of libido and quality of life is also very poor. So if you look at the hypo-hypo that is considered as idiopathic hypogonadropic hypogonadism, when there is an isolated GNRH secretion deficiency in individuals over the 18-year stage, but if it is less than 8 years, definitely you have to rule out the CDGP. And low blood testosterone levels and low pituitary hormone levels, they confirm the diagnosis of hypogonadropic hypogonadism. And in case of Kalman syndrome, definitely you should go for a cerebral MRI, which can show anomalous morphology or even the absence of the olfactory bulb.

How you diagnose all the laboratory evaluations, as you know, the hormonal profiles in the form of LH, FSH, prolactin, testosterone, of course, thyroid function is also very important. And also, you should go for other tests like, just a moment, seminal fluid examination, karyotyping, testicular biopsy. However, the endocrine society guideline says in case of males, just after puberty, the diagnosis of hypogonadism should be based on symptoms plus signs of hypogonadism plus presence of low testosterone level, at least measured on two occasions.

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And there are, of course, certain other tests, additional tests that is required. Suppose if you are suspecting CH, in that case, you need to have a STD stimulation test, GnRH analogue test, which is done by giving lipoid that is 10 microgramme per kg subcutaneously, which is done to distinguish between the true idiopathic hypogonadropic hypogonadism and CDGP. And hypo-hypo will have a subnormal response after lipoid injection, and CDGP will have a pivotal response.

And this GnRH test that is based basically on the principle that 4-hour sample that normally indicates the gonadotropin reserve and 24-hour sample that judges the gonadal response to the endogenous gonadotropin levels. The sample to be taken at 0 minutes would be LH, FSH, and 4-hour also it is LH and FSH. And at 24 hours, it is LH, FSH, and the testosterone should be taken.

And second, other testing that is very important is the testicular tissue testing is very important. That is very important in case of crypto-orchidism. In that case, you need to know whether testicular tissue is really there or not.

Otherwise, how will you treat again later on? So that is clarified by the SCG test. If the testes are not palpable, we can go for the SCG test and we should measure the testosterone response. Diagnosis is definitely concluded by the MRI that is used for pituitary, prolactin, and cranio-parenchyma.

And in Kalman syndrome, cerebral MRI can show anomalous morphology, absence of olfactory bulb, and it therefore plays an important role in presumptive diagnosis. Next comes the management. As you know, patients with hypogonadism, they are typically treated with sex steroids.

That is for the maintenance of the sexual characters, libido, and quality of life. However, the goal of the treatment should be to promote the development and development of the to maintain the secondary sexual characteristics and to maintain the normal sexual function. And also to build the sustained normal bone and muscle mass and to assist in the proper psychosocial adjustment of the adolescent with hypogonadism.

Fertility options should be explored when fertility is required. So as you know, most hypogonad young men, they want to be fertile definitely. Thus, it is very important to remember that the fertility of men with hypo-hypo is only reduced and that fertility may be restored through hormone therapy.

So the fertility of the patient with hypo-hypo, that can be restored through the use of GnRH when cases have a hypothalamic origin or maybe more commonly with the use of gonadotropins. You know about the various gonadotropins that is used either from the urinary source or the recombinant source and they are presently available also. The urinary gonadotropins, their forms are produced from the urine of the menopausal women, that is known as HMG and we have also HCG.

And HMG contains both urinary FSS and LH and another commonly used urinary gonadotropin that is highly purified known as FSS. So these are all the formulations and normally what should happen, there should be high intratesticular testosterone levels which is necessary for the initiation and maintenance of this dermatogenesis and that is definitely achieved by injecting HCG. So the first phase is known as the induction phase.

So after all the baseline investigations, so we have to inject the HCG, that should be started with administration of about 1,000 to 2,500 IU weekly for 8 to 12 weeks or until the testicular atrophy is reversed or the testosterone levels are really high enough to induce dermatogenesis. That is also followed by addition of subcutaneous injection of the recombinant FSH in a dose of 150 IU three times per week to support and then maintain the dermatogenesis. This is very crucial for the following testosterone levels to increase.

In certain cases, even HCG alone also can induce dermatogenesis. So in the individuals who do not have sufficient endogenous FS in that case, treatment should be continued with co-administration of 75 to 150 IU of HMG three times per week at least for 18 months as the presence of FSH which is crucial for stimulating and maintaining dermatogenesis. So this combined treatment that provides a considerable testicular growth in most of the patient in addition to dermatogenesis that happens in 90% of the patient and the therapy should be continued at least for 9 to 18 months and GnRH infusion pump also, another mode of the formulation of the therapy if the injection therapy has failed but normally it is very expensive and it is also very inconvenient.

So we don't use it. Normally we just give a scheduled HCG and HMG. Men on gonadotropin therapy, they should learn the self-injection so that they can inject themselves and monitoring the side effect of the therapy is very important in the form of bloating, fatigue and maybe sometimes pain in the breast and look for the evidence of this dermatogenesis every three to four months and testosterone normally should be normalised in three months after starting the HCG therapy and appreciable spermatosis normally is achieved at 9 to 12 months and regardless of the hormone used for the treatment, the total number of sperm usually remains below the threshold and there are of course certain predictors of the treatment success like increased baseline testicular volume, no history of cryptorchidism, history of sexual maturation and if no previous testosterone therapy was given.

So even individuals with testicular volume of 3 ml also they can be benefited with this drug. Next comes the what is the outcome of this treatment. Vast majority of the patient they will be able to conceive and although 71 percent of the patients subsequent fertility have sperm concentration that is considerably lower although they become pregnant and 10 percent of the patient may maintain normal serum testosterone level level after the endocrine therapy but in patients who have developed hypogonadism before therapy that can take a longer period.

They may need a one or two years of therapy to achieve sperm production. Even spontaneous conception is also achieved within six to nine months of the therapy but can go up to two years also. If spontaneous pregnancy doesn't occur after 20 months or eight months after achieving a sperm concentration of at least 5 million then assisted reproductive technology may be considered to achieve pregnancy.

So there are certain ranges of ART in the form of IUI, IVF, then ICSI. So acquisition of the viable sperms can be taken from the ejaculate or maybe a hypohypopatient with persistent azospermia despite long periods of hormone therapy takes sperm directly from the testis through the testicular sperm ejaculation that is called a STACY or testicular microdissection also can be done depending on the potential for the pregnancy and the quality and quantity of the sperm. IUI as you know there is a good option for the pregnancy.

So in that case also you can go for IUI and it is a less expensive and more natural way to conceive. So before going for IUI definitely go for SHG to rule out tubal block and ICSI also is the treatment of choice for those patients who have completed at least one year of therapy and exhibit sperm concentration less than 1 million or those who have sperm concentration more than 2 million but have failed to achieve impregnation after 20 months. Contraception is advisable for cases where pregnancy is achieved after the spermatogenesis and may continue after the therapy stops.

So, contraception should be explained to the patient. In up to 10 percent of the cases the patient exhibits a sustained sperm response and adequate serum testosterone levels even after the completion of withdrawal of the medication. So, this is normally called as the hypogonadotropic hypogonadism reversal.

The mechanism in these cases is definitely not known but it appears to be a neuronal plasticity in GNRH producing cells. And the recent advances regarding this topic is in 2010 there was FSH analogue that was known as chorifolitropin in alpha therapy which is when combined with the SHG treatment can significantly increase the testicular volume and induce spermatogenesis. It was approved in the year 2010 and patient in this study they remained azoospermic though with a normalised testosterone level after 16 weeks of SHG treatment under weight 50 the SHG therapy and it is a long-acting FSH analogue.

You can give it once weekly along with SHG therapy.

Case Study:

A 25 year old gentleman who presented with endocrine clinic with history of tiredness reduced libido and inability to father a child that is for more than a year and he had a child with a previous partner and his current female partner had already been fully evaluated by the fertility specialist in 2007. He took anabolic steroid during bodybuilding training but stated that he had symptoms of tiredness, reduced libido before then and 2011 he stopped taking the steroid because he wanted to father a child. After a year of no success he and his partner they decided for fertility treatment on examination he was absolutely normal.

There was no previous investigation result to suggest that patient had hypogonadism, predated anabolic steroid use. After the baseline investigation he had gonadotropin therapy. He had three to four monthly investigation to monitor for the side effects, hormonal response to the treatment and for evidence of the spermatogenesis and once adequate spermatogenesis was confirmed by serial semen analysis but still there was no conception with non-assisted conception and his semen samples were present for the assisted conception treatment.

And then the results of the baseline and follow-up investigations are baseline test, rebuilt hypogonadism as well as azoospermia on two separate occasions and MRI showed nothing that was normal. Appreciable spermatogenesis was observed at 9 to 12 months after starting the gonadotropin therapy. He consisted of subcutaneous SCG gonadotropin that is SCG 1500 IU three times a week until serum testosterone level was normal.

A negative semen analysis prompted the addition of subcutaneous recombinant FSS at a dose of 150 three times a week while the dose of SCG was reduced to 1500 IU twice a week. At six months the SCG was stopped temporarily because of there was an increase in the PSA level which returned to normal within six weeks. Then SCG was restarted at a lower dose that is 1500 IU once a week.

Combined therapy was continued until after appreciable levels of spermatogenesis for non-assisted conception and for semen freezing and assisted conception treatment. Then the recombinant FSS was stopped when non-assisted conception failed and enough frozen semen samples were stored. After several months of unsuccessful non-assisted conception the patient subsequently achieved conception through the assisted conception treatment on the second atom using the stored frozen sample.

Then he had a child and after stopping the gonadotropin his testosterone levels declined. Then finally the patient was on testosterone replacement therapy. So the take-home message is the male hypogonatropic hypogonadism is defined as reduced androgen levels because the testes do not produce androgens and thus form and is the consequence of maybe congenital or acquired diseases that affect the hypothalamus and or the pituitary gland.

So signs and symptoms of hypo-hypo that can vary according to the age that depends on the adolescent age or the adult age and diagnosis requires the determination of all the hormonal profiles in the form of FSH, LS, testosterone and MRI scan also should be done. MRI scan of the brain and scella should be considered and androgen replacement should be done when fertility is not required but when fertility is required definitely in that case you have to go for a scheduled treatment with SCG and HMG. So hypogonatropic hypogonadism represents one of the rare conditions in which specific medical treatment that can reverse infertility and the induction and maintenance of both spermatogenesis and androgen production they are achieved by exogenous administration of gonadotropins and results are really good and spermatogenesis even has been seen in 80 to 90 percent of the cases but just after withdrawing treatment maybe everything will be over and patients should be continued with the injectable testosterone therapy for maintenance of the androgenisation.

Treatment of hypogonadotropic hypogonadism goes beyond the restoration of sperm production; the ultimate goal is to assist couples in achieving safe and healthy pregnancies, which would otherwise be difficult or impossible. At Dr. Kamini Rao Hospitals, the practice of male infertility is closely linked with advanced assisted reproductive technologies, including IUI, IVF, and ICSI. With extensive experience in reproductive medicine, this IVF Centre in Bangalore offers individualized treatment protocols, close monitoring, and established ART options best suited for each couple. This continued care ensures that when medical treatment results in a response, the man can be directed toward fertility solutions in time to enhance his potential for parenthood.