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CAN MALE INFERTILITY BE TREATED

Author Name: Dr. Rashmi Dilip Kumar || Mentor Name: Dr. Ramesh Gaikwad on April 27, 2020

INTRODUCTION
Infertility is defined as, when a couple fails to conceive after one year of unprotected intercourse.Amongst this, around 30-35% cases are due to female infertility,in 35% of cases male factor is responsible ,20% cases are due to combined causes and 10% are due to unexplained causes.

The main function of male reproductive system is to produce sperm and testosterone, but some other underlying mechanisms are far more complex and yet to be completely understood .Disruption of male fertility may be reflected by impaired sperm parameters through multivariate factors at different levels . Causes of male infertility may be at the pre testicular or neuroendocrine regulatory levels, intratesticular sites, affecting the functions of Sertoli cells, Leydig cells, and germ cells, or at the post testicular level, impairing sperm maturation and transport. Also,in some cases male reproductive immunological factors as well as reproductive genetics modulations may also be responsible. Hence, proper evaluation of male infertility at different levels is of utmost importance for its effective management,so that targeted treatment to specific male factor according to the causes responsible for infertility ,can be given.

MALE REPRODUCTIVE PHYSIOLOGY: AN OVERVIEW

The male reproductive system has three fundamental functions: Production of spermatozoa (spermatogenesis) and hormones (steroidogenesis), as well as storage followed by ejaculation of the sperm into the female reproductive tract. The male reproductive system along with its regulatory entity comprises of brain centers, which regulate pituitary release of gonadotropins and sexual behavior; a pair of testes, which produce sperm and hormones; a ductal system(vas deferens and epididymis), which stores and transports sperm;accessory sex glands (seminal vesicles, prostate, and bulbourethral glands) to support sperm viability; and the penis.

Due to the pulsatile release of gonadotropin-releasing hormone (GnRH), it stimulates the secretion of LH and FSH,by anterior pituitary which binds to receptors on the testicular cells Leydig cells, and Sertoli cells, respectively. Leydig cells produce testosterone,Sertoli cells lie along the lining of the seminiferous tubules, supporting the germ cells to develop through the stages of spermatogenesis. Testosterone is the main androgen that sends feedback to the hypothalamus and pituitary, regulates spermatogenesis directly, monitors sexual behavior, and serves as the primary male sex hormone that aids primary and secondary sex development. Spermatogenesis is a continuous process throughout a man’s lifetime after puberty with individual germ cells requiring about 72–74 days to reach maturity. The optimum temperature for spermatogenesis is about 34°C. The process occurs within seminiferous tubules,the duct system, comprising of epididymis, vas deferens, and urethra, stores the sperm until they acquire the capability to fertilize with sufficient motility and then transports them to female genital tract through penis.

EVALUATION OF THE INFERTILE MALE

Proper evaluation of male will guide the treating doctor about the probable causes responsible for the male infertility and hence help him to formulate the best treatment plan according to individual needs.

Clinical evaluation:
• Family history-of inferility,genetic disorders,cystic fibrosis,myotonic dystrophy ,autoimmunity.
• Past history-
During infancy and childhood-any history of fetal rubella,presence of hypospadias,undescended testis,genital ambiguity,childhood injuries,micropenis,history of irradiation or chemotheraphy,congenital syndromes(kallmans syndrome,prader willi syndrome)

During puberty and aduldhood-timing and progreesion of puberty,any history of irradiation or chemotherapy,orchitis,testicular injuries,autoimmune disorders,surgery in inguinoscrotal areas,growth delay or precocious puberty.

• Medical history-chronic sinusits,bronchieatasis alcohol,smoking,chemotherapy,radiation,toxic chemicals,steroids,heroin,antihypertensives,antipsychotics,antiandro gens.

Physical examination:
• Short stature-in hypopituitarism,genetic syndrome
• Enunchidal body proportion-in klinefilters syndrome
• Hyposmia/anosmia-in kallmans syndrome.
• Optic atrophy-pituitary tumors,retinitis pigmentosa
• History of gynecomastia,sexual dysfunction,poor facial and body hair development,decreased shaving frequency.
• External genitalia-Normal male external genitalia consists of –
-pubic hair tanner 5
-penile length above 3.6cm
-scrotal skinpigmented with rugosity
-testicular volumeabove 15Ml.

Semen analysis:
According to WHO
• Volume-1.5Ml
• Sperm concentration-15 million spermatozoa/Ml.
• Total sperm number-39 million spermatozoa per ejaculate.

• Morphology-4% normal forms.
• Vitality-58 % live.

Endocrine assessment:
• Serum testosterone-(300-800 ng/DL)-Low level seen in obesity,thyroid disorders,liver disease,pituitary
tumors,testicular failure.
• Serum FSH and LH-(1-8miu/ml)-
High FSH:semeniferous tubule damage High LH:leydig cell damage.

• Serum prolactin: raised in intake of certain medications like antihypertensives and pituitary tumors.
• Serum estradiol level Imaging:
• Ultrasonography of scrotum and testis.
• MRI brain-for hypothalamic or pituitary tumors

CAUSES OF MALE INFERTILITY

After the basic evaluation of male partner,we need to establish the causes of male infertility so that treatment can be individualized and the causative factor can be treated.Most of the male factor infertility is idiopathic.The list of known factor is divided into four major categories:

• hypothalamic-pituitary disorder (1 to 2%)
• disorder of sperm transport (10 to 20 %)
• primary gonadal disorder (30 to 40 %)
• idiopathic (40 to 50 %)

1. Hypothalmic pituitary disorders:
It contains both congenital and acquired causes. Congenital – kallmann syndrome.
Acquired – pituitary tumor, hyperprolactinemia, use of anabolic steroids (athletes, gym users), head trauma, chronic illness like diabetes millites, infections like meningitis and obesity.
Hypothalmic pituatry disorders are one of the cause of male factor infertility which can be treated medically.

2. Sperm transport defects:
The factors which affects the transport of the sperm from testes to ejaculation comes under these defects.These defects could be at the level of epididymis, ejaculatory ducts or due to ejaculatory failure.
These defects can be both congenital and acquired. congenital causes – cbavd, kartagener’s syndrome, young syndrome causes primary infertility.

Acquired defects – vasectomy, ejaculatory dysfunction (spinal cord disease), infection like tuberculosis (causing epididymal obstruction), gonorrhoea and chlamydia also causes sperm transport defects.

3. Primary gonadal disorders (defect at the level of testes):
Congenital- klinefelter’s syndrome, y chromosome microdeletions, single gene polymorphism.
Acquired causes- varicoceles is an important cause especially grade 3 varicocele which impairs sperm parameters.
Infections like tuberculosis, leprosy, mumps can also cause gonadal dysfunction

Chronic illness like cancers, chronic renal disease, cirrhosis Drugs used in treatment of cancers, radiotherapy
Environmental gonadal toxins like (excessive heat, smoking, pesticides) also effect testicular function leading to infertility.

4. Unexplained/Idiopathic infertility:
Responsible for 10%-30% cases of infertility.The diagnosis of unexplained infertility is made when the semen analysis is normal, ovulatory functions is normal, uterine cavity is normal and at least one tube is patent, there is occult causes of infertility like abnormality in sperm, ovum or fertilization for which there is no valid test.Unexplained infertility could be because of fertilization failure, decreased endometrial receptivity, implantation failure, zona pellucid or receptor defects.

TREATMENT

Male infertility can occur due to many causes as discussed above.Some,like ductal obstruction and hypogonadotrophic hypogonadisnn,can be treated effectively.Others,like primary testicular failure,seminiferous tubule dysfunction cannot be corrected, but can be overcome by IUI or ART.
• Men with hypogonadotropic hypogonadism-are the group in which medical treatment can be successful,after its cause has been found out.

1. In case of hypogonadotropic hypogonadism,due to hyperprolactinemia-treatment with dopamine agonist,bromocriptine or cabergoline restores normal prolactin and testosterone and hence improves libido,potency and semen quality.Treatment of 3-6 months is required.

2. In patients with congenital hypogonadotropic hypogonadism,and those with postpuberal onset
–normal spermatogenesis can be induced by combined treatment with hCG and hMG or pure FSH(75-150IU three times weekly.With this treatment,maximum sperm concentrations are achieved within 6-24 months.

3. In those patients ,with adult onset hypogonadotropic hypogonadism,hCG (2,000-5,000)iu three times weekly,can restore spermatogenesis,within 6-24 months.

4. Men with hypogonadotropic hypogonadism,unrelated to hyperprolactinemia,or hypothalamic or pituitary mass lesion- treatedwith,exogenous,pulsatileGnRHtheraphy,given subcutaneously.However,this treatment is costly and may require extended period of time for achieving desired results.

• In patients with Eugonadotropic hypogonadism,like those with severe oligospermia,low serum testosterone levels and an abnormally low serum testosterone/estradiol ratio-may benefit from medical treatment with aromatase inhibitor in the form of tab anastrazole 1mg daily,improves semen quality.

• In those with hypergonadotropic hypogonadism-no form of treatment can improve semen quality and fertility in infertile men,the reason being the complete spermatogenic failure.In such cases,the only treatment option is IUI with donor sperm.

• Retrograde ejaculation-medical management with sympathomimetics(imipramine 25mg twice daily or 50 mg at bedtime,pseudoephedrine 60mg,Ephedrine 25-50mg four times daily, helps in controlling internal sphincter.Alternatively sperm can be retrieved directly from bladder after masturbation, and IUI or ICSI.

• Leukocytospermia Antibiotics treatment(doxycycline,erythromycin,trimethoprim-sulfamethoxazole.

• Idiopathic male infertility-No medical treatment has been proven effective for improving semen parameters or fertility in men with idiopathic subfertility.

• IUI- artificial insemination has been used in treatment of men with severe hypospadias,retrograde ejaculation,neurologic impotence or sexual dysfunction..also used in patients with oligospermia,asthenospermia,low ejaculate volumes.

• Absolute Asthenozoospermia- modifiable causes can be treated if the reason is Infection –to offer antibiotics Any endocrinopathy thyroid/DM)-hormone therapy Varicocele grade ¾-microsurgical varicocele repair. Along with these antioxidants can also be given

If on viability test-
viable sperms are seen-ICSI with self sperm can be done
viable sperms not seen-Donor sperm is the only option available.


• Surgical treatment of male infertility-

1. Vasovasotomy and vaso epididymostomy-done in patients with vasectomy done in past so that patency of ductal system is restored and sperms return to the ejaculate.success rate is less

2. Transuretheral resection of the ejaculatory ducts-done in patients with low ejaculate volumes,low or normal sperm concentration,low or absent motility.this surgery helps in increased semen volume in two thirds of affected men and returns sperm to the ejaculate in half of azoospermic men.

3. Varicocele repair-varicocele causes infertility by its adverse effects on spermatogenesis,increased testicular temperatures its effect on venous reflux.varicocelectomy is done usually in patients with abnormal semen quality associated with a palpable varicocele.,young age with infertility of short duration.however,the results achieved with varicocele repair vary and its role in improving fertility is still lacking.

4. Orchiopexy-useful in patients wiyh undescended testis.it has shown good results in spermatogenesis.

5. Vibratory stimulation-in men with spinal cord injuries,diabetes,vibratory stimulation and electoejaculation can be used to obtain sperms for IUI or ICSI.

• ASSISTED REPRODUCTIVE TECHNIQUES

1. Obstructive azoospermia- in which there is normal sperm production and obstruction is due to patient being vasectomized,post infectious or due to congenital causes.After proper evaluation in the form of physical examination,hormonal evaluation and genetic evaluation, the techniques being used to retrieve sperm is by
PESA(percutaneous epididymal sperm aspiration.
MESA(microsurgicalepididymal sperm aspiration.
TESA(testicular sperm aspiration).
Success rate is 70%-80%

2. Non obstructive azoospermia- in which sperm production is deficient or absent.The reasons being cryptorchidism,post radiotherapy or chemotherapy, trauma, varicocele, antitoxins or unexplained causes.
Medical management-to measure FSH,testosterone,estradiol.
If these hormones are normal-no medical treatment-direct TESA with ICSI.
If T/E <10 or T<300 ng/dl-tab anastrozole 1mg QID If T/E >10 or T<300ng/dl-recombination HCG 250mg/sc weekly If T/E <10 or T>300ng/dl-tab anastrazole 1mg QID
Doses are titrated monthly to maintain T level >800ng/dl and T/E >10 for a minimum of 3 months.semen analysis is done 2- 3 months of therapy.If viable sperms are not seen, sperm is retrieved by:
TESA((testicular sperm aspiration) TESE(testicular sperm extraction) or
Micro-TESE( micro surgical testicular sperm extraction).

CONCLUSION
Hence to conclude,sperm production involves a normal functioning of higher centers in brain hypothalamic pituitary axis,normal testicular and accessory glands,normal genetics , detailed physical and clinical evaluation and basic investigations to understand about potential causes of male infertility and hence to help the clinician to decide about the best treatment modalities according to individual cases and can identify those men with treatable conditions,who may benefit from treatment.

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