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 Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 1  |  Issue : 2  |  Page : 27-34

Evaluation of the infertile male


1 Department of Obstetrics and Gynaecology, Infertility and Reproductive Medicine Unit, Ahmadu Bello University Teaching Hospital, Shika-Zaria, Kaduna, Nigeria
2 Department of Surgery, Division of Urology, Ahmadu Bello University Teaching Hospital, Shika-Zaria, Kaduna, Nigeria

Date of Web Publication20-Sep-2017

Correspondence Address:
Hajaratu Umar Sulayman
Department of Obstetrics and Gynaecology, Infertility and Reproductive Medicine Unit, Ahmadu Bello University Teaching Hospital, Shika-Zaria, Kaduna
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ajiac.ajiac_7_17

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  Abstract 

Infertility in a couple was for a long time, attributed mostly to the female partner. However, recent evidence indicates that the male contributes equally to the the male contributes equally to the problem, hence the need for a review of current evaluation of the infertile male. Common causes of infertility in the male can be due to pretesticular, testicular, and posttesticular factors. This categorization allows for a systematic evaluation ranging from simple semen analysis through serum hormonal assays, radiological investigations, and to testicular tissue biopsy for histological analysis. Following this evaluation, a rational treatment plan can be implemented. Male factor infertility should not be ignored in the management of the infertile couple and requires careful evaluation of the male partner and planning of appropriate treatment.

Keywords: Etiology, evaluation, infertility, male, management


How to cite this article:
Sulayman HU, Ameh N, Adesiyun AG, Avidime S, Bakari F, Muhammed A. Evaluation of the infertile male. Afr J Infertil Assist Concept 2016;1:27-34

How to cite this URL:
Sulayman HU, Ameh N, Adesiyun AG, Avidime S, Bakari F, Muhammed A. Evaluation of the infertile male. Afr J Infertil Assist Concept [serial online] 2016 [cited 2018 Jun 20];1:27-34. Available from: http://www.afrijiac.org/text.asp?2016/1/2/27/215113


  Introduction Top


Infertility is defined as the lack of pregnancy (regardless of cause) after 12 months of unprotected intercourse.[1] It affects about 15% of couples who are within the reproductive age.[1] The past 50 years have noticed the stable prevalence though there are variations in the etiological factors and the population affected in recent times.[1]

Most investigations for infertility focus on the female whereas 30%–40% of the causes of infertility are due to male factor and factors affecting both the female and the male account for 20%.[2] Male factor infertility is still under diagnosed and undertreated.[3] The initial evaluation of the male patient should be rapid, noninvasive, and cost-effective.[2],[4]


  Global Decrease in Male Fertility Top


Several published studies from the developing world have reported a decrease in quality of the semen and sperm density, especially among patients and donors in assisted conception facilities.[5],[6],[7],[8],[9] More so, another study that monitored normal men over 11 years came to the same conclusion.[10] Factors attributed to this decline are estrogenic environmental pollution that accumulates in the ecosystem, and Western type of diet that ultimately results in increase in estrogen concentration in the body.[5] There are findings from studies that attest to correlation between decline in sperm density and increase rate of cancer of the testis, hypospadias, and cryptorchidism.[11]

Environmental pollution are usually from industrial estrogenic chemicals and wastes such as organochlorine pesticides, polychlorinated biphenyls, surfactants, and products of machinery combustion.[9] Pollution of drinking water by synthetic estrogens such as diethylstilbesterol and etinyloestradiol has been linked to decline in male fertility necessitating the use of indirect methods to assess estrogen levels in rivers and dams by finding the percentage of fish that is hermaphrodite or finding the levels of yolk protein vitellogen, whose production is initiated by estrogens.[5] A study reported significantly high sperm count in organic farmers compared to printers, welders, and electricians, which may well support the link between environmental pollution and decreased male fertility.[12]

Diets with high levels of animal fat, proteins, and refined carborhydrate as seen mainly in the Western type of diet are rich in endogenous estrogens and could affect the male fetus in utero.[13] Cow milk contains estrogens in high levels, likewise, some plants such as soya beans contain phytoestrogens which are weak estrogens. Authors have reported a link between consumption of increased quantity of beef in pregnancy and low sperm count and infertility in the male child later in life.[14]

Although decline in male fertility is mainly based on studies from the developed countries, the scenario in some developing countries like Nigeria with fast increasing urbanization may be similar or even more. This may be explained by the impact of urbanization and inorganic farming on the environment. Furthermore, the changing lifestyle toward the Western way of life resulting in the consumption of Western type of diet with little exercise resulting in obesity may also be contributory. Alcohol intake, cigarette smoking, and the ever-present impact of infections, chronic debilitating illness such as acquired immune deficiency syndrome (AIDS), and cancer are additional link to decline in male fertility in Sub-Saharan Africa. These preventable causes of male infertility that may be on the rise in a society already burdened with the high prevalence of infertility could soon be an escalated issue to contend with in the settings.[15],[16]


  Physiology of Male Fertility Top


The hypothalamic–pituitary–gonadal axis which is a closed-loop system controls the gonadal and sexual function with feedback control from the testicles. The hypothalamus, the primary integration center, responds to a variety of signals from the central nervous system, pituitary, and testicles to secrete releasing factors, such as gonadotropin-releasing hormone (GnRH), which modulate pituitary function [Figure 1].
Figure 1: Physiology and control of male fertility

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GnRH whose half-life is 2–5 min is released from the medial basal hypothalamus in a pulsatile fashion every 70–90 min. It then travels down the portal system to the anterior pituitary, where it stimulates the release of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Its diurnal release may be due to melatonin from the pineal gland. GnRH release is inhibited by negative feedback signals from the testicle, specifically by testosterone and inhibin. Corticotropin-releasing hormone, released during stress, and opiates, both internal and external, leads to a decrease in GnRH secretion GnRH secretion. The body responds to illness and stress by a decreased production of LH and FSH.[17]

The pulsatile nature of GnRH is essential to normal gonadotropin release; a continuous stimulation inhibits their secretion. After release into the systemic circulation, FSH and LH from the pituitary exert their effect by binding to plasma membrane receptors of the target cells. LH mainly functions to stimulate testosterone secretion from the Leydig cells of the testicle, whereas FSH stimulates  Sertoli cells More Details to facilitate germ cell differentiation. The pituitary also secretes prolactin (PRL), which stimulate breast development and lactation. PRL inhibits the production of GnRH from the hypothalamus and LH and FSH from the pituitary.[18]

The end organ of the axis is the testicles and it contains the Leydig cells and Sertoli cells that respond to LH and FSH, respectively, by the secretion of testosterone and maturation of the germ cells. Sertoli cells provide a microenvironment that facilitates spermatogenesis and maintains the germ cells in an immunologically privileged environment. Sertoli cells secrete inhibin, a feedback molecule, and androgen-binding protein, which helps modulate androgen activity in the seminiferous tubules. Sertoli cell function is modulated by FSH, a high level of intratesticular testosterone as well as signals from other areas in the testicle such as the peritubular myoid cells bordering the seminiferous tubules.[18]

The Leydig cells are located in the interstitium between the seminiferous tubules and secrete testosterone in response to LH. Testosterone is converted to dihydrotestosterone by the action of 5-alpha reductase, both locally and in the periphery, and to estrogen in the periphery. For normal spermatogenesis, a high level of intratesticular testosterone is needed. Testosterone and estradiol also function as feedback inhibitors of gonadotropin release.[18]

Interactions between the Sertoli cells, Leydig cells, and germ cells are needed for normal spermatogenesis.

For normal conception to take place, sperm must reach the cervix and penetrate the cervical mucus, migrate up the uterus to the oocyte in the  Fallopian tube More Details, and penetrate its zona pellucida and cell membrane. The cervical mucus changes during ovulation are hospitable and easily penetrated at mid-cycle by the sperm. The sperm must be able to survive within the female genital tract and also migrate to the site of fertilization, undergo capacitation and the acrosome reaction to digest the zona pellucida of the oocyte, attach to the inner membrane, and release its genetic contents within the oocyte. After fertilization within the fallopian tube, implantation may then take place within the uterus. Abnormality in any of the above steps may lead to infertility.


  Etiology of Male Infertility Top


The causes and examples of more common causes of male infertility are detailed in [Figure 1] and [Table 1].[2]
Table 1: Causes of male infertility could be pretesticular, testicular, and posttesticular factors

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Pretesticular causes

These are causes arising mainly from the hypothalamus including insufficiency syndromes (e.g., isolated gonadotropin deficiency or Kallmann's Syndrome, isolated LH deficiency, isolated FSH deficiency, and congenital hypogonadotropic syndromes) and pituitary gland conditions (e.g., pituitary insufficiency such as tumors, infiltrative processes, surgical ablation or radiation, hyperprolactinemia, hemochromatosis, and exogenous hormones such as estrogen–androgen excess, glucocorticoid excess, hyper- or hypo-thyroidism).[19]

Testicular causes

Causes arising from the testes may be the result of chromosomal abnormalities (e.g., Klinefelter's syndrome, XX disorder such as sex reversal syndromes, XYY syndrome, Noonan's syndrome, or male Turner's syndrome). Gonadotoxins (drugs and radiation) and systemic diseases (e.g., renal failure, hepatic failure, and sickle cell disease) may interfere with testicular function. Several conditions including trauma, orchitis, testicular torsion, cryptorchidism as well as varicocele may interfere with spermatogenesis resulting in infertility.

Posttesticular causes

Impediments to sperm transport cause obstruction to the movement of sperm into the ejaculate. These impediments may be congenital in nature (e.g., cystic fibrosis, bilateral absence of the vas deferens, bilateral absence of seminal vesicles, bilateral ejaculatory duct obstruction) or acquired (e.g., vasectomy during hernia repair, functional anejaculation from diabetic neuropathy, urethral stricture, and retrograde ejaculation). Erectile dysfunction and sexually transmitted diseases (e.g., chlamydia infection, gonorrhea) may also result in infertility.


  Diagnostic Evaluation of the Infertile Male Top


Male infertility is the cause of approximately 30%–40% of all couples' inability to conceive.[20],[21],[22],[23] Thus, the gynecologist should be familiar with the available diagnostic and treatment approaches to the infertile male.

Clinical evaluation

The history and physical examination are used to identify evidence of possible pretesticular, testicular, or posttesticular disorders that may result in male infertility by one of several mechanisms: (1) abnormalities of sperm production, (2) disordered maturation within the male reproductive tract, (3) abnormal sperm function, or (4) problems with sperm delivery to the female reproductive tract during coitus.[24],[25]

The history should search for evidence of above pathophysiologic mechanisms by looking for developmental abnormalities (cryptorchidism, hypospadias, delayed, or precocious puberty as well as a similar history amongst other siblings), genital trauma, surgery, sexual dysfunction, impotence, or infection. These could suggest possible anatomic or immunologic causes. A history of recent febrile illness (which could depress spermatogenesis for up to 3–4 months), environmental exposure, drugs (eg. tobacco, marijuana and ethanol) use, and medication use should also be elicited. The examination searches for evidence of endocrinopathy (e.g., inadequate virilization, gynecomastia, and abnormal hair distribution) or other systemic illness. Careful genital examination includes evaluation of the penis and its meatus; palpation of the scrotum for evidence of varicocele or abnormalities of the vas deferens or epididymis; and assessment of the position, size (using an orchidometer), and consistency of the testes. The seminiferous tubules comprise 85% of the testicular volume; hence, a decrease in testicular volume implies loss of germinal epithelium.[26],[27] A urologist should be involved the multidisciplinary evaluation and management.

Diagnostic testing

Semen analysis

Semen analysis is highly predictive of the functional status of the male reproductive hormonal cycle, spermatogenesis, and the patency of the reproductive tract. Normal semen volume is between 1.5 and 5 ml.[29] Incomplete collection, retrograde ejaculation, ejaculatory duct obstruction, and androgen deficiency are associated with low semen volume.

Sperm motility is one of the most important measures of semen quality and can serve as a compensatory factor in men with low sperm counts. Rating of sperm motility includes the number of motile sperm as a percentage of the total and the quality of forward progressive sperm movement, that is, how fast and how straight the sperm swims. The normal range is from 0 (no movement) to 4 (excellent forward progression). At least 50% of the sperm with good forward progression is acceptable.[28]

Microscopic evaluation of the liquefied semen may show agglutination (clumping) of sperm which may be head-to-head, head-to-tail, or tail-to-tail and may suggest an inflammatory or immunologic process. Sperm morphology is subject to great variation and it is unusual to see specimens that contain >80% normal sperm heads. Morphology is assessed on stained seminal smears and is subjected to a scoring system after viewing at least 100 cells. The current WHO manual (5th edition) utilizes the Tygerberg “strict” criteria similar to the 1999 Kruger “strict” criteria. At about 30% of the sperm cells with normal oval heads, mid piece, and tail are normal.[28]

There has been no consensus around the suitability of previous the WHO manual reference values (1980, 1987, 1992, and 1999) because of the inherent limitations of the sources of the data, which included ill-defined populations of men of unconfirmed fertility and variable laboratory methodologies.[29] Thus, some centers consider the values as either too high or too low. The WHO published its updated 5th edition laboratory manual in late 2010, and for the first time, multi-country semen analysis results from recent fathers with a known time-to-pregnancy were utilized. The 2010 (5th edition) WHO manual reference lower limits (5th centile at 95% confidence interval) is shown in [Table 2].[29]
Table 2: 2010 WHO manual reference lower limits (5th centiles)

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Normal semen coagulates and then liquefies over 20–30 min.[29] Delayed liquefaction >60 min may indicate disorders of accessory gland function.

It is difficult to differentiate between white blood cells and immature spermatozoa on routine analysis, because both may appear as round cells in the semen. Peroxidase stain and more recently monoclonal antibodies have been utilized to aid in the differentiation. Excessive white cells (>1 million/ml) may indicate an infection which may contributory to poor fertility. If no spermatozoa are observed, a qualitative test for fructose should be performed. A low ejaculate volume and lack of fructose, along with failure of the semen to coagulate, suggests congenital absence of the vas deferens and seminal vesicles or obstruction of the ejaculatory ducts. Fructose is androgen-dependent and is produced in the seminal vesicles.[30],[31]

Computer-assisted semen analysis (CASA) systems couple video technology and sophisticated microcomputers for automatic image digitalization and processing. This technology was developed for more objective measurements of seminal parameters over the subjective measures of standard semen analysis. CASA permits the measurement of additional motility parameters such as curvilinear velocity, straight-line velocity, linearity, and flagellar beat frequency. Under certain circumstances, CASA has been found to be less accurate than the standard semen analysis and the biological and clinical relevance of some of these new parameters are yet to be validated.[30],[31],[32],[33]

Hormonal evaluation

Low gonadotropin values (LH and FSH) associated with low testosterone levels indicate hypogonadotropic hypogonadism. Elevated FSH and LH values are useful in distinguishing primary testicular failure (hypergonadotropic hypogonadism) from secondary testicular failure (hypogonadotropic hypogonadism). Most patients with the primary hypogonadism have severe, irreversible testicular defects, whereas those with secondary hypogonadism have a hypothalamic or pituitary origin and their infertility may be correctable. Elevated FSH levels are usually a reliable indicator of germinal epithelial damage and are linked with azoospermia or severe oligospermia, depicting significant and usually irreversible germ cell damage.[34]

Chromosomal studies

It is rare for infertility to be associated with a specific chromosomal abnormality. Subtle genetic studies can be done in men with severe oligospermia and azoospermia to look for both autosomal and sex chromosomal abnormalities. The diagnostic yield is greatest in men with small testes, azoospermia, and elevated FSH levels.[35]

Immunological studies

Abnormal postcoital test may be pointer to the presence of antisperm antibodies which appear to interfere with normal penetration and transit of sperm through normal cervical mucus.[36]

Sperm function tests

These study the sperm and cervical mucous interaction where cervical mucus is examined 2–8 h after intercourse at the time of suspected ovulation. The presence of >10–20 motile sperm per high-power field is accepted as a normal postcoital test. Other sperm function tests include sperm penetration assay, sperm DNA assay, acrosome evaluation, and hypo-osmotic swelling.[37],[38]

Bacteriological investigations

Without evidence of inflammation, there is no indication for routine culture or antibiotic treatment of the infertile men. Sexually transmitted organisms such as chlamydia trachomatis, mycoplasma hominis, and ureaplasma urealyticum have been implicated in reproductive failure in animals and humans.[39]

Testicular biopsy and vasography

In azoospermic patients or selected cases of severe oligospermia that have normal FSH levels, primary spermatogenic defects cannot be differentiated from obstructive lesions by hormonal investigation alone, and testicular biopsy and sometimes vasography should be performed.[40]

Imaging investigations

Color flow duplex ultrasonography is a superior way to measure the diameters of the spermatic cord veins by imaging these vessels, at rest and during a Valsalva maneuver, as well as to quantify and qualify the flow of blood through these veins. It has been shown to be 85% sensitive in the detection of subclinical varicoceles when venography was used as the “gold standard.”[41]


  Treatment of Male Infertility Top


The definitive treatment of male infertility depends on the cause and ranges from surgical measures to medical treatment, or a combination of both [Table 2]. An algorithm for the management of these patients is provided in [Figure 2].
Figure 2: Algorithm for the management of male infertility. LH: luteinizing hormone; FSH: Follicle-stimulating hormone; M/C/S: Microscopy/culture/sensitivity; USS: Ultrasound; IVF: In vitro fertilization; ET: Embro transfer; ICSI: Intracytoplasmic sperm injection; PESA: Percutaneous epididymal sperm aspiration; MESA: Microsurgical epidydimal sperm aspiration; TESA: Testicular sperm aspiration; TESE: Testicular sperm extraction

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Surgical measures

Varicocelectomy

Varicocele causes abnormality in spermatogenesis and subsequent infertility; hence; varicocelectomy is a common surgical procedure for the treatment of infertility in males. The procedure involves internal spermatic vein ligation, the veins are not removed. This leads to improvement in semen quality in about 60% of men and basically doubles the chance of conception.[42],[43],[44]

Vasovasostomy and epididymovasostomy

Up to 8–10 years postvasectomy, the rate of successful reapproximation with sperm present in the ejaculate is 80%–90% with a functional success rate or pregnancy rate of 50%–60%.[45]

Transurethral resection of ejaculatory duct

In select cases, transurethral resection of the ejaculatory ducts has resulted in marked improvement in semen parameters, and pregnancies have been achieved.[46]

Microsurgical epidydimal sperm aspiration

This is an alternative treatment method for obstructive azoospermia to obtain sperm from the epididymis with the use of an operating microscope. Its indications include all those obstructive disorders that are not amenable to surgery such as congenital bilateral absence of the vas deferens, bilateral ejaculatory duct obstruction not corrected by transurethral surgery, obstructive azoospermia secondary to surgical removal of the vassal ampullae, and seminal vesicles during cystoprostatectomy or radical prostatectomy, failed vasoepididymostomy where the prognosis for repeat surgery is poor.[47]

Ablation of pituitary adenomas

Therapeutic use of the dopamine agonist bromocriptine (Parlodel) or in selected cases, transphenoidal surgical ablation of pituitary micro- or macro-adenoma may be required in individuals with impotence and a spermatogenic defect associated with elevated PRL levels.[48]

Prophylactic surgical measures

Few undescended testes descend into the scrotum spontaneously after 9 months of age. Histological data have shown a progressive decrease in the number of spermatogonia per tubule beginning before age 2 years. Therefore, orchidopexy is recommended before this age. Early recognition and treatment of testicular torsion would also help to prevent irreversible damages to the seminiferous tubules and spermatogenesis.

Medical and nonsurgical measures

Electroejaculation and vibratory stimulation

Electroejaculation had been used successfully for many years in animal studies and has since been adopted in the past decade successfully for men with ejaculatory dysfunction. Through a rectal probe, an electrical current stimulates the postganglionic sympathetic nerve endings that innervate the structures involved in seminal emission and ejaculation. The semen recovered has variable parameters. The specimens are processed and then utilized for either intrauterine insemination or in conjunction with the various assisted reproductive techniques. A multidisciplinary approach is required for treating both the husband and the wife to optimize the outcome. Reported pregnancy rate is 30%–35%.[49]

Endocrine therapy

Infertile men with hypogonadotropic hypogonadism (secondary hypogonadism) are the only appropriate candidates for exogenous gonadotropin therapy. For initiation of spermatogenesis, LH must be given to stimulate the Leydig cells to produce high intratesticular testosterone levels. Human chorionic gonadotrophin; (Pregnyl or Profasi) 2000 IU intramuscularly three times a week is usually effective in stimulating adequate production of testosterone for full virilization.[50]

Therapy for immunologic infertility

When detectable antisperm antibodies are clinically relevant, treatment is challenging. Several innovative methods of semen manipulation have also been attempted. Immediate dilution and washing of the semen following ejaculation, use of sperm surface fragments as immunoabsorbents to remove “unbound” antibody, in vitro cleavage of sperm-bound antibodies with proteases, and the absorption of sperm with bound antisperms on indifferent types of columns to allow separation and capture of the unbound sperm have all been used. Unfortunately, most of these techniques have not proven to be routinely effective. Most patients end up trying superovulation with sperm washing and intrauterine insemination. Despite the theoretical advantages of the above, intrauterine insemination pregnancies for antibodies have not exceeded 20%.[51]

Assisted reproductive techniques

In vitro fertilization (IVF) was originally intended for individuals with tubal disease and female factor unexplained infertility. It has now been expanded to include couples with male factor infertility. Human ova can be fertilized using this technique with concentrations of 20,000–100,000 motile sperm. IVF alone AIDS many of the formidable obstacles to human sperm in the female reproductive tract. Although patients with male factor have a lower fertilization rate compared to nonmale factor groups, once fertilization has taken place in male factor couples, the pregnancy rate is as high as in nonmale factor couples.

Therapy for retrograde ejaculation

Antegrade ejaculation may be induced by the treatment with alpha-adrenergic stimulation using sympathomimetic agents such as chlorpheniramine/phenylpropanolamine (Ornade), pseudoephedrine (Sudafed), and Imipramine (Tofranil). Alkalization of the bladder urine with oral sodium bicarbonate or polycitra and retrieval of sperm from the bladder after ejaculation have been used successfully for artificial insemination with fair results.

Treatment of infection

Individuals with symptomatic or documented genitourinary tract infection should be treated with the appropriate antibiotics based on sensitivity pattern. Tetracycline-based drugs are often the first-line drug of choice.[52]

Artificial insemination

This involves the use of the husband's sperm for insemination when there is low semen volume or in cases where repeated postcoital tests have shown cervical hostility. The advantage in individuals with oligospermia or asthenospermia is minimal. The use of ultrasound to document enlarging follicles and urine testing to predict the timing of the LH surge and ovulation leads to increased success rate. Therapeutic donor insemination is by far the most successful and cost-effective form of therapy for couples with male infertility.[53]

Micromanipulation

Despite the high success rate associated with IVF and gamete intrafallopian transfer, additional refinements have been necessary for patients whose concentration of functional sperm is extremely poor. Micromanipulation of gametes and assisted fertilization allows the surgical manipulation of sperm and ova. The methods of micromanipulation currently utilized include partial zone dissection, subzonal sperm injection, and intracytoplasmic sperm injection. Overall, fertilization rates ranged from 20% to 40%, with clinical pregnancy rates reported as high as 30% but averaging for severe male factor closer to 10%.[54]

Empiric therapy

Since up to 40% of male infertility is classified as idiopathic many patients end up being treated empirically. A great number of these therapeutic modalities are nonspecific. Arginine, bromocriptine, corticosteroids, and thyroid preparations should be relegated to the shelf as they have not had any effect on infertility when used empirically. Clomiphene citrate (Clomid or Serophene) is used in male infertility and it is a weak antiestrogenic effect that interferes with the normal feedback of circulating estrogens and results in an increase in GnRH that stimulates androgenous gonadotropin secretion. The resulting elevation in LH and FSH increases intratesticular testosterone levels and in theory should improve spermatogenesis. Clomiphene citrate is given in a dose of 25–50 mg/day for 3–6 months.[55]


  Conclusion Top


Male infertility is becoming a significant cause of infertility in this environment; hence, meticulous evaluation is required to achieve successful pregnancy and complete families.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Introduction
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