A 37-year-old man presents with severe oligoasthenoteratozoospermia (OAT): sperm concentration was 3 million/ml with 100% immotile sperms and 90% with abnormal morphology. His testes were evaluated by ultrasound: with normal volume and structure. There were no signs of varicocele. FSH and inhibin B levels were in the normal range: 2.24 IU/L and 187 pg/ml, respectively. After 3.5 months of treatment with clomiphene 25 mg/day (an estrogen receptor blocker) in combination with 1 capsule FertilAid (vitamins and antioxidants supplement) 3 times daily his spermiogramm revealed: sperm concentration 75 million/ml, 13% forward motility, and 65% with abnormal morphology.

This case illustrates that normal values of inhibin B and FSH were prognostic for the benefit of empiric therapy (this will be discussed in more detail in the Section “Therapy: Hormonal Treatment of Idiopathic Infertility”).

Hypogonadism results from testicular failure (primary hypogonadism), or as a consequence of the hypothalamus and/or pituitary dysfunction (secondary hypogonadism). Male hypogonadism is a clinical syndrome of androgen deficiency and/or failure of producing normal number of spermatozoa with normal quality. Clinical signs and symptoms of androgen deficiency include absent puberty, small testes, decreased or absent body and facial hair, decreased muscle strength, visceral obesity, decreased bone mineral density, depressed libido, reduced morning erections, erectile dysfunction, and male-factor infertility [8]. Hypogonadism can be further separated into congenital and acquired forms. Characteristics for the male hypogonadism are serum levels of total testosterone below the normal values of 12 nmol/l and/or free testosterone below 250 pmol/l [9]. Hypogonadism may not always be evident by low testosterone levels: some patients with primary testicular failure may have normal testosterone concentrations but high LH, which is referred as subclinical or compensated hypogonadism [8]. The prevalence of hypogonadism varies between 2.1 and 5.1% [1].

Among the most relevant forms of male hypogonadism of hypothalamic–pituitary origin are hyperprolactinaemia, isolated hypogonadotropic hypogonadism (IHH), and Kallmann syndrome (hypogonadotropic hypogonadism with anosmia) [8]. Male hypogonadotropic hypogonadism is rare with a prevalence 1 in 10,000 men [2]. The most widespread form of male hypogonadism of gonadal origin (primary hypogonadism) is Klinefelter syndrome with an incidence of 0.1–0.2% of male neonates [9]. Primordial germ cells degenerate early, so that by the beginning of the reproductive period of life the spermatogenesis is preserved only in very few seminiferous tubules.

Androgen receptor defects result in complete or partial androgen insensitivity syndrome [2] with infertility as an obligate feature.

The classification of hypogonadism is important also from therapeutic point of view: in males with hypogonadotropic (secondary) hypogonadism hormonal replacement therapy can successfully induce fertility [8].

Prolactin is 23 kDA polypeptide hormone produced by the lactotrophs of the anterior pituitary; it is under tonic hypothalamic inhibition via dopamine D2 receptors [10]. Its physiological role in males remains unknown. A trophic effect of prolactin on male accessory glands is discussed [11]. While low prolactin may reflect a decreased serotoninergic signaling in the brain and is associated with a poor control of ejaculation [10, 11], elevated secretion of this hormone has serious pathological consequences. Processes causing pituitary stalk compression or section may give rise to hyperprolactinaemia because of the reduction or interruption of tonic negative dopaminergic influence of the hypothalamus on the pituitary lactotrophs [12]. High (>1500–2000 mU/L) blood levels of the hormone are often due to prolactin-secreting pituitary tumors (prolactinomas), which can be either microadenomas (less than 10 mm in diameter) and macroadenomas (more than 10 mm in diameter). Hyperprolactinemia can be caused also by pituitary tumors secreting both prolactin and growth hormone as well as by empty sella syndrome. Hyperprolactinaemia is observed in chronic renal failure as well as in primary hypothyroidism where, because of the insufficient thyroid function sustained elevated thyrotropin-releasing hormone (TRH) secretion also may involve prolactin production. Hyperprolactinemia may also result from systemic use of drugs with dopamine antagonistic effects, such as metoclopramide and haloperidol, dopamine synthesis inhibitors (α[alpha]-methyldopa), opiates, calcium channel blockers, as well as medications stimulating prolactin synthesis and secretion (H2-blockers, estrogens). Whatever the cause, hyperprolactinaemia suppresses the gonadal axis on several mechanisms. It disturbs the pulsatile secretion of GnRH from the hypothalamus, which in turn decreases the FSH and LH secretion with testicular failure as a consequence [12]. Recently, it was shown that hyperprolactinemia via suppression of the kisspeptin decreases the GnRH secretion [13]. The tumor can also press and destroy the pituitary gonadotrophs. Direct effect of hyperprolactinaemia on the testes in men is still a matter of debate [2]. Symptoms of excessive prolactin secretion include depressed libido and erectile dysfunction; galactorrhoea in men and gynecomastia are rare. Usually, spermatogenesis is not heavily disturbed and often the sperm parameters remain in referent values. A study from Italy concluded that systematically evaluating prolactin levels in male infertility is not justified [11]. Because symptoms are usually not pronounced and not specific, hyperprolactinemia in men is usually discovered with some delay. This seems to be the cause for the higher prevalence of macroprolactinomas in men in comparison to the women. Hypoactive sexual desire as well as a hypogonadotropic hypogonadism raises the suspicion for hyperprolactinaemia.

Thyroid disorders are quite prevalent in people of reproductive age; 4–5 times more frequent in women than in men [14]. Thyroid hormone receptors have been described in human testis [14]. Since 1905 it has been observed that thyroid disorders, both hypo- and hyperthyroidism, affect the reproductive system [15].

Primary hypothyroidism (Table 5.1) results in a decrease of sex hormone-binding globulin (SHBG) and total testosterone concentrations, with free testosterone levels reduced in about 60% of hypothyroid males [15]. Elevation of serum prolactin concentrations might be observed. Normal FSH and LH levels and blunted gonadotropin responses to gonadotropin-releasing hormone indicate that in primary hypothyroidism the defect is not in the gonads but rather in the hypothalamus or pituitary [15]. Short-term post-pubertal hypothyroidism might decrease semen volume and sperm forward motility [14]. The conclusion of a prospective, controlled study was that in hypothyroidism only sperm morphology was significantly affected [15]. However, some years ago I treated a man with severe asthenozoospermia. He did not show any signs of hypothyroidism, but his TSH levels, measured routinely, were surprisingly high (>100 mIU/L). In the following months normalization of TSH levels was achieved with L-thyroxine replacement and sperm forward motility gradually increased without additional therapy.

Thyroid hormone metabolism is mediated by cellular deiodinases, which belong to a large family of human proteins containing selenocysteine [16]. A multisystem selenoprotein deficiency disorder was described. Its features include male infertility, skeletal myopathy, hearing loss along raised free thyroxine, normal or low free triiodothyronine, and normal thyrotropin because of functional deiodinases deficiencies [16].

The interplay of thyroid autoimmunity and male infertility is not clear yet. Whether thyroid antibodies alter semen parameters directly still remains a matter of debate [14, 15].

In males with hyperthyroidism SHBG is elevated, total and bound testosterone are increased, free testosterone is reduced or without detectable changes, but the metabolic clearance rate of testosterone is reduced; circulating estradiol levels are elevated (Table 5.1) [14, 15, 17]. The lack of unbound sex steroids in hyperthyroid conditions is more pronounced in male patients than in women, probably because of the higher affinity of SHBG for testosterone than for estradiol [17]. The response of Leydig cells to hCG administration is blunted [15]. Disturbances in the gonadal steroid equilibrium with the estrogen increase and decreased free testosterone/free estradiol ratio [17] might be the cause of gynecomastia, which can develop in the course of thyreotoxicosis. In an extensive study of men with Grave’s disease [17] more pronounced co-pulsatility of LH and FSH was observed than in the controls (Table 5.1). In the same study, results of GnRH stimulation testing were preserved showing adequate gonadotropin reserve capacity of the pituitary, which suggests intact function of the hypothalamic–pituitary unit and even more coordinate secretion of hypophyseal hormones [17]. The gonadal insufficiency is due to the increased need for sex steroids to compensate for elevated SHBG levels, thus presenting a relative endocrine testicular insufficiency, which may explain the infertility in longstanding hyperthyroidism [17]. Asthenozoospermia can be revealed in men with untreated Grave’s disease [17]. In a prospective study of 23 hyperthyroid males the semen volume was unchanged, sperm density, sperm motility and morphology were lower in comparison to the healthy men; after treatment of thyrotoxicosis motility normalized but not morphology [18].

Patients with thyroid abnormalities report decreased libido, erectile dysfunction, and ejaculatio praecox or delayed ejaculation [14, 15, 17].

Radioactive iodine (I¹³¹) is widely employed in the treatment of hyperthyroidism and thyroid cancer [14]. The radiation leads to transient suppression of spermatogenesis along with temporarily elevations of FSH serum levels and inhibin B suppression [14, 15].

All these data suggests that screening for thyroid abnormalities in males with disorders of spermatogenesis and/or hypoactive sexual desire and erectile dysfunction is justified.

Both abnormally low and high body mass index (BMI) are associated with disturbances in spermatogenesis.

Obesity has increased worldwide over the last decades. Overweight and obese couples are at a higher risk of being infertile [19]. The metabolic syndrome (MTS) represents the clustering of abdominal (visceral) obesity, insulin resistance, dyslipidemia, and elevated blood pressure and is associated with other comorbidities among which are reproductive disorders [20]. MTS is increasing to a worldwide epidemic affecting developed as well as developing countries. Men with MTS appear to have a greater prevalence of hypogonadism; on the other hand androgen insufficiency seems to be a risk factor for the development of MTS and type 2 diabetes mellitus [20]. In a large meta-analysis it was found that men with low concentrations of total testosterone, SHBG, and free testosterone were more likely to have MTS compared to those having high sex hormone levels [21]. It is not clear which components of MTS cause the hypogonadism. As hypogonadotropic hypogonadism is rare in patients with diabetes mellitus type 1, impairment of the gonadal axis in those with diabetes mellitus type 2 probably is not mediated only by hyperglycemia [22]. Large prevalence of hypogonadotropic hypogonadism was recently proved in males with moderate to severe obesity [23]. According to Brand et al. [21], total testosterone was most strongly associated with hypertriglyceridemia and abdominal obesity. Total testosterone, SHBG, and free testosterone fraction in obese men are lower in comparison to lean men. Peripheral conversion of testosterone to estrogen in increased peripheral adipose tissue may lead to elevated circulating estrogen levels, which via negative feedback decrease the gonadotropin secretion thus causing hypogonadotropic hypogonadism [24, 25]. Excessive adipose tissues have elevated aromatase activity and adipokines production. The relationship between adipose tissue and estradiol might be modulated by the aromatase polymorphism [19]. In obesity there is an increase of leptin, the obese gene product secreted from adipocytes. Its receptors are present in testicular tissues [25]; therefore, excessive leptin may be another factor for reducing androgens in obese men. The kisspeptin system being superior to GnRH neurons in the hierarchy of the neuroendocrine regulation triggers the GnRH secretion. Functional leptin receptors are not expressed in GnRH neurons, but kisspeptin neurons have leptin receptors [22], and this may be the site of central inhibiting action of excessive obesity. There is inverse relationship between serum total testosterone, free testosterone, and SHBG with visceral fat [25]. Viscerally accumulated fat can serve as a major endocrine disrupter [19]. It is associated with elevated concentrations of insulin and glucose. Increased insulin reduces the SHBG levels. Our study has found that in young males with MTS total testosterone was significantly lower compared with nonobese age-matched subjects and negatively correlated with insulin level, insulin resistance, and BMI [26]. Insulin resistance and maybe also hyperglycemia appear to influence negatively the GnRH pulse generator [22]. Hypotestosteronemia in obesity and MTS seems to be due to several factors, among them the decreased testosterone production, the suppressed gonadotropin secretion, and inhibition of SHBG synthesis [24]. The cause-and-effect relationship between obesity, insulin resistance, and type 2 diabetes mellitus on one side and androgen deficiency on the other remains unclear. Stronger associations of sex hormones with prevalent than incident MTS found in the already mentioned large meta-analysis by Brand et al. suggest that low testosterone and SHBG are merely a result rather than cause of MTS [21]. Weight loss has been associated with an increase in testosterone and SHBG levels in obese men with MTS. Polymorphisms in the SHBG gene have been associated with risk of type 2 diabetes mellitus [21], which puts forward the possibility that this career protein may be a causative factor for MTS. In addition a great body of evidence has accumulated in the last years that testosterone replacement therapy in hypogonadal men reduces visceral fat and increases lean body mass, as well as is associated with reduction of blood glucose. All these data suggest the bidirectional relationships between reproductive system and MTS [21].

Obesity as well as MTS is associated with disturbances in spermatogenesis: decreased sperm concentration and motility and increased sperm DNA damage [24]. Moreover, we have found decreased levels of anti-Müllerian hormone and inhibin B in patients with MTS, which suggests impairment of the Sertoli cells function [27]. They can be a result of altered testosterone secretion and elevated estrogen levels due to overweight and obesity, but alterations in reproductive hormones might not fully explain the poor semen quality in obesity [19]. Leptin receptors are present on the sperm membrane [19], so in obesity and MTS increased leptin may contribute to infertility. Another important factor for sperm disturbances could be the oxidative stress due to the inflammatory adipokines and dyslipidemia [19, 24]. Toxins from the closest environment (excessive scrotal skin) may have a pathogenic role for the spermatogenesis [19]. Suprapubic and thigh fat are factors for the increase of scrotal temperature in severely obese men [24].

In any infertility couple, regardless of the suspected cause, the male factor should be evaluated simultaneous to the female partner. Similar to any other medical condition, work-up starts with a detailed history. Attention should be paid to cryptorchidism and/or testicular torsion, pubertal development, scrotal trauma, and/or radiation or surgeries in this region, as well as past or current use of tobacco, anabolic steroids, and alcohol consumption [28]. Physical examination includes body height and weight, body proportions, hair distribution, testicular size (evaluated with orchidometer or by ultrasound), and presence of gynecomastia or varicocele.

When the patient is able to ejaculate, semen quality should be determined in accordance with World Health Organization (WHO) guidelines and standards [29].

An endocrine evaluation is mostly indicated for men with sperm density below 10 million/ml, impaired sexual function, and other clinical findings indicating specific hormonal disorder [28]. Because of the circadian variations in secretion, serum samples for hormone levels should be obtained in the morning between 8 a.m. and 11 a.m. In healthy men of reproductive age, serum levels of testosterone are above 12 nmol/l. Hypogonadism is marked by testosterone serum levels below 8 nmol/l, while the values between 8 and 12 nmol/l require further evaluation [2]. Liquid chromatography—tandem mass spectrometry—is the strongly recommended method for testosterone determination but the conventional methods are still in use in the routine practice [1, 2]. About 2% of total testosterone in circulation is not bound. This is the free, biologically active fraction of testosterone. For estimation of the free testosterone the gold standard is the equilibrium dialysis [25], which is a complicated method not routinely used at present. Morning salivary testosterone correlates well with free testosterone [25]. Free testosterone level can also be derived from measuring total testosterone and SHBG [30]. This is particularly important when alterations in SHBG are expected and thus making the diagnostic values of the serum total testosterone concentration questionable as in obese patients or those with nephrotic syndrome, hyperthyroidism or hypothyroidism, chronic liver disease, on therapy with steroids, or in older men [1, 31].