Hypogonadism

Fred F. Ferri MD, FACP , in Ferri's Clinical Advisor 2022 , 2022

Etiology

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The importance of a careful history and examination cannot be overstated to determine the etiology of possible hypogonadism. Primary hypogonadism is a result of a decrease in testicular testosterone secretion and/or a decrease in spermatogenesis with an associated increase in gonadotropin levels as in Klinefelter syndrome, cryptorchidism, and following orchitis, testicular trauma, chemotherapy, and irradiation. The causes of primary hypogonadism are summarized in Table 1.

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Secondary hypogonadism is due to hypothalamic-pituitary dysfunction, which results in a decrease in testosterone levels and/or spermatogenesis with gonadotropin levels that are subnormal or inappropriately within the normal range.Table 2 summarizes causes of secondary hypogonadism.

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Combined primary and secondary hypogonadism is a result of deficits at both the level of the hypothalamic-pituitary axis and testes with variable gonadotropin levels depending upon the predominance of the level of the defect.

Endocrinology

Naila Goldenberg MD , Arno K. Kumagai MD , in Clinical Men's Health, 2008

Classification of Male Hypogonadism

MHG is classified according to the locus on the hypothalamic-pituitary-gonadal axis where the causative lesion occurs. A list of disorders associated with primary and secondary hypogonadism, as well as disorders involving combinations of primary and secondary hypogonadism, is presented in Table 9-1.

Primary hypogonadism occurs in conditions that involve a primary gonadal (testicular) abnormality or failure. These disorders may be either congenital or acquired later in life and may be associated with multiple causes. Since the lesion involves a primary defect in the production of testosterone and inhibin B and a lack of negative feedback on the hypothalamus and pituitary, this class of MHG is associated with increased levels of gonadotropins and is therefore called hypergonadotropic hypogonadism.

Secondary and tertiary hypogonadism are the result of pituitary and hypothalamic failure, respectively. Since hypothalamic causes of hypogonadism are relatively rare, our focus will primarily be on secondary causes. An absence of secretion of gonadotropin-releasing hormone (GnRH) or luteinizing hormone (LH) and follicle-stimulating hormone (FSH) results in the lack of adequate stimulation of testicular development or function. These disorders may be due to congenital pituitary or hypothalamic abnormalities or acquired later in life. Since the inherent defect is due to the lack of hypothalamic or pituitary gonadotropin production, this class of disorders is associated with low serum levels of LH and FSH and is therefore called hypogonadotropic hypogonadism. Some conditions and disorders are associated with a defect in both pituitary and testicular levels of sex hormones. There are few conditions associated with tissue resistance or insensitivity to testosterone, leading to hypogonadism.

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Physiology and Disorders of Puberty

Shlomo Melmed MB ChB, MACP , in Williams Textbook of Endocrinology , 2020

Isolated Hypogonadal Hypogonadism

A defect involving the GnRH pulse generator or gonadotrophs without an anatomic lesion causes selective deficiency of gonadotropins, producing IHH (Tables 26.17 and 26.18). 477 Puberty fails to begin by 14 years in boys and 13 years in girls, or pubertal maturation is incomplete or transient. In boys, micropenis (the penis is normally formed but stretched length is less than 2 cm in length, which is 2.5 SD below the mean length in average newborn males) or undescended testes or both findings are evidence of a fetal testosterone deficiency caused by gonadotropin deficiency. Prepubertal concentration of gonadal sex steroid values (testosterone in boys; estradiol in girls) and low serum gonadotropin levels or values within the normal range (i.e., normal in the basal state but not in the stimulated state) are characteristic. Concentrations of gonadal sex steroids and gonadotropins are low, pulsatile LH secretion is often virtually absent, and the LH response to GnRH or GnRH agonist administration is deficient in the severe form. The testes are small (1–2 mL), and serum inhibin B, an estimate of seminiferous tubule function, is lower than in CDP in initial studies. 478

IHH may occur in families (about 20–30% of patients), or it may occur sporadically. There are a growing list of gene defects that cause hypogonadotropic hypogonadism. 479 Some patterns of inheritance are rare and follow the classic mendelian schema; others are oligogenetic, whereby multiple defects of common genes synergize to bring about a condition no single one of them could cause alone. 454,480

Oligogenicity is more common in IHH than CDP, and IHH genes are more common in IHH than CDP, suggesting a different genetic architecture in IHH compared to CDP. 456

In contrast to CNS tumors (in which patients usually have GH deficiency and growth failure) and to CDP (in which patients are short for chronologic age), height is appropriate for age in patients with IHH (Fig. 26.39). Because the levels of estradiol are too low to cause epiphyseal fusion at the normal age, increased arm span for height and a decreased ratio of upper to lower body segments (i.e., eunuchoid body proportions) are present. If the condition is left untreated, growth continues, and adult height is tall. 481–483

Remarkably, about 22% of affected patients with IHH and severe delay of puberty spontaneously increase their testicular size and enter full puberty. 484 Five men who experienced reversal once again became hypogonadal. Thus long-term follow-up is essential.

Environmental Issues Resulting in Andropause and Hypogonadism

Shubhadeep Roychoudhury , Rudrarup Bhattacharjee , in Bioenvironmental Issues Affecting Men's Reproductive and Sexual Health, 2018

Epidemiology

Hypogonadism is an incessant and conceivably undertreated condition in men. Various longitudinal epidemiologic studies, including the Baltimore Longitudinal Study of Aging, the New Mexico Aging Process Study, and the Massachusetts Male Aging Study, have exhibited age-related increment in the probability of developing hypogonadism. Notwithstanding the propelling age, expanding body mass index and type II diabetes mellitus are believed to be connected with lower coursing androgen levels. In the United States, the demographic pattern toward expanding populace age together with the rising pandemic of diabetes as well as an expanding predominance of obesity, clinicians are probably going to experience higher instances of hypogonadism in near future [14]. On the other hand, clinical and research data on hypogonadism and/or andropause remain largely deficient in the case of developing nations, such as India. Formulation of strategies and streamlining them on extrinsic causative factors of reproductive pathologies including hypogonadism and/or andropause is a prime need in the South Asian countries. Environmental factors, life style–related issues, and drug use/abuse need to be emphasized because they may cause either primary or secondary hypogonadism by a number of pathways [15]. Increasing age, prolonged life expectancy by virtue of improved medication, and prevalence of obesity and type II diabetes mellitus significantly contribute to the development of hypogonadism. In India, 44 million people currently suffer from diabetes mellitus and many of them show hypogonadal conditions [16]. The growing need for research on male reproductive health has raised concern in the South and the Southeast Asia especially in the following areas: (1) male contraceptive technology; (2) male reproductive health behavior and male adolescent reproductive health; (3) male reproductive aging including andropause; (4) other diseases such as male RTIs, STDs, HIV/AIDS; (5) prevalence, management, and prevention of male infertility; and (6) environment- and semen quality–associated male reproductive problems [15]. Various clinical conditions including prostate carcinoma, hematuria, urinary problems, delayed puberty, azoospermia, and obesity have also been correlated positively with hypogonadism [17]. Fig. 16.1 presents the correlation of such issues with hypogonadism. Although exposure to pesticides, radiation, and life style–related issues show positive correlation with hypogonadism [1,2], more investigation is warranted for elucidation of the impact of these environmental factors that might help attaining a better diagnosis and treatment criterion for hypogonadism and associated problems (Figs. 16.2 and 16.3).

Figure 16.1. Association of hypogonadism with clinical conditions. Data remain deficient on the percentage contribution of the factors such as pesticide exposure, radiation exposure, and life style issues.

Figure 16.2. Hypothalamic–pituitary–gonadal axis. Hypothalamic gonadotropin-releasing hormone (GnRH) stimulates the pituitary gland to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which in turn stimulate spermatogenesis and testosterone production, respectively. The Sertoli cells produce inhibin B that imparts negative feedback to the pituitary for inhibiting the hyperproduction of FSH and LH. Leydig cells stimulate testosterone production, which in turn produces dihydrotestosterone and estradiol by 5α-reductase and aromatase, respectively. Excessive testosterone imparts negative feedback to both the pituitary and hypothalamus to prevent hypersecretion. Kisspeptin also plays a role in enhancing the GnRH production.

Figure 16.3. Prevalence of hypogonadism in males (starting age: 45   years). Positive correlation between age and occurrence of hypogonadism is illustrated.

 Adapted partially from Mulligan et al. International Journal of Clinical Practice 2006.

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Hypofunction of the Testes

Robert M. Kliegman MD , in Nelson Textbook of Pediatrics , 2020

Chemotherapy and Radiation-Induced Hypogonadism

Testicular damage is a frequent consequence of chemotherapy and radiotherapy for cancer. The frequency and extent of damage depend on the agent used, total dose, duration of therapy, and posttherapy interval of observation. Another important variable is age at therapy; germ cells are less vulnerable in prepubertal than in pubertal and postpubertal males. Chemotherapy is most damaging if more than 1 agent is used. Although many chemotherapeutic agents produce azoospermia and infertility, Leydig cell damage (leading to low testosterone levels) is less common. In many cases the damage is transient and sperm counts recover after 12-24 mo. It has been suggested that prepubertal testes are less prone to damage than pubertal testes, but the evidence is not conclusive. The use of alkylating agents such as cyclophosphamide in prepubertal children may not impair pubertal development, even though there may be biopsy evidence of germ cell damage. Cisplatin causes transient azoospermia or oligospermia at lower doses, whereas higher doses (400-600 mg/m2) can cause permanent infertility. Interleukin 2 can depress Leydig cell function, whereas interferon-α does not seem to affect gonadal function. Both chemotherapy and radiotherapy are associated with an increase in the percentage of abnormal gametes, but data concerning the outcomes of pregnancies after such therapy havenot shown any increase in genetically mediated birth defects, possibly because of selection bias against abnormal sperm.

Radiation damage is dose-dependent. Temporary oligospermia can be seen with doses as low as 0.1 Gy, with permanent azoospermia seen with doses greater than 2 Gy. Recovery of spermatogenesis can be seen as long as 5 yr (or more) after irradiation, with higher doses leading to slower recovery. Leydig cells are more resistant to irradiation. Mild damage as determined by elevated LH levels can be seen with up to 6 Gy; doses greater than 30 Gy cause hypogonadism in most patients. Whenever possible, testes should be shielded from irradiation. Testicular function should be carefully evaluated in adolescents after multimodal treatment for cancer in childhood. Replacement therapy with testosterone and counseling concerning fertility may be indicated. The storage of sperm prior to chemotherapy or radiation treatment in postpubertal males is an option. Even in those cases where sperm counts are abnormal, recovery is possible, though the chances of recovery decline with increasing dose of radiation. If sperm counts remain low, fertility is still possible in some cases with testicular sperm extraction and intracytoplasmic sperm injection.

Gonadotrophin Hormones

Ursula B. Kaiser , in The Pituitary (Fourth Edition), 2017

Chronic Renal Failure and Gonadal Dysfunction

Hypogonadism is very common in patients with end-stage renal disease. Abnormalities at multiple levels of the hypothalamic–pituitary–gonadal axis contribute to hypogonadism. Sperm concentrations and semen quality are usually depressed; steroidogenesis is also suppressed to varying degrees. Depression of libido and potency is common in uremic men, and menstrual irregularities and infertility are common in premenopausal women. Reproductive dysfunction in uremic patients is usually multifactorial in nature; atherosclerotic disease, neuropathy, malnutrition, chronic illness, hypertension, diabetes mellitus, and drugs all contribute. Hypogonadism usually does not improve after initiation of dialysis. However, restoration of normal kidney function after transplantation will often, although not always, lead to improvement.

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Rothmund–Thomson Syndrome

ROBERTA A. PAGON , in Neurocutaneous Diseases, 1987

Hypogonadism

Hypogonadism and infertility appear to be exceedingly common in Rothmund–Thomson syndrome, although most reported cases lack sufficient detail to determine the incidence. At least one-third of the 60 cases reviewed by Rook et al. [ 5] had clinical hypogonadism. The cause of hypogonadism in this condition has not been well studied, and the few existing reports are contradictory. Werder et al. [23] evaluated two cases in detail and found normal FSH and LH but low estrogen levels in a 36-year-old woman with primary amenorrhea, and elevated FSH and LH in a 19-year-old male who had small testes but normal testosterone levels. Three siblings, ages 16, 17, and 18 years, reported by Kirkham and Werner [11] had hypogonadism with prepubertal levels of FSH, LH, and gonadal steroids. These meager data suggest that both hypogonadotrophic hypogonadism and end organ unresponsiveness can be causative. Micropenis (penile length less than 2.5 cm at birth), a common manifestation of hypogonadotrophic hypogonadism, has been reported in two young boys [27].

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Metabolic Syndrome Impairs Erectile Function

Robert Fried Ph.D. , in Erectile Dysfunction As a Cardiovascular Impairment, 2014

5.35 Prevalence of Hypogonadism and Links to Hypertension, Atherosclerosis, and Diabetes

The Hypogonadism in Males (HIM) study estimated the prevalence of hypogonadism defined as total testosterone (TT) less than 300  ng/dL in men 45 years old or older visiting primary care practices in the United States. Free testosterone (FT) and bioavailable testosterone (BAT) were assessed, and common symptoms of hypogonadism, co-existing medical conditions, demographics, and reason for visit were recorded.

Prevalence rate of hypogonadism was 38.7%. Similar trends were observed for FT and BAT. Figure 5.10 shows "comorbidity," or medical disorders that coexist with low testosterone. Compared to men with normal testosterone, there is about 15% greater prevalence in hypertension, about 12% higher prevalence of elevated cholesterol, and somewhat more than 10% higher prevalence of diabetes. 80

Figure 5.10. Comorbidities in hypogonadal men: The HIM Study. First bar: hypogonadal. Second bar: non-hypogonadal.

 Source: Mulligan, T., Fric, M. F., Zuraw, Q. C., Stemhagen, A., McWhirter, C., (2006). Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract, 60, 762–769. Reproduced with kind permission from the International Journal of Clinical Practice.

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Male Reproduction

Fiona Yuen , ... Ronald S. Swerdloff , in Encyclopedia of Reproduction (Second Edition), 2018

Hypogonadism and Its Effects

Hypogonadism has various effects depending on the stage of development of the patient. In fetal development, androgen insensitivity syndrome or congenital defects in testosterone synthesis leads to ambiguous genitalia. In prepubertal children, androgen deficiency causes eunuchoidism, signs of which include small testes (<  4   mL), infantile genitalia, high-pitched voice, and disproportionately long arms and legs relative to height, which may manifest as arm span greater than height or increased lower-to-upper body ratio. Adults who develop hypogonadism may have changes in their mental status, including lower motivation, decreased energy, depressed mood or irritability, and decreased concentration or memory. There is a decrease in libido/sexual function and fertility. They may have hyperlipidemia and insulin resistance. On examination of their semen, they may have sperm with abnormal morphologies (teratozoospermia), sperm with reduced motility (asthenozoospermia), low sperm count (oligozoospermia), or no sperm cells in the ejaculate (azoospermia). With longstanding androgen deficiency, there may be loss of androgen-dependent hair, reduced muscle mass, development of fine facial wrinkles, gynecomastia, reduction in prostate size, decreased bone mineral density, and decrease in testes volume. If the development of testosterone deficiency is rapid, they may have hot flushes and sweats.

Hypogonadism can be primary (primary testicular failure) or secondary (central hypogonadism or hypogonadotrophic hypogonadism) (Fig. 1). Primary testicular failure can be differentiated from hypogonadotrophic hypogonadism by measurement of FSH, LH, and testosterone levels. In both primary and secondary hypogonadism, testosterone levels are low. However, in primary hypogonadism, FSH and LH levels are elevated, whereas in secondary hypogonadism, FSH and LH are low. Causes of primary testicular failure include Klinefelter syndrome, testicular injury, and chemotherapeutic agents and irradiation. Causes of hypogonadotrophic hypogonadism include pituitary tumors, hemochromatosis, injury to the pituitary, Kallmann's syndrome, acute and chronic illnesses, medications including opioids, and obesity.

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The Human Hypothalamus

Maithé Tauber , Gwenaelle Diene , in Handbook of Clinical Neurology, 2021

Gonadotropins and sex steroids

Hypogonadism is seen in most PWS patients, and in both genders. Secondary to hypogonadism, also their sexual development, appearance of body gender, body composition, bone mineral density, quality of life, and fertility are affected. Mini-puberty, described as the rise in testosterone levels in the first months of life, has been reported to occur almost normally in boys ( Fillion et al., 2006; Hirsch et al., 2014). The hypogonadism was originally considered to be of hypothalamic origin, but more recent studies have shown a significant number of cases of peripheral hypogonadism, particularly in boys with Sertoli cell damage, and a continuum from almost pure gonadic hypogonadism, through varied combinations of both forms of hypogonadism, to pure central hypogonadism (Eldar-Geva et al., 2010; Radicioni et al., 2012; Siemensma et al., 2012a; Hirsch et al., 2015). A cross-sectional study of 37 males reported normal LH, low testosterone, elevated FSH, and low inhibin B, but normal anti-Mullerian hormone levels (Hirsch et al., 2009). One study reported normal sperm counts in some biopsies (Vogels et al., 2008).

In females, many infants display hypoplasia of the labia minor that is not easy to diagnose. Extremely low or undetected inhibin B but normal anti-Mullerian hormone levels are observed in most females with PWS, suggesting a stage-specific defect in folliculogenesis (Eldar-Geva et al., 2009). In contrast to the severe defect in ovarian function, hypothalamic dysfunction (normal-to-low LH and normal-to-high FSH) seems to be mild and variable (Eldar-Geva et al., 2009) and pure hypogonadotropic hypogonadism is rarely found in PWS females (Eldar-Geva et al., 2010; Siemensma et al., 2012b).

More recently, the conservation of the primordial follicle pool and a number of small antral follicles was confirmed in girls and female adolescents with PWS, even though the maturation of follicles and progression of pubertal development were both impaired (Siemensma et al., 2012b), possibly due to a dysregulation of LH secretion. Despite the hypogonadism, adults with PWS often express strong romantic thoughts, an interest in sexual experiences, and the desire to have children, although normal intercourse seems to very rarely occur. Five pregnancies have been reported in women with PWS (Akefeldt et al., 1999; Schulze et al., 2001), whereas no male with PWS has fathered a child. Measurable inhibin B levels in women with PWS may indicate potential fertility. Fertility in women with PWS raises many medical and ethical issues, given their intellectual disability and lack of autonomy, particularly regarding food intake, and appropriate anticipatory guidance, counseling, and education are crucial.

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