Chapter 10 The gonads
The testes are responsible for the synthesis of the male sex hormones (androgens) and the production of spermatozoa. The most important androgen, both in terms of potency and the amount secreted, is testosterone. Other testicular androgens include androstenedione and dehydroepiandrosterone (DHEA). These weaker androgens are also secreted by the adrenal glands but adrenal androgen secretion does not appear to be physiologically important in the male. In the female, however, it contributes to the development of certain secondary sexual characteristics, in particular the growth of pubic and axillary hair. The pathological consequences of increased adrenal androgen secretion are discussed in Chapter 8 and on p. 174.
Testosterone is a powerful anabolic hormone. It is essential both to the development of secondary sexual characteristics in the male and for spermatogenesis. It is secreted by the Leydig cells of the testes under the influence of luteinizing hormone (LH). Spermatogenesis is also dependent on the function of the Sertoli cells of the testicular seminiferous tubules. These cells are follicle-stimulating hormone (FSH) dependent; they secrete inhibin, which inhibits FSH secretion, and androgen-binding protein, the function of which is probably to ensure an adequate local testosterone concentration.
In the circulation, approximately 97% of testosterone is protein bound, principally to sex hormone-binding globulin (SHBG) and to a lesser extent to albumin. The free fraction is readily available to tissues; albumin binds testosterone more loosely than SHBG, and albumin-bound testosterone may be in part available. Free testosterone is considered a better indicator of effective androgen availability than total testosterone, but its measurement is technically difficult, and the ratio of testosterone/SHBG concentration may not accurately reflect free testosterone status. The biological activity of testosterone is mainly due to dihydrotestosterone (DHT). This is formed from testosterone in target tissues in a reaction catalysed by the enzyme 5α-reductase. In a rare condition in which there is deficiency of this enzyme, DHT cannot be formed; male internal genitalia develop normally (Wolffian duct development in the fetus is testosterone dependent) but masculinization, which requires DHT, is incomplete. In states of androgen insensitivity, defects of the receptors for either testosterone or DHT, or both, can cause a spectrum of clinical abnormalities ranging from gynaecomastia to disorders of sex development.
The cyclical control of ovarian function during the reproductive years is discussed in Chapter 7. The principal ovarian hormone is 17β-oestradiol, but some oestrone is also produced by the ovaries. Oestrogens are also secreted by the corpus luteum and the placenta.
Oestrogens are responsible for the development of many female secondary sexual characteristics. They also stimulate the growth of ovarian follicles and the proliferation of uterine endometrium during the first part of the menstrual cycle. They have important effects on cervical mucus and vaginal epithelium, and on other functions associated with reproduction.
Plasma concentrations of oestrogens are low before puberty. During puberty, oestrogen synthesis increases and cyclical changes in concentration occur thereafter until the menopause, unless pregnancy occurs. After the menopause, the sole source of oestrogens is from the metabolism of adrenal androgens; plasma concentrations fall to very low values. In the plasma, oestrogens are transported bound to protein, 60% to albumin and the remainder to SHBG. Only 2–3% remains unbound. Oestrogens stimulate the synthesis of SHBG and also that of other transport proteins, notably thyroxine-binding globulin (TBG) and transcortin, and thus increase total thyroxine and total cortisol concentrations in the plasma.
Slowly rising or sustained high concentrations of oestrogens, together with progesterone, inhibit pituitary gonadotrophin secretion by negative feedback, but the rapid rise in oestrogen concentration that occurs prior to ovulation stimulates LH secretion (positive feedback).
Oestradiol is present in low concentrations in the plasma of normal men. Approximately one-third is secreted by the testes, the remainder being derived from the metabolism of testosterone in the liver and in adipose tissue.
Progesterone is an important intermediate in steroid hormone biosynthesis but is secreted in appreciable quantities only by the corpus luteum and the placenta. Its concentration in plasma rises during the second half of the menstrual cycle but then falls if conception does not take place. In the plasma, it is extensively bound to albumin and transcortin: only 1–2% is free. Progesterone has many important effects on the uterus, including preparation of the endometrium for implantation of the conceptus, and also on the cervix, vagina and breasts. It is pyrogenic and mediates the increase in basal body temperature that occurs with ovulation. Progesterone can be measured in plasma, and this assay is used in the investigation of infertility in women (see p. 175).
SHBG binds both testosterone and oestradiol in the plasma, although it has greater affinity for testosterone. The plasma concentration of SHBG in males is about half that in females. Factors that alter SHBG concentration (Fig. 10.1) alter the ratio of free testosterone to free oestradiol. If SHBG concentration decreases, the ratio of free testosterone to free oestradiol increases, although there is an absolute increase in the concentrations of both hormones. If SHBG concentration increases, the ratio decreases. Thus in either sex, the effect of an increase in SHBG is to increase oestrogen-dependent effects, while a decrease in SHBG increases androgen-dependent effects (Fig. 10.2).
Figure 10.2 Effect of a change in serum sex hormone-binding globulin (SHBG) concentration on free oestradiol and testosterone concentrations. A decrease in SHBG increases free testosterone concentration more than free oestradiol and thus is androgenic; an increase in the concentration of SHBG is anti-androgenic. The normal ranges of SHBG in males and females are shown.
It is uncommon for a boy to enter puberty before the age of nine years. Precocious puberty is discussed in Chapter 21. Boys who have not entered puberty by the age of 14 years are considered to have delayed puberty. They often present earlier than this, more often with short stature (a result of the delayed pubertal growth spurt) than with concern about gonadal development. Delayed puberty can be constitutional (i.e. idiopathic, often associated with a family history), related to chronic illness (e.g. coeliac disease, cystic fibrosis) or a consequence of hypogonadism. Delayed puberty should be investigated to diagnose any pathological disorder: constitutional delayed puberty is essentially a diagnosis of exclusion.
The term hypogonadism implies defective spermatogenesis or testosterone production or both. It can be primary (i.e. due to testicular disease) or occur secondarily to pituitary or hypothalamic disease. Primary hypogonadism is sometimes referred to as ‘hypergonadotrophic hypogonadism’ (decreased feedback causes increased gonadotrophin secretion) and secondary hypogonadism as ‘hypogonadotrophic hypogonadism’ (the hypogonadism is a consequence of decreased gonadotrophin secretion because of either pituitary or hypothalamic disease). Some of the causes are indicated in Figure 10.3. Primary hypogonadism can be due to only defective seminiferous tubule function, only defective Leydig cell function, or both. The former leads to infertility through decreased production of spermatozoa, but masculinization is usually normal. Defective Leydig cell function, on the other hand, results in a failure of testosterone-dependent functions, including spermatogenesis. The effects of decreased testosterone secretion depend on age at the time of onset of the disorder. Secondary sexual characteristics are in part preserved if secretion is lost after puberty.
The basic biochemical characteristics that distinguish between primary and secondary hypogonadism are not always clear-cut. This is partly because most currently available assays for gonadotrophins are insufficiently sensitive to distinguish between low and normal concentrations. The plasma concentration of testosterone shows a circadian rhythm, and the usual recommendation is to measure it at 09:00 h. Also, the secretion of gonadotrophins and testosterone is pulsatile, and so, ideally, when basal concentrations or the effects of chronic stimulation are to be assessed, measurements should be made on more than one occasion.
Although biochemical tests are important in establishing that a patient has primary, rather than secondary, gonadal failure, they are less useful in distinguishing between the various causes of primary hypogonadism. In general, seminiferous tubule defects are associated with raised plasma FSH concentrations; Leydig cell defects are associated with raised plasma LH concentrations. Human chorionic gonadotrophin (hCG), which has an action similar to LH, can be used to test Leydig cell function (Fig. 10.4). Semen analysis will provide an indication of seminiferous tubule function, and testicular biopsy is valuable in patients with low sperm counts if the cause is not obvious clinically. Careful clinical examination is essential in all cases of gonadal failure.
Case history 10.1
A 20-year-old man presented with impotence. On examination, he was eunuchoid; there was only sparse pubic and axillary hair, the genitalia were infantile, muscular development was poor and his span exceeded his height with a sole–pubic symphysis distance greater than symphysis to crown.
|Serum: testosterone||3 nmol/L|
|Serum: LH||<1.5 U/L|
|Time (min)||FSH (U/L)||LH (U/L)|
|(after 100 µg GnRH s.c. daily for 2 weeks)|
Boys with constitutional delayed puberty occasionally do not enter puberty until 16–18 years of age, but this patient is clearly hypogonadal. The low testosterone and gonadotrophins in this case suggest a lesion at the level of either the pituitary or hypothalamus. This is confirmed by the failure of response to clomifene. This drug competes with gonadal steroids for hypothalamic receptors and in normal men results in an increase in gonadotrophin secretion and thus testosterone secretion. Patients with pituitary lesions may have clinical or biochemical evidence of other pituitary abnormalities (none was present in this case).
The GnRH test is sometimes used in an attempt to distinguish between pituitary and hypothalamic causes of hypogonadism, but in practice is of limited value. In pituitary disease, it might be expected that the luteinizing hormone (LH) and follicle-stimulation hormone (FSH) responses to gonadotropin-releasing hormone (GnRH) would be diminished or absent, but they can be normal. In hypothalamic disease, the response can be delayed (greater at 60 min than 20 min, cf. thyrotrophin-releasing hormone (TRH) test, p. 159), normal or decreased; in this case, it is both subnormal and delayed. The pituitary can become insensitive to exogenous GnRH in hypothalamic disease, and repeated injections of the hormone may correct this. When the GnRH test was repeated after GnRH priming, this patient’s response was normal, indicating a hypothalamic, rather than a pituitary, defect. He was later found to be anosmic (lacking a sense of smell). The association between anosmia and hypogonadotrophic hypogonadism is called ‘Kallman’s syndrome’. The eunuchoid habitus is a direct consequence of testosterone deficiency. Testosterone promotes epiphyseal fusion, and when its secretion is inadequate there is continued growth of long bones, which become disproportionate to the axial skeleton.
Had the FSH and LH concentrations been elevated in this patient, and with nothing in the history to suggest acquired testicular failure, the next investigation would have been karyotyping, to investigate for possible Klinefelter’s syndrome.
The treatment of hypogonadism in males should be directed towards the underlying cause wherever possible. Testosterone is given in testosterone deficiency syndromes, but if fertility is required treatment must be with gonadotrophin replacement or, in hypothalamic disorders, pulsatile gonadotropin-releasing hormone (GnRH) administration. Even in constitutional delayed puberty, a course of testosterone can be beneficial, giving a ‘kick-start’ to puberty, which often continues naturally thereafter. Testosterone replacement should aim to maintain plasma concentrations in the reference range for as long as possible between doses. The actual targets vary with the preparation and only apply once steady state has been reached (after a minimum of four treatments). With implants or injected long-acting testosterone the concentrations should be measured before the next dose is due, with a target range of 10–15 nmol/L; with transdermal patches or gel, 4–6 h after application, with a target range of 15–20 nmol/L. It is prudent to check liver function tests, prostate-specific antigen (PSA), haematocrit and plasma lipid concentrations at yearly intervals. Because prostate cancer is testosterone dependent, testosterone replacement treatment should be used with caution in older men.