Male Reproduction Pathophysiology
Male infertility has a large number of causes, both endocrine and non-endocrine in origin and few are specifically treatable. In the majority of cases an exact diagnosis is not reached despite investigation and the condition may result from previous testicular damage, varicocoele or non-specific inflammation. All patients should be assessed with their partner in a specialist fertility unit and in the undiagnosed group the use of intracytoplasmic sperm injection may offer the best chance of fertility. The clinical features of male infertility are shown in Table 33.1.
Male reproductive pathophysiology Hypogonadism is the failure of the testes to function, that is to produce testosterone and spermatozoa, and can be due to genetic defects (see Chapter 23). Primary hypogonadism refers to abnormalities within the gonad, for example Leydig cell agenesis (non-development), or failure of Leydig cells in adult life. Leydig cell failure can occur after mumps. Secondary hypogonadism refers to gonadotrophin deficiency or failure to secrete gonadotrophin-releasing hormone (GnRH), and is also called hypogonadotrophic hypogonadism.
Hypergonadism means the excess activity of the gonad, which can be virilizing due to androgen-secreting Leydig cell tumours, or feminizing due to estrogen-producing Leydig cell tumours. This is primary hypergonadism, whereas that pro- duced through excess GnRH and/or gonadotrophin production is secondary hypergonadism.
Androgen resistance is caused by mutations of the androgen receptor, which no longer binds androgen with sufficient affinity for a normal androgenic response to be maintained, or by the complete absence of the androgen receptor.
Gynaecomastia is breast enlargement in males. It usually occurs through abnormal endogenous or exogenous estrogens. Gynaecomastia accompanied by galactorrhoea (milk production) may be indicative of a prolactin-secreting tumour. Gynaecomastia sometimes occurs in ageing men, which may be because of an increasing estrogen/ androgen ratio in the blood. The condition has also been reported after the smoking of cannabis, which is known to decrease testosterone synthesis and to drive down libido.
Impotence (erectile dysfunction) is the failure to achieve erection of the penis, and has numerous vascular and neurologi- cal causes, although few of endocrine origin. Erection is caused by nerve impulses passing through parasympathetic efferents, the nervi erigentes, to the penis. The result is vasodilatation of penile arteries, which allows the build-up of arterial blood in the corpus cavernosum and the corpus spongiosum.
The treatment of impotence was revolutionized by the introduction of sildenafil (Viagra). The drug dilates penile blood vessels by blocking the enzyme phosphodiesterase-5, which normally metabolizes the second messenger cyclic GMP, which in turn is permitted to prolong vascular smooth muscle relaxation in the penis, which is thus engorged with blood.
Benign prostatic hyperplasia (BPH) is the growth of the medial lobe of the human prostate, most often in late middleaged men, until it presses on and begins to occlude the urethra. It is termed ‘benign’ because it does not invade other tissues and destroy them, or metastasize to distant sites in the body. BPH is androgen-dependent, being strongly stimulated by dihydrotestosterone (DHT), the active androgenic metabolite of testosterone in the prostate gland. The most effective treatment has been the surgical removal of all or part of the gland. The operation can be performed through the bladder (transvesical prostatectomy) or through the urethra (transurethral resection), when prostate tissue is burned away using a heated element. Recently, inhibitors of the enzyme 5α-reductase, which converts testosterone to DHT, have been introduced to treat BPH.
Prostate cancer. Carcinoma of the prostate is virtually always androgen-dependent. Various approaches to treatment are shown in Fig. 33a. The aim is to remove the tumour and all sources of androgen production. Medical treatment may involve the administration of stable analogues of GnRH, such as buserelin. These, if continuously present in the bloodstream, down regulate anterior pituitary production of gonadotrophins by rendering the gonadotrophs insensitive to GnRH from the hypothalamus. The result is a chemical castration, which can be reversed by stopping treatment. Another approach is the administration of androgen receptor blockers such as flutamide, finasteride or cyproterone acetate.
When using GnRH analogues, it is advisable when starting treatment to administer the drug together with an antiandrogen. This is because the initial effect of the GnRH analogue is to stimulate a transient increase in testosterone production, which may in turn cause stimulation of tumour activity. Radiotherapy may be necessary as an adjunctive therapy or for the relief of pain due to metastatic spread.