Gonadotropin Deficiency And Suppression

3.0 GONADOTROPIN DEFICIENCY AND SUPPRESSION

Clinical Characteristics

Most men seeking treatment for infertility associated with gonadotropin deficiency have been treated with androgens, following presentation in adolescence with delayed puberty.
The main diagnoses are Kallmann syndrome, other isolated gonadotropin deficiencies, combined gonadotropin and growth hormone deficiency and rarely pituitary tumours, trauma or craniopharyngiomas treated in childhood. Occasionally men with previously undiagnosed prepubertal gonadotropin deficiency present with infertility.
The clinical features are usually very small testes (<4mL) and severe androgen deficiency.
There may be a child like appearance with lack of secondary sex hair development, failure of male pattern scalp hair recession and balding and eunuchoidal proportions.
Gonadotropin deficiency may develop after puberty because of tumours, surgery or trauma of the pituitary or hemochromatosis.
These men usually note loss of libido and may note reduced beard and body hair growth, low ejaculate volume and decreased testicular size.
General lethargy, muscular weakness and hot flushes are also common but non-specific symptoms.

Physical examination

Physical examination may show
Testicular atrophy,
Reduced secondary sex hair
Dry finely wrinkled skin on the face.
Gynaecomastia may be present.

Features of underlying or associated conditions may be present for example:

Headache
Visual disturbance
Hormone excess or deficiency with pituitary tumours, or pigmentation,
Liver disease or diabetes with haemochromatosis.
Hyperprolactinemia is uncommon in men. It usually presents with loss of libido and impotence,
Low testosterone levels and variable semen analysis results from azoospermia to relatively normal.
Galactorrhea may occur,
Sometimes with only minimal gynaecomastia.
There is usually a pituitary tumour.
Hyperprolactinemia associated with a pituitary macroadenoma is rare but important: as well as loss of libido there is usually progressively severe headache and visual field impairment.
A number of paediatric syndromes include mental deficiency and gonadotropin deficiency but the patients rarely seek treatment for infertility as adults.
Mutations of DAX1 cause adrenal hypoplasia and gonadotropin deficiency.
Gonadotropin suppression may occur in a variety of circumstances.
The most common now appears to be the illicit use of anabolic and androgenic steroids or chorionic gonadotropin.
Other hormones and drugs can cause gonadotropin suppression.
Selective suppression of LH with intrathecal opioids for chronic pain has been discovered recently.
Rarely men are seen with hormone producing tumours for example adrenal adenomas, Leydig cell tumours or hCG producing teratomas which will suppress gonadotropins, usually there are features of marked hyperestrogenization with progressive gynecomastia.
Very rarely men are seen with congenital adrenal hyperplasia with gonadotropin suppression and azoospermia who can be treated successfully by glucocorticoid suppression of ACTH.
Spermatogenesis may occur despite severe androgen deficiency - the so-called fertile eunuch syndrome.
This is believed to be due to predominant LH deficiency or partial gonadotropin deficiency.
There may be normal sperm concentrations but usually there is low ejaculate volume and sperm motility.
The fertile eunuch syndrome commonly occurs with hyperprolactinemia, hemochromatosis, starvation, illness or in athletes in negative energy balance.
It is also seen with partial or mild Kallmann syndrome.

Pathophysiology

Commonly gonadotropin deficiency is caused by genetic disorders of gonadotropin releasing hormone production or the GnRH receptor, loss of function of gonadotrophes, or suppression of gonadotropin secretion by extraneous steroids, other drugs or illness.
There is usually a combined defect of androgen and gamete production.
If the underlying cause cannot be corrected life long androgen replacement therapy is required.
This is usually with a form of testosterone but when fertility is desired, treatment must be changed to gonadotropins.
While experimental conditions may be found to indicate that either FSH or LH alone may be able to initiate spermatogenesis in humans, for practical clinical purposes treatment with LH alone (as hCG) is effective for fertile eunuch syndrome and may be effective where spermatogenesis has been stimulated before, either by natural puberty or previous gonadotropin therapy. In other situations both FSH and LH are required.

Differential Diagnosis

In men with gonadotropin deficiency it is necessary to determine the cause of the disorder, or if this is not possible to exclude a serious underlying cause such as a pituitary tumour.
With Kallmann syndrome there is hyposmia or anosmia from malformations of the rhinencephalon.
Other abnormalities may also be present including colour blindness, cleft lip and cerebellar ataxia.
Except where the diagnosis is obvious, detailed radiological examination of the pituitary and hypothalamic area is necessary, together with full pituitary function tests to determine if there are other hormone deficiencies.

Treatment

Gonadotropin suppression from administration of Ayurvedic drugs is treated by withdrawal of the agents, and starvation induced gonadotropin suppression by refeeding.
Hyperprolactinemia can be treated with bromocriptine or other dopamine agonist.
Gonadotropin deficiency caused by of gonadotrophe destruction or abnormalities of the GnRH receptor require treatment with gonadotropins.
Some men with gonadotropin releasing hormone deficits can be treated successfully with pulsatile GnRH administration.