Haemochromatosis as an endocrine cause of subfertility

British Medical Journal, March 21, 1998 by Michael J. Tweed, Jonathan M. Roland

Haemochromatosis is well established as a cause of infertility in both men and women, usually because iron deposition in the pituitary or the gonads leads to hypogonadism. As haemochromatosis is a fairly common disorder it should be considered when subfertility from an endocrine disorder is being investigated. We report on two related patients being investigated for subfertility in whom haemochromatosis was diagnosed only when one of them became diabetic.

Case reports

Case 1

A 32 year old man was referred to a tertiary referral centre for subfertility. He complained of failure of ejaculation and limited facial hair growth. Examination revealed female type and scanty axillary and pubic hair, soft testes (volume 8 ml), full visual fields, and a reduction in his sense of smell. Investigation confirmed a male karyotype. Testosterone, follicle stimulating hormone, and luteinising hormone concentrations were undetectable even after gonadotrophin releasing hormone had been given intravenously. Thyroid stimulating hormone and prolactin concentrations and a computed tomogram of the head were normal. Initially he was treated with testosterone esters and then chorionic gonadotrophin and menotrophin. Subsequently his partner had two successful pregnancies.

Four years later he became diabetic and was referred to our hospital clinic. He was noted to be pigmented. Haemochromatosis was confirmed by an iron saturation of 93.4%, a ferritin concentration of 1036 [Mu]g/l, and typical pre-cirrhotic changes in a liver biopsy specimen.

Case 2

The family of the patient in case 1 was screened for haemochromatosis. His 34 year old sister had an iron saturation of 99.9% and a ferritin concentration of 2130 [Mu] g/l. A liver biopsy confirmed haemochromatosis and established nodular cirrhosis.

At 24 years of age she had presented with amenorrhoea after stopping taking the contraceptive pill. Her gonadal function at that time was normal. Five years later she was still amenorrhoeic. Luteinising hormone and follicle stimulating hormone concentrations were undetectable. Prolactin and thyroid stimulating hormone concentrations were normal. Dye testing and examination under anaesthesia showed a small uterus and patent tubes. She was referred to a tertiary referral centre, but despite further investigation and treatment she did not become pregnant.

Discussion

Haemochromatosis is arguably the most common genetic disorder in Europeans.[1] The homozygote frequency is 0.3-0.5% and the carrier frequency 6.7-10%.[2] In prospective epidemiological studies of the general population the frequency of haemochromatosis was 0.37%, with a gene frequency of 6.1% and a heterozygote frequency of 11.5%.[3] Hypogonadism caused by haemochromatosis may be due to hypothalamic,[4] pituitary,[5] or gonadal dysfunction or to a combination of these.[6-8] Iron deposition at these sites has been seen at biopsy and on magnetic resonance imaging.[9, 10]

An early diagnosis of haemochromatosis is important as aggressive venesection can restore hypothalamic-pituitary-gonadal[4, 11] and reproductive[12] function. In older patients with more established disease venesection does not restore hypothalamic-pituitary-gonadal function.[13] Testosterone may, however, restore potency and libido in men,[14] and gonadotrophin treatment may restore fertility in women.[15]

Young patients presenting with endocrine abnormalities have a poor prognosis, but early diagnosis and prompt iron depletion may improve the prognosis with regard to other organ damage.[16] Survival analysis has shown that in the absence of cirrhosis or diabetes venesection leads to a normal life expectancy.[3]

Despite its frequency and effect on the endocrine system, haemochromatosis has attracted surprisingly little attention in endocrinology[17, 18] and fertility text books,[19] although it is mentioned in the larger general medical textbooks.[20, 21] A normal ferritin concentration is needed to confirm a diagnosis of adult onset idiopathic hypogonadotrophic hypogonadism.[22] Haemochromatosis should be considered when subfertility from an endocrine disorder is being investigated.

[1] Beutler E. Genetic irony beyond haemochromatosis: clinical effects of HLA-H mutations. Lancet 1997 349:296-7.

[2] Gluckman E. Hemochromatosis in heterozygotes. N Engl J Med 1996:24:1837-8.

[3] Nideru C, Stremmel W, Strohmeyer G. Clinical spectrum and management of haemochromatosis Baillieres Clin Haematol 1994;7:881-901.

[4] Piperno A, Rivolta MR, D'Alba R, Fargion S, Rovelli F, Ghezzi A, et al. Preclinical hypogonadism in genetic haemochromatosis in the early stage of the disease: evidence of hypothalamic dysfunction. J Endocrinol Invest 1992;15:423-8.

[5] Duranteau L, Chanson P, Blumberg-Tick C, Brailly S, Lubetzki J, Schaison G, et al. Non-responsiveness of serum gonadotrophins and testosterone to pulsatile GnRH in haemochromatosis suggesting a pituitary defect. Acta Endocrinol 1993;128:351-4.

[6] Bhansali A, Banerje PK, Dash S, Radortra B, Dash RJ. Pituitary and testicular involvement in primary haemochromatosis. A case re port J Assoc Physicians India 1992;40:757-9.