Human Reproduction, Vol. 14, No. 1, 252-254,
January 1999
© 1999 European Society of Human Reproduction and Embryology
Case Report: Secondary infertility as early symptom in a man with multiple endocrine neoplasia-type 1
1 Andrology Unit, Department of Dermatology, Heinrich Heine University, Postfach 10 10 07, D-40001, Dusseldorf, 2 Institute for Hormone Research at the University of Hamburg, Hamburg, and 3 Department of Endocrinology, Heinrich Heine University, Dusseldorf, Germany
 |
Abstract |
|---|
 Top Abstract IntroductionCase reportDiscussionReferences |
|---|
Multiple endocrine neoplasia-type 1 (MEN1) is an autosomal dominant familial cancer syndrome characterized by parathyroid hyperplasia, pancreatic endocrine tumours and pituitary adenomas. Here, we report a patient with a history of insulinoma who developed secondary infertility as a further symptom of the disease. When he was first examined at the age of 36 years, he complained of weakness, reduced libido and impotence. Laboratory evaluation revealed non-obstructive azoospermia and hyperprolactinaemia. In contrast to sexual activity and serum prolactin, semen quality did not significantly respond to bromocriptine therapy. During follow-up, a growing pituitary adenoma caused acromegaly with elevated serum concentrations of growth hormone, insulin-like growth factor 1 (IGF-1), and prolactin. After microsurgery of the tumour at the age of 44 years, sperm concentration persistently increased up to 5.6x106/ ml. In accordance with the clinical diagnosis of MEN1, DNA sequencing revealed a mutation in exon 2 of the menin gene which results in a truncated, inactive protein product. In conclusion, MEN1 with pituitary lesions may cause severe hypogonadism and infertility. Both hyperprolactinaemia and overproduction of growth hormone and IGF-1 seem to be involved in testicular dysfunction in the present case. The possible role of menin in the testis, however, remains to be elucidated.
Key words: growth hormone/hypogonadism/hyperprolactinaemia/male infertility/multiple endocrine neoplasia-type 1
|
Introduction |
|---|
|
TopAbstractIntroductionCase reportDiscussionReferences |
|---|
Multiple endocrine neoplasia-type 1 (MEN1) is an autosomal dominant familial cancer syndrome characterized by parathyroid hyperplasia, entero-pancreatic endocrine tumours, and anterior pituitary adenomas (Samaan et al., 1989
). The tendency to develop these tumours with 94% penetrance at the age of 50 years results from mutations in a recently cloned tumour suppressor gene (menin gene) localized on chromosome 11q13 (Chandrasekharappa et al., 1997). About 30–65% of affected individuals reveal pituitary lesions with amenorrhoea and galactorrhoea as the main presenting symptoms in females and impaired sexual activity in males (Samaan et al., 1989). Previous reports, however, did not elucidate whether MEN1 may cause male hypogonadism and infertility. Here, we report a patient presenting with a history of secondary infertility and impotence as early symptoms of MEN1, in whom non-obstructive azoospermia was reversible after microsurgery of a pituitary adenoma. |
Case report |
|---|
|
TopAbstractIntroductionCase reportDiscussionReferences |
|---|
The patient was referred for andrological examination with a 10 year history of secondary infertility at the age of 36 years. He had suffered from hypoglycaemic episodes since puberty until a multicentric insulinoma of the pancreas was resected 5 years earlier. Moreover, unilateral gynaecomastia had been treated by mastectomy. For the previous 3 years, he had also noticed chronic weakness, reduced libido and impotence.
His general physical examination was unremarkable. Both testes were found in normal position with volumes of 15 ml. Testicular consistency, however, was diminished and small hydroceles could be detected. No other genital abnormalities were observed.
Initial semen analysis showed azoospermia with increased numbers of immature germ cells and normal secretory function of accessory glands (Table I). Basal serum concentrations of gonadotrophins were normal and testosterone slightly lowered, whereas the concentration of prolactin was significantly elevated (Table I). Other laboratory parameters including serum calcium were within normal range. A computerized tomography (CT) scan of the pituitary did not reveal any signs of a tumour.
|
Bromocriptine therapy at doses up to 10 mg/day resulted in prompt suppression of hyperprolactinaemia and normalization of serum testosterone. Sexual activity returned to normal. However, repeated semen analyses consistently showed sperm concentrations below 0.5x106/ml (Table I
). Hyperprolactinaemia, and hypoandrogenaemia, and azoospermia recurred when bromocriptine treatment was discontinued by the patient. During follow-up, he developed acromegaly with markedly elevated serum concentrations of growth hormone and insulin-like growth factor 1 (IGF-1), in addition to high prolactin and low testosterone (Table I). A CT scan now revealed an adenoma of the anterior pituitary with a diameter of 1.5 cm. Bromocriptine allowed normalization of prolactin concentrations and stopped further tumour growth. Growth hormone and IGF-1 concentrations, however, were not sufficiently controlled although additional somatostatin therapy was started. Therefore the patient underwent trans-sphenoidal microsurgery of the pituitary at the age of 44 years. After resection of the adenoma and normalization of respective hormone concentrations, semen quality significantly improved with sperm concentrations up to 5.6x106/ml, 40% motility and 13% morphologically normal spermatozoa (Table I). It should be noted that surgical treatment of hyperparathyroidism with elevated parathormone concentrations and hypercalcaemia at this time point had no further effect on semen parameters.
Recently, the clinical diagnosis of MEN1 in our patient (insulinoma, pituitary adenoma, hyperparathyroidism) was confirmed by molecular genetic analysis. The coding region of the menin gene (Chandrasekharappa et al., 1997), exon 2 to 10, was amplified by polymerase chain reaction and analysed by direct sequencing. A heterozygote mutation in exon 2, codon 108 was detected (CGA TGA) converting the codon for the amino acid arginine into a stop codon. This mutation results in a truncated, inactive menin protein. DNA sequencing revealed the same heterozygote mutation in one of the two daughters of the patient.
|
Discussion |
|---|
|
TopAbstractIntroductionCase reportDiscussionReferences |
|---|
In the present case, the development of impaired sexual activity and hypogonadism with non-obstructive azoospermia resulting in secondary infertility can be attributed to MEN1 causing pituitary tumourigenesis. Hyperprolactinaemia due to pituitary adenoma has been recognized as an uncommon cause of male infertility (Segal et al., 1979
; Cunnah and Besser, 1991). Excessive prolactin may impair production or pulsatile release of gonadotrophins and subsequently result in testicular dysfunction with hypospermatogenesis or spermatogenic arrest and decreased serum testosterone concentrations. Whether or not prolactin has direct effects on human spermatogenesis and sperm function is controversial and both association of hyperprolactinaemia with impaired sperm quality as well as lack of any correlation between serum prolactin concentrations and semen parameters were reported among infertile patients (Eggert-Kruse et al., 1991; Gonzales et al., 1992; Okada et al., 1996; Merino et al., 1997). In our patient, the poor response of semen quality to bromocriptine therapy indicates that hypogonadism was not solely related to hyperprolactinaemia. Progression of the pituitary lesion leading to markedly elevated growth hormone concentrations obviously continued to disturb normal function of the hypothalamic–pituitary–gonadal axis. Notably, high-dose bromocriptine stopped further tumour growth and allowed normalization of serum prolactin but did not control growth hormone release. Although growth hormone, its main mediator IGF-1, and other growth factors such as the fibroblast growth factors have been described as participating in the regulation of spermatogenesis (Spiteri-Grech and Nieschlag, 1993), our observation suggests that their overproduction during the course of MEN1 exerted negative effects on testicular function. This assumption contrasts with the beneficial effects of growth hormone treatment recently described in a group of subfertile males (Ovesen et al., 1996).
Although semen parameters in our patient significantly improved after microsurgery of the pituitary, he did not achieve normozoospermia. The following hypotheses should be considered. First, the long-standing pituitary disorder as manifestation of MEN1 caused partially irreversible damage of spermatogenesis. Second, despite the fact that he fathered two children before, the patient had a pre-existing testicular disorder, e.g. related to peri- and post-puberal metabolic disease due to insulinoma. Third, the transcript of the menin gene is ubiquitously expressed, including in the testes. The mutation of the menin gene identified in our patient results in a truncated, inactive protein product (Chandrasekharappa et al., 1997) and could therefore affect testicular function. Menin, however, has not yet been extensively studied at the protein level and its physiological role in the testis remains to be elucidated.
|
Notes |
|---|
4 To whom correspondence should be addressed
|
References |
|---|
|
TopAbstractIntroductionCase reportDiscussionReferences |
|---|
Chandrasekharappa, S.C., Guru, S.C., Manickam, P. et al. (1997) Positional cloning of the gene for multiple endocrine neoplasia-type I. Science, 276, 404–407.
Cunnah, D. and Besser, M. (1991) Management of prolactinomas. Clin. Endocrinol., 34, 231–235.[Medline]
Eggert-Kruse, W., Schwalbach, B., Gerhard, I. et al. (1991) Influence of serum prolactin on semen characteristics and sperm function. Int. J. Fertil., 36, 243–251.[Medline]
Gonzales, G.F., Garcia-Hjarles, M. and Velasquez, G. (1992) Hyperprolactinaemia and hyperserotoninaemia: their relationship to seminal quality. Andrologia, 24, 95–100.[Medline]
Merino, G., Carranza-Lira, S., Martinez-Chequer, J.C. et al. (1997) Hyperprolactinemia in men with asthenozoospermia, oligozoospermia, or azoospermia. Arch. Androl., 38, 201–206.[Medline]
Okada, H., Iwamoto, T., Fujioka, H. et al. (1996) Hyperprolactinaemia among infertile patients and its effect on sperm functions. Andrologia, 28, 197–202.[Web of Science][Medline]
Ovesen, P., Jorgensen, J.O., Ingerslev, J. et al. (1996) Growth hormone treatment of subfertile males. Fertil. Steril., 66, 292–298.[Medline]
Samaan, N.A., Ouais, S., Ordonez, N.G. et al. (1989) Multiple endocrine syndrome type I. Clinical, laboratory findings, and management in five families. Cancer, 64, 741–752.[Medline]
Segal, S., Yaffe, H., Laufer, N. and Ben-David, M. (1979) Male hyperprolactinemia: effects on fertility. Fertil. Steril., 32, 556–561.[Medline]
Spiteri-Grech, J. and Nieschlag, E. (1993) Paracrine factors relevant to the regulation of spermatogenesis – a review. J. Reprod. Fertil., 98, 1–14.
Submitted on July 8, 1998; accepted on October 8, 1998.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||