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Department of Obstetrics and Gynecology, and Division on Endocrinology, Department of Medicine, Helsinki University Central Hospital, FIN-00029 Helsinki, Finland
Address all correspondence and requests for reprints to: Aila Tiitinen, M.D., Ph.D., Department of Obstetrics and Gynecology, Helsinki University Central Hospital, P.O. Box 140, FIN-00029 Helsinki, Finland. E-mail: . aila.tiitinen{at}hus.fi
Abstract
We describe a 45-yr-old man, who presented with primary infertility of 2 yr. He had small testicles with severe oligoasthenozoospermia and low serum gonadotropins, but normal serum T. The suppression of gonadotropin secretion by increased adrenal steroids due to untreated 21-hydroxylase deficiency appeared to underlie the failure in spermatogenesis. Hydrocortisone treatment was started and was modified later to include prednisolone to get optimal suppression of the secretion of ACTH and adrenal steroids. Within a few months, the gonadotropin levels became normal, and spermatogenesis was improved. A normal pregnancy was achieved.
IN MANY INFERTILE men with severe oligoasthenoteratozoospermia, no specific treatment is available to improve sperm quality. Various assisted reproductive techniques, especially intracytoplasmic sperm injection (ICSI), are increasingly used. However, specific diagnosis should be made to avoid unnecessary therapeutic procedures. Gonadotropin deficiency is a rare cause of male infertility and accounts for less than 1% of all cases.
Gonadotropin suppression may occur in a number of circumstances. Very rarely, excessive adrenal steroid production underlies the inhibition of the hypothalamic-pituitary axis, resulting in failure of normal testicular maturation. Information on the fertility of males with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is limited and controversial. A recent Finnish study (1) found normal pituitary and gonadal function but a reduced fertility rate in treated adult males with CAH. In this study, sperm counts were not evaluated. Thus, it could not be stated whether the subfertility was due to the effect of suboptimal treatment on the hypothalamo-pituitary-gonadal axis or suboptimal psychosocial adaptation to the chronic disease. It has even been reported that in males with CAH the fertility is normal and that the glucocorticoid therapy may not be necessary for fertility (2). However, a high frequency of gonadal abnormalities in adult males with classical CAH has been described (3). Reversible infertility in untreated CAH has been reported only in a few males (3, 4, 5, 6).
Case Report
A 45-yr-old man presented to the Department of Obstetrics and Gynecology, Helsinki University Central Hospital, with primary infertility of 2 yr. His wife was 34 yr old, healthy, and had not been pregnant before. Her fertility check-up was normal: ovulatory cycles with normal PRL levels and thyroid function; the transvaginal ultrasound revealed normal uterus and ovaries. The couple had not used contraception during the previous 2 yr and reported normal sexual intercourse at least twice a week.
In the primary evaluation, the husband presented no history of chronic diseases or usage of any medication including T and anabolic steroids. He revealed no history of abnormalities of pubertal development. He was normally built and virilized, but short, with actual height of 162 cm. His blood pressure was normal (130/80 mm Hg). On examination, he was found to have soft and small testicles (volume, 10 ml) but no palpable testicular nodules. The initial sperm analysis revealed low sperm volume (0.5 ml), very low sperm counts with poor motility (sperm density, 1.8 million/ml; progressive motility, 9%). Sperm analysis was performed according to the 1999 World Health Organization laboratory manual. Thereafter, the endocrine status was analyzed, and the subject was found to have low gonadotropin values (LH, 0.2 IU/liter, and FSH, 0.4 IU/liter; normal range, LH, 1.0–9.0 IU/liter, and FSH, 1.0–7.0 IU/liter) but normal T level, (17.0 nmol/liter; normal range, 10.0–38.0 nmol/liter). The karyotype was normal 46XY, and no microdeletion of Y chromosome was found. Due to very low gonadotropins, magnetic resonance imaging of the pituitary was performed and was found to be normal. The patient remembered having been examined at the age of 7 yr because of excessive growth. The old hospital charts with a photograph and results for urinary 17-ketosteroids and pregnanetriol levels showed that a diagnosis of CAH was already made at that time. However, the treatment was not started, and the patient was lost from the follow-up. The patient had had no episodes of symptomatic hypocortisolism, but he had felt tiredness. He reported occasionally lessened libido.
Additional studies were performed to ascertain the diagnosis of 21-hydroxylase deficiency. Basal ACTH levels were high (877 ng/liter; normal, 10–50 ng/liter) as were 17-hydroxyprogesterone (17-OHP) levels (978 nmol/liter; normal, 1.2–5.0 nmol/liter). Androstenedione was high (83 nmol/liter; normal, 1.4–7.0 nmol/liter), dehydroepiandrosterone (DHEA) was slightly elevated (57 nmol/liter; normal, 7.0–45.0 nmol/liter), but estradiol was normal (0.06 nmol/liter; normal, <0.13 nmol/liter). An ACTH stimulation test was performed by administering an iv bolus of 250 µg ACTH and sampling blood before and 20 and 60 min after the injection, but it revealed no further stimulation of 17-OHP, and cortisol levels were constantly low normal (Table 1
). A GnRH test was performed by administering an iv bolus of 100 µg GnRH and sampling blood before and 20 and 60 min after the injection. It revealed subnormal responses of the gonadotropins (Table 2). Serum inhibin B level, as measured using ELISA, was low normal 75 ng/liter (normal mean ± SD, 153 ± 60 ng/liter for 53 healthy men with a mean age 39 yr by the same assay) (7).
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). Serum inhibin B had increased to 144 ng/liter. Computer tomography scanning showed that the adrenal glands were enlarged in size. The ultrasound examination of the testes did not reveal any adrenal rest tumors. The diagnosis of 21-hydroxylase deficiency was ascertained using molecular analyses (8). The patient appeared to have the I172N mutation in one of his alleles, whereas the second allele contained a combination of six different mutations (I172N + Cluster E6 + V281L + L307insT + Q318X + R356W).
Discussion
Our patient had primary infertility with small testicles, severe oligoasthenozoospermia, low serum gonadotropins, but normal circulating T levels. Primarily, he offered a diagnostic challenge, because the first biochemical evaluation did not comprise the determination of serum ACTH, 17-OHP, or androstenedione. The clinical and biochemical findings fitted well also to the use of T preparations that the patient denied. He aided the diagnosis by recalling the investigations performed nearly 40 yr earlier. In the biochemical evaluation, the lack of the response of serum 17-OHP to an ACTH bolus was exceptional. We reasoned it to be due to the maximally stimulated adrenal steroidogenesis, with the basal 17-OHP being 200 times the upper limit of normal. The diagnosis of 21-hydroxylase deficiency was ascertained by gene analysis that exhibited an I172N mutation in one allele, whereas the second allele contained a combination of different mutations. This type of multiply mutated allele has previously been seen in the Finnish population (9). Untreated 21-hydroxylase deficiency has to be remembered as one cause of the suppressed gonatropin levels because it is possible that substantial numbers of men with the deficiency fail to see the need for therapy and go untreated.
The literature on the fertility of males with CAH is controversial. It has been postulated that the fertility is normal in CAH males and that the therapy may not be necessary for fertility (2). Apparent normal fertility, indicated by paternity and normal sperm counts, was found in 18 of 20 men in that patient series. The authors even described two patients who never had been treated and two patients without treatment for several years before the evaluation, who all had one to three children. On the biochemical evaluation, they had normal plasma gonadotropin and T levels. In the population of all the adult Finnish males with the diagnosis of classical CAH and treatment with glucocorticoids, the fertility rate was reduced (1). In the absence of sperm analyses, the reason remained open, but a suboptimal psychosocial adaptation to the chronic disease or an insufficient substitution by glucocorticoids were considered. On the other hand, a high frequency of gonadal abnormalities and abnormal sperm counts has recently been reported in a group of 30 males (age > 15 yr) who had a regular follow-up at one institution (3). Nine of 16 patients with the fertility tested by either the sperm count or the history of fathering a child had azo- or oligospermia; 7 men had normal fertility. The fertility problems were due either to the suppression of the hypothalamic-pituitary-gonadal axis with resultant small testes and decreased spermatogenesis or to ectopic testicular adrenal rests that had become hypertrophic under chronic ACTH stimulation (3). It has been suggested that these nodules gradually expand and destroy the testicular parenchyma, resulting in low T production and infertility (4). Recently, Murphy et al. (10) described a patient with azoospermia due to obstruction by adrenal rest tissue, strategically situated at the hilum of the testes. Adrenal rest tumors, often related to infertility, have been found in 10% of males with classical CAH (11, 12).The distinction between the two pathogenetic mechanisms can be made not only by the testicular sonogram but also by measuring the serum gonadotropin levels, which are either normal or even high in the case of the testicular rest tumors (3).
In our patient, the suppression of gonadotropin secretion appeared to be the main reason for the failure of spermatogenesis. He did not have any palpable testicular nodules, and the testicular sonogram was normal. The sonogram was, however, performed when the patient was already on treatment, and it is well known that with adequate glucocorticoid treatment these masses usually disappear, which can lead to a subsequent return of fertility (4). Our patient had normal serum T level, but the intratesticular T concentration may have been low and contributed to impaired spermatogenesis, because up to 90% of the circulating T can originate from peripheral interconversion from androstenedione (5). Note that on treatment, the patient exhibited lowering serum T levels at the same time when the spermatogenesis improved and serum gonadotropin levels rose, which may have been the case also for the intratesticular T concentration.
The excessively increased production of adrenal steroids in CAH males has been considered as a main reason for the inhibition of the release of gonadotropins, resulting in failure of normal testicular maturation. Which of the increased adrenal androgens or their precursors and metabolites is responsible for the gonadotropin suppression is not exactly established (6).
In one case, the suppression of serum gonadotropins was explained by the very high circulating concentrations of T (5). It has been related also to increased serum estrogens, originating directly from the adrenals or through the peripheral transformation from adrenal androgens and acting at the hypothalamic level to inhibit the GnRH secretion (13). In our patient, serum estradiol and T were normal. Unfortunately, we did not measure serum estrone. Androstenedione is a more efficient estrogen precursor than T, and it was produced in high amounts in our patient. It seems probable that an increase of hypothalamic estrogen production due to local androstenedione aromatization to estrone might be present in male patients with CAH and responsible for the inhibition of the hypothalamic release of GnRH (6). This hypothesis was enforced by the increase in FSH and LH levels after the use of antiestrogen clomiphene (6). Recently, it was demonstrated that in terms of sex steroid feedback, estrogens are the predominant regulators of FSH secretion in the human male and that T exerts its feedback effect on FSH largely by aromatization to estrogens (14). Thus, the role of the hypothesized increase of local estrogen production may have contributed more to the suppression of FSH than LH secretion in the present patient. Keeping in mind that he had normal circulating (even though not necessarily intratesticular) T concentration, the FSH deficiency alone may have been the major reason for his infertility.
Our patient is unique in the respect that the fertility was achieved by a short treatment with glucocorticoids, despite his rather high age of 45 yr and the long duration of gonadotropin deficiency. Reversible infertility due to gonadotropin suppression in untreated CAH males has been reported earlier, but in much younger men (3, 5, 6). Nevertheless, in some cases the suppression of the pituitary-gonadal axis has not disappeared despite suppression of adrenal hormones with dexamethasone (3).
Circulating FSH is a valuable marker for Sertoli cell function and spermatogenesis. The regulation of gonadotropin secretion in the human male involves a complex interplay between stimulation by GnRH secretion and inhibitory feedback by sex steroids comprising T and estradiol. It has also been increasingly appreciated that for FSH there is an additional level of complexity mediated by nonsteroidal factors. On the basis of a very recent paper (15), among these nonsteroidal factors inhibin B is likely to be the major feedback regulator of FSH secretion in the human male. It has been proposed that serum inhibin B could be used as a marker of spermatogenesis in studies on male reproductive health (16). As in our patient with low levels of both FSH and inhibin B, the normal negative correlation between serum inhibin B and FSH concentrations could not be found in the Finnish CAH patient group, which was compatible with the suppression of FSH secretion by excessive amounts of adrenal steroids (1). In our patient during the glucocorticoid treatment, serum inhibin B levels were normalized at the same time as sperm counts. This suggests that in CAH males serum inhibin B could be used as a biomarker for spermatogenesis.
Undiagnosed and/or untreated 21-hydroxylase deficiency may underlie male infertility due to the suppression of gonadotropin secretion. Our patient shows that even after a long duration of gonadotropin deficiency the fertility can be achieved with appropriate treatment with glucocorticoids.
Acknowledgments
Footnotes
Abbreviations: CAH, Congenital adrenal hyperplasia; ICSI, intracytoplasmic sperm injection; 17-OHP, 17-hydroxyprogesterone.
Received January 31, 2001.
Accepted March 18, 2002.
References
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