Male hypogonadism: an extended classification based on a developmental, endocrine physiology-based approach.

Normal testicular physiology results from the integrated function of the tubular and interstitial compartments. Serum markers of interstitial tissue function are testosterone and insulin-like factor 3 (INSL3), whereas tubular function can be assessed by sperm count, morphology and motility, and serum anti-Müllerian hormone (AMH) and inhibin B. The classical definition of male hypogonadism refers to testicular failure associated with androgen deficiency, without considering potential deficiencies in germ and Sertoli cells. Furthermore, the classical definition does not consider the fact that low basal serum testosterone cannot be equated to hypogonadism in childhood, because Leydig cells are normally quiescent. A broader clinical definition of hypogonadism that could be applied to male patients in different periods of life requires a comprehensive consideration of the physiology of the hypothalamic-pituitary-testicular axis and its disturbances along development. Here we propose an extended classification of male hypogonadism based on the pathophysiology of the hypothalamic-pituitary-testicular axis in different periods of life. The clinical and biochemical features of male hypogonadism vary according to the following: (i) the level of the hypothalamic-pituitary-testicular axis primarily affected: central, primary or combined; (ii) the testicular cell population initially impaired: whole testis dysfunction or dissociated testicular dysfunction, and: (iii) the period of life when the gonadal function begins to fail: foetal-onset or postnatal-onset. The evaluation of basal testicular function in infancy and childhood relies mainly on the assessment of Sertoli cell markers (AMH and inhibin B). Hypergonadotropism should not be considered a sine qua non condition for the diagnosis of primary hypogonadism in childhood. Finally, the lack of elevation of gonadotropins in adolescents or adults with primary gonadal failure is indicative of a combined hypogonadism involving the gonads and the hypothalamic-pituitary axis.

Síndrome de Klinefelter en las distintas edades: experiencia multicéntrica / Klinefelter Syndrome at differents ages: multicentric experience

El Síndrome de Klinefelter (SK) es la anormalidad cromosómica más frecuente en los varones, con una prevalencia estimada de 1:600 recién nacidos. El objetivo de este trabajo fue establecer las distintas características de presentación del SK a distintas edades, incluyendo signos y síntomas clínicos, parámetros de laboratorio y otros exámenes complementarios. La franja etaria más frecuente de diagnóstico de SK fue entre los 11 y 20 años (46,8%). En 4 casos el diagnóstico fue prenatal. Los motivos de consulta más frecuentes en forma global fueron la presencia de testículos pequeños, infertilidad y criptorquidia. El cariotipo más prevalente fue el clásico 47,XXY (83,7%), seguido del mosaico 47,XXY/46,XY (7,1%). El promedio de talla de nuestros pacientes prepuberales no mostró diferencia con la población general. Por otro lado, los pacientes puberales presentaron un promedio de talla significativamente más alto, hallándose alrededor de 1 SDS. Hubo correlación entre la edad y el SDS de talla. La media de talla de los adultos fue 178,8 ± 9,0 cm; se observó un 62,5% de sobrepeso/obesidad (IMC ≥ 25,0 kg/m²). El 50% de nuestros pacientes con SK menores de 18 años presentaron trastornos neurocognitivos. El hallazgo clínico más frecuente entre los pacientes prepuberales fue la criptorquidia. En los puberales las consultas y hallazgos clínicos más frecuentes fueron: testículos pequeños, criptorquidia y ginecomastia. Todos nuestros pacientes en estadio de Tanner igual o mayor de III presentaron testículos más pequeños para su grado de desarrollo. Los valores de FSH y LH fueron normales en los pacientes prepuberales y comenzaron a aumentar en la pubertad. Los adultos consultaron más frecuentemente por hipotrofia testicular, infertilidad y en menor grado ginecomastia. Todos los pacientes presentaron testículos hipotróficos, con una mediana de volumen testicular de 3,5 (1-8) ml. El 56,4% presentaron función sexual normal; el resto tuvo algún tipo de disfunción sexual. La testosterona total (TT) fue normal en 45% de los pacientes, con descenso consistente con la edad, donde todos los pacientes mayores de 40 años presentaron TT subnormal. El 10,7% de los pacientes que efectuaron espermograma tuvo oligospermia severa, el resto presentó azoospermia. La densitometría ósea fue anormal en el 46,4% de los adultos estudiados. Sin embargo, no hubo diferencias significativas en la prevalencia de osteopenia y osteoporosis entre los pacientes con TT normal o subnormal.

Klinefelter syndrome (KS) is the most common chromosomal aberration among men, with an estimated prevalence of 1:600 newborns. It is an X chromosome polysomy, with X disomy being the most common variant (47,XXY). The aim of this study was to establish the characteristics of KS presentation at different ages, including signs and symptoms, laboratory parameters and other diagnostic tests. The diagnosis of KS was more frequent in the age group between 11 and 20 years (46.8%). Most of the patients (83.7%) showed the classic 47,XXY karyotype and 7.1% showed a 47,XXY/46,XY mosaicism. While mean prepubertal height was not different from the control population, it was significantly higher at puberty. Patients consulted most frequently for small testes, infertility and cryptorchidism. In four cases the diagnosis was prenatal. 50% of our patients younger than 18 years presented neurocognitive disorders. The more frequent clinical findings were cryptorchidism in prepubertal patients; small testes, cryptorchidism and gynecomastia in pubertal patients. All our patients in Tanner stage III or more presented small testes. FSH and LH levels were normal in prepubertal patients and increased abnormally at puberty. On the other hand, most adults consulted for small testes, infertility and gynecomastia. 43.6% of patients had decreased libido, sexual and/or ejaculatory dysfunction. In adults average height (178.8 ± 9.0 cm) and weight (83.6 ± 21.0 kg), were higher than in the normal population, however 8 patients (19%) had a height less tan 170 cm. There was 62.5% of overweight / obesity (BMI ≥ 25.0 kg/m²) in the whole group of adult patients. 35.2% had eunuchoid proportions. All patients had testicular hypotrophc, with a median testicular volume of 3.5 ml (range 1-8 ml). Total testosterone (TT) levels were normal in 45% of adult patients, showing significant correlation with age. All patients aged 40 or more years had subnormal TT levels. In patients who underwent semen analysis, severe oligospermia and azoospermia were found in 10.7% and 89.3% respectively. Bone mineral densitometry showed low bone mass in 46.4% of cases. No significant differences in the prevalence of osteopenia and osteoporosis were observed among patients with normal or subnormal TT.

Diferentes respuestas somáticas y densitométricas sobre el hueso cortical y trabecular a la androgenoterapia en varones hipogonádicos / Different somatic and densitometric responses of cortical and trabecular bone to androgen therapy in hypogonadal men

Una consecuencia clínica de la deficiencia de testosterona en el varón es el descenso de la densidad mineral ósea (DMO), asociado a mayor riesgo de fractura (con la consiguiente morbi-mortalidad en el hombre añoso), y cambios de la composición y el contenido de calcio corporal total. Para cuantificar los efectos de la androgenoterapia sobre la composición corporal y el contenido de calcio corporal, correlacionar los cambios hormonales con los densitométricos y de la composición corporal, y constatar posibles diferencias densitométricas regionales, se incluyeron 15 varones hipogonádicos. Se determinaron variables antropométricas, bioquímicas, densitométricas y de la composición corporal en condiciones basales y bajo la terapia sustitutiva. Como resultado, se logró compensar el déficit androgénico y duplicar la concentración de estradiol. El eugonadismo inducido incrementó la DMO como el contenido del calcio corporal total. Además, redujo el porcentaje de masa grasa corporal total (principalmente abdominal) y aumentó la masa muscular corporal total, con incremento de la relación masa magra/masa grasa, sin cambios del índice de masa corporal. En conclusión, nuestros resultados afirman el papel preponderante de los esteroides sexuales sobre la composición corporal y su rol en el hueso. El hipogonadismo masculino constituye un factor de riesgo para osteoporosis y enfermedad cardiovascular.

A clinical consequence of testosterone deficiency in males is the reduction of bone mineral density (BMD), associated with a higher risk of fracture (and a subsequent increase in morbi-mortality in elderly men) and with changes in body composition and total body calcium content. In order to quantify the effects of androgen therapy on body composition and body calcium content, and to correlate changes in hormone levels with densitometric changes and changes in body composition changes, as well as to determine potential regional densitometric differences, 15 hypogonadal men were included in the present study. Anthropometric, biochemical, densitometric and body composition variables were analyzed under basal conditions, and under replacement therapy. As a result, androgen deficiency was compensated, and estradiol level was twice as high. Induced eugonadism increased both BMD and total body calcium content. Also, replacement treatment reduced the percentage of total body fat, (primarily abdominal fat) and increased total muscle mass, with an increment of the lean mass/fat mass ratio, and no change in BMI. In conclusion, our results strengthen the preponderant role of sexual steroids on body composition, and its effect on bones. Male hypogonadism is a risk factor for osteoporosis and cardiovascular disease.

PCR analysis of Y-chromosome sequences in a 45,X male patient and a review of the literature.

The 45,X karyotype is usually associated with Turner syndrome, while male phenotype is exceptional. The authors report a 45,X male patient with normal external genitalia and sex behavior, but who was azoospermic. He had a normally developed musculature and pilose distribution, testicular volume of 15 mL and no gynecomastia but clinical stigmata of Turner syndrome (short stature, short neck and 4th metacarpal bones) and azoospermia. Hormonal plasma levels of testosterone, estradiol, prolactin, and gonadotrophins were within the normal range as was the response of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (30 and 60 min) after 100 microg iv of LH-RH administration. Testicular biopsy could not be performed. Karyotype was 45,X without evidence of mosaicism. Polymerase chain reaction of genomnic DNA studied with 12 different sequences of Y chromosome revealed only the presence of SRY gene (testis determining factor). It is possible that SRY/autosomal translocation had occurred in this patient. The study of 45,X male should be of great value in elucidating the complex mechanisms involved in normal male sex differentiation.

Recombinant human follicle-stimulating hormone administration increases testosterone production in men, possibly by a Sertoli cell-secreted nonsteroid factor.

We previously showed that recombinant human FSH (R-FSH) in males increased the testosterone (T) concentration in spermatic venous blood (SB). To investigate the effect of R-FSH on spermatic steroid levels and the action of steroid- and LH-free SB on isolated Leydig cells, nine normospermic males were studied during spermatic cord surgery. Peripheral blood and SB samples were collected before and 30 min after iv administration of 150 U R-FSH to measure LH, FSH, T, estradiol, 17alpha-hydroxyprogesterone, and sex hormone-binding globulin, and in SB, androstenedione (delta4) and dehydroepiandrosterone (DHEA) were also measured. LH bioactivity was assessed by in vitro production of T in isolated Leydig cells. The actions of R-FSH and SB (steroid and LH free) were analyzed in the bioassay. Data are expressed as the mean +/- SE. FSH in peripheral blood and SB increased by 411% and 477% after R-FSH administration. R-FSH induced a significant increase in spermatic T (basal vs. 30 min, 326.4 +/- 98.5 vs. 732.4 +/- 152.8 ng/mL; P < 0.047) and in spermatic estradiol (289.5 +/- 66.9 vs. 535.6 +/- 83.4 pg/mL; P < 0.036). The T/delta4 ratio (36.9 +/- 9.2 vs. 74.5 +/- 13.3; P < 0.019) and the T/DHEA ratio (10.8 +/- 1.1 vs. 22.4 +/- 4.9; P < 0.024) increased significantly. In isolated Leydig cells, R-FSH did not change T production, but the SB (steroid and LH free) after R-FSH administration induced an increase in T production (3.3 +/- 0.6 vs. 4.9 +/- 0.6 ng/tube; P < 0.04). LH-like activity was found in a more than 50,000-Da fraction after centrifugation in Amicon filters, even in the presence of anti-LH. These results suggest that R-FSH increases the production of T by Leydig cells through a Sertoli cell-released nonsteroid factor with a molecular mass greater than 50 kDa. The increase in the T/delta4 and T/DHEA ratios indicates that this factor would act by amplifying the LH response through the delta5 pathway and the 17beta-hydroxysteroid dehydrogenase enzyme.

Binding of 125I-prolactin to spermatozoa from normospermic and asthenospermic men.

Scatchard analysis of prolactin binding sites (PRL-BS) from ejaculated spermatozoa showed a single population of binding sites (apparent association constant: 2.51+/-0.186 nmol/l[-1]) with 0.317+/-0.0743 fmol/10(6) sperm binding sites. Different pools of spermatozoa were incubated with increasing concentrations of several hormones. There was a decrease in [125I]-oPRL binding with purified ovine prolactin (oPRL) and human growth hormone (hGH) which was not observed in the presence of synthetic ACTH and recombinant FSH, suggesting that binding was hormone specific. When the patient's samples were analyzed using the single point assay at saturation concentration, asthenospermic patients showed a significantly higher concentration of binding sites compared to normospermic ones. Both groups of patients displayed similar PRL levels in seminal plasma measured by DELFIA. Moreover, individual values of PRL levels in seminal plasma did not correlate with PRL-BS concentrations. We thus conclude that [125I]-oPRL binding to ejaculated spermatozoa was hormone specific and with similar parameters as seen in other target tissues. PRL-BS concentration in asthenospermic patients was significantly higher than in normospermic but this was not due to different levels of PRL in seminal plasma.

Serum luteinizing hormone pulsatility and intratesticular testosterone and oestradiol concentrations in idiopathic infertile men with high and normal follicle stimulating hormone serum concentrations.

The purpose of the study was to evaluate pulsatile luteinizing hormone (LH) release and intratesticular concentrations of testosterone and oestradiol in infertile men, to determine if alterations in gonadotrophin secretion are associated with changes in the testicular concentrations of steroids. Patients with idiopathic oligo/azoospermia were divided into a high follicle stimulating hormone (FSH) group (n = 5) and a normal FSH group (n = 6). Blood samples were taken every 15 min for 6 h to determine LH, FSH, testosterone, oestradiol, sex hormone binding globulin, bioactive LH and bioavailable testosterone. The patients underwent a bilateral testicular biopsy for histological assessment and to determine testosterone and oestradiol concentrations. Serum measurements were compared with those of seven fertile men. The high FSH group had a higher concentration of serum LH and oestradiol than normal men (P < 0.01) and showed a lower frequency of LH pulses than the normal FSH group and control men (P < 0.01). Intratesticular oestradiol was higher in the high FSH group (P < 0.001), with a lower testosterone/oestradiol ratio (P < 0.01). Patients showed a negative correlation between the serum testosterone/LH ratio and FSH (r = -0.75; P < 0.01) and a positive correlation between the testicular oestradiol concentration and serum FSH (r = 0.86; P < 0.01). The histopathological examination only showed a smaller tube diameter in the high FSH group (P < 0.05). These data seem to indicate that a higher intratesticular concentration of oestradiol with a lower testosterone/oestradiol ratio in the high FSH group could have a deleterious effect on spermatogenesis.

Effect of an antiestrogen on the testicular response to acute and chronic administration of hCG in normal and hypogonadotropic hypogonadic men: tamoxifen and testicular response to hCG.

The effect of the antiestrogen tamoxifen (Tx) on the acute and chronic hCG administration was evaluated in patients with hypogonadotropic hypogonadism (HH) and in normal men. An hCG test (5000 IU hCG) was performed before, after two months of hCG administration (2000 IU hCG three times weekly) and after two months of hCG + Tx (2000 IU hCG three times weekly plus 20 mg/day of tamoxifen). Blood samples were obtained before and following 24 and 72 h of every test to determine T, E, 17OHP and SHBG. T increased only in HH with both treatments (X +/- SEM: Basal: 97.9 +/- 19.7; hCG: 237.7 +/- 43.2; hCG +/- Tx: 204.7 +/- 10.7 ng/100 ml). 17OHP rose with hCG alone, but not with hCG + Tx in both groups. E, SHBG and 17OHP/T ratio did not change after treatments. hCG tests: E increased 24 h following hCG administration in every test. The ratio 17OHP/T rose at 24 h in the first and second test but in the third test it did not change. These results support the role of E in the acute hCG-induced Leydig cell desensitization. However, the association of Tx does not improve T serum levels, suggesting that E might not be the unique factor involved in the mechanisms for testicular desensitization.