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Context: Choosing the sex of rearing of an XY neonate with a major sexual ambiguity and a mutated androgen receptor remains one of the more difficult questions of neonatal endocrinology. A direct consequence of this choice is the accomplishment of sexual function in adulthood. There is very limited knowledge of the sexual performance of patients with partial androgen insensitivity syndrome., Objective: The objective of this study is to describe physical acts of sexuality in partial androgen insensitivity syndrome patients reared as males., Design: We were able to obtain factual information regarding the sexual activity of 15 adult patients who had been reared as males and followed at our institution since birth. We evaluated their sexual performance using two validated questionnaires (Golombok-Rust Inventory of Sexual Satisfaction and International Index of Erectile Dysfunction)., Results: We documented a major impairment of all parameters of sexual activity., Conclusion: This long-term insight into the consequences of male sex assignment will have to be balanced by a study of the consequences of female sex assignment.

Kallmann syndrome (KS) is a developmental disease that combines hypogonadotropic hypogonadism and anosmia/hyposmia. Other congenital abnormalities may also coexist. This present report describes two sisters, aged 13 and 12 years, born from Lebanese consanguineous parents. The two sisters have complete androgen insensitivity (normal female appearance and an XY karyotype) due to a novel mutation, a C-to-G transversion in intron 2 of the androgen receptor gene, resulting in an aberrant splicing leading to an insertion of 66 nucleotides in the mRNA. In addition, the older sister has KS, together with synkinesia and multiple skeletal abnormalities, mainly kyphosis, vertebral abnormalities, and short right hand and feet. Her testosterone, FSH and LH levels were very low compared with her younger sister. No mutation in the KAL1 and FGFR1/KAL2 genes were found. This unique report raises the possibility of an autosomal recessive or X-linked form of KS with new phenotypic expression.

Androgen insensitivity syndrome (AIS) is caused by mutations in the androgen receptor gene and is associated with a variety of phenotypes in 46,XY individuals, ranging from phenotypic women [complete form (CAIS)] to men with minor degrees of undervirilization or infertility [partial form (PAIS)]. We studied 32 subjects with male pseudohermaphroditism from 20 families (9 CAIS, 11 PAIS) with the following criteria for AIS: 46,XY karyotype, normal male basal and human chorionic gonadotropin-stimulated levels of serum testosterone and steroid precursors, gynecomastia at puberty, and, in prepubertal patients, a family history suggestive of X-linked inheritance. The entire coding region of the androgen receptor gene was analyzed, and mutations were found in all families with CAIS and in eight of 11 families with PAIS. Fifteen different mutations were identified, including five (S119X, T602P, L768V, I898F, and P904V) that have not been described previously. Detailed clinical and hormonal features were compared with genotype in 25 subjects with AIS and confirmed by mutational analysis. LH hormone levels and the LH x testosterone product were high in all postpubertal subjects with AIS. All subjects with PAIS maintained at postpubertal age the gender identity and social sex that was assigned to them in infancy, in contrast to other forms of pseudohermaphroditism.

Objective: Testicular feminised (Tfm) mice express a non-functional androgen receptor, and also have reduced levels of circulating testosterone. Recent studies support a cardio-protective role for testosterone since it elicits systemic and pulmonary vasodilatation. The aim of the present study was to determine whether androgen insensitivity and hypotestosteronaemia in the Tfm mouse are associated with abnormal vascular reactivity or hormone status., Methods: Adult male Tfm and littermate control mice were killed and the blood collected. Femoral (diameter range = 183-508 microm) and pulmonary (diameter range = 320-816 microm) arteries were dissected and loaded in either a wire or pressure myograph, at 100 mmHg or 17.5 mmHg respectively. Pharmacological assessment of the vasoreactivity to potassium chloride (KCl, 80 mmol/l) and either noradrenaline (NA, 1 nmol/l-100 micromol/l) and acetylcholine (ACh, 0.1-100 micromol/l) or testosterone (1 nmol/l-100 micromol/l) was then made., Results: Tfm mice had reduced levels of testosterone (1.8+/-0.3 nmol/l) compared with controls (9.3+/-2.0 nmol/l, P<0.001) and elevated levels of cholesterol (3.6+0.1 mmol/l) compared with controls (3.2+0.1 mmol/l, P<0.05). Femoral arteries from Tfm mice exhibited reduced vasoconstriction to 80 mmol/l KCl (3.27+/-0.23 mN/mm) compared with vessels from controls (4.44+/-0.41 mN/mm, P<0.05), and reduced endothelial-dependent vasodilatation to 0.1-100 micromol/l ACh (23.3+/-3.6% relaxation) compared with vessels from controls (41.6+/-5.4% relaxation, P<0.05). Vasoconstriction to NA (1 nmol/l-100 micromol/l) and vasodilatation to testosterone were unaffected., Conclusions: Androgen receptor deficiency and hypotestosteronaemia in the Tfm mouse reduced endothelial function and impaired voltage-operated calcium channel activity, which may pre-dispose to cardiovascular disease. Testosterone-induced vasodilatation was unaffected, demonstrating no involvement of the androgen receptor in this response.

Androgen insensitivity syndromes (AIS) result from the incapacity for T and dihydrotestosterone to virilize male embryos and is mainly attributable to molecular defects of the AR gene. In normal males, T and LH rise during the first few months of life, and this physiological surge is commonly used to evaluate the gonadotropic axis at this age. This neonatal surge has not been evaluated in detail in newborns with AIS. We sequentially measured plasma T, LH, and FSH during the first 3 months of life in 15 neonates with AIS and AR mutation. A GnRH and an human CG stimulation test were also performed. Patients were divided in 2 groups with complete (n = 10) or partial (n = 5) AIS (CAIS or PAIS), based on the clinical phenotype. In patients with PAIS, T levels were in the high-normal range at d 30 (18.4 +/- 6.9 nM) and d 60 (12.8 +/- 3.8 nM). In contrast, plasma T values were below the normal range in 9 of 10 patients with CAIS at d 30 (1 +/- 0.3 nM) and d 60 (1.4 +/- 0.7 nM, both P < 0.004 vs. PAIS). Plasma LH values were low in CAIS at d 30 (0.7 +/- 0.1U/liter) and increased normally in PAIS (8.7 +/- 2.5 U/liter, P = 0.004). We conclude that the postnatal T and LH surge occurs expectedly in neonates with PAIS but is absent in those with CAIS and that the postnatal T rise requires the receptivity of the hypothalamo-pituitary axis to T.

Administration of opiate receptor antagonists augmented pulsatile LH release in six estrogen-treated, orchidectomized individuals with testicular feminization. In response to an opiate antagonist, LH pulse frequency increased from 3.0 +/- 0.55 (+/- SE) to 5.0 +/- 0.45 pulses/8 h (P = 0.034). Since these patients have inborn target tissue resistance to androgens, we infer that sustained androgen action is not obligatory to the emergence of endogenous inhibitory opiate tone in man. Rather, these observations document that the suppressive effects of opiates on gonadotropin secretion can be unmasked in the presence of an unopposed estrogen milieu.

We compared the secretion of uncombined alpha-subunit with LH secretion, as measured by RIA in six normal men, an agonadal adult man, and an adult woman with testicular ferminization. Blood samples were drawn every 10 min for 12 h to evaluate pulsatile LH and free alpha secretion. Spontaneous alpha pulses occurred every 120 +/- 60 min (mean +/- SD; range, 40-260) in eugonadal men. The mean alpha pulse amplitude was 0.49 +/- 0.11 ng/ml, representing an increase of 60 +/- 18% above the preceding nadir value. alpha pulses were generally associated with LH pulses, and the amplitudes of concordant alpha and LH pulses were highly positively correlated (r = 0.58; P less than 0.01). The absolute amplitude of concordant alpha peaks was 1.5 +/- 0.7% that of corresponding LH peaks. Additional alpha pulses were noted in each subject for which simultaneous LH fluctuations failed to meet the criteria for pulses. Studies in the agonadal man and in the patient with testicular feminization revealed that the frequency of both spontaneous alpha and LH pulses was increased to approximately twice that in normal men. Gel filtration analysis indicated that all alpha radioimmunoactivity in normal male sera coeluted with [125I]alpha. By contrast, in hypogonadal sera, only 50-60% of alpha immunoreactivity coeluted with [125I]alpha, the remaining activity appeared in the region of LH and FSH and resulted from RIA cross-reactivity. We conclude that uncombined alpha-subunit, as well as LH is normally released into the peripheral blood in discrete pulses. In the absence of exposure to androgen, the frequency of these pulses increases, presumably as a consequence of the accelerated release of LRH. However, alpha RIAs overestimate the concentration of uncombined alpha in hypogonadal sera. We propose that the coanalysis of LH and alpha secretory episodes may prove useful in resolving some of the complexities associated with gonadotropin secretory patterns.

The cytosol fractions of the anterior pituitary, hypothalamus, preoptic area and brain cortex of androgen "insensitive" (Tfm) rats possess androgen receptors. However, in the Tfm rats the androgen binding per mg protein was only 10-15% of that in the corresponding normal littermates (Nl). The physicochemical properties of the androgen receptors in the anterior pituitary of the Tfm rat were indistinguishable from those of the normal rat. Thus, no distinctive differences were observed with regard to electrophoretic mobility in 3.25% polyacrylamide gels, isoelectric point (pI=5.8), binding affinity (KD=1.5 X 10(-9)M), temperature stability, sulfhydryl dependence and steroid specificity. It is, therefore, likely that the very low androgen binding capacity by the anterior pituitary and the central nervous system is due to an extreme reduction in the receptor number rather than to the presence of abnormal receptors. Since in the Tfm animals the androgen receptor number is reduced by 85-90%, it is to be expected that very high doses of androgens would be required to achieve hormonal effects. In fact, low doses of 5alpha-dihydrotestosterone propionate (50 mug/100 g body weight) given sc daily for 12 days had no effect on serum levels of LH and FSH. However, very high doses (2 mg/100 g body weight) of testosterone propionate and 5alpha-dihydrotestosterone propionate, which maintained circulating androgen levels above 20 ng/ml, significantly reduced serum gonadotropin levels in castrated Tfm rats. In normal littermates both low and high doses of the androgens suppressed gonadotropin secretion to low levels. These findings strongly indicate that androgen receptors are essential to androgen action on the anterior pituitary and central nervous system in the rat. The serum levels of testosterone (7.7+/-0.15 (SE) ng/ml) and 5alpha-dihydrotestosterone (0.37+/-0.06 ng/ml) were significantly higher in intact Tfm rats than in normal littermates (2.6+/-0.03 and less than 0.1 ng/ml, respectively). The failure of the elevated concentrations of serum androgens to reduce the high serum levels of LH and FSH in intact Tfm rats is most likely due to the extreme reduction of the androgen receptor number and the consequent insufficient hypothalamic and/or pituitary response to androgens.

Both the androgen-induced decline in serum sex hormone-binding globulin (SHBG) levels during puberty and the anabolic effect of exogenous testosterone are absent in patients with androgen insensitivity (testicular feminization). To determine whether the androgen-induced decline in serum SHBG could be used as a test of androgen sensitivity, we studied the effect of the anabolic-androgenic steroid stanozolol (17 beta-hydroxy-17 alpha-methyl-5 alpha-androstano-[3,2-c]pyrazol) on serum SHBG in 25 control subjects, 3 patients with complete androgen insensitivity, and 4 patients with partial androgen insensitivity. Stanozolol was administered orally for 3 days (0.2 mg/kg.day); blood samples were taken before and 5, 6, 7, and 8 days after the beginning of the test for measurements of serum SHBG. The lowest value (i.e. the peak response) in each subject was used as the measure of the response to stanozolol. In the control subjects the mean nadir serum SHBG level was 51.6 +/- 5.9% (+/- SD) of the initial value (P less than 0.001). In the 4 patients with partial androgen insensitivity the nadir serum SHBG ranged from 73-89%, and in the 3 patients with complete androgen insensitivity it ranged from 93-97% of the initial value. Thus, the decrease in serum SHBG after short term administration of stanozolol reflects androgen responsiveness and, thus, may be used to differentiate patients with androgen insensitivity syndromes from those with other causes of male pseudohermaphroditism.