Roberto Romoli

Isolated follicle-stimulating hormone (FSH) deficiency in a young man with normal virilization who did not have mutations in the FSHβ gene

OBJECTIVE To determine the cause of isolated FSH deficiency in a young infertile man. DESIGN Case report. SETTING Clinical and genetic studies in an academic research environment. PATIENT(S) A 19-year-old man with normal virilization, azoospermia, and isolated FSH deficiency. INTERVENTION(S) Pituitary and gonadal functions were evaluated at baseline and after repeated GnRH stimulation. FSH was tested with both immunological and biological methods. The FSHbeta gene was sequenced in the patient and in a series of 50 controls. MAIN OUTCOME MEASURE(S) Clinical, endocrine, and genetic characterization of an infertile patient with isolated FSH deficiency. RESULT(S) LH and T secretions were normal. No interference in FSH measurement was detected, and serum FSH concentrations were very low and completely unresponsive to repeated GnRH stimulation. No circulating FSH-like bioactivity was detected by means of rat Sertoli cell bioassay. Other pituitary functions were unaffected, and no lesions were seen at pituitary nuclear magnetic resonance (NMR). Inhibin B and activin levels were normal, but a progressive decrease of activin concentrations was seen during GnRH stimulation. The coding sequence of the FSHbeta gene was normal, but the patient was homozygous for a novel G/T substitution in the promoter region within a P response element. This substitution was present in heterozygosity in eight out of 50 controls and in homozygosity in one man with normal FSH levels. CONCLUSION(S) We report an infertile male with isolated FSH deficiency but no evidence of mutations in the FSHbeta gene. The G/T substitution in the FSHbeta promoter represents a novel silent polymorphism, indicating that other defects in factors involved in FSH-specific expression should be taken into account.

Mutations of LH and FSH receptors

Gonadotropins control male and female gonadal function by acting through specific recptors. The recent description of several mutations in LH and FSH receptors has significantly improved our understanding of the pathophisiology of several sexual disorder. Both gain- and loss-of-function germline mutations leading to constitutive receptor activation or to hormone resistance have been described. The clinical impact of these mutant receptors can be markedly different, depending upon the sex of the affected patient and the degree of functional alteration. Numerous mutations were described in LH receptor gene. Constitutive activation of this receptor leads to male-limited precocious pseudopuberty, whereas hypergonadotropic hypogonadism is the clinical phenotype of LH resistance. On the other hand, few mutations of FSH receptor were described so far. Inactivating mutations of FSH receptor are involved in some cases of hypergonadotropic hypogonadism with a more severe impairment of fertility in female patients. Only one gain-of-function mutation of FSH receptor was reported to maintain fertility in one hypophysectomized man. This review is focused on the known genetic alterations of gonadotropic receptors in humans and their impact on male sexual differentiation and fertility.

Serum FSH bioactivity and inhibin levels in patients with gonadotropin secreting and nonfunctioning pituitary adenomas

It has been reported that serum FSH bioactivity and inhibin levels can be used as markers of the presence of true gonadotropin-secreting pituitary adenoma (Gn-oma). To verify this hypothesis, we have investigated the bioactivity of FSH and serum inhibin α-α and α-βA levels in a series of patients with either Gn-oma or nonfunctioning pituitary adenoma (NFPA). Nine patients with Gn-oma (6 men and 3 women), 21 with NFPA (9 men and 12 women) and 30 normal subjects were included in the study. We studied FSH biological activity (FSH-B) by using Sertoli cell aromatase bioassay (SAB) and α-α and α-βA inhibin levels by two noncompetitive immunometric assays (IEMA). In male patients with Gn-oma, serum immunoreactive FSH (FSH-I) and FSH-B levels ranged from 5.1 to 35.5 U/L and from 8.3 to 48 U/L, respectively, FSH B/l ratio being elevated in 2 (2.5 and 4.1; normal male range: 0.3–1.5), while female patients with Gn-oma had serum FSH-I and FSH-B levels ranging from 43.2 to 162 U/L and from 41.2 to 112.8 U/l, respectively, with a normal FSH B/l ratio. In male patients with NFPA, FSH-I and FSH-B levels ranged from 2.7 to 10.7 U/l and from 2.4 to 11.4 U/l while in females they ranged from 3.4 to 67.9 and from 4.6 to 60.8 U/l, respectively. FSH B/l ratio was elevated in 1 male (3.3) and normal in the remaining patients with NFPA. Serum α-α inhibin levels were normal or low in patients with Gn-oma and NFPA, while α-βA inhibin concentrations were slightly elevated in 1 of 6 postmenopausal women (0.9; normal range <0.7 U/ml). The present study confirms and extends previous reports indicating that male patients with Gn-oma may secrete FSH molecules with increased bioactivity. However, this abnormality was also observed in one male patient with NFPA. Moreover, the measurement of inhibin levels does not appear to be a reliable in vivo marker of pituitary tumors of gonadotroph origin, as it was normal or low in almost all patients with either Gn-oma or NFPA.

Impaired estrogen-induced negative feedback on gonadotropin secretion in patients with gonadotropin-secreting and nonfunctioning pituitary adenomas

Background Several in vitro studies suggest that gonadotropin‐secreting pituitary adenomas (Gn‐omas) and non functioning pituitary adenomas (NFPA) originate from gonadotroph cells. Patients with Gn‐oma and NFPA frequently show abnormal gonadotropin response to TRH. The aim of the study was to investigate whether the estrogen‐induced negative feedback is operating in either patients with Gn‐oma or NFPA.

Absence of thyroid transcription factor-1 expression in human parathyroid and pituitary glands.

Thyroid transcription factor-1 (TTF-1), a tissue-specific nuclear transcription factor involved in the embryogenesis and differentiation of human thyroid, lung and brain, has been recently identified in other rat tissues, including parafollicular C cells and parathyroid chief cells. Based on this distribution, a possible role for this factor in calcium homeostasis has been suggested. This study investigated the presence of TTF-1 transcripts and protein in human tissues expressing the calcium sensing receptor (CaSR). Using a RT-PCR technique, complemented by Southern blot analysis, TTF-1 expression was detected in human C cells (two medullary thyroid carcinomas), but not in normal and adenomatous (four adenomas and three hyperplasia) parathyroid, and normal and adenomatous (six adenomas) pituitary tissues. CaSR was expressed in all samples. The absence of expression was confirmed by Western blot. In contrast to previous studies in the rat, this study demonstrates the absence of TTF-1 transcripts in the human adult parathyroid and pituitary glands, although a role for this factor during the ontogeny of these organs cannot be excluded.