Kallmann syndrome combines anosmia, related to defective olfactory bulb morphogenesis, and hypogonadism due to gonadotropin-releasing hormone deficiency. Loss-of-function mutations in KAL1 and FGFR1 underlie the X chromosome-linked form and an autosomal dominant form of the disease, respectively. Mutations in these genes, however, only account for approximately 20% of all Kallmann syndrome cases. In a cohort of 192 patients we took a candidate gene strategy and identified ten and four different point mutations in the genes encoding the G protein-coupled prokineticin receptor-2 (PROKR2) and one of its ligands, prokineticin-2 (PROK2), respectively. The mutations in PROK2 were detected in the heterozygous state, whereas PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state. In addition, one of the patients heterozygous for a PROKR2 mutation was also carrying a missense mutation in KAL1, thus indicating a possible digenic inheritance of the disease in this individual. These findings reveal that insufficient prokineticin-signaling through PROKR2 leads to abnormal development of the olfactory system and reproductive axis in man. They also shed new light on the complex genetic transmission of Kallmann syndrome. Kallmann syndrome is a developmental disease that affects both the hormonal reproductive axis and the sense of smell. In addition, various nonreproductive and nonolfactory anomalies are occasionally observed in a fraction of the patients. There is a developmental link between the reproductive and olfactory disorders: neuroendocrine cells producing the gonadotropin-releasing hormone that is deficient in the patients normally migrate from the nose to the forebrain along olfactory nerve fibers during embryonic life, and they most probably fail to do so in the patients. Affected individuals usually do not undergo spontaneous puberty. Hormone replacement therapy is the treatment to initiate virilization in males or breast development in females, and later, to develop fertility in both sexes. This is a hereditary disease with complex genetic transmission. Mutations in either of two different genes, KAL1 and FGFR1, have been found in approximately 20% of the affected individuals. The authors report on the identification (in a further 10% of patients) of various mutations in the prokineticin receptor-2 or prokineticin-2 genes, encoding a cell surface receptor and one of its ligands, respectively. Notably, some of the mutations were also detected in clinically unaffected individuals. This clearly indicates that additional, still unknown genetic or non-genetic factors are involved in disease production.

Context: Both biallelic and monoallelic mutations in PROK2 or PROKR2 have been found in Kallmann syndrome (KS). Objective: The objective of the study was to compare the phenotypes of KS patients harboring monoallelic and biallelic mutations in these genes. Design and Patients: We studied clinical and endocrine features that reflect the functioning of the pituitary-gonadal axis, and the nonreproductive phenotype, in 55 adult KS patients (42 men and 13 women), of whom 41 had monoallelic mutations and 14 biallelic mutations in PROK2 or PROKR2. Results: Biallelic mutations were associated with more frequent cryptorchidism (70% vs. 34%, P < 0.05) and microphallus (90% vs. 28%, P < 0.001) and lower mean testicular volume (1.2 ± 0.4 vs. 4.5 ± 6.0 ml; P < 0.01) in male patients. Likewise, the testosterone level as well as the basal FSH level and peak LH level under GnRH-stimulation were lower in males with biallelic mutations (0.2 ± 0.1 vs. 0.7 ± 0.8 ng/ml; P = 0.05, 0.3 ± 0.1 vs. 1.8 ± 3.0 IU/liter; P < 0.05, and 0.8 ± 0.8 vs. 5.2 ± 5.5 IU/liter; P < 0.05, respectively). Nonreproductive, nonolfactory anomalies were rare in both sexes and were never found in patients with biallelic mutations. The mean body mass index of the patients (23.9 ± 4.2 kg/m² in males and 26.3 ± 6.6 kg/m² in females) did not differ significantly from that of gender-, age-, and treatment-matched KS individuals who did not carry a mutation in PROK2 or PROKR2. Finally, circadian cortisol levels evaluated in five patients, including one with biallelic PROKR2 mutations, were normal in all cases. Conclusion: Male patients carrying biallelic mutations in PROK2 or PROKR2 have a less variable and on average a more severe reproductive phenotype than patients carrying monoallelic mutations in these genes. Nonreproductive, nonolfactory clinical anomalies associated with KS seem to be restricted to patients with monoallelic mutations.

In most mammalian species aromatase is encoded by a single gene ( Cyp19 ), which contains 18 exons, nine of them being translated. In man, the presence of a biologically active aromatase and oestrogen receptors (ERα and ERβ) has been reported in Leydig cells, and also in immature germ cells and ejaculated spermatozoa. Concerning aromatase, the amount of transcript and enzymatic activity are decreased in immotile compared with motile sperm. We have amplified aromatase mRNA by real-time polymerase chain reaction in spermatozoa from asthenospermic, teratospermic and asthenoteratospermic men and recorded, respectively, 44, 52 and 67 per cent decreases of the amount of transcripts compared with fertile donors. A high degree of correlation ( r = −0.64) between the abnormal spermatozoa (especially microcephaly and acrosome malformations) and aromatase/GAPDH transcript ratio has been observed. Idiopathic infertility is a wide health problem and no treatment is currently available. In humans, even if the role of oestrogens in spermatogenesis is still a matter of debate, the observations of decreased sperm number and motility in men genetically deficient in aromatase, together with our data and those reported in the literature, may suggest a role for aromatase/oestrogens not only during the development and maintenance of spermatogenesis but also in the final maturation of spermatozoa.

BACKGROUND Visfatin, a protein secreted by adipose tissue, is suggested to play a role in pathogenesis of insulin resistance. In polycystic ovary syndrome (PCOS), insulin resistance might be involved in the development of endocrine and metabolic abnormalities. The aim of the study was to asses the relation between serum visfatin concentration and insulin sensitivity and markers of hyperandrogenism in lean and obese PCOS patients.

Endocrine-disrupting chemicals (EDCs) are exogenous compounds that can cause disturbances in the endocrine system and have multiple harmful effects on health by targeting different organs and systems in the human body. Mass industrial production and widespread use of EDCs have resulted in worldwide contamination. Accumulating evidence suggest that human exposure to EDCs is related to the impairment of male reproductive function and can interrupt other hormonally regulated metabolic processes, particularly if exposure occurs during early development. Investigation of studies absent in previous reviews and meta-analysis of adverse effects of EDCs on functioning of the male reproductive system is the core of this work. Four main modes of action of EDCs on male fertility have been summarized in this review. First, studies describing estrogen- pathway disturbing chemicals are investigated. Second, androgen-signaling pathway alterations and influence on androgen sensitive tissues are examined. Third, evaluation of steroidogenesis dysfunction is discussed by focusing on the steroid hormone biosynthesis pathway, which is targeted by EDCs. Last, the reportedly destructive role of reactive oxygen species (ROS) on sperm function is discussed. Spermatogenesis is a remarkably complex process, hence multiple studies point out various dysfunctions depending on the development state at which the exposure occurred. Collected data show the need to account for critical windows of exposure such as fetal, perinatal and pubertal periods as well as effects of mixtures of several compounds in future research.