Congenital hypogonadotropic hypogonadism (CHH) is a disorder with a prevalence of 1:4,000–10,000, which is caused by the defect in gonadotropin-releasing hormone (GnRH) release, action, or both (1). It is characterized by absent or incomplete sexual maturation. In addition, some patients with CHH exhibit other developmental defects, including anosmia, synkinesia, cleft lip/palate, sensorineural hearing loss, renal agenesis, syndactyly, or brachydactyly (2).

During the embryonic period, GnRH neurons were accompanied by olfactory axons migrating from the olfactory placode to the hypothalamus (3). The failure of the migration process results in hypogonadotropic hypogonadism and hypoplasia or aplasia of the olfactory system, namely, Kallmann syndrome (KS), which accounts for about 50%–60% of CHH (4). CHH patients with normal olfactory function are normosmic CHH (nCHH).

The evaluation tools of the olfactory function include objective tools and subjective tools (5). Olfactory event-related potentials (OERPs) are considered as the gold standard method to objectively evaluate olfactory function. However, this technique is complex, time-consuming, and not routinely performed in clinical practice (6). Psychophysical evaluation of the olfactory function is a low-cost and simple way, such as the University of Pennsylvania Smell Identification Test (UPSIT, USA) and the Sniffin’ Sticks (SS, Germany), which have been widely used in clinical and research settings (7). However, in mainland China, the olfactory function is scantly tested in clinical practice, partially due to the lack of a culturally appropriate smell identification test. Some odors in UPSIT and SS are unfamiliar to most Chinese (e.g., sauerkraut, raspberry, and rum), which leads to inaccurate results. In 2019, Wen Zhou et al. developed the Chinese smell identification test (CSIT) through two experiments. In the first experiment, the researchers obtained 45 odorants, which were the highest ranked odorants based on the familiarity and identifiability of 105 odor items in 296 participants. In the second experiment, 46 participants were shown the 45 odorants and were asked to make a choice of each odorant’s name from a list of four options. The odors misidentified by more than 30% of participants were excluded, and finally, the 40 most familiar odors of Chinese people were chosen in the CSIT (8). The researchers also verified that the identification accuracy of CSIT was higher than that of the UPSIT or SS-16 (8). It provides an effective tool for the assessment of olfactory function in the Chinese population. CSIT has been studied in Parkinson’s disease (PD) (9), but it has not been used in CHH in any studies so far.

In this study, we evaluated the olfactory function of 71 Chinese CHH patients using the Chinese Olfactory Function Test (COFT) and analyzed the influence factors of the olfactory function in CHH patients.

In this study, we firstly used the COFT to evaluate the olfactory function of 71 CHH patients. Thirty-six patients were categorized as nCHH and the other 35 patients were categorized as KS. The CSTT, CSDT, and CSIT scores of nCHH patients were higher than those of KS patients.

Although olfactory event-related potentials (OERPs) are considered as the gold standard of olfactory function evaluation, they are rarely used in clinical practice because they are complex and time-consuming (11). The OB plays a relay station role in the processing of olfactory information. It receives the input signal from the olfactory epithelium and outputs it to the olfactory cortex (12). The OB is a neuronal structure of the forebrain and is easily detected on coronal weighted MR images (13). Studies have identified the positive correlation between electrophysiological and morphological changes of the olfactory pathway and psychophysical testing of olfactory functions in patients with olfaction loss, which means the lower amplitude in OERPs, the smaller OBV, the lower olfactory test score (14, 15). Thus, MRI of the olfactory apparatus is an objective method to evaluate the olfactory function.

In 1987, Klingmüller et al. (16) firstly used magnetic resonance imaging (MRI) to investigate alterations in structures related to olfactory function and found that in all four KS patients, the olfactory sulci are either absent or hypoplasic. Since then, other studies confirmed that MR can detect the absence of OBs and tracts in patients with KS, and it could be an objective method to evaluate the olfactory function of CHH patients (13, 17). Studies have found that the OBV is significantly associated with olfactory function scores (18–21), which is consistent with our study.

Studies have reported that the main characteristic of the olfactory apparatus of Kallmann patients was the absence of OBs and tracts, which were usually bilateral or unilateral (22–24). In our study, 27 out of 28 KS patients showed bilateral OB aplasia with or without olfactory sulcus aplasia. One KS patient showed normal olfactory apparatus. As reported in previous studies, normal olfactory apparatus can be found in patients with confirmed olfaction disorder (23).

However, unlike previous studies, our study found that the six CHH patients with unilateral olfactory apparatus dysplasia were on the left side and their olfactory function was normal and assigned to nCHH patients. It is speculated that it may be related to the compensation of olfactory function. Interestingly, three nCHH patients showed bilateral OB aplasia in our study, which has been considered as normal olfaction without apparent olfactory bulbs (NOWAOB). In 2019, Weiss et al. (25) first reported this phenomenon. They found 2 out of 1,113 patients combined with NOWAOB, and the 2 patients were female and left-handed. Thus, they reported that the NOWAOB was associated with left-handed women, while in our study, three right-handed male patients showed NOWAOB, which expanded the phenotype of NOWAOB. The detailed mechanism of NOWAOB was unclear. It is speculated that it may be related to OBs having migrated to a different brain location or OBs are just too tiny for the current MRI technology to detect since the slice thickness of MRI is 3 mm. Furthermore, a previous study had reported that CHH patients with normal olfactory function but abnormal olfactory apparatus showed declined olfactory function with age (26). The study showed the presence of a possible age effect on the olfactory function. Therefore, the olfactory function should be evaluated for our three nCHH patients with NOWAOB in their later age.

It is worth noting that our study found that the olfactory pathway structure and olfactory function are not always consistent. However, studies have indicated the discordance of OBV and OERP. Patients with the agenesis of OB may have identifiable OERPs (27–29). Thus, the olfactory function of these patients may be underestimated for the lack of OERP test. Furthermore, nasal polyposis, asthma, septal deviation, turbinate hypertrophy, and allergic rhinitis are related to olfactory dysfunction (30). The related medical history was obtained by inquiring the patients enrolled in our study who did not have the rhinoscopy examination. This may also lead to underestimate the olfactory function (31), which is the limitation of our study.

The self-reported smell is the most commonly used method to evaluate olfactory function in clinical practice, although it is noteworthy that SROS may overestimate the olfactory function of CHH patients (19, 21). Our study showed that the accuracy of SROS in the diagnosis KS was about 91.5%. Similar to other studies (32), the results also showed that self-reported normal olfaction is more unreliable, since the sensitivity was 85.7% and the specificity was 97.2%. Our study showed that the accuracy of MRI in the diagnosis of KS was about 92.7%, the sensitivity was 96.4%, and the specificity was 88.9%, which is consistent with other studies that had reported the sensitivity was 76%–100% (33). Thus, our study revealed that SROS is more reliable in the diagnosis of KS and MRI is more reliable in the diagnosis of nCHH.

CHH is a genetic disease and more than 40 pathogenic genes of the disease have been identified (34, 35). Theoretically, nCHH and KS have different genetic backgrounds. The KS occurs due to the migration failure of GnRH neurons during the embryonic period, which causes GnRH deficiency and a defective sense of smell, while nCHH occurs due to isolated GnRH deficiency without olfactory involvement (36, 37). However, most of the known CHH-related genes can cause both KS and nCHH (38–41), which indicate that these genes may contribute to different processes of the pathogenesis of CHH. Sykiotis et al. reported two patients diagnosed as having KS and nCHH, but they had the same gene variants (FGFR1 and R250Q) (42). Thus, the differential diagnostic value of gene sequencing technology in KS and nCHH needs to be further explored.

For clinical characteristics, KS and nCHH show differences in developmental abnormalities. Previous studies reported that these phenotypes are more common in KS than in nCHH (43). The incidence of cryptorchid, hearing defect, renal agenesis, and syndactyly in nCHH and KS was 20%–40% vs. 12.5%–75%, 0%–11.1% vs. 7%–37.5%, 0%–6% vs 8%–15%, and 0%–6% vs. 0%–12.5%, respectively (43–46). In our study, although there is no significant statistical difference, the incidence of these abnormalities was higher in KS than in nCHH, which is consistent with the previous study.

Some studies suggested that the sex hormone may have an influence on olfactory function. Kırgezen et al. (47) evaluated olfactory function in 70 patients with prostate cancer and found that testosterone level was significantly correlated with olfactory function score, and the score of patients with low testosterone level was lower than that of the control group. Lee et al. analyzed the olfactory function of 3,863 women participants. It showed that the incidence of olfactory dysfunction in postmenopausal women was higher than that in premenopausal women. The longer the breastfeeding period of premenopausal women, the higher the risk of olfactory dysfunction, while the younger the postmenopausal women start to menopause, the higher the risk of olfactory dysfunction. Therefore, the study suggested that olfactory dysfunction was associated with endogenous estrogen deprivation (48). In clinical practice, our team also found that some KS patients with hormone replacement therapy subjectively reported an improved sense of smell. However, in this study, the results showed no difference in olfactory function between treated and untreated CHH patients, and there is no significant correlation between treatment time and sex hormone levels and olfactory function. Because this is a cross-sectional study, prospective studies are needed to confirm the results.

In conclusion, our study evaluated the olfactory function of 71 CHH patients. The olfactory function of the CHH patients with unilateral olfactory apparatus dysplasia is usually normal and few CHH patients without apparent OBs had normal olfaction. These remind us that the abnormal structure of the olfactory apparatus does not always support the diagnosis of KS, which could be beneficial to the precise diagnosis and classification of CHH patients.

This study is a cross-sectional study, and prospective studies are needed to analyze the effect of hormone replacement therapy on olfactory function in patients with CHH. It is unable to analyze the influence of genes on olfactory function because of the lack of genetic test in these patients.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

This study was reviewed and approved by Peking Union Medical College Hospital. The patients/participants provided their written informed consent to participate in this study.

XYW, JM and MN conceived and designed the study. BY conducted the COFT and wrote the paper. KC and WZ provided the COFT tool. BH, HY and FF collected the MRI data. XW, QH, RZ, YZ and BS helped collect the clinical data. All authors contributed to the article and approved the submitted version.

This work was supported by the Natural Science Foundation of Beijing (Grant No. 7212080 and 7202151).

We thank the subjects and their family members for their participation in this research study.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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