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CASE REPORT
Congenital Hypogonadotropic Hypogonadism withEarly-Onset Coronary Artery Disease
Akira Takashima1,2, Shusuke Yagi2, Koji Yamaguchi2, Kiyoe Kurahashi3, Yuko Kojima2, Robert Zheng2,Takayuki Ise2, Kenya Kusunose2, Sumiko Yoshida3, Hirotsugu Yamada2, Takeshi Soeki2, Tetsuzo Wakatsuki2,Ken-ichi Aihara4, Masashi Akaike5, and Masataka Sata2
1
Department of Cardiovascular Medicine, Kitajima Taoka Hospital, Tokushima, Japan, 2Department of Cardiovascular Medicine, Tokushima
University Hospital, Tokushima, Japan, 3Department of Haematology, Endocrinology and Metabolism, Tokushima University Graduate Schoolof Biomedical Science, Tokushima, Japan, 4Department of Community Medicine for Diabetes and Metabolic Disorders, Tokushima University
Graduate School of Biomedical Science, Tokushima, Japan, 5Department of Medical Education, Tokushima University, Tokushima, Japan

Abstract : The patient with congenital hypogonadotropic hypogonadism (HH) shows low serum levels of androgen, which is a group of sex hormones including testosterone, caused by the decreased gonadotropin release in
the hypothalamus. Recent reports showed androgens exert protective effects against insulin resistance or atherosclerotic diseases, such as diabetes mellitus or coronary artery disease. However, whether the juvenile hypogonadism affects the diabetes or cardiovascular disease is unclear. We report a case of a middle-aged man withcongenital HH who had severe coronary artery disease complicated with metabolic disorders. J. Med. Invest. 68: 189-191, February, 2021
Keywords : congenital hypogonadotropic hypogonadism, coronary artery disease, diabetes mellitus, Kallmann syndrome, testosterone

INTRODUCTION
Idiopathic congenital hypogonadotropic hypogonadism (HH) isa rare reproductive disorder that is caused by a gonadotropin-releasing hormone (GnRH) deficiency (1). HH shows low plasma
levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) accompanied with low or undetectable circulating
androgen concentrations, which are male sex hormones including testosterone. Congenital HH induces delayed puberty andinfertility that is related to various metabolic disorders such as
diabetes mellitus (DM), dyslipidemia or atherosclerotic disease(2, 3). Low testosterone concentrations in men are linked withinsulin resistance, hyperglycemia, hypertension, dyslipidemia,
and an increased risk of vascular disease (3). However, suchcases in the real world are very rare. Here we presented a patient
who had HH along with DM and coronary artery disease.

CASE
A 48-year-old man with hypertension, dyslipidemia and DM
was referred to our hospital due to dyspnea. He had untreatedDM with diabetic neuropathy, proliferative diabetic retinopathy,
and stage 3 diabetic nephropathy beginning at the age of 43years. His family history was negative for dyslipidemia ; however, his mother and younger brother—who died unexpectedly
in his thirties—had DM. The patient’s height was 169.5 cm,body weight was 85 kg (indicated body mass index was 29.6),
arm span was 175 cm, blood pressure was 100 / 64 mmHg, pulse
rate was 92 beats per minute, body temperature was 37.3 ˚C,and saturation of percutaneous oxygen was 96% in room air. He
Received for publication January 31, 2020 ; accepted September 3,2020.
Address correspondence and reprint requests to Akira Takashima, MD,PhD, Department of Cardiovascular Medicine, Tokushima UniversityHospital, Tokushima 770-8503, Japan and Fax : +81-88-633-7894.

had bipedal edema with bacterial infection and coarse crackles
in both lower lungs. Furthermore, he manifested abnormal
physical examination results such as anosmia, high-pitchedvoice, gynecomastia, impotence, and absence of pubic hair. His
laboratory findings revealed severe inflammation (white bloodcell count, 18300 [4000-9000] / μL ; C-reactive protein level,
16.2 [ < 0.3] mg / dL). He demonstrated hyperglycemia (plasma
glucose level, 306 [60-110] mg / dL ; hemoglobin A1c, 9.9 [4.66.2] %). He additionally demonstrated dyslipidemia (level of
low-density lipoprotein, 162 [70-140] mg / dL ; triglyceride level,
141 [35-150] mg / dL ; high-density lipoprotein level, 61 [40-100]
mg / dL), and he exhibited severe heart failure (brain natriureticpeptide, 1398 [< 18.4] pg / mL). Chest radiography revealed cardiomegaly and pulmonary congestion. Additionally, a 12-leadelectrocardiogram showed ST-level depression in V5 and V6, andtransthoracic echocardiography revealed a low left ventricularejection fraction of 20%. Computed tomography images revealed
gynecomastia, a small penis, and cryptorchidism of the left
testis (Figure 1). The estimated volume of each testis was approximately 1 ml. Coronary angiography exposed three-vessel
disease, including total left anterior descending artery occlusionand severe stenosis of the left circumflex and right coronary arteries (Figure 2). These findings indicated that the dyspnea wascaused by ischemic heart failure.
We used insulin and sodium-glucose cotransporter 2 inhibitors for diabetes and an angiotensin receptor blocker and loop
diuretic for heart failure. The patient did not agree to undergo
coronary artery bypass grafting ; hence, percutaneous coronary
intervention was performed. Ischemic heart failure successfully
improved after revascularization of the left anterior descending
and right coronary arteries. The level of brain natriuretic peptide improved from 1398 to 300 pg / mL, and his left ventricularejection fraction, as measured by echocardiography, also improved from 20% to 30%.
His physical examination showed no findings of secondary
sex characteristics. Blood tests revealed very low serum levelsof LH ( < 0.1 [0.6-12.1] mIU / mL), FSH (0.1 [0.9-12.0] mIU / mL),and testosterone (0.6 [2.6-8.7] ng / mL). Although the levels ofThe Journal of Medical Investigation Vol. 68 2021

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A. Takashima, et al. CHH with Early-Onset CAD

growth hormone and thyroid-stimulating hormone were slightly
elevated, the other anterior pituitary hormones were normal.
Contrast enhanced magnetic resonance imaging showed no abnormal pituitary grand or hypothalamic findings. The LH andFSH serum levels did not increase after the GnRH stimulation
test (Figure 3). As these findings indicated HH, we had further
diagnosed the patient to have congenital HH with early-onset
DM and coronary artery disease.

Figure 3. Serum luteinizing hormone (LH) and follicle-stimulating
hormone (FSH) concentrations during the gonadotropin-releasing
hormone (GnRH) stimulation test. Serum LH and FSH concentrations
are very low at baseline and these hormones show no response toGnRH stimulation.

Figure 1. Computed tomography (CT) image showing gynecomastia(yellow arrowhead) (A) and cryptorchidism (arrow) (B). Reconstructed
CT image showing gynecomastia and a small penis (C).

Figure 2. Coronary angiography shows three-vessel disease. (A)Total occlusion of the left anterior descending artery (arrow) ; (B)Total occlusion of the distal portion of the left circumflex artery (arrow)and severe stenosis of the middle portion of the left circumflex artery(arrowhead) ; (C) Severe stenosis of the proximal portion of the rightcoronary artery (arrowhead) and collateral arteries toward the leftanterior descending artery (arrow).

DISCUSSION
Although many reports showed that low testosterone level
induces metabolic disorder, we report a patient who had HH,
type 2 diabetes, and early-onset coronary artery disease. Idiopathic congenital HH is caused by the decreased gonadotropin
release in the hypothalamus and is classified by some phenotype.
Obesity may induce hypogonadism ; however, the patient’s bodymass index was normal when he was young and his weight gain
began at the age of 30 years. Some congenital HH cause mental retardation, but his mental status was normal. Kallmann
syndrome (KS) is one of the phenotypes of HH, which featured
idiopathic GnRH deficiency and anosmia (1). The frequency ofoccurrence of KS is estimated to be approximately one in 8,000
male individuals and it is featured in several disorders related
to genes, including KAL1 and FEZF1 (1, 4). In this case, althoughanosmia with hypogonadism indicated the possibility of KS, thepatient never consented to undergo urological, otolaryngological,
and genetic examinations. Consequently, we could not obtain thediagnosis of KS and that is a limitation.
Recent reports showed testosterone deficiency induced metabolic disorder through hyperglycemia, insulin resistance, andprogression of atherosclerosis regardless of age, body mass index
or visceral fat (3, 5). In fact, the patient had arteriosclerosis
obliterans of his bilateral below-knee arteries, typical of atherosclerotic disease. As for the vascular function, brachial-ankle
pulse wave velocity showed higher-than-average levels given hisage. A patient with type 2 diabetes or prediabetes reportedly hada high prevalence of low testosterone levels (6). Interestingly,testosterone replacement therapy prevented the progression ofprediabetes to type 2 diabetes and improved glycemic control(7). Although evidences of testosterone therapy in men showed
controversial results on cardiovascular disease prevention (8,9), many reports supported the protective effect of androgen
against atherosclerosis (3, 7). In this case report, the patient did
not undergo testosterone replacement therapy ; however, thistreatment is an effective choice for patients with testosterone

The Journal of Medical Investigation Vol. 68 February 2021
deficiency.
Androgens have anti-atherosclerotic effects because the androgen receptor (AR) is widely distributed in the cardiovascularsystem, including the endothelial and smooth muscle cells aswell as fibroblasts. The AR predominantly mediates biologicalactivities of androgens by the transcriptional control of target
genes and interaction with multiple signaling pathways (10).
AR activation decreases vascular remodeling through the phosphoinositide 3 / Akt / endothelial nitric oxide synthase activationand oxidative stress through the transforming growth factor beta / Smad pathway and improves angiotensin II-induced
cardiac fibrosis (11, 12). As illustrated in Figure 4, androgen
deficiency can induce various metabolic disorders that cause
macroangiopathy (Figure 4). In this patient, both the activating
renin-angiotensin-aldosterone system caused by heart failure orDM and low level of androgen would promote severe coronary
atherosclerosis progression.
In male patients who have congenital HH, we should pay
attention to metabolic disorders and atherosclerotic diseases,
including early-onset coronary artery disease.

Figure 4. Prospective scheme of the main pathogenic pathway oftestosterone deficiency. NO, nitric oxide ; PI3, phosphoinositide 3

CONFLICT OF INTEREST STATEMENT
The authors have no conflicts of interest to declare.

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ACKNOWLEDGEMENTS
The authors thank Dr. Toshiki Otoda (Department of Community
Medicine and Medical Science, Tokushima University Graduate
School of Biomedical Sciences, Tokushima) for measurement ofthe patient’s arm span.

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