Description

The hormonal changes that occur during the menopausal transition and after menopause affect multiple organ systems and are associated with a range of symptoms and chronic diseases. The prevalence of several endocrine disorders, including hypothyroidism, primary hyperparathyroidism, osteoporosis, and adrenal tumors, increases markedly during and after menopause. In addition, postmenopausal women are at increased risk of obesity, type 2 diabetes, hypertension, cardiovascular disease, and osteoporosis. While menopausal hormone therapy can alleviate symptoms and reduce bone loss, concerns regarding breast cancer and thromboembolic risk limit its use, highlighting the need for a better understanding of the biological mechanisms underlying menopausal symptoms and long-term health complications.

Menopause is characterized not only by declining estrogen concentrations but also by a marked increase in circulating luteinizing hormone (LH). Most metabolic and skeletal changes associated with menopause have traditionally been attributed to estrogen deficiency. However, several important changes, including accelerated bone loss and weight gain, often begin during perimenopause when estrogen concentrations remain relatively stable but LH levels increase substantially. This observation suggests that elevated LH may have physiological effects beyond its established role in the reproductive system.

LH exerts its biological effects through the luteinizing hormone/choriogonadotropin receptor (LHCGR), which is also activated by human chorionic gonadotropin (hCG). Although hCG is generally considered a pregnancy-associated hormone, measurable concentrations are frequently observed in postmenopausal women and in men with hypergonadotropic hypogonadism. Emerging evidence from our group suggests that LH and hCG have previously unrecognized effects on calcium homeostasis, adipose tissue, thyroid hormone metabolism, adrenal function, and potentially the development and progression of endocrine diseases.

Experimental and clinical studies conducted by our group indicate that LH and hCG stimulate urinary calcium excretion, leading to compensatory increases in parathyroid hormone (PTH) and increased bone resorption. These findings suggest the existence of a novel physiological interaction between the hypothalamic-pituitary-gonadal axis and mineral metabolism. Such mechanisms may contribute to osteoporosis development and other disorders of calcium homeostasis, particularly in postmenopausal women exposed to prolonged elevations in LH.

In addition to skeletal effects, our data indicate that adipose tissue expresses LHCGR and responds directly to LH stimulation. Elevated LH levels may influence adipocyte function, brown adipose tissue activity, energy expenditure, weight regulation, and thyroid hormone activation through inhibition of type II iodothyronine deiodinase (DIO2). These findings suggest that LH may contribute to metabolic alterations associated with aging and menopause.

Furthermore, LHCGR expression has been identified in the adrenal gland and in a substantial proportion of benign adrenal tumors. Preliminary clinical and experimental findings indicate that LH may influence adrenal steroidogenesis and could be involved in the pathophysiology of adrenal incidentalomas, including mild autonomous cortisol secretion (MACS). Elevated LH concentrations may therefore represent a novel biomarker for adrenal dysfunction and disease progression.

Recent epidemiological evidence also suggests that elevated LH and altered testosterone-to-LH ratios are associated with increased mortality risk. Collectively, these observations support the hypothesis that LH and hCG function as systemic endocrine regulators with biological effects extending well beyond the gonads.

To further investigate this concept, we propose a prospective observational study of adult patients referred for endocrine evaluation. The study will systematically assess circulating concentrations of LH, follicle-stimulating hormone (FSH), and hCG and examine their associations with endocrine disease severity, biochemical phenotypes, and long-term clinical outcomes through linkage with national health registries. The overarching aim is to determine whether LH and hCG can serve as clinically useful biomarkers and contributors to disease mechanisms across multiple endocrine disorders.