What causes low Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH) levels?

Causes of Low FSH and LH

Low FSH and LH levels result from secondary (hypogonadotropic) hypogonadism, which is caused by impairment of the hypothalamic-pituitary-gonadal (HPG) axis rather than primary gonadal failure. 1

Primary Mechanism

The fundamental pathophysiology involves reduced pulsatile secretion of GnRH from the hypothalamus, which leads to decreased LH pulse frequency and reduced FSH secretion. 1 Slow GnRH pulse frequency particularly favors decreased LH secretion while affecting FSH to a lesser extent, since reduced GnRH pulsatility actually favors FSH secretion relative to LH. 1

Congenital/Developmental Causes

Idiopathic Hypogonadotropic Hypogonadism (IHH)

• Kallmann syndrome (IHH with anosmia) 1
• Normosmic IHH 1
• Isolated LH gene mutations 1
• Prader-Willi syndrome 1
• Combined pituitary hormone deficiency 1

Genetic Syndromes

• Rare chromosomal abnormalities (XX male, 47 XYY, 48 XXYY syndrome) 1
• Trisomy 21 (Down syndrome) 1
• Noonan syndrome 1
• Kennedy disease (spinal and bulbar muscular atrophy) 1

Drug-Induced Causes

Exogenous Hormones

• Testosterone or androgenic anabolic steroids suppress the HPG axis through negative feedback 1
• Estrogens 1
• Progestogens (including cyproterone acetate) 1
• GnRH agonists or antagonists 1

Other Medications

• Opiates are a common and often overlooked cause 1
• Glucocorticoids 1
• Hyperprolactinemia-inducing drugs (antipsychotics, metoclopramide) 1

Localized Hypothalamic-Pituitary Problems

Structural Lesions

• Pituitary neoplasms (micro/macroadenomas) 1
• Hypothalamic tumors 1
• Pituitary stalk diseases 1
• Traumatic brain injury 1

Iatrogenic

• Surgical hypophysectomy 1
• Pituitary or cranial irradiation 1

Inflammatory/Infectious

• Lymphocytic hypophysitis 1
• Pituitary infections 1
• Granulomatous lesions (sarcoidosis, Wegener's granulomatosis) 1
• Encephalitis 1
• Langerhans' histiocytosis 1

Hyperprolactinemia

• Prolactinomas or other pituitary masses suppress GnRH pulsatility 1
• Rule out hypothyroidism, which can cause secondary hyperprolactinemia 1

Systemic Diseases/Conditions

Metabolic Disorders

• Type 2 diabetes mellitus/metabolic syndrome 1
• Obesity affects the HPG axis 1
• Cushing syndrome (glucocorticoid excess) 1

Chronic Systemic Diseases

• HIV infection 1
• Chronic organ failure (renal, hepatic, cardiac) 1
• Chronic inflammatory arthritis 1

Functional Hypothalamic Amenorrhea (in women)

This represents a functional reduction in GnRH pulse frequency without identifiable organic causes: 1

• Excessive exercise/endurance training 1
• Energy deficit/weight loss 1
• Eating disorders (anorexia nervosa, bulimia) 1
• Psychological stress and stress sensitivity 1

The mechanism involves kisspeptin neurons bridging the hypothalamic-pituitary-adrenal axis (stress response) and the HPG axis. 1

Other Systemic Conditions

• Acute and critical illness 1
• Aging (late-onset hypogonadism) 1
• Celiac disease 1

Important Clinical Distinctions

Differentiating from Primary Hypogonadism

In secondary hypogonadism, FSH and LH are low or inappropriately normal despite low sex steroids, whereas primary gonadal failure causes elevated FSH and LH. 1 The LH/FSH ratio may be <2 in secondary hypogonadism, compared to >2 in some conditions like PCOS. 1

Functional vs. Organic Hypogonadism

Functional hypogonadism is diagnosed when no organic alterations in the HPG axis are found, and low gonadotropins result from comorbidities that should be treated first. 1 This is distinct from organic causes requiring hormone replacement.

Common Pitfalls

• Do not measure gonadotropins immediately post-seizure or post-stress, as prolactin may be transiently elevated and gonadotropins suppressed 1
• Measure FSH and LH in the early follicular phase (days 3-6) in women with menstrual cycles 1
• Calculate based on an average of three measurements taken 20 minutes apart for accurate assessment 1
• LH <7 IU/ml is considered low 1