What are the causes of low Follicle-Stimulating Hormone (FSH) levels?

Causes of Low FSH Levels

Low FSH levels result from secondary (hypogonadotropic) hypogonadism, where impairment of the hypothalamic-pituitary-gonadal (HPG) axis leads to reduced pulsatile GnRH secretion from the hypothalamus, subsequently decreasing both LH pulse frequency and FSH secretion. 1

Primary Pathophysiologic Mechanism

The fundamental problem in low FSH is reduced pulsatile secretion of GnRH from the hypothalamus, which disrupts the normal feedback loop between the gonads and the pituitary gland. 1 This distinguishes secondary hypogonadism (low FSH with low sex steroids) from primary gonadal failure (elevated FSH with low sex steroids). 1

Congenital/Genetic Causes

• Kallmann syndrome (idiopathic hypogonadotropic hypogonadism with anosmia) represents a congenital failure of GnRH neuron migration, resulting in lifelong low FSH and LH. 1
• Normosmic idiopathic hypogonadotropic hypogonadism causes low gonadotropins without the olfactory defects seen in Kallmann syndrome. 1
• Klinefelter syndrome and other karyotype abnormalities can present with variable FSH levels, though typically FSH is elevated; however, in males with azoospermia and FSH <7.6 IU/L, obstructive causes should be suspected rather than primary testicular failure. 2

Drug-Induced Causes

• Testosterone or androgenic anabolic steroids suppress the HPG axis through negative feedback, causing profound suppression of both FSH and LH. 1 This is one of the most common iatrogenic causes in clinical practice.
• Opiates are a frequently overlooked but common cause of hypogonadotropic hypogonadism with low FSH and LH. 1
• GnRH analogs, corticosteroids, and certain antiepileptic drugs can suppress gonadotropin secretion. 3
• Combined oral contraceptives completely suppress FSH and LH levels in women. 2

Functional Hypothalamic Causes (Primarily in Women)

• Functional hypothalamic amenorrhea (FHA) is characterized by both LH and FSH levels <2 IU/L, typically with LH <3 IU/L, caused by hypothalamic inhibition from stress, excessive exercise, eating disorders, or low body weight. 2, 3
• Energy deficit states including eating disorders, excessive exercise (>6 hours/week of intense activity), and preoccupation with weight lead to hypothalamic suppression. 2
• Low BMI is strongly associated with lower FSH levels in women with functional hypothalamic amenorrhea. 2

Systemic Diseases and Metabolic Conditions

• Type 2 diabetes mellitus and metabolic syndrome disrupt the HPG axis, leading to inappropriately low FSH and LH despite low sex steroid levels. 1
• Obesity affects gonadotropin secretion through multiple mechanisms including increased aromatization of androgens to estrogens and altered GnRH pulsatility. 1, 3
• Cushing syndrome (glucocorticoid excess) suppresses the hypothalamic-pituitary axis, resulting in low FSH and LH. 1
• Chronic liver disease disrupts the hypothalamic-pituitary axis with low FSH and LH, leading to anovulation and amenorrhea in more than 25% of women with advanced disease. 3

Pituitary and Hypothalamic Structural Lesions

• Hyperprolactinemia (from prolactinomas or other causes) suppresses GnRH pulsatility, leading to low LH and FSH. 3 This is a common and treatable cause requiring immediate measurement of serum prolactin.
• Pituitary adenomas (both functioning and non-functioning) can cause central hypogonadism through mass effect or hormonal disruption. 3
• Hypophysitis, particularly in patients with history of immune checkpoint inhibitor therapy, can impair gonadotropin secretion. 3
• Cranial irradiation history can permanently impair gonadotropin secretion. 3

Special Populations and Conditions

• Women with temporal lobe epilepsy have hypothalamic amenorrhea in approximately 12% of cases compared to 1.5% in the general population, with functional hyperprolactinemia potentially resulting from seizures or epileptic activity propagated to the hypothalamus. 3
• Undertreatment in congenital adrenal hyperplasia leads to hypogonadotropic hypogonadism with low LH pulse levels and frequency due to elevated progesterone and androgen concentrations suppressing the gonadotropic axis. 4

Critical Clinical Distinctions

• In secondary hypogonadism, FSH and LH are low or inappropriately normal despite low sex steroids, whereas primary gonadal failure causes elevated FSH and LH as the pituitary attempts to stimulate failing gonads. 1
• **The LH/FSH ratio may be <2 in secondary hypogonadism**, compared to >2 in conditions like PCOS. 1
• In males with azoospermia, FSH <7.6 IU/L suggests obstructive azoospermia rather than spermatogenic failure, particularly when testes are normal size with dilated epididymides. 2

Important Diagnostic Pitfalls

• Low FSH alone is not diagnostic; interpretation must be made in the context of other hormonal parameters (LH, sex steroids, prolactin) and clinical presentation. 3
• Transient fluctuations in FSH occur; confirmation with repeat morning measurements is essential before making definitive diagnoses. 3
• The "normal" range for FSH may need reconsideration in specific contexts—research suggests FSH >4.5 IU/L may be associated with abnormal semen parameters in infertile men, despite laboratory reference ranges extending to 18.1 IU/L. 5
• In recently postmenopausal women, FSH is not invariably elevated, and some women demonstrate subclinical pituitary dysfunction with inappropriately low FSH despite low estradiol, possibly representing a variant of normal or subclinical pituitary failure. 6