What does low follicle‑stimulating hormone (FSH) and luteinizing hormone (LH) indicate in women?

Low FSH and LH in Women: Clinical Significance

Low FSH and LH in women indicates secondary (hypogonadotropic) hypogonadism, which results from impairment of the hypothalamic-pituitary-gonadal axis rather than primary ovarian failure. 1, 2

Fundamental Pathophysiology

The core mechanism involves reduced pulsatile secretion of GnRH from the hypothalamus, leading to decreased LH pulse frequency and reduced FSH secretion. 1 This distinguishes secondary hypogonadism from primary ovarian failure, where FSH and LH would be elevated as the pituitary attempts to stimulate failing ovaries. 1, 2

In secondary hypogonadism, FSH and LH are low or inappropriately normal despite low sex steroids (estradiol), whereas primary gonadal failure causes elevated FSH and LH. 1, 2

Major Etiologic Categories

Congenital/Genetic Causes

• Kallmann syndrome (hypogonadotropic hypogonadism with anosmia) represents congenital failure of GnRH neuron migration, resulting in lifelong low FSH and LH 1, 2
• Normosmic idiopathic hypogonadotropic hypogonadism causes low gonadotropins without olfactory defects 1, 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, 2
• Opiates are a frequently overlooked but common cause of hypogonadotropic hypogonadism 1, 2
• Combined oral contraceptives completely suppress FSH and LH levels in women 2
• GnRH analogs, corticosteroids, and certain antiepileptic drugs can suppress gonadotropin secretion 2

Functional Hypothalamic Amenorrhea

This condition is characterized by both LH and FSH levels <2 IU/L, typically with LH <3 IU/L, caused by hypothalamic inhibition. 2 Key triggers include:

• Stress, excessive exercise, eating disorders, or low body weight lead to energy deficit states that suppress the hypothalamus 2
• Low BMI is strongly associated with lower FSH levels in women with functional hypothalamic amenorrhea 2
• Preoccupation with weight and energy deficit states disrupt normal GnRH pulsatility 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, 2
• Obesity affects gonadotropin secretion through increased aromatization of androgens to estrogens and altered GnRH pulsatility 1, 2
• Cushing syndrome (glucocorticoid excess) suppresses the hypothalamic-pituitary axis 1, 2
• 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, 2

Pituitary and Hypothalamic Structural Lesions

• Hyperprolactinemia suppresses GnRH pulsatility, leading to low LH and FSH 2
• Pituitary adenomas can cause central hypogonadism through mass effect or hormonal disruption 2
• Direct irradiation of the hypothalamus-pituitary may induce central hypogonadism by impairing secretion of FSH and LH, especially at doses ≥40 Gy 3

Clinical Consequences

Absent or low pituitary secretion of FSH and LH leads to anovulation, amenorrhea, and absent ovarian follicular development. 4 Specific manifestations include:

• Anovulation and infertility due to inadequate follicular stimulation 3, 4
• Amenorrhea or oligomenorrhea seen in women with advanced liver disease and other systemic conditions 3
• Estrogen deficiency with associated symptoms and long-term health risks 3
• Impaired bone mineral density requiring evaluation in hypogonadal patients 3

Critical Diagnostic Distinctions

The LH/FSH ratio may be <2 in secondary hypogonadism, compared to >2 in conditions like PCOS. 1, 2 This ratio helps differentiate between various causes of reproductive dysfunction.

When evaluating patients with delayed puberty, irregular menses, primary or secondary amenorrhea, and/or clinical signs of estrogen deficiency, measure LH, FSH, and estradiol levels. 3 The pattern of low or inappropriately normal gonadotropins with low estradiol confirms secondary hypogonadism. 1, 2

Management Approach

Treatment of hypogonadism seeks to normalize ovarian hormone levels through estrogen replacement with oral, micronized, or transdermal preparations. 3 Progesterone therapy is also needed to avoid unopposed estrogen effect and maintain endometrial health in women with a uterus. 3

Referral to endocrinology or gynecology is warranted for delayed puberty, persistently abnormal hormone levels, or hypogonadism. 3 Reproductive endocrinology consultation should be considered for infertility evaluation and assisted reproduction options. 3

Common Pitfalls

• Failing to recognize opiates as a cause of hypogonadotropic hypogonadism, as this is frequently overlooked 1, 2
• Missing functional hypothalamic amenorrhea in women with excessive exercise, eating disorders, or stress-related weight loss 2
• Not screening for hyperprolactinemia when evaluating low gonadotropins, as this is a treatable cause 2
• Overlooking chronic liver disease as a cause of disrupted HPG axis function 3, 2