What endocrine disorders cause menstrual irregularities?

Endocrine Disorders Causing Menstrual Irregularities

The primary endocrine disorders causing menstrual irregularities are polycystic ovary syndrome (PCOS), thyroid dysfunction (both hypothyroidism and hyperthyroidism), hyperprolactinemia, hypothalamic amenorrhea, premature ovarian failure, and Cushing's syndrome. 1, 2, 3

Major Endocrine Causes

Polycystic Ovary Syndrome (PCOS)

• PCOS is the most prevalent endocrine disorder among women of reproductive age, characterized by hyperandrogenism, chronic anovulation, and menstrual irregularities (oligomenorrhea or amenorrhea). 4, 5, 6
• The syndrome presents with elevated androgens (testosterone, androstenedione), elevated LH/FSH ratio (>2), and polycystic ovarian morphology on ultrasound (>10 peripheral cysts, 2-8 mm diameter). 7
• PCOS is associated with hyperinsulinemia and insulin resistance, which drives both the ovarian androgen excess and metabolic complications. 5, 8
• Oligomenorrhea is the most common menstrual pattern, occurring in approximately 71% of adolescent cases. 4

Thyroid Dysfunction

• Primary hypothyroidism causes menstrual irregularities in a substantial proportion of affected women, with hyperprolactinemia occurring in 43% of women with frank hypothyroidism and 36% with subclinical hypothyroidism. 2, 3
• Hypothyroidism causes menstrual irregularities through multiple mechanisms: direct effects on ovarian function, TRH-mediated prolactin elevation, and altered sex hormone binding globulin (SHBG) levels. 3
• Menstrual cycles typically normalize within 2-5 days of achieving adequate thyroid hormone replacement with levothyroxine. 3
• Hyperthyroidism can also cause menstrual irregularities, though the mechanism differs from hypothyroidism. 3

Hyperprolactinemia

• Hyperprolactinemia causes anovulation by inhibiting gonadotropin secretion via suppression of kisspeptin, resulting in oligomenorrhea, amenorrhea, or polymenorrhea. 1, 2
• Prolactin levels >4,000 mU/L typically indicate prolactinoma, though microprolactinomas can present with lower levels. 2
• Functional hyperprolactinemia (without structural pituitary pathology) also causes menstrual irregularities and may be associated with subfertility, galactorrhea, and hirsutism. 1
• Primary hypothyroidism must be excluded immediately when hyperprolactinemia is detected, as treating hypothyroidism alone may normalize prolactin and restore regular menses. 2, 3

Hypothalamic Amenorrhea (Hypogonadotropic Hypogonadism)

• Hypothalamic amenorrhea is characterized by disturbed gonadotropin secretion with low LH levels, causing amenorrhea or oligomenorrhea without signs of hyperandrogenism. 1
• This disorder affects approximately 12% of women with temporal lobe epilepsy compared to 1.5% of the general population, though it can occur in any woman with hypothalamic-pituitary axis dysfunction. 1

Premature Ovarian Failure

• Premature ovarian failure presents with amenorrhea and FSH values above 50 mIU/L in women under age 40, occurring in approximately 4% of women with certain neurological conditions compared to 1% in the general population. 1
• This represents primary gonadal failure and causes permanent cessation of menstrual function. 1

Cushing's Syndrome

• Cushing's syndrome causes menstrual irregularities in approximately 70% of affected women of reproductive age, presenting with oligomenorrhea, amenorrhea, or polymenorrhea. 9
• The mechanism involves cortisol-induced suppression of the hypothalamic-pituitary-gonadal axis, with higher cortisol levels causing hypogonadotropic hypogonadism. 9
• Polycystic ovarian morphology is found in 46% of women with Cushing's syndrome, demonstrating overlap with PCOS phenotype. 9

Diagnostic Approach

Initial Screening

• Measure TSH and free T4 immediately to exclude thyroid dysfunction, as this is a common and readily treatable cause of menstrual irregularities. 2, 3
• Check prolactin levels with morning resting samples (repeat 2-3 times at 20-60 minute intervals if modestly elevated to exclude stress-related elevation). 2
• Obtain pregnancy test in all reproductive-age women regardless of reported contraceptive use. 3

Hormonal Evaluation for PCOS

• Measure total testosterone, free testosterone, androstenedione, and DHEA-S to characterize the androgen profile. 2, 7
• Obtain LH and FSH levels between days 3-6 of the menstrual cycle (average of three measurements 20 minutes apart), with LH/FSH ratio >2 suggestive of PCOS. 2, 7
• Check mid-luteal progesterone with levels <6 nmol/L indicating anovulation. 7, 3
• Screen for metabolic complications with fasting glucose, 2-hour oral glucose tolerance test, and fasting lipid panel. 7

Imaging Studies

• Order pituitary MRI if prolactin remains persistently elevated (>20 μg/L or >4,000 mU/L) to exclude prolactinoma or other pituitary pathology. 2
• Perform pelvic ultrasound (transvaginal preferred) to evaluate for polycystic ovaries or structural abnormalities when hormonal tests suggest ovarian pathology. 7, 3

Exclusion of Adrenal Pathology

• Markedly elevated DHEA-S suggests adrenal pathology including non-classical congenital adrenal hyperplasia or adrenal tumor, requiring further evaluation. 2, 7
• Androstenedione >10.0 nmol/L or age-adjusted DHEA-S elevation (>3800 ng/ml for ages 20-29, >2700 ng/ml for ages 30-39) requires imaging. 7

Critical Clinical Pitfalls

Overlapping Presentations

• Hyperprolactinemia itself causes anovulation, making it difficult to initially distinguish from PCOS until prolactin is normalized. 2
• The combination of hyperprolactinemia and elevated DHEA-S is unusual and requires investigation of both pituitary and adrenal axes separately. 2
• Women with Cushing's syndrome may present with a phenotype identical to PCOS (menstrual irregularity, hyperandrogenism, polycystic ovaries), requiring cortisol evaluation when clinical suspicion exists. 9

Medication Effects

• Certain antiepileptic drugs (valproate, carbamazepine, phenytoin, phenobarbital) can cause or worsen menstrual irregularities through multiple mechanisms: direct effects on hypothalamic-pituitary axis, peripheral endocrine gland effects, altered hormone metabolism, and drug-induced weight changes. 1, 3
• Valproate is particularly associated with PCOS development, with 45% of women on valproate monotherapy experiencing menstrual irregularities. 1
• Levothyroxine itself can cause menstrual irregularities as an adverse effect of over-replacement. 10

Age-Related Considerations

• Menstrual cycle characteristics in PCOS and early-life irregularity become more similar to regular cycles with advancing age, with differences diminishing through the 20s and 30s. 6
• Cycle irregularity (within-individual standard deviation) decreases with age in women with PCOS or early-life irregularity. 6