Test for missed periods negative pregnancy test

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Missed Period with a Negative Pregnancy Test: Evaluation & Causes

A negative pregnancy test is the essential first step when a woman misses a period. Once pregnancy is ruled out, the evaluation focuses on finding the underlying cause of amenorrhea (absent menses). This is classified as secondary amenorrhea when a woman who previously had periods stops menstruating for 3 or more months.

Step 1: Confirm the Negative Test is Reliable

Before investigating further, consider whether the test could be falsely negative:

Too early testing - urine hCG may not reach detectable levels until 10-14 days after conception. Repeat in 1 week if last period was recent.
Dilute urine - test first-morning urine for the highest hCG concentration.
Ectopic pregnancy - a tubal or other ectopic pregnancy can give a weakly positive or even negative urine hCG. If any pelvic pain or risk factors are present, a serum beta-hCG should be obtained (more sensitive than urine), along with pelvic ultrasound.

Step 2: Systematic Evaluation After Confirmed Negative Pregnancy Test

According to Berek & Novak's Gynecology, when pregnancy is excluded in a reproductive-age woman with normal secondary sexual characteristics and normal pelvic exam, the workup is:

Test	Purpose
Serum TSH	Rule out hypo- or hyperthyroidism
Serum prolactin	Rule out hyperprolactinemia (obtained fasting, no recent breast stimulation)
Serum FSH	Categorize as hyper-, hypo-, or eugonadotropic amenorrhea
Serum estradiol	Assess estrogen status (>40 pg/mL suggests adequate production)
Vaginal/pelvic ultrasound	Assess antral follicle count, endometrial thickness, rule out PCOS morphology
Pituitary MRI	If prolactin is elevated or hypothalamic cause is suspected

(Berek & Novak's Gynecology, p. 1889)

Step 3: Common Causes - Organized by FSH Level

A. High FSH (>25-40 mIU/mL on two samples) = Hypergonadotropic Amenorrhea

This means primary ovarian insufficiency (POI) - the ovaries are not responding to gonadotropins.

Additional testing if POI confirmed:

FMR1 premutation (fragile X carrier status - relevant for future fertility and family)
Karyotype (to detect Turner syndrome, presence of Y chromosomal material)
21-hydroxylase antibody (to detect autoimmune adrenal insufficiency risk)
AMH (very low or undetectable in POI; high in PCOS)

Causes of POI include: autoimmune disease, chemotherapy/radiation, Turner syndrome (45,XO), fragile X premutation, galactosemia, and often idiopathic.

B. Low/Normal FSH with Low Estrogen = Hypogonadotropic Amenorrhea

The problem is at the hypothalamus or pituitary level (not enough GnRH/gonadotropin drive).

Functional Hypothalamic Amenorrhea (FHA) - very common, caused by:

Stress - psychological or physical stress alters hypothalamic GnRH pulsatility
Excessive exercise - decreased GnRH pulse frequency (common in runners, ballet dancers); osteoporosis risk from low estrogen
Weight loss / eating disorders - loss of >10% body mass in 1 year is associated with amenorrhea; anorexia nervosa causes multiple hormonal disruptions (low LH/FSH, low T3, high cortisol)
Dieting - even without reaching low weight, caloric restriction can suppress the hypothalamic-pituitary axis

(Berek & Novak's Gynecology, p. 1887-1888)

Pituitary lesions - if hypoestrogenic and FSH is not elevated:

Prolactinoma (most common pituitary tumor causing amenorrhea)
Non-prolactin-secreting pituitary tumors
Sheehan's syndrome (pituitary necrosis after postpartum hemorrhage)
Empty sella syndrome

MRI of pituitary/hypothalamus is indicated if prolactin is elevated or if no other explanation for FHA is found, especially with CNS symptoms.

C. Normal FSH with Evidence of Hyperandrogenism = Eugonadotropic Amenorrhea

Polycystic Ovary Syndrome (PCOS) is the most common cause of chronic anovulation and secondary amenorrhea overall. Suspect PCOS if:

Signs of hyperandrogenism: acne, hirsutism, androgenic alopecia
Polycystic ovarian morphology on ultrasound
Elevated LH:FSH ratio

Work up with:

Total testosterone + SHBG (or free testosterone)
Serum 17-hydroxyprogesterone - to exclude late-onset congenital adrenal hyperplasia (CAH due to 21-hydroxylase deficiency)
Fasting glucose / HbA1c + lipid profile - screen for metabolic syndrome once PCOS is diagnosed

(Berek & Novak's Gynecology, p. 1890)

D. Thyroid and Prolactin Disorders (Can Cause Any Pattern)

Hypothyroidism - elevated TRH stimulates prolactin release, leading to hyperprolactinemia and anovulation. Even mild hypothyroidism should be treated. Checked with TSH.
Hyperprolactinemia - suppresses GnRH pulsatility. Causes: prolactinoma, dopamine-blocking medications (antipsychotics, metoclopramide, domperidone), hypothyroidism, chest wall stimulation, renal failure.

E. Uterine/Outflow Tract Causes (Normal Hormones)

If all hormonal tests are normal, consider structural causes:

Asherman's syndrome - intrauterine adhesions from previous D&C, uterine infection, or surgery. Diagnosed by hysteroscopy or sonohysterography.
Cervical stenosis - outflow obstruction, can follow LEEP or cone biopsy.

These patients often have normal FSH, LH, estradiol, and prolactin.

Quick Summary

FSH Level	Estrogen	Likely Cause
High	Low	Primary Ovarian Insufficiency (POI)
Low/Normal	Low	Hypothalamic (stress, exercise, weight loss) or pituitary lesion
Normal	Normal/Variable	PCOS, thyroid disease, hyperprolactinemia, Asherman's
Normal	Normal	Asherman's / outflow tract obstruction

Medications That Can Cause Amenorrhea

Many drugs can suppress menstruation (Textbook of Family Medicine, p. 1047), including: antipsychotics and dopamine antagonists, amiodarone, beta-blockers, calcium channel blockers, opioid analgesics, methotrexate, phenytoin, and cyclosporine.

When to Seek Care

See a clinician promptly if:

Any pelvic or abdominal pain (rule out ectopic pregnancy)
Missed periods for 3+ months
Symptoms of thyroid disease, galactorrhea, hirsutism, or severe weight loss
History of D&C, uterine surgery, or chemotherapy/radiation

Sources:

Berek & Novak's Gynecology, pp. 1887-1890 - primary evaluation framework
Textbook of Family Medicine 9e, p. 1047-1050 - causes of amenorrhea and drug list

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