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Monday, August 18, 2025

Periods (missed or late)


Missed or Late Periods (Amenorrhea and Oligomenorrhea)


Introduction

The menstrual cycle is a complex physiological process regulated by the hypothalamic-pituitary-ovarian (HPO) axis. A typical cycle lasts between 21 and 35 days, with menstruation usually occurring for 3–7 days. Variations in the timing, frequency, or absence of menstruation often reflect underlying physiological, pathological, or lifestyle factors.

When a period is missed or delayed, it may be categorized as:

  • Amenorrhea: the absence of menstruation.

    • Primary amenorrhea: no menarche by age 15, or three years after breast development.

    • Secondary amenorrhea: absence of menses for at least three months in women with previous regular cycles, or six months in those with irregular cycles.

  • Oligomenorrhea: menstrual cycles longer than 35 days but not complete absence.

These irregularities can be temporary and benign, or they may indicate systemic, endocrine, or reproductive pathology.

Causes of Missed or Late Periods

1. Physiological Causes

  • Pregnancy: the most common cause of missed periods in reproductive-age women.

  • Lactation (lactational amenorrhea): prolactin suppresses gonadotropin release.

  • Menopause and perimenopause: declining ovarian reserve leads to irregular cycles.

  • Adolescence: anovulatory cycles are common during the first 1–2 years after menarche.

2. Lifestyle and Environmental Factors

  • Stress: affects the hypothalamus, disrupting GnRH pulsatility.

  • Excessive exercise (athletic amenorrhea): common in endurance athletes.

  • Low body weight or eating disorders: insufficient fat stores reduce leptin, leading to hypothalamic suppression.

  • Obesity: associated with polycystic ovary syndrome (PCOS) and insulin resistance.

3. Endocrine and Gynecological Conditions

  • Polycystic Ovary Syndrome (PCOS): hyperandrogenism, irregular cycles, and polycystic ovaries.

  • Thyroid disorders: both hypothyroidism and hyperthyroidism can cause menstrual irregularities.

  • Hyperprolactinemia: prolactin-secreting pituitary adenomas suppress GnRH.

  • Premature ovarian insufficiency (POI): cessation of ovarian activity before age 40.

  • Asherman’s syndrome: intrauterine adhesions following surgery or infection.

4. Medications

  • Hormonal contraceptives: combined oral contraceptives, progestin-only methods, or intrauterine systems can cause lighter or absent periods.

  • Antipsychotics and antidepressants: dopamine antagonism can raise prolactin.

  • Chemotherapy agents: cytotoxic drugs may induce ovarian failure.

Pathophysiology

The menstrual cycle is coordinated by the hypothalamic-pituitary-ovarian axis:

  1. Hypothalamus releases gonadotropin-releasing hormone (GnRH) in a pulsatile manner.

  2. Pituitary gland secretes follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

  3. Ovaries respond by producing estrogen, progesterone, and developing follicles.

Disruption at any point (hypothalamic, pituitary, ovarian, or uterine) can cause missed or delayed menstruation.

Clinical Presentation

  • Absence of menstrual bleeding (3 months or longer).

  • Delayed cycles (>35 days).

  • Possible associated symptoms:

    • Breast tenderness, nausea, fatigue (suggestive of pregnancy).

    • Galactorrhea (hyperprolactinemia).

    • Hirsutism, acne, weight gain (PCOS).

    • Hot flashes, vaginal dryness (premature ovarian insufficiency).

    • Headaches, visual changes (pituitary tumor).

Diagnostic Evaluation

1. History and Physical Examination

  • Menstrual history (onset, frequency, flow, last menstrual period).

  • Sexual and contraceptive history.

  • Symptoms of pregnancy.

  • Weight changes, stress, exercise, eating habits.

  • Family history (early menopause, PCOS, thyroid disease).

  • Physical exam: BMI, signs of androgen excess, galactorrhea, thyroid enlargement.

2. Investigations

  • Pregnancy test (urine hCG) – first-line in all reproductive-aged women.

  • Blood tests:

    • FSH, LH, estradiol → ovarian function.

    • Prolactin → pituitary adenoma or other causes.

    • TSH, free T4 → thyroid disorders.

    • Androgens (testosterone, DHEAS) → PCOS or adrenal tumor.

  • Pelvic ultrasound: ovarian morphology, uterine abnormalities.

  • MRI brain (pituitary): if prolactin is elevated.

  • Hysteroscopy: if intrauterine adhesions suspected.

Management and Treatment

The treatment depends on the underlying cause, the patient’s reproductive goals, and associated symptoms.

1. General and Lifestyle Measures

  • Stress reduction: mindfulness, therapy, yoga.

  • Nutritional optimization: adequate calories, balanced diet.

  • Weight management: weight gain in underweight women or weight loss in obese patients can restore ovulation.

  • Exercise moderation: avoid overtraining.

2. Treatment of Specific Causes

a) Pregnancy

  • Confirm with urine or blood hCG.

  • Initiate antenatal care.

  • No drug treatment required unless complications arise.

b) Hypothalamic Amenorrhea

  • Increase caloric intake, reduce exercise, manage stress.

  • Estrogen replacement (oral contraceptives or hormone therapy) may be considered if prolonged hypoestrogenism threatens bone density.

c) Polycystic Ovary Syndrome (PCOS)

  • Lifestyle changes: weight loss improves ovulation.

  • First-line pharmacological treatment:

    • Combined oral contraceptives (COCs): e.g., ethinylestradiol + levonorgestrel (30 µg/150 µg daily for 21 days, 7-day break).

    • Metformin (generic: metformin hydrochloride): 500–850 mg orally 2–3 times daily, especially for insulin resistance.

  • For infertility:

    • Clomiphene citrate: 50 mg orally daily for 5 days starting on day 2–5 of cycle.

    • Letrozole: 2.5–5 mg orally daily for 5 days starting day 3–5 of cycle (increasingly used as first-line ovulation induction).

d) Thyroid Disorders

  • Hypothyroidism: levothyroxine sodium, typical starting dose 25–50 µg daily orally, adjusted by TSH levels.

  • Hyperthyroidism: antithyroid drugs such as carbimazole (10–40 mg/day orally) or propylthiouracil (50–150 mg orally 2–3 times daily).

e) Hyperprolactinemia

  • Dopamine agonists:

    • Bromocriptine: start with 1.25 mg orally at bedtime, increase to 2.5–7.5 mg daily.

    • Cabergoline: 0.25–1 mg orally twice weekly.

  • These reduce prolactin levels and restore ovulation.

f) Premature Ovarian Insufficiency (POI)

  • Hormone replacement therapy (HRT):

    • Oral or transdermal estrogen (estradiol valerate 1–2 mg daily or estradiol patch 25–100 µg/day) plus progesterone (medroxyprogesterone acetate 10 mg daily for 10–14 days/month).

  • If fertility desired: egg donation with assisted reproduction.

g) Asherman’s Syndrome

  • Surgical hysteroscopic lysis of adhesions.

  • Estrogen therapy postoperatively to promote endometrial regrowth.

Pharmacological Summary (Generic Names and Doses)

  • Metformin hydrochloride: 500–850 mg orally 2–3 times daily.

  • Clomiphene citrate: 50 mg daily for 5 days (day 2–5 of cycle).

  • Letrozole: 2.5–5 mg daily for 5 days (day 3–5 of cycle).

  • Levothyroxine sodium: 25–50 µg daily (adjust as per TSH).

  • Carbimazole: 10–40 mg daily.

  • Propylthiouracil: 50–150 mg orally 2–3 times daily.

  • Bromocriptine: 1.25–7.5 mg daily.

  • Cabergoline: 0.25–1 mg twice weekly.

  • Estradiol valerate: 1–2 mg daily.

  • Medroxyprogesterone acetate: 10 mg daily for 10–14 days/month.

  • Combined oral contraceptives (e.g., ethinylestradiol 30 µg + levonorgestrel 150 µg).

Complications and Long-Term Consequences

  • Infertility due to chronic anovulation.

  • Osteoporosis in prolonged hypoestrogenism.

  • Cardiovascular risk: associated with premature ovarian insufficiency and PCOS.

  • Endometrial hyperplasia and cancer in women with unopposed estrogen exposure (common in PCOS).

  • Psychological impact: stress, anxiety, or depression due to uncertainty, infertility, or underlying conditions.

Prognosis

  • Transient causes (stress, travel, mild weight change) usually resolve without treatment.

  • PCOS: chronic but manageable with lifestyle and medical therapy.

  • POI or menopause: irreversible but treatable for symptom control and bone protection.

  • Pituitary or thyroid disease: good prognosis if treated promptly.

Preventive and Supportive Measures

  • Maintain a healthy BMI (18.5–24.9).

  • Balanced diet with adequate calcium and vitamin D.

  • Moderate physical activity without overtraining.

  • Early evaluation of persistent irregularities (>3 months).

  • Psychological counseling for stress or eating disorders.




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