The Menstrual Cycle: Physiology and Management of Irregularities
Normal Menstrual Cycle Physiology
A normal menstrual cycle lasts 21-35 days with 3-7 days of bleeding, driven by coordinated hormonal interactions between the hypothalamus, pituitary, and ovaries that produce a mature oocyte each month. 1, 2
Cycle Phases and Hormonal Regulation
The menstrual cycle consists of three distinct phases 2:
Follicular Phase: FSH rises at the luteal-follicular transition, stimulating follicle growth and inhibin B secretion in early follicular phase. The dominant follicle is selected mid-follicular phase and increasingly secretes estradiol and inhibin A for approximately one week before ovulation. 1
Ovulatory Phase: Two-thirds of women show two follicle waves per cycle, while one-third show three waves. Women with three-wave cycles have longer cycles and later estradiol rise and LH surge. 1
Luteal Phase: The corpus luteum secretes progesterone, estradiol, and inhibin A in response to LH pulses, reaching peak size and secretion 6-7 days after ovulation. Luteal regression occurs passively unless prevented by hCG from trophoblast implantation starting 8 days after conception. 1
Normal Cycle Variability
Cycle length varies considerably even in healthy women, with normal range of 26-35 days, though cycles of 21-45 days are acceptable in adolescents. 3, 1, 2
The fertile window extends from 5 days before ovulation to the day of ovulation itself, though timing of this 6-day window varies greatly even among women with regular cycles. 3, 1
Hormonal profiles differ substantially between women with different cycle lengths (22-day vs. 28-day vs. 35-day cycles), yet all represent normal eumenorrheic patterns. 3
Defining Abnormal Menstrual Patterns
Menstrual irregularity requiring evaluation includes cycles <23 days or >35 days, absence of bleeding for >6 months, or bleeding lasting ≥8 days. 4, 2
Red Flags Warranting Immediate Evaluation
Amenorrhea >90 days (3 consecutive months) is abnormal even in early gynecologic years, as the 95th percentile for time between cycles is 90 days. 3, 4, 5
Primary amenorrhea by age 15 years requires comprehensive workup. 4, 2
Bleeding duration ≥8 days with or without heavy flow necessitates investigation. 2
Common Causes of Irregular Cycles
Polycystic Ovary Syndrome (PCOS)
PCOS affects 4-6% of the general population and is the most common cause of secondary amenorrhea, characterized by hyperandrogenism, chronic anovulation, and accelerated GnRH pulsatility. 3, 4, 6
Diagnostic criteria include LH/FSH ratio >2 (though less likely with elevated SHBG), total testosterone >2.5 nmol/L, and >10 peripheral ovarian cysts of 2-8 mm diameter on ultrasound. 3, 7
Natural history: Women with PCOS have longer and more irregular cycles in their 20s and 30s, but these differences diminish with age as cycle characteristics become more similar to women with regular cycles. 8
Prevalence in epilepsy: PCOS affects 10-25% of women with temporal lobe epilepsy even without antiepileptic drug use, compared to 4-6% in general population. 3
Hypothalamic Amenorrhea
Hypothalamic amenorrhea (hypogonadotropic hypogonadism) affects 12% of women with temporal lobe epilepsy versus 1.5% of the general population, presenting with low LH levels and disturbed gonadotropin secretion. 3
Associated factors include weight loss, excessive exercise, emotional stress, and low energy availability. 4
Treatment priority: Increase caloric intake and reduce excessive exercise to restore normal HPG axis function. 4
Low Energy Availability and RED-S
Energy availability (EA) of <30 kcal/kg fat-free mass per day discriminates between amenorrheic versus eumenorrheic status, with 47.3% of female athletes at risk for low EA. 3
Calculation: EA = [Energy Intake (kcal) - Exercise Energy Expenditure (kcal)] / Fat-Free Mass (kg) per day. 3
Clinical manifestations: Linear relationship exists between EA and menstrual disturbances, with disruptions to LH pulsatility causing oligo-amenorrhea through HPG axis dysfunction. 3
Thyroid Dysfunction
Hypothyroidism causes menstrual irregularities through TRH-mediated hyperprolactinemia and direct effects on reproductive hormones, with cycles normalizing within 2-5 days of adequate thyroid replacement. 6
Target TSH: 0.4-4.5 mIU/L for resolution of menstrual irregularities. 6
Levothyroxine dosing: 1.6 mcg/kg/day for patients without cardiac risk factors. 6
Hyperprolactinemia
Prolactin levels >20 μg/L are abnormal and cause menstrual irregularity through disruption of GnRH pulsatility. 4, 6
- Epilepsy association: Functional hyperprolactinemia prevalence is increased in women with epilepsy, with postictal prolactin elevations following generalized or temporal lobe seizures. 3
Drug-Induced Menstrual Irregularities
Antiepileptic drugs (valproate, carbamazepine, phenytoin, phenobarbital) affect reproductive hormones by inducing hepatic cytochrome P450-dependent steroid breakdown and SHBG production, reducing biologically active sex hormone concentrations. 3, 6
- Carbamazepine specifically causes menstrual disturbance with low estradiol and low estradiol/SHBG ratio in 25% of treated women. 3
Diagnostic Evaluation Algorithm
Initial Assessment
Perform pregnancy test first in all reproductive-age women regardless of reported contraceptive use, followed by targeted hormonal evaluation based on clinical presentation. 4, 6
Core Laboratory Tests
TSH and free T4: Measure to identify thyroid dysfunction as primary cause. 6
Prolactin: Obtain if galactorrhea present or cycles irregular; levels >20 μg/L are abnormal. 4, 6
LH and FSH: Measure on cycle days 3-6 with three estimations 20 minutes apart (due to pulsatile release); LH/FSH ratio >2 suggests PCOS. 3, 7, 4, 6
Mid-luteal progesterone: Levels <6 nmol/L indicate anovulation. 6
Total testosterone: >2.5 nmol/L suggests hyperandrogenism. 7
Imaging Studies
Perform transvaginal pelvic ultrasound (or transabdominal if virginal) on cycle days 3-9 if hormonal tests suggest ovarian pathology or to evaluate for PCOS (>10 peripheral cysts of 2-8 mm diameter). 3, 7, 4, 6
- Pituitary MRI is indicated if prolactin elevated or clinical features suggest hypothalamic-pituitary abnormalities. 4
Management Strategies
Treatment of Underlying Causes
Address the primary etiology first: normalize thyroid function with levothyroxine, increase energy availability in hypothalamic amenorrhea, or manage PCOS with lifestyle modification and hormonal therapy. 4, 6
Symptomatic Management of Irregular Bleeding
For Light Bleeding or Spotting
Use NSAIDs as first-line treatment: mefenamic acid 500 mg three times daily for 5 days OR celecoxib 200 mg daily for 5 days during bleeding episodes. 7, 6
- Avoid aspirin as it may increase blood loss in women with baseline menstrual blood loss <60 mL. 6
For Heavy or Prolonged Bleeding
Tranexamic acid is second-line treatment, significantly reducing menstrual blood loss, but contraindicated in women with active thromboembolic disease or thrombosis history/risk. 6
- Short-term hormonal therapy: Low-dose combined oral contraceptives for 10-20 days if medically eligible and no contraindications (increases VTE risk 3-4 fold). 7, 6
Hormonal Contraception for Cycle Regulation
Combined oral contraceptives provide excellent cycle control for contraception and medical management of dysmenorrhea, heavy menstrual bleeding, and acne. 4
Progestin IUD: Levonorgestrel-releasing IUD reduces menstrual blood loss by 71-95% and is effective for long-term management and menstrual suppression in adolescents with complex medical conditions. 4, 6
Depot medroxyprogesterone acetate (DMPA): Highly effective (3% failure rate) but causes menstrual irregularities in nearly all patients initially; contraindicated in women with positive antiphospholipid antibodies or high osteoporosis risk. 3, 4
Progestin-only pills: Safe in all women with RMD with 5-8% failure rate, but higher breakthrough bleeding than combined contraceptives and must be taken same time daily. 3
Contraceptive Safety Considerations
Long-acting reversible contraceptives (copper IUD, progestin IUD, progestin implant) have <1% failure rate and are safe in all women with rheumatic and musculoskeletal diseases. 3
Combined estrogen-progestin methods are contraindicated in women with positive antiphospholipid antibodies or very active SLE. 3
Fertility awareness methods (including Standard Days Method) have 24% failure rate and are inappropriate for women with consistently irregular cycles (<26 or >32 days). 3
Referral Criteria
Refer to endocrinology and/or gynecology when amenorrhea persists >6 months, abnormal hormone levels suggest specific pathology, signs of hyperandrogenism with menstrual irregularity are present, or bleeding persists despite two treatment attempts. 7, 4, 6
Infertility concerns (inability to conceive after 12 months of unprotected intercourse) warrant specialist referral. 7
Suspected structural abnormalities on imaging require gynecologic evaluation. 4
Follow-Up Monitoring
Monitor response to symptomatic bleeding management within 1-2 cycles, reassess menstrual pattern, and continue TSH monitoring every 6-12 months once stable on thyroid replacement if applicable. 7, 6
- Evaluate patient satisfaction with contraceptive method if hormonal treatment initiated. 7
Critical Pitfalls to Avoid
Do not dismiss amenorrhea >90 days as normal even in adolescents, as this represents the 95th percentile and warrants evaluation. 5
Do not delay evaluation of menstrual disorders, as estrogen deficiency increases osteoporosis and hip fracture risk. 5
Review all medications that may impact reproductive hormones, particularly antiepileptic drugs. 3, 6
Reassess for structural pathology (polyps, fibroids, adenomyosis, endometrial hyperplasia) when irregularities persist despite euthyroid state. 6