Can you provide a detailed explanation of the female menstrual cycle?

The Female Menstrual Cycle: A Detailed Explanation

Overview and Duration

The menstrual cycle is a coordinated hormonal process lasting 21-35 days (average 28 days) that prepares the female reproductive system for pregnancy through integrated actions of the hypothalamus, pituitary gland, ovaries, and uterus. 1, 2

The cycle exhibits high variability in length between women and even cycle-to-cycle in the same woman, with typical menstrual bleeding lasting 5 days. 2

Hormonal Control: The Hypothalamic-Pituitary-Ovarian Axis

The Hypothalamic Pulse Generator

• The hypothalamus acts as the cycle's metronome, releasing gonadotropin-releasing hormone (GnRH) in pulsatile fashion. 3
• GnRH pulses occur every 1-1.5 hours during the follicular phase and slow to every 2-4 hours during the luteal phase. 3
• This pulsatile pattern is essential—continuous GnRH would paradoxically suppress the system. 3

Pituitary Response

• Pulsatile GnRH stimulates the anterior pituitary to secrete two key gonadotropins: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). 3
• The pituitary translates hypothalamic signals into hormones that the ovarian follicles can respond to. 3

The Four Phases of the Menstrual Cycle

Phase 1: Menstrual Phase (Days 1-5)

• Day 1 is defined as the first day of menstrual bleeding. 2
• Menstruation represents shedding of the functional endometrial layer in the absence of pregnancy. 2
• This process is initiated by progesterone-responsive decidual cells and executed through prostaglandins (PGE and PGF2α), vasoconstriction, and matrix metalloprotease secretion by leukocytes. 2
• The endometrium breaks down as progesterone and estradiol levels fall, triggering an inflammatory-like response. 4

Phase 2: Follicular Phase (Days 1-14, Variable Length)

Early Follicular Phase (Days 1-7):

• FSH rises at the luteal-follicular transition, stimulating a cohort of follicles to begin growing. 2
• Baseline FSH and LH measurements taken between days 3-6 provide the most accurate assessment of ovarian reserve (calculated as average of three measurements taken 20 minutes apart). 1, 5
• Growing follicles secrete inhibin B, which provides negative feedback to reduce FSH levels. 2
• Normal early follicular FSH should be <10 IU/L; levels >35 IU/L suggest ovarian failure. 1, 5

Mid-Follicular Phase (Days 7-10):

• One follicle becomes dominant (the "dominant follicle" or DF) through superior FSH responsiveness, IGF binding protein expression, and enhanced vascularization. 2
• The dominant follicle increasingly secretes estradiol as it grows, while other follicles undergo atresia (programmed cell death). 2, 6
• Two-thirds of women show two follicle waves per cycle, while one-third show three waves; three-wave women have longer cycles. 2

Late Follicular Phase (Days 10-14):

• The dominant follicle grows rapidly and secretes increasing amounts of estradiol and inhibin A for approximately one week before ovulation. 2
• Theca cells (stimulated by LH) produce androstenedione, which granulosa cells (stimulated by FSH) convert to estradiol via aromatase enzyme. 3
• Rising estradiol initially suppresses LH and FSH through negative feedback. 3

Phase 3: Ovulation (Day 14, Variable)

The LH Surge:

• When estradiol reaches a critical threshold (sustained levels >200 pg/mL for 48+ hours), it switches from negative to positive feedback. 3
• This triggers a massive LH surge (and smaller FSH surge) through the kisspeptin system in the hypothalamus. 3
• The LH surge typically occurs 24-36 hours before ovulation. 7

Follicle Rupture:

• The LH surge initiates the ovulation process, causing the mature follicle (typically 18-25mm) to rupture and release the oocyte. 3
• Ovulation generally occurs on days 9-20 of the cycle, depending on cycle length. 8
• For a standard 28-day cycle, ovulation occurs around day 14; for shorter 25-day cycles, it occurs around days 11-12. 7

Fertile Window:

• The fertile period spans 5 days before ovulation through the day of ovulation. 2
• Sperm can survive up to 5 days in the female reproductive tract, while the oocyte remains viable for 12-24 hours after ovulation. 7

Phase 4: Luteal Phase (Days 15-28, Fixed Duration)

Corpus Luteum Formation:

• After ovulation, the ruptured follicle transforms into the corpus luteum ("yellow body"). 3
• The corpus luteum secretes progesterone, estradiol, and inhibin A in response to LH pulses. 2
• Peak corpus luteum function occurs 6-7 days after ovulation (around day 21 in a 28-day cycle). 2

Progesterone Dominance:

• Progesterone levels rise dramatically, reaching peak levels in the mid-luteal phase. 3
• Progesterone prepares the endometrium for implantation and suppresses the inflammatory response that would otherwise reject an embryo. 3, 4
• Mid-luteal progesterone ≥6 nmol/L (≥5 ng/mL) confirms ovulation occurred; levels <6 nmol/L indicate anovulation. 1, 8

Luteal Regression or Rescue:

• The corpus luteum has a fixed lifespan of approximately 14 days unless rescued by human chorionic gonadotropin (hCG) from an implanting embryo. 2
• Without pregnancy, the corpus luteum passively regresses, causing progesterone and estradiol to fall. 2
• Falling hormone levels trigger menstruation and allow FSH to rise, initiating the next cycle. 2

Endometrial Changes Throughout the Cycle

Proliferative Phase (Corresponds to Follicular Phase)

• Rising estradiol stimulates endometrial proliferation and thickening. 3
• The functional endometrial layer regenerates after menstruation. 2
• Endometrial glands elongate and blood vessels proliferate. 9

Secretory Phase (Corresponds to Luteal Phase)

• Progesterone transforms the proliferative endometrium into secretory tissue. 3
• Endometrial glands become tortuous and begin secreting glycogen-rich fluid. 9
• The endometrium becomes optimally receptive for embryo implantation during the mid-luteal phase (days 19-23). 3
• Specific implantation markers (such as integrins) are expressed during this "window of implantation." 6

Cervical and Tubal Changes

• Cervical mucus changes throughout the cycle: thick and impenetrable during most of the cycle, becoming thin, clear, and stretchy ("spinnbarkeit") around ovulation to facilitate sperm transport. 9
• The uterine tubes undergo cyclical changes in ciliary activity and secretions to support oocyte and embryo transport. 9

Normal Hormonal Values and Patterns

Early Follicular Phase (Days 3-6):

• FSH: <10 IU/L (normal ovarian reserve); >35 IU/L suggests ovarian failure 1, 5
• LH: <7 IU/mL may indicate hypothalamic dysfunction; >11 IU/L may suggest ovarian failure 1
• LH:FSH ratio: Should be <2; ratio >2 suggests PCOS 1
• Estradiol: Low baseline levels 5

Mid-Cycle (Ovulation):

• LH surge: Dramatic rise, typically 2-3 times baseline 3
• Estradiol: Peak levels >200 pg/mL 3

Mid-Luteal Phase (Day 21 in 28-day cycle):

• Progesterone: ≥6 nmol/L (≥5 ng/mL) confirms ovulation 1, 8
• Estradiol: Secondary rise 2

Common Abnormalities and Pitfalls

Anovulation

• Anovulation (failure to ovulate) can occur despite regular bleeding patterns. 1
• Common causes include polycystic ovary syndrome (PCOS), hypothalamic amenorrhea, hyperprolactinemia, and thyroid disorders. 1
• PCOS affects 4-6% of women generally but 10-25% of women with temporal lobe epilepsy, characterized by LH:FSH ratio >2, hyperandrogenism, and chronic anovulation. 1

Timing Errors in Hormone Assessment

• Hormone measurements must occur at specific cycle points: FSH/LH on days 3-6, progesterone 7 days post-ovulation (approximately day 21 for 28-day cycles). 1, 5, 8
• For irregular cycles, progesterone should be measured approximately 7 days before expected menses, not automatically on day 21. 8
• Hormonal contraceptives must be discontinued at least 2 months before testing to allow normal pituitary-ovarian axis function to return. 5

Luteal Phase Defects

• Inadequate progesterone production can prevent successful implantation even if ovulation occurs. 8
• This requires mid-luteal progesterone measurement, not just confirmation of ovulation. 8

Energy Deficiency in Athletes

• Female athletes are at high risk (47.3%) for low energy availability, which can disrupt the menstrual cycle. 1
• Energy availability should be ≥45 kcal·kg⁻¹ fat-free mass·day⁻¹ for optimal reproductive function. 1
• Common micronutrient deficiencies (iron, vitamin D, calcium) can further impact menstrual health. 1

Clinical Implications

Contraception Timing

• Combined hormonal contraceptives can be started at any time if pregnancy is reasonably excluded, though backup contraception is needed for 7 days if started >5 days after menstrual bleeding begins. 1
• Understanding the fertile window is crucial for both achieving and avoiding pregnancy. 7, 2

Fertility Assessment

• Normal baseline hormones (FSH, LH, estradiol) do not guarantee ovulation; mid-luteal progesterone measurement is essential for confirmation. 5
• Women with regular cycles can still be anovulatory, requiring hormonal documentation. 1