Medical School · Year 2 · Reproductive · includes a quiz and discussion video

Lecture 4: Menstrual Cycle and Ovulation

Unit 2.4: Reproductive System

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the hormonal changes throughout the menstrual cycle
2. Explain folliculogenesis and the dominant follicle selection
3. Describe the mechanism and timing of ovulation
4. Explain the formation and function of the corpus luteum
5. Describe the endometrial changes during the menstrual cycle
6. Explain the clinical assessment of ovulation

Lecture Outline

I. Menstrual Cycle Overview

The menstrual cycle is the recurring sequence of physiologic changes in the reproductive system that prepares for potential pregnancy each month. Understanding the menstrual cycle is fundamental to reproductive medicine, informing the diagnosis of menstrual disorders, management of infertility, and mechanisms of hormonal contraception.

The phases of the menstrual cycle can be described from either the ovarian or uterine perspective. The ovarian cycle comprises the follicular phase (follicle development and estrogen production), ovulation (oocyte release), and luteal phase (corpus luteum function and progesterone production). The uterine cycle comprises the menstrual phase (endometrial shedding), proliferative phase (estrogen-driven growth), and secretory phase (progesterone-driven maturation). These parallel classifications describe the same cycle from different anatomic perspectives: the ovarian cycle focuses on the source of hormones, while the uterine cycle focuses on the target tissue response.

Cycle timing follows characteristic patterns. Day 1 of the cycle is defined as the first day of menstrual bleeding, providing a clear clinical marker. The average cycle length is 28 days, though normal cycles range from 21 to 35 days. Critically, cycle length variability is almost entirely due to variation in the follicular phase; the luteal phase is remarkably consistent at approximately 14 days (±2 days). This means that in a 35-day cycle, ovulation occurs around day 21, while in a 21-day cycle, ovulation occurs around day 7. Understanding this principle is essential for fertility timing and for interpreting hormone measurements, which must be timed to the appropriate cycle phase.

The menstrual phase (typically days 1-5) begins when falling progesterone and estrogen levels from the regressing corpus luteum trigger endometrial shedding. The functionalis layer is sloughed, leaving the basalis layer intact for regeneration. Average menstrual blood loss is 30-80 mL, and normal duration is 2-7 days. Heavier or prolonged bleeding suggests pathology.

<image>Panel A: Timeline of the 28-day cycle with ovarian cycle (follicular phase days 1-14, ovulation day 14, luteal phase days 15-28) and uterine cycle (menstrual days 1-5, proliferative days 6-14, secretory days 15-28) displayed in parallel tracks. Panel B: FSH and LH curves across the cycle showing FSH elevated early follicular and declining mid-follicular with small ovulation surge, and LH low follicular with dramatic ovulation surge. Panel C: Estradiol curve rising throughout follicular phase, peaking before LH surge, with secondary luteal rise, and progesterone low follicular then rising to mid-luteal peak. Panel D: Comparison of variable follicular phase versus fixed 14-day luteal phase duration, with day 1 marked as first day of menstrual bleeding.</image>

II. Follicular Phase - Hormones

The follicular phase extends from menstruation through ovulation and is characterized by follicle development under FSH influence and rising estrogen production. The hormonal dynamics during this phase set the stage for ovulation.

The early follicular phase (approximately days 1-5) is characterized by rising FSH and low estrogen. As the corpus luteum from the previous cycle regresses and progesterone falls, the negative feedback on the pituitary is released, allowing FSH to rise. This intercycle FSH rise is the critical stimulus for recruiting a new cohort of antral follicles. LH levels remain low but are sufficient to stimulate thecal androgen production, providing substrate for estrogen synthesis. Estradiol begins to rise as recruited follicles grow and produce estrogen. Inhibin B, produced by granulosa cells, begins to rise in parallel with follicular development.

The mid-follicular phase (approximately days 6-10) features dominant follicle selection and FSH decline. As estradiol rises from the growing follicle cohort, it exerts negative feedback on FSH secretion. The falling FSH creates a selection pressure: only the follicle with the highest sensitivity to FSH (typically the one with the most FSH receptors and the largest head start) can continue to thrive in the declining FSH environment. This dominant follicle selection typically occurs around days 5-7. Non-dominant follicles, deprived of adequate FSH support, undergo atresia. The dominant follicle continues to grow and produce increasing amounts of estradiol.

The late follicular phase (approximately days 11-14) is characterized by high estradiol and preparation for ovulation. The dominant follicle, now approximately 18-20 mm, produces large quantities of estradiol. When estradiol exceeds approximately 200 pg/mL and this level is sustained for approximately 50 hours, it triggers a switch from negative to positive feedback—a unique feature of female reproductive physiology. FSH remains suppressed by estrogen and inhibin B. LH begins to rise in response to the positive feedback. The dominant follicle's granulosa cells, which have acquired LH receptors under FSH stimulation, become responsive to LH and begin to produce small amounts of progesterone, priming the system for ovulation.

<image>Panel A: Early follicular phase showing FSH rising (intercycle rise after corpus luteum regression), LH low, estradiol beginning to rise, and cohort of small antral follicles being recruited. Panel B: Mid follicular phase with FSH declining due to estradiol negative feedback, dominant follicle selection (one larger follicle, others beginning atresia), and estradiol continuing to rise. Panel C: Late follicular phase showing FSH suppressed, estradiol high and sustained (>200 pg/mL for 50 hours), LH beginning to rise in response to positive feedback. Panel D: Dominant follicle characteristics at 18-20 mm diameter with granulosa cells acquiring LH receptors, preparing for ovulation.</image>

III. Folliculogenesis

Folliculogenesis is the process of follicular development from the primordial stage through ovulation. Understanding this process explains the timeline of fertility, the concept of ovarian reserve, and the mechanisms of both natural and assisted reproduction.

Follicle development stages span months, not just the single cycle. The progression from primordial to primary follicle takes approximately 150 days and is gonadotropin-independent, driven by local paracrine factors. The transition from primary to secondary (preantral) follicle takes approximately 120 days and involves the development of multiple granulosa cell layers and the theca cell layer. The progression from secondary to early antral follicle takes approximately 70 days as the antrum (fluid-filled cavity) develops. Only the final approximately 14 days of development—from early antral to preovulatory follicle—is gonadotropin-dependent and occurs during the follicular phase of a single menstrual cycle. Thus, the follicle that ovulates this month began its journey from the primordial stage nearly a year earlier.

The follicle pool represents a finite reserve. At birth, the ovaries contain approximately 1-2 million primordial follicles. Through continuous atresia (follicle death), this number declines to approximately 300,000-400,000 at puberty. Throughout reproductive life, approximately 400-500 follicles will ovulate; the rest undergo atresia. By menopause, the follicle pool is essentially exhausted. This concept underlies ovarian reserve testing and the biological clock of fertility.

Recruitment describes the transition from quiescent to growing follicles. In gonadotropin-independent recruitment, a continuous slow trickle of primordial follicles enters the growth phase, driven by factors like anti-Müllerian hormone (AMH) and local growth factors. These growing follicles eventually reach the antral stage. In gonadotropin-dependent recruitment, the intercycle FSH rise rescues a cohort of antral follicles (typically 6-12) from atresia, initiating the final growth phase. Only these recruited follicles are candidates for ovulation in the current cycle.

Dominant follicle selection is the process by which a single follicle emerges to ovulate. The follicle with the greatest FSH sensitivity—typically the one with the most FSH receptors and the highest estrogen production—has a survival advantage when FSH levels fall. This dominant follicle produces enough estrogen to suppress FSH through negative feedback, depriving the non-dominant follicles of the FSH support they require. Additionally, the dominant follicle's granulosa cells express LH receptors (induced by FSH), preparing them for ovulation and luteinization. This process normally results in a single dominant follicle and single ovulation, though multiple follicles may mature in fraternal twin pregnancies or with ovulation induction therapy.

<image>Panel A: Follicle development timeline from primordial (flat granulosa cells) to primary (cuboidal granulosa, ~150 days) to secondary/preantral (multiple granulosa layers, theca forms, ~120 days) to early antral (~70 days) to Graafian/preovulatory (~14 days, FSH-dependent). Panel B: Follicle pool showing numbers at birth (1-2 million), puberty (400,000), and menopause (depleted), with approximately 400 ovulating versus majority undergoing atresia. Panel C: Gonadotropin-independent versus dependent phases clearly demarcated along the development timeline. Panel D: Dominant follicle selection showing cohort of similar-sized antral follicles at recruitment, one enlarging while others regress based on FSH sensitivity, estrogen production, and LH receptor acquisition.</image>

IV. Ovulation

Ovulation is the release of the oocyte from the mature follicle, triggered by the LH surge. This precisely timed event is essential for fertility and is the target of ovulation prediction methods.

The LH surge is the proximate trigger for ovulation. When estradiol from the dominant follicle reaches a threshold (approximately 200 pg/mL) and is sustained for approximately 50 hours, it triggers positive feedback on GnRH release and pituitary LH secretion. The resulting LH surge represents a 10-fold or greater increase in LH levels, typically lasting 48-50 hours. A smaller FSH surge occurs simultaneously. The LH surge typically begins in the early morning hours, with urinary LH detection (using ovulation predictor kits) becoming positive 24-36 hours before ovulation.

The events leading to ovulation are initiated by the LH surge. Within hours of the LH surge, the oocyte resumes meiosis, completing meiosis I and arresting again at metaphase II. The oocyte is now a secondary oocyte; meiosis II will only complete upon fertilization. Luteinization begins as granulosa cells respond to LH by increasing progesterone synthesis, causing the slight progesterone rise detectable before ovulation. The LH surge activates proteolytic enzymes (plasminogen activator, collagenases, matrix metalloproteinases) that weaken the follicle wall. Inflammation-like changes increase blood flow and vascular permeability. The cumulus cells surrounding the oocyte expand, facilitated by hyaluronic acid synthesis. A localized area of the follicle wall, the stigma, thins and ruptures. Approximately 36-40 hours after the LH surge onset, the oocyte with its surrounding cumulus-corona complex is released.

The oocyte at ovulation has specific characteristics determining its fate. The oocyte is a secondary oocyte arrested in metaphase II, surrounded by the zona pellucida, corona radiata (innermost layer of cumulus cells), and additional cumulus cells. The ovulated oocyte remains viable for approximately 12-24 hours. If fertilization does not occur within this window, the oocyte degenerates. If fertilization occurs (sperm penetration triggers completion of meiosis II), the resulting zygote begins development.

Ovulation signs may be noticed by women and used for fertility awareness. Mittelschmerz is mid-cycle pelvic discomfort or pain, felt by some women at ovulation, possibly related to follicular fluid irritating the peritoneum. Cervical mucus changes to a thin, watery, clear, and stretchy (spinnbarkeit) quality, optimally facilitating sperm transport. Some women notice increased libido around ovulation. The basal body temperature rise occurs after ovulation, reflecting progesterone's thermogenic effect.

<image>Panel A: LH surge graph showing estradiol rising to threshold (>200 pg/mL), triggering positive feedback, resulting in dramatic 10-fold LH increase over 48-50 hours, with ovulation occurring 36-40 hours after surge onset. Panel B: Ovulation sequence showing oocyte meiosis resumption (primary to secondary oocyte arrested in metaphase II), proteolytic enzyme activation (collagenase, plasmin) weakening follicle wall, cumulus expansion, and stigma formation. Panel C: Cross-sectional diagram of mature follicle with oocyte, cumulus, corona radiata, antrum, and thinning stigma leading to rupture and oocyte release. Panel D: Oocyte fate showing viable window (12-24 hours) with two outcomes: fertilization (meiosis II completes, zygote forms) versus no fertilization (degeneration), plus ovulation signs (mittelschmerz, mucus changes, BBT rise).</image>

V. Luteal Phase

The luteal phase extends from ovulation to the onset of the next menstruation and is dominated by progesterone production from the corpus luteum. This phase prepares the endometrium for potential implantation and, in the absence of pregnancy, culminates in the withdrawal of hormonal support that triggers menstruation.

Corpus luteum formation occurs immediately after ovulation. The collapsed follicle, now deprived of its oocyte and antral fluid, rapidly transforms into the corpus luteum through a process called luteinization. Granulosa cells become granulosa lutein cells, which produce large quantities of progesterone and contribute to estrogen production. Theca cells become theca lutein cells, continuing to produce androgens that serve as substrate for estrogen synthesis. The corpus luteum undergoes dramatic vascularization, becoming one of the most vascular structures in the body per unit weight. A mature corpus luteum measures 2-3 cm and has a characteristic yellowish color from lipid (cholesterol and cholesterol esters) accumulation in the lutein cells.

Corpus luteum function centers on progesterone production. Progesterone rises dramatically after ovulation, reaching peak levels of approximately 10-20 ng/mL at mid-luteal phase (approximately day 21-23 of a 28-day cycle). Estradiol also rises during the luteal phase, producing a secondary peak lower than the preovulatory peak. Inhibin A (in contrast to inhibin B during the follicular phase) is the predominant inhibin during the luteal phase. The combination of progesterone and estrogen suppresses FSH and LH through negative feedback, preventing new follicle development during the luteal phase.

LH dependence is a critical feature of corpus luteum function. The corpus luteum requires ongoing LH stimulation to maintain progesterone production. Without continued LH support, the corpus luteum will regress. The corpus luteum has a built-in lifespan of approximately 14 days in the absence of pregnancy. If pregnancy occurs, the embryo produces human chorionic gonadotropin (hCG), which binds to the same receptor as LH and "rescues" the corpus luteum, maintaining progesterone production until the placenta can take over this function at approximately 8-10 weeks of gestation.

Luteolysis (corpus luteum regression) occurs if pregnancy does not occur. The mechanisms are not fully understood but involve declining LH sensitivity, local prostaglandin production, and possibly immune-mediated processes. As the corpus luteum regresses, progesterone and estrogen levels fall sharply during the last few days of the luteal phase. This hormone withdrawal triggers endometrial shedding (menstruation) and releases FSH from negative feedback, allowing the intercycle FSH rise that recruits follicles for the next cycle. The corpus luteum leaves behind a white scar tissue remnant called the corpus albicans.

<image>Panel A: Corpus luteum formation showing collapsed follicle transforming post-ovulation with granulosa cells becoming granulosa lutein cells (producing progesterone) and theca cells becoming theca lutein cells, with dramatic vascularization. Panel B: Mature corpus luteum characteristics (yellowish, 2-3 cm) with hormone production graphs showing progesterone rising to 10-20 ng/mL at mid-luteal and estradiol showing secondary rise. Panel C: LH dependence illustrated with LH receptors on lutein cells sustaining the corpus luteum for approximately 14 days. Panel D: Two outcomes contrasted: pregnancy (hCG rescuing corpus luteum until placental takeover at 8-10 weeks) versus no pregnancy (luteolysis, hormone decline, menstruation, corpus albicans formation, FSH rising for next cycle).</image>

VI. Endometrial Cycle

The endometrial cycle describes the sequential changes in the uterine lining that prepare for potential implantation each month. The endometrium is exquisitely sensitive to ovarian hormones, and its histologic appearance can be precisely correlated with cycle day.

The menstrual phase (days 1-5) is triggered by the withdrawal of progesterone and estrogen from the regressing corpus luteum. The spiral arteries, which supply the functionalis layer, are uniquely sensitive to these hormones. Falling progesterone causes the spiral arteries to constrict, producing ischemia in the functionalis layer. Prostaglandin production increases, further promoting vasoconstriction and myometrial contractions. The ischemic functionalis undergoes necrosis and is shed, along with blood from ruptured vessels. The basalis layer, supplied by basal arteries that are not hormone-sensitive, remains intact to regenerate the endometrium. Normal menstrual blood loss is 30-80 mL (average approximately 50 mL); blood loss exceeding 80 mL is defined as menorrhagia.

The proliferative phase (days 6-14) is driven by rising estrogen from the developing follicle. Under estrogen influence, the endometrium regenerates and grows from approximately 1-2 mm at the end of menstruation to 8-14 mm by ovulation. Glands proliferate and are straight to slightly tortuous. Stroma is compact with numerous mitotic figures. Spiral arteries elongate, growing with the thickening endometrium. The histologic appearance shows pseudostratified columnar epithelium with mitoses. This phase corresponds to the follicular phase of the ovarian cycle.

The secretory phase (days 15-28) is driven by progesterone from the corpus luteum, acting on estrogen-primed tissue. Progesterone transforms the proliferative endometrium into a receptive, secretory tissue suitable for implantation. Glands become increasingly tortuous and accumulate glycogen-rich secretions. Stromal cells accumulate glycogen and lipid, becoming larger and more eosinophilic (pre-decidualization). Spiral arteries become increasingly coiled. The window of implantation (approximately days 20-24, or 6-10 days after ovulation) represents the period when the endometrium is optimally receptive to embryo implantation. If implantation occurs, the embryo signals its presence through hCG, and decidualization (complete transformation of stroma into decidua) proceeds.

Endometrial dating uses histologic features to determine the cycle day. Classic features include subnuclear vacuoles (glycogen beneath the nucleus) appearing on day 16 (day 2 post-ovulation), vacuoles moving to the apical portion of cells by day 18, peak glandular secretion around day 20, stromal edema around day 22, and predecidual changes (stromal cells surrounding spiral arteries) beginning around days 24-25. This dating system, though historically important, is now less commonly used clinically due to imperfect correlation with fertility.

<image>Panel A: Menstrual phase showing spiral artery constriction due to progesterone withdrawal, ischemia and necrosis of functionalis, shedding with blood loss (30-80 mL normal, >80 mL = menorrhagia), and intact basalis for regeneration. Panel B: Proliferative phase with estrogen-driven regeneration and growth (1-2 mm to 8-14 mm), straight/slightly tortuous glands, compact mitotic stroma, and elongating spiral arteries. Panel C: Secretory phase with progesterone-induced changes, increasingly tortuous glands with glycogen accumulation, subnuclear vacuoles (day 16), apical vacuoles (day 18), peak secretion (day 20), stromal edema (day 22), and predecidual changes (days 24-25). Panel D: Window of implantation (days 20-24) highlighted with comparative histology of proliferative versus secretory endometrium.</image>

VII. Cervical Mucus Changes

Cervical mucus undergoes dramatic changes throughout the menstrual cycle that influence sperm transport. These changes provide the basis for fertility awareness methods of family planning.

Follicular phase (estrogen-dominant) mucus facilitates sperm passage. As estrogen rises during the follicular phase, the cervical glands produce increasing quantities of thin, watery, clear mucus. The mucus becomes progressively more favorable to sperm until it reaches peak quality around ovulation. Characteristics of fertile mucus include abundant quantity, thin and watery consistency, clear or translucent appearance, and high spinnbarkeit (stretchiness)—the ability to stretch to 6 cm or more before breaking. Microscopically, the mucus shows a "ferning" pattern: when dried on a glass slide, the high salt content causes crystallization in a fern-leaf pattern. The molecular structure of fertile mucus includes parallel glycoprotein channels that allow sperm to swim through while filtering out abnormal sperm and debris.

Luteal phase (progesterone-dominant) mucus impedes sperm passage. After ovulation, progesterone from the corpus luteum dramatically alters cervical mucus. The mucus becomes scant, thick, sticky, and opaque or cloudy. Spinnbarkeit is lost; the mucus breaks immediately when stretched. The ferning pattern is absent on microscopy. The molecular structure becomes a dense, cross-linked mesh that is essentially impenetrable to sperm. This hostile mucus environment is one mechanism by which progesterone-only contraceptives prevent pregnancy.

Clinical applications of mucus assessment include fertility timing and contraception. In the Billings method (cervical mucus method) of natural family planning, women monitor their mucus daily. The progression from dry days to increasingly wet, slippery, stretchy mucus indicates approaching ovulation. The peak day of fertile mucus closely correlates with ovulation. Abstinence or barrier methods are used during the fertile window. The method requires instruction and consistent monitoring but can be effective when used correctly. Mucus assessment is also used in infertility evaluation to confirm estrogenic effect and adequate mucus production. The historical post-coital test (Huhner test), which examined sperm survival in cervical mucus, has largely been abandoned due to poor standardization and unclear clinical value.

<image>Panel A: Follicular phase (estrogen effect) showing thin, clear, stretchy mucus with spinnbarkeit demonstrated (stretching >6 cm) and parallel glycoprotein channels allowing sperm passage. Panel B: Microscopic ferning pattern in follicular mucus showing crystalline fern-leaf arrangement indicating fertile mucus. Panel C: Luteal phase (progesterone effect) showing thick, opaque, sticky mucus that breaks immediately, absent ferning pattern, and dense cross-linked mesh blocking sperm. Panel D: Clinical applications with Billings method tracking chart showing progression from dry to tacky to wet/stretchy to peak to thick, with fertile window identified.</image>

VIII. Assessment of Ovulation

Clinical assessment of ovulation is essential for evaluating infertility and for timing conception or contraception. Various methods provide either retrospective confirmation that ovulation has occurred or prospective prediction of impending ovulation.

Basal body temperature (BBT) monitoring provides retrospective evidence of ovulation. Progesterone has a thermogenic effect, raising body temperature by 0.3-0.5°C (0.5-1.0°F) after ovulation. The temperature remains elevated throughout the luteal phase, falling with menstruation. The characteristic biphasic pattern—lower in the follicular phase, higher in the luteal phase—confirms that ovulation has occurred. BBT must be taken immediately upon waking, before any activity, using a sensitive thermometer, and recorded daily. The temperature rise identifies ovulation only in retrospect (after it has occurred), limiting its utility for timing intercourse in the current cycle. However, accumulated data over several cycles can help predict the fertile window in subsequent cycles. Limitations include need for consistent timing, interference from illness or disrupted sleep, and difficulty identifying the exact day of ovulation.

Urinary LH testing (ovulation predictor kits) provides prospective prediction of ovulation. These home test kits detect the LH surge in urine. A positive result indicates that the LH surge has begun and ovulation will likely occur within 24-36 hours. Testing is typically begun a few days before expected ovulation (around day 10-12 in a 28-day cycle) and performed daily, usually in late morning or early afternoon (avoiding first morning urine, which may miss the surge). The kits are highly accurate for detecting the surge. For couples trying to conceive, intercourse is recommended on the day of the positive test and the following day. Limitations include cost if testing is prolonged and potential for false positives in conditions with elevated LH (such as polycystic ovary syndrome or perimenopause).

Serum progesterone measurement provides retrospective confirmation of ovulation. A mid-luteal progesterone level (drawn approximately 7 days after expected ovulation, or day 21 of a 28-day cycle) confirms that ovulation occurred and corpus luteum function is adequate. A level above 3 ng/mL indicates that ovulation has occurred. A level above 10 ng/mL suggests adequate luteal function. If the cycle length is not 28 days, the timing must be adjusted (progesterone is drawn 7 days before expected menses). Serial progesterone measurements are not necessary; a single well-timed level is sufficient.

Ultrasound monitoring provides the most detailed assessment of follicular development and ovulation. Transvaginal ultrasound can track follicle growth, with the dominant follicle typically growing 1-2 mm per day and reaching 18-24 mm before ovulation. Signs of imminent ovulation include a large follicle with a thin wall. Signs that ovulation has occurred include collapse or disappearance of the dominant follicle, presence of free fluid in the pelvis, and development of a corpus luteum with its characteristic appearance. Ultrasound monitoring is commonly used in assisted reproduction to time procedures and in infertility evaluation.

<image>Panel A: BBT charting showing sample 28-day chart with low follicular phase temperatures, slight dip at ovulation, sustained rise (0.3-0.5°C) during luteal phase, fall at menstruation, and biphasic pattern identification with proper technique instructions. Panel B: Urinary LH testing showing test strips with negative and positive results, timeline of testing (days 10-12 onward), LH surge detected 24-36 hours before ovulation, and intercourse timing recommendations. Panel C: Ultrasound assessment showing transvaginal images of growing dominant follicle (12mm to 18mm to 22mm), collapsed follicle post-ovulation with free fluid, and corpus luteum appearance. Panel D: Serum progesterone assessment showing mid-luteal measurement at day 21 with thresholds (>3 ng/mL = ovulation occurred, >10 ng/mL = adequate luteal function).</image>

IX. Abnormal Menstrual Cycles

Understanding normal menstrual cycle physiology provides the foundation for recognizing and treating abnormalities. Menstrual cycle disorders are among the most common gynecologic complaints.

Terminology for menstrual disorders uses standardized definitions. Amenorrhea is the absence of menstruation—primary if menarche has not occurred by age 15, secondary if previously menstruating women have no menses for 3 or more months. Oligomenorrhea describes infrequent menstruation with cycle lengths greater than 35 days. Polymenorrhea describes overly frequent menstruation with cycle lengths less than 21 days. Menorrhagia (now often called heavy menstrual bleeding) is excessive blood loss (>80 mL per cycle) or prolonged duration (>7 days) with regular cycles. Metrorrhagia is bleeding between regular menstrual periods. Menometrorrhagia is heavy, prolonged, and irregular bleeding. Dysmenorrhea is painful menstruation.

Anovulation is the failure to ovulate and is a common cause of menstrual irregularity. Without ovulation, no corpus luteum forms, and therefore no cyclic progesterone is produced. The endometrium remains in a proliferative (estrogen-stimulated) state and may shed unpredictably when estrogen levels fluctuate. Causes of anovulation include polycystic ovary syndrome (PCOS), the most common cause; hypothalamic dysfunction (stress, excessive exercise, eating disorders); hyperprolactinemia; thyroid disorders; obesity; and premature ovarian insufficiency. The menstrual pattern in anovulation is typically irregular and unpredictable, ranging from amenorrhea to frequent, irregular bleeding. Long-term anovulation with unopposed estrogen exposure increases the risk of endometrial hyperplasia and endometrial cancer. Laboratory findings include absence of the expected mid-luteal progesterone rise.

Luteal phase defect (LPD) refers to inadequate corpus luteum function, either in progesterone quantity or duration. The luteal phase may be shortened (<10-11 days) or progesterone production may be insufficient. This has been proposed as a cause of infertility and recurrent pregnancy loss, as inadequate progesterone may impair implantation or early pregnancy support. However, LPD as a clinical entity is controversial; diagnostic criteria are not well standardized, and treatment (progesterone supplementation) has not been definitively proven effective outside of assisted reproduction. Nonetheless, progesterone supplementation is commonly used in IVF cycles and in women with recurrent pregnancy loss.

Abnormal uterine bleeding (AUB) is evaluated using the PALM-COEIN classification, which identifies structural causes (Polyp, Adenomyosis, Leiomyoma, Malignancy/hyperplasia) and non-structural causes (Coagulopathy, Ovulatory dysfunction, Endometrial, Iatrogenic, Not yet classified).

<image>Panel A: Menstrual terminology with visual timelines showing normal cycle (regular, moderate flow), amenorrhea (no menses), oligomenorrhea (>35-day cycles), polymenorrhea (<21-day cycles), and dysmenorrhea (pain). Panel B: Menorrhagia (heavy flow, regular timing) and metrorrhagia (irregular bleeding) patterns illustrated. Panel C: Anovulation showing absent LH surge, no corpus luteum formation, unopposed estrogen stimulating endometrium without progesterone transformation, unpredictable bleeding, with causes listed (PCOS, hypothalamic dysfunction, hyperprolactinemia). Panel D: Luteal phase defect showing shortened luteal phase (<10 days) or low progesterone with potential consequences, plus PALM-COEIN classification for abnormal uterine bleeding.</image>

X. Hormonal Summary

A comprehensive understanding of menstrual cycle hormones integrates the preceding sections and provides the basis for interpreting clinical laboratory tests.

Hormone profiles by phase summarize the dynamic changes throughout the cycle. FSH rises in the early follicular phase (recruiting follicles), declines in the mid-to-late follicular phase (as estrogen provides negative feedback), shows a small surge at ovulation (with LH), and remains low during the luteal phase. LH is low during the follicular phase, surges dramatically at ovulation (triggering oocyte release), and is moderate during the luteal phase (supporting the corpus luteum). Estradiol rises progressively throughout the follicular phase, peaks just before the LH surge, drops briefly after ovulation, then shows a secondary rise during the luteal phase (from the corpus luteum), and falls at the end of the cycle. Progesterone is low throughout the follicular phase, begins to rise just before ovulation, increases dramatically during the luteal phase (peaking at mid-luteal), and falls at the end of the cycle if pregnancy does not occur. Inhibin B (from granulosa cells) rises during the follicular phase and peaks around ovulation. Inhibin A (from the corpus luteum) rises during the luteal phase.

Feedback relationships explain the hormonal dynamics. Estradiol exerts negative feedback on FSH and LH during most of the cycle, but when sustained above threshold (>200 pg/mL for ~50 hours), it switches to positive feedback, triggering the LH surge. Progesterone (with estrogen) exerts negative feedback during the luteal phase, suppressing gonadotropins and preventing new follicle development. Inhibins specifically suppress FSH (inhibin B in follicular phase, inhibin A in luteal phase).

Clinical correlations apply these principles to laboratory testing. Day 3 FSH and estradiol are measured in the early follicular phase to assess ovarian reserve. An elevated FSH at this time suggests diminished ovarian reserve (the pituitary is working harder to stimulate the ovary). Elevated estradiol at day 3 may suppress FSH and mask diminished reserve. AMH (anti-Müllerian hormone), produced by granulosa cells of small antral follicles, is a cycle-independent marker of ovarian reserve. LH surge detection (day 12-14 in a 28-day cycle) predicts ovulation. Mid-luteal progesterone (day 21 in a 28-day cycle, or 7 days after ovulation) confirms ovulation and adequate luteal function.

<image>Panel A: Complete graphical representation of FSH (elevated early, declining mid-follicular, small ovulation surge, low luteal) and LH (low follicular, dramatic ovulation surge, moderate luteal) across the 28-day cycle. Panel B: Estradiol curve (rising follicular, peak before LH surge, secondary luteal rise, falling late luteal) and progesterone (low follicular, rising after ovulation, peak mid-luteal, falling late luteal) with inhibin B (follicular) and inhibin A (luteal). Panel C: Feedback diagram showing estradiol negative feedback switching to positive at threshold and progesterone negative feedback in luteal phase. Panel D: Clinical correlations showing timing and interpretation of common tests: day 3 FSH/E2 (ovarian reserve), LH surge detection (ovulation prediction), and day 21 progesterone (ovulation confirmation).</image>

Summary

The menstrual cycle averages 28 days (range 21-35) with a variable follicular phase and relatively fixed 14-day luteal phase. Day 1 is the first day of menstrual bleeding.

The follicular phase is characterized by FSH-driven follicle recruitment, dominant follicle selection, and rising estradiol production. When estradiol exceeds threshold and is sustained, it triggers positive feedback and the LH surge.

Ovulation occurs 36-40 hours after the LH surge onset. The oocyte is released as a secondary oocyte arrested in metaphase II, viable for approximately 24 hours.

The luteal phase is dominated by the corpus luteum producing progesterone. Without pregnancy, luteolysis occurs at approximately 14 days, progesterone falls, and menstruation is triggered.

The endometrium cycles through menstrual (shedding), proliferative (estrogen-driven growth), and secretory (progesterone-driven maturation) phases. Cervical mucus is thin and stretchy with estrogen, thick and impenetrable with progesterone.

Ovulation can be assessed retrospectively (BBT, progesterone) or predicted prospectively (LH kits, ultrasound).

Key Terms

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