Menstrual Cycle and Hormones

The menstrual cycle is the monthly sequence of physiologic events in reproductive-age women involving coordinated hormonal signaling from the hypothalamic-pituitary-ovarian (HPO) axis that culminates in ovulation and endometrial shedding. This approximately 28-day cycle (range 21-35 days) is characterized by predictable fluctuations in estrogen, progesterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), each serving critical roles in follicular development, ovulation, corpus luteum formation, and endometrial proliferation and secretion. Understanding normal menstrual physiology is essential for the evaluation of menstrual disorders, infertility, contraceptive counseling, and hormone replacement therapy, making this foundational knowledge critical for all physicians. Disruption of this finely-tuned system accounts for significant morbidity in reproductive-age women and influences clinical decision-making across multiple specialties. The menstrual cycle is present in approximately 400 million menstruating women globally and represents one of the most important physiologic processes to understand for board examination preparation and clinical practice.

The menstrual cycle represents an intricate neuroendocrine feedback system orchestrated by the hypothalamic-pituitary-ovarian (HPO) axis. Understanding the normal cycle requires knowledge of the four distinct phases and their underlying hormonal mechanisms:

The cycle begins with pulsatile secretion of gonadotropin-releasing hormone (GnRH) from hypothalamic neurons into the hypophyseal portal circulation. GnRH acts on GnRH receptors on anterior pituitary gonadotropes in a frequency-dependent manner: slower pulse frequencies (approximately every 90 minutes during the follicular phase) preferentially stimulate FSH release, while faster pulse frequencies (every 30-60 minutes in the luteal phase) favor LH secretion. This differential regulation arises from varying gonadotrope sensitivity to GnRH frequency and differential expression of FSH-β and LH-β subunit genes. The pituitary releases FSH and LH into systemic circulation where they govern ovarian steroidogenesis and gametogenesis. Critically, estrogen exerts negative feedback at low-to-moderate concentrations on both GnRH and gonadotropin secretion, while a sustained rise in estrogen above a threshold (~200 pg/mL for 48 hours) produces a dramatic positive feedback surge that triggers the LH surge and ovulation.

The follicular phase begins with menstruation, defined as shedding of the endometrial stratum functionalis triggered by progesterone withdrawal from the declining corpus luteum. Falling progesterone and estrogen levels remove negative feedback inhibition on the hypothalamus and pituitary, allowing FSH levels to rise by approximately 50-100% above baseline. Rising FSH stimulates growth of 5-15 primary follicles in the ovary through binding to FSH receptors on granulosa cells. FSH promotes aromatase (CYP19A1) expression in granulosa cells, which converts androstenedione (produced by ovarian theca cells) into estradiol, the primary circulating estrogen. Early follicular phase FSH also induces LH receptor expression on granulosa cells, priming them for subsequent LH signaling. Follicles compete for FSH; the follicle that achieves the lowest FSH threshold for growth becomes dominant by day 5-7 and expresses the greatest aromatase activity. This produces rising estradiol levels that suppress FSH through negative feedback, causing the growth arrest and atresia of subordinate follicles (this process is called "FSH-driven follicle selection"). The dominant follicle continues to grow because its higher FSH receptor density allows continued growth despite suppressed FSH levels. By the late follicular phase, the dominant follicle reaches 18-25 mm in diameter and produces estradiol levels exceeding 200 pg/mL. This high estradiol plateau sustained for approximately 48 hours triggers the critical positive feedback mechanism on the pituitary and hypothalamus.

The positive feedback from elevated estradiol on GnRH neurons increases GnRH pulse frequency and amplitude, and directly stimulates pituitary gonadotropes to increase LH (and to a lesser extent FSH) synthesis and secretion. The resulting LH surge reaches a peak of approximately 40-100 IU/L and lasts 24-48 hours. The LH surge triggers nuclear envelope breakdown and meiosis I completion within the oocyte approximately 35-40 hours after the LH surge begins, resulting in extrusion of the first polar body. LH also stimulates thecal cells to increase 17α-hydroxylase and 17,20-lyase activity, shifting androgen production toward more potent androgens. Simultaneously, LH triggers luteinization of follicular granulosa cells through increased cholesterol side-chain cleavage enzyme (P450scc) activity, redirecting the biochemical pathway toward progesterone synthesis. The progesterone surge inhibits the smooth muscle contractions of the fallopian tube and promotes formation of the cumulus expansion that facilitates oocyte release. Proteolytic enzymes are activated in the follicular wall, and increased prostaglandin E2 (PGE2) and F2α (PGF2α) amplify smooth muscle contractions and stromal digestion, leading to ovulation (rupture of the follicle and extrusion of the oocyte with its surrounding cumulus cells) approximately 12-24 hours after the LH peak.

Following ovulation, granulosa and theca cells undergo transformation into the corpus luteum, a specialized endocrine structure that secretes predominantly progesterone and lesser amounts of estradiol and inhibin A. The luteal phase is divided into an early luteal phase (days 15-20) characterized by rising progesterone and a late luteal phase (days 21-28) with peak progesterone levels. Progesterone induces decidualization of the endometrium through increased PRL (prolactin) and prolactin-induced protein (PIP) expression, promoting secretion of mucopolysaccharides and glycogen to prepare the endometrium for potential embryo implantation. Progesterone also exerts negative feedback on GnRH pulsatility, slowing pulse frequency to approximately every 60-90 minutes and decreasing overall gonadotropin secretion. This low gonadotropin environment prevents further follicle development during the luteal phase. The corpus luteum has a fixed lifespan of approximately 14 days (range 12-16 days) in the absence of pregnancy. This predetermined lifespan results from the progressive depletion of luteal cells and declining expression of steroidogenic acute regulatory (StAR) protein and P450scc. If fertilization does not occur, the corpus luteum undergoes luteolysis (programmed cell death) triggered by prostaglandin F2α (PGF2α) from the endometrium and possibly declining LH support. Falling progesterone and estradiol levels lead to menstrual shedding, completing the cycle.

The endometrium undergoes dramatic structural and biochemical transformation coordinated by cyclic estrogen and progesterone exposure. During the proliferative phase (corresponding to the follicular phase), rising estradiol stimulates estrogen receptor (ER) signaling in endometrial stromal and epithelial cells, promoting mitotic activity and angiogenesis through increased vascular endothelial growth factor (VEGF) expression. The endometrium thickens from approximately 2 mm at menstruation to 8-12 mm by ovulation. During the secretory phase (luteal phase), progesterone acts via progesterone receptor (PR), inducing transformation of glandular epithelium into secretory tissue with increased glycogen accumulation, spiral artery development, and stromal edema. Downregulation of estrogen and progesterone receptors in the late secretory phase renders the endometrium refractory to continued hormonal stimulation and permits the "window of implantation" approximately 6-10 days after ovulation. With corpus luteum decline, endometrial inflammation increases with recruitment of leukocytes, upregulation of tumor necrosis factor-α (TNF-α) and interleukins, activation of matrix metalloproteinases (MMPs), and hypoxia from spiral artery vasoconstriction. These mechanisms produce endometrial shedding and menstruation.

Ovarian steroidogenesis follows the Δ5 and Δ4 pathways, with cholesterol as the substrate. Theca cells possess 17α-hydroxylase and 17,20-lyase activity (cytochrome P450c17), producing 17-hydroxypregnenolone and dehydroepiandrosterone (DHEA) via the Δ5 pathway, or 17-hydroxyprogesterone and androstenedione via the Δ4 pathway. These androgens diffuse across the basement membrane to adjacent granulosa cells, which express aromatase (CYP19A1) but lack 17α-hydroxylase, converting androstenedione to estrone and testosterone to estradiol (this division of labor is the "two-cell, two-gonadotropin" model). Estradiol circulates bound to sex hormone-binding globulin (SHBG), with approximately 60% bound to SHBG, 38% loosely bound to albumin, and only 1-2% free. SHBG levels are regulated by estrogen (increases SHBG) and androgens and insulin (decrease SHBG), affecting the bioavailable estrogen available to tissues. Progesterone is produced primarily by the corpus luteum and, to a lesser extent, by the adrenal glands; approximately 90% circulates bound to cortisol-binding globulin (CBG) and albumin, with only 1-10% free.

Inhibin B, produced by granulosa cells of growing follicles, selectively suppresses FSH secretion in the early-to-mid follicular phase through paracrine effects on pituitary gonadotropes and hypothalamic GnRH neurons. This selective FSH suppression prevents multiple follicles from reaching the preovulatory stage. Inhibin A, produced by the corpus luteum, continues to suppress FSH during the luteal phase. Activin, produced by granulosa cells and anterior pituitary cells, amplifies FSH signaling and GnRH responsiveness. Anti-Müllerian hormone (AMH), produced by granulosa cells of preantral and small antral follicles, inhibits FSH-dependent follicle growth and serves as a biomarker of ovarian reserve. Understanding these regulatory peptides is essential for interpreting hormone levels in the context of follicular development.

The menstrual cycle is a normal physiologic process in reproductive-age women, not a disease entity; therefore, the concept of "etiology" and "risk factors" applies to disruption of normal menstrual cycling rather than to the cycle itself. The following factors influence menstrual cycle characteristics and regulation:

The menstrual cycle begins at menarche (average age 12-13 years in developed nations, earlier in some populations) and continues until menopause (average age 51 years, range 40-60 years). The cycle is often irregular in the first 2-5 years after menarche due to immaturity of the HPO axis, with frequent anovulatory cycles. Cycle length gradually becomes more regular by the late teens. In the perimenopausal period (5-8 years preceding menopause), cycles become increasingly variable and anovulatory, with declining estradiol and rising FSH levels. Age is the most important determinant of ovarian reserve and oocyte quality, with dramatic declines after age 35.

Underweight status (BMI <18.5 kg/m²) and rapid weight loss suppress GnRH pulsatility through multiple mechanisms including reduced leptin secretion from adipose tissue. Leptin acts as a permissive signal for normal GnRH function; leptin deficiency or resistance (seen in congenital leptin deficiency, lipodystrophy, or functional hypothalamic amenorrhea from caloric deficit) suppresses GnRH neurons and causes secondary amenorrhea. Overweight and obesity (BMI ≥25 kg/m²) increase aromatase activity in adipose tissue, raising estrone and estradiol levels while decreasing SHBG and increasing insulin resistance. Elevated insulin impairs SHBG production and increases free androgens, potentially causing irregular cycles and anovulation. The relationship between weight and menstrual function is non-linear; both extremes disrupt normal cycling.

Chronic systemic illness (malignancy, chronic kidney disease, inflammatory bowel disease, celiac disease), nutritional deficiency (iron, vitamin D, folate, vitamin B12), and psychological stress suppress HPO axis function through unclear mechanisms potentially involving corticotropin-releasing hormone (CRH) inhibition of GnRH neurons and elevated cortisol suppression of gonadotropins. Intense exercise, particularly in athletes with low body fat or inadequate energy intake relative to expenditure, causes exercise-associated amenorrhea through combined effects of low leptin, elevated CRH, and altered GnRH pulsatility.

Hypothyroidism elevates thyrotropin-releasing hormone (TRH), which stimulates prolactin (PRL) secretion, suppressing GnRH; thyroid hormone is also required for normal SHBG and estrogen metabolism. Hyperprolactinemia (from prolactinoma, medications like antipsychotics and metoclopramide, or primary hypothyroidism) suppresses GnRH pulsatility and prevents the LH surge. Polycystic ovary syndrome (PCOS) features insulin resistance, elevated androstenedione and testosterone, and abnormal GnRH pulsatility with increased LH:FSH ratio (typically >2:1 or 3:1), preventing normal follicle selection and causing anovulation. Cushing syndrome (from pituitary or adrenal ACTH-secreting tumors) elevates cortisol, suppressing GnRH and causing hypogonadism. Diabetes mellitus, particularly if poorly controlled, may disrupt menstrual cycling through metabolic derangements.

Primary ovarian insufficiency (POI), defined as elevated FSH >40 IU/L (on two occasions ≥4 weeks apart) in women aged <40 years with oligo- or amenorrhea, results from premature depletion or dysfunction of ovarian follicles from autoimmune destruction, genetic mutations (FMR1 premutations, FSHR mutations), infiltrative disorders (sarcoidosis), chemotherapy or radiation, or idiopathic causes. Diminished ovarian reserve (declining numbers of follicles with advancing age, genetic predisposition, or from prior chemotherapy) reduces FSH-responsive follicles, extending the follicular phase and causing irregular cycles before progressing to amenorrhea.

Combined hormonal contraceptives (CHCs) suppress endogenous FSH and LH, preventing follicle development and ovulation; the withdrawal of exogenous hormones triggers "withdrawal bleeding" rather than true menstruation. Progestin-only methods similarly suppress ovulation. Medications with antidopaminergic effects (antipsychotics, some antiemetics) elevate PRL, suppressing GnRH. Chemotherapy agents (alkylating agents like **cycl