Menstrual Cycle

Overview

Terminology

• Menarche: 1st menstrual period 
• Menses: monthly cycles of menstruation
• Perimenopause: interval of menstrual irregularities leading up to the total cessation of cycles
• Menopause: cessation of menses for 12 months or more

Phases

The menstrual cycle is divided into 2 phases: ovarian and endometrial.

• Average adult menstrual cycle is 28–35 days.
• Intervals in cycles usually remain consistent until perimenopause, when follicular phases become shorter and more frequent.

Ovarian phases:

• Follicular phase
  • Spans from menses onset (day 1) to the day before the surge of luteinizing hormone (LH), leading to ovulation
  • Length: 14 to 21 days
• Luteal phase
  • Spans from the day of LH surge until the onset of the next menses
  • Length: 15 days

Endometrial phases:

• Desquamation: shedding of the endometrial lining (menses) 
• Proliferative phase: endometrial proliferation with straight, tubular glands
• Secretory phase: preparation of the spiral arteries and endometrial glands for potential oocyte implantation

Ovarian Cycle

Follicular phase

The follicular phase of the ovaries coincides with menses and the proliferative phase of the endometrium.

• Takes place during days 1–14 (up to day 21) of the menstrual cycle
• Primarily under the control of estrogen
• Gonadotropin-releasing hormone (GnRH) is released from the hypothalamus → stimulates the release of FSH from the anterior pituitary → stimulates the primary follicles of the ovary to begin developing
  • Maturing primary follicles produce (via granulosa and theca cells):
    • Inhibin A → inhibits the release of FSH from the anterior pituitary (negative feedback)
    • Estradiol → stimulates development of a dominant follicle → the follicle secretes estradiol until just before the LH surge (beginning of luteinizing phase)
• Primary ovarian follicles develop due to ↑ FSH
• Dominant follicle continues to develop and to secrete estradiol, while the others undergo atresia and die.
• ↑ Estradiol from the dominant follicles causes the ovary to be more sensitive to GnRH
• The anterior pituitary releases a luteinizing burst or “surge” → triggers ovulation approximately 12 hours later
  • During ovulation, a mature oocyte is released from the dominant follicle.
  • The LH surge ends the follicular phase.

Luteal Phase

The luteal phase of the ovaries coincides with the secretory phase of the endometrium.

• Takes place typically during days 15–28 of the menstrual cycle, when the oocyte is released. 
• Under the control of progesterone
• The corpus luteum of the mature oocyte produces progesterone.
  • Progesterone feedback inhibits LH secretion from the anterior pituitary.
  • If conception does not occur, LH levels continue to ↓ and the corpus luteum recedes into a corpus albicans.
  • If pregnancy occurs, the secretion of human chorionic gonadotropin (hCG) saves the corpus luteum and allows it to continue its secretory function.
• Oocyte migrates to the fimbria of the Fallopian tube (can take 3 days).
• Potential of fertilization by sperm at this phase

Endometrial Cycle

There are 3 phases of the endometrial cycle:

1. Desquamation or menses 
2. Proliferative phase
3. Secretory phase

Menses

Day 1 of menstrual bleeding marks the beginning of the next cycle.

• Coincides with day 1 of the follicular phase
• If conception does not occur, the corpus luteum degenerates and progesterone levels decrease → causes desquamation of the functional layer of the endometrium (menses) 
  • Spiral arteries constrict.
  • Endometrium dies secondary to apoptosis.
  • Uterine contractions shed and expel the endometrium.
• The oocyte is lost in menstrual bleeding.

Proliferative phase

• Proliferative phase (days 4–14) → creation of a new endometrium for the new cycle
• Growing follicles make estrogen → granulosa cells release aromatase → converts androgens into estrogens → stimulates endometrial proliferation
• Endometrial proliferation with straight, tubular glands

Secretory phase

• Between days 13 and 15 of the menstrual cycle (later in some individuals) 
• Preparation of the spiral arteries and endometrial glands for potential oocyte implantation
  • Triggered by estradiol and progesterone release 
  • Increased endometrial gland tortuosity
  • Glycogen-rich secretions
  • Edematous stromal cells
• Uterine spiral arteries extend the full length of the endometrium.
• Ovulation is dependent on the LH surge.
• If no pregnancy, progesterone levels decrease → inducing apoptosis of the functional layer of the endometrium, leading to menses

Regulation of the Menstrual Cycle

The menstrual cycle is regulated by the hypothalamic-pituitary-ovarian axis.

• Hypothalamus: releases GnRH → stimulates gonadotropes of the anterior pituitary
• Anterior pituitary:
  • Stimulated by GnRH → releases FSH and LH
  • FSH and LH → stimulate the ovaries
• Ovaries:
  • Estrogens: 
    • Estradiol is the most notable.
    • Secreted by the granulosa cells of ovarian follicles → stimulated by FSH
    • Negative feedback inhibition on the hypothalamus and pituitary until halfway through the cycle, when feedback becomes positive
  • Progestins:
    • Progesterone is the most notable.
    • Secreted by the theca-lutein and granulosa lutein cells in the corpus luteum (stimulated by LH)
    • Effects of progesterone during pregnancy:
      • Breast
      • ↑ Lobular development
      • Inhibition of milk production
    • Reproductive organs
    • ↓ endometrial growth
    • ↑ Endometrial secretions (↑ secretion thickness)
    • ↑ Body temperature
  • Activins: 
    • Secreted by the granulosa cells of ovarian follicles (stimulated by FSH)
    • Provides positive feedback to gonadotropes
  • Inhibins: 
    • Secreted by the granulosa cells of ovarian follicles (stimulated by FSH)
    • Provides negative feedback to gonadotropes

Clinical Relevance

Pregnancy: the period of time in which a fetus develops inside a uterus. When the oocyte is fertilized by a sperm cell and the developing embryo is implanted into the endometrium, the menstrual cycle is halted to prevent the evacuation of the uterine lining and embryo via uterine contractions. Pregnancy lasts 40 weeks and creates a physiological state in the body to support a fetal gestation.

The following conditions are related to abnormalities of the menstrual cycle:

• Amenorrhea: the absence of menses due to hypothalamic, pituitary, ovarian, uterine, or vaginal causes. Amenorrhea can be primary (absence of menarche by the age of 15) or secondary (absence of menses for more than 3 cycles or 6 months in girls and women with previously normal cycles).
• Menorrhea: normal menstrual flow with regular menstrual intervals
• Menorrhagia: regular menstrual intervals with an excessive menstrual flow (> 80 ml for > 7 days)
• Metrorrhagia: irregular uterine bleeding in between menstrual periods or at irregular intervals
• Menometrorrhagia: a combination of menorrhagia and metrorrhagia, both heavy menstrual flow (> 80 mL for > 7 days) and menses at irregular intervals
• Dysmenorrhea: recurrent abdominal pain associated with menstruation; may be primary or secondary in nature
• Oligomenorrhea: menstrual interval > 35 days
• Polymenorrhea: menstrual interval < 21 days
• Endometrial hyperplasia: occurs when the endometrium receives prolonged stimulation by estrogens to proliferate. Presents as abnormal uterine bleeding. Women who suffer from endometrial hyperplasia are at increased risk of developing dysplasia and endometrial cancer.