Regulation of the Menstrual Cycle
Douglas Danforth, Ph.D.
The Ohio State University
Objectives
Describe the interplay of feedback mechanisms that affect the menstrual cycle.
1. Describe the phases of the menstrual cycle and how hormone concentrations vary
in each phase.
2. Describe the histological characteristics of the endometrium at each phase of the
menstrual cycle.
3. Correlate changes in reproductive hormones with changes in ovarian and uterine
structure.
The regulation of the human menstrual cycle involves the coordinated interaction of the
hypothalamus, pituitary, the ovaries, and uterus. By describing the physiological
regulation of the normal menstrual cycle, we can understand how disorders can alter
reproductive function and how hormonal treatments can control or enhance fertility.
This is an overview of the hypothalamic pituitary
gonadal axis. The hypothalamus secretes a
releasing hormone, gonadotropin releasing
hormone or GnRH, which travels through the
hypothalamic-pituitary portal system to act on
gonadotropes in the pituitary. These
gonadotropes secrete both LH and FSH which
enter the peripheral circulation, and act on the
ovaries to make estrogen and/or progesterone
depending upon the stage of the menstrual
cycle. Estrogen and progesterone feed back at
the level of the hypothalamus and pituitary to
regulate the production of GnRH and LH/FSH.
As such this is a classic closed-loop negative
feedback system. Let's now look at how these
systems interact to regulate the normal
menstrual cycle.
These are the sequence of events in the normal human menstrual cycle.
1. At the beginning of the menstrual cycle, designated as Day 1, LH and FSH levels
increase.
2. The increase in FSH causes multiple early antral follicles to grow. These follicles
secrete estrogen and inhibin.
3. As a result, the levels of estrogen in the circulation increase.
4. From the cohort of growing follicles, one follicle will become selected and become
the dominant follicle.
5. This dominant follicle secretes large amounts of estrogen and inhibin. As a result,
the circulating levels of estrogen and inhibin increase markedly.
6. The high levels of estrogen and inhibin produced by the dominant follicle, feed
back on the hypothalamus and pituitary to decrease circulating FSH levels.
7. At the end of the follicular phase, when estrogen levels have reached their peak,
feedback on the hypothalamus switches from negative feedback to a positive
feedback event.
8. The positive feedback of estrogen results in a hypothalamic GnRH surge, which
triggers an LH surge from the pituitary.
9. The high circulating levels of LH resulting from the LH surge cause three things:
a. Oocyte in preovulatory follicle completes meiosis 1
b. Ovulation occurs
c. Granulosa and theca cells become luteinized to form Corpus Luteum (CL).
The CL secretes large amounts of progesterone (and some estrogen and
inhibin).
10. Circulating levels of P, E, and inhibin increase during the early luteal phase and
remain elevated for about 10 days.
11. FSH and LH levels are inhibited due to the negative feedback of P, E, and inhibin
secreted by the CL.
12. Near the end of the luteal phase (10 – 12 days after ovulation) the CL begins to
regress. In humans, the cause of luteolysis is unknown.
13. The regressing CL secretes lower amounts of P, E, and inhibin – thus circulating
levels decrease.
14. The decrease in circulating P, E, and inhibin results in loss of negative feedback at
the hypothalamus and pituitary, and circulating levels of LH and FSH increase.
15. This cycle ends – the next cycle begins (Step 1)
Now that we understand what happens in the hypothalamus pituitary and ovaries
throughout the menstrual cycle, let's look at the corresponding changes that occur in the
uterine endometrium. Recall that day one of the menstrual cycle is defined as the start of
menstruation and
the menstrual phase
lasts for several
days. During this
time the
endometrium is
shed and menstrual
flow consists of a
mixture of venous
blood and
endometrial tissue.
During the early
follicular phase FSH
stimulates early
antral follicles to
accelerate their
growth and begin
producing greater
amounts of
estrogen. Estrogen
from these follicles stimulates the uterine endometrium to proliferate, and endometrial
thickness increases substantially during the follicular or proliferative phase of the cycle.
During this phase the endometrial glands are straight and narrow, and secretions from
the endometrium and uterine cervix are thin and watery. As the dominant follicle is
selected and estrogen levels continue to rise, endometrial proliferation continues until the
midcycle LH surge and ovulation. Recall that the primary functions of the LH surge are to
1) cause resumption of meiosis one in the pre-ovulatory oocyte, 2) ovulation of the
preovulatory follicle, and 3)corpus luteum formation by luteinizing the granulocyte and
theca cells from the preovulatory follicle that remained in the ovary after ovulation. The
primary function of the newly formed corpus luteum is to produce progesterone which
transforms the proliferative endometrium into a secretory endometrium in preparation for
implantation of the embryo. Progesterone causes the endometrial glands to become
sacculated and torturous, and along with the cervix they produce a thick and viscous
mucus. The appropriate secretions of the secretory endometrium are essential for normal
implantation of the developing embryo. In the non-fertile menstrual cycle the corpus
luteum produces progesterone for approximately 2 weeks and then regresses. The cause
of corpus luteum regression in humans is unclear. As the corpus luteum undergoes
luteolysis its production of progesterone declines, and circulating levels of progesterone
along with estrogen and inhibin, the other primary hormones of the corpus luteum,
decline. This loss of progesterone support to the endometrium causes destabilization of
the glands and stroma, and results in sloughing of the endometrium initiating
menstruation. The decrease in progesterone, estrogen and inhibin also removes negative
feedback at the level of the hypothalamus and pituitary, and circulating FSH levels
increase which initiates the start of the next cycle.
Let's review what we've learned so far. Normal regulation of the menstrual cycle requires
the coordinated interactions of the hypothalamus, pituitary, ovaries, and uterus. The
beginning of the menstrual cycle or day one is defined as the start of menstruation.
Increased FSH levels at this time result in accelerated follicular growth and recruitment of
the follicular cohort. From this cohort of growing follicles one follicle is selected to ovulate
and becomes the dominant follicle. This dominant follicle secretes large amounts of
estrogen as well as inhibin. Estrogen and inhibin feed back to the pituitary to inhibit
gonadotropin secretion. Similarly estrogen acts at the endometrium to stimulate
proliferation of the glands of the endometrium. At the end of the follicular phase at
midcycle, the dominant follicle secretes high levels of estrogen. This estrogen feedback
switches from negative feedback to a positive feedback to initiate the LH surge. It does
this by stimulating a GnRH surge. The LH surge does three things: initiates completion of
meiosis one in the oocyte of the pre-ovulatory follicle, it causes ovulation of that oocyte,
and third it causes luteinization of the granulosa and theca cells of that follicle resulting in
corpus luteum formation. The newly formed corpus luteum secretes progesterone for
approximately 2 weeks during the luteal phase. The main function of progesterone is to
cause a proliferative endometrium to transform into a secretory endometrium in
preparation for implantation, should the oocyte be fertilized. Another consequence of
elevated progesterone levels is the classic negative feedback at the level of the
hypothalamus and pituitary to inhibit gonadotropin secretion. At the end of the luteal
phase when the corpus luteum regresses, progesterone levels decline. The fall in
progesterone causes destabilization of the endometrium which results in initiation of the
menstrual flow. At the same time the decline in progesterone levels reduces negative
feedback at the level of the hypothalamus and pituitary, which results in increased FSH
production. This increase in FSH stimulates follicular growth and recruitment of the
follicular cohort to start the next cycle