Amenorrhea is the
absence of menstrual bleeding. Amenorrhea is a normal feature in prepubertal,
pregnant, and postmenopausal females. In females of reproductive age,
diagnosing amenorrhea is a matter of first determining whether pregnancy is
the etiology. In the absence of pregnancy, the challenge is to determine the
exact cause of absent menses. This article reviews the physiologic aspects
of menstruation and presents an approach for ascertaining the etiology of
amenorrhea. Only the main components of amenorrhea are highlighted. Many
minor components of physiology are important but cannot be discussed within
the context of this overview.
Pathophysiology
The menstrual cycle is an orderly progression of hormonal events in the
female body that results in the release of an egg. Menstruation occurs when
an egg released by the ovary remains unfertilized; subsequently, the soggy
decidua of the endometrium (which was primed to receive a fertilized egg) is
sloughed in a flow of menses in preparation for another cycle.
The menstrual cycle can be divided into 3 physiologic phases—follicular,
ovulatory, and luteal. Each phase has a distinct hormonal secretory milieu.
When diagnosing the disease processes responsible for amenorrhea,
consideration of the target organs of these reproductive hormones
(hypothalamus, pituitary, ovary, uterus) is helpful.
Follicular phase
Physiologically, the first day of menses is considered the first day of
the menstrual cycle. The following 13 days of the cycle are designated the
follicular phase. The hypothalamus is the initiator of the follicular phase.
The gonadotropin-releasing hormone (GnRH) pump located within the
hypothalamus releases GnRH in a pulsatile fashion into the portal vessel
system surrounding the anterior pituitary gland. GnRH interacts with the
anterior pituitary gland to release follicle-stimulating hormone (FSH) in
the follicular phase. FSH is secreted into the circulation and interacts
with the granulosa cells surrounding the developing oocytes.
As levels of progesterone, estradiol, and inhibin decline 2-3 days before
menses, the hypothalamus begins to release higher levels of FSH, which
recruits oocytes for the next menstrual cycle. As FSH increases during the
early portion of the follicular phase, it interacts with granulosa cells to
stimulate the aromatization of androgens into estradiol.
Early in the follicular phase, both estradiol and FSH increase the FSH-receptor
content of the developing follicles. Over the next several days, the steady
increase of estradiol (E2) levels exerts a progressively greater
suppressive influence on pituitary FSH release. Only one selected lead
follicle, with the largest reservoir of estrogen, can withstand the
declining FSH environment. The remaining oocytes that initially were
recruited with the lead follicle undergo atresia. Immediately prior to
ovulation, the combination of estradiol and FSH leads to the production of
luteinizing-hormone (LH) receptors on the granulosa cells surrounding the
lead follicle.
During the late follicular phase, estrogen, instead of suppressing
pituitary LH secretion as it usually does, positively influences LH
secretion. To have this positive effect, the estradiol level must achieve a
sustained elevation for several days. The LH surge promotes luteinization of
the granulosa in the dominant follicle, resulting in progesterone
production. The appropriate level of progesterone arising from the maturing
dominant follicle contributes to the precise timing of the mid-cycle surge
of LH.
Ovulatory phase
Ovulation occurs approximately 34-36 hours after the onset of the LH
surge or 10-12 hours after the LH peak and 24-36 hours after peak estradiol
levels. The rise in progesterone increases the distensibility of the
follicular wall and enhances proteolytic enzymatic activity, which
eventually breaks down the collagenous follicular wall.
After the ovum is released, the granulosa cells increase in size and take
on a yellowish pigmentation characteristic of lutein. The corpus luteum then
produces estrogen, progesterone, and androgens and becomes increasingly
vascularized.
Luteal phase
The lifespan and steroidogenic capacity of the corpus luteum depend on
continued tonic LH secretion from the pituitary gland. The corpus luteum
secretes progesterone that interacts with the endometrium of the uterus to
prepare it for implantation. This process is termed endometrial
decidualization. In the normal ovulatory menstrual cycle, the corpus luteum
declines in function 9-11 days after ovulation. If the corpus luteum is not
rescued by human chorionic gonadotropin (hCG) hormone from the developing
placenta, menstruation reliably occurs 14 days after ovulation. If
conception occurs, placental hCG maintains luteal function until placental
production of progesterone is well established.
The menstrual cycle is a complex but coordinated system of hormonal
changes and organ responses. The main directive of the menstrual cycle is to
stimulate growth of a follicle to release an egg and prepare a site for
implantation if fertilization should occur. Absence of fertilization results
in the timely release of the prepared endometrium, which is termed menses.
At birth, female infants have a predetermined number of primordial
follicles that are arrested in the diplotene stage of meiotic prophase until
stimulation at puberty. Until puberty, the hypothalamus is in a quiescent
state. At age approximately 8 years, GnRH is synthesized in the hypothalamus
and released. The adrenal cortex begins to produce dehydroepiandrostenedione
to initiate the start of adrenarche (ie, the development of sexual hair).
The orderly progression of puberty begins with breast budding (thelarche)
then continues with the growth of pubic hair (pubarche), accelerated growth,
and menses (menarche). In the United States, the average age of girls at
menarche is 12.8 years, with a range of 9-16 years.
nopausis : meno- + Greek pausis, pause;
see pause.]
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