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PCOS, is a condition clinically associated
with Infertility, oligomenorrhea (prolonged menstrual cycle
length), and hyperandrogenism (excess male hormone effect
- such as increased thick body hair, acne, oily skin, and
not unusual to have smaller breasts).
This syndrome probably encompasses multiple
conditions and is expressed to varying degrees in different
individuals. It has some genetic transmission and has long
been associated with increased adipose tissue, especially
at onset of puberty. There are a lot of similarities with
the findings of PCOS and obesity, which can be explained
on the physiology of obesity. However, thin women also have
PCOS quite frequently. Therefore, one can see the overlap
of different conditions.
Menstrual Cycle
To understand PCOS one has to understand the
menstrual cycle. A normal menstrual cycle usually is of
28 days, plus or minus only a day or two. This does not
mean that if one has a menstrual length out of this range
that they cannot get pregnant, but rather that this is the
norm.
The first half of the menstrual cycle is termed
the follicular or proliferative phase. It is during this
period that the follicle matures. The follicle is the unit
in the ovary where the follicle resides. At birth a normal
female is born with approximately 500,000 follicles and
by age 30 only approximately 30,000 remain. Each month up
to 200 follicles are recruited (awakened from their deep
sleep) and are growing for the next 2-3 months. At the beginning
of this cycle one follicle is selected to be the one that
continues to grow and to ovulate the one egg. This selection
process is not well understood, but more than one follicle
can be selected by increasing the level of FSH (follicle
stimulating hormone) the hormone which stimulates the follicle
to grow.
The follicular phase is associated with estrogen
production, which causes growth of the lining of the uterus
(endometrium) and is the cause of the stretchy cervical
mucus that is associated with ovulation. The estrogen level
usually peaks at the time of the LH surge and subsequently
falls to lower levels during the second half of the menstrual
cycle, called the luteal phase.
Once the follicle is mature a surge of a hormone,
called LH (luteinizing hormone), occurs to ultimately result
in ovulation. This is termed the LH surge and is what one
measures when she does the ovulation predictor test. The
LH surge also causes the follicle to change over its manufacturing
function from that of producing estrogen to that of producing
progesterone. The luteinized follicle is termed the corpus
luteum.
Progesterone is responsible for preparing the
endometrium for the process of implantation of the embryo.
The mechanisms are complex but necessary for good implantation.
If there are not adequate amounts of progesterone production
the endometrium does not prepare the endometrium adequately
for implantation. This may result in failure of implantation
or even a poor implantation, which could result in difficulties
in the growth of the embryo.
If implantation of the embryo occurs, it begins
production of HCG (human chorionic gonadotropin). This hormone
is responsible for keeping the corpus luteum growing and
to produce progesterone. If pregnancy does not occur, the
corpus luteum begins regressing at approximately 10 days
of age and the progesterone drops to a level, which no longer
supports the structure of the endometrium resulting in breakdown
of the tissue. This endometrial tissue then begins shedding
and is known commonly as the menstrual period, which heralds
a new menstrual cycle.
Dysfunctional Menstrual Cycle
In PCOS the normal flow of the menstrual cycle
is altered and the follicles do not mature normally and
the selection process is altered. Therefore, either no follicle
is selected or the follicle fails to grow adequately, resulting
in a defect in folliculogenesis (follicle development).
This ultimately results in failure of the LH surge or, if
the LH surge does occur, a poorly developed corpus luteum.
The progesterone is subsequently inadequate for normal preparation
of the endometrium for implantation of the embryo resulting
in failure of implantation. This is assuming that a follicle
was to mature enough to ovulate and that the LH surge does
actually occur. Also, the follicle may not be mature enough
to actually ovulate, and if so the egg may not be mature
enough for fertilization.
Androgens (male hormones) are elevated because
of a higher than normal baseline level of LH (not to be
confused with the LH surge). Androgens are necessary in
small amounts for the follicle to produce estrogen, using
androgens as the raw material for the process. However,
if the androgen level is too high from over production,
it leaks out into the bloodstream where it produces effects
that are not normal. The higher levels of androgens decreases
the production of FSH resulting in reduced folliculogenesis,
which results in poor egg development and poor corpus luteum
even if the LH surge were to occur.
Androgens also block development of the endometrium,
even if the estrogen level is adequate, by blocking the
receptors in the endometrium. This ultimately results in
a poor implantation site for the embryo if it were to be
present. Excess androgens cause many of the commonly associated
stigmata of PCOS, namely the acne and excess hair growth
(hirsutism).
Excess production of androgens can come from
the adrenal gland and/or can be associated with obesity.
Several mechanisms are involved with the over production
of androgens caused by obesity. Insulin resistance and peripheral
conversion of androgens into estrogens are the main mechanisms
involved in this process. Insulin resistance is discussed
in the section on this topic.
Obesity
Adipose tissue (fat tissue) has the ability
to convert androgens into estrogen. However, the estrogen
is different from the normal estrogen. Estradiol, which
is the normal estrogen, directly causes a decrease in the
production of FSH and LH. The estrogen, which is produced
by adipose tissue, on the other hand, causes a decrease
in production of FSH but NOT of LH, in fact causing an increase
in LH. This increase in LH further causes and increase in
androgens by the ovaries. The increase in androgen thus
results in decreased FSH production and therefore decreased
folliculogensis.
Adipose tissue also secretes a hormone leptin,
which acts on the satiety center of the brain to increase
appetite. On the other hand, exercise and fasting decrease
leptin. This fact is useful in understanding the mechanisms
that can be used to decrease obesity.
PCOS and obesity are associated with insulin
resistance, which behaves in a similar manner in causing
anovulation.
Treatment
Treatment of PCOS for purposes of infertility
will be described. However, the medical consequences of
PCOS are such that they cannot be ignored. Therefore, if
the PCOS patient is not attempting pregnancy she may do
well to stay on the combination oral contraceptive. This
will be effective at reducing the LH and subsequently the
circulating androgens. By decreasing the androgens the lipid
profile will be improved. Also, the combination oral contraceptive
will largely prevent dysfunctional uterine bleeding and
endometrial hyperplasia/neoplasia. A further benefit will
be at reducing the potential for recurrent ovarian cysts
formation.
For infertility, giving drugs for normalizing
ovulation or for ovulation induction is foremost in treatment
of this condition. The first level of drug used is an oral
medication metformin. PCOS patients are usually insulin
resistance and metformin sensitizes the cells to insulin
thus lowering circulating levels. Hi levels of insulin lead
to overproduction of androgens by the ovaries and anovulation.
If metformin does not establish regular ovulation
clomiphene citrate (Clomid) is a relatively safe and inexpensive
drug for this purpose
Gonadotropins FSH and LH) or FSH are the next
line of treatment for ovulation induction. This treatment
has significantly more efficiency than clomiphene citrate.
However, this therapy is significantly more expensive, more
time consuming, and with more risks than clomiphene citrate.
Other drugs, such as corticosteroids, may be
used in conjunction with the other treatment modalities
to reduce the adrenal gland production of androgens, thereby
improving the environment for the proper development of
the follicles.
Rarely, surgical treatment of PCOS is
used to reduce the androgen production by the ovaries. The
early successful surgical treatment of PCOS was the wedge
resection of the ovary. This was quite effective in induction
of ovulation, but for only a few months when the ovulatory
defect would return. It was also fraught with a high incidence
of ovarian adhesions that could interfere with the ovum
pickup mechanism (pickup of the egg by the tube).
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