PCOS is a health problem that can affect a woman’s
menstrual cycle, fertility, hormones, insulin production,
heart, blood vessels, and appearance. Among these key
features were hyperandrogenism, menstrual dysfunction, and
exclusion of other causes of hyperandrogenism, such as
congenital adrenal hyperplasia, androgen-secreting tumors,
and hyperprolactinemia.
PCOS is the most common hormonal
reproductive problem in women of childbearing age. An
estimated five to 10 percent of women of childbearing age
have PCOS. This theme has been well highlighted by Shekharan
P 1. This chapter draws many citations from this with due
appreciation.
ETIOLOGY
Despite the extensive investigations, the etiology of
PCOS remains poorly understood. The most recent knowledge
indicates that abnormal insulin response to glucose stimulus
is a key underlying factor in PCOS. 2,3 Other etiological
factors include derangement of the sympathetic nervous
control of the ovaries, 4 estrogen dominance and elevated
androgens. Some of the literature suggests a genetic
susceptibility to insulin stimulation of androgen secretion,
blocking follicular maturation.
Although the exact etiology is not clear, PCOS is an
abnormality of the hypothalamic-pituitary-ovarian system. A
characteristic of the syndrome is inappropriate gonadotropin
secretion, which is more likely a result of, rather than a
cause of, ovarian dysfunction. LH is tonically elevated
throughout the menstrual cycle, FSH is normal or low, the LH/FSH
ratio is often greater than 3, and there is an exaggerated
response of LH to gonadotropin-releasing hormone (GnRH).
Androgens such as testosterone, free testosterone, and
dehydroepiandrosterone sulfate (DHEAS), may or may not be
measurably elevated in the peripheral circulation, yet these
hormones and their metabolites account for the physical
characteristics of the syndrome. The source of androgens may
be from the ovaries, adrenals, or both. Other contributing
factors to androgen excess include an elevated serum level
of androstenedione, which is converted in adipose tissue to
testosterone, and a greater percentage of unbound active
testosterone in women with PCOS compared to women without
PCOS.
The primary abnormality in polycystic ovary syndrome could
reside within the ovaries or the ovarian abnormalities could
be secondary to extra ovarian disturbances. One of the most
fascinating but yet unreturned question is whether PCOS is
an inborn error or an acquired disease. It is possible that
a large number of endocrine, paracrine and metabolic factors
are involved. Anyhow, PCOS starts with puberty and
definitely ends with menopause. The essential endocrine
feature of PCOS is an increased production of androgens. The
main source of hyperandrogenism is the ovary. The ovary
contains a large number of sub-cortical antral follicles,
which are lined by a few layers of granulosa cells while the
surrounding theca cells and the underlying stroma are
plentiful. The presence of a large number of follicles of
size varying from 6-10 mm set in the periphery in a necklace
outline and the increase in ovarian volume mainly due to an
increase in stroma is the classical finding on
ultrasonography.
It is now clear that many patients with PCOS have
compensatory hyperinsulinemia due to some degree of insulin
resistance. Insulin and insulin-like growth factor-I (IGF-I)
augments the effect of LH on ovarian steroidogenic activity
and on the GnRH pulse generator. Obesity seen in at least
half of PCO subjects has an addictive effect on insulin
resistance. Both obese and non-obese PCOS women display
marked impairment of catecholamine-induced lipolysis. As a
result of catecholamine resistance, a compensatory increase
in sympathetic activity may also induce insulin resistance.
Androgens are converted by peripheral aromatization to
estrogens, which stimulate synthesis of LH but suppress the
secretion of FSH. Chronic stimulation with LH supports the
production of androgens by theca cells. The peripheral pool
of androgens is supplemented by an activated adrenal
production of androgens. Due to the low FSH levels, the
introversion conversion of androgens to estrogens is
partially inhibited keeping the ovaries in a hyper
androgenic state with arrest of follicular maturation. Many
factors concur to establish and perpetuate PCOS. Their vital
role is evident by the fact that different therapeutic
interventions can restore ovulation or interrupt the
perpetuating cycle.
THE HYPOTHALAMIC CONNECTION:-
One of the main characteristics of PCOS is the abnormal
LH/FSH ratio. The hypothalamic-pituitary axis imbalance can
contribute significantly to the etiology of PCOS. The result
of increased gonadotrophin releasing hormone (GnRH) output
causes an elevation in the pulsatile output of LH and
results in an elevated LH to FSH ratio (typically 2:1
respectively). 2,5 FSH is not increased as a result of
elevated LH in this case, likely due to the hypothalamus
responding via negative feedback to the already chronically
elevated estrogen levels.
Compared to
the gonadotropin levels, in the early follicular phase or
ovulatory cycle, LH secretion is increased while FSH levels
remain subnormal and constant. This inappropriate secretion
of gonadotropins is the key issue in the continuation of the
anovulatory state of PCOS subjects. Although the
intraovarian regulation of steroid genesis is a complex
matter, simplified it can be proposed that increased LH
levels induces increased androgen steroid genesis by the
theca cells and stroma, which are in abundance, and that a
reduced FSH secretion is responsible for the decreased
conversion of the androgens to estrogens in the granulose.
However, it is not clear, whether the inappropriate
gonadotropin secretion is the result of normal feedback
mechanisms at the pituitary level while the hypothalamus is
only playing a permissive role by providing an intermittent
but steady production of GnRH: or does the hypothalamic
control of the pituitary function play a primary role in the
genesis and continuation of PCO syndrome.
THE GNRH PULSE GENERATOR:
LH secretion in PCO patients is characterized both by an
increased pulse frequency and amplitude. The gonadotropin
pattern of high LH and low FSH can be due to an increased
frequency of GnRH pulsatile secretion. Chronically elevated
estrogen levels can affect pituitary sensitivity to GnRH
both by direct action on LH synthesis and by up-regulating
GnRH receptors causing an increased response of LH. The
selective negative feedback effect of estrogens on the FSH
on the other hand mitigates the response of FSH. The
enhanced pulsatile secretion of GnRH is attributed to a
reduction in hypothalamic opioid inhibition because of the
chronic absence of progesterone. High-frequency GnRH pulses
up-regulate the synthesis of the LH B-subunit and
down-regulate B-subunit of FSH resulting in relatively
greater synthesis and secretion of LH than FSH. One
explanation for the accelerated GnRH pulse frequency is a
possible link between the neuroendocrine and metabolic
changes in PCOS.
Receptors for insulin, IGF-I and-IGF-II as well as A and B
estrogen receptors are expressed in GnRH neuronal cell
lines. Activation of IFG-I receptor induces cell
proliferation and GnRH gene-expression and secretion. Thus,
the GnRH neuron is a target for functional regulation both
by steroids and by insulin and the IGFS. Through this
pathway, a primary metabolic derangement could lead to
activation of the GnRH pulse generator.
INSULIN RESISTANCE AND MOLECULAR DEFECTS IN INSULIN
SIGNALING:-
Approximately 50-60 percent of PCOS patient’s sugar from
insulin resistance compared to the prevalence of insulin
resistance in the general population of 10-25 percent.
Insulin resistance in PCOS leads to compensatory
hyperinsulinemia, which seems to play a major role in the
pathogenesis of hyperandrogenism of PCOS. Hyper-insulinemia
stimulates androgen secretion by the ovarian theca, excess
growth of the basal cells of the skin resulting in
acanthosis nigricans, and abnormal hepatic and peripheral
lipid metabolism. Insulin resistance and hyperinsulinemia
cause many features of PCOS, is supported by the fact that
the various insulin sensitizing agents like Diaz oxide,
metformin, troglitazone and d-chiro-inositol has been found
to improve clinical features.
Dunaif et al 6 determined in vivo insulin action on
peripheral glucose utilization and found that insulin
resistance was present in both “lean” and “obese” women with
PCOS, but they noted that the resistance was greater in
obese subjects. Dunaif et al have suggested a post receptor
defect as a cause of insulin resistance in PCOS. It has been
shown that insulin receptor autophosphorylation and tyrosine
kinase activity are necessary for the cellular response to
insulin. The final effectors system involved in glucose
uptake into the cell involves the insulin regulatable
glucose transporter (GLUT-4). Serine phosphorylation has
been shown to impair insulin receptor tyrosine kinase
activity, and excessive serine phosphorylation has been
demonstrated in insulin receptors of skeletal muscle and
fibroblasts from insulin resistant patients with polycystic
ovary syndrome Enlarged adipocytes from obese individuals
overproduce tumor necrosis factor alpha (TNF α) and result
in increased serine phosphorylation of the insulin receptor:
and further aggravates the insulin resistance in obese PCO
subjects.
STIMULATION OF OVARIAN CYTOCHROME P45OC17A BY INSULIN:
P450C17A is a key enzyme in the biosynthesis of ovarian
androgens, and is a bi-functional enzyme that possesses both
17a- hydroxylase and 17, 20-lyase activities. In the theca
cell of the ovary, P450C17A converts progesterone to 17 a-hydroxy-progesterone
via its 17 a- hydroxylase activity, and then converts 17 a
hydro progesterone to androstenedione is converted into
testosterone by the enzyme 17 B-reductase. Many women with
PCOS manifest increase P450C17A - activity and the recent
evidence suggests that is due to the hyperinsulinemia and is
partially reversible with metformin.
HYPERINSULINEMIA LEADS TO HYPERANDROGENEMIA:-
Hyperandrogenemia seen in PCOS is as a result of the
insulin stimulation of the ovarian androgen production. PCOS
and insulin resistance are intimately related endocrine
disorders. The most common causes of insulin resistance are
obesity, poor diet and stress. Hyperinsulinemia is not a
characteristic of hyperandrogenism in general, but is
uniquely associated in PCOS. (2) In obese women with PCOS,
30 to 40% of these have impaired glucose tolerance or
diabetes. However, women with ovulatory hyperandrogenism can
present with normal insulin and glucose tolerance, (1,2)
indicating additional factors are potentially involved in
the etiology. The possible mechanisms for hyperandrogenemia
in polycystic ovary syndrome is the stimulation of
Cytochrome P450C17A activity in the theca cells by insulin,
effect of insulin to increase the pulse and amplitude of LH
secretion, and decrease in the production of serum sex
hormone binding globulin (SHBG). Hyperinsulinemia can reduce
serum SHBG levels in obese women with PCOS independently of
any effect of serum sex steroids.
The ovarian
and adrenal glands of women with PCOS are usually the sites
of production of elevated androgens. It is postulated that
these women have a hyperactive production of CYP17 enzyme,
which is responsible for forming androgens in the ovaries
and adrenals (from DHEA-S). (2) Elevated total and free
testosterone correlate with the typically elevated LH
levels. Serum total testosterone is usually up to twice the
normal range (20 to 80 ng/dL). High androgen levels in the
ovary inhibit FSH, thereby inhibiting development and
maturation of the follicles. 1,2 The ovarian and adrenal
glands of women with PCOS are usually the sites of
production of elevated androgens. It is postulated that
these women have a hyperactive production of CYP17 enzyme,
which is responsible for forming androgens in the ovaries
and adrenals (from DHEA-S).2 Elevated total and free
testosterone correlate with the typically elevated LH
levels. Serum total testosterone is usually up to twice the
normal range (20 to 80 ng/dL). High androgen levels in the
ovary inhibit FSH, thereby inhibiting development and
maturation of the follicles. 1,2
Hyperandrogenemia is also due to the adrenal androgen excess as a result
of a genetic trait or due to the increased serine
phosphorylation of P450C17A leading to increased production
of DHEAS, a mechanism that is activated by hyperinsulinemia.
Adrenal hyperandrogenism occurs in about 50 percent of PCOS
patients, concurrently with ovarian hyperandrogenism, the
indicator is an elevated level of DHEAS.
THE SKIN AND ADIPOSE TISSUE:
The skin and adipose tissue add to the complex etiology of
PCOS. Women who develop hirsutism have the presence and
activity of androgens in the skin which stimulate abnormal
patterns of hair growth. Aromatase and
17-beta-hydroxysteroid activities are increased in the fat
cells and peripheral aromatization increases with body
weight. The metabolism of estrogens by way of
2-hydroxylation and 17-alpha-oxidation is decreased.
Estrogen levels increase as a result of peripheral
aromatization of androstenedione. This cascade results in a
chronic hyper-estrogen production (estrogen dominance). 2
Hirsutism
occurs in 70% of women with PCOS in the US, as opposed to
only 10 to 20% of Japanese women diagnosed with PCOS. 3 This
may be explained by the genetically determined differences
in 5-alpha-reductase activity between different cultures, or
from a holistic standpoint, may reflect differences in
endocrine behavior in accordance with local diet and levels
of physical fitness.
HYPERPROLACTINEMIA IN PCOS:-
About 25% of PCOS patients exhibit elevated prolactin, 1,2
Hyperprolactinemia results from abnormal estrogen negative
feedback via the pituitary gland. Elevated prolactin can in
turn contribute to elevated estrogen levels.
LEPTIN:-
Leptin is a protein hormone synthesized and secreted by
adiposities. It is a product of the ob gene that signals the
amount of energy stores to the brain and has been implicated
in the regulation of food intake and energy balance. The
observation that leptin levels were significantly elevated
in approximately 30 percent of lean and obese women with
PCOS suggests that Leptin may have a role in the
pathogenesis of PCOS. The development of new leptin
analogues with high penetrating capacity to cross the
blood-brain barrier and the investigation of other
approaches to overcome the leptin resistance at the level of
hypothalamus are awaited.
DIAGNOSIS:
Clinical diagnosis in PCOS encompasses a spectrum of
findings from hyperandrogenism in lean. The accepted
definition of PCOS is a state of chronic an ovulation
accompanied by hyperandrogenism, with clinical manifestation
including hirsutism, acne, elevated testosterone and
androstenedione, androgen-dependent alopecia, and
frequently, not always, obesity.
Menstrual symptoms, often with peri-menarchial onset, are
the most common complaints among women with PCOS.
Menstrual irregularity in the form of
eight or fewer menstrual cycles per year. The cycles are
unpredictable menstrual cycles. There can be amenorrhea for
longer than 4 months in the absence of pregnancy or
menopause. There can also be excessive or heavy bleeding.
Amenorrhoea was reported in 47-66 percent of cases while
16-30 percent of patients will have regular periods. About
60 percent of patients with PCOS have hirsutism.
Virilization is uncommon. Acne has been described in 25 to
35 percent of patients in large series. Up to 50 percent of
patients presenting with infertility will have PCOS and are
more common in women with recurrent pregnancy loss.
Manifestation of unopposed estrogenic stimulation, including
menorrhagia, endometrial hyperplasia, and endometrial
carcinoma, occurs in a significant proportion of patients.
Obesity defined as a body mass index
(BMI) greater than 25, is found in 35 to 50 percent of women
with PCOS. Obesity is found in 50% of patient with PCOS. 2,5
The body fat is usually located centrally around the trunk.
A higher waist to hip ratio indicates an elevated risk of
cardiovascular disease and diabetes. Insulin resistance and
metabolic syndrome are commonly seen in PCOS patients and
insulin resistance is now recognized as a risk factor for
the development of diabetes mellitus type 2. Approximately
one-third of obese PCOS patients have impaired glucose
tolerance and up to 10% have diabetes mellitus type 2. 2
Therefore clinically a BMI >27 and a waist to hip ratio >.85
with sonological picture of PCO is strongly sugesting the
diagnosis. Obese women with PCOS are more likely to be
hirsute and infertile. In one study, the incidence of
infertility were 40 percent higher among PCOS women with a
BMI greater than 30 kg/m when compared with women whose BMI
was less than 30.
Skin complications can be in the form of acne, cystic acne
on face, neck, back shoulders and hirsutism with excessive
hair on face, body, upper lip, chin, neck, abdomen, thinning
of the head hair or male pattern balding. There is
acanthosis nigricans which is a discoloration or darkening
of skin (may be in patches) around neck, groin, under arms,
skin folds or skin tags. Acanthosis nigricans is associated
with hyperandrogenism and insulin resistance (HAIR-AN) is
seen in many obese patients.
Family history is an important clinical feature of PCOS. The
pattern of inheritance was thought to be autosomal dominant
with decreased penetrance. The phenotype also includes
hyperandrogenism, early balding in men, and glucose
intolerance.
ULTRASONOGRAPHIC APPEARANCE:
As per Adams
et al 7, the typical polycystic pattern was defined by the
presence of 10 or more cysts measuring 2 to 18 mm in
diameter in a single plane arranged peripherally around an
increased amount of central stroma is diagnostic of PCOS.
The sub capsular arrangement of the multiple cysts gives the
appearance of “necklace” distribution. Transnational
ultrasonography will show small multiple echo free cysts of
2 to 8 mm in diameter, arranged around a prominent highly
echogenic stroma. An increase in the amount and echogenicity
of the ovarian stroma distinguishes the PCO from
multi-follicular ovary seen in normal puberty and
hypothalamic an ovulation.
ENDOCRINE SCREENING:-
Prolactin and TSH levels are tested to rule out pituitary or
thyroid disease as an etiology of an ovulation. LH and FSH
may be analyzed and they are usually seen in a ratio of >
2.5 to 3. However, a normal LH/FSH ratio does not exclude
the possibility of PCOS. An FSH level will also help rule
out premature ovarian failure in women with amenorrhea.
Total testosterone and DHEAS are evaluated to rule out
androgen-producing neoplasms. Total testosterone level of
200 ng/dL is suggestive of a virilizing tumor. A virilizing
tumor of adrenal may be suspected if the value of DHEAS
greater than 800 mcg/dL. A level of 17 hydroxyprogesterone
more than 5 ng/ml is diagnostic of late onset congenital
adrenal hyperplasia.
GLUCOSE TOLERANCE TEST:
The incidence of impaired glucose tolerance amongst PCO
subjects is 35 to 45 percent and about 7 to 10 percent of
them will have type II diabetes mellitus. A fasting glucose
to fasting insulin ratio less than 4.5 is predictive of
insulin resistance. Values on the 2 hr glucose tolerance
test are as follows: < 140 mg/dL (normal), 140-199 mg/dL
(impaired glucose tolerance), and >200 mg/dL (type 2
diabetes). Associated with impaired glucose tolerance is the
abnormal lipoprotein profile that can be seen commonly in
patients with PCOS. The typical PCOS lipoprotein profile
includes:
* Elevated total cholesterol
* Elevated triglycerides
* Elevated low density lipoproteins (LDL)
* Low high density lipoproteins (HDL)
* Low apoprotein A-1 2
Insistence on a specific endocrine or clinical criterian for
the diagnosis of th polycystic ovary syndrome results in the
inclusion of a collection of patients that represents a
focussed segment isolated from the broad clinical spectrum
in which these patients really belong. This especially
applies to the use of ultrasonography to make the diagnosis
of the PCOS ( The presence of an increased number of
ocvarian follicles often in a necklace like pattern, and
increase in ovarian volume, largely due to an increase in
stroma). From 8% to 25% of normal women will demonstrate
ultrasonographic findings typical of polycystic ovries! Even
14% of women on oral contraceptives hav been found to have
this ultrasonographbic picture. Ultrasonography as a
diagnostic tool for this condition is unneccessary.
It is argued that normally ovulating women with PCO on USG
have underlying metabolic anomalies. However, the great
majority of ovulatory women with polycystic ovaries on USG
are endocrinoliogically normal, and only occassionally if an
androgen level minimally elevated. However , whether this
has any clinical bearing is debated.
Overall, the clinical presentation is critical to the
diagnosis of PCOS, which has been defined as ovulatory
dysfunction and hyperandrogenism in the absence of other
causes. Most ovulatory dysfunction can be suspected based on
history, with targeted hormonal testing. Physical findings
suggestive of hyperandrogenism provide the next important
step in the diagnosis. An assessment of obesity and fat
distribution should be part of the clinical examination.
Typical Hormonal Disturbances Associated with PCOS
diagnosis include:
* LH is elevated while FSH is usually low at a ratio of 2:1
* Progesterone can be low
* Sex Hormone Binding Globulin (SHBG) is usually low
* Androgens such as testosterone and DHEA-S are usually
elevated
REFERENCES:
Sekharan P. K: Polycystic Ovarian Syndrome: Chapter
in Infertility Manual Ed. Rao K et al: Ed. 2, Jaypee
Publications, Delhi,
Hopkinson Z, Satar N, Fleming R, Greer A: Polycystic
ovarian syndrome: the metabolic syndrome comes to
gynaecology, BMJ, 317, 329-332, 1998.
Visnova H, Ventruba P, Crha I, Zanova J: Importance of
sensitization of insulin receptors in the prevention of
ovarian hyperstimulation syndrome, Cesca Gynekol, 68, 3,
155-62, 2003.
Lara HE, Ferruz LJ, Luza S, et al: Activation of ovarian
sympathetic nerves in polycystic ovarian syndrome,
Endocrinology, 133, 2690-2695, 1993.
Stenchever MA et al: Comprehensive Gynecology 4th ed,
Polycystic ovarian syndrome, St Louis, 2001, Mosby.
Dunaif A, Segal Kr: Profound insulin resistance,
independent of Obesity in PCOS: Diabetes 1989; 38;
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Adams j, Frank S: Multi follicular ovaries, Clinical and
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