Theories of PCOS Development.

There are several hypotheses concerning the etiology of PCOS. It is a syndrome that may have several
etiologies and contributing factors.1 These may be genetic, endocrine, metabolic, neurologic, and
environmental factors.1,2

Genetic. Various modes of transmission have been suggested, including autosomal dominant.3

Endocrine. Possible endocrine factors that may contribute to the development of PCOS include an
increased LH/FSH ratio and increased insulin and androgen concentrations. Increased 17-
hydroxyprogesterone levels in thecal cells may play a role in the development of PCOS.

Metabolic. Insulin resistance decreases the release of SHBG in the liver, which increases free androgen
levels.2

Neurologic. The epileptic discharges from the amygdala to the hippocampus that affect the secretion of
gonadotrophin-releasing hormone (GnRH) may contribute to PCOS development in epilepsy.3

Environmental. Drugs, such as anabolic steroids and antiepileptic drugs (AEDs), have been implicated in
the development of PCOS.

Association Between Weight Gain and PCOS.

Obesity has been associated with menstrual cycle abnormalities by many authors.1 For example, Hartz et
al found a significantly higher prevalence of anovulation, oligomenorrhea, and hirsutism in obese
women than in normal-weight women.2 It has been observed that up to 50% of women with PCOS are
moderately obese or overweight to some degree. Obesity is associated with decreased levels of SHBG
and elevated levels of estrogen.1 Obesity may promote PCOS through such mechanisms as increased
peripheral aromatization of androgen to estrogen within adipose tissue and consequent sensitization of
gonadotropins by constant acyclic estrogen feedback. Also, decreased levels of SHBG associated with
obesity may produce increased relative levels of free serum testosterone.1

The obesity in women with PCOS is usually the android type, with increased waist-to-hip ratios.3 When
present, obesity worsens insulin resistance and increases the risk for diabetes and cardiovascular
disease. The treatment of obesity should be a major focus of preventive health care for women with
PCOS.

Impaired Ovarian Function as a Cause of PCOS.

Studies focusing on women with PCOS suggest that the disorder may be caused by increased
steroidogenic activity that is an intrinsic, presumably genetic, defect in the ovary. 1 In vitro studies
show that women with PCOS secrete increased amounts of androstenedione (an androgen) and 17-
hydroxyprogesterone (a steroid that is an intermediate in the androgen and glucocorticoid
biosynthetic pathway) from thecal cells (the androgen-producing cells of the ovary).1 This increased
secretion by thecal cells may be a result of dysregulation of the rate-limiting enzyme in androgen
biosynthesis, cytochrome P-450c17.2

Insulin Resistance and PCOS.

Several findings suggest that insulin resistance plays an important role in the pathogenesis of
anovulation in women with PCOS. Research has shown that experimentally raising insulin levels can
directly stimulate ovarian androgen production in women with PCOS.1 Results from similar studies
suggest that insulin can stimulate adrenal steroidogenesis by enhancing sensitivity to
adrenocorticotrophic hormone (ACTH) and can increase pituitary LH release.1 These reproductive
effects of insulin appear to be limited to women with PCOS. Another significant finding is that insulin-
lowering therapies can restore ovulatory menstrual cycles in some chronically anovulatory women
with PCOS.1

A genetic defect may be responsible for the insulin resistance found in women with PCOS.2 Defects in
insulin receptors have been reported in up to half of women with PCOS; also a decrease in tyrosine
phosphorylation and an increase in serine phosphorylation, which all contribute to impaired insulin
activity. There is also evidence that dysfunction of -cells (responsible for pancreatic insulin
production) is also evident among women with PCOS.2 Women with PCOS also have a higher
incidence of impaired glucose tolerance (31%-35% versus 7.8%) and undiagnosed type 2 diabetes
(7.5%-10% versus 1%) compared with the general US female population.

Polycystic Ovarian Syndrome. Genetic Influences.

A genetic basis for PCOS appears to be likely, with increasing evidence pointing to a genetic defect in
ovarian and adrenal androgen biosynthesis that may interact with an insulin abnormality. 1,2
Investigators report familial aggregation of hyperandrogenism in first-degree relatives of patients
with PCOS, consistent with an autosomal dominant inheritance pattern. Familial clustering of PCOS
has been documented and is consistent with a genetic susceptibility to the disorder. 1 In addition,
brothers of women with PCOS often show evidence of insulin resistance and elevated
dehydroepiandrosterone levels, findings that suggest their reproductive and metabolic phenotype
resembles that of their sisters with PCOS.1

Epilepsy and Reproductive Endocrine Dysfunction.

Some investigators have suggested that epilepsy may play a role in the development of PCOS. PCOS
has been reported to occur in 20% of women in one group with temporal lobe epilepsy and 25% of 20
women with complex partial seizures, most of whom were unmedicated.1 Another investigator
reported PCOS in 15% of 20 women with primary generalized epilepsy. In general, it has been
reported that PCOS occurs in 13% to 25% of women with epilepsy.2

Several factors could explain epilepsy’s role in the development of PCOS in women with epilepsy 1 :
Epileptic discharges from the amygdala to the hippocampus may affect the secretion of GnRH, a
hypothalamic hormone that controls the cyclic release and concentration of the pituitary
gonadotrophins FSH and LH, and may induce the development of PCOS.

Anovulatory cycles can trigger limbic seizure discharges, which can reduce serum dopamine levels, in
turn producing hyperprolactinemia, which can promote elevated levels of LH that lead to
androgenization.

It is also possible that both epilepsy and reproductive endocrine disorders might be caused by a
common dysfunction in neurotransmission or genetic vulnerability.