Polycystic Ovary Syndrome

case 1

11 y/o girl, presented with acnes over face, chest and upper back, more hair growth over lower legs, with no M.C.

testosterone   155.7   (高)
progesterone < 0.14
estradiol          58.99   (高)
LH                    3.48     (高)  
FSH                 4.94
normal thyroid and cortisol

PCOS
  -the  most  common  form  of  chronic  anovulation a/w androgen excess;
  -5% to 10%  of  reproductive-age  women.

Dx: (women  with chronic anovulation and androgen excess)
  -先排除 other hyperandrogenic d/o
     -nonclassic  adrenal  hyperplasia,
     -androgen-secreting  tumors, (腎上腺,卵巢)
     -hyperprolactinemia)

Criteria for the Definition of PCOS
NIH Statement (1990)
To include all of the following:
1.  Hyperandrogenism and/or hyperandrogenemia
2.  Oligo-ovulation
3.  Exclusion of related disorders*

ESHRE/ASRM Statement (Rotterdam, 2003)
To include two of the following, in addition to exclusion of related
disorders*:
1.  Oligo-ovulation or anovulation (e.g., amenorrhea, irregular uterine
bleeding)
2.  Clinical and/or biochemical signs of hyperandrogenism (e.g., hirsutism,
elevated serum total or free testosterone)
3.  Polycystic ovaries (by ultrasonography)

AES Suggested Criteria for the Diagnosis of PCOS (2006)
To include all of the following:
1.  Hyperandrogenism: hirsutism and/or hyperandrogenemia
2.  Ovarian dysfunction: oligo-anovulation and/or polycystic ovaries
3.  Exclusion of other androgen excess or related disorders*

*Including but not limited to 21-hydroxylase-deficient nonclassic adrenal hyperplasia, thyroid dysfunction, hyperprolactinemia, neoplastic androgen secretion, drug-induced androgen excess, the syndromes of severe insulin resistance, Cushing’s syndrome, and glucocorticoid resistance.

NIH, National Institutes of Health;
ESHRE, European Society for Human Reproduction and Embryology;
ASRM, American Society for Reproductive Medicine;
AES, Androgen Excess Society.

PCOS 病生理

-A deficient in vivo response of the ovarian follicle to physiologic quantities of FSH, possibly because of an impaired interaction between signaling pathways associated with FSH and insulin-like growth factors (IGFs) or insulin, may be an important defect responsible for anovulation in PCOS.
-insulin resistance associated with increased circulating and tissue levels of insulin and bioavailable estradiol (E2 ), testosterone (T), and IGF1 gives rise to abnormal hormone production in a number of tissues.
-Oversecretion of LH and decreased output of FSH by the pituitary, decreased production of sex hormone–binding globulin (SHBG) and IGF-binding protein 1 (IGFBP-1) in the liver, increased adrenal secretion of dehydroepiandrosterone sulfate (DHEAS), and increased ovarian secretion of androstenedione (A) all contribute to the feed-forward cycle that maintains anovulation and androgen excess in PCOS.
-Excessive amounts of E2  and T arise primarily from the conversion of A in peripheral and target tissues.
-T is converted to the potent steroids estradiol or DHT (dihydrotestosterone).
-Reductive 17β-hydroxysteroid dehydrogenase  (17β-HSD)  enzyme  activity  may  be  conferred  by  protein  products  of  several  genes  with  overlapping  functions;
-5α-reductase  (5α-red)  is encoded by at least two genes, and aromatase is encoded by a single gene.
GnRh, gonadotropin-releasing hormone.


Extraovarian  conversion  of  androstenedione  to  androgen and estrogen

-Androstenedione of adrenal or ovarian origin, or both, acts as a dual precursor for androgen and estrogen.
-Approximately 5% of circulating androstenedione is converted to circulating testosterone, and approximately 1.3% of circulating androstenedione is converted to circulating estrone in
peripheral tissues.
-Testosterone and estrone are further converted to bio-logically potent steroids, dihydrotestosterone and estradiol, in peripheral and target tissues.
-Biologically active amounts of estradiol in serum are measured in  picograms  per  milliliter  (pg/ml,  or  pmol/l),  whereas  biologically  active levels of testosterone in serum are measured in nanograms per milliliter (ng/ml, or nmol/l).
-the 1.3% conversion of normal quantities of androstenedione to estrone may have a critical biologic impact in settings such as postmeno-pausal endometrial or breast cancer.
-significant androgen excess is observed in  conditions  with  abnormally  increased  androstenedione  formation  (e.g., polycystic ovary syndrome).


DDx:
 -Idiopathic hirsutism
 -Hyperprolactinemia, hypothyroidism.
 -Nonclassic adrenal hyperplasia, Adrenal tumors, Cushing’s syndrome, Glucocorticoid resistance.
 -Ovarian tumors
 -Other rare causes of androgen excess

CHAR:
 -infertility,
 -irregular  uterine  bleeding,  and
 -↑ pregnancy  loss.

-endometrium biopsy,  because  long-term  unopposed  estrogen stimulation leaves these patients at ↑risk for endometrial cancer.

-↑metabolic  and  CV  risk  factors.
   -->linked  to  insulin  resistance  and
   -->are  compounded  by  the common occurrence of obesity, (although insulin resistance also occurs in nonobese women with PCOS.)

-considered to be a heterogeneous disorder with multifactorial  causes.
-PCOS  risk  is
   -significantly  increased with a positive family history of chronic anovulation and androgen excess, and
   -may be inherited in a polygenic fashion.

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Historical Perspective
In their pioneering studies, Stein and Leventhal described
an association between the presence of bilateral polycystic
ovaries and signs of amenorrhea, oligomenorrhea, hirsut-
ism,  and  obesity  (Fig.  17-29). 250   At  the  time,  these  signs
were strictly adhered to in the diagnosis of what was then
known as Stein-Leventhal syndrome. These investigators also
reported  the  results  of  bilateral  wedge  resection  of  the
ovaries, in which at least half of each ovary was removed
as  a  therapy  for  PCOS.  Most  of  their  patients  resumed
menses and achieved pregnancy after ovarian wedge resec-
tion. They postulated that removal of the thickened capsule
of the ovary would restore normal ovulation by allowing
the  follicles  to  reach  the  surface  of  the  ovary.  The  exact
mechanism responsible for the therapeutic effect of removal
or destruction of part of the ovarian tissue is still not well
understood.
On the basis of Stein and Leventhal’s work, a primary
ovarian  defect  was  inferred,  and  the  disorder  was  com-
monly referred to as polycystic ovarian disease. Subsequent
clinical,  morphologic,  hormonal,  and  metabolic  studies
uncovered multiple underlying pathologies, and the term
polycystic ovary syndrome was introduced to reflect the het-
erogeneity of this disorder.
One  of  the  most  significant  discoveries  regarding  the
pathophysiology  of  PCOS  was  the  demonstration  of  a
unique form of insulin resistance and associated hyperin-
sulinemia. 142   Burghen  and  coworkers  first  reported  this
finding  in  1980. 251   The  presence  of  insulin  resistance  in
PCOS  has  since  been  confirmed  by  a  number  of  groups
worldwide. 142


Diagnosis of Polycystic Ovary Syndrome  and Laboratory Testing

臨床
 -ovulatory dysfunction  (i.e.,  amenorrhea,  oligomenorrhea, or other forms of irregular uterine bleeding) of pubertal onset.
 -A  clear  history  of  cyclic  predictable  menses  of menarchal  onset  makes  the  diagnosis  of  PCOS  unlikely.
 -Acquired  insulin  resistance  associated  with  significant weight gain or an unknown cause may induce the clinical picture of PCOS in a woman with a history of previously normal ovulatory function.
 -Hirsutism may develop prepubertally  or  during  adolescence,  or  it  may  be  absent  until
the third decade of life.
 -Seborrhea, acne, and alopecia are other common clinical signs of androgen excess.
 -In extreme cases of ovarian hyperthecosis (a severe variant of PCOS), clitoromegaly  may  be  observed.  Nonetheless,  rapid  progression of androgenic symptoms and virilization are rare in PCOS.
 -Some women may never have signs of androgen excess  because  of  hereditary  differences  in  target  tissue sensitivity to androgens. 148
 -Infertility related to the anovulation may be the only presenting symptom.
 -During the physical examination, it is essential to search for  and  document  signs  of  androgen  excess  (hirsutism, virilization, or both), insulin resistance (acanthosis nigricans, Fig. 17-30), and the presence of unopposed estrogen action (well-rugated vagina and stretchable, clear cervical mucus) to support the diagnosis of PCOS.
 -None of these signs is specific for PCOS, and each may be associated with
any of the conditions listed in the differential diagnosis of
PCOS (Table 17-5).