Intro to PCOS Flashcards
What is PCOS
Arguably the most prevalent medical condition in women
Patients with PCOS have systemic metabolic manifestations with multiple symptomatology:
endocrine, gynaecological, diabetic, dermatological, eating disorder, psychiatry
Insulin resistance (IR) likely to have a life-long impact on patient. Annual economic cost of diagnosis and treatment of PCOS in USA recently calculated to be $4.36 billion and 40% of this was IR/T2D-related
Definition of polycystic ovaries
The ovary contains increased numbers (>12) of small antral follicles (2-9mm) visible on u/s
There is a disorder of follicle growth at all stages
Possibly increased proportion of primordial follicles & increased number of activated (primary) follicles
Arrested antral follicle growth before they mature
Lower rates of atresia » antral follicles persist (visible on u/s)
In some cases there is a failure of dominant follicle selection and therefore anovulation
The main problem with PCO is that it has
Disorder of follicle growth occurs across all stages.
How is PCOS diagnosed, why is it not easy, and what conditions are similar to PCOS and therefore needs diagnosis by exclusion?
First described in 1935 by Stein and Leventhal -
syndrome described as obesity, hirsutism and anovulation in the presence of bilaterally enlarged sclerocystic ovaries.
Discovered that many women have the change in the ovaries and do not necessarily have the symptoms
Spectrum of presentation has led to lack of consensus regarding the definition
Diagnosis of exclusion i.e. disorders that mimic PCOS:
congenital adrenal hyperplasia (most common is deficiency of 21-hydroxylase → ↑17-hydroxyprogesterone & androgens)
Hyperprolactinemia, thyroid disease, Cushing’s syndrome
Ovarian hyperthecosis (very rare) - nests of luteinized theca cells Ovarian hyperthecosis – excess androgen production due to nests of luteinized theca cells scattered throughout ovarian stroma. Ovary slightly enlarged but devoid of antral follilces – hence distinct from PCOS. Serum testo levels>women with PCOS but
Describe the rotterdam criteria
There are 3 criteria: Polycystic ovaries, ovulatory dysfunction, hyper androgenism. Need 2 out of these 3 for a PCOS diagnosis
Polycystic ovaries:(either 12 or more follicles measuring 2-9mm diameter and/or increased ovarian volume >10ml in either ovary & no DF >10mm). Technique and equipment dependent. T/V imaging not always appropriate
Hyper androgensim: Needs clinical/biochemical evidence: assays not standardized across labs; normative data not clearly defined; clinical hyperandrogenism difficult to quantify; ethnicity.
Clinical hyperandrogenism includes hirsutism, acne, or male pattern alopecia or biochemical signs of hyperandrogenism i.e. elevated levels of total or free testosterone.
Ovulatory dysfunction: Oligomenorrhea and anovulation
Frequent bleeding <21d or infrequent bleeding >35d. To confirm ovulation serum progesterone level at mid-luteal phase (d21-22) of cycle (values ≥7ng/ml needed for regular luteal function)
Definition of PCO vs PCOS
By Ultrasound:
Normal
no more than 5 follicles in an ovary with a small amount of stroma in a woman with regular cycles
PCO
In at least one ovary ≥ 12 follicles of 2-9mm diameter arranged peripherally around an enlarged core of dense stroma - ovarian volume >10mls, without a dominant follicle
PCOS
PCO on scan plus one or more symptoms
The terms cyst and follicles used interchangeably but not correct – what you seen in PCO are NOT cysts but follicles – has lead to confusion.
Scanning is not a science but an art ie. very operator dependent. It is easy to miss follicles and it also depends on where you are in the cycle. Also age – adolescents can have multi-follicular morphology until puberty is complete. Ideal would be to scan sequentially.
Describe anovulation and how it can help distinguish between PCO and PCOS
Most women with PCO probably have regular or almost regular cycles
Most women with PCOS and cycle problems have oligomenorrhoea
There are a number of candidates for follicle arrest
androgens,
intra-follicular inhibitors eg AMH
defect in apoptosis
dysregulated gonadotrophin secretion (both FSH and LH)
Main difference between ov and anov is also the level of insulin resistance
Adult rhesus macaques fed a western style diet (high fat/sugar) & exposed to chronically elevated T from pre-puberty to menopause altered small AF numbers, morphology and transcriptome (Bishop CV et al, 2015, Fertil.Steril.)
Aetiology of PCOS and consider the Chinese study
Familial aggregation
Sisters more likely to be affected
first-degree relatives have higher rates of metabolic abnormalities (including insulin resistance, decreased beta-cell function etc)
Male relatives of women with PCOS increased prevalence of metabolic syndrome & obesity compared to general US male population
Monozygotic twins twice as likely to both have PCOS than dizygotic.
common finding of raised androgen led to belief that PCOS is caused by an inherited disorder -most likely in the steroid biosynthetic pathway
Many candidate genes were investigated: all ‘obvious’ ones ruled out
Complex polygenic disease – involves subtle interaction with environmental factors (intra- & extra-uterine)
Definitely runs in families
Because of hyperandrogenimia thought that gene in biosynthetic pathway for androgens was responsible.
GWAS study in China: 1st Genome-wide association study (GWAS) identified causative genes in Han Chinese women (2011) 744 women with PCOS & 895 controls 3 loci linked and candidate genes within these loci are: LHCGR FSHR THADA….linked to T2D DENND1A ...linked with obesity
Confirming the biological relevance of PCOS-associated variants by molecular analysis (e.g. expression analysis, targeted genetic disruption in cell culture or organism) is critical to confirming findings from GWAS – rarely done.
Forced expression of DENND1A.V2 in normal thecal cells, resulting in androgen and progestin production
Theca cells were transfected with DENND1A isoform and treated with/without forskolin (to stimulate cAMP)
Measured production of various androgens and progestegins
DENND1A overexpression recapitulated hyperandrogenic theca cell function
How does PCOS cause downstream ovarian consequences due to disordered gonadotrophin secretion
Consistent feature of PCOS is disordered gonadotrophin secretion leading to downstream ovarian consequences
Elevated/upper-normal mean LH
Low/low-normal FSH
Rapid GnRH frequency → favouring rapid LH pulse secretion
Elevated LH pulse frequency and increased LH:FSH ratio impairs downstream ovarian folliculogenesis and alters steroid hormone production. In PCOS the “FSH threshold” that is required for follicle maturation is not reached (due to this dysregulated gonadotrophins and also increased AMH, which alters FSH sensitivity) causing follicles to arrest in antral stages.
What may be more important in PCOS is the LH:FSH ratio.
Why does impaired gonadotrophin secretion occur
Impaired negative regulation of GnRH pulse generator
High Testosterone impairs negative feedback by Progesterone in presence of oestradiol
Proof: block AR with flutamide → progesterone then able to↓ LH & FSH
Also see that in late puberty girls without HA respond to progesterone with ↓LH pulse frequency o/n, which did not occur in HA girls at same pubertal stage
The higher LH will drive thecal cell hyperplasia and the hyper-androgenemia, but HA is also intrinsic and can be independent of LH.
PCOS and androgens
Increased androgen
Most consistent biochemical abnormality in women with PCOS is hypersecretion of androgens
ideal to measure free (T) i.e. SHBG and total testosterone to work out free T
anov> ov>normal
increased androgen production by the ovary, even in ovPCO
Increased LH leads to increased androgen production
May lead to hirsutism and acne
consistently reported as most distressing symptoms in young women
Androgens and hirsutism
Testosterone converted to DHT at hair follicle
DHT more potent androgen
5a-reductase may be higher in PCOS
Not just absolute levels of testosterone per se but the sensitivity to AR – see this with acne
Testosterone converted to DHT at hair follicle by 5alpha-reductase
For treatment, sometimes give 5alpha-inhibitors
Excess androgens coming from either the ovary and/or cells of adrenal cortex. Which cells in ovary – theca?
Suppress ovary with GnRH analogues and measure adrenal androgens.
Then suppress adrenals with dex. and measure.
In normal women the adrenal glands and ovaries secrete androgens in response to ACTH and LH respectively. Approximately half the androgen production stems from direct secretion and half from peripheral conversion by enzymes in skin, liver and adipose tissue. In women with PCOS the ovary is main source of androgen, though adrenals do contribute in about 30-50% of women
Steroid production in theca cells
Theca grown in vitro and steroids measured.
Be aware that it’s a log scale.
Androstenedione is the main androgen from ovary and not testo. Comparing the androgen output/1000 theca cells from normal nad PCOS. Remember it’s not just androgens that are higher but also progesterone
Stable phenotype of PCOS theca
CYP17 promoter is more active
CYP17 mRNA degrades more slowly
CYP 17
Both 17α-hydroxylase and C17-20-lyase reside on a single protein and are encoded by a single gene, namely, CYP17
Due to ↑in number of arrested follicles will see a slight ↑E2 but not DF levels in spite of ↑T – why?
Levels of AR may not be increased in GC, hence cannot bind excess T
No massive increase in aromatase levels
Morphometric studies of ovaries over time
Hughesden 1982
counted follicle numbers in sections from 17 PCOs and 17 normal ovaries
found 2x all of the growing stages in PCO
First was pathologist Hughesden – who spent his life slicing ovaries and counting follicles – know now there were errors in his counting methods, but still borne out by other studies that an increase even in preantral follicles.
This finding supports the idea that primary follicles are stockpiled in PCOS. Hence the question: does PCOS cause more primordial follicles to start growing or does it prevent atresia of preantral follicles already stimulated to grow? If recruitment were accelerated, then PCOS ovaries would be expected to contain fewer primordial follicles. This was not found. Nor were atretic preantral follicles identified in the control and PCOS ovaries. Taken together, these results support the hypothesis that primary follicles in PCOS ovaries are growing more slowly than normal.
Webber et al (2003)..Lancet
counted follicles in biopsies
six times more primary follicles
no significant increase in primordials
Maciel GA et al, (2004)…JCEM
Counted follicles in sections
‘stockpiling’ of primary follicles
