L'endocrinologia della PCOS - Paolo Moghetti Endocrinologia, Diabetologia e Malattie del Metabolismo - Società Italiana di Endocrinologia
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L’endocrinologia della PCOS
Paolo Moghetti
Endocrinologia, Diabetologia e Malattie del Metabolismo
Università e Azienda Ospedaliera Universitaria Integrata di Verona
Criteri ESHRE/ASRM per la diagnosi di PCOS
- Consensus di Rotterdam -
La diagnosi richiede almeno due elementi fra:
- Iperandrogenismo (clinico e/o biochimico)
- Oligo-anovulazione cronica
- Ovaie micropolicistiche
dopo aver escluso altre cause
Hum Reprod & Fertil Steril, 2004
Fenotipi clinici della PCOS in
base ai criteri di Rotterdam
Fenotipo
Fenotipo completo
classico
Oligoanovulazione Iperandrogenismo
Fenotipo Fenotipo
normoandrogenico ovulatorio
Morfologia policistica dell’ovaio
The NIH Evidence-based Methodology
Workshop on PCOS (December 3–5, 2012)
Panel Recommendations
1. ….
2. We recommend maintaining the broad,
inclusionary diagnostic criteria of Rotterdam while
specifically identifying the phenotype.
3. We recommend …to improve the methods and
criteria used to assess androgen excess, ovulatory
dysfunction, and polycystic ovarian morphology.
4. ….
Frequency of PCOS phenotypes in studies
carried out in unselected populations
completo classico ovulatorio normoandrogenico
Lizneva D et al, Fertil Steril 2016
Frequenza di fenotipi clinici e categorie di BMI
in 246 donne con PCOS del Verona 3P Study
Fenotipo clinico Categoria di BMI
% 70 % 70
68.1
60 68% 60
50 50
40 40 41.0 42%
36.2
30 30 36%
20 20 22%
22.8
17.5
17%
10 15%
14.4 10
0 0
classico normopeso
ovulatorio sovrappeso
normoandrogenico obesità
Comparison of PCOS women referred to a tertiary
care clinic vs unselected PCOS and control women identified
at a pre-employment medical screening
(Ezeh U et al, JCE&M 2013)
Bidirectional Mendelian randomization
indicates a causal relationship between
increased BMI and PCOS, while the reverse is not the case
(750 individuals of European origin with PCOS and 1567 BMI-matched
controls, 92-SNP for BMI with PCOS as the outcome,
16-SNP for PCOS with BMI as the outcome)
Brower MA, Hai Y, et al, Hum Reprod 2019
Linea guida Endocrine Society sulla PCOS
- esclusione di altre patologie -
• Dosaggio sistematico di:
– 17OHP
– PRL
– TSH
• Altre ipotesi da considerare, in base alla presentazione
clinica:
– Gravidanza
– Amenorrea ipotalamica
– Insufficienza ovarica primitiva
– Neoplasie androgeno-secernenti
– S. di Cushing
– Acromegalia Legro et al, JCE&M 2013
Presenting symptoms in 218 women with
Nonclassic Congenital Adrenal Hyperplasia
Moran C et al, Am J Obstet Gynecol 2000Androgen levels in androgen-secreting tumors
• Virilization of recent onset and rapid progression, a serum total
testosterone >150 ng/dL (5.2 nmol/L), or a serum DHEAS >700-
800 mcg/dL (18.9-21.7 micromol/L) suggests a neoplastic
source of hyperandrogenism.
• Caution must be exercised ... Approximately 20% of ovarian
androgen-secreting neoplasms result in testosterone levels
under 150 ng/dL,… and small tumors can cause fluctuating
androgen levels.
• …there are case reports of adrenal tumors that secrete
testosterone directly and exclusively, and some adrenal tumors
may cause only a mild elevation in DHEAS.
www.uptodate.com, December 2018Increased LH ?
? Insulin resistance
Androgen excess ?
Hyperinsulinemia
PCOST and A4 by LC-MS/MS
DHEAS by CLIA
(≤50yr) (>50yr) Final diagnosis in
1205 women
investigated for
hyperandrogenism
at a single tertiary
referral center
in Birmingham
between 2012-2016
Elhassan YS et al, JCEM 2018
CAH: congenital adrenal hyperplasia; ACC: adrenocortical carcinoma; CD: Cushing dis.;
ACA: adrenocortical adenoma; OHT: ovarian hyperthecosis; OvTu: ovarian tumorsProvenienza degli androgeni circolanti
nella donna normale
SURRENE
25% 50% 90% 100%
50%
(DHT) Testosterone Androstenedione (DHEA) DHEAS
25% 50% 10%
OVAIOFrequenza di alterazioni degli androgeni circolanti
(misurati con LC-MS/MS e dialisi all’equilibrio)
in 254 donne con PCOS della coorte del Verona 3P Study
Considerando insieme
iperandrogenismo clinico e
biochimico, la frazione di soggetti
PCOS iperandrogenici sale a 88%PCOS women recognized as hyperandrogenemic by gold
standard methods, either without or with FT measurement
AUC
Tosi F et al, J Clin Endocrinol Metab 2016Come stimare il testosterone libero
(se non è possibile misurarlo in modo accurato)?
Free androgen index (FAI)
Testosterone totale / SHBG x 100
oppure (meglio)
Calcolo con la formula di Vermeulen
- ISSAM online calculator -
(http://www.issam.ch/freetesto.htm)Impact of inaccuracy in routine androgen assays
in the classification of 204 women with PCOS
Deming regression of gold Misclassification of androgen excess
standard vs routine fT assay by routine methods in ~30% of patients
Tosi F et al, J Clin Endocrinol Metab 2016Relationship between serum free testosterone and hirsutism
score in 254 PCOS women of the Verona 3P Study cohort
Free Testosterone (ng/dL)
Ferriman-Gallwey scorePathways of adrenal steroidogenesis
(11-oxygenated androgens are highlighted in black)
Dashed arrow denotes minor conversion to product
11KA: 11-ketoandrostenedione; 11OHA: 11b-hydroxyandrostenedione
11KT: 11-ketotestosterone; 11OHT: 11b-hydroxytestosterone
Rege J et al, J Clin Endocrinol Metab 2018Classic and 11-oxygenated serum androgens
in PCOS women and controls
O’Reilly MW et al, JCEM 2017Serum concentrations of steroids in girls with premature adrenarche vs age-matched girls (4-7 years) Rege J et al, J Clin Endocrinol Metab 2018
Androgen-dependent gene regulation
in response to C19 steroids in CV1-ARLuc cells
(Selective adrogen-responsive model derived from cells engineered to
express androgen receptor and an AR-driven bioluminescence signal)
Most highly upregulated
genes in cells after treatment
with 100 nM of T or 11KT, as
identified by RNA-Seq.
3/4 vs T
1/20 vs T
* P < 0.05 vs basal
Rege J et al, J Clin Endocrinol Metab 2018Hormonal changes during
an ovulatory menstrual cycle
Marshall JC and Eagleson CA, Endocrinol Metab Clin North Am 1999GnRH pulsatility and PCOS
• The GnRH pulse generator shows an intrinsic firing
frequency of approximately one pulse per hour, which is seen
in isolated hypothalamus, and in vivo after menopause, in
premature ovarian failure, in the physiological late follicular
phase, but also, persistently, in many PCOS women.
• Rapid GnRH pulsatility favours pituitary synthesis of LH
over that of FSH and contributes to the increased LH
concentrations and LH : FSH ratios typical of PCOS.
• Inadequate FSH levels contribute to impaired follicular
development, whereas elevated LH levels augment ovarian
androgen production.
Blank SK, McCartney CR and Marshall JC, Hum Reprod Update 2006Typical plasma gonadotropin pattern
in an amenorrheic PCOS woman
LH pulses
Blank SK, McCartney CR and Marshall JC, Hum Reprod Update 2006Absolute change in LH pulses/12 hours
following 7 days of estradiol and progesterone,
with or without flutamide co-administration,
as a function of mean plasma progesterone on day 7
Shaded areas: range of
responses after E2 and
progesterone for 7 days.
Closed circles: findings
when flutamide was
also administered,
before and during E2
and progesterone
treatment.
Eagleson CA et al, J Clin Endocrinol Metab 2000Schema for the potential action of excess
androgens in modifying GnRH secretion during
pubertal maturation in susceptible adolescent girls
Blank SK, McCartney CR and Marshall JC, Hum Reprod Update 2006Model of AMH secretion and action
in the ovary
Dewailly D, La Marca A et al Hum Reprod Update 2014Correlation
between follicle
count and serum
AMHSerum AMH is increased
in pregnant women with PCOS
(16-19 weeks)
Tata B et al, Nat Med 2018Peripherally administered AMH in pregnancy
reprograms the fetus and induces PCOS in
In the mother: adulthood in female progeny
• Neuroendocrine changes (increased serum LH)
• Androgen excess
• Impaired fertility (increase in aborted embryos/litter)
In the offspring:
• Masculinization of the exposed female fetus (longer ano-genital
distance, neonatal LH and T surge, masculinization of dimorphic
brain areas)
• PCOS-like neuroendocrine (persistently hyperactivated GnRH
neurons with increased LH and testosterone levels) and
reproductive phenotype (disrupted estrous cyclicity and impaired
fertility) in adulthood
• No changes in weight
AMH detectable in the maternal brain areas where GnRH terminals
are located. However, AMH cannot cross the placental barrier.
AMH effects prevented by co-administration of a GnRH antagonist.
Tata B et al, Nat Med 2018Frequency of insulin resistance and metabolic
syndrome in 137 consecutive PCOS women
(mean age 23 yr, BMI 28.5 kg/m2)
80
% 70
60
71
50
40
30
33
20
10
0
Insulin resistance Metabolic syndrome
(clamp, WHO criteria) (IDF 2009 criteria)
from Moghetti P et al, JCE&M 2013
SHBG LH (?)
Ipofisi
(?)
Insulina Ovaio
androgeni
Muscolo
Surrene
effetti
metabolici
modificato da Dunaif A, Endocr Rev 1997Obesity induced infertility and hyperandrogenism
are corrected by selective deletion of the insulin
receptor in theca cell
Wild type - lean KO - lean Wild type - obese KO - obese
Fertility rate Serum testosterone
100 16
% pg/dl
80
12
60
8
40
4
20
0 0
Wu S et al, Diabetes 2014BASAL AND INSULIN-STIMULATED GLUCOSE UPTAKE IN
HYPERANDROGENIC WOMEN BEFORE AND AFTER
ANTIANDROGEN TREATMENT vs HEALTHY CONTROLS
Glucose uptake (µmol/kg FFM · min)
90
90
pFrequency of insulin resistance in PCOS women
according to BMI categories
(n= 375, glucose clamp methodology)
100
80
normal-weight
60
overweight
40 obese
20
0
Tosi F, Bonora E & Moghetti P, Hum Reprod 2017Performance dell’indice HOMA nell’identificare
i soggetti insulinoresistenti, definiti dal clamp,
fra le donne con PCOS (n=375)
M-clamp
(mg/KgFFM x min-1)
20 R=0.622 pPerformance of several surrogate indexes in
identifying insulin resistant subjects, as defined
by the hyperinsulinemic euglycemic clamp,
in women with PCOS (n=375)
Tosi F, Bonora E & Moghetti P, Hum Reprod 2017Fraction of subjects, subdivided according to BMI categories
or presence/absence of metabolic syndrome, recognized as
insulin resistant by the hyperinsulinemic euglycemic clamp
and by several surrogate indexes, among women with PCOS
Tosi F, Bonora E & Moghetti P, Hum Reprod 2017Divergences in insulin resistance
between the PCOS phenotypes derived from
Rotterdam diagnostic criteria
M-clamp values in PCOS phenotypes
and healthy controls
PChanges in mestruation rate
in individual PCOS women
given metformin
1.0
1.0
responders
0.8
0.8 (55%)
cycles per month
0.6
0.6
0.4
0.4
0.2
0.2
non
responders
0
0.0
(45%)
-0.2
1.5 2.5 3.5
Baseline After metformin
Moghetti P et al, JCE&M 2000Conclusioni • La PCOS è una sindrome eterogenea e molto complessa dal punto di vista endocrino. • L’eccesso di androgeni è l’aspetto più caratterizzante della PCOS, ma nell’accezione attuale non è obbligatorio. L’iperandrogenismo clinico e quello biochimico sono considerati equivalenti ai fini diagnostici, ma sottendono differenze cliniche. • Le alterazioni neuroendocrine partecipano alla fisiopatologia dell’iperandrogenismo e forse delle alterazioni metaboliche, anche se le influenze reciproche fra questi aspetti rendono difficile stabilire la causa iniziale. L’AMH sembra essere un anello importante in questa catena fisiopatologica. • L’insulinoresistenza è un altro elemento centrale della sindrome, in termini fisiopatologici e clinici, ma la sua valutazione nella pratica clinica resta problematica.
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