SANGUINAMENTO UTERINO DISFUNZIONALE Rossella E' Nappi Centro di Ricerca per la Procreazione Medicalm

1
SANGUINAMENTO UTERINO DISFUNZIONALERossella E.
NappiCentro di Ricerca per la Procreazione
Medicalmente Assistita, Dipartimento di Scienze
Morfologiche, Eidologiche e Cliniche, Università
di Pavia Endocrinologia Ginecologica e della
Menopausa, UO di Medicina Interna
Endocrinologia,IRCCS Fondazione S. Maugeri,
Pavia
2
THE HUMAN ENDOMETRIUM IS A DYNAMIC TISSUE
From Wathen et al, 1995

• IN RESPONSE TO THE PREVAILING STEROID
  ENVIRONMENT
• THE FUNCTIONAL LAYER IS SHED RIGENERATED

3
TWO ALTERNATIVES FOR A PROGESTERONE-PRIMED
ENDOMETRIUM

• MENSTRUATION IS THE RESPONSE OF THE ENDOMETRIUM
  TO
• THE WITHDRAWAL OF P (AND ESTROGEN) IN THE ABSENCE
  OF
• PREGNANCY
• PROLIFERATION
• DIFFERENTIATION
• TISSUE BREAKDOWN

Progesterone Secretion
PREGNANCY
Estradiol Peak
P dominance
P withdrawal
Menstruation
MENSTRUATION
Ovulation
Adapted from Jabbour et al, 2006
4
PROGESTERONE THE HUMAN ENDOMETRIUM

• PROGESTERONE (PROGESTOGENS) EXERT AN
• ANTIESTROGENIC EFFECT WITH INHIBITION OF
• ENDOMETRIAL GROWTH AND INDUCTION OF
• MATURATION AND DIFFERENTIATION OF THE
• GLANDULAR AND STROMAL CELLS.
• PRs EXPRESSION REQUIRES PREVIOUS EXPOSURE TO
  ESTROGEN.

Adapted from Jabbour et al, 2006
5
MENSTRUATION IS A HIGHLY ORCHESTRATED EVENT
THE MOLECULAR MECHANISMS BY WHICH SEX
STEROIDS REGULATE MENSTRUATION INVOLVE COMPLEX
INTERACTIONS BETWEEN THE ENDOCRINE THE IMMUNE
SYSTEM, INCLUDING AUTOCRINE/PARACRINE EVEN
INTRACRINE FACTORS
Progesterone Secretion
Vessel Permeability Vessel Fragility Tissue
Breakdown
Estradiol Peak
Vasoactive agents Chemotactic factors uNK
cells Monocytes migration MMP activation
Menstruation
MENSTRUATION
Ovulation
Adapted from Jabbour et al, 2006
6
STEROID CONTROL IN ENDOMETRIUM
EXPRESSION OF ENDOMETRIAL SEX STEROID RECEPTORS
(PRs, ERa, ERb, AR) VARIES TEMPORALLY SPACIALLY
ACROSS THE MENSTRUAL CYCLE ERa AND PRs ARE
UP-REGULATED DURING THE PROLIFERATIVE PHASE BY
ESTRADIOL DOWN-REGULATED BY PROGESTERONE IN
THE SECRETORY PHASE THE FUNCTION OF ERb IN THE
ENDOMETRIAL PHYSIOLOGY IS NOT FULLY ELUCIDATED,
AS WELL AS THE ROLE OF AR AND EVEN OF GR.
Jabbour et al, 2006
7
ABNORMAL MENSTRUATION
LENGHT, INTENSITY, DURATION
DYSFUCTIONAL UTERINE BLEEDING (DUB)
RE Nappi, 2006
8
DYSFUNCTIONAL UTERINE BLEEDING (DUB)
Heavy and/or irregular menses in the absence of
recognizable pelvic pathologies or general
bleeding disorders1. ANOVULATORY(inadequate
signal, impaired positive feedback)2. OVULATORY
(idiopathic)
RE Nappi, 2006
9
PROGESTINS IN CLINICAL PRACTICE
REGULATION OF MENSTRUAL CYCLE PREVENTION OF
ENDOMETRIAL HYPERPLASIA TREATMENT OF ABNORMAL
UTERINE BLEEDING CONTRACEPTION
THE PURPOSE TO ADD PROGESTINS TO ESTROGENS IS
NOT TO CAUSE BLEEDING BUT TO PROTECT THE
ENDOMETRIUM
RE Nappi, 2005
10
PROGESTOGENIC EFFECTS IN THE ENDOMETRIUM

• Progestins exert antiproliferative effects on the
  endometrium by
• reducing DNA synthesis and decreasing the
  number of estrogen receptors
• stimulating estradiol conversion into less
  active estrogens (estrone, estrone sulphate)
  throughout intracrine mechanisms
• decreasing the activity of growth factors
  (IGF-1, etc.)
• inducing secretory transformation,
  decidualization and shedding.

S Palacios, 2006
11
CLASSIFICATION OF PROGESTINS

• PROGESTERONE
• C21 PROGESTOGEN DERIVATIVES
• PREGNANES medroxyprogesterone acetate,
  megestrol acetate, dydrogesterone, cyproterone
  acetate, chlormadinone acetate
• 19-NOR PREGNANE DERIVATIVES nomegestrol
  acetate, trimegestone, promegestone
• 19-NORTESTOSTERONE DERIVATIVES
• ESTRANES norethisterone, norethisterone
  acetate, ethynodiol acetate, lynestrenol,
  norethynodrel
• GONANES norgestrel, levonorgestrel,
  norgestimate desogestrel, gestodene
• SPIROLACTONE DERIVATIVES
• DROSPIRENONE

From Schindler et al, 2003
12
PROGESTINS IN CLINICAL PRACTICE
ALL PROGESTINS AVAILABLE EXERT A PROGESTATIONAL
EFFECT OPPOSE THE PROLIFERATIVE EFFECT OF
ESTROGENS ON THE ENDOMETRIUM PROGESTATIONAL
POTENCY VARIES ACCORDING TO THEIR ORIGIN,
STRUCTURE PHARMACOKINETIC PROPERTIES
The efficacy of PROGESTINS in DUB/HMB is
variable depending on the clinical and endocrine
condition of the woman (estrogenic state). Poor
compliance and undiagnosed intrauterine
pathologies may also play a role.
RE Nappi, 2006