Prima meta’ del ciclo mestruale
DF= dominant follicule
Seconda meta’ del ciclo mestruale
androstenedione (A)
estradiol (E)
keratinocyte
growth factor
(KGF),
hepatocyte
growth factor
(HGF), and Kit
ligand (KL).
FIG. Proposed schematic of thecal cell-granulosa cell interactions
during follicular development. Mesenchyme-derived thecal cells produce
KGF and HGF that regulate epithelial-derived granulosa cell
functions. Granulosa cell expression of KL is stimulated (1) by KGF
and HGF. Granulosa cell-derived KL feed back on thecal cells to
regulate thecal cell growth and differentiated functions. Thecal cell
expression of KGF and HGF is stimulated (1) by KL. Also illustrated
is the previously established positive effect (1) of KL on oocyte development.
Endocrine regulation of ovarian development is represented
at the top with the actions of FSH and LH. Thecal cells produce
androstenedione (A) under the control of LH. Androstenedione is
aromatized to estradiol (E) by granulosa cells under the control of
FSH. High levels of estradiol further stimulate androstenedione production
by thecal cells. LH also stimulates granulosa cell function
during later stages of follicular development (not shown).
ESTROGENI
Gli estrogeni giocano un ruolo importante nello sviluppo e
il mantenimento della funzione sessuale e riproduttiva. Sia
nell’uomo che nella donna esercitano una varietà di effetti
a livello cardiovascolare, muscolo scheletrico sistema
immunitario e sistema nervoso centrale. L’estrogeno più
potente è il 17b-estradiolo detto E2. Due metaboliti dell’E2
sono l’estrone e l’estriolo i quali sono agonisti molto più
deboli al recettore degli estrogeni (ERa ed ERb).
17b-estradiolo
ESTROGENI di sintesi
Receptor Actions in Cells
E
E
Growth
Factors
Estrogen
Peptides and
Neurotransmitters
GF
R
E
Second Messengers
and
Protein Kinase Cascades
Signaling
E
EREs
R
R
E
E
Receptor
Co-Regulators
TAFs
B
TBP
A
TATA
Transcription
F
polII
(B. Katzenellenbogen et al. Recent Prog. Horm. Res.,2
Gli estrogeni hanno un’azione morfogena e quest ‘ azione
morfogenica è evidente in strutture quali l’utero, le ovaie le
ghiandole mammarie, la prostata, i polmoni e il sistema nervoso
centrale di topi knockout per entrambi i recettori degli estrogeni
ERa ed ERb. A livello di promotori genici i due recettori ERa ed
ERb hanno effetti opposti e quindi la risposta proliferativa all’E2 è
il risultato di un equilibrio tra i segnali mandati dall’attivazione del
recettore ERa e quello ERb.
FIG. 3. Model representing the mechanistically distinct molecular pathways
used in the regulatory actions of ERs.
The classical (direct) pathway includes ligand activation and a direct DNA
binding to estrogen response elements (ERE) before modulation of gene
regulation.
The tethered pathway includes protein-protein interaction with other
transcription factors after ligand activation, and thereby gene regulation
is affected by indirect DNA binding.
A third mechanism, also called nongenomic with rapid effects, is not as
well understood as the genomic mechanism but has been observed in
many tissues. The ligand activates a receptor, possibly associated with
the membrane; either it is a classical ER (33, 138, 243), an ER isoform
(141, 305), or a distinct receptor (38) or, alternatively, a signal activates a
classical ER located in the cytoplasm. After this rather unclear event,
signaling cascades are initiated via second messengers (SM) that affect
ion channels or increase nitric oxide levels in the cytoplasm, and this
ultimately leads to a rapid physiological response without involving
gene regulation.
The ligand-independent pathway includes activation through
other signaling pathways, like growth factor signaling. In this case,
activated kinases phosphorylate ERs and thereby activate them to
dimerize, bind DNA, and regulate genes.
1) Morfogenesi della ghiandola mammaria:
L’accrescimento dei dotti della ghiandola mammaria dipende dalla
presenza dei recettori ERa in quanto non avviene in topi
knockout per questo recettore.
2) Gli effetti degli estrogeni sulla crescita neuronale sono
mediati da sostanze neurotrofiche quali il nerve growth factor
(NGF) e i suoi recettori nei neuroni colinergici, il Transforming
growth factor (TGF-b ) nell’ipotalamo, il brain-derived
neurotrophic factor (BDNF) nella corteccia cerebrale, i recettori
del Nerve growth factor (NGF) in neuroni sensori e dall’ insulinlike growth factor e i suoi recettori nell’ipotalamo.
3. Morfogenesi polmonare. I recettori per gli estrogeni giocano
un ruolo importante nella formazione di tessuto elastico.
Ruolo degli estrogeni nella crescita ossea
Figure 1
Summary of possible pathways for
androgens to regulate bone mass in
males. Experimental animal studies
using mouse models with inactivation of
the androgen receptor (AR), estrogen
receptor a (ERa), ERb or the recently
suggested ER GPR30 have
demonstrated that the AR and ERa,
but not ERb or GPR30, are involved
in the regulation of cortical and
trabecular bone in males.
ERa
activation resulted both
in preserving the
thickness and number
of trabeculae.
Antiestrogeni
The story of the development of tamoxifen as a pioneering medicine in cancer
treatment has its origins in two separate areas of research that converged almost by
accident, in the early 1970s.
The first research path, followed between 1900 and 1974, sought to understand why
only some of the women who developed breast cancer, responded to endocrine
therapies.
The second research path, which started in 1958, was unconnected to the first and
started with the chance discovery of nonsteroidal antioestrogens, in the
pharmaceutical industry.
SERMs
I modulatori selettivi dei recettori degli estrogeni (SERMs), quali il toremifene,
droloxifene and idoxifene) erano basati sulla struttura del tamoxifene.
Questi agenti non hanno mostrato nessun ulteriore beneficio rispetto al
tamoxifene ed hanno mostrato anche un’attività di parziale agonismo ed
alcuni studi hanno dimostrato una resistenza crociata tra i SERMs di prima
generazione.
Raloxifene ed arzoxifene rappresentano i SERMs di seconda generazione. Il
fulvestrant, rappresenta l’ultima generazione ed è un antagonista puro con
nessun effetto di parziale agonismo ed è utilizzato nel cancro alla mammella
avanzato in donne in post menopausa
Droloxifene
idoxifene
Usi terapeutici dei SERMS
Clomiphene citrate versus high doses of gonadotropins for in vitro fertilisation
in women with compromised ovarian reserve: a randomised controlled noninferiority trial
1 Paolo E Levi-Setti,2 Rubens Fadini,3 Claudio Brigante,4 Claudia Scarduelli,1 Federica Alagna,1 Veronica Arfuso,2 Mario Mignini-Renzini,3 Massimo
4
1
Candiani, Alessio Paffoni, and Edgardo Somigliana
Guido Ragni,
1
Background
The aim of the present randomised controlled non-inferiority trial is to test whether in women with
compromised ovarian reserve requiring in vitro fertilisation, a protocol of ovarian stimulation using
exclusively clomiphene citrate performs similarly to a regimen with high doses of gonadotropins.
Methods
Women with day 3 serum FSH > 12 IU/ml on at least two occasions or previous poor response to hyperstimulation were recruited at four Italian infertility units. Selected women were allocated to clomiphene
citrate 150 mg/day from day 3 to day 7 of the cycle (n=145) or to a short protocol with GnRH agonist 0.1
mg and recombinant FSH 450 IU daily (n=146). They were randomised by means of a computer-generated
list into two groups. The study was not blinded. The main outcome of the study was the delivery rate per
started cycle.
Results
The study was interrupted after the scheduled two years of recruitment before reaching the sample size.
148 women were allocated to clomiphene citrate and 156 to the short protocol with high doses of
gonadotropins; 124 and 125 participants were analysed in the groups, respectively. Women allocated to
high doses of gonadotropins retrieved more oocytes and had a higher probability to perform embryotransfer. However, the chances of success were similar. The delivery rate per started cycle in women
receiving clomiphene citrate and high-dose gonadotropins was 3% (n=5) and 5% (n=7), respectively
(p=0.77). The mean estimated cost per delivery in the two groups was 81,294 and 113,107 Euros,
respectively. No side-effects or adverse events were observed.
Conclusions
In women with compromised ovarian reserve selected for in vitro fertilisation, ovarian stimulation
with clomiphene citrate or high-dose gonadotropins led to similar chances of pregnancy but the
former is less expensive.
Progesterone
Il progesterone viene sintetizzato dal pregnenolone che a sua volta
è un prodotto del metabolismo del colesterolo
Espressione dei recettori per il progesterone
I recettori per il P4 sono presenti nelle cellule della granulosa e nelle cellule
del corpo luteo.
Il progesterone è il più importante progestinico nell’uomo. E’
sintetizzato nelle ovaie, nei testicoli e nelle ghiandole surrenali
a partire dal colesterolo. Grandi quantità sono anche
sintetizzate e rilasciate in circolo dalla placenta durante la
gravidanza. Nelle ovaie è prodotto principalmente dal corpo
luteo. Inoltre il progesterone serve come precursore nella
sintesi di estrogeni, androgeni e corticosteroidi.
Negli uomini vengono secreti da 1 a 5 mg di progeterone al
giorno. Le concentrazioni ematiche di progesterone nelle donne
è leggermente più alto nella fase luteale del ciclo mestruale.
Nella fase luteale e nel primo trimestre di gravidanza la donna
secerne dai 10 ai 20 mg al giorno di progesterone e molti di più
durante la parte finale del parto.
Nel plasma il progesterone è legato per il 90% all’albumina e
alla Corticosteroid Binding Globulin.
Gli effetti del progesterone sono:
1)
2)
3)
4)
5)
6)
Conversione di un endometrio proliferativo in un endometrio secretorio
Riduce l’efficacia del sistema immunitario
Diminuisce la contrattilità uterina
Produce un aumento della temperatura corporea durante l’ovulazione
Aumenta la proliferazione delle cellule epiteliali mammarie
La sua carenza insieme all’estradiolo produce osteoporosi
Ci sono evidenze negli ultimi anni che il progesterone (P4) abbia
potenti effetti neuroprotettivi e neurogenerativi a livello
dell’ippocampo e della corteccia cerebrale.
Uso:
1) Minacce di aborto
2) Miomi uterini
Il progesterone ha un effetto inibitorio sulla motilità delle tube
di fallopio riducendo la frequenza delle contrazionei nella
fase luteale. (Lindblom et al., 1980).
PROGESTINICI
Norethindrone
Levonorgestrel
Uso Progestinici
■KEY POINTS
-Hormonal contraceptives have a number of
noncontraceptive benefits, such as regulating
the menstrual cycle.
-The Pearl index is the number of unintended
pregnancies per 100 women per year. Rates
are 15% using male condoms, 8% with oral
contraceptives, 3% with depot
medroxyprogesterone acetate (Depo-Provera)
injections, and less than 1% with intrauterine
devices or female or male sterilization.
-Estrogen-containing products should be
avoided in patients with hypertension or who
are at risk of venousthromboembolism.
DOSAGGIO CONTRACCETTIVI
Enovid, the pill formulated by Dr. John Rock
and Dr. Gregory Pincus in the 1950s,
contained 150 μg of mestranol
(equivalent to 90 μg of ethinyl estradiol)
and 9.85 mg of norethynodrel, a very
potent progestin.
Our current oral contraceptive pills
contain much lower hormone doses and
have fewer androgenic side effects.
Pillola contraccettiva
Nomegestrol acetate-17b-estradiol for oral contraception
Anne Burke
Johns Hopkins University School of Medicine, Baltimore, MD, USA
Correspondence: Anne Burke, Johns Hopkins University School of Medicine, Bayview Medical Center, 4940 Eastern Ave, A-101,
Baltimore, MD 21224, USA Email [email protected]
Oral contraceptives remain a popular method of contraception over 50 years after their
introduction. While safe and effective for many women, the failure rate of oral
contraception is about 8%. Concerns about the risk of venous thromboembolism
continue to drive the search for the safest oral contraceptive formulations. The oral
contraceptive NOMAC-E2 contains nomegestrol acetate (NOMAC) 2.5 mg + 17b-estradiol
(E2) 1.5 mg. The approved dosing regimen is 24 days of active hormone, followed by a 4-day
hormone-free interval. NOMAC is a progestin derived from testosterone, which has high
bioavailability, rapid absorption, and a long half-life. Estradiol, though it has a lower
bioavailability, has been successfully combined with NOMAC in a monophasic oral
contraceptive. Two recently published randomized controlled trials demonstrate that NOMACE2 is an effective contraceptive, with a Pearl Index less than one pregnancy per 100
woman-years. The bleeding pattern on NOMAC-E2 is characterized by fewer
bleeding/spotting days, shorter withdrawal bleeds, and a higher incidence of amenorrhea than
the comparator oral contraceptive containing drospirenone and ethinyl estradiol. The adverse
event profile appears to be acceptable. Few severe adverse events were reported in the
randomized controlled trials. The most common adverse events were irregular bleeding,
acne, and weight gain. Preliminary studies suggest that NOMAC-E2 does not seem to have
negative effects on hemostatic and metabolic parameters. While no one oral contraceptive
formulation is likely to be the optimum choice for all women, NOMAC-E2 is a formulation with
effectiveness comparable with that of other oral contraceptives, and a reassuring safety
profile.
Meccanismo di azione della Pillola contraccettiva
Il feedback negativo indotto dai progestinici diminuiscono la
frequenza di rilascio del GnRH ipotalamico. Una riduzione di questo
ormone fa rilasciare meno FSH ed LH dall’ipofisi anteriore . Livelli
plasmatici ridotti di FSH non porteranno a maturazione del follicolo
con una ridotta produzione di estrogeni.
Il feedback negativo dei progestinici e la mancanza del feedback
positivo degli estrogeni sul rilascio di LH prevengono il picco di LH a
metà ciclo con mancata ovulazione.
Inoltre si osserva un muco cervicale più denso impedendo allo
sperma di risalire; si è osservato che la pillola contraccettiva inoltre
inibisce il trasporto dello sperma a livello delle tube.
Effetti collaterali pillola contraccettiva
Gli effetti collaterali più comuni sono : nausea, dolore alle mammelle,
cloasma (macchie di pelle scura nel volto) e occasionalmente effetti di
alterazione della sfera emotiva e funzione sessuale.
Un effetto collaterale pericoloso della pillola contraccettiva è il
tromboembolismo venoso che ha un’incidenza di 1-2 casi su 10.000 donne
ogni anno.
In donne che hanno ipertensione arteriosa e fumano tabacco, la pillola
contraccettiva aumenta in modo significativo l’incidenza di infarto del
miocardio e ictus cerebrale.
Changes in:
Other Common side effects:
Weight
Sexual desire
Vaginal discharge
Menstrual flow
Breast size
Blood pressure
Complexion (macchie di pelle scura)
Breakthrough bleeding
Nausea headaches
Urinary tract infection
Depression
Gum inflammation
Uso degli estrogeni nella terapia ormonale di rimpiazzo
Estrogeno coniugato
Estrogeni presenti
nella formulazione
Enjuvia
Rischi da trattamento con estrogeni nella HRT
Uso degli estrogeni nell’endometriosi
Novel oral contraceptive for heavy menstrual bleeding: estradiol valerate and
dienogest
Sally Rafie,1 Laura Borgelt,2 Erin R Koepf,3 Mary E Temple-Cooper,4 and K Joy
Lehman5
Abnormal uterine bleeding (AUB) is associated with significant direct medical costs and impacts both society
and the quality of life for individual women. Heavy menstrual bleeding, a subset of AUB, also
referred to as menorrhagia, is defined as menstrual blood loss greater than 80 mL or the
patient’s perception of excessive blood loss. The newest treatment option available is a
novel combination oral contraceptive product containing estradiol valerate (E2V) and
dienogest (DNG). As with other combination oral contraceptives, E2V/DNG works primarily by preventing
ovulation. However, in contrast with other combination oral contraceptives, it is the progestin component of
E2V/DNG that is responsible for endometrial stabilization. Use of E2V/DNG for six months has led to
significant reductions in heavy menstrual bleeding with an average 65% reduction in mean blood
loss. Approximately half of the women with heavy menstrual bleeding who received E2V/DNG for six months
demonstrated an 80% reduction in mean blood loss. Additionally, significant improvements in hematologic
indicators (ie, ferritin, hemoglobin, and hematocrit) have been shown. Based on its chemical properties,
E2V/DNG may have fewer adverse effects on lipid and glucose metabolism and reduced risk of
thromboembolic complications compared with other combination oral contraceptives. This has not yet been
shown in clinical trials and until then it should be assumed that E2V/DNG has a safety profile similar to other
combination oral contraceptives containing 35 μg or less of ethinyl estradiol. E2V/DNG has been compared
with another combination oral contraceptive in healthy women without heavy menstrual bleeding and
demonstrated improved bleeding patterns. E2V/DNG has not been compared with the levonorgestrel
intrauterine device or other treatments for heavy menstrual bleeding. When compared with some other
treatment options for AUB, E2V/DNG provides the added advantage of effective contraception.
Int J Womens Health. 2013; 5: 313–321.
Patient Prefer Adherence. 2013; 7: 777–785.
Role of the levonorgestrel intrauterine system in effective contraception
Abdelhamid M Attia,1 Magdy M Ibrahim,1 and Ahmed M Abou-Setta2
The levonorgestrel-releasing intrauterine system (LNG IUS) provides a long-acting,
highly effective, and reversible form of contraception, with a pearl index of 0.18 per
100 women-years. The locally released hormone leads to endometrial
concentrations that are 200–800 times those found after daily oral use and a
plasma level that is lower than that with other forms of levonorgestrel-containing
contraception. The contraceptive effect of the LNG IUS is achieved mainly through
its local suppressive effect on the endometrium, leading to endometrial thinning,
glandular atrophy, and stromal decidualization without affecting ovulation. The LNG
IUS is generally well tolerated. The main side effects are related to its androgenic
activity, which is usually mild and transient, resolving after the first few months.
Menstrual abnormalities are also common but well tolerated, and even become
desirable (eg, amenorrhea, hypomenorrhea, and oligomenorrhea) with proper
counseling of the patient during the choice of the method of contraception. The
satisfaction rates after 3 years of insertion are high, reaching between 77% and
94%. The local effect of the LNG IUS on the endometrium and low rates of
systemic adverse effects have led to its use in other conditions rather than
contraception, as for the treatment of endometrial hyperplasia, benign menorrhagia,
endometriosis, adenomyosis, and uterine fibroids.
Progestinici di sintesi
Progestins
Antiprogestins
OH
H3C
H
O
H
H3C
N
CH3
O
Norethindrone
[oral contraceptives]
O
Progesterone
[natural]
OH
CH3
Et
O
H3C
Et
O
RU486 (Mifepristone)
O
OAc
O
H3C
R5020
(Promegestone)
O
CH3
H3C
Medroxyprogesterone
Acetate (MPA)
[HRT]
N
CH3
OH
O
OH
Et
H
O
O
ORG2058
ZK98299
(Onapristone)
1993
2005
Pillola del giorno dopo
Il regime di trattamento Yuzpe (0.1 mg etinilestradiolo e 0.5 mg
levonorgestrel somministrato entro le 72 h del rapporto sesuale e ripetuta
dopo) è stato il più comune metodo usto nella contraccezione di
emergenza.
Altri metodi sono oggigiorno la somministrazione di levonorgestrel 0.75
mg, ripetuti dopo 12 h oppure in una singola dose di 1.5 mg, oppure una
singola dose di 10 mg di mifepristone detto anche RU486.
Emergency Contraception around the World:
Country
Availability
Ireland
Requires a visit to a doctor or familyplanning clinic
Russia
Requires a prescription
Spain
Requires a visit to the doctor
Canada
Consultation with a pharmacist
United Kingdom
Available OTC to women only 16 & older
Romania
Requires a medical prescription
Italy
Requires a medical prescription
Finland
Available without a prescription, but only
1 pack may be purchased at a time
United States
Available without prescription to men and
women 17 and older with no limitations
Plan B One-Step’s Adverse Reactions
Most Common Adverse Events
Plan B One-Step
N = 1,359 (%)
Heavier menstrual bleeding
30.9
Nausea
13.7
Lower abdominal pain
13.3
Fatigue
13.3
Headache
10.3
Dizziness
9.6
Breast tenderness
8.2
Delay of menses ( > 7 days)
4.5
ORMONE ANTIMULLERIANO