Use of progesterone in obstetrics & gynaecology namkha presents

USE OF PROGESTERONE
IN OBSTETRICS
&
GYNAECOLOGY
Dr Namkha Dorji
Resident
Department of Obstetrics & Gynecology
Bangabandhu Sheikh Mujib Medical University
Progesterone has the chemical formula C21H30O2.

A LITTLE BIT OF HISTORY
• Progesterone was first isolated from hamster ovaries by
Willard Myron Allen, who co-discovered it with his
anatomy professor, George Washington Corner, at the
University of Rochester Medical School.
• Allen first determined its melting point, molecular
weight, and partial molecular structure.
• He also gave it the name Progesterone, derived from
PROGEstational STERoidal ketONE.
• An avid mathematician, Allen recognized that the
molecular weight of progesterone is 100 x π = 314 dalt.

NATURAL PROGESTERONE
 Progesterone (21 carbon steroid) is derived from
cholesterol
 It was first isolated in 1929
 Males also produce 1-5mg progesterone per day from
adrenals and testes [but role in males is not known]

PROGESTERONE
Secreted by:
Corpus luteum
Placenta: from 2nd trimester till term
Adrenal cortex
Adrenal Cortex: progesterone is an intermediate product
in the formation of cortisol
Adrenal cortex & ovary: Progesterone can be converted to
androgens & estrogens
Metabolised rapidly by the liver
Excreted: 20% in the urine as sodium pregnanediol
glucuronide

PROGESTOGEN
 Compound with progesterone like action
 Produces progestational changes in an
estrogen primed endometrium
 Transform a proliferative into a secretary
endometrium to support pregnancy

NATURAL
OR
SYNTHETIC (progestin)
Progestogens can be either

Classification of Progestogens
Progesterone Derivatives Progesterone Contents
I. Progesterone Natural Progesterone
II. Pregnane progestogens
They don’t alter carbohydrate
metabolism
•17 α hydroxy progesterone caproate
•Medroxyprogesterone acetate
•Chlormanidone acetate
•Cyproterone acetate
III. Norpregnone progestoens •Normegestrol acetate
•Gestonorone caproate
IV. Steroisomer of progesterone:
Retroprogesterone
They don’t inhibit ovulation
Dydrogesterone
(DUPHASTON®)
V. 19 norprogesterone derivative
(norpregnanes)
•Demegestone
•Promegestone
•Nestorone
•Trimegestone

CONTINUATION
VI. Alkyl derivatives of
19 nortestosterone
A. Estrone steroids
They alter carbohydrate metabolism
slightly. Metabolically, they are converted
into norethisterone
•Norethisterone
•Norethisterone acetate
•Norethynodrel
•Ethynodiol diacetate
•Lynestrenol
•Norgestrol
B. Gonane steroid
They have excellent contraceptive
efficacy and cycle control. Side effects
are less. They are more potent than
estrone steroids
•Levonorgestrol
•Desogestrol
•Etonogestrol(3ketodesoestrol)
•Gestodine
•Norgestimate
•Norelgestromim
•Dienogest
VII. Spironolactone derivatives Drospirenone
VIII. Unsaturated 19 norsteroid Gestrinone

PHYSIOLOGICAL & PHARMACOLOGICAL
ACTIONS
• Endocrine system low level(+Estrogen)>FSH surge & LH
secretion. High level-> Inhibit GnRH production(Inhibit
ovulation).
• Reproductive Tract decreases estrogen-driven endometrial
proliferation development of a secretory endometrium 
abrupt decline  onset of menstruation.
• Endocervical glands secretion turn to scant, viscid
material.
• Secondary sex organs  imp for maintenance of
pregnancy suppresses menstruation and uterine
contractility

• Mammary Gland. Development requires both estrogen &
progesterone.
• During pregnancy acting with estrogen, brings
proliferation of the acini of the mammary gland. Toward
the end of pregnancyacini fill with secretions & vasculature
of the gland increases
• After the levels of estrogen and progesterone decrease at
parturition does lactation begin.
• Under influence of progesterone mitotic activity in the
breast epithelium is very low in the follicular phase and then
peaks in the luteal phase .

CNS EFFECTS.
• During a normal menstrual cycle, an increase in basal body
temperature of about 0.6°C (1°F) at mid-cycle correlates
with ovulation.
• Progesterone also increases the ventilatory response of the
respiratory center to CO2 and leads to reduced arterial and
alveolar PCO2 in the luteal phase of the menstrual cycle
and during pregnancy.
• Progesterone may have depressant and hypnotic actions in
the CNS, possibly accounting for reports of drowsiness
after hormone administration.

METABOLIC EFFECTS
• Progesterone  increases basal insulin levels & the rise in
insulin after carbohydrate ingestion, but it does not normally
alter glucose tolerance.
• Long-term administration of more potent progestins
decrease glucose tolerance.
• Progesterone stimulates lipoprotein lipase activity and
seems to enhance fat deposition.
• Progesterone & analogs (MPA) increase LDL & no/little
reductions in HDL levels.

• 19-norprogestins (androgenic activity) effects on plasma
lipids
• Micronized progesterone does not significantly affect
beneficial estrogen effects on either HDL or LDL profiles
• Progesterone diminish effects of aldosterone in the renal
tubule and cause a decrease in Na+ reabsorption 
increase mineralocorticoid secretion from the adrenal
cortex

MECHANISM OF ACTION
• Single gene encodes two isoforms of the
progesterone receptor (PR): PR-A and PR-B.
The first 164 N-terminal amino acids of PR-B
are missing from PR-A.
• The ratios of the individual isoforms vary in
reproductive tissues as a consequence of tissue
type, developmental status, and hormone levels.
• Both PR-A and PR-B have AF-1 and AF-2
transactivation domains, but the longer PR-B
also contains an additional AF-3 that contributes
to its cell- and promoter-specific activity.

• Ligand-binding domains  PR isoforms are identical.
• In the absence of ligand, PR is present in the nucleus in an
inactive monomeric state bound to heat-shock proteins
(HSP-90, HSP-70, and p59).
• Binding progesterone, HSPs dissociate  receptors are
phosphorylated  form dimers (homo- and heterodimers)
that bind with high selectivity to PREs (progesterone
response elements) located on target genes

• Transcriptional activation by PR occurs primarily via recruitment of
co-activators such as SRC-1, NcoA-1, or NcoA-2.
• The receptor-co-activator complex then favors further interactions
with additional proteins such as CBP and p300, which have histone
acetylase activity remodeling of chromatin  increases the
accessibility of general transcriptional proteins, including RNA
polymerase II, to the target promoter.
• Progesterone antagonists also facilitate receptor dimerization and
DNA binding, but conformation of antagonist-bound PR is different
from that of agonist-bound PR.
• This different conformation favors PR interaction with co-repressors
such as NcoR/SMRT, which recruit histone deacetylasesincreases
DNA interaction with nucleosomes and renders a target promoter
inaccessible to the general transcription apparatus.

• In most cells, PR-B mediates the stimulatory activities of
progesterone; PR-A strongly inhibits this action of PR-B and
is also a transcriptional inhibitor of other steroid receptors.
• PR-A antiproliferative effect
• PR-B mediating hormone effects in the mammary gland .
• Progesterone increased Ca2+ mobilization in sperm
(membrane-bound progesterone receptors).  spermatozoa
and oocyte maturation .

MECHANISM OF ACTION
• PR nucleus of target cell(Female genital tract, breast, CNS
Pituitary)
• P binding the PR undergoes DIAMERIZATION
• Attaches to Progesteron Response Element(PRE) of target
gene.
• Regulates transcription through co-activators

ABSORPTION, FATE, AND EXCRETION
• Rapid first-pass metabolism
• IN PLASMA, bound by albumin and corticosteroid-binding
globulin.
• Elimination half-life 5 minutes eliminated in the urine
• 19-nor steroids have good oral activity  ethinyl substituent at
C17  slows hepatic metabolism
• Synthetic progestins longer half-lives (7 -24 Hrs)

INDICATIONS IN OBSTETRICS
• Threatened abortion
• Recurrent abortion
• Preterm Labour

INDICATIONS IN GYNAECOLOGY
• Disorders of menstruation & ovulation
1. Amenorrhoea
2. DUB
3. Spasmodic dysmenorrhoea
4. PMS
5. LPD
• LPS in ART
• HRT
• Endometriosis
• Contraception
• Cancer & Breast condition

ROUTES OFADMINISTRATION
• Oral
• Vaginal suppositories
• Deep intramuscular injections
• Implant
• Intrauterine system

SIDE EFFECTS OF PROGESTATIONALAGENT
• Natural(micronized) progesterone
Fatigue
Somnolence
• Synthetic progestins
Acne
Alopecia Anxiety
Hirsutism Depression
Hoarse voice Myalgia
Fluid retention Oedema
Abdominal bloating

CONTRAINDICATION (BNF 50th edition)
 Liver tumours & severe liver impairment
 Genital or breast cancer: unless used for treatment
 Severe arterial disease
 Undiagnosed vaginal bleeding
 Porphyria
 History during pregnancy of idiopathic jaundice, severe
pruritus, or pemhigoid gestationis
 Missed or incomplete abortion
 Hypersensitivity

CAUTIONS
 Condition that may worsen fluid retention (epilepsy,
hypertension, migraine, cardiac or renal dysfunction)
 Susceptible to thromboembolism
 Liver impairment
 History of depression
 Progesterone decrease glucose tolerance & diabetes
should be monitored closely

DATA ON PROGESTERONE AND PRETERM
LABOUR
Many studies have examined the use of progesterone for
prevention of preterm labour. Mackenzie et al. found 735
such studies, which showed that the use of progestins in
women at risk for preterm labour reduced its occurrence
by 43%
Mackenzie R, Walker M, Armson, A, Hannah, ME. Progesterone for the prevention of preterm birth among women at increased risk: a systematic review and meta-
analysis of randomized controlled trials. Am J Obstet Gynecol 2006;194(5):1234–42.

Meta-analyses by Dodd et al. concluded that women who
received progesterone were statistically significantly less
likely to give birth before 37 weeks (RR 0.58; 95% CI 0.48–0.70), to
have an infant with birth weight of > 2.5 kg (RR 0.62; 95% CI
0.49–0.78), or to have an infant diagnosed with
intraventricular hemorrhage (RR 0.25; 95% CI 0.08–0.82). Their
analysis showed no apparent benefit to early start of the
progesterone administration or in the use of higher doses.
Dodd JM, Flenady V, Cincotta R, Crowther CA. Prenatal administration of progesterone for preventing preterm birth. Cochrane Database Syst Rev 2006;1:CD004947

PRETERM LABOUR(SOGC TECHNICAL UPDATE NO. 202, JAN 2008)
 Lack of available data for many neonatal outcome variables and
about the lack of comparative data on dosing and route of
administration.
 Indication for prophylactic progesterone therapy : Previous
spontaneous preterm labour and/or short cervix (< 15 mm at 22–
26 weeks’ gestation) on transvaginal ultrasound.
 The therapy should be started after 20 weeks’ gestation and
stopped when the risk of prematurity is low.
 Following dosages:
 History of previous PTL: 17 alpha-hydroxyprogesterone 250 mg
IM weekly or progesterone 100 mg daily vaginally.
 Short cervix of <15 mm detected on transvaginal ultrasound at
22–26 weeks: progesterone 200 mg daily vaginally.
Farine, Dan, et al. "The use of progesterone for prevention of preterm birth." Journal of Obstetrics and Gynaecology Canada 30.1 (2008): 67-71.

PROGESTOGEN FOR TREATING THREATENED
MISCARRIAGE.
The use of progestogens is effective in the treatment of
threatened miscarriage with no evidence of increased rates of
pregnancy-induced hypertension or antepartum haemorrhage
as harmful effects to the mother, nor increased occurrence of
congenital abnormalities on the newborn.
However, the analysis was limited by the small number and the
poor methodological quality of eligible studies (four studies)
and the small number of the participants (421), which limit the
power of the meta-analysis and hence of this conclusion.
Cochrane Database Syst Rev. 2011 Dec 7;(12):

A RANDOMIZED TRIAL OF
PROGESTERONE IN WOMEN WITH
RECURRENT MISCARRIAGES(PROMISE
TRIAL)
This large multicenter, randomized, placebo-controlled
trial showed that progesterone therapy in the first
trimester of pregnancy did not result in a significant
increase in the rate of live births among women with a
history of unexplained recurrent miscarriages.
Coomarasamy, Arri, et al. "A randomized trial of progesterone in women with recurrent miscarriages." New England Journal of Medicine 373.22 (2015): 2141-2148.

PROGESTOGEN FOR PREVENTING
MISCARRIAGE (REVIEW)
 Subgroup analysis of four trials, 225 women: recurrent
miscarriages (three or more consecutive miscarriages)
 Progestogen treatment showed a statistically significant
decrease in miscarriage rate compared to placebo or no
treatment
 Poorer methodological quality.
 No significant differences in the rates of preterm birth, neonatal
death, or fetal genital anomalies/virilization were found
between progestogen therapy versus placebo/control
Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD003511.

HORMONES & MENSTRUAL CYCLE
Estrogen levels
increases gradually
during the follicular
phase and fall just
before ovulation
Estrogen levels
maintained during
the luteal phase and
fall before the
menstrual phase
Progesterone levels
increase during the
luteal phase and fall
sharply just before
the menstrual
phase.

AMENORRHOEA
Primary Secondary
Priming with oestrogen is
essential
Progesterone may be given
alone but is usually
combined with estrogen

DYSFUNCTIONAL UTERINE BLEEDING: FIRST
LINE TREATMENT
Progestogens are the first-line treatment for DUB, particularly
when associated with anovulation. There is no significant
difference among various types of progestogens with regard to
effectiveness in treating DUB. However, some believe that
medroxyprogesterone is associated with less unfavourable
effects on blood lipids

 Anovulation results in continuous unopposed oestrogen
stimulation of the endometrium. In cases of chronic anovulation
disorders, particularly polycystic ovary syndrome (PCOS), the
use of progestogens is helpful for treating DUB as well as
preventing the development of endometrial hyperplasia and
serious complications such as endometrial carcinoma
 May be delivered through progesterone-containing IUDs and
contraceptive implants.

SECOND LINE THERAPY
• Combined oestrogen & progestogen: when progestogen alone is not
associated with an adequate response
• Formulations: monophasic pill or triphasic pill
• Combined oestrogen and progestogen is effective in restoring menstrual
bleeding (withdrawal bleeding) in most cases of DUB whether
anovulatory or ovulatory. Sometimes higher doses are needed initially, for
example, 2 or 3 pills every day during the first few days until bleeding
stops.
• In addition to cycle regulation, this approach has the advantage of also
offering effective contraception
• Continuous administration of the COCP is licensed for up to 3
consecutive months with withdrawal bleeding at the end of the 3 months
of treatment. This approach is particularly beneficial in those with DUB-
associated anaemia.

PRMARY DYSMENORRHEA
• First line: Most patients with primary dysmenorrhea show
subjective improvement with NSAID treatment(64 to 100%).
• Second line: OCP provides another effective and well-studied
choice for therapy, especially in women desiring birth
control(effective in about 90%).
• Non responder (10%): laparoscopic surgery to acupuncture,
although with much less evidence to support their use.
• lack of pain relief should increase suspicion of a secondary
cause of dysmenorrhea.

PREMENSTRAL SYNDROME
“A condition which manifests with distressing physical,
behavioural and psychological symptoms, in the absence
of organic or underlying psychiatric disease, which
regularly recurs during the luteal phase of each menstrual
(ovarian) cycle and which disappears or significantly
regresses by the end of menstruation”

POSSIBLE TREATMENT REGIMEN FOR
THE MANAGEMENT OF SEVERE PMS
First Line Exercise, cognitive behavioural therapy, vitamin B6
Combined new-generation pill, such as Yasmin®, Cilest® (cyclically
or continuously)
Continuous or luteal phase (day 15–28) low-dose SSRIs
Second Line Estradiol patches (100 micrograms) + oral progestogen such
as
duphaston 10 mg D17-D28 or Mirena®
Higher-dose SSRIs continuously or luteal phase
Third Line GnRH analogues + addback HRT (continuous combined
estrogen
+ progestogen or tibolone)
Fourth Line Total abdominal hysterectomy and bilateral oophorectomy + HRT
(including testosterone)
RCOG Green-top Guideline No. 48
drospirenone and ethinyl estradiol Yasmin®

PREMENSTRUAL SYNDOME
• Newer contraceptive pill types may represent effective
treatment for PMS and should be considered as one of the
first-line pharmaceutical interventions.
• Treatment with the lowest possible dose of progestogen is
recommended to minimise adverse effects.
The National Association for Premenstrual
Syndrome
(Guidelines on Premenstrual Syndraome)
RCOG Green-top Guideline No. 48

POSTPONEMENT OR ADVANCMENT OF
MENSTRUATION
Postponement Advancement
COC (1 or 2 pills daily) or
progestogens
Start 3-6 days before the
expected onset of period and
continue until the crisis is
over.
Flow is expected 2-3 days
after the treatment is
suspended.
Start treatment early in the
cycle to suppress ovulation.
COC once daily from D5 &
continue for 14 days.
When suspended, flow
(anovular) begin in 2 to 3 days.

• Supplementation of progesterone can be given orally, vaginally, or
by the intramuscular (IM) route.
• Currently, there is no evidence that progesterone is beneficial in
natural unstimulated cycles.
• Currently, the only well documented indication for supplemental
vaginal or IM progesterone is for the improvement of ART
outcomes in GnRH agonist or antagonist stimulation cycles.
• Intramuscular progesterone is associated with the highest serum
levels, and vaginal progesterone increases endometrial tissue
levels.

• It has been agreed that oral progesterone should not be used
for luteal support; only 10% of micronized progesterone is
absorbed intact through the gastrointestinal tract, and
pregnancy rates are lower in ART cycles in which oral
progesterone is administered compared with those in which
vaginal or IM progesterone is used.
• Progesterone supplementation should be administered until
placental progesterone production is adequate, around 8–10
weeks of gestation

Use of progesterone in obstetrics & gynaecology namkha presents

Suppression of ovarian function for 6 months reduces endometriosis-
associated pain.
The hormonal drugs investigated (combined oral contraceptives, danazol,
gestrinone,medroxyprogesterone acetate and GnRH agonists) are equally
effective but their adverse effect and cost profiles differ.
Some adverse effects limit their long-term use and often
produce poor compliance.
Symptom recurrence is common following medical treatment of
endometriosis.
Evidence suggests that the LNG-IUS reduces endometriosis-associated
pain with symptom control maintained over 3 years

ENDOMETRIAL HYPERPLASIA
Hyperplasia without atypia
Revised 2014 World Health Organization
classification

HYERLASIA WITHOUT ATYPIA
• Risk of progressing to endometrial cancer <5% over 20 years
• Majority will regress spontaneously during follow-up.
• Reversible risk factors such as obesity and the use of HRT should be
identified and addressed if possible.
• Observation alone with follow-up endometrial biopsies to ensure disease
regression can be considered,
• Treatment with progestogens has a higher disease regression rate
compared with observation alone.
• Progestogen is indicated in who fail to regress following observation
alone and in symptomatic women with abnormal uterine bleeding.
Green-top Guideline No. 67
RCOG/BSGE Joint Guideline | February 2016

• Both continuous oral and local intrauterine (levonorgestrel-
releasing intrauterine system [LNG-IUS]) progestogens are
effective in achieving regression of endometrial hyperplasia
without atypia.
• The LNG-IUS should be the first-line medical treatment
• Continuous progestogens should be used
medroxyprogesterone 10–20 mg/day or norethisterone
10–15 mg/day) decline the LNG-IUS.
• Cyclical progestogens should not be used
• Duration: 6 months to 5 years
Green-top Guideline No. 67
RCOG/BSGE Joint Guideline | February 2016

CONTRACEPTION
• POP
• COCP
• Injectables
• Subdermal implants
• LNG IUS
Mechanism:
1. Inhibit ovulation
2. Cervical mucus hostile to spermatozoa
3. Endometrium unreceptive to fertilized ovum

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