Progesterone in

pregnancy
Dr Karuna SR MRH
• Introduction
• Role in menstrual cycle
• Action
• Classification
• Role in RPL
• Role in preterm birth
• Role in infertility management
• Role in medical abortion
• Role in contraception
Introduction
• Discovery and isolation- Professor Willard Allen and Professor
George Corners
• In Embryology laboratory
• As a substance in the corpus lutuem that sustained pregnancy
• Secreted primarily by
• Ovaries in females
• Testes in males
• Adrenal glands
• Brain and glial cells
• Precursor to hormones
• Estrogen
• Testosterone
• Adrenal hormones - cortisol and aldosterone
• No role in secondary sexual characteristics development at
puberty
• No great quantitative differences between men and women (at
least outside the luteal phase)
• Essential to maintain pregnancy
Chemistry
• C21H30O2 (Carbon 21, Hydrogen 30, Oxygen 2)
• Molecular weight 314.46g
• Derived from cholesterol.
• Hydrophobic
• Bioavailability - prolonged absorption
• Protein binding - 96%-99%
• Metabolism- hepatic to pregnanediols and pregnanolones
• Excretion renal
Levels of progesterone in the menstrual
cycle
Action of progesterone
• Progesterone’s physiological effects- amplified in the presence
of estrogen.
• increases the core temperature during ovulation
• Anti-inflammatory agent
• Converts endometrium to secretory stage for implantation.
• Prevents contractions of the uterus- maintain pregnancy
• Make cervical mucus- thick and impenetrable to sperms
• Reduces spasm and relaxes smooth muscle
• Reduces gall-bladder activity
• Contribute to development of thrombosis in the predisposed
• alveolobular development of the breast secretory apparatus
• prevent ovulation and reduce menstrual bleeding
• decreases SHBG and is responsible for acne and hirsutism
• Fat metabolism –
• Promotes fat deposition
• Decreases HDL
• Increases triglycerides
• No effect on LDL
• Carbohydrate metabolism –
• increases basal insulin levels
• increases insulin response to glucose,
• promotes glycogen storage (liver) and
• promotes ketogenesis
• Protein metabolism – no significant effect
Classification of progesterone
Generations of progestins :
Comparison

First Second Third Fourth

• Strong inhibitory action on • Lipid friendly • Analogue of
pituitary gonadotrophins • Potent spironolactone
• Strong Hemostatic activity antiovulatory • High affinity for
• effective contraceptives agents mineralocorticoid
receptor with
antimineralocorticoi
d properties
Pharmaco-dynamics
Pharmaco-kinetics
Preparations
Preparation Half life (t1/2 )
DMPA 2-3 days

Dydrogesterone 4-5 hrs

LNG 16 hrs

Gestodene 12-18hrs

Desogestrel 12 hrs

Norethindrone 8hrs
Natural progesterones

• Injuglansregia , progesterone has been detected

• Progesterone-like steroids are found indioscorea
mexicana plant, yam family native to mexico
• Contains steroid called ‘diosgenin’ that is taken from the
plant and is converted into progesterone
Advantages of natural progesterones:

• Well tolerated.
• Safe in pregnancy.
• Available in all routes of administration
• Improved bioavailability
• Typical ‘progesterone’ side effects of bloating, breast
tenderness, mood changes etc. Are less.
• No change in coagulation process or blood pressure
• Types and brand available
Micronized progesterone
• Natural progesterone
• Decreasing particle size increases absorption & bioavailability
• Dose dependent increase achieved
• To fully protect endometrium- 300mg/day in divided doses is
required.
• Maximum absorption after food than on empty stomach
• Short acting- needs multiple doses
• Lipid friendly
• Suitable for treatment of LPD, DUB, HRT, premenstrual syndrome and
for progesterone challenge test
Safety of progesterone
Side effects:
• Injectable progestogens- injection site reactions and urticaria
• Vaginal progesterone gel- vaginal discharge in 8-9%
• Other- sleepiness, fatigue, headaches and gastrointestinal
disturbances are more with oral preparations than with vaginal
and oral sustained release preparations
Risk of congenital malformations
• No virilisation of female fetus has been found
• Only concern- possible increased risk of hypospadias in male
offspring exposed to exogenous progestins, even if real, however,
this risk is limited to exposure prior to 11 weeks of gestation
Progesterone and preterm birth
 March 2012
1. Singleton gestations, no prior PTB and short CL 20mm at 24 weeks- vaginal
progesterone, (90-mg gel or 200-mg suppository)- reduction in PTB and perinatal
morbidity and mortality
2. Universal CL screening of singleton gestations without prior PTB for prevention of
PTB -object of debate
3. Singleton gestations with prior PTB 20-36 6/7 weeks, 17-alpha-hydroxy-
progesterone caproate 250 mg intramuscularly weekly, preferably starting at 16-20
weeks until 36 weeks, is recommended.
4. Not associated with prevention of PTB in women who have in the current
pregnancy multiple gestations, preterm labor, or preterm premature rupture of
• Double blind randomized placebo controlled trial
• Involved 1228 women with singleton pregnancies at risk for preterm birth
because of a positive fetal fibronectin test, a history of spontaneous
preterm birth at 34 weeks of gestation or earlier, or a cervical length 25 mm
or less.
• randomized to use vaginal progesterone 200 mg daily from 22 to 24 weeks
through to 34 weeks of gestation or placebo.
• Progesterone had no significant effect on either the obstetric or childhood
 2016
OPPTIMUM studied 1197 women
1. Inclusion criteria- broad
2. Randomised at 22–24 weeks of gestation
3. Trial has been broadly described as a negative one.
4. No significant reduction in the composite primary outcomes was
identified
5. Vaginal progesterone associated with a significant reduction in
neonatal death (odds ratio OR 0.17; 95% confidence interval, 0.49)
95% ci 0. And Neo brain injury (OR 0.50; 95% 0.84). Ci 0.
 VAGINAL PROGESTERONE IS AS EFFECTIVE
AS CERVICAL CERCLAGE TO PREVENT PRETERM
BIRTH IN WOMEN WITH A SINGLETON
GESTATION, PREVIOUS SPONTANEOUS
PRETERM BIRTH AND A SHORT CERVIX:
UPDATED INDIRECT COMPARISON META-
24 March 2018
ANALYSIS

• Updated systematic review and adjusted indirect comparison meta-

analysis
• Primary outcomes were preterm birth <35 weeks of gestation and
perinatal mortality
• Vaginal progesterone and cerclage are equally effective.
• The choice of treatment will depend on adverse events and cost-
effectiveness of interventions, and patient/physician’s preferences.
 November 2018.

• Searched Medline, EMBASE, CINAHL, Cochrane CENTRAL, and Web of

Science up to 1 January 2018.
• Included 40 trials (11 311 women)
• Vaginal progesterone was the only intervention with consistent
effectiveness for preventing preterm birth in singleton at-risk pregnancies
overall and in those with a previous preterm birth.
 MARCH 2017

• Affirm use of vaginal progesterone to prevent PTB in women with

a sonographically short cervix of 20mm without a history of a
prior spontaneous PTB
• Recommend continuation of 17OHP-C in women with a history of
a prior spontaneous PTB throughout the pregnancy despite the
development of cervical shortening (with or without cervical
cerclage placement)
Progesterone and threatened abortion/
RPL
• Multicenter, double-blind, placebo-controlled, randomized trial
• Vaginal suppositories- 400 mg of micronized progesterone or
matched placebo after a positive UPT (and no later than 6
weeks) through 12 weeks
• NO STATISTICALLY SIGNIFICANT BENEFIT OF PROGESTERONE
OVER PLACEBO
Treatment efficacy for idiopathic recurrent
pregnancy loss – a systematic review and
meta-analysis- AOGS
• Systematic review- 21 RCTs
• Took these into consideration:
• acetylsalicylic acid
• low-molecular-weight heparin
• progesterone
• intravenous immunoglobulin
• leukocyte immune therapy
• Literature does not allow advice on any specific treatment for idiopathic
recurrent pregnancy loss, with the exception of progesterone from ovulation
• Conclusion : any treatment for RPL should be used within the context of a
RCT
Progesterone and ART pregnancies
Luteal phase support
• Necessary to optimize the results
• Supplementary administration of HCG brings no advantage
when progesterone is administered
• Support with HCG brings an increased risk, as compared with
progesterone, of OHSS
• At present, insufficient data are available for a direct
comparison of i.M. With vaginal progesterone
Use of vaginal suppositories as luteal phase support significantly
improved clinical pregnancy rates in controlled ovarian stimulation
and intrauterine insemination in patients with unexplained or mild
male factor infertility
Medical termination of pregnancy
Mifepristone :
• Selective progesterone receptor modulator- synthetic steroid
• Competitive receptor antagonist of progesterone receptor
• In early pregnancy- decidual breakdown by blockade of uterine
progesterone receptors- detachment of blastocyst- decrease in
corpus luteum secretion of progesterone
• Oral route- rapidly absorbed
• Plasma t1/2- 20-40 hours
• Metabolised in liver
• Teratogenicity –
• One case mentioned sirenomelia
• Complete lack of amniotic sac
• No fetal stomach, gall bladder or urinary tract
Recommendedmifepristone plus
misoprostol regimens(WHO 2012)

Upto 7 400 mg misoprostol

weeks
Upto 9 200 mg mifepristone + 800 mcg misoprostol
weeks vaginally/ sublingually/ buccally after 24-48
hours
Progesterone and contraception
Mechanism of action
highly effective contraceptives
1. The progestin suppresses the luteinizing hormone (LH)
surge necessary for ovulation.
2. sustained release prolonged effect on the cervical mucus.
3. The progestin suppresses the estradiol -induced cyclic
maturation of the endometrium atrophy prevents
implantation.
Generations of OCPs
• 1 generation OCPs :Products containing progestins norethynodrel,
st

norethindrone, norethindrone acetate, or ethynodiol acetate 50 mg or

more of ethinyl estradiol.eg ovral G

• Second-Generation Oral Contraceptives :Products containing

levonorgestrel, norgestimate, and other members of the norethindrone
family + 20 to 35 mg ethinyl estradiol. Eg Ovral L

• Third-Generation Oral Contraceptives: Products containing desogestrel or

gestodene+ 20 to 30 mg ethinyl estradiol.eg novelon

• Fourth-Generation Oral Contraceptives: Products containing drospirenone,

dienogest, or nomegestrol acetate. Eg yasmin
 Long-Acting reversible
Contraception(LARC)
Contraceptive implants Depot-
medroxyprogesterone
acetate (depo-provera).
Systems with the sustained release of a Not a “sustained-release”
progestin, coated with a compound to prevent system .
fibrosis
1. Implanon/nexplanon(68 mg of etonogestrel)
2. Norplant(levonorgestrel 6X36)
3. Jadelle/ norplant-2(chinese version is
called sinoplant II)(levonorgestrel 2X75)
3rd generation The Hormone-Releasing IUD

LNG-IUS/ levonorgestrel-releasing intrauterine system/

Mirena:
MEC WHO Guidelines
1 A condition for which there is no
restriction for the use of the
contraceptive method
2 A condition where the advantages of
using the method generally outweigh
the theoretical or proven risks
3 A condition where the theoretical or
proven risks usually outweigh the
advantages of using the method.
4 A condition which represents an
unacceptable health risk if the
contraceptive method is used
Use method in any
circumstances
Generally use the method
Use of method not usually
recommended unless other
more appropriate methods
are not available or not
acceptable
Method not to be used
Postpartum COC POP DMPA LNG implants
Breastfeeding
a) < 6 weeks postpartum 4 2 2 2
b) ≥ 6 weeks to < 6 months 3 1 1 1
(primarily breastfeeding)
c) ≥ 6 months postpartum 2 1 1 1
Non-breastfeeding women
a) < 21 days 1 1 1
With or without other risk factors for
VTE
b) ≥ 21 days to 42 days 1 1 1
With or without other risk factors for
VTE
c) > 42 days 1 1 1
 COC POP DMPA LNG implants
H/O high BP during 2 2 2 2
pregnancy
Valvular heart disease 2 2 2 2
uncomplicated
Valvular heart disease 4 4 4 4
complicated
SLE
A)POSITIVE APLA 4 4 4 4
B)thrombocytopenia/ 2 2 2 2
immunosuppressive therapy
GTN 1 1 1 1
H/O GDM 1 1 1 1
Thank you
• NEWER CONCEPTS:
• 1. Advances in the prevention of spontaneous preterm birth (SPTB) with 17-OHP can be made if
women most likely to respond to 17-OHP can be identified prospectively by genotype and if an
appropriate individualized prevention regimen can be outlined. If this strategy is applied to
nulliparous women with other risk factors for preterm birth (such as a personal history of mullerian
anomalies or a family history of preterm birth), those women with a high-risk genotypecould be
studied to determine whether treatment with 17-OHP during their first pregnancy could reduce the
risk of primary SPTB. There are 8 genes in the nitric oxide synthase pathway with different allele
frequencies between responders and nonresponders; including SPTA2, GA2L2, DMD,SYNE1,NOS1,
MICA2, SMTL2, and DESP. (41)
• 2. There is rising evidence that PCOS is a leading cause of cervical incompetence and PPROM.
Progesterone supplementation prevents onset of miscarriage and PTL in these pts., but doesn’t
replace the role of cerclage in patients with short cervix. (42)
• 3. There are studies which show that altered calcium homeostasis leads to cell death in chorion and
decidual cell of fetal membranes especially in PPROM and Progesterone offers protective role by
decreasing Calcium influx through voltage gated Ca channels(