Progesterone in clinical practice

Progestogens in clinical practice Aboubakr Elnashar Benha university, Egypt
Aboubakr Elnashar

Contents
Progeterone, Progestagen, Progestins
Therapeutic uses of progestagens
Obstetrics
Gynecology Conclusion
Aboubakr Elnashar

Progeterone, Progestagen, Progestins If there is difference?
Aboubakr Elnashar

Progesterone
Secreted by: corpus luteum Placenta Adrenal cortex
Adrenal cortex: progesterone is an intermediate product in the formation of cortisol.
Adrenal cortex and the ovary: progesterone can be converted to androgens and oestrogens
Metabolised: rapidly by the liver
Excreted: 20% in the urine as sodium pregnanediol glucuronide.
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Progestogen
Compound with progesterone-like action
Produces progestational changes in an oestrogen-primed endometrium.
Transform a proliferative into a secretory endometrium to support pregnancy.
Natural or synthetic.
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Natural progestagens
Obtained:
primarily from: plant sources: soybeans and Mexican yam roots
occasionally from: animal ovaries. The hormone is not available from any natural source without extraction and synthesis
Forms:
oral
Intravaginal
Injectable
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Oral Micronized Progesterone.
Micronization
decreases particle size
enhances the dissolution
increase the half-life
reduce destruction in GIT (Peterson et al, 1995).
 improved bioavailability
Absorption: enhanced twofold when the hormone is taken with food.
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Micronized Vs synthetic progestins
Fewer side effects
No effect on mood (Sherwin et al, 1991)
No decrease HDL cholesterol levels (PEPI Trial, 1995)
Not adversely affect pregnancy outcome (Cornet et al, 1990). .
Micronized Vs injected progesterone: Maximal serum concentrations achieved more rapidly (Simon et al, 1993).
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Transvaginal Progesterone. :uterine effects with minimal systemic side effects (Fanchin et al, 1997).
One hour after application Four hours after application
Endometrial Diffusion: Targeted delivery : Micronised Vaginal Progesterone
Progressive diffusion of progesterone from the cervix to the fundus of the uterus Bulletti et al. Hum Reprod. 1997;12:1073.
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Synthetic Progestogens= Progestins
Pharmacologic effects
Differ from those of natural progesterone.
Androgenic effects: fluid retention reduction of HDL cholesterol levels headaches and mood disturbance
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Classification confusion.
 Based on time since market introduction: 1st 2nd 3rd 4th generation
 Based on structural derivation: Estranes Gonanes Pregnanes.
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Classification by structure
First
Second
Third
Estranes
Ethynodiol diacetate (with ethinyl estradiol: Demulen)
—
—
Norethindrone (Micronor)
Norethindrone acetate (Aygestin)
Gonanes
Norgestrel (Ovrette)
Levonorgestrel (Norplant; with ethinyl estradiol: Alesse, Nordette)
Desogestrel (with ethinyl estradiol: Desogen)
Gestodene
Norgestimate (with ethinyl estradiol: Ortho- Cyclen, Ortho Tri- Cyclen)
Pregnanes
Medroxyprogesterone acetate (Provera)
—
—
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Progesterone derivatives: 17α-oH progesterone caproate, medroxyprogesterone acetate, megestrol acetate chlormadinone acetate.
Stereoisomers of progesterone dydrogesterone.
Testosterone derivatives ethisterone dimethisterone.
19-norsteroids (nortestosterone derivatives) norethisterone norethisterone acetate Norethynodrel Allyloestrenol ethynodiol diacetate Dienogest: selective 19-nortestosterone
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Newer’ progestogens Desogestrel Gestodene Norgestimate Drosprinone
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Natural (micronized) progesterone
Fatigue
Somnolence
Synthetic progestins
Edema
Abdominal bloating
Anxiety
Irritability
Depression
Myalgia
Side Effects of Progestational Agents (Apgar and Greenberg, 2000)
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Synthetic progestogens (Romero and Stanczky, 2013)
should not be applied to natural progesterone
e.g. medroxyprogesterone acetate, norethindrone, and levonorgestrel
used as agents for contraception and hormone replacement.
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Therapeutic uses
I. Obstetrics
1.Threatened abortion
2.Recurrent abortion
3.PTL
II. Gynecology I. Disorders of Menstruation and Ovulation
1.Amenorrhoea
2.DUB
3.Spasmodic dysmenorhea
4.PMS
5.LPD II. LPS in ART III. Breast condition IV. HRT V. Endometriosis VI. Contraception VII. Cancer
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A. Obstetrics
1.Threatened abortion: Evidence of a reduction in the rate of spontaneous miscarriage with the use of progestogens compared to placebo or no treatment (risk ratio (RR) 0.53; 95% confidence interval (CI) 0.35 to 0.79). Cochrane Database Syst Rev. 2011 However, analysis was limited by:
1.small number and the poor methodological quality of studies (four studies)
2.small number of the participants (421): limit the power of the meta-analysis and hence of this conclusion
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2. Recurrent abortion: 3 or more consecutive miscarriages; four trials, 225 women Cochrane Database Syst Rev. 2013 Progestogen treatment showed a statistically significant decrease in miscarriage rate compared to placebo or no treatment (Peto OR 0.39; 95% CI 0.21 to 0.72). However, these four trials were of poorer methodological quality.
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3. Preterm labour Use of progestational agents results in a reduction of preterm deliveries and an increase in birth weight. Cochrane Database Syst Rev.2014 The use of a progestational agent may also reduce the frequency of uterine contractions, prolong pregnancy and attenuate the shortening of cervical length. However, the analysis was limited by the relatively small number of available studies. The power of the meta-analysis was also limited by the varying types, dosages and routes of administration of progesterone
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Vaginal progesterone reduced the incidence of PTL with a short cervix(Fonseca et al, 2007; Hassan et al, 2011) 17a OH P C did not. (Grobman et al, 2012) 17aOHPC reduced the incidence of PTL with a prior PTL (Meis et al, 2003); vaginal progesterone did not.(O’Brien et al, 2007)
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universal CL screening of singleton gestations without prior PTB for the prevention of PTB remains an object of debate.
cannot yet be universally mandated.
 reasonable, and can be considered by individual practitioners, following strict guidelines.
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B. Gynecology I. Disorders of Menstruation and Ovulation 1. Amenorrhoea:
Primary: Priming with oestrogen is essential.
2ndry: Progestogens may be given alone but are usually combined with oestrogen.
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2. Dysfunctional uterine bleeding:
Although used for all types of DUB, progestogens are chiefly indicated for anovulatory bleeding and correction of endometrial hyperplasia.
Oral progestogens given during the luteal phase only should not be used (NICE, 2009)
 D5-26 of the cycle
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3. Spasmodic dysmenorrhoea:
Progestogens combined with oestrogen: inhibit ovulation: relives pain.
Progestogens alone: decrease production of PGF2α and vasopressin: relieve primary dysmenorrhoea.
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4. Premenstrual syndrome:
The trials did not show that progesterone is an effective tt for PMS nor that it is not.
Neither trial distinguished a subgroup of women who benefited, nor examined claimed success with high doses Cochrane Database Syst Rev.2012
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5. Postponement or advancement of a menstrual period:
Postponement: COC (one or two pills daily), or Progestogen. Start 3-6 days before the expected onset of the period and continue until the crisis is over. The flow is expected 2 or 3 days after the tt is suspended.
Advancement start tt early in the cycle and to suppress ovulation. COC once daily from fifth day of the cycle and continued for 14 days. When it is suspended, menstruation (anovular) begin within 2 or 3 days
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6. luteal phase defect
No reliable methods to diagnose LPD
Midluteal serum progesterone between day 5-9 after ovulation <10 ng/ml
Progestin replacement has not been correlated with conception and tt decisions mostly are empiric
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II. Luteal phase support in ART
Necessary to optimize the outcome of ART
HCG is not superior to P, HCG increases OHSS
IM P has side effects: Painful, sterile abscess, allergic reaction (oil vehicle)*,needs to be administered by nurse (Lightman et al., 1999)
Oral P is inferior to IM or vag
Micronised vag P has solid evidence of effectiveness and convenience (Elenany et al, 2011)
Micronised P capsules are more cost effective than P gel: Gel is at least 4 times more expensive than Capsules
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Vaginal progesterone increases ENDOMETRIAL tissue levels (Fert.Steril, 2012)
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Intramuscular Progesterone is associated with the HIGHEST SERUM levels Fert.Steril, 2012
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For IDEAL LPS: IM P for the Highest Serum levels and Vaginal P for increasing the Endometrial levels, Until Placental progesterone production adequate, around week 8-10 w of gestation. (Fert.Steril, 2012)
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Start P from day of OR or ET
Minimum’ 14 days from the day of ET until the day of a positive HCG test. (Andersen et al., 2002)
‘Minimum’ 18 days following OR (Mochtar et al., 2006)
First trimester P supplementation may support early pregnancy through 7 ws by delaying miscarriage but does not improve LBR
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III. Breast Conditions 1 Fibrocystic disease
when other measures have failed.
American Board of obstetric and gynaecology guidelines.
After ruling out breast cancer the treatment is: reassurance, pain killers, primrose oil, vitamin E, Danazol, bromocriptine, diuretics and pyridoxine.
If no relief then progesterone therapy can be tried. The pain response and relief is charted by cardiff breast score.
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2 Premenstrual mastalgia when other measures have failed.
Reassurance, a thorough clinical examination ultrasound and mammography.
Supportive therapy helps like a good supporting Bra, low caffeine and mild anti-inflammatory drugs.
Hormone therapy in form of use of Progesterone, Bromocriptine,Tamoxifen, Danazol, Gestrinone, Lisuride Maleate, LHRH analogues and thyroid hormone have been tried.
Use of Evening primrose oil, Vit E and Diuretics may also help.
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IV. Hormone Replacement Therapy
In postmenopausal women
an intact uterus: administration of oestrogen must be accompanied by the administration of progestogens {prevent the development of endometrial hyperplasia and cancer}.
 Hysterectomised women. {The addition of progestagen to oestrogen may also potentiate its effect in correcting osteoporosis}.
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V. Endometriosis & pain (RCOG,2000) :
COC, progestagens, danazol & GnRHa: equal in relieve pain associated with E.
Prescribe the safest & cheapest.
COC, ideally administered continuously, should be considered as 1st line agents. (I-A)
Administration of progestin alone orally, IM, or SC may also be considered as 1st line therapy. (I-A)
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VI. Contraception: POP COC IUCD Injectables Subdermal implant
cervical mucus hostile to spermatozoa
endometrium unreceptive to a fertilised ovum, inhibit ovulation.
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VII. Pelvic Cancer Progestogens in large doses:
1.Endometrial carcinoma and its metastases {glandular exhaustion}: valuable adjuncts to surgery, especially for recurrent disease.
2.Adenocarcinoma of the vagina, tube and ovary, and for other types of malignant disease of the uterine corpus: less certain action
Aboubakr Elnashar

Progesterone in clinical practice

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Progesterone in clinical practice