PROGESTERONE Supplementation - Epithelial Delivery (Transdermal, Vaginal, Rectal)
Method (Using hormonal cream/gel)
tissue forms the covering or lining of all
internal and external body surfaces)
cream applied externally to skin)
Delivered transdermally, PROGESTERONE
the blood stream fully bio-available
(i.e. not bound to protein in serum) - PROGESTERONE
is absorbed through the epithelial tissue of the skin and into the bloodstream
without passing through the liver.
The increase in PROGESTERONE is very apparent
in saliva testing (a serum test will show little or no change, since blood tests
do not accurately reflect body’s PROGESTERONE
status. See: Testing for
Dermal fatigue from long-term skin application -
Used in the short-term,
the transdermal method has been employed for the past several years with much
success. HOWEVER, a problem, identified
as “dermal fatigue”, has become apparent with its long-term use . Being
fat-soluble, fat cells in the skin store the hormone, which is fine at first,
since fat stores are low. Unfortunately, after a few weeks of applying cream to skin, the skin tissue
fat cells become saturated with PROGESTERONE
(or any other steroid hormone used), which results in disruptions to adrenal
hormones, such as DHEA,
CORTISOL and TESTOSTERONE.
This not only stops the effectiveness
of the hormone, it may even make symptoms worse.
Users of transdermal
long-term can have excessively elevated levels of this
those with excessively high
PROGESTERONE levels from using transdermal
supplementation may need to go off the cream for up to two years, to allow the
excess PROGESTERONE to leave their body.
Neck, arms, chest, legs, stomach
delivery to the prostate gland in
A World Intellectual Property Organization
describes the successful absorption of
through the scrotal membranes using substances
(polyethylene glycols or peptide/fatty acid complexes)
to enhance absorption
“Permeation rate enhancers allow for rapid
absorption of the PROGESTERONE composition
across the scrotal sac, after which the lipophilic
PROGESTERONE hormone is stored in adipose cells.
PROGESTERONE hormone reaches a saturation level in the adipose cells, it
diffuses into the circulatory system for eventual uptake by the prostate gland.
The present invention therefore can deliver a sustained effective dosage amount
of PROGESTERONE to the prostate gland.”
delivery via vaginA
Avoids hormonal build-up in fat cells -
This improvement to
delivery method avoids the hormonal build-up in fat cells that occurs
with the transdermal method. Dr. Jonothon Wright, another pioneer in
bioidentical hormone supplementation (in addition to the now deceased Dr. John
Lee), uses this method in his clinics.
preferred method of supplementation for
particularly when uterine effects need to be maximized or blood concentrations
minimized to limit side effects.
gel, suppositories or cream is applied to the mucous epithelial membrane lining
the vagina. This delivery method avoids
“first-pass” liver metabolism problems of oral delivery
Vaginal route mimics ovarian
into blood stream - ideally, a woman wants to mimic the way
pre-menstrual ovaries get hormones
directly into the blood stream.
The ovaries are in the pelvis, and have direct
access to the blood stream via a pelvic plexus of veins
absorbed through the vaginal membranes also enter the same pelvic plexus of
veins emptied into by the ovaries - Hormones
are then transported to the heart and lungs and distributed to your tissues just
as if your ovary had actually produced them.
Vaginal application closely
mimics the body’s own hormonal delivery system
There seems to be a preferential distribution of
to the uterus following vaginal administration –
Studies strongly suggest a direct local “portal’ vagina-to-uterus transport of
phenomenon was found to involve the
vascular system and confirmed the existence of the so-called “first uterine pass
Plasma concentrations of PROGESTERONE are higher in the uterine artery than in
the radial artery after vaginal administration of micronized PROGESTERONE in an oil-based solution to postmenopausal women.
The lymphatic system of the upper part of
the vagina, being in direct communication with the lymph vessels of the uterus
may also represent a potential route for direct passage to the uterus of
substances applied to the vagina.
PROGESTERONE: evidence for a new functional “portal system” flowing from the
vagina to the uterus, Human Reprod 1999, Vol 5, No4 pp365-372
results in a high concentration at the
local uterine/endometrial level, despite generally lower plasma levels
than transdermal or intergluteal routes
“First Uterine Pass
Effect” - The vaginal route is a better choice if the uterus /endometrium is the
target area -
has a direct impact on the uterus before entering circulation
(the so-called first uterine pass effect).
Von Eye Corleta H, Capp E, Cardoso Ferreira MB.
Pharmacokinetics of natural PROGESTERONE vaginal suppository. Gynecol Obstet
Alam V, Vega M, Risquez F. Luteal phase support. Reprod
Biomed Online 2001;3:250-262.
Weckstein LN, Jacobson A, Galen D, Hampton K, Ivani K,
Andres J. Improvement of pregnancy rates with oocytes donation in older
recipients with the addition of PROGESTERONE vaginal suppositories. Fertl Steril
Maddocks S, Hahn P, Moller F, Reid RL. A double-blind
placebo- controlled trial of PROGESTERONE vaginal suppositories in the treatment
of premenstrual syndrome. Am J Obstet Gynecol 1986;154:573- 581.
de Ziegler D.
Hormonal control of endometrial receptivity.
Hum Reprod. 1995
Studies showing that
resulted in low serum levels, but
endometrial concentrations – since PROGESTERONE
is absorbed locally, it does not permit high plasma levels of
it therefore has less undesirable
Vaginal gel dose used in the luteal phase at 45mg
every 48 hours resulted in low serum PROGESTERONE
but endometrial efficacy was unhampered
does not predict effects of vaginal
De Ziegler D,
administration of PROGESTERONE.
Miles and coworkers also demonstrated that
vaginal administration led to lower serum and higher endometrium
PROGESTERONE concentrations compared to
measurements after I.M. delivery.
Sauer MV. Pharmacokinetics and endometrial tissue levels of progesterone
after administration by intramuscular and vaginal routes: a comparative study.
Fertil Steril. 1994 Sep;62(3):485-90. [PubMed]
Gibbons and coworkers compared vaginal
and PROGESTERONE delivery in women
undergoing egg-donor programs, with higher mean
in I.M. group - All subjects in both groups had an endometrial histology that was “in
phase” (meaning the 4 phases, menstrual, proliferative, secretory, and
pre-menstrual, of the menstrual cycle were on schedule: )
delivery has been shown as effective as
intramuscular injections for raising endometrial levels and maintaining
Experience with a novel vaginal PROGESTERONE preparation in a donor oocyte
program.Fertil Steril. 1998 Jan;69(1):96-101. [PubMed]
absorption may be influenced by the degree of
vaginal mucosa estrogen content after estrogen treatment
administration of PROGESTERONE: enhanced absorption after estrogen treatment.
absorption may be influenced by the type of the
Different bases of suppositories –
tests on glycerinated gelatin, cocoa butter and
polyethylene glycol found that they all raised levels above baseline for the
same duration, but polyethylene glycol
raised the mean peak level of circulating
of the suppository base on PROGESTERONE delivery from the vagina.Fertil Steril. 1983 Apr;39(4):490-3
particle size -
non-liquefying cream showed promise for a goal of a single daily application
Grimes GJ Jr,
Absorption of micronized PROGESTERONE from a nonliquefying vaginal cream.
delivery has been successful for HRT for various
(Warren et al 1999, including menopause (de Zeigler et al, 1999)
concentration at uterine
level has advantages when supplementing
for luteal phase support
(E.g. for pregnancy or HRT) - which has the goal of inducing adequate
endometrial secretory transformation. Before
levels in a woman's body remain relatively low, but rise after ovulation during
the latter part of a woman's menstrual cycle which is called the luteal phase.
The luteal phase begins with the production of
PROGESTERONE and ends with either pregnancy or menstruation, when
the uterus sheds its lining. During pregnancy,
PROGESTERONE helps to maintain the lining of the uterus,
providing necessary nutrients to support and nurture a fertilized egg.
For pregnancy, the dose
amount and timing is crucial -
Act in favor of implantation as a permissive
factor in a certain range of concentration
implantation when its concentrations are lower or higher than cut-off values
Yen SS. Intravaginal administration of progesterone: enhanced absorption
after estrogen treatment.
Fertil Steril. 1981 Apr;35(4):433-7.
Erny R, Simoncini C, Chastclliere N, de Lignres B.
Variation de la progesterone plasmatiquc induites par l’administration vaginale
d’Utrogcstan. J Gynecol Biol Reprod 1989; 18:229-234.
E.g. Some of the first contraceptives
used a high dose of
PROGESTERONE. The timing of the dose should lend support to the natural
luteal phase. Penzias et al used Crinone 8%, a vaginal gel containing 90 mg
micronized PROGESTERONE in a polycarbophil
base, to support luteal phase to support pregnancy after IVF, with rates
comparable to intramuscular administration or vaginal suppositories.
Alpcr MM. Luteal support with vaginal micronized PROGESTERONE gel in assisted
reproduction. Reprod Biomed Online 2003;6:287-295.
Anserini P, Costa M, Remorgida V, Sarli R, Guglielminetti
E, Ragni N. Luteal phase support in assisted reproductive cycles using cither
vaginal (Crinonc 8) or intramuscular (Prontogcst) PROGESTERONE: results of a
prospective randomized study. Minerva Ginecol 2001;53:297-301.
Lightman A, KoI S, Itskovitz-Eldor J. A prospective
randomized study comparing intramuscular with intravaginal natural PROGESTERONE
in programmed thaw cycles. Hum Reprod 1999; 14:2596- 2599.
Is Equally Effective In Achieving Pregnancy Outcomes As
In Donor Egg Cycles –
at Boston IVF treated with vaginal PROGESTERONE
achieved a 58.1% pregnancy rate and a 51.4% delivery rate, versus a 53.3%
pregnancy rate (p=0.503) and a 48.3% delivery rate (p=0.689) for patients
receiving intragluteal PROGESTERONE.
[Med News Today,
16 Apr 2008]
Commonly used in many
countries for luteal support in reproduction-assisted therapies -
E.g. for IVF (In vitro fertilization)
Van Waesberghe L,
Van Steirteghem AC,
Effects of natural
PROGESTERONE on the morphology of the endometrium in patients with primary
Hum Reprod. 1990 Jul;5(5):537-43.
randomized study of three different PROGESTERONE support of the luteal phase
following IVF/ET program.
J Endocrinol Invest. 1995 Jan;18(1):51-6.
(for men and
can administer hormone creams via the rectum -
which has a similar mucosal epithelial
surface to the vagina, to avoid the aforementioned complications. Chakmakjian et
al found that rectal administration of
in normally menstruating women (during the follicular phase) yielded increased
under-the-curve areas of serum
PROGESTERONE compared to doses of sublingual, oral or vaginal
Chakmakjian ZH, Zachariah NY.
Bioavailability of PROGESTERONE with different modes of administration. J Reprod
Med 1987;32:443- 448. [PubMed]
administration has wide range of absorbability
from the lower end of the rectum is
directly into systemic circulation via the vena cava –
Drainage is via both venous blood capillaries and lymphatic vessels. When an
active component is absorbed in the
lower portion of the rectum (via the inferior hemorrhoidal veins) it
reaches the general circulation directly -
bypassing the hepatic first-pass elimination.
WA. Targeting in the
gastrointestinal tract: new approaches. Methods Find Exp CUn Pharmacol
if the compounds are absorbed by the
upper part of the rectum
(superior rectal ampulla)
they will reach
the portal circulation
(via the superior hemorrhoidal vein) – and thus
the liver gets the “first pass” at the
PROGESTERONE with the inherent problems seen in oral
de Boer AG, Moolcnaar F, de Lecdc LG, Breimcr DD. Rectal
drug administration: clinical pharmacokinetic considerations. Clin Pharmacokinct
Drawbacks of rectal drug administration - include defecation affecting absorption, and lack
of patient acceptability.
Form of rectal administration is by using