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PROGESTERONE Supplementation - Epithelial Delivery (Transdermal, Vaginal, Rectal)

PROGESTERONE Supplementation

Epithelial Delivery Method  (Using hormonal cream/gel)

 (Epithelial tissue forms the covering or lining of all internal and external body surfaces)




(PROGESTERONE cream applied externally to skin)


      Delivered transdermally, PROGESTERONE enters 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 Hormones);


      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 PROGESTERONE cream long-term can have excessively elevated levels of this hormone - 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.


      Application areas


-       Neck, arms, chest, legs, stomach


-       Scrotal Route  (for delivery to the prostate gland in men)


         A World Intellectual Property Organization patent (WO2005079317) describes the successful absorption of PROGESTERONE 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. After the 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.” 




Epithelial delivery via vaginA (for  women) or rectuM (for men or women)


      Avoids hormonal build-up in fat cells - This improvement to PROGESTERONE 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.




Vaginal delivery (for  women)


      Vaginal PROGESTERONE is the preferred method of supplementation for women - particularly when uterine effects need to be maximized or blood concentrations minimized to limit side effects. PROGESTERONE as 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 PROGESTERONE delivery 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


          Hormones 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

Vaginal Plexus


      There seems to be a preferential distribution of PROGESTERONE to the uterus following vaginal administration – Studies strongly suggest a direct local “portal’ vagina-to-uterus transport of PROGESTERONE. This phenomenon was found to  involve the vascular system and confirmed the existence of the so-called “first uterine pass effect”.


Cicinelli E, Cignarelli M, Sabatelli S, Romano F, Schonauer LM, Padovano R, Einer-Jensen N. 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. Fertil Steril. 1998 Mar;69(3):471-3. [PubMed]


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.

Transvaginal PROGESTERONE: evidence for a new functional “portal system” flowing from the vagina to the uterus, Human Reprod 1999, Vol 5, No4 pp365-372   



      Vaginal PROGESTERONE administration 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 - PROGESTERONE 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 Invest 2004;58:105-108.

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 1993;60:573-575.

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 Jan;10(1):4-7.



-       Studies showing that vaginal PROGESTERONE resulted in low serum levels, but efficacious endometrial concentrations since PROGESTERONE is absorbed locally, it does not permit high plasma levels of PROGESTERONE, it therefore has less undesirable systemic effects.


         Vaginal gel dose used in the luteal phase at 45mg every 48 hours resulted in low serum PROGESTERONE  but endometrial efficacy was unhampered - also, serum PROGESTERONE does not predict effects of vaginal PROGESTERONE on endometrium 

Fanchin R, De Ziegler D, Bergeron C, Righini C, Torrisi C, Frydman R. Transvaginal administration of PROGESTERONE. Obstet Gynecol. 1997 Sep;90(3):396-401.[PubMed]


         Miles and coworkers also demonstrated that vaginal administration led to lower serum and higher endometrium PROGESTERONE concentrations compared to measurements after I.M. delivery.

Miles RA, Paulson RJ, Lobo RA, Press MF, Dahmoush L, 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 serum PROGESTERONE  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: ) Vaginal PROGESTERONE delivery has been shown as effective as intramuscular injections for raising endometrial levels and maintaining pregnancy

Gibbons WE, Toner JP, Hamacher P, Kolm P. Experience with a novel vaginal PROGESTERONE preparation in a donor oocyte program.Fertil Steril. 1998 Jan;69(1):96-101. [PubMed]


-       Vaginal PROGESTERONE absorption may be influenced by the degree of vaginal mucosa estrogen content after estrogen treatment

Villanueva B, Casper RF, Yen SS. Intravaginal administration of PROGESTERONE: enhanced absorption after estrogen treatment. Fertil Steril. 1981 Apr;35(4):433-7. [PubMed]


-       Vaginal PROGESTERONE absorption may be influenced by the type of the formulation used:


         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 PROGESTERONE the highest.

Price JH, Ismail H, Gorwill RH, Sarda IR.Effect of the suppository base on PROGESTERONE delivery from the vagina.Fertil Steril. 1983 Apr;39(4):490-3 [PubMed]


         PROGESTERONE particle size - Micronized PROGESTERONE in non-liquefying cream showed promise for a goal of a single daily application

 Kimzey LM, Gumowski J, Merriam GR, Grimes GJ Jr, Nelson LM. Absorption of micronized PROGESTERONE from a nonliquefying vaginal cream. Fertil Steril. 1991 Nov;56(5):995-6.[PubMed]


-       Vaginal PROGESTERONE delivery has been successful for HRT for various conditions (Warren et al 1999, including menopause (de Zeigler et al, 1999)



      High PROGESTERONE concentration at uterine level has advantages when supplementing PROGESTERONE for luteal phase support (E.g. for pregnancy or HRT) - which has the goal of inducing adequate endometrial secretory transformation. Before ovulation, PROGESTERONE 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 -  PROGESTERONE  may:


(i)     Act in favor of implantation as a permissive factor in a certain range of concentration




(ii)    Block implantation when its concentrations are lower or higher than cut-off values


Villanueva B, Casper RF, Yen SS. Intravaginal administration of progesterone: enhanced absorption after estrogen treatment. Fertil Steril. 1981 Apr;35(4):433-7. [PubMed]

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.

Penzias AS, Alpcr MM. Luteal support with vaginal micronized PROGESTERONE gel in assisted reproduction. Reprod Biomed Online 2003;6:287-295. [PubMed]

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. [PubMed]

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. [PubMed]


-       Vaginal PROGESTERONE Is Equally Effective In Achieving Pregnancy Outcomes As Injectable PROGESTERONE In Donor Egg Cycles – 105 recipients 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)

Bourgain C, Devroey P, Van Waesberghe L, Smitz J, Van Steirteghem AC, Effects of natural PROGESTERONE on the morphology of the endometrium in patients with primary ovarian failure. Hum Reprod. 1990 Jul;5(5):537-43. [PubMed]

Artini PG, Volpe A, Angioni S, Galassi MC, Battaglia C, Genazzani AR. A comparative, randomized study of three different PROGESTERONE support of the luteal phase following IVF/ET program. J Endocrinol Invest. 1995 Jan;18(1):51-6. [PubMed]




Rectal route (for men and women)


      Men (and women) 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 micronized PROGESTERONE 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 micronized PROGESTERONE.

Chakmakjian ZH, Zachariah NY. Bioavailability of PROGESTERONE with different modes of administration. J Reprod Med 1987;32:443- 448. [PubMed]


      Rectal PROGESTERONE administration has wide range of absorbability


-       Blood drainage 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.

Ritschel WA. Targeting in the gastrointestinal tract: new approaches. Methods Find Exp CUn Pharmacol 1991;13:313-336. [PubMed]


-       However, 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 administration.

de Boer AG, Moolcnaar F, de Lecdc LG, Breimcr DD. Rectal drug administration: clinical pharmacokinetic considerations. Clin Pharmacokinct 1982;7:285-311. [PubMed]



      Drawbacks of rectal drug administration - include defecation affecting absorption, and lack of patient acceptability.


      Form of rectal administration is by using suppositories/pessaries





Related Links:


PROGESTERONE – “Precursor to Androgens, Estrogens and Corticoids”

 Production in the body

 Levels in the body

Estrogens and PROGESTERONE in Lifestage Events


 Functions in the body


BPH / Prostate Cancer

Conception and Pregnancy

Body/Mind Hormonal Balance

Osteoporis / Bone Building

Thyroid Function / Fat-burning

Traumatic Brain Injury



How to supplement PROGESTERONE

Before considering PROGESTERONE supplementation

 Bioidentical PROGESTERONE

  What to Look For in a Bioidentical PROGESTERONE Cream or Gel

  Delivery Method Choices



      Epithelial:      Transdermal,   Vaginal,  Rectal

      Intramuscular (I.M.) Injection

 Supplementation to aid conception / prevent miscarriage with Luteal Phase Deficiency (LTD)






Hormones Links


HORMONES- Related Links:


Hormones 101 – “Feel Good, Look Good”

Chart of Human Hormones

Testing Hormone Levels

 > Take Hormone Test

 Synthetic Hormones

        – “Frankenstein Version of Natural Hormones”

Balance Adrenal "Stress Managment" Glands  


5-HTP – “SSRI Alternative”

SEROTONIN – “Mood Hormone”

MELATONIN – “Darkness Hormone”

 > The Biological Clock

T3 and T4  - “Thyroid Hormones (Triiodothyronine and Thyroxine)”

HISTAMINE – “Inflammatory Response Hormone”

Fight or Flight Catecholamines:


DOPAMINE –  “Go Get it! /Reward Hormone” 


Low Dose Naltrexone (LDN)  - “For auto immune disease, cancer, AIDS, COPD and the common cold”

FSH, LH and GnRH

PROLACTIN – “Cool Down Hormone”

INSULIN – “Blood Sugar Uptake”,  GLUCAGON, IGF

LEPTIN – “Curb appetite / Burn Fat”

GHRELIN – “Hunger Hormone”


Steroid Hormones

Steroid enzymes affecting Steroid Production /Activity 


 CORTISOL – “Stress Hormone”


ALDOSTERONE – “Water Retentive Hormone”

Sex Steroid Hormones

Sex Steroid Hormones

Sex hormone-binding carriers

Estrogens – “Predominantly Female Sex Hormones”



PROGESTERONE – “Precursor to Androgens, Estrogens and Corticoids”

Estrogens and PROGESTERONE in Lifestage Events

Androgens -"Predominately Males Sex Hormone"


Vitamin D - The Sunshine Vitamin

  CALCITRIOL (active form)

  CALCIDIOL (circulating form)

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