Percutaneous administration of progesterone

[Guest guest]

Thought this was interesting, so passing along!Kam

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When monitoring hormone levels while on transdermal replacement therpapy serum testing is not accurate. This is because once absorbed through the skin hormones bind to red blood cell membranes in the blood in order to minimise unfavorable interactions with the aqueous water and the fat loving hormones. Once your blood sample is taken it is centrifuged and the red blood cells along with the hormones are removed prior to analysis. This phenomenon was described by Z. Stanczyk (see references) for transdermal progesterone but it also seems to occur to a lesser extent for all other hormones. Serum tests show no increase in progestreone levels after weeks of applying progesterone cream whereas saliva tests show an increase only after a couple of hours! This is a significant problem monitoring levels if you are using transdermal hormone creams. To illustrate this problem further clinical trials performed by the American Academy of Anti-Aging on over 300 patients revealed that every patient whose hormone levels were deemed at optimal levels by serum blood tests had in actual fact excessive levels based on saliva tests. The doses used to achieve optimal serum levels were higher than standard physiological doses which was all that was required to achieve optimal levels by saliva tests. In every case the patients doses were reduced until saliva tests reflected optimal levels. In our own practice we see this same phenomena on a regular basis with those patients being monitored by serum blood tests – that is their current doses are too high!

The facts are there has never been a single study correlating serum values for topically administered hormones to actual tissue levels or to long term effectiveness. Most mainstream physicians have accepted serum testing as the “gold standard†without any science which is based on some false assumptions. You should never use serum testing for judging effectiveness or hormone levels from topical application - Stanzyck’s article proves this for progesterone and clinical observation sees it occuring with most other hormones as well.

http://www.custommedicine.com.au/hormone-analysis/

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Percutaneous administration of progesterone: blood levels and endometrial protection

Stanczyk, Z. PhD; son, J. MD; Roy, Subir MD

Abstract

There is controversy about the beneficial effects of topical progesterone creams used by postmenopausal women. A major concern is that serum progesterone levels achieved with progesterone creams are too low to have a secretory effect on the endometrium. However, antiproliferative effects on the endometrium have been demonstrated with progesterone creams when circulating levels of progesterone are low. Thus, effects of topical progesterone creams on the endometrium should not be based on serum progesterone levels, but on histologic examination of the endometrium. Despite the low serum progesterone levels achieved with the creams, salivary progesterone levels are very high, indicating that progesterone levels in serum do not necessarily reflect those in tissues. The mechanism by which the serum progesterone levels remain low is not known. However, one explanation is that after absorption through the skin, the lipophilic ingredients of creams, including progesterone, may have a preference for saturating the fatty layer below the dermis. Because there appears to be rapid uptake and release of steroids by red blood cells passing through capillaries, these cells may play an important role in transporting progesterone to salivary glands and other tissues. In contrast to progesterone creams, progesterone gels are water-soluble and appear to enter the microcirculation rapidly, thus giving rise to elevated serum progesterone levels with progesterone doses comparable to those used in creams.

http://journals.lww.com/menopausejournal/Abstract/2005/12020/Percutaneous_administration_of_progesterone__blood.19.aspx

Very extensive info here. You can see the list of reactions. Also talks about things that increase clearance of P. I believe this site lifted this from a site that requires a password and likely a subscription fee. I couldn't find another version for free.

Check out the list of adverse effects. I got anaphylaxis response from P. No allergies in my life until on P. I'd get a sudden sting near my lip and suddenly half my face would be swollen. Never experienced such a thing until exogenous P.

Laurelhttp://healthandprostate.com/index.php/drugs/progesterone

(British Approved Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Synonyms: Corpus Luteum Hormone; Luteal Hormone; Luteine; Luteohormone; NSC-9704;Pregnenedione; Progesteron; Progesterona; Progesteronas; Progesteroni; Progesteronum; Progeszteron

BAN: Progesterone

INN: Progesterone [rINN (en)]

INN: Progesterona [rINN (es)]

INN: Progestérone [rINN (fr)]

INN: Progesteronum [rINN (la)]

INN: ПрогеÑтерон [rINN (ru)]

Chemical name: Pregn-4-ene-3,20-dione

Molecular formula: C21H30O2 =314.5

CAS: 57-83-0

ATC code: G03DA04

Read code: y07kn; y07ko

Pharmacopoeias. In China, Europe, International, Japan, US.

European Pharmacopoeia, 6th ed. (Progesterone). Awhite or almost white crystalline powder or colourless crystals. It exhibits polymorphism. Practically insoluble in water freely soluble in dehydrated alcohol sparingly soluble in acetone and in fatty oils. Protect from light.

The United States Pharmacopeia 31, 2008 (Progesterone). A white or creamy-white, odourless, crystalline powder. Practically insoluble in water soluble in alcohol, in acetone, and in dioxan sparingly soluble in vegetable oils. Store in airtight containers at a temperature of 25°, excursions permitted between 15° and 30°. Protect from light.

Adverse Effects

Progesterone and the progestogens may cause gastrointestinal disturbances, changes in appetite or weight, fluid retention, oedema, acne, chloasma (melasma), allergic skin rashes, urticaria, mental depression, breast changes including discomfort or occasionally gynaecomastia, changes in libido, hair loss, hirsutism, fatigue, drowsiness or insomnia, fever, headache, premenstrual syndrome-like symptoms, and altered menstrual cycles or irregular menstrual bleeding. Anaphylaxis or anaphylactoid reactions may occur rarely. Alterations in the serum lipid profile may occur, and rarely alterations in liver-function tests and jaundice. Pain, diarrhoea, and flatulence have followed rectal use. Injection-site reactions have followed parenteral use.

Adverse effects vary depending on the dose and type of progestogen. For example, androgenic effects such as acne and hirsutism are more likely to occur with nor-testosterone derivatives such as norethisterone and norgestrel. These derivatives may also be more likely to adversely affect serum lipids. Conversely, adverse effects on serum lipids appear less likely with gestodene and desogestrel, but these 2drugs have been associated with a higher incidence of thromboembolism than norethisterone and norgestrel when used in combined oral contraceptives. High doses of progestogens such as those used in treating cancer have also been associated with thromboembolism. For a discussion of the effect of progestogens on the cardiovascular risk profile of menopausal HRT. Breakthrough uterine bleeding is more common with oral progestogen-only contraceptives than when progestogens are used for menstrual irregularities or as part of menopausal HRT.

Some progestogens when given during pregnancy have been reported to cause virilisation of a female fetus. This appears to have been associated with those progestogens with more pronounced androgenic activity such as norethisterone the natural progestogenic hormone progesterone and its derivatives such as dydrogesterone and medroxyprogesterone do not appear to have been associated with such effects. For the adverse effects of progestogens when administered either alone or with oestrogens as contraceptives. For those ofmenopausal HRT.

Carcinogenicity. In a cohort study of women aged 40 to 64 years, the premenopausal use of oral progestogens alone, mainly for benign breast, uterine, and ovarian conditions, and irregular menstruation, was not associated with an increased risk of breast cancer. However, the data did suggest that there was an increased risk for current users of progestogens for longer than 4.5 years (relative risk 1.44, 95% confidence interval 1.03 to 2.00) compared with women who had never used progestogens. Limitations of this study included the lack of analysis of different progestogens or a record of the reasons for progestogentreatment.

Effects on the skin. Auto-immune progesterone dermatitis includes reactions such as eczema, urticaria, and angioedema that usually begin 3 to 10 days before the onset of menstrual flow and end 1 to 2 days into menses, which correlates with raised endogenous progesterone concentrations during the luteal phase of the menstrual cycle. The onset of the condition can be as early as menarche, and many women have never been exposed to exogenous progesterone, but it has also occurred in women with a history of oral contraceptive use. Management has been based on the suppression of endogenous progesterone secretion and oral contraceptives are usually tried first, although they appear to have limited success possibly because of the progestogen component. Other drugs that have been used include corticosteroids, conjugated oestrogens, gonadorelin analogues, androgens, and tamoxifen, but all have significant adverse effects associated with long-term use. Bilateral oophorectomy has been used in severe cases, when drug therapy has been unsuccessful.

A woman with a history of auto-immune progesterone dermatitis developed pruritic, pink, oedematous plaques and macules on the upper thighs, axillae, and buttocks after the use of vaginal progestogen gel during infertility treatment. The reaction was managed with topical corticosteroids. In another woman, with a history of chronic urticaria exacerbated by progesterone, the use of progesterone and various other progestogens as a component of HRT after oophorectomy caused urticaria and angioedema.Desensitisation using micronised progesterone was successful in this case.

Precautions

Progesterone and the progestogens should be used with caution in patients with hypertension, cardiac or renal impairment, asthma, epilepsy, and migraine, or other conditions which may be aggravated by fluid retention. Progestogens can decrease glucose tolerance and diabetic patients should be carefully monitored. They should also be used with care in persons with a history of depression. High doses should be used with caution in patients susceptible to thromboembolism. Progesterone and the progestogens should not be given to patients with undiagnosed vaginal bleeding, nor to those with a history or current high risk of arterial disease and should generally be avoided in hepatic impairment, especially if severe. Unless progestogens are being used as part of the management of breast or genital-tract carcinoma they should not be given to patients with these conditions.

Although progestogens have been given as hormonal support during early pregnancy such use is not now generally advised. However, the use of a progesterone-type progestogen might still be considered for women who are progesterone-deficient. Such use may prevent spontaneous evacuation of a dead fetus, therefore careful monitoring of pregnancy is required. Progestogens should not be used diagnostically for pregnancy testing and should not be given in missed or incomplete abortion.

For precautions to be observed when progestogens are used as contraceptives, see p.2065. For those to be observed when progestogens are used in preparations for menopausal HRT.

Abuse. A case report of abuse of and dependency on progesterone.

Breast feeding. A large study compared a contraceptive progesterone-releasing vaginal ring and a copper IUD for 1 year in breast-feeding women. There was little difference in infant weight gain during the study, although at 12 months the infants of mothers using the IUD were breast-fed less frequently, receiving more supplementary feeding, and were heavier. There was no adverse effect of progesterone on lactation or infant growth. Further smaller studies have also found no adverse effect on lactation or infant growth. The American Academy of Pediatrics has found no reports of adverse effects in breast-fed infants of mothers given progesterone, and therefore considers it to be usually compatible with breast feeding.

Porphyria. Progesterone and progestogens have been associated with acute attacks of porphyria and are considered unsafe in patients with porphyria (but medroxyprogesterone has been used with buserelin to suppress premenstrual exacerbations of porphyria). Progestogens should generally be avoided by all women with porphyria however, where non-hormonal contraception is inappropriate, progestogens may be used with extreme caution if the potential benefit outweighs the risk. The risk of an acute attack is greatest in women who have had a previous attack or are under 30 years of age. Long-acting progestogen preparations should never be used in those at risk.

Pregnancy. In Hungary, where 30% of all pregnant women were given hormonal support therapy with progestogens during the early 1980s, a case-control study suggested that there was a causal relationship between such treatment and hypospadias in their offspring. Mixed results have been reported in other studies of the association between maternal progestogen use and the risk of hypospadias, but the indications and types of progestogens used in early pregnancy have also changed over time (for example, withdrawal bleeding induced by progestogens as a form of pregnancy testing is no longer used, and progestogen luteal support in early pregnancy is no longer recommended for routine use see also Miscarriage, below). Nevertheless, results from a more recent case-control study of deliveries between October 1997 and December 2000 suggested an increase in risk of at least twofold.

There have also been reports of nongenital malformations, including limb reduction defects, neural tube defects, and congenital heart malformations, following intra-uterine exposure to progestogens in early pregnancy. However, numerous analyses of accumulated data have found no evidence of a recognisable malformation syndrome.

For details of individual case reports, see Pregnancy under Dydrogesterone, Hydroxyprogesterone, Norethisterone, and Noretynodrel. For the effects of hormonal contraceptive use during early pregnancy. For the risk of ectopic pregnancy with progestogen-only contraceptives.

Veterinary use. An FAO/WHO expert committee examining the risks from residue of veterinary drugs in foodstuffs established an acceptable daily intake for progesterone, but concluded that there would be no need to specify a numerical maximum residue limit for progesterone in the edible tissues of cattle when products are used as growth promotors according to good practice. However, it should be noted that in the EU the use of ster-oidal hormones such as progestogens in veterinary practice is restricted, and their use as growth promotors is banned.

Interactions

Enzyme-inducing drugs such as carbamazepine, griseofulvin, phenobarbital, phenytoin, and rifampicin may enhance the clearance of progesterone and the progestogens. These interactions are likely to reduce the efficacy of progestogen-only contraceptives, and additional or alternative contraceptive measures are recommended.

Aminoglutethimide markedly reduces the plasma concentrations of medroxyprogesterone acetate andmegestrol, possibly through a hepatic enzyme-inducing effect an increase in progestogen dose is likely to be required.

Since progesterone and other progestogens can influence diabetic control an adjustment in antidiabetic dosage could be required. Progestogens may inhibit ciclosporin metabolism leading to increased plasma-ciclosporin concentrations and a risk of toxicity.

Pharmacokinetics

Progesterone has a short elimination half-life and undergoes extensive first-pass hepatic metabolism when given orally oral bioavailability is very low although it may be increased somewhat by an oily vehicle and by micronisation. Progesterone is absorbed when given buccally rectally or vaginally and rapidly absorbed from the site of an oily intramuscular injection. Various derivatives have been produced to extend the duration of action and to improve oral activity. Esters of progesterone derivatives such as hydroxyprogesterone caproate are used intramuscularly, and megestrol acetate is orally active. The ester medroxyprogesterone acetate is used orally and parenterally 19-Nortestoster-one progestogens have good oral activity because the 17-ethinyl substituent slows hepatic metabolism. Progesterone and the progestogens are highly protein bound progesterone is bound to albumin and corticosteroid binding globulin esters such as medroxyprogesterone acetate are principally bound to albumin and 19-nortestosterone analogues are bound to sex-steroid binding globulin and albumin. Progesterone is metabolised in the liver to various metabolites including pregnanediol, which are excreted in the urine as sulfate and glucuronide conjugates. Similarly, progestogens undergo hepatic metabolism to various conjugates, which are excreted in the urine. Progesterone is distributed into breast milk.

Uses and Administration

Progesterone is a natural hormone whereas progestogens are synthetic compounds, derived from progesterone or 19-nortestosterone, with actions similar to those of progesterone. Progestogens derived from 19-nortestosterone are used as hormonal contraceptives, either alone or combined with an oestrogen. The progesterone derivative medroxyprogesterone acetate is also used, and progesterone itself has been used. Progestogens, and sometimes progesterone, are used with oestrogens for menopausal HRT to reduce the increased risk of endometrial hyperplasia and carcinoma that occurs when long-term oestrogen therapy is unopposed.

Similarly, drugs with progestogenic actions may be used in menstrual disorders such as dysmenorrhoea and menorrhagia associated with dysfunctional uterine bleeding (below). Progestogens may also be used in the management of endometriosis. Although progestogens and progesterone have been used for themanagement of the premenstrual syndrome (below), such a practice is of debatable value.

Progestogens may be valuable in advanced endometrial cancer and have been tried in some other malignancies. The progestogens typically used for malignant disease include medroxyprogesterone acetate, megestrol, and norethisterone. Some progestogens such as megestrol and medroxyprogesterone are used for the cachexia or wasting associated with severe illness including cancer and AIDS.

Progestogens have been widely advocated for either the prevention of recurrent miscarriage or thetreatment of threatened miscarriage (below). However, there is little evidence of any benefit from such a practice and the use of progestogens in early pregnancy is not now generally advised, with the exception of the use of progesterone or a progesterone derivative in women who are progesterone deficient (see also Precautions, above). Progesterone is, however, the preferred drug for luteal support in women undergoing assisted reproductive techniques such as IVF (see Infertility).

USES AND ADMINISTRATION OF PROGESTERONE. Progesterone is usually given as an oily intramuscular injection, a vaginal gel or pessaries, or as suppositories. Preparations containing micronised progesterone are also available for oral and vaginal use.

In dysfunctional uterine bleeding or amenorrhoea 5 to 10 mg daily of progesterone may be given by intramuscular injection for about 5 to 10 days until 2 days before the anticipated onset of menstruation. Alternatively, progesterone may be given for amenorrhoea as a vaginal gel at a usual dose of 45 mg on alternate days for up to 6 doses the dose may be increased to 90 mg in those who do not respond to the lower dose. An oral dose of 400 mg given daily at bedtime for 10 days may also be used for amenorrhoea