Long-Term Effects of Topical Progesterone Cream Application: A Case Study
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Article by Elias F. Ilyia, Ph.D., Deborah McLure, B.Sc., and Michel Y. Farhat, Ph.D

Abstract: Key words: Progesterone cream, female hormone profile, salivary hormone testing, hormone free fraction, hormone overdose.

It has been observed that the premenstrual tension, bloating as well as mood swings and depression, experienced by perimenopausal women can be relieved by exogenous progesterone administration, as part of a well-balanced hormone replacement regimen. Natural progesterone is derived from plants, is isomolecular to human progesterone and is available to women in over-the-counter gels and creams. The pharmacodynamics of transdermal creams are unknown, and thus self-medication may lead to overuse and overdose as well as exacerbation of the symptoms. We describe the case of a forty five year-old woman showing excessive elevations in salivary progesterone, following use of low pharmacological concentrations of progesterone cream. The elevated progesterone levels were maintained for months after cessation of cream use. Salivary testing, a measure of the free fraction of the hormone, is used to assess the patient hormonal profile. This report illustrates the problem of overdosing with topical application of progesterone creams and the long-term side effects associated with it.

Discussion

Self-medication with over-the-counter progesterone (as well as estrogen) creams is widespread among women to relieve premenstrual-like symptoms, and in some cases as a form of hormone replacement therapy. Transdermal delivery of hormonal steroids offers a number of advantages over other modes of administration. Transdermal delivery normally allows the use of small amounts of the hormone for a long-lasting effect by avoiding chemical or metabolic degradation of drugs that may occur in the gut. The high efficiency of this system may also result from the ability to modify the properties of the stratum corneum to absorption by using iontophoretic devices and flux enhancers (3). Moreover, by bypassing the liver, transdermal delivery eliminates the potential drawbacks associated with hepatic steroid metabolism (4). However, the absence of wide-range controlled studies to monitor the pharmacokinetics and biological effects of transdermal progesterone application in the general population makes the efficacy of this mode of treatment, at least with regard to certain applications, questionable. xxSteroid hormones in plasma are either free or bound to specific and non-specific binding proteins. More than 95 per cent of steroids in plasma are bound, leaving target tissues exposed to less than 5 per cent of the total plasma concentration which constitutes the free fraction of the hormone (5). The free concentration of a hormone depends on the affinity and total binding capacity of various binding proteins in plasma. The entry of steroid hormones in saliva occurs primarily by passive diffusion, and is driven by the plasma concentration gradient of its free fraction. Thus, saliva levels will reflect the free concentration of hormones in plasma. In the absence of both a high affinity, high capacity binding protein in the plasma, the concentration of a particular hormone in saliva will correlate with its total plasma concentration. Wong et al. (1), monitoring ovarian function in a group of Chinese women, found very similar salivary and serum estradiol and progesterone profiles during the menstrual cycle. Moreover, Bolaji et al. (6) have shown that in patients using oral micronized progesterone, saliva and serum levels peaked simultaneously and a high degree of correlation (r=0.89) existed between saliva and plasma progesterone concentrations measured concurrently. A similar correlation was also observed between saliva and plasma concentration of other steroids, such as cortisol (7,8). These observations suggest that the free progesterone concentration in saliva closely reflect that in plasma, and thus provide credence to the role of saliva as a diagnostic tool for assessment of hormone levels.

References

1. Wong YF, Mao K, Panesar NS, Loong EPL, Chang AMZ, Mi ZJ. Salivary estradiol and xxxxprogesterone during the normal ovulatory menstrual cycle in chinese women. Eur J Obstet Gynecol xxxReprod Biol 1990; 34:129-135.

2. Vuorento T, Lahti A, Hovatta O, Huhtaniemi I. Daily measurements of salivary progesterone reveal a high xxxxrate of anovulation in healthy students. Scand J Clin Lab Invest 1989; 49:395-401.

3. Berner B, John VA. Pharmacokinetic characterization of transdermal delivery systems. Clin Pharmacokinet xxxx1994; 26: 121-134.

4. Donaldson AS, Jeffcoate L, Sufi SB. Assays of oestradiol and progesterone in saliva in the assessment of xxxxovarian function. Front Oral Physiol 1984; 5:80-86.

5. Quissell DO. Steroid hormone analysis in human saliva. Ann NY Acad Sci USA 1993; 264:143-145.

6. Bolaji II, Tallon DF, O'Dwyer E, Fottrell PF. Assessment of bioavailability of oral micronized xxxxprogesterone using a salivary progesterone enzymeimmunoassay. Gynecol Endocrinol 1993; 7: 101-110.

7. Kahn JP, Rubinow DR, Davis CL, Kling M. Post RM. Salivary cortisol: A practical method for evaluation xxxxof adrenal function. Biol Physchiatry 1988; 23: 335-349.

8. Vining RF, McGinley RA. The measurement of hormones in saliva. J Steroid Boichem 1987; 27: 81-94. 9.xxScheuplein RJ. Percutaneous absorption: Theoretical aspects. In: Mauvais-Jarvis P, Vickers CFH, xxxxWepierre J, Eds. Percutaneous Absorption of steroids. London: Academic Press, 1980: 1-17.

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