Vaginal progesterone: from IVF to menopause

Dominique de Ziegler
Hôpital de Nyon and Department of Obstetrics and Gynecology, Geneva University Hospital

1. Vaginal progesterone: the only practical option to avoid painful IM injections.

It has been approximately 15 years since the first successes with donor egg IVF were reported in women suffering from premature ovarian failure. In these women, the objective of the treatment regimens was to prime endometrial receptivity with the sole support of exogenous hormones. While estrogens can be administered by various routes that succeed at duplicating menstrual cycle effects (1), the delivery of progesterone is more problematic. In micronized form, progesterone is almost entirely absorbed when ingested orally, but the hepatic metabolism is so extensive that endometrial changes seen in the menstrual cycle cannot be duplicated, even with the highest doses. This led investigators to focus on IM progesterone administration (synthetic progestins can not be used in women attempting to become pregnant), despite the obvious practical inconvenience of this option. Later, it was shown that similar results could be achieved when progesterone is administered vaginally (2,3).

The original preparations used for administering progesterone vaginally were locally made cocoa butter-based suppositories or products designed for oral use. Today, a vaginal progesterone gel, Crinone 8%, was recently developed and found as effective as IM progesterone in either, actual donor egg IVF cycles or a large multi-center trial conducted in regular IVF. vaginal progesterone was found to be as effective as IM progesterone.

2. Vaginal progesterone: a direct access to the uterus through a newly discovered functional "portal" system

The recent development of a new sustained release vaginal progesterone gel, Crinone 4%, showed that using less progesterone (because of the sustained release effects) nonetheless achieved endometrial results similar to findings made with IM progesterone administration or in the menstrual cycle. This led to the unexpected discovery of uterine trophicity of vaginal progesterone. In a prospective trial, Fanchin et al. (4) demonstrated that every other day administration of 1.1 g of Crinone 4% gel containing 45 mg of progesterone induced full endometrial decidualization, despite progesterone levels in peripheral blood that were in the "luteal phase defect" range (peaks at < 5 ng/mL and troughs at ≤ 1 ng/mL).

The discrepancy between low peripheral levels of progesterone and full effects on the nedometrium led us to postulate that some of the progesterone administered vaginally is directly transported into the uterus through a "first uterine pass effect" (5). In a recent study (6), we showed that vaginal progesterone administration resulted in higher uterine tissue concentrations of progesterone and lower peripheral blood levels as compared to IM progesterone administration. These results also refuted the objections raised by Miles data hypothesizing that the study findings might reflect a contamination of the biopsy specimens by progesterone still present in the vagina. the vaginal gel Crinone confirmed the prior work of Miles et al (7) that used locally made vaginal progesterone capsules. The results also refuted the objection raised to the Miles data that higher uterine tissue concentrations following vaginal progesterone administration resulted from contamination of the uterine aspirate by progesterone still present in the vagina. In Cicinelli’s study, endometrial tissue was obtained from hysterectomy specimens which, thus, ruled out any possible contamination.

3. Vaginal progesterone: a long-term option for menopause

Progesterone and synthetic progestins have different effects on CNS

By limiting the number of administrations needed, the sustained-release vaginal progesterone gel, Crinone, has allowed us to envision long-term treatments with vaginal progesterone such as notably, for menopause. The justification for using the native ovarian hormone progesterone in menopause lies in the importance of side effects linked to the use of synthetic progestins, notably, MPA. Synthetic progestins, designed to resist enzymatic degradation and remain active orally, duplicate well the anti-proliferative action of progesterone on the endometrium. Yet, these products exert effects on CNS that often markedly differ from those of progesterone. Today, we suspect that any difference between the neuro-psychological effects of progesterones and progestin result from divergent non-genomic properties of these molecules.

It is important to recognize this phenomenon, because often, the neurological side effects of progestins are severe enough to discourage women from continuing HRT. The clinical experience with the vaginal progesterone gel, Crinone 4%, also strongly supports that progesterone and synthetic progestins impact differently on the CNS. In their clinical trial, Warren et al (8) observed that women taking Crinone 4% in cyclical combination with conjugated equine estrogens (CEE) felt better, i.e., experienced less treatment-associated side effects, during the CEE-Crinone 4% phase of their treatment than when they received CEE alone. This finding was particularly striking in that the prevailing belief at the time was that women would experience more side effects when taking a progestin (Warren). It has been our experience that approximately 10-20% of women will opt for the vaginal progesterone option once aware of the difference between synthetic progestins and vaginal progesterone.

Peri- and early menopause: predicatable withdrawal bleeding with cyclical administration of Crinone 4% 10 days/month

Cyclical regimens are best for women in peri- and early menopause (HRT?). This is also true with vaginal progesterone. Every-other-day administration of Crinone provides a bleeding pattern similar to that seen with oral use of 5 mg or 10 mg of medroxyprogesterone acetate (MPA (10). A more predictable bleeding pattern however, is achieved when Crinone 4% is administered daily for 10 days each month. As illustrated in Table 1, we observed that >90% of menopausal women receiving Crinone 4% daily x 10 days/month exclusively experienced withdrawal bleeding, i.e., bleeding that starts only after the last Crinone administration was taken or "pill-like" bleeding (12). Remarkably, we observed that women, who self-opted for starting vaginal progesterone because of personal preferences for "natural" options, were likely to continue on this regimen for extended periods of time. In their opinion, the lack of side effects largely outweighed the inconvenience of receiving a drug vaginally (10).

Women >53 years old: amenorrhea with twice a week administration of Crinone 4%

Women several years into menopause ( 53 and/or more than3 years after menopause) most often prefer "no bleed" regimens. Unfortunately however, existing combined regimens that seek "no bleed" ambitions suffer from excessive treatment failures. Lackwood’s team at NYU (13) identified perivascular changes and evidence of tissue fragilization as the probable primary causes of the dysfunctional bleeding seen in women receiving constant progestin treatment. The NYU team also showed that increasing the progestin treatment induced by progestin treatment. Fortunately, we observed that intermittent administration of vaginal progesterone achieved higher rates of amenorrhea—providing a treatment advance towards a "true no bleed regimen." As illustrated in Table I, Crinone 4% administered twice weekly in combination with estrogen (when using transdermal estrogen change days serve as a reminder to administer Crinone 4%) resulted in complete and persistent amenorrhea. Because of systemic side effects of vaginal progesterone, the efficacy of this regimen can play a significant role in maximizing patient satisfaction and long-term compliance.

Conclusion

Vaginal progesterone that was originally prescribed for indications such as PMS is now is in fully recognized scientifically for hormonal treatments for IVF. Now that a sustained-release product specially designed for vaginal use , Crinone 4%, exists, the number of administrations has been reduced and therefore, long-term treatment for menopause, can be contemplated. Daily administration of Crinone 4% for 10 days each month provides predictable "pill-like" withdrawal bleeding for perimenopausal women. Women over 53 years of age are likely to prefer administering Crinone 4% every other day for a true no bleed regimen—achieved in over 80% of women. The lack of systemic side effects indicates that vaginal progesterone has a role to play for enhancing long-term HRT compliance in women that prefer "natural" options.

References

1. Steingold KA, Matt DW, De Ziegler D, Sealey JE, Fratkin M, Reznikov S. Comparison of transdermal to oral estradiol administration on hormonal and hepatic parameters in women with premature ovarian failure. J Clin Endocrinol Metab 1991;73:275-280.

2. 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;5:537-543.

3. Schmidt CL, de Ziegler D, Gagliardi CL, Mellon RW, Taney FH, Kuhar MJ, et al. Transfer of cryoperserved-thawed embryos: the natural cycle versus controlled preparation of the endometrium with gonadotropin-releasing hormone agonist and exogenous estradiol and progesterone (GEEP). Fertil Steril 1989;52:609-616.

4. Fanchin R, De Ziegler D, Bergeron C, Righini C, Torrisi C, Frydman R. Transvaginal administration of progesterone: dose-response data support a first uterine pass effect. Obstet Gynecol 1997;90:396-401.

5. de Ziegler D. Hormonal control of endometrial receptivity.

6. Cicinelli E, de Ziegler D, Bulletti C, Matteo MG, Schonauer LM, Galantino P. Direct transport of progesterone from vagina to uterus. Obstet Gynecol 2000; 95:403-406.

7. 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;62:485-490.

8. Warren MP, Biller BMK, Shangold MM. A new clinical option for hormone replacement therapy in women with secondary amenorrhea: effects of cyclic administration of progesterone from the sustained-release vaginal gel Crinone (4% and 8%) on endometrial morphologic features and withdrawal bleeding. Am J Obstet Gynecol 1999;180:42-48.

9. Warren MP, Shantha S. Use of progesterone in clinical practice. Int J Fertil 1999;44:96-103.

10. de Ziegler D, Bulletti C, Cicinelli E. Vaginal progesterone: direct access to the uterus, physiological hormone replacement in infertility and gynecology. In: Sitruk-Ware R, Mishell DR, editors. New York, NY: Marcel Dekker, Inc; 2000:77-99.

11. Archer DF, Pickar JH, Bottiglioni F et al. Bleeding patterns in postmenopausal women taking continuous combined or sequential regimens of conjugated estrogens with medroxyprogesterone acetate. Obstet Gynecol 1994;686-692.

12. Runic R, Schatz F, Krey L, Demopoulos R, Thung S, Wan L Lockwood CJ. Alterations in endometrial stromal tissue factor protein and messenger ribonucleic acid expression in patients experiencing abnormal uterine bleeding while using Norplant-2 contraception. J Clin Endocrinol Metab 1997;82;1983-1988.

Table 1. Vaginal Progesterone gel in HRT

Mean Age

Type of bleeding

n %

Expected

Withdrawal only

63/69

91.3

Abnormal

Breakthrough and/or other abnormal bleeding

6/69

8.7

Expected

Amenorrhea (no bleed)

54/67

80.6

Acceptable

Isolated spotting -mild bleeding

9/67

13.4

Unacceptable

Heavy bleeding - repeated spotting

4/67

6

1 Cyclical regimen : Crinone 4% daily x 10 days per month.

2 Constant combined regimen : Crinone 4% twice weekly.


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Edited by Aldo Campana,