New progestins eyed for HRT and OC use

Would your patients use a hormone replacement therapy (HRT) product in a gel form, featuring a mixture of an established estrogen and a new progestin? How about an oral HRT preparation using the most-recognized oral estrogen product in combination with a new progestin, or the same new progestin combined with ethinyl estradiol in oral contraceptive (OC) form?

Research is under way on such products, say representatives of two companies.

When used in OCs, progestins inhibit ovulation by suppressing luteinizing hormone, hamper the transport of sperm by thickening cervical mucus, and impede implantation by producing a decidualized endometrial bed with exhausted and atrophied glands.1 In HRT preparations, progestins protect the uterus against endometrial cancer by keeping the endometrium from thickening. Depending on the formulation, some women may shed the endometrial lining from the uterus through the vagina. That HRT-induced bleeding may be regarded as unacceptable.2

Scientists are interested in developing new progestins, particularly for HRT applications, with improved blood lipids, reduction in nuisance side effects, and better bleeding control.

Nestorone in HRT gel

Orion Pharma of Helsinki, Finland, has entered into a licensing agreement with the New York City-based Population Council for worldwide exclusive rights to develop, manufacture, and market the Population Council’s synthetic progestin, Nestorone, for HRT transdermal dosage forms other than the patch. (The Population Council negotiated an exclusive license with Miramar, FL-based Sano Corp. for the North American rights to use Nestorone in transdermal patches for female contraception and HRT. See Contraceptive Technology Update, October 1997, p. 121.) The company now will begin clinical trials to prove the effectiveness of the progestin in an HRT gel formulation.

Elof Johansson, Population Council vice president and head of its Center for Biomedical Research, sees the situation as a "win/win" for the Council and Orion Pharma. Orion Pharma has developed gels for estrogen replacement therapy and has examined several progestins for HRT use, says Johansson.

"[They] found that the Nestorone that we are working with goes through the skin very readily and also is quite effective per weight so you don’t need that much," he explains. The Population Council will continue to work with Nestorone in other applications.

Nestorone provides an efficacious, invisible progestin treatment for menopausal disorders to prevent endometrial hyperplasia or to reduce the risk of endometrial carcinoma associated with estrogen-only treatments, says Jyrki Mattila, Orion Pharma president. In transdermal form, it is very easy and comfortable to use, he notes.

Unlike most progestins, Nestorone effectively penetrates the skin, exerts good progestational effects, and is well-tolerated, observes Mattila.

"Currently, there are no gel preparations available combining estrogen and progestin," he says. "The market is steadily growing."

The company offers five HRT products, none of which are offered in the United States:

• Divina, a biphasic estrogen and progestin combination;

• Divitren, a biphasic combination preparation in which natural estrogen and progestin are given sequentially, with withdrawal bleeding occurring four times a year;

• Indivina, a continuous combined product in which estrogen and progestin are administered continuously, resulting in HRT without any withdrawal bleeding;

• Diviseq, a triphasic estrogen and progestin combination;

• Divigel, an opalescent estrogen gel.

Divina, Divitren, and Indivina also are indicated for the prevention of osteoporosis, says Mattila. The company is seeking what it terms "an appropriate partner" for introduction of such products in the U.S. market.

Philadelphia-based Wyeth-Ayerst Laboratories is examining the use of another new progestin, trimegestone, for HRT and OC applications. Trimegestone is a novel norpregnane progestin, which in human recombinant receptor binding studies demonstrates potent progesterone receptor, very low androgen receptor affinities, and no detectable affinity to estrogen receptor.3

Phase III trials under way

Trimegestone with Wyeth-Ayerst’s own Premarin hormone replacement therapy is in phase III clinical trials in the Unites States, confirms Audrey Ashby, company spokeswoman.

Trimegestone with 17 ß-estradiol for use in hormone replacement therapy with endometrial protection has been registered outside the United States, she notes. Researchers also are evaluating trimegestone with ethinyl estradiol for oral contraception in Phase II trials.

In a European dose-ranging study using oral trimegestone administered at 0.05, 0.1, 0.25, and 0.5 mg per day (days 15 to 28) and 2 mg of oral micronized ethinyl estradiol daily, the majority of women in the four dose groups experienced relief of climacteric symptoms by the end of the third treatment cycle.4 The incidence of premenstrual-type (PMT-type) symptoms was low and did not differ among the dose groups.

After six months of treatment, scientists found the bleeding pattern showed a clear dose-dependent modulation: The higher the dose of trimegestone administered, the more predictable the day of onset of bleeding. Also, bleeding episodes were shorter and lighter with higher doses.

"Its lipids-friendly profile is very close to unopposed estrogen," says Farook Al-Azzawi, MA, PhD, FRCOG, who has studied its use in HRT preparations. Al-Azzawi is director of the gynecology research unit in the department of obstetrics and gynecology at University of Leicester (UK) school of medicine and biological sciences. "The adverse progestogenic effects, namely PMT-type of symptoms, were minimal, and despite the wide dose range, no dose-related effect was demonstrated."

When progestin is added sequentially in an HRT preparation, uterine bleeding is re-initiated.3 If the pattern of bleeding is poorly predictable and heavy, it may discourage HRT use. If trimegestone proves effective, it might help women’s long-term acceptance of HRT.

References

1. Hatcher RA, Trussell J, Stewart F, et al. Contraceptive Technology. 17th ed. New York City: Ardent Media; 1998.

2. North American Menopause Society. Menopause Basics. Cleveland; 1997.

3. Al-Azzawi F. New progestin — How strong is the evidence? Presented at the 1st Congress on Controversies in Obstetrics, Gynecology, and Infertility. Prague, Czech Republic; Oct. 29, 1999.

4. Al-Azzawi F, Wahab M, Thompson J, et al. Acceptability and patterns of uterine bleeding in sequential trimegestone-based hormone replacement therapy: A dose-ranging study. Hum Reprod 1999; 14:636-641.