A Better Way to Take Progesterone

A Better Way to Take Progesterone
New delivery system improves bioavailability of this natural hormone
By Will Block

ou can’t judge a book by its cover, goes the old saying. Book publishers, however, know that people do just that, so they try hard to design covers that will appeal to consumers. Packaging matters. Whether it’s a mundane consumer product made to look sexy through attractive packaging, or an attractive woman making herself look more sexy with seductive makeup, or a politician seducing the voters by making up lies about what he will do for them if elected, it’s often the packaging that clinches the deal.

A similar principle holds for supplements (and drugs)—but in a different way. Regardless of their intrinsic worth, often these products are only as good as the ability of their packaging to clinch the deal. In this case, however, “packaging” refers not to the container the supplement came in, but to the physical and chemical form of the supplement itself, and the “deal” is to get the supplement to where it needs to go inside the human body so that it can do its designated job. In a sense, the supplement is only as good as the method of its delivery.

The “delivery vehicle”—the physical and chemical form in which the supplement is provided—is thus vital for success, and manufacturers and pharmacists are ever alert for ways to improve the supplement’s bioavailability to the tissues that need it. As Thomas Edison said, “If there’s a way to do it better … find it!”

Edison would probably be fascinated by a method that has been found for improving our ability to deliver the natural female sex hormone progesterone as a supplement. We’ll get to that in a moment, but first let’s recall an important fact about progesterone.

How to Sneak Progesterone into Your Body

With few exceptions, progesterone is not taken orally, because it’s extensively metabolized by the liver. Nutrients that pass through the intestinal walls to enter the bloodstream are sent via the portal vein to the liver, which gets first crack at them—and a lot can happen there before they’re released into the general circulation. If the liver doesn’t “like” a given nutrient that comes to it via the portal vein, it will change it or dispose of it in any number of ways. The liver—an organ with an attitude.

An easy way to bypass the liver is to apply progesterone to the skin in the form of a penetrating cream or gel. This transdermal (“through-the-skin”) route provides a relatively slow delivery of the progesterone, which, where hormones are concerned, is preferable to a speedy delivery—the idea is to produce steady release rates of the hormone rather than spikes, which could be detrimental. Creams and gels may not be as convenient as capsules, but they’re easy enough to use. And although they work well, by and large, there’s always room for improvement.

Liposomes Are Manmade Cells

The better way that is now available for taking progesterone transdermally is via a type of gel composed of liposomes. To understand what a liposome is, think of a cell. It consists of (1) a cell membrane, made of lipids (fatty molecules, not water-soluble), which encloses and contains (2) the largely aqueous contents of the cell, in which are suspended or dissolved innumerable organelles and chemical compounds. The cell membrane is exceedingly thin, being composed of a lipid bilayer, i.e., a sheet of lipids only two molecules thick. The bilayer consists mainly of a special class of lipids called phospholipids, whose unique ability to form such delicately thin yet surprisingly strong membranes makes cellular life possible. (See the sidebar “Water or Lipid—Big Difference!”)

Water or Lipid—Big Difference!

Pharmacists have been ingenious in devising ways for getting drugs and supplements into your body, using just about every conceivable avenue. For starters, the physical form of the agent can be solid (tablets, capsules, lozenges, suppositories, powders, skin patches, etc.), or it can be liquid or semiliquid (solutions, suspensions, injections, sprays, drops, ointments, lotions, creams, gels, etc.), and it can even be gaseous (oxygen, nitrous oxide, etc.).

The chemical forms are of nearly infinite variety, but for practical purposes, most agents can be broadly categorized as either water-soluble or lipid-soluble. Lipids are fatty substances, which, by definition, do not dissolve appreciably in water—they do dissolve readily in other lipids and in many organic solvents, however. In the human body, there are four types of lipids: fats, phospholipids, steroids, and waxes. Depending on the conditions, they may be in the solid state or the liquid state (fats that are liquid at room temperature are called oils).

Whether a chemical compound is primarily water-soluble or primarily lipid-soluble (some compounds are both, to significant degrees) makes a huge difference in where it can go in the human body and what it can do there. The fact that phospholipids, which are rather long molecules, have one end with a chemical affinity for lipids and one end with a chemical affinity for water accounts for their remarkable ability to form lipid bilayers, of which cell membranes and liposome membranes are made.

Lipid bilayers also make possible the creation of liposomes, which can be thought of as manmade cells. Here too, a bilayer membrane completely encloses and contains aqueous contents. Both the membrane and its contents are much simpler than those of a living cell, but the basic structure is the same. There are, however, variations on this theme. For example, whereas living cells assume many odd shapes, most liposomes are spherical. And whereas living cells have just one membrane and one aqueous interior, liposomes can have hundreds of membranes, as concentric shells, containing hundreds of concentric aqueous interiors between them. Liposomes can also be nonspherical, and they can be segmented and compartmented in more complex ways.

The smallest liposomes are about 20 nanometers (billionths of a meter) in diameter, but the diameter of liposomes can be in the micrometer (millionths of a meter) range, and the largest are fractions of a millimeter, which can be seen with the naked eye.

Liposomes Trap Active Agents

Well, fine, you say, but what do liposomes do? They serve as delivery vehicles for a great variety of drugs (and some supplements, such as progesterone); let’s call these the active agents. The active agents are suspended (as fine particles) or dissolved in the aqueous interior(s) of the liposomes, where they remain trapped until the liposomes break down and spill their payload. Only then, actually, do these agents have the opportunity to become biologically active.

In this way, it’s possible to protect the active agents from being broken down in the body—or, if they’re drugs, from exerting potentially toxic effects—before they reach the place where their therapeutic action is needed, such as the liver or a tumor. How the liposomes know when they’ve reached their destination is beyond the scope of this article; suffice it to say that there are biochemical tricks for allowing them to accomplish this remarkable feat in some cases.

Liposomes Go the Transdermal Route

Liposomes were discovered in the 1960s, but their use as drug carriers did not begin until the 1990s.1 They can be administered in different ways, such as by intravenous, intramuscular, or subcutaneous injection, or transdermally via topical gels. Oral administration is problematic because of the hostile environment of the digestive tract, but if the problems can be overcome, this route holds promise for being able to deliver agents that cannot now be taken orally, such as insulin and glutathione. The challenge for biochemists is to make the liposomes tough enough to survive the stomach, sneaky enough to pass through the intestinal wall, and smart enough to break down later, spilling their contents when and where they’re needed—a very tall order.

There are countless formulations for liposomes, which can be tailored to many different needs. A formulation that has gained wide acceptance for transdermal delivery is Pluronic lecithin organogel, or PLO (see the sidebar “What Is PLO?”). PLO is now being used to deliver progesterone, for which it appears to be superior to the creams that have traditionally been used. Because progesterone will not dissolve in the aqueous interior of liposomes, it must be micronized (processed into extremely fine particles) and suspended in the aqueous medium.

What Is PLO?

If you read the papers, PLO stands for Palestine Liberation Organization—terrorists who blow people up to make a point. Here, however, PLO stands for something much kinder and gentler: Pluronic lecithin organogel, a versatile and effective transdermal delivery vehicle for pharmaceutical agents that was invented in the early 1990s. PLO consists of an aqueous phase and a lipid phase. When these ingredients, together with a drug or supplement (such as progesterone), are mixed in a particular way, they form liposomes that contain the drug or supplement in the aqueous interior. The product is actually an emulsion that has the look and feel of a gel.

The Pluronic part of the name refers to a proprietary commercial polymeric product, Pluronic® F-127, which is a powder that forms a gel when dissolved in water. That’s the aqueous phase.

Lecithin is a natural, lipid-soluble (water-insoluble) substance found in egg yolks and the membranes of plant and animal cells. Its principal constituent is the chemical compound phosphatidylcholine, a phospholipid that is an integral component of all cell membranes. Lecithin also contains other phospholipids (mainly phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol), and it contains small amounts of triglycerides (fats), fatty acids, and carbohydrates. The composition of lecithin varies with the source (soybeans are a common source) and the degree of purification.

Lecithin is used as an emulsifier in a wide range of commercial products, including foods, pharmaceuticals, cosmetics, paints, and plastics. It can also be taken as a supplement to enhance brain function by providing nutrients needed for cell-membrane construction. The most useful form of lecithin in this regard is one with a preponderance of phosphatidylserine, which is known for its positive effects on memory.

In addition to lecithin, the lipid phase of PLO (which constitutes the lipid bilayer of the liposome) contains the same amount of either isopropyl palmitate or isopropyl myristate. These are common organic liquids that are used as emollients and solvents and as delivery vehicles for fat-soluble compounds. The formulation may also contain some propylene glycol, a glycerin-like liquid.

PLO is used for a wide variety of pharmaceutical products, including supplements, for which it can be particularly beneficial. Beyond its conventional use, it’s helpful for administering drugs with a minimum of hassle in situations where the oral or rectal route is difficult or impossible, e.g., in demented or hostile patients, in patients with nausea or diarrhea, and in children who are distraught and uncooperative because of nausea or some other ailment. It’s also used by veterinarians, who have special problems of their own.

Although progesterone is usually applied transdermally, it can also be applied transmucosally, i.e., to the mucous membranes of the vagina or the inner labia. Experience has shown that the effectiveness of transdermal application diminishes with time, but this problem appears not to occur with the transmucosal route.

Schematic diagram of a liposome, a manmade analog of a living cell.
Progesterone—For Women Only

Supplemental progesterone, although derived from plant sources, is chemically identical (and therefore biologically identical) to human progesterone, a hormone that plays vital roles in the female reproductive system. Its principal use as a supplement is for perimenopausal and postmenopausal hormone replacement therapy (HRT), for which it offers significant advantages over conventional HRT; it may also be of benefit in treating premenstrual syndrome.2 According to one recent survey, eight of the top ten HRT compound preparations sold in the United States contain progesterone as the active ingredient.3

In addition, there is intriguing evidence that progesterone may be helpful in preventing and treating osteoporosis.2 A study published in 1990 cites experimental, epidemiological, and clinical evidence indicating that progesterone is active in bone metabolism and tends to increase bone formation.4 The author suggests that postmenopausal osteoporosis may be, in part, a progesterone deficiency disease.

Vitamin K for Healthy Bones

Another nutrient that plays an essential role in bone metabolism and that is helpful in combating osteoporosis is vitamin K, which is required for bone calcification and mineralization.5 Vitamin K consists of several compounds—the most common is phylloquinone—that aid in blood clotting, thus helping to prevent hemorrhages. This vitamin is widely used to minimize bleeding during and after surgical operations. (One might think that it would also be useful in treating hemophilia, but, sadly, it isn’t.)

High Technology in a Bottle

The next time you go shopping, take a hard look at the packaging and ask yourself if it’s trying to make the product seem better than it really is. For that matter, ask yourself if the packaging costs more than the actual product, which is often the case, especially with cosmetics.

When you go to purchase supplements (from reputable manufacturers), however, this is definitely not the case. Here the real value is in the supplement and its delivery vehicle. There may be some seriously high technology embodied in even the most mundane-looking vehicle, and you can be sure that it was developed for your benefit.


  1. Lian T, Ho RJY. Trends and developments in liposome drug delivery systems. J Pharm Sci 2001;90:667-80
  2. Murray JL. Natural progesterone: what role in women’s health care? Women’s Health Primary Care 1998 Sep;1(8):671-87.
  3. Anon. The top ten HRT compound preparations. Int J Pharm Compound 1999;3(5):342
  4. Rev 1990; 11(2):386-98.
  5. Schaafsma A, Muskiet FAJ, Storm H, Hofstede GJH, Pakan I, Van der Veer E. Vitamin D3 and vitamin K supplementation of Dutch postmenopausal women with normal and low bone mineral densities: effects on serum 25-hydroxyvitamin D and carboxylated osteocalcin. Eur J Clin Nutr 2000; 54:626-31.

Will Block is the publisher and editorial director of Life Enhancement magazine.

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