norgestrel; ethinyl estradiol and 1-norgestrel; and megestrol and medroxyprogesterone acetate. 

[0099] For female HRT, it may be desirable to co-adminis› ter a small amount of an androgenic agent along with the progestin and the estrogen, in order to reproduce the complete hormone profile of the premenopausal woman, since low levels of certain androgens are present in premenopausal women. Suitable androgenic agents are discussed herein. 

[0100] Any of the aforementioned steroid drugs may be naturally occurring steroids, synthetic steroids, or derivatives thereof. 

[0101] Administration of a combination of steroidal active agents is useful in a variety of contexts, as will be readily appreciated by those skilled in the art. For example, the trans› dermal administration of a progestin with an estrogen may be used in female hormone replacement therapy, so that the symptoms or conditions resulting from altered hormone lev› els is mitigated or substantially prevented. The present inven› tion is also useful to administer progestins and estrogens to treat other conditions and disorders that are responsive to topical or transdermal administration of the combination of active agents. For example, the aforementioned combination is useful to treat the symptoms of premenstrual stress and for female contraception. Exemplary combinations useful for contraception include, by way of illustration and not limita› tion, estradiol in combination withnorethindrone acetate, and ethinyl estradiol in combination with norelgestromin. 

[0102] For female hormone replacement therapy, the woman undergoing treatment will generally be of childbear› ing age or older, in whom ovarian estrogen, progesterone and androgen production has been interrupted either because of natural menopause, surgical procedures, radiation, chemical ovarian ablation or extirpation, or premature ovarian failure. For hormone replacement therapy, and for the other indica› tions described herein including female contraception, the compositions or drug delivery systems are preferably used consecutively so that administration of the active agents is substantially continuous. Transdermal drug administration according to the invention provides highly effective female hormone replacement therapy. That is, the incidence and severity of hot flashes and night sweats are reduced, post› menopausal loss of calcium from bone is minimized, the risk of death from ischemic heart disease is reduced, and the vascularity and general health of the individual, is improved. Generally, the maximum concentration is determined by the amount of agent that can be received in the carrier without producing adverse histological effects such as irritation, an unacceptably high initial pulse of agent into the body, or adverse effects on the characteristics of the delivery device such as the loss of tackiness, viscosity, or deterioration of other properties. However, preferred transdermal composi› tions and systems for hormone replacement therapy are capable of delivering about 0.5-10.0 mg progestin, e.g., nore› thindrone, norethindrone acetate or the like, and about 10-200 µg estrogen, e.g., 17~-estradiol, ethinyl estradiol, mestranol or the like, over a periodofabout 24 hours. However, it will be appreciated by those skilled in the art that the desired dose of each individual active agent will depend on the specific active agent as well as on other factors; the minimum effective dose of each active agent is of course preferred. 

[0103] The methods and compositions of the invention are expected to provide an enhanced flux of estrogens and progestins in the range ofat least about 2- to 5-fold, preferably at least about 9- to 17-fold and most preferably at least about 

20- to 31-fold, as compared to the flux observed in the absence of the basic enhancers described herein. 

[0104] D. Androgenic Drugs 

[0105] Suitable androgenic agents that may be adminis› tered using the methods, compositions and systems of the invention include, but are not limited to: the naturally occur› ring androgens and derivatives thereof, including androster› one, androsterone acetate, androsterone propionate, andros› terone benzoate, androstenediol, androstenediol-3-acetate, androstenediol-17 -acetate, androstenediol-3, 1 7-diacetate, androstenediol-17-benzoate, androstenediol-3-acetate-17- benzoate, androstenedione, dehydroepiandrosterone (DHEA; also termed "prasterone"), sodium dehydroepi› androsterone sulfate, 4-dihydrotestosterone (DHT; also termed "stanolone"), 5a-dihydrotestosterone, dromo› stanolone, dromostanolone propionate, ethylestrenol, nan› drolone phenpropionate, nandrolone decanoate, nandrolone furylpropionate, nandrolone cyclohexanepropionate, nan› drolone benzoate, nandrolone cyclohexanecarboxylate, oxandrolone, stanozolol and testosterone; pharmaceutically acceptable derivatives (e.g., salts and esters) thereof, as well as combinations of any of the foregoing. 

[0106] Pharmaceutically acceptable esters of testosterone and 4-dihydrotestosterone are of particular interest, typically esters formed from the hydroxyl group present at the C-17 position, including, but not limited to, the acetate, buciclate, caprate, cypionate, decanoate, enanthate, heptanoate, isobu› tyrate, isocaprate, phenylacetate, propionate, and unde› canoate. Pharmaceutically acceptable derivatives of testoster› one such as fluoxymesterone, methyl testosterone, oxymetholone, and testolactone, are also of interest. 

[0107] Testosterone and testosterone esters, such as test› osterone cypionate, testosterone enanthate, and testosterone propionate, are particularly preferred androgenic agents for use in conjunction with the present invention. The aforemen› tioned testosterone esters are commercially available or may be readily prepared using techniques known to those skilled in the art or described in the pertinent literature. 

[0108] The aforementioned androgenic agents are selected from the group consisting of naturally occurring androgens, synthetic androgens, and derivatives thereof. The active agents may be incorporated into the present dosage units and thus administered in the form of a pharmaceutically accept› able derivative, analog, ester, salt, or amide, or the agents may be modified by appending one or more appropriate function› alities to enhance selected biological properties such as pen› etration through the mucosa! tissue. In general, with regard to androgenic agents, esters are preferred relative to salts or other derivatives. Preparation of esters, as noted herein, involves functionalization of hydroxyl and/or carboxyl groups that may be present, as will be appreciated by those skilled in the arts of pharmaceutical chemistry and drug deliv› ery. For example, to prepare testosterone esters, the 17-hy› droxyl group of the testosterone molecule is generally caused to react with a suitable organic acid under esterifying condi› tions, such conditions typically involving the use of a strong acid such as sulfuric acid, hydrochloric acid, or the like, and a temperature sufficient to allow the reaction to proceed at reflux. Esters can be reconverted to the free acids, if desired, by using conventional hydrogenolysis or hydrolysis proce› dures. 

[0109] Androgenic drugs such as testosterone (17~-hy› droxyandrost-4-en-3-one) are required for sperm production and promote general growth of body tissues. The primary 

