Aug. 30, 2012  11  US 2012/0220962 Al  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 