High-dose estrogen therapy
Drug class
Estradiol valerate, an estrogen which has been used as a means of HDE.
Class identifiers
Synonyms	Pseudopregnancy (when used in combination with a progestogen)
ATC code	G03C
Biological target	Estrogen receptors (ERα,ERβ,mERs (e.g.,GPER, others))
Chemical class	Steroidal;Nonsteroidal
Legal status
In Wikidata

High-dose estrogen therapy (HDE) is a type ofhormone therapy in which high doses ofestrogens are given.^[1] When given in combination with a high dose ofprogestogen, it has been referred to aspseudopregnancy.^[2][3][4][5] It is called this because the estrogen and progestogen levels achieved are in the range of the very high levels of thesehormones that occur duringpregnancy.^[6] HDE and pseudopregnancy have been used in medicine for a number of hormone-dependent indications, such asbreast cancer,prostate cancer, andendometriosis, among others.^[1][7][2] Bothnatural orbioidentical estrogens andsynthetic estrogens have been used and bothoral andparenteralroutes may be used.^[8][9]

HDE and/or pseudopregnancy have been used in clinical medicine for the following indications:

• Estrogen receptor-positivebreast cancer in women^[1]
• As a means ofandrogen deprivation therapy forprostate cancer andbenign prostatic hyperplasia in men^[7][8][10]
• In combination withprogestins forendometriosis in women. Although initially used alone, progestins were added in the 1960s and 1970s.^[11] In addition, the estrogendiethylstilbestrol is an example ofmedical reversal as it increases the risk of endometriosis in the treated women and in their female children.^[12][13]
• Osteopenia andosteoporosis in women^[3]
• Prevention oftall stature in tall adolescent girls^[14]
• Suppression ofIGF-1Tooltip insulin-like growth factor 1 levels inacromegaly andgigantism^[15]
• As a component ofhormone therapy fortransgender women to achievefeminization and suppressandrogens^[16][17]
• Breast hypoplasia or as a means of hormonal breast enhancement in women^[18][19]
• Uterine hypoplasia in women^[20][3][4]
• Premenstrual syndrome andpremenstrual dysphoric disorder in women^[21]
• Postpartum depression andpsychosis in women^[22][23]

Thenonsteroidal estrogendiethylstilbestrol as well as otherstilbestrols were previously used to supportpregnancy and reduce the risk ofmiscarriage, but subsequent research found that diethylstilbestrol was both ineffective andteratogenic.^[24]

HDE should be combined with a progestogen in women with an intactuterus as unopposed estrogen, particularly at high dosages, increases the risk ofendometrial hyperplasia andendometrial cancer.^[25] The majority of women with an intact uterus will develop endometrial hyperplasia within a few years of estrogen treatment even with mere replacement dosages of estrogen if a progestogen is not taken concomitantly.^[25] The addition of a progestogen to estrogen abolishes the increase in risk.^[26]

The followingsteroidal estrogens have been used in HDE therapy:^[1][27][28]

• Conjugated estrogens (Premarin)
• Estradiol andestradiol esters (e.g.,estradiol benzoate,estradiol undecylate,estradiol valerate,polyestradiol phosphate)
• Estramustine phosphate (an estradiol ester that is also acytostatic antineoplastic agent; used for prostate cancer only)
• Ethinylestradiol, itsethermestranol, and itsesterethinylestradiol sulfonate

As well as the following nonsteroidal estrogens (which are now little or not at all used):^[27]

• Diethylstilbestrol (stilbestrol),fosfestrol (diethylstilbestrol diphosphate),bifluranol, and otherstilbestrols

Progestogens that have been used in pseudopregnancy regimens includehydroxyprogesterone caproate,medroxyprogesterone acetate, andcyproterone acetate, among others.^[2]Progesterone has been little-used for such purposes likely due to its poorpharmacokinetics (e.g., low oralbioavailability and shortelimination half-life).^[29]

Generaladverse effects of HDE may includebreast enlargement,breast pain and tenderness,nipple enlargement andhyperpigmentation,nausea andvomiting,headache,fluid retention,edema,melasma,hyperprolactinemia,galactorrhea,amenorrhea, reversibleinfertility, and others.^[30] More uncommon but serious side effects may includethrombus andthrombosis (e.g.,venous thromboembolism), othercardiovascular events (e.g.,myocardial infarction,stroke),prolactinoma,cholestatic jaundice,gallbladder disease, andgallstones.^[30] In women, HDE may causeamenorrhea and rarelyendometrial hyperplasia orendometrial cancer, but the risk of adverse endometrial changes is minimized or offset with pseudopregnancy regimens due to the progestogen component. Thetolerability profile of HDE is worse in men compared to women. Side effects of HDE specific to men may includegynecomastia (breast development),feminization anddemasculinization in general (e.g., reducedbody hair, decreasedmuscle mass andstrength,feminine changes infat mass anddistribution, and reducedpenile andtesticular size), andsexual dysfunction (e.g., reducedlibido anderectile dysfunction).^[30]

The use of HDE in men has been associated withcellulite, which has been attributed toandrogen deficiency.^[31]

This sectionis missing information about why it works in ER+ breast cancer. Please expand the section to include this information. Further details may exist on thetalk page.(September 2021)

Estrogens areagonists of theestrogen receptors (ERs), thebiological target ofendogenousestrogens such asestradiol. When used in high doses,estrogens are powerfulantigonadotropins, strongly inhibitingsecretion of thegonadotropinsluteinizing hormone andfollicle-stimulating hormone from thepituitary gland, and in men are able to completely suppressgonadalandrogen production and reducetestosterone levels into thecastrate range.^[32] This is most of the basis of their use in prostate cancer and benign prostatic hyperplasia.^[32][28] Whenestradiol or anestradiol ester is used for HDE in men, levels of estradiol of at least approximately 200 pg/mL are necessary to suppress testosterone levels into the castrate range.^[33]

Synthetic and nonsteroidal estrogens likeethinylestradiol anddiethylstilbestrol are resistant tohepaticmetabolism and for this reason have dramatically increased localpotency in the liver.^[34][9][35] As a result, they have disproportionate effects onhepatic protein production and a greatly increased risk ofblood clots relative toendogenous and bioidentical forms of estrogen likeestradiol andestradiol esters.^[36] Unlike synthetic estrogens, bioidentical estrogens are efficiently inactivated in the liver even at high dosages or high circulating levels, as in pregnancy, although changes in hepatic protein production can still occur.^[34][9][35]

A study that used high- to very-high-doseoral estradiol to treat postmenopausal women withestrogen receptor-positivebreast cancer found that mean steady-state estradiol levels in the 6 mg/day group were about 300 pg/mL and in the 30 mg/day group were about 2,400 pg/mL.^[37] An example pseudopregnancy regimen in women which has been used in clinical studies isintramuscular injections of 40 mg/weekestradiol valerate and 250 mg/weekhydroxyprogesterone caproate.^[3] It has been found to result in estradiol levels of about 3,100 pg/mL at 3 months of therapy and 2,500 pg/mL at 6 months of therapy.^[3]

Levels of estrogen andprogesterone in normal human pregnancy are very high.^[6] Estradiol levels are 1,000 to 5,000 pg/mL during the first trimester, 5,000 to 15,000 pg/mL during the second trimester, and 10,000 to 40,000 pg/mL during the third trimester,^[38] with a mean of 25,000 pg/mL at term and levels as high as 75,000 pg/mL measurable in some women.^[39] Levels of progesterone are 10 to 50 ng/mL in the first trimester and rise to 50 to 280 ng/mL in the third trimester,^[40] with a mean of around 150 ng/mL at term.^[41] Although only a small fraction of estradiol and progesterone are unbound in circulation, the amounts of free and thus biologically active estradiol and progesterone increase to similarly large extents as total levels during pregnancy.^[41] As such, pregnancy is a markedlyhyperestrogenic andhyperprogestogenic state.^[42][43] Levels of estradiol and progesterone are both up to 100-fold higher during pregnancy than during normal menstrual cycling.^[44]

Pseudopregnancy simulates the hormonal profile of the first trimester ofpregnancy.^[45]

HDE has been used since the discovery and introduction of estrogens in the 1930s.^[44] It was first found to be effective in the treatment of prostate cancer in 1941^[46] and in the treatment of breast cancer in 1944.^[1][47] HDE was the first medical therapy for prostate cancer and breast cancer.^[48] Pseudopregnancy was developed in the 1950s following the introduction ofprogestins with improvedpotency andpharmacokinetics, at which time it was used to treat hypoplasia of the uterus and breasts and endometriosis.^[3][4][49] In modern times, pseudopregnancy is rarely used.^[4] However, studies in the mid-1990s were conducted and found it to be rapidly effective for increasingbone mineral density in women withosteopenia due tohypoestrogenism.^[3][4] HDE has also commonly been used in transgender women since the 1960s.^[50][51][52]

Oral HDE for prostate cancer with diethylstilbestrol was used widely in men with prostate cancer until the mid-1960s, when it was compared directly toorchiectomy and was associated with improved cancer-relatedmortality but worseoverall survival, mainly due to previously unrecognizedcardiovascular side effects.^[46][53] As a result of this study, HDE for prostate cancer fell out of favor.^[46] However, in recent times there has been a resurgence in interest of HDE for prostate cancer with safer, bioidentical and parenteral forms of estrogen that don't share the same risks, includingpolyestradiol phosphate and transdermal estradiol.^[54] Modern HDE for prostate cancer has a variety of advantages and benefits over conventional androgen deprivation therapy with castration, including fewer side effects likeosteoporosis,hot flashes, and impairment in cognitive, emotional, and sexual domains, potentially superiorquality of life, and considerable cost savings.^[54] The main drawback of modern HDE for prostate cancer is a high incidence ofgynecomastia of about 40 to 77%, although it is generally only mildly or modestly discomforting.^[54] In addition,prophylacticirradiation of the breasts can be used to prevent it and has minimal side effects, mostly consisting of temporaryskin discoloration.^[54]

Following continued clinical research after the discovery of the effectiveness of HDE for breast cancer in 1944, HDE, most commonly with diethylstilbestrol and to a lesser extent ethinylestradiol, became thestandard of care for the treatment of breast cancer in postmenopausal women from the early 1960s onwards.^[1] In the 1970s, theantiestrogentamoxifen was found to be effective for the treatment of breast cancer and was introduced for medical use.^[1] Comparative studies found that the two therapies showed equivalent effectiveness, but that tamoxifen had reducedtoxicity.^[1] As a result, antiestrogen therapy became the first-line treatment for breast cancer and almost completely replaced HDE.^[1] However, in the 1990s, HDE was revisited for breast cancer and was found to be effective in the treatment of women with acquired resistance to antiestrogen therapy.^[1] Since then, research on HDE for breast cancer has continued, and safer, bioidentical forms of estrogen like estradiol and estradiol valerate have also been studied and found to be effective.^[1] A major review was published in 2017 summarizing the literature to date.^[1]

Pseudopregnancy has been suggested for use in decreasing the risk of breast cancer in women, though this has not been assessed in clinical studies.^[55] Natural pregnancy before the age of 20 has been associated with a 50% lifetime reduction in the risk of breast cancer.^[56] Pseudopregnancy has been found to produce decreases in risk ofmammary glandtumors in rodents similar to those of natural pregnancy, implicating high levels of estrogen and progesterone in this effect.^[56]

• Hormone replacement therapy
• Estrogen deprivation therapy
• Hyperestrogenism

• Antigonadotropins
• Estrogens
• Hormonal antineoplastic drugs
• Medical treatments

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