High-dose estrogen therapy

Last updated

High-dose estrogen therapy
Drug class
Estradiol valerate.svg
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 of hormone therapy in which high doses of estrogens are given. [1] When given in combination with a high dose of progestogen, it has been referred to as pseudopregnancy. [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 these hormones that occur during pregnancy. [6] HDE and pseudopregnancy have been used in medicine for a number of hormone-dependent indications, such as breast cancer, prostate cancer, and endometriosis, among others. [1] [7] [2] Both natural or bioidentical estrogens and synthetic estrogens have been used and both oral and parenteral routes may be used. [8] [9]

Contents

Medical uses

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

The nonsteroidal estrogen diethylstilbestrol as well as other stilbestrols were previously used to support pregnancy and reduce the risk of miscarriage, but subsequent research found that diethylstilbestrol was both ineffective and teratogenic. [24]

HDE should be combined with a progestogen in women with an intact uterus as unopposed estrogen, particularly at high dosages, increases the risk of endometrial hyperplasia and endometrial 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]

Available forms

The following steroidal estrogens have been used in HDE therapy: [1] [27] [28]

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

Progestogens that have been used in pseudopregnancy regimens include hydroxyprogesterone caproate, medroxyprogesterone acetate, and cyproterone acetate, among others. [2] Progesterone has been little-used for such purposes likely due to its poor pharmacokinetics (e.g., low oral bioavailability and short elimination half-life). [29]

Side effects

General adverse effects of HDE may include breast enlargement, breast pain and tenderness, nipple enlargement and hyperpigmentation, nausea and vomiting, headache, fluid retention, edema, melasma, hyperprolactinemia, galactorrhea, amenorrhea, reversible infertility, and others. [30] More uncommon but serious side effects may include thrombus and thrombosis (e.g., venous thromboembolism), other cardiovascular events (e.g., myocardial infarction, stroke), prolactinoma, cholestatic jaundice, gallbladder disease, and gallstones. [30] In women, HDE may cause amenorrhea and rarely endometrial hyperplasia or endometrial cancer, but the risk of adverse endometrial changes is minimized or offset with pseudopregnancy regimens due to the progestogen component. The tolerability profile of HDE is worse in men compared to women. Side effects of HDE specific to men may include gynecomastia (breast development), feminization and demasculinization in general (e.g., reduced body hair, decreased muscle mass and strength, feminine changes in fat mass and distribution, and reduced penile and testicular size), and sexual dysfunction (e.g., reduced libido and erectile dysfunction). [30]

The use of HDE in men has been associated with cellulite, which has been attributed to androgen deficiency. [31]

Pharmacology

Estrogens are agonists of the estrogen receptors (ERs), the biological target of endogenous estrogens such as estradiol. When used in high doses, estrogens are powerful antigonadotropins, strongly inhibiting secretion of the gonadotropins luteinizing hormone and follicle-stimulating hormone from the pituitary gland, and in men are able to completely suppress gonadal androgen production and reduce testosterone levels into the castrate range. [32] This is most of the basis of their use in prostate cancer and benign prostatic hyperplasia. [32] [28] When estradiol or an estradiol 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 like ethinylestradiol and diethylstilbestrol are resistant to hepatic metabolism and for this reason have dramatically increased local potency in the liver. [34] [9] [35] As a result, they have disproportionate effects on hepatic protein production and a greatly increased risk of blood clots relative to endogenous and bioidentical forms of estrogen like estradiol and estradiol 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-dose oral estradiol to treat postmenopausal women with estrogen receptor-positive breast 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 is intramuscular injections of 40 mg/week estradiol valerate and 250 mg/week hydroxyprogesterone 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 and progesterone 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 markedly hyperestrogenic and hyperprogestogenic 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 of pregnancy. [45]

History

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 of progestins with improved potency and pharmacokinetics, 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 increasing bone mineral density in women with osteopenia due to hypoestrogenism. [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 to orchiectomy and was associated with improved cancer-related mortality but worse overall survival, mainly due to previously unrecognized cardiovascular 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, including polyestradiol 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 like osteoporosis, hot flashes, and impairment in cognitive, emotional, and sexual domains, potentially superior quality of life, and considerable cost savings. [54] The main drawback of modern HDE for prostate cancer is a high incidence of gynecomastia of about 40 to 77%, although it is generally only mildly or modestly discomforting. [54] In addition, prophylactic irradiation of the breasts can be used to prevent it and has minimal side effects, mostly consisting of temporary skin 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 the standard of care for the treatment of breast cancer in postmenopausal women from the early 1960s onwards. [1] In the 1970s, the antiestrogen tamoxifen 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 reduced toxicity. [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]

Research

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 of mammary gland tumors in rodents similar to those of natural pregnancy, implicating high levels of estrogen and progesterone in this effect. [56]

See also

Related Research Articles

<span class="mw-page-title-main">Progestogen (medication)</span> Medication producing effects similar to progesterone

A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a synthetic progestogen. Progestogens are used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestogens are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.

<span class="mw-page-title-main">Diethylstilbestrol</span> Chemical compound

Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication, which is presently rarely used. In the past, it was widely used for a variety of indications, including pregnancy support for those with a history of recurrent miscarriage, hormone therapy for menopausal symptoms and estrogen deficiency, treatment of prostate cancer and breast cancer, and other uses. By 2007, it was only used in the treatment of prostate cancer and breast cancer. In 2011, Hoover and colleagues reported on adverse health outcomes linked to DES including infertility, miscarriage, ectopic pregnancy, preeclampsia, preterm birth, stillbirth, infant death, menopause prior to age 45, breast cancer, cervical cancer, and vaginal cancer. While most commonly taken by mouth, DES was available for use by other routes as well, for instance, vaginal, topical, and by injection.

<span class="mw-page-title-main">Ethinylestradiol</span> Estrogen medication

Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological disorders, and certain hormone-sensitive cancers. It is usually taken by mouth but is also used as a patch and vaginal ring.

<span class="mw-page-title-main">Polyestradiol phosphate</span> Chemical compound

Polyestradiol phosphate (PEP), sold under the brand name Estradurin, is an estrogen medication which is used primarily in the treatment of prostate cancer in men. It is also used in women to treat breast cancer, as a component of hormone therapy to treat low estrogen levels and menopausal symptoms, and as a component of feminizing hormone therapy for transgender women. It is given by injection into muscle once every four weeks.

<span class="mw-page-title-main">Norethisterone</span> Progestin medication

Norethisterone, also known as norethindrone and sold under the brand name Norlutin among others, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication is available in both low-dose and high-dose formulations and both alone and in combination with an estrogen. It is used by mouth or, as norethisterone enanthate, by injection into muscle.

<span class="mw-page-title-main">Dydrogesterone</span> Chemical compound

Dydrogesterone, sold under the brand name Duphaston among others, is a progestin medication which is used for a variety of indications, including threatened or recurrent miscarriage during pregnancy, dysfunctional bleeding, infertility due to luteal insufficiency, dysmenorrhea, endometriosis, secondary amenorrhea, irregular cycles, premenstrual syndrome, and as a component of menopausal hormone therapy. It is taken by mouth.

Feminizing hormone therapy, also known as transfeminine hormone therapy, is hormone therapy and sex reassignment therapy to change the secondary sex characteristics of transgender people from masculine or androgynous to feminine. It is a common type of transgender hormone therapy and is used to treat transgender women and non-binary transfeminine individuals. Some, in particular intersex people, but also some non-transgender people, take this form of therapy according to their personal needs and preferences.

Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. Effects of menopause can include symptoms such as hot flashes, accelerated skin aging, vaginal dryness, decreased muscle mass, and complications such as osteoporosis, sexual dysfunction, and vaginal atrophy. They are mostly caused by low levels of female sex hormones that occur during menopause.

<span class="mw-page-title-main">Estradiol benzoate</span> Chemical compound

Estradiol benzoate (EB), sold under the brand name Progynon-B among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in women, in hormone therapy for transgender women, and in the treatment of gynecological disorders. It is also used in the treatment of prostate cancer in men. Estradiol benzoate is used in veterinary medicine as well. When used clinically, the medication is given by injection into muscle usually two to three times per week.

<span class="mw-page-title-main">Medroxyprogesterone acetate</span> Injectable form of birth control

Medroxyprogesterone acetate (MPA), also known as depot medroxyprogesterone acetate (DMPA) in injectable form and sold under the brand name Depo-Provera among others, is a hormonal medication of the progestin type. It is used as a method of birth control and as a part of menopausal hormone therapy. It is also used to treat endometriosis, abnormal uterine bleeding, paraphilia, and certain types of cancer. The medication is available both alone and in combination with an estrogen. It is taken by mouth, used under the tongue, or by injection into a muscle or fat.

<span class="mw-page-title-main">Nomegestrol acetate</span> Chemical compound

Nomegestrol acetate (NOMAC), sold under the brand names Lutenyl and Zoely among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. It is available both alone and in combination with an estrogen. NOMAC is taken by mouth. A birth control implant for placement under the skin was also developed but ultimately was not marketed.

<span class="mw-page-title-main">Estradiol undecylate</span> Chemical compound

Estradiol undecylate, also known as estradiol undecanoate and formerly sold under the brand names Delestrec and Progynon Depot 100 among others, is an estrogen medication which has been used in the treatment of prostate cancer in men. It has also been used as a part of hormone therapy for transgender women. Although estradiol undecylate has been used in the past, it was discontinued. The medication has been given by injection into muscle usually once a month.

<span class="mw-page-title-main">Conjugated estrogens</span> Estrogen medication

Conjugated estrogens (CEs), or conjugated equine estrogens (CEEs), sold under the brand name Premarin among others, is an estrogen medication which is used in menopausal hormone therapy and for various other indications. It is a mixture of the sodium salts of estrogen conjugates found in horses, such as estrone sulfate and equilin sulfate. CEEs are available in the form of both natural preparations manufactured from the urine of pregnant mares and fully synthetic replications of the natural preparations. They are formulated both alone and in combination with progestins such as medroxyprogesterone acetate. CEEs are usually taken by mouth, but can also be given by application to the skin or vagina as a cream or by injection into a blood vessel or muscle.

<span class="mw-page-title-main">Estradiol (medication)</span> Steroidal hormone medication

Estradiol (E2) is a medication and naturally occurring steroid hormone. It is an estrogen and is used mainly in menopausal hormone therapy and to treat low sex hormone levels in women. It is also used in hormonal birth control for women, in feminizing hormone therapy for transgender women and some non-binary individuals, and in the treatment of hormone-sensitive cancers like prostate cancer in men and breast cancer in women, among other uses. Estradiol can be taken by mouth, held and dissolved under the tongue, as a gel or patch that is applied to the skin, in through the vagina, by injection into muscle or fat, or through the use of an implant that is placed into fat, among other routes.

<span class="mw-page-title-main">Progesterone (medication)</span> Medication and naturally occurring steroid hormone

Progesterone (P4), sold under the brand name Prometrium among others, is a medication and naturally occurring steroid hormone. It is a progestogen and is used in combination with estrogens mainly in hormone therapy for menopausal symptoms and low sex hormone levels in women. It is also used in women to support pregnancy and fertility and to treat gynecological disorders. Progesterone can be taken by mouth, vaginally, and by injection into muscle or fat, among other routes. A progesterone vaginal ring and progesterone intrauterine device used for birth control also exist in some areas of the world.

<span class="mw-page-title-main">Estrogen (medication)</span> Type of medication

An estrogen (E) is a type of medication which is used most commonly in hormonal birth control and menopausal hormone therapy, and as part of feminizing hormone therapy for transgender women. They can also be used in the treatment of hormone-sensitive cancers like breast cancer and prostate cancer and for various other indications. Estrogens are used alone or in combination with progestogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of estrogens include bioidentical estradiol, natural conjugated estrogens, synthetic steroidal estrogens like ethinylestradiol, and synthetic nonsteroidal estrogens like diethylstilbestrol. Estrogens are one of three types of sex hormone agonists, the others being androgens/anabolic steroids like testosterone and progestogens like progesterone.

The pharmacology of estradiol, an estrogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.

<span class="mw-page-title-main">Estradiol valerate/hydroxyprogesterone caproate</span> Pharmaceutical combination

Estradiol valerate/hydroxyprogesterone caproate (EV/OHPC), sold under the brand names Gravibinon and Injectable No. 1 among others, is a combined estrogen and progestogen medication which is used in the treatment of threatened miscarriage and other indications and as a form of combined injectable birth control to prevent pregnancy. It contains estradiol valerate (EV), an estrogen, and hydroxyprogesterone caproate (OHPC), a progestin. The medication is given by injection into muscle once a day to once a month depending on the indication.

<span class="mw-page-title-main">Pharmacology of cyproterone acetate</span>

The pharmacology of cyproterone acetate (CPA) concerns the pharmacology of the steroidal antiandrogen and progestin medication cyproterone acetate.

<span class="mw-page-title-main">Estradiol valerate/gestonorone caproate</span> Combination drug

Estradiol valerate/gestonorone caproate (EV/GC), known by the developmental code names SH-834 and SH-8.0834, is a high-dose combination medication of estradiol valerate (EV), an estrogen, and gestonorone caproate, a progestin, which was developed and studied by Schering in the 1960s and 1970s for potential use in the treatment of breast cancer in women but was ultimately never marketed. It contained 90 mg EV and 300 mg GC in each 3 mL of oil solution and was intended for use by intramuscular injection once a week. The combination has also been studied incidentally in the treatment of ovarian cancer.

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