Estrogen

Estrogen, or oestrogen, is the primary female sex hormone. It is responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens in females that have estrogenic hormonal activity: estrone (E1), estradiol (E2), and estriol (E3). Estradiol, an estrane, is the most potent and prevalent. Another estrogen called estetrol (E4) is produced only during pregnancy.

This article is about estrogens as hormones. For their use as medications, see Estrogen (medication).

Estrogen
Drug class
Estradiol, the major estrogen sex hormone in humans and a widely used medication.
Class identifiers
Use	Contraception, menopause, hypogonadism, transgender women, prostate cancer, breast cancer, others
ATC code	G03C
Biological target	Estrogen receptors (ERα, ERβ, mERs (e.g., GPER, others))
External links
MeSH	D004967
In Wikidata

Estrogens are synthesized in all vertebrates[1] and some insects.[2] Their presence in both vertebrates and insects suggests that estrogenic sex hormones have an ancient evolutionary history. Quantitatively, estrogens circulate at lower levels than androgens in both men and women.[3] While estrogen levels are significantly lower in males compared to females, estrogens nevertheless have important physiological roles in males.[4]

Like all steroid hormones, estrogens readily diffuse across the cell membrane. Once inside the cell, they bind to and activate estrogen receptors (ERs) which in turn modulate the expression of many genes.[5] Additionally, estrogens bind to and activate rapid-signaling membrane estrogen receptors (mERs),[6][7] such as GPER (GPR30).[8]

In addition to their role as natural hormones, estrogens are used as medications, for instance in menopausal hormone therapy and hormonal birth control.

Types and examples

Structures of major endogenous estrogens Estrone (E1) Estradiol (E2) Estriol (E3) Estetrol (E4) Note the hydroxyl (–OH) groups: estrone (E1) has one, estradiol (E2) has two, estriol (E3) has three, and estetrol (E4) has four.

The four major naturally occurring estrogens in women are estrone (E1), estradiol (E2), estriol (E3), and estetrol (E4). Estradiol is the predominant estrogen during reproductive years both in terms of absolute serum levels as well as in terms of estrogenic activity. During menopause, estrone is the predominant circulating estrogen and during pregnancy estriol is the predominant circulating estrogen in terms of serum levels. Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.[9] Thus, estradiol is the most important estrogen in non-pregnant females who are between the menarche and menopause stages of life. However, during pregnancy this role shifts to estriol, and in postmenopausal women estrone becomes the primary form of estrogen in the body. Another type of estrogen called estetrol (E4) is produced only during pregnancy. All of the different forms of estrogen are synthesized from androgens, specifically testosterone and androstenedione, by the enzyme aromatase.

Minor endogenous estrogens, the biosyntheses of which do not involve aromatase, include 27-hydroxycholesterol, dehydroepiandrosterone (DHEA), 7-oxo-DHEA, 7α-hydroxy-DHEA, 16α-hydroxy-DHEA, 7β-hydroxyepiandrosterone, androstenedione (A4), androstenediol (A5), 3α-androstanediol, and 3β-androstanediol.[10][11] Some estrogen metabolites, such as the catechol estrogens 2-hydroxyestradiol, 2-hydroxyestrone, 4-hydroxyestradiol, and 4-hydroxyestrone, as well as 16α-hydroxyestrone, are also estrogens with varying degrees of activity.[12] The biological importance of these minor estrogens is not entirely clear.

Biological function

Reference ranges for the blood content of estradiol, the primary type of estrogen, during the menstrual cycle.[13]

The actions of estrogen are mediated by the estrogen receptor (ER), a dimeric nuclear protein that binds to DNA and controls gene expression. Like other steroid hormones, estrogen enters passively into the cell where it binds to and activates the estrogen receptor. The estrogen:ER complex binds to specific DNA sequences called a hormone response element to activate the transcription of target genes (in a study using an estrogen-dependent breast cancer cell line as model, 89 such genes were identified).[14] Since estrogen enters all cells, its actions are dependent on the presence of the ER in the cell. The ER is expressed in specific tissues including the ovary, uterus and breast. The metabolic effects of estrogen in postmenopausal women have been linked to the genetic polymorphism of the ER.[15]

While estrogens are present in both men and women, they are usually present at significantly higher levels in women of reproductive age. They promote the development of female secondary sexual characteristics, such as breasts, and are also involved in the thickening of the endometrium and other aspects of regulating the menstrual cycle. In males, estrogen regulates certain functions of the reproductive system important to the maturation of sperm[16][17][18] and may be necessary for a healthy libido.[19]

Affinities of estrogen receptor ligands for the ERα and ERβ

Ligand	Other names	Relative binding affinities (RBA, %)^a		Absolute binding affinities (Ki, nM)^a		Action
		ERα	ERβ	ERα	ERβ
Estradiol	E2; 17β-Estradiol	100	100	0.115 (0.04–0.24)	0.15 (0.10–2.08)	Estrogen
Estrone	E1; 17-Ketoestradiol	16.39 (0.7–60)	6.5 (1.36–52)	0.445 (0.3–1.01)	1.75 (0.35–9.24)	Estrogen
Estriol	E3; 16α-OH-17β-E2	12.65 (4.03–56)	26 (14.0–44.6)	0.45 (0.35–1.4)	0.7 (0.63–0.7)	Estrogen
Estetrol	E4; 15α,16α-Di-OH-17β-E2	4.0	3.0	4.9	19	Estrogen
Alfatradiol	17α-Estradiol	20.5 (7–80.1)	8.195 (2–42)	0.2–0.52	0.43–1.2	Metabolite
16-Epiestriol	16β-Hydroxy-17β-estradiol	7.795 (4.94–63)	50	?	?	Metabolite
17-Epiestriol	16α-Hydroxy-17α-estradiol	55.45 (29–103)	79–80	?	?	Metabolite
16,17-Epiestriol	16β-Hydroxy-17α-estradiol	1.0	13	?	?	Metabolite
2-Hydroxyestradiol	2-OH-E2	22 (7–81)	11–35	2.5	1.3	Metabolite
2-Methoxyestradiol	2-MeO-E2	0.0027–2.0	1.0	?	?	Metabolite
4-Hydroxyestradiol	4-OH-E2	13 (8–70)	7–56	1.0	1.9	Metabolite
4-Methoxyestradiol	4-MeO-E2	2.0	1.0	?	?	Metabolite
2-Hydroxyestrone	2-OH-E1	2.0–4.0	0.2–0.4	?	?	Metabolite
2-Methoxyestrone	2-MeO-E1	<0.001–<1	<1	?	?	Metabolite
4-Hydroxyestrone	4-OH-E1	1.0–2.0	1.0	?	?	Metabolite
4-Methoxyestrone	4-MeO-E1	<1	<1	?	?	Metabolite
16α-Hydroxyestrone	16α-OH-E1; 17-Ketoestriol	2.0–6.5	35	?	?	Metabolite
2-Hydroxyestriol	2-OH-E3	2.0	1.0	?	?	Metabolite
4-Methoxyestriol	4-MeO-E3	1.0	1.0	?	?	Metabolite
Estradiol sulfate	E2S; Estradiol 3-sulfate	<1	<1	?	?	Metabolite
Estradiol disulfate	Estradiol 3,17β-disulfate	0.0004	?	?	?	Metabolite
Estradiol 3-glucuronide	E2-3G	0.0079	?	?	?	Metabolite
Estradiol 17β-glucuronide	E2-17G	0.0015	?	?	?	Metabolite
Estradiol 3-gluc. 17β-sulfate	E2-3G-17S	0.0001	?	?	?	Metabolite
Estrone sulfate	E1S; Estrone 3-sulfate	<1	<1	>10	>10	Metabolite
Estradiol benzoate	EB; Estradiol 3-benzoate	10	?	?	?	Estrogen
Estradiol 17β-benzoate	E2-17B	11.3	32.6	?	?	Estrogen
Estrone methyl ether	Estrone 3-methyl ether	0.145	?	?	?	Estrogen
ent-Estradiol	1-Estradiol	1.31–12.34	9.44–80.07	?	?	Estrogen
Equilin	7-Dehydroestrone	13 (4.0–28.9)	13.0–49	0.79	0.36	Estrogen
Equilenin	6,8-Didehydroestrone	2.0–15	7.0–20	0.64	0.62	Estrogen
17β-Dihydroequilin	7-Dehydro-17β-estradiol	7.9–113	7.9–108	0.09	0.17	Estrogen
17α-Dihydroequilin	7-Dehydro-17α-estradiol	18.6 (18–41)	14–32	0.24	0.57	Estrogen
17β-Dihydroequilenin	6,8-Didehydro-17β-estradiol	35–68	90–100	0.15	0.20	Estrogen
17α-Dihydroequilenin	6,8-Didehydro-17α-estradiol	20	49	0.50	0.37	Estrogen
Δ^8-Estradiol	8,9-Dehydro-17β-estradiol	68	72	0.15	0.25	Estrogen
Δ^8-Estrone	8,9-Dehydroestrone	19	32	0.52	0.57	Estrogen
Ethinylestradiol	EE; 17α-Ethynyl-17β-E2	120.9 (68.8–480)	44.4 (2.0–144)	0.02–0.05	0.29–0.81	Estrogen
Mestranol	EE 3-methyl ether	?	2.5	?	?	Estrogen
Moxestrol	RU-2858; 11β-Methoxy-EE	35–43	5–20	0.5	2.6	Estrogen
Methylestradiol	17α-Methyl-17β-estradiol	70	44	?	?	Estrogen
Diethylstilbestrol	DES; Stilbestrol	129.5 (89.1–468)	219.63 (61.2–295)	0.04	0.05	Estrogen
Hexestrol	Dihydrodiethylstilbestrol	153.6 (31–302)	60–234	0.06	0.06	Estrogen
Dienestrol	Dehydrostilbestrol	37 (20.4–223)	56–404	0.05	0.03	Estrogen
Benzestrol (B2)	–	114	?	?	?	Estrogen
Chlorotrianisene	TACE	1.74	?	15.30	?	Estrogen
Triphenylethylene	TPE	0.074	?	?	?	Estrogen
Triphenylbromoethylene	TPBE	2.69	?	?	?	Estrogen
Tamoxifen	ICI-46,474	3 (0.1–47)	3.33 (0.28–6)	3.4–9.69	2.5	SERM
Afimoxifene	4-Hydroxytamoxifen; 4-OHT	100.1 (1.7–257)	10 (0.98–339)	2.3 (0.1–3.61)	0.04–4.8	SERM
Toremifene	4-Chlorotamoxifen; 4-CT	?	?	7.14–20.3	15.4	SERM
Clomifene	MRL-41	25 (19.2–37.2)	12	0.9	1.2	SERM
Cyclofenil	F-6066; Sexovid	151–152	243	?	?	SERM
Nafoxidine	U-11,000A	30.9–44	16	0.3	0.8	SERM
Raloxifene	–	41.2 (7.8–69)	5.34 (0.54–16)	0.188–0.52	20.2	SERM
Arzoxifene	LY-353,381	?	?	0.179	?	SERM
Lasofoxifene	CP-336,156	10.2–166	19.0	0.229	?	SERM
Ormeloxifene	Centchroman	?	?	0.313	?	SERM
Levormeloxifene	6720-CDRI; NNC-460,020	1.55	1.88	?	?	SERM
Ospemifene	Deaminohydroxytoremifene	2.63	1.22	?	?	SERM
Bazedoxifene	–	?	?	0.053	?	SERM
Etacstil	GW-5638	4.30	11.5	?	?	SERM
ICI-164,384	–	63.5 (3.70–97.7)	166	0.2	0.08	Antiestrogen
Fulvestrant	ICI-182,780	43.5 (9.4–325)	21.65 (2.05–40.5)	0.42	1.3	Antiestrogen
Propylpyrazoletriol	PPT	49 (10.0–89.1)	0.12	0.40	92.8	ERα agonist
16α-LE2	16α-Lactone-17β-estradiol	14.6–57	0.089	0.27	131	ERα agonist
16α-Iodo-E2	16α-Iodo-17β-estradiol	30.2	2.30	?	?	ERα agonist
Methylpiperidinopyrazole	MPP	11	0.05	?	?	ERα antagonist
Diarylpropionitrile	DPN	0.12–0.25	6.6–18	32.4	1.7	ERβ agonist
8β-VE2	8β-Vinyl-17β-estradiol	0.35	22.0–83	12.9	0.50	ERβ agonist
Prinaberel	ERB-041; WAY-202,041	0.27	67–72	?	?	ERβ agonist
ERB-196	WAY-202,196	?	180	?	?	ERβ agonist
Erteberel	SERBA-1; LY-500,307	?	?	2.68	0.19	ERβ agonist
SERBA-2	–	?	?	14.5	1.54	ERβ agonist
Coumestrol	–	9.225 (0.0117–94)	64.125 (0.41–185)	0.14–80.0	0.07–27.0	Xenoestrogen
Genistein	–	0.445 (0.0012–16)	33.42 (0.86–87)	2.6–126	0.3–12.8	Xenoestrogen
Equol	–	0.2–0.287	0.85 (0.10–2.85)	?	?	Xenoestrogen
Daidzein	–	0.07 (0.0018–9.3)	0.7865 (0.04–17.1)	2.0	85.3	Xenoestrogen
Biochanin A	–	0.04 (0.022–0.15)	0.6225 (0.010–1.2)	174	8.9	Xenoestrogen
Kaempferol	–	0.07 (0.029–0.10)	2.2 (0.002–3.00)	?	?	Xenoestrogen
Naringenin	–	0.0054 (<0.001–0.01)	0.15 (0.11–0.33)	?	?	Xenoestrogen
8-Prenylnaringenin	8-PN	4.4	?	?	?	Xenoestrogen
Quercetin	–	<0.001–0.01	0.002–0.040	?	?	Xenoestrogen
Ipriflavone	–	<0.01	<0.01	?	?	Xenoestrogen
Miroestrol	–	0.39	?	?	?	Xenoestrogen
Deoxymiroestrol	–	2.0	?	?	?	Xenoestrogen
β-Sitosterol	–	<0.001–0.0875	<0.001–0.016	?	?	Xenoestrogen
Resveratrol	–	<0.001–0.0032	?	?	?	Xenoestrogen
α-Zearalenol	–	48 (13–52.5)	?	?	?	Xenoestrogen
β-Zearalenol	–	0.6 (0.032–13)	?	?	?	Xenoestrogen
Zeranol	α-Zearalanol	48–111	?	?	?	Xenoestrogen
Taleranol	β-Zearalanol	16 (13–17.8)	14	0.8	0.9	Xenoestrogen
Zearalenone	ZEN	7.68 (2.04–28)	9.45 (2.43–31.5)	?	?	Xenoestrogen
Zearalanone	ZAN	0.51	?	?	?	Xenoestrogen
Bisphenol A	BPA	0.0315 (0.008–1.0)	0.135 (0.002–4.23)	195	35	Xenoestrogen
Endosulfan	EDS	<0.001–<0.01	<0.01	?	?	Xenoestrogen
Kepone	Chlordecone	0.0069–0.2	?	?	?	Xenoestrogen
o,p'-DDT	–	0.0073–0.4	?	?	?	Xenoestrogen
p,p'-DDT	–	0.03	?	?	?	Xenoestrogen
Methoxychlor	p,p'-Dimethoxy-DDT	0.01 (<0.001–0.02)	0.01–0.13	?	?	Xenoestrogen
HPTE	Hydroxychlor; p,p'-OH-DDT	1.2–1.7	?	?	?	Xenoestrogen
Testosterone	T; 4-Androstenolone	<0.0001–<0.01	<0.002–0.040	>5000	>5000	Androgen
Dihydrotestosterone	DHT; 5α-Androstanolone	0.01 (<0.001–0.05)	0.0059–0.17	221–>5000	73–1688	Androgen
Nandrolone	19-Nortestosterone; 19-NT	0.01	0.23	765	53	Androgen
Dehydroepiandrosterone	DHEA; Prasterone	0.038 (<0.001–0.04)	0.019–0.07	245–1053	163–515	Androgen
5-Androstenediol	A5; Androstenediol	6	17	3.6	0.9	Androgen
4-Androstenediol	–	0.5	0.6	23	19	Androgen
4-Androstenedione	A4; Androstenedione	<0.01	<0.01	>10000	>10000	Androgen
3α-Androstanediol	3α-Adiol	0.07	0.3	260	48	Androgen
3β-Androstanediol	3β-Adiol	3	7	6	2	Androgen
Androstanedione	5α-Androstanedione	<0.01	<0.01	>10000	>10000	Androgen
Etiocholanedione	5β-Androstanedione	<0.01	<0.01	>10000	>10000	Androgen
Methyltestosterone	17α-Methyltestosterone	<0.0001	?	?	?	Androgen
Ethinyl-3α-androstanediol	17α-Ethynyl-3α-adiol	4.0	<0.07	?	?	Estrogen
Ethinyl-3β-androstanediol	17α-Ethynyl-3β-adiol	50	5.6	?	?	Estrogen
Progesterone	P4; 4-Pregnenedione	<0.001–0.6	<0.001–0.010	?	?	Progestogen
Norethisterone	NET; 17α-Ethynyl-19-NT	0.085 (0.0015–<0.1)	0.1 (0.01–0.3)	152	1084	Progestogen
Norethynodrel	5(10)-Norethisterone	0.5 (0.3–0.7)	<0.1–0.22	14	53	Progestogen
Tibolone	7α-Methylnorethynodrel	0.5 (0.45–2.0)	0.2–0.076	?	?	Progestogen
Δ^4-Tibolone	7α-Methylnorethisterone	0.069–<0.1	0.027–<0.1	?	?	Progestogen
3α-Hydroxytibolone	–	2.5 (1.06–5.0)	0.6–0.8	?	?	Progestogen
3β-Hydroxytibolone	–	1.6 (0.75–1.9)	0.070–0.1	?	?	Progestogen
Footnotes: ^a = (1) Binding affinity values are of the format "median (range)" (# (#–#)), "range" (#–#), or "value" (#) depending on the values available. The full sets of values within the ranges can be found in the Wiki code. (2) Binding affinities were determined via displacement studies in a variety of in-vitro systems with labeled estradiol and human ERα and ERβ proteins (except the ERβ values from Kuiper et al. (1997), which are rat ERβ). Sources: See template page.

Relative affinities of estrogens for steroid hormone receptors and blood proteins

Estrogen	Relative binding affinities (%)
	ER	AR	PR	GR	MR	SHBG	CBG
Estradiol	100	7.9	2.6	0.6	0.13	8.7–12	<0.1
Estradiol benzoate	?	?	?	?	?	<0.1–0.16	<0.1
Estradiol valerate	2	?	?	?	?	?	?
Estrone	11–35	<1	<1	<1	<1	2.7	<0.1
Estrone sulfate	2	2	?	?	?	?	?
Estriol	10–15	<1	<1	<1	<1	<0.1	<0.1
Equilin	40	?	?	?	?	?	0
Alfatradiol	15	<1	<1	<1	<1	?	?
Epiestriol	20	<1	<1	<1	<1	?	?
Ethinylestradiol	100–112	1–3	15–25	1–3	<1	0.18	<0.1
Mestranol	1	?	?	?	?	<0.1	<0.1
Methylestradiol	67	1–3	3–25	1–3	<1	?	?
Moxestrol	12	<0.1	0.8	3.2	<0.1	<0.2	<0.1
Diethylstilbestrol	?	?	?	?	?	<0.1	<0.1
Notes: Reference ligands (100%) were progesterone for the PR, testosterone for the AR, estradiol for the ER, dexamethasone for the GR, aldosterone for the MR, dihydrotestosterone for SHBG, and cortisol for CBG. Sources: See template.

Affinities and estrogenic potencies of estrogen esters and ethers at the estrogen receptors

Estrogen	Other names	RBA (%)^a	REP (%)^b
		ER	ERα	ERβ
Estradiol	E2	100	100	100
Estradiol 3-sulfate	E2S; E2-3S	?	0.02	0.04
Estradiol 3-glucuronide	E2-3G	?	0.02	0.09
Estradiol 17β-glucuronide	E2-17G	?	0.002	0.0002
Estradiol benzoate	EB; Estradiol 3-benzoate	10	1.1	0.52
Estradiol 17β-acetate	E2-17A	31–45	24	?
Estradiol diacetate	EDA; Estradiol 3,17β-diacetate	?	0.79	?
Estradiol propionate	EP; Estradiol 17β-propionate	19–26	2.6	?
Estradiol valerate	EV; Estradiol 17β-valerate	2–11	0.04–21	?
Estradiol cypionate	EC; Estradiol 17β-cypionate	?^c	4.0	?
Estradiol palmitate	Estradiol 17β-palmitate	0	?	?
Estradiol stearate	Estradiol 17β-stearate	0	?	?
Estrone	E1; 17-Ketoestradiol	11	5.3–38	14
Estrone sulfate	E1S; Estrone 3-sulfate	2	0.004	0.002
Estrone glucuronide	E1G; Estrone 3-glucuronide	?	<0.001	0.0006
Ethinylestradiol	EE; 17α-Ethynylestradiol	100	17–150	129
Mestranol	EE 3-methyl ether	1	1.3–8.2	0.16
Quinestrol	EE 3-cyclopentyl ether	?	0.37	?
Footnotes: ^a = Relative binding affinities (RBAs) were determined via in-vitro displacement of labeled estradiol from estrogen receptors (ERs) generally of rodent uterine cytosol. Estrogen esters are variably hydrolyzed into estrogens in these systems (shorter ester chain length -> greater rate of hydrolysis) and the ER RBAs of the esters decrease strongly when hydrolysis is prevented. ^b = Relative estrogenic potencies (REPs) were calculated from half-maximal effective concentrations (EC50) that were determined via in-vitro β‐galactosidase (β-gal) and green fluorescent protein (GFP) expression assays in yeast expressing human ERα and human ERβ. Both mammalian cells and yeast have the capacity to hydrolyze estrogen esters. ^c = The affinities of estradiol cypionate for the ERs are similar to those of estradiol valerate and estradiol benzoate (figure). Sources: See template page.

Selected biological properties of endogenous estrogens in rats

Estrogen	ER RBA (%)	Uterine weight (%)	Uterotrophy	LH levels (%)	SHBG RBA (%)
Control	–	100	–	100	–
Estradiol	100	506 ± 20	+++	12–19	100
Estrone	11 ± 8	490 ± 22	+++	?	20
Estriol	10 ± 4	468 ± 30	+++	8–18	3
Estetrol	0.5 ± 0.2	?	Inactive	?	1
17α-Estradiol	4.2 ± 0.8	?	?	?	?
2-Hydroxyestradiol	24 ± 7	285 ± 8	+^b	31–61	28
2-Methoxyestradiol	0.05 ± 0.04	101	Inactive	?	130
4-Hydroxyestradiol	45 ± 12	?	?	?	?
4-Methoxyestradiol	1.3 ± 0.2	260	++	?	9
4-Fluoroestradiol^a	180 ± 43	?	+++	?	?
2-Hydroxyestrone	1.9 ± 0.8	130 ± 9	Inactive	110–142	8
2-Methoxyestrone	0.01 ± 0.00	103 ± 7	Inactive	95–100	120
4-Hydroxyestrone	11 ± 4	351	++	21–50	35
4-Methoxyestrone	0.13 ± 0.04	338	++	65–92	12
16α-Hydroxyestrone	2.8 ± 1.0	552 ± 42	+++	7–24	<0.5
2-Hydroxyestriol	0.9 ± 0.3	302	+^b	?	?
2-Methoxyestriol	0.01 ± 0.00	?	Inactive	?	4
Notes: Values are mean ± SD or range. ER RBA = Relative binding affinity to estrogen receptors of rat uterine cytosol. Uterine weight = Percentage change in uterine wet weight of ovariectomized rats after 72 hours with continuous administration of 1 μg/hour via subcutaneously implanted osmotic pumps. LH levels = Luteinizing hormone levels relative to baseline of ovariectomized rats after 24 to 72 hours of continuous administration via subcutaneous implant. Footnotes: ^a = Synthetic (i.e., not endogenous). ^b = Atypical uterotrophic effect which plateaus within 48 hours (estradiol's uterotrophy continues linearly up to 72 hours). Sources: See template.

Overview of actions

• Structural
  • Mediate formation of female secondary sex characteristics
  • Accelerate metabolism
  • Increase fat store
  • Stimulate endometrial growth
  • Increase uterine growth
  • Increase vaginal lubrication
  • Thicken the vaginal wall
  • Maintenance of vessel and skin
  • Reduce bone resorption, increase bone formation
• Protein synthesis
  • Increase hepatic production of binding proteins
• Coagulation
  • Increase circulating level of factors 2, 7, 9, 10, plasminogen
  • Decrease antithrombin III
  • Increase platelet adhesiveness
  • Increase vWF (estrogen -> Angiotensin II -> Vasopressin)
  • Increase PAI-1 and PAI-2 also through Angiotensin II
• Lipid
  • Increase HDL, triglyceride
  • Decrease LDL, fat deposition
• Fluid balance
  • Salt (sodium) and water retention
  • Increase cortisol, SHBG
• Gastrointestinal tract
  • Reduce bowel motility
  • Increase cholesterol in bile
• Melanin
  • Increase pheomelanin, reduce eumelanin
• Cancer
  • Support hormone-sensitive breast cancers (see section below)
• Lung function
  • Promotes lung function by supporting alveoli (in rodents but probably in humans).[20]
• Uterus lining
  • Estrogen together with progesterone promotes and maintains the uterus lining in preparation for implantation of fertilized egg and maintenance of uterus function during gestation period, also upregulates oxytocin receptor in myometrium
• Ovulation
  • Surge in estrogen level induces the release of luteinizing hormone, which then triggers ovulation by releasing the egg from the Graafian follicle in the ovary.
• Sexual behavior
  • Promotes sexual receptivity in estrus,[21] and induces lordosis behavior.[22] In non-human mammals, it also induces estrus (in heat) prior to ovulation, which also induces lordosis behavior. Female non-human mammals are not sexually receptive without the estrogen surge, i.e., they have no mating desire when not in estrus.
  • Regulates the stereotypical sexual receptivity behavior; this lordosis behavior is estrogen-dependent, which is regulated by the ventromedial nucleus of the hypothalamus.[23]
  • Sex drive is dependent on androgen levels[24] only in the presence of estrogen, but without estrogen, free testosterone level actually decreases sexual desire (instead of increases sex drive), as demonstrated for those women who have hypoactive sexual desire disorder, and the sexual desire in these women can be restored by administration of estrogen (using oral contraceptive).[25] In non-human mammals, mating desire is triggered by estrogen surge in estrus.

Female pubertal development

Estrogens are responsible for the development of female secondary sexual characteristics during puberty, including breast development, widening of the hips, and female fat distribution. Conversely, androgens are responsible for pubic and body hair growth, as well as acne and axillary odor.

Breast development

See also: Breast development § Biochemistry

Estrogen, in conjunction with growth hormone (GH) and its secretory product insulin-like growth factor 1 (IGF-1), is critical in mediating breast development during puberty, as well as breast maturation during pregnancy in preparation of lactation and breastfeeding.[26][27] Estrogen is primarily and directly responsible for inducing the ductal component of breast development,[28][29][30] as well as for causing fat deposition and connective tissue growth.[28][29] It is also indirectly involved in the lobuloalveolar component, by increasing progesterone receptor expression in the breasts[28][30][31] and by inducing the secretion of prolactin.[32][33] Allowed for by estrogen, progesterone and prolactin work together to complete lobuloalveolar development during pregnancy.[29][34]

Androgens such as testosterone powerfully oppose estrogen action in the breasts, such as by reducing estrogen receptor expression in them.[35][36]

Female reproductive system

Estrogens are responsible for maturation and maintenance of the vagina and uterus, and are also involved in ovarian function, such as maturation of ovarian follicles. In addition, estrogens play an important role in regulation of gonadotropin secretion. For these reasons, estrogens are required for female fertility.

Neuroprotection and DNA repair

Estrogen regulated DNA repair mechanisms in the brain have neuroprotective effects.[37] Estrogen regulates the transcription of DNA base excision repair genes as well as the translocation of the base excision repair enzymes between different subcellular compartments.

Brain and behavior

Sex drive

See also: Sexual motivation and hormones

Estrogens are involved in libido (sex drive) in both women and men.

Cognition

Verbal memory scores are frequently used as one measure of higher level cognition. These scores vary in direct proportion to estrogen levels throughout the menstrual cycle, pregnancy, and menopause. Furthermore, estrogens when administered shortly after natural or surgical menopause prevents decreases in verbal memory. In contrast, estrogens have little effect on verbal memory if first administered years after menopause.[38] Estrogens also have positive influences on other measures of cognitive function.[39] However the effect of estrogens on cognition is not uniformly favorable and is dependent on the timing of the dose and the type of cognitive skill being measured.[40]

The protective effects of estrogens on cognition may be mediated by estrogen's anti-inflammatory effects in the brain.[41] Studies have also shown that the Met allele gene and level of estrogen mediates the efficiency of prefrontal cortex dependent working memory tasks.[42][43]

Mental health

Estrogen is considered to play a significant role in women's mental health. Sudden estrogen withdrawal, fluctuating estrogen, and periods of sustained low estrogen levels correlate with significant mood lowering. Clinical recovery from postpartum, perimenopause, and postmenopause depression has been shown to be effective after levels of estrogen were stabilized and/or restored.[44][45][46] Menstrual exacerbation (including menstrual psychosis) is typically triggered by low estrogen levels,[47] and is often mistaken for premenstrual dysphoric disorder.[48]

Compulsions in male lab mice, such as those in obsessive-compulsive disorder (OCD), may be caused by low estrogen levels. When estrogen levels were raised through the increased activity of the enzyme aromatase in male lab mice, OCD rituals were dramatically decreased. Hypothalamic protein levels in the gene COMT are enhanced by increasing estrogen levels which are believed to return mice that displayed OCD rituals to normal activity. Aromatase deficiency is ultimately suspected which is involved in the synthesis of estrogen in humans and has therapeutic implications in humans having obsessive-compulsive disorder.[49]

Local application of estrogen in the rat hippocampus has been shown to inhibit the re-uptake of serotonin. Contrarily, local application of estrogen has been shown to block the ability of fluvoxamine to slow serotonin clearance, suggesting that the same pathways which are involved in SSRI efficacy may also be affected by components of local estrogen signaling pathways.[50]

Parenthood

Studies have also found that fathers had lower levels of cortisol and testosterone but higher levels of estrogen (estradiol) compared to non-fathers.[51]

Binge eating

Estrogen may play a role in suppressing binge eating. Hormone replacement therapy using estrogen may be a possible treatment for binge eating behaviors in females. Estrogen replacement has been shown to suppress binge eating behaviors in female mice.[52] The mechanism by which estrogen replacement inhibits binge-like eating involves the replacement of serotonin (5-HT) neurons. Women exhibiting binge eating behaviors are found to have increased brain uptake of neuron 5-HT, and therefore less of the neurotransmitter serotonin in the cerebrospinal fluid.[53] Estrogen works to activate 5-HT neurons, leading to suppression of binge like eating behaviors.[52]

It is also suggested that there is an interaction between hormone levels and eating at different points in the female menstrual cycle. Research has predicted increased emotional eating during hormonal flux, which is characterized by high progesterone and estradiol levels that occur during the mid-luteal phase. It is hypothesized that these changes occur due to brain changes across the menstrual cycle that are likely a genomic effect of hormones. These effects produce menstrual cycle changes, which result in hormone release leading to behavioral changes, notably binge and emotional eating. These occur especially prominently among women who are genetically vulnerable to binge eating phenotypes.[54]

Binge eating is associated with decreased estradiol and increased progesterone.[55] Klump et al.[56] Progesterone may moderate the effects of low estradiol (such as during dysregulated eating behavior), but that this may only be true in women who have had clinically diagnosed binge episodes (BEs). Dysregulated eating is more strongly associated with such ovarian hormones in women with BEs than in women without BEs.[56]

The implantation of 17β-estradiol pellets in ovariectomized mice significantly reduced binge eating behaviors and injections of GLP-1 in ovariectomized mice decreased binge-eating behaviors.[52]

The associations between binge eating, menstrual-cycle phase and ovarian hormones correlated.[55][57][57][58]

Masculinization in rodents

In rodents, estrogens (which are locally aromatized from androgens in the brain) play an important role in psychosexual differentiation, for example, by masculinizing territorial behavior;[59] the same is not true in humans.[60] In humans, the masculinizing effects of prenatal androgens on behavior (and other tissues, with the possible exception of effects on bone) appear to act exclusively through the androgen receptor.[61] Consequently, the utility of rodent models for studying human psychosexual differentiation has been questioned.[62]

Skeletal system

Estrogens are responsible for both the pubertal growth spurt, which causes an acceleration in linear growth, and epiphyseal closure, which limits height and limb length, in both females and males. In addition, estrogens are responsible for bone maturation and maintenance of bone mineral density throughout life. Due to hypoestrogenism, the risk of osteoporosis increases during menopause.

Cardiovascular system

Women suffer less from heart disease due to vasculo-protective action of estrogen which helps in preventing atherosclerosis.[63] It also helps in maintaining the delicate balance between fighting infections and protecting arteries from damage thus lowering the risk of cardiovascular disease.[64] During pregnancy, high levels of estrogens increase coagulation and the risk of venous thromboembolism.

Absolute and relative incidence of venous thromboembolism (VTE) during pregnancy and the postpartum period

Absolute incidence of first VTE per 10,000 person–years during pregnancy and the postpartum period
	Swedish data A		Swedish data B		English data		Danish data
Time period	N	Rate (95% CI)	N	Rate (95% CI)	N	Rate (95% CI)	N	Rate (95% CI)
Outside pregnancy	1105	4.2 (4.0–4.4)	1015	3.8 (?)	1480	3.2 (3.0–3.3)	2895	3.6 (3.4–3.7)
Antepartum	995	20.5 (19.2–21.8)	690	14.2 (13.2–15.3)	156	9.9 (8.5–11.6)	491	10.7 (9.7–11.6)
Trimester 1	207	13.6 (11.8–15.5)	172	11.3 (9.7–13.1)	23	4.6 (3.1–7.0)	61	4.1 (3.2–5.2)
Trimester 2	275	17.4 (15.4–19.6)	178	11.2 (9.7–13.0)	30	5.8 (4.1–8.3)	75	5.7 (4.6–7.2)
Trimester 3	513	29.2 (26.8–31.9)	340	19.4 (17.4–21.6)	103	18.2 (15.0–22.1)	355	19.7 (17.7–21.9)
Around delivery	115	154.6 (128.8–185.6)	79	106.1 (85.1–132.3)	34	142.8 (102.0–199.8)	–
Postpartum	649	42.3 (39.2–45.7)	509	33.1 (30.4–36.1)	135	27.4 (23.1–32.4)	218	17.5 (15.3–20.0)
Early postpartum	584	75.4 (69.6–81.8)	460	59.3 (54.1–65.0)	177	46.8 (39.1–56.1)	199	30.4 (26.4–35.0)
Late postpartum	65	8.5 (7.0–10.9)	49	6.4 (4.9–8.5)	18	7.3 (4.6–11.6)	319	3.2 (1.9–5.0)
Incidence rate ratios (IRRs) of first VTE during pregnancy and the postpartum period
	Swedish data A		Swedish data B		English data		Danish data
Time period	IRR* (95% CI)		IRR* (95% CI)		IRR (95% CI)†		IRR (95% CI)†
Outside pregnancy	Reference (i.e., 1.00)
Antepartum	5.08 (4.66–5.54)		3.80 (3.44–4.19)		3.10 (2.63–3.66)		2.95 (2.68–3.25)
Trimester 1	3.42 (2.95–3.98)		3.04 (2.58–3.56)		1.46 (0.96–2.20)		1.12 (0.86–1.45)
Trimester 2	4.31 (3.78–4.93)		3.01 (2.56–3.53)		1.82 (1.27–2.62)		1.58 (1.24–1.99)
Trimester 3	7.14 (6.43–7.94)		5.12 (4.53–5.80)		5.69 (4.66–6.95)		5.48 (4.89–6.12)
Around delivery	37.5 (30.9–44.45)		27.97 (22.24–35.17)		44.5 (31.68–62.54)		–
Postpartum	10.21 (9.27–11.25)		8.72 (7.83–9.70)		8.54 (7.16–10.19)		4.85 (4.21–5.57)
Early postpartum	19.27 (16.53–20.21)		15.62 (14.00–17.45)		14.61 (12.10–17.67)		8.44 (7.27–9.75)
Late postpartum	2.06 (1.60–2.64)		1.69 (1.26–2.25)		2.29 (1.44–3.65)		0.89 (0.53–1.39)
Notes: Swedish data A = Using any code for VTE regardless of confirmation. Swedish data B = Using only algorithm-confirmed VTE. Early postpartum = First 6 weeks after delivery. Late postpartum = More than 6 weeks after delivery. * = Adjusted for age and calendar year. † = Unadjusted ratio calculated based on the data provided. Source: [65]

Immune system

Estrogen has anti-inflammatory properties and helps in mobilization of polymorphonuclear white blood cells or neutrophils.[64]

Associated conditions

Estrogens are implicated in various estrogen-dependent conditions, such as ER-positive breast cancer, as well as a number of genetic conditions involving estrogen signaling or metabolism, such as estrogen insensitivity syndrome, aromatase deficiency, and aromatase excess syndrome.

Biochemistry

See also: Estradiol § Biochemistry

Biosynthesis

Steroidogenesis, showing estrogens at bottom right as in pink triangle.[66]

Estrogens, in females, are produced primarily by the ovaries, and during pregnancy, the placenta.[67] Follicle-stimulating hormone (FSH) stimulates the ovarian production of estrogens by the granulosa cells of the ovarian follicles and corpora lutea. Some estrogens are also produced in smaller amounts by other tissues such as the liver, pancreas, bone, adrenal glands, skin, brain, adipose tissue,[68] and the breasts.[69] These secondary sources of estrogens are especially important in postmenopausal women.[70] The pathway of estrogen biosynthesis in extragonadal tissues is different. These tissues are not able to synthesize C19 steroids, and therefore depend on C19 supplies from other tissues[70] and the level of aromatase.[71]

In females, synthesis of estrogens starts in theca interna cells in the ovary, by the synthesis of androstenedione from cholesterol. Androstenedione is a substance of weak androgenic activity which serves predominantly as a precursor for more potent androgens such as testosterone as well as estrogen. This compound crosses the basal membrane into the surrounding granulosa cells, where it is converted either immediately into estrone, or into testosterone and then estradiol in an additional step. The conversion of androstenedione to testosterone is catalyzed by 17β-hydroxysteroid dehydrogenase (17β-HSD), whereas the conversion of androstenedione and testosterone into estrone and estradiol, respectively is catalyzed by aromatase, enzymes which are both expressed in granulosa cells. In contrast, granulosa cells lack 17α-hydroxylase and 17,20-lyase, whereas theca cells express these enzymes and 17β-HSD but lack aromatase. Hence, both granulosa and theca cells are essential for the production of estrogen in the ovaries.

Estrogen levels vary through the menstrual cycle, with levels highest near the end of the follicular phase just before ovulation.

Note that in males, estrogen is also produced by the Sertoli cells when FSH binds to their FSH receptors.

Production rates, secretion rates, clearance rates, and blood levels of major sex hormones

	Sex hormone	Reproductive phase	Blood production rate	Gonadal secretion rate	Metabolic clearance rate	Reference range (serum levels)
						SI units	Non-SI units
Men	Androstenedione	–	2.8 mg/day	1.6 mg/day	2200 L/day	2.8–7.3 nmol/L	80–210 ng/dL
	Testosterone	–	6.5 mg/day	6.2 mg/day	950 L/day	6.9–34.7 nmol/L	200–1000 ng/dL
	Estrone	–	150 μg/day	110 μg/day	2050 L/day	37–250 pmol/L	10–70 pg/mL
	Estradiol	–	60 μg/day	50 μg/day	1600 L/day	<37–210 pmol/L	10–57 pg/mL
	Estrone sulfate	–	80 μg/day	Insignificant	167 L/day	600–2500 pmol/L	200–900 pg/mL
Women	Androstenedione	–	3.2 mg/day	2.8 mg/day	2000 L/day	3.1–12.2 nmol/L	89–350 ng/dL
	Testosterone	–	190 μg/day	60 μg/day	500 L/day	0.7–2.8 nmol/L	20–81 ng/dL
	Estrone	Follicular phase	110 μg/day	80 μg/day	2200 L/day	110–400 pmol/L	30–110 pg/mL
		Luteal phase	260 μg/day	150 μg/day	2200 L/day	310–660 pmol/L	80–180 pg/mL
		Postmenopause	40 μg/day	Insignificant	1610 L/day	22–230 pmol/L	6–60 pg/mL
	Estradiol	Follicular phase	90 μg/day	80 μg/day	1200 L/day	<37–360 pmol/L	10–98 pg/mL
		Luteal phase	250 μg/day	240 μg/day	1200 L/day	699–1250 pmol/L	190–341 pg/mL
		Postmenopause	6 μg/day	Insignificant	910 L/day	<37–140 pmol/L	10–38 pg/mL
	Estrone sulfate	Follicular phase	100 μg/day	Insignificant	146 L/day	700–3600 pmol/L	250–1300 pg/mL
		Luteal phase	180 μg/day	Insignificant	146 L/day	1100–7300 pmol/L	400–2600 pg/mL
	Progesterone	Follicular phase	2 mg/day	1.7 mg/day	2100 L/day	0.3–3 nmol/L	0.1–0.9 ng/mL
		Luteal phase	25 mg/day	24 mg/day	2100 L/day	19–45 nmol/L	6–14 ng/mL
Notes and sources Notes: "The concentration of a steroid in the circulation is determined by the rate at which it is secreted from glands, the rate of metabolism of precursor or prehormones into the steroid, and the rate at which it is extracted by tissues and metabolized. The secretion rate of a steroid refers to the total secretion of the compound from a gland per unit time. Secretion rates have been assessed by sampling the venous effluent from a gland over time and subtracting out the arterial and peripheral venous hormone concentration. The metabolic clearance rate of a steroid is defined as the volume of blood that has been completely cleared of the hormone per unit time. The production rate of a steroid hormone refers to entry into the blood of the compound from all possible sources, including secretion from glands and conversion of prohormones into the steroid of interest. At steady state, the amount of hormone entering the blood from all sources will be equal to the rate at which it is being cleared (metabolic clearance rate) multiplied by blood concentration (production rate = metabolic clearance rate × concentration). If there is little contribution of prohormone metabolism to the circulating pool of steroid, then the production rate will approximate the secretion rate." Sources: See template.

Distribution

Estrogens are plasma protein bound to albumin and/or sex hormone-binding globulin in the circulation.

Metabolism

See also: Estradiol § Metabolism, and Estradiol (medication) § Metabolism

Estrogens are metabolized via hydroxylation by cytochrome P450 enzymes such as CYP1A1 and CYP3A4 and via conjugation by estrogen sulfotransferases (sulfation) and UDP-glucuronyltransferases (glucuronidation). In addition, estradiol is dehydrogenated by 17β-hydroxysteroid dehydrogenase into the much less potent estrogen estrone. These reactions occur primarily in the liver, but also in other tissues.

Estrogen metabolism in humans Estradiol Estrone sulfate Estrone glucuronide 2-Hydroxyestrone Estrone 4-Hydroxyestrone 2-Methoxyestrone 16α-Hydroxyestrone 4-Methoxyestrone 17-Epiestriol Estriol 16-Epiestriol 17β-HSD EST STS UGT1A3 UGT1A9 CYP450 CYP450 COMT CYP450 COMT unidentified 17β-HSD unidentified Description: The metabolic pathways involved in the metabolism of estradiol and other natural estrogens (e.g., estrone, estriol) in humans. In addition to the metabolic transformations shown in the diagram, conjugation (e.g., sulfation and glucuronidation) occurs in the case of estradiol and metabolites of estradiol that have one or more available hydroxyl (–OH) groups. Sources: See template page.

Excretion

Estrogens are excreted primarily by the kidneys as conjugates via the urine.

Levels

Endogenous estradiol production rates and plasma estrogen levels

Group	E2 (prod)	E2 (levels)	E1 (levels)	Ratio
Pubertal girls^a   Tanner stage I (childhood)   Tanner stage II (ages 8–12)   Tanner stage III (ages 10–13)   Tanner stage IV (ages 11–14)   Tanner stage V (ages 12–15)     Follicular (days 1–14)     Luteal (days 15–28)	? ? ? ?   ? ?	9 (<9–20) pg/mL 15 (<9–30) pg/mL 27 (<9–60) pg/mL 55 (16–85) pg/mL   50 (30–100) pg/mL 130 (70–300) pg/mL	13 (<9–23) pg/mL 18 (10–37) pg/mL 26 (17–58) pg/mL 36 (23–69) pg/mL   44 (30–89) pg/mL 75 (39–160) pg/mL	? ? ? ?   ? ?
Prepubertal boys	?	2–8 pg/mL	?	?
Premenopausal women   Early follicular phase (days 1–4)   Mid follicular phase (days 5–9)   Late follicular phase (days 10–14)   Luteal phase (days 15–28)   Oral contraceptive (anovulatory)	30–100 µg/day 100–160 µg/day 320–640 µg/day 300 µg/day ?	40–60 pg/mL 60–100 pg/mL 200–400 pg/mL 190 pg/mL 12–50 pg/mL	40–60 pg/mL ? 170–200 pg/mL 100–150 pg/mL ?	0.5–1 ? 1–2 1.5 ?
Postmenopausal women	18 µg/day	5–20 pg/mL	30–70 pg/mL	0.3–0.8
Pregnant women   First trimester (weeks 1–12)   Second trimester (weeks 13–26)   Third trimester (weeks 27–40)	? ? ?	1,000–5,000 pg/mL 5,000–15,000 pg/mL 10,000–40,000 pg/mL	? ? ?	? ? ?
Men^a	20–60 µg/day	27 (20–55) pg/mL	20–90 pg/mL	0.4–0.6
Footnotes: ^a = Format is "mean value (range)" or just "range". Sources: See template.

Medical use

Main article: Estrogen (medication)

Estrogens are used as medications, mainly in hormonal contraception, hormone replacement therapy,[72] and to treat gender dysphoria in transgender women and other transfeminine individuals as part of feminizing hormone therapy.[73]

Chemistry

See also: List of estrogens

The estrogen steroid hormones are estrane steroids.

History

See also: Estradiol § History, Estrone § History, and Estrogen (medication) § History

In 1929, Adolf Butenandt and Edward Adelbert Doisy independently isolated and purified estrone, the first estrogen to be discovered.[74] Then, estriol and estradiol were discovered in 1930 and 1933, respectively. Shortly following their discovery, estrogens, both natural and synthetic, were introduced for medical use. Examples include estriol glucuronide (Emmenin, Progynon), estradiol benzoate, conjugated estrogens (Premarin), diethylstilbestrol, and ethinylestradiol.

The word estrogen derives from Ancient Greek. It is derived from "oestros"[75] (a periodic state of sexual activity in female mammals), and genos(generating).[75] It was first published in the early 1920s and referenced as "oestrin".[76] With the years, American English adapted the spelling of estrogen to fit with its phonetic pronunciation. Nevertheless, both estrogen and oestrogen are used nowadays, yet some still wish to maintain its original spelling as it reflects the origin of the word.

Society and culture

Etymology

The name estrogen is derived from the Greek οἶστρος (oistros), literally meaning "verve or inspiration" but figuratively sexual passion or desire,[77] and the suffix -gen, meaning "producer of".

Environment

A range of synthetic and natural substances that possess estrogenic activity have been identified in the environment and are referred to xenoestrogens.[78]

• Synthetic substances such as bisphenol A as well as metalloestrogens (e.g., cadmium).
• Plant products with estrogenic activity are called phytoestrogens (e.g., coumestrol, daidzein, genistein, miroestrol).
• Those produced by fungi are known as mycoestrogens (e.g., zearalenone).

Estrogens are among the wide range of endocrine-disrupting compounds (EDCs) because they have high estrogenic potency. When an EDC makes its way into the environment, it may cause male reproductive dysfunction to wildlife.[79] The estrogen excreted from farm animals makes its way into fresh water systems.[80] During the germination period of reproduction the fish are exposed to low levels of estrogen which may cause reproductive dysfunction to male fish.[81][82]

Cosmetics

Some hair shampoos on the market include estrogens and placental extracts; others contain phytoestrogens. In 1998, there were case reports of four prepubescent African-American girls developing breasts after exposure to these shampoos.[83] In 1993, the FDA determined that not all over-the-counter topically applied hormone-containing drug products for human use are generally recognized as safe and effective and are misbranded. An accompanying proposed rule deals with cosmetics, concluding that any use of natural estrogens in a cosmetic product makes the product an unapproved new drug and that any cosmetic using the term "hormone" in the text of its labeling or in its ingredient statement makes an implied drug claim, subjecting such a product to regulatory action.[84]

In addition to being considered misbranded drugs, products claiming to contain placental extract may also be deemed to be misbranded cosmetics if the extract has been prepared from placentas from which the hormones and other biologically active substances have been removed and the extracted substance consists principally of protein. The FDA recommends that this substance be identified by a name other than "placental extract" and describing its composition more accurately because consumers associate the name "placental extract" with a therapeutic use of some biological activity.[84]

See also

• List of steroid abbreviations
• Breastfeeding and fertility

References

1. Ryan KJ (August 1982). "Biochemistry of aromatase: significance to female reproductive physiology". Cancer Research. 42 (8 Suppl): 3342s–3344s. PMID 7083198.
2. Mechoulam R, Brueggemeier RW, Denlinger DL (September 2005). "Estrogens in insects". Cellular and Molecular Life Sciences. 40 (9): 942–944. doi:10.1007/BF01946450. S2CID 31950471.
3. Burger HG (April 2002). "Androgen production in women". Fertility and Sterility. 77 Suppl 4: S3–5. doi:10.1016/S0015-0282(02)02985-0. PMID 12007895.
4. Lombardi G, Zarrilli S, Colao A, Paesano L, Di Somma C, Rossi F, De Rosa M (June 2001). "Estrogens and health in males". Molecular and Cellular Endocrinology. 178 (1–2): 51–5. doi:10.1016/S0303-7207(01)00420-8. PMID 11403894. S2CID 36834775.
5. Whitehead SA, Nussey S (2001). Endocrinology: an integrated approach. Oxford: BIOS: Taylor & Francis. ISBN 978-1-85996-252-7.
6. Soltysik K, Czekaj P (April 2013). "Membrane estrogen receptors – is it an alternative way of estrogen action?". Journal of Physiology and Pharmacology. 64 (2): 129–42. PMID 23756388.
7. Micevych PE, Kelly MJ (2012). "Membrane estrogen receptor regulation of hypothalamic function". Neuroendocrinology. 96 (2): 103–10. doi:10.1159/000338400. PMC 3496782. PMID 22538318.
8. Prossnitz ER, Arterburn JB, Sklar LA (February 2007). "GPR30: A G protein-coupled receptor for estrogen". Molecular and Cellular Endocrinology. 265–266: 138–42. doi:10.1016/j.mce.2006.12.010. PMC 1847610. PMID 17222505.
9. A. Labhart (6 December 2012). Clinical Endocrinology: Theory and Practice. Springer Science & Business Media. pp. 548–. ISBN 978-3-642-96158-8.
10. Baker ME (March 2013). "What are the physiological estrogens?". Steroids. 78 (3): 337–40. doi:10.1016/j.steroids.2012.12.011. PMID 23313336. S2CID 11803629.
11. Miller KK, Al-Rayyan N, Ivanova MM, Mattingly KA, Ripp SL, Klinge CM, Prough RA (January 2013). "DHEA metabolites activate estrogen receptors alpha and beta". Steroids. 78 (1): 15–25. doi:10.1016/j.steroids.2012.10.002. PMC 3529809. PMID 23123738.
12. Bhavnani BR, Nisker JA, Martin J, Aletebi F, Watson L, Milne JK (2000). "Comparison of pharmacokinetics of a conjugated equine estrogen preparation (premarin) and a synthetic mixture of estrogens (C.E.S.) in postmenopausal women". Journal of the Society for Gynecologic Investigation. 7 (3): 175–83. doi:10.1016/s1071-5576(00)00049-6. PMID 10865186.
13. Häggström, Mikael (2014). "Reference ranges for estradiol, progesterone, luteinizing hormone and follicle-stimulating hormone during the menstrual cycle". WikiJournal of Medicine. 1 (1). doi:10.15347/wjm/2014.001. ISSN 2002-4436.
14. Lin CY, Ström A, Vega VB, Kong SL, Yeo AL, Thomsen JS, Chan WC, Doray B, Bangarusamy DK, Ramasamy A, Vergara LA, Tang S, Chong A, Bajic VB, Miller LD, Gustafsson JA, Liu ET (2004). "Discovery of estrogen receptor alpha target genes and response elements in breast tumor cells". Genome Biology. 5 (9): R66. doi:10.1186/gb-2004-5-9-r66. PMC 522873. PMID 15345050.
15. Darabi M, Ani M, Panjehpour M, Rabbani M, Movahedian A, Zarean E (2011). "Effect of estrogen receptor β A1730G polymorphism on ABCA1 gene expression response to postmenopausal hormone replacement therapy". Genetic Testing and Molecular Biomarkers. 15 (1–2): 11–5. doi:10.1089/gtmb.2010.0106. PMID 21117950.
16. Raloff J (6 December 1997). "Science News Online (12/6/97): Estrogen's Emerging Manly Alter Ego". Science News. Retrieved 4 March 2008.
17. Hess RA, Bunick D, Lee KH, Bahr J, Taylor JA, Korach KS, Lubahn DB (December 1997). "A role for oestrogens in the male reproductive system". Nature. 390 (6659): 509–12. Bibcode:1997Natur.390..509H. doi:10.1038/37352. PMC 5719867. PMID 9393999.
18. "Estrogen Linked To Sperm Count, Male Fertility". Science Blog. Retrieved 4 March 2008.
19. Hill RA, Pompolo S, Jones ME, Simpson ER, Boon WC (December 2004). "Estrogen deficiency leads to apoptosis in dopaminergic neurons in the medial preoptic area and arcuate nucleus of male mice". Molecular and Cellular Neurosciences. 27 (4): 466–76. doi:10.1016/j.mcn.2004.04.012. PMID 15555924. S2CID 25280077.
20. Massaro D, Massaro GD (December 2004). "Estrogen regulates pulmonary alveolar formation, loss, and regeneration in mice". American Journal of Physiology. Lung Cellular and Molecular Physiology. 287 (6): L1154–9. doi:10.1152/ajplung.00228.2004. PMID 15298854. S2CID 24642944.
21. Christensen A, Dewing P, Micevych P (November 2011). "Membrane-initiated estradiol signaling induces spinogenesis required for female sexual receptivity". The Journal of Neuroscience. 31 (48): 17583–9. doi:10.1523/JNEUROSCI.3030-11.2011. PMC 4709636. PMID 22131419.
22. Handa RJ, Ogawa S, Wang JM, Herbison AE (January 2012). "Roles for oestrogen receptor β in adult brain function". Journal of Neuroendocrinology. 24 (1): 160–73. doi:10.1111/j.1365-2826.2011.02206.x. PMC 3348521. PMID 21851428.
23. Kow LM, Pfaff DW (May 1998). "Mapping of neural and signal transduction pathways for lordosis in the search for estrogen actions on the central nervous system". Behavioural Brain Research. 92 (2): 169–80. doi:10.1016/S0166-4328(97)00189-7. PMID 9638959. S2CID 28276218.
24. Warnock JK, Swanson SG, Borel RW, Zipfel LM, Brennan JJ (2005). "Combined esterified estrogens and methyltestosterone versus esterified estrogens alone in the treatment of loss of sexual interest in surgically menopausal women". Menopause. 12 (4): 374–84. doi:10.1097/01.GME.0000153933.50860.FD. PMID 16037752. S2CID 24557071.
25. Heiman JR, Rupp H, Janssen E, Newhouse SK, Brauer M, Laan E (May 2011). "Sexual desire, sexual arousal and hormonal differences in premenopausal US and Dutch women with and without low sexual desire". Hormones and Behavior. 59 (5): 772–9. doi:10.1016/j.yhbeh.2011.03.013. PMID 21514299. S2CID 20807391.
26. Brisken C, O'Malley B (December 2010). "Hormone action in the mammary gland". Cold Spring Harbor Perspectives in Biology. 2 (12): a003178. doi:10.1101/cshperspect.a003178. PMC 2982168. PMID 20739412.
27. Kleinberg DL (February 1998). "Role of IGF-I in normal mammary development". Breast Cancer Research and Treatment. 47 (3): 201–8. doi:10.1023/a:1005998832636. PMID 9516076.
28. Johnson LR (2003). Essential Medical Physiology. Academic Press. p. 770. ISBN 978-0-12-387584-6.
29. Norman AW, Henry HL (30 July 2014). Hormones. Academic Press. p. 311. ISBN 978-0-08-091906-5.
30. Coad J, Dunstall M (2011). Anatomy and Physiology for Midwives, with Pageburst online access,3: Anatomy and Physiology for Midwives. Elsevier Health Sciences. p. 413. ISBN 978-0-7020-3489-3.
31. Haslam SZ, Osuch JR (1 January 2006). Hormones and Breast Cancer in Post-Menopausal Women. IOS Press. p. 69. ISBN 978-1-58603-653-9.
32. Silbernagl S, Despopoulos A (1 January 2011). Color Atlas of Physiology. Thieme. pp. 305–. ISBN 978-3-13-149521-1.
33. Fadem B (2007). High-yield Comprehensive USMLE Step 1 Review. Lippincott Williams & Wilkins. pp. 445–. ISBN 978-0-7817-7427-7.
34. Blackburn S (14 April 2014). Maternal, Fetal, & Neonatal Physiology. Elsevier Health Sciences. pp. 146–. ISBN 978-0-323-29296-2.
35. Strauss JF, Barbieri RL (13 September 2013). Yen and Jaffe's Reproductive Endocrinology. Elsevier Health Sciences. pp. 236–. ISBN 978-1-4557-2758-2.
36. Wilson CB, Nizet V, Maldonado Y, Remington JS, Klein JO (24 February 2015). Remington and Klein's Infectious Diseases of the Fetus and Newborn Infant. Elsevier Health Sciences. pp. 190–. ISBN 978-0-323-24147-2.
37. Zárate S, Stevnsner T, Gredilla R (2017). "Role of Estrogen and Other Sex Hormones in Brain Aging. Neuroprotection and DNA Repair". Front Aging Neurosci. 9: 430. doi:10.3389/fnagi.2017.00430. PMC 5743731. PMID 29311911.CS1 maint: multiple names: authors list (link)
38. Sherwin BB (February 2012). "Estrogen and cognitive functioning in women: lessons we have learned". Behavioral Neuroscience. 126 (1): 123–7. doi:10.1037/a0025539. PMC 4838456. PMID 22004260.
39. Hara Y, Waters EM, McEwen BS, Morrison JH (July 2015). "Estrogen Effects on Cognitive and Synaptic Health Over the Lifecourse". Physiological Reviews. 95 (3): 785–807. doi:10.1152/physrev.00036.2014. PMC 4491541. PMID 26109339.
40. Korol DL, Pisani SL (August 2015). "Estrogens and cognition: Friends or foes?: An evaluation of the opposing effects of estrogens on learning and memory". Hormones and Behavior. 74: 105–15. doi:10.1016/j.yhbeh.2015.06.017. PMC 4573330. PMID 26149525.
41. Au A, Feher A, McPhee L, Jessa A, Oh S, Einstein G (January 2016). "Estrogens, inflammation and cognition". Frontiers in Neuroendocrinology. 40: 87–100. doi:10.1016/j.yfrne.2016.01.002. PMID 26774208.
42. Jacobs E, D'Esposito M (April 2011). "Estrogen shapes dopamine-dependent cognitive processes: implications for women's health". The Journal of Neuroscience. 31 (14): 5286–93. doi:10.1523/JNEUROSCI.6394-10.2011. PMC 3089976. PMID 21471363.
43. Colzato LS, Hommel B (1 January 2014). "Effects of estrogen on higher-order cognitive functions in unstressed human females may depend on individual variation in dopamine baseline levels". Frontiers in Neuroscience. 8: 65. doi:10.3389/fnins.2014.00065. PMC 3985021. PMID 24778605.
44. Douma SL, Husband C, O'Donnell ME, Barwin BN, Woodend AK (2005). "Estrogen-related mood disorders: reproductive life cycle factors". Advances in Nursing Science. 28 (4): 364–75. doi:10.1097/00012272-200510000-00008. PMID 16292022.
45. Osterlund MK, Witt MR, Gustafsson JA (December 2005). "Estrogen action in mood and neurodegenerative disorders: estrogenic compounds with selective properties-the next generation of therapeutics". Endocrine. 28 (3): 235–42. doi:10.1385/ENDO:28:3:235. PMID 16388113. S2CID 8205014.
46. Lasiuk GC, Hegadoren KM (October 2007). "The effects of estradiol on central serotonergic systems and its relationship to mood in women". Biological Research for Nursing. 9 (2): 147–60. doi:10.1177/1099800407305600. PMID 17909167. S2CID 37965502.
47. Grigoriadis S, Seeman M (July 2002). "The role of estrogen in schizophrenia: Implications for schizophrenia practice guidelines for women". The Canadian Journal of Psychiatry. 47 (5): 437–442. doi:10.1177/070674370204700504. PMID 12085678.
48. "PMDD/PMS". The Massachusetts General Hospital Center for Women’s Mental Health. Retrieved 12 January 2019.
49. Hill RA, McInnes KJ, Gong EC, Jones ME, Simpson ER, Boon WC (February 2007). "Estrogen deficient male mice develop compulsive behavior". Biological Psychiatry. 61 (3): 359–66. doi:10.1016/j.biopsych.2006.01.012. PMID 16566897. S2CID 22669945.
50. Benmansour S, Weaver RS, Barton AK, Adeniji OS, Frazer A (April 2012). "Comparison of the effects of estradiol and progesterone on serotonergic function". Biological Psychiatry. 71 (7): 633–41. doi:10.1016/j.biopsych.2011.11.023. PMC 3307822. PMID 22225849.
51. Berg SJ, Wynne-Edwards KE (June 2001). "Changes in testosterone, cortisol, and estradiol levels in men becoming fathers". Mayo Clinic Proceedings. 76 (6): 582–92. doi:10.4065/76.6.582. PMID 11393496.
52. Cao X, Xu P, Oyola MG, Xia Y, Yan X, Saito K, Zou F, Wang C, Yang Y, Hinton A, Yan C, Ding H, Zhu L, Yu L, Yang B, Feng Y, Clegg DJ, Khan S, DiMarchi R, Mani SK, Tong Q, Xu Y (October 2014). "Estrogens stimulate serotonin neurons to inhibit binge-like eating in mice". The Journal of Clinical Investigation. 124 (10): 4351–62. doi:10.1172/JCI74726. PMC 4191033. PMID 25157819.
53. Jimerson DC, Lesem MD, Kaye WH, Hegg AP, Brewerton TD (September 1990). "Eating disorders and depression: is there a serotonin connection?". Biological Psychiatry. 28 (5): 443–54. doi:10.1016/0006-3223(90)90412-u. PMID 2207221.
54. Klump KL, Keel PK, Racine SE, Burt SA, Burt AS, Neale M, Sisk CL, Boker S, Hu JY (February 2013). "The interactive effects of estrogen and progesterone on changes in emotional eating across the menstrual cycle". Journal of Abnormal Psychology. 122 (1): 131–7. doi:10.1037/a0029524. PMC 3570621. PMID 22889242.
55. Edler C, Lipson SF, Keel PK (January 2007). "Ovarian hormones and binge eating in bulimia nervosa". Psychological Medicine. 37 (1): 131–41. doi:10.1017/S0033291706008956. PMID 17038206.
56. Klump KL, Racine SE, Hildebrandt B, Burt SA, Neale M, Sisk CL, Boker S, Keel PK (September 2014). "Ovarian Hormone Influences on Dysregulated Eating: A Comparison of Associations in Women with versus without Binge Episodes". Clinical Psychological Science. 2 (4): 545–559. doi:10.1177/2167702614521794. PMC 4203460. PMID 25343062.
57. Klump KL, Keel PK, Culbert KM, Edler C (December 2008). "Ovarian hormones and binge eating: exploring associations in community samples". Psychological Medicine. 38 (12): 1749–57. doi:10.1017/S0033291708002997. PMC 2885896. PMID 18307829.
58. Lester NA, Keel PK, Lipson SF (January 2003). "Symptom fluctuation in bulimia nervosa: relation to menstrual-cycle phase and cortisol levels". Psychological Medicine. 33 (1): 51–60. doi:10.1017/s0033291702006815. PMID 12537036.
59. Wu MV, Manoli DS, Fraser EJ, Coats JK, Tollkuhn J, Honda S, Harada N, Shah NM (October 2009). "Estrogen masculinizes neural pathways and sex-specific behaviors". Cell. 139 (1): 61–72. doi:10.1016/j.cell.2009.07.036. PMC 2851224. PMID 19804754.
60. Rochira V, Carani C (October 2009). "Aromatase deficiency in men: a clinical perspective". Nature Reviews. Endocrinology. 5 (10): 559–68. doi:10.1038/nrendo.2009.176. PMID 19707181.
61. Wilson JD (September 2001). "Androgens, androgen receptors, and male gender role behavior". Hormones and Behavior. 40 (2): 358–66. doi:10.1006/hbeh.2001.1684. PMID 11534997. S2CID 20480423.
62. Baum MJ (November 2006). "Mammalian animal models of psychosexual differentiation: when is 'translation' to the human situation possible?". Hormones and Behavior. 50 (4): 579–88. doi:10.1016/j.yhbeh.2006.06.003. PMID 16876166. S2CID 7465192.
63. Rosano GM, Panina G (1999). "Oestrogens and the heart". Thérapie. 54 (3): 381–5. PMID 10500455.
64. Nadkarni S, Cooper D, Brancaleone V, Bena S, Perretti M (November 2011). "Activation of the annexin A1 pathway underlies the protective effects exerted by estrogen in polymorphonuclear leukocytes". Arteriosclerosis, Thrombosis, and Vascular Biology. 31 (11): 2749–59. doi:10.1161/ATVBAHA.111.235176. PMC 3357483. PMID 21836070.
65. Abdul Sultan A, West J, Stephansson O, Grainge MJ, Tata LJ, Fleming KM, Humes D, Ludvigsson JF (November 2015). "Defining venous thromboembolism and measuring its incidence using Swedish health registries: a nationwide pregnancy cohort study". BMJ Open. 5 (11): e008864. doi:10.1136/bmjopen-2015-008864. PMC 4654387. PMID 26560059.
66. Häggström, Mikael; Richfield, David (2014). "Diagram of the pathways of human steroidogenesis". WikiJournal of Medicine. 1 (1). doi:10.15347/wjm/2014.005. ISSN 2002-4436.
67. Marieb E (2013). Anatomy & physiology. Benjamin-Cummings. p. 903. ISBN 978-0-321-88760-3.
68. Hemsell DL, Grodin JM, Brenner PF, Siiteri PK, MacDonald PC (March 1974). "Plasma precursors of estrogen. II. Correlation of the extent of conversion of plasma androstenedione to estrone with age". The Journal of Clinical Endocrinology and Metabolism. 38 (3): 476–9. doi:10.1210/jcem-38-3-476. PMID 4815174.
69. Barakat R, Oakley O, Kim H, Jin J, Ko CJ (September 2016). "Extra-gonadal sites of estrogen biosynthesis and function". BMB Reports. 49 (9): 488–96. doi:10.5483/BMBRep.2016.49.9.141. PMC 5227141. PMID 27530684.
70. Nelson LR, Bulun SE (September 2001). "Estrogen production and action". Journal of the American Academy of Dermatology. 45 (3 Suppl): S116–24. doi:10.1067/mjd.2001.117432. PMID 11511861.
71. Labrie F, Bélanger A, Luu-The V, Labrie C, Simard J, Cusan L, Gomez JL, Candas B (1998). "DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: its role during aging". Steroids. 63 (5–6): 322–8. doi:10.1016/S0039-128X(98)00007-5. PMID 9618795. S2CID 37344052.
72. Kuhl, H (2005). "Pharmacology of estrogens and progestogens: Influence of different routes of administration". Climacteric. 8: 3–63. doi:10.1080/13697130500148875. PMID 16112947.
73. Wesp, Linda M.; Deutsch, Madeline B. (March 2017). "Hormonal and Surgical Treatment Options for Transgender Women and Transfeminine Spectrum Persons". Psychiatric Clinics of North America. 40 (1): 99–111. doi:10.1016/j.psc.2016.10.006. ISSN 0193-953X. PMID 28159148.
74. Tata, Jamshed R (2005). "One hundred years of hormones". EMBO Reports. 6 (6): 490–6. doi:10.1038/sj.embor.7400444. PMC 1369102. PMID 15940278.
75. "Origin in Biomedical Terms: oestrogen or oestrogen". Bioetymology. Retrieved 24 January 2018.
76. "Council on Pharmacy and Chemistry". Journal of the American Medical Association. 107 (15): 1221–3. 1936. doi:10.1001/jama.1936.02770410043011.
77. "Greek Word Study Tool: oistros". Perseus Digital Library. Retrieved 28 December 2011.
78. Fang H, Tong W, Shi LM, Blair R, Perkins R, Branham W, Hass BS, Xie Q, Dial SL, Moland CL, Sheehan DM (March 2001). "Structure-activity relationships for a large diverse set of natural, synthetic, and environmental estrogens". Chemical Research in Toxicology. 14 (3): 280–94. CiteSeerX 10.1.1.460.20. doi:10.1021/tx000208y. PMID 11258977.
79. Wang S, Huang W, Fang G, Zhang Y, Qiao H (2008). "Analysis of steroidal estrogen residues in food and environmental samples". International Journal of Environmental Analytical Chemistry. 88 (1): 1–25. doi:10.1080/03067310701597293.
80. Wise A, O'Brien K, Woodruff T (January 2011). "Are oral contraceptives a significant contributor to the estrogenicity of drinking water?". Environmental Science & Technology. 45 (1): 51–60. doi:10.1021/es1014482. PMID 20977246. Lay summary – Chemical & Engineering News.
81. Liney KE, Jobling S, Shears JA, Simpson P, Tyler CR (October 2005). "Assessing the sensitivity of different life stages for sexual disruption in roach (Rutilus rutilus) exposed to effluents from wastewater treatment works". Environmental Health Perspectives. 113 (10): 1299–307. doi:10.1289/ehp.7921. PMC 1281270. PMID 16203238.
82. Jobling S, Williams R, Johnson A, Taylor A, Gross-Sorokin M, Nolan M, Tyler CR, van Aerle R, Santos E, Brighty G (April 2006). "Predicted exposures to steroid estrogens in U.K. rivers correlate with widespread sexual disruption in wild fish populations". Environmental Health Perspectives. 114 Suppl 1 (Suppl 1): 32–9. doi:10.1289/ehp.8050. PMC 1874167. PMID 16818244.
83. Sanghavi DM (17 October 2006). "Preschool Puberty, and a Search for the Causes". The New York Times. Retrieved 4 June 2008.
84. FDA (February 1995). "Products containing estrogenic hormones, placental extract or vitamins". Guide to Inspections of Cosmetic Product Manufacturers. Archived from the original on 14 October 2007. Retrieved 24 October 2006.

External links

• Nussey and Whitehead: Endocrinology, an integrated approach, Taylor and Francis 2001. Free online textbook.