Estrogens are synthesized in all vertebrates[4] and some insects.[5] Quantitatively, estrogens circulate at lower levels thanandrogens in both men and women.[6] While estrogen levels are significantly lower in males than in females, estrogens nevertheless have important physiological roles in males.[7]
Synthetic and natural estrogens have been found in the environment and are referred to asxenoestrogens. Estrogens are among the wide range of endocrine-disrupting compounds (EDCs) and can cause health issues and reproductive disfunction in both wildlife and humans.[12][13]
Note thehydroxyl (–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 areestrone (E1),estradiol (E2),estriol (E3), andestetrol (E4). Estradiol (E2) is the predominant estrogen during reproductive years both in terms of absolute serum levels as well as in terms of estrogenic activity. Duringmenopause, estrone is the predominant circulating estrogen and during pregnancy estriol is the predominant circulating estrogen in terms of serum levels. Given bysubcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.[14] Thus, estradiol is the most important estrogen in non-pregnant females who are between themenarche and menopause stages of life. However, duringpregnancy this role shifts to estriol, and in postmenopausal women estrone becomes the primary form of estrogen in the body. Another type of estrogen calledestetrol (E4) is produced only during pregnancy. All of the different forms of estrogen are synthesized fromandrogens, specificallytestosterone andandrostenedione, by theenzymearomatase.[citation needed]
The actions of estrogen are mediated by theestrogen receptor (ER), a dimeric nuclear protein that binds to DNA and controlsgene 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 ahormone 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).[19] 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.[20]
While estrogens are present in bothmen andwomen, they are usually present at significantly higher levels in cis women of reproductive age. They promote the development of femalesecondary sexual characteristics, such asbreasts, darkening and enlargement ofnipples,[21] and thickening of theendometrium and other aspects of regulating the menstrual cycle. In males, estrogen regulates certain functions of thereproductive system important to the maturation ofsperm[22][23][24] and may be necessary for a healthylibido.[25]
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 ofin-vitro systems withlabeled estradiol and humanERα andERβ proteins (except the ERβ values from Kuiper et al. (1997), which are rat ERβ).Sources: See template page.
Notes: Referenceligands (100%) wereprogesterone for thePRTooltip progesterone receptor,testosterone for theARTooltip androgen receptor,estradiol for theERTooltip estrogen receptor,dexamethasone for theGRTooltip glucocorticoid receptor,aldosterone for theMRTooltip mineralocorticoid receptor,dihydrotestosterone forSHBGTooltip sex hormone-binding globulin, andcortisol forCBGTooltip Corticosteroid-binding globulin.Sources: See template.
Anabolic: Increasesmuscle mass and strength, speed of muscle regeneration, andbone density, increased sensitivity to exercise, protection against muscle damage, strongercollagen synthesis, increases the collagen content ofconnective tissues,tendons, andligaments, but also decreases stiffness oftendons andligaments (especially duringmenstruation). Decreased stiffness of tendons gives women much lower predisposition to muscle strains but soft ligaments are much more prone to injuries (ACL tears are 2-8x more common among women than men).[26][27][28][29]
Estradiol also regulates energy expenditure, body weighthomeostasis, and seems to have much stronger anti-obesity effects than testosterone in general.[34]
Estrogen is known to cause darkening of skin, especially in the face andareolae.[38] Pale skinned women will develop browner and yellower skin during pregnancy, as a result of the increase of estrogen, known as the"mask of pregnancy".[39] Estrogen may explain why women have darker eyes than men, and also a lower risk of skin cancer than men; a European study found that women generally have darker skin than men.[40][41]
Estrogen together withprogesterone promotes and maintains the uterus lining in preparation for implantation of fertilized egg and maintenance of uterus function during gestation period, also upregulatesoxytocin receptor in myometrium
Sex drive is dependent onandrogen levels[46] only in the presence of estrogen, but without estrogen, free testosterone level actually decreases sexual desire (instead of increasing sex drive), as demonstrated for those women who havehypoactive sexual desire disorder, and the sexual desire in these women can be restored by administration of estrogen (using oral contraceptive).[47]
Estrogens are responsible for maturation and maintenance of thevagina anduterus, and are also involved inovarian function, such as maturation ofovarian follicles. In addition, estrogens play an important role in regulation ofgonadotropinsecretion. For these reasons, estrogens are required for femalefertility.[citation needed]
Estrogen regulatedDNA repair mechanisms in thebrain have neuroprotective effects.[59] Estrogen regulates thetranscription of DNAbase excision repair genes as well as the translocation of the base excision repair enzymes between different subcellular compartments.
Verbal memory scores are frequently used as one measure of higher levelcognition. 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.[60] Estrogens also have positive influences on other measures of cognitive function.[61] 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.[62]
The protective effects of estrogens on cognition may be mediated by estrogen's anti-inflammatory effects in the brain.[63] Studies have also shown that the Met allele gene and level of estrogen mediates the efficiency ofprefrontal cortex dependent working memory tasks.[64][65] Researchers have urged for further research to illuminate the role of estrogen and its potential for improvement on cognitive function.[66]
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 enzymearomatase in male lab mice, OCD rituals were dramatically decreased.Hypothalamic protein levels in the geneCOMT 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.[72]
Local application of estrogen in the rat hippocampus has been shown to inhibit the re-uptake ofserotonin. Contrarily, local application of estrogen has been shown to block the ability offluvoxamine 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.[73]
Estrogen may play a role in suppressingbinge 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.[75] The mechanism by which estrogen replacement inhibits binge-like eating involves the replacement ofserotonin (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.[76] Estrogen works to activate 5-HT neurons, leading to suppression of binge like eating behaviors.[75]
It is also suggested that there is an interaction between hormone levels and eating at different points in the femalemenstrual cycle. Research has predicted increased emotional eating during hormonal flux, which is characterized by highprogesterone andestradiol 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.[77]
Binge eating is associated with decreased estradiol and increased progesterone.[78] Klump et al.[79] 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.[79]
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.[75]
The associations between binge eating, menstrual-cycle phase and ovarian hormones correlated.[78][80][81]
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;[82] the same is not true in humans.[83] 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.[84] Consequently, the utility of rodent models for studying human psychosexual differentiation has been questioned.[85]
Estrogens are responsible for both the pubertal growth spurt, which causes an acceleration in linear growth, andepiphyseal closure, which limitsheight andlimb length, in both females and males. In addition, estrogens are responsible for bone maturation and maintenance ofbone mineral density throughout life. Due to hypoestrogenism, the risk ofosteoporosis increases duringmenopause.[citation needed]
Women are less impacted by heart disease due to vasculo-protective action of estrogen which helps in preventing atherosclerosis.[86] It also helps in maintaining the delicate balance between fighting infections and protecting arteries from damage thus lowering the risk of cardiovascular disease.[87] Duringpregnancy, high levels of estrogens increasecoagulation and the risk ofvenous thromboembolism. Estrogen has been shown to upregulate thepeptide hormoneadropin.[35]
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)
NФВяы
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:[88]
The effect of estrogen on theimmune system is in general described asTh2 favoring, rather than suppressive, as is the case of the effect of male sex hormone – testosterone.[89] Indeed, women respond better tovaccines,infections and are generally less likely to developcancer, the tradeoff of this is that they are more likely to develop anautoimmune disease.[90] TheTh2 shift manifests itself in a decrease of cellular immunity and increase in humoral immunity (antibody production) shifts it from cellular to humoral by downregulating cell-mediated immunity and enhancing Th2 immune response by stimulating IL-4 production and Th2 differentiation.[89][91]Type 1 andtype 17 immune responses are downregulated, likely to be at least partially due toIL-4, which inhibits Th1. Effect of estrogen on different immune cells' cell types is in line with its Th2 bias. Activity ofbasophils,eosinophils, M2macrophages and is enhanced, whereas activity ofNK cells is downregulated. Conventionaldendritic cells are biased towards Th2 under the influence of estrogen, whereas plasmacytoid dendritic cells, key players in antiviral defence, have increasedIFN-g secretion.[91] Estrogen also influencesB cells by increasing their survival, proliferation, differentiation and function, which corresponds with higher antibody and B cell count generally detected in women.[92]
On a molecular level estrogen induces the above-mentioned effects on cell via acting on intracellularreceptors termed ER α and ER β, which upon ligation form either homo or heterodimers. The genetic and nongenetic targets of the receptors differ between homo and heterodimers.[93] Ligation of these receptors allows them to translocate to thenucleus and act astranscription factors either by binding estrogen response elements (ERE) onDNA or binding DNA together with other transcriptional factors e.g.Nf-kB orAP-1, both of which result inRNA polymerase recruitment and furtherchromatin remodelation.[93] A non-transcriptional response to oestrogen stimulation was also documented (termed membrane-initiated steroid signalling, MISS). This pathway stimulates the ERK and PI3K/AKT pathways, which are known to increase cellular proliferation and affect chromatin remodelation.[93]
Estrogens, in females, are produced primarily by theovaries, and during pregnancy, theplacenta.[96]Follicle-stimulating hormone (FSH) stimulates the ovarian production of estrogens by thegranulosa cells of theovarian follicles andcorpora lutea. Some estrogens are also produced in smaller amounts by other tissues such as theliver,pancreas,bone,adrenal glands,skin,brain,adipose tissue,[97] and thebreasts.[98] These secondary sources of estrogens are especially important in postmenopausal women.[99]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[99] and the level of aromatase.[100]
In females, synthesis of estrogens starts intheca interna cells in the ovary, by the synthesis ofandrostenedione fromcholesterol. Androstenedione is a substance of weak androgenic activity which serves predominantly as aprecursor for more potent androgens such as testosterone as well as estrogen. This compound crosses thebasal 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 by17β-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 lack17α-hydroxylase and17,20-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.[citation needed]
Notes: "Theconcentration 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. Thesecretion 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. Themetabolic clearance rate of a steroid is defined as the volume of blood that has been completely cleared of the hormone per unit time. Theproduction 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.
The word estrogen derives fromAncient Greek. It is derived from "oestros"[106] (a periodic state of sexual activity in female mammals), and genos (generating).[106] It was first published in the early 1920s and referenced as "oestrin".[107] With the years, American English adapted the spelling of estrogen to fit with its phonetic pronunciation.
The nameestrogen is derived from theGreekοἶστρος (oîstros), literally meaning "verve" or "inspiration" but figuratively sexual passion or desire,[108] and the suffix-gen, meaning "producer of".
A range of synthetic and natural substances that possess estrogenic activity have been identified in theenvironment and are referred toxenoestrogens.[109]
Estrogens are among the wide range ofendocrine-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 and humans.[12][13] The estrogen excreted from farm animals makes its way into fresh water systems.[110][111] During the germination period of reproduction the fish are exposed to low levels of estrogen which may cause reproductive dysfunction to male fish.[112][113]
Some hairshampoos on the market include estrogens and placental extracts; others containphytoestrogens. In 1998, there were case reports of four prepubescent African-American girls developing breasts after exposure to these shampoos.[114] In 1993, the FDA determined that not allover-the-counter topically applied hormone-containing drug products for human use aregenerally 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.[115]
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.[115]
^abcHuether SE, McCance KL (2019).Understanding Pathophysiology. Elsevier Health Sciences. p. 767.ISBN978-0-32-367281-8.Estrogen is a generic term for any of three similar hormones derived from cholesterol: estradiol, estrone, and estriol.
^Satoskar RS, Rege N, Bhandarkar SD (2017).Pharmacology and Pharmacotherapeutics. Elsevier Health Sciences. p. 943.ISBN978-8-13-124941-3.The natural estrogens are steroids. However, typical estrogenic activity is also shown by chemicals which are not steroids. Hence, the term 'estrogen' is used as a generic term to describe all the compounds having estrogenic activity.
^Delgado BJ, Lopez-Ojeda W (20 December 2021)."Estrogen".StatPearls [Internet]. StatPearls Publishing.PMID30855848.Estrogen is a steroid hormone associated with the female reproductive organs and is responsible for the development of female sexual characteristics. Estrogen is often referred to as estrone, estradiol, and estriol. ... Synthetic estrogen is also available for clinical use, designed to increase absorption and effectiveness by altering the estrogen chemical structure for topical or oral administration. Synthetic steroid estrogens include ethinyl estradiol, estradiol valerate, estropipate, conjugate esterified estrogen, and quinestrol.
^Ryan KJ (August 1982). "Biochemistry of aromatase: significance to female reproductive physiology".Cancer Research.42 (8 Suppl):3342s –3344s.PMID7083198.
^Mechoulam R, Brueggemeier RW, Denlinger DL (September 2005). "Estrogens in insects".Cellular and Molecular Life Sciences.40 (9):942–944.doi:10.1007/BF01946450.S2CID31950471.
^Lombardi G, Zarrilli S, Colao A, Paesano L, Di Somma C, Rossi F, et al. (June 2001). "Estrogens and health in males".Molecular and Cellular Endocrinology.178 (1–2):51–55.doi:10.1016/S0303-7207(01)00420-8.PMID11403894.S2CID36834775.
^Soltysik K, Czekaj P (April 2013). "Membrane estrogen receptors – is it an alternative way of estrogen action?".Journal of Physiology and Pharmacology.64 (2):129–142.PMID23756388.
^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):175–183.doi:10.1016/s1071-5576(00)00049-6.PMID10865186.
^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):11–15.doi:10.1089/gtmb.2010.0106.PMID21117950.
^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):466–476.doi:10.1016/j.mcn.2004.04.012.PMID15555924.S2CID25280077.
^Max SR (December 1984). "Androgen-estrogen synergy in rat levator ani muscle: glucose-6-phosphate dehydrogenase".Molecular and Cellular Endocrinology.38 (2–3):103–107.doi:10.1016/0303-7207(84)90108-4.PMID6510548.S2CID24198956.
^Koot RW, Amelink GJ, Blankenstein MA, Bär PR (1991). "Tamoxifen and oestrogen both protect the rat muscle against physiological damage".The Journal of Steroid Biochemistry and Molecular Biology.40 (4–6):689–695.doi:10.1016/0960-0760(91)90292-d.PMID1958566.S2CID44446541.
^Rubinow KB (2017). "Estrogens and Body Weight Regulation in Men".Sex and Gender Factors Affecting Metabolic Homeostasis, Diabetes and Obesity. Advances in Experimental Medicine and Biology. Vol. 1043. Springer. pp. 285–313.doi:10.1007/978-3-319-70178-3_14.ISBN978-3-319-70177-6.PMC5835337.PMID29224100.
^Hernando B, Ibarrola-Villava M, Fernandez LP, Peña-Chilet M, Llorca-Cardeñosa M, Oltra SS, et al. (18 March 2016)."Sex-specific genetic effects associated with pigmentation, sensitivity to sunlight, and melanoma in a population of Spanish origin".Biology of Sex Differences.7 (1): 17.doi:10.1186/s13293-016-0070-1.PMC4797181.PMID26998216. "The results of this study suggest that there are indeed sex-specific genetic effects in human pigmentation, with larger effects for darker pigmentation in females compared to males. A plausible cause might be the differentially expressed melanogenic genes in females due to higher oestrogen levels. These sex-specific genetic effects would help explain the presence of darker eye and skin pigmentation in females, as well as the well-known higher melanoma risk displayed by males."
^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):169–180.doi:10.1016/S0166-4328(97)00189-7.PMID9638959.S2CID28276218.
^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):374–384.doi:10.1097/01.GME.0000153933.50860.FD.PMID16037752.S2CID24557071.
^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):772–779.doi:10.1016/j.yhbeh.2011.03.013.PMID21514299.S2CID20807391.
^Douma SL, Husband C, O'Donnell ME, Barwin BN, Woodend AK (2005). "Estrogen-related mood disorders: reproductive life cycle factors".ANS. Advances in Nursing Science.28 (4):364–375.doi:10.1097/00012272-200510000-00008.PMID16292022.S2CID9172877.
^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):235–242.doi:10.1385/ENDO:28:3:235.PMID16388113.S2CID8205014.
^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):147–160.doi:10.1177/1099800407305600.PMID17909167.S2CID37965502.
^Berg SJ, Wynne-Edwards KE (June 2001). "Changes in testosterone, cortisol, and estradiol levels in men becoming fathers".Mayo Clinic Proceedings.76 (6):582–592.doi:10.4065/76.6.582.PMID11393496.
^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.PMID12537036.S2CID21497515.
^Baum MJ (November 2006). "Mammalian animal models of psychosexual differentiation: when is 'translation' to the human situation possible?".Hormones and Behavior.50 (4):579–588.doi:10.1016/j.yhbeh.2006.06.003.PMID16876166.S2CID7465192.
^Rosano GM, Panina G (1999). "Oestrogens and the heart".Therapie.54 (3):381–385.PMID10500455.
^abNelson LR, Bulun SE (September 2001). "Estrogen production and action".Journal of the American Academy of Dermatology.45 (3 Suppl):S116 –S124.doi:10.1067/mjd.2001.117432.PMID11511861.
^Labrie F, Bélanger A, Luu-The V, Labrie C, Simard J, Cusan L, et al. (1998). "DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: its role during aging".Steroids.63 (5–6):322–328.doi:10.1016/S0039-128X(98)00007-5.PMID9618795.S2CID37344052.
^Schreinder WE (2012)."The Ovary". In Trachsler A, Thorn G, Labhart A, Bürgi H, Dodsworth-Phillips J, Constam G, Courvoisier B, Fischer JA, Froesch ER, Grob P (eds.).Clinical Endocrinology: Theory and Practice. Springer Berlin Heidelberg. p. 530.ISBN978-3-642-96158-8. Retrieved12 October 2023.
^Fuentes N, Silveyra P (2019). "Estrogen receptor signaling mechanisms".Advances in Protein Chemistry and Structural Biology. Vol. 116. Elsevier. pp. 135–170.doi:10.1016/bs.apcsb.2019.01.001.ISBN9780128155615.ISSN1876-1623.PMC6533072.PMID31036290.Physiologically, the metabolic conversion of estrogens allows their excretion from the body via urine, feces, and/or bile, along with the production of estrogen analogs, which have been shown to present antiproliferative effects (Tsuchiya et al., 2005).
^Wesp LM, Deutsch MB (March 2017). "Hormonal and Surgical Treatment Options for Transgender Women and Transfeminine Spectrum Persons".The Psychiatric Clinics of North America.40 (1):99–111.doi:10.1016/j.psc.2016.10.006.PMID28159148.
^Fang H, Tong W, Shi LM, Blair R, Perkins R, Branham W, et al. (March 2001). "Structure-activity relationships for a large diverse set of natural, synthetic, and environmental estrogens".Chemical Research in Toxicology.14 (3):280–294.CiteSeerX10.1.1.460.20.doi:10.1021/tx000208y.PMID11258977.
^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.PMID20977246.
