Fig. 1.1
Schematic of GnRH synthesis. A, Representation of prepro-GnRH, including a 23-amino acid signal sequence, GnRH, a proteolytic processing site (Gly-Lys-Arg), and GnRH-associated peptide (GAP). The arrow indicates the site of proteolytic cleavage and C-amidation. B, Schematic of neuronal GnRH synthesis and secretion. Reproduction with the permission [1]
Most GnRH neurons are located in the preoptic area of the hypothalamus and project their axons to the median eminence. GnRH molecules that are stored in secretory granules in the nerve endings of the neuron are released via neuroendocrine mechanisms, travel through the hypophyseal portal system, bind to GnRH receptors that are primarily expressed on anterior pituitary cells, and stimulate the secretion of gonadotropins such as FSH and LH from the anterior pituitary gland (Fig. 1.2) [1].
Fig. 1.2
Anatomical relationship between hypothalamic GnRH neurons and their target cell populations in the adenohypophysis (anterior pituitary). GnRH neuron cell bodies are located in the preoptic area and the mediobasal hypothalamus. GnRH axonal projections terminate at the median eminence, where GnRH is secreted into the hypophyseal portal system. Reproduction with the permission [1]
- a.
Rhythmic secretion of GnRH
GnRH is secreted in a rhythmic fashion, and in response to this, gonadotropins are also secreted rhythmically from the pituitary. GnRH secretion is extremely crucial in the maintenance of the menstrual cycle. In the follicular phase of the menstrual cycle, GnRH pulses occur every 60–90 min. Under such physiological conditions, GnRH induces a priming effect of gonadotropin-secreting cells in the pituitary, consequently upregulating GnRH receptors and enhancing their responsiveness to GnRH molecules. However, when GnRH is activated with a continual pulse or with pulses that occur at a greater frequency than physiological levels, GnRH receptors decline and responsiveness also decreases (downregulation) (Fig. 1.3) [1]. In the latter half of the follicular phase, GnRH secretion cycles become shorter, and the amount of secretion increases as ovulation approaches; however, in the luteal phase, these cycles rapidly become longer and the amount of secretion further increases.
Fig. 1.3
The influence of pulsatile versus continuous GnRH administration to GnRH-deficient monkeys. Intermittent exogenous GnRH administration reconstitutes normal gonadotropin secretion. However, continuous GnRH infusion leads to a marked reduction (downregulation) in luteinizing hormone (green) and follicle-stimulating hormone (purple) concentrations. Resumption of pulsatile GnRH administration restores LH and FSH secretions. Reproduction with the permission [1]
- b.
Mechanism of regulation of GnRH secretion
GnRH secretion is regulated by neurotransmitters, such as noradrenaline, dopamine, and opioid peptides. External stimuli influence the cell body of GnRH neurons in the preoptic area and arcuate nucleus via noradrenaline synapses in the optic nerve or brain stem. Furthermore, other substances including opioids and dopamine in the arcuate nucleus of the hypothalamus act as neurotransmitters and affect the GnRH neuron cell body either directly or via a synapse. Some of these substances include molecules that are associated with appetite, sleep, and emotion, and it is postulated that these substances are involved in the onset of menstrual disorders that are observed under extreme stress. In addition, prolactin secreted from the anterior pituitary gland increases the dopamine neuron activity via a short feedback loop and subsequently suppresses GnRH secretion. This signifies that under hyperprolactinemic conditions, GnRH secretion decreases, triggering the onset of hypothalamic–pituitary dysfunction.
- c.
GnRH secretion regulated by kisspeptin
There is growing interest in the newly discovered molecule kisspeptin, which is a neuropeptide involved in the ovarian cycle. The rhythmic secretion or surge of GnRH is thought to occur due to the positive and negative feedback of estrogen; however, estrogen receptors are virtually nonexistent on GnRH neurons, and the specific mechanism of GnRH secretion control has been a mystery for a long time. As a molecule that may underlie the details of such a mechanism, kisspeptin has recently become a molecule of interest. Moreover, because the biological neural network that produces kisspeptin also produces neurokinin B as well as opioid dynorphin, this network is currently called the kisspeptin–neurokinin B–dynorphin (KNDy) network [2].
Kisspeptin is a peptide encoded by Kiss1, and its human version is composed of 54 amino acids (Fig. 1.4) [3]. The receptor for this peptide is GPR54, an orphan G-protein-coupled receptor. Based on structural similarities, these were globally termed kisspeptins, as they are derived from differential proteolytic processing of a common precursor. In humans, the KiSS-1 precursor contains 145 amino acids, with a putative 19-amino acid signal sequence, two potential dibasic cleavage sites (at amino acids 57 and 67), and one putative site for terminal cleavage and amidation [3]. Kisspeptin was originally discovered in 1996 as a suppressor of metastasis of human malignant melanoma [4]. The peptide is named after the famous Kisses chocolate as it was discovered in Hershey, Pennsylvania, and the “SS” portion also means “suppressor sequence” [5]. In addition, it is sometimes called “metastin” due to its characteristic of suppressing cancer metastasis [6].
Fig. 1.4
Structural features of human kisspeptins generated by cleavage form a common precursor, the prepro-kisspeptin. Prepro-kisspeptin, encoded by the KiSS–1 gene, is a 145-amino acid protein that contains a 19-amino acid signal peptide and central 54-amino acid region, flanked by two consensus cleavage sites (denoted by X), which gives rise to metastin or kisspeptin-54. Further cleavage of metastin generates kisspeptins of lower molecular weight: kisspeptin-14 (Kp-14), Kp-13, and Kp-10. All kisspeptins are able to bind and activate GPR54. Besides general structural organization, the complete amino acid sequences of human metastin and kisspeptin-10 are shown. The consensus C-terminal RF-amide motif, hallmark of this peptide superfamily, is indicated in bold (with the permission reproduced from [3])
GnRH neurons extend from the preoptic area to the infundibular nucleus (homologous to the arcuate nucleus in other species) of the hypothalamus in humans, whereas in rodents, GnRH neurons reside predominantly in the preoptic area [5]. Kisspeptin neurons are localized in the anteroventral periventricular nucleus and arcuate nucleus in the preoptic area of the hypothalamus in rodents such as rats (Fig. 1.5) [5]. Similarly, kisspeptin neurons are located in the rostral preoptic area and the infundibular nucleus in the human hypothalamus [7]. In humans, the majority of kisspeptin cell bodies are found in the infundibular nucleus, but a second dense population of kisspeptin cells has been identified in the rostral preoptic area [7]. Although kisspeptin neurons are located in the infundibular/arcuate nucleus across all species including humans, the rostral population is species specific [5, 7]. In rodents, the rostral population is located in the anteroventral periventricular nucleus, the periventricular nucleus, and the continuum of this region, which is known as the rostral periventricular region of the third ventricle (Fig. 1.5) [5].
Fig. 1.5
Schematic diagram showing the neuroanatomy of the kisspeptin–GnRH pathway and the relationship between KNDy neurons and GnRH neurons in humans and rodents. Kisspeptin signals directly to the GnRH neurons, which express kisspeptin receptor. The location of kisspeptin neurone populations within the hypothalamus is species specific, residing within the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus in rodents, and within the preoptic area (POA) and the infundibular nucleus in humans. Kisspeptin neurons in the infundibular (humans)/arcuate (rodents) nucleus coexpress neurokinin B and dynorphin (KNDy neurons), which via neurokinin B receptor and kappa opioid peptide receptor autosynaptically regulate pulsatile kisspeptin secretion, with neurokinin B being stimulatory and dynorphin inhibitory. Negative (red) and positive (green) sex steroid feedback is mediated via distinct kisspeptin populations in rodents, via the AVPV and the arcuate nucleus, respectively. In humans, KNDy neurons in the infundibular nucleus relay both negative (red) and positive (green) feedback. The role of the POA kisspeptin population in mediating sex steroid feedback in humans is incompletely explored. ME, median eminence; +, stimulatory; −, inhibitory; ERα, estrogen receptor alpha; PR, progesterone receptor; Kiss I/kiSS I, kisspeptin; NKB, neurokinin B; and Dyn, dynorphin (with the permission reproduced from [5])
Kisspeptin stimulates the secretion of both LH and FSH in humans [8]. Kisspeptin 54 has an immediate and dose-dependent effect with a half-life of 26.6 min; in contrast, kisspeptin 10 has an extremely short half-life of 4 min [9]. The effects of kisspeptin differ depending on the type of exposure, route of administration, gender, and isoform [5, 8, 9]. Some studies suggest that kisspeptin directly stimulates pituitary gonadotrophs to release LH and FSH, based on the expression of Kiss1 and Kiss1r in gonadotrophs and the secretion of gonadotropins from pituitary explants treated with kisspeptin [5, 10]. Because GnRH secretion is pulsatile, the effect of kisspeptin on the characteristics of that pulsatility (as reflected in LH pulses) has been investigated. Intravenous infusion of kisspeptin 54 [subcutaneous bolus 0.3 nmol/kg (1.76 mg/kg) and 0.6 nmol/kg (3.5 mg/kg)] in healthy women increases the LH pulse frequency and amplitude [11].
Kisspeptin in the infundibular nucleus mediates negative feedback of estrogen in humans (Fig. 1.5). In postmenopausal women, kisspeptin neurons in the infundibular nucleus become hypertrophied and express more KISS1 mRNA than in premenopausal women [12]. These hypertrophied neurons express both ESR1 (encoding estrogen receptor alpha) and neurokinin B mRNA, show increased expression of neurokinin B, and show a similar distribution as that of kisspeptin neurons [13]. Kisspeptin and neurokinin B in the infundibular nucleus may act synergistically to mediate estrogen-negative feedback [5]. Estrogen may mediate negative feedback by suppressing kisspeptin and neurokinin B release from KNDy neurons, which reduces their stimulatory input to GnRH neurons (Fig. 1.5) [5].
In addition, kisspeptin may mediate estrogenic positive feedback. Estrogen feedback switches from negative to positive in the late follicular phase to induce the GnRH/LH surge at the time of ovulation. However, the neuroendocrine mechanisms involved in this critical physiological event are unclear. Emerging data suggest that although the negative feedback of sex steroids is mediated by KNDy neurons in the infundibular/arcuate nucleus, the positive feedback of sex steroids is more site specific and species specific (Fig. 1.5) [5]. The expression of Kiss1 mRNA in the anteroventral periventricular nucleus is dramatically increased after estrogen replacement and at the time of the GnRH/LH surge [14]. KNDy neurons may play a role in positive estrogen feedback [5]. Furthermore, kisspeptin neurons in the anteroventral periventricular nucleus are activated during ovulation. It has also been shown that the expression of kisspeptin in the arcuate nucleus increases with the removal of the ovaries and decreases with the presence of estrogen. Based on these findings, the high concentration of estrogen secreted by mature follicles acts on kisspeptin neurons in the anteroventral periventricular nucleus, and the activated kisspeptin neurons influence the preoptic area and stimulate GnRH neuron cell bodies. Through these mechanisms, the positive feedback loop of estrogen is formed, evoking the LH surge after the GnRH surge [5].
Gonadotropins
Gonadotropin is a collective term for FSH and LH that are secreted from the anterior pituitary gland. These hormones promote follicular development in the ovary, elicit ovulation of a mature egg through the LH surge, and induce follicle luteinization after ovulation, indicating that they play many different roles in the body. Gonadotropins bind to FSH receptors and LH receptors that are present in the theca cells and granulosa cells of the ovary, and they regulate steroid production in the ovary through this mechanism. In addition, steroid hormones and inhibin secreted from the ovary through these stimuli affect the central nervous system, thereby influencing gonadotropin secretion. As described here, the interaction of the hypothalamus–pituitary–ovary axis is essential in the regulation of ovarian function, and in particular, gonadotropins and their receptors play a pivotal role in this pathway.
- a.
Construction of Gonadotropins
Gonadotropin is a glycoprotein hormone that is synthesized and secreted by the anterior pituitary gland and is used as a general term for FSH and LH. These hormones are heterodimers formed by a covalently bound α-chain and β-chain. The α-chain is common between the hormones, and the same α-chain is also found in non-gonadotropin molecules such as thyroid-stimulating hormone and human chorionic gonadotropin. This indicates that the β-chain determines the function of each hormone (Fig. 1.6) [15].
Fig. 1.6
Schematic presentation of sizes, locations of the carbohydrate side chains, and currently known mutations and polymorphisms in the gonadotropin subunits (i.e., common α-subunit [Ca], LHβ, FSHβ, and hCGβ). The numbers below the right ends of the bars indicate the number of amino acids in the mature subunit proteins. Symbols “Y” and “O” indicate the locations of N-linked and O-linked carbohydrate side chains, respectively. The arrows below the bars indicate the locations of point mutations and polymorphisms (with the permission reproduced from [15])
- b.
Gonadotropin receptors
The cDNA sequence of the gonadotropin receptor, specifically the LH receptor, was first identified in rats and pigs in 1989 [16]. Subsequently, the cDNA sequences of gonadotropin receptors from various species including humans were determined [17]. Both FSH and LH receptors are G-protein-coupled receptors and form a subgroup together with thyroid-stimulating hormone receptors [15].
The FSH receptor consists of 17 single peptides and 678 amino acids, and its molecular weight is predicted to be about 75,500. The human FSH receptor gene is located on the short arm of chromosome 2 (2p21). The LH receptor is composed of 26 single peptides and 673 amino acids, and its molecular weight is predicted to be approximately 75,000. However, with posttranslational modifications with sugar residues, the actual molecular weight is considered to be about 85,000–92,000. The human LH receptor gene is located on the short arm of chromosome 2 (2p21), similar to the FSH receptor [15].
It is generally considered that gonadotropin receptors are activated in the following manner: The long extracellular N-terminal domain recognizes the β-chain of gonadotropins, and the seven-pass transmembrane domain subsequently forms a ringlike pocket where the α-chain of the gonadotropins binds, which in turn activates the receptor. When the receptor becomes activated in this manner, the intracellular domain binds to a G-protein, which subsequently becomes activated. As a result, adenylate cyclase, a target enzyme of G-proteins, becomes activated, and cAMP is synthesized intracellularly. These cAMP molecules are thought to act as intracellular second messengers in intracellular signal transduction and subsequently activate protein kinase A and affect gene transcription regulation [18].
In addition, gonadotropin receptors are involved in cell proliferation via Ras-mediated activation of MAP (mitogen-activated protein) kinase [19]. Furthermore, gonadotropic receptor-mediated activation of the inositol triphosphate pathway leads to an elevation in the intracellular Ca2+ concentration, suggesting that they may also play a role in the activation of protein kinase C [20]. It is generally considered that cAMP and Ca2+ do not act independently, but rather in concert with each other in the G-protein-coupled receptor signaling cascade, and this is also considered to be true of gonadotropin receptors.
- c.
Localization of gonadotropin receptors
In the ovary, FSH receptors are present only on granulosa cells and are absent on theca cells. In human ovaries, the expression of FSH receptors increases in the early and middle stages of the follicular phase but rapidly decreases after ovulation. In other words, FSH receptor expression declines with the progression of luteinization of granulosa cells that occurs after the LH surge and consequent ovulation. In contrast, LH receptors are expressed in theca cells, and their expression is upregulated with follicular development. Furthermore, due to FSH stimulation, the expression of LH receptors is also upregulated in granulosa cells of mature follicles immediately before ovulation [15].
These gonadotropin receptors are thought to function by influencing each other, and this phenomenon is classically known as the “two-cell theory” (Fig. 1.7). In the early stages of steroid hormone production in the ovary, androgen synthesis increases within the theca cells due to LH stimulation of these cells. These androgen molecules are then transported to the granulosa cells and are synthesized into estrogen by aromatase actions. The activity of this aromatase is augmented by FSH stimulation. The synthesized estrogen molecules act together with FSH and further enhance the efficiency of FSH and LH stimulation to augment the expression of FSH and LH receptors.
Fig. 1.7
The schema of “two-cell theory.” Androgen synthesis increases within the theca cells due to LH stimulation. These androgen molecules are then transported to the granulosa cells and are synthesized into estrogen by aromatase actions. The activity of this aromatase is augmented by FSH stimulation. The synthesized estrogen molecules act together with FSH and further enhance the efficiency of FSH and LH stimulation to augment the expression of FSH and LH receptors
- d.
Regulation of gonadotropin secretion (effects of estrogen on the central nervous system)
LH is secreted in two different ways, basic secretion (pulse secretion) and ovulatory secretion (surge secretion), and GnRH released by the hypothalamus controls such secretion through the central nervous system. GnRH is also thought to be secreted via two different methods, pulse and surge, and the aforementioned kisspeptin has also been indicated to control GnRH through the central nervous system.
Steroid Hormones
Steroid hormones are a type of steroids with a steroid nucleus structure (Fig. 1.8) and are typically synthesized from cholesterol in the adrenal glands and gonads [21]. These hormones are broadly classified into the following five types depending on the specific receptors to which they bind. From the perspective of the synthetic mechanisms of steroid hormone metabolism, they are precursors, intermediate products, or metabolites of each other.
Fig. 1.8
Basic steroid structure showing a fully saturated 21 carbon steroid with the alphabetical naming of the individual rings and the numbering sequence of the carbon atoms. All steroids share the same basic 17 carbon structure with the presence of four linked rings (three six sided and one five sided) known as the cyclopentanophenanthrene (or cyclopentanoperhydrophenanthrene) ring. The rings are alphabetically labeled with the carbon atoms which are numbered sequentially. Cholesterol is recognized as the parent steroid and contains 27 carbon atoms, whereas the three main groups of steroids of interest in clinical endocrinology consist of 18, 19, or 21 carbon atoms, representing the estrange, androstane, and pregnane skeleton (with the permission reproduced from [21])
- a.
Progestogen (gestagens);
- b.
Androgens (androgenic hormones);
- c.
Estrogens;
- d.
Glucocorticoids; and
- e.
Mineralocorticoids.
Of these, a–c are sex steroid hormones, and d and e are called corticoids. Mineralocorticoids are a collective term for molecules with aldosterone-like actions that regulate osmotic pressure, predominantly by affecting the salt concentration balance. Glucocorticoids play a role in glucose metabolism. Unlike proteins, steroids are fat soluble and can diffuse both intra- and extracellularly. For this reason, unlike peptide hormones that transmit signals via cell-surface receptors, steroid hormones can bind directly to receptors that are expressed intracellularly.
In addition, each of the steroid hormones undergoes various modifications, such as hydroxylation, sulfation, methoxylation, and glucuronidation, thereby becoming metabolized into a low-activity state and eliminated into the bile or urine. Furthermore, the actions and activities of steroid hormones differ greatly from molecule to molecule, even if the differences in side-chain modifications are minute. Figure 1.9 shows the structures and metabolic pathways of steroids [21]. In addition, each sex steroid hormone is described.
Fig. 1.9
The structures and metabolic pathways of steroids. Mineralocorticoids are typified by aldosterone that regulates osmotic pressure. Glucocorticoids play a role in glucose metabolism. In addition, each of the steroid hormones undergoes various modifications, such as hydroxylation, sulfation, methoxylation, and glucuronidation. The actions and activities of steroid hormones differ greatly. And also, contrary to adrenal cortex, androgens are converted to estrogens by aromatase on the ovary. (with the permission reproduced from [21])
Sex Steroid Hormones
- a.
Progestogens
This class of hormones is composed of a basic structure of 21 carbons called the “pregnane backbone” (C21 pregnane) and is produced by a variety of organs including the ovary (primarily the corpus luteum), placenta, adrenal cortex, and testis. Progestogens, as the name suggests, play an important role in the maintenance of pregnancy. Their levels significantly fluctuate within the menstrual cycle during the non-pregnant state. Progestogens are present in men at a level similar to those in women during the follicular phase. Progestogens are the most upstream molecules of the steroid metabolic pathway, and thus, they are considered to be precursors of all steroid hormones. In the first step of steroid metabolism, pregnenolone is synthesized from cholesterol. Progestogens are primarily metabolized by the liver in the form of pregnanediol and eliminated in urine. Therefore, the urine pregnanediol concentration reflects the function of progestogen-producing organs. Representative progestogens are shown below.
- i.
Progesterone ( Prog: P4 )
Molecular formula (MF): C21H30O2, molecular weight (MW): 314.46, biological half-life (t1/2): 34.8–55.13 h
This hormone is produced primarily by the corpus luteum of the ovary, the adrenal gland, and the placenta and is also secreted by adipose tissue. The blood concentration of progesterone changes during the menstrual cycle. Although progesterone levels are low from the follicular phase to the ovulation phase, they rapidly increase during the luteal phase due to secretion from luteinized granulosa cells. Subsequently, with luteal regression, progesterone levels decrease. When pregnancy is established, the placenta begins to produce progesterone, contributing to the maintenance of pregnancy.
- ii.
Pregnenolone ( Preg: P5 )
MF: C21H32O2, MW: 316.483
Pregnenolone is the furthest upstream in the steroid hormone metabolic pathway and is a precursor of all steroid hormones. Pregnenolone is synthesized in the mitochondria of adrenal glands, testes, ovarian theca cells, and the placenta via side-chain cleavage of cholesterol.
- iii.
17α – hydroxyprogesterone ( 17 – OH progesterone: 17P4 or 17 – OH P )
MF: C21H30O3, MW: 330.46
Although this hormone is synthesized primarily in the adrenal glands, it is also produced by the corpus luteum. Its blood concentration during pregnancy is 10–1000 times greater than the P4 concentration during the normal menstrual cycle. Measurement of 17-OHP is important for evaluating the state of luteal function during pregnancy.
- iv.
17α – hydroxypregnenolone ( 17 – OH pregnenolone: 17P5 or 17 – OH P)
MF: C21H32O3, MW: 332.48
This hormone is produced in the adrenal glands and gonads. Measurement of 17-OHP is useful for diagnosing congenital adrenocortical hyperplasia, which is caused by mutations in steroid hormone conversion enzymes such as HSD3β2 and CYP17A1.
- b.
Androgens
The structure of androgens is an androstane backbone consisting of 19 carbons (C19 androstane). Androgens are primarily produced in the testis, ovary, and adrenal cortex, and their synthesizing enzymes are found in the smooth endoplasmic reticulum. Androgens are metabolized predominantly by the liver. Their physiological roles include proliferation of cells in the prostate gland, seminal vesicle, and epididymis, promotion of spermatogenesis in the seminiferous tubules, promotion of renal tubule function in the kidneys, increase in the glomerular filtration rate, promotion of sebum sebaceous matter secretion from the sebaceous glands, proliferation of muscle and bone cells, suppression of LH secretion from the anterior lobe of the hypophysis, and suppression of GnRH secretion from the hypothalamus.
- i.
Testosterone
MF: C19H28O2, MW: 288.42, t1/2: 2–4 h
Testosterone is predominantly produced in the testicles of men during puberty and later. Its blood concentration ranges from 3–13 ng/ml, although this level decreases slightly with age. It is also produced by the ovaries in women, although its blood concentration is 0.2–1 ng/ml, which is lower than in men. In addition, the adrenal glands produce a small amount of testosterone. The majority of testosterone molecules are bound to globulin and albumin in the blood. Unbound active testosterone accounts for only 1–2% of the overall amount.
- ii.
Dehydroepiandrosterone ( DHEA )
MF: C19H28O2, MW: 288.424, t1/2: 12 h
Mainly produced in the adrenal glands, DHEA is the most abundant steroid hormone and has the highest blood concentration of all the steroid hormones in humans. Synthetic levels of DHEA peak in the early 20 s and decrease with age. DHEA possesses weak androgenic properties, comprising 3–34% of the activity of testosterone.
- iii.
Androstenedione ( andro: A4: AE )
MF: C19H26O2, MW: 286.4
Androstenedione is produced in the testis, ovary, and adrenal cortex. It possesses weak androgenic properties that account for 20–40% of the activity of testosterone. In premenopausal women, a total of approximately 3 mg/day of androstenedione is synthesized in the adrenal glands and ovaries in nearly equivalent amounts. For this reason, androstenedione levels are reduced by half after menopause. This hormone is also used as a supplement in steroid replacement therapy.
- iv.
5α – dihydrotestosterone ( DHT: 5α – DHT )
MF: C19H30O2, MW: 290.42
Approximately 7% of testosterone is converted to this hormone in the testis, adrenal cortex, and hair root. Because estrogen cannot be directly synthesized from 5α-DHT, it is frequently used in experiments involving the androgen receptor. This hormone is catabolized in the body to 3α- and 3β-androstanediol. It exhibits the strongest androgenic properties of all the androgens, approximately 2.5 times greater than that of testosterone.
- c.
Estrogens
Estrogens are steroid hormones that possess an estrane backbone consisting of 18 carbons (C18 estrane). Estrogens play a key role in female reproduction in all vertebrate animals. Estrogen synthesis occurs irreversibly by aromatase using androgens as substrates. Estrogen is predominantly produced in developing follicles, the corpus luteum, and the placenta. Synthesis and secretion are promoted by gonadotropins, which are released from the anterior lobe of the hypophysis. In women, blood estrogen levels fluctuate throughout the menstrual cycle, and similar to progesterone, estrogen levels increase with the number of gestational weeks. Furthermore, aromatase is present in adipocytes, the liver, adrenal glands, testes, mammary glands, and brain, and these cells and tissues also produce small amounts of estrogen. Therefore, although no periodicity in estrogen production occurs, estradiol levels of about 100 pM (30 ng/L) are maintained in both postmenopausal women and men. In addition, when estrogen is supplemented orally, most of it is rapidly degraded by the liver through the portal vein.
Specific actions of estrogens include the promotion of secondary sex characteristics, maintenance of germ cells, and especially, the development and maturation of the female reproductive organs. Estrogens also affect the bones, liver, and brain and promote feminization. Primary examples of estrogens are indicated below.
- i.
Estrone ( oestrone: E1 )
MF: C18H22O2, MW: 270.366, t1/2: 19 h
Estrone is synthesized irreversibly from androstenedione and reversibly from estradiol and also exists in a sulfation state, making it less vulnerable to metabolism. Estrone sulfate, estrone, and estradiol can easily be converted to each other in the body, and these characteristics are thought to be essential for the regulation of estrogenic activities. In addition, estrone sulfate is the primary component of estrogens used in hormone replacement therapy; its administration is conducted with the assumption that it will be converted to estradiol. Similar to estradiol, blood estrone levels fluctuate depending on the menstrual cycle. Moreover, blood estrone levels during pregnancy also gradually increase with increasing gestational weeks. The estrogenic activities of estrones are weak and exhibit 12.5% of the estrogenic activities of estradiol in rats.
- ii.
Estradiol ( 17s – estradiol: oestradiol: E2 )
MF: C18H24O2, MW: 272.38, t1/2: ~13 h
Estradiol is irreversibly synthesized in the granulosa cells of the ovary, adrenal cortex, and testis by the aromatization of testosterone and from estrone. Blood estradiol levels change throughout the menstrual cycle, peaking before the ovulation phase, and also increase during pregnancy. Of the molecules synthesized in the body, estradiol has the greatest estrogenic activity. However, because it is degraded relatively quickly, estradiol is also administered in the form of estrone.
- iii.
Estriol ( oestriol: E3 )
MF: C18H24O3, MW: 288.38
Pregnenolone, which transfers from the mother to the fetus via the placenta, is sulfated in the fetal adrenal glands, hydroxylated in the fetal liver, and finally aromatized upon return to the placenta, thereby completing estriol synthesis. This series of reactions is essential for the development of the fetal liver and placenta. The pregnenolone level rapidly begins to increase, later than other estrogens, at 12 weeks of gestation. Additionally, because E3 and its metabolites are abundantly present in the urine of pregnant women, it is utilized as an index of fetal development. Normally, estriol levels are very low in both men and women. The activity of estriol is extremely weak and comprises about 1% of the activity of estradiol.
Key Molecules in the Biosynthesis and Catabolism of Steroid Hormones
The important molecules involved in the synthesis and metabolic regulation of steroid hormones are listed below [1] and summarized in Table 1.1 [21].
Table 1.1
The important molecules involved in the synthesis and metabolic regulation of steroid hormones, reproduction with the permission [21]
Enzyme | Gene | Chromosome locus | Tissue/organs of expression | Major function | Role in human steroidogenesis |
|---|---|---|---|---|---|
P450 scc | CYP11A1 | 15q23-q24 | All layers of adrenal cortex, Leydig cells, theca cells, brain | 22-hydroxylation 20-hydroxylation 20,22-desmolase | Converts cholesterol to pregnenolone |
3β-HSD1 | HSD3B1 | 1p13.1 | Placenta, breast, liver, brain | 3β-dehydrogenase Δ5-Δ4 isomerase | Perioheral conversion of Δ5 compounds to Δ4 |
3β-HSD2 | HSD3B2 | 1p13.1 | All layers of adrenal cortex, Leydig cells, theca cells | 3β-dehydrogenase Δ5-Δ4 isomerase | Conversion of Δ5 compounds to Δ4 in adrenal and gonads |
17-hydroxylase/ 17,20-lyase | CYP17A1 | 10q24.3 | ZF, ZR, Leydig cells, theca cells, brain | 17α-hydroxylase 17,20 lyase | Conversion of pregnenolone and progesterone to 17-hydroxylated products, conversion of 17-OH-Preg to DHEA and 17-OHP to androstenedione |
P450-oxidoreductase | POR | 7q11.2 | Widely expressed in human tissues | Electron transfer | Electron donor for 17-hydroxylase, 21-hydroxylase and aromatase |
21-hydroxylase (21α-hydroxylase) | CYP21A2 | 6p21.1 | ZG, ZF | 21-hydroxylation | Conversion of progesterone to DOC and 17-OHP to 11-deoxycortisol |
11β-hydroxylase | CYP11B1 | 8q21-q22 | ZF, to a lesser extent in ZR, brain | 11β-hydroxylation | 11-Deoxycortisol to cortisol, 11-DOC to corticosterone |
Aldosterone synthase | CYP11B2 | 8q21-q22 | ZG, brain | 11β-hydroxylation 18-hydroxylase 18-oxidation | DOC to aldosterone in 3 reactions |
17β-HSD1 | HSD17B1 | 17q11-q21 | Placenta, granulosa cells | 17β-ketosteroid reductase | Oestrone to oestradiol |
17β-HSD2 | HSD17B2 | 16q24.1-q24.2 | Endometrium, placenta, ovary | 17β-hydroxysteroid dehydrogenase | Oestradiol to oestrone, testosterone to androstenedione, DHT to 5α-androstanediol |
17β-HSD3 | HSD17B3 | 9q22 | Leydig cells | 17β-ketosteroid reductase | Androstenedione to testosterone |
17β-HSD5 | HSD17B5 (AKR1C3) | ZR, fetal adrenal, liver, prostate | 17β-ketosteroid reductase | Androstenedione to testosterone | |
17β-HSD6 | HSD17B6 | 12q13.3 | Prostate, probable role in alternative pathway | Dehydrogenase | Androstanediol to DHT
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