Mechanism Of Sex Steroid Hormones 

Mechanism Of Sex Steroid Hormones 

Cholesterol is a 27-carbon molecule that is the starting point for the synthesis of all steroid hormones. And the carbon gets taken out step by step.  Progestins and corticoids are examples of pregnane derivatives; they contain 21 carbons.

Androgens are also androstane derivatives; there are 19 carbons in them. Another type of chemical that is estrogen and has 18 carbons is called an estrane derivative. With the exception of the placenta, all of the body's steroid-producing glands are able to produce cholesterol from acetate.

Because the body needs steroids too much, the amount of steroid created from the cholesterol made from acetate will not be sufficient to make steroid hormones. The LDL cholesterol found in blood circulation provides the majority of the cholesterol required for the synthesis of steroid hormones.

When LDL cholesterol enters steroid-producing cells, it travels from the cytoplasm to the mitochondria, where it is converted into steroid hormones (this is a rate-limiting process that occurs from the outside to the inner mitochondrial membrane). The STAR protein (steroid acute regulatory protein) is the enzyme that is in charge of this transport. Additionally, the tropic hormones stimulate it.

Steroidogenesis

Pregnenolone is created when the P450 side chain cleavage enzyme acts on cholesterol. Depending on the order of the stages and the enzymes operating on the substrate, pregnenolone can proceed either the progesterone pathway or the endrogen pathway.

If the pregnenolone is acted upon by P450c17, it forms 17-hydroxypregnenolone, which when acted upon by P450c17 forms dehydroepiandrosterone (DHEA). If the 3βHSB acts upon the pregnenolone, it forms progesterone, which again, by the action of P450c17, forms 17-hydroxyprogesterone, which is acted upon by P450c17 forms androstenedione.3βHSB metabolizes this DHEA to generate androstenedione. that P450aram acts upon to create estrone (E).

These can then be converted to testosterone or estradiol.The type of enzymes that are primarily present or absent determines the type of steroid hormone that an organ or tissue will secrete. Even still, the route is still the same as it was for the previous choices.

The ovary and gonads lack 11βhydroxylase and 21αhydroxylase activity, respectively, which is present in the adrenal gland. Progesterone and 17-hydroxyprogesterone therefore diverge into the glucocorticoid and mineralocorticoid pathways in the adrenal gland.  The main pathway in the corpus luteum will be via 3βHSB, which will mostly form the progesterone production. Estrogens and androgens can also be obtained here.

 The main pathway in these tissues follows the androgen route via the 17 hydroxylase enzyme (P450c17), as observed in the ovarian theca cells, the Leydig cells at the testes, and the adrenal reticularis. It's crucial to remember that the primary androgen produced in the ovaries is androstenedione.

As the direct antecedent to estrogen synthesis, testosterone will be the decisive factor.  The aromatase enzyme converts androstenedione into estrone; this process is one-way or single-directional, with testosterone also being aromatized by androstenedione.  Because the enzyme aromatase is present in both the placenta and the ovarian granulose cells, estrone is generated predominately; nevertheless, enzyme 17βHSB will ultimately cause estradiol to be the main byproduct.

Male testes include distinct types of 17βHSB (types 3 and 5), which convert the majority of androgen to testosterone. In addition, there exist two other types of 17βHSB (types 2 and 4), which function through inactivation to change estradiol into estrone.

Also Read: Neuroendocrinology Of Female Reproduction And Steroid Hormones

Two Cell- Two Gonadotropin Theory

Theca cells and granulose are found in the ovarian follicle. Theca cells have LH receptors, which the LH acts upon.

These receptors, which are located on the cell membrane, also function by communicating with the second messenger system. Here, the cyclic AMP (cAMP) generation of the second messenger system drives the synthesis of steroid hormones, leading to the formation of androstenedione and small amounts of testosterone via the androgen pathway.

After diffusing and entering the granulose cell, these substances (androstenedione and testosterone) bind to FSH receptors on the granulose cell membrane. As a secondary messenger system for signaling, cAMP activates aromatase, converting androstenedione into estrone (E1) and testosterone into estradiol (E2). Additionally, some of the estrone is aromatized to produce estradiol.Estradiol will be the main product created, however a sizable amount of estrone is also produced. 

One of the peripheral metabolites of E1 and E2 is estriol. It has an extremely short half-life and is quickly digested and removed from the body. It is also the least powerful. This explains why in a woman who is not pregnant, it is essentially unnoticeable. Given that the placenta secretes significant amounts of it during pregnancy, it becomes increasingly relevant.  The placenta is the only organ that produces estradiol (E4).

Estrogens In Circulation

In women of reproductive age, estradiol has the highest concentration of estrogen, followed by estrone. Because estrogen levels vary throughout the menstrual cycle, a relatively wide range of values are regarded as normal.  A lower amount of estrogen than. The menopausal level is defined as estrogen levels below 20 pg/ml.

Estradiol and estrone come from the ovaries. The adrenal glands are the primary source of androgens released into the bloodstream. Most of this androgen is androstenedione. This androstenedione is aromatized in peripheral skin and fat cells to produce estrone. It is also possible to convert this estrone into estradiol.

This is pertinent to postmenopausal women who are obese and have a dominating estrogen level. This becomes considerably more important when there is excess androgen.

Progesterone Production

The direct precursor is low-density lipoprotein (LDL). The corpus luteum, the ovaries, is the main source of progesterone. The adrenal gland also produces a minor quantity of it. The stage of the menstrual cycle affects the amount of progesterone produced.

Also Read: Puerperium: Understanding the Postpartum Period

Androgens In Female

DHEA-S, DHEA, androstenedione, and finally testosterone, make up the descending order of androgen concentration in a woman of reproductive age. Weak androgens include androstenedione, DHEA, and DHEA-S. They must be present in large concentrations in order to have an androgenic impact, and they must somehow be transformed into testosterone in order to do so.

The adrenal gland is the only source of DHEA-S in the bloodstream. The adrenal gland produces around half of the DHEA, while the ovaries provide the remaining 25%. The remaining DHEA is being converted from DHEA-S to DHEA. The ovaries and adrenal glands contribute equally to the blood's supply of androstenedione (50%–50%).

The most powerful hormone is testosterone, which is produced at a rate of 0.2 to 0.3 mg per day and has a blood concentration of 20–80 ng per day. Approximately 25% of testosterone is produced by the adrenal gland and the remaining 25% by the ovaries.

The peripheral conversion of androstenedione to testosterone accounts for the remaining 50% of testosterone.In cases such as stromal hyperplasia, androgen-producing ovarian tumors, or androgen-producing malignancies from the adrenal gland as well, the ovarian contribution of androgen and testosterone becomes considerable.

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Blood Transport Of Steroid Hormones

 Very little hormone circulation occurs in the free form and a great deal in the bound form. The form that is biologically active is the free form.
Less than 2% of progesterone and just 1% of testosterone and estradiol are in their free forms; the remainder are bound. • The majority of bound testosterone and estradiol is around 70% bound to the sex hormone binding globulin (SHBG) and the remaining 30% bound to the albumin. Approximately 80% of progesterone is bound to the albumin and approximately 18% to the CBG. Very little in relation to CBG (cortisol binding globulin). The liver produces the SHBG.

As total hormone production rises during pregnancy, there is an increased amount of SHBG production to maintain the free form of the hormones at a normal level.

Oral contraceptive tablets, which contain estrogen, are utilized in diseases like PCOD where there is an increase in androgen levels because they also promote levels of SHBG. Considering that they aid in lowering androgen levels.

The levels of SHBG have an impact on the levels of testosterone and free estrogen in the circuit. Obesity, insulin/IGF-1, corticoids, androgens, progestins, and growth hormones are among the conditions that lower SHBG. The amounts of free hormones in the blood rise as a result of these circumstances.

Also Read: From HPO Axis To Ovulation

Mechanism Of Action-steroid Hormones

 Nuclear receptors are found on steroids, and intra-nuclear receptors are found on sex hormone receptors such as estrogen, progesterone, and androgens.

One hormone enters the cell, another enters the nucleus and attaches itself to a receptor; the hormone and receptor complex subsequently binds to the DNA, which is followed by transcription, translation, and so forth. The type of protein that is generated last determines how much of an impact steroid hormone has.

Due to its greatest receptor affinity, estradiol is the most powerful hormone. Although estrone's potency is lower than that of estradiol, its consistently elevated level is likely to produce effects that are comparable to those of estradiol.
Just as crucial as the hormone's dosage is the length of time it is exposed.In the target tissues, estrogen stimulates both progesterone and its own receptors.

Progesterone stimulates the 17βHSD, which converts estradiol to esttrone, and reduces the concentration of estrogen receptors in target tissues, especially in the uterine linings.

In the absence of progesterone, estrogen activity is physiologically antagonistic; androgens also reduce the number of estrogen receptors in target tissue, particularly in the nucleus; and 5α reductase converts testosterone into the more potent form of dihydrotestosterone.

The androgen receptor shared by testosterone and DHT is where this conversion occurs in the target tissue. Dihydrotestosterone is mostly responsible for the effects on the skin, hair follicles, and reproductive tissue, whereas testosterone is responsible for the effects on muscle mass and voice.

Moreover, the kind of 5α reductase determines these effects. If 5α reductase type 2 is present in reproductive tissue and type 1 is primarily located in the skin.

In the target tissue itself, DHT can also degrade and transform into the weaker compounds. As a result, the serum concentration is exceedingly low (1/10th of testosterone) compared to testosterone.

When administered in pharmacological concentrations (larger amounts), synthetic androgens and progestins compete with each other for the same receptor, the androgen receptor, by occupying and fighting it.  Androgenic side effects are another possibility with synthetic progestins.  Progesterones with anti-androgenic properties, such as spironolactone and cyproterone acetate, also have progestational effects.

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