Neuroendocrinology Of Female Reproduction And Steroid Hormones

Hypothalamo-Pituitary Ovarian Axis

Throughout a woman's reproductive lifespan, the hypothalamus secretes the hormone GnRH (gonadotropin releasing hormone), which signals to the anterior pituitary, which in turn secretes gonadotropins, or the FSH and LH hormones in response to this ovary releases estrogen and progesterone in different phases of the ovarian cycle.

These hormones also send feedback signals to the hypothalamus (positive and negative feedback signals) at different points in the menstrual cycle to bring about a precisely timed periodic menstrual cycle. Additionally, there are intra-pituitary autocrine and paracrine regulators present that fine-tune the LH and FSH hormones from anterior pituitary to induce periodic menstrual cycles.

Hypothalamic- Hypophyseal Portal Circulation

The present paraventricle and supraoptic nuclei are in charge of oxytocin secretion. Neurons that release growth hormones are found in the hypothalamic Arcuate nucleus. There are two pituitaries: the anterior pituitary, also termed adenohypophysis, and the posterior pituitary gland, also called Neurohypophysis. It is also believed that the posterior pituitary extends the neuronal network of the hypothalamus.

The pituitary stalk, also known as the infundibulum, connects the hypothalamus' region of median eminence to the pituitary. The neuronal hormone GnRH is released by the arcuate nucleus's neurons. They get signals from the higher centers or other neurons in the central nervous system as well as from peripheral feedback signals through their response to the signals circulating in the bloodstream. This allows them to regulate their actions. This is why the field studying this entire functioning is known as neuroendocrinology.

The superior hypophyseal artery branches out to produce the portal circulation, a capillary network that descends along the infundibulum. Similar to the capillaries of the peripheral system, these portal circulation capillaries are fenestrated.The blood-brain barrier is thus not crossed by this portal circulation in the median eminence region.

GnRH is secreted by neurons and reaches the portal circulation by traveling through exons.The hypothalamus and pituitary are the primary locations of the portal circulation.
Thus, GnRH cannot reach the anterior pituitary if the hypothalamic-hypophyseal circulation is disturbed for any cause (such as by a tumor). Furthermore, the hypothalamo-pituitary-ovarian axis may be upset by this.

The posterior hypophyseal artery provides a separate supply to the posterior pituitary. This is one of the explanations for why the anterior pituitary's varying blood supply makes it more vulnerable to Sheehan syndrome.

Gonadotropin Releasing Hormone 

The arcuate nucleus of the hypothalamus secretes GnRH, and chromosome 8 contains the gene that codes for GnRH.
•It is a peptide made up of ten amino acids, or a decapeptide. Its metabolism is extremely quick because of its small size.

GnRH has a short half-life of two to four minutes. This is because this hormone is rapidly cleaved by proteases.GnRH secretion is pulsatile. The anterior pituitary is stimulated by this pulsatile secretion.

The nature of the pulsatile secretion determines which type of gonadotropin (FSH or LH) is secreted from the anterior pituitary in response to the GnRH signal from the hypothalamus. This pulsatile secretion is caused by intrinsic oscillatory changes in intracellular calcium concentration among several GnRH-secreting neurons at a time.

Pulsatile Secretion Of GnRH

The LH pulsatile secretion is clinically observed when discussing pulsatile secretion. Since it is exceedingly difficult to measure GnRH pulses in the blood circulation due to its short half-life, we instead employ LH pulses to determine the nature of GnRH signals.

Increased pulse frequency and amplitude somewhere around the late follicular phase (mid-cycle) is very important as it will favor LH secretion from the anterior pituitary. • There is a pulse every 90 minutes in the early follicular phase and a more rapid pulse every 60–70 minutes in the late follicular phase.

There is a pulse in the luteal phase once every 100 to 200 minutes (one pulse in the early luteal phase and one in the late luteal phase). As a result, the pulsatile secretion swings. • The FSH secretion is favored by the slow pulse frequency. This facilitates switching between cycles.

Receptor Action Of GnRH Hormone 

The IP3-DAG pathway is how the GnRH receptor, which is a cell membrane receptor and G-protein coupled receptor, functions.  GnRH attaches to the receptor, activates it, and then the hormone is digested and the receptor becomes free once more as a result of fast proteolytic cleavage. This cycle is then repeated with pulsatile secretion.Therefore, the anterior pituitary is stimulated by this pulsatile character.The Gn is secreted by gonadotroph cells. To prevent the receptor from becoming downregulated or desensitized to continuous GnRH, pulsatile secretion is necessary.

The whole complex has the ability to migrate within the cell, internalize, and undergo metabolism and degradation. This will lead to any GnRH being bound by the lack of receptor. We refer to this as downregulating receptors.

Any new GnRH will not be able to affect the anterior pituitary gland when the receptor downregulation takes place at the anterior pituitary level. Additionally, a process known as pituitary downregulation will occur in which the anterior pituitary production is inhibited.

 Anovulation will occur if the GnRH pulsatile secretion occurs at a slow frequency since there won't be a gonadotropin spike.
  Constant exposure to GnRH or high-frequency pulses, as in PCOD, can cause receptor desensitization or downregulation, which can then result in anovulation once more.

GnRH Analogues

 Long-acting GnRH analogs can be administered intramuscularly or subcutaneously once every three to four weeks. They also succeed in downregulating the pituitary.
  When the GnRH analogue binds to the GnRH receptor, internalization and downregulation result because the long-acting analogue is not easily digested and binds and remains with the receptor for a longer period of time.These GnRH analogs can either be agonists or antagonists of GnRH.

The GnRH agonists first trigger a flare reaction due to some initial receptor activation, which increases the release of LH and FSH.Such flare reactions will not occur with GnRH antagonists.

In the end, both of them will lead to receptor desensitization and downregulation, which will produce anterior pituitary suppression. This will also lower FSH and LH, which will suppress ovarian hormones.This can be used clinically to induce a state akin to the pseudomenopause. While gonadotropin is high in real menopause, there is a lack of estrogen.

This can be applied to therapies that require suppression of the production of ovarian hormones. The original application of this was for the management of early puberty. Additional circumstances include endometriosis, fibroids, or any other location where we wish to halt ovarian hormone production.

Tropic Hormones 

The tropic hormones, which are glycopeptides in nature, are FSH, LH, TSH, and hCG.  Chromosome 9 encodes a common α chain for them.  They have a unique β chain; chromosome 11 encodes the β chain of FSH, while chromosome 19 encodes the β chain of LH, TSH, and hCG.

The structures of LH and hCG are comparable.  In IVF cycles, hCG is used as an ovulation trigger.  An excessive hCG surge during molar pregnancy results in the presence of theca lutein cysts.  These hormones' half-lives are influenced by the extent of their glycosylation since they are glycopeptides. TSH has a half-life of three to four hours, while LH has a half-life of twenty minutes. One of the hormones with the highest glycosylation is hCG, which has a 24-hour half-life.
The gonadotropins that affect ovarian follicles are FSH and LH. These have receptors that are located on the ovarian follicle cells' cell walls. G-protein coupled receptors are what these receptors are.

The granulosa cells of ovarian follicles contain FSH receptors, while the theca and stromal cells of ovarian follicles contain LH receptors.

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.

When the pregnenolone is acted upon by P450c17, it forms 17-hydroxypregnenolone, which when acted upon by P450c17 forms dehydroepiandrosterone (DHEA). • When the 3βHSB acts upon the pregnenolone, it forms progesterone, which again, through the action of P450c17, forms 17-hydroxyprogesterone, which is acted upon by P450c17 forms androstenedione.

 Androstenedione and 3βHSB develop in response to this DHEA. that P450aram acts upon to create estrone (E). These can then be converted to estradiol or testosterone. 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.

For instance, the ovary and gonads lack the 21αhydroxylase and 11βhydroxylase activities found 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.

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 into estradiol.

 Although a sizable amount of estrone is also generated, estradiol will be the main substance that is formed.  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. In cases of excess androgen, this becomes even more important.

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.

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%. DHEA-S is being converted to DHEA for the remaining DHEA.
The ovaries and adrenal glands each supply 50% to 50% of the androstenedione in the blood.

 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.

Also Read: Puerperium: Understanding the Postpartum Period

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. Because the estrogen in oral contraceptive tablets boosts SHBG levels, they are useful in situations like PCOD where there is an increase in androgen levels. Considering that they aid in lowering androgen levels.

SHBG Levels Impact Free Estrogen And Testosterone Circulating Levels

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.

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.

The length of the hormone's exposure is just as crucial as its dosage.  In the target tissues, estrogen stimulates both progesterone and its own receptors. In addition to stimulating the 17βHSD, which converts estradiol to esttrone, progesterone also lowers the concentration of estrogen receptors in target tissues, especially in the uterine linings. In the absence of progesterone, the physiological action of estrogen is inhibited.

Additionally, androgens reduce the number of estrogen receptors in the target tissue, particularly in the nucleus.

The enzyme 5α reductase transforms testosterone into the more potent form dihydrotestosterone, which occurs in the target tissue itself.

The androgen receptor shared by testosterone and DHT.
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, the DHT can also degrade and transform into the lesser 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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