Introduction

Steroid hormones are hormones which derive from cholesterol and carry out their effects by binding to the receptors in different cell types. There are two types of steroid hormones, these being corticosteroids and sex hormones. The sex hormones include estrogen, progestrone and testosterone, these are primarily produced by the male and female reproductive system, while corticosteroids are primarily produced by the adrenal glands. Steroid hormones travel in the bloodstream until they bind to their particular receptor, some receptors will be located on the surface of cells but most are located inside of the cell and even inside of the nucleus of the cell, but because of the similar structures of the steroid hormones, some steroid hormones can bind to some receptors for other steroid hormones, at times this complex will activate gene transcription but other times the complex may not do anything, the effects usually carried out by the steroid hormone which is meant to bind to that receptor therefore decreases.

Testosterone

Testosterone is produced in the testes as well as the ovaries and adrenal glands in small amounts. In men lutenizing hormone (LH) and follicle stimulating hormone (FSH) will stimulate the development of the leydig cells of the testes so LH, LDL, and acetate can combine in the mitochondria to form pregnenolone, a series of reactions then occur in the sarcoplasmic reticulum to form testosterone, which enters the bloodstream and is carried to target tissues. In the bloodstream about 60% of testosterone is bound to sex hormone-binding globulin (SHBG), 38% is bound to albumin, and the remaining 2% is unbound and ready to be taken up by bodily cells. Unbound testosterone or testosterone bound to albumin or SHBG travels in the bloodstream until it reaches a target tissue, testosterone can then bind to receptors on the cell membrane and become unbound from albumin or testosterone and then enter the tissue. Testosterone is strongly bound to SHBG meaning that it is harder for this form of testosterone to become biologically active, on the other hand, testosterone is weakly bound to albumin meaning that it is more likely to become biologically active. 

When testosterone enters a cell it can bind to androgen receptors in the cytoplasm of cells and travel over to the nucleus of the cell and signal for gene transcription, testosterone can be converted to dihydrotestosterone (DHT) in the cytoplasm of cells or testosterone can be converted to estrogen in the cytoplasm of cells.

Testosterone must be converted to DHT by the enzyme 5α-Reductase in certain cell types to carry out their effects once it has bound to an androgen receptors, such cells include the seminal vesicles, hair follicles, cells of the skin, gonadal tissue and prostate gland, after puberty DHT’s main purpose is to help in the process of sperm production. Symptoms of excessive DHT in the body include excessive facial and body hair, deepening of the voice in females, male pattern hair loss, benign prostatic hyperplasia and prostate cancer. 5α-Reductase inhibitors have been shown to be effective in preventing the production of DHT. The process of testosterone being converted to DHT produces several metabolites which carry out antidepressant, anxiolytic, hedonic, anti-stress and pro-cognitive effects. One metabolite produced is 3β androstanediol which binds to and activates estrogen receptors and thus has estrogenic effects. It is interesting to note that in the liver and bone marrow 5β-Reductase is responsible for producing DHT, not 5α-Reductase, which produces an isomer of DHT which has no androgenic effects.

Testosterone can also be converted to 17-beta-estradiol, and androstenedione can be converted to estrone by the enzyme aromatase in a process known as aromatization. Androstenedione is an androgen that can be created in the sarcoplasmic reticulum from pregnenolone, it can either be converted to testosterone or estrone. Anabolic steroids can also be aromatised to 17-beta-estradiol which is responsible for their estrogenic effects. Aromatization has also been linked to the development of cancer (particularly breast cancer in women) and it has been linked to the development of gynecomastia in men. Aromatase inhibitors either bind to and deactivate the enzyme aromatase or compete with androgens to bind to the enzyme aromatase, and this helps to mitigate any negative side effects caused by aromatization. Aromatization can occur in a number of tissues, such as adipose tissue, testis, placenta, ovaries, brain, bone, breast, liver and blood vessels.

In males normal testosterone levels are 265-923 ng/dL and in females, it is 15-46 ng/dL.

Estrogen

There are three forms of estrogen:

• Estrone (E1) 
• 17-beta-estradiol (E2)
• Estriol (E3)

All estrogen has the same main purpose of supporting the reproductive system in different ways for women and even men, but each type of estrogen still has slightly different properties. Estrone is higher than the other forms of estrogen following menopause because following menopause the ovarian follicles have run out and there are no more theca and granulosa cells left to produce 17-beta-estradiol while estrone is produced by fat cells and the adrenal glands. Estrone is produced when androstenedione is aromatised to this form of estrogen. 17-beta-estradiol is the most potent form of estrogen and it is typically what people are talking about when referring to estrogen because it is responsible for producing female characteristics. Estradiol is produced when testosterone is aromatised to this form of estrogen. Estriol is the least potent estrogen and it is most important during pregnancy, during pregnancy this form of estrogen is produced in the placenta in order to help the uterus grow and stay healthy as well as prepare the breasts for lactation following delivery with the help of progesterone. 

In women FSH and LH will travel to the ovaries and stimulate them to develop and secrete hormones of their own. The production of estrogen in the ovaries begins when cholesterol enters the theca cells of the ovaries, the enzyme cholesterol desmolase then converts cholesterol to pregnenolone, the enzyme 17β-Hydroxysteroid dehydrogenase then converts pregnenolone to 17 hydroxypregnenolone or it may convert pregnenolone to progesterone which is a hormone responsible for preparing the lining of the uterus for a fertilised egg. 17 hydroxypregnenolone is converted by the enzyme 17β-Hydroxysteroid dehydrogenase to dehydroepiandrosterone (DHEA), which is then converted by 17β-Hydroxysteroid dehydrogenase to androstenedione, which diffuses out of the theca cells and into the granulosa cells, here the enzyme 17β-Hydroxysteroid dehydrogenase converts androstenedione to testosterone, which can leave the ovaries here but most testosterone is converted to 17-beta-estradiol by the enzyme aromatase. The 17-beta-estradiol will then be released into the bloodstream where it binds to SHBG which carries it to target tissues in the body, inside of cells estrogen can bind to estrogen receptors and then travel to the nucleus to signal for gene transcription.

Males usually have estradiol levels of 10-40 pg/ml and an estrone level of 10-50 pg/ml, premenapausal women have estradiol levels of 30-400 pg/ml and an estrone level of 37-299 pg/ml, the range of normal hormonal levels vary greatly during different phases of the menstrual cycle and they vary to even a greater extent throughout a woman's life, and the same goes for progesterone. 

Progesterone

To inform you of some terminology, progesterone is the endogenous form of progestogen, while progestin is the synthetic form of progestogen. Progesterone is produced in the granulosa cells of the ovaries of women and the testes of men, in men levels usually remain around 0.8ng/ml while in women it varies greatly during different phases of their menstrual cycle, in the follicular phase levels are often as low as men’s levels while in the luteal phases it can be as high as 33 ng/ml. During pregnancy the placenta produces its own progesterone and levels can rise to all the way up to 300ng/ml.

In the production of all steroid hormones, they are all converted to progesterone before converting to their final form. Progesterone carries out its effects once it has bound to a progesterone receptor, but it can also bind to other types of receptors, it can bind to and activate glucocorticoid receptors and the reason for this is unknown, on top of this it can downregulate the production of estrogen receptors and bind to estrogen receptors without activating them, for this reason progesterone is useful particulary in males to counteract the effects of estrogen. Progesterone can also bind to androgen and mineralocorticoid receptors without activating them and thus their actions are inhibited. 

The relationship between the female menstrual cycle and the production of estrogen and progesterone

The hypothalamus will release gonadotropin-releasing hormone (GnRH) which will stimulate the anterior pituitary gland to release LH and FSH. At the start of the follicular phase GNRH is on a steady rise, you may expect therefore FSH and LH to do the same thing, but this is not the case, as the FSH and LH which is released from the pituitary will stimulate the ovaries follicles (which are made up of granulosa, theca and oocyte cells) to mature from primary to secondary follicles and produce estrogen, in this phase the estrogen levels will steadily rise. Estrogen will go back to the anterior pituitary gland where it will downregulate the release of LH and FSH, and so levels of LH neither rise of fall during the first half of the folicular phase. In the very start of the follicular phase FSH will have a slight rise because of the rise in GnRH but as estrogen levels steadily rise FSH levels will start to drop. For 10 days the granulosa cells of the ovaries will continue to mature and the production of estrogen will continue to rise, then because the concentration of estrogen gets so high estrogen will switch from being a negative regulator of LH to a positive regulator of LH, LH levels will therefore rise dramatically causing ovulation, which is when the most mature follicle in the ovaries releases the oocyte into the fallopian tube for fertilisation, during this FSH will also have a slight spike due to the rise in LH. After ovulation comes the luteal phase. FSH, LH and GnRH will all decline. The mature follicle which released the oocyte now becomes what is known as a corpus luteum, this is basically a dead folicle, and it secretes estrogen, progesterone and inhibin, this means that progesterone and inhibin begins to gradually rise following ovulation. Inhibin will inhibit the release of FSH from the pituaitary gland as it is no longer needed. Progesterone will work to inhibit the release of GnRH from the hypothalamus, which of course will further inhibit the release of FSH and LH. These factors cause a drop in estrogen levels initially but then estrogen levels begin to rise due to the quantity of estrogen produced by the corpus luteum. Progesterones purpose in the luteal phase is to stimulate endometrium growth in preparation for an egg to be implanted if it is fertilised in the fallopian tube. Eventually, the corpus luteum will degenerate entirely and therefore estrogen, progesterone and inhibin levels will all drop, and without as much progesterone GnRH levels can begin to rise again, also due to the drop in estrogen and progesterone it means that the endometrium of the uterus can no longer be maintained and it is shed in what is known as menstruation, following this, the follicular phase of the menstrual cycle will start again.

Corticosteroids

Corticosteroids are a type of steroid hormone which are produced in the adrenal glands. There are two types of corticosteroids, these being glucocorticoids and mineralocorticoids. The adrenal glands sit on top of the kidneys. The adrenal glands consist of the adrenal medulla in the centre and the adrenal cortex on the outside. The adrenal medulla is stimulated by the sympathetic nerves leaving the spinal cord and they stimulate the release of epinephrine (adrenaline) and norepinephrine (noradrenalinecorticotropin-releasing for the fight or flight response, on the other hand, the adrenal cortex is responsible for the long term stress response, and it is made up of 3 layers, the outside layer is known as the zona glomerulosa, the middle layer is known as the zona fasciculate and the deepest layer is the zona reticularis. The hypothalamus in the brain is responsible for the release of corticotropin releasing hormone which stimulates the anterior pituitary gland to release adrenocorticotropin hormone (ACTH) which travels to and targets cell within the adrenal gland, particularly the adrenal cortex. In the adrenal cortex, ACTH will stimulate the zona glomerulosa to release mineralocorticoids (such as aldosterone), the zona fasciculate to release glucocorticoids (such as cortisol), and the zona reticularis to release small amounts of androgens. Glucocorticoids provide a negative feedback to the brain inhibiting the release of corticotropin-releasing hormone. Corticosteroids are lipid soluble, and therefore to stop the steroid from entering fat cells once it has entered the bloodstream it must be bound to a carrier protein such as transcortin.

The mineralocorticoid aldosterone is responsible for increasing blood pressure, it does this by stimulating the resorption of water and sodium from the kidneys back into the blood in exchange for potassium. High mineralcorticoid levels results hypertension, hypernatremia (high blood sodium levels) and hypokalemia (low blood potassium levels). When blood pressure is low the nephrons of the kidneys will filter waste out of the bloodstream at a slower rate due to the decreased pressure on the nephrons from the arterioles. The decreased in pressure on the nephrons stimulates the release of renin from the juxtaglomerular cells of the kidney, renin will downstream activate angiotensin II which stimulates the zona glomerulosa to release mineralocorticoids in an attempt to raise blood pressure.

Glucocorticoids work to cause hyperglycemia, it does this by stimulating protein breakdown, glucose synthesis and glucogenesis in the liver, and when the liver is full it will stimulate the release of glucose into the bloodstream. Additionally, prolonged high glucocorticoid levels lead to increased fat deposition and increased insulin resistance leading to hyperglycemia in the bloodstream as glucose can not be taken into cells adequately. Glucocorticoids have also been shown to increase blood pressure.

Glucocorticoids are also anti-inflammatory and they are immunosuppressive. Pro-inflammatory cytokines inside of cells and certain cellular stressors activate nuclear factor kappa b (NF-κB) which stimulates gene transcription for more pro-inflammatory cytokines causing even more inflammation. In the same cell glucocorticoids bind to a receptor, this complex can work to inhibit the actions of NF-κB, and this is one of the methods which glucocorticoids take to suppress inflammation, another method is by glucocorticoids inhibiting enzymes phospholipase 2 and cyclooxygenase (COX). The enzyme phospholipase 2 is responsible for converting the phospholipid membrane of certain cell types, such as white blood cells, during the inflammatory response to arachidonic acid which is then converted by the enzyme COX to pro-inflammatory prostanoids.

Hydrocortisone and prednisone are a form of synthetic glucocorticoids which can be injected for pain relief or for their anti-inflammatory effects, the problem with regularly taking these or having natural high glucocorticoid levels is that they have an immunosuppressive response, by decreasing the production of white blood cells, which makes the person taking them more prone to infection, long term use of hydrocortisone or prednisone also has been proven to lead to a decreased natural production of pro-inflammatory molecules, additionally, it can also lead to cushing syndrome because glucocorticoids can also act like mineralocorticoids, and it can lead to osteoporosis, due to glucocorticoids ability to inhibit osteoblast activity and increase osteoclast activity.