Introduction

The term 'Sex Hormones' refers to a group of steroid hormones  that bind to intracellular receptors in target tissues in order to regulate sexual development and reproduction.

Steroids hormones are defined as any of numerous hormones (as oestrogen, testosterone, cortisone, and aldosterone) having the characteristic ring structure of steroids and formed in the body from cholesterol. There are 5 classes of steroid hormones:

  1. Mineralocorticoids (for which the major actor is Aldosterone)
  2. Glucocorticoids (for which the major actor is Cortisol)
  3. Oestrogens (which all share a common C18 carbon skeleton)
  4. Androgens (which all share a common C19 carbon skeleton)
  5. Progestogens (which all share a common C21 carbon skeleton)

Oestrogens, Progestogens, and Androgens constitute the 'Sex Hormone' group, as they are all directly involved in the development, functioning, and regulation of both the male and female reproductive systems.

Most sex hormones are synthesised in the gonads (the testes or ovaries), the cortex of the adrenal glands (more specifically the zona reticularis), and the placenta (during a pregnancy). Steroid hormones can also be the product of the conversion of another steroid hormone in tissues such as adipose tissue or the ovaries.

Diagram adapted from http://commons.wikimedia.org/wiki/File:Steroidogenesis.svg

I. Oestrogens

These hormones are named for their role in the oestrus cycle

The four major naturally-occurring oestrogens in women are:

  • Oestrone (E1) – the predominant oestrogen in post-menopausal women
  • 17-beta-Oestradiol (E2) – the predominant and most potent oestrogen hormone in a non-pregnant woman between her menarche and menopause.
  • Oestriol (E3) – the predominant oestrogen in pregnant women
  • Estetrol (E4) – this hormone is produced by the foetal liver during pregnancy

a. Biosynthesis

In females, oestrogens are synthesised and secreted by the Ovaries and by the placenta. Secondary sources of oestrogens include the liver, the zona reticularis of the adrenal glands, adipose tissue, and the breasts.

In the ovaries, their production is stimulated by the pituitary Follicle-Stimulating Hormone (FSH) - a glycoprotein hormone produced by Gonadotroph cells of anterior pituitary, which, in turn, are under the hormonal control of hypothalamic Gonadotrophin-Releasing Hormone (GnRH).

High levels of Oestrogen suppress the release of GnRH, thereby providing a negative feedback control of oestrogen levels in the body.

 

The cells of the ovarian follicle and Corpus Luteum

  1. The Thecal cells of the developing follicles convert Cholesterol to Androstenedione (an androgenic hormone) when stimulated by the Luteinising Hormone (LH).
  2. The Androstenedione then shifts into the Granulosa cells, where they can either be directly transformed into Oestrone or turned into Testosterone then Oestradiol. The conversion of these androgens into oestrogens is catalysed by the Aromatase enzyme, and regulated by FSH.

b. Mechanism of Action

Oestrogens travel the bloodstream bound to plasma proteins. These are:

  • Sex-Hormone Binding Globulin (which can also bind to Testosterone) and/or
  • Albumin.

 

Because steroids are fat-soluble molecules, oestrogens can diffuse across plasma membranes. Once inside the cell, they can bind to one of two classes of intracellular oestrogen receptors:

  • Estrogen Receptor (ER), which is present in the nucleus
  • G-Coupled Protein Receptor 30 (GPR30), which is membrane-bound


These Hormone-Receptor Complexes act as DNA-binding transcription factors: they bind to specific DNA sequences called Hormone Response Elements, located in promoters of their target genes, and modulate genes’ transcription, and therefore expression, thereby producing a response in their target cells.

c. Functions

Oestrogens play an important part in a number of structural changes related to the female reproductive system:

  • Promote formation of female secondary sexual characteristics (such as the development of breast, and the growth of pubic and axillary hair)
  • Increase formation of adipose tissue
  • Increase growth of endometrium, myometrium, and vaginal wall
  • Increase vaginal lubrication
  • Increase bone formation and reduce bone resorption (which is why postmenopausal women, which have decreased oestrogen levels, often develop osteoporosis)
  • Increases contractility of the myometrium

 

      Oestrogens also have non-reproductive functions such as:

      • Antagonising the effects of the ParaThyroid Hormone (PTH), hence minimising the loss of calcium from bones
      • Promoting blood clotting
      • A Neurosteroid

       

        Oestrogen are also produced in males and are thought to aid in regulation of spermatogenesis.

        d. Things that are good to know

        As a woman undergoes the beginning of menopause (around the average age of 51 in the UK), her follicles progressively become less responsive to FSH and LH, resulting in a drop of oestrogen secretion by her ovaries.

        This causes a progressive decrease in her blood's oestrogen levels, causing ovulation and menstruation to become irregular and finally cease.  This stimulates the hypothalamus to secrete up to ten times the former concentrations of FSH and LH, leading to a variety of symptoms such as hot flushes and fatigue.

        Hormone Replacement Therapy (HRT) is a treatment given to women undergoing the menopause to reduce unpleasant symptoms and the risk of osteoporosis. HRT consists in a combination of synthetic oestrogen and progesterone used to cause the hormonal change to occur more progressively.

          Certain tumour cells possess oestrogen and progesterone receptors, using these steroid hormones as growth factors to proliferate. Examples include certain forms of breast cancer and endometrial carcinoma. The plan of treatment and patient's prognosis (patient's response to endocrine therapy) will heavily depend on the tumours' oestrogen and progesterone receptor status that can be determined by tumour biopsy, in other words, the affected tissue can be tested for presence of such receptors. If cancer is ER-negative and PR-negative, it is very unlikely the patient will benefit from the endocrine therapy.

            Synthetic Oestrogens are used in Combined Hormonal Contraceptives (which contain both oestrogens and progestogens), as a modified dose of circulating oestrogens in the blood. In the UK, a single oestrogen derivative is used in CHC, its trade name is Ethinyl Estradiol. Through inhibiting the synthesis and release of GnRH by the hypothalamus, the drug:

            • Suppresses the secretion of FSH thus leading to the inhibition of follicular development
            • Inhibition of GnRH by synthetic oestrogens and progestins inhibits the mid-cycle LH surge which results in the inhibition of ovulation. As a result, there is no egg produced to be fertilised.

            Usually preparation is taken for about three weeks and then stopped long enough for normal menstruation to occur.

            Main side effects of the Pill stem from an increased risk of blood clots to form (since oestrogen enhances the blood clotting).

                      II. Progestogens

                      These hormones are named after their role during pregnancy: they are pro-gestational. Progestogens prepare the female body for a potential pregnancy and maintaining it until foetal birth.

                      They are also secreted during the regular menstrual cycle (where they play a role in the hypertrophy of the endometrium) in females as well as in men, where they counteract the effects of oestrogens (thus preserving the body's masculinity).

                      Progestogens are precursors of both testosterone and oestrogen hormones. 

                      Progesterone is the major naturally occurring protestogen in humans.

                       

                      a. Biosynthesis

                      Pregnenolone (P5) is the first steroid hormone synthesised from cholesterol. This process occurs in all steroid-producing tissues: the adrenal glands, the placenta, the testes, and the ovaries. It also acts as a neurosteroid and as a prohormone. 

                       

                      It is the precursor of three other progestogens:

                      • Progesterone (P4)
                      • 17a-hydroxypregnenolone
                      • 17a-hydroxyprogesterone  

                      These hormones are equally precursors to other steroid hormones, including mineralocorticoids, glucocorticoids, androgens and oestrogens.

                       



                      In females, Progesterone is secreted by the corpus luteum in the ovaries during the luteal phase (i.e. after ovulation), as enzymes turn cholesterol to pregnenolone and then to progesterone. Progesterone continues the preparation of the endometrium for the possible implantation of an embryo as well as inhibit uterine contractions and the development of a new follicle. If no implantation occurs,  the levels of progesterone decrease, causing necrosis of the endometrial lining. This process is the origin of menstruation.

                      If pregnancy does occur, progesterone is then further secreted by the placenta in addition to the corpus luteum. This continues until the placenta secretes sufficient hormone levels to maintain pregnancy independently from the corpus luteum, causing it to degenerate.

                       

                      b. Mechanism of Action

                      Analogous to oestrogens, progestogens travel the bloodstream bound to plasma proteins. These are:

                      • Transcortin molecule (which can also bind to corticosteroid hormones such as Aldosterone and Cortisol) and/or
                      • Albumin

                      After diffusion through the plasma membranes of their target cells, progestogen hormones can bind to their corresponding intracellular Progesterone Receptor for which they have a very high affinity. Oestrogens can have an up-regulating effect on the number of progesterone receptors present in the cell.

                       

                      c. Functions

                      The target cells of progesterone are disseminated all over the human body, both male and female. This confers a number of roles to the hormone, including several effects on the female reproductive system:

                      • It stimulates the endometrium to enter its secretory stage during the follicular stage of the ovaries (before ovulation).
                      • It causes the vaginal epithelium and cervical mucus to thicken, making them and almost impermeable to sperm.
                      • It inhibits lactation during pregnancy, as progesterone inhibits the upregulation of prolactin receptors by oestrogens as well as reduce the binding of oestrogen to these cells. Because prolactin stimulates the production and secretion of milk by the breast during a pregnancy, this mechanism inhibits lactation.
                      • It decreases contractility of the uterine’s smooth muscle (the myometrium), thus preventing the miscarriage of a developing foetus.

                       

                      Progestogens can also be synthesised in the central and peripheral nervous system, where it facilitates neurotransmission and performs glial functions such as myelin formation. Progestogens are thus now considered to have an additional role of a 'neurosteroid'. 

                       

                       

                      d. Things that are good to know

                        Progestins (synthetic progestogens) are used in both Combined Hormonal Contraceptives and Progestogen-Only Contraceptives, as a modified dose of circulating progestogens in the blood. They represent a reliable contraceptive method as they:

                          • Inhibit the secretion of FSH and LH which prevents follicular development as well as ovulation (only in 25% of women)
                          • cause an asynchronous development of the endometrium (leading to stromal thinning) and, as a result, produces an environment less receptive to implantation
                          • decrease motility in Fallopian tubes which affects fertility
                          • thicken the cervical mucus (formation of a "cervical plug") that produces an environment hostile to sperm penetration

                          Progestins are also used in the forementioned Hormonal Replacement Therapy (HRT) in order to reduce the risk of endometrial cancer, as well as in the treatment of oligomenorrhea (irregular periods) and prevention of a premature birth. It can also be used as a vaginal cream in the treatment of female fertility.

                            Common progestins include:

                              • Norgestrel (used as an oral contraceptive)
                              • Levonorgestrel (used in emergency oral contraceptives post-intercourse as well as in the IntraUterine Device (IUD) named Mirena)
                              • Norethindrone (used in Hormonal Replacement Therapy under the trade name 'Aygestin')

                              III. Androgens

                              The word “androgen” comes from the greek expression meaning “pertaining to a man”. This is because androgen hormones are crucial to the development and maintenance of male characteristics.  Androgen hormones are also the precursors of oestrogen hormones.

                              The main androgen hormones are:

                              • Testosterone – the principal androgen  
                              • 5α-Dihydrotestosterone - synthesised in the adrenal cortex, it is more potent than testosterone, from which it is a metabolite
                              • Dehydroepiandrosterone - synthesised in the adrenal cortex, it is the primary precursor of oestrogens
                              • Androstenedione - is converted either to testosterone or oestradiol
                              • Androstenediol - is the main precursor of testosterone

                               

                                a. Biosynthesis

                                Androgen hormones are steroids: they are synthesised from cholesterol. The main circulating androgen, Testosterone, is manufactured by the Leydig cells in the testis of males from the 6th week of pregnancy. In females, it is secreted in lesser quantities by the ovaries (by the Thecal cells of the follicles). In both sexes, androgens can also be secreted by the adrenal cortex as well as produced via bioconversion in the blood.

                                Androgen secretion increases sharply at puberty and is responsible for the development of secondary sexual characteristics especially in males, but also in females (where it causes the appearance and growth of pubic and axillary hair).

                                Testosterone also plays an essential role in the production of the sperm and in the process of spermatogenesis (the production of sperm cells).

                                Production of testosterone is controlled by the release of LH from anterior lobe of the pituitary gland, which in turn, is controlled by the release of GnRH from hypothalamus. Its concentration in the blood is under a negative-feedback control i.e. the rising level of testosterone suppresses the release of GnRH from hypothalamus (analogous to the control of oestrogen secretion in females).

                                 

                                b. Mechanism of Action

                                When Testosterone reaches its target cells, an enzyme called 5α-reductase converts it to 5α-dehydrotestosterone, a more potent form of the hormone, which then binds to theintracellular androgen receptor. The receptor then travels to the nucleus where it acts as a Transcription Factor, thus activating or deactivating the expression of specific genes.

                                 

                                c. Functions

                                Androgen hormones have a wide variety of roles:

                                • Testes formation (from the 4th week of fertilisation) and Masculinisation of a developing male foetus
                                • Inhibition of adipose tissue formation in males
                                • Enlargement of muscle mass in males
                                • Regulation of aggressiveness
                                • Sperm production in males (Spermatogenesis)

                                However, potential side-effects of the ilicit use of androgens include acne, a decrease in libido, decrease in testicle size and sperm count.

                                  d. Things that are good to know

                                  The primary therapeutic use of androgens is in the treatment of male hypogonadism (when the testis secrete too little testosterone), in a hormonal replacement therapy. Testosterone Replacement Therapy (TRT) is thus used to maintain testosterone blood levels within a normal range.

                                  As androgen levels decrease with age, Androgen Replacement Therapy (ART) can be used by men undergoing the andropause

                                  However, synthetic androgens can also be prescribed in the treatment of infertility, erectile dysfonction, low libido in both men and post-menopausal women, as well as in the management of osteoporosis. Because it is considered to be the masculinising hormone of choice, testosterone is sometimes used to encourage penile enlargement.

                                  Testosterone, because it promotes muscle growth, is known for its use by athletes (e.g. weight lifters) in order to improve their performance. The use of anabolic steroids as doping agents is forbidden in most official competitions as they increase protein synthesis in muscles to dangerous levels.

                                  IV. The Regulation of Sex Steroids Synthesis

                                  The secretion of oestrogens and progestogens is regulated by peptide hormones released in the bloodstream by the anterior pituitary gland and hypothalamus (in the brain). These hormones monitor the levels of the sex steroids through a negative feedback mechanism which forms a loop, enabling the concentrations to evolve healthily throughout the gamete producing cycle, whether it be oogenesis and the endometrial cycle, or spermatogenesis. 

                                    

                                  Gonadotropin-Releasing Hormone (GnRH) is a neurohormone released by the neurons of the hypothalamus into a network of capillaries called the hypophyseal portal plexus. It is secreted in a pulsatile pattern in both males and female, the difference being primarily the frequency of the pulses. In females, the frequency varies throughout the menstrual cycle, a large surge occurring before ovulation. Meanwhile, males secrete GnRH at a constant rate.

                                  The hormone then travels the bloodstream to the anterior pituitary gland, where it binds to GNRH Receptors (GnRHR) on the Gonadotrope cells. This stimulates the cells in question to secrete two hormones mentioned earlier:

                                  • The Follicle-Stimulating Hormone (FSH)
                                  • The Luteinising Hormone (LH)

                                   

                                    LH and FSH are then carried by the blood to target cells, most of which are in the gonads and breast. 

                                     

                                    a. In Females

                                    LH and FSH both play a crucial role in the menstrual cycle:

                                     

                                     

                                     

                                    • FSH is released by the anterior pituitary gland in order to stimulate follicular growth until the Graafian follicle (which is the only recruited follicle that will eventually ovulate) has become antral. This hormone triggers the secretion of both oestrogens and progesterone by the granulosa cells of the follicles by activating Aromatase and the enzymes of the p450 cytochrome. It also causes the granulosa cells to develop LH receptors. 

                                     

                                    • LH has a predominant role in the trigger of ovulation of the Graafian follicle as well as itsluteinisation (conversion to a corpus luteum) during the luteal phase of the cycle. LH also stimulates the development of thecal cells, activating their synthesis of androgen hormones as well as increase the number of LH receptors on the granulosa cells (thus creating a positive feedback loop).

                                     

                                    At the beginning of the cycle, Oestradiol has a negative feedback effect on the secretion of FSH and LH by the developing follicle. However, as the follicles mature, they secrete progressively more and more oestrogens until their concentration peaks at 200pg/mL around the 12th day of the cycle. This causes the negative feedback loop to become a positive feedback mechanism, thus inducing a proliferation of the granulosa cells in the Graafian follicles as well as of the endometrial cells lining the uterus. The environment has thus been made optimal for both the fertilisation of an ovum and implantation of a zygote.

                                     

                                     



                                    b. In Males

                                    In Males, the Luteinising Hormone (LH) stimulates the secretion of Androgens by the Leydig Cells. The testosterone and its derivatives then travel in the bloodstream until they reach FSH-stimulated Sertoli Cells, which either:

                                    • aromatises the Androgens into Oestradiol
                                    • convert the Androgens into Androgen Binding Protein (which maintains testosterone levels high enough for the spermatogonium cells to develop and mature into healthy spermatozoa), 
                                    • or uses the Androgens to directly stimulate Spermatogenesis

                                     

                                    The Sertoli cells also synthesise and release Inhibin and Oestradiol into the bloodstream. These hormones both inhibit the release of gonadotropins (FSH and LH), thus regulating spermatogenesis through a negative feedback loop.

                                     

                                     



                                    For further reading

                                    Oestrogens in the Male Reproductive System: http://www.endotext.org/male/male17/maleframe17.htm

                                    Androgens in the Male Reproductive System: http://www.endotext.org/male/male3/index.html

                                    Overview of the Hormones of the Female Menstrual Cycle: http://sprojects.mmi.mcgill.ca/menstrualcycle/endocrinology.html

                                    Functions and Roles of Prolactin: http://library.med.utah.edu/kw/human_reprod/lectures/prolactin

                                     

                                     

                                    Diagrams adapted from

                                    • http://commons.wikimedia.org/wiki/File:Steroidogenesis.svg
                                    • http://www.nature.com/nrc/journal/v10/n3/fig_tab/nrc2795_F1.html
                                    • http://www.passthecscsexam.com/endocrine-responses-to-resistance-exercise-part-2ch-3-cscs-exam-notes/
                                    • http://www.humanbodydetectives.com/blog/2011/05/healthy-woman-series-menstrual-cycles/

                                    References

                                    • Ryan KJ (August 1982). "Biochemistry of aromatase: significance to female reproductive physiology".Cancer Res. 42 (8 Suppl): 3342s–3344s. PMID 7083198
                                    • Brook CG. Mechanism of puberty. Horm Res. 1999;51 Suppl 3:52-4. Review. PubMed PMID: 10592444.
                                    • Stephen Nussey and Saffron Whitehead (2001). Saffron A. Whitehead and Stephen Nussey, ed.Endocrinology: an integrated approach. Oxford: British Institute of Organ StudiesISBN 1-85996-252-1.
                                    • Muller, M.; Den Tonkelaar, I.; Thijssen, J. H.; Grobbee, D. E.; Van Der Schouw, Y. T. (2003). "Endogenous sex hormones in men aged 40-80 years". European journal of endocrinology / European Federation of Endocrine Societies 149 (6): 583–589. PMID 14641001
                                    • Wilson JD. Androgens, androgen receptors, and male gender role behavior. Horm Behav. 2001 Sep;40(2):358-66. Review. PubMed PMID: 11534997.
                                    • Nelson LR, Bulun SE. Estrogen production and action. J Am Acad Dermatol. 2001 Sep;45(3 Suppl):S116-24. Review. PubMed PMID: 11511861. 
                                    • Hess RA, Bunick D, Lee KH, Bahr J, Taylor JA, Korach KS, Lubahn DB. A role for oestrogens in the male reproductive system. Nature. 1997 Dec 4;390(6659):509-12. PubMed PMID: 9393999. 
                                    • Neumann F. The physiological action of progesterone and the pharmacological effects of progestogens--a short review. Postgrad Med J. 1978;54 Suppl 2:11-24. Review. PubMed PMID: 368741.
                                    • de Lignières B, Silberstein S. Pharmacodynamics of oestrogens and progestogens. Cephalalgia. 2000 Apr;20(3):200-7. Review. PubMed PMID: 10997774.
                                    Advertisement

                                    Fastbleep © 2019.