Hormones of the Reproductive System

Index to this page

Females

The ovaries of sexually-mature females secrete:

Estrogens

Estrogens are steroids. They Estrogens also have non-reproductive effects.

Progesterone

Progesterone is also a steroid. It has many effects in the body, some having nothing to do with sex and reproduction. Here we shall focus on the role of progesterone in the menstrual cycle and pregnancy [Link to a special page on progesterone].

How estrogens and progesterone achieve their effects

Steroids like estrogens and progesterone are small, hydrophobic molecules that are transported in the blood bound to a serum globulin.
Link to a discussion of steroid receptors and their response elements along with a stereo view of a steroid receptor bound to the DNA helix of its response element.

Some "target" cells also have other types of estrogen and progesterone receptors that are embedded in a membrane (endoplasmic reticulum and plasma membrane respectively). Binding of the hormone to them produces more rapid effects than those of the nuclear receptors. For example, human sperm have receptors that within a second of being exposed to progesterone activate the sperm to increased motility [Link].

Regulation of Estrogen and Progesterone

The synthesis and secretion of estrogens is stimulated by follicle-stimulating hormone (FSH), which is, in turn, controlled by the hypothalamic gonadotropin releasing hormone (GnRH).

HypothalamusGnRHPituitaryFSHFollicleEstrogens

High levels of estrogens suppress the release of GnRH (bar) providing a negative-feedback control of hormone levels.

It works like this: Secretion of GnRH depends on certain neurons in the hypothalamus which express a gene (KISS-1) encoding a protein of 145 amino acids. From this are cut several short peptides collectively called kisspeptin. These are secreted and bind to G-protein-coupled receptors on the surface of the GnRH neurons stimulating them to release GnRH. However, high levels of estrogen (or progesterone or testosterone) inhibit the secretion of kisspeptin and suppress further production of those hormones.

Progesterone production is stimulated by luteinizing hormone (LH), which is also stimulated by GnRH.

HypothalamusGnRHPituitaryLHCorpus luteumProgesterone

Elevated levels of progesterone control themselves by the same negative feedback loop used by estrogen (and testosterone).

The Menstrual Cycle

About every 28 days, some blood and other products of the disintegration of the inner lining of the uterus (the endometrium) are discharged from the uterus, a process called menstruation. During this time a new follicle begins to develop in one of the ovaries. After menstruation ceases, the follicle continues to develop, secreting an increasing amount of estrogen as it does so.

Fertilization

Fertilization of the egg is also influenced by progesterone. Sperm swim towards the egg by chemotaxis following a gradient of progesterone secreted by cells surrounding the egg. Progesterone opens CatSper ("cation sperm") channels in the plasma membrane surrounding the anterior portion of the sperm tail. This allows an influx of Ca2+ ions which causes the flagellum to beat more rapidly and vigorously.

More details of the process of fertilization are presented at this link.

Pregnancy

As the fertilized egg passes down the fallopian tube, it undergoes its first mitotic divisions. By the end of the week, the developing embryo has become a hollow ball of cells called a blastocyst. At this time, the blastocyst reaches the uterus and embeds itself in the endometrium, a process called implantation. With implantation, pregnancy is established.

The blastocyst has two parts:

HCG is a glycoprotein. It is a heterodimer of

HCG behaves much like FSH and LH with one crucial exception: it is NOT inhibited by a rising level of progesterone. Thus HCG prevents the deterioration of the corpus luteum at the end of the fourth week and enables pregnancy to continue beyond the end of the normal menstrual cycle.

Because only the implanted trophoblast makes HCG, its early appearance in the urine of pregnant women provides the basis for the most widely used test for pregnancy (which can provide a positive signal even before menstruation would have otherwise begun).

As pregnancy continues, the placenta becomes a major source of progesterone, and its presence is essential to maintain pregnancy. Mothers at risk of giving birth too soon can be given a synthetic progestin to help them retain the fetus until it is full-term.

Birth

Toward the end of pregnancy,

Three or four days after the baby is born, the breasts begin to secrete milk.

Other Hormones

Oral contraceptives: the "pill"

The feedback inhibition of GnRH secretion by estrogens and progesterone provides the basis for the most widely-used form of contraception. Dozens of different formulations of synthetic estrogens or progestins (progesterone relatives) — or both — are available. Their inhibition of GnRH prevents the mid-cycle surge of LH and ovulation. Hence there is no egg to be fertilized.

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

The main side-effects of the pill stem from an increased tendency for blood clots to form (estrogen enhances clotting of the blood).

RU-486

RU-486 (also known as mifepristone) is a synthetic steroid related to progesterone. Unlike the synthetic progestins used in oral contraceptives that mimic the actions of progesterone, RU-486 is a progesterone antagonist; that is, it blocks the action of progesterone. It does this by binding more tightly to the progesterone receptor than progesterone itself but without the normal biological effects:

These properties of RU-486 have caused it to be used to induce abortion of an unwanted fetus. In practice, the physician assists the process by giving a synthetic prostaglandin (e.g., misoprostol [Cytotec®]) 36–48 hours after giving the dose of RU-486. Use of RU-486 is generally limited to the first seven weeks of pregnancy.

RU-486 has been used for many years in some countries. However, the controversies surrounding abortion in the United States kept it from being authorized for use here until September 2000.

Menopause

The menstrual cycle continues for many years. But eventually, usually between 42 and 52 years of age, the follicles become less responsive to FSH and LH. They begin to secrete less estrogen. Ovulation and menstruation become irregular and finally cease. This cessation is called menopause.

With levels of estrogen now running one-tenth or less of what they had been, the hypothalamus is released from their inhibitory influence (bar). As a result it now stimulates the pituitary to increased activity. The concentrations of FSH and LH in the blood rise to ten or more times their former values. These elevated levels may cause a variety of unpleasant physical and emotional symptoms.

Hormone replacement therapy (HRT)

Many menopausal women elect to take a combination of estrogen and progesterone after they cease to make their own. The benefits are: It was also believed that HRT reduced the risk of cardiovascular disease. However, a recent study of 16,000 menopausal women was stopped 3 years early when it was found that, in fact, HRT increased (albeit only slightly) not decreased the incidence of cardiovascular disease.

Perhaps synthetic selective estrogen response modulators or SERMs (raloxifene is an example) will provide the protective effects without the harmful ones. Stay tuned.

Environmental estrogens

Some substances that find their way into the environment, such as

can bind to the estrogen (and androgen) receptors and mimic (weakly) the effects of the hormone. This has created anxiety that they may be responsible for harmful effects such as cancer and low sperm counts.

However, there is as yet little evidence to support these worries.


Males

The principal androgen (male sex hormone) is testosterone. This steroid is manufactured by the interstitial (Leydig) cells of the testes. Secretion of testosterone increases sharply at puberty and is responsible for the development of the so-called secondary sexual characteristics (e.g., beard) of men.

Testosterone is also essential for the production of sperm.

Link to diagram showing location and structure of the testes.

Production of testosterone is controlled by the release of luteinizing hormone (LH) from the anterior lobe of the pituitary gland, which is in turn controlled by the release of GnRH from the hypothalamus. LH is also called interstitial cell stimulating hormone (ICSH).

HypothalamusGnRHPituitaryLHTestesTestosterone

The level of testosterone is under negative-feedback control: a rising level of testosterone suppresses the release of GnRH from the hypothalamus. This is exactly parallel to the control of estrogen secretion in females. [Look back]

In mice, osteocalcin, a hormone secreted by osteoblasts of the bone [Link], stimulates the synthesis of testosterone by Leydig cells even more powerfully than LH. Whether this effect occurs in humans remains to be seen.

Males need estrogen, too!

In 1994, a man was described who was homozygous for a mutation in the gene encoding the estrogen receptor. A single nonsense mutation had converted a codon (CGA) for arginine early in the protein into a STOP codon (TGA). Thus no complete estrogen receptor could be synthesized.

This man was extra tall, had osteoporosis and "knock-knees", but was otherwise well. His genetic defect confirms the important role that estrogen has in both sexes for normal bone development.

It is not known whether this man was fertile or not. However, mutations in their estrogen receptor gene have been found in other men who are sterile, and male mice whose estrogen receptor gene has been "knocked out" are sterile.

Another function of estrogen in males. The accumulation of fat in the abdomen, so characteristic of aging males (including yours truly), is caused by declining levels of estrogen.

Anabolic steroids

A number of synthetic androgens are used for therapeutic purposes. These drugs promote an increase in muscle size with resulting increases in strength and speed. This has made them popular with some athletes, e.g., weight lifters, cyclists, runners, swimmers, professional football players.

Usually these athletes (females as well as males) take doses far greater than those used in standard therapy. Such illicit use carries dangers (besides being banned from an event because of a positive drug test): acne, a decrease in libido, and — in males — testicle size and sperm counts to name a few.

Genetic abnormalities of gonadal function.

Many things can go wrong with sexual development in both males and females; fortunately rarely. Let's look at a few that clearly result from the inheritance of single-gene mutations.
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12 September 2013