Reproductive hormones

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Chapter 38 Reproductive hormones

There are several major classes of steroid hormone:

• Female sex hormones: oestrogens and progesterones.

• Male sex hormones: androgens.

• Adrenocorticoids: glucocorticoids.

These are all derived from cholesterol. There is an interconversion between male and female hormones, as the structures are very similar (see Figure 38.3, p. 305). This occurs naturally in both males and females, although in females there is a predominance of female hormones and in males a predominance of male hormones.

Figure 38.3 Structure of various reproductive hormones and related plant compounds.

Female Hormones

• Oestrogen: secreted by the adrenal cortex as well as the ovaries.

• Progesterone: prepares the uterus for implantation of a fertilized egg and maintains pregnancy. The ovaries of sexually mature females secrete a mixture of oestrogens and progesterone.

• Adrenocorticoids: maintain electrolyte balance (see Chapter 26 ‘Cardiovascular disorders’, p. 198).

The Menstrual Cycle

Gonadotrophin-releasing hormone (GnRH) stimulates the pituitary gland, which secretes follicle-stimulating hormone (FSH) and is responsible for the synthesis and secretion of oestrogen in the ovaries. When oestrogen levels rise to a critical point, production is switched off by shutting off the GnRH release from the hypothalamus (Figure 38.1).

Figure 38.1 Hormonal feedback in the female reproductive system.

Progesterone production is stimulated by luteinizing hormone (LH), which is produced by the pituitary as a result of stimulation by GnRH. Progesterone levels cannot rise too high, as they are controlled in the same way as oestrogen. A new follicle begins to form in one of the ovaries at this stage and, when menstruation ceases, the follicle continues to develop while at the same time secreting oestrogen (Figure 38.2). The rising oestrogen levels cause the endometrium to thicken and become richly supplied with blood vessels and glands.

Figure 38.2 The menstrual cycle, showing the effects on the ovary and hormonal fluctuations.

Rising levels of LH create a change in the follicle until a sudden surge in LH levels at about 2 weeks triggers ovulation (mid-cycle). The unfertilized egg is then released into the fallopian tube. The presence of LH encourages the empty follicle to develop into a corpus luteum, which then starts to secrete progesterone. This:

• continues preparation of the endometrium for pregnancy

• inhibits the contraction of the uterus

• inhibits the development of a new follicle.

If fertilization does not occur then the elevated levels of progesterone inhibit the release of GnRH, which inhibits further production of progesterone. When the progesterone levels drops, the:

• corpus luteum and endometrium break down

• uterus is able to contract and menstruation begins.

Menstruation occurs every 28 days, when the lining of the uterus breaks down and is discharged.

Pregnancy

The menstrual cycle is arrested. The fertilized egg embeds itself in the wall of the uterus and forms a blastocyst, which has two parts:

• the inner cell mass, which becomes the fetus

• the trophoblast, which develops into amnion, placenta and umbilical cord. This part of the blastocyst starts to secrete human chorionic gonadotrophin (hCG), which maintains the corpus luteum and stops it disintegrating. It is not inhibited by rising levels of progesterone.

The placenta then becomes a major source of progesterone, which is necessary to maintain the pregnancy.

Birth

• The placenta releases corticotrophin-releasing hormone (CRH).

• This stimulates the pituitary of the fetus to secrete adrenocorticotrophic hormone (ACTH).

• ACTH acts on the adrenal glands of the fetus.

• This releases an oestrogen precursor, which is converted to oestrogen by the placenta; the placental secretion of oestrogen rises.

• The rising level of oestrogen causes the muscle wall of the uterus to contract. This effect is increased by oxytocin, which is secreted by the posterior lobe of the pituitary as well at the uterine wall.

• Prostaglandins that encourage muscle contraction also appear in the mother’s blood as well as in the amniotic fluid. The combination of the oxytocin and the prostaglandins start the labour.

Oral Contraceptives

The feedback inhibition of GnRH secretion by oestrogen and progesterone is utilized by most forms of contraceptive pill. The inhibition of GnRH prevents the mid-cycle surge of LH and therefore ovulation. With no egg to be fertilized there should, in theory, be no possibility of pregnancy.

Side Effects of Taking the Pill

There can be an increased tendency for blood clots to form, thereby increasing the risk of strokes and heart attacks, as oestrogen enhances the clotting of blood.

Infertility Treatment

Both the male and female partners are examined, although orthodox treatment in most cases is directed towards the female member of the partnership:

• Structural: to ensure that all the reproductive organs are normal and there are no obstructions.

• Viability: to ensure patients are capable of producing the appropriate amounts of viable eggs and sperm.

• Disease: sexually transmitted infections (STI) such as Chlamydia trachomatis can cause asymptomatic inflammation of the fallopian tubes.

• Metabolic disorders: systemic conditions, e.g. polycystic ovarian syndrome (see Chapter 37 ‘Metabolic disorders’, p. 293).

Treatment

• Infection

Any infection is identified and treated with antibiotics. Both parties can be treated in this case.

• Improvement of General Health of the Patients

Diet and lifestyle should be addressed if this is an issue for both parties, including vitamin supplementation.

• Infertility Drugs

Generally three classes of drug are used:

• selective oestrogen receptor modulators (SERM) – anti-oestrogens

• human menopausal gonadotrophin

• dopamine agonists (see Chapter 19 ‘Pharmacodynamics: how drugs elicit a physiological effect’, p. 140 and Chapter 31 ‘The nervous system’, p. 242).

Dopamine Agonists: Bromocriptene

• Usually offered to women with hyerprolactinaemia (high levels of prolactin in the blood).

• Hyperprolactinaemia can be due to a pituitary tumour, which is usually benign.

• Medication such as antidepressants, opiate drugs and painkillers can raise prolactin levels in the blood because they interfere with dopamine inhibition of prolactin response.

Adverse Effects

• Excessive sleepiness.

• Fibrotic reactions.

Menopause

This can start in the early forties and is due to the follicles becoming less responsive to FSH and LH. As the follicles secrete less oestrogen, ovulation and menstruation become irregular and finally cease. At this point, menopause occurs.

With the reduction of oestrogen, the hypothalamus is no longer inhibited and is able to stimulate the pituitary to secrete hormones at a much higher level. The high concentrations of FSH and LH can cause a variety of physical and emotional symptoms.

Hormone Replacement Therapy

This is a combination of oestrogens and progesterones. It is believed to be of benefit because:

• Unpleasant menopausal symptoms are reduced.

• Loss of calcium from the bones is reduced, decreasing the risk of osteoporosis.

This occurs only while HRT is being administered.

• Progestins

Progestins are chemical or drug imitations of progesterone. Provera (medroxyprogesterone acetate) is the most common progestin. Most are made by taking natural progesterone and altering the chemical structure so it can be patented. Another type of progestin is made by altering a synthetic form of testosterone.

What are the Natural Alternatives?

Diadzein

Diadzein is naturally occurring isoflavone (Figure 38.3), which is classed as a phytoestrogen because it possesses oestrogen-like properties. It appears to have both weak oestrogenic and antioestrogenic effects and might also be an antioxidant, anticarcinogenic, antiatherogenic and provide some protection against osteoporosis. It is found as the glycoside diadzein in:

• Fabaceae: Glycine max (soy bean), Psoraleae corylifolia (Bu Gu Zhi), Puerariae spp. (Ge Gen), Trifolium pratense (red clover).

Dioscorea spp. (Shan Yao)

The plant sterol diosgenin (see Figure 38.3) comes from Dioscorea spp. (wild yam). It occurs as a glycoside. Diosgenin can be converted to progesterone via a chemical process called ‘Marker degradation’, which gives access to many important steroids, e.g. testosterone and oestradiol.

Diosgenin has been shown to have some oestrogenic activity, but lacks progesterogenic activity. Neither can it be converted to progesterone in the body. This process can only occur in the laboratory.

Vitex Agnus Castus

This herb is used a great deal in Western herbal medicine. The decrease in oestrogen effects is thought to be mediated through the pituitary gland, by inhibition of anterior pituitary function. Vitex seems to be able to raise progesterone levels.

Casticin (Figure 38.3), a flavonoid, may be one of the active components, but its activity is far from clear.

Black Cohosh (Cimicifuga racemosa)

Pharmacological studies have shown that Cimicifugia can inhibit oestrogen-dependent breast cancer cells. The sudden release of LH during menopause leads to hot flushes. Cimicifugia prevents the release of LH and decreases the hormone’s ability to bind with receptors in the hypothalamus.

The exact mechanism of the antioestrogenic activity of black cohosh is unknown, as extracts of black cohosh do not bind to the oestrogen receptors. However cimigenol (see Figure 38.3), which is found in Cimicifugia, has a steroidal configuration.

The Male Reproductive System

Testosterone

Testosterone, like progesterone and oestrogen, is derived from cholesterol. Testosterone is also secreted by the ovaries and placenta, as well as by the adrenal glands in women (although in very small amounts). Testosterone is significantly metabolized by the gastrointestinal tract. Approximately 44% is lost in the first-pass metabolism. Testosterone promotes protein synthesis and growth of tissues with androgen receptors, resulting in:

• muscle growth

• increased strength

• increased bone density

• maturation of the male reproductive organs

• a deepening of the voice: although this also occurs in females to a lesser degree due to a slight increase in testosterone

• increased body and facial hair.

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