Sex determination in utero

The sex of an individual may be considered in terms of genetic sex, chromosomal sex, gonadal sex and genital sex. The gene for maleness is carried on the Y chromosome so that embryos with the XY sex chromosome pair become males. The primary effect of this gene is to cause the primitive gonads to form testes in utero, producing a gonadal male. The testes secrete testosterone, the male sex hormone, and this, in turn, leads to the development of the rest of the internal and external male sex organs. The testes also secrete an inhibitory substance (antimüllerian hormone), which actually blocks the formation of the uterus and vagina from the embryonic müllerian duct. Therefore, the development of the male genitalia relies on the endocrine activity of the testes in utero. In the absence of the relevant gene on the Y chromosome, the primitive gonads appear to be programmed to develop into ovaries (producing a gonadal female) and the other relevant embryonic structures form female sex organs (a genital female).

Puberty

Puberty is the term given to the development of full reproductive function and normally commences in the early teenage years. On average, its onset is 1–2 years earlier in females than males. Pubertal changes extend over a period of years and there is an associated spurt in growth. At the same time, the secondary sex characteristics emerge. These include the development of an adult distribution of pubic hair in both sexes, with breast development in females. In males the penis and testes enlarge, the voice ‘breaks’, and facial and body hair appears. Puberty may be delayed in girls of low body weight (athletes and eating disorders).

The trigger for the onset of puberty is unknown, but some change affecting the hypothalamus seems to be crucial. In both sexes, one of the first detectable developments is an increase in the plasma concentrations of the gonadotrophins, i.e., follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These are protein hormones secreted by the anterior pituitary gland, but their secretion is controlled by gonadotrophin-releasing hormone (GnRH), a peptide secreted by the hypothalamus (Section 8.2). Why GnRH secretion should rise at puberty is not known, but the resulting increase in gonadotrophin levels stimulates the previously dormant testes or ovaries. This initiates spermatogenesis in the male and cyclical follicular development and ovulation in the female. At the same time, the endocrine activity of the gonads causes an increase in the levels of the sex steroids—testosterone in the male and oestrogens in the female—promoting the secondary sex characteristics.

Relevant structure

The male gonad is the testis (Fig. 167). This is the source of the male gametes, the spermatozoa, and produces the male sex hormone testosterone. These functions rely on two different structures in the testis. Spermatogenesis occurs in the seminiferous tubules, while testosterone is secreted by specialized cells in the interstitium between these tubules known as the interstitial cells of Leydig (Fig. 168).

Fig. 167 Lateral view of the male reproductive tract.

Fig. 168 A cross-section of the testis.

During the last months of fetal development, the testes descend through the inguinal canals from their initial position in the body cavity, so that at birth they lie within the scrotum. Like other aspects of male sexual development, this migration is stimulated by fetal testosterone. Normal sperm production (spermatogenesis) only occurs 2–3 °C below body core temperature, and if a testis fails to descend into the scrotal sac it will not function properly. Testicular temperature can actually be regulated using the cremaster muscle around the spermatic cord and the dartos muscle in the wall of the scrotum. In cold weather these contract, pulling the testis and scrotum towards the body and thus conserving heat.

Once structurally mature, spermatozoa are flushed into the epididymis which encloses the posterior pole of the testis (Fig. 167). Removal of fluid leaves a condensed mass of sperm which reach functional maturity within the epididymis, becoming motile. They then move on into the vas deferens, a muscular tube which acts as a storage reservoir for sperm. At its distal end, the vas fuses with the duct from the seminal vesicle, a reproductive exocrine gland, to form the ejaculatory duct. This passes through the prostate gland at the base of the bladder and several ducts from the prostate empty into the ejaculatory duct before it opens into the urethra.

Spermatogenesis

Sperm production continues throughout life from puberty onwards. The development of spermatozoa from spermatogonia, which are distributed around the periphery of the seminiferous tubules in the testes, is called spermatogenesis (Fig. 169). Spermatogonia first divide mitotically and then mature into primary (1 °) spermatocytes. Since only some of the cells resulting from division develop further, however, leaving others in reserve for future replication, the total number of spermatogonia is not depleted. This allows continuous production of gametes from puberty onwards, and contrasts with oogenesis in the female, in which no new primary oocytes are formed after birth (Section 9.4).

Fig. 169 Summary of the sequence of events involved in spermatogenesis.

Next, the primary spermatocytes (diploid cells containing 23 homologous chromosome pairs) undergo meiosis (Fig. 169). The DNA is replicated prior to the first meiotic division, with each chromosome forming two sister chromatids. There is then exchange of genetic material (crossing over) between the partner chromosomes in each chromosome pair, and this leads to new gene combinations in the daughter cells. Separation of the chromosome pairs followed by cell division completes the first meiotic division, producing two secondary (2 °) spermatocytes. Each of these contains half the normal complement of chromosomes (one chromosome from each pair), i.e., these are haploid cells. It is important to realize, however, that each chromosome still consists of two connected sister chromatids, so 2 ° spermatocytes actually contain the normal number of genes. There is no further replication of DNA prior to the second meiotic division, however, during which the chromatids separate. This produces four haploid spermatids, each containing one chromosome from each chromosome pair and one gene from each gene pair.

There is no further cell division, but the spermatids must still undergo a final maturation process to produce spermatozoa. This is sometimes referred to as spermiogenesis and results in the head, midpiece and tail structures of the mature spermatozoon (Fig. 170). The head consists of the chromosomal material covered by an enzyme-filled sac called the acrosome. The midpiece contains mitochondria, which provide the ATP necessary for sperm motility. This motility is the result of the swimming action of the tail, which is driven by the contractile activity of its microtubular core.

Fig. 170 Structural components of a mature spermatozoon.

Sertoli cell function

At each stage of spermatogenesis, there is a close association between the developing sperm and large cells which line the seminiferous tubules, known as Sertoli cells (Fig. 171). These fulfil the following functions:

• nutrition of the sperm

• phagocytosis of dead or damaged cells

• protection of the sperm from blood-borne toxins (the blood–testis barrier)

• formation of seminiferous tubule fluid; this flushes the structurally mature, but immotile, spermatozoa into the epididymis.

Fig. 171 Cross-section of a seminiferous tubule.

Hormonal control of male reproduction

Control of male reproductive function depends on a series of hormones whose secretion is regulated through negative feedback loops (Fig. 172). The overall pattern has several similarities to that seen in control of the female reproductive system (see Fig. 176). The hypothalamus produces GnRH which is carried in the hypophyseal portal system to the anterior pituitary (Section 8.2). This stimulates release of the gonadotrophins, FSH and LH, which are carried in the circulation to the testes, their site of action. Each acts on a different target cell, with FSH stimulating spermatogenesis through its action on the Sertoli cell, while LH promotes testosterone secretion from the interstitial cells of Leydig. This results in a high tissue concentration of testosterone in the testis, which is necessary for spermatogenesis. Circulating testosterone exerts a negative feedback effect by inhibiting hypothalamic and anterior pituitary secretion (Fig. 172). Sertoli cells also secrete a peptide hormone called inhibin, which has a relatively specific effect in reducing FSH secretion.

Fig. 172 Endocrine control of testicular function. Note the negative feedback loops (−).

Erection

Erection results from engorgement of the vascular spaces in the penis. This may be initiated by erotic cognitive stimuli and is reinforced by stimulation of mechanoreceptors on the glans penis. These activate a spinal cord reflex causing dilatation of the penile arterioles. This depends both on activation of parasympathetic dilator nerves and inhibition of sympathetic constrictor nerves. As engorgement progresses, the veins draining the penis are mechanically compressed, further promoting erection.

Ejaculation

Ejaculation is a two-stage process.

Normally about 3 ml of semen is released. Male fertility requires both adequate numbers and quality of sperm, as measured in terms of the sperm count (typically around 120 × 10⁶ ml⁻¹) and the percentage of abnormally shaped or immotile spermatozoa. Semen contains secretions from the seminal vesicles, which provide fructose, an energy source for sperm, along with prostaglandins and other hormones. Prostatic secretion is alkaline and helps to neutralize vaginal acid. It also contains a mixture of clotting factors and fibrinolysin. Lubricating mucus is added by the bulbourethral glands.

Relevant structure

The female gonad is the ovary which produces ova and secretes the female sex steroids, i.e., oestrogens (particularly estradiol) and progesterone. The ovaries are loosely enfolded in the frond-like fimbriae which guide ova into the Fallopian, or uterine, tubes (Fig. 173). These are connected to the uterus, which opens through the cervix into the vagina below.

Fig. 173 Anatomy of the female reproductive tract.

Oogenesis

Oogenesis refers to the development of mature ova from their primitive precursors, the oogonia (Fig. 174). Initially, the oogonia multiply by mitotic division and then undergo a maturation process to form the primary oocytes within the ovary. Multiplication only occurs during fetal life, however, and the 1–2 × 10⁶ primary oocytes present at birth are the source for all the mature ova which will develop during reproductive life. This should be contrasted with the continuous replication of spermatogonia in postpubertal males. Only 400–500 primary oocytes ever reach maturity, while the rest simply degenerate.

Fig. 174 Summary of the sequence of steps involved in the development of an ovum (oogenesis).

The primary oocytes (diploid cells) begin, but do not complete, the first meiotic division before birth (Fig. 174). All further development is arrested until after puberty, when the first meiotic division may finally be concluded. This produces a secondary oocyte (a haploid cell), which contains nearly all the available cytoplasm and a small polar body, which consists largely of chromosomal material. Formation of the secondary oocyte is delayed until just prior to ovulation, and the secondary oocyte only completes the second meiotic division if it is fertilized. Under these circumstances, a further uneven division of cell resources occurs, producing the mature ovum (containing 22 autosomes and a single sex chromosome) and a second polar body.

Since no new primary oocytes form during reproductive life, the age of a woman’s ova increases as she grows older. This may explain why certain genetic defects, such as Down’s syndrome, occur with a higher frequency in the children of older mothers. Presumably, the risk of chromosomal abnormalities caused by problems during meiosis increases as the age of the primary oocyte increases.

The female reproductive cycle

During reproductive life the female reproductive system develops and regresses in a cyclical fashion, each cycle lasting approximately 28 days. This involves changes in the ovary (the ovarian cycle) and the endometrial lining of the uterus (the uterine cycle). A single ovum is released around the middle of each cycle at a time when the endometrium is thickened and nutrient rich in preparation for pregnancy, should fertilization occur. If it does not, the endometrial lining is shed during menstruation, and the cycle is repeated.

Ovarian cycle and follicular development

Ova develop within structures known as follicles. Primordial follicles form in utero and consist of a primary oocyte surrounded by the basal lamina and a single layer of granulosa cells. At any time from late intrauterine life onwards, primordial follicles may mature further to form primary follicles. Granulosa cells multiply and lay down a jelly-like, mucopolysaccharide layer, the zona pellucida, around the oocyte, and a layer of cells outside the basal lamina differentiates to form theca cells (Fig. 175).

Fig. 175 Main structural changes during the ovarian cycle.

Although many primary follicles simply regress during life, a proportion will go on to develop further during the ovarian cycles of reproductive life. These cycles commence at puberty and each cycle is normally 28 days long, consisting of a 14-day follicular phase followed by ovulation and a 14-day luteal phase.

Follicular phase

From puberty onwards, about 5–15 primary follicles begin to develop at the start of each reproductive cycle. Granulosa cells multiply and secrete fluid which eventually pools to form the antrum, thus producing an antral or Graafian follicle (Fig. 175). The theca cells also multiply and differentiate to form the theca interna surrounded by the theca externa. After 7–10 days, one follicle becomes dominant and enlarges further, while the rest become atretic. By 14 days, the developing follicle actually distorts the ovarian surface. Rapid fluid accumulation increases the intrafollicular pressure and proteolytic enzymes digest the overlying tissues. Ovulation follows as the follicle ruptures, releasing the ovum (a secondary oocyte) surrounded by the zona pellucida and adherent granulosa cells (the corona radiata) into the Fallopian tube (see Fig. 178). Some women report that they can feel the rupture of the follicle, which may be painful.

Luteal phase

Following ovulation, the follicular remains seal over and become luteinized, forming the corpus luteum. Granulosa and thecal cells become swollen with fatty droplets, giving them a yellow appearance (hence the name corpus luteum, meaning yellow body) and the structure becomes more vascular. The resulting increase in blood supply serves to promote the endocrine function of the corpus luteum. If a fertilized ovum fails to implant in the endometrium, however, the corpus luteum degenerates after a further 10 days, i.e., about day 24 of a 28-day cycle. A new batch of primary follicles then starts to develop.

Hormonal control of the ovarian cycle

This is similar to control of male reproduction (Fig. 172), except for the monthly cycling of hormone levels seen in women. As in males, the hypothalamus produces GnRH, which causes release of the gonadotrophins FSH and LH from the anterior pituitary gland (Fig. 176). As its name suggests, FSH stimulates follicular development by activating granulosa cell division and secretion of oestrogens (e.g., estradiol). During the follicular phase, LH plays a supporting role as it stimulates androgen secretion by the theca cells. These androgens diffuse into the granulosa cells, which use them as precursors for the synthesis of oestrogens. LH is also responsible for triggering ovulation once follicular development is complete, and it then stimulates luteinization of the follicular remnants to form the corpus luteum. This secretes both progesterone and oestrogen.

Fig. 176 Endocrine control of ovarian function.

Gonadotrophin secretion is under feedback control from both oestrogens and progesterone. Their effect is normally inhibitory, but very high oestrogen levels can actually exert positive feedback on LH secretion. This may explain the sudden surge in LH levels immediately preceding ovulation.

Using the ideas outlined above, we can attempt to explain the normal pattern of hormonal changes seen during a single, 28-day, reproductive cycle (Fig. 177). At the beginning of the cycle, oestrogen and progesterone levels are low, so they exert little negative feedback and FSH levels are high. This stimulates follicular development, leading to a rise in oestrogen levels with resultant inhibition of gonadotrophin release. FSH and LH concentrations fall to a minimum about day 10–12. At this stage, the very high oestrogen concentrations appear to generate a positive feedback effect, however, leading to a dramatic peak in LH concentrations. This LH surge stimulates ovulation, which occurs about day 14. Thereafter, increasing production of progesterone and oestrogen by the corpus luteum leads to a steady decline in LH and FSH. At about day 22–24, the corpus luteum undergoes programmed regression, or atresia, causing a rapid decline in the levels of ovarian hormone. The resulting reduction in feedback inhibition allows gonadotrophin levels to rise once more, and the cycle repeats.

Fig. 177 Endocrine control of ovarian function. Oestrogens and progesterone normally inhibit (−) gonadotrophin release, but very high levels of oestrogen may also stimulate (+) LH production just prior to ovulation.

Female sex hormones

Oestrogens and progesterone are female sex hormones secreted by the ovaries. These steroids have a range of effects, among the most important of which are their actions on the endometrial lining of the uterus. It is the cyclical changes in oestrogen and progesterone levels which control the uterine cycle, as considered below. Some other actions are listed here.

Oestrogens are a group of related chemicals. Oestradiol and oestrone make up most of the circulating oestrogen in the non-pregnant state during the reproductive years, but oestrone levels exceed estradiol postmenopausally. Placental oestriol becomes important during pregnancy.

Oestrogens:

• promote granulosa cell proliferation in response to FSH (Fig. 176)

• are responsible for the development of some female secondary sex characteristics at puberty, particularly fat accumulation in the subcutaneous tissues, round the hips and in the breasts

• promote conditions necessary for the maintenance of pregnancy after implantation

• promote further breast development during pregnancy by stimulating duct growth.

Progesterone:

• promotes conditions necessary for the maintenance of pregnancy

• promotes breast development, both at puberty and during pregnancy, by stimulating the formation of the secretory lobules.

Menopause

With increasing age, menstruation decreases in frequency and then finally ceases at about age 50. This is referred to as the menopause and reflects depletion of the follicular reserves during reproductive life. Oestrogen levels fall as a result, giving rise to many of the associated changes, including atrophy of the breasts, skin and genitalia. Loss of bone tissue (osteoporosis) can eventually lead to bone fractures, but this may be limited by long-term oestrogen replacement therapy.

Fertilization

For fertilization to occur, spermatozoa and ovum must first come into contact with each other. Following ovulation, the ovum is propelled by the movement of the cilia lining the fimbriae and Fallopian tube. Progress is rather slow relative to the upward migration of the sperm through the female genital tract, and fertilization usually occurs in the outer third of the Fallopian tube. The spermatozoa are deposited in the vagina during sexual intercourse and first have to pass through the mucus which plugs the cervical canal (Fig. 173). This is only penetrable towards the end of the follicular phase of the ovarian cycle, around ovulation, when the ratio of oestrogen to progesterone is at its peak (Fig. 177). For a few days the mucus plug becomes much less dense, allowing sperm to swim through it, but even then less than 5% actually enter the uterus. Further transport depends on the contractile activity of the uterus, which randomly distributes sperm throughout the uterine cavity. Some enter the Fallopian tube and are propelled towards the ovum by retrograde peristalsis. Of as many as 300 × 10⁶ spermatozoa released during ejaculation, perhaps only a few thousand are likely to reach the ovum. This explains the need for high sperm counts if a male is to be fertile. It should also be noted that the fertilizing ability of sperm is enhanced following several hours exposure to the female reproductive tract, a process referred to as capacitation.

Fertilization requires that a spermatozoon must first penetrate the corona radiata and the zona pellucida which surround the ovum (Fig. 178). The motility of the sperm orients their heads towards these barriers and forces them between the granulosa cells of the corona radiata. They then bind to receptors on the outer surface of the zona pellucida and digest a tunnel through it by releasing acrosomal enzymes. When the first spermatozoon contacts the plasma membrane of the secondary oocyte, the zona pellucida changes chemically, becoming impenetrable to other sperm. This prevents multiple fertilizations of the same ovum. The secondary oocyte completes the second meiotic division and the genetic material from the haploid gametes fuses to produce a diploid zygote. This then divides, initiating embryonic development.

Fig. 178 Fertilization of the ovum.