Reproductive System Development

Introduction

Development of the reproductive system is a complex process relying on numerous systems and conditions to ensure appropriate structures and rate of development are maintained within the embryo. There are several important criteria that determine appropriate reproductive system development; genetic sex which determines the sex of the embryo, gonadal sex and phenotypic sex which both determine sexual differentiation. Genetic sex determines gonadal sex which in turn determines phenotypic sex. Sex determination relates to the genetic or environmental process which determines the sex of an individual whilst sexual differentiation represents the development of internal and external genitalia.

Sex Determination in Mammals

In mammals the male is the heterogametic species (XY chromosomes) and females are the homogametic species (XX chromosomes) and this is the first stage in the development of the reproductive system. This stage occurs in the zygote and genes in the Y chromosome regulate the development of gonads towards the male phenotype. Therefore the Y chromosome must be present for the development of the male gender, regardless of the number of X chromosomes (see Developmental Abnormalities section below). Each Y chromosome contains a Sex Determining Region (SRY) and testes must be present for the formation of male characteristics. Sex hormones produced by the developing gonads affect the further development of the reproductive organs and the nervous system and are therefore crucial. For further information in sexual differentation please see here.

Fetal development in mammals occurs in a highly hormonal environment with relatively high concentrations of oestrogens and progesterone and therefore during the early stages of embryonic development the gonads must produce testosterone and other developmental signalling molecules in order for the testes to develop. If no testosterone is produced, the reproductive organs will take on female characteristics as a default. Abnormalities can occur if the gonads in a genetic male do not produce sufficient levels of testosterone.

Genital development under testosterone therefore induces the penis and scrotum to develop. Testosterone is converted to dihydrotestosterone which is the signalling molecule responsible for the external appearence of the penis and scrotum. An absence of testosterone results in the development of the clitoris, labia and vaginal opening.

Sex Determination in Birds

Birds have sex chromosomes labelled Z and W. The chromosomal requirements for a male in birds is the opposite of that in mammals as the female is the heterogametic species rather than the male. Therefore ZZ results in a male and ZW results in a female.

Sex Determination in Reptiles

Crocodilians, marine turtles, some terrestrial turtles and lizards undergo environmental sex determination. The important factor for sex determination in these species is the incubation temperature of the eggs as this determines the development of the gonads towards testes or ovaries. In crocodiles a higher temperature is male determining whilst in turtles a higher temperature is female determining.

Sexual Differentiation of the Brain

In the male testosterone is secreted from the fetal testes into the blood and is able to cross the blood brain barrier as it does not bind to alpha-fetoprotein. Once across this barrier the testosterone is converted into estradiol and dihydrotestosterone via the enzyme aromatase. Although it is counter-intuitive, esradiol actually causes masculinisation of the male brain. This brain masculinisation process results in the prevention of the development of a surge centre.

In the female alpha-fetoprotein binds to estradiol which has been secreted by the fetal ovary. This binding results in the complex being unable to cross the blood brain barrier. This mechanism protects the female brain from the masculinising effects of estradiol and allows the development of a 'feminising' surge centre at the point of the rostral part of the mesencephalon.

Normal Sexual Development

Throughout normal sexual development there are series of defined phases;

Pregonadal Phase

The pregonadal phase represents the stage where germ cells begin to migrate from the yolk sac of the developing embryo. Primitive primordial germ cells are formed in the yolk sac (the yolk sac is part of the digestive system in the embryo). These primitive germ cells migrate from the yolk sac through the mesentry to the genital ridges which are small elongated pieces of tissue beneath the peritoneum situated at the dorsal aspect of the abdominal cavity. These germ cells then begin to divide by mitosis and the gonads are developed from these genital ridges.

Migration & Proliferation of Germ Cells

Germs cells migrate via an amoeboid movement. These germs cells travel from the primitive streak in the yolk sac to the allantois, then to the hind gut before reaching the urogenital ridge and gonads. In the male the XY germ cells undergo mitosis from leaving the primitive streak until reaching the urogenital ridge and/or the gonads. At this stage the XY germ cells arrest at the G₀ phase of the cell cycle due to a meiosis inhibitor factor.

In females the XX germ cells undergo the same migration but on reaching the urogenital ridge and gonads no such meiosis inhibitor factor is present. Therefore the XX germ cells undergo mitosis between the primitive streak until the urogenital ridge where they switch to meiosis. This process continues in the female until birth.

Bipotential Gonadal Phase

This phase represents the development of gonadal precursor tissue near the kidneys from the genital ridges.

Pimary Sexual Differentiation Phase

This phase represents the initial phase of differentiation of reproductive tissues. The male Y chromosome in mammals contains genetic code that results in the production of testes-determining factor (TDF) which is responsible for causing the gonads to develop into testes. In the female fetus, TDF is not produced as there is no Y chromosome and therefore the gonads develop into ovaries.

At this stage of development the gonads do not have their own excretory ducts. In males the excretory ducts from the developing kidney, the Wolfian Ducts facilitate the excretion of spermatozoa away from the testes. These Wolfian Ducts develop into male accessory reproductive structures that include the epididymis and spermatic ducts aswell as connecting the developing testes where they connect a system of tubules, the rete testis. These tubular connections collect spermatozoa from the seminiferous tubules resulting in a continuous tube system that facilitates the transport of spermatozoa to the external environment. In females the Wolfian ducts undergo regression at this stage of development.

In both sexes a pair of Mullerian ducts are formed which are epithelialised ducts which extend from the lumbar region to the urogenital cleft. In females, the fallopian tubes or oviducts, uterus and internal elements of the vagina all develop from these ducts. Although the Mullerian ducts are formed in males, they eventually regress.

Secondary Sexual Differentiation Phase

This phase corresponds to the development of secondary sexual characteristics.

EMBRYOLOGICAL DEVELOPMENT OF THE GENITAL TRACT

Early embryo

• Small indifferent gonads.
• Primitive structures which will become gonads and genital tract are identical at this stage.
• Paired mesonephric ducts (Wolffian) or paramesonephric (Mullerian) ducts fuse caudally with urogenital sinus.

(Metanephros - becomes the kidney).

Gonadal differentiation

• Determined by the presence of the SRY gene of the Y chromosome (sex determining region of the Y chromosome) which encodes “testicular determining factor” protein (SRY protein).
• Lack of SRY gene (i.e. XX females) leads to ovarian differentiation.

Development of phenotypic sex

• The sex of the embryonic gonad normally determines which reproductive duct system develops.
• Testes induce development of mesonephric (Wolffian) duct system in to epididymis and vas deferens and cause regression of paramesonephric (Mullerian) duct by ”mullerian inhibitory substance”, (MIS).
• Absence of testes in presence of ovaries allows paramesonephric ducts to develop under influence of oestrogen to oviduct, uterus, cervix and cranial vagina.

Summary of determinants of sexual development

Chromosomal or genetic sex = sex chromosomes
Gonadal sex = ovary or testis
Phenotypic sex = usually determined by gonad

Information by permission of Professor RW Else