Female reproductive system


The female reproductive system has six major functions:

  • Production of female gametes, the ova , by the process of oogenesis

  • Reception of male gametes, the spermatozoa

  • Provision of a suitable environment for the fertilisation of ova by spermatozoa

  • Provision of an environment for the development of the fetus

  • Expulsion of the developed fetus to the external environment

  • Nutrition of the newborn

These functions are all integrated by an elegant system of hormonal and nervous mechanisms. The female reproductive system may be divided into three structural units on the basis of function:

  • The ovaries , which are the site of oogenesis, are paired organs lying on either side of the uterus adjacent to the lateral wall of the pelvis. In sexually mature mammals, ova are released by the process of ovulation in a cyclical manner, either seasonally or at regular intervals throughout the year. This cycle is suspended during pregnancy. The ovaries are also endocrine organs, producing the hormones oestrogen and progesterone . Both ovulation and ovarian hormone production are controlled by the cyclical release from the anterior pituitary of the gonadotrophic hormones luteinising hormone (LH) and follicle stimulating hormone (FSH). Oestrogen and progesterone in turn regulate LH and FSH production by feedback mechanisms. Thus, ovulation is coordinated with preparation of the uterus to receive the fertilised ovum.

  • The genital tract extends from near the ovaries to an opening at the external surface and provides an environment for reception of male gametes, fertilisation of ova, development of the fetus and expulsion of the fetus at birth. The genital tract begins with a pair of Fallopian tubes , also called oviducts or uterine tubes , which conduct ova from the ovaries to the uterus where fetal development occurs. Fertilisation of ova by spermatozoa occurs within the Fallopian tubes. The uterus is a muscular organ, the mucosal lining of which undergoes cyclical proliferation under the influence of ovarian hormones. This provides a suitable environment for implantation of the fertilised ovum and subsequent development of the placenta . This is the means by which the developing fetus is nourished throughout gestation. At birth ( parturition ), strong contractions of the muscular uterine wall expel the fetus through the lower part of the uterus, the uterine cervix , into the birth canal or vagina . The vagina is an expansile muscular tube specialised for the reception of the penis during coitus and for the passage of the fetus to the external environment. At the external opening of the vagina there are thick folds of skin, the labia which, along with the clitoris , constitute the vulva .

  • The breasts are highly modified apocrine sweat glands which, in the female, develop at puberty and regress at menopause. During pregnancy, the secretory components expand greatly in size and number in preparation for milk production ( lactation ).

In the non-pregnant state, the female reproductive system undergoes continuous cyclical changes from puberty to menopause. When ovulation is not followed by the implantation of a fertilised ovum, the thickened mucosal lining, the endometrium , degenerates and a new ovulation cycle commences. In humans, the thickened endometrium is shed in a period of bleeding known as menstruation . The first day of bleeding marks the beginning of a new cycle of endometrial proliferation which is known as the menstrual cycle . In humans, the standard menstrual cycle is of 28 days duration, but there is considerable variation among normal individuals. Ovulation usually occurs at the midpoint of the cycle.

In other mammals, the proliferated uterine mucosa is absorbed rather than shed, and the female is receptive to the male only during the period of ovulation, which is known as oestrus (or heat). The remaining part of the cycle is called the dioestrus , and the whole cycle is known as the oestrus cycle .

The general anatomy of the female genital tract is illustrated in Figs. 19.1 and 19.2 .

Embryology of the female genital tract

Most of the structures of the female genital tract are derived from the paired Müllerian or paramesonephric ducts . These give rise to the right and left Fallopian tubes and fuse centrally to form the structures of the uterus, cervix and vagina.

Occasionally, congenital anomalies can occur because of failure of this process of embryological fusion. This can result in a persistent short septum dividing the fundus of the uterus resulting in a bicornuate or septate uterus . In more extreme cases, reduplication of the uterus ( didelphys ), cervix and vagina may occur.

The structures of the male genital tract are derived from the Wolffian or mesonephric duct system; in the female, these structures normally regress during fetal life. Small embryological remnants of the Wolffian ducts may persist into adulthood and can be noted in sites such as the paratubal tissue (or mesosalpinx) and in the lateral walls of the cervix. An awareness of these embryological remnants is important for diagnostic pathologists, as the unexpected finding of small epithelial-lined tubules in unusual sites may lead to misdiagnosis of malignancy.

The ovaries

Whilst most of the structures of the female reproductive system arise from the Müllerian duct system as described above (see textbox), the ovaries arise from the genital ridge , a thickening in the mesothelium high on the posterior wall of the peritoneal cavity. The ovaries later descend to their adult position in the pelvis. As a result, the blood supply and lymphatic drainage of the ovaries is derived from the upper abdomen, with the paired ovarian arteries arising from the abdominal aorta, just proximal to the origin of the renal arteries. This rather unexpected fact is important in understanding why ovarian (and, indeed, testicular) tumours typically spread to para-aortic lymph nodes, rather than to local lymph nodes in the pelvic or inguinal area.

Fig. 19.8, Corpus luteum of menstruation

Fig. 19.11, Corpus albicans H&E (LP)

Fig. 19.10, Atretic follicles

Fig. 19.16, Endometrium, the onset of menstruation

Fig. 19.17, Endometrial surface H&E (HP)

Fig. 19.18, Proliferative endometrium

Fig. 19.19, Secretory endometrium

A corpus albicans CL corpus luteum D degenerating corpus luteum F follicle FT Fallopian tube H helicine artery L broad ligament M medulla

Fig. 19.1, Female reproductive system, sagittal view

Fig. 19.2, Female reproductive system, coronal view

Follicular Development

During early fetal development, primordial germ cells called oogonia migrate into the ovarian cortex where they multiply by mitosis. By the fourth and fifth months of human fetal development, some oogonia enlarge and assume the potential for development into mature gametes. At this stage, they are called primary oocytes and commence the first stage of meiotic division (see Ch. 2 ). By the seventh month of fetal development, a single layer of flattened follicular cells surrounds the primary oocytes to form primordial follicles , of which there are approximately 500 000 in the human ovary at birth. This encapsulation arrests the first meiotic division and no further development of primordial follicles then occurs until after the female reaches sexual maturity ( puberty ). The process of meiotic division is only completed during follicular maturation, leading up to ovulation and fertilisation. Thus, all the female germ cells are present at birth, but the process of meiotic division is only completed some 15 to 50 years later! In contrast, in males, meiotic division of germ cells commences only after sexual maturity and formation and maturation of spermatozoa are accomplished within about 70 days (see Ch. 18 ). Female germ cells may undergo degeneration ( atresia ) at any stage of follicular maturation.

During each ovarian cycle, a cohort of up to 20 primordial follicles is activated to begin the maturation process. Usually, only one follicle reaches full maturity and undergoes ovulation while the remainder regress before this point. The reason for this apparent wastage is unclear. During maturation, however, the follicles have an endocrine function which may be far beyond the capacity of a single follicle and so the primary purpose of the other follicles may be to act as an endocrine gland.

Follicular maturation involves changes in the oocyte, in the follicular cells and in the surrounding stromal tissue. Follicular maturation is stimulated by FSH ( follicle stimulating hormone ) secreted by the anterior pituitary gland .

CO cumulus oophorus CR corona radiata F follicular cells FA follicular antrum G granulosa cells O oocyte PF primordial follicle TE theca externa TF theca folliculi TI theca interna ZG zona granulosa ZP zona pellucida

B blood clot G granulosa lutein cells S septum Sh vascular sheath of theca cells T theca lutein cells TE theca externa cells TI theca interna cells V blood vessel

Ovarian cysts

Ovarian cysts are common and can be broadly divided into neoplastic and non-neoplastic cysts. Non-neoplastic cysts include follicular cysts, due to enlargement of normal follicles, and corpus luteum cysts, which result from a similar expansion of a normal corpus luteum .

e-Fig. 19.1, Non-neoplastic ovarian cysts

There are many different types of neoplastic cysts. Most are derived from epithelial cells and are classed as benign (cystadenoma), borderline or malignant. There are many subtypes of epithelial cyst such as serous and mucinous. High grade serous carcinoma, the commonest malignant tumour found in the ovary, is now thought to arise from pre-cancerous (dysplastic) lesions at the end of the fallopian tube. A fairly common type of ovarian cyst in young women is the dermoid cyst or mature cystic teratoma, which is usually benign .

e-Fig 19.2, Mucinous ovarian tumours

e-Fig. 19.3, Serous carcinoma

e-Fig. 19.4, Benign (mature) cystic teratoma (MP)

Another common type of cyst is the endometriotic cyst or endometrioma, where abnormal deposits of endometrial glands and stroma are found in the ovary and, indeed, in many other sites in the body .

e-Fig. 19.5, Adenomyosis and endometriosis

Endometriosis is often associated with infertility, as is polycystic ovarian syndrome, a condition where multiple follicular cysts are associated with obesity, hirsuitism and other metabolic abnormalities such as impaired glucose tolerance.

The type of cyst, along with other pathological factors influences the treatment (surgical and/or oncological). Diagnosis often requires biopsy, oophorectomy (removal of the ovary) or cystectomy (removal of the cyst).

C corpus albicans CL corpus luteum G granulosa cells GM glassy membrane M macrophages O oocyte P primordial follicle S stroma

The Genital Tract

The genital tract consists of the Fallopian tubes , the uterus and the vagina , all of which have the same basic structure, consisting of a wall of smooth muscle with an inner mucosal lining and an outer layer of loose supporting tissue.

The mucosal and muscular components vary greatly according to their location and functional requirements. The whole tract undergoes cyclical changes under the influence of ovarian hormones which are released during the ovarian cycle. The cyclical changes which occur in the genital tract facilitate the entry of ova into the Fallopian tube, the passage of spermatozoa through the uterine cervix and into the Fallopian tube, the passage of the fertilised ovum into the uterus and the implantation and development of the fertilised ovum in the mucosal lining ( endometrium ) of the uterus.

Implantation of a fertilised ovum results in secretion of hormones that inhibit the ovarian cycle and produce changes in the genital tract necessary for fetal development and parturition.

Pathology of the Fallopian tube

The Fallopian tube can be damaged by a variety of pathological processes and such tubal injury may then lead to a range of other problems including subfertility and even tubal ectopic pregnancy, where the fertilised ovum implants in the wall of the Fallopian tube, rather than passing along to enter the uterine cavity.

Common causes of tubal injury include pelvic inflammatory disease (where tubal inflammation and scarring occurs due to infection with organisms such as Chlamydia or Gonococcus ) and endometriosis, a disorder in which small deposits of endometrium are found outside the uterine cavity.

Endometriosis often affects the Fallopian tubes and, again, this results in scarring and peritoneal adhesions which can block the Fallopian tubes, leading to reduced fertility. As well as preventing the normal passage of the ovum to the uterus, such tubal blockage can result in cystic dilatation of the tube, forming a hydrosalpinx. If such a fluid collection becomes infected and consists of pus, it is called a pyosalpinx.

The Human Menstrual Cycle

The uterus is a flattened pear-shaped organ approximately 7 cm long in the non-pregnant state. Its mucosal lining, the endometrium , provides the environment for fetal development. The thick smooth muscle wall, the myometrium , expands greatly during pregnancy and provides protection for the fetus and a mechanism for the expulsion of the fetus at parturition .

The endometrium is variable in thickness, measuring between 1 and 5 mm at different stages of the menstrual cycle. The myometrium makes up the bulk of the uterus, measuring up to about 20 mm in a woman of reproductive age (see Fig. 19.2 ).

In women of child-bearing age, the endometrial lining of the uterine cavity consists of a pseudostratified columnar ciliated epithelium forming numerous simple tubular glands, supported by the cellular endometrial stroma . Under the influence of oestrogen and progesterone secreted during the ovarian cycle, the endometrium undergoes regular cyclical changes so as to offer a suitable environment for implantation of a fertilised ovum. These changes are summarised in Fig. 19.15 . For successful implantation, the fertilised ovum requires an easily penetrable, highly vascular tissue and an abundant supply of glycogen for nutrition until vascular connections are established with the maternal circulation.

Fig. 19.15, The hormonal integration of the ovarian and menstrual cycles

The cycle of changes in the endometrium proceeds through three distinct phases: menstruation , proliferation and secretion . These changes involve both the epithelium and supporting stroma.

  • The menstrual phase . The first day of menstruation is, by convention, taken as the first day of the cycle, simply because it is easily identified. This is the phase of endometrial shedding that only occurs if there is failure of fertilisation and/or implantation of the ovum. Progesterone production by the corpus luteum is inhibited by negative feedback on the anterior pituitary, thus suppressing LH release and leading to involution of the corpus luteum. In the absence of progesterone, the endometrium cannot be maintained. Reactivation of FSH secretion initiates a new cycle of follicular development and oestrogen secretion. This, in turn, initiates a new cycle of proliferation of the endometrium from the endometrial remnants of the previous cycle.

  • The proliferative phase . The endometrial stroma proliferates, becoming thicker and richly vascularised. The simple tubular glands elongate to form numerous long, coiled glands that begin secretion coincident with ovulation. The proliferative phase is initiated and sustained until ovulation by the increasing production of oestrogens from developing ovarian follicles.

  • The secretory phase . Release of progesterone from the corpus luteum after ovulation promotes production of a copious, thick, glycogen-rich secretion by the endometrial glands.

A typical menstrual cycle is 28 days in length, although there is wide variation among normal women. Menstruation lasts on average 5 days. The proliferative phase continues until about the 14th day when ovulation occurs and the secretory phase begins. The secretory phase culminates at the onset of menstruation on about the 28th day.

The endometrium is divided into three histologically and functionally distinct layers. The deepest or basal layer, the stratum basalis , adjacent to the myometrium, undergoes little change during the menstrual cycle and is not shed during menstruation. The broad intermediate layer is characterised by a stroma with a spongy appearance and is called the stratum spongiosum . The thinner superficial layer, which has a compact stromal appearance, is known as the stratum compactum . The compact and spongy layers exhibit dramatic changes throughout the cycle and both are shed during menstruation. These layers are jointly referred to as the stratum functionalis .

The arrangement of the arterial supply of the endometrium has important influences on the menstrual cycle. Branches of the uterine arteries pass through the myometrium and immediately divide into two different types of arteries, straight arteries and spiral arteries . Straight arteries are short and pass a small distance into the endometrium, then bifurcate to form a plexus supplying the stratum basalis. Spiral arteries are long, coiled and thick-walled and pass to the surface of the endometrium, giving off numerous branches which give rise to a capillary plexus around the glands and in the stratum compactum. Unlike the straight arteries, the spiral arteries are responsive to the hormonal changes of the menstrual cycle. The withdrawal of progesterone secretion at the end of the cycle causes the spiral arteries to constrict and this precipitates an ischaemic phase that immediately precedes menstruation.

BL broad ligament E epithelial cells M muscular wall S serosa ST supporting tissue

The menstrual cycle

The illustration above shows the changes which occur during a typical 28-day-long menstrual cycle, but there is significant variation in the length of the menstrual cycle in normal women, often ranging from 21 days up to 40 days or sometimes more. In such cases, there is variation in the duration of both the follicular and the luteal phases of the menstrual cycle, but the luteal phase seems to be of more fixed duration and typically lasts around 14 days, with more of the difference in cycle length being attributable to variation in the duration of the follicular part of the cycle.

Endometrial cancer

Endometrial cancer is the commonest type of gynaecological cancer in women. Risk factors include increasing age, hyperoestrogenic states including certain medications such as oestrogen therapies, high BMI and genetic syndromes. Hormonal overstimulation of the uterus can result in overgrowth (hyperplasia) of the endometrium, which may be associated with invasive cancer. There are many different types of EC, the commonest of which is endometrioid adenocarcinoma, a gland-forming malignant tumour which resembles normal endometrial glands.

e-Fig. 19.6, Endometrial carcinoma

B apoptotic bodies F stratum functionalis L leakage of blood

B stratum basalis C stratum compactum F stratum functionalis G endometrial gland M mitotic figure My myometrium S stratum spongiosum Se secretions V vacuoles

Hormonal effects on the endometrium

A variety of drug treatments have effects on the endometrium. Commonly used agents include the oral contraceptive pill (OCP) and post-menopausal hormone replacement therapy (HRT). These treatments may use a combination of oestrogenic and progestogenic agents to mimic the changes of a normal menstrual cycle or sometimes use progestogenic agents alone.

Other drugs used in treatment of malignant disease have hormonal effects, including the anti-oestrogenic drugs which are used in patients with hormone-sensitive breast cancer. These agents may have unpredictable effects on the endometrium.

Smooth muscle tumours

The uterine leiomyoma, colloquially known as a fibroid, is a very common benign tumour of women of reproductive age. They tend to increase in size and number with age and cause a range of symptoms, including abnormal bleeding, a feeling of pain or dragging in the lower abdomen, urinary frequency if they compress the bladder, and infertility. A typical leiomyoma is illustrated in Fig. 19.22 . Uterine fibroids are often multiple.

Fig. 19.22, Uterine leiomyoma H&E (LP)

In contrast, leiomyosarcomas, the malignant counterpart of the benign fibroid, are much rarer, are typically solitary and occur in older women. These tumours are characterised by features such as an infiltrative margin, marked cytological atypia, necrosis and increased mitotic activity.

C cystic gland E endometrium G gland L longitudinal smooth muscle bundle Le leiomyoma M myometrium O oblique smooth muscle bundle S stroma T transverse smooth muscle bundle

A adventitia E stratified squamous epithelium EC endocervical canal J squamocolumnar junction LP lamina propria SM smooth muscle V vagina

e-Fig. 19.7, Cervical intraepithelial neoplasia (CIN)

e-Fig. 19.8, Invasive squamous cell carcinoma of the cervix

e-Fig. 19.9, Cervical tunnel clusters (LP)

e-Fig. 19.10, Cervical cytology (HP)

The Placenta

The placenta is formed from elements of the membranes that surround the developing fetus, as well as the uterine endometrium, and provides the means for physiological exchange between the fetal and maternal circulations. The structure of the placenta varies greatly from one species to another and the following discussion is thus necessarily confined to the human placenta. At various stages during fetal development, the placenta performs a remarkable range of functions until the fetal organs become functional. These include gaseous exchange, excretion, maintenance of homeostasis, hormone secretion, haematopoiesis and hepatic metabolic functions.

D decidua G endometrial gland I intermediate trophoblast S syncytiotrophoblast cell V blood vessel

Abnormalities of the placenta

The normal placenta invades into the uterine wall in order to establish circulation with a supply of oxygen and nutrients for the developing fetus. In some cases, the placenta becomes abnormally adherent and invades too deeply into the uterus, preventing the normal process of separation which occurs after parturition. This can lead to serious maternal blood loss. The least severe form of this is known as placenta accreta, where the placenta does not invade significantly into the myometrium. Placenta increta describes deeper attachment which extends further into the myometrium. In its most severe form, placenta percreta, the placenta may penetrate through to the serosal surface of the uterus and can even attach to other pelvic organs.

BM basement membrane C cytotrophoblast D desmosome E nucleated erythrocytes G Golgi apparatus I intermediate trophoblast L lacuna M mesenchyme MC mesenchymal cell Mi mitochondrion Mv microvilli Nu nucleolus R polyribosomes rER rough endoplasmic reticulum S syncytiotrophoblast sER smooth endoplasmic reticulum V villus

A umbilical artery Am amniotic membrane BM basement membrane C capillary Ch chorionic membrane D outer collagenous layer E epithelial cells F fused basement membranes I inner collagenous layer of chorionic membrane In intermediate zone K syncytial knot L lacuna M mesenchymal layer MC mesenchymal cell T trophoblast V blood vessel Ve umbilical vein W Wharton’s jelly

Fig. 19.4, Ovarian cortex

Fig. 19.5, Secondary follicle Azan (MP)

Fig. 19.31, Early placenta

Fig. 19.28, Decidua formation and early placental development

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