A detailed analysis of about 600 charts, several kept over a period of 2-4 years (totally more than 12,000 cycles), showed that several young women normally charted a number of days with yellow stamps ("yellow days") in the infertile phases, despite the fact that their gynaecological examinations were perfectly normal. Most of these young women were virgins who had never experienced any genital infection. A careful study of their slides showed the existence of a mucus which resembled G- or G+ mucus, but leucocytes and lymphocytes were very rare. Precise aspiration of this mucus showed that it was produced not in the crypts but in the epithelium covering the endocervical wall between the openings to the crypts (Figure 1).

The cells which cover the walls of the canal are probably more original or fundamental than the cells which differentiate in the crypts. This assumption is sustained by the observation that the younger the woman the more abundant is the quantity of mucus of this type. I have called this secretion F (- fundamental) mucus and the cells F cells.

The description of the mature cervix and crypts, shown in Figures 1 and 12, is valid for the fertile years of the healthy woman. To understand the mature cervix it is important to study the development of the cervix during embryonic life, during infancy, adolescence and also its regression during and after the menopause.

Reports on embryonic development are plentiful (e.g. Davies and Kusuma 1962; Copplesson et al. 1967; Hiersche 1970; O'Rahilly 1973; Forsberg 1976; Graham 1976; Pixley 1976). The following description is perhaps admissible.

In an embryo 8-12 mm long (Figure 13a) the urogenital organs are rather similar in both sexes. On each side in the abdominal cavity there is a fold, the urogenital fold (UGF) containing two ducts (from the beginning solid cell strings), called the Wolffian duct (W) and the Müllerian duct (Mü). The Wolffian duct is localized nearer the mid-plane of the body and has three groups of horizontal ramifications to three primitive organs denominated the pronephros (P), the primitive gonad (Ov) and the metanephros (K). The pronephros soon disappears completely, the primitive gonad develops. into a testicle or an ovary. The metanephros develops into the kidney and is displaced upwards, while the gonad is displaced downwards. This downward movement of the gonad is supported by a fibrous structure called the gubemaculum (Gu). The testicle descends considerably through the inguinal canal to the scrotum, while the ovary only descends a little, but retains a fibrous connection via the gubemaculum through the inguinal canal with blood and lymph vessels.

In the male the Müllerian ducts undergo regression while the Wolffian ducts develop into the vas deferens and the epididymis. In the female the Wolffian ducts undergo regression and the Müllerian ducts develop into the tubes, the uterus (with the cervix) and the upper part of the vagina. Remnants of the Wolffian ducts may, however, be present in some women.

In the female embryo the gubemaculum and the Müllerian duct cross each other (at x in Figure 13a) and they adhere to each other at the point of crossing. The Müllerian duct above the crossing point becomes the tube. Below the crossing point the two Müllerian ducts fuse to one single structure and form the uterus and the upper part of the vagina. The lower part of the vagina (including the pockets of Shaw) develop from the urogenital sinus (UGS).

The fused part of the Müllerian ducts is from the beginning a solid cell string, but it liquefies centrally and forms the cervical canal with its epithelial lining. Glandular structures are visible in the cervix 2-3 months before birth. The epithelium of the cervix is, however, very different from the mature mucous membrane. Before birth it is composed of two or more layers of cells (Figure 13b). The superficial cells have the appearance of the secretory cells of the mature cervix and a secretory activity can be demonstrated by histochemical methods (Nonnis-Marzano and Zinelli 1959). The basal cells are clear and transparent. Reid et al. (1967) have proposed that these cells may be derived from monocytes which traverse the capillary walls and move to their epithelial positions.

Clear or transparent cells are subject to regression and finally they are found in certain locations only. The physiological meaning of this distribution is not known to this day. My suggestion is that these islands of basal cells produce inductor substances leading to a differentiation of F cells into P, S, L and cells (Figures 13a and 13b).

(a)

(b)

Figures 13(a) and 13(b) indicate schematically the development of the cervical crypts. Figure 13(a) covers the period from embryo to mid- gestation and Figure 13(b) from mid-gestation up to the period of late puberty and adulthood. The stages are (i) embryo 8-12 mm in length, 35-40 days old; (ii) embryo 27-33 mm in length, 50-55 days old; (iii) longitudinal section of (ii) on an expanded scale; (iv) fetus 4-5 months of age; (v) fetus 1-2 months before birth, induction complete; (vi) 2-4 months after birth - primordial crypts; (vii) childhood secondary crypts; (viii) beginning of asolescence: P, S, L crypts develop; (ix) end of adolescence, maturity. G crypts also develop. Stages (v) to (vi) and (vi) to (vii) may be stimulated by the hormones GH, EGF and thyroxine. The code for the shading indicating the different types of cells present is given at the right hand side of Figure 13(b). Mü, Müllerian ducts; W, Wolffian ducts; Pr, pronephros; Ov, primitive ovary; Me, metanephros (which become the kidneys); UGF, urogenital fold; UGS, urogenital sinus; x, crossing point of gubernaculum (Gu) and Müllerian ducts.

The first secreting structures may be designated primordial G, L, S or P crypts. Later they are stimulated hormonally to develop into mature G, L, S and P crypts (Figure 13b). A transient stimulus, which depends on the production of placental oestrogen, takes place in the last month before birth. After birth, this stimulus ceases and the crypts atrophy, "the genital crisis of the newborn" (Courrier 1945). New proliferation commences before and during puberty. At first, L, S and P crypts are stimulated; after several years G crypts are stimulated by progesterone, when ovulatory cycles commence.

The mechanisms whereby F cells are transformed into G, L, S or P cells are still unknown. Probably an understanding will be reached by molecular biology studies by the introduction of transparent fetal cells into the groups of F-cell culture in vitro.

During infancy, the mucous membrane of the cervix is flat or folded or sometimes lumpy, but few crypts are present. It produces only minimum quantities of mucus. The cells are probably more frequently F cells. Similarly, after menopause, differentiated cells are unusual and F cells are more frequent, the differentiated G, L, S and P cells have exfoliated or degenerated.

F mucus is probably made up of a large excess of membranous glycoproteins of F cells which are exfoliated and visible in the mucus. Leucocytes and lymphocytes are rare. Crystals of F secretion are few and indistinct or they are not present at all, and usually the nuclei of F cells are only visible on slides after the F mucus has dried out. Often minimum quantities of F mucus are mixed with G, L, S or P secretions and L, S, and P crystals are altered and form irregular patterns. In women of reproductive age F mucus amounts to 1-4% of the total cervical mucus (Figure 14b).

It was propounded already by Jost (1947) that there could be a factor, later denominated the Müllerian inhibition substance (MIS), or Jost factor, which aids in the regression of the Müllerian duct in the male fetus. Later studies (Takahashi et al. 1986; Vigier et al. 1989) have shown that MIS is also present in the female, and may inhibit oocyte meiosis at puberty and reduce ovarian aromatase activity, a biochemical step in the biosynthesis of oestrogens. In male fetuses and young male infants MIS promotes the descent of the testes into the scrotum. Biochemically MIS appears to be a glycoprotein with a general "anti-Müllerian" and "pro-Wolffian" activity. Functionally it is classified as transforming growth factor beta (TGF-b ).

I have suggested that MIS might be involved in the development of the "missed mucus symptom", a rare but interesting disease which was first publicly presented at the 1990 Annual Meeting of the Natural Family Planning Council of Victoria in Melbourne, Australia. Women with this condition often seek help for infertility. Their charts reveal that they sometimes miss their mucus symptom, apparently due to a temporary closing of the external os. This in turn is due to contraction in the two sacro-uterine ligaments which contain muscle bundles stimulated to contractions by oestrogenic hormones. The tension at contraction is mediated to the region of the external os by fibrous strings, remnants of the Wolffian ducts, one on each side of the cervix. These women may have other signs of "anti-Müllerian" activity such as a small amount of cervical mucosa and impaired ovarian function.