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Female Reproductive Endocrinology

by Robert G. Brzyski, MD, PhD, Jennifer Knudtson, MD

Hormonal interaction between the hypothalamus, anterior pituitary gland, and ovaries regulates the female reproductive system. The hypothalamus secretes a small peptide, gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone–releasing hormone. GnRH regulates release of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from specialized cells (gonadotropes) in the anterior pituitary gland (see see Figure: The CNS-hypothalamic-pituitary-gonadal target organ axis.and see Luteinizing hormone (LH) and follicle-stimulating hormone (FSH)). These hormones are released in short bursts (pulses) every 1 to 4 h. LH and FSH promote ovulation and stimulate secretion of the sex hormones estradiol (an estrogen ) and progesterone from the ovaries.

Estrogen and progesterone circulate in the bloodstream almost entirely bound to plasma proteins. Only unbound estrogen and progesterone appear to be biologically active. They stimulate the target organs of the reproductive system (eg, breasts, uterus, vagina). They usually inhibit but, in certain situations (eg, around the time of ovulation), may stimulate gonadotropin secretion.

The CNS-hypothalamic-pituitary-gonadal target organ axis.

Ovarian hormones have direct and indirect effects on other tissues (eg, bone, skin, muscle). FSH =follicle-stimulating hormone; GnRH =gonadotropin-releasing hormone; LH =luteinizing hormone.

Puberty

Puberty is the sequence of events in which a child acquires adult physical characteristics and capacity for reproduction. Circulating LH and FSH levels are elevated at birth but fall to low levels within a few months and remain low until puberty. Until puberty, few qualitative changes occur in reproductive target organs.

The age of onset of puberty and the rate of development through different stages is influenced by different factors. Over the last 150 yr, the age at which puberty begins has been decreasing, primarily because of improved health and nutrition, but this trend has stabilized. Puberty often occurs earlier than average in moderately obese girls and later than average in severely underweight and undernourished girls. Such observations suggest that a critical body weight or amount of fat is necessary for puberty. Many other factors can influence when puberty begins and how rapidly it progresses. For example, there is some evidence that intrauterine growth restriction, especially when followed by postnatal overfeeding, may contribute to earlier and more rapid development of puberty. Puberty occurs earlier in girls whose mothers matured earlier and, for unknown reasons, in girls who live in urban areas or who are blind. The age of onset of puberty also varies among ethnic groups (eg, tending to be earlier in blacks and Hispanics than in Asians and non-Hispanic whites).

Physical changes of puberty occur sequentially during adolescence (see see Figure: Puberty—when female sexual characteristics develop.). Breast budding (see see Figure: Diagrammatic representation of Tanner stages I to V of human breast maturation.) and onset of the growth spurt are usually the first changes recognized. Then, pubic and axillary hair appear (see see Figure: Diagrammatic representation of Tanner stages I to V for development of pubic hair in girls.), and the growth spurt peaks. Menarche (the first menstrual period) occurs about 2 to 3 yr after breast budding. Menstrual cycles are usually irregular at menarche and can take up to 5 yr to become regular. The growth spurt is limited after menarche. Body habitus changes and the pelvis and hips widen. Body fat increases and accumulates in the hips and thighs.

Mechanisms initiating puberty are unclear. Central influences may inhibit release of GnRH during childhood, then initiate its release to induce puberty in early adolescence. Early in puberty, hypothalamic GnRH release becomes less sensitive to inhibition by estrogen and progesterone . The resulting increased release of GnRH promotes LH and FSH secretion, which stimulates production of sex hormones, primarily estrogen . Estrogen stimulates development of secondary sexual characteristics. Pubic and axillary hair growth may be stimulated by the adrenal androgens dehydroepiandrosterone (DHEA) and DHEA sulfate; production of these androgens increases several years before puberty in a process called adrenarche.

Puberty—when female sexual characteristics develop.

Bars indicate normal ranges.

Diagrammatic representation of Tanner stages I to V of human breast maturation.

From Marshall WA, Tanner JM: Variations in patterns of pubertal changes in girls. Archives of Disease in Childhood 44:291–303, 1969; used with permission.

Diagrammatic representation of Tanner stages I to V for development of pubic hair in girls.

From Marshall WA, Tanner JM: Variations in patterns of pubertal changes in girls. Archives of Disease in Childhood 44:291–303, 1969; used with permission.

Ovarian Follicular Development

A female is born with a finite number of egg precursors (germ cells). Germ cells begin as primordial oogonia that proliferate markedly by mitosis through the 4th mo of gestation. During the 3rd mo of gestation, some oogonia begin to undergo meiosis, which reduces the number of chromosomes by half. By the 7th mo, all viable germ cells develop a surrounding layer of granulosa cells, forming a primordial follicle, and are arrested in meiotic prophase; these cells are primary oocytes. Beginning after the 4th mo of gestation, oogonia (and later oocytes) are lost spontaneously in a process called atresia; eventually, 99.9% are lost. In older mothers, the long time that surviving oocytes spend arrested in meiotic prophase may account for the increased incidence of genetically abnormal pregnancies.

FSH induces follicular growth in the ovaries. During each menstrual cycle, 3 to 30 follicles are recruited for accelerated growth. Usually in each cycle, only one follicle achieves ovulation. This dominant follicle releases its oocyte at ovulation and promotes atresia of the other recruited follicles.

Menstrual Cycle

Menstruation is the periodic discharge of blood and sloughed endometrium (collectively called menses or menstrual flow) from the uterus through the vagina. It is caused by the rapid decline in ovarian production of progesterone and estrogen that occurs each cycle in the absence of a pregnancy. Menstruation occurs throughout a woman’s reproductive life in the absence of pregnancy. Menopause is the permanent cessation of menses (see Menopause).

Average duration of menses is 5 (± 2) days. Blood loss per cycle averages 30 mL (normal range, 13 to 80 mL) and is usually greatest on the 2nd day. A saturated pad or tampon absorbs 5 to 15 mL. Menstrual blood does not usually clot (unless bleeding is very heavy), probably because fibrinolysin and other factors inhibit clotting.

The median menstrual cycle length is 28 days (usual range, about 25 to 36 days). Generally, variation is maximal and intermenstrual intervals are longest in the years immediately after menarche and immediately before menopause, when ovulation occurs less regularly. The menstrual cycle begins and ends with the first day of menses (day 1).

The menstrual cycle can be divided into phases, usually based on ovarian status. The ovary proceeds through the follicular (preovulatory), ovulatory, and luteal (postovulatory) phases (see see Figure: The idealized cyclic changes in pituitary gonadotropins, estradiol (E 2 ), progesterone (P), and uterine endometrium during the normal menstrual cycle.). The endometrium also cycles through phases (see Female Reproductive Endocrinology:Endometrium).

Follicular phase

This phase varies in length more than other phases. In the first half of the follicular phase (early follicular phase), the primary event is growth of recruited follicles. At this time, the gonadotropes in the anterior pituitary contain little LH and FSH, and estrogen and progesterone production is low. As a result, overall FSH secretion increases slightly, stimulating growth of recruited follicles. Also, circulating LH levels increase slowly, beginning 1 to 2 days after the increase in FSH. The recruited ovarian follicles soon increase production of estradiol; estradiol stimulates LH and FSH synthesis but inhibits their secretion.

During the 2nd half of the follicular phase (late follicular phase), the follicle selected for ovulation matures and accumulates hormone-secreting granulosa cells; its antrum enlarges with follicular fluid, reaching 18 to 20 mm before ovulation. FSH levels decrease; LH levels are affected less. FSH and LH levels diverge partly because estradiol inhibits FSH secretion more than LH secretion. Also, developing follicles produce the hormone inhibin, which inhibits FSH secretion but not LH secretion. Other contributing factors may include disparate half-lives (20 to 30 min for LH; 2 to 3 h for FSH) and unknown factors. Levels of estrogen, particularly estradiol , increase exponentially.


Ovulatory phase

Ovulation (ovum release) occurs. Estradiol levels usually peak as the ovulatory phase begins. Progesterone levels also begin to increase. Stored LH is released in massive amounts (LH surge), usually over 36 to 48 h, with a smaller increase in FSH. The LH surge occurs because at this time, high levels of estradiol trigger LH secretion by gonadotropes (positive feedback). The LH surge is also stimulated by GnRH and progesterone . During the LH surge, estradiol levels decrease, but progesterone levels continue to increase. The LH surge stimulates enzymes that initiate breakdown of the follicle wall and release of the now mature ovum within about 16 to 32 h. The LH surge also triggers completion of the first meiotic division of the oocyte within about 36 h.


Luteal phase

The dominant follicle is transformed into a corpus luteum after releasing the ovum. The length of this phase is the most constant, averaging 14 days, after which, in the absence of pregnancy, the corpus luteum degenerates. The corpus luteum secretes primarily progesterone in increasing quantities, peaking at about 25 mg/day 6 to 8 days after ovulation. Progesterone stimulates development of the secretory endometrium, which is necessary for embryonic implantation. Because progesterone is thermogenic, basal body temperature increases by 0.5° C for the duration of this phase. Because levels of circulating estradiol, progesterone , and inhibin are high during most of the luteal phase, LH and FSH levels decrease. When pregnancy does not occur, estradiol and progesterone levels decrease late in this phase, and the corpus luteum degenerates into the corpus albicans.

If implantation occurs, the corpus luteum does not degenerate but remains functional in early pregnancy, supported by human chorionic gonadotropin that is produced by the developing embryo.

The idealized cyclic changes in pituitary gonadotropins, estradiol (E 2 ), progesterone (P), and uterine endometrium during the normal menstrual cycle.

Days of menstrual bleeding are indicated by M. FSH = follicle-stimulating hormone; LH = luteinizing hormone. (Adapted from Rebar RW: Normal physiology of the reproductive system. In Endocrinology and Metabolism Continuing Education Program, American Association of Clinical Chemistry , November 1982. Copyright 1982 by the American Association for Clinical Chemistry; reprinted with permission.)


Cyclic Changes in Other Reproductive Organs

Endometrium

The endometrium, which consists of glands and stroma, has a basal layer, an intermediate spongiosa layer, and a layer of compact epithelial cells that line the uterine cavity. Together, the spongiosa and epithelial layers form the functionalis, a transient layer that is sloughed during menses.

During the menstrual cycle, the endometrium cycles through its own phases: menstrual, proliferative, and secretory phases. After menstruation, the endometrium is typically thin with dense stroma and narrow, straight, tubular glands lined with low columnar epithelium. As estradiol levels increase, the intact basal layer regenerates the endometrium to its maximum thickness late in the ovarian follicular phase (proliferative phase of the endometrial cycle). The mucosa thickens and the glands lengthen and coil, becoming tortuous. Ovulation occurs at the beginning of the secretory phase of the endometrial cycle. During the ovarian luteal phase, progesterone stimulates the endometrial glands to dilate, fill with glycogen, and become secretory while stromal vascularity increases. As estradiol and progesterone levels decrease late in the luteal/secretory phase, the stroma becomes edematous, and the endometrium and its blood vessels necrose, leading to bleeding and menstrual flow (menstrual phase of the endometrial cycle). Fibrinolytic activity of the endometrium decreases blood clots in the menstrual blood.

Because histologic changes are specific to the phase of the menstrual cycle, the cycle phase or tissue response to sex hormones can be determined accurately by endometrial biopsy.


Cervix

The cervix acts as a barrier that limits access to the uterine cavity. During the follicular phase, increasing estradiol levels increase cervical vascularity and edema and cervical mucus quantity, elasticity, and salt (sodium chloride or potassium chloride) concentration. The external os opens slightly and fills with mucus at ovulation. During the luteal phase, increasing progesterone levels make the cervical mucus thicker and less elastic, decreasing success of sperm transport. Menstrual cycle phase can sometimes be identified by microscopic examination of cervical mucus dried on a glass slide; ferning (palm leaf arborization of mucus) indicates increased salts in cervical mucus. Ferning becomes prominent just before ovulation, when estrogen levels are high; it is minimal or absent during the luteal phase. Spinnbarkeit, the stretchability (elasticity) of the mucus, increases as estrogen levels increase (eg, just before ovulation); this change can be used to identify the periovulatory (fertile) phase of the menstrual cycle.


Vagina

Early in the follicular phase, when estradiol levels are low, the vaginal epithelium is thin and pale. Later in the follicular phase, as estradiol levels increase, squamous cells mature and become cornified, causing epithelial thickening. During the luteal phase, the number of precornified intermediate cells increases, and the number of leukocytes and amount of cellular debris increase as mature squamous cells are shed.


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