IN-DEPTH: REPRODUCTIVE ENDOCRINOLOGY


concentrations. Progesterone as low as 2.5 ng/mL can even be seen at this stage of normal pregnancy, although somewhat higher concentrations between 4 and 10 ng/mL are often considered the “normal range” for the first trimester.3 Fluctuations in pe- ripheral progesterone levels have been shown to oc- cur throughout the day, though not with a specific diurnal pattern.5 In the pregnant mare, unique structures known


as the endometrial cups form by approximately day 35 after ovulation.1 The cells that form the basis of the endometrial cups are from the embryo, specifi- cally from the trophoblast chorionic girdle. These embryonic cells invade the maternal endometrium in a ring-like fashion around the developing umbili- cus at the base of the uterine horn. There may be as many as 30 or more grossly visible, small, raised, whitish endometrial cups on the endometrial sur- face. The embryonic cup cells produce a hormone called equine chorionic gonadotropin (eCG), for- merly known as pregnant mare’s serum gonadotro- pin. This hormone is first detectable systemically between days 35 to 40 of pregnancy. The cups are mature and robustly secreting eCG at approxi- mately days 50 to 60, but they will subsequently undergo sloughing by days 100 to 150 in most mares. This hormone is stimulatory to the ovary and causes follicular development, followed by either ovulation or luteinization (without ovulation) of these follicles. New luteal structures, called supplementary cor- pora lutea, are thus produced. As the result of the increased number of corpora lutea now present on the ovaries, systemic progesterone rises. The pri- mary CL is also stimulated by eCG; therefore it remains active and secretes even more progesterone as well. This resurgence phase of progesterone se- cretion by the primary CL is termed the “secondary luteal phase” or “output 2,” whereas the production by supplementary corpora lutea is termed the “third luteal phase” or “output 3.”1 To summarize, progesterone rises after ovulation (diestrous phase) as the result of the primary CL. Because of maternal recognition of pregnancy, the primary CL does not undergo luteolysis but con- tinues to secrete progesterone after day 14 of di- estrus (first luteal phase). Subsequent to the stimulation by eCG, the primary CL increases pro- duction (second luteal phase), combined with pro- duction from the supplementary corpora lutea (third luteal phase).1,4 Progesterone from ovarian sources is required for


early pregnancy maintenance to day 45. If preg- nant mares are ovariectomized between days 50 to 70, many but not all will abort. It is during this stage that the feto-placental unit begins taking over the role of pregnancy maintenance by ramping up its progestogen production. The production of feto- placental estrogens also begins at this time.1,2 The corpora lutea continue to produce large quan-


tities of progesterone, with high systemic concen- trations (approximately 10–15 ng/mL) peaking at


approximately 60 to 120 days of gestation6; they are active until regression begins at approximately 150 to 180 days after ovulation. Actual progester- one is quite low in the pregnant mare after approx- imately 180 days of gestation. By this time, the feto-placental unit has taken over the production of all progestogens. The term “progestogen” means progesterone-like substances or metabolites. The term “progestin” is also often used in a similar fash- ion, or “progestin” may be reserved for medications having progesterone-like function. All ovarian lu- teal structures will regress by approximately 200 days of gestation.1,2 Feto-placental progestogens, especially 5-- pregnanes, are detectable in maternal serum/ plasma by 60 days of gestation when measured by means of advanced laboratory techniques (gas chro- matography/mass spectrometry, which are not com- mercially available).7 The substrate for these progestogens is maternal cholesterol. Cholesterol is metabolized to pregnenolone (P5) and then to 5--pregnanes and other progestogens. The sites of progestogen conversion include utero-placental tis- sues as well as the fetal gonads and adrenals. It is thought that the fetal adrenals play a critical role in progestogen metabolism through their production of P5. Total progestogen concentrations are rela- tively high in the second and third trimesters; they will then increase dramatically during the last few weeks of gestation and peak in the last days of gestation, only to drop precipitously near term.1,2 Although sometimes overlooked, estrogen plays


an endocrinological role in early pregnancy. The embryo produces small amounts of locally active estrogens. However, it is not until approximately day 35 that systemic estrogen rises. The source of this estrogen is the ovary, more specifically, the corpora lutea and possibly follicles. The stim- ulation of the ovaries by eCG is responsible for the timing of this increase in estrogen. It appears that estrogen is not actually necessary for preg- nancy maintenance, because ovariectomized mares administered only exogenous progestins will main- tain pregnancy without the administration of estrogens.1,2 At approximately 80 days of gestation, the feto- placental unit increases the production of estrone, estradiol-17, estradiol-17, and the equine-specific estrogens equilin and equilenin. The gonads of both male and female fetuses produce estrogen pre- cursors, such as dehydroepiandrosterone, which are then metabolized at the level of the placenta into the various estrogenic hormones. The fetal gonads are grossly hypertrophied during gestation when large quantities of these estrogen precursors are being made. High levels of these estrogenic com- pounds will be present throughout much of the re- mainder of pregnancy, decreasing only in the last 2 to 3 months of gestation. These estrogens are pos- tulated to increase blood flow to the fetal compart- ment and to promote uterine tonicity.1,2


AAEP PROCEEDINGS  Vol. 59  2013 351


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