Progestin withdrawal at parturition in the mare.

Mammalian pregnancies need progestogenic support and birth requires progestin withdrawal. The absence of progesterone in pregnant mares, and the progestogenic bioactivity of 5α-dihydroprogesterone (DHP), led us to reexamine progestin withdrawal at foaling. Systemic pregnane concentrations (DHP, allopregnanolone, pregnenolone, 5α-pregnane-3ß, 20α-diol (3ß,20αDHP), 20α-hydroxy-5α-dihydroprogesterone (20αDHP)) and progesterone) were monitored in mares for 10days before foaling (n=7) by liquid chromatography-mass spectrometry. The biopotency of dominant metabolites was assessed using luciferase reporter assays. Stable transfected Chinese hamster ovarian cells expressing the equine progesterone receptor (ePGR) were transfected with an MMTV-luciferase expression plasmid responsive to steroid agonists. Cells were incubated with increasing concentrations (0-100nM) of progesterone, 20αDHP and 3α,20ßDHP. The concentrations of circulating pregnanes in periparturient mares were (highest to lowest) 3α,20ßDHP and 20αDHP (800-400ng/mL respectively), DHP and allopregnanolone (90 and 30ng/mL respectively), and pregnenolone and progesterone (4-2ng/mL). Concentrations of all measured pregnanes declined on average by 50% from prepartum peaks to the day before foaling. Maximum activation of the ePGR by progesterone occurred at 30nM; 20αDHP and 3α,20ßDHP were significantly less biopotent. At prepartum concentrations, both 20αDHP and 3α,20ßDHP exhibited significant ePGR activation. Progestogenic support of pregnancy declines from 3 to 5days before foaling. Prepartum peak concentrations indicate that DHP is the major progestin, but other pregnanes like 20αDHP are present in sufficient concentrations to play a physiological role in the absence of DHP. The authors conclude that progestin withdrawal associated with parturition in mares involves cessation of pregnane synthesis by the placenta.

Progestogen deficiency and endometrial cancer risk.

There is a close relationship between the amount of estogen and progesterone secreted by the ovary from puberty to menopause and the development of hyperplastic endometrium of all types and finally endometrial cancer. The endogenous endocrine pattern reflects progesterone deficiency (corpus luteum deficiency). Such deficiency can also develop when treatment with exogenous estrogen and progestogen is done and a deficiency of the progestogen in comparison to the used estrogen is induced in pre- and postmenopausal women. This risk is particular accentuated in the climacteric female when the endocrine milieu was unfavorable in the years before (menstrual cycle disorders, PCOS, obesity, no full-term pregnancy, no breast feeding, etc.). However, there are the additional factors, which modify the biological end result: "Progestogen deficiency". One main factor is the level of SHBG determined by the amount of free, biologically active estradiol. A low level of SHBG is for instance induced by high body weight. Therefore, the amount of overweight correlates with increased risk of endometrial hyperplasia and finally endometrial cancer. In addition, increasing body weight negatively affects proper ovarian function leading to corpus luteum deficiency and this in addition increases the risk of endometrial cancer. The classical risk increase for endometrial cancer is associated with oligomenorrhea or polymenorrhea combined with corpus luteum deficiency or anovulation. Therefore, women with PCOS are at increased risk for endometrial cancer in the pre- and postmenopausal years. Examples from the therapeutic point of view have been the risk increase found with biphasic estrogen high-dosed oral contraceptives with a long estrogen phase and a short progestogen phase. In climacteric females estrogen-only treatment results in a predictable increase in endometrial cancer risk. Therefore, it is mandatory to use estrogen/progestogen combinations. The lowest risk is achieved when a continuous estrogen/progestogen regimen is used. In addition, the lowest dose of estrogens for the individual woman should be chosen.

Progesterone, progestogens and psychosomatic health of the climacteric woman.

Psychosomatics as a medical perspective and discipline focuses on the interaction of physical and mental health in a specific life situation of a patient, taking into account the physical and emotional wellbeing, role functioning, satisfaction with the partner and family relationship, as well as sexual function and satisfaction. The role of progesterone for the psychosomatic health of the climacteric woman depends on the individual symptom cluster and the pre-existing receptivity of the progesterone receptors which are widely distributed in the body and especially the brain of the woman. The complex action and interaction of progesterone is reflected in controversial empirical results about the impact of progesterone on the physical, mental and sexual health of climacteric women. From biological rationale and clinical experience there are however two important effects of P on the combined physical, mental and sexual wellbeing of climacteric patient: the antiestrogenic effect of progesterone is important on the peripheral physical level not only to protect the endometrium against overstimulation but also to reduce the individual suffering from heavy bleeding, breast tension, bloating and general discomfort. The positive anxiolytic and sedative effects of progesterone on the central nervous system depend on the type of progestogen, the dosage, the timing of application, the combination with estrogen etc. It can be concluded that progesterone and progestogens have an important potential to maintain or improve the psychosomatic health of the climacteric women. Their use must however be tailored to specific symptom clusters and to the individual's pre-existing psychosomatic health status.

Noninvasive reproductive monitoring in the okapi (Okapia johnstoni).

Fecal progestagen analysis in okapis (Okapia johnstoni) was used for diagnosis of pregnancy and reproductive disorders, including a comparison of urinary and fecal progestagen analysis and endocrine data on the postpartum period. Data were generated on reliability of fecal progestagen analysis in early pregnancy diagnosis, and case reports were compiled involving single animals with missing luteal activity, abortion after twin pregnancy, and abortions due to deficient placental progestagen production. There was approximately 100-200-fold higher progestagen concentration in feces than in urine, thus explaining the high reliability of fecal progestagen evaluations in diagnosing luteal function and pregnancy. The postpartum period was characterized by lactational anestrus of several months duration, and a postpartum estrous cycle about 2-3 wk after parturition was observed in two of eight animals. An animal with five abortions due to deficient placental progestagen production was treated with altrenogest in a subsequent pregnancy and carried the fetus to term.

Matrix metalloproteinase and matrix metalloproteinase inhibitor expression in endometrial stromal cells during progestin-initiated decidualization and menstruation-related progestin withdrawal.

Estradiol (E) primes human endometrial stromal cells (HESCs) for the decidualizing effects of progesterone in vivo and in vitro. Matrix metalloproteinase (MMP) expression was evaluated in confluent HESCs incubated in control medium, and in medium supplemented with either E, or the synthetic progestin medroxyprogesterone acetate (P), or E + P. Measurements with a specific ELISA indicated that basal pro-MMP-1 output was unaffected by E, whereas E + P, which induces the expression of several decidualization-related markers, produced a time-dependent inhibition in HESC-secreted levels of pro-MMP-1. Consistent with progestin inhibition of MMP-1 protein expression in the HESCs, P but not E, reduced steady state levels of MMP-1 messenger RNA (mRNA) as determined by Northern analysis. By contrast, mRNA levels for MMP-2 and the MMP inhibitor TIMP-1 were not altered by either P or E. Steroid withdrawal studies indicated that after MMP-1 expression was suppressed by incubation of the HESCs with E + P, 4 days of exposure to the antiprogestin RU 486 (mifepristone) significantly up-regulated MMP-1 levels in the conditioned medium by severalfold compared with cultures maintained in E + P. The change to steroid-free control medium required a more prolonged period of withdrawal to attain up regulatory effects that were comparable with those evoked by RU 486. The ELISA measurements were validated by immunoblot analysis with a specific MMP-1 antibody, which showed corresponding changes in a band at the expected mobility of about 50 kDa. Moreover, Northern analysis revealed parallel changes in MMP-1 mRNA levels, whereas neither MMP-2 nor TIMP-1 mRNA levels were modulated by adding or withdrawing steroids. The contrast between regulated MMP-1 expression and constitutive MMP-2 expression observed in the cultured HESCs is consistent with the demonstrated presence on the MMP-1 promoter of regulatory elements such as AP-1 and PEA-3 that are absent from the MMP-2 promoter. Extrapolation of these in vitro changes in HESCs to in vivo endometrial events suggests that: 1) inhibition of MMP-1 expression by E and progesterone would stabilize the perivascular endometrial ECM to prevent local hemorrhage during endovascular invasion by the implanting trophoblast; 2) enhanced expression of MMP-1 evoked by steroid withdrawal would mediate endometrial ECM degradation leading to sloughing of the functional layer during menstruation.

[The role of hyperprolactinaemia in sterility where the cycle is anovulatory and where there is deficit of progestogen. (Investigations of the pituitary reserves of FSH, LH and prolactin) (author's transl)]. / Du rôle de l'hyperprolactinémie dans la stérilité par cycle anovulatoire et par insuffisance progestative. (Investigations sur la réserve hypophysaire de FSH, LH et prolactine.

We have measured by radio-immunological assays the levels of prolactin (PRL), of FSH and of LH in the plasma in 7 cases where sterility was due to persistent anovulatory cycles and in 6 cases where there was a progesterone deficiency as the sole aetiological factor. Then we stimulated the release of these three hormones by giving 300 micrograms of TRF, PRL, and 100 micrograms of LH-RH, of FSH and of LH. The results were compared with those obtained in 7 cases of normal young women with clear-cut biphasic cycles used as controls. These results show that a rise in the reserves of prolactin in the pituitary is very common in anovulatory cycles and in progesterone deficiency. In every case where the prolactin is raised LH is significantly lowered, where as the levels of FSH do not show much variation between those found in normal women. Thus an inverse relationship between PRL and LH has been demonstrated and its significance has been commented on.

Clinical pharmacology of the steroidal oral contraceptives.

PIP: Clinical pharmacology of the steroidal oral contraceptives (OCs) is reviewed. The review includes: effectiveness and mechanism of action; structure-activity relationship; minor side effects (estrogen excess, estrogen deficiency, progestogen excess, progestogen deficiency, management of minor side effects); major side effects (thromboembolic disease, hypertension, OCs and neoplasia); and selection of an OC (effectiveness, safety, patient acceptability). Over the past 2 decades the steroidal OCs have proved to be among the most effective pharmacologic products ever marketed. OCs have proved to be relatively benign in terms of morbidity and mortality. Because the decision to use OCs is complex, only contraindications to its use have been considered here. Absolute contraindications include: 1) history of cerebrovascular disease, thromboembolic disease, thrombophlebitis, or conditions predisposing to these disorders; 2) active liver disease or impaired liver function; 3) carcinoma of the breast; 4) estrogen-dependent neoplasia; 5) undiagnosed genital bleeding; and 6) pregnancy. Relative contraindications include: 1) women over age 40; 2) migraine headaches; 3) Hypertension; 4) leiomyomata of the uterus; 5) epilepsy; and 6) history of idiopathic jaundice of prepregnancy. There is no firm evidence that OC use results in an increased incidence of benign neoplasms of the liver and breast.^ieng