Elevated Serum Progesterone Levels Research Articles

Percutaneous administration of progesterone: blood levels and endometrial protection

There is controversy about the beneficial effects of topical progesterone creams used by postmenopausal women. A major concern is that serum progesterone levels achieved with progesterone creams are too low to have a secretory effect on the endometrium. However, antiproliferative effects on the endometrium have been demonstrated with progesterone creams when circulating levels of progesterone are low. Thus, effects of topical progesterone creams on the endometrium should not be based on serum progesterone levels, but on histologic examination of the endometrium. Despite the low serum progesterone levels achieved with the creams, salivary progesterone levels are very high, indicating that progesterone levels in serum do not necessarily reflect those in tissues. The mechanism by which the serum progesterone levels remain low is not known. However, one explanation is that after absorption through the skin, the lipophilic ingredients of creams, including progesterone, may have a preference for saturating the fatty layer below the dermis. Because there appears to be rapid uptake and release of steroids by red blood cells passing through capillaries, these cells may play an important role in transporting progesterone to salivary glands and other tissues. In contrast to progesterone creams, progesterone gels are water-soluble and appear to enter the microcirculation rapidly, thus giving rise to elevated serum progesterone levels with progesterone doses comparable to those used in creams.

Elevated progesterone at initiation of stimulation is associated with a lower ongoing pregnancy rate after IVF using GnRH antagonists.

The objective of this prospective study was to assess the impact of elevated serum progesterone levels on day 2 of the cycle on pregnancy rates in patients treated by IVF using GnRH antagonists. Ovarian stimulation was started on day 2 of the cycle if progesterone levels were normal (normal-P group, n = 390). In the presence of elevated progesterone, initiation of stimulation was postponed for 1 or 2 days (high-P group, n = 20) and was started if repeat progesterone levels returned to normal range (n = 16). Stimulation was performed with recombinant FSH (rFSH) and GnRH antagonist was always started on day 6 of stimulation. A significantly higher exposure to progesterone and a significantly lower exposure to estradiol was present in the high-P as compared with the normal-P group from day 1 to day 8 of stimulation. In addition, a significantly lower ongoing pregnancy rate both per started cycle (5.0% versus 31.8%; P = 0.01) and per embryo transfer (6.3% versus 36.9%; P = 0.01) was present in the high-P compared with the normal-P group, respectively. The presence of elevated serum progesterone on day 2 of the cycle is associated with a decreased chance of pregnancy in patients treated with rFSH and GnRH antagonists.

The prognostic value of serum inhibin, 17β-estradiol and progesterone in cases of hydatidiform mole

The purpose of this study was to provide a diagnostic and a prognostic variable that could easily be measured in the laboratory, and that would predict the need for future therapy of persistent gestational trophoblastic disease. There would no longer be a need to treat all cases of hydatidiform mole prophylactically, to improve the outcome in only about 20% predicted to develop malignant gestational trophoblastic tumors. Circulating β-human chorionic gonadotropin (β-hCG), progesterone, 17β-estradiol and inhibin levels were measured using standard radioimmunoassays in 60 patients with complete hydatidiform mole and in 20 normal pregnant women of a corresponding duration of pregnancy and having a maternal indication for therapeutic abortion. There were no significant statistical differences between the two groups as regards gravidity, parity and gestational age. There was a significant statistical difference between patients with a molar pregnancy who developed gestational trophoblastic tumors (GTT) and those who did not develop GTT as regards pre-evacuation and follow-up mean serum β-hCG, mean serum progesterone and mean serum 17β- estradiol levels. These findings together with the persistently elevated mean serum progesterone and mean serum 17β-estradiol levels at 6 weeks after evacuation in all cases who developed GTT suggested that progesterone as well as 17β-estradiol serum levels might be of prognostic value in cases of molar pregnancy. However, larger numbers of cases are required to correlate findings to β-hCG serum level. Although mean serum inhibin level was significantly higher in women with hydatidiform mole than in normal pregnant women, it lacks any prognostic value for detection of subsequent gestational trophoblastic tumors.

Effects of running exercise on the mandible and tibia of ovariectomized rats.

To examine the effects of running exercise on the mandible and tibia of ovariectomized (OVX) rats, 26-week-old sham-operated (Sham) and OVX rats 1 week post-ovariectomy were subjected to non-exercise (Sham-Cont and OVX-Cont) and exercise (Sham-Exc and OVX-Exc) for 8 weeks. OVX induced a significant decrease in alkaline phosphatase (ALP) and an increase in tartrate-resistant acid phosphatase (TRAP) activity and a reduction of 17beta-estradiol in the serum. In OVX-Cont rats, histology and bone mineral density (BMD) showed bone loss in the proximal tibia, and histology, soft X-ray photographs and bone marrow area (BMA) revealed enlargement of the bone marrow cavity in the neck of the condylar process. In OVX-Exc rats, exercise significantly increased ALP activity, decreased TRAP activity and markedly elevated serum progesterone levels. Histology and BMD in the tibia and histology, X-ray photographs and BMA in the mandible were comparable to those in Sham rats. In Sham-Exc rats, unexpected decreases were observed in serum enzymes and hormones, but the histology and BMD in the tibia and histology, X-ray photographs and BMA in the mandible were very similar to those in Sham-Cont rats, suggesting a decrease of bone turnover with no change of bone mass in the tibia and mandible. We conclude that exercise has a beneficial effect not only on bone loss in the tibia, but also on differential changes in the neck of the condylar process, perhaps by increasing serum levels of progesterone in OVX rats.

Elevated serum progesterone level on the day of human chorionic gonadotropin administration does not adversely affect implantation rates after intracytoplasmic sperm injection and embryo transfer

Objective: To evaluate the association between serum P levels on the day of hCG administration and the outcome of intracytoplasmic sperm injection (ICSI). Design: Retrospective case study. Setting: Assisted reproduction unit of a tertiary care private hospital. Patient(s): Nine hundred eleven ICSI cycles that proceeded to ET were studied. Intervention(s): The decision to administer hCG was based on serum E 2 levels and follicle size. Serum P was measured from frozen sera obtained on the day of hCG administration. Cycles were stratified according to serum P levels of <0.9 ng/mL (n = 298) or ≥0.9 ng/mL (n = 613). This cutoff level was selected because it yielded the highest sensitivity and specificity according to a receiver operator characteristic curve. Main Outcome Measure(s): Implantation and clinical pregnancy rates. Result(s): In cycles with high serum P levels, more oocytes were retrieved and more embryos were available for transfer. Clinical pregnancy rates per ET in the low and high P groups were 36.9% and 45.4%, respectively ( P<.05). The implantation rate per embryo was similar in the two groups (14.9% and 16.4%, respectively, in cycles with P levels <0.9 vs ≥0.9 ng/mL). Abortion rates were 22.7 and 25.8%, respectively ( P>.05). Conclusion(s): Our data showed no adverse effect of high serum P levels on the day of hCG administration on implantation rates after ICSI and ET.

Transgenic models to study gonadotropin function: the role of follicle-stimulating hormone in gonadal growth and tumorigenesis.

The role of FSH in gonadal tumorigenesis and, in particular, in human ovarian cancer has been debated. It is also unclear what role the elevated FSH levels in the inhibin-deficient mouse play in the gonadal tumorigenesis. To directly assess the role of FSH in gonadal growth, differentiation, and gonadal tumorigenesis, we have generated both gain-of-function and loss-of-function transgenic mutant mice. In the gain-of-function model, we have generated transgenic mice that ectopically overexpress human FSH from multiple tissues using a mouse metallothionein-1 promoter, achieving levels far exceeding those seen in postmenopausal women. Male transgenic mice are infertile despite normal testicular development and demonstrate enlarged seminal vesicles secondary to elevated serum testosterone levels. Female transgenic mice develop highly hemorrhagic and cystic ovaries, have elevated serum estradiol and progesterone levels, and are infertile, mimicking the features of human ovarian hyperstimulation and polycystic ovarian syndromes. Furthermore, the female transgenic mice develop enlarged and cystic kidneys and die between 6-13 weeks as a result of urinary bladder obstruction. In a complementary loss-of-function approach, we have generated double-homozygous mutant mice that lack both inhibin and FSH by a genetic intercross. In contrast to male mice lacking inhibin alone, 95% of which die of a cancer cachexia-like syndrome by 12 weeks of age, only 30% of the double-mutant male mice lacking both FSH and inhibin die by 1 yr of age. The remaining double-mutant male mice develop slow-growing and less hemorrhagic testicular tumors, which are noted after 12 weeks of age, and have minimal cachexia. Similarly, the double-mutant female mice develop slow-growing, less hemorrhagic ovarian tumors, and 70% of these mice live beyond 17 weeks. The double-mutant mice demonstrate minimal cachexia in contrast to female mice lacking only inhibin, which develop highly hemorrhagic ovarian tumors, leading to cachexia and death by 17 weeks of age in 95% of the cases. The milder cachexia-like symptoms of the inhibin and FSH double-mutant mice are correlated with low levels of serum estradiol and activin A and reduced levels of aromatase mRNA in the gonadal tumors. Based on these and our previous genetic analyses, we conclude that elevated FSH levels do not directly cause gonadal tumors. However, these results suggest FSH is an important trophic modifier factor for gonadal tumorigenesis in inhibin-deficient mice.

The luteal phase of cycles utilizing controlled ovarian hyperstimulation and the possible impact of this hyperstimulation on embryo implantation

OBJECTIVE: Our purpose was to evaluate the early luteal phase of assisted reproductive cycles utilizing controlled ovarian hyperstimulation and to compare these results with those obtained in unstimulated cycles. STUDY DESIGN: We undertook a descriptive study analyzing luteal phase serum progesterone levels, endometrial histologic features, and endometrial surface ultrastructure by scanning electron microscopy of cycles utilizing controlled ovarian hyperstimulation. Study samples were obtained from 7 oocyte donors undergoing controlled ovarian hyperstimulation for the purpose of follicle aspiration in oocyte donation. Control (unstimulated) serum progesterone samples were obtained from 19 patients undergoing in vitro fertilization in unstimulated cycles. Prospective recipients of oocyte donation ( n = 20) undergoing mock cycles of exogenous estradiol and progesterone acted as controls for the endometrial biopsies. RESULTS: Serum progesterone levels on the day of human chorionic gonadotropin administration were twofold higher in the study group than in the unstimulated group (1.1 ± 0.6 vs 0.5 ± 0.2 ng/ml, mean ± SD, p < 0.01). On the day of follicle aspiration, progesterone levels were much higher in the study group (8.5 ± 2.2 vs 0.5 ± 0.1 ng/ml, p < 0.001). Histologic dating of endometrial biopsies revealed that the study group was advanced by nearly 2 days as compared with the group having artificial cycles. Pinopods, ultrastructural markers of the implantation window, were present in only one of seven study cycles as compared with all of the four artificial cycles. CONCLUSIONS: The early luteal phase of cycles undergoing controlled ovarian hyperstimulation is characterized by markedly elevated serum progesterone levels during the periovulatory period, advanced endometrial histologic features, and an absence of endometrial pinopods at the time of embryo implantation. We speculate that these high levels of progesterone in the early luteal phase cause premature endometrial luteinization and a premature appearance of the implantation window, thus providing an explanation for the observed decrease in endometrial receptivity. (Am J Obstet Gynecol 1997;176:1262-9.)

Elevated serum progesterone levels during pituitary suppression may signify adrenal hyperandrogenism

Objective: To investigate whether elevated serum P levels after pituitary down-regulation signify adrenal enzyme defects or hyperandrogenism. Design: Prospective study. Setting: Assisted reproduction unit in a university medical center. Patient(s): Two hundred twenty-seven IVF patients treated by the long down-regulation protocol. Intervention(s): Oral dexamethasone (DEX) administration if P level exceeded 0.8 ng/mL (conversion factor to SI unit, 3.180) after pituitary suppression. Main Outcome Measure(s): Serum concentrations of P, E 2, LH, DHEAS, and 17α-hydroxy progesterone and ACTH stimulation tests. Result(s): In eight patients (3.5%), serum P levels exceeded 0.8 ng/mL and E 2 and LH levels confirmed pituitary down-regulation. Mean DHEAS levels in the patients in this group were significantly higher than in the other patients. All eight patients demonstrated a significant decrease in serum P level after DEX administration. In five patients the ACTH stimulation test suggested an adrenal defect. Five pregnancies were achieved after the addition of DEX to the treatment protocol. Conclusion(s): High serum P levels after pituitary down-regulation appear to be of adrenal origin and may be the first indication of an adrenal enzyme defect. Further investigation such as an ACTH stimulation test is recommended, followed by treatment with DEX if indicated.

Assessment of luteal rescue and desensitization of macaque corpus luteum brought about by human chorionic gonadotrophin and deglycosylated human chorionic gonadotrophin treatment

The objective of the current study was to investigate the mechanism by which the corpus luteum (CL) of the monkey undergoes desensitization to luteinizing hormone following exposure to increasing concentration of human chorionic gonadotrophin (hCG) as it occurs in pregnancy. Female bonnet monkeys were injected (im) increasing doses of hCG or dghCG beginning from day 6 or 12 of the luteal phase for either 10 or 4 or 2 days. The day of oestrogen surge was considered as day ‘0’ of luteal phase. Luteal cells obtained from CL of these animals were incubated with hCG (2 and 200 pg/ml) or dbcAMP (2.5,25 and 100 M) for 3h at 37°C and progesterone secreted was estimated. Corpora lutea of normal cycling monkeys on day 10/16/22 of the luteal phase were used as controls. In addition thein vivo response to CG and deglycosylated hCG (dghCG) was assessed by determining serum steroid profiles following their administration. hCG (from 15–90 IU) but not dghCG (15-90 IU) treatment in vivo significantly (P < 0.05) elevated serum progesterone and oestradiol levels. Serum progesterone, however, could not be maintained at a elevated level by continuous treatment with hCG (from day 6–15), the progesterone level declining beyond day 13 of luteal phase. Administering low doses of hCG (15-90 IU/day) from day 6–9 or high doses (600 IU/day) on days 8 and 9 of the luteal phase resulted in significant increase (about 10-fold over corresponding control P < 0.005) in the ability of luteal cells to synthesize progesterone (incubated controls) in vitro. The luteal cells of the treated animals responded to dbcAMP (P < 0.05) but not to hCC added in vitro. The in vitro response of luteal cells to added hCG was inhibited by 0,50 and 100% if the animals were injected with low (15-90 IU) or medium (100 IU) between day 6–9 of luteal phase and high (600 IU on day 8 and 9 of luteal phase) doses of dghCG respectively; such treatment had no effect on responsivity of the cells to dbcAMP. The luteal cell responsiveness to dbcAMP in vitro was also blocked if hCG was administered for 10 days beginning day 6 of the luteal phase. Though short term hCG treatment during late luteal phase (from days 12—15) had no effect on luteal function, 10 day treatment beginning day 12 of luteal phase resulted in regain ofin vitro responsiveness to both hCG (P < 0.05) and dbcAMP (P < 0.05) suggesting that luteal rescue can occur even at this late stage. In conclusion, desensitization of the CL to hCG appears to be governed by the dose/period for which it is exposed to hCG/dghCG. That desensitization is due to receptor occupancy is brought out by the fact that (i) this can be achieved by giving a larger dose of hCG over a 2 day period instead of a lower dose of the hormone for a longer (4 to 10 days) period and (ii) the effect can largely be reproduced by using dghCG instead of hCG to block the receptor sites. It appears that to achieve desensitization to dbcAMP also it is necessary to expose the luteal cell to relatively high dose of hCG for more than 4 days

Elevated serum progesterone levels on the day of human chorionic gonadotropin administration do not predict outcome in assisted reproduction cycles

To determine if the level of serum P drawn on the day of hCG administration predicts assisted reproductive technology (ART) outcome in patients undergoing stimulation with hMG under GnRH agonist (GnRH-a) suppression. Retrospective P assay of stored serum. One hundred seventy-one patients (189 cycles) who had undergone GnRH-a suppression (leuprolide acetate or nafarelin) and stimulation with hMG for an ART procedure. Progesterone RIA of serum obtained on the day of hCG administration. Measurement of sequential serum LH values by RIA in those patients with the highest P levels. Pregnancy rates per oocyte retrieval were not correlated with the P level before hCG administration. There were 18 of 54 (33.3%) clinical pregnancies in those cycles with P < 0.9 ng/mL (conversion factor to SI unit, 3.180) and 42 of 135 (31.1%) clinical pregnancies in cycles with a P > or = 0.9 ng/mL. Significantly higher serum E2 levels and numbers of of follicles and oocytes obtained were observed in the high P cycles. There were no differences in the number of oocytes fertilized, the number of embryos transferred, or the implantation rate. However, a significantly higher percentage of mature oocytes were fertilized in the low P cycles (73%), as compared with the high P cycles (60%). Serum P levels before hCG administration do not predict the outcome of ART cycles in patients suppressed with GnRH-a before hMG stimulation. Lower fertilization rates observed in the high P cycles did not have an effect on clinical outcome.

Elevated serum progesterone levels on the day of human chorionic gonadotropin administration in in vitro fertilization cycles do not adversely affect embryo quality

To assess the effect of an elevated serum P level on the day of hCG administration in an IVF cycle on resulting embryos by evaluating their performance at subsequent frozen ET. A retrospective study. Ninety-six consecutive patients undergoing frozen ET cycles were studied in a tertiary care center. Serum obtained on the day of hCG administration in an IVF cycle was assayed for E2 and P by RIA. The main outcome measured was the development of a clinical pregnancy in a subsequent frozen ET cycle. Using a previously described breakpoint in serum P concentration of 0.9 ng/mL (2.86 nmol/L), 8 of 69 (11.6%) frozen ETs in which embryos from low P level IVF cycles were transferred and 7 of 27 (25.9%) frozen ETs of embryos from elevated P level IVF cycles were transferred resulted in the development of clinical pregnancies. Although this does not clearly demonstrate superiority of embryos obtained from elevated P cycles, employing a power calculation, the probability that the pregnancy rate in the elevated serum P group is at least equal to the observed rate in the low P group is 92.8%. These data suggest that an elevated serum P level on the day of hCG administration does not adversely affect the quality of oocytes or resulting embryos.

Noncoordinated expression of luteal cell messenger ribonucleic acids during human chorionic gonadotropin stimulation of the primate corpus luteum

In nonfertile cycles, the absolute steroidogenic capacity of the primate corpus luteum, as reflected in the expression of messenger RNA (mRNA) for the progesterone biosynthetic enzymes cytochrome P450 cholesterol side-chain cleavage (P450SCC) and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), progressively declines until luteal regression. Despite this progressive loss in luteal cell function, the elaboration of CG by the implanted blastocyst is able to prolong the functional lifespan of the corpus luteum. It was the purpose of this study to investigate the relationship between aging of the primate corpus luteum and the cellular mechanisms by which the decline in luteal cell function is arrested by CG. Corpora lutea were obtained from cynomolgus monkeys on days 11 or 16 of the luteal phase after a 7-day treatment period with increasing doses of human CG (hCG) given intramuscularly beginning on days 5 or 10. Corpora lutea were also obtained from control animals on days 5, 10, 11, and 16 of the luteal phase. Human CG treatment significantly (P < 0.05) elevated both serum progesterone and estradiol levels throughout the treatment period; however, progesterone production in animals treated with hCG late in the luteal phase (days 10-16) steadily declined after the third treatment day. Expression of mRNA for P450SCC and 3 beta-HSD was markedly stimulated (P < 0.05) by hCG treatment early in the luteal phase. However, 3 beta-HSD message levels in corpora lutea from animals treated with hCG on days 10-16 were not different from those of day-16 control corpora lutea, whereas P450SCC mRNA was only minimally stimulated. There was a dramatic (P < 0.05) increase in mRNA levels for the aromatase enzyme and low density lipoprotein receptor in animals given hCG in both the early and the late luteal phase. In conclusion, there appears to be a differential responsiveness of the primate corpus luteum to hCG stimulation dependent upon luteal age. The loss in responsiveness to hCG in terms of maintenance of mRNA levels is reflective of the inability of the late luteal phase corpus luteum for continued progesterone biosynthesis in the face of heightened luteotropic stimulation.

Noncoordinated expression of luteal cell messenger ribonucleic acids during human chorionic gonadotropin stimulation of the primate corpus luteum.

In nonfertile cycles, the absolute steroidogenic capacity of the primate corpus luteum, as reflected in the expression of messenger RNA (mRNA) for the progesterone biosynthetic enzymes cytochrome P450 cholesterol side-chain cleavage (P450SCC) and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), progressively declines until luteal regression. Despite this progressive loss in luteal cell function, the elaboration of CG by the implanted blastocyst is able to prolong the functional lifespan of the corpus luteum. It was the purpose of this study to investigate the relationship between aging of the primate corpus luteum and the cellular mechanisms by which the decline in luteal cell function is arrested by CG. Corpora lutea were obtained from cynomolgus monkeys on days 11 or 16 of the luteal phase after a 7-day treatment period with increasing doses of human CG (hCG) given intramuscularly beginning on days 5 or 10. Corpora lutea were also obtained from control animals on days 5, 10, 11, and 16 of the luteal phase. Human CG treatment significantly (P < 0.05) elevated both serum progesterone and estradiol levels throughout the treatment period; however, progesterone production in animals treated with hCG late in the luteal phase (days 10-16) steadily declined after the third treatment day. Expression of mRNA for P450SCC and 3 beta-HSD was markedly stimulated (P < 0.05) by hCG treatment early in the luteal phase. However, 3 beta-HSD message levels in corpora lutea from animals treated with hCG on days 10-16 were not different from those of day-16 control corpora lutea, whereas P450SCC mRNA was only minimally stimulated. There was a dramatic (P < 0.05) increase in mRNA levels for the aromatase enzyme and low density lipoprotein receptor in animals given hCG in both the early and the late luteal phase. In conclusion, there appears to be a differential responsiveness of the primate corpus luteum to hCG stimulation dependent upon luteal age. The loss in responsiveness to hCG in terms of maintenance of mRNA levels is reflective of the inability of the late luteal phase corpus luteum for continued progesterone biosynthesis in the face of heightened luteotropic stimulation.

Insulin and Insulin-Like Growth Factor-I Stimulate the 3α-Hydroxysteroid Dehydrogenase Activity of Human Placental Cytotrophoblasts*

The placenta is the primary source of progesterone during pregnancy. Because pregnant diabetic women are reported to have higher serum progesterone levels than nondiabetic pregnant women, we studied the roles of insulin and insulin-like growth factor-I (IGF-I) in the regulation of human cytotrophoblastic 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) activity. Incubation of cytotrophoblasts with insulin or IGF-I for 24 h significantly increased the ability of these cells to convert pregnenolone to progesterone by 75.8 +/- 16.5% (+/- SE) and 65.4 +/- 12.7%, respectively. Treatment with either insulin or IGF-I did not alter cytotrophoblastic production of 20 alpha-hydroxypregn-4-en-3-one (the primary metabolite of progesterone), thus demonstrating that these peptides increased progesterone synthesis (i.e. 3 beta HSD activity) rather than decreased progesterone catabolism. Insulin and IGF-I stimulated 3 beta HSD activity at concentrations as low as 50 and 10 ng/ml, respectively. Insulin- and IGF-I-stimulated 3 beta HSD activities were completely inhibited by concurrent treatment with either actinomycin-D or cycloheximide, suggesting that new mRNA and protein synthesis are required for these peptides to exert their effects. Blockade of the IGF-I receptor of cytotrophoblasts with alpha IR-3, a monoclonal anti-IGF-I receptor antibody, prevented the stimulation of 3 beta HSD activity by IGF-I, but did not alter insulin's stimulatory effect. Thus, the two hormones can each stimulate 3 beta HSD activity via activation of their respective receptors. These studies indicate that insulin and IGF-I can regulate human cytotrophoblastic 3 beta HSD activity in vitro. Since pregnant diabetic women manifest peripheral hyperinsulinemia, and IGF-I levels in fetal cord sera from diabetic pregnancies may be elevated, these observations may help explain the elevated serum progesterone levels associated with pregnancy in the diabetic patient.

High serum progesterone in hyperthyroid men with Graves' disease.

We measured serum progesterone in five men with hyperthyroidism due to Graves' disease. All had elevated serum progesterone levels before treatment with an antithyroid drug, and their serum progesterone levels declined concomitantly with their serum thyroid levels during treatment. Progesterone enhances estrogen's stimulation of mammary gland growth, and our findings suggest that progesterone may play a role in the gynecomastia that occurs in men with hyperthyroidism.

Progesterone secreting sertoli cell tumor of the ovary

A 33-year-old woman presenting with secondary amenorrnea and galactorrhea was found to have a Sertoli cell tumor of the ovary. The neoplasm also had a sex cord tumor with annular tubules (SCTAT) component. Further investigations revealed that in many respects the patient was endocrinologically pregnant. She had markedly elevated serum estrogen and progesterone levels and the endometrium demonstrated pronounced decidualization, but there was no evidence of actual pregnancy. Estrogen and progesterone were demonstrated by immunohistochemistry to be present in both the Sertoli cell and SCTAT portions of the tumor.

Effect of pinealectomy on heat-induced endocrine changes in female rats.

Exposure of pinealectomized rats to high ambient temperature (35 degrees C; PXH) brought about a diminution in pituitary weight and LH content when compared to their sham-operated peers (35 degrees C) or to pinealectomized controls (22 degrees C). Serum corticosterone level of PXH rats was significantly depressed while heat or pinealectomy alone had no effect. Mean oestrous cycle length was prolonged and blood serum progesterone was increased in the heat-exposed rats. However, the extended oestrous cycles and elevated serum progesterone levels of heat-exposed rats were depressed or abolished by pineal ablation. Thus, the pineal appears to exert a moderating effect on heat-induced endocrine changes in female rats. No changes were noticed in uterine and ovarian weights corrected for body weights either on the day of vaginal opening, at occurrence of the oestrous phase expressed as percentage of total oestrous cycle, or in N-acetyltransferase and hydroxyindole-O-methyltransferase activities.

The luteotrophic effects of estradiol and prolactin in the absence of LH in the hysterectomized, pseudopregnant rat.

The ability of estradiol and prolactin to substitute for LH as luteotrophins was investigated in Day 5 (Day 1 = ovulation)-hysterectomized pseudopregnant (PSP) rats. All animals received either a sc injection of oil, 1 pg estradiol (E-1), or 150 pg prolactin (PRL) on Day 9 in combination with either a normal horse serum (NHS) or LH antiserum (LHAS) injection. The ability of oil, E-1, or PRL to maintain luteal function was assessed by monitoring serum progesterone levels through Day 12 and their direct effects on the ovary monitored by measuring luteal and extra-luteal ovarian tissue concentrations of estradiol and progesterone on Day 12. NHS treatment in combination with either oil, E-1, or PRL main- tained elevated serum progesterone levels through Day 12 of PSP. LHAS/oil-treated rats underwent luteolysis while E-1 and PRL effectively maintained luteal function in LHAS- treated animals. PRL raised luteal and extraluteal ovarian estradiol concentrations com- pared to oil/NHS-treated controls and LHAS/oil-treated rats. E-1 induced an intraluteal rise in estradiol levels in LHAS-treated rats. While luteal progesterone concentrations fell fol- lowing oil/LHAS treatment, E-1 and PRL effectively counteracted this LHAS-induced fall. The results of these studies indicate that (i) E-1 and PRL can effectively replace LH as luteotrophins during PSP in the rat and (ii) that PRL and E-1 effectively maintain luteal levels of estradiol and progesterone following LH deprivation. It is suggested that E-1 and PRL may exert their luteotrophic actions by either an E-1-induced increase in PRL which, in turn, acts on the luteal cells to increase intraluteal estradiol concentrations, or by a direct effect of E on the corpus luteum to bypass the requirement for LH.

Demonstration of an early abortifacient effect of norethisterone (NET) in the primate (baboon)

A long-acting injectable contraceptive which provides continuous controlled release of norethisterone (NET) for three months following a single intramuscular injection was tested for antifertility effects in baboons using a low dose of microcapsules (total NET dose 2.5 mg; daily dose approximately 0.03 mg/day) which has no effect on ovarian function or ovulation. The continuous administration of NET during the cycle of conception had no effect on ovulation, fertilization or implantation as evidenced by the occurrence of nine pregnancies following 23 test matings. Pregnancy was diagnosed by the measurement of baboon chorionic gonadotropin hormone and the maintenance of elevated serum progesterone levels past the normal time of menstruation. Six of the nine pregnancies, however, ended in abortion between days 27 and 35 of pregnancy. The remaining three pregnancies continued to term and normal, healthy babies were delivered. Five control baboons included in this study became pregnant and all delivered normal, healthy infants. The results of this study demonstrate that early abortion should be considered as a mechanism of antifertility action for NET when administered continuously in low doses. These findings are contrary to the generally accepted explanation that low-dose synthetic progestins exert their contraceptive effect by inhibiting sperm transport and/or preventing implantation.

Effects of antibodies to progesterone on early pregnancy in rabbits.

Effects of antibodies to progesterone on early pregnancy were studied in rabbits. A total of 124 rabbits were employed to determine the effects of active immunization with progesterone-11alpha hemisuccinate couple to bovine serum albumin (P-BSA) on progesterone-dependent responses. P-BSA was administered by multiple intradermal injections in complete Freund's adjuvant. The rabbits were bled immediately after mating to obtain an estimate of the levels of antibodies to progesterone (anti-P) and were sacrificed 1.25, 3, 5, 6, 7, or 12 days later. Immunization with P-BSA did not cause marked changes in the numbers of corpora lutea, fertilization rate or the weights of corpora lutea, adrenal glands and ovaries. Mean serum progesterone levels in rabbits immunized with P-BSA were 8-15 times higher than controls on Days 3, 5, and 7 of pregnancy. There was a highly significant positive correlation (r=.85, p less than .01) between levels of anti-P at the time of mating and serum progesterone at necropsy. The elevation in serum progesterone and the correlation with the anti-P levels were not markedly affected by replacement therapy with medroxyprogesterone acetate (MPA). In P-BSA-immunized rabbits uterine weights were significantly lower than controls (p=.05 or less than .01). Inhibition of the progestational response of the uterus in the presence of markedly elevated serum progesterone levels indicates that progesterone bound to antibody was not readily available to target organ cells. Progestational changes in the uteri of P-BSA-immunized rabbits were delayed as compared to controls. Embryo survival in the immunized rabbits was lower (p less than .01) at Days 5, 6, 7, and 12 and embryo diameters were lower (p less than .01) at Days 5, 6 and 7 of pregnancy. Embryo survival rates and diameters at Day 5, 6, and 7 were both negatively correlated (p less than .05) with the levels of anti-P at the time of mating. The detrimental effects of P-Basa immunization on progesterone-dependent responses were completely or partially blocked by MPA.