Exogenous Progestins Research Articles

Alterations in embryo development in progestogen-supplemented cows administered prostaglandin F2?

The objective was to examine effects of elevated prostaglandin F 2α (PGF) on embryo development in cows supplemented with exogenous progestogen. Cows were artificially inseminated at estrus (Day 0) and a synthetic progestogen supplemented in the feed from Days 3 to 8. Cows were allotted randomly to receive either 15 mg PGF (TRT) or saline (CON) at 06:00, 14:00 and 22:00 h from Days 5 to 8. Blood samples were collected at 06:00 and 22:00 h from Days 5 to 8 for determination of progesterone and 13,14-dihydro-15-keto-PGF 2α (PGFM). Single embryos were recovered on Day 8, assigned a quality score, and stage of development recorded. Progesterone was lower from Days 5 to 8 in TRT versus CON cows ( P =0.0001). Concentrations of PGFM from Days 5 to 8 were elevated in TRT compared to CON cows ( P =0.0001). Embryo quality was reduced in TRT cows compared to CON cows ( P =0.059). Percentage of embryos considered transferable was decreased by administration of PGF ( P =0.003). Sixty-four percent of TRT embryos were retarded in development at Day 8, whereas 80% of CON embryos had developed to expanded blastocysts ( P =0.003). In conclusion, treatment of progestogen-supplemented cows with PGF reduced quality and retarded development of embryos. Decreased fertility in conditions causing elevated concentrations of PGF may result from altered embryo development and quality.

The effect of exogenous estradiol benzoate and altrenogest on uterine and ovarian blood flow during the estrous cycle in mares

In recent years, a positive relationship between genital perfusion and fertility has been established; in species other than horses, uterine and ovarian perfusion was improved by exogenous estrogen but impaired by exogenous progestin. The goal of the present study was to investigate the effect of exogenous estrogen and progestin on uterine and ovarian blood flow in cycling mares. Five Trotter mares were examined daily during three estrous cycles. Mares were given no treatment, altrenogest (0.044 mg/kg BW) orally from Day 0 (ovulation) to Day 14 and estradiol benzoate (5 mg i.m.) on Days 0, 5, and 10, in three cycles, respectively. There was no difference ( P>0.05) in the length of untreated versus estrogen-treated cycles (22.8±1.3 days and 23.2±1.5 days, respectively), but cycle length was increased ( P<0.05) in progestin-treated cycles (26.0±1.2 days). To facilitate comparisons among cycles with different lengths, data from Days 0 to 15 (diestrus) and from Days −6 to −1 (estrus) were analyzed. Transrectal Doppler sonography was used to evaluate blood flow in both uterine arteries and in the ovarian artery ipsilateral to the preovulatory follicle during estrus and ipsilateral to the corpus luteum during diestrus. Blood flow was assessed semiquantitatively using the pulsatility index (PI); high PI values indicated high resistance and a low perfusion and vice versa. An immediate effect of treatments occurred only after the administration of estradiol benzoate on Day 0; uterine PI values decreased ( P<0.05) between Days 0 and 1 and estrogen-treated mares but increased ( P<0.05) at the corresponding time in untreated cycles. Mean PI values for the uterine and ovarian arteries during both diestrus and estrus were higher ( P<0.05) in estrogen-treated versus untreated mares. Furthermore, mean uterine PI values during diestrus and estrus were higher ( P<0.05) in altrenogest-treated versus untreated mares. Neither estrogen nor altrenogest treatments had a significant immediate effect on ovarian PI values. Compared to untreated cycles, mean ovarian PI values were elevated ( P<0.05) only in the estrus following altrenogest administration. In conclusion, exogenous estrogen and progestin both decreased genital perfusion in cycling mares.

Endocrine diseases in dogs and cats: similarities and differences with endocrine diseases in humans

Over several millennia, humans have created hundreds of dog and cat breeds by selective breeding, including fixation of mutant genes. The domestic dog is unique in the extent of its variation in height, weight and shape as well as its behavior. It is primarily the relatively long persistence of high levels of growth hormone (GH) release at a young age that accounts for the large body size in giant breeds of dogs. Several of the endocrine diseases of humans are also known to occur as similar entities in dogs and cats. With some variations, this is true for conditions such as diabetes mellitus and the hypofunction syndromes of the thyroid and adrenal cortex. Also, the hyperfunction syndromes of hypercortisolism and hyperparathyroidism in dogs and cats have many similarities with their human counterparts. The exception seems to be Graves' disease. This condition, which is due to production of thyroid-stimulating hormone (TSH)-receptor antibodies, has not been observed in dogs and cats. The very common form of hyperthyroidism in cats is due to toxic adenomas. In the 1980s it was discovered that in dogs exogenous progestins and endogenous progesterone can induce GH excess. This GH excess originates form the mammary gland and may give rise to acromegaly and insulin resistance. GH production by the mammary gland is not unique to the dog. It has become clear that cats and humans also express the GH gene in the mammary gland. There is increasing evidence that this locally produced GH not only plays a role in the morphologic changes of the mammary gland associated with the ovarian cycle and gestation, but that it is also involved in the development of breast cancer. In dogs, induction of mammary GH production by progestin administration allows for treatment of GH deficiency.

Low-grade endometrial stromal sarcoma: hormonal aspects☆

Objective The goal of this work was to determine whether exposure to estrogen following treatment of low-grade endometrial stromal sarcomas affects clinical outcome. Methods Twenty-two patients with low-grade endometrial stromal sarcomas were reviewed to determine whether they were exposed to exogenous or endogenous estrogen and/or progestins following their diagnosis and whether exposure to these hormones might have influenced their prognosis. Estrogen receptor (ER) α and β and progestin receptor (PR) status were analyzed from paraffin-embedded tissue by immunohistochemistry and ER mRNA was measured in fresh tissue by reverse transcription polymerase chain reaction (RT-PCR). Results Ten of the twenty-two patients with low-grade endometrial stromal sarcomas developed recurrent disease. Four of five patients (80%) who received estrogen replacement therapy (ERT) recurred. Four of eight patients (50%) with retained ovaries recurred. Eight of the ten specimens available for analysis were positive for ERα, none were positive for ERβ, and 9 of 10 were positive for PR. Four of thirteen patients who received progestins as adjuvant therapy recurred, compared with 6 of 9 patients who did not receive progestins (31% vs 67%). Eight recurrences were treated with progestin therapy and 7 (88%) of them had either stable disease (3/8, 38%) or complete response (4/8, 50%). Conclusions Our results suggest that ERT may be detrimental in patients with low-grade endometrial stromal sarcoma. Retention of normally functioning ovaries, on the other hand, may not significantly affect the recurrence rate following hysterectomy alone in Stage I patients. The lack of ERβ expression in endometrial stromal sarcomas compared with normal endometrial stromal cells suggests that loss of ERβ may be a marker for malignancy. Progestin therapy should be routinely considered for adjuvant therapy and for the treatment of recurrent endometrial stromal sarcomas.

Treatment of Fibroadenomatous Hyperplasia in Cats with Aglépristone

Fibroadenomatous hyperplasia (FAH) is characterized by a rapid proliferation of mammary stroma and duct epithelium of 1 or more glands and predominantly affects younger female cats. Endogenous progesterone and exogenous progestogens play an important role in the genesis of FAH. The presence of progesterone receptors in fibroadenomatous tissue allows for targeted endocrine therapy with progesterone receptor blockers. We report on 22 young cats with FAH, none of which had responded to the withdrawal of progestogens or ovariectomy. The common signs were tachycardia (11 cats); skin ulceration, painful mammary glands, or both (16 cats); lethargy (8 cats); and anorexia (4 cats). The cats were treated with subcutaneous injections of the progesterone receptor blocker aglépristone on 1 (7 cats, 20 mg/kg) or 2 consecutive days (15 cats, 10 mg/kg/d) once weekly. All but 1 cat responded with a complete and lasting remission of signs after 1–4 weeks of treatment. Two cats had a short‐term skin irritation at the site of the aglépristone injection. Two pregnant cats with FAH aborted after treatment with aglépristone and subsequently developed endometritis. In conclusion, the results of this study demonstrate that FAH in cats can be treated successfully with the progesterone receptor blocker aglépristone.

Reproduction in female yaks ( Bos grunniens) and opportunities for improvement

This paper reviews seasonal breeding, puberty, postpartum anestrus, embryonic loss and calf survival and their constraints in female yaks. Methods for improving fertility in postpartum yak cows are also considered. Yaks are seasonal breeders with mating and conception restricted in the warm season. Puberty generally occurs in the 2nd to the 4th warm season following birth, i.e. between 13 and 36 months of age. The cows usually have a long postpartum anestrus period; only a small proportion of the cows return to estrus in the 1st breeding season after calving, most come into estrus in the 2nd and 3rd years. Nutritional status is the most important determinant of reproduction in female yaks. Reproductive success is a direct result of the availability of pasture determined by climate, season, and management practices. Milking delays puberty by reducing milk intake (restricted suckling) and growth rate for the calf. Milking interferes with grazing and prolongs the duration of postpartum acyclicity in cows. Calves born early in the season have a longer suckling season than those born later in the season before the onset of winter. Thus, they can have their first cycle in the breeding season of the following year, while those born late in the season may not have their first estrus until 25 or 26 months of age. Cows calving early in the season are more likely to return to estrus in the year of calving because they have a longer period to recover from the demand on body reserves before the onset of winter. Inbreeding in smallholder yak farms is also discussed and minimizing inbreeding by exchanging bulls among different herds is suggested. Reproductive efficiency can be improved by nutritional supplementation during the winter, however, the most cost-effective and practical strategy for this needs to be determined. Early weaning or restricted suckling may shorten the duration of postpartum acyclicity, however, it is impractical due to reduced growth rates and increased winter mortality of early weaned calves. A single treatment with either GnRH, or PGF 2α+GnRH can successfully induce estrus in yak cows that calved in previous years (with or without calf) but did not calve in the current year, however, it has little effect in cows nursing a calf born in the current year. The effects of administration of exogenous progestogens plus GnRH on the fertility of yak cows are worthy of further study.

Control of VEGF expression by progestins

A recently published report suggests that, in human breast cancer cells, the expression of vascular endothelial cell growth factor (VEGF) (one of the most potent angiogenesis factors currently known) is stimulated by the presence of progestins. Salman M. Hyder et al. (University of Texas Health Science Center, Houston, TX, USA), writing in the International Journal of Cancer (15th May), suggest that anti-progestins might play a role in preventing tumor progression in patients with breast cancer.

Effects of oral contraceptives on breast epithelial proliferation.

The association between oral contraceptive (OC) use and breast cancer is not fully understood. Estrogen is a known mitogen to breast epithelial cells, but there is still a controversy about the effect of added progestogens. Fine needle aspiration (FNA) biopsies were used to assess epithelial proliferation in normal breast tissue from 106 healthy premenopausal women with and without oral contraceptives. In 26 women biopsies were performed before and after 2 months of OC use. Proliferation, expressed as percentage of Ki-67/MIB-1 positive cells, was correlated to endogenous progesterone, androgenic/anabolic compounds and exogenous progestogen. We found a higher proliferation (p = 0.03) in OC users compared to non users, with mean values of 4.8% and 2.2%, respectively. There was a positive correlation between proliferation and progesterone levels in non-users and with serum levonorgestrel concentrations in women using OCs containing this progestogen (rs = 0.43, p = 0.02). Women using OCs had significantly lower serum androgen levels compared to naturally cycling women and free testosterone levels displayed an inverse relation to breast epithelial proliferation. There was a marked variation in the response to exogenous sex steroids. In certain women after 2 months of OC use, the percentage of MIB-1 positive cells was as high as 40-50%. The results add to the growing evidence that progestogens may be mitogenic in breast tissue. Increased proliferation during hormonal contraception should be regarded as an unwanted and potentially hazardous side effect. Efforts should be made to define hormonal contraceptive regimens which minimize breast epithelial proliferation and to identify those women with the most pronounced proliferative response.

Small atypical leiomyomas: report of two cases

We describe two small atypical leiomyomas. The first was a 6-mm de novo lesion in a 53-year-old woman. The second was a 3-mm focus in a 12-mm leiomyoma in a 45-year-old woman. Both lesions showed moderate atypia and a mitotic rate of six per 10 high-power fields. Coagulative necrosis was not seen. Neither patient had received exogenous oestrogen or progestogen. There was no evidence of recurrence or metastasis in either patient after 60 months of follow-up. Our report provides evidence that atypical uterine leiomyomas may arise either de novo or within a leiomyoma.

The structure of endometrial microvessels.

Recent studies have provided substantial evidence to highlight abnormalities in the structure of endometrial microvessels in users of progestogen-only contraception. Structural changes alone are unlikely to lead to breakthrough bleeding, but appear to be associated with a reduction in vessel integrity, and may reflect alterations in the control and growth of endometrial microvessels in those exposed to exogenous progestogens. In users of low-dose progestogens, immunohistochemical studies have demonstrated changes in superficial endometrial vascular morphology, density and in endometrial migratory cell populations. In Norplant users the endometrial endothelial basal lamina is deficient in the initial months of exposure, when bleeding problems are most common. The basal lamina refers to the very thin structure consisting mostly of collagen IV and laminin seen underlying endothelial and epithelial cells at the electron microscope level. In addition, hysteroscopic studies have demonstrated increased fragility of superficial vessels. Changes in endometrial microvascular anatomy associated with normal menstruation have been reviewed, and are compared with those seen following contraceptive steroid exposure. Likely mechanisms of breakthrough bleeding such as increased superficial vascular fragility and the possible alterations in endometrial vascular structure leading to this are discussed.

Ability of induced corpora lutea to maintain pregnancy in beef cows.

Experiments were conducted in beef cows without a primary CL, in which pregnancy had been maintained with exogenous progestogen. In preliminary trials, replacement CL induced ipsilateral to the embryo and after, rather than before, d 36 of pregnancy, maintained more pregnancies after withdrawal of exogenous progestogen (13/13 vs 2/6; P < 0.05). In Exp. 1, in cows with replacement CL induced by treatment with hCG on d 28 of pregnancy, treatment with flunixin meglumine on d 31 through 37 did not increase maintenance of pregnancy. Experiment 2 was conducted to evaluate directly the effects of concentrations of PGF2alpha and estradiol-17beta during d 31 through 35 of pregnancy on maintenance of pregnancy by replacement CL induced between d 28 and 31. In cows that maintained pregnancy while progestogen was provided, maintenance of pregnancy after withdrawal of exogenous progestogen tended to be greater with high (5/5) than with low (2/6; P < 0.10) concentrations of PGF2alpha and greater with low (6/7) than with high (2/6; P = 0.10) concentrations of estradiol-17beta. Secretion of progesterone by replacement CL was greater (P < 0.05) in cows with high than in those with low concentrations of PGF2, during d 31 through 35. Prostaglandin F2alpha may facilitate attachment of the bovine embryo (d 30 to 40) in a manner similar to that reported for implantation in other species. Cows that did not form CL in response to hCG on d 28 to 31 responded well when retreated after d 36. Again, maintenance of pregnancy was greater when replacement CL were induced after (9/9) rather than before d 36 (8/16; P < 0.05).

The effect of one injection of Depo-Provera® on the human vaginal epithelium and cervical ectopy

Two studies in rhesus monkeys have shown that progesterone implants, Depo-Provera® and Norplant®, were associated with vaginal thinning. Progesterone implants have also been associated with an increased risk of simian immunodeficiemcy virus (SIV) acquisition. This study in 16 women was done to assess vaginal epithelial thickness and number of cell layers from biopsies taken in the untreated follicular and luteal phases, and at 1 month and 3 months after administration of Depo-Provera. There was no significant change over time in either parameter from biopsies obtained in the luteal phase compared with those at either time after Depo-Provera administration. There was also no change in the mean number of Langerhans cells in vaginal wall specimens and no change in cervical ectopy. It appears that women do not respond to exogenous progestins with the dramatic vaginal thinning seen in rhesus monkeys.

Effects of administration of oxytocin on embryonic survival in progestogen supplemented cattle

Embryonic survival after administration of oxytocin (OT) was examined in 42 beef cows. All cows were bred (Day 0) and randomly assigned to receive either 25 mL saline (CON; n = 10), 100 IU OT + 20 mL saline (OT; n = 12), 100 IU OT + 1 g flunixin meglumine (OT + FM; inhibitor of prostaglandin endoperoxide synthase; n = 10), or 100 IU OT + lutectomy (OT + LUT; n = 10) administered (i.m.) at 8-h intervals on Days 5–8 after mating. Lutectomies were performed by transrectal digital pressure prior to initiation of treatments (0600, Day 5). All cows were fed 4 mg/head/day of melengesterol acetate (an orally administered exogenous progestogen) through Days 3–30 and were bled by jugular venipuncture at 0600 and 0700 h on Day 5 for determination of 13,14-dihydro-15-keto-PGF 2a (PGFM). Pregnancy rates, as determined by transrectal ultrasonography at Day 30, were reduced in OT (33.3%) and OT + LUT (30%) groups compared to CON and OT + FM (80%; p ≤ 0.03). Number of short cycles were increased in OT ( n = 6/12) group compared to CON ( n = 0/10; p ≤ 0.009) and OT + FM ( n = 1/10; p ≤ 0.045). Mean change in PGFM from the 0600 to 0700 h bleed was different ( p ≤ 0.01) between the OT + LUT (31.6 ± 11.0 pg/mL) group versus CON (−11.2 ± 10.6 pg/mL) and OT + FM (−13.8 ± 10.6 pg/mL) groups. Administration of oxytocin appears to decrease embryonic survival by stimulating uterine PGF 2a. Thus, previous reports indicating that removal of the corpus luteum during progestogen supplementation and prior to PGF 2a administration increases embryonic survival can be explained through interruption of the luteal oxytocin-uterine PGF 2a feedback loop.

Effects of sex steroids on proliferation in normal mammary tissue

Numerous women are treated with a combination of oestrogen and progestogen for contraception and hormone replacement therapy worldwide. A possible increased risk of cancer in target organs has been discussed vividly for many years. While oestrogens are clearly mitogenic for breast epithelial cells, there has been considerable uncertainty about the effects of progestogens. This article reviews current knowledge on this field, including our own data. Oestrogen receptors are down-regulated during the luteal phase, while progesterone receptors remain at a high level throughout the menstrual cycle. According to most studies, in vivo proliferation of normal breast epithelial cells is higher during the luteal phase in the vast majority of women. Normal breast tissue can convert oestrone sulphate to oestradiol. A negative correlation between the levels of circulating oestradiol and the enzyme converting oestrone into oestradiol suggests a local regulatory mechanism of tissue oestradiol formation. Serum progesterone levels correlate positively with sulphatase activity while 19-norsteroid progestogens may be inhibitory. We found that long-term continuous combined hormonal treatment with conjugated equine oestrogens and medroxyprogesterone acetate induced a proliferative response in the breasts of surgically postmenopausal macaques. The effect of combined treatment was more pronounced than that of oestrogen treatment alone. Both endogenous progesterone and exogenous progestogens increase proliferation of breast epithelial cells. Exogenous progestogens down-regulate both oestrogen and progesterone receptors. Oestrogen and progestogens may have both direct and indirect stimulating effects on proliferation. The finding of a positive correlation between insulin-like growth factor I messenger RNA and proliferation found in hormonally treated women with low receptor levels suggests the possibility of nonreceptor-mediated effects of sex steroids on proliferation, which needs to be investigated further.

Equine chorionic gonadotropin regulates luteal steroidogenesis in pregnant mares.

The onset of eCG secretion in pregnant mares coincides with an increase in luteal steroid production and a relative shift toward androgen and estrogen synthesis. However, a cause-effect relationship between eCG and the shift in luteal steroidogenesis has not been demonstrated. In this study, we have investigated the effect of eCG on steroid production by the corpus luteum (CL) during equine pregnancy. All mares were supplemented with 44 mg altrenogest (a progestogen) per day on Days 18-50. Increasing doses of eCG were administered on Days 26-28, before the onset of endogenous eCG secretion, to four mares with and four mares without a functional CL (prostaglandin F2alpha administered on Day 18). Four mares with a functional CL received no exogenous eCG. In eCG-treated mares without a functional CL, progestin, androstenedione, and estrogen concentrations did not significantly increase after exogenous eCG administration or endogenous eCG secretion. In eCG-treated mares with a functional CL, progestin and estrogen production increased significantly after exogenous eCG administration and endogenous eCG secretion, whereas androstenedione concentrations tended to increase following exogenous eCG and increased significantly following endogenous eCG secretion. In mares with a functional CL that did not receive exogenous eCG, progestin and estrogen concentrations increased and androstenedione concentrations tended to increase only after the onset of endogenous eCG secretion. These data demonstrate that the increase in luteal steroidogenesis that coincides with the onset of eCG secretion is induced by eCG and results in an increase in luteal androgen and estrogen synthesis. Our findings support the hypothesis that eCG has a luteotropic action in pregnant mares.

Regulation of follicular activity and ovulation in ewes by exogenous progestagen

The success of estrus synchronization programs using progestagen sponges, particularly for fixed-time Al, varies considerably. In view of the recent evidence in cattle that exogenous progestins alter follicular dynamics, it may be that the stage of the estrous cycle at which the synchronization protocol is begun. affects the synchrony of ovulation. The goal of this study was to evaluate the effect of medroxyprogesterone acetate (MAP) intravaginal sponges on follicular dynamics, luteal function and interval to ovulation when inserted at 3 stages of the estrous cycle. Sponges were inserted for 12 d beginning on either Day 0, 6 or 12 (n=5) following ovulation. Ovarian activity was monitored using real-time ultrasound imaging during the treatment and the post-treatment estrous cycles. Information from the post-treatment cycle was used as a baseline to compare with the treatment cycle. Most ewes (79%) in the post-treatment cycle exhibited 3 follicular waves in an estrous cycle of 16 d, with the second wave follicles having smaller diameter (P <0.001). Treatment with MAP increased the number of follicular waves from 3 to 4 or 5 when sponges were inserted on Days 6 and 12, respectively. Size of the largest follicle was smaller (P >0.01) in waves in the early and middle of the 12-d MAP treatment period when compared with the last 4 days. This effect was most pronounced when endogenous progesterone concentrations were elevated concurrently with the presence of the sponge. Persistence of the ovulatory follicle was increased (P <0.001) when sponges were inserted on Day 12, the only treatment where these follicles were under the influence of MAP in the absence of functional corpora lutea. Follicles were regressing at sponge removal in the Day 6 treatment, which resulted in a delay in emergence of ovulatory follicles, the LH surge and ovulation (P < 0.08) in relation to Day 0 and Day 12. Treatment with MAP sponges does not adequately synchronize estrus and ovulation among cyclic ewes due to the different follicular patterns that result depending on the stage of cycle at the time of sponge insertion.

Does Puerperal Norplant Insertion Predispose Teens To Postpartum Depression?• 18

Progestins alter central neurotransmitter levels and can cause depression. Administration of exogenous progestins during the puerperium could exacerbate postpartum depression. We hypothesized that teens who have a Norplant inserted during the puerperium are more apt to become depressed then those who do not. We tested this hypothesis by comparing the incidence of depression (score≥17 on the CESD-depression scale) 1 year postpartum in 212, consecutively delivered, ≤18 yr olds. Participants were divided into 3 groups: 100 (47%) had Norplant inserted during the puerperium; 72 (34%) had Norplant inserted during the next 10 mos; and 40 (19%) used other contraceptives (40% pills; 17% condoms; 43% nothing). Bivariate analyses revealed no group differences in: age (17±1 yrs), medicaid use (93% users), parity (80% primiparas); school drop out (35%), race/ethnicity (47% minority), the prevalence of teen parents in the environment, or risk factors for postpartum depression(depression before/during pregnancy, adverse pregnancy outcome, no longer involved with baby's father, and inadequate social support). Teens who had puerperal Norplant insertions were more apt to have been abused in the past(p=.01) & less apt to have new boyfriends (p=.03). Complaints of dysphoria and moodiness were common among Norplant users (70%), but puerperal Norplant insertion was not associated with depression. The mean CESD scores of puerperal Norplant users and users of other contraceptives were significantly lower than those of other Norplant users (13±11 v 11±8 v 18±13, respectively; p=.004), as was the incidence of depression (30% v 23% v 45%, respectively; p=.04). Multivariate analyses did not alter this finding. Postpartum contraceptive group remained the most important determinant of CESD-score and depression. This study shows that progestins are more apt to cause depression when administered after the puerperium. The pathophysiologic mechanisms underlying this intriguing finding remain to be elucidated. We hypothesize that this differential effect of exogenous progestins on these young mothers' moods is related to the resumption of endogenous ovarian cycling.

Thrombosis and Heart Attacks with Contraceptive and Menopausal Hormones

It has been known since the 1960s that exogenous progestogens and oestrogens (the pill and hormone replacement therapy (HRT)) increase the risk of both venous and arterial thrombosis. Claims that HRT prevents heart attacks in older women are mostly based on non-randomized epidemiological studies. Healthier women are selected for hormone taking and those with established diseases are excluded, either before or during the studies. Risks may be greatly underestimated. Thrombosis and heart attacks are evident after short-term exposure to hormones and relate mainly to immediate changes in blood vessels and clotting factors. Recent studies record increases of 4-400 times for thrombosis and heart attacks.

Addiction to Oestrogen and Progesterone

Exogenous oestrogens, progesterone and progestogens are prescribed for a variety of conditions in spite of lack of proof of efficacy. Supraphysiological levels of oestrogen and progesterone have occurred in some individuals due to demands for increased doses. Brain function, amine metabolism and nutritional status can be altered by exposure to exogenous hormones. Direct and indirect mechanisms of psychoactivity may induce dependency. A doctor's severe 'menopausal type' withdrawal symptoms after exposure to oral conjugated oestrogens (Premarin 625 mu g/day) are reported.

Insulin-like growth factors in endometrial function

Growth factors and related peptides are believed to mediate and modulate the actions of hormones at their target tissues through autocrine/paracrine mechanisms. Endometrial stromal cells produce insulin-like growth factors I and II (IGF-I and IGF-II) as well as the high-affinity IGF binding proteins (IGFBPs), whereas epithelial cells and, in a lesser amount, also stromal cells contain cell membrane receptors for IGFs. IGFs have proliferative, differentiative and metabolic effects. Estrogen stimulates IGF-Igene expression in the endometrium, and IGF-I is assumed to mediate estrogen action. IGF-II gene expression is associated with endometrial differentiation. All six high-affinity IGFBPs are expressed in human endometrium, the most abundant being IGFBP-1. This is secreted by predecidualizedldecidualized endometrial stromal cells in late secretory phase endometrium and pregnancy decidua, i.e. under the action of progesterone. The primary negative regulator of IGFBP-1 expression is insulin, by inhibiting IGFBP-1 transcription. IGFBP-1 inhibits the receptor binding and biological actions of IGF-I in the endometrium and in cultured human trophoblastic cells. These findings support the view that the IGF system has autocrine and paracrine functions in the regulation of endometrial proliferation and differentiation. After implantation, decidual IGFBP-1 may regulate IGF actions at the embryo—endometrial interface, since trophoblast cells contain IGF receptors and express IGF-II, but do not express IGFBP-1. Clinical conditions that are known to increase the risk of endometrial cancer are all characterized by the absence of IGFBP-1. Thus, like unopposed estrogen, unopposed IGF-I action may also lead to uncontrolled endometrial proliferation and favor the development of endometrial cancer. The measurement of mRNAs encoding the IGF system might provide a novel tool to evaluate the endometrial response to endogenous and exogenous estrogens and progestins at the molecular level.