hMG Treatment Research Articles

Comparison of ovarian stimulation regimens for in vitro fertilization (IVF) with and without a gonadotropin-releasing hormone (GnRH) agonist: Results of a randomized study

In order to diminish the cancellation rate due to a premature endogeneous LH surge and/or to a poor ovarian response and thus increasing the pregnancy rate, a GnRH agonist (Buserelin) was applied in patients starting their first ovarian stimulation with gonadotropins for IVF. All patients suffered from tubal infertility and were not older than 40 years. Each woman was allocated randomly to one of three groups: the conventional treatment with hMG alone (group I), patients from group II started the hMG treatment shortly after the LH rise caused by the GnRH agonist and patients in group III commenced the hMG treatment when an hypogonadotropic state was achieved after a long treatment of Buserelin. All male partners had a normal spermiogram. A reduction of poor responders to the superovulation is seen in the short-term group (6%), compared with the other two groups (14%). In some cases from group III ovarian cyst formation led to the cancellation of the treatment. The long-term group differs significantly from the other two in the duration of the gonadotropin stimulation and the number of ampoules hMG used. A severe ovarian overstimulation syndrome was not observed. There is no difference in the number of retrieved oocytes and the fertilization rate among the three groups. The pregnancy rate per cycle or per patient in the group with a short-term GnRH-agonist regimen is significantly higher compared to that of the group using the conventional hMG treatment.

Protein concentration in pre-ovulatory follicular fluid related to ovarian stimulation

Sixty follicular fluids obtained from 26 women with either clomiphene citrate and human menopausal gonadotropins (hMG) or hMG-induced ovulation were analyzed for the contents of total proteins, fibrinogen, plasminogen, antithrombin III, ceruloplasmin, α-2 macroglobulin, α-1 antitrypsin and immunoglobulins (IgG, IgA, IgM). Concentrations of these proteins was correlated to the type of ovarian follicle growth induction. Follicular fluids from patients stimulated with clomiphene citrate-hMG contained significantly higher concentrations of ceruloplasmin than those treated with hMG alone. No significant differences in the concentrations of other proteins were noted between the two types of ovarian induction. A multivariate data analysis resulted in three Varimax factors (VRX I) suggesting that proteins with antiprotease activity in the follicular fluid may play a role in human follicle maturation. Follicular fluid Ig may reflect the degree of follicular wall permeability under hMG treatment. Accordingly, it may be assumed that a combination of different proteins described by VRX factors could be used for evaluation of ovarian stimulation.

Serum Inhibin Concentrations before and during Gonadotropin Treatment in Men with Hypogonadotropic Hypogonadism: Physiological and Clinical Implications*

We measured by RIA the inhibin concentrations in the sera of 20 men with hypogonadotropic hypogonadism before and during treatment with gonadotropins in order to determine the role of gonadotropins in the control of inhibin secretion and the utility of the serum inhibin concentration in assessing the spermatogenic response to gonadotropin treatment in these patients. Before treatment the mean serum inhibin concentration in the 20 hypogonadotropic men as a group (391 +/- 49 U/L) was significantly lower (P less than 0.001) than that in 27 normal men (741 +/- 52 U/L). In the 7 men whose hypogonadism was of postpubertal onset, the mean serum inhibin concentration (559 +/- 69 U/L) was not significantly lower than that in normal men. In the 13 men whose hypogonadism was of prepubertal onset, the serum inhibin level was significantly lower [381 +/- 74 U/L (P less than 0.01) in the 7 without a history of cryptorchidism and 207 +/- 46 U/L (P less than 0.01) in the 6 with a history of cryptorchidism]. All 20 patients were azoospermic or severely oligospermic and had distinctly subnormal serum testosterone concentrations, even those whose serum inhibin values were normal. In the 7 patients with postpubertal hypogonadism, treatment with hCG alone for 6 months increased the serum testosterone concentration and maximum sperm count to normal, even though the previously normal inhibin concentration was not increased further. In the 13 patients with prepubertal hypogonadism, treatment with hCG alone increased the serum inhibin concentration, and combined treatment with hCG and human menopausal gonadotropin (hMG) increased inhibin further, to well within the normal range (742 +/- 143 U/L) in the patients without a history of cryptorchidism and to just within the normal range (487 +/- 96 U/L) in those with such a history. In the 7 patients with prepubertal hypogonadism but no history of cryptorchidism, treatment with hCG and hMG increased the maximum sperm count to normal in 5. In the 6 patients with prepubertal hypogonadism who did have a history of cryptorchidism, hCG and hMG treatment produced a normal sperm count in only 1. Of 12 patients whose serum inhibin level was more than 300 U/L before treatment, 11 developed a normal maximum sperm count in response to treatment, but of 8 patients whose inhibin concentration was less than 300 U/L before treatment, only 2 developed a normal sperm count in response to treatment (P less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)

Contraceptive potential of RU 486 by ovulation inhibition: I. Pituitary versus ovarian action with blockade of estrogen induced endometrial proliferation

In previous studies, RU 486 administration arrested spontaneous folliculogenesis. To investigate the central versus peripheral effects of RU 486 on the ovarian/menstrual cycle, including endometrial proliferation, RU 486 was administered daily (10 mg/kg/day, im) from menstrual cycle day 3 or 7 to day 25 in normal adult cynomolgus monkeys receiving hMG treatment (37.5 IU/day) from days 3-8 (n = 6). RU 486 administration with hMG/hCG therapy did not inhibit ovarian response, as evidenced by steroidogenesis and ovulation. Nine of 23 oocytes retrieved by lavage or follicular aspiration at laparotomy after ovulation induction were morphologically classified as mature preovulatory status. Whereas an endometrial biopsy performed on cycle day 25 in control monkeys revealed an in phase mature secretory endometrium, histologic sections from RU 486 plus hMG/hCG treated females uniformly demonstrated atrophic to weakly proliferative endometrium on cycle day 25, despite serum estradiol levels greater than 300 pg/ml. Three months after the initial 25-day study endometrial biopsies revealed persistent atrophic endometrium, even though repeated ovulation induction with hMG/hCG therapy elevated serum estrogen concentrations. The findings prevailed whether RU 486 treatment began on cycle day 3 or 7. The intermenstrual interval was significantly (P less than 0.01) lengthened by RU 486 treatments (28.5 +/- 2.0, control vs 131.3 +/- 11.5 days, RU 486). In summary, RU 486 consistently blocked ovulation unless hCG was provided and elicited a persistent retardation of early proliferative endometrium when administered daily beginning in early or mid-follicular phase. The normal mitogenic effects of elevated ovarian estrogen secretion on endometrial tissue were quelled, uniformly resulting in amenorrhea. The long-lasting action of RU 486, causing ovulation inhibition and atrophic endometrium, may be due to the depot effect of im injection. In addition, RU 486 did not prevent ovarian steroidogenesis, ovulation or oocyte maturation when an ovulation induction regimen of hMG/hCG was given. These findings show that RU 486 prevented ovulation by diminishing pituitary gonadotropin secretion, rather than by direct effects on ovarian folliculogenesis, and induced amenorrhea by inhibiting estrogen-induced endometrial proliferation.

The potentiating effect of growth hormone on follicle stimulation with human menopausal gonadotropin in a panhypopituitary patient

A hypogonadotropic patient with primary pituitary insufficiency who has been previously treated for four cycles with hMG/hCG for ovulation induction is described. The hMG consumption was 76 to 96 ampules/cycle. Addition of GH (16 to 24 units/cycle) to hMG treatment was associated with a significant diminution in hMG consumption (35 to 36 ampules/cycle). The patient conceived on the second cycle of combined hMG/GH/hCG treatment. The possible role of GH as an adjunct to gonadotropin treatment is discussed, as well as the possible mechanisms of GH effects on the ovary.

Clinical experience in the induction of ovulation and pregnancy with pulsatile subcutaneous administration of human menopausal gonadotropin: a low incidence of multiple pregnancy

The pulsatile subcutaneous administration of human menopausal gonadotropin (hMG) or follicle-stimulating hormone (FSH) was used for induction of ovulation in 26 patients with hypothalamic/pituitary amenorrhea or polycystic ovary syndrome (PCO). Ovulation was observed in 116 (90.6%) of 128 treatment cycles, and 15 (16 treatment cycles) of 26 patients became pregnant. All 14 fetuses, excluding two pregnancies interrupted spontaneously at weeks 6 and 9, were singleton conceptions. Ovarian hyperstimulation was observed in 15.6% of treatment cycles. Five patients with PCO who failed to conceive on the hMG regimen also received pulsatile FSH administration. Although ovulation rates in PCO patients did not differ significantly between the hMG (88.1%) and FSH (88.2%) regimens, a significant reduction in the average dose of FSH (P less than 0.05) was observed with pulsatile FSH administration. Furthermore, the number of patients who conceived during the FSH regimen was significantly greater than that found with hMG treatment. The present data demonstrate that pulsatile subcutaneous administration of hMG or FSH is effective in induction of successful ovulation and establishment of singleton pregnancy in patients with various types of anovulatory infertility.

Efficacy of human menopausal gonadotropins as therapy for abnormal cervical mucus

Traditional therapies for abnormal cervical mucus, other than timed intrauterine insemination, are noteworthy for being ineffectual. Patients (n = 27) with documented abnormal Insler scores in repetitive cycles and failure to conceive with traditional treatments were screened with conjugated equine estrogens (CEE) for estrogen responsiveness of the cervix. Only 5 patients were found unresponsive. Seventeen patients with CEE-responsive cervices then were treated with human gonadotropins (hMG), initially 1 ampule days 5 to 11. If the mucus failed to improve, the hMG was increased to standard doses. Eight patients responded to 1 ampule hMG with improved mucus and conception. The remainder required 2 ampules hMG. In patient cycles with corrected cervical mucus, the viable fecundibility (fv) was 0.35. This is significantly higher than predicted for this population (fv = 0.09; P less than 0.01). In all, 14 of 17 patients conceived viable pregnancies during hMG treatment. It is concluded that graduated hMG is efficacious in treating patients with abnormal cervical mucus responsive to CEE. It is preferable to either in vitro fertilization or gamete intrafallopian transfer, based on both cost and efficacy for most patients.

HCG-Treatment Alone is Unsufficient for Restitution of Spermatogenesis in a State with Arrest at the Spermatogonial Level

In an infertile man with azoospermia and arrest at the spermatogonial stage, hCG treatment alone improved the spermatogenesis but not beyond the primary spermatocyte stage. During hCG treatment steroid conversion in vitro in testicular biopsy material, as well as serum testosterone concentrations increased dramatically. When hMG treatment was added, spermatogenesis was complete. Combined hCG/hMG treatment seems to be an efficient therapy in well-selected infertile men, whereas increased testosterone production induced by hCG-treatment may be insufficient for restitution of spermatogenesis.

IVF: Induction of ovulation in poor responders

All IVF programs have a consistent rate of failure in inducing ovulations. Pharmacological induction of ovulation is otherwise crucial for an IVF program because of the need for more than one ovum. Since it is well known that the best candidates for HMG treatment are hypogonadotropic women a short reversible hypogonadotropic state was induced in IVF patients by LH-RH agonist (Buserelin). Superovulation was then achieved with very high initial doses of FSH (Metrodin) in order to maximize the ovarian response. This technique used in 116 IVF women induced a satisfactory follicle growth even in 70% of the patients already poorly responsive to HMG stimulation.

Stimulation of Ovarian Follicular Maturation with Pure Follicle-Stimulating Hormone in Women with Gonadotropin Deficiency

According to the 2-cell theory, ovarian steroidogenesis requires the coordinate action of both FSH and LH. To evaluate the relative importance of these hormones in follicular maturation, a randomized cross-over study was performed in 10 women with complete gonadotropin deficiency (absence of pulsatile LH secretion and no LH response to LHRH). Five women were treated with highly purified FSH (LH bioactivity, 0.09%) and 3 months later with human menopausal gonadotropin (hMG; LH bioactivity, 65%), each given for 10 days at a daily dose of 225 IU FSH, im. The sequence was reversed in the other 5 women. hCG (5000 IU) was administered im 24 h after the last injection of FSH or hMG. Plasma estradiol (E2), estrone (E1), androstenedione (A), testosterone, LH, and FSH concentrations and urinary LH and FSH were measured daily by RIA. Ultrasonography was performed during each treatment and 2 days after each hCG injection. After FSH treatment, mean plasma and urinary FSH levels increased, mean plasma LH did not change, and urinary LH increased slightly but not significantly from 91 +/- 32 (SE) to 164 +/- 55 mIU/24 h (10(-3) IU/24 h). After hMG treatment, mean plasma and urinary LH and FSH levels increased accordingly. The mean basal plasma E2 [11 +/- 1 pg/mL (40 +/- 4 pmol/L)] and E1 [14 +/- 4 pg/mL (52 +/- 15 pmol/L)] levels increased after FSH treatment to 207 +/- 69 pg/mL (760 +/- 253 pmol/L) and 82 +/- 21 pg/mL (303 +/- 78 pmol/L), respectively (P less than 0.01), but plasma A did not change. In response to hMG, the mean plasma E2, E1, A, and testosterone levels increased more than during FSH treatment. Ultrasonography revealed multiple preovulatory follicles (greater than or equal to 16 mm) in 2 women after hMG and 1 woman after FSH treatment; therefore, hCG was not administered. In 3 women given FSH, hCG did not induce ovulation. hCG induced ovulation in 8 women given hMG and in 6 women given FSH, based on ultrasonography and plasma progesterone levels. Thus, in the presence of profound gonadotropin deficiency pharmacological doses of FSH, with minute LH contamination, are capable of stimulating ovarian follicular maturation, underlining the key role of FSH in folliculogenesis.

Testicular gonadotropin receptors in men with hypogonadotropic hypogonadism.

To investigate the reason(s) why human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG) treatment is not always effective for men with hypogonadotropic hypogonadism (HH), we measured hCG and follicle-stimulating hormone (FSH) receptors in testicular tissues obtained by biopsy from 5 men with idiopathic HH and 2 men with secondary HH. The difference between these 7 men and age-matched controls in the numbers of testicular hCG and FSH receptors were not significant. Histologic examination of the testes also showed that Leydig and Sertoli cells had a normal appearance. Therefore, responsiveness to gonadotropins seems to be preserved in the testes of men with HH. Fro these results it could be concluded that combined hCG and hMG treatment may be used with good results for the treatment of HH.

HCG AND HMG treatment of male infertility with pituitary problems

A case is presented of a twenty-nine-year-old acromegalic man with sexual problems and fertility disturbance due to pituitary adenoma, who successfully fathered. Various endocrinologic studies, skull x-ray film, and computerized tomography (CT) scan revealed a pituitary adenoma. Testicular biopsy specimen also supported that the cause of sexual problems and fertility disturbance was secondary in origin. One month after transsphenoidal pituitary adenectomy, administration of human chorionic gonadotropin and human menopausal gonadotropin was started. His potency was improved immediately after start of the treatment, and his wife became pregnant five months later.

Ovulation induction with pulsatile gonadotropin-releasing hormone and continuous human menopausal gonadotropin in polycystic ovarian disease

Various treatments have been applied to polycystic ovarian (PCO) type of anovulation. However, none of them was definitive in terms of the efficacy and side effects. Six anovulatory women of PCO type were treated with pulsatile gonadotropin-releasing hormone (GnRH) of various pulse intervals and continuous human menopausal gonadotropin (hMG). The efficacy and rationale of the treatments were discussed. The subjects were diagnosed PCO by GnRH test and/or laparoscopy. They did not ovulate with clomiphene, clomiphene-hCG and hMG-hCG therapies. Their pretreatment serum FSH and LH levels and FSH/LH ratios were 6.9 +/- 1.2 mIU/ml, 15.7 +/- 5.1 mIU/ml, and 0.54 +/- 0.19 (Mean +/- SD), respectively. The treatment consisted of 3 protocols: 1) pulsatile GnRH (5-10 micrograms/pulse) of 90 min interval, 2) pulsatile GnRH (5-10 micrograms/pulse) of 120 min interval and 3) continuous hMG (150 IU/day) through subcutaneous route. Follicular growth was monitored sonographically and an intramuscular bolus of 10,000 IU hCG was given when the dominant follicle reached 20 mm in diameter. During both GnRH treatments serum FSH levels and FSH/LH ratios did not elevate substantially. Serum LH, E2 and PRL levels elevated acutely and transiently during the initial phase of GnRH treatments. Follicular growth was observed in a small fraction of the cases, but none of them ovulated. In contrast, continuous hMG treatment induced significant elevation in serum FSH levels (8.2 +/- 1.7 mIU/ml; p less than 0.01) and FSH/LH ratios (1.73 +/- 0.57; p less than 0.001). Transient hyperprolactinemia was accompanied with the preovulatory E2 rise. All the cases ovulated and 3 singleton pregnancies followed. These findings draw conclusions as follows. Pulsatile GnRH administration may desensitize the pituitary presumably due to increased GnRH pulse frequency as a consequence of two independent pulse generators, intrinsic and exogeneous. It may induce transient hyperprolactinemia through a paracrine system between gonadotrophs and lactotrophs. As a due course pulsatile GnRH therapy is questionable for ovulation induction in cases with functioning hypothalamic-pituitary axis. The fact that continuous hMG effectively induced follicle maturation with elevated FSH/LH ratios suggested that FSH dominance might be a prerequisite for folliculogenesis. The fluctuating nature of gonadotropins might not be mandatory for folliculogenesis.

Endogenous luteinizing hormone surge during superovulation induction with sequential use of clomiphene citrate and pulsatile human menopausal gonadotropin.

There is dispute as to whether an endogenous LH surge occurs in women during follicle stimulation with human menopausal gonadotropin (hMG) for in vitro fertilization (IVF). In this study, 12 consecutive normally cycling women with tubal infertility were treated with clomiphene citrate and hMG for ovulation induction and subsequent IVF. Beginning on the fifth day of clomiphene administration (150 mg daily for 5 days), 225 IU hMG were given daily sc in a pulsatile manner (28 IU/3 h). All women had an endogenous LH surge which started on the seventh to ninth day of hMG administration. The mean duration [25.5 +/- 1.0 (+/- sem) h] and the mean peak value (38.9 +/- 4.7 U/liter) of the LH surge were less than those in spontaneous cycles. However, luteinization of at least some of the follicles occurred, based on findings of supraphysiological levels of serum progesterone during the surge and subsequent increase in urinary pregnanediol levels (luteal phase). Preovulatory oocytes were recovered via laparoscopy 34-35 h after the onset of the surge, and these oocytes cleaved after IVF. One pregnancy was achieved after embryo transfer, which resulted in abortion. These results represent the first demonstration that an attenuated LH surge is obtained in normally cycling women during superovulation induction with sequential clomiphene/pulsatile hMG treatment.

Excretion of total estrogens and estrone-3-glucuronide during treatment with human menopausal gonadotropins

HMG treatment is usually monitored by the evaluation of the cervical mucus, the determination of plasma 17β-estradiol, total urinary estrogens, ultrasonographic evaluation or a combination of these. We evaluated the daily validity of estrone-3-glucuronide excretion in urine as an indicator of follicular growth and maturation in 28 infertile women who were treated with HMG (Pergonal 500). Total urinary estrogens and estrone-3-glucuronide were measured in 24 h urine collections, and 11 of the women collected the early-morning urine separately. This allowed comparison of the concentrations and excretion of total estrogens and estrone-3-glucuronide of the 24 h urine with that found in the urine collected overnight. This comparison was made on 83 urine samples. The correlation between either the total excretion per 24 h or the concentration per liter in the 24 h urine collection of the two systems of determination was good in all determinations. Also in the urine collected on the day prior to HCG administration, total estrogens measurement was in good correlation with the estrone-3-glucuronide. However, there was statistically a significant difference in the concentrations of total estrogens and estrone-3-glucuronide between the women who ovulated and those who did not. Estrone-3-glucuronide, when calculated as a percentage of the total estrogens, was 60.86% in the women who ovulated and 33.15% in those who did not. These results demonstrate that although estrone-3-glucuronide reflects ovarian function in women treated with HMG, it may serve as a better predictor to ovulation.

The use of ovarian ultrasonography in monitoring ovulation induction.

Ovarian ultrasonography is a new diagnostic technique which has become almost essential in monitoring ovulation. Recent improvements in ultrasound technology have allowed for accurate assessment of the number and size of the developing follicles and their rate of growth, as well as ovulation and postovulatory events. In the nonstimulated cycle follicular size correlates well with optimal maturation and there is a linear correlation between follicular diameter and plasma estradiol (E2 levels). In stimulated cycles, because of asynchrony of various recruited cohorts of follicles, these rules are not as steadfast. These observations indicate that when there is endogenous gonadotropic activity, follicular growth stimulated by human menopausal gonadotropins (hMG) does not develop synchronously. The aim should be, therefore, not only to improve the monitoring system but mainly to synchronize the cohorts of follicles recruited for development in any one cycle by a better regimen for ovulation induction. In view of the high success rate of hMG treatment in patients without endogenous gonadotropin secretion, it is tempting to speculate that inducing similar conditions in women with endogenous gonadotropin production may have a significant change in the pattern of follicular development in their conception rate.

A comparison of clinical and laboratory methods in monitoring human menopausal gonadotropin therapy

Twenty infertile, anovulatory women were treated with human menopausal gonadotropin (hMG) for a total of 61 treatment cycles. Cervical scores (all cycles) and vaginal maturation indices (23 cycles) were compared with serum concentrations of total immunoreactive estrogens to determine their clinical efficacy in monitoring hMG treatment. All courses of therapy were judged to have induced ovulation. Singleton pregnancies occurred in nine patients, and one patient conceived twice. All pregnancies were uncomplicated. There was good clinical correlation between cervical score and increasing estrogen levels in approximately one-third of the cycles. Most of these good correlations occurred in patients with low estrogen status. Very poor correlation was found with vaginal cytologic changes. Therefore, in conjunction with serum estrogen determinations, the cervical score is a safe and less expensive means of monitoring hMG therapy in selected patients.

Response of blood coagulation parameters to elevated endogenous 17β-estradiol levels induced by human menopausal gonadotropins

To elucidate the relationship between estrogen and thrombosis, we studied blood coagulation parameters in women whose ovaries were stimulated with human menopausal gonadotropins (hMG). Daily hMG administration over 1 to 2 weeks in seven anovulatory women increased plasma 17β-estradiol levels fivefold over the pretreatment value. Of the coagulation parameters, the fibrinogen level increased significantly from an initial value of 248 ± 11.7 mg/dl (mean ± SEM) to 353 ± 32.2 mg/dl after hMG treatment (P < 0.05), with a significant positive correlation between estrogen and fibrinogen levels (r = +0.762). In addition, a thrombokinetics study showed that the maximal rate of change in optical density of the prothrombin time and activated partial thromboplastin time was significantly increased, suggesting that the coagulation factors involved in extrinsic, intrinsic, and common pathways could be increased by estrogen. Antithrombin III levels decreased gradually during hMG administration. Thus, increased endogenous estrogen levels appear to induce the so-called “hypercoagulable state” through both an increase in coagulation factors in the coagulation cascade system and a decrease in antithrombin III, a potent natural inhibitor of activated coagulation factors. Patients on a regimen of hMG treatment for induction of ovulation serve as excellent models for the study of alteration of “natural” estrogen-mediated coagulation parameters.

A Comparison of Clinical and Laboratory Methods in Monitoring Human Menopausal Gonadotropin Therapy

Twenty infertile, anovulatory women were treated with human menopausal gonadotropin (hMG) for a total of 61 treatment cycles. Cervical scores (all cycles) and vaginal maturation indices (23 cycles) were compared with serum concentrations of total immunoreactive estrogens to determine their clinical efficacy in monitoring hMG treatment. All courses of therapy were judged to have induced ovulation. Singleton pregnancies occurred in nine patients, and one patient conceived twice. All pregnancies were uncomplicated. There was good clinical correlation between cervical score and increasing estrogen levels in approximately one-third of the cycles. Most of these good correlations occurred in patients with low estrogen status. Very poor correlation was found with vaginal cytologic changes. Therefore, in conjunction with serum estrogen determinations, the cervical score is a safe and less expensive means of monitoring hMG therapy in selected patients.

Plasma c-AMP during the normal menstrual cycle and under different hormonal treatment.

There is a highly significant difference between the plasma c-AMP value of the first and the second half of the normal menstrual cycle (days 1-12: 10.5 +/- 2.0 pmol, x +/- SEM; days 13-16: 21.9 +/- 4.5; days 17-28: 19.9 +/- 2.0; p less than 0.001). In amenorrheic patients plasma c-AMP levels were nearly the same as in normal women during the first half of the menstrual cycle (11.1 +/- 2.5). Plasma c-AMP of amenorrheic women was significantly higher under HMG treatment (16.7 +/- 2.5; p less than 0.01). Under oral contraception with estrogens (alone) or with low doses of gestagens the plasma c-AMP values were comparable to those of the amenorrheic women, but there was a dose-dependent increase of plasma c-AMP under gestagen application. It is concluded that the midcyclic plasma c-AMP increase is mainly caused by the gonadotropin effect, and is followed by the progesterone effect during the second half of the menstrual cycle. Therefore, plasma c-AMP levels are in accordance to the stages of the menstrual cycle reflecting their different endocrine pattern.