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PubMed2001

Molecular approaches to contraceptive development.

The next generation of contraceptives will be based on the identification of novel molecules essential for reproductive processes and will rely on the refinement of older as well as newer technologies. Functional analysis of naturally occurring reproductive genetic disorders and creation of mice null for specific genes would greatly assist in the choice of genetic targets for contraceptive development. Structure-based design of drugs as exemplified by the preparation of an orally active non-peptide gonadotropin releasing hormone (GnRH) would revolutionize drug formulation and delivery for a peptide analogue. This review examines some of the molecular targets that may change contraceptive choices in the future.

Algorithms↗
PubMed1983

Reproductive hormone studies in three subjects with a Robertsonian translocation.

The reproductive hormone function was investigated in three subjects, two brothers and one unrelated patient, with a Robertsonian translocation, who had come to us because of infertility. Basal levels of LH, FSH, testosterone, 17-beta-estradiol and prolactin were repeatedly measured by radioimmunoassays. In addition, clomiphene citrate, synthetic LH-RH, hCG and TRH tests were carried out. Karyotypes complemented by G-banding and C-banding, repeated semen analyses, and testicular biopsies were also obtained. The karyotype of all three subjects was 45, XY-13, -14, +t(13; 14) (p11; q11). Semen analyses showed oligozoospermia, and reduced or reduced/normal sperm motility. In addition, a high percentage of atypical forms was present in all three subjects. Reproductive hormone measurements in our three patients were substantially normal. Only one of the two brothers exhibited slightly low LH and testosterone levels. Both brothers also had elevated estradiol levels. Gonadotropin and testosterone responses to respective provocative stimuli, as well as prolactin elevation following TRH, were normal. In conclusion, the semen abnormalities observed in these three subjects with Robertsonian translocation appear to be responsible for their impaired fertility. However, the reason why some carriers of the same translocation are fertile and some others are subfertile or infertile remains unclear. It might be speculated that an individual genetic variability is responsible for different degrees of spermatogenic failure, accompanied, in more severe cases, also by reproductive hormone disorders.

Adult↗
PubMed1996

[Unfulfilled desire for children in the man: coping and pain. Results of a psychosomatic-andrologic cooperative study].

115 andrological patients were studied with psychological self-assessment tests to assess both their motivation concerning parenthood, and their own explanations for the causes. Additionally self-esteem was evaluated in 51 patients. The main results were: Motivation concerning parenthood is of greater importance in coping with involuntary childlessness than objective andrological data. Patients assess their situation quite realistically; no tendency to misinterpret the medical data in order to defend negative feelings and to protect self-esteem could be found. Most patients with reduced fertility consider this situation a challenge and are willing to mobilize resources and the help of others in order to cope. Self-esteem was only threatened in those patients with longlasting unvoluntary childlessness and little acceptance of medical infertility treatment and parenting substitutes, e.g. adopting a child.

Adaptation, Psychological↗
PubMed2004

Cyclic sciatica caused by infiltrative endometriosis: MRI findings.

Endometriosis, an important gynecological disorder of reproductive women, affects most commonly the ovaries and less frequently the gastrointestinal tract, chest, urinary tract, and soft tissues. Endometriosis classically appears on MRI as a mass with a large cystic component and variable signal intensities on T1- and T2-weighted images due to the presence of variable degradation of hemorrhagic products. Endometriosis in an atypical location, an infiltrative appearance and without cystic-hemorrhagic components has rarely been described. We report on a 33-year-old woman with cyclic sciatica due to histologically documented infiltrative endometriosis involving the area of the left sciatic notch.

Adult↗
PubMed1976

Aspects of the normal psychology of pregnancy: the midtrimester.

In this study of nonpregnant women were compared with pregnant women. A set of feelings and attitudes along with questions relevant to the anatomy and physiology of parturition were the measures of comparison. The pregnant women and the nonpregnant women had almost identical feelings and attitudes. There were, however, three exceptions to this general condordance. They were: (1) the nonpregnant women's regard of pregnancy as a depressive and withdrawing experience, (2) a greater fear for the fetus among the nonpregnant women, and (3) higher scores on a pregnancy information inventory among the pregnant women.

Adjustment Disorders↗
PubMed1977

Bromocryptine therapy in cases of amenorrhea-galactorrhea.

Of 28 patients presenting with amenorrhea-galactorrhea, pituitary tumors were confirmed in eight. Six patients had occult hypothyroidism and the rest had an endocrine profile suggestive of pituitary tumor or of an idiopathic etiology. Treatment with bromocryptine resulted in suppression of the inappropriate lactation and restoration of regular menstrual function. In five cases, however, the galactorrhea was only diminished and in four of these cases, normal ovarian function did not return. Of the 19 patients that were seeking fertility and continued the medication for at least 20 days, nine pregnancies resulted. A similar response to bromocryptine was observed regardless of the underlying cause of the amenorrhea-galactorrhea.

Adult↗
PubMed1978

The significance of galactorrhea in patients with normal menses, oligomenorrhea, and secondary amenorrhea.

Thyroid-stimulating hormone and prolactin (PRL) were measured in a group of 149 women with galactorrhea. Three of these patients were found to have primary hypothyroidism. In the remaining 146 patients, the PRL assay was correlated with the menstrual history and the results of hypocycloidal polytomography. Sixty-two per cent of these patients had hyperprolactinemia and 35 per cent had abnormal tomograms. Nine patients with abnormal x-rays had normal prolactin levels. None of the patients with normal menses and normal PRL was found to have an abnormal x-ray. Fourteen of the 15 patients with PRL levels greater than 200 ng. per milliliter had abnormal tomograms. Almost 70 per cent of patients with secondary amenorrhea and low estrogen status had abnormal x-rays. In patients with oligomenorrhea and secondary amenorrhea with normal estrogen status, it was not possible to differentiate between patients with normal or abnormal tomograms based on the level of serum PRL. Polytomography remains the single most important diagnostic test in establishing the presence of a pituitary tumor.

Adolescent↗
PubMed1981

Hyperprolactinemia--a significant factor in female infertility.

A prospective study was undertaken to determine the incidence of hyperprolactinemia in a group of referred infertile women, and to determine the association with (a) abnormal menstrual function and (b) presence or absence of galactorrhea. Of 113 referred infertile patients, 22 (19.5%) had elevated levels of serum prolactin. Five (4.4%) patients with hyperprolactinemia had neither abnormal menstrual function nor galactorrhea. This study demonstrates that hyperprolactinemia is a common finding in an infertile population, more so when galactorrhea and/or menstrual dysfunction is also present.

Adult↗
PubMed1981

Reduced menstrual blood loss by release of an antifibrinolytic agent from intrauterine contraceptive devices.

Lippes Loop and Multiload intrauterine contraceptive devices (IUDs) were fitted with silicone rubber sleeves which either did not contain any compound (blank) or contained the antifibrinolytic agent, epsilon-aminocaproic acid (EACA. In vitro measurements showed that the antifibrinolytic agent was released from the sleeves for a period of 20 days. After insertion into women, the blank Lippes Loop IUDs and Multiload IUDs as well as copper-containing Multiload IUDs caused a significant increase in blood loss beginning with the first menstrual cycle after insertion. The enhanced blood loss was generally retained during subsequent menstrual cycles. By contrast, the menstrual blood loss induced by IUDs containing EACA sleeves was not significantly greater during the first menstrual cycle after insertion that the preinsertion levels. When no more EACA was released, menstrual blood loss increased to approximately the same level as that observed with the blank and copper IUDs. Thus, release of EACA from an IUD retains menstrual blood loss at approximately physiologic levels. These results encourage the development of IUDs that are capable of releasing antifirbrinolytic agents over a long period so that the antimenorrhagic effect is maintained.

Aminocaproic Acid↗
PubMed1981

Changes in the milk composition of nonpuerperal women.

Studies were undertaken to determine the effect of expressing small volumes of breast fluid (less than 3.0 ml) on the progressive changes in concentrations of lactose, proteins, and electrolytes in the mammary secretions of four nonpuerperal women with galactorrhea and two nonpuerperal women who artificially induced lactation by breast hyperstimulation. The changes in the concentration of the milk constituents in the mammary secretion of these women are compared to the levels in colostrum, transitional and mature milk obtained from normal lactationg women. In one woman galactorrhea was associated with hypothyroidism and abnormally elevated blood levels of prolactin and thyroid-stimulating hormone. The breast secretion contained lactose, protein, and alpha-lactalbumin at colostrum-like levels over the entire 53 days of sampling. In two women with galactorrhea and amenorrhea associated with a pituitary tumor and hyperprolactinemia, a colostrum-like secretion was expressed on the first day of sampling but with daily sampling during a period of a month the composition approached that of normal milk. Similar results were obtained in another woman with galactorrhea, which appeared to be induced by a psychotropic drug (haloperidol), when she expressed breast fluid at 2-day intervals over a period of a month. In a second series of samples collected from this woman at intervals of 5 days or more over a period of a month, the concentration of lactose and proteins remained at colostrum levels. The composition of the breast secretion produced by two women who induced lactation artificially by breast hyperstimulation was close to the composition obtained for women during established lactation following normal pregnancy. These findings are discussed in relation to breast function and endocrine disorders.

Adult↗
PubMed1983

Evidence for triiodothyronine receptors in human endometrium and myometrium.

Thyroid gland dysfunction in humans may cause various female reproductive tract disorders. Thyroid hormone action is thought to be mediated by high-affinity low-capacity receptor proteins located in the nucleus. The studies detailed in this report were undertaken to determine if uterine nuclei contain specific high-affinity receptors for thyroid hormone. Nuclei from human endometrium and myometrium were prepared by homogenization and centrifugation following routine surgical procedures. With the use of isolated nuclei, binding experiments with 125I-triiodothyronine (T3) revealed a dissociation constant of approximately 1 X 10(-9) M in both endometrium and myometrium with a maximum number of binding sites equivalent to 0.06 and 0.21 pmol/mg of DNA, respectively. The solubilized binding sites were destroyed largely by trypsin treatment. Competition experiments revealed the following relative binding affinities for these nuclear binding sites: L-T3 greater than D-T3 greater than L-thyronine greater than reverse T3. These results indicate the presence in the human uterus of specific high-affinity binding sites with characteristics expected of a T3 receptor and thus raise the possibility that thyroid hormone may exert effects on the uterus through these receptors.

Binding Sites↗
PubMed1995

Potent pituitary-gonadal axis suppression and extremely low anaphylactoid activity of a new gonadotropin releasing hormone (GnRH) receptor antagonist "azaline B".

We report here the biological characterization of azaline B, a new gonadotropin releasing hormone (GnRH) receptor antagonist, with the following amino acid sequence: [Ac-D-Nal1, D-Cpa2, D-Pal3, Aph5(atz), D-Aph6(atz), Ilys8, D-Ala10]-GnRH. Azaline B was shown to suppress several reproductive processes in rats including ovulation, and had very low anaphylactoid activity compared with other GnRH antagonists. Azaline B inhibited histrelin (a GnRH agonist)-mediated follicle stimulating hormone (FSH) and luteinizing hormone (LH) release from cultured rat pituitary cells. Three antagonists ([Nal-Glu]-GnRH, [Nal-Lys]-GnRH ("antide"), and azaline B) inhibited 0.1 nM histrelin-mediated gonadotropin release to baseline levels with EC50 values of approximately 0.6 nM. Azaline B, when injected s.c. into rats on the afternoon of proestrus, was more potent at inhibiting ovulation than either [Nal-Glu]-GnRH or [Nal-Lys]-GnRH. The relative order of antiovulatory potencies of the three antagonists was azaline B > [Nal-Glu]-GnRH > [Nal-Lys]-GnRH. Similar azaline B potency was shown by its ability to suppress gonadotropin levels in castrated rats. The improved selectivity of azaline B was demonstrated when it was compared with other GnRH antagonists in the cutaneous anaphylactoid assay (local wheal response) in rats. Results with azaline B were not significantly different from results with vehicle in this assay. [Nal-Glu]-GnRH was more than twice as potent as [Nal-Lys]-GnRH in stimulating a wheal response. Furthermore, the maximal wheal response produced by azaline B was only 0.6 times that of [Nal-Lys]-GnRH, currently one of the most selective antagonists identified. Finally, both azaline B and [Nal-Lys]-GnRH were much less potent than [Nal-Glu]-GnRH in the guinea pig cardiopulmonary anaphylactoid assay after i.v. administration. These data show that azaline B is a potent and selective GnRH receptor antagonist with little or no anaphylactoid activity in animal models, and therefore has potential for use in the treatment of many reproductive endocrine disorders, as well as for use as a contraceptive.

Amino Acid Sequence↗
PubMed1980

Transfer of cyproterone acetate to the milk of lactating women.

Cyproterone acetate (CPA) was administered in a dose of 50 mg to 6 lactating women delivered by caesarean section. All women had to discontinue breast feeding the day before treatment. Prior to, and 3 and 9 hours after ingestion of the drug, plasma and milk specimens were taken. Total daily milk volume was recorded. Concentration of CPA in plasma and milk was determined by RIA. The plasma levels of CPA were in the range of 65 - 450 ng/ml at 3 h and 76 - 270 ng/ml after 9 hours. The respective concentrations in milk were 16 - 260 ng/ml (3 h) and 55 - 130 ng/ml (9 h). The plasma/milk ratio of drug concentration varied between 1.1 and 9.3 (3 h) and 0.6 and 2.9 (9 h). The mean of all values amounted to 2.8 +/- 2.3. Taking into account a daily milk production of 1050 +/- 230 ml, 0.2% of the dose administered (range: 0.06 - 0.41 % of dose) would have been transferred to the newborn. Use of the CPA-containing oral contraceptive DIANER (2 mg of CPA + 50 microgram of ethinyl estradiol) by nursing women would therefore result in the transfer of 1 microgram/kg to the child.

Adult↗
PubMed1995

A multicentred phase III comparative clinical trial of Mesigyna, Cyclofem and Injectable No. 1 given by intramuscular injection to Chinese women. II. The comparison of bleeding patterns.

Between 1988 and 1992, a randomized phase III clinical trial was conducted in China to compare three monthly injectable contraceptives: Mesigyna, Cyclofem and Injectable No. 1. This paper presents a detailed analysis of the menstrual diaries provided by 5098 (89%) of the subjects. In total, 902, 903 and 913 diaries were analyzed to compare bleeding patterns induced by Mesigyna, Cyclofem and Injectable No. 1. The first withdrawal bleeding usually occurs 14-20 days after the first injection for all three of these preparations. Thereafter, 50% of Mesigyna users had precisely 3 bleeding/spotting episodes every 90 days, 50% of Cyclofem users had 2-3 and 50% of Injectable No. 1 users had 3-4 episodes every 90 days. Relative to users of Mesigyna or Cyclofem, Injectable No. 1 users had 2-3 more bleeding/spotting days, and a shorter length of bleeding/spotting-free intervals in each period. 63.7%, 41.4% and 60.6% of subjects using Mesigyna, Cyclofem and Injectable No. 1, respectively, had bleeding patterns similar to their untreated patterns in the first 90-day period. The percentages increased to 82.2% 67.8% and 75.0% in the fourth 90-day period. A total of 1815 diaries for Mesigyna and 1802 for Cyclofem were analyzed for more in depth comparison of these two methods. The number of bleeding/spotting days over four periods showed little difference between the two group, but there were more spotting days and there was greater individual variability among Cyclofem users.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1996

The effect of desogestrel, gestodene, and other factors on spotting and bleeding.

Spotting and bleeding are among the most common side effects associated with oral contraceptive (OC) use and their occurrence is a prime determinant of whether a new user will continue to use OCs. Desogestrel and gestodene are two new progestins that were developed in part to minimize the occurrence of these side effects. Assessing the effect of these progestins is difficult, however, in part because their effects may be subtle, requiring a large sample size and possibly being overshadowed by other factors. To address these issues, we analyzed data from two comparative multicenter clinical trials that included 15,421 cycles among 2767 women. One study compared 75 micrograms gestodene + 30 micrograms ethinyl estradiol (EE) with 150 micrograms desogestrel + 30 micrograms EE, the other compared the same gestodene preparation with 150 micrograms desogestrel + 20 micrograms EE. Both studies found a higher risk of spotting or bleeding in all cycles among users of the desogestrel-containing preparation, with the differences ranging between 20% and 70% higher for the first study and 40% and 140% in the second. These differences were statistically significant in four of six cycles in each study and persisted after controlling for consistency and recency of OC use as well as smoking. After pooling the data and controlling for estrogen dose, the desogestrel-containing preparation was significantly associated with more frequent spotting or bleeding in five of six cycles. Smoking and consistency and recency of OC use were also independent predictors of spotting or bleeding.

Adolescent↗
PubMed1982

Menorrhagia associated with the wearing of IUD--the results of treatment with clomiphene citrate.

The influence of clomiphene citrate was tested in 206 women suffering from menorrhagia following the insertion of an intrauterine device (IUD). Eighty-three percent felt relief during the therapy, 10% did not benefit and 7% complained of a worsening of their symptoms. Among the women who felt an improvement, 85% responded to the 250 mg/cycle dosage, and 15% required the 350 mg/cycle dosage. Women with shortened menstrual cycles required the higher dose treatment, i.e. 350 mg, compared with women with normal cycles (36% vs. 28%, respectively). The influence of placebo was 6%. The hypothesis is raised that the mechanism of action of clomiphene citrate is the correction of the hormonal disturbances in the luteal phase of the cycle following insertion of the IUD.

Clomiphene↗
PubMed2005

Genetic mechanisms of fetal male undermasculinization: a background to the role of endocrine disruptors.

Fetal male sex development proceeds along an orderly sequence of events coordinated by an interplay of genetic and hormonal events. These operate in a time- and concentration-dependent manner. Once a testis is formed (the female sex being constitutive in nature), differentiation of the internal and external male genitalia is androgen dependent. A number of genetic syndromes of sex reversal are well characterized at the biochemical and molecular levels. They fall into three principal categories: defects in formation of the testis, defects in production of androgens, and defects in the action of androgens. In many instances, the precise cause is not established, although the investigative evidence points in the direction of one of the three stated classifications. Polymorphic variants in several of the genes involved in male development are associated with certain degrees of male undermasculinization. While the genetic background is essentially static, it is plausible that the effect of endocrine disruptors during fetal life acting through epigenetic mechanisms may partly explain the observed changing trends in male reproductive tract disorders.

Animals↗