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PubMed1999

The effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive.

BACKGROUND: Rifampin (INN, rifampicin), a CYP34A inducer, results in significant interactions when coadministered with combination oral contraceptives that contain norethindrone (INN, norethisterone) and ethinyl estradiol (INN, ethinylestradiol). Little is known about the effects of rifabutin, a related rifamycin. OBJECTIVES AND METHODS: The relative effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of ethinyl estradiol and norethindrone were evaluated in a prospective, randomized, double-blinded crossover study in 12 premenopausal women who were on a stable oral contraceptive regimen that contained 35 microg ethinyl estradiol/1 mg norethindrone. Subjects were randomized to receive 14 days of rifampin or rifabutin from days 7 through 21 of their menstrual cycle. After a 1-month washout period (only the oral contraceptives were taken), subjects were crossed over to the other rifamycin. RESULTS: Rifampin significantly decreased the mean area under the plasma concentration-time curve from time 0 to 24 hours [AUC(0-24)] of ethinyl estradiol and the mean AUC(0-24) of norethindrone. Rifabutin significantly decreased the mean AUC(0-24) of ethinyl estradiol and the mean AUC(0-24) of norethindrone. The effect of rifampin was significantly greater than rifabutin on each AUC(0-24). Despite these changes, subjects did not ovulate (as determined by progesterone concentrations) during the cycle in which either rifamycin was administered. Levels of mean follicle-stimulating hormone increased 69% after rifampin. CONCLUSION: In this study, rifampin (600 mg daily) was a more significant inducer of ethinyl estradiol and norethindrone clearance than rifabutin (300 mg daily), but neither agent reversed the suppression of ovulation caused by oral contraceptives. The carefully monitored oral contraceptive administration and the limited exposure to rifamycins may restrict the application of this study to clinical situations.

Adult↗
PubMed1998

The risks of venous thromboembolic disease among German women using oral contraceptives: a database study.

This study investigated the risk of venous thromboembolic disease (VTE) between second and third generation combined oral contraceptives, using the German MediPlus database of patient records. Women studied included 42 patients between the ages of 18 and 49 years, with a diagnosis of VTE treated with an anticoagulant, who were exposed to an oral contraceptive (OC). Four controls per patient (168), matched by year of birth and exposure to an OC on the even day, were identified. More women were users of second generation than third generation OC, and none were using progestogen-only pills. There was no significant difference between patients and control subjects with respect to the type of OC used on the event day (unadjusted odds ratio for third versus second generation users was 0.77; 95% confidence interval [CI] 0.38-1.57). There was no significant age difference between second and third generation users among patients or control subjects. Between January 1 and the event date, there was no significant difference between the patients and control subjects in terms of the number of oral contraceptive prescriptions, number of consultations for psychotherapeutic complaints, or mixed physical and psychotherapeutic consultations; however, patients did demonstrate significantly more consultations for purely physical complaints compared with control subjects (p < 0.0001). There were no significant consultation differences between patients with pulmonary emboli (n = 6) and other VTE patients (n = 36). No significant differences with respect to VTE risk between users of second and third generation oral contraceptives were found in this study. Consultations (physical) for patients were higher than for control subjects before the VTE event. If consultation rate relates to the general health status of a person, this might indicate that VTE risk is higher among women of poorer health, but that this is not related to the type of progestogen in the oral contraceptive that they use.

Adolescent↗
PubMed1994

High doses of oral contraceptives do not alter endometrial alpha 1 and alpha v beta 3 integrins in the late implantation window.

OBJECTIVE: To assess the effects of an emergency contraceptive agent on the distribution of integrin heterodimers during that part of the implantation window. DESIGN: Prospective, case-controlled study in a university-based Population Program. In the first ovulatory control cycle after the detection of LH surge, patients had endometrial sampling 11 days after the surge. In the next cycle the procedure was repeated 2 days after the administration of a postcoital contraceptive agent on day 9 after LH surge (100 g ethinyl E2 and 2 mg norgestrel). MAIN OUTCOME MEASURES: The effects of postcoital contraceptives on the expression of integrin heterodimers (alpha 1 and alpha v beta 3 subunits) reported to be unique to secretory phase was determined. RESULTS: All six specimens were consistent histologically with days 24 and 25 of the menstrual cycle by light microscopy. Using immunohistochemistry, strong membrane staining of endometrial glandular cells and superficial epithelium for both alpha 1 subunit and vitronectin (alpha v beta 3) receptor was observed in treatment and controls. No diminution of intensity or distribution was observed relative to pretreatment controls. CONCLUSIONS: There is no apparent change in the level of these two integrins in the human endometrium when high-dose oral contraceptives are given in the later stages of the implantation window. This suggests that the high doses of steroids used in emergency contraceptives may exert their effect through more complex mechanisms than endometrial cell surface changes.

Contraceptives, Oral↗
PubMedDate not supplied

Impact of patient counseling on acceptance of the levonorgestrel implant contraceptive in the United Kingdom.

Patient counseling is an important aspect of family planning. Patient choice, compliance, and satisfaction with a contraceptive method depend heavily on the counseling experience. This is especially true in the United Kingdom where contraceptives are provided to patients at no direct cost to them. Women are therefore more likely to choose a contraceptive option based on perceived desirability as opposed to cost. We surveyed physicians from six family planning centers in the United Kingdom who have extensive experience with levonorgestrel contraceptive implants with respect to counseling issues and patient acceptability of levonorgestrel implants. The physicians reported on their experience with 521 women. They acknowledged the need for and importance of counseling, and these centers provided preinsertion counseling 100% of the time. Primary responsibility for counseling was handled by the physician who spent, on average, 19 minutes per patient discussing the advantages and risks of levonorgestrel implants. Physicians felt that the majority of women (82%) accepting levonorgestrel implants had a positive experience. The incidence of bleeding irregularities was consistent with that reported in clinical trials, and this did not substantially affect the postinsertion acceptability of the product. Effective counseling is no doubt responsible for the high level of patient acceptance of these side effects. In a review of the literature, we found counseling to be a significant factor in a woman's tolerance of contraceptive-induced bleeding irregularities, which are frequently experienced with levonorgestrel implants. The results of our survey support the literature findings.

Adolescent↗
PubMed1983

Apparent oral contraceptive failure associated with antibiotic administration.

The concomitant use of antibiotics and oral contraceptives should be included in the assessment of contraceptive failure. A case of unwanted adolescent pregnancy during the use of a semisynthetic penicillin and an oral contraceptive is presented and discussed. Advising a different contraceptive method or an additional contraceptive modality may be indicated in adolescents taking long-term antibiotic medication.

Adolescent↗
PubMed1997

Haemostatic changes and the oral contraceptive pill.

Oral contraceptives have been linked to an increased incidence of thrombovascular disease. This may be mediated by their effects on the haemostatic system. An increase in the activity of coagulation Factors VII, X and fibrinogen occur with pill usage. Increased Factor VII levels are dependent on both the oestrogen and progestogen component of the oral contraceptive. A reduction in antithrombin III levels has also been observed in some but not all studies. Increased fibrinolysis has also been shown in oral contraceptive users which should balance the changes in the coagulation pathway. The increase in fibrinolytic potential is thought to be due to a decrease in the levels of plasminogen activator inhibitor I combined with an increase in the levels of plasminogen; tissue plasminogen activator antigen is decreased in most studies. The increased levels of endpoints of coagulation and fibrinolysis in pill users indicate that enhanced activity of both systems is occurring in vivo. The increased coagulation activity appears to be balanced by the rise in fibrinolytic activity, so preserving haemostatic balance. Enhanced platelet activity has also been shown in women taking oral contraceptives. Thrombus formation can result, however, when local vascular wall damage exists, or when other risk factors for thrombo-embolism, such as older age and smoking, coexist and create a local activation resulting in a thrombus. In these situations, the small differences in levels of coagulation factors in women taking different oral contraceptive formulations may be important. Pills containing the lowest doses of oestrogen (20 micrograms ethinyloestradiol) have shown the least changes in haemostatic factors. The progestogen component of the pill modifies the effect of oestrogen on the haemostatic system.

Adult↗
PubMed1998

Thrombotic diseases in young women and the influence of oral contraceptives.

OBJECTIVE: In the evaluation of the clinical impact of thrombotic diseases in young women, age-specific incidence rates must be calculated for both arterial and venous thrombotic diseases, but also the case-fatality rate and figures for the clinical consequences among those who survive thrombosis must be included. The aim of this analysis was to quantify the clinical impacts of both arterial and venous thrombotic diseases among young, nonpregnant women and thereafter to assess the influences of oral contraceptives on these measures. STUDY DESIGN: Nationwide register data on the morbidity and mortality of venous thromboembolism, myocardial infarction, and thrombotic stroke in Denmark, 1980-1993, and 3 ongoing case-control studies to assess the influence of oral contraceptives on the risk for development of these thrombotic diseases. RESULTS: In women 15-29 years old venous thromboembolism is about twice as common as arterial complications, whereas in women 30-44 years old the number of arterial complications exceeds that of venous diseases by about 50%. The mortality rate from arterial diseases is 3.5 times higher than that from venous diseases among women <30 years old and 8.5 times higher than that from venous diseases in women 30-44 years old. The proportion of women with a significant disability among women who had an arterial complication was about 30%; the proportion was about 5% among women with venous thromboembolism. CONCLUSION: Anticipating a differential influence on venous and arterial diseases from oral contraceptives with second- and third-generation progestogens, it was calculated that users of oral contraceptives with second-generation progestogens had 30% greater increased risk of thrombotic diseases, 260% greater increased risk of thrombotic deaths, and 220% greater increased risk of thrombotic disability than users of oral contraceptives with third-generation progestogens.

Adolescent↗
PubMed1984

Severe and prolonged oral contraceptive jaundice.

Oral contraceptives frequently produce mild hepatocellular dysfunction, but only rarely cause jaundice. The syndrome of oral contraceptive jaundice is usually mild, with rapid resolution upon withdrawal of the drug. We describe a patient who had a severe illness with marked jaundice after one cycle of oral contraceptives. Her symptoms progressively worsened and serum bilirubin increased for almost 3 months after discontinuation of oral contraceptives. Full recovery ultimately occurred. Her severe and prolonged course demonstrates the wide spectrum of oral contraceptive jaundice.

Adult↗
PubMed1979

Chorea induced by oral contraceptives.

A rare complication of oral contraceptive therapy is the induction of chorea. We here describe five cases of chorea in patients receiving low- or high-dose estrogen-containing contraceptives. All patients were nulliparous, young (average age 19 years), and became symptomatic shortly (average of 5 weeks) after initiation of contraceptive therapy. Two patients previously suffered an episode of Syndenham chorea; one experienced chorea in the course of Henoch-Schönlein purpura; and two had a history of congenital cyanotic heart disease without chorea. Dyskinesia resolved in all patients upon discontinuing the medication. Patients with preexisting striatal abnormalities appear more susceptible to oral contraceptive-induced chorea which is reversible on drug discontinuation. The mechanism of oral contraceptive-induced chorea is unknown, but clinical and experimental data suggest that it involves altered central dopaminergic activity.

Adolescent↗
PubMed1998

[Contraception after heart transplantation].

It was observed that fertility and menstrual function in heart-transplanted women, impaired before the operation, become normal with a new heart. The restoration of reproductive function is also confirmed by many cases of pregnancy in heart-transplant recipients, reported in the literature. Twenty-four cases were published worldwide up to 1997, out of which eighteen had a positive result. Also a case personally treated was successful. The outcome of a pregnancy after heart transplantation is, then, generally positive. Nevertheless, such a pregnancy involves important maternal and fetal risks. Thus, the gynecologist has to provide correct information about both such risks and the most suitable contraceptive methods, for these patients. Oral contraceptives are very effective and, in the new low-dose formulations, free from serious adverse effects. No adverse effects have been observed in our patient, who represents the only case, reported in the literature, in which an estroprogestinic contraception was utilized before a pregnancy. In conclusion, during an oral contraception or after a tubal sterilization, pregnancy is really unlikely to occur. Thus, when the couple either has completed the familial nucleus or does not desire offspring, a doubt is at least justified as to whether these safer methods of contraception are advisable in such women.

Contraceptives, Oral, Hormonal↗
PubMed1994

A study on the discontinuation and failure of contraception among newly married couples in Shanghai.

The authors investigate contraceptive failure and discontinuation among newly married couples in Shanghai, China, with a focus on the questions, "What percentage of births is due to contraceptive failure? What socio-psychological and demographic characteristics of a couple are related to the discontinuation or failure of contraception? How do the continuation rate and failure rate of contraception among newly married couples reflect the acceptance and effectiveness of various forms of contraception?"

Asia↗
PubMed2001

Diabetes and depot medroxyprogesterone contraception in Navajo women.

BACKGROUND: Depot medroxyprogesterone acetate contraception is widely used in Navajo women, a high-risk population for diabetes mellitus. However, depot medroxyprogesterone may lead to weight gain and independently decrease insulin sensitivity. We studied the association between depot medroxyprogesterone and development of diabetes in Navajo women. METHODS: We studied Navajo women aged 18 to 50 years who had seen a health care provider at a Navajo Area Indian Health Service clinic at least once in 1998. Diabetic cases (n = 284) and nondiabetic controls (n = 570) were matched by age. Medical records were reviewed to determine contraception use before the diagnosis date of diabetes. RESULTS: Users of depot medroxyprogesterone were more likely to develop diabetes than patients who had used combination estrogen-progestin oral contraception only (odds ratio [OR], 3.8; 95% confidence interval [CI], 1.8-7.9). The excess risk persisted after adjustment for body mass index (OR, 3.6; 95% CI, 1.6-7.9). Longer use was associated with greater risk of diabetes. Users of depot medroxyprogesterone were also more likely to develop diabetes than patients who had never used hormonal contraception, although excess risk was smaller (OR, 2.4; 95% CI, 1.4-3.6). CONCLUSIONS: Depot medroxyprogesterone contraception was associated with a greater risk of diabetes compared with combination oral contraceptive use only. Risk was associated with length of use and persisted after adjustment for body mass index. Additional research is needed for confirmation, but this risk should be considered in contraceptive choice for women at high risk for diabetes.

Adult↗
PubMed1990

Decreased risk of symptomatic chlamydial pelvic inflammatory disease associated with oral contraceptive use.

Studies have shown that oral contraceptive use may protect against pelvic inflammatory disease (PID), but it is not known whether oral contraceptives protect against the disease among women already infected with Chlamydia trachomatis or Neisseria gonorrhoeae. The relationship between oral contraceptive use and PID was analyzed in a case-control study of 141 women with verified PID and 739 randomly selected, sexually active women with no clinical evidence of the disease. Case and control subjects were stratified on the basis of infection with C trachomatis, N gonorrhoeae, or neither organism. Among women infected with C trachomatis alone, those with PID were less likely than control subjects to use oral contraceptives. The association was significant when oral contraceptive use was compared with nonuse (odds ratio, 0.22; 95% confidence interval, 0.08 to 0.64) and with noncontraception (odds ratio, 0.17; 95% confidence interval, 0.06 to 0.53) and remained so after adjusting for potential confounding variables by logistic regression analysis. Among women infected with N gonorrhoeae alone, no association was found between use of oral contraceptives and PID. These data suggest that oral contraceptive use protects against symptomatic PID among women infected with C trachomatis but not among those infected with N gonorrhoeae.

Adolescent↗
PubMed2001

Hormonally impregnated intrauterine systems (IUSs), versus other forms of reversible contraceptives as effective methods of preventing pregnancy.

OBJECTIVES: To assess the contraceptive efficacy, tolerability and acceptability of hormonally impregnated intrauterine systems (IUSs) in comparison to other reversible contraceptive methods. SEARCH STRATEGY: Literature was identified through database searches, reference lists and individuals/organisations working in the field. SELECTION CRITERIA: All randomised controlled trials comparing IUSs with other forms of reversible contraceptives and reporting on pre-determined outcomes in women of reproductive years. The primary outcomes were pregnancy due to method/user failure and continuation rate. DATA COLLECTION AND ANALYSIS: The quality assessment of studies and data extraction were completed independently by two blinded reviewers. A quality checklist was designed to identify general methodological and contraceptive specific factors which could bias results. Events per women months and single decrement life table rates were extracted where possible for pregnancy, continuation, adverse events and reasons for discontinuation. Events per total number of women at follow up were collected for hormonal side effects and menstrual disturbance. When appropriate, data were pooled at the same points of follow up to calculate rate ratios in order to determine the relative effectiveness of one method compared to another. For the single decrement life table rates, the rate differences were pooled to determine the absolute difference in effectiveness of one method compared to another. Interventions were only combined if the contraceptive methods were similar. Non-hormonal IUDs were divided into three categories for the purpose of comparison with IUSs: IUDs >250mm2 (i.e. CuT 380A IUD and CuT 380 Ag IUD), IUDs <=250mm2 (i.e. Nova-T, Multiload, CuT 200 and CuT 220 IUDs) and non-medicated IUDs. MAIN RESULTS: Nineteen RCTs comparing hormonally impregnated IUSs to a reversible contraceptive method met the inclusion criteria and it was possible to include eight of these in the meta-analyses, four comparing LNG-20 IUSs with non-hormonal IUDs, one comparing the LNG-20 IUS with Norplant-2 and three comparing Progestasert with non-hormonal IUDs. No significant difference was observed between the pregnancy rates for the LNG-20 users and those for the IUD >250mm2 users. However, women using the LNG-20 IUS were significantly less likely to become pregnant than those using the IUD <=250mm2. Women using the LNG-20 IUS were more likely to experience amenorrhoea and device expulsion than women using IUDs >250mm2. LNG-20 users were significantly more likely than all the IUD users to discontinue because of hormonal side effects and menstrual disturbance, which on further breakdown of the data was due to amenorrhoea. When the LNG-20 IUS was compared to Norplant-2, the LNG-20 users were significantly more likely to experience amenorrhoea and oligomenorrhoea, but significantly less likely to experience prolonged bleeding and spotting. No other significant differences were observed. Progestasert users were significantly less likely to become pregnant and less likely to continue on the method than non-medicated IUD users after one year, but no significant differences was noted for these two outcomes when Progestasert users were compared to IUD<=250mm2 users. The only other significant differences found in the meta-analyses were that Progestasert users were less likely to expel the device and more likely to discontinue the method because of menstrual bleeding and pain than users of IUDs <=250mm2. REVIEWER'S CONCLUSIONS: Current evidence suggests LNG-20 IUS users are no more or less likely to have unwanted pregnancies than IUD >250mm2 and Norplant-2 users. The LNG-20 IUS was more effective in preventing either intrauterine or extrauterine pregnancies than IUDs <=250mm2. The contraceptive effectiveness of Progestasert was significantly better than non-medicated IUDs, but no difference was observed when compared to IUDs<=250mm2. Continuation of LNG-20 IUS use was similar to continuation of the non-hormonal IUDs and Norplant-2. Amenorrhoea was the main reason for the discontinuation for the LNG-20 IUS and women should be informed of this prior to starting this method.

Contraceptive Agents, Female↗
PubMed1993

Contraception in Germany: a review.

In this paper studies on current contraceptive use and attitudes toward various contraceptive methods in Germany are reviewed. Both the former West and East Germany are considered. On the basis of the existing studies it is difficult to have a clear impression of which methods are currently used in both countries and how contraceptive practice developed over time, due to methodological differences between studies. Nevertheless, it can be concluded that use of reliable contraceptive methods is widespread in both East and West Germany. In this respect East Germany differs considerably from other previously communistic countries. Attitudes were mainly assessed in West Germany, and with respect to oral contraceptives and IUDs great concern appeared to exist regarding the safety of both methods. As far as oral contraceptives are concerned, selective mass media attention toward possible side-effects of oral contraceptives may have contributed to this situation.

Adolescent↗
PubMed1992

Influence of oral contraceptive agents on kidney function and protein metabolism.

The present study was an investigation of the effect of oral contraceptives on kidney function as well as a brief examination of protein metabolism, since glomerular filtration rate depends to a large extent on daily protein intake. 28 healthy women not taking contraceptives and 46 healthy women (aged 20-28 y) on one of three different types of oral contraceptive (combination preparations) were investigated [Minulet/Femovan, Marvelon, Diane]. In all groups on oral contraceptives the endogenous creatinine clearance was significantly increased. The potassium excretion rate was significantly elevated in the groups taking Marvelon and Diane, and the sodium excretion rate was significantly increased in those on Minulet/Femovan and Diane. In all groups on contraceptives the albumin excretion rate was numerically but not significantly elevated. No significant differences were found in the daily oral protein intake or the nitrogen excretion rate on comparing the groups taking contraceptives with the control group. However, the ratio nitrogen excretion rate/daily protein intake was significantly increased in those on Minulet/Femovan and Diane. The study has shown that besides their various effects on renal tubular function, oral contraceptives are able to increase the glomerular filtration rate, and certain types have a protein catabolic effect.

Adult↗
PubMed2005

The CYP2C19 genotype and the use of oral contraceptives influence the pharmacokinetics of carisoprodol in healthy human subjects.

AIMS: The aim of the present study was to investigate if subjects with one normal and one non-functional CYP2C19 allele (intermediate metabolizers; IMs) metabolized carisoprodol differently than individuals with two normal CYP2C19 alleles (extensive metabolizers; EMs) We also wanted to investigate whether the use of oral contraceptives influences the metabolism of carisoprodol in EMs and IMs. Impairing effects on psychomotor coordination and feelings of sedation were studied by comparing IMs with EMs following their ingestion of a single dose of 700 mg carisoprodol. METHODS: Thirty-seven healthy Caucasian volunteers participated in the study, of whom 25 were not using any drugs known to interact with CYP2C19, including two poor metabolizers (PMs) (CYP2C19 *2/*2 or CYP2C19 *2 /*4), 11 IMs (CYP2C19 *1/*2 or CYP2C19 *1/*4) and 12 EMs (CYP2C19 *1/*1); the remaining 12 participants were six EMs and six IMs using oral contraceptives. A single oral dose of 700 mg of carisoprodol was given, and blood drug concentrations were followed for 11 h and 45 min. During this time period, different pharmacodynamic measurements were made. RESULTS: IMs had a longer elimination half life (T(1/2)) (127 min; 95% confidence interval (CI) 95, 159) than EMs (96 min; 95% CI 84, 107) and a larger area under the concentration-time curve from 0 to infinity (AUC(0-infinity)) for carisoprodol (16.3 microg h ml(-1) ; 95% CI 11.9, 20.7) than EMs (11.3 microg h ml(-1) ; 95% CI 7.8, 14.8). The use of oral contraceptives was accompanied by larger AUC(0-infinity) for carisoprodol in both EMs (18.5 microg h ml(-1); 95% CI 10.7, 26.3) and IMs (26.0 microg h ml(-1) ; 95% CI 18.8, 33.2). EMs using oral contraceptives also had a longer T(1/2) (117 min; 95% CI 92, 143) and higher maximum carisoprodol concentration than EMs not using oral contraceptives. No significant differences in pharmacodynamic parameters were found between subjects in the different genotype groups or between users and non-users of oral contraceptives. CONCLUSIONS: Subsequent to a single-dose administration of carisoprodol, the carisoprodol AUC was approximately 45% larger in CYP2C19 IMs than in EMs. The use of oral contraceptives increased the AUC by approximately 60% in both EMs and IMs. Despite these pharmacokinetic effects, no significant differences with respect to the CYP2C19 IM and EM genotypes were observed in the acute impairing effects of a single dose of carisoprodol.

Area Under Curve↗
PubMed2001

Oral contraceptives alter sleep and raise body temperature in young women.

Female reproductive steroids, oestrogen and progesterone, not only affect reproductive function, but also thermoregulation and sleep. Chronic administration of synthetic steroids, as occurs in women taking oral contraceptives, may affect these regulatory systems differently from endogenous oestrogen and progesterone. We therefore investigated body temperature and sleep in ten young women taking oral contraceptives, in the active and placebo phases of the contraceptive pack, and compared them to a group of nine women with ovulatory cycles, in the mid-follicular and mid-luteal phases. Body temperature was raised throughout 24 h in the women taking oral contraceptives in the active phase, and in the naturally cycling women in the luteal phase, compared to the follicular phase. The women taking oral contraceptives in the placebo phase, however, continued to have raised body temperatures, similar to those in the active phase, indicating a prolonged action of synthetic reproductive steroids on body temperature. Sleep also was influenced by the endogenous and synthetic reproductive steroids, but independently of body temperature. The women taking oral contraceptives had more stage-2 non-rapid eye movement sleep in the active phase, both compared to their placebo phase and the naturally cycling women. The naturally cycling women, however, had more slow wave sleep in the luteal phase compared to the contraceptive group of women. Exogenous reproductive steroids therefore influence body temperature and sleep differently from endogenous progesterone and oestrogen.

Adult↗